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Editorial
Indian Heart J 2001; 53: 23–24
Indian Heart Journal – A Clarion Call
Dear Colleagues,
It is with a great sense of pride that I present to you the first issue of the Indian Heart
Journal of the new millennium. Over the last 50 years, the Indian Heart Journal, the voice
of the Cardiological Society of India, has achieved a distinctive place of its own. This has
been possible due to the hard work and collaborative efforts of its members, and also due
to the vision and wisdom of my predecessors. I feel greatly honored and humbled in
taking over as the editor of the Indian Heart Journal, following those stalwarts. While I
am delighted to assume this onerous responsibility, I have a sense of trepidation when I
look at the achievements of the past and the daunting task ahead. It will be my endeavor
to strive and maintain the academic excellence of the Journal. Towards this end, I shall
always look forward to your inputs and advice.
We are fortunate to live in an era of tremendous advances in knowledge, particularly
in the field of cardiology. This gives us unprecedented opportunities in patient care, but
also poses the challenge of keeping ourselves updated with recent advances, so as to
provide optimal medical care to our patients. The need for a medium that provides
continuous medical education, serves as a platform for exchange of ideas and research,
and provides a perspective and direction to the contemporary knowledge is perhaps more
than ever before.The Indian Heart Journal is well-poised to serve this pivotal role by virtue
of its mandate, and because of the will and commitment of its contributors. Education
and dissemination of core information through the medium of the Indian Heart Journal
will continue to remain our top priority. Various amendments and efforts in this direction
will be evident gradually.
It is my belief that the Indian Heart Journal must particularly focus on the problems
and prospects of Indian cardiology. The magnitude of the cardiovascular disease burden
in India is stupendous. While we are still besieged with the burden of rheumatic heart
disease, the epidemic of coronary artery disease is not round the corner anymore, but
bang in the middle of our lives. Thus, the double burden of “modern” and “not so modern”
diseases is a cruel reality like the recent earthquake that shook parts of our country.
With our poor level of socioeconomic development and health infrastructure, a routine
lukewarm response to the challenge of cardiovascular diseases would not be enough. We
need innovative research and ways of solving our problems. Such research, yielding
context-specific solutions in one developing country, will be more relevant to others in a
similar health care system than research from developed nations. Indian research in
cardiology, therefore, now has a unique opportunity to influence the practice of cardiology
in large parts of the world. The Indian Heart Journal will seek to play its role by becoming
a vehicle for publication of high quality research with outreach in application and impact.
While a journal merely publishes research, I wish and pray that research on preventive
cardiological issues, on cost-containing measures, and on rheumatic heart disease gain
momentum, so that we are relevant to our society.
Friends, a lot has been achieved but much more remains to be done. If you put your
best foot forward for the Indian Heart Journal, I am sure that we can make a higher impact
on the international arena. We will continuously strive to make the Journal more readable.
Please do not hesitate to communicate your ideas, comments and criticism for improving
the Journal to me personally. We have started a new section on cardiovascular images
and request you to send photographs of Chest X-ray, ECG or any other material of
Editorial.p65
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24 Bahl
Indian Heart J 2001; 53: 23–24
A Clarion Call
educational value. The section on recent trials would be coupled with expert comments.
A section on current perspective, where eminent professionals in the field will express
their opinion on matters such as policy, education and research is also envisaged.
An unbiased, quick, high quality peer-review process remains the backbone of any
Journal. Much of the delay in publishing relates to the delay during the review process. I
seek your cooperation in this process, even as we try to expedite the procedure. With
advances in information technology, the time lag should be reduced further. Gradually,
we shall move towards electronic submission of manuscripts. The Journal is now available
online at www.indianheartjournal.org.
Through the editorial column of the Indian Heart Journal, I wish to thank the authors
of review articles and the reviewers of manuscripts submitted to the Journal. I cannot
overemphasize the fact that it is through their selfless contributions and due to their
academic spirit that a Journal derives its sustenance. I also thank all the editorial
consultants of various subdisciplines for their willingness to help. I am grateful to my
departmental colleagues for their unreserved help and support. I also appreciate the
generous fiscal support from the industry.
Finally, I thank you once again for reposing the confidence in me and look forward to
a fruitful and continuing interaction in the future.
With Best Wishes,
(VK BAHL)
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Review Article
Indian Heart J 2001; 53: 25–34
Can We Eradicate Rheumatic Fever in the 21st Century?
Gene H Stollerman
Emeritus Professor of Medicine and Public Health,
Boston University, USA
T
he 20th century was distinguished by the identification
of group A streptococcal (GAS) pharyngitis as the cause
of acute rheumatic fever (ARF), and by the demonstration
that both primary and secondary attacks of ARF are
preventable by the appropriate use of penicillin to treat and
prevent these infections. Notwithstanding these brilliant
achievements, ARF and rheumatic heart disease (RHD)
remain major public health problems throughout the
developing countries of the world, that is to say, in most of
the world's population. Moreover, the spectacular decline
in ARF and RHD in developed countries cannot be attributed
to penicillin therapy alone. The decline in ARF began well
before the widespread use of penicillin and was coincident
with improved living conditions, especially better housing.
Moreover, in the face of the virtual disappearance of ARF
in developed countries, GAS is still identified in up to 25%
or more of throat cultures made in schoolchildren with
pharyngitis. Although many of these positive throat
cultures may represent carriage of GAS rather than true
infection, a significant number, if not most, have been
documented immunologically as actual infections.
Obviously, these sporadic streptococcal sore throats are not
of the same rheumatogenic potential as those that caused
military ARF epidemics with attack rates as high as 3% or
more in patients with untreated GAS pharyngitis (see
below). If the GAS pharyngitis currently encountered in
schoolchildren of developed countries were rheumatogenic,
treatment of GAS sore throat alone would not have
accounted for the decline in ARF because most patients with
sore throats do not present themselves for treatment, and
those who do so do not now regularly receive or complete
the rigorous regimens required for preventing the disease.
So, why did ARF virtually disappear during the 1960s
and 1970s when GAS pharyngitis did not? And why did it
reappear in the 1980s in focal outbreaks at both US military
bases and in civilian populations and then subside again
without apparent change in the incidence of GAS throat
infection? And in these focal outbreaks, why did ARF affect
middle-class populations who had no apparent deficit in
health care? To help explain these observations, one needs
Correspondence: Professor Gene H. Stollerman, # 21, The Courtyard,
Hanover, New Hampshire 03755, USA, e-mail: [email protected]
IHJ-IA-004-01.p65
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to appreciate the fact that the great array of clinical
syndromes produced by GAS, and the secular fluctuations
in their epidemiology speak for remarkable diversity of
strains found within what we have classified taxonomically
as a single species.
Current concepts of the pathogenesis of ARF:
Although the pathogenesis of ARF remains obscure, certain
requirements for its development have been well established.1
The site of infection must be pharyngeal.2 Regardless of
how virulent an invasive strain may be, ARF does not result
when it is introduced extra-pharyngeally, e.g. through skin
lesions or wound infections, or from puerperal sepsis.
Moreover, to cause ARF, GAS pharyngitis also requires
certain conditions. Throat carriage alone is not causative.2
An immune response is required and even in rheumatogenic
infections, the attack rate of ARF varies directly with the
intensity of the immune response.3 Thus, there seems to
be a quantitative factor related to the magnitude of
antigen stimulation. Although a precise pathogenetic
"rheumatogenic" factor has not been identified, all GAS
strains that have been clearly shown to produce ARF by
prospective studies have similar virulence characteristics.
GAS virulence: GAS is a natural pathogen only for human
beings. Whereas all members of the species are identified
by their group-specific carbohydrate cell wall, its outer
surface is composed of tiny hair-like coiled projections by
which the organism adheres to tissues4 (Fig. 1). In virulent
strains, these structures contain an extractable and
remarkably heterotypic antigen, the M protein.5 More than
100 immunologically specific M serotypes have so far been
identified. Immunity to virulent GAS infection is only M
type-specific, accounting for the frequency of GAS
infections. When fully virulent, each chain of cocci is
surrounded by a capsule of hyaluronic acid that is
responsible for the "mucoid" appearance of GAS colonies
on blood agar6 (Fig. 2). The larger the capsule, the smaller
the chains7 (Fig. 3). The capsule is produced only during
active growth of the organism. Streptococcal hyaluronate
is chemically identical to that occurring ubiquitously in
human connective tissues so that antibodies to it are not
readily raised. Thus, anti-capsular immunity does not occur
4/10/01, 11:53 AM
26 Stollerman
Fig. 1. Electron microphotograph of group A streptococci adhering to the surface
of a buccal mucosal cell. Prominent surface projections (fibrillae) contain both
M protein and lipoteichoic acid.4
Fig. 2. Low power micrograph of encapsulated, mucoid group A streptococcal
colonies growing on blood agar.6
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Indian Heart J 2001; 53: 25–34
Can We Eradicate Rheumatic Fever?
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Fig. 3. Electron micrograph of a chain of group A streptococci (type M-24)
isolated during a rheumatic fever epidemic in a military population. The cocci
are enclosed by a large hyaluronate capsule which is shadowed by type M-24
antibody precipitated on its surface. (Stollerman GH. Rheumatogenic group A
streptococci and the return of rheumatic fever. Adv Intern Med 1990; 35:
1–26).
and the host defense to virulent strains depends on anti-M
antibodies.
Both components, M protein and capsule, are primarily
responsible for the striking resistance of virulent strains of
GAS to phagocytosis.8 But M protein and capsule are rapidly
lost during convalescence from acute pharyngitis,9 or
shortly after leaving the host, when landing on fomites, or
when grown in artificial media. After fresh isolation, strain
virulence may be maintained, however, by frequent transfer
through fresh human blood or by intraperitoneal mouse
passage. Once host defenses are penetrated, strains of GAS
excrete many extracellular toxic substances that enhance
tissue destruction and promote invasion (streptolysin S and
O, streptokinase, DNA nucleases, hyaluronidase,
erythrogenic toxins, anticomplementary proteins, etc.).
On blood agar cultures, clones of encapsulated variants
form large "mucoid" colonies resembling a drop of oil,
whereas loss of encapsulation results in colonies that are
opaque and "pearly" in appearance 6 (Figs 2a and b).
Considering the potential significance of this observation
epidemiologically, it is surprising how infrequently clinical
microbiology laboratories recognize and report the presence
of mucoid colonies on throat cultures. In the past, their
appearance in throat cultures from military cohorts who
were under prospective surveillance regularly predicted
severe epidemics of streptococcal pharyngitis and
rheumatic fever (RF).10 Many years ago, my colleagues and
I demonstrated that even antibody-free germ-free mice
readily destroyed GAS clones lacking M protein and
hyaluronate capsules.11
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Indian Heart J 2001; 53: 25–34
Throat carriage, however, may sometimes stubbornly
persist during convalescence when strains have lost these
virulence factors. Such persisters may retain mucosal
adherence ligands, such as surface lipoteichoic acid12 and
F proteins13 that stimulate internalization of the organisms
by epithelial cells. 14 Such internalization is actually
inhibited by the hyaluronate capsule15,16 whose genetic
expression is associated with that of other virulence factors
(e.g. M protein, streptolysins and erythrogenic toxins),
causing cellular injury and promoting the invasion of
deeper tissues.17–19
Thus, the human throat is readily colonized by a variety
of GAS strains of varying virulence, accounting for a
spectrum of infection ranging from an asymptomatic
colonization to local inflammation and extension to deeper
tissues. Confirmation of the diagnosis of actual
streptococcal pharyngitis therefore requires more than
positive cultures—a significant increase in the titer of
streptocccal antibodies (e.g. antistreptolysin O, anti-DnaseB,
etc.).
Evolution of the concept of rheumatogenic strains:
The World War II epidemics of RF that occurred among
military recruits, assembled from many different areas of
the US, were shown to be caused by GAS strains belonging
to but a few prominent M serotypes.20–22 These epidemic
strains were heavily encapsulated, M protein-rich variants.
When introduced into the ranks of close-living recruits, they
spread rapidly, not by fomites but by droplet infection
through close person-to-person contact. Infections by
strains representing several M serotypes were associated
with a strikingly similar post-infection ARF attack rate of
approximately 3% in untreated individuals.23 This attack
rate varied with the intensity of the immune response.3
In subsequent studies in the 1950s, it became clear,
however, that common sporadic GAS sore throats in US
schoolchildren were associated with little or no RF.20 Indeed,
subsequent literature searches confirmed that GAS strains
within but a limited number of M serotypes had actually
been associated with previous well-studied military
epidemics of ARF. In the civilian population of
schoolchildren the "mucoid" GAS strains belonging to these
M types seemed to have virtually disappeared.1, 24
Non-rheumatogenic GAS: As early as the late 1930s,
Alvin Coburn noted that ARF was not reactivated by throat
infections due to strains representing certain M-protein
serotypes.25 By the 1950s, it was further reported that
strains within certain M types caused acute
glomerulonephritis (AGN)26 rather than ARF, the two
complications very rarely occurring from the same
IHJ-IA-004-01.p65
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Stollerman
Can We Eradicate Rheumatic Fever?
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antecedent infection. By the 1960s, GAS strains causing
streptococcal pyoderma (impetigo), a primary skin
infection, were shown to be different from those primarily
infecting the throat. Some pyoderma strains caused AGN,
but none caused ARF.27–29 Therefore, the so-called "skin
strains" must be regarded as non-rheumatogenic.
Properties of known rheumatogenic strains: Some
characteristics of the GAS strains clearly responsible for the
great ARF epidemics of World War II have been defined.1
Briefly, they are very rich in M-protein (i.e. have very large
M molecules), are heavily encapsulated, and are highly
mouse-virulent. They produce striking "mucoid" colonies
on blood agar plates. They are tropic primarily for the throat
rather than the skin, infecting the latter only secondarily
through wounds or skin lesions. They evoke strong typespecific immune responses in humans and in mice, much
more so than M type-specific responses from pyoderma
strains. They do not contain the lipoproteinase commonly
found in skin strains (serum opacity factor). They have been
found so far to be distributed among a limited number of
serotypes, such as M 1, 3, 5, 6, 18, 19 and 24, and some
others.22
It should be emphasized, however, that the M serotype
alone does not equate with rheumatogenicity because strain
variation is common within a given serotype. This fact has
caused confusion and controversy about the concept of
rheumatogenic M serotypes. On the other hand, very few
studies have routinely assessed encapsulation and many
strains identified as M-positive may have relatively small or
no capsules.
Why are rheumatogenic strains difficult to identify?
In a severe epidemic of GAS pharyngitis, one strain of a
given M serotype often becomes prevalent. In such cases,
the attack rate of ARF following such specific infections can
be accurately calculated. In clinical practice, however, by
the time rheumatic fever is diagnosed the infecting strain is
usually not recoverable, or the clones persisting in the
patient's throat may have attenuated so that their M type
may no longer be recognizable. Moreover, new GAS strains
may have been acquired during the latent period between
the antecedent infection and the onset of ARF.
ARF patients are often referred to centers (especially
pediatric cardiology clinics) where in-depth studies of
streptococcal strains are not usually made. Reference
laboratories often receive strains that dissociate during
transfer and no longer express all the virulence factors.
When clinical laboratories make throat cultures, colony
morphology is rarely observed or reported. Yet the
appearance of mucoid colonies in a cohort may signal
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28 Stollerman
danger. For example, in the late 1950s, in a prospective
surveillance of throat cultures from naval recruits of the
Great Lakes Naval Training Center, Great Lakes, Illinois, the
sudden appearance of a predominant highly "mucoid" M
type accurately predicted the onset of a severe epidemic of
ARF.10
Disappearance and reappearance of rheumatogenic
strains in the USA: The disappearance of the notorious
rheumatogenic M types from a population of Chicago
schoolchildren was an observation made by my collegues
and myself several decades ago.20 In the 1980s, however,
an outbreak of ARF re-appeared at the San Diego Naval
Base, at Fort Leonard Wood, Missouri, and among
schoolchildren in several other regions of the United States,
most notably in Utah and the Rocky Mountain area.30,31 In
these regions, investigating teams of the USPH's Centers
for Disease Control discovered that the mucoid,
rheumatogenic strains belonging to the notorious M types
of the past were seeded among contacts of index cases of
ARF.32 This outbreak has included more than 500 cases
since then in the Salt Lake City area alone.33 Moreover, the
outbreak occurred among middle-class Caucasian children
with no risk factors other than perhaps household
crowding.32
Obviously, identification of rheumatogenic and other
specifically pathogenetic strains requires prospective studies
of GAS pharyngitis by clinical investigators, knowledgeable
about the microbiology of the GAS, its epidemiology, and
its clinical sequelae. Unfortunately, in many areas of the
world where ARF still rages, a search for local
rheumatogenic strains has not been systematically
conducted. In populations where rampant pyoderma
coexists with a high incidence of ARF in the same cohorts,
such as among the aborigines of the Northern Australian
territories, and where efforts at strain identification have
been made, investigators understandably have found it
difficult to sort out the throat strains causing ARF from
pyoderma strains.34 Pyoderma strains are notoriously
transmissible from skin lesions to the throat where they may
persist, resulting in a confusing array of carried strains.27, 28
In Trinidad, however, where extensive impetigo, acute
glomerulonephritis (AGN) and ARF once coexisted closely,
painstaking studies revealed that strains colonizing the skin,
although periodically causing an epidemic of AGN, were
not associated with concordant increase in the prevalence
of ARF on the island.29 In Memphis, Tennessee, a southern
city of the US, the seasonal separation of pyoderma and
AGN in the summer and ARF in the late fall and winter
further demonstrated the inability of skin strains to cause
ARF. In the colder months, however, the precise strains
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Can We Eradicate Rheumatic Fever?
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causing ARF could not be identified for reasons noted
above.28
The molecular biology and genetics of well-known
rheumatogenic GAS: By the 1980s, the primary
molecular structure of M protein was determined35 and its
type-specific antigen was shown to reside in its small
terminal N-acetyl peptide.36 Two highly conserved epitopes
within M protein divide GAS immunologically into Class I
(throat) and Class II (skin) strains.37 All RF strains fall clearly
into Class I throat strains and individuals who had
contracted RF were shown to have higher than normal titers
against the Class I epitope, whereas they lacked antibodies
to the Class II epitope.38 Moreover, in the large M protein
molecules of Class I rheumatogenic strains, distinct epitopes
were identfied that cross-react with cardiac, synovial, and
brain tissues and these were separable from the terminal
type-specific antigen.
The genes of M protein (eem) have now been shown to
be divided into four subfamilies of nucleotide sequences,
arranged in five distinctive chromosomal patterns, identified
as A–E.39
By these genetic patterns, rheumatogenic pharyngitis
strains are clearly differentiated from impetigo strains, but
not yet clearly from all other throat strains. Whether
epitopes that cross-react with host tissues are present
exclusively in RF strains is not clear. An attractive hypothesis
is that the deposition of a heavy antigenic load of these
cross-reactive epitopes in pharyngeal lymphoid tissues,
already hypersensitized during early childhood by repeated
streptococcal infections, causes a break in the immune
tolerance of susceptible hosts that leads to the various
stigmata of RF.
Swallowing large amounts of such antigens seems to
have a powerful immunizing effect. It is an old observation
that streptococcal pharyngitis produces a more striking
immune response to all streptoccal antigens in those who
develop rheumatic fever compared to those who do not,
whereas RF patients respond normally to other common
test antigens. After nasal administration of synthetic M
vaccines, mice produce type-specific IgA antibodies and are
protected from experimental systemic challenge with
homologous M-type strains.40 In addition, the adjuvant
effect of the superantigenic properties of the proximal
conserved part of the M protein (see below) may also
promote exaggerated immune responses and
autoimmunity.
Recently, the M protein genes and those of hyaluronic
acid, streptolysin S, erythrogenic toxins, and others have
been identified19 and now provide a genomic approach to
characterizing GAS strains. Other than quantitative features
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Indian Heart J 2001; 53: 25–34
of virulence as measured by M protein and hyaluronate
content 11 , however, molecular differences between
rheumatogenic and non-rheumatogenic throat strains are
not yet clear.
Immunological theories of pathogenesis have been
recently reviewed exhaustively.41 Numerous streptococcal
antigens have been shown to be cross-reactive with a variety
of cardiac, brain and synovial tissues. The probable role of
the immune system of the gut in regulating autoimmunity
should be considered more seriously in the future since a
heavy load of antigens and toxins are swallowed in the
course of severe GAS pharyngitis and the GI route of entry
is one that is bypassed by extrapharyngeal GAS infections
that do not cause ARF. Moreover, autoimmunity may be
controlled to a great extent by the immune system of the
gut.
Nor has the role of many streptococcal toxins in ARF
pathogenesis been excluded. For example, the membranedestroying toxin, streptolysin S, whose expression is
controlled by GAS virulence genes,19 may release some host
intracellular antigens that may provoke cell-mediated
autoimmunity. More than 50 years ago, streptolysin S was
shown to be nonantigenic and therefore not neutralized in
ARF patients despite their repeated GAS infections.42
Recently, the valvular endothelium of patients with RHD
who required valve replacement, has been found to be
reactive with the adhesion molecules of CD4+ and CD8+
lymphocytes penetrating through the valvular
subendothelial layers. Such an infiltration may represent
an important cell-mediated autoimmune step in the
pathogenesis of rheumatic valvulitis.43 The conserved, nontype-specific "superantigen" portion of the M molecule44
contains nontype-specific epitopes to which we become
progressively hypersensitized by repeated childhood GAS
infections. In genetically susceptible hosts, these heighten
the immune responses to streptococcal antigens, as
observed in ARF patients. Such immunologic stress may
also break immune tolerance and may account for the
variety of cross-reactive antibodies found in synovia, skin,
brain and heart tissues of RF patients.41 Immune complexes
may produce nondestructive synovitis of the joints in
patients with ARF and nondestructive reactions in the basal
ganglia observed in Sydenham's chorea, whereas cellmediated autoimmune cytotoxic reactions may destroy
heart valves. The varied clinical manifestations of ARF are
therefore not unexpected.
The rheumatic host: The degree to which host factors
are acquired or genetic is unclear. Both factors may be
important. No race or ethnic group, however, is intrinsically
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Can We Eradicate Rheumatic Fever?
29
resistant or unusually susceptible to ARF, but age and
gender differences are sometimes apparent. ARF is very rare
in young children before full maturation of the immune
system reaches its peak by the end of the first decade and
wanes with age thereafter. Carditis is most common and
severe in the young and arthritis more common in adults.
Sydenham's chorea, equally common in both sexes before
puberty, is virtually non-existent in sexually mature males
and is exacerbated in women by pregnancy. Also well
recognized is a greater propensity in women to develop lateonset, tight mitral stenosis. Rheumatic recurrences tend to
be mimetic, suggesting host predisposition. Isolated
polyarthritis, chorea and carditis tend to recur
independently, and susceptibility to all manifestations of
rheumatic recurrences wanes with age. Host factors might
also be expected to predispose to the chronicity of all
rheumatic manifestations, especially valvulitis.
However, specific genetic susceptibility is unclear. ARF
is less concordant in identical twins (about 20%) than it is
in twins with other immunologic diseases such as atopic
allergy and hyperthyroidism, or in infections such as
tuberculosis or poliomyelitis.45 An association with the gene
products of human haplotypes, so productive in many
autoimmune disorders, has not been as clear in ARF.46,47
An increased frequency of HLA-DR4 and HLA-DR2 among
White and Black patients with rheumatic heart disease has
been noted. Other studies have implicated DR1 and DRW6
as susceptibility factors in South African Black rheumatic
heart disease patients, and recently of DR7 and DW53 in
Brazilian patients. These conflicting results have raised
speculation that the observed associations might be of Class
II genes close to, or in linkage disequilibrium with a putative
RF susceptibility gene.47
Fig. 4. Foci of recent outbreaks of rheumatic fever in the US (Stollerman GH.
The return of rheumatic fever. Hospital Practice 1988; 23: 100–113).
4/10/01, 11:53 AM
30 Stollerman
John Zabriskes and his colleagues have reported the
frequent expression of a B cell alloantigen, unrelated to
MHC, in diverse populations of RF individuals, principally
those with rheumatic heart disease. A monoclonal antibody
(D8/17) prepared by immunizing mice with B cells from an
ARF patient is expressed on increased numbers of B cells in
all rheumatic heart disease patients of diverse ethnic origins
but in only 10% of normal individuals.46 This antigen shows
no association or linkage to any of the known HLA
haplotypes, nor does it appear to be related to B cell
activation antigens.48 Its source and pathophysiologic role
remains obscure. Obviously, it would be of considerable
importance if it turns out to be a reliable marker of
susceptibility of rheumatic heart disease at birth. It has not
been adequately studied in ARF patients with isolated
polyarthritis or chorea.
Prevention of rheumatic fever
The above discussion brings complexity to what is, on the
face of it, a disarmingly simple fact: treatment and
prevention of GAS pharyngitis prevents ARF. For the
prevention of recurrences (secondary prophylaxis), rather
than primary attacks (primary prevention), the issues are
simpler because the susceptible rheumatic host is already
identified. Current issues of secondary prophylaxis are
therefore considered first.
Secondary prevention of rheumatic fever: For
prevention of rheumatic recurrences, continuous antibiotic
prophylaxis is now recommended by health authorities
throughout the world.49 Monthly injection of benzathine
penicillin G is, by far, the most stringent and effective
regimen. In some populations with a high prevalence of
ARF, however, some observers have reported that the last
week of the month is not completely covered by this regimen
and they choose to administer it every three weeks.50,51 One
should be sure, in any case, that the commercial formulation
of the drug contains the full dose of 1.2 million units of
benzathine penicillin G and not the commonly marketed
confusing formulations containing smaller amounts of
benzathine penicillin G mixed with shorter-acting penicillin
G compounds. Where ARF is no longer prevalent, oral
penicillin V 600 000 units b.i.d. now suffice. For that matter,
sulfadiazine, 0.5 g b.i.d. is also effective and inexpensive and
thus useful for secondary (but not primary) prevention.
How long to continue these regimens is a matter of
clinical judgement, recognizing the major variables that
affect the decision:52 (i) how frequently RF occurs among
cohorts, (ii) how recent and severe the rheumatic attack,
(iii) the presence and severity of rheumatic heart disease.
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Can We Eradicate Rheumatic Fever?
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Penicillin prophylaxis has been safely suspended after
several years of treatment when rheumatogenic
streptococci have been shown to have disappeared from the
community.53,54
In a 5-year follow-up study that stratified recurrences
by various risk factors, patients without rheumatic heart
disease developed recurrences following GAS infections
with attack rates that varied from 4% in patients with a
small increase in ASO titer to 36% in those with a marked
rise.49 The recurrent attack rate was, of course much higher
in patients with rheumatic heart disease where it may
exceed 50% in those with the greatest immune reponses.
The duration of prophylaxis is therefore a variable to be
decided by the local prevalence of ARF and the presence or
absence of heart disease and its severity. For those
individuals with RHD, including adults exposed to schoolaged children, discontinuation of prophylaxis at any age
may be hazardous. In the US, however, recommendations
for discontinuing prophylaxis have become more
permissive, especially for patients without RHD55 for whom
prophylaxis is recommended "for 5 years or until age 21
years, whichever is longer".55 Obviously, recommendations
for the US population may not apply to all cohorts in
developing countries that require a recommendation
formulated by their own expert committees.
Primary prophylaxis: Treatment of GAS pharyngitis is
in a state of some turmoil in developed countries and varies
greatly depending on the local prevalence of ARF.1 On the
one hand, the emergence of throat flora resistant to
antibiotics (gratefully, not GAS, but particularly S.
pneumoniae), is a consequence of overuse of antibiotics for
the treatment of non-bacterial respiratory infections.56 On
the other hand, fear of ARF has made some expert
committees reluctant to compromise on the penicillin
regimens that are required to prevent ARF following
rheumatogenic GAS pharyngitis.57 There is little doubt that
treatment of GAS pharyngitis with a single intramuscular
injection of 1.2 million units of benzathine penicillin G is
the most reliable way to prevent primary attacks of ARF,
but it is now rarely prescribed in the US and other developed
countries. For developing countries, however, effective as it
may be, the problem of delivering injections for sore throats
is also an overwhelmingly practical one. But wherever
injections of benzathine penicillin G for GAS pharyngitis
have been widespread, ARF has rapidly declined, not
because all cases of GAS pharyngitis disappeared but
probably because the most virulent clones of GAS were
driven out of the population.
More convenient is the alternative treatment of 10 days
4/10/01, 11:53 AM
Indian Heart J 2001; 53: 25–34
Fig. 5. Recombinant octavalent M protein vaccine. (Dale JB Group A
streptococcal vaccines. Infect Dis Clin North Am 1999; 13: 227–243).
of oral penicillin V 500 000 units twice daily, but
compliance with the required full 10 days of therapy is at
best uncertain. Avoiding overuse of penicillin therapy for
the sore throats that are predominantly of viral etiology
requires throat cultures or rapid antigen diagnostic tests
(RADTs).57 The predictive value of such negative tests may
reduce the use of antibiotics by about 80%. Whereas this
strategy may be the most practical and cost-effective
approach to primary prevention in developed countries, its
widespread application to underprivileged and underserved
populations of the world is problematic. Nonetheless, we
are still dependent on penicillin therapy for primary
prevention of ARF and it is reasonable to focus intensive
therapy on cohorts in whom RHD is most prevalent, and
where the greatest reservoirs of rheumatogenic GAS are
stored. Perhaps their spread can at least be somewhat
inhibited.
Streptococcal vaccines: We will probably not eradicate
RF from the world without a GAS vaccine. Several
investigators are approaching the problem. James Dale and
associates, for example, have prepared a recombinant
multivalent vaccine composed of the end-to-end
combination of the type-specific epitopes representing
many of the most common M serotypes in which
rheumatogenic strains are usually found58 (Fig. 4). Trials
of efficacy in humans are currently underway. Oral
immunization with similar vaccines is also promising since
an M type-specific IgA response to this route of
immunization has been well demonstrated.40 Considering
how much M antigen is swallowed in the course of a GAS
sore throat, the oral route for production of protective IgA
to type-specific M determinants (free of host cross-reacting
antigens) may be the most effective one. And considering
the great number of M serotypes, we must focus on those
known to contain strains of greatest rheumatogenic
potential.
Diagnosis
Some limitations to the modified Jones Criteria have been
emphasized,59 and these criteria are, after all, useful only
IHJ-IA-004-01.p65
7
Stollerman
Can We Eradicate Rheumatic Fever?
31
as general guidelines. For example, in contrast to arthritis,
Sydenham's chorea, the major manifestation with the
longest latent period following the antecedent infection,
may present without any other major or minor features of
ARF—so-called "pure chorea". Also, isolated asymptomatic
acute carditis may first come to medical attention several
months into or after the rheumatic attack. By then, antibody
titers may have declined to normal levels and the minor
manifestations of systemic inflammation (fever, ESR, Creactive protein, etc.) may have abated.
Recurrent ARF in patients with pre-existing rheumatic
valvular disease is particularly problematic in the absence
of non-cardiac major manifestations (e.g. polyarthritis or
chorea). When rheumatic valvular disease pre-exists, clear
recognition of a new bout of carditis requires evidence of
fresh cardiac injury such as pericarditis, acute cardiac
enlargement and/or sudden congestive heart failure, or a
newly detected murmur from a valve not previously
affected. The Jones Criteria therefore, apply most readily to
initial attacks, and more diagnostic latitude is needed to
interpret recurrent carditis in patients with pre-existing
rheumatic heart disease. The steps in the evolution of
modifications of the Jones Criteria have been reviewed
recently in detail.60
Problems in the diagnosis of isolated polyarthritis and
the place of so-called "post-streptococcal reactive arthritis"
in the diagnosis of ARF has been discussed elsewhere in
detail61 as has the diagnosis of isolated Sydenham's chorea
and its possible relation to the so-called post-infectious
autoimmune neurological diseases (PANDAs).62,63 These
diseases include tics, Tourette's syndrome, and obsessive–
compulsive behaviour, all of which have been observed in
some patients during or after an attack of rheumatic chorea.
Isolated Carditis: Rheumatic carditis is almost always
associated with valvulitis. Isolated myocarditis or
pericarditis without valvulitis is rarely, if ever, due to ARF.
So, the finding of valvular involvement is critical and is
greatly aided by noninvasive imaging methods.
Echocardiography (EC) and Doppler studies:60,64–66
Most cases of rheumatic carditis are not severe enough to
be symptomatic and the diagnosis of isolated carditis
previously depended on auscultation alone. Eighty percent
or more cases of mitral regurgitation that are detected by
EC are also readily diagnosed by experienced physicians by
auscultation alone. The remaining "subauscultatory" cases
are those with the mildest degree of mitral or aortic
regurgitation. If rheumatic in origin, more than 80% of
these valvular lesions are likely to heal without scarring.
Moreover, the sensitivity of EC may detect degrees of valvular
4/10/01, 11:53 AM
32 Stollerman
regurgitation within the physiologic range, and not
functionally significant, especially in children and in very
thin, active individuals with highly elastic valve leaflets and
rings.
Although EC, particularly accompanied by Doppler
studies, offers greater sensitivity and specificity for the
assessment of valvular regurgitation, it need not be
considered essential for the diagnosis of RF by experienced
primary care physicians, especially in settings where the
disease is common and medical resources limited.
Nonetheless, cardiologists proficient in echo-Doppler
technology, now use this method routinely to distinguish
abnormal from physiologic valve leaks more sensitively and
accurately than is possible by auscultation alone. Despite
the relatively good prognosis of "silent" rheumatic mitral
regurgitation, EC does, indeed, provide an accurate
assessment of the presence and severity of valvulitis,
especially in an era when cardiac auscultation has been
taught less extensively and is used with less confidence by
young clinicians. In any case, it is doubtful that a powerful
diagnostic tool such as EC will be neglected in the
assessment of valvular disease wherever the instrument is
available, and certainly where its expense may not be too
great a concern.
In my view, whether or not subauscultatory mitral
regurgitation should be accepted as the sole criterion of
carditis in the absence of other major manifestations of RF
remains an issue and dependent on the experience of the
examining cardiologist. Whether or not the Jones Criteria
should be modified to incorporate these newer techniques
is being debated by expert committees. Differences of
opinion are tempered by considerations of the availability
and cost–benefit of EC to developing countries, since the
outcome of treatment and management of such minimal
valvular inflammation may not differ significantly, whether
they are detected or not.60
Right ventricular endomyocardial biopsy: When the
characteristic murmurs of rheumatic carditis are detected
early in the course of a rheumatic attack and are associated
with other major manifestations of ARF, such as arthritis
and fever, the yield of useful additional clinical information
from endomyocardial biopsy67 (EB) is low. Its diagnostic
sensitivity in one relatively large study was only 27%.
Endomyocardial biopsy has, however, confirmed the
presence of underlying carditis in unexplained congestive
heart failure of acute onset in some patients with preexisting rheumatic heart disease and elevated
antistreptolysin titers, suggesting a rheumatic recurrence.
In patients with chronic rheumatic heart disease, however,
IHJ-IA-004-01.p65
Indian Heart J 2001; 53: 25–34
Can We Eradicate Rheumatic Fever?
8
EB does not appear to provide additional diagnostic
information. In my opinion, in patients with rheumatic
carditis, EB should be limited to clinical investigation.
Treatment
Treatment has not changed much in recent decades.1
Because valvular scarring is suspected to be the result of
cytotoxic cellular autoimmunity, anti-TNF drugs that seem
to delay or reduce joint destruction in rheumatoid synovitis
possibly might reduce valvular scarring in rheumatic
carditis. However, there is no longer much argument, that
corticosteroids, though symptomatically beneficial, do not
prevent valvular damage.68 The new COX-2 inhibiting
NSAIDs, though currently expensive, may be welcome as
they reduce the adverse gastrointestinal effects of large
doses of aspirin, although for four- to six-week therapeutic
courses, such side-effects have not been a great problem,
especially in children.
For mild rheumatic carditis, lingering doubt in the minds
of some investigators about the possible long-term benefit
of corticosteroids over salicylates was based upon the results
of a few studies suggesting a favorable outcome of such
treatment for minimal rheumatic mitral regurgitation.68
These minimal mitral murmurs are most difficult to
standardize (perhaps EC will help) but spontaneous healing
occurs in 80% or more of patients with ARF, so that the
putative advantages of corticosteroids for these mild cases
of carditis are not likely to be resolved. For the present, most
physicians choose to use corticosteroids over salicylates in
rheumatic carditis simply because they are more potent
anti-inflammatory agents, a practice many authorities do
not endorse except in patients with severe carditis with
congestive heart failure for whom the powerful suppression
of inflammation may at times make management easier by
suppressing fever and reducing toxicity and anemia.1
Summary and conclusions
In the latter half of the 20th century, the clinical
importance of variation in the virulence of strains of GAS
has been clearly demonstrated. Although still obscure, the
pathogenesis of ARF requires immunologically significant
infection of the throat by virulent GAS strains. These strains
contain large hyaluronate capsules and large M-protein
molecules. The latter contain epitopes cross-reactive with
host tissues, and also contain superantigenic toxic moieties.
In areas where ARF has become rare, GAS pharyngitis
continues to be common but is caused predominantly by
GAS strains of relatively low virulence. These, however, may
4/10/01, 11:53 AM
Indian Heart J 2001; 53: 25–34
colonize the throat avidly and stubbornly. Molecularly distinct
pyoderma strains may cause acute glomerulonephritis, but
they are not rheumatogenic even though they may
secondarily infect the throat. In developing countries with a
very high incidence of rheumatic heart disease,
identification of the prevalent rheumatogenic GAS strains
and development of a multivalent vaccine against them is
currently an interesting strategy. Pending vaccine
development, intense primary and secondary penicillin
prophylaxis should continue to be sharply focused on
populations with the highest prevalence of RHD as such
measures may often succeed in driving away the most
virulent rheumatogenic clones of GAS from their midst.
Stollerman
17.
18.
19.
20.
21.
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Review Article
Indian Heart J 2001; 53: 35–37
Rheumatic Fever and Rheumatic Heart Disease in
India at the Turn of the Century
S Padmavati
Director, National Heart Institute, New Delhi, India
A
high incidence of rheumatic fever and rheumatic
heart disease was prevalent in the UK, USA and in the
Western Europe at the end of the nineteenth and in the early
years of the twentieth century. Today, it seems possible to
survey this problem over the last century. The earliest
reference in India was in 1910, stressing the low prevalence
of rheumatic heart disease (RHD) in autopsies. A similar
view was expressed by some British military physicians
about the clinical cases. However, by 1938 a high
prevalence was noted and publications after World War II
from all parts of India pointed to RHD being the most
common form of heart disease, accounting for nearly 40%
of cardiac cases seen in hospitals.1
Earlier, the prevalence of RHD was assessed from several
sources (Registrar General, population surveys, school
surveys, autopsy and hospital admissions). Today school
surveys appear to be the most informative source. With
echocardiogram and other diagnostic aids, it is possible to
assess fairly accurately the prevalence of RHD, while the
prevalence of rheumatic fever (RF) is unclear as the
symptoms are vague or mild. Between 1940 and 1983,
school surveys estimated the average prevalence of RHD to
be between 1.8 and 11 per 1000 in schoolchildren (average
6 per 1000), while from 1984 to 1995, the prevalence was
reported to be from 1 to 3.9 per 1000. The incidence of
acute RF, a less clear entity, was 0.05 to 1.7 per 1000 in the
first period and 0.18 to 0.3 per thousand in the second
period. However, the data are not comparable as the groups
surveyed in the second period were small. For these reasons,
conclusions regarding a decline are not warranted.2
Recent Data
Recent reports, however, point to a high prevalence of RHD,
as judged from the young age of children observed to be
suffering from the disease in school surveys, and at pediatric
clinics, and from juvenile patients coming for balloon mitral
valvotomy (BMV).
Thus in Delhi,3 in 1999, out of 191 children below 12
Correspondence: Dr S Padmavati, Director, National Heart Institute,
New Delhi, India
IHJ-IA-002-00.p65
1
years of age with definite acute RF, 7.9% were below 5 years,
31.4% between 5 and 9 years and 60% above 9 years. The
male–female (MF) ratio was 1.5:1. In 378 patients from
Orissa4 below 19 years, the mean age was 15.1±4.4 years.
The MF ratio was 4:1. Mild mitral stenosis (MS) was present
in 34.9% and severe MS in 33%. In 77 patients with
rheumatic chorea from Kerala,5 the age ranged from 4.5 to
18 years, the mean being 9.3 years, the MF ratio was 1.6:1,
and 1.57% had a mitral valve involvement. In 2000, in a
school survey involving 3963 children from the district of
Kanpur, the prevalence of RHD was 4.54 per 1000 (urban
2.56 and rural 7.42). The prevalence of RF was 0.75 per
1000 (rural 1.20, urban 0.42). Cases of RHD were
distributed equally between the ages of 7 to 11 and 12 to
15 years. The MF ratio was 1:0.8.6 In one series of 155
consecutive children below 12 years, the age range was
9.3±2.1 years and the MF ratio 1:0.6.7
These recent data suggest that a large number of cases
of RHD are still seen frequently in young children. There is
also no predominance of the female sex. It is not just old
cases coming to the hospital for treatment, e.g. congestive
heart failure (CHF), BMV, closed mitral commissurotomy
(CMV) or surgery. It must be pointed out that the prevalence
of RHD in western countries is below 0.5 per 1000 and
below 1 per 1000 for RF in primary schoolchildren.2
Balloon mitral valvotomy: Indications for BMV are
rapidly expanding. BMV is being performed not only in
young adults but also in young children with acute RF (age
10.9±9.2 years).8 BMV is also being carried out in young
pregnant women,9,10 and is increasing in popularity as
compared to CMV11 because of the short hospital stay and
lack of a scar. Even the prohibitive cost of the Inoue balloon
has been met by the reuse of the balloon 3 or 4 times.
Although such a reuse of catheters has been frowned upon
abroad,12 the Cardiological Society of India has issued
specific instructions for it.13 Open mitral commissurotomy
(OMV), mitral valve replacement (MVR) and MV repair
are beyond the capacity of most of the poor Indians who
suffer from the disease. BMV is now practised in many
centers, mostly in government hospitals in the major metros
where cases of rheumatic mitral stenosis are in
4/10/01, 11:44 AM
Indian Heart J 2001; 53: 35–37
36 Padmavati Rheumatic Fever in India
plenty. Refinement of the technique such as the use of
metallic commissurotomy is being reported with initial
success.14
Hospital admissions: Patients of RHD are usually
admitted for an acute exacerbation of RF, for treatment of
CHF or for BMV or surgery. With centers for cardiac
interventions sprouting all over the country, the number
of cases in a particular center may rise or fall according to
the purpose of admission. Thus data from CMC, Vellore
showed a fall between 1960 and 1989,15 while no such
reliable data are available from other hospitals. Death
certificates are also not reliable sources of data, and
autopsies are almost unavailable in India at present.
Prevention
There are 3 main methods used in prevention as given
below:
Primary and secondary prophylaxis: The Indian
Council of Medical Research (ICMR) projects on primary,
secondary and seasonal prophylaxis have shown the
efficacy of these methods.1 Further it has been shown that
these can effectively be given through the regular health
care systems of the country, viz. Primary Health Centres
(PHC)16 and School Health Services (SHS)17 and through
General Practitioners (GP). The SHS system is better than
the PHCs.
Secondary prophylaxis remains the cornerstone of
prevention. Primary prophylaxis is more difficult as it has
to be given for all cases of sore throat as streptococcal
isolation before treatment is near impossible.
However, no nationwide program exists, due to lack of
political will.
Public health education: While the government was
seized of the magnitude of the problem as early as 1966,
and the control of RF was included in the Fourth Five-year
Plan, it has not figured in any of the subsequent Plans.
The ICMR has had 6 nationwide research projects on
RF/RHD (1966–1990) and two "transfers of technology"
in 1987 and 1993. However, due to the lack of involvement
of Central and State Governments these programs have not
become widespread. Videos in English and local languages
have been made by the ICMR and the All India Heart
Foundation (AIHF) and made available on the national
network and to interested groups.
There is no doubt, thanks to these efforts, that there is
now awareness of RHD throughout the country and
injections and tablets of penicillin are being given freely to
children, both for primary and secondary prophylaxis.
IHJ-IA-002-00.p65
2
However, the government order banning penicillin injection
in government hospitals in some Indian states still exists.
Much more needs to be done, particularly in the
underdeveloped and troubled parts of the country and in
areas with low literacy like the states of Bihar, Madhya
Pradesh, Uttar Pradesh, the North East, and Jammu and
Kashmir. The two "transfers of technology" were not
enough for this vast country and need to be repeated over
many sessions jointly by the Central and State Government.
RF vaccine: With the availability of new technology18 and
thanks to the advances in molecular biology, the vaccine is
now a distinct possibility. The ICMR has been actively
involved in setting up research for an RF vaccine. It has
initiated the Jai Vigyan Mission Mode Project at Chandigarh
and Vellore wherein studies have already been initiated on
the development of such a vaccine. It has proposed to
undertake vaccine development using Indian strains.
Collection of strains is being done through the sub-study
on the epidemiology of group A streptococci and a study
on preparedness for primary prophylaxis using the vaccine
would be undertaken.
The ICMR has also initiated RF registries for secondary
prophylaxis at these centers and will extend them to other
regional centers through a network of satellite centers to
cover the entire country (DG, ICMR, personal
communication).
Epilogue
Some researchers believe that RF and RHD are getting
milder the world over. However, more evidence for this is
needed.
While in recent years some countries have reported a
milder form of the disease, the findings from others are the
reverse. India, Thailand and Sri Lanka were identified for
support in South-East Asia for secondary prevention after
the ad hoc committee on RF and RHD was set up by the
ISFC in 1982. The results, however, are not evident. The
project at Chandigarh is functioning. There is a decline in
RHD reported from Thailand, but the incidence in the
Middle East (Lebanon) is high.19
One hundred years is a long time for a disease of
infectious origin to continue its ravage unabated. Although
RF has now almost disappeared from the West, it can recur
as it did in the USA in 1987. It continues to kill and maim
the population in the developing countries of Asia, Africa
and South America. Whether it will vanish or not in the
new millennium due to change in the virulence of the
streptococcus or the new vaccine on the horizon is yet to be
seen.
4/10/01, 11:44 AM
Indian Heart J 2001; 53: 35–37
The big question is—has there been a significant decline
in RF and RHD in India? Can we now ignore the problem?
The answer is definitely no. The evidence points to many
children and young adults being affected in several parts
of the country. Overpopulation, poverty, illiteracy,
overcrowding and lack of access to medical care are all
responsible for the continuing high incidence. Hospitals in
both the private and public sectors are swamped by a large
number of admissions for coronary artery disease and
because of this preoccupation with adult cardiac disease
and its requirements (coronary care units, facilities for
angiography, angioplasty and bypass surgery), RHD receives
much less attention as it is a disease of poor children who,
as future citizens of the nation, should really receive high
priority.
At present, the early detection of RHD through the SHS
and PHC and secondary prophylaxis utilizing the SHS,
PHC and GP remains the best available option. Should a
safe vaccine become available, it would make a big difference
to the control of the disease. The Central and State
Governments should, meanwhile, cooperate in a major
technology transfer session.
Padmavati Rheumatic Fever in India 37
6.
7.
8.
9.
10.
11.
12.
13.
14.
References
15.
1. Rheumatic Fever and Rheumatic Heart Disease in India. In: Yu PN,
Goodwin JF, (eds). Progress in Cardiology. 15th ed. Philadelphia: Lea
and Febiger 1987; p. 169–183
2. Padmavati S. Present status of rheumatic fever and rheumatic heart
disease in India. Indian Heart J 1995; 47: 395–398
3. Sharma M, Saxena A, Kothari SS, Juneja R, Shrivastava S,
Manchanda SC. Acute rheumatic fever in children: experience from
a cardiac centre (Abstr). Indian Heart J 1999; 51: 652
4. Mishra TK, Rath PK, Mohanty NK, Mishra SK, Satapathy M. Juvenile
chronic RHD: our decade-long experience (Abstr). Indian Heart J
1999; 51: 653
5. Ahemad MZ, Jayasree P, Narayanan SN. Rheumatic chorea in
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16.
17.
18.
19.
children – A study of prevalence of clinical and echocardiographic
valvular involvement (Abstr). Indian Heart J 1999; 51: 694
Lalchandani A, Kumar HRP, Alam SM, Dwivedi RN, Krishna G,
Srivastava JP, et al. Prevalence of rheumatic fever and rheumatic
heart disease in rural and urban school children of district Kanpur
(Abstr). Indian Heart J 2000; 52: 672
Saxena A, Sharma M, Gupta D, Kothari SS, Juneja R. Active
rheumatic carditis in children: an acute and follow-up study of 155
patients in the era of Echo Doppler (Abstr). J Am Coll Cardiol 1999;
35: 2
Kothari SS, Yadav R, Juneja R, Saxena A. Percutaneous transseptal
mitral commissurotomy in children during acute rheumatic fever
(Abstr). Indian Heart J 2000; 52: 823
Panja M, Sinha DP, Mondal PC, Haque A, Majumder B, Sarkar NC, et
al. Mitral balloon valvotomy in pregnancy: long-term follow-up
results (Abstr). Indian Heart J 2000; 52: 822
Sai Satish O, Ramchandra VS, Patnaik AN, Ramesh G, Hanumanth
RK, Koshy G, et al. Percutaneous balloon mitral valvotomy for severe
mitral stenosis in pregnant women—NIMS Experience (Abstr). Indian
Heart J 2000; 52: 823
Bahl VK, Sharma G, Gupta D, Kothari SS, Saxena A, Juneja R, et al.
Acute and follow-up results of percutaneous transmitral
commissurotomy in 276 patients of juvenile mitral stenosis (Abstr).
Indian Heart J 2000; 52: 823
Martial G. Bourassa M. Is reuse of coronary angioplasty catheters
safe and effective? J Am Coll Cardiol 1994; 24: 1482–3
Sharma S, Panja M, Seth A, Kumar A, Ramesh SS, Lokhandwala Y.
Reuse of disposables in the catheterization laboratory. Indian Heart J
1997; 49: 329–331
Mittal P, Thoppil PS, Sriram S, Thomas JM, Sudarsana G, Abraham
KA. Percutaneous metal mitral commissurotomy: A comparison with
balloon mitral commissurotomy (Abstr). Indian Heart J 2000; 52: 823
Agarwal BL. Rheumatic Fever—Decline and resurgence. J Assoc
Physicians India 1994; 42: 10
Community Control of rheumatic fever and rheumatic heart disease.
Report of an ICMR task force study, ICMR, 1994
Pilot study on the feasibility of utilising the existing school and health
services in Delhi for the control of RF/RHD, ICMR Final Report 1990
Pruksakorn S, Currie B, Brandt E, Martin D, Galbraith A,
Phornphutkul C, et al. A vaccine for rheumatic fever: identification
of a conserved target epitope on M protein of group A streptococci.
Lancet 1994; 344: 639–642
Bitar FF , Hayek P, Obeid M, Gharzeddine W, Mikati M, Dbaibo GS.
Rheumatic fever in children: a 15-year experience in a developing
country. Pediatric Cardiol 2000; 21: 119–122
4/10/01, 11:44 AM
Current Perspective
Indian Heart J 2001; 53: 38–43
Cardiology at the Crossroads: Challenges for India
and Lessons from the West
Bernard Lown
Professor Emeritus, Harvard School of Public Health, Boston, USA
C
ardiology is now at a critical crossroad globally. We are
living in an age of unprecedented medical progress. The
innovations in cardiology, at times bordering on the
miraculous, are compelled by inexorable advances in
scientific knowledge. The present trajectory, though heady,
is not sustainable and furthermore threatens to denature
the moral core of our professionalism. Three developments
have brought the issue into prominence. First is the
emerging global pandemic of cardiovascular disease that
will impact most decisively on poor developing countries.
Second is the burgeoning cost of health care in rich
countries that forces rationing of medical care along class
lines. Third is the growing public discontent with, and
alienation from, a technology-centered medical profession.
These issues are interrelated and demand critical analysis.
As is true of crises wrought by human agency, they
challenge new thinking and offer opportunities for reaching
a higher plateau of human service and development.
The CVD Pandemic in Developing Countries
While unable to shake the disease of poverty, a mounting
epidemic of cardiovascular disease (CVD) is now sweeping
the urban populations of the developing world. For the first
time chronic degenerative ailments, generally associated
with affluent societies, constitute a major cause of death in
impoverished countries of the South. In 1990, two-thirds
of the 14 million cardiovascular fatalities worldwide
occurred in developing countries.1–3 These numbers are
likely to increase as more than half the population is under
15 years of age. Furthermore in the developing world, CVD
is emerging at an earlier age. In 1990 the proportion of
CVD deaths occurring below the age of 70 years was 26.5%
in rich countries as compared to 46.7% in poor countries.1
While the medical and socioeconomic consequences may
prove ruinous, astonishingly the CVD epidemic in the South
has received scant notice among physicians and public
health professionals.4
Correspondence: Dr Bernard Lown, Professor Emeritus, Harvard School of
Public Health and Senior Physician, Brigham and Women's Hospital, Boston, USA
*(Founder and Chairman of Satelife and ProCOR; Recipient of the Nobel Peace Prize)
IHJ-IA-003.p65
38
Reasons for the increase in CVD are not mysterious. One
important factor is the rising life expectancy. Other factors
relate to rapid and chaotic urbanization with accompanying
lifestyle changes and to the powerful economic and cultural
influences of globalization. 5 The shift in agricultural
production from small farmer to large corporation,
distribution from shopkeeper to supermarket, consumption
from fresh to processed foods, promote drastic changes in
nutrition. Junk food replaces dietary fiber and the complex
carbohydrates of fruits and vegetables. Consumption of fat
and salt increase and that of micronutrients diminish.
Calorie intake multiplies while physical activity lessens. The
mismatch between energy intake and energy output
manifests in a pandemic of obesity.6 Crowding, mass
unemployment and wanton violence engender social and
psychological stresses which are additional risk factors for
CVD and diabetes. When to this witch's brew is added the
rising consumption of tobacco, the outcome is as tragic as
it is preordained.
The mounting scourge of cigarette smoking deserves a
further comment. During the 1990s, the retreat of cigarette
companies had become a near route in some industrialized
nations. To make up for lost revenue, the tobacco companies
forged a long-range global strategy to maintain sales
roughly constant, where they were under siege, while
investing mammoth resources to increase market share in
the Third World. In the past decade tobacco consumption
in the United States dropped 17 per cent while exports have
skyrocketed 259 per cent.7 Tobacco promotion is pursued
aggressively in less developed countries, with advertising
budgets frequently surpassing national funds appropriated
for leading diseases. Among the primary targets are women
and children. These vulnerable groups are ill equipped to
cope with the slick marketing techniques and the dirty tricks
perfected by the tobacco industry.
Most developing countries have no advertising controls,
lack adequate health warning requirements, and have a
dearth of pressure groups campaigning for stricter tobacco
controls. They have set no age limits, nor imposed
restrictions on smoking in public places. Their populations
are poorly educated on the health hazards, nor is
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Indian Heart J 2001; 53: 38–43
information being provided to the burgeoning numbers of
teenagers who are most susceptible to advertising hype.8
The higher tar and nicotine content purveyed to the
developing world makes their cigarettes far more addictive
and therefore more lethal. When the spreading tobacco
habit is coupled with the rapidly rising prevalence of obesity
and high blood pressure, guaranteed is the fire storm spread
of ischemic heart disease.
How will India respond to this challenge? Current
developments suggest that it will follow stereotypically the
pattern evident worldwide. The role models are the
industrial nations, particularly the USA. The emulation is
in part driven by the fact that most developing countries
have weak or nonexistent public health infrastructures,9 by
their embrace of medical residency training programs
aimed to impart proficiency in interventional technologies,
and by the high incomes offered to those servicing wealthy
clienteles in superspecialized sectors. Corporate-sponsored
medical emporia are now mushrooming in urban centers
all over the developing world. Interventional cardiology is
a lucrative business. To attract "customers" no costs are
spared in acquiring cutting-edge equipment serviced by
highly trained professionals. Highlighted in these centers
is specialized tertiary care treatment for those with ischemic
heart disease while preventive strategies are largely ignored.
In addition to the exhorbitant social cost of such medical
practice, it short-changes the individual patient by
promoting unnecessary procedures which exact inevitable
and unjustified burdens of morbidity as well as death.
Momentary reflection indicates that half-way
technologies applied to advanced stages of disease are
counterproductive strategies for containing an evermounting epidemic. An important warning sign about the
road not to travel is now being provided by the USA, the
chief advocate of a technological approach to health. The
American people are now grappling with a health care crisis
without seeming exit.
USA—A Health System in Crisis
A glance at any American cardiological journal convinces
one that a majority of communications relate to promoting
high- tech solutions. One unexceptional example, that of
percutaneous transluminal coronary angioplasty (PTCA),
is illustrative of some of the underlying factors in the present
health care crisis. In 1978, Gruntzig et al.10 launched the
era of interventional cardiology with introduction of this
revolutionary approach. In 1991, a mere thirteen years
later, more than 300 000 PTCAs were performed annually
in the USA at an estimated cost of US$7 billion.11 In the
IHJ-IA-003.p65
39
Lown
Cardiology at the Crossroads 39
ensuing eight years, the number of coronary artery
angioplasties more than doubled and now exceeds 700 000
annually.12 This near-exponential dissemination of PTCA
occurred before the safety and efficacy of the procedure had
been established. Though balloon dilatation effectively
widens the caliber of a narrowed vessel in up to 90% of
cases, it presents problems as yet unsolved. Foremost is the
fact that restenosis occurs within six months in 30–50 per
cent of patients.11,13 Furthermore, PTCA does not protect
against plaque rupture, the major cause of mortality in
ischemic heart disease, nor does it deal with minor stenosis
which constitutes the nidus for abrupt closures and
resulting myocardial infarction. In fact, such unexpected
closures occur after 2–5 per cent of successful angioplasties.
The response to these limitations has been further
addition of technologies such as stenting. In some countries
intracoronary stent placement is used in 60% of
percutaneous recanalization procedures.14 While stents
reduce the restenosis rate of angioplasty by 30 per cent or
more, this is at a cost of neointimal proliferation. As could
be expected, novel technologies are now on the ready to
respond to this yet newer complication. Various types of
endoluminal beta- and gamma-radiation therapies are
purported to lessen neointimal growth,15,16 but not without
additional complications which indubitably will beget still
newer and costlier technologies.
When first introduced it was assumed that PTCA would
reduce the far more expensive coronary bypass operation.
This proved wrong. PTCA, by virtue of high rates of
restenosis, did not affect the anticipated large cost savings,
nor was there a decrease in the number of bypass
procedures. In fact, the two have continued to increase in
parallel. Furthermore, the exponential growth of PTCA,
irrespective of its limitation, is driven by the fact that
cardiologists who decide on its indication are the very ones
who perform the lucrative procedure. Such self-referral is
invariably associated with overuse of diagnostic or
therapeutic interventions. 17 Fueling the run-away
exponential rise in these procedures relates to the fact that
cardiology subspeciality academic programs overtrain
residents in interventional techniques. It is not unexpected
that those proficient in financially rewarding procedures
try to maximize their performance. The enormous
enrichment that awaits medical specialists has skewed the
distribution of doctors in the USA away from primary care,
with 70 per cent now providing speciality care.
The consequences of uncontrolled technology usage in
the USA, driven by other than evidence-supported medical
indications, when multiplied across disciplines has powered
astronomic health cost escalation. Last year, health
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Indian Heart J 2001; 53: 38–43
40 Lown Cardiology at the Crossroads
expenditures exceeded one trillion dollars (USA). My home
state of Massachusetts, with only 6.3 million inhabitants,
spends $5900 per person per year, which is more than is
budgeted by the Indian government for health care with a
population of one billion.
One would anticipate that with such mammoth
expenditures, every single American would be receiving first
class health care resulting in the best outcomes anywhere
in the world. This is not the case. Forty-four million
Americans are bereft of any health insurance and many
more millions have inadequate health protection. In terms
of outcomes, USA ranks an embarrassing 37th among 191
countries according to the World Health Organization.18
The ranking is based on such indicators as life expectancy,
child survival to age five, out-of-pocket health expenditures
and on a number of other factors which define high quality
of care. In fact, a technologically focussed approach neither
provides universal nor high quality health care.
The point is that the richest country in the world can
not afford these enormous expenditures which are projected
to double to 2.1 trillion dollars by the year 2007—a
whopping 16.6% of America's gross domestic product.19 To
stem the inflation of costs, the USA has promoted the
marketization of health services under the aegis of investorowned health maintenance organizations (HMO). The
intent is to enforce financial discipline by subjecting health
care to the efficiencies of industrialization. Ignored is the
commonsense fact that human beings cannot be
standardized; overlooked is the fact that health care is a
customized service resisting commodification and therefore
incompatible with the efficiencies of industrialized assembly
line or other mass production technologies.
The market solution is now widely acknowledged to have
failed. It has not contained costs, not promoted universal
access, nor maintained the quality of care. These outcomes
have not been unexpected. As in any business enterprise, a
paramount objective is to meet the profit expectations of
investors. To achieve this objective, HMOs have recruited
the healthy and short-shrifted the sick, have markedly
curtailed hospital stays, and have down-sized hospital staff
especially by reducing the cadre of experienced nurses. At
the same time, doctors have been inundated with a glut of
paper work responding to draconian measures to enhance
efficiency and profitability. Less money has been made
available for patient care as a large percentage of insurance
premiums have been diverted from health related programs
to dividends for investors, to increased market share
through costly promotion campaigns and for egregious
executive salaries, commonly in excess of one million dollars
annually.
IHJ-IA-003.p65
40
Limiting physician autonomy in patient management
has undermined the morale of the doctor and reduced it
to an all-time low. The lack of professional satisfaction has
led to early burn-out among increasing numbers of doctors.
There is a growing appreciation that the present direction
of health care in the USA is untenable. It is widely agreed
that though the American gross national product is $8
trillion annually, the growth in the level of health
expenditures in the long run is unaffordable. A curative
approach based on high technological investment surely is
not an appropriate direction for poor developing countries.
Preventive Cardiology
Far more attractive practically as well as fiscally is a
preventive strategy. Epidemiological studies extending over
half a century have unearthed a wealth of information as
well as forged an effective strategy for containing the
epidemic of ischemic heart disease. The initial impetus was
provided by the surveillance of nearly an entire population
in the small Massachusetts community of Framingham. As
a result of the accumulated evidence, primary prevention
is now a challenging possibility. The essential concept is
straightforward—readily identifiable risk factors long
antedate the emergence of CHD.20 Cardiovascular death
strikes not as an unexpected bolt of lightning but as the
culmination of a slowly evolving process marked by readily
recognizable signposts.
Much of the burden of heart disease is propelled by four
easily recognized and modifiable factors such as elevated
cholesterol, high blood pressure, cigarette smoking and
physical inactivity. Extensive population studies
demonstrate a continuous association between plasma
cholesterol levels and the risk of coronary artery disease.21,22
Multiple clinical trials have also established that treating
hypertension reduces the toll of cardiovascular disorders.23
This is true as well for cessation of smoking and physical
inactivity,
Availing themselves of these new insights, industrialized
societies have effected a substantial reduction in
cardiovascular mortality during the last half of the 20th
century. In the USA, during the three decades from 1960
to 1990, the CHD incidence receded about 1% annually
with a concomitant decline in CHD mortality. In large
measure the decline relates to modification of CHD risk
factors. 24–26 While improvement in treatment has
contributed to this trend, the onset of the decline antedates
the high volume of high-tech medical interventions.
That a concerted national effort can effect a striking
change in CVD mortality has been dramatically
4/10/01, 11:50 AM
Indian Heart J 2001; 53: 38–43
demonstrated in Finland. Heart disease mortality there, the
highest in the world, exhibited the steepest decline
anywhere recorded.27,28 Within a single generation the risk
factor profile of the Finnish people has been changed.
Dietary alteration involving lower fat consumption has
decreased mean levels of serum cholesterol, at the same
time, smoking has diminished among men while control of
hypertension has been improved. The exemplary health
dividend has been a 50% reduction in cardiovascular
mortality in both middle-aged men and women.29
Primary prevention is indispensable to reduce the CVD
burden. Although considering the big canvas, more
promising is a population-based strategy to prevent the
emergence of risk factors rather than their amelioration in
individual patients. 30 Primordial prevention was first
suggested by Strasser in 1980, to focus on preventing the
emergence of major risk factors as a prominent component
of public health strategy for containing the toll of CVD.31
As elegantly argued by Geoffrey Rose, a small shift in the
population mean of a particular risk factor is associated
with a large change in the prevalence of high values.32 For
example, if the mean of cholesterol distribution in a
population is reduced by 6%–7%, the prevalence of
hypercholesterolemia (defined by the top decile) will be
halved. Likewise a reduction in the population mean of
systolic blood pressure of 8 mm will reduce the prevalence
of hypertension by 50%. Rose cogently reasoned that a
population-based approach is likely to be far larger, less
costly, much safer and better sustained than the current
practice of dealing with the individual patient. Primordial
and primary prevention are complementary. Their essence
is the promotion of healthier lifestyles for entire populations.
For cardiologists the principal responsibility is the
optimal management of individual patients entrusted to
their care. But I would maintain that our professional
commitment to health mandates also a leadership role in
community education on the optimal thoroughfare to
healthy living. These are interrelated mutually reinforcing
strategies.
Even in managing the individual patient, a higher
premium has to be given to secondary prevention. Here the
cardiologist confronts a pharmacological revolution that
has drastically improved the prognosis of heart disease and
has reduced the need for costly hospital-based interventions.
Novel therapies are being introduced for each of the
multifactorial elements contributing to the disease, such as
beta-blockers, aspirin, antihypertensives, angiotensinconverting enzyme inhibitors, antidiabetic agents, etc.
Introduction of hydroxymethylglutaryl coenzyme A
reductase inhibitors (statins) has been among the most
IHJ-IA-003.p65
41
Lown
Cardiology at the Crossroads 41
effective. It is clear that treating hypercholesterolemic
patients with statins reduces the incidence of fatal and
nonfatal myocardial infarction by 30%–35%, as well as
lowering the incidence of strokes and the need for bypass
surgical procedures.33–36
To cite further examples, we at the Lown Cardiovascular
Group, have over many years focused on secondary
prevention and shown that it is possible to reduce by a
formidable 80% the need for coronary bypass, angioplasty,
and stenting in patients with multivessel coronary artery
disease. Long range outcomes in survival, incidence of
myocardial infarction, as well as the quality of life have been
of an order achieved with far more costly interventions.37–39
Whether focusing on the individual patient or on the
larger community, the objective is a changed lifestyle.
Central to its achievement is an informed public. Health
education, therefore, can no longer be viewed as a
discretionary component of care, rather, it needs to be
considered essential to a comprehensive approach to CVD.39
In this respect a basis for hope is the ongoing digital
information revolution, a social transformation of true epic
proportions. In public imagination the information age is
embodied in the Internet promising new vistas for
democracy, education, and personal enrichment. Indeed,
nothing in prior human history has provided as much
potential for making readily available more information for
more people at lower cost. In the USA the most popular are
health websites. The existing 100 000 such sites are visited
by 30 million Americans.
New Directions and Novel Approaches
Since the North has lived with the cardiovascular epidemic
for half a century, the broad contours of this experience
should prove instructive as the developing world confronts
its own epidemic of CVD. Exploiting the new possibilities of
the digital age is the unique, dynamic international forum,
ProCOR, (a joint undertaking of the Lown Cardiovascular
Research Foundation and SateLife,40 a leading provider of
health information and communication services to health
workers in developing countries), an ongoing, e-mail and
web-based (www.ProCOR.org) electronic conference intent
on fostering a global dialogue. This is to be a dialogue of
equals where members of diverse constituencies from the
medical profession, from among health care providers, from
among those responsible for shaping and implementing
health policy, and from community groups involved with
health care, share know-how, timely information,
experience, ideas, and proposals. Among key goals is to
stimulate research in areas where there exists but a paucity
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Indian Heart J 2001; 53: 38–43
42 Lown Cardiology at the Crossroads
of reliable epidemiological data about incidence and trends
in CHD risk factor prevalence. A further objective is to
arouse the awareness of the cardiovascular community in
the industrialized world, far too long blinded to the plight
of the majority of humankind. Similarly to respond to the
specific problems in particular countries, regional and
national AmiCOR groups, (friends of ProCOR) have been
promoted. In this global enterprise AmiCOR-India
(registered domain name is http://www.amicorindia.org)
is of special significance. This is supported by experts from
Cardiology, Internal Medicine, Public Health and all other
walks of life.
To launch an effective preventive strategy will mandate
training a cadre of cardiovascular professionals who are
sensitized to the issues and possess the appropriate public
health tools. Discarding its past support to conventional
cardiology training, the Lown Cardiovascular Group in
collaboration with the Brigham and Women's Hospital and
the Harvard School of Public Health has initiated a new
program for the exclusive training of cardiologists from the
developing world. This encompasses a novel curriculum
that will foster competence in both an holistic as well as a
resource-conserving approach to patient management.
Competence will be promoted in a number of disciplines
related to identification of cardiovascular risk factors as well
as community-based cardiovascular prevention programs.
In addition to classical cardiovascular subjects, the
curriculum will hone proficiency in an array of subjects;
among these epidemiology, nutrition, biostatistics, costeffectiveness analyses, informatics, medical technology
assessment, socioeconomic determinants of health, and
such unique areas as the utilization of mass communication
to effect behavioral changes as well as reshape cultural
norms relating to health. Trainees will be encouraged to
carry out research relevant to the particular needs in their
countries. The program is to begin this year.
A growing understanding in the rich countries of the
North is that without good health there cannot be economic
development, a prerequisite for a stable world order. An
important expression of that understanding is the CVD
Research Initiative for the Developing Countries. Launched
in 1998 through a partnership of Global Forum for Health
Research (GFHR) and the World Health Organization,
among its key goals is to promote research that will help
direct policies and programs for controlling CVD. One focus
in on high blood pressure. While hypertension is a growing
problem in the developing world, it is a key risk factor
in India where one out of three deaths is due to heart
disease.
IHJ-IA-003.p65
42
Conclusions
Preventive cardiology has now come of age. It is no longer
tolerable to our conscience as health professionals to ignore
this effective strategy. The stakes are not to be measured
merely in unaffordable economic costs, but in preventing
untold misery and denying people a longer life span. The
cardiology profession is challenged to lead this important
campaign for promoting good health for all segments of
society. We have just crossed the threshold of a new century.
The start of a new millennium is reason enough for an
innovative and determined resolve.
Acknowledgments
The author acknowledges gratefully the constructive
comments of RS Vasan, MD, DM, Framingham Heart Study
(USA), and A Chockalingam, PhD, Ottawa (Canada).
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8. Lown B. The opium wars of the 21st century: tobacco and the
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9. Garrett L. Betrayal of Trust. The collapse of global public health
hyperion. New York, 2000
10. Gruntzig AR. Transluminal dilatation of coronary artery stenosis.
Lancet 1978; 1: 263–266
11. Nicod P, Scherrer U. Explosive growth of coronary angioplasty:
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12. Sapirstein W, Zuckerman B, Dilard J. FDA approval of coronary artey
brachytherapy. New Engl J Med 2001; 344: 297–299
13. Frischman DL, Leon MB, Baim DS, et al. A randomized comparison
of coronary-stent placement and balloon angioplasty in treatment
of coronary artery disease. N Engl J Med 1994; 331: 496–501
14. Schwartz L, Blew B, Bui S. Intracoronary-stent placement for
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15. Verin V, Popwski Y, Bruyne De B, Baumgart D, Sauerwein W, Lins H,
et al. Endoluminal beta-radiation therapy for the prevention of
coronary restenosis after balloon angioplasty. N Engl J Med 2001;
344: 243–249
16. Leon MB, Paul S, Teirstein PS, Moses SW, Tripuraneni P, Lansky AJ,
et al. Localized intracoronary gamma-radiation therapy to inhibit
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www.ProCOR.org ProCOR commentary 1999
4/10/01, 11:50 AM
Original Article
Absence of Association Between Serum Homocysteine
Levels and Coronary Artery Disease in South Indian Males
R Deepa, K Velmurugan, G Saravanan, K Karkuzhali, V Dwarakanath, V Mohan
Madras Diabetes Research Foundation, Gopalapuram, Chennai
Department of Cardiothoracic Surgery, Government General Hospital, Chennai
Backround: Asian Indians are reported to have a very high prevalence of premature coronary artery disease.
However, traditional risk factors do not explain this excess of coronary artery disease. Elevated levels of
homocysteine are reported to be associated with coronary artery disease among Europeans. This study looked
at the association of serum homocysteine levels with coronary artery disease in South Indians.
Methods and Results: Four groups of patients were studied: Group 1 consisted of healthy nondiabetic subjects
without coronary artery disease (n=18); Group 2 consisted of nondiabetic subjects with coronary artery disease
(n=21); Group 3 consisted of type 2 diabetic patients without coronary artery disease (n=18) and Group 4
consisted of type 2 diabetic patients with coronary artery disease (n=20). The mean homocysteine value was
12.4±3.4 µmol/L in Group 1; 12.6±4.6 µmol/L in Group 2; 10.1±4.4 µmol/L in Group 3; and 10.4±3.9 µmol/
L in Group 4. There was no significant difference in the homocysteine levels between the groups studied. The
prevalence of hyperhomocysteinemia, defined as a level of 17.1 µmol/L (the 95th percentile for serum
homocysteine in the control group) was not significantly different among the groups.
Conclusions: Elevated serum homocysteine levels are not associated with coronary artery disease in South
Indian male subjects with or without diabetes. However, the results must be interpreted with caution because of
the small numbers studied. (Indian Heart J 2001; 53: 44–47)
Key words: Hyperhomocysteinemia, Coronary disease, Risk factors
H
yperhomocysteine, a thiol containing amino acid
generated during the metabolism of methionine,1,2
occurs in almost all human tissues. Elevated levels of
homocysteine are associated with vascular disease3,4 and
hyperhomocysteinemia is thus considered to be an
independent risk factor for coronary artery disease (CAD).5,6
Factors which influence the levels of homocysteine include
age, 7 genetics, 8,9 and nutrition. 10,11 Since genetic
background and nutritional intake vary in different
populations, studies on homocysteine levels in different
ethnic groups are necessary.
Asian Indians have very high prevalence rates of
premature CAD occurring below the age of 50 years.12–14
Conventional risk factors do not fully explain the excess of
CAD among Indians, hence the need for studying newer
cardiovascular risk factors. The increased susceptibility to
CAD in this ethnic group suggests that genetic factors may
Correspondence: Professor V Mohan, Director, Madras Diabetes Research
Foundation, 35, Conran Smith Road, Gopalapuram, Chennai 600086
e-mail: [email protected]
IHJ-916-00.p65
44
play a role. As homocysteine levels are genetically
determined,8,9 we undertook a study of homocysteine levels
in South Indian diabetic and nondiabetic subjects with and
without CAD in Tamil Nadu state (South-East India).
Methods
Study Groups: We restricted the study to males as we could
not obtain a sufficient number of well-characterized female
subjects. The following groups of subjects were studied.
Group 1 consisted of 18 healthy nondiabetic control
subjects, selected from an ongoing population-based study
by the Chennai Urban Population Study (CUPS),15 Chennai.
The inclusion criteria were: normal glucose tolerance test,
absence of angina, myocardial infarction or any history
of vascular disease and a normal resting 12-lead
electrocardiogram (ECG).
Group 2 consisted of nondiabetic patients with CAD.
Twenty-one male patients were selected from the
department of Cardiothoracic Surgery, Government
General Hospital, Chennai. CAD was diagnosed on the basis
4/10/01, 11:33 AM
Indian Heart J 2001; 53: 44–47
Deepa et al.
Homocysteine and Coronary Artery Disease in South Indians 45
of coronary angiography and all the subjects had severe
(>70%) stenosis of two or more coronary arteries.
Groups 3 and 4 were type 2 diabetic patients selected
from the MV Diabetes Specialities Centre, a tertiary diabetes
care center at Chennai. The diagnosis of diabetes was based
on past medical history, drug treatment for diabetes (insulin
or oral hypoglycemic agents) and/or criteria laid down by
the WHO Consultation Report,16 i.e. fasting plasma glucose
> 126 mg/dl and/or 2 hour plasma glucose > 200 mg/dl.
Group 3 consisted of 18 type 2 diabetic patients without
CAD. All patients in this group denied any history of angina
or myocardial infarction, had no history of any vascular
disease and had normal resting 12-lead ECGs.
Group 4 consisted of 20 type 2 diabetic patients with
CAD, which was diagnosed angiographically using criteria
similar to those for Group 2.
The study protocol was approved by the ethical
committee of our center and informed consent was obtained
from all the study subjects. Clinical examination included
measurement of height, weight, calculation of body mass
index, blood pressure measurement and cardiovascular
examination.
Biochemical Methods: A fasting blood sample was taken
from all the study subjects for the estimation of plasma
glucose, serum lipids and homocysteine. Homocysteine was
assayed by enzyme-linked immunoassay (ELISA) using an
Axis Biochemicals kit (Bio Rad, CA, USA). Briefly, proteinbound homocysteine in the serum sample is reduced to free
homocysteine and converted enzymatically to S-adenosyl
homocysteine (SAH) before the immunoassay. This is
followed by a solid-phase enzyme immunoassay based on
competition between SAH in the sample and immobilized
SAH bound to the wall of the microtiter plate for binding
sites on a monoclonal anti-SAH antibody. After removal of
the unbound anti-SAH antibody, a secondary rabbit antimouse antibody labeled with the enzyme horseradish
peroxidase is added. The peroxidase activity is measured
spectrophotometrically after addition of the substrate. The
absorbance is inversely related to the concentration of total
homocysteine in the sample. A calibration curve is
constructed using a standard (2.0 – 50.0 mg/dl) provided
with the kit. The inter- and intra-assay coefficient of
variation of the homocysteine assay was 8.3% and 9.8%,
respectively. Total serum cholesterol, serum triglyceride and
HDL cholesterol were assayed with a commerical kit
(Boehringer Mannheim, Germany) using the Hitachi 912
Autoanalyser (Boehringer Mannheim, Germany). LDL was
calculated using the Friedewald equation.17
Hypertension was diagnosed based on a history of drug
IHJ-916-00.p65
45
Table 1. Clinical characteristics of the study groups
Nondiabetic
without CAD
Group 1
(n=18)
Age (years)
BMI (kg/m2)
Hypertension (%)
Smoking (%)
Fasting plasma
glucose (mmol/L)
Serum cholesterol
(mmol/L)
Serum triglycerides
(mmol/L)
HDL cholesterol
(mmol/L)
LDL cholesterol
(mmol/L)
Serum homocysteine
Mean (µmol/L)
>10.0 µmol/L
>17.1 µmol/L
Nondiabetics Diabetics
with CAD without CAD
Group 2
Group 3
(n=21)
(n=18)
Diabetics
with CAD
Group 4
(n=20)
53±8
23.5±2.3
10
15
53±7
23.0±2.9
55*
50*
53±9
25.6±4.7
50*
15
56±9
24.2±4.7
69*
19.2
4.93±0.71
4.78±1.14
9.18±2.98# 8.72±3.73#
4.68±0.68
4.90±1.04
5.0±0.88
5.10±1.07
1.50±0.90
1.93±1.13
1.94±0.84
2.23±1.80
1.04±0.21
1.0±0.15
1.0±0.19
0.95±0.15
2.95±0.61
3.07±0.79
2.92±0.94
3.07±0.65
12.4±3.4
83.3%
5.6%
12.6±4.6
71.4%
19.0%
10.1±4.4
55.6%
5.6%
10.4±3.9
55.0%
5.0%
* p<0.05 compared to healthy controls
# p<0.05 compared to healthy controls and non-diabetics with CAD
treatment or if the blood pressure was greater than 140/
90 mmHg.18
Statistical analysis: One-way ANOVA was used to
compare the mean of the continuous variables among the
study groups. Chi-square test or Fisher's exact "t" test were
used as appropriate to compare the proportions. All analyses
were performed with the SPSS statistical software package
(Version 4.0.1. SPSS, Chicago) and p values <0.05 were
considered significant.
Results
Table 1 shows the clinical and biochemical features of the
study population. Both the diabetic and nondiabetic patients
with CAD had a higher prevalence of hypertension and
smoking. Both the diabetic groups had higher serum
cholesterol and serum triglyceride levels compared to the
respective nondiabetic groups.
There was no difference in the mean homocysteine levels
in the subjects, with or without CAD, either in the diabetic
or in the nondiabetic subjects. The 95th percentile for
serum homocysteine in the control group was 17.1 µmol/
L. Using this as the definition, the prevalence of hyperhomocysteinemia was not significantly different among the
groups.
There was a wide scatter of the values in the distribution
of homocysteine in the study groups as seen in Fig. 1.
4/10/01, 11:33 AM
46
Deepa et al.
Fig. 1. Scatter diagram of serum homocysteine levels in the study groups. The
horizontal bars represent the mean values in each group.
Discussion
Recent reports on homocysteine suggest that it is an
independent predictor of vascular disease, including stroke
and CAD. 3–6 A recent study has demonstrated the
association of plasma homocysteine with increased CAD
among immigrant Indians in the UK.19 However, a study
from Singapore showed no increase in homocysteine levels
in Indians compared to the Malays and Chinese.20 There are
very few studies on homocysteine levels in native Indians.
The present study shows a lack of association of
homocysteine with CAD in native Indians. Similar results
were obtained in a study from Kerala in South-West India.21
However, these results must be interpreted with caution in
view of the limitations of the study mentioned below.
Studies on the association of hyperhomocysteinemia
with CAD in different populations have yielded conflicting
results, with some studies providing evidence for an
association19,22,23 while others have found none.21,24,25 This
may be attributed to ethnic differences or due to differences
in the definition of cases or sample sizes.
Recent studies on homocysteine in Indian diabetic
patients have revealed an association of body weight with
plasma homocysteine levels.26 The study by Munshi et al.27
showed elevated homocysteine levels in diabetic subjects
compared to age-matched controls. Hoffman et al. 28
reported that hyperhomocysteinemia is more common in
type 1 diabetic patients with nephropathy. It was recently
demonstrated that insulin may play a role in homocysteine
metabolism29 and obese type 2 diabetics tend to have higher
levels of homocysteine due to hyperinsulinemia.26 Our data
show that there was no significant increase of homocysteine
levels in diabetes per se or in diabetic patients with CAD.
IHJ-916-00.p65
Indian Heart J 2001; 53: 44–47
Homocysteine and Coronary Artery Disease in South Indians
46
This could be attributed to the fact that the body-mass index
was similar among the study groups.
One of the reasons for the discrepancy in results obtained
from studies carried out on Europeans and Indians may be
due to the differences in dietary habits. In India, many
people are vegetarians and there is a higher intake of green
leafy vegetables that are rich in folate which is an essential
co-factor in the metabolism of homocysteine.29 It is well
known that hyperhomocysteinemia can be corrected by
increasing folic acid and pyridoxine intake. 30–32
Unfortunately, we did not carry out any measurements of
pyridoxine or B12 in our study.
A recent study from the Hammersmith Hospital, UK has
reported that supplementation of folic acid and vitamin B12
improves vascular endothelial function. This effect is
probably mediated through reduction in plasma
homocysteine concentrations.33 However, in contrast a
report from Addenbrooke's Hospital, UK reported no
significant change in arterial stiffness in acute
hyperhomocysteinemia induced by an oral methionine
load.34 Overall, the association of homocysteine with CAD
is still unclear and the American Heart Association has not
recommended testing for homocysteine as part of the
screening for cardiovascular risk in population-based
studies.35
Conclusions: The present study suggests a lack of
association between homocysteine and CAD in urban South
Indian male diabetic and nondiabetic subjects. The results,
however, must be interpreted with caution due to several
limitations of this study. Firstly, the sample size was very
small. Secondly, we did not adjust for other cardiovascular
risk factors, again due to the small sample size. Moreover,
while the groups with CAD were diagnosed based on
coronary angiography, the diagnosis in patients without
CAD was made on clinical grounds and resting ECG
findings. One cannot exclude the possibility that had
coronary angiography been performed, some of these
individuals might have had CAD. This could not, however,
be done because of logistic, ethical and socio-economic
reasons. Finally, only a fasting homocysteine (basal) sample
was estimated. If an oral methionine load was given, the
results may well have been different. Prospective studies are
clearly needed to study the role of homocysteine in the
development of CAD in native Indians.
Acknowledgments
Mr AK Mathai, for statistical analysis and Mrs G Malarvizhi
and Mrs Muthuvalli Nayaki for secretarial assistance.
4/10/01, 11:33 AM
Indian Heart J 2001; 53: 44–47
Deepa et al.
Homocysteine and Coronary Artery Disease in South Indians 47
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Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS.
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Christen WG, Ridker PM. Blood levels of homocysteine and
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199
4/10/01, 11:33 AM
Original Article
Does Inhaled Nitric Oxide Improve Survival in Operated
Congenital Disease with Severe Pulmonary Hypertension?
R Sharma, N Raizada, SK Choudhary, A Bhan, P Kumar,
R Juneja, SS Kothari, A Saxena, P Venugopal
Cardiothoracic Center, All India Institute of Medical Sciences, New Delhi
Background: The present study aimed to assess the impact of inhaled nitric oxide on survival following correction
of congenital heart defects with residual pulmonary arterial hypertension.
Methods and Results: Inhaled nitric oxide was utilized for the management of residual pulmonary hypertension
in 24 children following surgical correction of their underlying heart defects. Their ages ranged from 15 days to
14 months (median 5 months). Pulmonary artery hypertension was diagnosed either by direct pulmonary artery
pressure monitoring or by echocardiography. Inhaled nitric oxide was used electively in 22 patients when the
ratio of the mean pulmonary arterial pressure and mean systemic arterial pressure exceeded 0.5. In the remaining
2 patients, nitric oxide was used only to manage a pulmonary hypertensive crisis. Inhaled nitric oxide was also
used a second time in 2 patients who developed delayed pulmonary hypertensive crisis. Twenty-two patients
showed an initial response to therapy and the pulmonary artery pressures dropped significantly. Of the patients
on direct pulmonary artery pressure monitoring, a pulmonary artery to systemic artery pressure ratio below
0.3 on prolonged therapy was associated with a survival ratio of 4/6 (including 1 neurological death and one reoperation); that between 0.3 and 0.5 with a survival ratio of 3/4. Three out of four patients with sustained
echocardiographic and clinical response also survived and were discharged from the hospital. All the patients
who showed a lack of response to (n=2), tolerance to (n=1), or dependence on (n=6) the use of inhaled nitric
oxide died. In addition, all 5 patients who had a pulmonary hypertensive crisis died, 3 in spite of successful
resuscitation with nitric oxide. Thus, excluding one neurological death and one re-operation, only 9 (41%) out
of 22 patients survived.
Conclusions: Though inhaled nitric oxide is effective in lowering pulmonary pressure, it does not appear to
improve the survival rate following repair of congenital heart disease in those with associated severe pulmonary
hypertension. A randomized trial between the use and non-use of inhaled nitric oxide is warranted to determine
its exact role in influencing survival in patients with residual pulmonary hypertension following surgical repair.
(Indian Heart J 2001; 53: 48–55)
Key Words: Pulmonary hypertension, Nitric oxide, Congenital heart defects
S
everal reports of the beneficial effect of inhaled nitric
oxide (iNO) in lowering pulmonary artery pressure
(PAP) following repair of congenital heart disease are
available.1–5 Yet, it is not clear whether this translates into
survival benefit. Most centres with experience of iNO belong
to the developed world where surgey for congenital heart
disease associated with significant pulmonary arterial
hypertension (PAH) is undertaken in the neonate or very
young infant. At this age, an accurate surgical repair is
Correspondence: Dr Rajesh Sharma, Additional Professor, Department of
Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences,
Ansari Nagar, New Delhi 110029. e-mail: [email protected]
IHJ-913-00.p65
48
generally sufficient to prevent life-threatening PAH in the
postoperative period.
The situation in the developing world is different in that
late presentation of congenital heart disease is not
uncommon and postoperative PAH is the principal
determinant of the final outcome.6 The present report
describes our early experience with iNO in the management
of postoperative PAH.
Methods
Patient population: Twenty-four children operated upon
for various congenital heart diseases with severe PAH during
4/10/01, 11:26 AM
Indian Heart J 2001; 53: 48–55
Sharma et al.
May–October 1999, who were put on iNO in the immediate
postoperative period, form the basis of this report.
Morphological diagnoses included ventricular septal defect
(VSD, n=7), obstructed total anomalous pulmonary venous
drainage (TAPVC, n=4), atrioventricular septal defects
(AVSD, n=2), single ventricle (n=1), transposition of the
great arteries (TGA, n=8), and double outlet of the right
ventricle (DORV, n=2). The ages ranged from 15 days to 14
months (median 5 months). Patient details are summarized
in Table 1.
Preoperative evaluation: A diagnosis was reached by
two-dimensional echocardiography. Operability was
assessed based on the clinical features, i.e. age, presence of
congestive heart failure, cardiomegaly, features of left
ventricular volume overload, presence of a mitral or
tricuspid flow rumble, plethoric lung fields on plain chest
Nitric Oxide in Pulmonary Hypertension 49
X-ray and arterial oxygen saturation in room air and with
oxygen. In borderline cases, cardiac catheterization was
carried out to calculate the pulmonary vascular resistance
in room air and on 100% oxygen. Systemic and pulmonary
flows were calculated by the Fick technique and oxygen
consumption was calculated from the assumed oxygen
consumption formula.7
Surgical management: Standard techniques of
cardiopulmonary bypass with deep or moderate
hypothermia were utilized. Intracardiac repair was
accomplished during a period of aortic cross-clamping with
cardiac asystole achieved by 1 or more doses of anterograde
cardioplegia delivered to the aortic root. Patients were
routinely weaned away from cardiopulmonary bypass on a
low dose of dopamine. Most patients had monitoring lines
inserted for the measurement of pulmonary arterial (n=14)
Table 1. Preoperative characteristics
S. No. Morphological
diagnosis
Additional
information
Age
Systemic arterial
oxygen saturation
Room
100%
air
oxygen
CTR
QP/QS
PAP/SAP
PVRI
Room 100%
air
oxygen
1
2
3
4
5
6
7
8
9
10
VSD
VSD
VSD
VSD
VSD
VSD
VSD
TAPVC
TAPVC
TAPVC
8 months
8 months
12 months
9 months
6 months
4 months
5 months
1 month
53 days
15 days
100%
100%
100%
100%
100%
100%
100%
92%
91%
50%
–
–
–
–
–
–
–
–
–
60%–66%
0.6
0.6
0.5
0.5
0.6
0.7
0.5
0.5
0.5
0.5
1.8/1
>2/1
1.6/1
1.2/1
>2/1
1.4/1
1.5/1
*
*
*
0.9
0.7
1.0
1.0
1.0
0.9
0.8
*
*
*
11
8
6
13
8
8
10
*
*
*
2
3.4
3
3.2
2
2
2.5
*
*
*
11
12
13
14
15
16
17
18
19
20
21
22
23
24
TAPVC
CAVC
CAVC
SV
TGA
TGA
DORV
TGA
TGA
TGA
TGA
TGA
DORV
TGA
–
Absent LPA
–
Down syndrome
Small RV
Small RV
–
Infradiaphragmatic
Supracardiac
Infradiaphragmatic,
meconium aspiration
Infradiaphragmatic
Down syndrome
Down syndrome
BAS+PA band at 2 months
VSD
VSD
VSD
VSD
VSD
VSD
VSD
VSD
VSD
IVS, Post-Senning
pulmonary vein
obstruction
3 months
8 months
5 months
6 months
7 months
3 months
2 months
2 months
8 months
4 months
5 months
14 months
12 months
8 months
40%–60%
80%
82%
60%
60%
57%
80%
90%
75%
88%
60%
90%
85%
90%
60%–80%
88%
92%
70%
75%
65%
92%
92%
82%
95%
70%
94%
92%
92%
0.5
0.5
0.6
0.5
0.5
0.7
0.7
0.7
0.7
0.5
0.6
0.6
0.6
0.5
*
2/1
>2/1
0.8/1
0.5/1
*
*
*
>2.5/1
*
>2/1
>2/1
>2/1
*
*
1.0
1.0
1
1.0
*
*
*
0.7
*
1/1
1/1
1/1
*
*
11
10
7
8
*
*
*
5
*
13
10
8
*
*
3.5
3.0
3.0
2
*
*
*
2
*
2
4
3
*
* Not catheterized
CTR : cardiothoracic ratio; QP/QS : pulmonary to systemic blood flow ratio; PAP/SAP: ratio of mean pressure in pulmonary artery and systemic artery; PVRI: pulmonary
vascular resistance (indexed); VSD: ventricular septal defect; LPA: left pulmonary artery; TAPVC: total anomalous pulmonary venous connection; CAVC: complete atrioventricular
canal; BAS: balloon atrial septostomy; TGA: transposition of the great arteries; IVS: intact ventricular septum; DORV: double outlet right ventricle; RV: right ventricle; SV:
single ventricle
IHJ-913-00.p65
49
4/10/01, 11:26 AM
50 Sharma et al.
and left atrial (n=16) pressures to assist in postoperative
management. After arrival in the intensive care unit (ICU)
a check echocardiogram was carried out in all patients to
exclude significant residual defects.
Diagnosis of postoperative PAH: Fourteen of the 24
patients had direct PAP monitoring via a 20-gauge catheter
inserted into the main pulmonary artery at the conclusion
of surgery. Two had a pressure monitoring line in the right
ventricular cavity inserted via the right atrial appendage
and one patient's PAP was reflected in the internal jugular
pressure tracing by virtue of a superior vena cava to
pulmonary artery anastomosis. The remaining 7 patients
were diagnosed to have PAH in the post-repair period based
on indirect evidence corroborated by Doppler
echocardiography. Echocardiographic visualization of the
dilated right heart chambers along with a Doppler velocity
predictive of near-equalization of right ventricular and
systemic pressures were taken to indicate the existence of
severe PAH.
Conventional management protocol for PAH:
Complete neuromuscular blockade using intermittent
intravenous pancuronium and deep sedation by means of
an infusion of fentanyl, for a period of at least 48 hours
after surgery, were uniformly practised. In addition, an
alkaline pH (>7.45) and hypocarbia (pCO2 between 30 and
35 mmHg) in the arterial blood gas was ensured. An
inspired FIO 2 of 1.0 was used in all patients with
preoperative PAH in the early period following surgery and
whenever the PAP showed a tendency to rise. In addition, a
number of pulmonary vasodilators (nitroglycerine,
isoprenaline, and prostaglandin E) were also used.
Criteria for starting elective iNO therapy: To use iNO,
permission was taken from the hospital ethics committee.
Informed consent was also taken from the parents of the
children.
Any patient with a mean pulmonary artery to systemic
artery pressure ratio (PAP/SAP) exceeding 0.5, which was
sustained in spite of the above steps, was put on iNO therapy.
In those without direct pulmonary artery pressure
monitoring, indirect evidence that prompted
echocardiographic interrogation for PAH included an
episode of systemic hypotension with a high right atrial
pressure (patients #17 and 20), unresolving pulmonary
haemorrhage following repair (patient #18), features of a
low cardiac output with resistant metabolic acidosis (patient
#22), poor systemic perfusion with features of right heart
failure (hepatomegaly, ascites) (patient #21) and
hypoxemia and respiratory arrest in an extubated patient
(patients #7 and 10). The temporal relationship between
IHJ-913-00.p65
Indian Heart J 2001; 53: 48–55
Nitric Oxide in Pulmonary Hypertension
50
initiation of iNO therapy and the time after completion of
surgical repair in each patient is mentioned in Table 1.
iNO delivery system: Medical grade nitric oxide (NO) in a
concentration of 1000 parts per million (ppm) in nitrogen
(Air Liquide®, France) was delivered via a Siemens Servo300 ventilator modified for NO delivery and fitted with an
electrochemical NO/NO2 analyzer (Siemens Elema, AB,
Sweden).
iNO therapy protocol: Therapy with iNO was begun at
an initial dose of 10 ppm and increased in multiples of 10
ppm every 15 to 20 minutes in the absence of a significant
response. Once a response was obtained, the dosage of iNO
was decreased to the minimum at which this response
persisted. In the absence of direct PAP monitoring,
disappearance of an undesirable feature (e.g. metabolic
acidosis or hepatomegaly), or improvement in systemic
pressure, rise in peripheral skin temperature, improvement
in diuresis, or increase in arterial oxygenation were sought
and the minimum dose of iNO achieving that response was
continued. Echocardiographic confirmation of the response
was also looked for once a steady baseline had been
achieved. No alterations in ventilator settings or drug
infusions were made while the iNO therapy was being
initiated and till the lowest possible steady maintenance
dose was arrived at. Monitoring of toxicity was done by
surveillance of the methemoglobin level and the percentage
of inhaled nitrogen dioxide (NO2). Methemoglobin levels,
expressed as a percentage of the total hemoglobin, were
measured every 12 hours during therapy. The
electrochemical analyzer was used to monitor inhaled levels
of NO2. The protocol dictated reduction or cessation of
therapy if the methemoglobin level exceeded 5%, or if the
NO2 level was 2.5 ppm or more.
Weaning away from iNO: An attempt to reduce iNO to
the lowest effective dose was routinely made every 24 hours
if hemodynamic stability and arterial oxygenation were
maintained. If there was no adverse response to weaning
at a rate of 2 to 5 ppm (especially if direct PAP was available),
this was attempted every 6 hours. When down to a dose of
5 ppm, iNO was left on for at least 24 hours before further
reduction was attempted. In general, complete cessation of
iNO therapy and stability in this state for at least 24 hours
were required before weaning away from mechanical
ventilation. Some patients were kept on iNO (10 ppm)
through an airtight hood with scavenging if they exhibited
an elevation of PAP following extubation.
Emergency use of iNO: In the situation of a pulmonary
hypertensive crisis with or without cardiorespiratory arrest,
4/10/01, 11:26 AM
Indian Heart J 2001; 53: 48–55
Sharma et al.
iNO therapy was started at a dose of 80 ppm, if routine
resuscitation measures failed to provide a prompt response.
This was then reduced, if possible, in the steps described. A
pulmonary hypertensive crisis was defined as an acute
elevation of PAP such that PAP/SAP >1 accompanied by
systemic arterial desaturation with an impending or
existent drop in systemic arterial pressure.
Nitric Oxide in Pulmonary Hypertension 51
Results
Following completion of surgery, iNO therapy was initiated
at a mean interval of 20 hours (range 0 – 72 hours). The
duration of therapy ranged from 1 to 10 days (mean 4.9
days). The response to iNO and final outcomes are
summarized in Table 2.
Based on the initial response to iNO therapy, patients
could be divided into 2 groups.
Table 2. Response to nitric oxide and final outcome
iNO Therapy before extubation
Reference
no.
(Table 1)
Operation
performed
Indication
1
2
3
4
5
VSD closure
VSD closure
VSD closure
VSD closure
VSD closure
6
7
8
9
10
VSD closure
VSD closure
Repair
Repair
Repair
11
12
13
14
Repair
PAP/SAP >0.5
Two-patch repair PAP/SAP >0.5
Two-patch repair PAP/SAP >0.6
Bidirectional
SVC pressure
Glenn shunt +
24–26 mmHg
atrial septectomy
ASO+VSD
PAP/SAP >0.5
closure
ASO+VSD
PAP/SAP >0.5
closure
ASO+VSD
Severe PAH on
closure
echocardiography
ASO+VSD
Severe PAH on
closure
echocardiography
ASO+VSD
Severe PAH on
closure
echocardiography
ASO+VSD
Severe PAH on
closure
echocardiography
ASO+VSD
Severe PAH on
closure
echocardiography
ASO+VSD
Severe PAH on
closure
echocardiography
Kawashima
PAP/SAP >0.5
repair
Repair of
PAP/SAP >0.5
pulmonary
venous obstruction
15
16
17
18
19
20
21
22
23
24
Extubation
Interval
PAP/SAP
between
surgery and
therapy Res- Duration
(hours) ponse (days)
Secondary iNO
Lung
(after extubation) infection
Indication
Final
outcome
PAP/SAP >0.6
PAP/SAP >0.5
PAP/SAP >0.5
Not required
PAP/SAP >0.8
12
12
24
+
+
+
4
3
5
48
+
2
–
–
PAP/SAP >0.6
PAP/SAP >0.8
–
–
–
+
+
–
Alive
Alive
Alive
Alive
Died
PAP/SAP >0.8
Not required
PAP/SAP >0.6
PAP/SAP=0.5
Not required
18
+
5
0
0
+
+
3
4
+
–
–
–
–
Died
Died
Alive
Alive
Died
6
0
0
6
+
+
+
+
5
7
9
1
# Never extubated
**Never extubated
**Never extubated
#
–
PAP/SAP=1.0
–
–
Cardiorespiratory
arrest
–
–
–
–
–
+
+
–
Died
Died
Died
Alive
48
+
5
0.2
Ñ
–
Died
12
+
7
0.5
Died
12
+
2
*
Cardiorespiratory +
arrest
–
–
18
+
5
*
72
+
2
12
+
48
0.3–0.5
0.3–0.6
0.3
0.3
Never extubated
to neurological
complication
**Never extubated
0.4
0.2
0.2
*
Alive
Alive
*
Cardiorespiratory –
arrest after 7 days
–
–
2
*
–
–
Alive
+
9
* Never extubated
–
+
Died
4
+
10
* Never extubated
–
+
Died
12
+
8
** Never extubated
–
+
Died
12
+
2
0.5
–
–
Alive
Alive
* No pulmonary artery catheter; ** NO dependence; = tolerance to NO; # reoperated with takedown of Bidirectional Glenn + banding of main pulmonary artery; Ñ :
cardiorespiratory arrest but NO was not available; PAP/SAP: ratio of mean pressures in pulmonary artery and systemic artery; RV: right ventricle; PAH: pulmonary
arterial hypertension
IHJ-913-00.p65
51
4/10/01, 11:26 AM
52 Sharma et al.
Responders: Twenty-two patients (#1–3, 5, 6, 8–24)
showed an initial response to iNO. In those patients where
direct PAP recording was available (n=15), mean PAP
dropped from 47±18.0 mmHg to 23.5±15.1 mmHg
(p<0.001). The fall in mean PAP ranged from 6 to 35 mmHg
(mean 23.6±4.8 mmHg) and the PAP/SAP ratio stabilized
to less than 0.5 in 10 patients. Seven patients without PAP
monitoring showed echocardiographic evidence of a drop
in PAP. In general there was improvement in the systemic
arterial pressure, urine output and toe temperature in all 7
patients. One patient (#22) who had a persistent base deficit
along with carbon dioxide retention in spite of
supramaximal ventilation since arrival from the operating
room, had a dramatic normalization of blood gases, so that
ventilator settings could be rapidly revised. Another patient
(#18) had pulmonary hemorrhage continuing into the
second day following surgery. After echocardiogram
detected a severe PAH based on a high-velocity pulmonary
regurgitation jet filling the entire right ventricular cavity,
iNO therapy was instituted expeditiously. Within an hour
of starting 10 ppm iNO, the pulmonary hemorrhage
became negligible. A check echocardiogram demonstrated
significant reduction in the velocity of pulmonary
regurgitation with improvement in right ventricular
function.
Non-responders: Two patients (#4 and 7) showed no
change in PAP irrespective of the iNO concentration. The
first was a 9-month-old child with Down syndrome who
had low PAP till the second day following extubation.
Subsequently, he developed lung opacities with fever and
his PAP rose from moderately to severely elevated levels
without any response to iNO. He later succumbed to lung
infection. Patient #7, who had been operated for a large
VSD, developed systemic level PAP only following extubation
which was completely unresponsive to repeated
endotracheal intubation, 100% oxygen and iNO.
All “responders” received a trial of long-term (1–10 days)
iNO therapy.
The following patient groups could be defined based on
the PAP/SAP resulting from therapy and subsequent
response to weaning away of iNO.
PAP/SAP <0.3: PAP/SAP remained below 0.3 in 6 patients
on iNO therapy (#3, 5, 8, 9, 14, 15). Patient #3 was
dependent on 1 ppm of iNO after extubation and was
supplied iNO for 12 hours through a hood. He was
subsequently oxygen-dependent for the next 10 days.
Patient #5 responded well to iNO from which she was
successfully weaned away but could not be taken off the
ventilator because of a neurological complication to which
IHJ-913-00.p65
Indian Heart J 2001; 53: 48–55
Nitric Oxide in Pulmonary Hypertension
52
she later succumbed. Patients #8 and 9 recovered
uneventfully. Patient #14 had superior vena cava (and
therefore pulmonary artery) pressures of 24–28 mmHg
after bidirectional Glenn Shunt, main pulmonary artery
ligation and atrial septectomy, that dropped to 20–22
mmHg on iNO. However, failure of further reduction in PAP
along with progressive upper body swelling prompted
removal of the Glenn Shunt, re-implantation of the superior
vena cava onto the right atrium and rebanding of the main
pulmonary artery. Patient #15 was kept on oxygen in the
ICU for 15 days as his oxygen saturation (monitored
percutaneously) was maintained only on oxygen supplied
through a hood. Finally, when he was transferred to the
ward on oxygen he reportedly developed incessant crying
and became cyanosed. He was transferred back to the ICU
but could not be resuscitated following a cardiorespiratory
arrest. The cause of sudden deterioration could not be
ascertained but was presumably a PAH crisis. iNO was not
available for resuscitation.
PAP/SAP 0.3–0.5: Four patients (#1, 2, 16, 24) were
weaned away from iNO while their PAP/SAP ratio was
between 0.3 and 0.5. This was because their PAP did not
drop any further irrespective of the dosage of iNO. Moreover,
they were hemodynamically stable at this PAP when iNO
was finally discontinued for more than 24 hours. All of
them were extubated successfully. However, patient #16 had
a PAH crisis leading to respiratory arrest 4 days after
extubation. He could be resuscitated only with iNO but
this time could not be weaned away from iNO or the
ventilator.
NO dependence: Four patients (#6, 12, 13, 23) developed
NO dependence and had a recurrence of acidosis and
hypoxemia whenever either iNO or ventilatory weaning was
attempted. They finally succumbed to overwhelming lung
infection.
NO tolerance: Patient #11, a 3-month-old child with
obstructed infradiaphragmatic TAPVC demonstrated an
initial response to iNO but later became non-responsive as
his PAP gradually rose beyond the systemic level irrespective
of the maximal dose of iNO. Before demise his PAP/SAP
was 3/1.
Patients without PAP monitoring could not have an exact
quantification and had to be grouped based on
echocardiographic estimation of PAP reduction and clinical
response.
Patients without PAP monitoring (#10, 17–22):
Patient #10, who was on mechanical ventilation
preoperatively for respiratory failure resulting from
4/10/01, 11:26 AM
Indian Heart J 2001; 53: 48–55
meconium aspiration, had been doing well without the need
for iNO in the entire postoperative period, but developed
respiratory arrest 12 hours after extubation from which she
could be resuscitated only with the use of iNO, once
echocardiogram confirmed severe PAH. Patients #17, 18,
19 and 20, all of whom had TGA or DORV with large VSD,
could be weaned away from iNO and from the ventilator.
Patient #18 had a PAH crisis 7 days after successful weaning
away from iNO and the ventilator and could only be
resuscitated by restarting iNO. The other 3 recovered
uneventfully. Patients #21 and 22 became iNO dependent
and became hypoxemic and acidotic on reducing iNO
concentration. Both finally expired.
PAH crisis: Five instances (#7, 10, 15, 16, 18) of PAH
crises were encountered (4 confirmed and #15 presumed).
All presented with respiratory arrest either immediately or
up to 15 days after extubation. Two (# 7 and 10) did not
require iNO prior to extubation. The other three recovered
well and were weaned away from both iNO and mechanical
ventilation. Patient #7 showed no response to iNO while
patients #10, 16 and 18 could be resuscitated only with
use of iNO in the inhaled gas mixture. iNO was not available
for #15. The 3 who were resuscitated successfully developed
lung infection and could not be weaned away from iNO or
the ventilator. None of the patients with a PAH crisis
survived.
Overall survival: Two patients could not be completely
evaluated with respect to the end-points of separation from
iNO and the ventilator due to premature demise (#5,
neurological problem) and re-operation (#14) for reversal
of surgical repair. If these 2 were to be excluded, only 9 of
22 patients receiving iNO could be referred to as "successes".
All nonsurvivors were either nonresponders, or those
who developed iNO dependence, or had a PAH crisis
following an initial satisfactory recovery.
Discussion
Most patients with reversible PAH of any etiology would
show a reduction in PAP with iNO. This has been amply
demonstrated in neonates with persistent fetal circulation,8,9
adult respiratory distress syndrome,10 and adults with
operated valvular heart disease. 11 In most of these
conditions and others, however, it is unclear if the use of
extrinsic NO can alter disease outcomes.12–17
In the case of congenital heart disease per se, iNO has
been introduced into the clinical arena in an era when the
standard of health care in the developed world has made
antenatal or immediate postnatal diagnosis of congenital
IHJ-913-00.p65
53
Sharma et al.
Nitric Oxide in Pulmonary Hypertension 53
heart disease a routine, thereby ensuring timely corrective
surgery.
Because of the paucity of reports on the effect of the use
of iNO in late presenters of congenital heart disease the role
of iNO in this setting is as yet undefined.
Strategies for the management of the child with
congenital heart disease with severe PAH who presents late
are not clear. Operability denoted by conventional criteria
such as a drop in pulmonary vascular resistance to
acceptable levels on oxygen or iNO merely signifies a reactive
pulmonary vascular bed. Patients, though declared operable
by cardiac catheterization data, may have problems with
persistent or episodic elevations of PAP. Final outcomes are
then dependent on the subsidence of PAP or the capacity
of the pulmonary ventricle to tolerate residual PAH. On
clinical examination, 14 of the 24 children were thought
to be within the borderline operable range and were
therefore subjected to cardiac catheterization. As shown in
Table 1, all 14 were deemed to be operable based on the
catheterization data. As all patients showed a reduction in
pulmonary vascular resistance to "operable" levels on
oxygen, preoperative histological examination of the
pulmonary vasculature was not thought to be necessary.
Even with postoperative use of iNO, the safest and most
potent pulmonary vasodilator known today, only 4 of these
patients had a successful outcome.
Down syndrome (3 children in this series) is known for
its rapid progression of pulmonary vascular disease when
associated with a VSD or AVSD.18, 19 Patient #4 (Down
syndrome with a large VSD) had significant pulmonary
vascular disease according to his preoperative data. He,
however, had a benign postoperative course, till he
developed pneumonia. Subsequent course (PAH
unresponsive to iNO) demonstrates the lethal combination
of PAH and pulmonary infection. The children with AVSD
had only partial response to iNO and gradually worsened
in the face of persistently elevated PAP. TGA with VSD is
another lesion well known for early pulmonary vascular
disease.20, 21 Assessing pulmonary vascular resistance by the
Fick principle in TGA is known to be fallacious22 as the
arteriovenous oxygen differences are small and the assumed
values for oxygen consumption are not reliable. What is
more reliable with respect to pulmonary vascular resistance
in patients of TGA with VSD is the clinical assessment and
arterial oxygenation on room air and on 100% oxygen.
Thus, given good mixing, the lower the arterial oxygenation
the more the likelihood of an elevated pulmonary vascular
resistance. Only 1 patient above 4 months of age with TGA
and VSD survived. However, 2 patients less than 4 months
of age also succumbed to PAH crises. Obstructed TAPVC is
4/10/01, 11:26 AM
54 Sharma et al.
also well known for accelerated pulmonary vascular
changes.23 In our series, patient #12 who had an obstructed
infradiaphragmatic TAPVC which was corrected at the age
of 3 months, was certainly not a candidate for corrective
surgery considering his postoperative behaviour in the
presence of an unobstructed pulmonary venous chamber
to left atrial anastomosis. Patient #9, in spite of presenting
at almost 2 months of age with the same diagnosis, had a
completely benign postoperative recovery.
Reactivity of the pulmonary vascular bed changed from
the preoperative state following reparative surgery and was
even seen to undergo a change in the postoperative phase
of the same patient with time. Pulmonary capillary
endothelial injury as a result of cardiopulmonary bypass is
a well recognized cause of this state.24 Another factor that
seemed to play an important role in aggravating PAH was
pulmonary infection. None of the delayed pulmonary
hypertensive crises could progress to hospital discharge due
to the development of secondary iNO dependence in patients
who had previously been well controlled on iNO. The
presence of pulmonary opacities with positive endotracheal
cultures in these and other iNO-dependent patients in this
series may point to a strong link between PAH and
pulmonary infection. Exacerbation of subclinical infection
or acquired infection secondary to prolonged endotracheal
intubation could be one possibility. The other possibility is
that of the pulmonary opacities being secondary to
prolonged therapy with iNO. This cannot be dispelled25, 26
entirely even though the NO2 concentration in the inhaled
mixture never rose beyond 2 ppm and was usually below 1
ppm. It is disconcerting that other clinical series have
also noted an increased incidence of pulmonary
complications. 4,5 It is important to note that these
pulmonary opacities were seen in those patients who had
received higher doses of iNO because of the relative nonresponsiveness to lower initial doses.
The point at which iNO therapy should be initiated is
unclear. In this study, a persistent PAP/SAP ratio of >0.5
was taken as an indication for starting iNO. However, there
were patients who were weaned away from iNO at this level
of PAP/SAP if the other parameters did not suggest
interference with normal cardiac performance. Perhaps iNO
therapy should be initiated only if the PAP/SAP ratio is 0.5
and rising, and if the hemodynamics at that moment
suggest interference with normal cardiac performance. The
important question to answer is if any deleterious effect was
caused by the suppression of endogenously derived
relaxation factor by continuous administration of iNO27 and
its possible role in the NO dependence that was observed in
some patients.
IHJ-913-00.p65
Indian Heart J 2001; 53: 48–55
Nitric Oxide in Pulmonary Hypertension
54
In such a heterogeneous group of patients, in whom an
elevated PAP is probably the only common denominator, it
is not surprising that varied responses to iNO were observed.
Thus there were patients who did not respond at all, there
was one who responded initially and later became
completely unresponsive, there were others who responded
but became dependent on NO, and there were others who
responded predictably throughout and could be weaned
away and taken off mechanical ventilation. The 9 successful
cases in this experience were indistinguishable from the 13
non-survivors based on preoperative characteristics like age,
arterial oxygenation, pulmonary vascular resistance, etc.
It is possible that preoperative histological grading of the
lung vasculature may have provided some differentiation.28
Two questions are unavoidable in a study of this nature:
Are the successes (9 patients) attributable to iNO? Would
patients who later became iNO dependent have had a
different outcome if iNO had not been used at all? A
randomized study with survival as an end-point is clearly
indicated if we are to answer these questions.
Finally, based on this study, we would at best regard the
outcome benefit with use of iNO as equivocal. Our initial
impression (and expectation) from existing reports was one
that forbade withholding iNO therapy from any patient with
postoperative PAH. With the results of this initial experience
we are now in a position to initiate a controlled trial with
certain well-defined cross-over points between iNO and
conventional therapy.
References
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2. Miller OI, Celermajer DS, Deanfield JE, Macrae DJ. Very low-dose
inhaled nitric oxide: a selective pulmonary vasodilator after
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3. Russell IA, Zwass MS, Fineman JR, Balea M, Rouine-Rapp K, Brook
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4/10/01, 11:26 AM
Original Article
Plasma Lipoprotein(a) Levels in Patients With
Pulmonary Arterial Hypertension
Satyendra Tewari, Deepak Gupta, Sudeep Kumar,
Naveen Garg, Madan M Godbole, Nakul Sinha
Department of Cardiology & Endocrinology
Sanjay Gandhi PGIMS, Lucknow
Background: Pulmonary artery hypertension is a common sequelae of a variety of cardiac and lung diseases.
Pathogenesis of primary and secondary pulmonary artery hypertension is still debatable.
Methods and Results: We studied the serum lipoprotein(a) levels in patients with primary (n=27) and secondary
(n=19) pulmonary artery hypertension (Eisenmenger syndrome). The results were compared with age and sex
matched controls (n=46). We also studied the frequency of high levels of lipoprotein(a) (>30 mg/dl) in pulmonary
artery hypertension. Mean lipoprotein(a) levels were significantly higher in the pulmonary artery hypertension
group compared to age- and sex-matched controls (31.60±15.49 mg/dl v. 14.66±14.7; p=0.0001). All patients
were classified into two groups on the basis of their lipoprotein(a) levels (<30 mg/dl and >30 mg/dl). There was
a higher frequency of lipoprotein(a) >30 mg/dl in patients of pulmonary artery hypertension v. controls (52% v.
24%; p= <0.001). Younger age, higher functional class, more severe congestive heart failure, shorter duration
of symptoms, and more cases of hemoptysis were observed in the group with lipoprotein(a) >30 mg/dl.
Conclusions: High lipoprotein(a) may be a marker and be associated with a more adverse prognosis in severe
pulmonary artery hypertension. Larger prospective studies are needed to establish lipoprotein(a) as a risk factor
for the development of pulmonary artery hypertension. (Indian Heart J 2001; 53: 56–60)
Key Words: Lipoproteins, Pulmonary hypertension, Thrombosis
L
ipoprotein(a) is a complex lipoprotein (Lp)
macromolecule that contains apolipoprotein(a), which
shares 80% to 90% homology with plasminogen.1,2 It acts
as a competitive inhibitor of tissue type plasminogen
activator and thereby helps in modulating the fibrinolytic
system.2,3 Moreover Lp(a) is an important regulator of
synthesis of plasminogen activator inhibitor (PAI-1) by
endothelium. All these lead to a prothrombotic state.4–6
Pulmonary artery hypertension (PAH) is the common
sequelae of a variety of cardiac and lung diseases. Exact
pathogenesis of primary and secondary PAH is still
debatable. Pulmonary thrombosis is an important feature
of both primary and secondary PAH.7–9 Various defects of
coagulation including von Willebrand factor,10 PAI-111 and
defective fibrinolysis12–14 have been demonstrated in primary
pulmonary artery hypertension (PPH). Lp(a) has also been
implicated in thrombogenesis. The fact that PAH develops
Correspondence: Dr Nakul Sinha, Professor & Head, Department of
Cardiology, Sanjay Gandhi PGIMS, Lucknow, 226014
e-mail: [email protected]
IHJ-0122-01.p65
56
in only 6% of patients with secundum atrial septal defect
(ASD) suggests that genetic predisposition may be
necessary.15 Whether the Lp(a) is a novel risk factor for
development of PAH has not been investigated. We studied
the serum Lp(a) levels in patients with PPH and secondary
PAH (Eisenmenger syndrome) and compared it with similar
numbers of age- and sex-matched healthy volunteer
controls.
Methods
Forty-six patients of severe PPH and PAH due to congenital
left to right shunt were included in the study. PPH was
diagnosed by exclusion of any form of secondary
pulmonary hypertension (pulmonary embolism, chronic
obstructive pulmonary disease, primary cardiac shunt, or
connective tissue disease). Patients with secondary PAH
included those with an intracardiac shunt lesion. The
patients with PAH secondary to valvular heart disease, left
ventricular dysfunction, collagen vascular disease and lung
disease were excluded from the study. Other exclusion
4/10/01, 10:38 AM
Indian Heart J 2001; 53: 56–60
criteria were renal failure, proteinuria, diabetes mellitus,
acute inflammation, female patients taking oral
contraceptive pills and alcoholism, as these are known to
influence the Lp(a) level.16 Informed consent was obtained
from each patient and the study protocol conformed to
ethical guidelines. The initial assessment of patients
included a complete history and physical examination,
complete blood count, arterial blood gas analysis,
biochemical screening, roentgenogram and urine analysis.
Drug status of all patients was recorded, and they
were then subjected to a 12-lead ECG, and a detailed
echocardiography (two-dimensional, Doppler and color
flow examination) performed on HP sonos 5500 Ultrasound
system (Hewlett Packard, Massachusetts; USA). Sera of all
those in the study group (46 patients) and a similar number
of age- and sex-matched control group (healthy volunteers)
were taken for quantitative Lp(a) measurements.
Echocardiographic study: Estimated systolic pulmonary
artery pressure (SPAP) was calculated by using a simplified
Bernoulli’s equation [SPAP = 4 × (tricuspid regurgitation
velocity) 2 + CVP]. A value of 10 mmHg was assumed for
central venous pressure (CVP) in patients without any
evidence of systemic venous congestion. Estimated systolic
pulmonary arterial pressure >70 mmHg was taken as
evidence of severe PAH. Two observers independently
verified the echocardiographic measurements. Right
ventricular systolic pressure (RVSP) equal to or more than
70 mmHg was taken as evidence of severe PAH. In patients
with septal defects the pattern of flow across the shunt
lesion was recorded, using colour flow imaging and pulsed
wave Doppler examination. Contrast echocardiography
using an agitated saline flush was done to evaluate shunt
flow if colour flow imaging was unsatisfactory.
Blood sampling and assay: Fasting venous blood samples
were collected. Blood was centrifuged for 10 minutes at 4°C
and the serum stored at –70°C until analyzed (3–6 months).
The Lp(a) level was measured with a commercially available
ELISA kit (TintElize® Lp(a), Biopool International, Ventura,
Ca, USA). The assay utilizes affinity-purified polyclonal
antibodies raised against Lp(a).
Statistical analysis: All clinical, biochemical and
echocardiographic data were recorded prospectively. We
compared the Lp(a) level of patients with severe PAH with
those of age- and sex-matched controls. Previous reports
have suggested that >30 mg/dl,17, 18 is the threshold value
linked to its pathological effects. Based on this value, we
defined subjects with >30 mg/dl as those with high Lp(a)
and examined its frequency in severe PAH. We also studied
the association of high Lp(a) with demographic, clinical and
IHJ-0122-01.p65
57
Tewari et al.
Plasma Lipoprotein(a) Levels in PAH
57
echocardiographic variables. Continuous variables were
reported as mean ± standard deviation. Differences in mean
group values were analyzed by unpaired 2-tailed t-test for
parametric data. The difference in categorical variables was
compared with the use of the chi-square test. A value of
p<0.05 was considered significant.
Results
Baseline characteristics of patients including the spectrum
of symptoms, severity of right ventricular systolic pressure
and mean Lp(a) level are shown in Table 1. The PPH group
consisted of 27 patients whereas 19 patients had
Eisenmenger syndrome (ES). The majority of ES patients
had ASD (16 out of 19), while the rest had a ventricular
septal defect (VSD). As shown in table 2, mean Lp(a) level is
significantly higher in the PAH group compared to the ageand sex-matched controls (31.60±15.49 mg/dl v.
14.66±14.7 mg/dl; p=0.0001). Serum Lp(a) levels by
quintile is illustrated in Fig. 1. There was higher frequency
Table 1. Baseline characteristics of study subjects (n=46)
Patients with severe PAH
Age (in years)
Sex (M/F)
NYHA
Class II
Class III
Class IV
Duration of symptoms (in years)
Congestive cardiac failure
Hemoptysis (%)
RVSP (mmHg)
Lipoprotein(a) (mg/dl)
Disease
Primary
ES
ASD
VSD
25.4±6.92
18/28
14(30.43%)
13(28.26%)
19(41.3%)
2.05±0.6
19(41.3%)
10(21.74%)
94.15±15
31.60±15.49
27(58.69%)
16(34.78%)
3(6.5%)
NYHA= New York Heart Association; RVSP= right ventricular systolic
pressure; ASD= atrial septal defect; VSD= ventricular septal defect;
ES=Eisenmenger syndrome
Table 2. Lipoprotein(a) levels of patients with PAH, and
age, sex matched control group
Age (years)
Sex (M/F)
Lp(a) (mg/dl)
Patients with PAH
Control group p value
25.4±6.92
18/28
25.0±17.0
18/28
31.60±15.49
14.66±14.7
Abbreviations: Lp(a)= lipoprotein(a)
4/10/01, 10:38 AM
NS
NS
<0.0001
Indian Heart J 2001; 53: 56–60
58 Tewari et al. Plasma Lipoprotein(a) Levels in PAH
Table 5. Demographic, clinical and echocardiographic
characteristics of PPH and ASD–Eisenmenger syndrome patients
with Lp(a) levels >30 mg/dl
PPH
(n=16)
Fig. 1. Percentage of PAH patients for each quintile on the basis of plasma
lipoprotein(a) concentration
of Lp(a) >30 mg/dl in patients of PAH than the control
group (52% v. 24%; p<0.001). All patients were classified
into two groups on the basis of their Lp(a) levels (Table 3).
Younger age, higher functional class, more severe
Table 3. Clinical and echocardiographic profile in Lp(a) >30 mg/
dl and Lp(a) <30 mg/dl group
Lp(a) >30 mg/dl Lp(a) <30 mg/dl p value
(n=25)
(n=21)
Age (years)
Sex (M/F)
NYHA
Class II
Class III
Class IV
Congestive cardiac failure
Duration of symptoms (years)
Hemoptysis
RVSP (mmHg)
Disease
PPH
Eisenmenger syndrome
22.84±5.26
12/13
28.62±7.6
6/15
0.002
0.17
5(20%)
4(16%)
16(64%)
15(60%)
1.84±0.5
9(36%)
100.64±12.86
9(42.8%)
9(42.8%)
3(14.4%)
4(19%)
2.29±0.6
1(4.76%)
86.42±13.9
0.004
0.003
0.002
0.012
0.005
0.02
<0.001
16(64%)
9(36%)
11(52.4%)
10(47.6%)
0.82
0.76
NYHA= New York Heart Association; RVSP= right ventricular systolic pressure;
PPH= primary pulmonary hypertension
Age (years)
Sex (M/F)
Duration of illness (years)
NYHA
Class II
Class III
Class IV
Heomptysis no (%)
RVSP
CHF
ASD–Eisenmenger p value
(n=9)
21.32±6.5
8/8
1.79±0.5
25.55±5.2
4/5
1.9±0.6
0.02
0.78
0.27
1
3
12
6(37.5%)
101.0±14
10(62.5%)
4
1
4
3(33.3%)
100.0±10.7
5(55.5%)
0.07
0.08
0.05
0.83
0.42
0.73
NYHA= New York Heart Association; RVSP= right ventricular systolic pressure;
PPH= primary pulmonary hypertension; CHF= congestive heart failure.
congestive heart failure, shorter duration of symptoms, and
more hemoptysis were observed in the group with Lp(a)
>30 mg/dl. RVSP was also significantly higher in this group
(100.64±12.86 mmHg v. 86.42±13.9 mmHg; p<0.001).
No significant difference in disease distribution was
observed. We analyzed the clinical, echocardiographic and
serum Lp(a) levels in PPH and ASD–Eisenmenger group
(because the majority of the Eisenmenger group had ASD)
(Table 4). There were no differences in variables including
RVSP and Lp(a) >30 mg/dl. Table 5 shows demographic,
clinical and echocardiographic comparison of PPH and
ASD–Eisenmenger patients, who had Lp(a) levels >30 mg/
dl. Except for a younger age group, no differences in other
variables were noticed. On univariate regression analysis
only the NYHA class was found to correlate significantly
when the effect of 9 variables was taken with a dependent
variable Lp(a) >30 mg/dl.
Discussion
Table 4. Demographic, clinical, echocardiographic profile and
Lp(a) levels in PPH and Eisenmenger patients
PPH
ASD–Eisenmenger p value
(n=27)
(n=16)
Age (years)
Sex (female)
Duration of symptoms (years)
NYHA
Class II
Class III
Class IV
Congestive cardiac failure
Hemoptysis
RVSP
Lp(a)
Patients with Lp(a) >30 mg/dl
25.85±7.7
62.96 %
1.9±0.5
25.56±5.9
62.5 %
2.19±0.7
0.44
0.83
0.08
5(18.5%)
8(29.6%)
14(51.8%)
16(59%)
6(22%)
93.44±15.9
33.14±15.6
59%
8(50%)
4(25%)
4(25%)
4(25%)
3(18.7%)
94.12±13.44
33.15±13.9
56%
0.06
0.81
0.06
0.18
0.78
0.44
0.49
0.81
NYHA= New York Heart Association; RVSP= right ventricular systolic pressure;
PPH= primary pulmonary hypertension
IHJ-0122-01.p65
58
The serum Lp(a) levels were significantly higher in the
severe PAH group and were associated with a more
advanced form of the disease. To the best of our knowledge,
this study is the first Indian report to demonstrate a
relationship between the Lp(a) level and PAH. Lp(a) was first
described by Berg et al.19,20 as a lipoprotein-associated
antigen with pre-beta electrophoretic mobility. Studies in
Indian population have shown that Lp(a) levels are
significantly higher among coronary artery disease (CAD)
patients as compared to controls.21–24 Mohan et al.25 showed
that Lp(a) was an independent risk factor for CAD in diabetic
patients. In previously reported studies on Indian
subjects,25–29 the mean values have ranged from 15.0 to
34.0 mg/dl in healthy controls and 20.0 to 41.0 mg/dl in
patients with CAD. In a study of 1150 subjects involving
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Indian Heart J 2001; 53: 56–60
seven ethnic groups, Lp(a) levels were almost twice as high
in Asian Indians as compared to Caucasians, Malays, and
Chinese residents of Singapore.30 In the CADI study on the
immigrant Indian population Lp(a) levels >30 mg/dl were
found in a higher proportion of Asian Indians as compared
to Whites (25% v. 17%).31
Thrombosis in situ is considered as one of the pathogenic
mechanisms in PPH.32 A thrombus may result from injury
to the endothelium, abnormal fibrinolysis, enhanced procoagulant activity and/or platelet abnormalities.33 Both a
retrospective analysis and a small nonrandomized
prospective study suggest that anticoagulants prolonged the
life span of patients with PPH.10,34 This also indirectly
supports the role of thrombosis in the progression, if not
the development, of PPH. There are in vitro and in vivo
studies which support the theory that Lp(a) has a
thrombogenic effect. 3,4,6 In addition to PPH,
thromboembolic phenomena have also been considered as
the etiological basis of pulmonary hypertension in patients
with left to right congenital shunts.35 Why a left to right
shunt would produce miliary embolization in the lung has
never been adequately addressed. In congenital heart
disease it is probable that the increased pulmonary blood
flow and development of high pressure over a period of time
is associated with a high shear stress, resulting in one type
of endothelial injury (VSD and plexogenic arteriopathy);
whereas high pulmonary blood flow without increased
pressure and shear stress produce a different endothelial
response (ASD and thrombotic arteriopathy).36 The fact that
pulmonary hypertension develops in only 6% of patients
with ASD also suggests that a genetic predisposition may
be important.
Recently serum Lp(a) has also been implicated as a risk
factor for left atrial thrombus in patients with chronic atrial
fibrillation.37 There are scanty reports of high Lp(a) levels
in primary and secondary PAH patients. Increased plasma
Lp(a) level in patients with chronic thromboembolic PAH
has been reported by Ignastescu et al.17 Significantly high
Lp(a) have been reported in both primary and secondary
PAH by Santos et al.38 They compared the Lp(a) level of 32
caucasian PAH patients (both primary and secondary) with
an equal number of healthy controls. Median Lp(a) level
was significantly higher in PAH patients than in the control
group [31.0 mg/dl (9.0–43.5) v. 12.0 mg/dl (6.4–23.3)
p=0.01]. There was also a higher frequency of Lp(a) (>30
mg/dl) in patients with PAH than in the control group (90%
and 50% respectively, p=0.006) in that study. In our study
also, 52% of severe PAH patients showed high Lp(a) (>30
mg/dl) as compared to only 24% of the control group. Mean
Lp(a) levels were significantly higher in PAH patients
IHJ-0122-01.p65
59
Tewari et al.
Plasma Lipoprotein(a) Levels in PAH
59
compared to the control group. Patients in the high Lp(a)
(>30 mg/dl) group were younger, had more advanced heart
failure with rapid progression of the disease, had more
hemoptysis and higher pulmonary artery pressure as
compared to the group with Lp(a) <30 mg/dl. Subgroup
analysis of PPH and Eisenmenger groups showed no
significant difference in demographic variables, severity of
PAH (RVSP) and Lp(a) levels.
Our study suggests that a high Lp(a) level may be a novel
risk factor for the development of both primary as well as
secondary PAH due to congenital left to right shunt,
particularly ASD. This newly described risk factor for
development of PAH raises the issue of the importance of
early therapeutic intervention in congenital heart disease
with left to right shunt, particularly in patients with ASD
with high Lp(a) level. In future there may be therapeutic
methods to reduce Lp(a) levels which may prove to be useful
in patients of PAH with less severe forms.
Study limitation: The study group consists of only a small
number of patients. Other components of the fibrinolytic
system were not evaluated. Therefore the relationship
between Lp(a) and the fibrinolytic system remains unclear.
Lp(a) of ASD-Eisenmenger patients was not compared with
those of similar size of ASD with normal pulmonary artery
pressure.
Conclusions: In patients with severe PAH the serum Lp(a)
levels were significantly higher. High Lp(a) may be
associated with a more adverse prognosis in severe PAH.
Larger prospective studies are needed to establish Lp(a) as a
risk factor for the development of PAH.
References
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4/10/01, 10:38 AM
Original Article
Indian Heart J 2001; 53: 000–000
Plasma Plasminogen Activator Inhibitor-1 Activity in
Normoglycemic Hypertriglyceridemic North Asian
Indian Subjects: A Preliminary Case–Control Study
Rupa Sarkar, Anoop Misra, Renu Saxena, Ravindra M Pandey,
Debashish Chaudhary
Departments of Medicine, Hematology, and Biostatistics
All India Institute of Medical Sciences, New Delhi
Background: Recent evidence suggests that increased activity of plasma plasminogen activator inhibitor-1, an
important component of the insulin resistance syndrome, plays a crucial role in the pathogenesis of
atherosclerosis.
Methods and Results: In this case–control study, relationships between plasma plasminogen activator inhibitor1 activity, serum triglyceride levels and hyperinsulinemia were explored in 40 non-diabetic patients with primary
hypertriglyceridemia (Group 1) and 40 non-diabetic normotriglyceridemic controls (Group 2) matched for
potential confounders like smoking and physical activity. Mean values of fasting serum insulin levels were
increased in Group 1 (p>0.05). Hyperinsulinemia was observed in 14 (17.5%) individuals in Group 1 and 11
(13.8%) individuals in Group 2. Mean plasma plasminogen activator inhibitor-I activity in Group 1 (9.8±8.4
IU) was higher than in Group 2 (7.0±7.7 IU), though the difference was not significant (p>0.05). However,
when only subjects with elevated levels of plasma plasminogen activator inhibitor-1 activity were taken into
account, mean values were significantly higher in Group 1 (p<0.05). The plasma plasminogen activator inhibitor1 activity was higher in subjects with body mass index >25 in both the groups, significantly so in males (p=0.05).
Hyperinsulinemic subjects with a body mass index >25 and raised serum triglyceride levels had higher mean
values of plasma plasminogen activator inhibitor-1 activity (18.42±11.15 IU) than subjects with similar
characteristics and normal triglyceride levels (14.22±8.20 IU, p<0.05).
Conclusions: Though in the current study a trend for hyperinsulinemia and high plasma plasminogen activator
inhibitor-1 activity was observed in hypertriglyceridemic subjects, a larger study is needed to achieve significant
differences and correlations. Obese male subjects, irrespective of their lipid profile, are at risk for thrombotic
events in view of their significantly higher plasma plasminogen activator inhibitor-1 values. Procoagulant
tendency is further enhanced if hypertriglyceridemia and hyperinsulinemia are added on to obesity. (Indian
Heart J 2001; 53: 61–65)
Key Words: Plasminogen activators, Hypertriglyceridemia, Obesity
A
sian Indians have an increased tendency to develop
insulin resistance syndrome (IRS) presenting with
hyperinsulinemia, hypertriglyceridemia, decreased highdensity lipoprotein cholesterol (HDL-c), increased very lowdensity lipoprotein cholesterol (VLDL-c) and visceral
adiposity. Recently, there is persuasive evidence to suggest
that alteration in the coagulation pathway is an important
component as well. Besides hyperfibrinogenemia and
Correspondence: Dr Anoop Misra, Professor of Medicine, All India Institute
of Medical Sciences, New Delhi 110029, e-mail: [email protected]
IHJ-885-00.p65
1
alteration in the coagulation factors, increased plasminogen
activator inhibitor-1 (PAI-1) has been hailed as one of the
important components of IRS.1 A critical factor in the
coagulation pathway, PAI-1 leads to thrombotic tendency
when its levels are high, thus aiding in acute and chronic
atherothrombotic events.
There is a close correlation between plasma PAI-1 levels
and increased levels of serum triglycerides (TG), as
demonstrated earlier in patients with type IV
hyperlipoproteinemia.2 Plasma PAI-1 antigen correlated
significantly with peripheral insulin resistance and fasting
4/10/01, 11:14 AM
62 Sarkar et al.
plasma insulin levels. Even in people with normal glucose
tolerance, fasting serum insulin levels are associated with
elevated levels of plasma PAI-1 activity and other indicators
of the hypercoagulable state.3 In addition, there was a close
relationship with the other components of IRS:
hypertension and high waist–hip ratio (W–HR).4
Most of the studies which show an association between
hypertriglyceridemia and high levels of plasma PAI-1
activity did not have a control component. In particular,
matching for potential confounders such as hypertension,
body mass index (BMI), and smoking was not done.
Furthermore, no data are available in the native Asian
Indian population predisposed to develop insulin resistance
and hypertriglyceridemia.
We hypothesized, therefore, that non-diabetic
north Asian Indian subjects with non-familial
hypertriglyceridemia have high levels of plasma PAI-1
activity, and this is related to insulin resistance. In this
matched case–control study we explored the relationship
between plasma PAI-1 activity with serum levels of TG and
hyperinsulinemia in hypertriglyceridemic patients and
compared them with normotriglyceridemic controls.
Methods
This study was conducted between January 1999 and June
2000 at a tertiary care referral center in north India. Forty
non-diabetic subjects in the age group of 18 to 70 years
with serum TG levels greater than 200 mg% with no clinical
and electrocardiographic evidence of coronary heart
disease (CHD), secondary dyslipidemias, and significant
pulmonary, hepatic, or renal disorders, attending medical
outpatient departments and lipid research clinics were
selected as cases. They were also carefully screened for the
intake of anticoagulant or similar drug therapy. Forty
healthy subjects selected from among the physicians and
students of the hospital community, responding to a local
advertisement, were selected as the control group. These
subjects were in the age group of 18 to 70 years with serum
TG levels of less than 200 mg%. They were selected on the
basis of entry criteria defined for the cases. They were
matched with the cases with respect to sex, blood pressure,
and BMI. Potential confounders such as smoking and
physical activity were also taken into account.
The institutional ethics committee approved the study.
Informed consent was taken from all the subjects. Subjects
included in the study were admitted for a short period in a
General Clinical Research Center for complete evaluation
which included clinical history, physical examination, and
laboratory investigations. The same physician recorded all
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Indian Heart J 2001; 53: 61–65
PAI-1 in Hypertriglyceridemia
2
the clinical information for all the subjects. Blood pressure
was recorded in the sitting position with a mercury
sphygmomanometer after 5 minutes of rest according to
the standard guidelines.
Anthropometric measurements: Weight was measured
to the nearest kilogram and height to the nearest centimeter.
The BMI was calculated using the formula, BMI=weight
(kg)/height(m)2. Standard guidelines were followed for
measuring the body circumferences and skinfolds. The
subjects were examined in the minimum possible clothes
and the same instruments of measurement were used in
all the subjects. Waist circumference (WC) was measured
midway between the iliac crest and the lowermost margin
of the ribs. Hip circumference was measured at the
maximum circumference of the buttocks using the greater
trochanter as the reference point. The mean of three
readings of each was taken for the calculation of W–HR.
The biceps, triceps, subscapular and supra-iliac skinfolds
were measured using Lange skinfold callipers. The biceps
skinfold was measured at the level of the nipple line with
the right arm dependent. For the triceps skinfold, the fat
pad midway between acromion process of scapula and
olecranon process was measured. Fat pads at the inferior
angle of scapula, and superiorly on the iliac crest in the
midaxillary line were measured for subscapular and suprailiac skinfolds. All skinfolds were measured to the nearest 1
mm. A mean of three readings was recorded at each site.
The same observer recorded all the anthropometric measurements to minimize the inter-observer bias. Percentage
body fat (% BF) was calculated from the sum of the four
skinfolds using an equation5 validated in Asian Indians.6
Metabolic measurements: All the subjects underwent a
glucose tolerance test after a 75 g oral glucose load,
performed according to the WHO guidelines.7 Blood for lipid
analysis was collected after a 12-hour overnight fast, while
for the previous three days the subjects consumed normal
diet. Total cholesterol (TC), TG and HDL-c were measured
according to the method described earlier.8 The value of
LDL-c was calculated using Friedwald's formula: LDL-c=TC
– (HDL-c + TG/5). Serum insulin assay was performed by
double antibody radioimmunoassay according to the
method described earlier. 8 There was no inter-assay
variation since all samples were analyzed in one assay.
Plasma PAI-1 estimation: Venous samples were
immediately stored at –70 °C. For the estimation of plasma
PAI-1 acitivity enzyme immunoassay was done using a
commerical kit (Diagnostica Stago, Seine, France). The
reaction was taken as positive when a monoclonal anti-PAI-
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Indian Heart J 2001; 53: 61–65
1 antibody labelled with enzyme horseradish peroxidase was
observed to bind to the anti-PAI-1/PAI-1 complex previously
formed in the well of the polystyrene microplate strips. A
blue colour results on incubation of the complex with the
enzyme substrate and the amount of colour produced is
proportional to the amount of PAI-1originally present in
the sample or standard.
Definitions: Central skinfold thickness indicated the sum
of the subscapular and supra-iliac skinfold thickness.
Peripheral skinfold thickness included a sum of the biceps
and triceps skinfold thickness. A hypertriglyceridemic
subject was defined as one with a serum TG level greater
than 200 mg% while any value of serum TG less than 200
mg% was accepted as normal. A nonobese subject was
defined as having a BMI less than 25 kg/m2. Diabetes
mellitus was excluded by criteria defined by the WHO.7
Plasma PAI-1 values greater than 7.00 IU were considered
to be high. The insulin values were subdivided into four
quartiles (quartile 1: 0–60 µIU, quartile 2: 61–120 µIU,
quartile 3: 121–180 µIU and quartile 4: 180 µIU–max).
The values of serum insulin in the last two quartiles were
taken as an indication of hyperinsulinemia.
Statistical methods: The data were recorded on a predesigned proforma, managed on an Excel worksheet and
entries were checked several times for any possible error.
Statistics for most parameters were computed by mean and
standard deviation for the study and control groups. The Ztest was used to compare the difference in mean values
among the two groups for all variables. For statistical
significance, p values smaller than 0.05 were considered.
Results
Forty subjects (mean age 32.8±10.5 years) comprised the
study group (Group 1), and similar numbers were taken as
controls (Group 2, mean age 39.3±10.1 years).
Anthropometric profile: The mean BMI, WC, W–HR, all
skinfolds, central and peripheral skinfolds, percentage body
fat and % BF/BMI ratio did not show any significant
difference between the two groups (Table 1).
Metabolic profile: Levels of total cholesterol and TG were
significantly increased in Group 1 (p<0.01, Table 2). The
level of LDL-c was also increased in Group 1 as compared
to Group 2 (p>0.05) while HDL-c was significantly lower
(p<0.05)
Serum insulin: Mean values of fasting serum insulin were
increased in Group 1 (p>0.05, Table 2). Hyperinsulinemia
was seen in 14 (17.5%) individuals in Group 1 and 11
IHJ-885-00.p65
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Sarkar et al. PAI-1 in Hypertriglyceridemia
63
Table 1. Anthropometric parameters
Parameters
Group 1 (n=40) Group 2 (n=40)
Body mass
Index (kg/m2)
Body fat (%)
%Body fat/body
mass index
Biceps skinfold (cm)
Triceps skinfold (cm)
Subscapular skinfold (cm)
Supra-iliac skinfold (cm)
Subscapular–triceps
skinfold ratio
Total skinfolds (cm)
Peripheral skinfolds (cm)
Central skinfolds (cm)
Waist circumference (cm)
Waist–hip ratio
p value
22.71±4.75
23.89±8.84
24.52±10.20
24.28±7.50
>0.05
>0.05
1.05±0.32
8.59±7.26
14.10±8.88
20.08±12.11
20.18±12.11
1.04±0.34
10.04±8.51
14.04±8.93
19.13±9.72
19.21±10.70
>0.05
>0.05
>0.05
>0.05
>0.05
1.62±0.59
62.96±36.16
22.70±15.81
40.26±22.71
80.21±19.79
0.89±0.08
1.54±0.57
62.44±31.84
24.08±16.66
38.35±18.73
71.17±20.41
0.87±0.07
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
All values in mean ± SD
Table 2. Metabolic profile
Variables
Group 1 (n=40) Group 2 (n=40) p value
Fasting venous blood
glucose (mg%)
86.2±11.0
85.5±10.0
>0.05
Total serum cholesterol (mg%)
217.1±58.9
182.6±41.9 =0.01
Serum triglycerides (mg%)
346±29.5
116.6±31.2 =0.01
Serum HDL cholesterol (mg%)
34.5±5.5
39.6±8.1
>0.05
Serum LDL cholesterol (mg%)
124.1±47.1
118.1±43.9 =0.05
Fasting serum insulin (µIU)
125.5±94.3
120.1±25.1 >0.05
Mean value in subjects with high
fasting serum insulin* (µIU)
222.0±87.1(14) 215.4±123.8(11) =0.05
HDL: high-density lipoprotein, LDL: low-density lipoprotein, *serum insulin >120 µIU
The values in parenthesis denote the number of subjects with hyperinsulinemia.
All values in mean ± SD
(13.75%) individuals in Group 2 (Table 2). The mean values
of raised serum insulin in Group 1 and Group 2 were found
to be 222.0±87.2 µIU and 215.4±123.9 µIU, respectively
(p>0.05). In both groups, the mean serum insulin levels in
subjects with hyperinsulinemia and BMI<25 was
225.3±114.5 µIU, whereas in subjects with BMI >25 it was
202.1±94.4 µIU, (p>0.05).
Plasma PAI-1: Mean plasma PAI-1 activity in Group 1
(9.8±8.4 IU) was higher than Group 2 (7.0±7.7 IU) though
the difference was not significant (p>0.05). The plasma PAI1 activity in both groups was found to be less in those with
a BMI <25 compared to subjects with BMI >25. However,
the difference was significant in males (9.2±6.9 IU for a
BMI >25 and 6.1±6.5 IU for a BMI <25, p=0.05), but not
in females (12.8±8.9 IU for BMI>25 and 12.0±8.9 IU for
BMI<25, p<0.05). Plasma PAI-1 activity was not
significantly correlated to W–HR in both groups.
The mean plasma PAI-1 activity in hyperinsulinemic
subjects in Groups 1 and 2 was 10.0±8.9 IU and 9.7±7.7
4/10/01, 11:14 AM
64 Sarkar et al.
IU, respectively (p>0.05). In both groups, mean values of
plasma PAI-1 activity in hyperinsulinemic subjects was
higher (10.0±8.9 IU) than in normoinsulinemic subjects
(9.7±8.3 IU, p>0.05). The mean activity of plasma PAI-1
in the upper two quartiles of serum insulin levels (16.7±7.4
IU) was more than that observed in the lower two quartiles
of insulin values (15.7±4.6 IU, p>0.05).
When subjects with only elevated levels of plasma PAI-1
activity were analyzed, mean values were significantly
higher in Group 1 (17.5±4.1 IU in Group 1 [n=20] v.
14.4±4.5 IU in Group 2 [n=20], p<0.05). However, there
was no difference between the hyperinsulinemic and
normoinsulinemic subjects (p>0.05). Hyperinsulinemic
subjects with a BMI >25 and raised serum triglyceride levels
had higher mean values of plasma PAI-1 activity
(18.42±11.15 IU) than subjects with similar characteristics
and normal triglyceride levels (14.22±8.20 IU, p<0.05).
Discussion
Several studies emphasize the close correlation betweeen
plasma PAI-1 activity and increased serum TG in patients
with and without CHD. In a study conducted in 75 Asian
Indian patients with CHD, there was a significant
association between serum TG and plasma PAI-1 activity.
It was concluded that hypertriglyceridemia was positively
related to elevated plasma levels of PAI-1, particularly in
elderly persons with CHD. The limiting factor in this study
was the absence of any data regarding serum insulin levels
and its correlation with plasma PAI-1 activity and serum
levels of TG. Furthermore, the study group, unlike the one
for the current study, was not matched with respect
to smoking and hypertension, which are associated with
IRS.9
In a trial carried out in normoglycemic healthy subjects,
plasma levels of PAI-1 activity were strongly associated with
serum TG in both men and women. Multivariate analysis
revealed that serum TG had a definite positive correlation
with plasma PAI-1 activity.10 Serum TG and parameters of
fibrinolytic activity were related to plasma PAI-1 in 54
subjects with different types of primary hyperlipidemia.2
In a population-based study,11 and another recent trial,12
similar conclusions were reached. It must be mentioned,
however, that none of the above studies were conducted in
a case–control manner with satisfactory matching of
confounders similar to that carried out in the current study,
where significantly high activity of plasma PAI-1 was
observed in the subjects having hypertriglyceridemia, when
compared to normotriglyceridemic subjects.
In their study, Mykkanen et al.10 showed that in subjects
IHJ-885-00.p65
Indian Heart J 2001; 53: 61–65
PAI-1 in Hypertriglyceridemia
4
with normal serum levels of TG, plasma PAI-1 activity was
raised when the BMI was >25. In the current study, obese
subjects, particularly males, had a significantly high activity
of plasma PAI-1, regardless of their lipid profile. Plasma PAI1 activity was significantly associated with BMI, W–HR,
serum TG and several other factors in a randomly selected
sample of 38-year-old healthy men.13 Though plasma PAI1 activity is correlated with generalized obesity, visceral
adipose tissue has been proposed as an important source of
plasma PAI-1 in humans.14 Of note is the fact that increase
in visceral adiposity is an important component of IRS. This
is particularly relevant in Asian Indians, where high
prevalence of visceral adiposity has been observed, and this
has been correlated with levels of plasma PAI-1.15 In the
present study, however, we did not observe any correlation
of W–HR with plasma PAI-1 levels.
Plasma PAI-1 activity is closely regulated by, and
correlated to, the serum insulin levels. In vitro studies on
hepatocytes show that insulin stimulates synthesis of
plasma PAI-1.16 In a controlled study carried out in 38
patients with type 2 diabetes mellitus, the plasma PAI-1
activity correlated significantly with serum insulin level.
Furthermore, the highest values were found in diabetics
with CHD.17
As mentioned earlier, this study was conducted strictly
on normoglycemic subjects. Though the serum insulin
values and plasma PAI-1 activity were found to be raised in
subjects with hypertriglyceridemia, statistical significance
was not reached except in obese subjects. Several studies
correlating raised serum TG and raised serum insulin as
components of IRS have already been carried out.4,18
However, Mykkanen et al.10 showed that insulin sensitivity
is not an independent determinant of plasma PAI-1 activity.
The present study also showed a considerable rise in plasma
PAI-1 levels in the upper tertiles of serum insulin values in
comparison to the lower tertiles. In a population-based
study, plasma PAI-1 activity and fasting hyperinsulinemia
correlated positively only in subjects with
hypertriglyceridemia.11 Carlson et al.11 further noted that
fasting serum insulin levels correlated positively with
plasma PAI-1 activity in obese individuals. However, in lean
subjects there was no such association. Again, there was
no documentation as regards confounders such as smoking
and hypertension in this study. None of these studies
explores the relationship of plasma PAI-1 activity, IRS, and
hyperlipidemia in Asian Indians residing in India.
However, not all workers concur with the correlation of
serum levels of TG and plasma PAI-1 activity. In a controlled
clinical study, the level of plasma PAI-1 was determined in
38 type 2 diabetic patients and 20 age-matched controls.
4/10/01, 11:14 AM
Indian Heart J 2001; 53: 61–65
No significant correlation between serum TG level and
plasma PAI-1 activity was observed. 17 The authors
concluded that the stronger association between plasma
PAI-1 activity and serum TG levels in other studies was
apparently due to correlation of hyperinsulinemia and
plasma PAI-1 on the one hand and hyperinsulinemia and
serum TG levels on the other, thus explaining the observed
relationship between plasma PAI-1 activity and serum TG
levels. Observations of Vague et al.,17 however, may also be
taken to explain the correlations as observed in the current
study.
Observations of the present study, therefore, suggest that
in north Indian patients with hypertriglyceridemia, there
is a trend for increased plasma PAI-1 activity as compared
to normotriglyceridemic patients, and this persists in
hyperinsulinemic subjects as well. Obese patients, in
particular, regardless of their serum levels of TG, had
significantly high levels of plasma PAI-1 activity. Further,
the concomitant presence of all three factors (obesity,
hyperinsulinemia and hypertriglyceridemia) enhances the
activity of plasma PAI-1, leading further to a procoagulant
tendency. Asian north Indians would be at a higher risk for
atherothrombotic events due to high plasma PAI-1 activity
since they are predisposed to develop abdominal obesity, an
important contributor to raised plasma PAI-1 levels. The
contribution of hyperinsulinemia and high levels of serum
TG needs to be tested in larger trials on Asian Indians.
Acknowledgments
The authors express their appreciation to the staff of the
Department of Haematology and SRB Centre of Clinical
Pharmacology, Department of Medicine, All India Institute
of Medical Sciences, New Delhi including Dr I Taneja,
Mr R Giri, Mr G Chand and Mrs Alice Jacob for performing
various investigations, Mr RL Taneja for performing quality
control of various biochemical tests, and Miss Jyoti for
typing and editing the manuscript.
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3. Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, MurphySheehy PM, et al. Hyperinsulinemia, hyperglycemia, and impaired
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4/10/01, 11:14 AM
Original Article
Operative Outcome and Intermediate Term Follow-up of
Neonatal Blalock–Taussig Shunts
K Sivakumar, K Shivaprakasha, Suresh G Rao, R Krishna Kumar
Departments of Pediatric Cardiology and Cardiac Surgery, Amrita Institute of Medical Sciences, Cochin
Background: The neonatal age group is considered to be one of the important risk factors for perioperative
morbidity and mortality as well as poor long-term patency following Blalock–Taussig shunts.
Methods and Results: Out of a total of 190 patients who underwent Blalock–Taussig shunts in our institute
between July 1998 and July 2000, 20 patients were aged less than 30 days and this neonatal cohort was studied
retrospectively. The mean age was 18±11 days (range: 3–30 days). The mean weight of the babies was 3.1±0.7
kg, the smallest weighed 2.1 kg. The cardiac anatomy was tetralogy of Fallot with pulmonary atresia in 6,
pulmonary atresia with intact ventricular septum in 3, tricuspid atresia in 5 and complex single ventricle
physiology in the rest. All patients were deeply cyanotic and preoperative prostaglandin E1 was needed in 10
patients to ensure ductal patency and maintain oxygen saturations prior to the shunt operation. The mean hilar
right and left pulmonary artery sizes were 3.99±0.44 mm and 3.69±0.79 mm, respectively. Three patients
(15%) had significant stenosis at the site of duct insertion. The shunts were accomplished with 3.5 mm
polytetrafluoroethylene grafts in 7 patients (35%) and 4 mm in the rest. The mean duration of mechanical
ventilation was 2.0±2.83 days, one patient who developed bronchopneumonia needed prolonged ventilation
for 14 days. The mean intensive care unit stay was 4.79±2.66 days. The mean hospital stay was 11.7±6.4 days.
Five patients who developed sepsis stayed beyond 14 days. There were 3 deaths (immediate post-operative shock
and possibly shunt malfunction in 1, bronchopneumonia in 1 and late shunt thrombosis at 3 months in 1). Two
patients had late shunt block, one of those mentioned above and the other at 3 months secondary to infective
endarteritis of the right pulmonary artery. All these infants received 4 mm grafts. All the 3.5 mm grafts were
patent at follow-up. Seventeen patients were alive and well at follow-up (mean: 9 months, range: 3–21 months)
with a mean resting systemic oxygen saturation of 77% (66%–95%).
Conclusions: The overall shunt patency rate after neonatal Blalock–Taussig shunt is about 80% on intermediate
term follow-up. A smaller graft size (3.5 mm) does not appear to be an incremental risk factor for shunt blockade
and operative mortality. (Indian Heart J 2001; 53: 66–70)
Key Words: Tetralogy of Fallot, Shunts, Congenital heart defects
T
he surgical creation of a systemic artery-to-pulmonary
artery anastomosis to improve pulmonary blood flow
in tetralogy of Fallot (TOF) was conceptualized by Blalock
and Helen Taussig in 1945.1 The modified Blalock–Taussig
shunt (BT shunt) interposes a polytetrafluoroethylene
(PTFE) graft between the subclavian artery and the
ipsilateral pulmonary artery and provides a controlled blood
flow to the lungs, since the subclavian artery orifice of the
BT shunt acts as a flow regulator.2 These modified BT shunts
provide good palliation in many cyanotic congenital cardiac
defects with reduced pulmonary blood flow.
Correspondence: Dr R Krishna Kumar, Consultant Pediatric Cardiologist,
Amrita Institute of Medical Sciences, Cochin 684026
e-mail: [email protected]
IHJ-914-00.p65
66
In developing countries, the neonatal cardiac surgical
program is poorly developed in many centers. Limited
studies are available from India on these neonatal surgical
procedures. Moreover, since febrile illnesses and diarrheal
diseases are common in developing countries with higher
ambient temperatures resulting in dehydration, patency
rates following the modified BT shunt may be different from
those of developed countries. The neonatal age group, (age
less than 30 days) has been recognized as an incremental
risk factor for postoperative mortality and shunt failure in
studies from developing countries.3–5 Our study aimed to
analyze the immediate outcome and intermediate-term
follow-up results after modified BT shunts performed in
neonatal age group.
4/10/01, 11:29 AM
Indian Heart J 2001; 53: 66–70
Methods
A total of 190 patients with various forms of cyanotic
congenital heart defects with reduced pulmonary blood flow
underwent modified BT shunts over a two-year period
(October 1998 to October 2000). There were 20 infants
aged less than 30 days and this neonatal age subgroup
(11%) formed the subject of this study. This study is a
retrospective analysis based on a review of patient records.
A detailed preoperative echocardiographic evaluation
was done in all patients to assess the intracardiac anatomy
by the segmental approach. No infant underwent
preoperative cardiac catheterization for visualization of the
pulmonary arteries. High-resolution echocardiogram was
performed with HP Sonos 5500 echocardiography machine
using high-frequency transducers with bandwidths of 3–8
MHz and 5–12 MHz. On the echocardiogram, the entire
pulmonary artery anatomy from one hilum to the other
was delineated using multiple views. Z-scores were
calculated for the sizes of hilar right pulmonary artery
(RPA) and left pulmonary artery (LPA) from computerized
nomograms for their respective body surface area, derived
from the body weight and length of the infant. The other
anatomic variables of interest included the side of the aortic
arch, its branching pattern, presence of patent duct, site of
duct insertion into the pulmonary arteries, and presence
of stenosis at the site of duct insertion.
Preoperative stabilization of these sick neonates was
achieved by admission in the intensive care unit (ICU),
maintenance of adequate hydration, prevention of
hypothermia, assessment of metabolic parameters and
correction of anomalies detected, if any. Very sick infants
received immediate infusions of prostaglandin PGE1 to
maintain the ductal patency required for stabilization of
saturation and metabolic profile. PGE1 infusions were
started at initial doses of 0.05 µg/kg/min and later tapered
to the lowest possible doses to maintain stable systemic
saturations.
Surgery was performed using the conventional approach
of posterolateral thoracotomy. Non-stretchable, thinwalled 3.5 mm or 4 mm Gore-Tex expanded polytetrafluoroethylene (EPTFE) grafts were used to create the BT
shunts. The distal end of the shunt was anastomosed to the
pulmonary artery through a transverse arteriotomy. The
decision to use a 3.5 mm or 4 mm EPTFE graft was taken
based on the size of the pulmonary artery seen on the
operating table. The neonates were started on low doses of
dopamine to maintain systemic pressure and electively
ventilated for 1 day. Low-dose heparin infusions at 5–10
units/kg/hour (APTT maintained at 1.5–2 times control)
IHJ-914-00.p65
67
Sivakumar et al. Outcome of Neonatal BT Shunts 67
were started after achieving hemostasis following the shunt
surgery and continued for 48 hours till oral feeds and oral
low-dose aspirin (3 mg/kg) could be started. The timing of
weaning away from ventilation and extubation was based
on conventional clinical, hemodynamic and radiographic
findings. The babies were shifted out of the ICU after
extubation, weaning away of inotropes and after initiation
of first feeds. Prior to discharge, all infants had a limited
echocardiographic study to document shunt patency.
After discharge, these babies were followed up once in 3
months. The parameters observed on follow-up included
shunt flows, pulse oximeter saturations, and growth and
development of the infant. Echocardiography was repeated
during postoperative visits for the pulmonary artey
anatomy, evidence of shunt site distortion of the pulmonary
arteries, shunt patency, ventricular function, evidence of
ventricular volume overload, and timing and planning of a
definitive repair procedure.
Results
The study group comprised 20 neonates and their
demographic parameters are detailed in Table 1. The body
surface area was calculated from the weight and length of
the neonate using standard nomograms and ranged from
0.15 to 0.29 m2. A 28-day-old preterm neonate with
pulmonary atresia, intact ventricular septum and ductdependent pulmonary circulation had the lowest weight of
2.1 kg at the time of surgery.
Table 1. Patient demographics
Number of patients in study group
20
Age in days
8.2±10.7
Mean
Range
3–30
Median
14
Body weight
Mean
3.1±0.7 kg
Range
2.1–4.7 kg
Body surface area
Mean
0.21±0.04 m2
Males:Females
9:11
Pulse oximeter saturation on presentation 45±18%
Hilar RPA diameter
Mean
3.99±0.44
Z-score of hilar RPA Mean
–0.88±0.67
Range
–1.78+0.61
Mean
3.69±0.79
Hilar LPA diameter
Z-score of hilar LPA
Mean
–0.86±0.94
Range
–3.38+0.84
RPA: Right pulmonary artery, LPA: Left pulmonary artery
4/10/01, 11:29 AM
Indian Heart J 2001; 53: 66–70
68 Sivakumar et al. Outcome of Neonatal BT Shunts
The intracardiac anatomy of these 20 neonates is
shown in the Table 2. Based on detailed preoperative
echocardiographic assessment, the anatomy was suitable
for biventricular repair in 6 infants, one-and-a-half
ventricular repair in one infant with pulmonary atresia, and
intact ventricular septum and univentricular repair in the
rest of the subgroup.
Table 2. Intracardiac anatomy in the study group
Diagnosis
No. of patients
Pulmonary atresia, intact IVS
3
TOF
2
TOF, pulmonary atresia
5
Tricuspid atresia
5
DORV, VSD, pulmonary stenosis
2
Single ventricle, pulmonary atresia
2
Complex malformations, heterotaxy
1
IVS: Interventricular septum, TOF: Tetralogy of Fallot, DORV: Double outlet
right ventricle, VSD: Ventricular septal defect
All babies presented with intense cyanosis and significant
systemic desaturation. Ten neonates were profoundly sick
and intensely cyanosed and needed stabilization in critical
care units. All these infants received immediate infusions
of prostaglandin PGE1 to maintain ductal patency for the
stabilization of saturation and metabolic profile. PGE1
infusions were started at initial doses of 0.05 µg/kg/min
and later tapered to the lowest possible doses to maintain
stable systemic saturations. Among the 10 neonates, 8
babies had pulmonary atresia and pulmonary circulation
was maintained exclusively by the patent ductus arteriosus.
The other two infants had very little antegrade flows,
one had a double outlet right ventricle (DORV) and
pulmonary stenosis and the other had tricuspid atresia and
restrictive ventricular septal defect (VSD). The other 10
neonates underwent insertion of modified BT
shunts without preoperative PGE1 infusions. Four babies
required preoperative ventilation to stabilize systemic
saturation.
The mean size of the hilar RPA was 3.99±0.44 mm and
the mean hilar LPA size was 3.69±0.79 mm. Three neonates
(15%) had significant duct site stenosis of the pulmonary
artery and asymmetric pulmonary artery sizes. All these
babies had ductal blood flows directed into the ipsilateral
pulmonary artery and modified BT shunts were performed
on the contralateral side of the duct. The other 17 patients
had symmetric pulmonary arteries.
The size of the PTFE graft used was 3.5 mm in 7 patients
(35%) and 4 mm in the rest. The mean duration of
mechanical ventilation was 2.0±2.8 days; one patient
needed prolonged mechanical ventilation for 14 days for
IHJ-914-00.p65
68
extensive postoperative nosocomial bronchopneumonia.
The mean ICU stay was 4.79±2.66 days and the mean
hospital stay was 11.7±6.4 days. There were no instances
of seroma around the graft or serous effusions in this cohort
of patients. Five neonates stayed for more than 14 days due
to postoperative sepsis in two and wound infection requiring
surgical resuturing in three. There were 2 immediate
postoperative deaths (10%). One 27-day-old neonate
weighing 3 kg with tricuspid atresia and restrictive VSD had
a 4 mm modified BT shunt and developed severe bradycardia
immediately after surgery and died, presumably due to
shunt malfunction. The other baby, a 5-day-old neonate
weighing 2.4 kg, again with tricuspid atresia, had a 4 mm
BT shunt, developed postoperative Gram-negative
septicemia with multi-organ dysfunction and died on the
14th day of surgery with a patent shunt.
All survivors were followed up once in 3 months. The
mean duration of the follow-up was 9 months, and the
longest follow-up was 21 months. The mean resting
saturation on follow-up was 77%, ranging from 66% to
95%. There was one late postoperative death 3 months after
surgery, due to acute shunt thrombosis and a marked fall
in systemic saturation. This baby was a 30-day-old neonate
weighing 4.5 kg at the time of surgery with tricuspid atresia
and restrictive VSD and had a 4 mm modified BT shunt.
There was another patient with a late shunt malfunction.
Three months after surgery, this baby with a DORV and
pulmonary stenosis developed infective endarteritis with a
Gram-negative non-fermenter organism. Parenteral
cefotaxime and netilmicin were given for 3 months.
She developed shunt occlusion, but saturation remained
stable at around 70% on beta-blocker therapy. Her
echocardiogram 6 weeks after discharge showed a
pseudoaneurysm of the RPA measuring 1.2 cm at the shunt
insertion site. There was no further progression of its size
on follow-up visits.
Seventeen patients (16 had patent shunts) were alive and
well at follow-up. Three infants with complex malformations
had mild growth and developmental delay. All 7 babies who
received 3.5 mm modified BT shunts were discharged from
hospital and remained well on follow-up. None of the
patients had shunt revisions. One patient with tricuspid
atresia underwent bi-directional Glenn anastomosis and
interruption of the BT shunt. The others await definitive
repair. Patients planned for univentricular repair are being
followed at 3-monthly intervals with close monitoring of
oxygen saturation. All patients continue to receive
antiplatelet doses of aspirin to maintain shunt patency.
Discussion
In neonates, BT shunts offer significant palliation for a
variety of cyanotic congenital malformations with duct-
4/10/01, 11:29 AM
Indian Heart J 2001; 53: 66–70
dependent pulmonary circulation. Young age remains an
important risk factor for poor outcome after BT shunts.6-9
The major problems we faced in these neonatal BT shunts
were related to difficult ICU issues. Sudden postoperative
increase in pulmonary circulation causing pulmonary
congestion, longer duration of mechanical ventilation
resulting in bronchopneumonia and central line-related
sepsis were of major concern. These were the major reasons
for prolonged stay in the ICU.
In infants less than 3 months of age, Tamisier et al.7
reported 21% early deaths and shunt failure in half of the
study group. The series of 28 neonates by Moulton et al.8
had an early mortality of 11%. Ilbawi et al.3 reported 0.6%
mortality following neonatal modified BT shunts in infants
with an exclusive diagnosis of TOF in which the pulmonary
arteries are often confluent. However, in a variety of other
congenital defects including pulmonary atresia and other
complex diseases, Kirklin et al.4 reported 12% mortality,
reflecting the impact of pulmonary artery anatomy on the
outcome. The immediate postoperative mortality in our
study group is 10%. In a study of classical BT shunts by
Aciniegas,5 there were 5.5% early deaths, but complex
defects had an increased mortality. Our group had a variety
of diagnoses, depicted in Table 1 and had hypoplastic
pulmonary arteries as shown by their mean Z-scores of hilar
pulmonary arteries (–0.88). In one large series of
78 neonates operated over a 13-year period, Al Jubair
et al.10 reported higher adverse outcome rates when the
mean PA diameter was less than 4 mm and weight was less
than 3 kg. Most of our patients had smaller pulmonary
arteries.
Gold et al.11 reviewed their results in 112 shunts done in
92 infants, which included neonates using 4 mm and 5 mm
grafts, and reported a 21% incidence of congestive heart
failure secondary to increased blood flow and 3% mortality.
In the series of Tsai et al.,12 young age and smaller graft size
were reported as incremental risk factors for shunt failure,
but there were only 3 patients who received grafts smaller
than 4 mm. Our group included grafts of size 3.5 mm and
4 mm and none of the patients were in heart failure on
follow-up. As mentioned previously, the decision to select a
3.5 mm or 4 mm EPTFE graft was based on the size of the
pulmonary artery as seen in the operating room. However,
in the earlier 6 patients, only 4 mm grafts were used due to
non-availability of the smaller grafts. A subgroup analysis
of the pre- and postoperative variables was made between
the 3.5 mm and 4 mm groups and is shown in Table 3. In
our group, 3.5 mm grafts were used more often in younger
neonates. The anatomy was similar, and both groups had a
similar postoperative course. There were no deaths or shunt
failures in this subgroup which received 3.5 mm grafts.
However, 3 babies in the 3.5 mm graft group (comprising
IHJ-914-00.p65
69
Sivakumar et al. Outcome of Neonatal BT Shunts 69
Table 3. Relation between size of graft and variables
Variables
3.5 mm graft 4 mm graft
n=7
n=13
Preop variables
Age in days
10.7±8.99
Weight of patient (kg)
2.85±0.36
2
Body surface area (m )
0.2±0.02
Hilar RPA size (mm)
4.16±0.63
Z-score hilar RPA
–0.59±0.78
Hilar LPA size (mm)
3.54±1.23
Z-score hilar LPA
–0.88±1.36
Preop PGE1 requirement
5(71%)
Postop variables
Days of ventilation
2.14±0.37
Days of ICU stay
5±0.82
Total hospital stay (days)
16.5±6.71
Mean saturation on follow-up 78.1±8.6
Deaths (immediate and late)
0
Shunt block
0
p
21.8±9.19 0.01*
3.13±0.8
0.4
0.21±0.04 0.52
3.88±0.25 0.18
–1.0±0.57 0.2
3.73±0.42 0.6
–0.8±0.63 0.4
5(38%)
2.84±3.43 0.6
4.6±3.2
0.76
9.53±4.66 0.01*
76.6±7.7 0.77
3
#
3
#
# Small sample size, * Statistically significant
younger babies) developed wound infection and hence had
prolonged hospital stay.
BT shunts performed in the neonatal period adversely
affect the intermediate-term patency rates (up to 2 years).
Kay et al.6 reported 74% freedom at 2-year follow-up in BT
shunts performed in neonates compared to 90% freedom
from adverse events in older infants. In our study, 2 patients
had intermediate-term shunt failure, one died due to late
presentation and the other secondary to infective
endocarditis. Sixteen patients (80%) had a patent shunt on
intermediate follow-up.
Ten neonates received preoperative PGE1 infusions to
stabilize their saturations before surgery. Administration of
PGE 1 improves the preoperative hemodynamic and
metabolic status and stabilizes the neonate. Browdie et al.13
reported the safe use of PGE1 followed by BT shunt in
cyanoic neonates. In our cohort, 12 patients had a patent
arterial duct. However, the duct flows were very restrictive
in all patients resulting in a marked fall in oxygen
saturations warranting urgent shunt surgery. All patients
who received PGE 1 infusions had closure of duct
documented on echo- cardiography after surgery when
PGE1 was discontinued. Two patients continued to have duct
flows that were very small and did not result in pulmonary
circulatory overload.
Three patients had significant duct site stenosis with
selective duct flows into the ipsilateral pulmonary artery.
In all these patients, shunts were placed on the contralateral
side. The option of a combined approach of repair of
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Indian Heart J 2001; 53: 66–70
70 Sivakumar et al. Outcome of Neonatal BT Shunts
confluence stenosis and a central BT shunt through a
median sternotomy was not carried out as it warrants a
cardiopulmonary bypass and open heart procedure, which
carries a high risk in the neonatal age. The additional cost
of open heart surgery is also of concern in an emergency
setting.
In this study, postoperative heparin was routinely
administered to all neonates. Heparinization remains an
issue of debate. In Al Jubair’s series,13 use of heparin
improved immediate shunt function while, in a study by
Mullen et al.,14 no additional benefit of heparinization was
seen. The timing of initiation of heparinization during
shunt surgery is another controversial issue. In all our
patients, low-dose heparinization was initiated after
achieving hemostasis. Heparinization before insertion of a
shunt increases the risk of seromas and serous effusions.
There were no instances of seromas or serous effusions in
our group. Mullen et al.14 have shown that there were no
instances of seroma when heparinization was not initiated
during surgery. The seromas were also more common when
porous Dacron tube grafts were used in the past, compared
to the currently used Gore-Tex EPTFE grafts. Heparinization
may not be important when prosthetic materials are not
used, as in the case of classical shunts in neonates.
Yoshimura,15 in a study of classical shunts in 31 neonates
over a 16-year period, reported only one instance of shunt
failure. None of our neonates received classic shunts since
the superiority of modified shunts over classic shunts in
neonates have been shown in many studies.16
One patient in this series developed infective endocarditis
and non-progressive pseudoaneurysm at the shunt
insertion site. Such pseudoaneurysms following shunts in
young patients have been reported17 and can occasionally
compress mediastinal structures. This patient, in spite of
shunt failure, maintained adequate resting saturations and
hence is on medical follow-up. These aneurysms may pose
problems during definitive repair and hence are of concern.
Ideally, patients planned for single ventricular repair
should have a staged approach towards definitive repair. Bidirectional Glenn is better done at around one year of age.
This approach prevents volume overload of the ventricles
resulting from the shunt and is a safer bet against shunt
blockade. In view of cost constraints of two open heart
procedures in a staged single ventricle repair, we continue
to follow patients to an age at which hemodynamics are
acceptable for a single-stage modified Fontan procedure.
However, if there is any significant fall in oxygen saturation,
bi-directional Glenn surgery is planned.
Conclusions: Neonatal modified BT shunts in a developing
country such as India offer safe and reasonable palliation
with acceptable mortality for congenital complex cyanotic
heart diseases with duct-dependent pulmonary circulation.
IHJ-914-00.p65
70
The neonatal age group has a higher morbidity resulting
in longer duration of mechanical ventilation and ICU stay
and has a higher propensity for sepsis. The overall shunt
patency rates after neonatal BT shunt is about 80% on
intermediate-term follow-up. Smaller graft size (3.5 mm)
does not appear to be an incremental risk factor for shunt
blockage and operative mortality. Immediate postoperative
low-dose heparinization, though controversial, is not
associated with any major adverse events.
References
1. Taussig H, Blalock A. Surgical treatment of malformations of heart
with pulmonary stenosis or pulmonary atresia. JAMA 1945; 128:
189–198
2. deLeval MR, McKay R, Jones M, Stark J, Mc Cartney FJ. Modified BT
shunts: use of subclavian artery orifice as flow regulator in prosthetic
systemic to pulmonary artey shunts. J Thorac Cardiovasc Surg 1981;
81: 112–119
3. Ilbawi MN, Grieco J, DeLeon SY, Idriss FS, Muster AJ, Berry TE et al.
Modified BT shunts in neonates. J Thorac Cardiovasc Surg 1984; 88:
770–775
4. Kirklin JW, Blackstone EH, Kirklin JK, Pacifico AD, Armendi J,
Bargeron LM. Surgical results and protocols in spectrum of TOF. Ann
Surg 1983; 198: 251–265
5. Arciniegas E, Farooki ZO, Halini M, Hakimi M, Perry BL, Green EW.
Classical shunting operations for congenital cyanotic heart defects.
J Thorac Cardiovasc Surg 1982; 84: 88–96
6. Kay PH, Capuani A, Franks R. Experience with modified BT shunts
using PTFE grafts. Br Heart J 1983; 49: 359–363
7. Tamisier D, Vouhe PR, Vernant F, Lecca F, Massot C, Neveux JY.
Modified BT shunts: results in infants less than 3 months. Ann Thorac
Surg 1990; 49: 797–801
8. Moulton AL, Brenner JL, Ringel R, Nordenberg A, Berman MA, Ali
S, et al. Classic versus modified BT shunts in neonates and infants.
Circulation 1985; 72: 1135–1144
9. McKay R, deLeval MR, Rees P, Taylor JF, Mc Cartney FJ, Stark J.
Postoperative angiographic asessment of modified BT shunts using
expanded PTFE. Ann Thorac Surg 1980; 30: 137–145
10. Al Jubair RA, Al Faigh MR, Al Jarallah A, Al Yousef S, Ali Khan MA,
Ashmeg A. Results of 546 BT shunts performed in 478 patients.
Cardiol Young 1998; 8: 486–490
11. Gold JP, Violaris R, Engle MA, Klein AA, Ehlers KH, Lang ST, et al. A
five-year clinical experience with 112 BT shunts. J Card Surg 1993;
8: 9–17
12. Tsai KT, Chang CH, Lin PJ. Modified BT shunts: statistical analysis
of potential factors influencing shunt outcome. J Cadiovasc Surg
1996; 37: 149–152
13. Browdie DA, Norberg W, Agnew R, Altenburg B, Ignacio R, Hamilton
C. The use of PGE1 and BT shunts in neonates with cyanotic
congenital heart disease. Ann Thorac Surg 1979; 27: 508–513
14. Mullen JC, Lemermeyer G, Bentley MJ. Modified BT shunts: to
heparinise or not to heparinise. Can J Cardiol 1996; 12: 645–647
15. Yoshimura N, Yamaguchi M, Ohashi H, Oshima Y, Toyoda Y, Ogawa
K. Classic BT shunts in neonates. J Cardiovasc Surg 1999; 40: 107–
110
16. Ullom RL, Sade RM, Crawford FA, Ross BA, Spinale F. The BT shunts
in infants, standard versus modified. Ann Thorac Surg 1987; 44: 539–
543
17. Jan SL, Hwang B, Fu YC, Chi CS. Pseudoaneurysm formation after
infected modified BT shunt: echocardiographic findings.
Echocardiography 2000; 17: 187–191
4/10/01, 11:29 AM
Original Article
Indian Heart J 2001; 53: 000–000
Left Ventricular Pacing through Coronary Sinus
Tributaries: Initial Experience
SK Dwivedi, RK Saran, AK Rathi, N Tripathi, VS Narain, VK Puri
Department of Cardiology, King George's Medical College, Lucknow
Background: Left ventricular pacing is increasingly being used as a part of biventricular pacing in congestive
heart failure but data on safety, feasibility, reliability and lead maturation are sparse.
Methods and Results: Seventeen patients (13 males and 4 females) with persistent symptomatic degenerative
complete heart block underwent temporary left ventricular pacing by a left subclavian puncture through the
coronary sinus to its tributaries using a unipolar permanent pacing lead connected to an external pulse generator.
The left ventricular pacing was done for two weeks. Permanent right ventricular apical pacing was also done at
the same time through a right cephalic vein cut-down or subclavian puncture and the pacing rate was kept
below that of the initial left ventricular pacing rate. Pacing parameters of the left and right ventricles were
assessed at the time of implantation and at two weeks. Out of 17 patients, left ventricular pacing was successful
in 11 (67.7%) patients. The time taken for the total procedure was 56±18.1 min. Lead displacement was noted
in one patient without loss of pacing. At the time of implant and after two weeks, left ventricular pacing threshold,
impedance, R wave height and slew rate were not different as compared to right ventricular pacing. Holter
recording for 24 hours revealed regular left ventricular pacing at the end of two weeks in all patients.
Conclusions: The present study shows that left ventricular pacing through coronary sinus tributaries is feasible
and reliable. Acute and subacute maturation of left ventricular pacing are similar to right ventricular apical
pacing. (Indian Heart J 2001; 53: 71–73)
Key Words: Pacing, Heart failure, Heart block
C
onventional treatment of symptomatic bradycardia due
to complete heart block (CHB) involves permanent
cardiac pacing from the right ventricular (RV) apex with or
without atrial pacing. Left ventricular (LV) pacing has been
suggested to be more physiological but direct LV pacing has
limitations due to long- and short-term problems of
transarterial access, systemic embolism, stability of pacing
lead and difficulty in getting an acceptable pacing
threshold.1,2 Few recent reports have shown that the LV can
be paced through tributaries of the coronary sinus. This
method of LV pacing has recently been used as a part of
biventricular pacing restricted to patients with congestive
heart failure (CHF).2
Despite these encouraging reports, LV pacing through
coronary sinus tributaries is still in its investigational stage.
The data on safety, feasibility and reliability of LV pacing
through coronary sinus tributaries are sparse. How the
pacing parameters change in subsequent days and weeks is
Correspondence: Professor SK Dwivedi, Department of Cardiology,
King George's Medical College, Lucknow
IHJ-911-00.p65
1
not known. The present study was done to evaluate the
feasibility, reliability, safety and lead maturation
characteristics of the LV free wall pacing through the
coronary sinus tributaries using a unipolar pacing lead
connected to the external pacemaker generator for 2 weeks
in symptomatic patients of CHB.
Methods
Seventeen consecutive patients of persistent symptomatic
degenerative CHB admitted for permanent RV pacing were
enrolled in the present study. Patients with prior myocardial
infarction (MI), LV ejection fraction (EF) of <50% on twodimensional echocardiography, significant valvular heart
disease, electrolyte abnormalities, advanced systemic
illness, chronic renal failure, those receiving antiarrhythmic
therapy or those who did not give informed consent for the
procedure were excluded from the study.
RV pacing was done traditionally by cephalic venous cutdown or subclavian puncture from the right side and a
permanent pacemaker was implanted with lead positioned
4/10/01, 11:19 AM
Indian Heart J 2001; 53: 71–73
72 Dwivedi et al. LV Pacing through Coronary Sinus
at RV apex. At the same time, LV pacing was done by left
subclavian puncture. A unipolar pacing lead (Medtronic
4024, Pacesetter E 1450, K58 or Teletronics 033–443) with
trimmed tines was advanced through the coronary sinus
ostia by preshaping the stylus in a smooth J curve at distal
3–4 cm. Once in the coronary sinus, the lead was advanced
to the lateral aspect of the heart. The stylus was then
reshaped by an angulation of 60° in the distal 0.5–1 cm
and coronary sinus tributaries were entered. Once in a
desired tributary, the lead was advanced to a wedge position
using a straight-end stylus. Lead entry was primarily
attempted in an anterolateral or lateral tributary, failing
which the posterolateral or inferior tributary was chosen.
A satisfactory lead position was defined as stable pacing with
an acute pacing threshold of <2 V without diaphragmatic
stimulation. LV pacing was done in the unipolar mode using
an external pacemaker by connecting the negative terminal
of the pacemaker to the lead and the positive (anodal)
terminal to the subcutaneous plane at the left subclavian
entry site by a metallic clip. The LV was paced at 5 V with a
pulse width of 0.5 msec and pacing was done through this
lead for 2 weeks. The LV pacing rate was kept at 70 bpm or
10 beats higher than the inherent rate, whichever was
more. Permanent RV (apical) pacing was done in the VVI
mode at a heart rate of 50 bpm. A 24-hour Holter recording
was done at the end of two weeks to assess the reliability of
pacing by the LV lead. Patients were discharged on
permanent RV pacing at a rate of 70 bpm after removing
the coronary sinus lead.
Parameters assessed at the time of implant and at the
end of two weeks of LV pacing were: (1) success rate in
achieving stable LV pacing through the coronary sinus as
defined above; (2) coronary sinus pacing lead stimulation
threshold (V), R wave height (mV), pacing impedance (ohm)
and slew rate of right- and left-sided ventricular pacing lead;
and (3) reliability of LV pacing through a coronary sinus
tributary assessed by continuous monitoring in the
intensive coronary care unit for two days, followed by ECG
recording once daily for 10 days and finally, Holter
monitoring for 24 hours before removing the coronary
sinus lead.
Results
Seventeen patients (13 males; mean age 58.6±8.6 years)
with symptomatic CHB formed the study group. LV pacing
through a coronary sinus tributary was successful in 11
patients (67.7%). Inability to pace the LV was mainly due
to an unacceptable acute threshold (>2V) at the time of
implant (3 patients) and inability to enter the desired
IHJ-911-00.p65
2
coronary sinus tributary (2 patients). The total procedure
time for coronary sinus LV pacing was 56±18.1 min (20–
220 min) in all patients and 30±6.5 min (20–68 min) in
the last 5 patients who underwent a successful procedure
(Table 1). The LV was paced through the anterior or
anterolateral tributary in 8 and posterolateral or inferior
tributary in 3 patients.
Table 1. Details of coronary sinus pacing
Total no. of patients
17
Successful coronary sinus pacing
11 (64.7%)
Total procedure time
56±18.1 min
(20–220 min)
Procedure time in last 5 patients
30±6.5 min
(20–68 min)
Causes of failure
Inability to hook CS
none
Inability to enter CS tributary
2 (11.8%)
Inability to achieve stable pacing
and diaphragmatic stimulation
2 (11.8%)
Inadequate threshold (>2V)
3 (17.7%)
In-hospital complications of LV pacing
Lead displacement (without pacing loss) 1 (5.9%)
Loss of pacing after 2 weeks
none
While in the hospital, one patient experienced lead
displacement (as diagnosed by increase in pacing threshold
from 0.9 V to 2.3 V along with diaphragmatic stimulation)
with persistent LV pacing. There was no episode of loss of
pacing during the observation period in any of the 11
patients. Holter recording for 24 hours at 2 weeks revealed
persistent LV capture by a coronary sinus pacing lead in all
patients. A return to normal sinus rhythm was observed in
6 patients during hospitalization (during coronary sinus
pacing) and the pacing rate was increased by 10 bpm above
the inherent sinus rhythm in all these patients. Removal of
the coronary sinus lead after 2 weeks of LV pacing was easy
and uneventful.
Lead parameters at the time of implant, i.e. pacing
threshold (0.7±0.5 v. 0.9±0.3 V), impedance (773±54 v.
704±69 ohm), R wave height (8.9±0.89 v. 9.2±6.3 mV)
and slew rate (3.1±1.2 v. 2.8±2.1 mV/sec) were similar in
both LV and RV pacing sites, respectively. A threshold of
<1 V was obtained in 8 patients (72.6%) with coronary
sinus leads as compared to 10 (90.9%) patients with RV
leads. Lead maturation parameters at the end of 2 weeks,
i.e. pacing threshold (0.9±0.5 v. 1.1±0.4 mV), and
impedance (839±73 v. 950±88 ohm) were comparable on
both sides (Table 2).
4/10/01, 11:19 AM
Indian Heart J 2001; 53: 71–73
Dwivedi et al. LV Pacing through Coronary Sinus 73
Table 2. Acute and subacute pacing parameters of LV and RV
pacing
Parameters
Pacing threshold (V)
acute
2 weeks
Impedance (ohm)
acute
2 weeks
R-wave height (mV)
Slew rate (V/sec)
LV pacing
RV pacing
0.7±0.5 (0.2–1.6)
0.9±0.5 (0.3–2.1)
0.91±0.3 (0.1–1.5)
1.1±0.4 (0.3–2.2)
773±54 (630–960)
839±73 (710–1088)
8.9±49 (6–24)
3.1±1.2
704±69 (576–844)
950±88 (690–1210)
9.2±6.3 (7–26)
2.8±1.2
Discussion
The present study shows that LV pacing through coronary
sinus tributaries is feasible and safe. LV pacing was
successful in 67.7% of our patients even without a special
preformed pacing lead and long guiding sheath. The lower
success rate may be due to the initial learning curve,
difficulty in entering the cardiac veins and obtaining a
reasonable threshold. A similar success rate of 53.3% has
been reported by Daubart et al.2 with a regular pacing lead.
However, with the use of special preformed pacing leads
and long guiding sheath the success rate has been shown
to be 81.8 %.2,3
Acute lead parameters of the LV and RV were comparable
in the present study. An acute pacing threshold of <1 V was
obtained in 72.6% of our patients which is comparable to
the pacing threshold of 1.18±0.8 V obtained by Daubart et
al.2 However, lower acute pacing threshold of 0.8±0.2 V and
a greater R-wave height with specially designed coronary
sinus pacing lead has been reported earlier.2 The subacute
threshold at 2 weeks was satisfactory and similar in the RV
and LV pacing groups in our study. Similar long-term results
were obtained by previous workers.2,4 The R- wave height
was similar in LV and RV pacing in our study group.
Impedance and slew rates were also similar in RV and LV
pacing. This suggests that maturation of LV pacing through
coronary sinus tributaries is similar to RV apical pacing.
Permanent LV pacing through the coronary sinus has
been anecdotally reported when passage of a lead through
the right atrio-ventricular valve is not feasible due to
underlying anatomical abnormalities. 4 Recently, its
application has been extended, as a part of biventricular
pacing, to patients with dilated cardiomyopathy with
electrocardiographic evidence of intraventricular
conduction defect. In such patients, it has been shown to
improve the cardiac hemodynamics in symptomatic
patients categorized as NYHA Classes II and III.2 However,
in such patients, it is not used for bradycardia support but
IHJ-911-00.p65
3
to produce a near-synchronized biventricular contraction
for obtaining a higher cardiac output.
Isolated LV pacing may prove to be hemodynamically
superior, since RV pacing is shown to produce a left bundle
branch block pattern, which is associated with an abnormal
sequence of LV activation, resulting in compromised LV
function in the short- as well as long-term.5–12 In another
recently reported study in a canine model of
cardiomyopathy, LV pacing through the coronary sinus has
been shown to produce improved contractility as compared
to both, RV apical and biventricular pacing.8 This provides
evidence that chronic pacing from an LV site in patients
with CHB may be hemodynamically superior to RV apical
pacing. However, there are no human studies where LV
pacing has been performed for bradycardia support as the
only pacing mode in patients with CHB. Further studies can
be planned to see the long-term benefit of this mode of
pacing on LV function.
References
1. Bai Y, Strathmore N, Mond H, Grigg L, Hunt D. Permanent ventricular
pacing via the great cardiac vein. Pacing Clin Electrophysiol 1994;
17: 678–683
2. Daubart JC, Ritter P, Le Breton H, Grass D, Leclercq C, Lazarus A, et
al. Permanent left ventricular pacing with transvenous leads inserted
into coronary vein. PACE 1998; 21: 239–245
3. Blanc JJ, Benditt DG, Gilard M, Etienne Y, Mansourati J, Lurie KG.
Methods for permanent transvenous left ventricular pacing. PACE
1998; 21: 2021–2024
4. Rosenthal E, Qureshi SA, Crick JC. Successful long term ventricular
pacing via coronary the sinus after the Fontan operation. PACE
1995; 18: 2103–2105
5. Sutton R. Ventricular pacing: what does it do. Eur JAPE, 1993; 3:
194–196
6. Rosenqvist M, Bergfeldt L, Haga Y, Ryden J, Ryden L, Owall A. The
effect of ventricular activation sequence on cardiac performance
during pacing. PACE 1996; 19: 1279–1285
7. Askenazi J, Alexander JH, Koenigsbery DI, Belic N, Lesch M.
Alteration of left ventricular performance by left bundle branch block
simulated with atrioventricular sequential pacing. Am J Cardiol
1984; 53: 99–104
8. Burkhoff D, Oikawa RY, Sagawa K. Influence of pacing site on canine
left ventricular contraction. Am J Physiol 1986; 251: H1341–1353
9. Stojnic BB, Stojanov PL, Angelkov L, Pavlovic SU, Radjen GA,
Velimirovic DB. Evaluation of asynchronous left ventricular
relaxation by Doppler echocardiography during ventricular pacing
with AV synchrony (VDD): Comparison with atrial pacing (AAI).
PACE 1996; 19: 990–994
10. Boerth RC, Covell JW. Mechanical performance and efficiency of the
left ventricle during ventricular stimulation. Am J Physiol 1971; 221:
1686–1691
11. Burkhoff D, Oikawa RY, Sagawa K. Influence of pacing on left
ventricular contraction. Am J Physiol 1986; 251: H428–H435
12. Zile MR, Blausteine AS, Shimuzu G. Right ventricular pacing reduces
the rate of left ventricular relaxation and filling. J Am Coll Cardiol
1990; 16: 702–709
4/10/01, 11:19 AM
Original Article
Efficacy and Safety of Carvedilol in Infants with Dilated
Cardiomyopathy: A Preliminary Report
Naomi Gachara, Suja Prabhakaran, Shardha Srinivas,
Farida Farzana, Usha Krishnan, Maully J Shah
Division of Pediatric Cardiology, Institute of Cardiovascular Disease,
Madras Medical Mission, Chennai
Background: Carvedilol has proven to be beneficial in a majority of adult patients with congestive heart failure.
Although the experience from adult patients may be extrapolated to older children, symptomatic infants remain
a subset for whom dosage, safety and efficacy need to be established. The purpose of this study was to assess
whether treatment with carvedilol is efficacious and safe for infants with dilated cardiomyopathy who do not
show satisfactory clinical improvement despite treatment with conventional medications.
Methods and Results: Eight infants with dilated cardiomyopathy (ejection fraction<30%) who were
symptomatic despite tailored treatment with decongestive medications, were enrolled in the study.
Echocardiographic findings and heart failure symptom scores were analyzed before and after starting carvedilol.
Patients were hospitalized and monitored for side-effects during up-titration of carvedilol. At a follow-up of
4.5±2.2 months, patients receiving carvedilol showed a significant improvement in the left ventricular ejection
fraction (38.5±11% v. 24.4±5%), and heart failure symptom score (p<0.05). No adverse events related to
carvedilol administration occurred. There were no deaths.
Conclusions: Carvedilol is well tolerated in infants with dilated cardiomyopathy and there is significant
improvement in their functional status. Optimal timing of starting therapy, dosage and long-term effects need to
be investigated with multi-institutional trials. (Indian Heart J 2001; 53: 74–78)
Key Words: Carvedilol, Cardiomyopathy, Heart failure
I
nfants with dilated cardiomyopathy (DCM) often
have clinical symptoms of severe congestive heart failure
(CHF) despite standard therapy with digoxin, diuretics and
angiotensin-converting enzyme (ACE) inhibitors. 1–5
Orthotopic heart transplantation is now an accepted
therapeutic option for patients with end-stage heart failure.
The early results in pediatric patients are encouraging.6–9
However, long-term results of this procedure are unknown
and there is a lack of donor organs in many parts of the
world. Also, despite having severe symptoms of CHF, infants
with DCM may show spontaneous improvement in cardiac
function. "Bridging" strategies include the use of aggressive
medical management, extracorporeal membrane
oxygenation, and mechanical ventricular assist devices. The
beneficial use of selective beta receptor blockers (e.g.
metoprolol) in the treatment of children with DCM has been
described.10–11 This report reviews the efficacy and safety
of carvedilol in infants with DCM in whom the symptoms
Correspondence: Dr Maully J Shah, Heart Center, Children's Hospital
4800 Sand Point Way NE, Seattle, WA 98105, e-mail: [email protected]
IHJ-863-00.p65
74
of CHF were refractory to conventional medical therapy.
Carvedilol is a nonselective beta-blocker with alpha 1
blocking and anti-oxidative properties. Its use in adults with
CHF has been widely investigated.12–16 These data can be
readily extrapolated to older children with DCM but its use
in infants (<2 years of age) with DCM has not been reported.
Methods
Study population: From October 1998 to October 1999,
8 patients from the 31 pediatric patients with DCM referred
to our institution were selected for the study based on the
following inclusion criteria: (1) DCM; (2) age less than 24
months; and (3) poor response to treatment with
conventional therapy. Conventional therapy was defined as
treatment with digoxin (10 µg/kg/day), diuretics
(furosemide 3–4 mg/kg/day, spironolactone 3–4 mg/kg/
day) and ACE inhibitor (captopril 3 mg/kg/day) for at least
1 month prior to initiation of carvedilol. Poor responders
were indentified as those patients who continued to have
4/10/01, 10:54 AM
Indian Heart J 2001; 53: 74–78
signs and symptoms of CHF and no significant improvement
in left ventricular ejection fraction (<30%) and/or fractional
shortening.
Gachara et al.
Carvedilol in Infants 75
Table 1. Heart failure scores for infants with congestive
heart failure
Symptoms
(score)
Frequent
(2)
Occasional
(1)
None
(0)
Study protocol: All patients underwent a physical
Breathing difficulties
examination, routine clinical laboratory tests (including
Interrupted feeds
complete blood count and blood biochemistry), chest X-ray,
Vomiting
electrocardiogram (ECG), and echocardiogram prior to
Sweating
starting carvedilol and at follow-up. In addition, 24-hour
Poor activity
Holter monitoring was performed at follow-up.
Irritability
Oedema
Echocardiographic studies included M-mode, twodimensional and Doppler echocardiographic variables.
Maximum score : 14
Estimates of left ventricular function included ejection
fraction (EF) measured from the apical 4-chamber view
Statistical analysis: Data are expressed as mean±SD,
using Simpson's rule and fractional shortening (FS)
range or percentage. Comparison between groups was made
measured from the parasternal short axis projection. All
by the student's t-test. Differences were considered
measurements were obtained in sinus rhythm as a mean of
significant for p<0.05.
3 consecutive beats. The degree of mitral valve insufficiency
was classified as: grade I (mild), grade II (moderate), and
Results
grade III (severe). ECG parameters that were evaluated
included heart rate, presence of arrhythmias, and
Patient characteristics: Eight patients fulfilled the criteria
measurement of electrocardiographic intervals. The results
required to be enrolled in the study of which 6 were male
of 24-hour Holter monitoring were analyzed for the
and 2 female. The age at which carvedilol was started was
maximum, minimum and average heart rate on carvedilol
11±6.8 months (range 2.5–23 months, median 9.5
as well as the presence of arrhythmias. The protocol for
months) and the weight of the patients was 6.9±1.8 kg.
starting carvedilol was extrapolated from studies in adults
Patients were evaluated frequently, with the most recent
with CHF.12,14,16 All patients were hospitalized during the
follow-up at 4.5±2.2 months (range: 2–9 months, median
starting and up-titrating of carvedilol. An initial dose of
4 months) after commencement of carvedilol. Seven of the
0.1 mg/kg/dose twice daily was started. The up-titration
eight patients had idiopathic dilated cardiomyopathy. None
regimen consisted of doubling the dose every 24 hours until
of them had clinical evidence of myocarditis. The remaining
a dose of 0.8 mg/kg/day was achieved when the dose was
patient had DCM secondary to an anomalous left coronary
increased to a mean of 1 mg/kg/day, if tolerated (range:
artery arising from the pulmonary artery (ALCAPA). He
0.7 mg/kg/day–2 mg/kg/day). Heart rate and blood
continued to have depressed left ventricular function after
pressure were monitored at 4-hourly intervals and one hour
surgical correction with a transpulmonary artery baffle.
prior to and one hour after the carvedilol dose during
Individual patient characteristics are listed in Table 2.
hospitalization. As all the patients in the study group were
<2 years of age, NYHA class
could not be determined.
Table 2. Patient characteristics at baseline and after receiving carvedilol
Instead, a heart failure
Before Carvedilol
After Carvedilol
symptom scoring system was
Patient
Age
Sympt
FS
EF MR F/U Sympt FS
EF MR
Final
Comments
designed to assess the clinical
#
(mo.)
score
(%) (%)
period score (%) (%)
dose
status of the patients. Parents
(mo.)
(mg/kg/day)
were given a questionnaire
1
18
8
11
26 ++
3
0 14
33 ++
1.2
doing well
to describe their child's
2
7
10
10
24 nil
4
2 12
31 nil
1.0
doing well
symptoms and the frequency
3
9
8
9
27 ++
5
0 22
49 ++
1.0
doing well
4
10
14
8
14 ++
7
6
4
26
+
2.0
symptomatic
of their occurrence (Table 1)
5
23
14
14
20 ++
6
0 17
50 nil
0.75
doing well
prior to starting carvedilol
6
6
6
26
29
+
5
0 33
34
+
0.8
doing well
and at follow-up. A higher
7
2
6
16
30 nil
4
4 17
30
+
1.0
doing well
8
13
2
4
25
+
10
0 24
56
+
1.0
doing well
score was proportional to
increased
severity
of
#: number, Mo.: months, EF: ejection fraction, FS: fractional shortening, MR: mitral valve regurgitation, F/U: follow up,
Sympt.: symptoms
symptoms.
IHJ-863-00.p65
75
4/10/01, 10:54 AM
76 Gachara et al.
Indian Heart J 2001; 53: 74–78
Carvedilol in Infants
Drug tolerability: During titration of carvedilol, no patient
had any untoward events. The dose of carvedilol used was
1.08±0.4 mg/kg/day (range: 0.7–2 mg/kg/day, median
1 mg/kg/day). Patients continued to receive concomitant
therapy with digoxin, diuretics and captopril. The dose of
captopril was reduced by 20% during initiation with
carvedilol.
ECG parameters, heart rate and arrhythmias: There
were no significant changes in ECG parameters (PR interval,
QRS and QTc duration) before and after carvedilol therapy.
Holter monitoring was performed in 6 of 8 patients on
carvedilol. The heart rate response is shown in Table 3.
Table 3. Analysis of 24-hour Holter monitoring in six patients
receiving carvedilol
Patient #
Min. HR
1
2
3
4
5
6
63
103
84
64
97
76
Ave. HR
Max. HR
104
138
119
96
153
100
135
179
154
126
179
166
Arrhythmias
Nil
Nil
PVC (0.02%)*
PVC (4%)
NS-SVT
Nil
*: % of rhythm, #: number, Min.: minimum, Ave.: average, Max.: maximum, HR:
heart rate, PVC: premature ventricular contractions, NS: non sustained, SVT:
supraventricular tachycardia
Effects on echocardiographic estimates of LV
function: The LVEF improved from 24.4±5% (range: 14%–
30%, median 25.5%) to 38.5±11% (range: 26%–55%,
median 33.5%) after starting carvedilol (p=0.01), (Fig. 1).
Four patients showed an increase of LVEF >10%. There was
only a marginal increase in the LVFS from 12.2±6.6 (range:
4%–16%, median 10.5%) to 17.9±8.7% (range: 4%–33%,
median 17.4%) (p=0.07). The LV end-diastolic dimensions
(LVEDD) did not change significantly (LVEDD pre-carvedilol
treatment 4.8±0.72 cm; post-carvedilol treatment 4.5±0.8
cm). There was no significant change in the degree of mitral
regurgitation after starting carvedilol. Patient #4 had a
deterioration in the estimated FS. In addition, there was
evidence of spontaneous echocardiographic contrast in the
left atrium and left ventricle of this patient, indicating
severely diminished function.
Effects on functional status: Five of the eight patients
are completely asymptomatic after starting carvedilol (Table
1). Of the three who are symptomatic, 2 patients have mild
symptoms (scores 2 and 4 out of 14). Only one patient
(patient #4) required hospitalization for further
management of congestive heart failure. Six of the eight
patients have demonstrated an average weight gain of 6%
(range 2%–18%) over a period of 4.6±2.2 months after
starting carvedilol (Fig. 2). Patient #4 has failed to thrive
and patient #1 has not shown any increase in weight over
a 2-month follow-up period.
Patient # 4 had ventricular arrhythmias that accounted for
14% of total beats recorded on the initial 24-hour Holter
monitoring. This included frequent single ventricular
ectopic beats and non-sustained ventricular tachycardia.
After increasing the dose of carvedilol to 2 mg/kg/day,
ventricular arrhythmias decreased to 4% of total recorded
beats. Patient # 5 had 4 episodes of non-sustained supraventricular tachycardia.
To the best of our knowledge, this is the first published study
describing the effects of carvedilol in very young children
Fig. 1. Individual changes in left ventricular ejection fraction (EF) after starting
carvedilol and after receiving carvedilol for a mean period of 4.5±2.2 months
(range 2–9 months).
Pre-carv: Pre-carvedilol therapy
Post-carv: Post-carvedilol therapy
Fig. 2. Individual changes in body weight (kg) after starting carvedilol and
after receiving carvedilol for a mean period of 4.5±2.2 months (range 2–9
months).
Pre-carv: Pre-carvedilol therapy
Post-carv: Post-carvedilol therapy
IHJ-863-00.p65
76
Discussion
4/10/01, 10:54 AM
Indian Heart J 2001; 53: 74–78
with DCM. Carvedilol, is a third-generation beta1-, beta2-,
and alpha 1 blocker with ancillary properties. The
mechanisms of action of carvedilol in CHF include reversal
of adrenergic-induced ventricular remodelling,
improvement in intrinsic ventricular function, vasodilation,
decreased stimulation of neurohumoral systems and
antioxidant effects.17–20 The use of carvedilol has been
shown to produce reduction of mortality and improvement
in symptoms in adults with heart failure.12,14,21,22 Our study
shows that at least the latter effects are reproduced in
children with DCM.
Tolerability of carvedilol: The primary finding of this
study was that carvedilol was tolerated by all patients.
Specific complications such as profound bradycardia,
hypotension, hypoglycemia or worsening heart failure were
not encountered. The dose of captopril was empirically
decreased by 20% due to its potential for producing
hypotension because of the combined vasodilatory effects
of carvedilol and ACE inhibitors. Hyponatremia, a
recognized predictor for risk of adverse events during
commencement of carvedilol was not encountered in any
patient.23,24 All infants were hospitalized during initiation
and titration of carvedilol.
Concomitant medical therapy: Digoxin, diuretics and
captopril were continued in all patients receiving carvedilol.
The mechanisms of action of vasodilatory effects of
carvedilol and ACE inhibitors are different. Experimental
studies have shown that vasodilation by carvedilol is
mediated by alpha1 receptor blockade and carvedilol does
not antagonize vasoconstriction induced by angiotensin II.25
While the short-term vasodilatory properties of carvedilol
have been established, some studies indicate that with time,
there appears to be an attenuation or even loss of its acute
vasodilator properties.13,26 For this reason, we chose to
continue the concomitant use of ACE inhibitors and
carvedilol. The dose of other anti-CHF medications was not
increased after starting carvedilol in any patient.
Effects on functional status: Carvedilol significantly
lessened the symptoms of heart failure as assessed by the
patient's family using the symptom score questionnaire and
by the clinician. Five of the 8 patients were completely
asymptomatic at a median follow-up of 4 months (range:
2–9 months). Patient #4 was the most ill in this cohort.
Despite lack of improvement in LVEF, his symptom score
decreased from 14 to 6 after carvedilol. He was also the only
patient in the study who was hospitalized (3 hopitalizations
over a period of 6 months) for the treatment of acute
exacerbation of CHF after starting carvedilol. Four patients
were referred for heart transplantation evaluation and three
IHJ-863-00.p65
77
Gachara et al.
Carvedilol in Infants 77
were removed from transplant consideration because of
their favourable response to carvedilol. Unique to infants is
the effect of increased metabolic demands on nutritional
status and weight gain. In this study, 6 of 8 patients
demonstrated an average weight gain of 6% (range 2%–
18%) over a period of 4.6±2.2 months after starting
carvedilol. Patient #4 lost 0.5 kg over 4 months and patient
#1 did not show any increase in weight over a 2-month
follow-up period. The median weight percentile for age is
50% (range: 30%–90%). All patients were able to feed orally
and nasogastric tube feeding was not required in any
patient.
Left ventricular size and function: Several studies have
demonstrated a favorable effect of carvedilol on LV
dimensions, shape and LV systolic function. 12,19 Even
though, in the present study, the duration of carvedilol
therapy was relatively short, there was improvement in the
LVEF from 24.4%±5% to 38.5%±11% over 4.5±2.2
months. There was also a marginal improvement in the
LVFS but it did not reach statistical significance. The
improvement in LVEF is comparable to that reported in
children with DCM treated with a selective beta blocker. The
natural history of DCM in children is quite variable with
the potential for spontaneous improvement in LV function.
It is possible that some patients in this study may have had
an improvement in LVFS and EF with a longer period of
conventional therapy alone.
Mortality: There were no deaths in this group of patients
during the study period. However, the total number of
patients is small and the follow-up period not long enough
to determine the impact of carvedilol on the survival of
children with DCM. Currently, no comparative data are
available in the pediatric literature.
Effect on heart rate and ventricular arrhythmias: As
expected, there was a significant decline in heart rate after
starting carvedilol (p<0.05). A slower heart rate may
ameliorate ventricular filling and decrease myocardial
energy consumption. Only one patient in the study group
showed ventricular arrhythmias on Holter monitoring. The
frequency of ventricular ectopy decreased after increasing
the dose of carvedilol. Carvedilol may have an additional
beneficial effect on the reduction of ventricular
arrhythmias.
Study limitations: Study limitations include a small
cohort of patients, a relatively short follow-up period, and
lack of blinding. Another limitation is the lack of
hemodynamic data from cardiac catheterization. The
optimal dose of carvedilol has been extrapolated from the
adult literature as there are no established guidelines for
4/10/01, 10:54 AM
78 Gachara et al.
Indian Heart J 2001; 53: 74–78
Carvedilol in Infants
pediatric dosage. Comparable improvement might have
been obtained with other beta blockers such as metoprolol,
but this was not tested as the study was specifically designed
to investigate the efficacy and safety of carvedilol.27
Conclusions: The results of the present study indicate that
carvedilol is tolerated well in very young patients with DCM
and there is significant improvement in the functional status
and LVEF in patients not responding to conventional
therapy. Although the optimal treatment for DCM in
children is not known, the addition of carvedilol to the
armamentarium of anti-failure strategies may improve
symptoms, ventricular function and survival. Patient
selection criteria, optimal timing of carvedilol therapy,
optimal dosage and its long term effects need to be
investigated with multi-institutional trials and a larger
number of patients.
13.
14.
15.
16.
17.
18.
19.
References
1. Griffin ML, Hernandez A, Martin TC, Goldring D, Bolman RM, Spray
TL, et al. Dilated cardiomyopathy in infants and children. J Am Coll
Cardiol 1988; 11: 139–144
2. Chen SC, Nouri S, Balfour I, Jureidini S, Appleton S. Clinical profile of
congestive cardiomyopathy in children. J Am Coll Cardiol 1990; 15:
189–198
3. Arola A, Tuominen J, Ruuskanen O, Jokinen E. Idiopathic dilated
cardiomyopathy in children: prognostic indicators and outcome.
Pediatrics 1998; 101: 369–376
4. Burch M, Siddiqui SA, Celermajer DS, Scott C, Bull C, Deanfield JE.
Dilated cardiomyopathy in children: determinants of outcome.
Br Heart J 1994; 72: 246–250
5. Scammell AM, Arnold R, Wilkinson JL. Captopril in treatment
of infant heart failure: a preliminary report. Int J Cardiol 1987; 16:
295–301
6. Kanter KR, Tam VK, Vincent RN, Cuadrado AR, Raviele AA, Berg
AM. Current results with pediatric heart transplantation. Ann Thorac
Surg 1999; 68: 527–530
7. Morrow WR, Naftel D, Chinnock R, Canter C, Boucek M, Zales V, et
al. Outcome of listing for heart transplantation in infants younger
than six months: predictors of death and interval to transplantation.
The Pediatric Heart Transplantation Study Group. J Heart Lung
Transplant 1997; 16: 1255–1266
8. Parisi F, Squitieri C, Carotti A, Abbattista AD, Cicni MP, Esu F, et al.
Ten-year follow-up after pediatric transplantation. J Heart Lung
Transplant 1999; 18: 275–277
9. Boucek MM, Novick RJ, Bennett LE, Fiol B, Keck BM, Hosenpud JD.
The registry of the international society of heart and lung
transplantation: second official pediatric report–1998. J Heart Lung
Transplant 1998; 17: 1141–1160
10. Shaddy RE, Tani LY, Gidding SS, Pahl E, Orasmond GS, Gilbert EM et
al. Beta-blocker treatment of dilated cardiomyopathy with congestive
heart failure in children: a multi-institutional experience. J Heart Lung
Transplant 1999; 18: 269–274
11. Shaddy RE. Beta-blocker therapy in young children with congestive
heart failure under consideration for heart transplantation. Am Heart
J 1998; 136: 19–21
12. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yandvitz FD, Bristow
MR, et al. Carvedilol improves left ventricular function and symptoms
IHJ-863-00.p65
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in chronic heart failure: a double-blind randomized study. J Am Coll
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Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short and long
term carvedilol administration on rest and exercise hemodynamic
variables, exercise capacity and clinical condition in patients with
idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994; 24: 1678–
1687
Packer M, Bristow MR, Cohn J, Colucci WS, Fowler MB, Gilbert EM,
et al. The effect of carvedilol on morbity and mortality in patients
with chronic heart failure. N Eng J Med 1996; 334: 1349–1355
Di Leonarda A, Sabbadini G, Salvatore L, Sinagra G, Mestroni L,
Pinamonti B, et al. Long-term effects of carvedilol in idiopathic dilated
cardiomyopathy with persistent left ventricular dysfunction despite
chronic metoprolol. J Am Coll Cardiol 1999; 33: 1926–1934
Macdonald PS, Keogh AM, Aboyoun CL, Lund M, Amor R, McCaffrey
DS, et al. Tolerability and efficacy of carvedilol in patients with New
York Heart Association class IV heart failure. J Am Coll Cardiol 1999;
33: 924–931
Bistow MR. Carvedilol treatment of chronic heart failure: a new era.
Heart (suppl 2) 1998; 79: S31–S34
Packer M. The neurohormonal hypothesis: a theory to explain the
mechanism of disease progression in heart failure. J Am Coll Cardiol
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Hall SA, Cigarroa CG, Marxoux L, Risser RC, Grayburn PA, Eichhorn
EJ, et al. Time course of improvement in left ventricular function, mass
and geometry in patients with congestive heart failure treated with
β-adrenergic blockade. J Am Coll Cardiol 1995; 25: 1154–1161
Yoshikawa T, Handa S, Anzai T, Nishimura H, Baba A, Akaishi M, et
al. Early reduction of neurohumoral factors plays a key role in
mediating the efficacy of β-blocker therapy for congestive heart
failure. Am Heart J 1996; 131: 329–335
Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB,
Hershberger RE, et al. Carvedilol produces dose-related improvements
in left ventricular function and survival in subjects with chronic heart
failure. Circulation 1996; 94: 2807–2816
Australia/New Zealand Heart Failure Research Collaborative Group.
Effect of carvedilol, a vasodilator-β-blocker, in patients with
congestive heart failure due to ischemic heart disease. Circulation
1995; 92: 212–218
Sachner-Bernstein J, Krum H, Goldsmith R. Should worsening heart
failure early after initiation of beta-blocker therapy for chronic heart
failure preclude long term treatment (abstr). Circulation 1995; 92
(Suppl I): 1–395
Dzau V, Colucci W, Hollenberg N, Williams G. Relation of the renin–
angiotensin aldosterone system to clinical state in congestive heart
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Ruffolo RR, Gellai M, Hieble JP, Willette RN, Nichols AJ. The
pharmacology of carvedilol. Eur J Clin Pharmacol 1990; 38(Suppl. 2):
S82–S88
Doughty RN, Whalley GA, Gamble G, MacMhai S, Sharpe N. Left
ventricular remodeling with carvedilol in patients with congestive
heart failure due to ischemic heart disease. J Am Coll Cardiol 1997;
29: 1060–1066
Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C,
Ocampo ON, et al. Prospective randomized comparison of effect of
long term treatment with metoprolol or carvedilol on symptoms,
exercise, ejection fraction and oxidative stress in heart failure.
Circulation 1999; 99: 2645–2651
Shaddy RE, Olsen SL, Bristow MR, Taylor DO, Bullock EA, Tani LY, et
al. Efficacy and safety of metoprolol in the treatment of doxorubicin
induced cardiomyopathy in pediatric patients. Am Heart J 1995; 129:
197–198
Quaife RA, Christian PE, Gilbert EM, Datz FL, Volkman K, Bristow
MR. Effects of carvedilol on right ventricular function in chronic heart
failure. Am J Cardiol 1998; 81: 247–250
4/10/01, 10:55 AM
Brief Report
Indian Heart J 2001; 53: 000–000
Percutaneous Transluminal Coronary Angioplasty with
Stenting of Anomalous Right Coronary Artery Originating
From Left Sinus of Valsalva Using the Voda Guiding
Catheter: A Report of Two Cases
Tarun K Praharaj, Gautamananda Ray
B.M. Birla Heart Research Centre, Calcutta
Coronary arteries of anomalous origin are uncommon and some forms seem to be predisposed to atherosclerosis.
We report two cases of successful stent implantation in an anomalous right coronary artery originating from
the left sinus of Valsalva using the Voda guiding catheter. (Indian Heart J 2001; 53: 79–82)
Key Words: Coronary anomalies, Angioplasty, Stents
C
oronary arteries of anomalous origin are uncommon
and found in only 0.2%–1.2% of patients undergoing
percutaneous transluminal coronary angioplasty
(PTCA).1–3 Anomalous origin of the right coronary artery
(RCA) from the left sinus of Valsalva (LSOV) has been found
in 6%–27% of patients with coronary anomalies4 and in
0.02%–0.17% of coronary angiogram. 5 Although
clinically thought to be a benign anomaly, it can cause
angina pectoris or myocardial infarction even in the absence
of any distinct atherosclerotic lesion.6 At times, it can lead
to faintness, ventricular fibrillation and sudden cardiac
death. 7 Anomalies cause technical problems during
coronary angiography as well as during PTCA. There are
few reports of PTCA of anomalous coronary arteries.8–12
We report two cases of successful stenting of anomalous
RCA originating from the LSOV using the Voda guiding
catheter.
anterior to the left main coronary artery and took a caudal
anterior course between the great vessels before it continued
on its normal course into the right atrioventricular groove.
The left ventricular function was normal with a left
ventricular ejection fraction (LVEF) of 64% . The anterior
location of the ostium in the left coronary cusp with
tortuous proximal portion of the artery with its caudal
anterior course posed specific problems for cannulation.
Diagnostic right coronary angiogram was done using a left
Amplatz II catheter (Fig. 2) and anomalous origin of RCA
from the LSOV was observed. The patient was re-admitted
2 weeks later for PTCA of the RCA because he remained
Case Report
Case 1: A 53-year-old male was admitted to our center with
a clinical diagnosis of crescendo angina of recent onset.
Coronary angiography revealed 70%–80% long segment
stenosis (16 mm) of the mid-RCA. The left circumflex and
the left anterior descending artery were free from any
disease. The 3 mm diameter-sized RCA was anomalous and
originated from the LSOV (Fig. 1). The anomalous RCA lay
Correspondence: Dr Tarun K Praharaj, Senior Consultant Cardiologist,
B.M. Birla Heart Research Centre, Library Avenue, Calcutta 700027
e-mail: [email protected]
IHJ-876-00.p65
79
Fig. 1. Left coronary sinus injection in left anterior oblique (LAO) view which
faintly shows the origin of the anomalous RCA from the left coronary sinus.
4/10/01, 11:01 AM
80 Praharaj et al.
Indian Heart J 2001; 53: 79–82
Stenting of Anomalous Right Coronary
Fig. 2. Right coronary angiogram was done using a left Amplatz Catheter in
LAO view showing severe long segment stenosis in the mid-RCA.
Fig. 4. Right coronary angiogram in LAO view showing the inflated balloon.
Fig. 3. Right coronary angiogram in LAO view showing left Voda guiding
catheter deeply engaged in the RCA with its tip well seated in the mid ostium.
Fig. 5. Final diagnostic angiogram following stenting.
symptomatic despite medical treatment. The artery could
not be cannulated even after using different catheters
including the Amplatz catheter. Finally, the RCA was
selectively cannulated by Voda Left 8 F guide catheter (inner
lumen diameter 0.080", Boston Scientific Corporation,
Minnesota) (Fig. 3). The RCA stenotic lesion was successfully
crossed with a 0.014" Hi-torque intermediate wire
(Advanced Cardiovascular System, Califorina), and dilated
with a 3×20 mm Rocket balloon (Advanced Cardiovascular
system, California) (Fig. 4). After predilatation of the
narrowed segment, a 3×18 mm MultiLink stent (Advanced
Cardiovascular System, California) was deployed at 16 atm.
A final diagnostic angiogram showed an excellent
angiographic result (Fig. 5). The immediate post-procedure
IHJ-876-00.p65
80
stay of the patient was uneventful and he was discharged
three days later on regular calcium channel blockers,
aspirin and ticlopidine (for 6 weeks). The patient continued
to remain asymptomatic with a good quality of life on oneyear follow-up.
Case 2: A 56-year-old male presented with a clinical
diagnosis of effort angina of recent onset with diabetes and
hypertension. His coronary angiography revealed a normal
left main coronary artery and left anterior descending
artery. However, the left circumflex artery was a small
caliber vessel, totally occluded in its mid-segment and filled
through collaterals from the left anterior descending artery.
Mid-RCA had a 70%–80% long segment narrowing with
subtotal occlusion in its distal segment. The distal RCA was
4/10/01, 11:01 AM
Indian Heart J 2001; 53: 79–82
Praharaj et al.
Stenting of Anomalous Right Coronary
81
Fig. 6. Left coronary sinus injection in left anterior oblique view showing the
origin of the anomalous RCA from the LSOV.
Fig. 8. Right coronary angiogram in LAO view showing the inflated balloon.
Fig. 7. Right coronary angiogram done using left Voda guiding catheter in
LAO view showing long segment stenosis in the mid-RCA and subtotal occlusion
of the distal RCA.
Fig. 9. Right coronary angiogram in LAO view showing the final diagnostic
angiogram.
seen to be filled through collaterals from the left anterior
descending artery. The RCA (3 mm diameter) originated
from the LSOV (Fig. 6) and passed between the pulmonary
artery and aorta to reach the right atrioventricular groove.
Thereafter it followed a normal course. The LVEF by twodimensional echocardiography was 52%. There was mild
hypokinesia of the inferior wall. The anomalous RCA had
an ostium located anteriorly and superiorly and could not
be cannulated with Judkin, Multipurpose and Amplatz
catheters. However, cannulation was easily possible with a
Voda 8 F guiding catheter (Fig. 7). The long segment
narrowing in mid-RCA and the subtotally occluded distal
RCA were successfully crossed with a 0.014" Hi-torque
intermediate wire and dilated with a 3×20 mm Rocket
balloon. The lesion in the mid-RCA was successfully dilated
at 10 atm and the distal segment was stented after
predilatation, using a 3×15 mm MultiLink stent at 16 atm
(Fig. 8). The final diagnostic angiogram revealed excellent
result (Fig. 9). A totally occluded left circumflex artery was
successfully crossed with a 0.014" Hi-torque intermediate
wire and predilated using a 2.5×20 mm balloon and a 2.5×
15 mm MultiLink stent was deployed at 12 atm with good
angiographic result. The immediate post-procedure stay of
the patient was uneventful and the patient was discharged
on regular medications. He remained asymptomatic at
follow-up after 7 months.
IHJ-876-00.p65
81
4/10/01, 11:01 AM
82 Praharaj et al.
Discussion
PTCA in patients with an anomalous RCA is technically
challenging. It demands a high degree of awareness, and
complete evaluation of the coronary artery anatomy and
distribution in order to avoid complications. The
complication rate of coronary arteriography and PTCA is
related to the duration of the procedure. Topaz et al.11 have
described various aspects of orifice configuration, anatomy
of the artery, location of atherosclerotic lesions and also
guiding catheter selection. Proper guiding catheter selection
decreases procedure time in PTCA involving anomalous
coronary arteries and thus increases success rate. In both
cases, we were able to cannulate the anomalous RCA using
the Voda guiding catheter. In the first case, the initial
angiography was done using the left Amplatz catheter.
However, during PTCA, the cannulation was not possible
with the Amplatz catheter. Use of the Voda guiding catheter
in both cases provided easy cannulation with enough backup support. The choice of the Voda guiding catheter was
based on its curvature, large area of support and location
of the artery just opposite to the left ostium. It provided the
maximum stable support required for the smooth passage
of the balloon as well as the stent. The tip of the catheter
sits well in the anomalous vessel and the secondary curve
rests stably against the opposite aortic wall. The anatomical
course of the anomalous RCA in both our cases corresponds
to the course described by Ilia.13 Usually, the anomalous
RCA originating from the LSOV almost invariably follows a
similar course.5 Thus, it appears that the Voda guiding
catheter may be the best for PTCA of a coronary artery with
similar anomaly.
Several techniques have been reported for PTCA in an
anomalous RCA.5, 11–14 However, we could cannulate the
anomalous RCA in both our cases with relative ease and
got good back-up support using the Voda guiding catheter.
Thus, after careful study of the course of the anomalous
artery, location of the lesion and selective use of the Voda
guiding catheter, angioplasty and stenting can be performed
IHJ-876-00.p65
Indian Heart J 2001; 53: 79–82
Stenting of Anomalous Right Coronary
82
in patients with an anomalous RCA originating from the
LSOV with excellent results.
References
1. Engel HJ, Torres C, Page HL Jr. Major variations in anatomical origin
of the coronary arteries: angiographic observations in 4250 patients
without associated congenital heart disease. Cathet Cardiovasc Diagn
1975; 1: 157–169
2. Kimbiris D, Iskandrian AS, Segal BL, Bemis CE. Anomalous aortic
origin of coronary arteries. Circulation 1978; 58: 606–615
3. Ogden JA. Congenital anomalies of the coronary arteries. Am J Cardiol
1970; 25: 474–479
4. Taylor AJ, Rogan KM, Virmani R. Sudden cardiac death associated
with isolated congenital coronary artery anomalies. J Am Coll Cardiol
1992; 20: 640–647
5. Douglas JS, French RH, King SB. Coronary artery anomalies. In: King
SB, Douglas JS (eds): Coronary angiography and angioplasty. New York:
McGraw-Hill, 1985, p. 33–85
6. Benge W, Martins JB, Funk DC. Morbidity associated with anomalous
origin of the right coronary artery from the left sinus of Valsalva.
Am Heart J 1980; 99: 96–100
7. Roberts WC, Siegel RJ, Zipes DP. Origin of the right coronary artery
from the left sinus of Valsalva with associated chest pain: report of
two cases. Cathet Cardiovasc Diagn 1976; 2: 397
8. Stauffer J, Sigwart U, Vogt P, Aymon D, Kappenberger L. Transluminal
angioplasty of a single coronary artery. Am Heart J 1991; 122: 569–
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9. Kimbiris D, Lo E, Iskandrian AS. Percutaneous transluminal
angioplasty of anomalous left circumflex coronary artery. Cathet
Cardiovasc Diagn 1987; 13: 407–410
10. Mooss A, Hentz M. Percutaneous transluminal angioplasty of
anomalous right coronary artery. Cathet Cardiovasc Diagn 1989; 16:
16–18
11. Topaz O, Di Sciascio G, Goudreau E, Cowley MJ, Nath A, Kohli RS, et
al. Coronary angioplasty of anomalous coronary arteries. Notes on
technical aspects. Cathet Cardiovasc Diagn 1990; 21: 106–111
12. Sohara H, Tsurukawa T, Kawabata K, Kawano R, Amitani S, Kurose
M, et al. Pitfalls of intervention therapy in a patient with anomalous
origin of the right coronary artery from the left sinus of Valsalva
associated with organic stenosis. J Cardiol 1997; 29: 111–115
13. Ilia R. Percutaneous transluminal angioplasty of coronary arteries
with anomalous origin. Cathet Cardiovasc Diagn 1995; 35: 36–41
14. Das GS, Wysham DG. Double wire technique for additional guiding
catheter support in anomalous left circumflex coronary artery
angioplasty. Cathet Cardiovasc Diagn 1991; 24: 102–104
4/10/01, 11:01 AM
Brief Report
Indian Heart J 2001; 53: 000–000
Mechanical Ventilation in the Prone Position: A Strategy for
Acute Respiratory Failure After Cardiac Surgery
Manish Firodiya, Yatin Mehta, Rajiv Juneja, Naresh Trehan
Departments of Anaesthesiology and Cardiovascular Surgery,
Escorts Heart Institute and Research Centre, New Delhi
Ventilation in the prone position, initially introduced in respiratory therapy to improve the drainage of secretions,
has been used in intensive care to improve oxygenation. We report a case of an obese male patient who underwent
elective coronary artery bypass grafting and had low PaO2 in the postoperative period. The PaO2 improved
whenever the patient was ventilated in the prone position. On each occasion, oxygenation improved without
any change in the hemodynamic parameters. The PaO2 increased from 57.8 to 249.7 mmHg on the first occasion,
from 48.7 to 194.6 mmHg on the second and 62.5 to 199.7 mmHg on the third at an FIO2 of 1.0. The shunt
fraction (Qva/Qt) decreased from 43.6% to 7.2% on the first occasion and from 46.7% to 12.5% on the second.
Ventilation in the prone position can be an effective method for improving oxygenation in patients suffering
from postoperative acute respiratory failure who are not responding to other ventilatory strategies. (Indian
Heart J 2001; 53: 83–86)
Key Words: Respiration, Ventilation, Surgery
A
cute respiratory failure is a major cause of
postoperative morbidity and mortality in cardiac
surgical intensive care units. This condition may require
the administration of high concentrations of oxygen, which
can itself be toxic and cause further lung damage.
Mechanical ventilation in the prone position and its positive
effect on gas exchange was described more than 25 years
ago but it still remains a relatively under-used technique.
Recent literature not only proves its positive results in
improving oxygenation but also advocates its early
application rather than using it as a last resort.1
Experience of prone mechanical ventilation in
postoperative cardiac surgical patients is limited.2 We report
the case of an obese male patient who underwent elective
coronary artery bypass grafting (CABG) and had low PaO2
in the postoperative period.
Case Report
A 49-year-old male patient weighing 103 kg, with a body
surface area of 2.07 m2 was scheduled for elective CABG.
The patient was a chronic smoker with a history of
Correspondence: Dr Y Mehta, Senior Consultant & Head, Department of
Anaesthesia, Escorts Heart Institute and Research Centre, Okhla Road,
New Delhi 110025, e-mail: [email protected]
IHJ-884-00.p65
1
hypertension for the past eight years. On physical
examination, the chest was clear. X-ray chest (PA view)
showed normal lung fields. Pulmonary function tests
showed values above 75% of the predicted values. Forced
vital capacity (FVC) was 3 L, forced expiratory volume in
one second (FEV1) was 2.61 L, peak expiratory flow rate
(PEFR) was 6.49 L and forced expiratory flow25–75 (FEF 25–75)
was 2.78 L. Two-dimensional echocardiogram revealed
inferior and lateral wall hypokinesia with a left ventricular
ejection fraction (LVEF) of 0.35. Routine cardiac medication
in the form of oral atenolol and isosorbide dinitrate was
continued till the morning of the surgery. Oral lorazepam
2 mg was given on the night prior to surgery. Premedication
one hour prior to surgery included intramuscular morphine
sulphate and oral lorazepam. The following parameters
were monitored: continuous two-lead (II and V5) ECG;
intra-arterial blood pressure; pulmonary artery pressure
and thermodilution cardiac output; end-tidal carbon
dioxide; rectal temperature; and urine output. Anesthesia
was induced with intravenous fentanyl citrate, midazolam,
thiopentone sodium and pancuronium bromide, and the
trachea was intubated with a 9.0 mm cuffed orotracheal
tube. Nitroglycerine infusion was used to control arterial
blood pressure.
Cardiopulmonary bypass was instituted at tepid
4/10/01, 11:08 AM
84 Firodiya et al.
Indian Heart J 2001; 53: 83–86
Mechanical Ventilation in the Prone Position
The patient remained hemodynamically stable without
any inotropic support. Cardiac enzymes and ECG were
normal, but there was no improvement in the PaO2. He was
then ventilated through the volume control mode in the
prone position, on three occasions—on day 2, day 3 and
day 5 of surgery for 8, 6 and 8 hours, respectively. Four
attendants turned the patient from the supine to the prone
position. During this period, he remained hemodynamically
stable and showed significant improvement in PaO 2
following all three occasions of prone ventilation. The PaO2
increased from 57.8 to 249.7 mmHg on the first occasion,
from 48.7 to 194.6 mmHg on the second and from 62.5 to
199.7 mmHg on the third occasion at an FiO2 of 1.0. The
shunt fraction (Qva/Qt) decreased from 43.6% to 7.2% on
the first occasion and from 46.7% to 12.5% during the
second. Due to the prone position, the patient developed
swelling over the lips and left eyelid, and subconjuctival
hemorrhage in the left eye on the third occasion, which
resolved on its own in two days. The total negative fluid
balance was 6.5 L by day 7 postoperatively. Chest X-ray
showed haziness in the lower and mid-zones initially which
cleared by postoperative day 6. Nutrition was maintained
parenterally from postoperative days 2 to 8. The patient
was extubated on postoperative day 8 at an FIO2 of 0.4 and
PaO2 98.4 mmHg, transferred out of the intensive care unit
on postoperative day 10 and from the hospital on
postoperative day 18. Respiratory data showing ventilatory
settings and corresponding arterial blood gas values during
supine and prone ventilation are shown in Table 1; the
temperature, allowing the rectal temperature to drift up to
32°C, using a membrane oxygenator, roller pump,
crystalloid prime, blood cardioplegia and pulsatile flow
between 2.4 and 3.8 L/min/m2. The left internal mammary
artery was anastomosed to the left anterior descending
artery, the radial artery to the right coronary artery and
the reverse segment of the saphenous vein graft to the first
obtuse marginal artery. Pulsatile flows were maintained
between 2.4 and 3.28L/min/m2 and perfusion pressure was
maintained in the range of 50 to 70 mmHg. The patient
remained hemodynamically stable during the course of the
surgery. The duration of surgery was 4 hours and 40
minutes, with a cardiopulmonary bypass time of 68
minutes and aortic cross-clamp time of 45 minutes. Alpha
stat pH management was used and arterial blood gas reports
were within normal limits intra-operatively. The patient was
shifted to the recovery room with a negative fluid balance
of 700 ml.
The patient was ventilated electively by volumecontrolled ventilation with a Servo 300 ventilator (Siemens,
Elema, Solna, Sweden). On the first day, PaO2 was 58.8
mmHg at an FIO2 of 1.0, and chest X-ray showed haziness
in both the lower lung zones. Bronchoscopic suction was
done and repeated after 4 hours. Positive end-expiratory
pressure (PEEP) was gradually increased to 12.5 cmH2O.
Subsequently, the mode of ventilation was changed to
pressure-controlled inverse-ratio ventilation with full
sedation using midazolam and muscle relaxation with
vecuronium bromide.
Table 1. Various parameters of patient and ventilator setting during mechanical ventilation in the supine and prone
position
Position
Vent. Mode
Day 1
Supine
VC
Day 2
Supine Prone
PC
PC
Day 3
Supine
Prone
PC
PC
Day 4
Supine
PC
Day 5
Supine
Prone
PC
PC
Day 6
Supine
PC
FiO2
0.7
1.0
0.5
0.6
0.6
0.6
0.6
0.6
0.5
PEEP (cmH2O)
8
7.5
7.5
7.5
7.5
10
12.5
12.5
7.5
PIP
25
28
32
23
24
30
36
38
30
Insp.%
50%
50%
65%
60%
60%
60%
60%
60%
35%
Day 7
Supine
PC
Day 8
Postextubation
(4 hrs.)
PH
7.33
7.36
7.46
7.47
7.46
7.43
7.39
7.41
7.51
7.56
7.51
PaCO2 (mmHg)
45.1
53.8
42.4
40.4
49.5
47.9
54.3
48.3
46.6
35
36.8
PaO2 (mmHg)
58.8
57.8
249.7
48.7
194.6
74.1
62.5
199.7
67.8
69.3
92.4
BE
-2.4
-3.8
5.4
7.7
9.7
6.4
6.0
4.2
12.7
7.4
6.0
SaO2 (%)
94
90
99
86
99
95
93
98
93
96.6
98.2
PaO2/FiO2
84
57.8
499.4
81.16
324.3
123.5
104.1
332.8
135.6
173.2
230
Qva/QT (%)
36.0
43.6
7.2
46.7
12.5
VC: volume-controlled ventilation; PC: pressure-controlled ventilation; FiO2: inspired fraction of oxygen; PEEP: positive end-expiratory pressure; PIP: airway pressure;
Insp %: percentage of the inspiratory cycle of ventilation; PaCO2: arterial carbon dioxide tension; PaO2: arterial oxygen tension; BE: base excess; SaO2: arterial oxygen
saturation; PaO2/FiO2: oxygenation index; QVA/QT(%): shunt fraction
IHJ-884-00.p65
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4/10/01, 11:08 AM
Indian Heart J 2001; 53: 83–86
Firodiya et al.
single best arterial blood gas reading during each event
is shown.
Discussion
Acute respiratory failure is a rare but serious complication
after cardiac surgery. Oxygenation and carbon dioxide
elimination may be severely disturbed despite supplemental
inspired oxygen and ventilation with increased tidal volume
and respiratory frequency. The impairment of gas exchange
is most likely multifactorial including the effects of
sternotomy, ventilation perfusion inhomogeneity during
mechanical ventilation and an impaired pulmonary
capillary endothelium secondary to the release of
biologically active substances during extracorporeal
circulation (ECC).2 In addition, the effects of anesthesia and
muscle paralysis may contribute to gas exchange
impairment.2,3,4
Increased extravascular lung water content has been
proposed as a major cause for the development of
respiratory insufficiency after cardiac surgery. Some studies
show that elevated extravascular lung water content is
present only immediately after extracorporeal circulation
and in the early postoperative period.2,3,4 This suggests that
additional mechanisms play an important role in the
development of respiratory insufficiency.
Acute respiratory failure after cardiac surgery may be
associated with atelectasis in dependent lung regions, which
can be confirmed by computerized tomographic scans of
the thorax. Conventional ventilatory therapy with moderate
PEEP may be insufficient for the recruitment of collapsed
alveoli. Ventilation in the prone position rapidly improves
oxygenation without significant alteration of the
hemodynamic state. 2, 5–8 Nonetheless, it is a grossly
under-used technique, most likely because of the difficulty
in providing nursing and other care to patients in this
position.
Prone positioning results in a more uniform distribution
of pleural pressure gradients, resulting in greater
ventilation of the dependent lung than in the supine
position. 9,10 The hypotheses offered to explain the
improvement in oxygenation in the prone position include:
(1) increased functional residual capacity, (2) change in
regional diaphragmatic motion, (3) redistribution of
perfusion, and (4) better clearance of secretions. Animal
models of ventilation/perfusion distribution have suggested
that gravity has far less influence on the distribution of
perfusion in the prone position, and the distribution of blood
flow to various regions of the lungs is relatively unaffected
by the change from the supine to the prone position.2,7
IHJ-884-00.p65
3
Mechanical Ventilation in the Prone Position 85
Another possible explanation for the improvement
associated with ventilation in the prone position is improved
lymphatic flow. Almost all animals in nature lie prone when
they are recumbent. Hence, it is reasonable to assume that
lung lymphatics are evolved to drain the lung best in this
position.7 Although only minor complications could be
attributed to the prone position, careful positioning and
regular examination to avoid pressure bruises are
recommended. This patient had edema of the eyelid,
conjunctival edema and subconjunctival hemorrhage,
which resolved without treatment.
Patients who are 20% above their ideal body weight are
obese.11 When they are 100% above this weight they are
said to be morbidly obese.11 Patients with severe obesity
generally have hypoxemia with a widened alveolar–arterial
oxygen gradient due to ventilation–perfusion mismatch.
Alveolar collapse at the bases of the lungs contributes to
this phenomenon. Reduction in the functional residual
capacity in the supine position increases ventilation–
perfusion mismatch. Obese patients are therefore more
likely to develop atelectasis and other postoperative
pulmonary complications especially after upper abdominal
and cardiovascular surgery.11
Brussel et al.2 studied ten patients with acute respiratory
failure after CABG using conventional mechanical
ventilation in the supine and prone positions. Thoracic
computed tomography scans revealed crest-shaped bilateral
densities in the dependent lung regions in all the patients.
In the supine position, systemic and pulmonary pressures
were within the normal range, but oxygenation was severly
impaired. After 2–5 hours of ventilation in the prone
position, hemodynamic parameters did not differ between
the supine and prone positions, but ventilation in the prone
position improved gas exchange significantly. This
study concluded that mechanical ventilation in the prone
position might effectively recruit collapsed lung tissue and
improve oxygenation without major hemodynamic
consequences2.
In our case, after bronchoscopic suctioning, PEEP was
increased gradually to 12.5 cmH2O and pressure-controlled
inverse ratio ventilation was tried later. All these did not
improve the PaO2 of the patient. Chest X-ray (PA view) was
normal. Computed tomography scan of the chest could not
be done. Each time the patient was ventilated in the prone
position, oxygenation improved significantly although
hemodynamic parameters did not change.
We conclude that ventilation in the prone position is an
effective method for improving oxygenation in patients with
acute postoperative respiratory failure not responding to
different ventilatory strategies.
4/10/01, 11:08 AM
86 Firodiya et al.
References
1. Albert RK. Turnabout may be more than fair play. Crit Care Med 2000;
2: 571–572
2. Brussel T, Hachenberg T, Roos N, Lemzen H, Lokin P. Mechanical
ventilation in the prone position for acute respiratory failure after
cardiac surgery. J Cardiothorac Vasc Anesth 1993; 17: 541–546
3. Hachenberg T, Brussel T, Roose N. Gas exchange impairment and
pulmonary densities after cardiac surgery. Acta Anaesthesiol Scand
1992; 36: 800–805
4. Westaby S. Complement and the damaging effects of cardiopulmonary bypass. Thorax 1983; 38: 321–325
5. Langer M, Marcheroni D, Marcolin R. The prone position in ARDS
patients. A clinical study. Chest 1998; 94: 1003–1007
6. Gattinoni L, Pelospi P, Vitale G. Body position changes redistributes
lung computed-tomography density in patients with acute
IHJ-884-00.p65
Indian Heart J 2001; 53: 83–86
Mechanical Ventilation in the Prone Position
4
respiratory failure. Anesthesiology 1991; 74: 15–23
7. Lamm WJ, Graham MM. Mechanisms by which the prone position
improves oxygenation in acquired lung injury. Am J Respir Crit Care
Med 1994; 150: 184–193
8. Pelozi P, Croci M, Calappi E. The prone position during general
anesthesia minimally affects respiratory mechanisms while
improving functional residual capacity and increasing oxygen
tension. Anesth Analg 1995; 80: 955–980
9. Pelozi P, Tubiolo D, Mascheroni D. Effects of the prone position on
respiratory mechanics and gas exchange during acute lung injury.
Am J Respir Crit Care Med 1998; 157: 387–393
10. Dellinger RP. Inhaled nitric oxide versus prone positioning in acute
respiratory distress syndrome. Crit Care Med 2000; 28: 572–574
11. Fisher A, Waterhouse CD, Adams AP. Obesity: its relation to
anaesthesia. Anaesthesia 1975; 30: 633–634
4/10/01, 11:08 AM
Brief Report
Indian Heart J 2001; 53: 000–000
“Concertina” Effect during Angioplasty of Tortuous Right
and Left Coronary Arteries and Importance of Using
Over-the-Wire System: A Case Report
Pravin K Goel, Ajay Agarwal, Aditya Kapoor
Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow
A case wherein “Concertina” effect appeared during angioplasty of both right and left coronary arteries is
described. Also, the advantages of using an over-the-wire system in such cases are stressed especially when
extreme tortuosity and total occlusion are present together. (Indian Heart J 2001; 53: 87–90)
Key Words: Angioplasty, Stents, Coronary disease
“Concertina” or “accordion” effect is the appearance of
artefactual or pseudolesions during the course of
percutaneous transluminal coronary angioplasty (PTCA)
in tortuous vessels.1–3 The mechanism generally suggested
is the partial straightening of a tortuous coronary artery
by the coronary guidewire that causes mechanical
invagination of the coronary arterial wall at various sites.4–6
Those performing angioplasties must be familiar with the
appearance and mechanisms thereof, as failure to do so
may lead to inappropriate intervention with its attendant
risks.7–10 We describe a case in which the “concertina” effect
appeared during the course of balloon angioplasty of both
the right and left coronary arteries (RCA and LCA). The
advantages of using an over-the-wire (OTW) system in
arriving at a correct diagnosis and its successful
management are also highlighted.
Case Report
A 58-year-old diabetic male patient presented with effort
angina of recent onset. Coronary angiogram revealed an
extremely tortuous RCA with an initial shephard's crook
curve and total occlusion in the mid portion, immediately
after a second near-90° bend (Figs 1a and b). Faint
retrograde filling of the RCA through collaterals revealed
the distal vessel to be even more sinuous. The LCA was free
of significant disease except for a localized tight stenosis in
the proximal part of a tortuous Ramus type vessel. The left
Correspondence: Dr Pravin K Goel, Additional Professor of Cardiology,
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road,
Lucknow 226014, e-mail: [email protected]
IHJ-812-01.p65
1
ventricular function was normal. The patient was taken up
for balloon angioplasty of the RCA followed by that of the
Ramus.
Balloon angioplasty procedure: The RCA was intubated
using an 8 F AL 1 guiding catheter which gave good support.
A 0.014" high torque guidewire was first used to cross the
lesion pre-loaded in a 3.0×20 mm OTW balloon. The lesion,
however, could be reached only with great difficulty and
additional balloon support was required because of extreme
tortuosity in the proximal vessel. At this point, the floppy
wire failed to cross the lesion. The balloon was then left in
place just proximal to the lesion and the wire was changed
to 0.014" intermediate. When this also failed to negotiate
the lesion, the balloon was left at the same location and the
wire was changed to a standard one. The standard wire was
then able to negotiate the lesion, but passage beyond it was
difficult because of extreme distal tortuosity. The balloon
and wire were then pushed together so as to float across
the next bend (Fig. 2) but the duo also could not go further.
At this stage, the balloon was again left in place in the RCA
distal to the lesion, and the wire changed to 0.014" extra
support, which gave the added support needed at this time.
It was finally possible to get a stable wire position in the
distal RCA. The balloon was then pulled back to the site of
the lesion and inflated to the minimum pressure needed to
get rid of the waist, following which a sustained inflation
at low pressure of nearly 4 atm was maintained for about
two minutes. Post-balloon dilatation contrast injection
showed a patent RCA but multiple lesions appeared in the
distal RCA (Fig. 3). The patient neither complained of any
chest pain nor were there any ECG changes on the monitor.
4/10/01, 10:45 AM
88 Goel et al.
Administration of intracoronary nitroglycerin did not
reverse these lesions. At this stage, it was difficult to
ascertain whether these distal narrowings were true lesions
or the result of the so-called “concertina” effect due to
stiffness of the intracoronary wire. In this case, there was
no opportunity of knowing the pre-procedure disease status
of the distal RCA, which was a totally occluded vessel with
poor filling from collateral circulation. However, because
an OTW system was in place, we advanced the balloon over
the coronary wire well beyond the segment showing the
multiple lesions and the guidewire was pulled back into the
guiding catheter. This removed the wire effect without loss
of access to the distal vessel, the OTW balloon already being
in place far distal to the lesion. Repeat injection showed total
resolution of all lesions except one about 3 cm beyond the
original dilated site (Fig. 4). It was then realized that this
was the only true lesion amongst all the new narrowings
that had been noted after opening of the total occlusion and
it was balloon-dilatated at low pressure. The result was
assessed with a second pullback of the wire and the balloon
advanced as before so as to maintain access without the
wire effect. Once the result was thought to be satisfactory,
a 3.5×25 mm Multi Link stent was deployed at the site of
the original occlusion and the entire system was pulled
back. The final angiographic picture without the wire and
balloon showed an excellent result with a widely patent
but extremely tortuous RCA as seen in the left anterior
oblique (LAO) and right anterior oblique (RAO) views
(Figs 5a and b).
The LCA was intubated next using an 8 F JL 4 guiding
catheter (Fig. 6). The lesion was crossed using a 0.014" extra
support wire and a 3×20 mm OTW balloon. The lesion
required a single dilatation at 8 atm. Immediately, we noted
a similar “concertina” effect in the mid-portion of the artery,
as seen in the RCA, well beyond the dilated segment (Fig. 7).
However, as the status of the distal vessel was known from
the native LCA injection and our experience in the RCA, we
were confident that this was a reversible phenomenon
occurring due to relative straightening of the tortuous
artery by the extra stiff wire. This was, however,
reconfirmed by repeating the steps of balloon advancement
and wire withdrawal performed in the RCA. A 3.5×15 mm
Multi Link stent was deployed in the Ramus without further
delay. The final outcome was excellent (Fig. 8). The patient
was discharged after 24 hours and was asymptomatic at
six months follow-up. The follow-up angiogram done six
months later showed almost normal-looking vessels with
no restenosis.
IHJ-812-01.p65
Indian Heart J 2001; 53: 87–90
“Concertina” Effect during Angioplasty
2
Discussion
The appearance of an unexpected flow-limiting narrowing
during the course of coronary angioplasty is a cause for
great concern and requires rapid recognition and
appropriate management. Frequently recognized causes
include spasm, dissection, thrombus or embolization.
Appearance of pseudolesions, or the so-called “concertina”
or “accordion” effect is not uncommon but a less frequently
recognized cause for such an appearance. 4 Initially
described by Grewe et al.1 in an internal mammary graft
during PTCA of the native LAD, it has subsequently been
described in several sporadic reports.2–10 There is a recent
report of this occurring in a peripheral vessel during
angiography.11 Most case reports describe this appearance
during RCA angioplasty; the overall incidence is about 0.4
per cent.3 To the best of our knowledge, there have been no
reports describing the effect in both the RCA and LCA in
the same patient.
Mechanism: The basic mechanism for the appearance of
these pseudolesions is the straightening of a tortuous
coronary artery along its luminal axis by relatively
stiff intracoronary equipment, usually the guidewire,
running down its length.2,7–9 As the total length of the vessel
has to remain constant, unless the wire system is flexible
enough to take the turns and bends in the artery, the excess
vessel tissue heaps up or invaginates along its length leading
to the appearance of luminal encroachment, or at times,
even a circulatory delay.
Management: Although it was initially reported that
intracoronary nitroglycerin may “disinvaginate” the
coronary wall,5 it is now well known that nitroglycerin is
ineffective in relieving these lesions, thus effectively
distinguishing them from a true spasm of the artery.
It is vital to recognize the possibility of this “concertina”
or “accordion” effect, because the mistaken diagnosis
of a true new lesion by an unsuspecting operator may
call for unwarranted repeat dilatations, turning a
fully reversible phenomenon into a true iatrogenic
complication.
The recommended routine for these cases has been the
removal of all intracoronary material (including the
guidewire and the balloon) into the guiding catheter
to facilitate the vessel to reconform to its normal curvature
with consequent disappearance of the pseudolesions.3
However, the problem with this approach is that if there
were a true dissection, recrossing may be difficult and often
4/10/01, 10:45 AM
Indian Heart J 2001; 53: 87–90
Goel et al.
“Concertina” Effect during Angioplasty 89
1a
1b
2
3
4
5a
5b
6
7
Fig. 1. RCA injection in (a) RAO and (b) LAO views showing the shephard's crook bend and second near 90ºbend before total occlusion.
Fig. 2. Coronary wire and balloon being negotiated together down the vessel tortuosities once the site of total
occlusion had been crossed with the standard wire. The multiple bends are well appreciated.
Fig. 3. “Concertina” effect seen in the RCA with wire in the distal vessel after balloon dilatation.
Fig. 4. Right coronary injection with the wire pulled back into the guiding catheter and the balloon left in
distal RCA (arrow). All the psuedolesions are seen to disappear except one moderately severe stenosis (arrow)
immediately beyond the site of original occlusion.
Fig. 5. Final result in the RCA after stent deployment showing extreme tortuosity of the vessel as seen in (a)
LAO and (b) RAO views.
Fig. 6. Left coronary injection showing the tight lesion in the Ramus vessel and extreme tortuosity of the
distal vessel.
Fig. 7. Left coronary injection after wire placement and balloon dilatation showing “concertina” effect.
Fig. 8. Left coronary injection showing the final result after stent deployment and guidewire withdrawal.
8
not free from the hazard of creating another dissection in
these tortuous vessels with all its attendant risks. Chalet et
al.10 proposed that the guidewire could be cautiously
withdrawn up to a point where the floppy segment lies
IHJ-812-01.p65
3
equally on either side of the pseudolesion, allowing the
vessel to reconform to its normal shape and still retain
contact with the distal tip of the wire lying beyond the
lesion.
4/10/01, 10:45 AM
90 Goel et al.
Our technique, however, goes a step further. Firstly, it
involves no unprotected wire withdrawal, i.e. wire
withdrawal without the balloon already in place in the distal
vessel and this is possible only with an OTW system. This is
of help to interventionists especially because it avoids the
not so uncommonly encountered difficulty experienced by
most interventionists in re-negotiating a tortuous vessel at
times, in spite of reaching beyond the main lesion with the
tip of the wire. Secondly, often the pseudolesions or the
“concertina” effect may appear along a long segment of
the vessel, as in our case, wherein withdrawing the
guidewire partially (so as to leave only the floppy tip across
that site) may not suffice. Thirdly, the risk of withdrawing
the guidewire too far back always exists in a monorail
system if one tries the technique of balloon advancement
and wire pull-back.
The other major advantage of an OTW system in such
cases is the ease of wire exchange. As described by us, this
is not infrequently called for and then there is no need to
repeat the initial steps in wire passage, with the balloon in
place acting as a guide. Also, often it is these initial steps of
vessel selection and wire passage that may be the most
difficult in the case of extreme tortuosities and would not
only call for extra time but could also damage the vessel at
any point.
Conclusions: It is important for interventionists to be
aware of the reversible “concertina” or “accordion” effect
seen during angioplasty of extremely tortuous vessels. This
would help in avoiding inappropriate dilatations due to a
mistaken diagnosis of coronary dissection. We recommend
the elective use of an OTW system while dealing with
tortuous anatomy, especially with total occlusion added
when distal vessel disease status is not known. Also,
advancement of the balloon catheter over the guidewire
IHJ-812-01.p65
Indian Heart J 2001; 53: 87–90
“Concertina” Effect during Angioplasty
4
into the distal vessel well beyond the site of the “concertina”
effect followed by removal of the guidewire from the artery
leads to complete resolution of this phenomenon.
References
1. Grewe K, Presti CF, Perez JA. Torsion of an internal mammary graft
during percutaneous transluminal coronary angioplasty: a case
report. Cathet Cardiovasc Diagn 1990; 19: 195–197
2. Deligonul U, Tatineni S, Johnson R, Kern MJ. Accordion right coronary
artery: an unusual complication of PTCA guidewire entrapment.
Cathet Cardiovasc Diagn 1991; 23: 111–113
3. Rauh RA, Ninneman RW, Joseph D, Gupta VK, Senior DG, Miller WP.
Accordion effect in tortuous right coronary arteries during
percutaneous transluminal coronary angioplasty. Cathet Cardiovasc
Diagn 1991; 23: 107–110
4. Tenaglia AN, Tcheng JE, Phillips HR, Stack RS. Creation of
pseudonarrowing during coronary angioplasty. Am J Cardiol 1991;
67: 658–659
5. Shea PJ. Mechanical right coronary artery shortening and vessel wall
invagination – a fourth cause of iatrogenic coronary obstruction
during coronary angioplasty. Cathet Cardiovasc Diagn 1992; 26: 136–
139
6. Garnic DJ, Lee DW, Garza JL. Pseudodissection of the coronary artery:
a variation caused by interventional tools. Cathet Cardiovasc Diagn
1993; 29: 298–300
7. Doshi S, Shiu MF. Coronary Pseudolesions induced in the left anterior
descending and right coronary artery by the angioplasty guidewire.
Int J Cardiol 1999; 68: 337–342
8. Blankenship JC. Right coronary artery pseudotransection due to
mechanical straightening during coronary angioplasty. Cathet
Cardiovasc Diagn 1995; 36: 43–45
9. Hays JT, Stein B, Raizner AE. The crumpled coronary: an enigma of
arteriographic pseudopathology and its potential for misinterpretation. Cathet Cardiovasc Diagn 1994; 31: 293–300
10. Chalet Y, Chevalier B, el Hadad S, Guyon P, Lancelin B. “Pseudonarrowing” during right coronary angioplasty: how to diagnose
correctly without withdrawing the guidewire. Cathet Cardiovasc Diagn
1994; 31: 37–40
11. Joseph D, Idris M. Catheter-Induced “accordion effect” in tortuous
right external iliac artery during peripheral angiography. Cathet
Cardiovasc Diagn 1995; 34: 318–320
4/10/01, 10:45 AM
Brief Report
Indian Heart J 2001; 53: 000–000
Hemangioma of the Pericardium:
A Case Report
I Sathyamurthy, K Jayanthi, Rajan Santhosham
Department of Cardiology, Apollo Hospitals, Chennai
A 52-year-old male presented with dyspnoea on exertion. He was found to have a clinically normal cardiac
status and a mass lesion in the anterior mediastinum, probably arising from the pericardium near the right
atrium, as shown by both echocardiography and a computerized tomographic scan of the chest. He was
successfully operated. The histopathology of the mass revealed it to be a hemangioma of the pericardium. This is
one of the rare tumors of the pericardium and only a few cases have been reported in the literature. (Indian
Heart J 2001; 53: 91–92)
Key Words: Hemangioma, Pericardium, Tumors
A
number of primary and secondary neoplasms may
involve the pericardium. Secondary neoplasia is much
more common than primary tumors.1 Mesothelioma is the
most common primary pericardial neoplasm. We report a
case of one of the rare primary benign neoplasms –
hemangioma of the pericardium. The most common
manifestation is pericardial effusion. Raised jugular venous
pressure (JVP) and intrathoracic mass leads to a differential
diagnosis of the superior vena cava (SVC) syndrome.
Case Report
A 52-year-old male presented with constant retrosternal
chest discomfort of 10 years duration not associated with
dyspnoea, palpitation, cough or giddiness. He was a
hypertensive for nearly the same duration and was on βblockers and angiotensin-converting enzyme (ACE)
inhibitors. He had undergone a coronary angiography in
1997 which was reported as normal.
Clinically he was found to have normal heart sounds.
JVP was not raised and BP was 100/70 mm Hg. There was
no murmur, gallop or pericardial rub. Systemic examination
did not reveal any abnormality. Electrocardiogram revealed
sinus rhythm, normal QRS complexes and “T” inversion in
the anterolateral leads. An X-ray chest PA view (Fig. 1)
revealed a borderline increase in the cardiothoracic ratio
(60%) and normal lung fields.
A two-dimensional transthoracic echocardiogram
Correspondence: Dr I Sathyamurthy, Director, Department of Cardiology,
Apollo Hospitals, Chennai
IHJ-791-00.p65
1
(Fig. 2) revealed normal cardiac chamber dimensions and
contractility. The valves appeared to be normal. The left
ventricular ejection fraction was 75%. There was no
pericardial effusion. A circular solid mass measuring 5×4.5
cm was seen attached to the pericardium near the right
atrium. This mass was not compressing any of the cardiac
structures. It appeared to move with each cardiac cycle. A
computerized tomographic (CT) scan of the chest done
subsequently revealed a 5.9×5.5 cm noncontrast
enhancing anterior mediastinal mass (Figs 3a and b).
The patient underwent surgical excision of the mass
which was found to be attached to the epicardium over the
right ventricle (RV) and extended to the RV outflow tract
(Fig. 4). There were multiple feeders from the myocardial
vessels to the mass. Histopathological examination of the
excised mass revealed it to be a hemangioma (Figs 5a and b).
Fig. 1. X-ray chest PA view (preoperative).
4/10/01, 10:42 AM
Indian Heart J 2001; 53: 91–92
92 Sathyamurthy et al. Hemangioma of the Pericardium
Fig. 2. Preoperative echocardiographic appearance of the mass.
Fig. 4. Picture showing the well-delineated mass over the RV free wall at the
time of surgery.
Fig. 3 (a). Preoperative CT scan chest Fig. 3 (b). Preoperative CT scan chest
(plain) showing the mass.
(contrast) showing the mass.
Fig. 5 (a). Histological picture Fig. 5 (b). Histology of the mass
showing the large blood-filled spaces under low power microscopy.
lined by endothelium under high power
microscopy which is diagnostic of
hemangioma.
Discussion
Tumors of the heart, though uncommon, are potentially
fatal. Sometimes they can be entirely removed by surgery
with complete recovery. Prognosis is related to histological
features, localization, rapidity of growth, and early
diagnosis. Case reports of hemangioma of the pericardium
describe surgical excision as the treatment of choice and
complete recovery has been the rule. A case of a voluminous
angioma adherent to the pulmonary artery2 and another
of an epicardial hemangioma, 3 have been previously
reported. Patients with cavernous hemangioma located over
the RV free well and extending to the RV outflow tract,4,5
similar to the present case, have been reported from Japan.
Our patient also underwent successful surgical excision. The
postoperative period was uneventful and a repeat
echocardiogram did not show any mass.
IHJ-791-00.p65
2
References
1. Mukai K, Shinkai T, Tominaga K, Shimosato Y. The incidence of
secondary tumors of the heart and pericardium. A ten-year study.
Jpn J Clin Oncol 1988; 18: 195
2. Minutiello L. Intrapericardial angioma adhering to the trunk of
pulmonary artery. Diagnostic value of computerized axial
tomography. Minerva Cardioangiol 1996; 44: 319–323
3. Caires G, Canada M, Couveia R, Aguiar C, Lino JS, Martins AP, et al.
Hemangioma of the right ventricle Rev Port Cardiol 1997; 16:
561–567
4. Ashino Y, Koike K, Okada S, Tanita T, Fujimura S, Nakada T. A case of
hemangioma of the heart. Kyobu Geka 1989; 42: 1119–1121
5. Harada H, Hirata T, Utoh J, Kunitomo R, Hara M, Kitamura N. Cardiac
hemangioma of the right ventricle: report of a case. Jpn T Thorac
Cardiovasc Surg 1998; 46: 629–633
4/10/01, 10:42 AM
Brief Report
Indian Heart J 2001; 53: 0
Batista Procedure as a Bridge to Cardiac Transplantation
N Madhu Sankar, AR Baruah, Benjamin Ninan, S Rajan, KM Cherian
Institute of Cardiovascular Diseases, Chennai
A 37-year-old male patient with dilated cardiomyopathy and end-stage heart failure underwent Batista procedure.
After 6 months, he underwent orthotopic heart transplantation. Though he did not survive the procedure, we
conclude that Batista procedure may serve as a cost-effective biological bridge to cardiac transplantation. (Indian
Heart J 2001; 53: 93–94)
Key Words: Cardiomyopathy, Transplantation, Surgery
E
nd-stage heart failure is a major cause of morbidity and
mortality among patients with severe dilated
cardiomyopathy. Partial left ventriculectomy, introduced by
Randas Batista, is being increasingly performed to treat
these patients.1,2 Resection of a portion of the left ventricle
with consequent reduction in left ventricular cavity leads
to improvement in the function of the left ventricle. Clinical
reports from various centers have shown improvement in
heart failure symptoms after this procedure.3–7 However,
consequent to redilatation, heart failure tends to progress
in the follow-up period which makes the Batista procedure
more suitable as an interim measure, i.e. a biological bridge
to cardiac transplantation. We describe a case of severe
dilated cardiomyopathy with end-stage heart failure. The
patient underwent Batista procedure and, subsequently,
cardiac transplantation.
Case Report
A 37-year-old male patient with worsening breathlessness
due to dilated cardiomyopathy in the preceding 3 years was
admitted in our institute for evaluation and management.
Clinically, he had moderate mitral and tricuspid
regurgitation which was confirmed by two-dimensional
echocardiography. His coronary angiogram revealed ectatic
coronary arteries with no flow-limiting lesion. Radionuclide
scan showed severe left ventricular dysfunction with an
ejection fraction of 11%. The left ventricular internal
systolic diameter was 63 mm and the diastolic diameter was
70 mm. He was on maximal medical therapy which failed
to improve his symptomatic status and he was put on the
Correspondence: Dr N Madhu Sankar, Cardiothoracic Surgeon, Institute
of Cardiovascular Disases, 4A, J.J. Nagar, Mogappair, Chennai 600050
e-mail: [email protected]
IHJ-862-00.p65
1
cardiac transplant waiting list. His condition deteriorated
and he needed elective ventilation and inotropic support to
evade impending cardiac arrest. Considering his severe
symptomatic status and the nonavailability of a donor heart
for transplant, we decided to perform the Batista procedure
for symptomatic relief. He underwent partial left
ventriculectomy by excision of the left ventricular wall
between the two papillary muscles. The first obtuse
marginal branch of the left circumflex artery was sacrificed
in the resection, leaving the diagonals and the last obtuse
marginal branch intact. The ventriculotomy was closed in
two layers with pericardial buttressing suture. A posterior
annular plication with pericardial buttressing was done for
the mitral valve while a modified DeVega's annuloplasty was
performed for the tricuspid valve. The postoperative course
was uneventful and the patient was discharged on
postoperative day 10. Two-dimensional echocardiography
at the time of discharge revealed a left ventricular ejection
fraction of 22% with trivial mitral and tricuspid
regurgitation.
He was followed-up regularly and showed substantial
symptomatic improvement during the first three months.
Then his symptomatic status deteriorated gradually and the
ejection fraction decreased to 17% without any increase in
the severity of mitral or tricuspid regurgitation. The patient
being young and severely symptomatic, cardiac
transplantation was the only option available and he was
put on the transplant list again. With a suitable donor heart
being available, he underwent orthotopic cardiac
transplantation. Recipient cardiectomy was extremely
difficult due to the recent Batista procedure as the heart
was densely adherent to the pericardium. Longer operative
time was required with excessive bleeding and the heart was
so adherent that a portion of the ventricular muscle had to
4/10/01, 10:49 AM
94 Sankar et al.
be left behind. He was shifted to the intensive care unit with
inotropic support. He continued to bleed in the postoperative
period leading to hemodynamic instability. Over the next
seven days, he remained in low output failure and then
succumbed to low cardiac output and multiple organ
failure.
Discussion
The Batista procedure offers a new hope for patients with
dilated cardiomyopathy and end-stage heart failure. Filho
et al.8 have described their experience with the Batista
procedure in 15 patients and concluded that this procedure
improved the quality of life in the majority of patients and
acted as a bridge to cardiac transplantation when donors
are not available. McCarthy and Sabik from Cleveland
Foundation have reported their experience with 53 patients:
1.9% perioperative mortality, 15% required left ventricular
assist-device support, and 72% did not require re-listing for
heart transplant. 9 Based on their experience with
ventricular remodelling surgery, Starling et al.6 have
concluded that this procedure may delay or supplant the
need for heart transplantation in selected patients. Takeshita
et al.7 have performed angiographic– hemodynamic studies
in 24 patients who underwent the Batista operation and
suggested that it reverses heart failure by reducing both
systolic and diastolic LV volume in selected patients
immediately after surgery.
Cardiac transplantation has evolved to become a highly
effective therapy in patients with dilated cardiomyopathy
and end-stage heart failure. Lack of sufficient donors and
socio-economic constraints associated with heart
transplant still remain a challenge. In this scenario, left
ventricular assist-devices may serve as a bridge to
IHJ-862-00.p65
Indian Heart J 2001; 53: 93–94
Batista Procedure
2
transplant, as an alternative to transplant or as a bridge to
recovery. These bridging devices rearrange patient priority
for transplantation and provide a reasonable quality of life
for extended periods.9 Despite the fact that the patient died
after cardiac transplant, we conclude that the Batista
procedure may serve as a cost-effective biological bridge to
transplant in patients with dilated cardiomyopathy and endstage heart failure.
References
1. Batista RJ, Santos JL, Takeshita N, Bocchino L, Lima PN, Cunha MA.
Partial left ventriculectomy to improve left ventricular function in
end-stage heart disease. J Card Surg 1996; 11: 96–97
2. Batista RJ, Verde J, Nery P, Bocchino L, Takeshita N, Bhayana JN, et
al. Partial left ventriculectomy to treat end-stage heart disease. Ann
Thorac Surg 1997; 64: 634–638
3. McCarthy JF, McCarthy PM, Starling RC, Smedira NG, Scalia GM,
Wong J, et al. Partial left ventriculectomy and mitral valve repair for
end stage congestive heart failure. Eur J Cardiothorac Surg 1998; 13:
337–343
4. Moreira LF, Stolf NA, Bocchi EA, Bacal F, Giorgi MC, Parga JR, et al.
Partial left ventriculectomy with mitral valve preservation in the
treatment of patients with dilated cardiomyopathy. J Thorac Cardiovasc
Surg 1998; 15: 800–807
5. Left ventricular reduction surgery (Society Position Paper). Ann Thorac
Surg 1997; 63: 909–910
6. Starling RC, Young JB, Scalia GM, Thomas JD, Vargo RL, Buda TM, et
al. Preliminary observations with ventricular remodelling surgery
for refractory congestive heart failure. (Abstr) J Am Coll Cardiol 1997;
29: 64A
7. Takeshita N, Kawaguchi AT, Lima PN, Bocchino L, Verde JL, Batista
JV. Hemodynamic changes in patients undergoing left ventricular
diameter reduction (Batista operation) (Abstr). J Am Coll Cardiol 1997;
29: 64A
8. Filho F, Pereira WM, Leases PE. End-stage heart disease: Is there a
role for Batista operation? Presented at International Meeting:
Surgical options for end stage heart failure. Bergamo, Italy, 1996
9. McCarthy PM, Sabik JF. Implantable circulatory support devices as a
bridge to heart transplantation. Semin Thorac Cardiovasc Surg 1994;
6: 174–180
4/10/01, 10:49 AM
Brief Report
Indian Heart J 2001; 53: 000–000
Aortic Valve Balloon Dilatation in a Newborn for Critical
Aortic Stenosis Diagnosed During Fetal Life
A Saxena, N Naik, R Juneja
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
A young primigravida was diagnosed to have a fetus with critical aortic stenosis at 30 weeks' gestation. A decision
to follow-up the fetus till term was taken as there was no evidence of congestive heart failure. Post-natal retrograde
aortic valve balloon dilatation was performed 36 hours after birth. There was marked improvement in left
ventricular function and the baby is doing well at 1-year follow-up. The need for accurate assessment of
intracardiac anatomy during fetal life in critical aortic stenosis and its impact on therapeutic interventions is
highlighted. (Indian Heart J 2001; 53: 95–96)
Key Words: Stenosis, Balloon, Valvuloplasty
F
etal echocardiography has enhanced the diagnostic
armamentarium of congenital heart disease (CHD). It
has permitted accurate prenatal assessment of cardiac
anatomy and functional significance of various lesions. It
has also made an impact, although modest, in prenatal
therapy.1 Due to various technical limitations, interventions
in fetal life have not been very successful. However, fetal
echocardiography, in combination with an appropriately
guided postnatal approach, can be used effectively in
treating severe forms of CHD. We report a case in which
diagnosis of a critical lesion during fetal life helped in
planning treatment in the neonatal period.
Case Report
A 21-year-old primigravida was incidentally diagnosed
to have a fetus with critical aortic stenosis (AS) at 30
weeks' gestation on obstetric ultrasound. A detailed
echocardiography done at our center revealed that the fetus
had a unicuspid aortic valve with a poorly contractile left
ventricle. The gradient across the valve was 25 mmHg. The
estimated fetal weight was 1.2 kg. Since there was no
evidence of congestive heart failure in the form of hydrops
fetalis, a decision to continue the pregnancy was taken and
the baby was delivered normally at 39 weeks. The birth
weight was 2.2 kg and Apgar score was 9 at both one and
five minutes. Postnatal echocardiography confirmed the
diagnosis of critical AS by demonstrating doming of the
aortic valve with a very thin streak of antegrade flow on
color Doppler (Fig. 1). The aortic annulus measured 4.2 mm
Correspondence: Dr Anita Saxena, Professor of Cardiology, All India
Institute of Medical Sciences, New Delhi
IHJ-906-00.p65
1
and although the gradient was only 20 mmHg across the
aortic valve, it was considered significant due to associated
severe left ventricular dilatation and dysfunction with an
estimated ejection fraction of only 15%–20%. At 24 hours
after birth, the baby developed hypotension with poor
peripheral perfusion and was put on prostaglandin E1 to keep
the ductus arteriosus open, thereby maintaining the
systemic circulation. Aortic valve balloon dilatation was
done 36 hours after birth by the retrograde transfemoral
route using a 5 mm balloon (Figs 1 and 2). The transaortic
gradient, which was only 10–15 mmHg prior to balloon
dilatation, was totally abolished. There was no aortic
regurgitation following balloon dilatation on the aortic root
angiogram (Fig. 2). The lower limb pulses on the side of
catheterization returned 6 hours after the procedure
following one dose of intravenous heparin. The baby
continued to require inotropic support and prostaglandin
E1 infusion for two more days to maintain the blood pressure
and peripheral perfusion after which this support was
weaned off. He made a gradual recovery and was discharged
from the hospital after 10 days and placed on decongestive
therapy and angiotensin converting enzyme inhibitors. The
left ventricular ejection fraction at the time of discharge was
35% and the gradient across the aortic valve was 8 mmHg.
The infant is now on follow-up for 13 months and the last
echo-Doppler showed a left ventricular ejection fraction of
47% with a transaortic gradient of 6–8 mmHg.
Discussion
Critical AS in the neonate represents the favorable end of
the spectrum of hypoplastic left heart syndrome.2 Patients
4/10/01, 11:17 AM
96 Saxena et al.
Indian Heart J 2001; 53: 95–96
Aortic Valve Dilatation in a Newborn
Fig. 1. Aortic root angiogram in left anterior oblique view showing a very thin
negative jet due to severe aortic valve stenosis.
Fig. 2. Balloon across the aortic valve during the dilatation procedure.
with aortic atresia, mitral atresia and hypoplastic left
ventricle have a poorer prognosis with extremely high
mortality rates and widely divergent therapeutic options.
These patients are either chosen for single ventricle repair
(Stage 1 Norwood or Fontan) or cardiac transplantation.
Those with isolated critical AS without hypoplastic left
ventricle represent a select group in whom the clinical
outcome can be favorably altered. Deterioration in these
infants, however, can be extremely rapid once the ductus
arteriosus starts closing as their systemic blood flow cannot
be maintained then. Therapeutic intervention is required
immediately in the neonatal period in those with ductusdependent systemic circulation. These neonates require
intensive care with correction of metabolic acidosis
resulting from low cardiac output and prostaglandin E1 to
maintain ductal patency.3
Transvenous balloon dilatation has been shown to be as
efficacious as surgical treatment in terms of appearance of
aortic regurgitation and relief of transvalvular gradient.
Moreover, the early and mid-term results after neonatal
aortic valve balloon dilatation have been shown to be good,
with survival rates better than those of the surgical series.4
Both the retrograde and antegrade routes have been
employed, though the latter method is technically more
demanding.5 Besides the femoral artery, the umbilical
artery, transcarotid approach and subscapular artery
cutdown have been used for retrograde approach to the
valve. Loss of the femoral artery pulse is a common
complication after this procedure which is now seen less
frequently with the use of low-profile catheters.
The need for an accurate assessment of cardiac anatomy
in the fetus with aortic stenosis cannot be overemphasized.
Therapeutic options and their timing are guided by fetal
echocardiography. Fetuses with a small fossa ovalis,
endocardial fibroelastosis, poor left ventricular function,
other obstructive lesions on the the left side and right
ventricular dysfunction have a poor prognosis. Absence of
growth of the left ventricle on serial echocardiographic
examination also carries a poor prognosis.6 It is imperative
to differentiate aortic stenosis from a primary
cardiomyopathy of the left ventricle. The presence of a
normal aortic valve with no Doppler gradient across it and
the absence of post-stenotic dilatation go against critical
aortic stenosis. In addition, it should be recognized that the
peak gradient alone does not reflect the severity of
obstruction across a valve. Severe left ventricular
dysfunction and prostaglandin E1 may markedly reduce
gradient across the aortic valve in critical AS. In this
situation, the width of the stenotic jet may help in assessing
the true significance of valvular stenosis.
In conclusion, the diagnosis of a critical cardiac lesion
during fetal life by echocardiography helps in the optimal
management of the baby. At the appropriate time, the
mother can be transferred to a center suitably equipped for
managing these newborns.
IHJ-906-00.p65
2
References
1. Kohl T, Sharland G, Allan LD, Gembruch U, Chauoi R, Lopes LM, et
al. World experience of percutaneous ultrasound-guided balloon
valvuloplasty in human fetuses with severe aortic obstruction. Am J
Cardiol 2000; 85: 1230–1233
2. Freedom RM. Balloon therapy of critical aortic stenosis in the
neonate: the therapeutic conundrum resolved? Circulation 1989; 80:
1087–1088
3. Leoni F, Huhta JC, Mackey R, de Leval R, Mac Cartney FJ, Stark J.
Effect of prostaglandin on early surgical mortality in lesions of the
systemic circulation. Br Heart J 1984; 52: 654–659
4. Egito ES, Moore P, O'Sullivan J, Colan S, Perry SB, Lock JE, et al.
Transvascular balloon dilatation for neonatal critical aortic stenosis:
early and midterm results. J Am Coll Cardiol 1997; 29: 442–447
5. Magee AG, Nykanen D, McCrindle BW, Wax D, Freedom RM, Benson
LN. Balloon dilatation of severe aortic stenosis in the neonate:
comparison of anterograde and retrograde catheter approach. J Am
Coll Cardiol 1997; 30: 1061–1066
6. Hornberger LK, Sanders LP, Rein AJ, Spevak PJ, Parness IA, Colan
SD. Left heart obstructive lesions and left ventricular growth in the
mid-trimester fetus: a longitudinal study. Circulation 1995; 92: 1531–
1538
4/10/01, 11:17 AM
Brief Report
Coronary Sinus Diverticulum with a Concealed
Posteroseptal Accessory Pathway: A Red Herring?
Anup Gupta, Amit M Vora, Yash Lokhandwala
Department of Cardiology, King Edward VII Memorial Hospital, Mumbai
A 21-year-old male presented with episodes of paroxysmal tachycardia mediated via a concealed posteroseptal
accessory pathway. He was also found to have a diverticulum of the coronary sinus. However, successful
radiofrequency ablation was achieved only endocardially under the mitral annulus and not within the
diverticulum. (Indian Heart J 2001; 53: 97–99)
Key Words: Radiofrequency ablation, Tachyarrhythmias, Conduction
C
oronary sinus (CS) anomalies such as diverticulum,
enlarged CS ostia and persistent left superior vena cava
(SVC) are found in 9% of patients with supra-ventricular
tachycardia.1 Diverticulum of the proximal CS is found in
7% of patients with manifest accessory pathways (APs),1–2
but have not been reported in those with concealed APs. In
patients with overt posteroseptal APs and CS diverticula,
the successful ablation site has always been found to be
epicardial, within the CS diverticulum, usually in the neck.3
We report a unique case of concealed left posteroseptal
AP and diverticulum of the CS in which successful
radiofrequency (RF) ablation could be achieved only
endocardially.
Case Report
Ventricular extra stimuli reproducibly induced orthodromic
atrioventricular re-entrant tachycardia using the left
posteroseptal AP in a retrograde direction. A 4 mm distal
tip quadripolar (Cordis–Webster) thermocouple small-curve
catheter was used for mapping. The earliest atrial activation
during ventricular pacing and orthodromic tachycardia
along the mitral annulus did not reveal early activation. At
this stage, a left coronary arteriogram was performed which
revealed a CS diverticulum, appreciated in the venous phase.
The CS angiogram confirmed a wide-mouthed, globular
diverticulum (Figs 1a and b). The mapping was performed
during orthodromic tachycardia. Mapping inside the
diverticulum showed the earliest atrial activation to be later
than the earliest activation in the decapolar catheter placed
in the coronary sinus (Fig. 2). Attempts at RF ablation along
the neck and body of the diverticulum were unsuccessful.
A 21-year-old man presented with three episodes of
paroxysmal palpitations associated with presyncope
requiring hospitalization. Adenosine successfully
terminated the narrow QRS tachycardia. The sinus rhythm
ECG was normal with no suggestion of pre-excitation.
Clinical examination, chest X-ray and echocardiography
were normal. He underwent electrophysiological study
(EPS) with a view to identify the mechanism of tachycardia
and for RF ablation.
EPS was performed using an EMS computerized system
(CARIM, Maastricht, The Netherlands). A deflectable
decapolar (Cordis–Webster) catheter was placed in the
coronary sinus, a quadripolar (Josephson curve) catheter
was placed in the His bundle region and right ventricle.
Correspondence: Dr Y Lokhandwala, Department of Cardiology, KEM
Hospital, Parel, Mumbai 400012. e-mail: [email protected]
IHJ-851-00.p65
1
Fig. 1a. Coronary sinus angiogram in 45° LAO view, showing globular
dilatation at the coronary sinus ostia suggestive of coronary sinus diverticulum
(arrow).
4/10/01, 10:47 AM
98 Gupta et al.
Indian Heart J 2001; 53: 97–99
Coronary Sinus Diverticulum
Fig. 1b. Coronary sinus angiogram in 30° RAO view, showing coronary sinus
diverticulum (arrow).
Fig. 3a. Site of RF ablation in 45° LAO view, showing the position of the
ablation catheter (arrow).
Fig. 3b. Site of RF ablation in 30° RAO view, showing the position of the
ablation catheter outside the coronary sinus diverticulum (arrow).
Fig. 2. Recording from inside the diverticulum (RFd) during orthodromic
tachycardia. The decapolar catheter was partly outside the coronary sinus as
seen in Figure 1a; CS56 electrodes are situated at the coronary sinus ostium.
The earliest atrial activation is seen in CS34, which is just within the coronary
sinus. The atrial activation in the mapping catheter (RFd) is later than that in
CS34.
IHJ-851-00.p65
2
Retrograde transaortic mapping was repeated and the
earliest activation was seen adjacent to the distal end of
the diverticulum (Figs 3a and b). At this site, there was a
clear pathway potential which preceded the earliest atrial
activation in the decapolar catheter (Fig. 4). Successful RF
ablation of the left posteroseptal pathway was performed
at this endocardial site; the tachycardia terminated within
5 seconds of starting the RF energy. Ventriculo-atrial (VA)
dissociation was seen after the RF ablation. After ablation,
a vigorous stimulation protocol, with isoprenaline as well,
failed to induce tachycardia.
Discussion
While enlargement of the CS ostium has been reported in
5% of patients with atrioventricular nodal re-entrant
4/10/01, 10:47 AM
Indian Heart J 2001; 53: 97–99
Gupta et al.
Coronary Sinus Diverticulum
99
tachycardia (AVNRT),2 diverticulum of the proximal CS is
associated with manifest posteroseptal APs. These APs are
difficult to ablate endocardially outside the diverticulum and
successful ablation is often performed from within the
diverticulum. Thus CS angiography is suggested prior to
catheter ablation of posteroseptal APs, especially when
endocardial signals are not optimal.4
Our patient was unique, with a CS diverticulum and
concealed AP as opposed to manifest pre-excitation. Also,
the site of successful ablation was endocardial, under the
mitral annulus, and not within the diverticulum. Thus the
CS diverticulum, as a misleading "red herring", was a purely
incidental finding in our patient.
References
Fig. 4. Recording from the endocardial site shown in Fig.3, during orthodromic
tachycardia. The mapping catheter (RFd) shows an accessory pathway potential
which clearly precedes the atrial activation in CS34.
IHJ-851-00.p65
3
1. Weiss C, Cappato R, Willems S, Meinertz T, Kuck KH. Prospective
evaluation of the coronary sinus anatomy in patients undergoing
electrophysiology study. Clin Cardiol 1999; 22: 537–543
2. Tebbenjohanns J, Pfeiffer D, Schumacher B, Jung W, Manz M, Luderitz
B. Direct angiography of the coronary sinus: impact on left
posteroseptal accessory pathway ablation. Pacing Clin Electrophysiol
1996; 19: 1075–1081
3. Tebbenjohanns J, Pfeiffer D, Schumacher B, Jung W, Manz M, Luderitz
B. Radiofrequency catheter ablation of a posteroseptal accessory
pathway within a coronary sinus diverticulum. Am Heart J 1993;
126: 1216–1219
4. Schumacher B, Tebbenjohanns J, Pfeiffer D, Omran H, Jung W,
Luderitz B. Prospective study of retrograde coronary venography in
patients with posteroseptal and left-sided accessory atrioventricular
pathways. Am Heart J 1995; 130: 1031–1039
4/10/01, 10:47 AM
Brief Report
Fatal Atypical Mycobacterial Infection in a Cardiac
Transplant Recipient
Ruma Ray, Soumitesh Chakravorty, Jaya S Tyagi, B Airan, KK Talwar,
P Venugopal, P Chopra
Departments of Pathology, Biotechnology, Cardiology and Cardiothoracic Surgery,
All India Institute of Medical Sciences, New Delhi
A 37-year-old female underwent heart transplantation for giant cell myocarditis. The patient died within threeand-a-half months of cardiac transplantation. Postmortem specimens from the heart and lung showed multiple
necrotizing granulomas with numerous acid-fast bacilli. Polymerase chain reaction done on both the postmortem
samples confirmed the presence of atypical mycobacterial infection. This fatal case of atypical mycobacteriosis
in a cardiac transplant patient is reported for its rarity. (Indian Heart J 2001; 53: 100–103)
Key Words: Transplantation, Infection, Myocarditis
G
iant cell myocarditis (GCM) is a rare and frequently fatal
disorder of unknown origin that is defined
histopathologically as diffuse myocardial necrosis with
multinucleated giant cells in the absence of sarcoid-like
granulomas.1,2 Cardiac transplantation is the treatment of
choice though the disease is known to recur in the donor
heart.2 Occurrence of atypical mycobacterial infection in
a cardiac transplant recipient is rare. We present a fatal case
of atypical mycobacterial infection in a cardiac transplant
recipient who underwent heart transplantation for GCM.
Case Report
This 37-year-old female was clinically diagnosed as dilated
cardiomyopathy. Pre-transplant endomyocardial biopsy
revealed non specific features, e.g. mild focal thickening of
the endocardium, myocyte hypertrophy with nucleomegaly
and sarcoplasmic degenerative changes. There was no
myocarditis in the material examined. The patient
underwent orthotopic cardiac transplantation for
intractable cardiac failure. In the postoperative period, the
patient was on immunosuppressive therapy with
cyclosporin, azathioprine and prednisolone. Four
endomyocardial biopsies were taken on days 10, 20, 30 and
60 following transplantation. The first two biopsies revealed
acute rejection of grade IA (ISHLT). The third biopsy showed
focal ischemic changes while the fourth one showed
interstitial fibrosis and myocyte hypertrophy. The patient
Correspondence: Dr Ruma Ray, Assistant Professor, Department of
Pathology, All India Institute of Medical Sciences, New Delhi 110029
IHJ-865-00.p65
100
expired on day 100 following transplantation. Postmortem
biopsies from the heart and left lung were taken for
pathological examination.
Pathology:
The native heart: The heart weighed 235 g. Due to the
operative technique, parts of both the atria and outflow
tracts of the ventricles were not included in the specimen.
On external examination, the pericardial surface showed a
few small 0.1–0.2 cm grey-white necrotic areas. On opening
the heart, part of the right atrium included in the specimen
and the tricuspid valve were normal. The right ventricular
cavity had focal endocardial thickening which was
especially prominent over the septal wall. The inflow tract
of the right ventricle just beneath the tricuspid valve had a
Fig. 1. Photomicrograph from the explanted native heart showing necrosis,
lymphohistiocytic infiltrate and giant cells. (H&E×180)
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Indian Heart J 2001; 53: 100–103
thrombus, 0.5 cm in diameter. The left atrium and the mitral
valve were normal. The left ventricular cavity was dilated
and showed diffuse endocardial thickening. The ventricular
myocardium had multiple small grey-white areas 0.1–0.2
cm in diameter. Segments of the epicardial coronary arteries
included in the specimen were normal.
On light microscopic examination, multiple sections
from all the chambers showed large areas of myonecrosis
and lymphohistiocytic infiltrate with numerous giant cells
(Fig. 1). There was endocardial thickening, widespread
myocyte degeneration and focal replacement fibrosis. No
definite epithelioid cell granuloma was noted. Periodic acid
Schiff and silver methenamine stains for fungus did not
demonstrate any fungal profile. Ziehl–Neelsen and
auramine–rhodamine stains for acid-fast bacili were
negative. The coronary arteries were histologically normal.
In view of the presence of numerous giant cells with
myonecrosis in the absence of distinct sarcoid-like
granulomas, the diagnosis of giant cell myocarditis was
considered.
Postmortem biopsy specimens: Postmortem biopsy samples
included tissues from the donor heart and the left lung of
the patient. On light microscopic evaluation, the
endocardium was normal. The myocardium revealed nonspecific changes like myofibre hypertrophy and focal
interstitial edema. The pericardium had multiple discrete
necrotizing granulomas showing central necrosis with a few
epithelioid and giant cells. Sections from the lung showed
similar epithelioid cell granulomas (Fig. 2). Ziehl–Neelsen
stain for acid-fast bacilli demonstrated numerous acid-fast
Myobacterium tuberculosis-like organisms both in the
pericardial and pulmonary granulomas. No fungal profile
or inclusion of cytomegalovirus infection was identified in
Ray et al.
Fatal Atypical Mycobacterial Infection
101
the specimen examined. A diagnosis of tuberculosis
involving the pericardium and lung was suggested.
Subseqently samples from the explanted native heart (on
which the diagnosis of GCM was earlier made) and
postmortem biopsies from the heart and lung (histologically
diagnosed as tubercular) were subjected to polymerase
chain reaction (PCR) analysis for the detection of
Mycobacteria in general and M. tuberculosis in particular.
Polymerase chain reaction:
Analysis of the native heart and postmortem samples: Samples
for PCR were retrieved in the form of scrapings of paraffinembedded tissue from paraffin blocks and transferred to
1.5 ml polypropylene tubes (Axygen Inc.). The samples were
deparaffinized by extraction with xylene. Residual xylene
was removed by extraction with 100% ethanol, tissue pellets
were dried using acetone and DNA was extracted using 10%
chelex 100.3 Polymerase chain reaction was performed with
the supernatant as follows:
(1) 23 S rDNA PCR assay specific for genus4 Mycobacterium
was done. An amplification product of 174 bps was seen
as expected in the postmortem lung (Fig. 3a) and donor
Fig. 3a. Amplification of mycobacterial DNA from paraffin-embedded lung
tissue. Amplification reaction products were electrophoresed and visualized by
ethidium bromide staining. Lane M, molecular weight marker; lanes 1 and 2,
DNA from postmortem lung tissue (undiluted and 1:10 dilution, respectively);
lane 3, DNA-negative control; lane 4, M. tuberculosis DNA-positive control;
lane 5, M. tuberculosis DNA-positive control; lanes 6 and 7, DNA-negative
control.
Fig. 2. Photomicrograph from the lung showing epithelioid cell granuloma with
Langhan's giant cells. (H&E×180)
IHJ-865-00.p65
101
Fig. 3b. Amplification of mycobacterial DNA from paraffin-embedded heart
tissue. Amplification reaction products were electrophoresed and visualized by
ethidium bromide staining. Lane M, molecular weight marker; lane 1, DNA
isolated from implanted donor heart tissue (postmortem); lane 2, DNA isolated
from explanted native heart; lane 3, M. tuberculosis DNA-positive control;
lane 4, DNA negative-control; lane 5, DNA isolated from implanted donor heart;
lane 6, M. tuberculosis DNA-positive control; lane 7, DNA-negative control.
4/10/01, 10:58 AM
102 Ray et al.
heart (Fig. 3b) samples, indicating the presence of an
organism belonging to the genus Mycobacterium. PCR
failed to amplify 23 S rDNA sequences from the
explanted native heart (Fig. 3b) and thereby, the
possibility of tuberculosis in the native heart could be
ruled out.
(2) DevR-based PCR assay was not performed in the
explanted heart tissue as the 23 S rDNA-based genusspecific PCR assay failed to amplify mycobacterial DNA
(Fig. 3b). Following step 1, devR-based PCR was
performed in the postmortem samples from the lung and
donor heart. This assay generates a 513 bps DNA
product specific for M. tuberculosis5 which was negative
in these samples (Figs 3a and 3b). The positivity of
23 S rDNA assay and a negative M. tuberculosis complexspecific assay suggested the presence of nontubercular
Mycobacteria (atypical Mycobacteria) in the postmortem
samples of the heart and lung. The causative
mycobacterial species could not be identified further due
to the nonavailability of species-specific PCR for assays
of nontubercular Mycobacteria in our PCR laboratory.
Discussion
Cardiac transplantation is an accepted therapeutic modality
in patients with intractable heart disease. GCM is a rare
disorder characterized histologically by the presence of
diffuse inflammatory infiltrates with multinucleated giant
cells in the absence of sarcoid-like granulomas. Cardiac
transplantation is a recommended therapeutic procedure
in this condition as the disease is otherwise fatal. 2,6
Histological examination of the explanted native heart in
the present case revealed myocardial necrosis with
lymphohistiocytic infiltrate and giant cells. There was no
obvious granulomatous reaction or presence of acid-fast
bacilli and thus the diagnosis of GCM was made.
In the post-transplant period, the patient underwent
episodes of acute rejection and finally succumbed to
disseminated atypical mycobacterial infection involving
the heart and lungs. While examining the pathological
material from transplant recipients, the possibility of
infection should always be considered as these patients are
immunosuppressed. The two most common infections
which can be identified and diagnosed on endomyocardial
biopsy are cytomegalovirus infection and toxoplasmosis.7
Though tuberculosis has occasionally been described in
cardiac transplant recipients,8,9 the occurrence of atypical
mycobacterial infection in such patients is distinctly rare.10
The incidence of tuberculosis among patients undergoing
antirejection therapy is considerably higher than that in the
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Fatal Atypical Mycobacterial Infection
102
general population and heart transplant recipients have
been found to carry the highest risk of tuberculosis.9
Though infections due to nontubercular Mycobacteria in
solid organ transplant recipients are infrequent, they may
be a major cause of morbidity in such patients. The reported
prevalence of disease in a heart transplantation program
due to nontubercular Mycobacteria is 0.24%. In the
disseminated form of the disease, the lungs and
subcutaneous tissue are commonly involved. Intestinal
involvement has rarely been reported in the literature.11 Our
patient is unique as she had a fatal outcome due to atypical
mycobacterial infection involving the lungs and heart
within 100 days of transplantation. Other organs could not
be examined as an autopsy was not conducted on the
patient.
A high degree of clinical suspicion of tubercular
infection is required in cardiac transplant recipients and the
diagnosis needs to be confirmed by histological examination
and/or cultures. Postmortem specimens from the heart and
lung in the present case revealed multiple small necrotizing
granulomas. Ziehl–Neelsen stain demonstrated numerous
acid-fast bacilli and a provisional diagnosis of tuberculosis
was offered. The final diagnosis of nontubercular
mycobacterial infection could only be made following PCR
analysis of tissues retrieved from the paraffin block as the
genus-specific PCR product was amplified without
amplification of M. tuberculosis DNA. Polymerase chain
reaction has revolutionized the entire spectrum of
molecular biology as it can offer rapid definitive diagnosis
of an infective organism including its species specification
and antibiotic resistance profile. Retrieval of tissue from
paraffin-embedded material and subsequent PCR analysis
can provide an accurate etiological diagnosis even when the
culture report is not available to the pathologist, as in the
present case. While examining the postmortem specimens,
we had a re-look at the original diagnosis of GCM made on
the explanted native heart. The possibility of undiagnosed
mycobacterial infection with widespread necrosis and giant
cell reaction could be ruled out due to the absence of
granulomas, negative Ziehl–Neelsen and auramine–
rhodamine staining and non-amplification of genus-specific
PCR product on retrospective PCR analysis. Thus, heart
transplantation should be considered an unheralded risk
factor for mycobacterial infection, particularly in countries
such as India where the disease is prevalent.
References
1. Cooper LT, Berry GJ, Rizeq M, Schroeder JS. Giant cell myocarditis. J
Heart Lung Transplant 1995; 14: 394–401
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2. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant cell myocarditis—
natural history and treatment. N Engl J Med 1997; 336: 1860–1866
3. Lambeverie X de, Zandotti C, Vigneli C, Bollet C, de Micro PA. Onestep microbial DNA extraction method using "Chelex-100" suitable
for gene amplification. Res Microbiol 1992; 143: 785–790
4. Verma A, Rattan A, Tyagi JS. Development of a 23 S rRNA-based
PCR assay for detection of Mycobacteria. Indian J Biochem Biophys
1994; 31: 288–294
5. Singh KK, Navi MD, Radha Krishnan K, Tyagi JS. Utility of PCR assay
in the diagnosis of en-plaque tuberculoma of the brain. J Clin Microbiol
1997; 37: 467–470
6. Laruelle C, Vanhaecke J, Van de Werf F, Flameng W, Verbaken E,
Meyns B, et al. Cardiac transplantation in giant cell myocarditis. A
case report. Acta Cardiol 1994; 49: 279–286
Ray et al.
Fatal Atypical Mycobacterial Infection
103
7. Tazelaar HD. Spectrum and diagnosis of myocardial rejection. Cardiol
Clinics 1990; 8: 119–139
8. Munoz RN, Pulpon LA, Yebra M, Segovia J, San Martin M, Salas C.
Three cases of tuberculosis after heart transplantation in Spain. Eur
J Clin Microbiol Infect Dis 1998; 17: 801–806
9. Diperri G, Luzzati R, Forni A, Allegranzi B, Cazzadori A, Bonora S, et
al. Fatal primary multidrug resistant tuberculosis in a heart
transplant recipient. Transpl Int 1998; 11: 305–307
10. Le Mense GP, Van Bakel AB, Crumbley AJ III, Jodson MN.
Mycobacterium scrofulaceum infection presenting as lung nodules in
a heart transplant recipient. Chest 1994; 106: 1918–1920
11. Munoz RM, Alonso-Pulpon L, Yebra M, Segovia J, Gallego JC, Daza
RM. Intestinal involvement by nontuberculous mycobacteria after
heart transplantation. Clin Infect Dis 2000; 30: 603–605
Foundation of Cardiovascular Sciences
Award of Financial Assistance for Attending International Conferences/Travelling Abroad on Fellowships
Applications are invited from medical scientists engaged in research in cardiovascular and allied sciences for grant of
financial assistance to participate in international conferences/travelling abroad on fellowships.
The foundation shall provide partial financial grants to cover travel and registration fee for applicants whose papers
have been accepted for presentation, or who have been invited to chair an important session. Cases would be decided
on individual basis and the decision of the trustees would be final.
Applications with full bio-data, proof of acceptance of paper for presentation/invitation to chair a session, four
copies of the abstract, and a copy of the brochure of the conference should be submitted at the following address at
least eight weeks before the date of the conference.
For requests to participate in fellowship programmes, full details of the programme along with the letter of "grant
of fellowship" should be submitted.
Managing Trustee
Foundation of Cardiovascular Sciences
3C, North West Avenue
Punjabi Bagh
New Delhi 110026
IHJ-865-00.p65
103
4/10/01, 10:58 AM
Future Directions in Cardiology
Indian Heart J 2001; 53: 104–109
Identification and Stabilization of Vulnerable
Atherosclerotic Plaques: The Role of Coronary
Thermography and External Heat Delivery
Christodoulos Stefanadis, Konstantinos Toutouzas, Eleftherios Tsiamis,
Christos Pitsavos, Lila Papadimitriou, Pavlos Toutouzas
University of Athens, Greece
T
he morphology and cellular component of
atherosclerotic plaques, rather than the degree of
stenosis, are considered to be the most important
determinants for the formation of thrombus leading to
acute coronary syndromes. The characteristics of the
plaque provide significant information regarding the
vulnerability and these may be obtained by several imaging
methods. Recently, new techniques have been proposed for
the identification of vulnerable plaques which may help in
understanding the pathophysiological mechanisms
implicated in the rupture of atherosclerotic coronary
lesions.
Morphology of vulnerable atherosclerotic plaques:
At present, the atherosclerotic plaque is not considered only
as a mass in the coronary artery which progressively
increases and obstructs the lumen of the artery. The plaque
contains active cells that play a significant role in its stability.
The cellular component of the lesions leads to multiple
pathophysiological pathways producing different clinical
syndromes.
Clinically stable plaques have thick fibrous caps and small
lipid cores with abundance of extracellular matrix.1 The
lesions do not necessarily produce significant degrees of
stenoses. In contrast, vulnerable plaques have thin fibrous
caps separating the core from the arterial lumen and thus
the risk for plaque rupture is increased. The fissure of an
atherosclerotic plaque primarily occurs in eccentric lesions
at the regions in which the fibrous cap is often thinnest and
has a reduced collagen content.2 In these regions, a high
circumferential stress develops and the risk for plaque
rupture is substantially increased.3 Moreover, the thickness
of the fibrous cap is inversely correlated with the
circumferential stress.3 In addition, atherosclerotic plaques
with large lipid cores occupying more than 40% of the
plaque volume are at high risk for thrombosis. The
consistency of the lipid core also plays an important role in
Correspondence: Dr Christodoulos Stefanadis, 9, Tepeleniou Street,
15452 Paleo Psychico, Athens, Greece, e-mail: [email protected]
IHJ-IA-001.p65
104
the vulnerability of the plaque, since if the lipid core is soft
the risk for plaque rupture is increased.4
Progression of a Plaque: The role of inflammation:
A significant factor that leads to the progression of an
atherosclerotic plaque from a stable to an unstable status is
inflammation. Adhesion molecules, such as vascular cell
adhesion molecule-1 (VCAM) increase the concentration
of leucocyte receptors on the endothelium. Thus, leucocytes
intrude into the lesion and by absorbing lipids become
macrophages. This process is primarily mediated by
cytokines (tumor necrosis factor-α, interleukins, monocyte
chemoattractant protein-1), which are proteins produced
by inflammatory cells, such as mastocytes, macrophages
and lymphocytes. The concentration of these inflammatory
cells within the coronary atherosclerotic plaque correlates
with the clinical syndrome. Accordingly, macrophages are
more frequently demonstrated in coronary specimens
obtained from patients suffering from unstable angina
compared with patients with stable syndromes.5 In addition,
lymphocytes are activated in patients with unstable angina
as compared with patients with effort angina or control
patients. Interleukin-2 receptors are also increased
substantially in patients with unstable syndromes.6 These
cellular components release growth factors by autocrine
and paracrine control. Growth factors lead to the
development of extracellular matrix, and hypertrophy and
hyperplasia of smooth muscle cells. However, macrophages
and other plaque-related cell types also release matrix
degrading proteases, the matrix metalloproteases (MMPs).7
MMPs are pro-inflammatory substances and they initiate
the degradation of fibrillar collagen leading to vulnerability
of the atherosclerotic plaque. Indeed, Sukhova et al.
demonstrated that concentrations of MMP-1 and MMP-13
were increased in vulnerable atheromatous plaques
compared to stable fibrous plaques.8
Thus, the progression of a stable lesion to a vulnerable
atheromatous plaque is mediated by the development of
lipids and the interactions of inflammatory cells. In
contrast, stabilization of a plaque is mediated by an increase
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Indian Heart J 2001; 53: 104–109
in the amount of extracellular matrix and smooth muscle
cells. The major problem, however, is the detection of
plaques that will become vulnerable and produce acute
coronary syndromes.
Detection of vulnerable plaques: The aim of diagnostic
procedures such as imaging techniques, is to provide
information regarding the morphological characteristics
of the atherosclerotic plaques, and also to assess the
physiological pattern of the coronary plaques.
Morphological characteristics are related to the anatomical
changes of the coronary vessel wall (lumen diameter, lumen
area, vessel area, remodeling index). For physiological
assessment, measurements of coronary pressure, flow,
temperature, and elasticity are required. Ideally, the
morphological and physiological parameters should be
obtained by noninvasive methods. Moreover, such methods
could be used as a "screening" test and if necessary,
therapeutic intervention could be initiated for the reduction
of future adverse cardiac events. However, a method
providing all this information is still not available and most
imaging techniques are invasive. In addition,
pharmacological or mechanical intervention based on the
findings of coronary plaque characteristics has not yet been
proved by clinical trials.
Intravascular ultrasound (IVUS) is a catheter-based
technique that provides tomographic images of the arterial
wall and morphometric data of lumen and vessel
dimensions. Recent studies have shown that lipid-rich areas
and the thickness of the fibrous cap may be visualized by
high-frequency IVUS. However, more histological studies
are required for the validation of these observations.
Another significant information provided by IVUS is the
remodeling of the vessel wall. Several reports demonstrate
a correlation between positive remodeling and vulnerability
of the plaque. This intriguing relation between remodeling
and vulnerability needs to be further investigated.9–13
Elastography is an IVUS catheter-based technique for tissue
characterization. In vitro studies have used validation of
elastography to discriminate lipid-rich areas from fibrous
plaques.14 The clinical application of this technique is
awaited with great interest. In addition, angioscopy is a well
described method that provides visualization of the plaque
with high sensitivity. The inability to provide morphological
characteristics of the plaque and the arterial wall layers
negates the diagnostic ability of angioscopy.15–17 Several
attempts have been made to improve the resolution of
magnetic resonance imaging (MRI). Although in
experimental studies the regression of atherosclerotic
plaques has been documented by MRI, its clinical
application provides information only for atheromatous
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Stefanadis et al.
Coronary Thermography
105
plaques in large arteries such as the aorta and the carotids.
Accordingly, intravascular MRI is currently under
investigation to address the limitations of the noninvasive
procedure. Furthermore, nuclear scintigraphy imaging
techniques are being examined for the detection of
vulnerable plaques.15–23 Lately, a new method has been
introduced for the visualization of the arterial wall. Optical
coherence tomography (OCT) represents a new imaging
modality at a level of resolution not previously achieved by
IVUS. OCT is a catheter-based technique utilizing backreflected infrared light to obtain in situ micron-scale
tomographic imaging. This method is attractive since it may
differentiate lipid-based and water-based constituents even
in heavily calcified tissue. The clinical application of this
method is eagerly awaited.24–25 Only preliminary results are
available for a new method for the identification of the
necrotic core and vulnerable atherosclerotic plaque. This
involves the detection of lysoecitin, one of the active
components of oxidized low-density lipoprotein by laserinduced fluorescence.26 Near-infrared spectroscopy is being
tested currently as a method for the detection of vulnerable
plaques.27
Coronary Thermography
It is known that most ruptured plaques are characterized
by a large pool of cholesterol or necrotic debris and a thin
fibrous cap with a dense infiltration of macrophages.
Casscells et al.28 postulated that both types of thrombotic
events may be predicted by the heat released by activated
macrophages either on the plaque surface or under a thin
cap. Thus, they measured the intimal surface temperatures
of carotid artery plaques taken at endarterectomy. The
living samples were probed with a thermistor (24-gauge
needle-tip; accuracy 0.1°C; time contrast 0.15 s). The
plaques had several regions in which surface temperatures
varied by 0.2–0.3 °C, but 37% of the plaques had
substantially warmer regions (0.4–2.2°C). Moreover, the
temperature correlated positively with cell density (r=0.68,
p=0.0001).
The results of this fundamental study raise the possibility
that a catheter which can localize heat or metabolic activity
might be able to identify plaques at high risk of rupture or
thrombosis.28 In order to measure the temperature of the
atherosclerotic plaques in vivo, we proceeded to design and
manufacture a "thermography" catheter to be able to apply
this technique in clinical practice.
Thermography Catheter: For the measurement of
temperature we use a thermistor probe (Microchip NTC
Thermistor, model 100K6MCD368, Beta THERM). The
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106 Stefanadis et al.
diameter of this probe is minimal (0.457 mm) and therefore,
it is appropriate for the human coronary arteries. The
technical characteristics of the thermistor include: (i)
temperature accuracy of 0.05 °C; (ii) time constant of 300
msec; (iii) spatial resolution of 0.5 mm; and (iv) linear
correlation of resistance v. temperature over the range of
33–43°C.29–31 The thermistor probe is attached to the distal
end of a long, 3 F shaft. The gold-plated lead wires of the
thermistor pass through the shaft and end in a connector
at the distal part of the thermography catheter. The catheter
also has a lumen for the guidewire. The guidewire enters at
the distal end of the catheter and it is extended 20 cm
proximal to the end of the catheter. In order to ensure
contact between the thermistor probe and the vessel wall, a
hydrofoil is positioned opposite the thermistor. At the site
of the hydrofoil and the thermistor the thickness of the
catheter is 4 F.
For data acquisition and processing, in our early
experience the thermistor leads were connected to a
Wheatstone bridge (a type of null comparator), which is
used to correlate the change of thermistor resistance (which
varies with temperature) to voltage changes. Subsequently,
voltage changes were fed into a personal computer with an
analog-to-digital converter and displayed in real-time mode.
Voltage changes were correlated with temperature values
by using commercially available software (Dataflow, Crystal
Biotech) after calibration at temperatures varying from
33 °C to 43 °C (balancing the Wheatstone bridge to 0.00 V
at 33 °C).
Presently, the thermistor leads are connected to a digital
multimeter (Protek 506) with an RS232C interface. The
multimeter is connected to a personal computer (200 MHz
Intel Pentium) and the resistance is displayed real-time.
Resistance changes are correlated with temperature
changes according to the Steinhart–Hart equation. This is
a single equation that relates the resistance and temperature
of thermistors. Finally, after the conversion of resistance
values to temperature values (by Microsoft Excel) the
temperature changes are demonstrated on the screen of the
personal computer. All data are stored in the computer.
Thermal Heterogeneity in Human Coronary Arteries:
After the successful experimental testing of the
thermography catheter we proceeded to the clinical
application. We perform quantitative coronary angiography
in all patients and the minimal lumen diameter and
reference diameter are measured by using the guiding
catheter filled with contrast as a scaling factor. Moreover,
an IVUS catheter is introduced into the target vessel for
detailed mapping of the area of interest. Thereafter, balloon
angioplasty is performed. Five minutes after a contrast
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Coronary Thermography
106
injection, the thermography catheter is advanced through
the guiding catheter, and blood temperature is measured
when the thermistor just emerges from the tip of the guiding
catheter without being in contact with the vessel wall.
Thereafter, the temperature of the lesion is measured. In
the preliminary studies we examined the heterogeneity of
the atherosclerotic plaques by measuring the temperature
of the plaque. Accordingly, the difference of temperature
(∆T) between the atherosclerotic plaque and the healthy
vessel wall is calculated by subtracting the background
temperature from the maximum temperature of the
atherosclerotic plaque.
In the first clinical study, we examined the thermal
heterogeneity of atherosclerotic plaques in patients with
different clinical syndromes. Thus, we measured the
thermal heterogeneity in patients with stable and unstable
angina, and acute myocardial infarction. The temperature
of the healthy vessel wall was constant and varied by only
0.05 °C (SD 0–0.026). The majority of atherosclerotic
plaques showed higher surface temperatures compared to
the normal vessel wall. Moreover, the differences in
temperature were not correlated with the degree of stenosis.
Heterogeneity within the atherosclerotic plaques was
shown in 20%, 40%, and 67% of the patients with stable
angina, unstable angina, and acute myocadial infarction,
respectively, whereas no heterogeneity was shown in the
control subjects. Greater values of ∆T were observed in
patients with unstable angina (maximum, 1.55 °C) and
acute myocardial infarction (maximum, 2.60 °C). ∆T was
different among the groups, increasing progressively from
patients with stable angina to those with acute myocardial
infarction. Multiple regression analysis revealed that Creactive protein was the only factor significantly associated
with ∆T.
The first study showing thermal heterogeneity ex vivo
within atherosclerotic plaques by Casscells et al.28 also
demonstrated a relationship between the number of
infiltrated macrophages and thermal heterogeneity. A
recent study by our group demonstrated that increased
plaque temperature in vivo is associated with acute phase
reactants, and that the increased temperature indicates an
aggressive inflammation.30 Accordingly, it seems that
inflammation plays a significant role in heat release from
atherosclerotic plaques. Previous studies showed that an
inflammatory process is involved at the onset of acute
coronary syndromes and is also present in culprit lesions
of patients with effort angina.32
The considerable overlap of plaque temperature in
patients with effort angina and those with acute coronary
syndromes leads to the hypothesis that the process leading
to increased temperature precedes plaque rupture.
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Indian Heart J 2001; 53: 104–109
Moreover, a percentage of patients with clinically stable
angina have unstable plaques. Previous studies have shown
that the concentration of C-reactive protein is associated
with coronary events in patients with stable or unstable
angina.33–35 In addition, a significant percentage of lesions
in patients with stable angina contain interleukin-2
receptor (CD25) positive cells.36 The APSIS study (Angina
Prognosis Study in Stockholm) demonstrated that
inflammatory activity is involved in disease progression in
stable angina pectoris, since fibrinogen and white blood cell
counts were independent predictors of cardiovascular death
or nonfatal myocardial infarction in this group of patients.37
Also, patients with stable angina pectoris who developed
myocardial infarction or died of cardiovascular causes had
elevated serum levels of soluble cell adhesion molecules
indicating increased inflammatory activity.38 Furthermore,
histologically stable atherosclerotic plaques are not
associated with the presence of clinically stable angina,
since a considerable overlap in inflammatory activity in
plaque tissues is observed within the clinical syndromes.36
Clinical application of thermography: In a recent study
we evaluated the clinical significance of temperature
measurement of atherosclerotic plaques for clinical
outcome following percutaneous coronary intervention. All
patients enrolled in this study had one-vessel disease and
were suffering from stable or unstable angina, or acute
myocardial infarction. Accordingly, in 86 patients ∆T was
measured and they were then followed up clinically for
approximately 2 years.31 During the follow-up period, 21
patients had an adverse cardiac event. ∆T was greater in
patients with adverse cardiac events compared to patients
without events (∆T: 0.939±0.49 v. 0.428±0.42, p
<0.0001). Moreover, in each group, ∆T was greater in
patients with adverse cardiac events, although in patients
with acute myocardial infarction this difference did not
reach statistical significance. The application of Cox
regression analysis revealed that ∆T was a strong predictor
for adverse cardiac events during the follow-up period (odds
ratio 1.92, p=0.008). Moreover, patients with ∆T ≥0.5 °C
had an almost 6 times (41% v. 7%) increased risk for an
adverse cardiac event compared to patients without
increased ∆T.
The relation between temperature and clinical outcome
is not clear. The early detection of lesions with infiltration
of inflammatory cells during percutaneous intervention
may indicate those lesions that are predisposed to future
alterations of plaque morphology. Moreover, macrophages
and T-lymphocytes are present in the majority of restenotic
lesions of patients presenting with unstable angina and this
inflammatory reaction is related to the underlying
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107
morphology. On the contrary, the smooth muscle cell area
is similar in restenotic lesions of patients with stable or
unstable angina.39
External heat delivery: It is known that thermotherapy
is currently applied in several proliferative diseases. Heat is
a physical agent whose biological effects depend on the
intensity, duration and means of application. Different heat
applications have been used, varying from laser devices to
high-intensity focused ultrasound and radiofrequency.40–42
Most of these methods are applied invasively. Hyperthermia
is emerging as an effective treatment in proliferating
conditions such as benign prostatic hyperplasia, brain
tumors and bone tumors.40–42 The goal of heating is to
destroy tissue by achieving temperatures that exceed the
cytotoxic threshold and induce cell death. The threshold
depends on the cell type and thus when heterogeneous
tissue is treated, only a percentage of cells within the treated
area will die.
In our center during the past few years, we performed
experimental studies in which magnetic energy was used
to heat noninvasively stented arterial segments from a
distance.43–45 This type of energy creates an alternating
magnetic field that exclusively targets metals such as stents.
An alternating magnetic field from an induction heating
furnace has also been applied by other investigators for
heating stents or bone cement. By this noninvasive method,
stents are heated externally from a distance and the heat is
transmitted by conduction in the stented arterial wall in a
controlled mode.
We used a high-power generator for the production of
electromagnetic energy (18 kW). The voltage and the
current drain were controlled by a software that was
designed in our institute. This energy was driven to a
specially designed inductor in order to create a periodically
alternating magnetic field (20 MHz). Thus, a magnetic force
was produced which changed with the same frequency as
the magnetic field. As the magnetic force changed
periodically on the stent, energy was drained from the
generator to compensate for the lagging of the magnetic
flux. Accordingly, the magnetic force appears on the
metallic target as heat. This type of energy heats only metals
such as stents from a distance. By regulating the generator's
output power, the magnetic force produced is completely
controlled.
In vivo experimental studies in porcine coronary arteries
were performed by applying magnetic force until the
temperature of the stent reached 43 °C. We implanted stents
in the left anterior descending artery in 15 animals and,
after a heating session, stents were implanted in the left
circumflex artery. Acute thrombosis was not observed in
4/10/01, 11:40 AM
108 Stefanadis et al.
any case. The in-stent luminal diameter at 4 weeks was
similar in the heated and control segments (2.74±0.55 mm
v. 2.71±0.49 mm, p=0.41). In histological studies, the
luminal surface of all the segments was covered by mature
endothelium providing a smooth surface. Compression of
the media was detected at the sites of stent struts. In several
sites, the internal elastic membrane was injured and the
arterial media was lacerated. In both groups, occasional
ridges in the luminal surface consisting of smooth muscle
cells and extracellular connective tissue matrix were seen.
In sections with heated stents, minimal smooth muscle cell
proliferation along with extracellular matrix was observed
in the neo-intimal layer. However, at the adjacent proximal
and distal nonstented segments, regions with intimal
hyperplasia were observed. Morphometric studies showed
that the mean luminal area was similar in the two groups 4
weeks after the implantation (heated group: 21.9±4.3 µm2
v. control group: 24.8±5.1 µm 2, p=0.43). The mean
maximal intimal thickness was greater in the control group
compared with heated segments (93.3±33.6 µm v.
183.8±51.3 µm, p=0.04). The mean thickness of the
arterial media was less in the heated segments as compared
with nonheated stented segments (65.6±13.1 µm v.
112±25.7 µm, p=0.02).
This study demonstrated that metallic stents may be
successfully heated up to 50 °C in vitro and in vivo from a
distance of at least 25 cm by using magnetic force.
Thrombosis of the stented segment was observed at high
temperatures. At a temperature of 43 °C, in-stent intimal
hyperplasia was reduced compared to nonstented segments.
However, an increased hyperplastic response was detected
at the edges of the stents.
A reason for concern in this method is the transmission
of heat to the arterial wall. Ideally, heat should be
homogeneously transmitted from the struts of the stent to
the arterial wall. However, it seems that although the
hyperplastic response is reduced close to the struts of the
stent, an increased proliferative response is observed at the
edges of the stent. Thus, it seems that close to the metallic
struts heat is distributed with favorable effect. In contrast,
in areas in which heat is not distributed homogeneously, a
hyperplastic response is detected. The range of heat is
limited, and although cells behind the stent struts may be
well heated by a single dose, cells proximal and distal to the
extremity of the stent, and areas injured by, the balloon
treatment may not be effectively covered by heat.
This method may be useful in preventing the
development of in-stent restenosis. The capability for
multiple sessions of hyperthermia by the noninvasive mode
during the first months after stent implantation may
IHJ-IA-001.p65
Indian Heart J 2001; 53: 104–109
Coronary Thermography
108
eliminate the in-stent intimal hyperplasia. Moreover, the
method is relatively simple and clinically applicable at low
cost. Studies are ongoing at our center with a new system
constituting an RF-generator connected to capacitors by a
fiber-optic connector. This system provides accurate tuning
range, as well as current and voltage control.
Conclusions
There seems to be fair knowledge of the morphology of the
atherosclerotic plaque. The pathophysiological mechanisms
leading to the progression of stable to unstable syndromes
is still under investigation. The role of inflammation seems
to be important in this process. Lately, new imaging
techniques have been developed for the early detection of
vulnerable plaques. Thermography provides considerable
information about the inflammatory process and thus it can
be used in clinical practice to evaluate the vulnerability of
atherosclerotic plaques. In addition, the use of heat applied
either invasively or noninvasively may contribute to the
stabilization of vulnerable atherosclerotic plaques.
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4/10/01, 11:40 AM
Cardiovascular Images
Indian Heart J 2001; 53: 110–111
Aortic Dissection into the Interatrial Septum
R Narang, SS Kothari, S Sharma, S Ramamurthy, KK Talwar, SC Manchanda
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
Fig. 1. Two-dimensional echocardiography
demonstrating a cavity in the interatrial septum. The
cavity (C) is partially filled with thrombus (T).
Fig. 2. Color Doppler echocardiogram showing a jet
of blood entering the cavity from aorta.
Fig. 3. Magnetic resonance image showing a large
cavity in relation to the atria partially filled with
thrombus. White areas indicate flowing blood.
Fig. 4. Selective coronary angiography showing
abnormal channel close to the origin of right coronary
artery feeding blood to the cavity.
Fig. 5. Fluroscopic image during the interventional
procedure showing guidewires placed in both right
coronary artery and the abnormal channel. The
microcatheter has been positioned with its distal end
in the abnormal channel.
Fig. 6. Selective angiography following the procedure
showing complete occlusion of abnormal channel by
coils.
A
64-year old woman presented with a 3-month history
of shortness of breath and mild congestive heart
failure. She was known to have brady-tachy syndrome for
which she underwent radiofrequency ablation of
Correspondence: Dr SS Kothari, Additional Professor of Cardiology,
All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029
IHJ-Arotic.p65
110
atrioventricular node and permanent pacemaker
implantation 6 years back. Echocardiographic picture
initially suggested thrombus in the right atrium. However,
on careful evaluation, a cavity in interatrial septum partially
filled with thrombus was identified (Fig. 1). Color and pulsed
wave Doppler demonstrated flow of blood from aorta into
the cavity and then into the right atrium through tiny
4/10/01, 11:36 AM
Indian Heart J 2001; 53: 110–111
openings (Fig. 2). Similar findings were obtained on
magnetic resonance imaging (MRI) (Fig. 3). On angiography,
a small channel close to the origin of right coronary artery
leading to the cavity was identified (Fig. 4). The precise
reason for this patho-anatomy remains unclear, however,
we believe this represented dissection into the interatrial
septum. Dissection of aorta into the interatrial septum is
rare but has been reported.1–4
In view of very small size of channel supplying blood to
the cavity, the patient was taken up for interventional
closure by coil embolization. Right coronary artery (RCA)
was hooked with 8 F right Judkin's percutaneous
transluminal coronary angioplasty (PTCA) guiding
catheter. The patient was anticoagulated with 7000 units
of heparin. A 0.014" PTCA guidewire (HannibalTM, Boston
Scientific Inc, USA) was placed in the RCA to ensure good
access in case it was injured during the procedure. Another
0.018" wire (V 18TM, Boston Scientific Inc, USA) was passed
through the guiding catheter into the anomalous channel
(Fig. 5). A microcatheter (Tracker 18TM, Boston Scientific
Inc, USA) was passed over V 18TM wire and positioned in
IHJ-Arotic.p65
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Narang et al. Aortic Dissection
111
the anomalous channel. The 0.018" wire was then removed
and 6 steel microcoils (3–5 mm in diameter and 3–4 cm
long) were delivered in the anomalous channel through the
microcatheter. Post-procedure angiograms showed
complete occlusion of the anomalous channel (Fig. 6).
Patient was well on follow-up at 6 months and investigations
(echocardiography and MRI) revealed that the cavity was
completely thrombosed and reduced in size.
References
1. Tseng CD, Hsu KL, Tseng YZ, Chiang FT, Hwang JJ, Lin FY. Penetration
of the interatrial septum: a rare complication of percutaneous
transluminal mitral commissurotomy. J Formos Med Assoc 1997; 96:
272–275
2. Jessen ME, Horn VP, Weaver DE, Boehrer JD, Ring WS. Successful
surgical repair of aortic dissection presenting with complete heart
block. Ann Thorac Surg 1996; 62: 1202-1203
3. Lorenzoni R, Santoro GM, Calamai G, Masini G. Total
atrioventricular block as the primary clinical manifestation of
undiagnosed aortic dissection. G Ital Cardiol 1995; 25: 1031–1035
4. Morris AL, Barwinsky J. Unusual vascular complications of
dissecting throacic aortic aneurysms. Cardiovasc Radiol 1978; 1:
95–100.
4/10/01, 11:36 AM
Selected Summaries
Indian Heart J 2001; 53: 112–113
Argentine Randomized Study: Coronary Angioplasty With Stenting Versus
Coronary Bypass Surgery in Patients With Multiple-Vessel Disease (ERACI II)
Alfredo Rodriguez et al.
J Am Coll Cardiol 2001; 37: 51–58
Summary
Comments
This multicenter randomized study compared percutaneous
angioplasty (PTCA) with stent implantation to coronary
artery bypass surgery (CABG) in selected high-risk patients
with multivessel disease. Four hundred and fifty patients
(92% with unstable angina) were randomized to PTCA with
stent implantation v. CABG (225 patients each). The
primary endpoints were major adverse clinical events
(MACE) – Death, Q-wave myocardial infarction (Q-MI), and
the need for repeat revascularization at 1 month and 1 year.
At 1 month, PTCA patients had lower MACE than CABG
(Death: 0.9% v. 5.7%, p<0.013; nonfatal Q-MI: 0.9% v.
5.7%, p<0.013; MACE: 3.6% v. 12.3%, p<0.002). At
follow-up (mean 18.5+6.4 months) patients undergoing
PTCA with stent implantation showed better results than
patients who had undergone CABG (survival: 96.9% v.
92.5%, p<0.017; freedom from MI: 97.7% v. 93.4%,
p<0.017). However, the requirement for repeat
revascularization was higher in PTCA with stent group as
compared to CABG (16.8% v. 4.8%, p<0.002). This study
showed that in the high-risk group of patients with
multivessel disease, PTCA with stent implantation group
had better survival and freedom from MI compared to the
patients who had undergone conventional surgery.
Earlier randomized trials which have compared angioplasty
with surgery in multivessel disease (ERACI 1, RITA, BARI,
EAST, GABI and CABRI) have shown that the mortality
rates and important clinical outcomes during the followup period ranging from one to five years are not significantly
different between the two revascularization techniques.
However, in all these studies the need for repeat
revascularization and recurrence of angina was lower in
the surgical group. The present study (ERACI II) is the first
to demonstrate a lower mortality and MACE both at 30 days
and one year in patients with multivessel disease undergoing
PTCA with stent implantation compared to CABG. This has
been due to a higher than expected mortality in the
surgically treated patients and lower than expected MACE
in the PTCA group. The proponents of this study attribute
their excellent results to the use of stents in their patients
and expect even better results with the concomitant use of
glycoprotein IIb/IIIa inhibitors. However, their opponents
are unable to accept such a high surgical mortality. They
further argue that the numbers are too small to get a robust
statistical analysis. The results of the future trials, i.e. stent
v. surgery trial (SOS) will provide additional data to answer
this important question.
Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated
Stents in Human Coronary Arteries
J Eduardo Sousa et al.
Circulation 2000; 102: r54–r57
Summary
Comments
The safety and efficacy of stents coated with sirolimus
(Rapamune), a cell cycle inhibitor, was determined in a pilot
study of 30 patients treated with 2 different formulations
of the drug: slow release formulation (>28-day drug
release) and fast release formulation (<15-day drug release).
Each stent was coated with 140 µg/cm2 of sirolimus. The
primary end point at 4 months was angiographic and
intravascular ultrasound (IVUS) analysis for intimal
hyperplasia and restenosis. The secondary end-points were
major adverse clinical events (MACE) – death, myocardial
infarction and repeat revascularization at 8 months. There
was no restenosis at four-month angiographic follow-up,
while only 3 patients showed about 15% intimal hyperplasia
on IVUS. No major adverse clinical events or stent
thrombosis was noted at 8 months. This is the first human
experience with the implantation of sirolimus-coated stents
and have shown 0% restenosis with minimal or no intimal
hyperplasia on follow up.
Various pharmacological approaches to prevent restenosis
have not been successful, possibly due to insufficient local
drug concentration. In order to overcome this problem,
polymeric-coated stents have been advocated. In this
elegantly performed small study, the authors have shown
0% restenosis in de novo lesions (<18 mm with diameter
of 3.0–3.5 mm) by sirulimus-coated stents. The minimal
amount of intimal hyperplasia in the present study (10.7%)
and almost 0% late loss, seems remarkable compared to
previous reports. The intimal hyperplasia in noncoated
stents ranges from 19% to 48% and lumen loss is 0.8 to 0.9
mm. Although the radioactive stents have shown an intimal
hyperplasia of 7%–17%, they are limited by edge restenosis
and late thrombosis. These side-effects were absent in the
sirolimus-coated stents. This is a small study and the results
need to be validated in larger, prospective randomized trials.
Further, 12 month angiographic follow-up is lacking. Other
drug coatings; taxol, phosphorylcholine, heparin and
paclitaxol are being studied. Further, newer strategies to
reduce restenosis include cryotherapy, sonotherapy,
photodynamic therapy and the use of coated and
biodegradable stents.
IHJ-Selected Summary.p65
4
4/10/01, 11:57 AM
Selected Summaries
Indian Heart J 2001; 53: 112–113
Hemodynamic Effects of Sildenafil in Men with Severe Coronary Artery Disease
Howard C Herrmann et al. N Engl J Med 2000; 342: 1622–1626
Summary
The cardiovascular effects of sildenafil (Viagra, Pfizer) are
important as patients being treated for erectile dysfunction
are usually in the age group of coronary artery disease. In
the present study, systemic, pulmonary and coronary
hemodynamic effects of oral sildenafil (100 mg) were
studied in 14 men (mean age: 61 years) with severe stenosis
of at least one coronary artery. Coronary blood flow velocity
and flow reserve were determined with a Doppler guide wire
and maximal hyperemia was induced with intracoronary
administration of adenosine both before and after sildenafil.
Oral sildenafil caused a small (<10%) decrease in systemic
and pulmonary arterial pressures. It had no effect on the
pulmonary capillary wedge pressure, right atrial pressure,
heart rate or cardiac output. Double product ( heart rate
times systolic blood pressure) fell significantly from
9435±1739 mmHg per minute to 8641±1722 mmHg per
minute (p=0.02). There were no significant changes in
average peak coronary flow velocity, coronary artery
diameter, volumetric coronary blood flow or coronary
vascular resistance. The coronary flow reserve increased
about 13% in stenosed and reference arteries after the
administration of sildenafil. In both groups of arteries
combined, it increased from 1.70±0.59 to 1.92±0.72,
(p=0.003). In this study, no adverse cardiovascular effects
of oral sildenafil were observed in men with severe coronary
artery disease.
Comments
Men with erectile dysfunction may also have cardiovascular
disease, as some of the risk factors are common for both
conditions. Further, serious cardiovascular events including
myocardial infarction and sudden death have been
temporally correlated with sildenafil use in the past.
However, this study demonstrates that oral sildenafil has
no direct adverse cardiovascular effects in men with severe
coronary artery disease and may have a small positive effect
on coronary blood flow reserve. This data supports the ACC/
AHA consensus view that sildenafil is safe for patients with
stable coronary artery disease who are not taking other
medications containing nitrates.
Endoluminal Beta-Radiation Therapy for the Prevention of Coronary
Restenosis after Balloon Angioplasty
Vitali Verin et al. N Engl J Med 2001; 344: 243–249
Summary
In this prospective randomized, multicenter, dose-finding
study using beta radiation (Yttriuim – 90), 181 patients
were randomized to receive 9, 12, 15 and 18 Gy at a tissue
depth of 1 mm following successful angioplasty of a previously untreated coronary artery. Adjunctive stenting was
required in 28% of the patients. The primary end-point was
the minimal luminal diameter (MLD) at 6 month follow-up
angiography and the secondary end-points were death,
myocardial infarction ( MI), coronary artery bypass
grafting(CABG) and target vessel revascularization (TVR ).
The results showed that MLD was maximum with a dose of
18 Gy, and there was a dose dependent increase in MLD
from 1.67+0.09 mm to 2.10+0.12 mm from 9 to 18 Gy,
respectively (p=0.006). Further, the restenosis rate was
29%, 21%, 16% and 15% with doses of 9, 12, 15 and 18
Gy, respectively in the total group. Interestingly, the
restenosis rate in the balloon angioplasty with radiation but
without a stent group ( n=130) was 28%, 17%, 16% and
4% with doses of 9, 12, 15 and 18 Gy, respectively (p=0.02).
At follow-up there was occlusion of the vessel in 3.3% patients who had had balloon angioplasty alone and in 14.3%
who had also required stents. TVR was required in 13%,
9%, 10%, and 10% patients in each of the four groups and
was not statistically different. Thus, this study showed that
IHJ-Selected Summary.p65
5
intracoronary beta-radiation therapy produces a significant
dose dependent decrease in the rate of restenosis after
angioplasty in nonstented arteries. A dose of 18 Gy actually induces lumen enlargement (0.04+0.10 mm).
Comments
The restenosis rate following stenting in a 100%
angiographic follow-up study has been shown to be up to
37%. Earlier trials with intracoronary gamma radiation—
SCRIPPS, WRIST, GAMMA-I have shown marked reduction in the restenosis rate in patients with instent restenosis.
The present study is one of the first human studies to focus
on previously untreated coronary lesions rather than previously dilated lesions in which restenosis has occurred. This
has shown a marked reduction of restenosis, up to 4% with
18 Gy in the arm wherein balloon angioplasty treated patients were electively treated with beta radiation. Further,
there was an increase in the MLD at follow up which has
been explained by positive remodeling occurring at doses
of up to 18 Gy. As the lowest rate of restenosis with the use
of stent is 16% at six months, restenosis rate of 4% achieved
in the present study of balloon angioplasty alone is remarkable. The late thrombotic occlusion rate of 14.3% in stented
patients is of concern and presumably may be reduced by
long term antiplatelet treatment.
4/10/01, 11:57 AM
Calendar of Conferences
May 2–5, 2001, NASPE’s 22nd Annual Scientific
Sessions, Boston Massachusetts, USA
Contact: Mark H Schoenfeld, NASPE, Six Strathmore
Road, Natick, MA 01760-2499, USA
Fax: 508-647-0124, e-mail: [email protected]
Website: www.naspe.org
May 22–25, 2001, Pediatric Interventional Cardiac
Symposium, Metro Convention Center, Toronto, Canada
Contact: Course Director: Dr Ziyad M Hijazi
Website: www.picsymposium.com
Fax: +1 978 475 1333
May 27–31, 2001, 3rd World Congress of Pediatric
Cardiology and Cardiovascular Surgery, Toronto,
Ontario, Canada
Contact: Dr Robert M Freedom, Division of Cardiology,
Hospital for Sick Children, University of Toronto,
Faculty of Medicine, 555 University Ave, Toronto,
Ontario M5G 1X8, Canada
Fax: 1 416 813 7547
June 24–27, 2001, 4th International Meeting on
Interventional Cardiology, Tel Aviv, Israel
Contact: The Secretariat, 4th International Meeting on
Interventional Cardiology
P.O. Box 50006, Tel Aviv 61500, Israel
Fax: 972 3 517 5674,
e-mail: [email protected]
June 27–30, 2001, American Society of
Echocardiography: 12th Annual Scientific Sessions,
Washington State Convention Center, USA
Contact: The Secretariat, Washington State Convention
Center, Seattle, WA, USA
Website: www.asecho.org
July 6–11, 2001, XVII World Congress of the
International Society for Heart Research, Winnipeg,
Manitoba, Canada
Contact: Institute of Cardiovascular Sciences, St. Boniface
General Hospital Research Centre, University of
Manitoba, Faculty of Medicine, 351 Tache
Avenue, Winnipeg, Manitoba R2H 2A6, Canada
Fax: 1 204 233 6723,
e-mail: [email protected]
July 29–Aug 10, 2001, 27th 10-Day Seminar on the
Epidemiology and Prevention of Cardiovascular
Diseases, Granlibakken Conference Centre, Tahoe, CA
Contact: David C Goff Jr, Seminar Director, c/o American
Heart Association, 7272 Greenville Avenue,
Dallas, Texas 75231, USA.
Fax: 1-214-373-3406
Cal of Conference.p65
114
Indian Heart J 2001; 53: 114
September 1–5, 2001, XXIII Congress of the
European Society of Cardiology, Stockholm, Sweden
Contact: European Congress Organization (ECOR), The
European Heart House, Stockholm, Sweden,
Fax: 33 4 9294 7620,
e-mail: [email protected]
October 3–6, 2001, 13th Asia-Pacific Congress of
Cardiology, Manila, Philippines
Contact: Dr Noe A Babilonia, Chairman, Organizing
Committee, 13th APCC, Suite 1108, 11th Floor,
East Tower, PSE Centre, Exchange Road, Ortigas
Commercial Complex, Pasig City, Manila 1605,
Philippines, Fax: 632 634 7441
October 13–16, 2001, VII Asian-Pacific Symposium
on Cardiac Pacing and Electrophysiology, Beijing, China
Contact: Dr Hu Da Yi, Secretary-General, VII APSPE,
Beijing Red Cross Chaoyang Hospital
8 Baijiazhang Road, Chaoyang District, Beijing
100020, People’s Republic of China
Fax: 86 10 6593 7858,
e-mail: [email protected]
November 11–14, 2001, 74th Scientific Session,
American Heart Association, Anaheim, California, USA
Contact: American Heart Association, 7320, Greenville
Avenue, Dallas, Texas 75231, USA
Fax: 1 214 373 3406
February 8–10, 2002, VIth World Congress of
Echocardiography and Vascular Ultrasound,
New Delhi, India
Contact: Dr (Col) SK Parashar, Secretary General,
C-144, Sarita Vihar, New Delhi - 110044,
Fax: 6 942222,
e-mail: [email protected]
March 17–20, 2002, 51st Annual Scientific Sessions,
American College of Cardiology, Atlanta, Georgia, USA
Contact: American College of Cardiology, 9111 Old
Georgetown Road, Bethesda, MD 20814, USA,
Fax: 1 301 897 9745
May 5–9, 2002, XIV World Congress of Cardiology,
Sydney, Australia
Contact: The Congress Secretariat, QVB Post Office Locked
Bag Q4002, Sydney, NSW 1230, Australia,
Fax: 61 2 9290 2400, e-mail: [email protected]
4/10/01, 12:01 PM