Download Consensus on Hypertrophic Cardiomyopathy.

1
CONSENSUS
ON HYPERTROPHIC
CARDIOMYOPATHY
CONSENSUS
ON HYPERTROPHIC
CARDIOMYOPATHY
Consensus on Hypertrophic Cardiomyopathy.
SAC Argentine Consensus
1. INTRODUCTION AND OVERVIEW
Organizing Committee
Director
Dr. J. Horacio Casabé
Editorial Staff
Drs. Rafael Acunzo, Adrián Fernández, José Gabay, Néstor
Galizio, Alejandro Hita, Gustavo Ontiveros,
Roberto Peidro
By the SAC Area of Standardizations and Consensus
Dr. Eduardo Alberto Sampó
Work Commissions
Introduction and overview, definition and
nomenclature, physiopathology
Dr. J. Horacio Casabé
Genetics
Drs. Gustavo Ontiveros, Jorge Scaglione, and
Alejandra Guerchicoff
Electrocardiogram
Drs. Rafael S. Acunzo, Isabel V. Konopka, and
M. Cristina Sacheri
Echocardiography
Drs. Alejandro Hita, Sergio Baratta, Jorge Lax, and
Eduardo Guevara
Natural history and medical treatment
Dr. J. Horacio Casabé
Surgical treatment
Drs. Roberto R. Favaloro and J. Horacio Casabé
Percutaneous ablation
Drs. José Manuel Gabay and Antonio Pocoví
Pacemaker
Dr. Néstor Galizio
Assessment of risk of sudden death
Dr. Adrián Fernández
End-stage phase of HCM
Dr. Adrián Fernández
Exercise and HCM
Dr. Roberto Peidro
Advisory Committee
Dr. Gabriela Hecht
Dr. Tomás F. Cianciulli
Dr. Augusto Torino
The hypertrophic cardiomyopathy (HCM) is a condition that was anatomopathologically described by the
French, and clinically described by Brock & Teare in
England fifty years ago. (1, 2) It occurs in 1 every 500
births (3). Two main aspects stand out in its natural
history: production of symptoms, which are at times
incapacitating and sudden death (SD), mainly among
young people, (4) although most patients have normal life expectancy. (5) This disease has triggered intense research in recent years. What is even more
important is that we currently have therapies that
abort life-threatening ventricular arrhythmias causing SD (6), and allow for better assessment and stratification. The purpose of this Consensus of the Argentine Society of Cardiology was to review existing evidences and set guidelines for clinicians, cardiologists,
and subspecialists in the diagnosis and treatment of
this multifaceted disease. To do this, the SAC convened a group of specialists in heart diseases, and a
group of molecular biologists with vast experience in
this disease to develop a series of updated guidelines
and practices based on their personal experience and
on the evidences from literature. Given the relatively
low prevalence of HCM, it is necessary to point out
that (3) as opposed to other areas in cardiology, there
are no large-scale randomized trials (level of evidence
A), and therefore the guidelines were based mainly
on unique randomized trials, or on major nonrandomized or retrospective cohort studies (level of
evidence B), or otherwise on consensus or experts’
opinions (level of evidence C). In this regard, it should
be noted that in 2003, the European Society of Cardiology, together with the American College of Cardiology, published an Expert Consensus document in
which all aspects of this disease (7) were fully developed, and which is fundamental for our own Consensus. However, it should be pointed out that there have
been important works after its publication that influenced on the conclusions of our Consensus. (6) In the
light of the above mentioned, we believe that the opinions expressed in this Consensus will stay in effect
for several years.
2. DEFINITION, NOMENCLATURE, AND CLASSIFICATION
HCM is defined as a non-dilated left ventricular hypertrophy in the absence of any other systemic or cardiac disease that causes it (for instance, aortic valve
2
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
stenosis or systemic hypertension). (8) Within the classification of primary cardiomyopathies (genetic,
mixed, or acquired), this is the most common genetic
primary cardiomyopathy. (8) Upon its description, it
has been called a variety of names, the most outstanding ones being asymmetrical septal hypertrophy, idiopathic hypertrophic subaortic stenosis, dynamic subaortic stenosis, and hypertrophic obstructive cardiomyopathy. The World Health Organization
(WHO) has adopted the term hypertrophic cardiomyopathy, which is the most accurate to describe this
primary hypertrophy that may occur with or without
left ventricular outflow tract obstruction. (9)
From a clinical point of view, it is important to
classify HCM hemodynamically as:
1. Obstructive: the left ventricular outflow tract obstruction (LVOTO) may be persistent during rest,
latent (provocable), or labile (variable). The two
types of obstruction include subaortic obstruction
(most frequent) and mid-ventricular obstruction
(approximately 5%). Subaortic obstruction is due
to systolic anterior motion (SAM) of the anterior
or posterior leaflet of the mitral valve, the tendinous cords or both; the mitral valve is swept towards the septum as a result of “dragging” (Venturi
effect), causing mitral regurgitation. Mid-ventricular obstruction is due to an anomalous insertion
of the anterior papillary muscle or to excessive
hypertrophy of the mid-ventricular septum or papillary muscle, with abnormal alignment. Both obstructions may coexist. (10­12)
2. Non-obstructive: the obstruction is neither at rest
nor provocable with Valsalva or exercise. They are
divided into those with preserved left ventricular
systolic function (LVSF) (or supranormal), and
those with altered LVSF (end-stage). (11)
Recent evidence has shown that about 70% of the
HCM patients have either resting or latent LVOTO,
(13) although the real meaning of this finding for
therapy management is still unclear. What is known
for certain is that patients with significant obstructions (> 30 mm Hg) have increasing progression of
severe symptoms, heart failure, and death, mainly
when they are not very symptomatic. (14, 15)
pler imaging in patients’ relatives with that condition who do not phenotypically have the disease. As
myocardial fibrosis increases, LV stiffness increases,
and atrial pressure also increases in order to complete
the ventricular filling. This may lead to high capillary wedge pressure, and cause dyspnea. (7, 16­19)
Left ventricular outflow tract obstruction
Patients with dynamic obstruction may have symptoms that improve with the obstruction relief due to
medication, surgical myomectomy,
or septal branch ablation. (10, ­12) As already
mentioned, the prognosis of patients with significant
LVOTO is worse than that of patients without that
obstruction, probably due to the chronic damage that
implies greater parietal stress, myocardial ischemia,
necrosis, and replacement fibrosis. (14, 20, 21)
Myocardial ischemia
In this disease, myocardial ischemia is sometimes evidenced by typical or atypical angina, presence of permanent or reversible perfusion defects, (22) impairment of coronary reserve (23, 24), and fibrosis areas
in the pathologic anatomy. (25) In HCM, there is an
imbalance between oxygen supply and demand: on the
one hand, there are anatomic abnormalities (intimal
hypertrophy of arterioles) (26) and functional abnormalities (23, 24) due to microvasculature narrowing;
on the other hand, there is significant hypertrophy
and muscular mass increase, which are typical of this
disease. It is important to remember that arteriosclerotic ischemic heart disease may complicate clinical
outcomes, thus worsening the prognosis. (27)
Mitral regurgitation
As mentioned above, (generally mild to moderate)
mitral regurgitation is mainly due to distortion of the
mitral apparatus as a result of SAM and Venturi “suction” effect: the direction of the regurgitant jet is lateral or posterior, especially during mid and late systole. In general, severity of regurgitation is directly
proportional to subaortic gradient. (28) When the jet
is central, anterior, or multiple, intrinsic anomalies
of the mitral valve may occur (myxomatous degeneration, valve fibrosis, anomalous insertion). (29)
The physiopathology of HCM is complex and multifactorial; one or more mechanisms may predominate
in each patient to produce the same symptom. These
mechanisms include: diastolic dysfunction, LVOTO,
myocardial ischemia, mitral regurgitation, atrial fibrillation, and autonomic dysfunction.
Atrial fibrillation
Atrial fibrillation (AF) is the most common sustained
arrhythmia in HCM, and is independently associated
with progressive heart failure, higher mortality rate
due to cardiac failure, and fatal and non-fatal stroke.
It may be poorly tolerated due to secondary diastolic
shortening at rapid ventricular rate and/or to lack of
atrial contraction to ventricular filling. (30, 31)
Diastolic dysfunction
All HCM patients have some degree of diastolic dysfunction; in fact, this can be diagnosed by tissue Dop-
Autonomic dysfunction
About 25% of HCM patients have an inadequate response to exercise, which is manifested by the impos-
3. PHYSIOPATHOLOGY
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
sibility to increase the BP above 20 mm Hg, or by the
BP fall. This response is due to systemic vasodilation
during exercise, and it occurs in spite of an adequate
minute volume to the effort; as we will see later, this
finding is associated with a higher incidence of sudden death. (32­34)
4. GENETICS
So far, more than 450 mutations have been identified
in the 20 genes that cause phenotypes compatible with
HCM. These genes include strictly sarcomeric genes,
Z-disc genes, calcium homeostasis genes, and within
differential diagnoses, genes involved in metabolic
processes (Table 1). (35, 36)
Sarcomeric gene mutations are passed on to the
offspring with autosomal dominant mode. (37) These
have been identified in 36% to 60% of familial cases
of HCM, and in 5% to 50% of sporadic forms of this
disease. However, the percentage may be even lower,
depending on the inclusion criteria used to carry out
the genotype study. An additional 2% to 7% of the
cases correspond to non-sarcomeric gene mutations.
Mutations in ±­myosin (MYH7) gene and in myosin
binding protein C (MYBPC3) are the most common
3
causes of HCM, and troponin T (TNNT2) gene mutations being in the third place. (38, 39)
Molecular-genetic physiopathology
The mutations observed most frequently are single
DNA base substitutions, which lead to amino acid
change (missense)
or a termination codon (nonsense). In gen MYH7
mutations, a dominant negative effect of the mutated
allele on the wild allele is usually observed, whereas
MYBPC3 mutations produce mainly an allelic haploinsufficiency. (40, 41) The molecular mechanisms
by which mutations lead to left ventricular hypertrophy (LVH) are not exactly known yet. The two most
firmly argued mechanisms do not necessarily exclude
each other. One of the hypotheses is that mutations
would give rise to disturbance in energy consumption
by the mutated protein, with deterioration of myocyte function, and the following LVH as a compensatory mechanism. (42) Another hypothesis postulates
that mutation in itself causes a structural disorder
through the conformational change of the altered sarcomeric protein. (43) In both of the postulated mechanisms, changes in the ATPase activity and the Ca++
homeostasis are considered important participants of
Table 1. Genes related to hypertrophic cardiomyopathy*
*Adapted from Bos et al. (40) Sarcomeric genes include: those which encode thin filament proteins (troponin T, I,
and C; ±-tropomyosin, actin), intermediate filament proteins (myosin binding protein C), and thick filament proteins
(²-myosin, and the essential or regulatory light chains of myosin). Z-disc genes are a group of genes that encode
proteins involved in the cytoarchitecture of cardiomyocytes, and in mechanosensitive signals. Their products include
titin, muscle LIM protein, and telethonin. Genes involved in calcium homeostasis include the sarcoplasmic reticulum
genes, which are the ones most involved in this pathology. Genes involved in metabolic processes include
mitochondrial genes, and lysosomal protein genes, whose alterations are evidenced as phenocopies of HCM.
4
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
the process, as well as a number of modifying factors
of the genic expression. (44)
Correlation between phenotype and genotype
It has been evidenced that cases of HCM with identified mutations in sarcomeric genes are associated
to a higher degree of median septal LVH, whereas Zgenes are associated to sigmoid forms of LVH, and to
greater functional left ventricular outflow tract obstruction. (45) In turn, phenocopies of HCM (patients with different genotypes with similar clinical
presentations) due to storage diseases show significant thickness of the LV wall, and greater incidence
of arrhythmias and accessory pathways, but they
mainly show more extracardiac lesions than the previous groups. (36)
HCM cases due to mutations in the BMH7 gene
have been associated to severe forms of hypertrophy
occurring early in life, with significant LVOTO and
sudden death. (46) Cases due to mutations in the
MYBPC3 gene have been associated to late development of the disease and good prognosis in general,
whereas cases due to mutations in the TNNT2 gene
have been related to mild or moderate levels of LVH,
but with high risk of sudden death. (47, 48) However,
such associations lack statistical significance, so it is
still not possible to reliably discern phenotypes on the
basis of the knowledge of the mutated gene. (49) Likewise, at present there are significant limitations to
establish an adequate phenotype-genotype correlation
for mutations already determined (allele-phenotype
correlation), due to the functional effects of numerous genetic modulators, and to the demonstrated degrees of phenotypic plasticity in this disease. (50, 51)
Conversely, it has been demonstrated that there
is a direct correlation between severity of the medical
condition and compound heterozygote mutations or
double mutations, since these show more aggressive
progress of the disease than those who are simple
heterocygotes. It is estimated that 5% of HCM patients have these compound genetic forms, and therefore stand for a subpopulation with increased risk for
the occurrence of an adverse clinical event. (52)
Genetic modifiers
Both genetic and environmental factors can act
as disease modifiers. The modulator effect of the phenotype expression on a mutation determined by sex
has been demonstrated, as well as by numerous genetic polymorphisms, mainly those from the genes
involved in the renin-angiotensin system. (53)
Moreover, environmental and acquired factors,
such as diet, physical exercise, and blood pressure level
of each individual, also exert modulating effects on
the genetic mutations that determine the phenotype
expression of the disease. The extent of these factors
still has to be properly characterized, both as possible
clinical event prediction markers and as markers of
disease modulation. (54)
Genetic testing
Genetic diagnosis aims at detecting disorders at molecular-genetic level, with clear clinical objectives.
Among the current techniques, the DNA direct
sequencing technique is the most used for that purpose. Undoubtfully, this technique has become the
most appropriate method to make HCM diagnosis.
This way, it is possible to confirm the correct etiology
in patients with echocardiographic diagnosis of HCM,
as well as to identify a vast population of patients who
have phenocopies of HCM in spite of being classified
within this category. (36, 55)
Through genetic analysis, it is also possible to identify relatives who are asymptomatic mutation carriers. It is estimated that up to 30% of the relatives
may be silent carriers. (56) Through presymptomatic diagnosis, it is possible to plan and optimize
a closer echocardiographic follow-up in carriers rather
than in non-carriers of mutations, and thus make an
early diagnosis of the disease. (57) To date, the possibility to stratify the risk for the occurrence of
unfavorable clinic events through these techniques is
still uncertain. It is possible that the inclusion of new
genetic markers will make it feasible in the near future. (50)
It should be mentioned that, in our sphere, there
is still a long way to go regarding basic research for
the realization of genetic analysis to be included in
health care practice for HCM patients. In addition,
several considerations will have to be resolved regarding the clinical and analytical validation of the method
before deciding to perform the analysis in some of the
international centers that offer it as a service, in order to interpret the results correctly. (58)
Genetic analysis. Conclusions
– In our sphere, genetic analysis is carried out in
the research field, but with no diagnostic ­purposes, until it is clinically­validated. Level of evidence C.
– In international centers, genetic analysis with diagnostic purposes is recommended with due considerations to its limitations. Level of­ evidence C.
– There is no consensus regarding recommendations
for genetic analysis with prognostic purposes.
5. DIAGNOSIS
A. Electrocardiogram
(10) A variety of electrocardiographic abnormalities
can be found in HCM; these abnormalities are determined by the extent, degree, and distribution of the
myocardial hypertrophy involved, the presence of fibrosis and/or necrosis of the cardiac muscle, and the
occurrence of intraventricular conduction disorders.
(20, 59­62)
About 95% of the patients who carry hypertrophic
cardiomyopathy show ECG alterations that are not
5
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
diagnostic of the condition. (20) Common abnormalities involve ST segment and T wave, and about 50%
of the patients show signs of left ventricular enlargement. (59, 60)
One of the most significant characteristics of the
ECG in young patients with hypertrophic cardiomyopathy is the presence of abnormal deep narrow Qwaves; they’re present in 30% of the cases, and sometimes precede the hypertrophy detected in the ECG.
(63) These Q-waves are usually present in the derivations that face the inferior and lateral walls of the
left ventricle. An example is shown in Figure 1.
As opposed to a myocardial necrosis due to arteriosclerotic coronary artery disease, Q-waves of HCM
occur due to the increase of electric forces generated
in hypertrophic areas. Their direction and magnitude
will be related to the vector resulting from the location of areas with major ventricular hypertrophy, and
the changes that they cause in cardiac geometry. (63,
64) Recognizing these characteristics in Q-waves is
very important, since they are often confused with
the presence of myocardial necrosis. (65)
Instead, wide Q-waves are related to greater disorganization of the hypertrophic muscle or to its fibrosis and/or necrosis. (66) While myofibrillar disorganization and interstitial fibrosis involve mainly the
common ventricular myocardium, they may also affect the specialized conduction system with the presence of a variety of intraventricular conduction disorders. (61, 62)
For first-grade relatives of HCM patients, the probability to be carriers of this disease is 50%; in this
context, the presence of abnormalities, whether in the
ECG and/or in the echocardiogram, have even more
clinical significance than in general population. In
1997, a group of specialists headed by McKenna posed
a series of echocardiographic, electrocardiographic,
and clinical criteria to diagnose the disease when this
is familial (with two or more affected members). (67)
Electrocardiographic criteria include:
Major criteria
1. Signs of left ventricular enlargement with changes
in ventricular repolarization (Romhilt - Estes score
≥ 5) (Table 2).
2. Negative Q-waves with amplitude ≥ 3 mm in derivations I, aVL with an angle between electric axes
of QRS complex and of T-wave ≥ 30 degrees, of V3
to V6 or ≥ 3 mm, and in derivations II, III, and
aVF ≥ 5 mm.
3. Abnormal Q-waves (duration above 40 msec or Rwave amplitude > 25% of its voltage) in at least
two derivations. (68)
Minor criteria
1. Total bundle branch block or intraventricular conduction disorders in derivations that explore the
left ventricle.
Fig. 1. ECG of a patient with HCM.
Table 2. Romhilt-Estes score
1. S wave in V1 or V2, or R wave in
V5 or V6 > 30 mm
3 points
2. Secondary ST segment changes
3 points
3. Left atrial enlargement
3 points
4. Left deviation of the QRS axis*
2 points
5. Onset of the intrinsecoid deflection 0.05 sec
1 points
* In the absence of anterior hemiblock.
Left ventricular hypertrophy is diagnosed when the total score is ≥ 5.
2. Minor abnormalities of ventricular repolarization
in left precordial derivations.
3. Deep S wave in V2 (>25 mm).
The main ECG abnormalities in patients with
hypertrophic cardiomyopathy are included in Table
3.
In the overall population, these ECG findings are
relevant for HCM diagnosis, in the absence of any
other cause that justifies them.
In the European guidelines, performing a resting
electrocardiogram has a class I recommendation, with
level of evidence B, for the exclusion of cardiovascular disease that may cause sudden death in individuals who are going to practice either recreational or
competitive physical activity. In contrast, in the United
States, performing an electrocardiogram is not yet
recommended as precompetitive screening, not even
in high-performance athletes. (70)
Apical HCM is a particular form of hypertrophic
cardiomyopathy; its typical ECG (Figure 2) shows the
absence of Q wave in I, aVL, and V5 and V6; the presence of high R waves in V2 derivation; a rectified ST
segment elevation mainly in V2 derivation; and “huge”
and “pseudo-ischemic” negative T waves in the anterolateral wall. These ECG abnormalities, typical of
apical HCM, are not present in all cases, especially
during the early and late stages of the condition, in
which diagnosis is difficult and usually mistaken for
other conditions. (59, 71)
6
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
Table 3. ECG abnormalities in patients with HCM
P wave
1 Left atrial enlargement: negative portion of P wave in V1 ≥ 0.1
mV in amplitude with a duration ≥ 0.04 sec. 2 Right atrial
enlargement: P wave amplitude in II, III, or V1 ≥ 0.25 mV
QRS complex
1 Right axis deviation of the QRS complex in the frontal plane ≥
1200, or left deviation from -30º to -90º
2 Voltage increase:
- Of R wave in the frontal plane≥ 2 mV or in V5 and V6 ≥ 3 mV
- Of S wave in V1 or V2 ≥ 3 mV
- R or R’ in V1 e≥ 0.5 mV
- R/S relation ≥ 1
Q wave (except in aVR)
1 Duration ≥ 0.04 sec
2 Q/R relation ≥ 25%
3 Amplitude ≥ 3 mm in two contiguous derivations
4 QS pattern in two or more derivations 5 Absence of the normal
Q wave
QRS complex duration
Left or right bundle branch block with a duration ≥ 0.12 sec.
Ventricular repolarization
1 ST segment
- ST segment elevation or depression in two or more contiguous
derivations
2 T wave
- Flat or inverted in more than two derivations, except in children
- Amplitude ≥ 10 mm
3 QTc interval
- Duration > 0.44 sec. in men or > 0.46 sec. in women
Rhythm and conduction disorders
- Early ventricular extrasystoles or complex ventricular arrhythmias
- Supraventricular tachycardia, flutter and/or atrial fibrillation
- Short PR interval (0.12 sec) with or without delta wave
- Resting sinus bradycardia (rate ≤ 40 bpm)
- First-degree AV blocks (PR ≥ 0.21 sec., except in athletes),
second-degree and third-degree AV blocks
Thus, the ECG in apical HCM carriers may vary
substantially in some cases, when the ventricular
hypertrophy progresses to other regions of the ventricular myocardium, or when all or most of the left
ventricular apical region necroses. (71)
B. Echocardiography
HCM is morphologically defined as a hypertrophied
non-dilated left ventricle, in the absence of any other
systemic or cardiac disease capable of producing such
magnitude of parietal thickening; (8) that is why the
echocardiography is so relevant as diagnostic tool.
Transthoracic Doppler echocardiography is the
most common method for HCM diagnosis, either by
confirming the clinical and/or electrocardiographic
diagnostic presumption, or by incidental finding. It
Fig. 2. ECG of a patient with apical HCM.
also provides information about type and morphology
of HCM, diastolic and systolic ventricular function,
occurrence and severity of dynamic left ventricular
outflow tract obstruction, degree and cause of mitral
regurgitation, prognosis, some physiopathological aspects, and acute and chronic response to therapies.
The best diagnostic criterion is the presence of left
ventricular hypertrophy that should be ≥ 15 mm in
some ventricular region (20), and that it is often over
20 mm thick. In some patients, it may be below 15
mm; in these patients, HCM diagnosis must be considered when the parietal thickening cannot be explained by other cardiac or extracardiac reasons, such
as hypertension, stenosis or aortic regurgitation, amyloidosis, athletes, glycosphingolipid intracellular deposits, or Fabry disease). Asymmetric septal hypertrophy is another echocardiographic finding, defined
as the septum/posterior wall relation ≥ 13 mm. It is
also closely associated with HCM diagnosis. (72)
To differentiate HCM from athlete’s heart, it is
necessary to include information related to parietal
thickening, distribution patterns of hypertrophy, cavity size, assessment of diastolic function, Doppler tissue imaging, family history, and response to rest from
sports activities in certain cases. (73, 74)
As regards prognosis, echocardiographic detection
of parietal thickening e” 30 mm is considered a major
risk factor of sudden death, mainly among adolescents
and young adults. (75­77) Moreover, the echocardiogram determines the type and extent of the ventricular hypertrophic compromise, which often varies
from one patient to another; it may be concentric and
symmetric, septal with or without left ventricular
outflow tract obstruction, apical, a compromise of the
left ventricular free wall, or of the right ventricle. (78,
78 bis) In some cases, the nuclear magnetic resonance
allows to detect hypertrophic regions that are subdiagnosed by the echocardiography (3 out of 48 cases).
(79) Papillary muscle hypertrophy has recently been
defined as a diastolic thickness of more than 11 mm.
(16) In fact, little is known about the clinical meaning
of solitary papillary muscle hypertrophy. Some cases
in which solitary papillary muscle hypertrophy preceded the development of HCM phenotype have been
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
detected when screening HCM patients’ first degree
relatives. Solitary papillary muscle hypertrophy is
presumed to represent either a subtype of localized
HCM or the early-stage of HCM. (79 bis)
In addition, the echocardiography allows for the
detection of left ventricular outflow tract obstruction,
expressed by systolic anterior motion of the mitral
valve, and a dynamic subaortic gradient at that level,
which can be screened by color Doppler, and measured by continuous Doppler. Left ventricular outflow
tract obstruction is detected in 25% of the HCM cases,
and may be basal or be caused by a physical effort, by
the Valsava manouver, or by pharmacologic tests (amyl
nitrite) that reduce the precharge or post-charge, or
else that increase contractility. In every echocardiographic study of HCM, Valsalva maneuver is indicated
to trigger an increase in the subaortic gradient. The
presence of a gradient > 30 mm Hg is considered a
low risk factor of sudden death given its low positive
predictive value (14), and it is an independent
evolutive predictor of heart failure; the assessment
by stress echocardiography identifies the dynamic obstructive component in 70% of HCM patients, making it one of the most adequate forms of detection.
(13)
(4) It is important to remember, particularly if a
therapy is being defined, that more than one dynamic
obstructive component may coexist, or that it may only
occur at midventricular level. (83)
Mitral valve regurgitation generally occurs together with the obstructive form, since it is the result of the systolic anterior motion of the mitral valve,
and its severity is variable; in this situation, the jet is
usually directed to the left atrial posterior wall. (84)
But it is also observed in the 20-30% of non-obstructive forms. In this case, regurgitation is generally mild,
and is the result of an abnormality in the valve, such
as prolapse, cordal rupture, valve ring calcification,
chordae tendineae rupture, (85) or altered papillary
muscle position. A jet not directed toward the posterior wall suggests some kind of structural abnormality associated with these mechanisms.
The presence of diastolic dysfunction screened by
pulsed Doppler may precede the symptomatic stage,
and be detected even in the absence of dynamic obstruction. It is a risk factor for sustained ventricular
tachycardia and death in children. (86) Myocyte hypertrophy, myofibrillar disorganization, alteration of ventricular geometry, ischemia, and fibrosis are the
mechanisms responsible for disturbed ventricular relaxation that may reach a restrictive filling pattern of
E/A higher than 2, and shortened mitral deceleration
time (140 msec). Tissue Doppler imaging measures
the myocardial velocity gradient, and allows not only
to assess diastolic dysfunction, but also to differentiate the diagnosis from athlete’s hypertrophy or hypertrophy in hypertensive patients. A tissue e’ wave 7
cm/sec differentiates HCM patients from healthy athletes, whereas a tissue a’ wave 2 cm/sec identifies HCM
7
patients from hypertensive patients. (87) Some studies suggest that alterations in the tissue Doppler precede the development of hypertrophy in HCM, so it
would be an early marker of the disease. (88, 89)
Systolic function assessment by tissue Doppler
imaging also shows significant alterations with clear
reduction of tissue s’ wave at septal level; this alteration is present even in the absence of hypertrophy,
and it is the field of study for preclinical and differential diagnosis of this condition. (90, 91)
Serial assessment of the systolic ventricular function is also a follow-up parameter, since a small
number of patients progress at a later stage to the
systolic dysfunction with parietal thinning and ventricular dilation, developing congestive heart failure
in its final stage. (81, 92, 93) On the other hand, it is
important to point out that the rates of ventricular
ejection function are not helpful to define the contractile state involvement in this condition.
Systolic myocardial deformation (systolic strain)
is involved in HCM, and it has been shown in several
works that its assessment is helpful for the differential diagnosis between non-obstructive HCM and hypertensive hypertrophy, (94, 95) since all systolic strain
components (longitudinal, transverse, circumferential,
and radial) are decreased compared to the control. (96)
Since HCM spreads in autosomal dominant form,
with a high level of penetrancy in most of its forms,
echocardiographic assessment should be prescribed
to all first-degree relatives. (82, 97) For children under 12, assessment is indicated only when symptoms
appear, when the family history of HCM includes high
risk factors, or when the child takes part in competitive sports. Most HCMs develop between the ages of
12 and 18, so it is advisable to start echocardiographic
assessment during adolescence, and repeat it annually. For people over 21, reassessment is encouraged
every 5 years.
The transesophageal echocardiography is another
useful tool for the transthoracic approach in patients
with inadequate echographic window, for completing
the assessment of complex mechanisms of mitral regurgitation, or during the therapeutic processes of
septal alcoholization and myomectomy. Detection of
new alterations in 17% of the cases and modifications
in intraoperative behavior in up to 9% of the cases
has been reported for this condition. (98)
Contrast echocardiography is a fundamental support for the treatment of HCM with dynamic subaortic
gradient, through septal ablation with ethanol infusion. It allows accurate delimitation of the extent of
the vascular territory corresponding to the septal artery, prior to infusion; this way, the extent of the infarction is determined, since it should be remembered
that this is a case of “planned but uncontrolled infarction”. In addition, since the anatomy of the septal
perforating branches is extremely variable from one
patient to another, (99) the use of contrast has reduced the procedure time, the amount of injected al-
8
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
cohol, and the infarction size; it has also improved
the procedure success (100) by reducing complications
such as the atrioventricular block that requires permanent pacemaker implantation. (101­103)
The echocardiography and the Doppler have
proved very useful in late follow-up after therapeutic
procedures such as septal alcoholization, by documenting progressive gradient reduction with the passing
of time, with parietal thickening reduction. (104)
Conclusions and recommendations
Transthoracic Doppler echocardiography
Class I (level of evidence B)
– Confirm HCM diagnosis by determining parietal
thickening, extent of the compromise, and presence, magnitude and location of the dynamic gradient.
– Research for HCM in first-degree relatives. -Reassessment after changes in clinical evolution, or after therapeutic maneuvers. -Myocardial contrast
echo to assess the infarction size resulting from
septal ablation.
Class II (level of evidence C)
– IIa Reassessment of relatives for HCM, annually
between the ages of 12 and 18, and every five years
over 21.
– IIa Tissue Doppler imaging to differentiate HCM
from hypertrophy due to hypertension, or in athletes.
– IIb Exercise echo stress test in symptomatic patients with exertion in their daily lives who do not
show significant gradient at rest or with Valsalva
manouver.
Transesophageal Doppler echocardiography
Class I (level of evidence B) -Patients with inadequate
transthoracic ultrasound window.
– Determine the valve involvement, mechanism, and
magnitude of mitral valve regurgitation when they
are not clearly set by transthoracic echocardiography (TTE).
– Intraoperative study in myomectomy and in septal ablation with ethanol procedures.
Class IIa (level of evidence B)
– Study to clarify the mechanism of atypical mitral
regurgitation.
– In order to provide surgeons with more orientation, ­the following should be assessed in the operating room:
­ marked septal protrusion
- more mitral-septal contact
6. NATURAL HISTORY AND TREATMENT
Life expectancy for HCM patients is variable, but in
general it does not differ from that of the general population (1% mortality/year). However, there are fami-
lies with multiple early sudden deaths (SD); their identification continues to be one of the biggest challenges
in this disease. (4, 5) Likewise, progress of symptoms
is very heterogeneous; some patients are asymptomatic for a long time, and others experience a complicated progress that includes congestive heart failure
(CHF) symptoms, atrial fibrillation (with systemic
embolism and/or CHF), SD, or, rarely, progress to endstage phase with CHF or SD. (7, 105) Infective endocarditis may develop in 4% to 5% of the patients, especially in the presence of LVOTO; it is usually located in the mitral valve, and sometimes in the aortic
valve. (106, 107)
Typical symptoms of this disease include dyspnea
on exertion, precordial pain (angor pectoris), and
presyncope and syncope –which, as mentioned above,
generally occur with a non-dilated ventricle and preserved systolic function, and due mainly to diastolic
dysfunction with myocardial ischemia and/or outflow
tract obstruction either with mitral regurgitation or
not. (7)
A. Medical treatment
HCM treatment focuses mainly on relieving the symptoms of heart failure and preventing sudden death.
Medical treatment is the first step, and it is generally
based on works carried out in 1960s. It is important
to point out that none of the drugs have proved useful to prevent sudden death or improve survival.
1) Beta blockers
Beta blockers are the cornerstone of the medical
therapy; most of the few works were carried out with
propranolol. (108116) It was observed that beta
blockers, together with exercise and decrease in basal obstructive gradient, improved angor, dyspnea, dizziness, and syncope. The negative inotrope and
chronotrope effects reduce myocardial oxygen consumption, and also improve diastole by prolonging it
rather than by a direct lusitropic action. (92) In patients with LVOTO, this improvement in diastolic filling entails an increase in volume and a decrease of
the obstruction. (117)
The first double blind study with propranolol versus practolol and placebo was carried out in England
in 1973: 16 patients (15 with LVOTO) were treated
for 4 weeks. With respect to placebo, propranolol reduced the frequency of angina and dyspnea, and
practolol was less effective (which has a certain degree of inherent sympathomimetic action). (118)
2) Calcium blockers
Since a significant number of patients do not respond
adequately to beta blockers, other negative inotrope
drugs have been tested, such as calcium blockers. The
most studied one is verapamil; (119131) it reduces
LVOTO and improves symptoms due to its negative
inotropic effect. (123126, 129, 131) Moreover, it has a
pronounced effect on diastole, since it causes ventricu-
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
lar relaxation, diastolic filling improvement, and decrease of LV filling pressure; (123­131) coronary
perfusion improves by direct effect. (128, 129)
Verapamil should be used very carefully, since due to
its pharmacological effects (peripheral vasodilation,
contractility decrease, and electrical conduction decrease), it may cause a reduction in postcharge with
increase of LVOTO, reflex tachycardia, and acute pulmonary edema or sudden death in LVOTO patients
with pulmonary hypertension or congestive lung. It
may also cause sinus dysfunction, and different degrees of AV block. (121)
Verapamil was compared to a beta blocker in two
studies. In the first double-blind study, Rosing et al.
administered placebo, verapamil, or propranolol to 19
patients with HCM (17 with LVOTO). Both drugs had
similar beneficial effects regarding exercise duration
improvement. The subjective assessment favored
verapamil, largely because of the asthenia on propranolol. (130) Gilligan et al. compared placebo to 80
mg of nadolol and 240 mg of verapamil in a double
blind design on 18 HCM patients (8 with LVOTO);
despite neither of the drugs showed objective improvement on exercise, symptoms were reduced with
verapamil. (131)
In spite of its beneficial effects on the diastolic function, diltiazem (132, 133) and dihydropyridines
(nifedipine) (134, 135) should be avoided in HCM because of their significant vasodilation effect.
3) Disopiramide
This drug is not available in our country. It is a class
I antiarrhythmic medication that could particularly
benefit those patients with atrial fibrillation and
HCM; this drug has a negative inotropic effect mediated through sodium-calcium exchange. (7, 117, 136­,
140) It decreases the gradient for LVOTO by means
of this mechanism, and also by causing systemic vasoconstriction. It has anticholinergic effects (with
uncomfortable side effects, such as urinary retention
and dry mucoses) that may cause accelerated atrioventricular nodal conduction; for this reason, it should
be administered together with beta blockers. A recent retrospective non-randomized multicentric study
poses a proarrhythmic effect of this drug; therefore,
QT should be periodically checked. (141) In general,
it is used when symptoms cannot be relieved with
betablockers or verapamil.
B. Therapy options for patients who are refractory
to drug therapy
1) Surgical treatment
There is a small group of patients (5% from non-specialized centers; may reach 30% from referral centers)
whose symptoms persist (dyspnea and/or angor NYHA
class III or IV) in spite of maximum doses of medication; they also have resting LVOTO or during exercise, equal to or higher than 50 mm Hg. At present,
9
transaortic septal myectomy (also known as Morrow’s
surgery) is considered the election therapy and the
“gold standard” in the treatment of these patients.
(92, 142­, 147) The classical septal myectomy is performed with extracorporeal circulation and cardiac
arrest with cardioplegia; by the resection of the proximal septal muscle (2 to 5 grams), it enlarges the LVOT,
and eliminates the drag forces (Venturi effect) that
cause the contact between the anterior mitral valve
leaflet and the hypertrophied septum, resulting in
reduction or abolition of LVOTO. Very recently, a
group of surgeons created a modification consisting
in an enlarged resection with greater distal expansion that allows for more adequate LVOT reconstruction, necessary for certain patients. (148, 150) Mitral
valve repair or replacement surgery may be performed
in patients with severe mitral regurgitation due to
intrinsic mitral valve disease (myxomatous valve).
(148­150) The learning curve to perform this procedure is important; the initial surgical experience was
associated with complete atrioventricular block, VSD,
damage to the mitral and/or aortic valves, incomplete
decrease of the LVOT obstruction, and operative mortality equal to or lower than 5%. However, over the
past years, the outcomes of this surgery in the few
specialized centers of United States and Canada have
been positive, with a mortality rate of almost 0%. (151)
Surgical risk is usually higher for elderly patients with
comorbidities, highly symptomatic and with pulmonary hypertension, and for those undergoing other
heart surgery procedures (coronary surgery, valve replacements). At present, complete atrioventricular
block (which requires permanent pacemaker implantation) and iatrogenic ventricular septal defect are
very rare (1-2%), whereas incomplete or complete left
bundle branch block is an almost inevitable outcome
of a correct myomectomy, and does not imply future
risks. (146) As it has already been mentioned,
intraoperative TEE is very useful for the surgeon in
guiding the septal myectomy extension, and in assessing the mitral valve disease and the outcome on regurgitation. (98) Both the obstruction relapse and the
need for reoperation are very rare. Myectomy outcomes are immediate and permanent: there is abolition of the LVOT mechanical obstruction (and of the
mitral regurgitation), with normalization of ventricular pressures and decrease or disappearance of
dyspnea and syncope, and with improvement of the
functional capacity and quality of life. (142, 147, 149,
152, ­154) In a recent analysis, 85% of the patients
were asymptomatic or slightly symptomatic (NYHA
class I or II dyspnea) in mean follow-up of 8 years
(and up to 25 years) after septal myectomy. (155)
In addition to symptomatic improvement, septal
myectomy has improved survival for these patients
compared to those who did not undergo surgery, and
has achieved a life expectancy similar to that of patients without that condition. Survival free from allcause mortality is 98%, 96%, and 83% in 1, 5, and 10
10
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
years, and survival free from HCM mortality (sudden
death and heart failure) is 99%, 98%, and 95% respectively. (155, 156)
In short, the advantages of septal myomectomy are
the immediate and permanent reduction of the symptoms, and survival improvement; as the surgeon has
a direct view of LVOT, he can identify mitral valve
pathology correctly; it does not form scar, it rarely
requires reoperation or pacemaker implantation, and
it allows to repair associated cardiac defects (subaortic
stenosis, mitral and aortic valve diseases, coronary
surgery). The disadvantages include the need for an
experienced surgeon, and the median sternotomy that
requires an in-hospital recovery period of 4 to 7 days.
(157)
Indication for myomectomy
Class I (level of evidence B)
– Patients showing NYHA class III­-IV symptoms
that are refractory to medical treatment, and a gradient at rest or during exercise ≥ 50 mm Hg with
septal thickness ≥ 18 mm, at surgery centers with
experience in this condition and low morbimortality.
2) Percutaneous septal ablation
In 1995, Sigwart (158) was the first one to describe
the occlusion effect followed by absolute ethanol embolization of septal perforating branch in LVOT pressure gradient in HCM patients with LVOTO (PSA).
At the same time, two centers from Germany shared
their experience on several hundreds of patients,
which they called transcoronary ablation of septal
hypertrophy (TASH). (159)
The major experience in the United States corresponds to the group from the Baylor College of Medicine, in Houston, (160) whereas in Europe, the German PSA registry has reported a significant number
of cases. (161)
At present, this technique has been spread all over
the world, and about 3,000 patients have been reported in a recently published revision. (162)
As we have mentioned, percutaneous septal ablation (PSA) with alcohol is a less invasive alternative
to surgery. This is a percutaneous technique that consists of injecting absolute ethanol in order to cause a
controlled infarction of the basal interventricular
septum to decrease its thickness. The final outcome
is the reduction in LVOT pressure gradient. (162, 163)
At first, gradient reduction is due to deterioration in
basal septum contraction, but then there is further
reduction due to thinning and fibrosis at this level.
This process leads to an increase of left ventricle diameters, a decrease of the systolic thickness and of
mitral regurgitation and, therefore, the subsequent
ventricular remodeling. (164)
However, correct selection of patients as to who
and when undergo surgery is controversial; moreo-
ver, interventional physicians are not properly trained.
This issue has induced some groups with vast experience in this cardiomyopathy to suggest that this technique should be indicated only for those patients with
comorbidities that increased their surgical risk. (157,
165)
The procedure is performed under the general
characteristics of a percutaneous coronary intervention, but taking into account that:
1. Coronary arteriography provides anatomic information regarding septal perforating branches
(their degree of development, magnitude of the irrigated area, the presence of collaterals, etc.). But
the presence of possible obstructive coronary lesions can also be identified; this would probably
lead to rule out the procedure for these patients.
2. A pacemaker lead should be placed inside the right
ventricle, since nearly 20-30% of the patients have
transient AVB during ablation. As opposed to surgery, PSA usually causes right bundle branch block.
3. Next, what follow are the steps in a conventional
coronary angioplasty, complete heparinization,
guide catheter, wire 0.014" used to canalize selectively the first septal branch or, otherwise, the
major adjacent septal branch (the first septal
branch should be avoided if it is of small caliber
and extension, since it often provides abundant
collaterals to the venous system). An over the wire
(OTW) balloon, with 1.5 or 2.0 mm diameter, is
inserted. Once in place, the balloon is then inflated
until the desired branch is occluded, in order to
eliminate the flow and avoid the eventual retrograde effusion. The wire is then removed; dye is
injected through the balloon lumen to opacify the
distal territory of the involved branch. This is a
very important step of the procedure, because the
amount of myocardium at risk, the dynamic characteristics (magnitude of gradient reduction), the
presence of collaterals to other coronary territories, etc. are assessed. It is at this step when the
contrast echocardiography and the experience of
the operator play a key role, since the procedure
should not be continued if there are no significant
changes in the gradient (this piece of information
can also be obtained through the invasive measurement of simultaneous left ventricular and aortic pressures), but even more if motility disorders
are observed in a wide territory that expresses the
potential infarction that alcoholization can cause.
The use of contrast echocardiography has probably helped to better identify the involved territory, resulting in less complications. (99­102)
4. Before deciding to administer alcohol, gradient
reduction of at least 30% should be checked for. In
general, for both basal and provoked gradients, the
reduction is 50%, or they disappear completely; this
usually occurs a minute after the balloon has been
inflated, and once the contrast dye has been injected. Then the absolute alcohol infusion is started
11
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
(96% ethanol), between 1-2 ml, slowly, because it
has been demonstrated that the incidence of total
AV block is related to the rate of administration,
among other reasons. (166)
5. Once the procedure is over, the patient will stay in
the intensive care unit for two days.
PSA is considered successful when there is a gradient reduction in the cardiac catheterization laboratory. Creatine kinase increases as an expression of the
infarction size (about 1,000, which would be equivalent to a necrosis area of 20% of the septum size, or 310% of the left ventricular mass).
A progressive gradient reduction in the following
6 to 12 months is sometimes observed, moment in
which it reaches the same outcome as the surgery. In
other cases, gradient reduction can be obtained with
a bimodal response, that is, an initial reduction followed by an increase of almost 50% the following day,
and then a definitive reduction in the following
months. (160­162) This may occur because once the
infarction occurs, it is followed by an inflammatory
process with interstitial edema, resulting in a new
reduction of the LVOT. Finally, once the scar is consolidated with the septal and left ventricular reconstruction, definitive gradient reduction is achieved,
with no significant fall in left ventricular ejection fraction.
Improvement of symptoms, and therefore of quality of life, is immediate in most patients, who show a
decrease in functional class (mostly in FC I), and an
increase in exercise tolerance and oxygen consumption. (160, 162) Since its introduction, PSA has undergone modifications that have lead to significant
reduction in morbimortality. The rate of complications
is relatively low; intraprocedural mortality is 0-5%,
and it is generally due to anterior descending artery
dissection, cardiac tamponade, or cardiogenic shock.
(167) The most common complication is the atrioventricular block, which was close to 20-30% according to initial series. At present, it is about 10%, probably due to decreasing the total volume of injected
alcohol and the rate of infusion, among other reasons.
However, the early success of PSA over time is discussed, especially if it is compared to septal myomectomy outcomes. Even though there are few studies
that compare surgery with PSA directly, and none of
them are randomized, trials show similar outcomes,
although it is possible that myectomy could get higher
early reduction in LVOT gradient. (103)
Observational studies prove that gradient reduction holds a value of ≥ 20 mm Hg in a two-year followup (166), and there are data that these values are held
for more than 5 years. Exercise tolerance, functional
class, and diastolic function undergo a similar evolution to that of the gradient.
To date, the true impact on sudden death incidence
is still unknown, since some argue that, due to the
scar it forms, PSA is adding an arrhythmogenic
substrate to a disease that already has one. (157) Conversely, studies have been carried out in which induction of re-entry ventricular arrhythmias was attempted, with no success. These data are important
when considering this treatment for a young person.
As selection criteria, we could confirm that eligible patients are those who have symptoms uncontrolled with complete medical treatment, those with
symptoms of heart failure (functional class III), with
asymmetric septal hypertrophy of at least 18 mm thick
confirmed by ultrasound, with the classical anterior
movement (SAM) of the mitral valve, and those patients who have a gradient at rest
or during exercise ≥ 50 mm Hg showed by the Doppler register, with accessible septal branch, absence
of atherosclerotic disease in the proximal anterior
descending artery, or severe involvement of three vessels. (117) As a result of what has been said, we could
undoubtedly confirm that percutaneous septal ablation is effective in reducing the LVOT gradient in
hypertrophic cardiomyopathy, and in achieving significant improvement of the symptoms of this disease.
However, these outcomes depend on a correct selection of the patients to be treated, together with an
adequate learning curve on the part of the interventionist group.
While data from late follow-up do not exceed 10
years, initial outcomes would seem to be the same
over time, and are compared to those obtained through
surgery. (168) Further randomized trials compared
with septal myomectomy would be necessary to give
an answer to this concern. Chances to carry them out
are low, or –in some experts’ opinions– even impossible. (169)
Indication for percutaneous septal ablation
Class IIa (level of evidence B)
– Patients showing NYHA class III-IV symptoms
who are refractory to medical treatment, with a
gradient at rest or during exercise e” 50 mm Hg
and septal thickness e” 18 mm, with accessible septal branch, no lesion in the anterior descending
artery and no three-coronary vessels lesion, and
with comorbidities that contraindicate surgical
myomectomy, in centers with experience in this
procedure and low morbimortality.
3) Pacemaker
Electrical stimulation in hypertrophic cardiomyopathy
DDD Stimulation with short AV When the stimulus
sent by a DDD pacemaker with programmed short
AV interval reaches the tip of the RV before the stimulus coming from the normal conducting system, preexcitation in the tip of the RV and the LV occurs. The
contraction sequence is inverted and it causes
dyssynchrony across the septal basal segments, which
produces paradoxical movement of the septum. The
12
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
septum is separated from the mitral annulus; this
increases LTOV diameter, reduces flow speed, and
reduces the systolic anterior movement (SAM) of the
mitral valve. As a result, the degree of mitral regurgitation, LTOV gradient, intraventricular pressure, and
parietal stress decrease, and the percentage of atrial
contribution to ventricular filling increases. (170­173)
Initial uncontrolled studies showed that DDD
stimulation with short AV reduces the LVOT gradient and improves the functional class in patients who
are refractory to medical treatment. (174­176)
Later on, a randomized crossover study on patients
with LVOT gradient at rest > 30 mm Hg showed that
DDD PM with short AV reduced the LTOV gradient
and the functional class, and improved symptoms with
a 3 year-long-term effect. (177, 178)
However, these outcomes did not coincide with the
outcomes of two minor randomized crossover studies. In one of them, the benefit was only evident in
patients over 65 years old with alteration of LV
diastolic function. The gradient was reduced in 3
months, but clinical improvement was only observed
in 12 months, which suggests a placebo effect. (179)
Despite DDD pacing with short AV produces improvement in many patients, there is no clear evidence
of who will benefit from this pacing. Gradient reduction is not correlated to clinical improvement in patients, so it is difficult to predict which ones will be
responders. (177­179)
For better therapeutic results:
1. The lead should be placed in the tip of the RV.
2. The short AV interval (shorter than the PR interval) should be the longest interval that, by causing maximum pre-excitation (wider QRS), provides
the longest diastole duration with the lowest LVOT
gradient and the optimal systolic volume.
3. The maximum programmed frequency limit should
be above the maximum heart rate during exercise,
so that the RV pre-excitation is not lost with the
stress.
There is no evidence that the DDD PM stops the
progress of the disease or reduces survival.
Clinical improvement and LVOT gradient reduction are lower than alcohol ablation or myomectomy.
Its main advantage is the programming and simplicity of the surgical procedure.
In view of the above said, it is recommended in
the following cases:
Class I
– Patients with obstructive HCM and sinus node disease or AV block, as a result of the natural evolution of the disease, secondary to septal myomectomy or septal alcoholization, or as a consequence
of the use of drugs required for the treatment,
when other alternatives are not valid. Level of
evidence C.
Class IIa
– Patients with obstructive HCM, refractory to
drugs, and contraindication for­ septal myomectomy or alcoholization. Particularly in the case of
elderly patients. Level of­ evidence B.
– Patients with high risk of sudden death that have
indication for ICD with significant LVOT gradient
at rest or with provocation maneuvers­ may benefit from DDD-ICD and ­ short AV interval.
7. SUDDEN DEATH
HCM is a disease characterized by having a benign
natural history for most patients. (7) However, one of
the biggest challenges in the assessment of this condition is identifying those patients with increased risk
for sudden death (SD). (75, 180) At present, HCM is
recognized as the most common cause of SD among
young people and those who practice sports competitively. (181­185) It should be pointed out that SD is
usually the first manifestation of this disease and
may occur in patients who have no premonitory
symptoms. (75)
The incidence of SD in HCM is almost 6% in tertiary care centers, and below 1% in non-selected
populations. While SD is more frequent among young
patients, it may occur in middle-aged persons, and in
20% of the people over 65. (186)
Several physiopathologic mechanisms leading to
SD have been proposed; these include atrial and ventricular tachyarrhythmias, diastolic dysfunction, systemic arterial hypotension, and myocardial ischemia.
(7) According to the International Consensus on HCM
in 2003, cardiac arrest due to documented ventricular fibrillation, spontaneous sustained ventricular
tachycardia, family history of early SD, syncope of unexplained origin, extreme ventricular hypertrophy, nonsustained ventricular tachycardia on Holter ECG, and
abnormal blood pressure response during exercise are
considered major predictors of SD (Figure 3). (7)
Possible risk factors for certain patients included
atrial fibrillation, myocardial ischemia, resting left
ventricular outflow tract obstruction, high-risk genetic
mutations, and vigorous exercise.
(7) Based on different publications from 2003 to
date, this group should also include young patients,
patients in the end-stage phase of HCM, patients who
have associated coronary artery disease, patients with
muscular bridges, those treated with alcohol ablation,
and those who evidence myocardial fibrosis. (27, 75,
187­193)
Sudden death due to documented ventricular
fibrillation and spontaneous sustained ventricular
tachycardia
Patients who have survived a ventricular fibrillation
event or spontaneous ventricular tachycardia are in
high risk of suffering a recurrent event, and should
13
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
receive an ICD as secondary prevention of SD. (194,
195)
Family history of early sudden death
Family history of early SD refers to one or more SD
in first-degree relatives before the age of 40. (92) Different studies have found out families whose members have identical genotype, but significant
phenotypical heterogeneity and completely different
prognosis. (196, 197) However, in clinical practice, the
presence of early sudden death in a family –particularly if it is multiple– is still a strong predictor of SD.
(198, 199)
Unexplained syncope
In HCM, syncope has low sensitivity and specificity
as SD predictor, since it may be caused by multiple
mechanisms, such as neurocardiogenic causes, supraventricular and ventricular arrhythmias, LV out-
flow tract obstruction, etc. (7, 200) Unexplained syncope has a value in children and young patients, or
when it is recurrent or occurs during exercise. (7,
201)
Extreme ventricular hypertrophy
Extreme ventricular hypertrophy is defined as the
ventricular wall thickness ≥ 30 mm, or its equivalent
in children. (76) There is a direct relationship between
the magnitude of cardiac hypertrophy and the risk of
SD. (76, 204) It is unusual to find such phenotypical
expression in patients over 50 years of age; this phenomenon could indicate that most of them died early
or presented ventricular remodeling with wall thinning. (77, 188) It is important to point out that while
this is a significant and easy to recognize risk factor,
the fact that the patient does not have extreme hypertrophy is not a synonym of absence of SD risk. (7)
Most patients with SD have a wall thickness < 30
* En los pacientes menores de 40 años se puede considerar la indicación de un CDI con un solo criterio mayor, salvo en el
caso de la respuesta anormal de la presión arterial durante el ejercicio, que tiene bajo valor predictivo positivo en forma
aislada, pero su valor aumenta cuando se asocia con mutaciones de la troponina T.
Fig. 3. Risk assessment for sudden cardiac death in HCM.
14
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
mm, and some even have normal wall thickness, as in
the case of those with troponin I and T gene mutations. (7, 196, 202) On the other hand, there are other
sites of hypertrophy, as in the case of apical HCM,
that –in the absence of other risk factors– usually have
a good prognosis. (7, 203)
Non-sustained ventricular tachycardia
Non-sustained ventricular tachycardia (NSVT) is considered a risk predictor of SD in HCM when the episodes are multiple and/or prolonged (with a HR3 120
bpm), and are evident on serial Holter ECG. (238)
The risk of SD due to NSVT in HCM is higher,
especially for young patients (under 30 years of age),
and for those who have a history of syncope or deterioration of systolic function. (187, 205­, 210)
Abnormal blood pressure response during exercise
Abnormal blood pressure response during exercise
occurs independently from whether the patient has
some form of obstruction or not. An exaggerated fall
in systemic vascular resistance or a diffuse subendocardial ischemia that leads to systolic dysfunction have been
the possible mechanisms proposed. (32, 211) The point
to be made is that this finding is clinically significant if
the stress test is performed with no drug effect.
Blood pressure response may be plain: high systolic
blood pressure < 20-25 mm Hg, or hypotensive: low
blood pressure > 15 mm Hg). It occurs in 22-37% of
the patients; in individual cases, it has a low positive
predictive value, and its value increases when it occurs in patients under 50 years of age (especially in
children or adolescents), and in cases associated with
troponin T mutations. (7, 212)
Left ventricular outflow tract obstruction
It has recently been demonstrated that HCM is mainly
an obstructive disease. (13) It was evidenced in two
different series that the left ventricular outflow tract
obstruction (LVOTO) has a low predictive value for
SD, 7% and 9% respectively. (14, 214) Therefore,
LVOTO is not enough to indicate an ICD as primary
prevention, and its predictive value increases when it
is associated with other risk factors. (215)
Atrial fibrillation
As commented above, atrial fibrillation (AF) in HCM
is an independent predictor of morbidity and mortality due to heart failure and stroke. (31, 105) At the
same time, atrial fibrillation can trigger malign ventricular arrhythmias, especially in the case of high
ventricular response. (216) However, evidence is not
yet enough to determine if the control of AF frequency
or rhythm may have an impact on SD prevention in
HCM patients. (199)
Myocardial fibrosis and ischemia
The main mechanisms that can cause ischemia in
HCM include: intramural small vessel disease, left
ventricular hypertrophy, muscular bridges, microvascular dysfunction with inadequate vasodilation, and
epicardial coronary artery disease, which occurs with
the same frequency as it does in the general population. (23, 217, ­220) A relationship between SD in
HCM and the presence of ischemia assessed with different non-invasive methods has been found out. (23,
217, 219) At the same time, the areas with myocardial fibrosis in HCM patients act as substrate for the
appearance of potentially malign ventricular
tachyarrhythmias. The areas with myocardial fibrosis may be detected by nuclear magnetic resonance
imaging with gadolinium. (221) There is not enough
evidence to indicate an ICD for primary prevention of
SD, just by presenting ischemia and/or fibrosis in the
absence of other risk factors. (199)
Vigorous exercise
HCM is the most frequent cause of SD in athletes.
(183, 184) It can occur with no previous symptoms,
and it has a significant social and emotional impact.
Patients diagnosed with HCM should be discouraged
from taking part in sports; they can only practice lowintensity sports like golf or bowling (184, 185) (see
Exercise and HCM).
Young age
The age at which it occurs is considered a significant
variable for risk stratification. (189, 199, 222) Sorajja
et al. have demonstrated, for example, that the annual incidence of SD in patients with extreme LVH is
2.2% for individuals under 30, and 0.73% for the age
group of 30-59. (189, 199) Monserrat et al. have demonstrated that the odds ratio for SD in patients with
documented NSVT is 4.35 (p = 0.0006) for those under 30, and 2.16 (not significant) for patients over 30.
(205)
End-stage phase of hypertrophic cardiomyopathy
During the end-stage phase of HCM, defined as an
ejection fraction lower than 50% at rest, patients usually progress to severe clinical deterioration; it is also
an important risk factor of SD. (187) For that reason,
this subgroup of patients should be indicated for an
ICD as a bridge to cardiac transplant. (213)
Muscular bridges
Muscular bridges in the anterior descending artery
increase the risk of sudden death in children, probably mediated by myocardial ischemia. (218, 223)
However, this relationship is not very clear in adults,
and the need to perform a routine invasive coronary
angiography to discard this condition reduces the incidence of muscular bridges as a risk factor of SD. (7)
Alcohol ablation
Alcohol ablation favors the development of a myocardial scar that acts as a substrate for ventricular
arrhythmias in a condition that is inherently
15
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
arrhythmogenic by nature. (224) Both early ventricular arrhythmias –that may occur during or immediately after alcohol ablation– and late ventricular
arrhythmias (i.e. that occur 72 hours following postablation) have been described. (191­, 193) HCM patients usually have polymorphic VT; however, patients
who underwent alcohol ablation evidenced monomorphic VT with left bundle branch block image, which
is a patent consistent with arrhythmias due to re-entry in the infarcted area and whose outflow tract is at
the interventricular septum level. (191) It is precisely
that risk for ventricular arrhythmias that made experts suggest that this procedure be carried out only
in patients contraindicated for surgery, such as the
elderly or those with concomitant diseases that increase surgical risk. (7)
Genetic testing
The diagnostic performance of genetic testing is 40%
on average (38, 225); so far, no prognostic usefulness
has been shown, since the phenotype depends not only
on the primary causal mutation, but also on the interaction with other genes, and on environmental factors. (226, 227) The tests to assess the genotype-phenotype correlation were performed on a reduced
number of patients or selected families, and in fact a
large number of families with positive genotype would
be necessary in order to determine if this relationship is present with other genes. (228) Genetic testing should not be indicated in a routine way to stratify
the risk of SD, and its usefulness is currently limited
to research studies. (227, 228)
Other complementary tests
The analysis of variability in the autonomic tone, the
high-resolution electrocardiogram, and the QT interval dispersion may be altered, but they are not useful
to identify high risk patients. (229, 230) Patients can
also have sinus node dysfunction, bradyarrhythmias,
AV block, and supraventricular arrhythmias. (230) As
for the electrophysiological study (EPS), it does not
appear to be efficient in the risk stratification of these
patients. (231, 232)
It is important to perform the following tests to
identify high-risk patients, particularly in those under 60 years of age: research into personal and family
history; cardiac echo-Doppler to assess the magnitude
of the hypertrophy and the ejection fraction, and to
determine if there is outflow tract obstruction; 48hour Holter monitoring to detect NSVT; graduated
stress test or, preferably, exercise stress echocardiogram to detect ischemia; assess blood pressure
during effort to determine if the patient has a latent
or provocable gradient with exercise. (7, 229) These
tests should be performed periodically, and when clinical changes are perceived. (7, 233) Recently, it has been
observed that T wave alternans voltage is present in
high-risk HCM patients, compared to controls; also,
a significant association between this finding and the
presence of NSVT in Holter monitor has been found.
(234, 235) Anyway, the evidence is currently poor to
consider this factor a SD predictor for HCM patients.
(199)
Therapeutic alternatives for HCM patients with
high risk of SD
Implantable cardioverter-defibrillator for primary
and secondary prevention of sudden death
Patients resuscitated from SD, and symptomatic patients due to ventricular tachycardia and/or syncope
related to ventricular arrhythmia have indication for
implantable cardioverter-defibrillator (ICD) as secondary prevention. (7, 180) A consensus has also been
currently reached on the indication for ICD as primary prevention for patients with significant risk factors of SD. (7, 180)
About 45% of HCM patients have evidence of increased risk, and only 3% of those with no risk factors experience SD. (75) It is also important to point
out that prognosis is more ominous when two or more
risk factors are associated. (75) At present, whether
it is necessary only one risk factor for primary prevention or whether patients must combine two or
more criteria is still controversial. It should be pointed
out that indication for ICD as primary prevention is
considerably different depending on the country of
origin, healthcare system, accessibility to devices, and
opinions from different experts. (182, 204, 233) Maron
et al. studied the ICD efficacy in preventing SD on
128 high-risk HCM patients over a three-year period.
For those who received ICD for secondary prevention,
the discharge rate was 11% per year in 40% of patients, and for those who received ICD for primary
prevention the appropriate discharge rate was 5% for
11.8% of the patients. (236) Maron et al. (6) have recently published a work that included 506 patients
from 42 different centers, with a follow-up period of
3.7 years. Appropriate ICD discharge rates for primary and secondary prevention were 11% and 4.4%
per year, respectively. In this work, it was evidenced
that the time from ICD implantation to the first appropriate shock may reach up to 10 years, and also
that one third of the patients under primary prevention who received appropriate shocks presented only
one risk factor. (6) This way, authors consider that
just one risk factor is enough to indicate ICD implantation for primary prevention of SD in certain patients.
(6) However, the authors clarify that indication for
ICD when there is just one risk factor should not apply for all patients. (6) For instance, SD is relatively
less frequent in elderly patients, and ICD should not
be indicated for these patients if the only risk factor
is, for example, syncope of unknown cause. (6, 237)
In Table 4, there is a summary of recommendations
and levels of evidence available, to indicate for ICD
for secondary and primary prevention of sudden cardiac death in HCM. (237, 238) On the basis of this, we
16
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
have developed an algorithm to be used as a guide to
select patients who can benefit from this therapy (see
Figure 3).
The rate of inappropriate shocks and complications
related to ICD implantation is high, and it should be
taken into account at the time of deciding whether or
not to implant these devices. (6, 239)
left ventricular remodeling with cavity dilation, and
this process is not complete in 48% of these patients,
including those with pronounced hypertrophy and
non-dilated cavity. (187) Clinical evolution of the endstage phase is variable, but it is generally unfavorable,
and usually adopts an aggressive course with significant clinical deterioration. (187, 242­247)
Mortality rate for end-stage phase is 11% per year,
and it increases to 50% per year for advanced cases.
(187, 242) The mechanisms responsible for the transformation of typical HCM into end-stage phase are
not fully clarified. Fighali et al. (243) showed that the
incidence for heart disease, muscular bridges, dynamic
outflow tract obstruction, and previous septal myomectomy is similar among patients who develop left
ventricular hypokinesia, and among those who do not
develop it. It is postulated that this process is the result of recurrent myocardial ischemia due to microvascular dysfunction. (218, 248, 251) Several arterioles
show an increase in their wall thickness with the resulting luminal narrowing, which provides the mechanism that determines ischemia and fibrosis replacement. (218, 248, ­251) HCM occurs with a decrease in
the coronary blood flow reserve, together with structural changes in microcirculation (coronary
remodeling), including a reduction of the arteriolar
density that is inversely correlated to myocyte hypertrophy. (22, 252, 253) Microvascular dysfunction may
precede clinical deterioration for several years. (218)
By means of the positron emission tomography (PET),
Cecchi et al. (218) evaluated the response to
dipiridamol, and showed that the degree of microvascular dysfunction is an independent predictor of clinical deterioration and death. Later, Olivotto et al. (248)
Pharmacological therapy
Various drugs have been proposed to prevent SD in
HCM, including β-blockers, calcium blockers, and various antiarrhythmics, but none of them has proved
effective in reducing this risk. (240, 241) Recently,
Maron et al. evidenced that 25% of the patients with
appropriate ICD shocks were taking amiodarone; this
shows the relative inefficacy of antiarrhythmic drugs
to prevent SD in these patients. (6, 15) In spite of
this, amiodarone therapy is used both for secondary
and primary prevention when ICD is not available or
is rejected by the patient (238) (see Table 4).
8. END-STAGE PHASE OF HCM
While HCM is usually associated to diastolic dysfunction, a few number of patients show a progressive
deterioration of systolic function, called end-stage (ES)
phase, defined by an ejection fraction at rest < 50%.
(187, 242) The reported prevalence of the end-stage
phase varies from 2.4% to 15% in different series. (187)
Harris et al. (187) studied 1,259 HCM patients and
found out 44 (3.5%) in end-stage phase with systolic
dysfunction (previous bibliography was limited to
small­groups, and have overestimated end-stage phase
occurrence). Most patients in end-stage phase show
Recommendation
Level of
evidence
I
B
Amiodarone
C HCM patient resuscitated from SD or syncope with SVT
and/or documented VF (when the ICD is not available or
is rejected by the patient)
IIa
C
Primary prevention
ICD
HCM with a major factor and two minor factors, or with
two or more major risk factors for SD
IIa
C
Amiodarone
HCM with a major factor and two minor factors, or with two or
MORE major risk factors for SD (when the ICD is not available or
is rejected by the patient)
IIb
C
Secondary prevention
ICD
Patient with HCD resuscitated from SD or syncope with SVT and/or
documented VF
HCM: Hypertrophic cardiomyopathy SVT: Sustained ventricular tachycardia. VF: Ventricular fibrillation. ICD:
Implantable cardioverter-defibrillator. SD: Sudden death.
Table 4. Prevention of sudden
cardiac death in patients with
hypertrophic cardiomyopathy
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
confirmed that microvascular dysfunction is a longterm strong predictor of adverse left ventricular
remodeling and systolic dysfunction in HCM. On the
other hand, some authors suggest that progression to
dilation may be genetically determined. (254­, 256)
Some patients improve with an optimal pharmacological therapy, or with other therapeutic alternatives
–such as biventricular pacing, resynchronization
therapy–, but a large number of them evolve with
rapid clinical deterioration and death due to heart
failure or sudden death. (187, 242, 257, 259) These
patients should be assessed for cardiac transplant, and
the indication for an ICD as a bridge to such procedure should also be considered for them. (242, 244,
245, 260)
9. EXERCISE AND HCM
The relationship between exercise and HCM can be
approached from two different perspectives. On the
one hand, by assessing the disease through stress
tests, and on the other hand, by recommending HCM
patients regarding sports and different physical activities.
A. Exercise tests and HCM
For a long time, ergometric test has been contraindicated in HCM patients. At present, its use has been
spread to stratify the risk, and to get prognostic information. The stress test provides independent value
to identify patients with an increased risk for sudden
death, and is included in the prognostic algorithm for
decision-making of preventive treatments. Together
with the measurement of peak O2 consumption (VO2),
this test has a key role in the differential diagnosis
from other conditions related to left ventricular hypertrophy (LVH), such as the athlete’s heart.
Assessment of functional capacity
Many HCM patients have their exercise capacity reduced. Cardiopulmonary exercise test is particularly
useful to evaluate the degree of intolerance to exercise and the causes of this intolerance. The peak VO2
is a useful marker of functional capacity in this population.
When compared to healthy controls, HCM patients
have lower peak VO2 values. Recent studies have
shown a positive correlation between the peak values
of ventilation equivalents for CO2 with pulmonary
pressure measures at rest, whereas there has been a
negative correlation between peak VO 2 and these
hemodynamic measures. (261)
From the cardiological point of view, the VO2 is
determined by the minute volume (MV) and the arteriovenous oxygen difference (dAVO2). During exercise,
VO2 increases as a result of the increase of these components.
HCM patients may show an inadequate increase
in SV during exercise, which may be due to inadequate
17
diastolic filling caused by ischemia, left ventricular
hypertrophy, and/or intramuscular fibrosis.
On the same note, some HCM patients present
skeletal myopathy with lower mitochondrial density
and lower peripheral extraction of O2.
In patients with LVOTO and intraventricular gradient at rest, there is an inverse linear correlation
between the gradient magnitude and the peak VO2.
This suggests that severe mechanical obstruction is
an important factor in exercise limitation.
Patients with abnormal response to systolic blood
pressure during exercise have significantly lower peak
VO2 anaerobic threshold, O2 pulse, and higher VE/
VCO2 slope, in comparison with those with normal
pressor response. (262)
In several HCM patients, the anaerobic threshold
is recorded early during exertion; this variable is due
to the inadequate reduced systolic volume caused by
metabolic demands of the exercised muscle. In these
patients, the O2 pulse (VO2 per beat) –a reflection of
the systolic volume– is usually reduced.
The ventilation/VCO2 slope is usually higher than
in healthy individuals. Two mechanisms are involved:
1) hyperventilation, or 2) ventilation/inadequate
perfusion due to lung perfusion abnormality during
exercise, secondary to the low cardiac output.
Cardiopulmonary exercise test is a useful method
for the differential diagnosis between HCM and the athlete’s heart or physiologic hypertrophy. While there are
multiple electrocardiographic and ultrasound variables
and signs that help differentiate them, there is a small
number of individuals who fall in the “shaded area”, in
which the differential diagnosis may be more difficult.
Sharma, McKenna et al. compared four groups of
patients: 1) HCM patients, 2) recreacional athletes,
3) elite athletes with LVH, and 4) elite athletes without LVH. There were no significant differences in cardiopulmonary parameters between the elite athletes
with and without LVH. (263) Peak VO2, aerobic
threshold, and O2 pulse values are high in elite athletes. Recreational athletes had higher peak VO2 than
HCM patients. There was no overlap in values among
the groups.
A cut- off peak VO2 value > 50 ml/kg/min or > 20%
over the theoretical maximum, an AT > 55% over the
theoretical maximun, and an O2 pulse > 20 ml/beat
differentiated HCM individuals from trained athletes.
Arrhythmia assessment
While the stress test is not the method to be chosen
for studying arrhythmias in HCM, sometimes it can
show them up even if they have not been detected
through 24-hour Holter monitoring.
ST segment changes observed during stress test
ST segment depression is frequent when there is LVH;
its specificity to detect associated coronary artery disease is low, and it is one of the confounding factors in
diagnostic stress test interpretation.
18
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
The probable mechanisms are related to systolic
compression of intraparietal small vessels, poor capillary development compared to the increase of myocardial mass, structural disease in small caliber arteries with disturbance in the vasodilatory capacity,
imbalance in O2 supply and demand due to increased
myocardial mass.
Repeated episodes of ischemia during heavy exercise could contribute to the onset of intramuscular
fibrosis. The presence of ST segment depression during stress test may have prognostic significance for
SD in young patients, mainly children and adolescents.
SD, syncope, or cardiac arrest would be primarily
ischemic episodes for children under 14 years old.
Most patients at this age show ischemia in perfusion
tests, and ST segment depression during exercise,
even in the absence of ventricular arrhythmias in
Holter or EPS. (264)
An association between ST segment depression
during exercise and systolic dysfunction has been discovered. Shimzu et al. studied 53 HCM patients with
ergometry and ambulatory ventricular function monitoring, and they found out that patients with ST segment depression showed a fall in the left ventricular
ejection fraction during stress. Conversely, those patients with no alteration of the ST segment had a normal response of ejection fraction. (265)
To sum up, the presence of ST segment shifts in
stress tests on HCM patients reveals ischemia, and
not coronary artery disease; therefore, its diagnostic
value is poor, but it may be a significant prognostic
marker.
Abnormal blood pressure response during stress
The most studied ergometric variable related to prognosis in HCM patients is the systolic blood pressure
(SBP) response to stress. The widespread and accepted
definitions of abnormal SBP response include: 1) the
fall ≥ 20 mm Hg compared to the previous record or
the continuous decrease during stress that reaches
20 mm Hg, and/or 2) the little increase or flat curve
in SBP, defined as an increase lower than 20 mm Hg
compared to basal, and over the course of the test.
Abnormal SPB response in the stress test is associated to poor late prognosis in patients under 50 years
of age. It does not identify in isolation a high risk population, but it should be considered together with the
rest of the variables. It has a screening value for low
risk patients, due to its high negative predictive value,
together with the absence of the rest of the risk factors. (140, 162, 266) Current consensuses include the
abnormal SPB response among the major risk factors
to predict sudden death in HCM patients. (7)
Indication for stress test on HCM patients
Class I (level of evidence B)
– Asymptomatic patients with no high-risk variables­
as associated element in prognostic stratification.
-Asymptomatic patients with no high-risk variables­ who want to do recreational exercises.
– Ergospirometry as associated element in the differential diagnosis between HCM and athlete’s
heart.
Class Ila (level of evidence C)
– Patients with equivocal symptoms not associated
with other high-risk variables.
– Submaximal stress test for patients with
­cardioverter-defibrillator who want to do low-intensity sports, in order to assess­ their tolerance
and heart rate response to­ exercise.
Class III
– Patients with high-risk variables and no
cardioverter-defibrillator.
– Conventional stress test in athletes for ­differential diagnosis between HCM and physiologic hypertrophy (athlete’s hypertrophy).
B. Sports and HCM
HCM diagnosis implies the athlete’s exclusion from
competitive sports practice.
(267) This assertion includes all HCM cases, even
those which do not present risk clinical variables, or
whose genotype is associated with low risk. HCM
prevalence is low in high-performance athletes, because there would be a natural selection for this type
of practice in patients with functional and structural
changes, which are secondary to this condition. (268)
Some exceptions are possible for asymptomatic patients with no risk variables, who are involved in lowintensity sports, such as golf, cricket, bowling, or
shooting.
Whereas it is true that many athletes have been
diagnosed with HCM once their competitive –and even
professional– sport activity was over, there are no clinical or genetic studies that ensure good prognosis. Intense exercise may be the cause of severe arrhythmias,
increase of left ventricular outflow tract obstruction,
and ischemia due to compression of the small vessels
(and eventual fibrosis as a result of repetitive
ischemia). These alterations may cause the athlete’s
sudden death during competence or training.
The extension of genetic studies, even more to relatives of HCM patients, has posed the situation of individuals with positive genotype and negative phenotype for HCM. This situation generates discussion
about the recommendations on competitive sports for
these patients.
At present, if there are no diagnostic clinical data
or risk variables, there is no strong evidence to discourage sports practice. However, certain troponin T
gene mutations (chromosome 1) may not manifest as
ventricular hypertrophy, but have histopathological
alterations in myocardial muscle fibers and result in
sudden death. (42)
The intense exertion needed to practice recreational (non-competitive) sports should be taken into
account. It is not always feasible to assess this inten-
19
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
sity, since the sport in itself will require different psychological and physical loads from the different participants.
As a general rule, it could be said that those sports
that require sudden changes –slowing down and speeding up unexpectedly (“acyclic”)– should be avoided,
as in the case of soccer, tennis, basketball, and handball, among others.
Preference is given to cyclic activities such as jogging, biking, swimming, or walking in which energy
expenditure is largely low and stable.
In certain cases in which the physician is well
aware of the patient’s reasoning and habits, it is possible to indicate the practice of “acyclic” sports as the
ones first above mentioned (soccer, tennis, basketball,
or handball), but with a detailed explanation as to
adapting to low intensity and no competitiveness.
Some consensuses categorize sports with regard
to the level of physical intensity required, and suggest whether patients with hypertrophic cardiomyopathy may or may not practice them. (269)
The American Heart Association Group suggests
levels of recommendation numbered from 0 to 5, with
0 to 1 designating activities strongly discouraged, and
4 to 5 indicating activities probably permitted. The
intermediate recommendation is subject to the physician’s consideration on an individual basis, and its
level goes from 2 to 3.
As an example, 0 to 1 values correspond to recreational sports, such as basketball, single tennis,
windsurfing, soccer and football, weight lifting, and
diving. (264)
The following recommendations arise from experiences and consensus: Attending physicians should
assess the patients on an individual basis, including
physical, psychological, and educational aspects.
Recommendations for patients with HCM who
want to practice sports
Class I (level of evidence C)
– HCM patients should be excluded from competitive sport activities –with the possible exception
of low-intensity ones (golf, shooting, billiard, bowling)–, for individuals with no high-risk variables
of sudden death, and for low-risk patients.
Recreational sports that require high intensity or
sudden intensity changes are not recommended.
– Individuals with positive genotype and negative
phenotype (with no clinical evidence of the disease)
can practice sports, even competitive ones, provided they undergo regular screenings.
– Patients with no high-risk variables and with normal stress test can perform recreational, cyclic, and
low-intensity exercise.
– Patients with implanted cardioverter-defibrillator
should ­be discouraged from practicing contact
sports.
Class Ila
– Patients with no high-risk variables and with normal stress test can practice recreational contact
sports of low intensity and volume, with regular
breaks, provided they can control the exertion intensity and the psychological burden of their participation.
Class III
– Asymptomatic HCM patients, with low clinical and
genetic risk, high functional capacity and no family history of sudden death, can practice high-intensity competitive sports.
BIBLIOGRAPHY
1. Brock R. Functional obstruction of the left ventricle; acquired aortic subvalvar stenosis. Guys Hosp Rep 1957; 106:221-38.
2. Teare D. Asymmetrical hypertrophy of the heart in young adults.
Br Heart J 1958; 20:1-8.
3. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild
DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in
the CARDlA Study. Coronary Artery Risk Development in (Young)
Adults. Circulation 1995; 92:785-9.
4. Maron BJ, Roberts WC, Epstein SE. Sudden death in hypertrophic
cardiomyopathy: a profile of 78 patients. Circulation 1982; 65:1388-94.
5. Fay WP, Taliercio CP, llstrup DM, Tajik AJ, Gersh BJ. Natural history of hypertrophic cardiomyopathy in the elderly. J Am Coll Cardiol
1990; 16:821-6.
6. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS
et al. lmplantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;
298:405-12.
7. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn
HJ, Seidman CE, et al; Task Force on Clinical Expert Consensus
Documents. American College of Cardiology; Committee for Practice
Guidelines. European Society of Cardiology. American College of
Cardiology/European Society of Cardiology clinical expert consensus
document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert
Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42:1687-713.
8. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett
D, et al; American Heart Association; Council on Clinical Cardiology,
Heart Failure and Transplantation Committee; Quality of Care and
Outcomes Research and Functional Genomics and Translational Biology lnterdisciplinary Working Groups; Council on Epidemiology
and Prevention. Contemporary definitions and classification of the
cardiomyopathies: an American Heart Association Scientific
State­ment from the Council on Clinical Cardiology, Heart Failure
and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology
lnterdisciplinary Working Groups; and Council on Epidemiology and
Prevention. Circulation 2006; 113:1807-16.
9. Ommen SR, Nishimura RA. Hypertrophic cardiomyopathy. Curr
Probl Cardiol 2004; 29:233-91.
10. Spirito P, Maron BJ. Patterns of systolic anterior motion of the
mitral valve in hypertrophic cardiomyopathy: assessment by
two­dimensional echocardiography. Am J Cardiol 1984; 54:1039-46.
11. Wigle ED. Cardiomyopathy: The diagnosis of hypertrophic cardiomyopathy. Heart 2001; 86:709-14.
12. Klues HG, Roberts WC, Maron BJ. Anomalous insertion of papillary muscle directly into anterior mitral leaflet in hypertrophic car-
20
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
diomyopathy. Significance in producing left ventricular outflow obstruction. Circulation 1991; 84:1188-97.
13. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin
JT, et al. Hypertrophic cardiomyopathy is predominantly a disease of
left ventricular outflow tract obstruction. Circulation 2006; 114:22329.
14. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA,
et al. Effect of left ventricular outflow tract obstruction on clinical
outcome in hypertrophic cardiomyopathy. N Engl J Med 2003; 348:295303.
15. Autore C, Bernabé P, Stella Barilli C, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms.
J Am Coll Cardiol 2005; 45:1076-80.
16. Wynne J, Braunwald E. The Cardiomyopathies and
Myocarditides. In: Braunwald E. Heart Disease. 5th ed. Philadelphia:
WB Saunders Company; 1997.
17. Nihoyannopoulos P, Karatasakis G, Frenneaux M, McKenna WJ,
Oakley CM. Diastolic function in hypertrophic cardiomyopathy: relation to exercise capacity. J Am Coll Cardiol 1992; 19:536-40.
18. Briguori C, Betocchi S, Romano M, Manganelli F, Angela Losi M,
Ciampi Q, et al. Exercise capacity in hypertrophic cardiomyopathy
depends on left ventricular diastolic function. Am J Cardiol 1999;
84:309-15.
19. Spirito P, Maron BJ. Relation between extent of left ventricular
hypertrophy and diastolic filling abnormalities in hypertrophic cardiomyopathy. J Am Coll Cardiol 1990; 15:808-13.
20. Maron BJ. Hypertrophic cardiomyopathy: A systematic review.
JAMA 2002; 287:1308-20.
21. Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD,
Klocke FJ, et al. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol
2002; 40:2156-64.
22. O’Gara PT, Bonow RO, Maron BJ, Damske BA, Van Lingen A,
Bacharach SL, et al. Myocardial perfusion abnormalities in patients
with hypertrophic cardiomyopathy: assessment with thallium-201
emission computed tomography. Circulation 1987; 76:1214-23.
23. Petersen SE, Jerosch-Herold M, Hudsmith LE, Robson MD,
Francis JM, Doll HA, et al. Evidence for microvascular dysfunction
in hypertrophic cardiomyopathy: new insights from multiparametric
magnetic resonance imaging. Circulation 2007; 115:2418-25.
24. Schwartzkopff B, Mundhenke M, Strauer BE. Alterations of the
architecture of subendocardial arterioles in patients with hypertrophic
cardiomyopathy and impaired coronary vasodilator reserve: a possible
cause for myocardial ischemia. J Am Coll Cardiol 1998; 31:1089-96.
25. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young: pathologic
evidence of myocardial ischemia. Hum Pathol 2000; 31:988-98.
26. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. lntramural
(“small vessel”) coronary artery disease in hypertrophic
cardiomyo­pathy. J Am Coll Cardiol 1986; 8:545-57.
27. Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik
AJ. Adverse prognosis of patients with hypertrophic cardiomyopa­thy
who have epicardial coronary artery disease. Circulation 2003;
108:2342-8.
28. Sherrid MV, Chu CK, Delia E, Mogtader A, Dwyer EM Jr. An
echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 1993; 22:816-25.
29. Petrone RK, Klues HG, Panza JA, Peterson EE, Maron BJ. Coexistence of mitral valve prolapse in a consecutive group of 528 patients
with hypertrophic cardiomyopathy assessed with echocardiography.
J Am Coll Cardiol 1992; 20:55:00-61.
30. Robinson K, Frenneaux MP, Stockins B, Karatasakis G, Poloniecki
JD, McKenna WJ. Atrial fibrillation in hypertrophic cardiomyopathy: longitudinal study. J Am Coll Cardiol 1990; 15:1279-85.
31. Olivotto l, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ.
lmpact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001; 104:2517-24.
32. Frenneaux MP, Counihan PJ, Caforio AL, Chikamori T, McKenna
WJ. Abnormal blood pressure response during exercise in hypertrophic
cardiomyopathy. Circulation 1990; 82:1995-2002.
33. Olivotto l, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi
F. Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999; 33:2044-51.
34. Ciampi Q, Betocchi S, Lombardi R, Manganelli F, Storto G, Losi
MA, et al. Hemodynamic determinants of exercise-induced abnormal
blood pressure response in hypertrophic cardiomyopathy. J Am Coll
Cardiol 2002; 40:278-84.
35. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W,
Vosberg HP, et al. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the
sarcomere. Cell 1994; 77:701-12.
36. Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, PerezAtayde AR, et al. Glycogen storage diseases presenting as hypertrophic
cardiomyopathy. N Engl J Med 2005; 352:362-72.
37. Pare JA, Fraser RG, Pirozynski WJ, Shanks JA, Stubington D.
Hereditary cardiovascular dysplasia. A form of familial cardiomyopathy. Am J Med 1961; 31:37-62.
38. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C,
et al; EUROGENE Heart Failure Project. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;
107:2227-32.
39. Morita H, Larson MG, Barr SC, Vasan RS, O’Donnell CJ,
Hirschhorn JN, et al. Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart
Study. Circulation 2006; 113:2697-705.
40. Olsson MC, Palmer BM, Stauffer BL, Leinwand LA, Moore RL.
Morphological and functional alterations in ventricular myocytes from
male transgenic mice with hypertrophic cardiomyopathy. Circ Res
2004; 94:201-7.
41. Rottbauer W, Gautel M, Zehelein J, Labeit S, Franz WM, Fischer
C, et al. Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization of cardiac transcript and protein. J Clin lnvest 1997;
100:475-82.
42. Sweeney HL, Feng HS, Yang Z, Watkins H. Functional analyses
of troponin T mutations that cause hypertrophic cardiomyopathy:
insights into disease pathogenesis and troponin function. Proc Natl
Acad Sci USA 1998; 95:14406-10.
43. Wang Q, Moncman CL, Winkelmann DA. Mutations in the motor
domain modulate myosin activity and myofibril organization. J Cell
Sci 2003; 116:4227-38.
44. Fatkin D, McConnell BK, Mudd JO, Semsarian C, Moskowitz lG,
Schoen FJ, et al. An abnormal Ca(2+) response in mutant sarcomere
protein-mediated familial hypertrophic cardiomyopathy. J Clin lnvest
2000; 106:1351-9.
45. Theis JL, Bos JM, Bartleson VB, Will ML, Binder J, Vatta M, et
al. Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy. Biochem Biophys Res Commun 2006;
351:896-902.
46. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W,
Seidman CE, et al. Characteristics and prognostic implications of
myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992; 326:1108-14.
47. Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C,
McKenna WJ, et al. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet 1995; 11:434-7.
48. Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M,
et al. Mutations in the cardiac troponin l gene associated with hypertrophic cardiomyopathy. Nat Genet 1997; 16:379-82.
49. Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML,
Nishimura RA, et al. Prevalence and severity of “benign” mutations
in the beta-myosin heavy chain, cardiac troponin T, and alpha-
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
tropo­myosin genes in hypertrophic cardiomyopathy. Circulation 2002;
106:3085-90.
50. Brito D, Richard P, Isnard R, Pipa J, Komajda M, Madeira H.
Familial hypertrophic cardiomyopathy: the same mutation, different
prognosis. Comparison of two families with a long follow-up. Rev
Port Cardiol 2003; 22:1445-61.
51. Hoedemaekers YM, Caliskan K, Majoor-Krakauer D, van de Laar
l, Michels M, Witsenburg M, et al. Cardiac beta-myosin heavy chain
defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies. Eur Heart J 2007; 28:2732-7.
52. Alpert NR, Mohiddin SA, Tripodi D, Jacobson-Hatzell J, VaughnWhitley K, Brosseau C, et al. Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavychain mutations. Am J Physiol Heart Circ Physiol 2005; 288:H1097102.
53. Marian AJ. Modifier genes for hypertrophic cardiomyopathy. Curr
Opin Cardiol 2002; 17:242-52.
54. Li HL, Liu C, de Couto G, Ouzounian M, Sun M, Wang AB, et al.
Curcumin prevents and reverses murine cardiac hypertrophy. J Clin
lnvest 2008; 118:879-93.
55. Miller TE, You L, Myerburg RJ, Benke PJ, Bishopric NH. Whole
blood RNA offers a rapid, comprehensive approach to genetic diagnosis of cardiovascular diseases. Genet Med 2007; 9:23-33.
56. Charron P, Dubourg O, Desnos M, lsnard R, Hagege A, Millaire
A, et al. Diagnostic value of electrocardiography and echocardiography
for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation 1997; 96:214-9.
57. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komajda M, et al.
Experience from clinical genetics in hypertrophic cardiomyopathy:
proposal for new diagnostic criteria in adult members of affected families. Heart 1997; 77:130-2.
58. McPherson E. Genetic diagnosis and testing in clinical practice.
Clin Med Res 2006; 4:123-9.
59. Acunzo RS. Manifestaciones clínicas y electrocardiográficas, la
estratificación del riesgo y el tratamiento de la miocardiopatía
hipertrófica. In: Elizari MV, Chiale P, editors. Arritmias cardíacas.
Bases celulares y moleculares, diagnóstico y tratamiento. 2nd ed. Buenos Aires, Argentina: Editorial Médica Panamericana SA; 2003. pp.
753-74.
60. Braudo M, Wigle ED, Keith JD. A distinctive electrocardiogram
in muscular subaortic stenosis due to ventricular septal hypertrophy.
Am J Cardiol 1964; 14:599-607.
61. Marriot HJL. Anomalías electrocardiográficas, trastornos de la
conducción y arritmias en la miocardiopatía hipertrófica. In:
Friedberg CK, director. Progresos en las enfermedades
cardiovasculares. Tomo V. Ed Científico Médica; 1966. cap Vll, p. 10115.
62. Acunzo RS, Konopka lV, Aldariz AE, Cianciulli T, Saccheri MC,
Elizari MV et al. Hallazgos electrocardiográficos en pacientes con
miocardiopatía hipertrófica. Rev Argent Cardiol 1998; 66:150. Abstract N° 381.
63. Konno T, Shimizu M, Ino H, Yamaguchi M, Terai H, Uchiyama
K, et al. Diagnostic value of abnormal Q waves for identification of
preclinical carriers of hypertrophic cardiomyopathy based on a molecular genetic diagnosis. Eur Heart J 2004; 25:246-51.
64. Maron BJ, Spirito P, Wesley Y, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med 1986; 315:610-4.
65. Prescott R, Quinn JS, Littmann D. Electrocardiographic changes
in hypertrophic subaortic stenosis which simulate myocardial infarction. Am Heart J 1963; 66:42-8.
66. Dumont CA, Monserrat L, Soler R, Rodríguez E, Fernandez X,
Peteiro J, et al. lnterpretation of electrocardiographic abnormalities
in hypertrophic cardiomyopathy with cardiac magnetic resonance.
Eur Heart J 2006; 27:1725-31.
67. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komajda M. Experience from clinical genetics in hypertrophic cardiomyopathy: pro-
21
posal for new diagnostic criteria in adult members of affected families. Heart 1997; 77:130-2.
68. Acunzo RS, Konopka lV, Halpern SM. La semiología del ECG
normal y patológico. In: Elizari MV, Chiale P, editors. Arritmias
cardíacas. Bases celulares y moleculares, diagnóstico y tratamiento.
2nd ed. Buenos Aires, Argentina: Editorial Médica Panamericana;
2003. Cap. 8, p. 163-204.
69. Corrado D, Pelliccia A, Bjørnstad HH, Vanhees L, Biffi A,
Borjesson M, et al; Study Group of Sport Cardiology of the Working
Group of Cardiac Rehabilitation and Exercise Physiology and the
Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol. Consensus Statement of the
Study Group of Sport Cardiology of the Working Group of Cardiac
Rehabilitation and Exercise Physiology and the Working Group of
Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:516-24.
70. Maron BJ, Thompson PD, Ackerman MJ, Balady G, Berger S,
Cohen D, et al; American Heart Association Council on Nutrition,
Physical Activity, and Metabolism. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition,
Physical Activity, and Metabolism: endorsed by the American College of Cardiology. Foundation. Circulation 2007;115:1643-55.
71. Konopka lV, Acunzo RS, Saccheri MC et al. Historia natural de la
miocardiopatía hipertrófica apical. Premio al mejor tema libre 9nas
Jornadas de Cardiología del Gobierno de la Ciudad de Buenos Aires.
2000; p. 58.
72. Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertrophy. Echocardiographic identification of the pathognomonic anatomic
abnormality of lHSS. Circulation 1973; 47:225-33.
73. Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spirito P. The
upper limit of physiologic cardiac hypertrophy in highly trained elite
athletes. N Engl J Med 1991; 324:295-301.
74. Abergel E, Chatellier G, Hagege AA, Oblak A, Linhart A,
Ducardonnet A, et al. Serial left ventricular adaptations in world­class
professional cyclists: implications for disease screening and fol­lowup. J Am Coll Cardiol 2004; 44:144-9.
75. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L,
Varnava A, et al. Sudden death in hypertrophic cardiomyopathy:
identifica­tion of high risk patients. J Am Coll Cardiol 2000; 36:22128.
76. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ.
Magnitude of left ventricular hypertrophy and risk of sudden death
in hypertrophic cardiomyopathy. N Engl J Med 2000; 342:1778-85.
77. Spirito P, Maron BJ. Relation between extent of left ventricular
hypertrophy and diastolic filling abnormalities in hypertrophic cardiomyopathy. J Am Coll Cardiol 1990; 15:1521-6.
78. Klues H, Schiffers A, Maron B. Phenotypic spectrum and pat­terns
of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two­dimensional
echocardiography in 600 patients. J Am Coll Cardiol 1995; 26:1699.
78 bis. Saccheri MC, Cianciulli TF, Konopka lV, Acunzo RS, Méndez
RJ, Gagliardi JA, et al. Right ventricular hypertrophy alone as a new
form of presentation of hypertrophic cardiomyopathy. Circulation 2008;
117:143.
79. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse
N, et al. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation 2005; 112:855-61. 79
bis. Cianciulli TF, Saccheri MC, Bermann AM, Lax JA, Konopka IV,
Acunzo RS, et al. Solitary papillary muscle hypertrophy can be a precursor of hypertrophic cardiomyopathy. Circulation 2008; 117:121.
80. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic
cardiomyopathy. Clinical spectrum and treatment. Circulation 1995;
92:1680-92.
81. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski
22
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
H, et al. Hypertrophic cardiomyopathy. The importance of the site
and the extent of hypertrophy. A review. Prog Cardiovasc Dis 1985;
28:1-83.
82. Nishimura RA, Holmes DR Jr. Clinical practice. Hypertrophic
obstructive cardiomyopathy: N Engl J Med 2004; 350:1320-7.
83. Schwammenthal E, Block M, Schwartzkopff B, L6sse B, Borggrefe
M, Schulte HD, et al. Prediction of the site and severity of obstruction
in hypertrophic cardiomyopathy by color flow mapping and continuous wave Doppler echocardiography. J Am Coll Cardiol 1992; 20:96472.
84. Yu EH, Omran AS, Wigle ED, Williams WG, Siu SC, Rakowski H.
Mitral regurgitation in hypertrophic obstructive cardiomyopathy: relationship to obstruction and relief with myectomy. J Am Coll Cardiol
2000; 36:2219-25.
85. Klues HG, Maron BJ, Dollar AL, Roberts WC. Diversity of structural mitral valve alterations in hypertrophic cardiomyopathy. Circulation 1992; 85:1651-60.
86. Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J.
Noninvasive assessment of left ventricular diastolic function by pulsed
Doppler echocardiography in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1987; 10:733-42.
87. Palka P, Lange A, Fleming AD, Donnelly JE, Dutka DP, Starkey
lR, et al. Differences in myocardial velocity gradient measured
throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to
hypertension. J Am Coll Cardiol 1997; 30:760-8.
88. Nagueh SF, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, et
al. Tissue Doppler imaging predicts the development of hypertrophic
cardiomyopathy in subjects with subclinical disease. Circulation 2003;
108:395-8.
89. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA,
Seidman JG, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002; 105:2992-7.
90. Nagueh SF, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, et
al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides
a novel means for an early diagnosis before and independently of
hypertrophy. Circulation 2001; 104:128-30.
91. Chejtman D, Baratta S, Fernández H, Marani A, Ferroni F, Bilbao J. Valor clínico del análisis de la fase sistólica de la contracción
ventricular con Doppler tisular en la discriminación de hipertrofia
fisiológica de formas patológicas. Rev Argent Cardiol 2006; 74:12935.
92. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med 1997; 336:77585.
93. Maron BJ, McKenna WJ, Elliott P, Spirito P, Frenneaux MP, Keren
A, et al. Hypertrophic cardiomyopathy. JAMA 1999; 282:2302-3.
94. Kato TS, Noda A, lzawa H, Yamada A, Obata K, Nagata K, et al.
Discrimination of nonobstructive hypertrophic cardiomyopathy from
hypertensive left ventricular hypertrophy on the basis of strain rate
imaging by tissue Doppler ultrasonography. Circulation 2004;
110:3808-14.
95. Baratta S, Chejtman D, Fernández H, Ferroni FE, Bilbao J, Kotliar
C, et al. Valor clínico de la utilización del strain rate sistólico en el
estudio de distintas formas de hipertrofia ventricular izquierda. Rev
Argent Cardiol 2007; 75:367-73.
96. Serri K, Reant P, Lafitte M, Berhouet M, Le Bouffos V, Roudaut
R, et al. Global and regional myocardial function quantification by
two-dimensional strain: application in hypertrophic cardiomyopathy.
J Am Coll Cardiol 2006; 47:1175-81.
97. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary
screening strategies in families with hypertrophic cardiomyopathy. J
Am Coll Cardiol 2004; 44:2125-32.
98. Grigg LE, Wigle ED, Williams WG, Daniel LB, Rakowski H.
Transesophageal Doppler echocardiography in obstructive hypertrophic cardiomyopathy: clarification of pathophysiology and impor-
tance in intraoperative decision making. J Am Coll Cardiol 1992;
20:42-52.
99. Singh M, Edwards WD, Holmes DR Jr, Tajil AJ, Nishimura RA.
Anatomy of the first septal perforating artery: a study with implications for ablation therapy for hypertrophic cardiomyopathy. Mayo Clin
Proc 2001; 76:799-802.
100. Faber L, Seggewiss H, Gleichmann U. Percutaneous transluminal
septal myocardial ablation in hypertrophic obstructive cardiomyopathy: results with respect to intraprocedural myocardial contrast
echocardiography. Circulation 1998; 98:2415-21.
101. Nagueh SF, Lakkis NM, He ZX, Middleton KJ, Killip D, Zoghbi
WA, et al. Role of myocardial contrast echocardiography during
non­surgical septal reduction therapy for hypertrophic obstructive
cardiomyopathy. J Am Coll Cardiol 1998; 32:225-9.
102. Faber L, Seggewiss H, Gleichmann U. Percutaneous transluminal
septal myocardial ablation in hypertrophic obstructive cardiomyopathy: results with respect to intraprocedural myocardial contrast
echocardiography. Circulation 1998; 98:2415-21.
103. Nagueh SF, Ommen SR, Lakkis NM, Killip D, Zoghbi WA, Schaff
HV, et al. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2001; 38:1701-6.
104. Mazur W, Nagueh SF, Lakkis NM, Middleton KJ, Killip D, Roberts
R, et al. Regression of left ventricular hypertrophy after nonsurgical
septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 2001; 103:1492-6.
105. Maron BJ, Olivotto l, Bellone P, Conte MR, Cecchi F, Flygenring
BP, et al. Clinical profile of stroke in 900 patients with hypertrophic
cardiomyopathy. J Am Coll Cardiol 2002; 39:301-7.
106. Frank S, Braunwald E. ldiopathic hypertrophic subaortic stenosis. Clinical analysis of 126 patients with emphasis on the natural
history. Circulation 1968; 37:759-88.
107. Spirito P, Rapezzi C, Bellone P, Betocchi S, Autore C, Conte MR,
et al. lnfective endocarditis in hypertrophic cardiomyopathy: prevalence, incidence, and indications for antibiotic prophylaxis. Circulation 1999; 99:2132-7.
108. Harrison DC, Braunwald E, Glick G, Mason DT, Chidsey CA,
Ross J Jr. Effects of beta adrenergic blockade on the circulation with
particular reference to observations in patients with hypertrophic
subaortic stenosis. Circulation 1964; 29:84-98.
109. Cohen LS, Braunwald E. Amelioration of angina pectoris in idiopathic hypertrophic subaortic stenosis with beta-adrenergic block­ade.
Circulation 1967; 35:847-51.
110. Cohen LS, Braunwald E. Chronic beta adrenergic receptor
block­ade in the treatment of idiopathic hypertrophic subaortic stenosis. Prog Cardiovasc Dis 1968; 11:211-21.
111. Flamm MD, Harrison DC, Hancock EW. Muscular subaortic stenosis. Prevention of outflow obstruction with propranolol. Circulation 1968; 38:846-58.
112. Sloman G. Propranolol in management of muscular subaortic
stenosis. Br Heart J 1967; 29:783-7.
113. Thompson DS, Naqvi N, Juul SM, Swanton RH, Coltart DJ,
Jenkins BS, et al. Effects of propranolol on myocardial oxygen consumption, substrate extraction, and haemodynamics in hypertrophic
obstructive cardiomyopathy. Br Heart J 1980; 44:488-98.
114. Adelman AG, Shah PM, Gramiak R, Wigle ED. Long-term
pro­pranolol therapy in muscular subaortic stenosis. Br Heart J 1970;
32:804-11.
115. Saenz de la Calzada C, Ziady GM, Hardarson T, Curiel R,
Good­win JF. Effect of acute administration of propranolol on ventricular function in hypertrophic obstructive cardiomyopathy measured by non-invasive techniques. Br Heart J 1976; 38:798-803.
116. Bourmayan C, Razavi A, Fournier C, Dussaule JC, Baragan J,
Gerbaux A, et al. Effect of propranolol on left ventricular relaxation
in hypertrophic cardiomyopathy: an echographic study. Am Heart J
1985; 109:1311-6.
117. Fifer MA, Vlahakes GJ. Management of symptoms in hypertrophic
cardiomyopathy. Circulation 2008; 117:429-39.
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
118. Hubner PJ, Ziady GM, Lane GK, Hardarson T, Scales B, Oakley
CM, et al. Double-blind trial of propranolol and practolol in hypertrophic cardiomyopathy. Br Heart J 1973; 35:1116-23.
119. Rosing DR, Kent KM, Borer JS, Seides SF, Maron BJ, Epstein
SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. l. Hemodynamic effects. Circulation 1979; 60:1201-7.
120. Rosing DR, Condit JR, Maron BJ, Kent KM, Leon MB, Bonow
RO, et al. Verapamil therapy: a new approach to the pharmacologic
treatment of hypertrophic cardiomyopathy: lll. Effects of long-term
administration. Am J Cardiol 1981; 48:545-53.
121. Epstein SE, Rosing DR. Verapamil: its potential for causing serious complications in patients with hypertrophic cardiomyopathy.
Circulation 1981; 64:437-41.
122. Kaltenbach M, Hopf R, Kober G, Bussmann WD, Keller M,
Petersen Y, et al. Treatment of hypertrophic obstructive cardiomyopathy with verapamil. Br Heart J 1979; 42:35-42.
123. Bonow RO, Rosing DR, Bacharach SL, Green MV, Kent KM,
Lipson LC, et al. Effects of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:787-96.
124. Bonow RO, Frederick TM, Bacharach SL, Green MV, Goose PW,
Maron BJ, et al. Atrial systole and left ventricular filling in hypertrophic cardiomyopathy: effect of verapamil. Am J Cardiol 1983;
51:1386-91.
125. Bonow RO, Dilsizian V, Rosing DR, Maron BJ, Bacharach SL,
Green MV. Verapamil-induced improvement in left ventricular
diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: short- and long-term effects. Circulation
1985; 72:853-64.
126. Hess OM, Murakami T, Krayenbuehl HP. Does verapamil improve left ventricular relaxation in patients with myocardial hypertrophy? Circulation 1986; 74:530-43.
127. Udelson JE, Bonow RO, O’Gara PT, Maron BJ, Van Lingen A,
Bacharach SL, et al. Verapamil prevents silent myocardial perfusion
abnormalities during exercise in asymptomatic patients with hypertrophic cardiomyopathy. Circulation 1989; 79:1052-60.
128. Gistri R, Cecchi F, Choudhury L, Montereggi A, Sorace O,
Salvadori PA, et al. Effect of verapamil on absolute myocardial blood
flow in hypertrophic cardiomyopathy. Am J Cardiol 1994; 74:363-8.
129. Petkow Dimitrow P, Krzanowski M, Nizankowski R, Szczeklik
A, Dubiel JS. Effect of verapamil on systolic and diastolic coronary
blood flow velocity in asymptomatic and mildly symptomatic patients
with hypertrophic cardiomyopathy. Heart 2000; 83:262-6.
130. Rosing DR, Kent KM, Maron BJ, Epstein SE. Verapamil therapy:
a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. ll. Effects on exercise capacity and symptomatic status.
Circulation 1979; 60:1208-13.
131. Gilligan DM, Chan WL, Joshi J, Clarke P, Fletcher A, Krikler S,
et al. A double-blind, placebo-controlled crossover trial of nadolol and
verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy. J Am Coll Cardiol 1993; 21:1672-9.
132. lwase M, Sotobata l, Takagi S, Miyaguchi K, Jing HX, Yokota M.
Effects of diltiazem on left ventricular diastolic behavior in patients
with hypertrophic cardiomyopathy: evaluation with exercise pulsed
Doppler echocardiography. J Am Coll Cardiol 1987; 9:1099-105.
133. Betocchi S, Piscione F, Losi M A, Pace L, Boccalatte M, PerroneFilardi P, et al. Effects of diltiazem on left ventricular systolic and
diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 1996;
78:451-7.
134. Betocchi S, Cannon RO 3rd, Watson RM, Bonow RO, Ostrow
HG, Epstein SE, et al. Effects of sublingual nifedipine on
hemodynamics and systolic and diastolic function in patients with
hypertrophic cardiomyopathy. Circulation 1985; 72:1001-7.
135. Lorell BH, Paulus WJ, Grossman W, Wynne J, Cohn PF. Modification of abnormal left ventricular diastolic properties by nifedipine
in patients with hypertrophic cardiomyopathy. Circulation 1982;
65:499-507.
23
136. Kondo N, Mizukami M, Shibata S. Negative inotropic effects of
disopyramide on guinea-pig papillary muscles. Br J Pharmacol 1990;
101:789-92.
137. Pollick C, Kimball B, Henderson M, Wigle ED. Disopyramide in
hypertrophic cardiomyopathy. l. Hemodynamic assessment after intravenous administration. Am J Cardiol 1988; 62:1248-51.
138. Fifer MA, O’Gara PT, McGovern BA, Semigran MJ. Effects of
diltiazem on left ventricular systolic and diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 1994; 74:405-8.
139. Matsubara H, Nakatani S, Nagata S, lshikura F, Katagiri Y, Ohe
T, et al. Salutary effect of disopyramide on left ventricular diastolic
function in hypertrophic obstructive cardiomyopathy. J Am Coll
Cardiol 1995; 26:768-75.
140. Pollick C. Disopyramide in hypertrophic cardiomyopathy. ll.
Noninvasive assessment after oral administration. Am J Cardiol 1988;
62:1252-5.
141. Sherrid MV, Barac l, McKenna WJ, Elliott PM, Dickie S,
Chojnowska L, et al. Multicenter study of the efficacy and safety of
disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll
Cardiol 2005; 45:1251-8.
142. McCully RB, Nishimura RA, Tajik AJ, Schaff HV, Danielson GK.
Extent of clinical improvement after surgical treatment of hypertrophic
obstructive cardiomyopathy. Circulation 1996; 94:467-71.
143. Robbins RC, Stinson EB. Long-term results of left ventricular
myotomy and myectomy for obstructive hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg 1996; 111:586-94.
144. Schulte HD, Borisov K, Gams E, Gramsch-Zabel H, L6sse B,
Schwartzkopff B. Management of symptomatic hypertrophic obstructive cardiomyopathy- long-term results after surgical therapy. Thorac
Cardiovasc Surg 1999; 47:213-8.
145. ten Berg JM, Suttorp MJ, Knaepen PJ, Ernst SM, Vermeulen
FE, Jaarsma W. Hypertrophic obstructive cardiomyopathy. lnitial results and long-term follow-up after Morrow septal myectomy. Circulation 1994; 90:1781-5.
146. Heric B, Lytle BW, Miller DP, Rosenkranz ER, Lever HM,
Cosgrove DM. Surgical management of hypertrophic obstructive cardiomyopathy. Early and late results. J Thorac Cardiovasc Surg 1995;
110:195-206.
147. Morrow AG, Reitz BA, Epstein SE, Henry WL, Conkle DM,
ltscoitz SB, et al. Operative treatment in hypertrophic subaortic stenosis. Techniques, and the results of pre and postoperative assessments in 83 patients. Circulation 1975; 52:88-102.
148. Minakata K, Dearani JA, Nishimura RA, Maron BJ, Danielson
GK. Extended septal myectomy for hypertrophic obstructive cardiomyopathy with anomalous mitral papillary muscles or chordae. J
Thorac Cardiovasc Surg 2004; 127:481-9.
149. Schoendube FA, Klues HG, Reith S, Flachskampf FA, Hanrath
P, Messmer BJ. Long-term clinical and echocardiographic follow-up
after surgical correction of hypertrophic obstructive cardiomyopathy
with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation 1995; 92 (9 Suppl):ll122-7.
150. D6rge H, Schmitto JD, Liakopoulos OJ, Walther S, Sch6ndube
FA. Extended myectomy for hypertrophic obstructive cardiomyopathy
after failure or contraindication of septal ablation or with combined
surgical procedures. Thorac Cardiovasc Surg 2004; 52:344-8.
151. Smedira NG, Lever HM, Miluk M, Krishnaswamy G, Laing G,
Thamilarasan M, et al. Septal myectomy: 324 consecutive procedures
without a mortality. J Am Coll Cardiol 2006; 47 (Suppl A):275A. Abstract.
152. Dearani JA, Ommen SR, Gersh BJ, Schaff HV, Danielson GK.
Surgery insight: Septal myectomy for obstructive hypertrophic cardiomyopathy– the Mayo Clinic experience. Nat Clin Pract Cardiovasc
Med 2007; 4:503-12.
153. Morrow AG, Reitz BA, Epstein SE, Henry WL, Conkle DM,
ltscoitz SB, et al. Operative treatment in hypertrophic subaortic stenosis. Techniques, and the results of pre and postoperative assessments in 83 patients. Circulation 1975; 52:88-102.
154. Schoendube FA, Klues HG, Reith S, Flachskampf FA, Hanrath
24
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
P, Messmer BJ. Long-term clinical and echocardiographic follow-up
after surgical correction of hypertrophic obstructive cardiomyopathy
with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation 1995; 92 (9 Suppl):ll122-7.
155. Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi
S, et al. Long-term effects of surgical septal myectomy on survival in
patients with obstructive hypertrophic cardiomyopathy. J Am Coll
Cardiol 2005; 46:470-6.
156. Seiler C, Hess OM, Schoenbeck M, Turina J, Jenni R, Turina M,
et al. Long-term follow-up of medical versus surgical therapy for hypertrophic cardiomyopathy: a retrospective study. J Am Coll Cardiol 1991;
17:634-42.
157. Maron BJ. Controversies in cardiovascular medicine. Surgical
myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation 2007; 116:196-206.
158. Sigwart U. Non-surgical myocardial reduction for hypertrophic
obstructive cardiomyopathy. Lancet 1995; 346:211-4.
159. Gietzen FH, Leuner CJ, Raute-Kreinsen U, Dellmann A,
Hegselmann J, Strunk-Mueller C, et al. Acute and long-term results
after transcoronary ablation of septal hypertrophy (TASH). Cath­eter
interventional treatment for hypertrophic obstructive cardio­myopathy.
Eur Heart J 1999; 20:1342-54.
160. Lakkis NM, Nagueh SF, Dunn JK, Killip D, Spencer WH 3rd.
Nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy: one-year follow-up. J Am Coll Cardiol 2000; 36:852-5.
161. Kuhn H, Seggewiss H, Gietzen FH, Boekstegers P, Neuhaus L,
Seipel L. Catheter-based therapy for hypertrophic obstructive cardiomyopathy. First in-hospital outcome analysis of the German TASH
Registry. Z Kardiol 2004; 93:23-31.
162. Alam M, Dokainish H, Lakkis N. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a systematic review of published
studies. J lnterv Cardiol 2006; 19:319-27.
163. Flores-Ramirez R, Lakkis NM, Middleton KJ, Killip D, Spencer
WH 3rd, Nagueh SF. Echocardiographic insights into the mechanisms
of relief of left ventricular outflow tract obstruction after nonsurgical
septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2001; 37:208-14.
164. van Dockum WG, Beek AM, ten Cate FJ, ten Berg JM,
Bondarenko O, G6tte MJ, et al. Early onset and progression of left
ventricular remodeling after alcohol septal ablation in hypertrophic
obstructive cardiomyopathy. Circulation 2005; 111:2503-8.
165. Maron BJ, Dearani JA, Ommen SR, Maron MS, Schaff HV, Gersh
BJ, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:2044-53.
166. Veselka J, Duchonová R, Páleníckova J, Zemánek D, Tiserová
M, Linhartová K, et al. lmpact of ethanol dosing on the long-term
outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy: a single-center prospective, and randomized study. Circ
J 2006; 70:1550-2.
167. Knight CJ. Alcohol septal ablation for obstructive hypertrophic
cardiomyopathy. Heart 2006; 92:1339-44.
168. Ralph-Edwards A, Woo A, McCrindle BW, Shapero JL, Schwartz
L, Rakowski H, et al. Hypertrophic obstructive cardiomyopathy: comparison of outcomes after myectomy or alcohol ablation adjusted by
propensity score. J Thorac Cardiovasc Surg 2005; 129:351-8.
169. Olivotto I, Ommen SR, Maron MS, Cecchi F, Maron BJ. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am
Coll Cardiol 2007; 50:831-4.
170. Jeanrenaud X, Goy JJ, Kappenberger L. Effects of dual-chamber pacing in hypertrophic obstructive cardiomyopathy. Lancet 1992;
339:1318-23.
171. Pavin D, de Place C, Le Breton H, Leclercq C, Gras D, Victor F,
et al. Effects of permanent dual-chamber pacing on mitral regurgitation in hypertrophic obstructive cardiomyopathy. Eur Heart J 1999;
20:203-10.
172. Nishimura RA, Hayes DL, llstrup DM, Holmes DR Jr, Tajik AJ.
Effects of sublingual nifedipine on hemody­namics and systolic and
diastolic function in patients with hyper­trophic cardiomyopathy. Acute
Doppler echocardiographic and catheterization hemodynamic study.
J Am Coll Cardiol 1996; 27:421-30.
173. Betocchi S, Losi MA, Piscione F, Boccalatte M, Pace L, Golino P,
et al. Effects of dual-chamber pacing in hypertrophic cardiomyopathy on left ventricular outflow tract obstruction and on diastolic function. Am J Cardiol 1996; 77:498-502.
174. McDonald K, McWilliams E, O’Keeffe B, Maurer B. Functional
assessment of patients treated with permanent dual chamber pacing
as a primary treatment for hypertrophic cardiomyopathy. Eur Heart
J 1988; 9:893-8.
175. Fananapazir L, Cannon RO 3rd, Tripodi D, Panza JA. lmpact of
dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and
beta-adrenergic blocker therapy. Circulation 1992; 85:2149-61.
176. Fananapazir L, Epstein ND, Curiel RV, Panza JA, Tripodi D,
McAreavey D. Long-term results of dual-chamber (DDD) pacing in
obstructive hypertrophic cardiomyopathy. Evidence for progressive
symptomatic and hemodynamic improvement and reduction of left
ventricular hypertrophy. Circulation 1994; 90:2731-42.
177. Kappenberger L, Linde C, Daubert C, McKenna W, Meisel E,
Sadoul N, et al. Pacing in hypertrophic obstructive cardiomyopathy.
A randomized crossover study. PIC Study Group. Eur Heart J 1997;
18:1249-56.
178. Kappenberger L, Linde C, Daubert C, McKenna W, Meisel E,
Sadoul N, et al. Clinical progress after randomized onloff pace­maker
treatment for hypertrophic obstructive cardiomyopathy. Pacing in Cardiomyopathy (PlC) Study Group. Europace 1999; 1:77-84.
179. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson
ME, Kieval RS. Assessment of permanent dual-chamber pacing as a
treatment for drug-refractory symptomatic patients with obstructive
hypertrophic cardiomyopathy. A randomized, double-blind, crossover
study (M-PATHY). Circulation 1999; 99:2927-33.
180. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK,
Daubert JP, et al. Efficacy of implantable cardioverter-defibrillators
for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365-73.
181. Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A,
Corrado D, Crosson JE, et al; Working Groups of the American Heart
Association Committee on Exercise, Cardiac Rehabilitation, and
Pre­vention; Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004; 109:2807-16.
182. Maron BJ. Contemporary considerations for risk stratification,
sudden death and prevention in hypertrophic cardiomyopathy. Heart
2003; 89:977-8.
183. Maron BJ, Pelliccia A. The heart of trained athletes: cardiac
remodeling and the risks of sports, including sudden death. Circulation 2006; 114:1633-44.
184. Maron BJ. Sudden death in young athletes. N Engl J Med 2003;
349:1064-75.
185. Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A,
Corrado D, Crosson JE, et al; Working Groups of the American Heart
Association Committee on Exercise, Cardiac Rehabilitation, and
Pre­vention; Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004; 109:2807-16.
186. Maron BJ, Olivotto l, Spirito P, Casey SA, Bellone P, Gohman
TE, et al. Epidemiology of hypertrophic cardiomyopathy-related death:
revisited in a large non-referral-based patient population. Circulation 2000; 102:858-64.
187. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F,
Lesser JR, et al. Prevalence, clinical profile, and significance of left
ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006; 114:216-25.
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
188. Maron BJ, Piccininno M, Casey SA, Bernabýÿ P, Spirito P. Relation of extreme left ventricular hypertrophy to age in hypertrophic
cardiomyopathy. Am J Cardiol 2003; 91:626-8.
189. Sorajja P, Nishimura RA, Ommen SR, Ackerman MJ, Tajik AJ,
Gersh BJ. Use of echocardiography in patients with hypertrophic cardiomyopathy: clinical implications of massive hypertrophy. J Am Soc
Echocardiogr 2006; 19:788-95.
190. Olivotto l, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi
F. Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999; 33:2044-51.
191. McGregor JB, Rahman A, Rosanio S, Ware D, Birnbaum Y, Saeed
M. Monomorphic ventricular tachycardia: a late complication of percutaneous alcohol septal ablation for hypertrophic cardiomyopathy.
Am J Med Sci 2004; 328:185-8.
192. Boltwood CM Jr, Chien W, Ports T. Ventricular tachycardia complicating alcohol septal ablation. N Engl J Med 2004; 351:1914-5.
193. Simon RD, Crawford FA 3rd, Spencer WH 3rd, Gold MR. Sustained ventricular tachycardia following alcohol septal ablation for
hypertrophic obstructive cardiomyopathy. Pacing Clin Electrophysiol
2005;28:1354-6.
194. Cecchi F, Maron BJ, Epstein SE. Long-term outcome of patients
with hypertrophic cardiomyopathy successfully resuscitated after cardiac arrest. J Am Coll Cardiol 1989; 13:1283-8.
195. Elliott PM, Sharma S, Varnava A, Poloniecki J, Rowland E,
McKenna WJ. Survival after cardiac arrest or sustained ventricular
tachycardia in patients with hypertrophic cardiomyopathy. J Am Coll
Cardiol 1999; 33:1596-601.
196. Mogensen J, Murphy RT, Kubo T, Bahl A, Moon JC, Klausen lC,
et al. Frequency and clinical expression of cardiac troponin l mutations in 748 consecutive families with hypertrophic cardiomyopathy.
J Am Coll Cardiol 2004; 44:2315-25.
197. Ko YL, Tang TK, Chen JJ, Hshieh YY, Wu CW, Lien WP. ldiopathic
hypertrophic cardiomyopathy in identical twins. Morphological heterogeneity of the left ventricle. Chest 1992; 102:783-5.
198. Moolman JC, Corfield VA, Posen B, Ngumbela K, Seidman C,
Brink PA, et al. Sudden death due to troponin T mutations. J Am
Coll Cardiol 1997; 29:549-55.
199. Miller MA, Gomes JA, Fuster V. Risk stratification of sudden
cardiac death in hypertrophic cardiomyopathy. Nat Clin Pract
Cardiovasc Med 2007; 4:667-76.
200. Fernández A, Casabé HJ, Coronel R, Galizio N, Torino A, Valero
de Pesce E. Alternativas terapéuticas en la miocardiopatía
hipertrófica. Rev Argent Cardiol 2003; 71:294-301.
201. Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death
and clinical deterioration. J Am Coll Cardiol 2003; 41:987-93.
202. Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, et
al. ldiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin l mutations. J Clin lnvest 2003; 111:209-16.
203. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Parker TG,
Wigle ED, et al. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol 2002; 39:638-45.
204. Elliot PM, Gimeno Blanes JR, Mahon NG; Poloniecki JD,
McKenna WJ. Relation between severity of left ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy.
Lancet 2001; 357:420-4.
205. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M,
McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic
cardiomyopathy: an independent marker of sudden death risk in young
patients. J Am Coll Cardiol 2003; 42:873-9.
206. Spirito P, Rapezzi C, Autore C, Bruzzi P, Bellone P, Ortolani P, et
al. Prognosis of asymptomatic patients with hypertrophic cardiomyopathy and nonsustained ventricular tachycardia. Circulation 1994;
90:2743-7.
207. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ.
Spectrum and prognostic significance of arrhythmias on ambulatory
25
Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll
Cardiol 2005; 45:697-704.
208. McKenna WJ, England D, Doi YL, Deanfield JE, Oakley C,
Good­win JF. Arrhythmia in hypertrophic cardiomyopathy. l: lnfluence
on prognosis. Br Heart J 1981; 46:168-72.
209. Maron BJ, Savage DD, Wolfson JK, Epstein SE. Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in
patients with hypertrophic cardiomyopathy: a prospective study. Am
J Cardiol 1981; 48:252-7.
210. Cecchi F, Olivotto l, Montereggi A, Squillatini G, Dolara A, Maron
BJ. Prognostic value of non-sustained ventricular tachycardia and
the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in na unselected non-referral based patient population. Heart 1998; 79:331-6.
211. Counihan PJ, Frenneaux MP, Webb DJ, McKenna WJ. Abnormal vascular responses to supine exercise in hypertrophic cardiomyopathy. Circulation 1991; 84:686-96.
212. Sadoul N, Prasad K, Elliott PM, Bannerjee S, Frenneaux MP,
McKenna WJ. Prospective prognostic assessment of blood pressure
response during exercise in patients with hypertrophic cardiomyopathy. Circulation 1997; 96:2987-91.
213. Sadoul Boriani G, Maron BJ, Shen W-K, Spirito P. Prevention of
sudden death in hypetrophic cardiomyopathy. But which defibrillator for which patient? Circulation 2004; 110:438-42.
214. Elliott PM, Gimeno JR, Tomé MT, Shah J, Ward D, Thaman R,
et al. Left ventricular outflow tract obstruction and sudden death risk
in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;
27:1933-41.
215. Maron BJ, Olivotto l, Maron MS. The dilemma of left ventricular outflow tract obstruction and sudden death in hypertrophic cardiomyopathy: do patients with gradients really deserve prophylactic
defibrillators? Eur Heart J 2006; 27:1895-7.
216. Cha YM, Gersh BJ, Maron BJ, et al. Electrophysiologic manifestations of ventricular tachyarrythmias provoking appropriate defibrillator interventions in high-risk patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2007; 18:483-7.
217. Basso C, Maron BJ, Corrado D, Thiene G. Clinical profile of
congenital coronary artery anomalies with origin from the wrong
aortic sinus leading to sudden death in young competitive athletes. J
Am Coll Cardiol 2000; 35:1493-501.
218. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici
PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med 2003; 349:1027-35.
219. Yamada M, Elliott PM, Kaski JC, Prasad K, Gane JN, Lowe CM,
et al. Dipyridamole stress thallium-201 perfusion abnormalities in
patients with hypertrophic cardiomyopathy. Relationship to clinical
presentation and outcome. Eur Heart J 1998; 19:500-7.
220. Fernández A, Vigliano C, Casabé JH, et al. Myocardial fibrosis
and progression to left ventricular dilatation in patients with hypertrophic cardiomyopathy. Eur Heart J 2005; 26:392 (abstract).
221. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC,
Pennell DJ. Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am
Coll Cardiol 2003; 41:1561-7.
222. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK,
Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999; 281:650-5.
223. Yetman AT, McCrindle BW, MacDonald C, Freedom RM, Gow R.
Myocardial bridging in children with hypertrophic cardiomyopathya
risk factor for sudden death. N Engl J Med 1998; 339:1201-9.
224. Valeti US, Nishimura RA, Holmes DR, Araoz PA, Glockner JF,
Breen JF, et al. Comparison of surgical septal myectomy and alcohol
septal ablation with cardiac magnetic resonance imaging in patients
with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2007;
49:350-7.
225. Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ.
Yield of genetic testing in hypertrophic cardiomyopathy. Mayo Clin
Proc 2005; 80:739-44.
26
REVISTA ARGENTINA DE CARDIOLOGÍA / VOL 77 Nº 2 / MARCH-APRIL 2009
226. Ho TC, Lai WW. Combination therapy for choroidal
neovascularization. Ophthalmology 2006; 113:1470-1.
227. Bos JM, Ommen SR, Ackerman MJ. Genetic basis of hypertrophic
cardiomyopathy: one, two, or more diseases? Curr Opin Cardiol 2007;
22:193-9.
228. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:2125-32.
229. Brugada J. Sudden death in hypertrophic myocardiopathy. Rev
Esp Cardiol 1998; 51: 991-6.
230. McKenna W, Deanfield J, Faruqui A, England D, Oakley C,
Good­win J. Prognosis in hypertrophic cardiomyopathy: role of age
and clinical, electrocardiographic and hemodynamic features. Am J
Cardiol 1981; 47:532-8.
231. Brugada P, Abdollah H, Heddle B, Wellens HJ. Results of a ventricular stimulation protocol using a maximum of 4 premature stimuli
in patients without documented or suspected ventricular arrhythmias.
Am J Cardiol 1983; 52:1214-8.
232. Fananapazir L, Chang AC, Epstein SE, McAreavey D. Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic,
and electrophysiological findings. Circulation 1992; 86:730-40.
233. Maron BJ, Estes NA 3rd, Maron MS, Almquist AK, Link MS,
Udelson JE. Primary prevention of sudden death as a novel treatment strategy in hypertrophic cardiomyopathy. Circulation 2003;
107:2872-5.
234. Momiyama Y, Hartikainen J, Nagayoshi H, Albrecht P, Kautzner
J, Saumarez RC, et al. Exercise-induced T-wave alternans as a marker
of high risk in patients with hypertrophic cardiomyopathy. Jpn Circ J
1997; 61:650-6.
235. Kuroda N, Ohnishi Y, Yoshida A, Kimura A, Yokoyama M. Clinical significance of T-wave alternans in hypertrophic cardiomyopathy.
Circ J 2002; 66:457-62.
236. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK,
Daubert JP, et al. Efficacy of implantable cardioverter-defibrillators
for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365-73.
237. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, et al; American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for
lmplantation of Cardiac Pacemakers and Antiarrhythmia Devices);
American Association for Thoracic Surgery; Society of Thoracic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of
Cardiac Rhythm Abnormalities: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002
Guideline Update for Implantation of Cardiac Pacemakers and
Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008; 117:e350-408.
238. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B,
Fromer M, et al; American College of Cardiology/American Heart
Association Task Force; European Society of Cardiology Committee
for Practice Guidelines; European Heart Rhythm Association and
the Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death– executive summary: A report of the
American College of Cardiology/American Heart Association Task
Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the
European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J 2006; 27:2099-140.
239. Woo A, Monakier D, Harris L, Hill A, Shah P, Wigle ED, et al.
Determinants of implantable defibrillator discharges in high-risk
patients with hypertrophic cardiomyopathy. Heart 2007; 93:1044-5.
240. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic
cardiomyopathy. Clinical spectrum and treatment. Circulation 1995;
92:1680-92.
241. Fananapazir L, Leon MB, Bonow RO, Tracy CM, Cannon RO
3rd, Epstein SE. Sudden death during empiric amiodarone therapy
in symptomatic hypertrophic cardiomyopathy. Am J Cardiol 1991;
67:169-74.
242. Yacoub MH, Olivotto l, Cecchi F. “End-stage” hypertrophic cardiomyopathy: from mystery to model. Nat Clin Pract Cardiovasc Med
2007; 4:232-3.
243. Fighali S, Krajcer Z, Edelman S, Leachman RD. Progression of
hypertrophic cardiomyopathy into a hypokinetic left ventricle: higher
incidence in patients with midventricular obstruction. J Am Coll
Cardiol 1987; 9:288-94.
244. Shirani J, Maron BJ, Cannon RO 3rd, Shahin S, Roberts WC.
Clinicopathologic features of hypertrophic cardiomyopathy managed
by cardiac transplantation. Am J Cardiol 1993; 72:434-40.
245. Coutu M, Perrault LP, White M, Pelletier GB, Racine N, Poirier
NC, et al. Cardiac transplantation for hypertrophic cardiomyopathy:
a valid therapeutic option. J Heart Lung Transplant 2004; 23:413-7.
246. Thaman R, Gimeno JR, Reith S, Esteban MT, Limongelli G,
Murphy RT, et al. Progressive left ventricular remodeling in patients
with hypertrophic cardiomyopathy and severe left ventricular hypertrophy. J Am Coll Cardiol 2004; 44:398-405.
247. Hina K, Kusachi S, lwasaki K, Nogami K, Moritani H, Kita T, et
al. Progression of left ventricular enlargement in patients with hypertrophic cardiomyopathy: incidence and prognostic value. Clin Cardiol
1993; 16:403-7.
248. Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami
F, et al. Relevance of coronary microvascular flow impairment to longterm remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol 2006; 47:1043-8.
249. Takemura G, Takatsu Y, Fujiwara H. Luminal narrowing of
coronary capillaries in human hypertrophic hearts: an ultrastructural morphometrical study using endomyocardial biopsy specimens.
Heart 1998; 79:78-85.
250. Waller TA, Hiser WL, Capehart JE, Roberts WC. Comparison of
clinical and morphologic cardiac findings in patients having cardiac
transplantation for ischemic cardiomyopathy, idiopathic dilated cardiomyopathy, and dilated hypertrophic cardiomyopathy. Am J Cardiol
1998; 81:884-94.
251. Fernández A, Casabé JH, Favaloro RR, et al. Prevalence and
clinical course of the end stage phase of hypertrophic cardiomyopathy
in patients referred to a tertiary care center. Circulation 2008; 117:50
(abstract).
252. Krams R, Ten Cate FJ, Carlier SG, Van Der Steen AF, Serruys
PW. Diastolic coronary vascular reserve: a new index to detect changes
in the coronary microcirculation in hypertrophic cardiomyopathy. J
Am Coll Cardiol 2004; 43:670-7.
253. Krams R, Kofflard MJ, Duncker DJ, Von Birgelen C, Carlier S,
Kliffen M, et al. Decreased coronary flow reserve in hypertrophic cardiomyopathy is related to remodeling of the coronary microcirculation. Circulation 1998; 97:230-3.
254. Fujino N, Shimizu M, lno H, Yamaguchi M, Yasuda T, Nagata
M, et al. A novel mutation Lys273Glu in the cardiac troponin T gene
shows high degree of penetrance and transition from hypertrophic to
dilated cardiomyopathy. Am J Cardiol 2002; 89:29-33.
255. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman
JG, et al. Development of left ventricular hypertrophy in adults in
hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol 2001; 38:315-21.
256. Marian AJ. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet 2000; 355:58-60.
257. Rogers DP, Marazia S, Chow AW, Lambiase PD, Lowe MD,
Frenneaux M, et al. Effect of biventricular pacing on symptoms and
cardiac remodelling in patients with end-stage hypertrophic cardiomyopathy. Eur J Cardiothorac Surg 2008; 10:507-13.
258. Ashrafian H, Mason MJ, Mitchell AG. Regression of
CONSENSUS ON HYPERTROPHIC CARDIOMYOPATHY
dilated­hypokinetic hypertrophic cardiomyopathy by biventricular
cardiac pacing. Europace 2007; 9:50-4.
259. Pezzulich B, Montagna L, Lucchina PG. Successful treatment of
end-stage hypertrophic cardiomyopathy with biventricular cardiac
pacing. Europace 2005; 7:388-91.
260. Biagini E, Spirito P, Leone O, Picchio FM, Coccolo F, Ragni L, et
al. Heart transplantation in hypertrophic cardiomyopathy. Am J
Cardiol 2008; 101:387-92.
261. Arena R, Owens DS, Arevalo J, Smith K, Mohiddin SA,
McAreavey D, et al. Ventilatory efficiency and resting hemodynamics
in hypertrophic cardiomyopathy. Med Sci Sports Exerc 2008; 40:799805.
262. Sharma S, Elliott P, Whyte G, Jones S, Mahon N, Whipp B, et al.
Utility of cardiopulmonary exercise in the assessment of clinical determinants of functional capacity in hypertrophic cardiomyopathy.
Am J Cardiol 2000; 86:162-8.
263. Sharma S, Elliott PM, Whyte G, Mahon N, Virdee MS, Mist B,
et al. Utility of metabolic exercise testing in distinguishing hypertrophic cardiomyopathy from physiologic left ventricular hypertrophy in athletes. J Am Coll Cardiol 2000; 36:864-70.
264. Dilsizian V, Bonow RO, Epstein SE, Fananapazir L. Myocardial
ischemia detected by thallium scintigraphy is frequently related to
cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1993; 22:796-804.
27
265. Shimizu M, lno H, Okeie K, Emoto Y, Yamaguchi M, Yasuda T,
et al. Exercise-induced ST-segment depression and systolic dysfunction in patients with nonobstructive hypertrophic cardiomyopathy.
Am Heart J 2000; 140:52-60.
266. Brión G, Peidro R, Angelino A, Zalazar T, Kriskovich J, Casabé
H, et al. Prognostic value of exercise testing in patients with hypertrophic cardiomyopathy. Eur Heart J 2005; 26:1696 (abstract).
267. Maron B, Ackerman M, Nishimura R, Pyeritz R, Towbin J,
Udelson J. Task Force 4: HCM and other cardiomyopathies, mitral
valve prolapse, myocarditis, and Marfan syndrome. In: Maron B,
Zipes D. 36th Bethesda Conference: Eligibility Recommendations for
Competitive Athletes with Cardiovascular Abnormalities. J Am Coll
Cardiol 2005; 45:29-33.
268. Basavarajaiah S, Wilson M, Whyte G, Shah A, McKenna W,
Sharma S. Prevalence of hypertrophic cardiomyopathy in highly
trained athletes: relevance to pre-participation screening. J Am Coll
Cardiol 2008; 51:1033-9.
269. Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A,
Corrado D, Crosson JE, et al; Working Groups of the American Heart
Association Committee on Exercise, Cardiac Rehabilitation, and Prevention; Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004; 109:2807-16.