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Band 05 ⁄ April 2016
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Journal für angeborene Herzfehler
EuroGUCH Meeting 2016
Harald Kaemmerer, Peter Ewert, Andreas Eicken (ed.)
Deutsches Herzzentrum München
des Freistaates Bayern
Klinik an der Technischen Universität München
Content
Elements Required to Build a Strong ACHD Program
6
Gary Webb
Echocardiographic evaluation of the tricuspid valve, the pulmonic valve
and the right ventricle
10
Jan Marek
Advanced echocardiographic modalities in the assessment of
right ventricular function
14
Satoshi Yasukochi
Assessment of RV function with pressure-volume loops –
impact on treatment indication for a volume-loaded RV
16
Christian Apitz
Cardiovascular Magnetic Resonance Evaluation of the tricuspid valve,
the pulmonary valve and the right ventricle
18
Christian Meierhofer
Exercise physiology and pathology in right ventricular dysfunction
20
Folkert Meijboom
Indications for treatment in adults with tricuspid valve dysfunction
due to a congenital cardiac anomaly
24
Markus Schwerzmann
Surgical techniques to improve tricuspid valve function
in congenital heart defects
26
Victor Tsang, Henri Haapanen
When Tricuspid Valvuloplasty fails … What is the best valve
in tricuspid position?
28
Alessandro Giamberti
Which valve is best in right ventricular outflow tract dysfunction?
30
Rüdiger Lange
Indications for pulmonary valve replacement in adults with
congenital heart disease
32
Werner Budts
Failing biological tricuspid valve – percutaneous tricuspid
valve replacement
36
Peter Ewert
Transcatheter Percutaneous Pulmonary Valve-in-Valve Implantation
38
Chessa Massimo
When treatment fails – indication for and results of transplantation
for failing hearts in Congenital Heart Disease (CHD)
40
Harald Gabriel
The John Hess Lecture – How to optimize ACHD patient care and
future directions in physician education
Gary Webb
2
42
Prognostic Value of Brain Natriuretic Peptides in ACHD
43
Olga Hajnalka Balint
Heart failure in ACHD: What is different from acquired heart disease?
47
Pedro Trigo Trindade
Hyponatremia in ACHD: From prognosis to treatment
50
Oktay Tutarel
Can we prevent the development of heart failure in ACHD?
52
Helmut Baumgartner
Endstage heart failure in ACHD: Medical and surgical treatment concepts
54
Felix Berger
Aortic root dilatation in adults with congenital heart disease and
effects of pharmacotherapy on aortic growth
56
Julie De Backer
Oral Anticoagulants in Adult Congenital Heart Disease
62
Harald Kaemmerer, Claudia Pujol, Anne-Charlotte Niesert, David Pittrow, Peter Ewert
Morbus Fabry: Too often overlooked?
64
Tomas Palecek, Ales Linhart
Hypertrophic Cardiomyopathy: the renewed ESC-guidelines
67
Hubert Seggewiss
Modern survival analysis in Eisenmenger-Syndrome
68
Gerhard-Paul Diller
Pulmonary vasoactive medication in adults with Fontan circulation
70
Jamil Aboulhosn
Diagnosis and management of iron deficiency and
hyperuricemia in cyanotic ACHD
73
Koichiro Niwa
Treat and repair strategies for adults with septal defects and
pulmonary arterial hypertension
74
Dietmar Schranz
The future of PAH treatment on the horizon
76
Stephan Rosenkranz
Electrophysiologic considerations in ACHD with heart failure
80
Karl-Heinz Kuck
Efficacy of Antiarrhythmic Pharmacotherapy in ACHD
82
Joachim Hebe
Sudden death in ACHD: Risk stratification
88
Johan Holm
Device Therapy: Indications and Future Aspects in Primary Prevention
of Cardiac Death
90
Christof Kolb
Imprint
92
3
Chairs and Speakers
Jamir ABOULHOSN (Chair)
Los Angeles, United States
Christian APITZ
Ulm, Germany
Julie DE BACKER
Gent, Belgium
Olga Hajnalka BALINT
Budapest, Hungary
Helmut BAUMGARTNER (Chair)
Münster, Germany
Felix BERGER
Berlin, Germany
Werner BUDTS (Chair)
Leuwen, Belgium
Massimo CHESSA
Mailand, Italy
Gerhard DILLER
Münster, Germany
Andreas EICKEN (Chair)
München, Germany
Peter EWERT
München, Germany
Harald GABRIEL
Wien, Austria
Alessandro GIAMBERTI (Chair)
Mailand, Italy
Joachim HEBE
Bremen, Germany
Johan HOLM
Lund, Sweden
Harald KAEMMERER
München, Germany
Christoph KOLB
München, Germany
Karl Heinz KUCK
Hamburg, Germany
Rüdiger LANGE (Chair)
München, Germany
Ivan MALCIC (Chair)
Zagreb, Croatia
Jan MAREK
Londo n, United Kingdom
Christian MEIERHOFER
München, Germany
Folkert MEIJBOOM (Chair)
Utrecht, The Netherlands
Ina MICHEL-BEHNKE (Chair)
Vienna, Austria
Koichiro NIWA (Chair)
Tokyo, Japan
Tomas PALECEK
Prag, Czech Republic
Jolien ROOS-HESSELINK
Rotterdam, The Netherlands
Stefan ROSENKRANZ
Köln, Germany
Hubert SEGGEWIß
Schweinfurt, Germany
Dietmar SCHRANZ
Gießen, Germany
Markus SCHWERZMANN (Chair)
Bern, Switzerland
Jane SOMERVILLE
London, United Kingdom
Heiko STERN
München, Germany
Öztekin OTO (Chair)
Izmir, Turkey
Pedro TRIGO-TRINDADE (Chair)
Geneva, Switzerland
Viktor TSANG
London, United Kingdom
Oktay TUTAREL
Hannover, Germany
Gary WEBB
Cincinnati, Unite States
Satoshi YASUKOCHI
Nagano, Japan
Dear colleagues and friends,
PD Dr. med. Andreas Eicken
Prof. Dr. Dr. Harald Kaemmerer
Prof. Dr. med. Peter Ewert
it is our great honour and pleasure to welcome you at the
occasion of the 7th annual scientific meeting of the ESCworking group on adults with Congenital Heart Disease.
It is worth mentioning, that this year the DACH-Symposium,
a GUCH-meeting of the German-speaking Central European
countries, has been integrated into this congress.
day is focuses on different clinically relevant topics for this
group of patients.
We believe the meeting will be attractive not only for adult –
or pediatric cardiologists and surgeons, but also for cardiac
anesthesiologists, intensivists, nurse specialists and other
health professional caring for GUCH patients.
The combined effort – cardiological and surgical – to treat
adults with congenital heart disease is a story of success.
Today an increasing number of patients, even with very
complex congenital heart disease, survive to adulthood
with a good quality of life.
However, since true „correction“ of a congenital cardiac
lesion is rarely achievable, these patients need lifelong
expert medical surveillance and close collaboration of
health professionals in many medical sub-specialities.
We hope that, besides an excellent scientific meeting, you
will enjoy Bavarian hospitality and a stimulating atmosphere
here in Munich.
It is an opportunity not only to share scientific thoughts but
to promote personal relationships.
The first day of the current meeting is concentrating on
the right ventricle in patients with congenital heart disease.
Diagnostic modalities, indication for treatment and treatment options are presented and discussed. The second
PD Dr. med. Andreas Eicken
Prof. Dr. Dr. Harald Kaemmerer
Last but not least, we would like to sincerely thank
“Actelion Pharmaceuticals Germany GmbH”. Without
their support it would not have been possible to provide
you with the companion volume of this meeting.
In addition, a printable pdf version of the booklet is
also available (see: www.dhm.mhn.de/de/
kliniken_und_institute/klink_fuer_kinderkardiologie_u.cfm).
Prof. Dr. med. Peter Ewert
5
Elements Required to Build a Strong ACHD Program
Gary Webb, M.D.
Cincinnati Adolescent and Adult Congenital Heart Center
Cincinnati Children’s Hospital
The Heart Center
Cincinnati, USA
Over the last couple of generations, the number of adult
patients with congenital heart defects has greatly increased,
and numerous ACHD clinics have opened. Perhaps you
are thinking of starting one. Let’s have a look at the things
you should be thinking about and planning for in order to
ensure that your clinic is successful, and that your patients
get excellent care.
The first consideration has to do with understanding where
your patients are going to come from. Will pediatric cardiologists send a lot of patients to you? Are you depending
on adult cardiologists doing so? Primary care physicians?
Patients and families finding you from their communities?
What will be the trajectory of new graduates from pediatric
cardiology practices? If the pediatric cardiologists are willing to refer their graduates to your ACHD program, that is
welcome news. If not, that spells trouble.
How many patients are needed to build a strong ACHD
program? In order to build a strong multidisciplinary ACHD
program, I believe if you need approximately 250 new referrals a year or a base of at least 1500 patients in order
to develop and maintain team skills, to train fellows, and
to provide adequate volumes for both diagnostic and interventional services.
6
Another issue has to do with an agreed age to transfer from
pediatric to adult care. In Canada, this occurs at age 18.
Most Western European countries have an agreed age of
transfer. To me, this is a critical factor in growing successful
ACHD programs. In the USA, there is no agreement on any
age of transfer, and this is a key factor in weakening ACHD
care in the USA. A notable exception is at Emory University
in Atlanta, where patients are routinely transferred at age
21 to the adult facility.
Another process that needs to be monitored virtually from
birth and the diagnosis of congenital heart defects is the
issue of attrition or loss to care of patients with moderate
and complex congenital heart conditions (1). Attrition of
patients who would benefit from ongoing lifelong care is a
widespread problem that will result in avoidable morbidity
and mortality for some of these patients. Accordingly, a
determined effort to identify these patients and keep them
in care in the pediatric institutions or practices would be
very valuable for all concerned. If appointments are missed,
the family/patient should be contacted and a follow-up
made unless it is known that patients are receiving appropriate care elsewhere.
For those patients who remain in pediatric cardiac care
after age 11 or 12, a consistent progressive patient and
family education program is in order. This is often called
“transition”, but I don’t like the word. At least in the USA,
pediatric cardiologists hear the word “transition” and assume that we are going to try to steal their patients. Unfortunately, I haven’t found a suitable replacement. In dealing
with adolescents and young adults, we need to remember
that our brains don’t mature until approximately age 25.
A transition program should include teenagers and young
adults and should be aimed at encouraging young people
to take appropriate responsibility for their own health.
Healthy attitudes and behaviors are encouraged. The
lifelong care message is emphasized for most patients.
Education should include career planning, lifestyle choices,
Figure 1: Key members of a multidisciplinary ACHD team
insurance planning, and reproductive counseling. Young
people who make good lifestyle choices are more likely
to take responsibility for their own health and lives, so
healthy lifestyles should be strongly encouraged.
Some patients are expected to be at low risk of adverse
outcomes over the course of their lifetime. Such patients,
such as those with closed secundum ASDs at a young age,
small VSDs, and repaired pulmonary stenosis, need to
learn of our favorable expectations for them at a young age
so they can lead a normal life and not think of themselves
as “heart patients”. The same facts need to be conveyed
to their parents. Transfer of such patients from pediatric
care is usually easy since good primary care physicians
and cardiologists can usually provide appropriate care.
The medium to high risk patients need expert lifelong surveillance. Expert care has been shown to have a survival
advantage for these patients (2). Group life expectancy is
clearly reduced in a lesion -dependent fashion (3). Many of
these patients will have limitations of their exercise capacity and lifestyle. Examples of moderately complex patients
are arterial switch patients, repaired tetralogy, moderate to
severe pulmonary valve lesions, repaired AV septal defects,
aortic coarctation, and Ebstein anomaly. Examples of very
complex patients include Fontan patients, severe pulmonary hypertensive patients, Mustard/Senning patients,
patients with conduits, truncus arteriosus repairs, and
cyanotic patients. It is critically important that such patients remain within expert care whether in the pediatric
clinic or, after a certain age, in an ACHD clinic. These
patients need to know not only the lifelong care message,
but how to identify expert care and where to find it (4).
Part of the education process includes teaching the patient
and family the basics. What is the name of the condition
the patient has? What treatment has he or she received?
What are future expectations? Are there any threats that
can be anticipated, or any precautions that should be
taken? What symptoms should be watched for? How frequently should the patient be seen, and by whom and
where?
A multidisciplinary ACHD clinic needs to be based in an
institution or at least a large multidisciplinary ambulatory
practice. Your ACHD clinic will need the support of the institution or practice group. Is there a long-term commitment
to build and maintain the program, and to provide excellent
care for ACHD patients? There needs to be an agreement
on goals, objectives, financial considerations, and other
matters.
If you have a choice, should the program be located in an
adult hospital or a children’s hospital? There is no best
answer to the question. The ideal situation would be one in
which both adult and pediatric services are provided in the
same institution. There is evidence that successful transfer
to adult care is more effective and successful when the patient can be transferred within the same facility (5, 6). The
availability of both adult and pediatric subspecialty providers improves your potential flexibility in identifying the
right resources for your patient. In my experience having an
ACHD clinic in an adult hospital means that you may lose
the opportunity to keep complex CHD children and adolescents in care unless you have remarkable support from your
pediatric cardiology colleagues. Having an ACHD clinic in an
adult hospital means you may not be able to negotiate the
smooth transfer of complex CHD patients to adult care,
especially in the USA. On the other hand, having an ACHD
clinic in a children’s hospital may help you to avoid the loss
to care of complex CHD children and adolescents and help
effect a smooth transfer to adult care.
Caring for ACHD outpatients is fairly straightforward and
can occur in either a pediatric or adult clinic location. On
the other hand, the care of ACHD inpatients is a much more
difficult challenge. Adult inpatients are not welcome in
children’s hospitals. ACHD inpatients in adult hospitals
may be cared for by teams not familiar with their conditions
or how best to treat them.
There are important cultural differences between adult
hospitals and children’s hospitals. Team members with an
adult background will align most easily with an adult envi-
7
ronment and team members with a pediatric background
will align best with a pediatric environment. The reverse
also applies, and alignment may be painful.
A related issue has to do with the need for separate and
distinct protocols for adult patients in any environment as
regards echocardiography, exercise testing, cardiac catheterization, cardiac surgery, and other diagnostic procedures
and therapies. Extension of pediatric protocols to adult
patients is not appropriate, even though it is widely done.
In countries with national healthcare, the importance of engaging the governmental health department’s interest and
support cannot be underestimated in helping to establish
and maintain a well-organized service.
You must commit yourself and your program to excellent
patient care. This will reduce the number of times you
do things you shouldn’t because of pride or self-interest.
Honoring this principle will help you build and maintain
your credibility.
You and your program should aim to be able to address the
needs of any patient that comes through your door. You may
not be able to do everything in your own institution or community. If not, you need to make sure that services of high
quality are available to your patients, and you should refer
them to the best available resources.
The members of a multidisciplinary ACHD care team are
many. Moreover, you don’t just want to have one person in
each of your key categories. You must at least duplicate key
skills.
You need at least two ACHD cardiologists. These can come
either from an adult cardiology or a pediatric cardiology
background. If from pediatric cardiology, that person needs
to practice differently when dealing with adults than when
dealing with children and their parents. The script used
needs to be fundamentally different. Life is theater, and
this is a good example of where changing roles and responsibilities and customers are needed. Ideally, both types of
cardiologists will have received specific training in ACHD. If
not, there is at least the need for a clear career commitment
to become an excellent ACHD cardiologist and to grow and
maintain one’s skills.
As a rule, we believe it’s important to have both adult-trained and pediatric-trained cardiologists in an ACHD clinic.
Each brings hopefully offsetting strengths and weaknesses
to the table.
As you begin building your program, you’ll need to identify
potential consulting team members. Once done, you will
need to develop and improve the capabilities of your consulting team in a constructive ongoing way.
You definitely need an excellent echocardiography service.
This includes both physicians and sonographers. Highquality echo work is critically important to the success of
an ACHD clinic. Adult echoes and pediatric echoes are very
different and are reported differently. Adult approaches
are needed for adult patients. A full range of echo services
8
for adult patients needs to be provided. Excellent nursing
support adds value to the team. Whether nursing team
members should come from an adult or pediatric background can be debated. A long-term commitment to ACHD
care will improve their knowledge and abilities.
Access to excellent congenital heart surgery is essential.
This does not need to be in your own institution, but it certainly needs to be accessible. This includes the entire surgical team and intensive care personnel. The most common
ACHD surgical procedure is pulmonary valve replacement.
In my opinion, these are best handled by congenital heart
surgeons. Indeed, there is evidence that there is a survival
advantage for ACHD patients being operated on by congenital rather than adult cardiac surgeons (7). There are other
patients that can be handled by adult cardiovascular surgeons skilled at aortic, mitral, aortic valve surgery, coronary
artery bypass, etc. If your ACHD program is going to include
patients with Marfan syndrome, there needs to be 24/7
availability of emergency surgical services to deal with
anticipated aortic dissections. If your program is going to
include patients with severe pulmonary hypertension,
special resources also need to be available to manage
these contingencies. If your program is going to include
cardiac patients who are pregnant, appropriate resources
must be available 24/7.
Access to excellent diagnostic and interventional catheterization services is also imperative. Again, they don’t need to
be in the same building, but they need to be accessible.
The cardiologists doing these procedures usually come
from a pediatric cardiology background, although adult cardiologists with training and experience in structural heart
disease a well be capable of managing many of these catheterization cases. In either case, the interests of the patient should be primary. The procedure should be done by
someone with appropriate expertise and experience and
whose equipment and resources offer the patient the best
possible chance of an excellent outcome. Is a biplane facility required? Does the lab have enough adult-sized catheters and devices to manage contingencies?
Access to excellent electrophysiology services are also very
important. EP issues are very prevalent amongst ACHD
patients. Pediatric EP cardiologists do very different work
from adult EP cardiologists, so selecting a consultant may
depend on the needs of the individual patient.
Heart failure and transplant services will also need to be
available. Heart failure is becoming an increasing issue in
ACHD programs. Access to pulmonary hypertension resources will also be needed. Many ACHD programs now include
team members with pulmonary hypertension expertise.
Reproductive services also need to be available locally. This
begins with the ability to counsel women of childbearing
age regarding contraceptive options and their pregnancy
risks. Some women should not use an estrogen-containing
preparation. Risk factors for pregnancy should be evaluated
according to several standard scales. One or more interested gynecologists may well make a valuable contribution
to the family planning aspects of your ACHD clinic. A good
primary care physician might provide many of the same
services. The availability of maternal fetal medicine services is also vital. The ACHD program should provide the
cardiac component of surveillance and treatment planning
in collaboration with one or more obstetrical teams.
Imaging services beyond echocardiography are also essential.
Excellence in MRI is particularly vital, and CT angiography
will need to be available. Specific training and experience
in congenital heart disease and/or ACHD is essential to
maximize value and minimize errors.
A number of other people might be important from time
to time. If you have Fontan patients, you should have a
knowledgeable hepatologist available. Many ACHD patients
have chronic kidney issues, so nephrology support and
involvement would be important. The availability of a geneticist and a genetics counselor may also be very important
to the assessment and management of some patients.
Hematology involvement may be required at times. Mental
health resources are an important part of a comprehensive
service.
In starting a new ACHD program, you need to have the
essential elements in place before you open the doors.
Once you do open the door and patients come in in sufficient numbers, your team will gain additional clinical experience and will become even more talented than they were
at the outset. The team would be well advised to focus on
quality outcome metrics in order to ensure themselves that
they are maintaining standards and following published
guidelines to ensure the best care of their patients (8–10).
The Adult Congenital Heart Association in the USA has created accreditation metrics for American ACHD clinics. This
information should, in my opinion, be accessed from all jurisdictions since it provides important reminders regarding
the many elements of high-quality ACHD patient care.
ACHD services need to be designed separately from pediatric cardiology services and from adult cardiology services.
This applies to a wide range of activities including echocardiography, exercise testing, heart catheterization, and
inpatient care. This is a difficult process, but extending
pediatric services into the adult age range is not a formula
for success, nor is the extension of acquired heart disease
services into the congenital heart population likely to be
successful. Parallel systems in all these dimensions should
be created.
If you want to build a strong ACHD program, you will need:
lots of suitable patients; a supportive institution; supportive colleagues; a talented team; a commitment to excellent
patient care; educated patients and families; an effective
transition/education process; and a clear transfer/graduation policy. You will need to focus mainly on medium risk to
high-risk ACHD patients, and will work to keep them in care
and to meet whatever health needs they may develop. You
may need to decide in what type of institution to locate your
program. Most of your care will be ambulatory, and you will
need to establish suitable and different diagnostic and
management protocols for the ACHD patients regardless of
whether you are in a pediatric institution or an adult institution. If you are based in a children’s hospital, the admission of adult patients will be trying until you develop an appropriately adult trained care team to take the load off the
pediatric practitioners. You will need to keep the interests
of the patient uppermost in your planning and will need to
be clear what services you will be able to provide locally,
and which services will need to be accessed elsewhere.
You will be challenged to develop your multidisciplinary
care team and this will take both persistence and patience.
Collaboration of at least one pediatric trained cardiologist
with at least one adult trained cardiologist is a good foundation for a program. An excellent echocardiography service
is essential, and will need to be different from both pediatric echo services and adult acquired heart disease echo
services. Success will not be easy, but there are an ever
increasing number of patients who are depending on you
to get the job done, and to get it done well.
References
1. Mackie, A.S., et al., Children and adults with congenital heart disease
lost to follow-up: who and when? Circulation, 2009. 120(4): p. 302–9.
2. Mylotte, D., et al., Specialized adult congenital heart disease care: the
impact of policy on mortality. Circulation, 2014. 129(18): p. 1804–12.
3. Diller, G.P., et al., Survival Prospects and Circumstances of Death in
Contemporary Adult Congenital Heart Disease Patients Under Follow-Up
at a Large Tertiary Centre. Circulation, 2015. 132(22): p. 2118–25.
4. Reid, G.J., et al., Prevalence and correlates of successful transfer from
pediatric to adult health care among a cohort of young adults with complex congenital heart defects. Pediatrics, 2004. 113(3 Pt 1): p. e197–205.
5. Goossens, E., et al., Transfer of adolescents with congenital heart
disease from pediatric cardiology to adult health care: an analysis of
transfer destinations. J Am Coll Cardiol, 2011. 57(23): p. 2368–74.
6. Norris, M.D., et al., Prevalence and patterns of retention in cardiac care
in young adults with congenital heart disease. J Pediatr, 2013. 163(3): p.
902–904 e1.
7. Karamlou, T., et al., National practice patterns for management of adult
congenital heart disease: operation by pediatric heart surgeons decreases in-hospital death. Circulation, 2008. 118(23): p. 2345–52.
8. Warnes, C.A., et al., ACC/AHA 2008 Guidelines for the Management of
Adults with Congenital Heart Disease: Executive Summary: a report of
the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (writing committee to develop guidelines
for the management of adults with congenital heart disease). Circulation, 2008. 118(23): p. 2395–451.
9. Silversides, C.K., et al., Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart
disease: shunt lesions. Can J Cardiol, 2010. 26(3): p. e70–9.
10. Baumgartner, H., et al., ESC Guidelines for the management of grownup congenital heart disease (new version 2010). Eur Heart J, 2010.
31(23): p. 2915–57.
9
Echocardiographic evaluation of the tricuspid valve,
the pulmonic valve and the right ventricle
Jan Marek
Great Ormond Street Hospital for Children
London, UK
KEY POINTS
Significant improvement has been achieved in assessing
RV function using conventional and advanced ECHO
techniques. Despite high sensitivity to loading conditions, many ECHO measures and indices can be applied to
clinical practice for their high predicting value, particularly in conditions where RV is exposed to high afterload.
Echocardiographic (ECHO) assessment of RV function is
complex and no single functional parameter is generally
accepted in clinical practice. Several cross-sectional imaging parameters have been tested and validated and many
article published suggesting advantages and limitations.
Major limitation of all of them is more or less load dependency; however, many of them are giving insight in understanding of mechanism of RV failure and should be routinely used in clinical practise (1.–4.). Parameters used for
assessment of RV function are based on conventional ECHO
methods (fractional area change - FAC/%, M-mode derived
fractional shortening – FS/%), Doppler derived E/A ratio,
10
S/D ratio, change of the pressure over the time (+dP/dt
max/mmHg-s), tricuspid annular plane systolic excursion
(TAPSE/mm), or based on Tissue Deformation Imaging techniques (tissue Doppler velocity and colour coded and 2D
Strain imaging measures) for assessing myocardial velocities (S`, E`, A`), measuring myocardial performance index
(MPI), Strain (S/%) or Strain rate (SR/-1), or isovolemic
acceleration index (IVA), perhaps least load dependent but
strongly heart-rate dependent parameter. Real-time 3D
ECHO appeared to be alternative to MRI in assessing RV
function. Twenty-three studies including 807 subjects however showed that 3D ECHO significantly underestimates
RV enddiastolic volumes as well as RV ejection function (5).
Right ventricle exposed to high preload (atrial septal defect – ASD, tetralogy of Fallot with postoperative pulmonary
regurgitation – TOF/PR, Ebstein anomaly – EA): In ASD
patients, longitudinal deformation measured conventional
and TDI showed in general normal or supra-normal functional parameters. Significant increase was found in the apical segment by using 2D Strain technique (6), apical strain
correlated with shunt-ratio, RV end-diastolic area, and
Figure 1. Clinical information (A) and RV
echocardiographic indices (B.-D.) before
and after cone operation for Ebstein anomaly.
NYHA = New York Heart Association,
TAPSE = tricuspid annular plane systolic
excursion, RV FAC = right ventricular fractioning
area change
Figure 2. Conventional LV echocardiographic indices
(4.B.), 2D Strain (C.) and dyssynchrony assessment
(D) before and after cone operation for Ebstein
anomaly. LVEF = left ventricular ejection fraction,
TTP = time-to-peak, HR = heart rate
RV stroke volume (7). Reduced functional parameters after
surgical closure as compared to preoperative finding and
post-catheter closure are related to reduced preload, cardiopulmonary bypass procedure and pericardial constrain.
In TOF/PR, functional parameters are compounded by several factors such as type and time of initial surgical interventions, degree of residual pulmonary regurgitation and
stenosis and QRS time. Several studies (8, 9, 10) confirm
reduced overall longitudinal deformation but more significantly in the more apical segments of the RV free wall and
the interventricular septum but predictive value of these
changes is still not clearly identified. Higher pulmonary regurgitation volume and larger RV end-diastolic volume can
also be associated with decreased LV radial strain (11) due
to apical RV dilatation. In our study (12) we confirmed that
the increase in early LV diastolic filling post percutaneous
pulmonary valve implantation correlated with the reduction
in RV to LV mechanical delay and change in septal curvature. Abnormally delayed septal contraction can be often
explained by electromechanical dyssynchrony due to QRS
prolongation (13, 14). Early septal activation leads to early
pre-stretch and late contraction of the RV basal lateral
segments that are hallmarks of electromechanical dyssynchrony similar to LV dysfunction and LBBB resulting in
mechanical inefficiency. Diastolic dysfunction is also well
described in these patients, potentially preceding systolic
functional impairment, concept of Doppler derived presystolic atrial antegrade flow in pulmonary artery suggestive
of restrictive RV physiology (15) has been routinely used
in clinical practise. Our study however suggested that RV
physiology is influenced by degree of PR and this Doppler
flow pattern can resolve once PR is eliminated (16).
In EA, the RV is chronically exposed to high preload (significant TR±ASD) and low afterload (low PVR). Despite the TR
and large atrialised portion of the RV together with underfilled LV, this physiology can be tolerated well even for
years. Successful cone operation eliminates TR and incorporates atrial RV into functional RV. This acute change leads
to rather dramatic RV dysfunction documented by ECHO
11
and MRI indices (17, 18) but in the other hand, improved
clinical condition is explained by increased cardiac index
due to increased net forward flow from the right ventricle.
Our recent unpublished data on assessment of the RV
(Figure 1.) and LV function (Figure 2.) did not show significant change in LV contractility or mechanical synchrony
(marginally better) before and after cone operation suggesting that obvious septal “dyskinesia” might be visual impression caused by competitive pressure/volume dynamics
between atrialised RV and functional LV rather than intrinsic myocardial impairment and this seems to be in agreement with recent MRI study (19).
Right ventricle exposed to high afterload (pulmonary arterial hypertension – PAH, congenitally corrected transposition of the great arteries (ccTGA), transposition of the
great arteries (TGA) operated via intra-atrial baffling, and
in hypoplastic left heart - HLHS (before or after staged
Fontan palliation),
In PAH patients, echocardiography provides several variables which correlate with right heart haemodynamics and
should always be performed in the case of suspected PAH
(20). In contrast to volume overloaded RV, conventional and
TDI ECHO values and indices in pressure overloaded RV are
more accurate and correlating better when compared to
12
MRI or catheter derived data (21). Simple measure of RV
longitudinal function TAPSE is associated with survival in
patients with PAH (22), however this parameter analyse
very small part of the RV. Other ECHO predictors of prognosis include pericardial effusion, indexed right atrial area,
the degree of septal shift toward the left ventricle in diastole, pulmonary vascular capacitance, and RV myocardial
performance index (MPI, Tei index) (23, 24). Relatively
simple methods such as Doppler derived systolic/diastolic
index (25) might be used effectively as well as rather sophisticated RV myocardial strain (26).
In patients with ccTGA, in TGA after intra-atrial baffling,
and in HLHS, the morphological RV is the systemic ventricle. Several studies in patients with ccTGA and TGA after
Mustard or Senning operation showed that quantitative
echocardiographic assessment of global systemic RV
function such as MPI highly correlates with RVEF obtained
by CMR and can be used in clinical practice (27). Speckle
tracking derived global longitudinal strain is lower especially in the apical segment, and tended to be lower in TGAMustard than ccTGA patients (28) and is related to adverse
clinical outcome (29).
References
1. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report from the
American Society of Echocardiography Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am
Soc Echocardiogr 2010; 23: 685–713.
2. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L,
Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt
JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
Eur Heart J Cardiovasc Imaging. 2015; 16: 233–70.
3. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, Lai
WW, Geva T. Recommendations for quantification methods during the
performance of a pediatric echocardiogram: a report from the Pediatric
Measurements writing Group of the American Society of echocardiography Pediatric and Congenital Heart Disease Council. J. Am. Soc. Echocardiogr. 2010; 23, 465–495.
4. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna
BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thébaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M,
Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory
G, Humpl T, Wessel DL. American Heart Association Council on cardiopulmonary, critical care, perioperative and resuscitation; Council on
Clinical Cardiology; Council on Cardiovascular Disease in the Young;
Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American
Heart Association and American Thoracic Society. Circulation. 2015; 24:
132: 2037–99.
5. Shimada YJ, Shiota M, Siegel RJ, Shiota T. Accuracy of right ventricular
volumes and function determined by three-dimensional echocardiography in comparison with magnetic resonance imaging: a meta-analysis
study. J Am Soc Echocardiogr. 2010; 23: 943–53.
6. Dragulescu A, Grosse-Wortmann L, Redington A, Friedberg MK, Mertens
L. Differential effect of right ventricular dilatation on myocardial deformation in patients with atrial septal defects and patients after tetralogy of Fallot repair. Int J Cardiol. 2013, 30; 168: 803–10.
7. Van De Bruaene A, Buys R, Vanhees L, Delcroix M, Voigt JU, Budts W. Regional right ventricular deformation in patients with open and closed atrial
septal defect. European Journal of Echocardiography 2011; 12, 206–213.
8. Kowalik E, Kowalski M, Ró a ski J, Ku mierczyk M, Hoffman P. The impact
of pulmonary regurgitation on right ventricular regional myocardial
function: an echocardiographic study in adults after total repair of
tetralogy of Fallot. J Am Soc Echocardiogr 2011; 24: 1199–204.
9. Sabate Rotes A, Bonnichsen CR, Reece CL, Connolly HM, Burkhart HM,
Dearani JA, Eidem BW. Long-term follow-up in repaired tetralogy of fallot: can deformation imaging help identify optimal timing of pulmonary
valve replacement? J Am Soc Echocardiogr. 2014.
10. Kempny A, Diller GP, Orwat S, Kaleschke G, Kerckhoff G, Bunck ACh,
Maintz D, Baumgartner H. Right ventricular-left ventricular interaction
in adults with Tetralogy of Fallot: a combined cardiac magnetic resonance and echocardiographic speckle tracking study. Int J Cardiol.
2012; 154: 259–64.
11. Menting ME, van den Bosch AE, McGhie JS, Eindhoven JA, Cuypers JA,
Witsenburg M, Geleijnse ML, Helbing WA, Roos-Hesselink JW. Assessment of ventricular function in adults with repaired Tetralogy of Fallot
using myocardial deformation imaging. Eur Heart J Cardiovasc Imaging.
2015; 16: 1347–57.
12. Lurz P, Puranik R, Nordmeyer J, Muthurangu V, Hansen MS, Schievano
S, Marek J, Bonhoeffer P, Taylor AM. Improvement in left ventricular filling properties after relief of right ventricle to pulmonary artery conduit
obstruction: contribution of septal motion and interventricular mechanical delay. European Heart Journal 2009, 30; 2266–2274.
13. Hui W, Slorach C, Dragulescu A, Mertens L, Bijnens B, Friedberg MK
Mechanisms of right ventricular electromechanical dyssynchrony and
mechanical inefficiency in children after repair of tetralogy of fallot.
Circ Cardiovasc Imaging. 2014; 7: 610–8.
14. Mueller M, Rentzsch A, Hoetzer K, Raedle-Hurst T, Boettler P, Stiller B,
Lemmer J, Sarikouch S, Beerbaum P, Peters B, Vogt M, Vogel M, AbdulKhaliq H. Assessment of interventricular and right-intraventricular dyssynchrony in patients with surgically repaired tetralogy of Fallot by twodimensional speckle tracking. Eur J Echocardiogr. 2010; 11: 786–92.
15. Redington AN, Oldershaw PJ, Shinebourne EA, et al. A new technique
for the assessment of pulmonary regurgitation and its application to
the assessment of right ventricular function before and after repair of
tetralogy of Fallot. Br Heart J 1988; 60: 57e65.
16. Frigiola A, Giardini A, Taylor A, Tsang V, Derrick G, Khambadkone S, Walker F, Cullen S, Bonhoeffer P, and Jan Marek. Echocardiographic assessment of diastolic biventricular properties in patients operated for severe pulmonary regurgitation and association with exercise capacity.
European Heart Journal Cardiovascular Imaging (2012) 13, 697–702.
17. Ibrahim M, Tsang VT, Caruana M, Hughes ML, Jenkyns S, Perdreau E,
Giardini A, Marek J. Cone reconstruction for Ebstein's anomaly: Patient
outcomes, biventricular function, and cardiopulmonary exercise capacity. J Thorac Cardiovasc Surg. 2015; 149: 1144–50.
18. Lange R, Burri M, Eschenbach LK, Badiu CC, da Silva JP, Nagdyman N,
Fratz S, Hörer J, Kühn A, Schreiber C, Vogt MO. Da Silva cone repair for
Ebsteon;s anomaly: effect on right ventricular size and function. Eur J
Cardiothorac Surg. 2015; 48: 316–20; discussion 320–1.
19. Goleski PJ, Sheehan FH, Chen SSM, Kilner PJ, Gatyoulis MA. The shape
and function of the left ventricle in Ebstein's anomaly. Int J Cardiol.
2014 15; 171: 404–12.
20.Authors/Task Force Members: Galie`N (Chairperson). Guidelines for the
diagnosis and treatment of pulmonary hypertension. The Task Force for
the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society
(ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). European Heart Journal 2009; 30, 2493–2537.
21. Lammers AE, Haworth SG, Riley G, Maslin K, Diller GP, Marek J. Value of
tissue Doppler echocardiography in children with pulmonary hypertension. J Am Soc Echocardiogr. 2012; 25: 504–10.
22.López-Candales A, Rajagopalan N, Saxena N, Gulyasy B, Edelman K,
Bazaz R. Right ventricular systolic function is not the sole determinant
of tricuspid annular motion. Am. J. Cardiol. 2006; 98: 973–977.
23. Bossone E, D'Andrea A, D'Alto M, Citro R, Argiento P, Ferrara F, Cittadini A,
Rubenfire M, Naeije R. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr. 2013; 26: 1–14.
24.Zimbarra Cabrita I, Ruisanchez C, Dawson D, Grapsa J, North B, Howard
LS, Pinto FJ, Nihoyannopoulos P, Gibbs JS. Right ventricular function in
patients with pulmonary hypertension; the value of myocardial performance index measured by tissue Doppler imaging. Eur J Echocardiogr.
2010; 11: 719–24.
25. Alkon J, Humpl T, Manlhiot C, McCrindle BW, Reyes JT, Friedberg MK.
Usefulness of the right ventricular systolic to diastolic duration ratio
to predict functional capacity and survival in children with pulmonary
arterial hypertension. Am J Cardiol. 2010; 106: 430–6.
26.Okumura K, Humpl T, Dragulescu A, Mertens L, Friedberg MK. Longitudinal assessment of right ventricular myocardial strain in relation to
transplant-free survival in children with idiopathic pulmonary hypertension. J Am Soc Echocardiogr. 2014; 27: 1344–51.
27. Salehian O, Schwerzmann M, Merchant N, Webb GD, Siu SC, Therrien J.
Assessment of systemic right ventricular function in patients with
transposition of the great arteries using the Myocardial Performance
Index. Comparison with cardiac Magnetic Resonance Imaging. Circulation. 2004; 110: 3229–3233.
28.Eindhoven JA, Menting ME, van den Bosch EA, McGhie JS, Witsenburg
M, Cuypers JAAE, Boersma E, Roos-Hesselink JW. Quantitative assessment of systolic right ventricular function using myocardial deformation
in patients with a systemic right ventricle. Eur Heart J Cardiovasc Imaging. 2015; 16: 380–8.
29.Diller GP, Radojevic J, Kempny A, Alonso-Gonzalez R, Emmanouil L,
Orwat S, Swan L, Uebing A, Li W, Dimopoulos K, Gatzoulis MA, Baumgartner H. Systemic right ventricular longitudinal strain is reduced in
adults with transposition of the great arteries, relates to subpulmonary
ventricular function, and predicts adverse clinical outcome. Am Heart J.
2012; 163: 859–66.
13
Advanced echocardiographic modalities in the assessment
of right ventricular function
Satoshi Yasukochi, MD
Heart Center, Nagano Children’s Hospital
Toyoshina, Azumino, Nagano, Japan
KEY POINTS
New imaging modalities of echocardiography could demonstrate the details of RV structure and mechanics
based on its fiber orientation (strain
analysis) and enables the blood flow
kinetic energy for assessing further
integrated cardiac performance.
14
The right ventricular (RV) structure
and function have been found to be an
important determinant of prognosis
and the outcome of the treatment in
congenital heart disease. Currently,
echocardiography and cardiac magnetic
resonance are the two major imaging
modalities to visualize the structure
and functions of the RV.
The newer echocardiographic technology provides more information to dissect out the detailed contractile mode
and intra-cardiac flow dynamics of RV,
besides the complexity of its geometrical shape and structure.
The contractile mode and morphology
of anatomical RV is different in case
of pulmonic ventricle from that of
systemic ventricle.
The 3D morphology of pulmonic RV is
Figure 1
lower 3D peak strain and longer timeto-peak strain, compared to those in
normal LV. Recently, the intra-blood
flow kinetics could be analyzed by
novel imaging modality using color
Doppler to calculate “blood flow
kinetic energy loss” (EL, mW) from the
reconstructed velocity vector components transformed into Cartesian coordinate system as previously reported
by K. Itatani et al., 2013.
Figure 2
The EL data were indexed by measuring a ratio of EL to the inflow kinetic
energy (KEin) through systemic atrioventricular valve in diastole. EL/KEin in
diastole of HLHS is higher than that of
normal LV. This means systemic RV of
HLHS may lose intracardiac blood flow
kinetic energy besides impairment of
chamber and wall kinetics. (Figure 2)
crescent while that of systemic RV is
ellipsoid. (Figure 1)
The contractile mode of pulmonic RV
shows peristaltic from inlet to outlet,
which means dominant longitudinal
strain with less circumferential strain.
On the other hand, the systemic RV
contracts more like a systemic left
ventricle which means more circumferential and longitudinal strain.
However, both pulmonic and systemic
RV DO NOT have a torsion or twist
which a normal systemic LV does have.
(Figure 1)
The systemic RV in hypoplastic left
heart syndrome (HLHS) demonstrates
References
1. Keiichi Itatani, Takashi Okada, Tokuhisa Uejima, Tomohiko Tanaka, Minoru Ono, Kagami
Miyaji and Katsu Takenaka. Intraventricular
Flow Velocity Vector Visualization Based on
the Continuity Equation and Measurements
of Vorticity and Wall Shear Stress. Japanese
Journal of Applied Physics, Volume 52, Number 7S. Published 22 July 2013
15
Assessment of RV function with pressure-volume loops –
impact on treatment indication for a volume-loaded RV
Prof. Dr. Christian Apitz
Division of Pediatric Cardiology
University Children’s Hospital Ulm
Ulm, Germany
The assessment of right ventricular function is aggravated
by the complex anatomy of the right ventricle and the
variable effects of abnormal loading conditions.
Pressure-volume loop analysis by conductance catheters
is extensively used in experimental studies especially in
models of acute and chronic right ventricular pressure or
volume overload and is generally considered the most reliable
way to quantify right ventricular contractile function. (1–6)
A conductance catheter is a specialised multi-electrode
catheter which allows accurate measurement of ventricular
volume and pressure continuously throughout the cardiac
cycle. A variety of physiological parameters can be derived
from pressure-volume loops.
16
By recording a family of pressure-volume loops during
reduction of preload, preferably achieved by temporary
balloon occlusion of the inferior caval vein, the systolic
ventricular function could be calculated by the slope of
the endsystolic pressure-volume relation (Figure).
Main drawback for the routine use of pressure-volume loop
analysis in clinical everyday practice is its invasive nature.
Nevertheless, in individual cases it might be a helpful
tool to support decision-making for change in therapy,
RVOT intervention or reoperation, as well as monitor
changes after treatment and as a predictor for outcome
of patients with congenital heart disease and adverse RV
loading condition.
References
Figure: Family of pressure-volume loops during reduction of preload
achieved by temporary balloon occlusion of the inferior caval vein.
1. Leeuwenburgh BP, Helbing WA, Steendijk P, Schoof PH, Baan J. Biventricular systolic function in young lambs subject to chronic systemic right
ventricular pressure overload. Am J Physiol Heart Circ Physiol. 2001
Dec; 281(6): H2697–704.
2. Redington AN, Oldershaw PJ, Shinebourne EA, Rigby ML. A new technique for measuring pulmonary regurgitation: Application to the assessment of right ventricular function before and after repair of tetralogy of
Fallot. Br Heart J 1988; 60: 57–65.
3. Chaturvedi RR, Kilner PJ, White PA, Bishop AJ, Szwarc R, Redington AN.
Increased airway pressure and simulated branch pulmonary artery stenosis increase pulmonary regurgitation after repair of tetralogy of Fallot. Real-time analysis with a conductance catheter technique. Circulation 1997; 95: 643–649.
4. Apitz C, Sieverding L, Latus H, Uebing A, Schoof S, Hofbeck M. Right
ventricular dysfunction and B-type natriuretic peptide in asymptomatic
patients after repair of tetralogy of Fallot. Pediatr Cardiol 2009; 30:
898–904.
5. Apitz C, Latus H, Binder W, et al. Impact of restrictive physiology on intrinsic diastolic right ventricular function and lusitropy in children and
adolescents after repair of tetralogy of Fallot. Heart 2010; 96: 1837–41.
6. Latus H, Binder W, Kerst G, Hofbeck M, Sieverding L, Apitz C. Right ventricular-pulmonary arterial coupling in patients after repair of tetralogy
of Fallot. J Thorac Cardiovasc Surg. 2013 Dec; 146(6): 1366–72.
17
Cardiovascular Magnetic Resonance Evaluation of
the tricuspid valve, the pulmonary valve and the right ventricle
Dr. Dr. med. Christian Meierhofer
Pediatric Cardiology and Congenital Heart Disease
Deutsches Herzzentrum München
Technical University Munich
Munich, Germany
KEY POINTS
The right ventricle can easily be assessed by cardiovascular magnetic resonance. Right ventricular volumes, flow
in the pulmonary artery and even through the tricuspid
valve are measured and provide valuable data on ventricular function and information about tricuspid and pulmonary valve regurgitation.
Cardiovascular Magnetic Resonance (CMR) has become a
valuable tool for assessment of right ventricular structures
in routine follow-up of right ventricular disease. Anatomic
reasons may limit assessment of the right ventricle by
echocardiography.
Is has been shown that right ventricular volumes and
function can be assessed very precisely by CMR, since
other methods tend to over- or underestimate right ventricular volumes. (1)
The main conditions for patients grown-up with congenital
heart disease to be referred to CMR assessment are situati-
18
ons after repair of tetralogy of Fallot for evaluation of right
ventricular volumes, function and assessment of pulmonary regurgitation.
In patients after atrial switch operation for transposition
of the great arteries failing of the systemic right ventricle
is the main focus of the assessment in CMR. Additionally,
tricuspid valve regurgitation can be evaluated. Evaluation
of the ventricular myocardium to detect myocardial scars
may be useful, but this issue is controversially discussed
in patients with systemic right ventricle. (2, 3) Therefore
we do not perform routinely late gadolinium enhancement
for detection of myocardial scars in follow-up assessment
of patients with systemic right ventricles.
The assessment of the systemic right ventricular myocardium for scientific purpose includes e. g. T1 mapping. Most
of the right ventricular disorders can be evaluated by CMR
with scan times less than one hour.
In patients after arterial switch the focus of the examination lies on the anteriorly positioned pulmonary artery that
may be become stenotic over time. The right and left pulmonary artery may also get stenotic mainly due to anatomic
reasons and due to tension on the pulmonary arteries due
to relocation of the pulmonary artery anterior to the aorta.
Further congenital cardiac conditions that are routinely evaluated in adulthood by CMR to evaluate the right ventricular
situation are congenital corrected transposition of the
great arteries, complex DORV situations, single ventricle
performance and Ebstein’s anomaly.
In Ebstein’s anomaly right ventricular function and tricuspid regurgitation play a target role.
Figure 1 shows a 68 years old woman with Ebstein’s anomaly with severe tricuspid regurgitation. Figure 2 shows
the same patient after cone repair of the tricuspid valve.
Generally, regurgitation of the tricuspid valve can be
also largely widened ECG complexes may cause problems.
Most CMR scans need a stable ECG signal for averaging
image information that has been measured over several
heart beats. Bad ECG trigger may impair the quantitative
analysis, but it may still be possible to qualitatively assess
ventricular volumes and function in such conditions. Volume overloaded ventricles may also be detected and enddiastolic volume indices can be used, but with precaution.
In such situations volume indices, structural assessment,
size and function of the right ventricle by eyeballing and
relation of size and function of the right ventricle to left
ventricle parameters may be used.
Figure 1: 68 years old woman with Ebstein’s anomaly.
Figure 2: Same patient after cone repair of the tricuspid valve.
(a) transversal view, arrows show position of the tricuspid valve;
(b) parasagittal view; (c) direct view on opening area of the tricuspid
valve, anatomic information; (d) direct view on opening area of the
tricuspid valve, phase contrast image with flow information;
(e) flow profile through the tricuspid valve.
evaluated by two methods in CMR. It can be assessed by
measuring directly the flow through the tricuspid valve.
This measurement implements some technical problems
since the tricuspid valve area is moving during the cardiac
circle and therefore during flow measurement. The second
method to assess tricuspid regurgitation is based on measuring the stroke volume of the right ventricle by evaluation
of the end-diastolic and the end-systolic volume. The stroke
volume is calculated and the flow in the main pulmonary
artery is measured. Further the part of the stroke volume
that is not running through the pulmonary artery is assumed to be regurgitated through the tricuspid valve. (Figure 3)
Major limitations for volume and flow assessment by CMR
are rhythm abnormalities that do not allow sufficient triggering of the ECG signal. Therefore, atrial fibrillation, atrial
flutter, many kinds of ectopic beats during the scan and
References
1. Sugeng L, Mor-Avi V, Weinert L, Niel J, Ebner C, Steringer-Mascherbauer
R, et al. Multimodality comparison of quantitative volumetric analysis
of the right ventricle. JACC Cardiovasc Imaging. 2010; 3: 10–8.
2. Babu-Narayan SV, Goktekin O, Moon JC, Broberg CS, Pantely GA, Pennell DJ, et al. Late gadolinium enhancement cardiovascular magnetic
resonance of the systemic right ventricle in adults with previous atrial
redirection surgery for transposition of the great arteries. Circulation.
2005; 111: 2091–8.
3. Fratz S, Hauser M, Bengel FM, Hager A, Kaemmerer H, Schwaiger M,
et al. Myocardial scars determined by delayed-enhancement magnetic
resonance imaging and positron emission tomography are not common
in right ventricles with systemic function in long-term follow up. Heart.
2006; 92: 1673–7.
(stroke volume right ventricle [ml] – forward flow main pulmonary artery [ml])
Tricuspid regurgitation (%) =
~ 100
(stroke volume right ventricle [ml] – pulmonary regurgitation [ml])
Figure 3: This formula is used to calculate tricuspid regurgitation
19
Exercise physiology and pathology in right ventricular dysfunction
Folkert Meijboom
Centre for Congenital Heart Disease Utrecht
Dept Cardiology
University Medical Centre Utrecht
Utrecht, The Netherlands
KEY POINTS
• The right ventricle is inseparably connected with the
venous system, that determines preload, and the
pulmonary vascular bed, that determines afterload.
• Right ventricular function can only be judged when
preload and afterload are taken into account.
• Understanding of both basics of the exercise physiology and the limitations in the non-invasive assessment of right ventricular function, helps in the assessment of right ventricular function in clinical practice.
Physiology of the circulation during exercise
During exercise, the metabolic demands of the body increase instantaneously. These increased demands should
be met by an increase in cardiac output. This is achieved
by the left ventricle, by increasing stroke volume and
heart rate. The left ventricle can only do so, if supplied
adequately by the right ventricle.
20
At the start of exercise, pulmonary vascular resistance
drops, allowing the right ventricle to increase pulmonary
perfusion with only limited rise of right ventricular pressure. There will be more pulmonary venous return to the
left atrium and thus the left ventricle. In turn, the right
ventricle can only increase pulmonary blood flow when
provided with more systemic venous return. This is achieved by increase of the vascular tone in the capacitance
vessels of the venous system, for which in increase of
sympatic nerve activity is responsible (1).
At rest, a large part of the circulating volume is in the
venous compartment. The thin-walled and very compliant
venous system holds approximately 10 times the volume
that the stiffer and thicker-walled arterial system holds (2).
In other words, the total systemic vascular capacitance
(or blood-holding capacity) is predominantly dependent on
the venous system. In this system, the biggest reservoirs
are in the splanchnic system, in the spleen and in the liver.
A small increase in vascular tone will directly lead to an
increase in venous return towards the right atrium. A prerequisite is that right atrial pressures remain low at exercise.
Only then, a higher systemic venous pressure will lead to a
Figure 1:
PAP = pulmonary artery pressure
RVP = right ventricular pressure
PEP = pre-ejection period
RVET = RV ejection time
(Figure used with permission of H. Hamer & E. Pieper)
higher pressure difference (gradient) between systemic
veins and right atrium and consequently more systemic
venous return towards the right atrium.
The main role of the right side of the heart during exercise
is to accommodate substantially larger quantities of blood,
without elevating right atrial pressure and to pump these
larger quantities of blood into the pulmonary vascular bed.
The instantaneous lowering of pulmonary vascular resistance during exercise will limit the increase of pulmonary
artery pressures, despite substantial increase in pulmonary
blood flow (3). In the large vessels of the pulmonary vascular tree, the pulmonary capacitance vessels, the antegrade
flow takes place predominantly in systole, during ventricular contraction.
The relation between stroke volume and pulmonary pressure is the elastance of the pulmonary vascular bed. The
pulmonary vascular elastance expresses to which extent
the right ventricle and the pulmonary vascular bed work
together at rest and during exercise: the ventricle-arterial
coupling. A good elastance implies a limited increase in
systolic pulmonary artery pressure during increase in stroke
volume.
In healthy individuals this works well during not too vigorous exercise: the ventriculo-arterial coupling is intact.
Pulmonary vascular resistance is dictated primarily by the
pulmonary capillary bed.
Beyond the pulmonary capillary bed is the pulmonary
venous vascular bed and eventually the left atrium and left
ventricle. At exercise, left ventricular systolic pressure rises
substantially, since it has to pump more blood into the
great arteries, which will have a higher resistance from the
onset of the exercise, due to the increased sympatic nerve
activity.
When a ventricle is confronted with a sudden increase in
afterload and/or a sudden increase in preload, we know
from the work of Anrep and Frank Starling (4) from the early
19th century, that the ventricle dilates first: with an unaltered contractility – ejection fraction when translated in
clinical practice - the stroke volume can only increase if the
ventricular volume increases. This was called heterometric
adaptation.
Within a few minutes, the contractility increase and ventricular volumes come down to the original size. This was
Frank Starling’s observation, that contractility of a muscle
fiber increases when stretched.
21
This is referred to as homeometric adaptation. If increased
loading condition are not chronic and do not last excessively long (extreme endurance sports), the right heart can
deal with exercise, without damage being done to the
myocardium (5).
Exercise almost always means physical activity, with skeletal muscles generating the physical activity. Specifically in
the muscle that do the exercise, the vascular resistance
will decrease, resulting in preferred blood flow towards that
muscles that do the work. The higher metabolic need of
these muscles is met this way. Due to increased muscle
activity, the “muscle pump” (6) will enhance venous return
towards the central venous system, which eventually contributes to the filling of the right heart.
Right ventricular function
In healthy individuals, all these mechanism work together
in close harmony. When one of these factors in the whole
chain that is necessary to augment cardiac output at
exercise is affected, it will influence exercise capacity.
The role of the left ventricle is studied extensively. Cardiac
imaging is well suited (especially designed) for assessment
of its morphology and changes in shape during the cardiac
cycle. Doing invasive assessment of left ventricular
function, the rectangular shape of its pressure-volume
curve will allow identification of end-systolic elastance,
“the” marker of ventricular function.
All measurements of ventricular function depend on the
loading conditions, but end-systolic elastance is considered to be the most stable marker of ventricular function:
during changes in pre- or afterload, the end-systolic elastance remains remarkably stable.
The right ventricle is notoriously difficult to catch. Its complex geometry – crescent-shaped, curved around the highpressure left ventricle – and its longitudinal, caterpillar-like
contraction, starting at the inlet and ending in the right
ventricular outflow tract, very different from the concentric
contraction pattern of the left ventricle, make imaging and
functional assessment based on imaging, very cumbersome.
Invasive studies of the right ventricular function, looking at
pressure-volume relation, are also more complicated than
on the left side of the heart. A pressure-volume curve of a
human right ventricle was produced for the first time in
1988. (7) Only in the subsequent years/decades the understanding of right ventricular function became more profound.
In a normal right ventricle, that is coupled with the low-resistant and very compliant pulmonary vascular bed, the
pressure-volume relation is very different from that of the
left ventricle. Its shape is triangular instead of rectangular.
There is no real isovolumetric contraction and after peaksystolic right ventricular pressure, the propulsion of blood
22
into the pulmonary artery continues, while right ventricular
pressure is already declining. This is called the “hang-out
period”. (see Figure 1) Simultaneous pressure recordings
show that pulmonary artery pressures are actually higher
than RV pressures in this phase. The hang-out interval is
only possible because of the very low impedance of the pulmonary vascular bed. The consequence is that, in contrast
to end-systolic elastance of the left ventricle, the elastance
at end-systole, defined by pulmonary valve closure, is not a
good representation of right ventricular function (but of pulmonary vascular impedance). Redington et al (8) showed that
peak-systolic (not end-systolic) elastance was a good marker of ventricular function: despite substantial variations in
pre-load, peak systolic elastance remained the same.
This marker, peak-systolic elastance, is the only measurement that truly represents right ventricular function. It is
related with– or represents – contractile reserve. All other
measurements of parameters that might represent right
ventricular function, are (very) load-dependent. The problem is that RV elastance can only be measured invasively,
in a research setting. It is considered the gold standard for
RV function, but it cannot be used in clinical practice. We
have to do with tools that we have in clinical practice, realizing their shortcomings.
If we talk about RV function in clinical practice, it is not well
defined what is meant. RV ejection fraction, assessed with
MRI, will come closest for most clinicians working in this
field, but 2D echo and especially 3D echo are used too (9).
RV dysfunction is not well defined either, but most will consider a measurement representing RV systolic function outside (below) the mean value minus > 2 standard deviations
RV dysfunction (10, 11). The next problem is, that there are
no consensus about what the normal ejection fraction is in
humans. Only small series have been published, with values for EF ranging form 48 % to 60 %, with different standard deviations (9). A RV with an ejection fraction of 60 %
will be normal, regardless the normal values one uses.
A RV EF of 50 % is abnormal in one study, but normal in the
other. The same is true for many other markers of RV
function, being either echo- or MRI-derived. RV failure can
be defined in different ways. Most clinicians will use the
combination of clinically visible signs of venous congestion,
RV dysfunction and complaints of early fatigue and exertional dyspnea.
RV dysfunction and exercise
We normally investigate patients at rest, either by echo or
by MRI. Whatever you choose – tricuspid annulus planar
systolic excursion (TAPSE, measuring the longitudinal
movement of the RV lateral wall), TDI of this lateral wall
(measuring the velocity of this displacement), RV dimensions, fractional area change (FAC) or currently RV strain or
strain rate determined with 2D speckle tracking – all these
measurements provide data about how the RV functions in
baseline condition, at rest, in supine or in left decubitus
position. The same is true for MRI assessment of the RV.
A completely normal RV function at rest – irrespective of
how it is determined non-invasively– does not necessarily
mean that at different loading conditions, during exercise,
function will remain normal. A few studies looked at RV
function at exercise, especially in pulmonary hypertension
(12), showing that the degree of RV dysfunction can better
be judged by doing measurements at rest and during exercise. Once the RV already has diminished systolic function
at rest, it will not improve during exercise. From clinical studies is known that many adult patients with (repaired) congenital heart defect, will have a diminished exercise capacity (13). It is likely that in many patients RV dysfunction will
contribute substantially to the reduced exercise capacity,
but, in contrast to in pulmonary hypertension, very few
studies have been done to understand the exact mechanisms of RV dysfunction in congenital heart disease.
Conclusion
Exercise physiology makes clear that all shackles in the
chain in the circulation are interdependent and all are important when cardiac output has to increase during exercise. The right ventricle is inseparably connected with the
systemic veins and the pulmonary vascular bed, but if hypothetically regarded is isolation, its specific function during exercise would be to increase blood flow to the lungs,
while keeping right ventricular filling pressures, i.e. right
atrial pressures, low. The best way to measure whether the
RV is up to this task, is peak-systolic pressure-volume relation. This can only be measured invasively, in a research
setting and is not useful in clinical practice. All parameters
we use in clinical practice that reflect RV function, are very
much load-dependent. If patients are studied at rest, which
is almost always the case, one can only judge RV performance in these resting conditions. Testing the RV in various
conditions, especially during exercise, will allow a better
judgement of RV function than the usual testing in resting
condition.
References
1. Guyton AC, Jones CE, Coleman TG. Normal cardiac output and its variations. Chap 1. In Circulatory Physiology: Cardiac Output and its Regulation. pp. 3–20. WB Saunders, London. 1973.
2. Young DB. Control of Cardiac Output. Chapter 2. Venous Return. San
Rafael (CA): Morgan & Claypool Life Sciences; 2010.
3. Naeije R, Brimioulle S, Dewachter L. Biomechanics of the right ventricle
in health and disease (2013 Grover Conference series). Pulm Circ 2014;
4(3): 395–406.
4. Patterson SW, Starling EH. On the mechanical factors which determine
the output of the ventricles. J Physiol. 1914; 48(5): pp. 357–79.
5. La Gerche A, Claessen G. Is Exercise Good for the Right Ventricle? Concepts for Health and Disease. Canadian Journal of Cardiology, Volume
31, Issue 4, 2015, 502–508.
6. Laughlin M.H. Skeletal muscle blood flow capacity: role of muscle
pump in exercise hyperemia. American Journal of Physiology – Heart
and Circulatory Physiology 1987; 253: 993–1004.
7. Redington AN, Gray HH, Hodson ME, et al. Characterisation of the normal right ventricular pressure-volume relation by biplane angiography
and simultaneous micromanometer pressure measurements. Br Heart J
1988; 59: 23–30.
8. Redington AN, Rigby ML, Shinebourne EA, et al. Changes in the pressure-volume relation of the right ventricle when its loading conditions
are modified. Br Heart J 1990; 63: 45–9.
9. van der Zwaan HB, Geleijnse ML, McGhie JS, Boersma E, Helbing WA,
Meijboom FJ & Roos-Hesselink JW 2011 Right ventricular quantifi- cation in clinical practice: two dimensional vs three-dimensional echocardiography compared with cardiac magnetic resonance imaging. European Journal of Echocardiography 12 656–664.
10. van der Zwaan HB, Geleijnse ML, Soliman OI, McGhie JS, WiegersGroeneweg EJ, Helbing WA, Roos-Hesselink JW & Meijboom FJ 2011 Testretest variability of volumetric right ventricular measurements using
real-time three-dimensional echocardiography. Journal of the American
Society of Echocardiography 24 671–679.
11. Shimada YJ, Shiota M, Siegel RJ & Shiota T 2010 Accuracy of right ventricular volumes and function determined by three-dimensional echocardiography in comparison with magnetic resonance imaging: a metaanalysis study. Journal of the American Society of Echocardiography 23
943–953
12. Grunig E, Tiede H, Enyimayew E; Ehlken N, Seyfarth H-J, Bossone E,
D’Andrea A, Naeije R, Olschewski H, Ulrich S, Nagel C, Halank M,
Fischer C. Assessment and Prognostic Relevance of Right Ventricular
Contractile Reserve in Patients With Severe Pulmonary Hypertension.
Circulation. 2013; 128: 2005–2015.)
13. Dimopoulos K, Diller G, Massimo F. Piepoli M, Gatzoulis M. Exercise
Intolerance in Adults with Congenital Heart Disease. Cardiology Clinics,
Volume 24, Issue 4, 2006, 641–660
23
Indications for treatment in adults with tricuspid valve
dysfunction due to a congenital cardiac anomaly
Prof. Dr. Markus Schwerzmann
Zentrumsleiter
Zentrum für angeborene Herzfehler
Unversitätsspital Inselspital
Bern, Switzerland
KEY POINTS
TR can be classified into primary and secondary TR (Figure 1).
The tricuspid valve is frequently affected in adults with
congenital heart disease (CHD). Valve failure can occur
primarily or develop secondary to changes in the right
ventricle caused by other defects.
Quantitative echocardiographic assessment of tricuspid
regurgitation is essential to predict prognosis.
Treatment options vary depending on the underlying defect and right ventricular function. Surgical management
of tricuspid valve disease is complex and evolving.
In adults with severe TR due to valve dysplasia, symptoms
in the absence of RV dysfunction or progressive RV dilatation and/or function deterioration in asymptomatic patients
are indications for TV surgery (4).
Tricuspid valve (TV) dysfunction in the setting of a congenital heart defect (CHD) consists most of the time of tricuspid
regurgitation (TR).
Its clinical significance is underestimated and guidelines
for management are less aggressive and more subjective
than those of other valves (1).
Quantitative grading of TR severity is in principle similar to
the grading of mitral regurgitation, but less robust (2). It is
nevertheless a powerful predictor of outcome and superior
to standard qualitative assessment (3).
In patients with a systemic RV and a previous atrial switch
procedure, TR is usually related to progressive RV failure.
Akin to functional mitral regurgitation, TV replacement is
not advised if there is significant systemic RV dysfunction.
Medical therapy and consideration of mechanical support
or cardiac transplantation are essential.
24
In adults with secondary TR due to a volume loaded RV
(e.g. due to an atrial septal defect or to severe pulmonary
regurgitation after Fallot repair), TR is expected to regress
after shunt closure or pulmonary valve replacement and
does not preclude percutaneous interventions (5–8).
In adults with a systemic RV and congenitally corrected
transposition (ccTGA), severe TR is more likely due to intrinsic TV disease and timely valve surgery is mandatory (9).
Figure 1: Classification of
tricuspid regurgitation
into primary and
secondary forms
For best results, TV replacement is advised before systemic
ejection fractions (EF) falls < 40 % or the subpulmonary
ventricular systolic pressure rises to > 50 mmHg (10).
In ccTGA patients, pre-operative EF is the single most
important predictor of post-operative EF.
References
1. Ginns J, Ammash N and Bernier PL. The tricuspid valve in adult congenital heart disease. Heart Fail Clin. 2014; 10: 131–53.
2. Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C,
Hagendorff A, Monin JL, Badano L, Zamorano JL and European Association of E. European Association of Echocardiography recommendations
for the assessment of valvular regurgitation. Part 2: mitral and tricuspid
regurgitation (native valve disease). Eur J Echocardiogr. 2010; 11: 307–32.
3. Topilsky Y, Nkomo VT, Vatury O, Michelena HI, Letourneau T, Suri RM,
Pislaru S, Park S, Mahoney DW, Biner S and Enriquez-Sarano M. Clinical
outcome of isolated tricuspid regurgitation. JACC Cardiovasc Imaging.
2014; 7: 1185–94.
4. Arsalan M, Walther T, Smith RL, 2nd and Grayburn PA. Tricuspid regurgitation diagnosis and treatment. Eur Heart J. 2015.
5. Toyono M, Krasuski RA, Pettersson GB, Matsumura Y, Yamano T and
Shiota T. Persistent tricuspid regurgitation and its predictor in adults
after percutaneous and isolated surgical closure of secundum atrial
septal defect. Am J Cardiol. 2009; 104: 856–61.
6. Kotowycz MA, Therrien J, Ionescu-Ittu R, Owens CG, Pilote L, Martucci G,
Tchervenkov C and Marelli AJ. Long-term outcomes after surgical versus
transcatheter closure of atrial septal defects in adults. JACC Cardiovasc
Interv. 2013; 6: 497–503.
7. Kogon B, Mori M, Alsoufi B, Kanter K and Oster M. Leaving Moderate
Tricuspid Valve Regurgitation Alone at the Time of Pulmonary Valve Replacement: A Worthwhile Approach. Ann Thorac Surg. 2015; 99:
2117–22; discussion 2122–3.
8. Cramer JW, Ginde S, Hill GD, Cohen SB, Bartz PJ, Tweddell JS and Earing
MG. Tricuspid repair at pulmonary valve replacement does not alter
outcomes in tetralogy of Fallot. Ann Thorac Surg. 2015; 99: 899–904.
9. Prieto LR, Hordof AJ, Secic M, Rosenbaum MS and Gersony WM. Progressive tricuspid valve disease in patients with congenitally corrected
transposition of the great arteries. Circulation. 1998; 98: 997–1005.
10. Mongeon FP, Connolly HM, Dearani JA, Li Z and Warnes CA. Congenitally
corrected transposition of the great arteries ventricular function at the
time of systemic atrioventricular valve replacement predicts long-term
ventricular function. J Am Coll Cardiol. 2011; 57: 2008–17.
25
Surgical techniques to improve tricuspid valve function in
congenital heart defects
Victor Tsang FRCS, Henri Haapanen MD
Great Ormond Street Hospital for Children,
Department of Cardiothoracic Surgery
London, United Kingdom
KEY POINTS
Also in adults with congenital heart disease and tricuspid valve (TV) anomalies the understanding of the physiological features of the valve anomalies and individualised technique selection are the keys to a good
decision-making and a durable valve repair in selected
cases.
Tricuspid valve (TV) anomalies form a wide spectrum of pathological defects in adults with congenital heart disease.
The surgical techniques and additional concomitant procedures to improve the tricuspid valve function are well
established, for example, tricuspid valve regurgitation (TR)
after tetralogy of Fallot repair, right atrioventricular valve
dysfunction after atrioventricular septal defect repair, and
reimplantation of straddling TV in biventricular repair.
26
It may be worth emphasising the surgical approach to the
very challenging Ebstein’s anomaly, which has been at its
turning point during the last decade. There have been a
„disproportionate“ number of technical approaches introduced for the Ebstein’s anomaly, including Danielson and
Carpentier’s techniques. In 2007, da Silva at al. described
cone technique, which consequently improves the functional anatomy of RV inflow (1). The reconstructed anteriorsuperior leaflet and the remnants of the delaminated septal
and posterior leaflets are rotated to form a cone with a RV
apical connection (Figure 1). The cone repair has been
shown to be effective technique for patients with severe regurgitation associated with Ebstein’s anomaly (2). However,
the very highly variable tricuspid valve anatomy and the
significant dilatation of the right heart cavity size and ventricular dysfunction in adults demand a very careful decision if a durable valve repair is possible and achievable.
Some important surgical details require further commenting, such as the adequacy of the tricuspid valve leaflet
tissue for repair, the placation of the atrialised right ventricular cavity, the reinforced annuloplasty sutures, the proxi-
Figure 1: The principle of cone repair in Ebstein’s Anomaly. The figure is originally published by da Silva and the colleagues (6)
mity of the right coronary artery and the posterior descending artery, and the conduction tissue.
Moving further to the boundaries of adult congenital heart
surgery, the management of tricuspid valve dysfunction in
the context of systemic morphological right ventricle is
difficult even for the experienced surgeons, including the
emerging population of patients following univentricular
palliation of hypoplastic left heart syndrome.
We have already described the range of surgical strategies
to deal with the moderate to severe tricuspid valve regurgitation in the younger age group (3) but the intrinsic tricuspid valve dysfunction would be more substantial in adulthood. Similarly, based on limited data, the anatomic repair
of atrioventricular discordance appears to provide better
functional results in selected patients in terms of TV
function (4), but at the expense of a long risky operation
and a high burden of reoperations (5). A less definitive approach using pulmonary artery banding as a palliative strategy offers a reconfiguration of the ventricular septal shift
leading to some regression of TR.
References
1. da Silva JP, Baumgratz JF, da Fonseca L, Franchi SM, Lopes LM, Tavares
GM, et al. The cone reconstruction of the tricuspid valve in Ebstein's
anomaly. The operation: early and midterm results. J Thorac Cardiovasc
Surg 2007 Jan; 133(1): 215–223.
2. Ibrahim M, Tsang VT, Caruana M, Hughes ML, Jenkyns S, Perdreau E, et
al. Cone reconstruction for Ebstein's anomaly: Patient outcomes, biventricular function, and cardiopulmonary exercise capacity. J Thorac Cardiovasc Surg 2015 Apr; 149(4): 1144–1150.
3. Tsang VT, Raja SG. Tricuspid valve repair in single ventricle: timing and
techniques. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu
2012; 15(1): 61–68.
4. Jahangiri M, Redington AN, Elliott MJ, Stark J, Tsang VT, de Leval MR. A
case for anatomic correction in atrioventricular discordance? Effects of
surgery on tricuspid valve function. J Thorac Cardiovasc Surg 2001 Jun;
121(6): 1040–1045.
5. Lim HG, Lee JR, Kim YJ, Park YH, Jun TG, Kim WH, et al. Outcomes of biventricular repair for congenitally corrected transposition of the great
arteries. Ann Thorac Surg 2010 Jan; 89(1): 159–167.
6. Silva JP, Baumgratz JF, Fonseca L, Afiune JY, Franchi SM, Lopes LM, et al.
Ebstein's anomaly: results of the conic reconstruction of the tricuspid
valve. Arq Bras Cardiol 2004 Mar; 82(3): 212–216.
The authors have the copyright for the portraits.
27
When Tricuspid Valvuloplasty fails …
What is the best valve in tricuspid position?
Alessandro Giamberti, MD
Head Congenital Cardiac Surgery Unit
IRCCS-Policlinico San Donato – University Hospital
Milan, Italy
KEY POINTS
Tricuspid valve problems in ACHD are treated not rarely
by valve replacement, especially in older patients.
The use of bioprostheses is preferable in term of performance, results, freedom from complications and the
possibility to perform transcatheter valve procedures.
Tricuspid valve (TV) replacement is a relatively infrequent surgical procedure and is reserved for those few
occasions where repair of the TV is not feasible or
attempts at repair have failed. For the TV replacement
there is no specific prosthesis. The mitral ones are used
but the choice between mechanical or biological prosthetic valve remains a controversial subject. The use
of bioprostheses is today preferable in term of performance, results, freedom from complications and the
possibility to perform transcatheter valve procedures.
28
Tricuspid valve problems, especially tricuspid regurgitation
(TR), in adults with congenital heart disease (ACHD) can be
associated with different anatomical or functional mechanisms. Different groups of patients have been identified
including:
1) patients with Ebstein anomaly
2) patients with TV damaged by previous surgical operations, cardiac catheterizations or pacemaker (or ICD)
placement
3) patients with a TV failing in its capacity as systemic
atrio-ventricular valve (status post Senning or Mustard
operation and congenitally corrected transposition of
great arteries)
4) patients with functional TR related to right ventricular
dilation or dysfunction (1).
Indications for surgery of the TV include symptoms, decreased exercise tolerance, structural valve abnormalities,
progressive right ventricular dilatation, the onset or progression of atrial tachyarrhythmias, and need for concomitant cardiac surgery (1, 2).
When surgery for TV is indicated, TV repair is preferable and
TV replacement is the second choice.
TV replacement is a relatively infrequent surgical proce-
Figure 1
Figure 2
dure, approximately 2 % of all valve replacement (3), especially compared with left-heart valve procedures, and is reserved for those few occasions where repair of the TV is not
feasible or attempts at repair have failed. In ACHD TV replacement is much more performed than in pediatric patients (2)
and usually used in 50 % of adults with Ebstein anomaly
(75 % of patients over 50 years) (4, 5), in case of rheumatic
disease, endocarditis, after repair failure, in patients that
had undergone three or more previous sternotomies, and
in patients where the leaflets are thicker and more rigid.
TV replacement is not technically challenging and, in the
absence of intra-cardiac communications, it is possible to
perform the procedure in beating-heart without aortic
cross-clamping.
There are three techniques most commonly used to suture
the prosthetic valve along the circumference of the annulus:
• everting sutures
• noneverting sutures, and
• continuous suture.
seems to be superior in term of freedom from complications
and overall survival.
Other important advantage using bioprostheses in tricuspid position is the possibility to perform balloon valvuloplasty and future transcatheter valve replacement with the
so called “valve-in-valve” procedure.
This approach, first performed by Leen van Garsse in 2011
(11), is actually used in selected cases both in acquired and
congenital heart disease (12) and is another factor in favor
of using bioprostheses in TV position.
To avoid injury of the conduction system it is better, in the
septal portion of the valve, not to touch the annulus but to
use the septal leaflet tissue to perform the suture (Figure 1).
Otherwise it is possible to perform a supra-annular implantation of the prostheses leaving the coronary sinus and the
AV-node on the ventricular side of the prosthetic valve (Figure 2).
For the TV replacement there is no a specific prosthesis. The
mitral ones are used but the choice between mechanical
and biological prosthetic valve remains a controversial subject (6).
Tricuspid or mitral homografts have been proposed as alternative to prostheses (7, 8), but the experience is limited,
technically not simple, and generally used in endocarditis
or rheumatic disease. Biological valves do not need anticoagulant therapy but these valves will inevitably experience wear and degeneration requiring a second implant;
mechanical valves, on the other hand, have potential unlimited duration but high risk of valve thrombosis, thromboembolic event, and bleeding complications correlated to
the anticoagulation treatment. The use of a bioprostheses
is today preferable to a mechanical valve in tricuspid position. Previous reports (9) have shown that a bioprosthesis
in the tricuspid position is more satisfactory than in mitral
position and in the Ebstein anomaly (10) a bioprosthesis
References
1. Giamberti A, Chessa M, Ballotta A, et al. Functional tricuspid valve regurgitation in adults with congenital herat disease: an emerging problem. J Heart Valve Dis 2011; 20: 565–570.
2. Said SM, Dearani JA, Burkhart HM, et al. Management of tricuspid regurgitation in congenital heart disease: is survival better with valve repair? J Thorac Cardivasc Surg 2014; 147: 412–419.
3. Sakata R, Fujii Y, Kuwano H. Thoracic and cardiovascular surgery in
Japan during 2009: annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg 2011; 59: 636–667.
4. Brown ML, Dearani JA, Danielson GK, et al. The outcome of operations
for 539 patients with Ebstein anomaly. J Thorac Cardiovasc Surg 2008;
135: 1120–1136.
5. Attenhofer Jost CH, Connolly HM, Scott CG, et al. Outcome of cardiac
surgery in patients 50 years of age or older with Ebstein anomaly. J Am
Coll Cardiol 2012; 59: 2101–2016.
6. Garatti A, Nano G, Bruschi G, et al. Twenty-five year out come of tricuspid valve replacement comparing mechanical and biological prostheses. Ann Thorac Surg 2012; 93: 1146–1153.
7. Vaidyanathan K, Agarwal R, Johari R, Cherian KM. Tricuspid valve replacement with a fresh antibiotic preserved tricuspid homograft. Interact
Cardiovasc Thorac Surg 2010; 10: 1061–1062.
8. Kalangos A, Sierra J, Beghetti M Trigo-Trindade P, Vala D, Christenson J.
Tricuspid valve replacement with a mitral homograft in children with
rheumatic tricuspid valvulopathy. J Thorac Cardiovasc Surg 2004; 127:
1682–187.
9. Omata T, Kigawa I, Tohda E, Wanibuchi Y. Comparison of durabilità of
bioprostheses in tricuspid and mitral position. Ann Thorac Surg 2001;
71: S240–S243.
10. Brown ML, Dearani JA, Danielson GK, et al. Comparison of the outcome
of porcine bioprosthetic versus mechanical prosthetic replacement of
the tricuspid valve in the Ebstein anomaly. Am J Cardiol 2009; 103:
555–561.
11. Van Garsse LAFM, ter Bekke RMA, van Ommen VGVA. Percutaneous
transcatheter valve-in-valve implantation in stenosed tricuspid valve
bioprostheses. Circulation 2011; 123: e219–e221.
12. Roberts PA, Boudjemline Y, Cheatham JP, et al. Percutaneous tricuspid
valve replacement in congenital and acquired heart disease. J Am Coll
Cardiol 2011; 58: 117–122.
29
Which valve is best in right ventricular outflow tract dysfunction?
Autor
Rüdiger Lange
Munich, Germany
30
Notes
31
Indications for pulmonary valve replacement in adults with
congenital heart disease
Werner Budts MD, PhD
Congenital and Structural Cardiology, University Hospitals Leuven,
and Department of Cardiovascular Sciences,
Catholic University Leuven, Leuven, Belgium.
KEY POINTS
The right ventricular outflow in adult congenital heart
disease requires lifelong attention. Patients with treated
or untreated pulmonary valve stenosis, after repair of a
tetralogy of Fallot, or after Ross or Rastelli repair might
suffer from increasing right ventricular outflow tract
obstruction or ongoing valve regurgitation. Not timely intervening on the persistent pressure or volume overload
of the right ventricle might compromise outcome. Guidelines do suggest when and how to intervene on the right
ventricular outflow tract. However, the shift from surgical
interventions to the promising and evolving technique
of percutaneous valve implantation raises the question
whether much earlier intervention is needed to keep
ventricular structure and function optimized.
The right ventricular outflow tract (RVOT) in adult patients
with congenital heart disease deserves lifelong attention.
The natural history of the underlying disease or the consequences of interventions in childhood exposes the RVOT
to anatomic and functional changes.
32
Some patients evolve to a progressive outflow tract obstruction that leads subsequently to increasing pressure
load of the right ventricle. This stenosis may occur at
different levels of the outflow tract: subvalvular, valvular,
and supravalvular.
In other patients is the right ventricle exposed to persistent
volume overload because of ongoing significant valve
regurgitation.
Congenital heart defects that require specific attention for
the RVOT are mainly
• pulmonary valve stenosis (PVS),
• tetralogy of Fallot (TOF), and
• lesions for which Ross or Rastelli repair was performed.
Several, currently adult patients with PVS underwent pulmonary valvulotomy or balloon valvuloplasty in childhood.
Unfortunately, the price paid to open (mainly surgically)
a stenotic valve is evoking valve regurgitation1. This valve
insufficiency might require in its turn revalvulation of the
outflow tract. Because the association with a relatively
large outflow tract leads to a surgical re-intervention and
implantation of a homograft, a valved conduit, or a biological valve prosthesis.
The same is true for patients after TOF repair. The ventricular septal defect is closed and the RVOT enlarged. This RVOT
enlargement may include infundibulectomy, pulmonary valvuloplasty, including valvulotomy, and relief of co-existing
supravalvular stenosis.
Immediate implantation of a biological valve or a homograft
is very rare, but in a substantial number of currently adult
patients transannular patching was performed. Subsequently, this led to a severe pulmonary valve regurgitation
and might require in its turn revalvulation.
Similarly to PVS, the association with a large outflow tract
requests mostly a surgical re-intervention and the implantation of a homograft, a valved conduit, or a biological valve
prosthesis.
Finally, in a more complex congenital anatomy, as after
Ross repair for aortic valve disease, or Rastelli repair for
transposition of the great arteries with ventricular septal
defect and pulmonary stenosis, or Rastelli repair for arterial
trunk, the right ventricle is bypassed to the pulmonary
trunk by the insertion of a homograft or valved conduit.
Unfortunately, all these implanted valves degenerate
subsequently over time so that a new intervention becomes
imperative later in life (2, 3).
Both volume and/or pressure overload of the right ventricle
open the question when and how to (re-)intervene.
The ESC guidelines for the management of grown-up congenital heart disease are very helpful to decide when to intervene in patients with a native right ventricular outflow tract
obstruction (table 1) or with a stenotic right ventricular to
pulmonary artery conduit (table 2) (4).
Symptomatology and right ventricular pressures at rest are
the main drivers for re-intervention that mainly consists of
surgical or percutaneous valve replacement.
Today, the growing expertise and the good results consider
percutaneous pulmonary valve implantation (PPVI) as first
choice of treatment where technically applicable (5). The
shift of last years from a surgical to a more percutaneous
approach raises the question whether no earlier interven-
33
Indications
Class Level
RVOTO at any level should be repaired
regardless of symptoms when Doppler
peak gradient is > 64 mmHg (peak velocity
> 4m/s), provided that RV function is normal and no valve substitute is required
I
C
In valvular PS, balloon valvotomy should
be the intervention of choice
I
C
In asymptomatic patients in whom balloon
valvotomy is ineffective and surgical
valve replacement is the only option,
surgery should be performed in the
presence of a systolic RVP > 80 mmHg
(TR velocity > 4.3 m/s)
I
C
Intervention in patients with gradient
< 64 mmHg should be considered in the
presence of:
• symptoms related to PS or,
• decreased RV function or,
• double-chambered RV
(which is usually progressive) or,
• important arrhythmias or,
• right-to-left shunting via an ASD or VSD
Peripheral PS, regardless of symptoms,
should be considered for repair if > 50 %
diameter narrowing and RV systolic
pressure > 50 mmHg and/or lung perfusion abnormalities are present
IIa
IIa
C
C
Indications
Class Level
Symptomatic patients with RV systolic
pressure > 60 mmHg (TR velocity > 3.5 m/s;
may be lower in case of reduced flow)
and/or moderate/severe PR should
undergo surgery
I
C
Asymptomatic patients with severe
RVOTO and/or severe PR should be
considered for surgery when at least
one of the following criteria is present:
• Decrease in exercise capacity (CPET)
• Progressive RV dilation
• Progressive RV systolic dysfunction
• Progressive TR (at least moderate)
• RV systolic pressure > 80 mmHg
(TR velocity > 4.3 m/s)
• Sustained atrial/ventricular arrhythmias
IIa
C
Table 1: Indications for intervention in right ventricular outflow tract
obstruction
Table 2: Indication for intervention in patients with right ventricular to
pulmonary artery conduits
Class = Class of recommendation; level = level of evidence
ASD = atrial septal defect; PS = pulmonary stenosis; RV = right ventricle;
RVOTO = right ventricular outflow tract obstruction; RVP = right ventricular
pressure; TR = tricuspid regurgitation; VSD = ventricular septal defect
Class = Class of recommendation; level = level of evidence
CPET = cardiopulmonary exercise testing; PR = pulmonary regurgitation;
RV = right ventricle; RVOTO = right ventricular outflow tract obstruction; TR
= tricuspid regurgitation
tion than suggested by the most recent ESC guidelines is indicated. Indeed, longstanding pressure overload of the
right ventricle might be not that harmless.
The question raises whether no earlier intervention is needed in stead of waiting until the first signs of ventricular
damage occur.
Revalvulation for PR is mostly done surgically, although
new percutaneous techniques and new valve designs might
encourage a percutaneous approach (7–9).
The ESC guidelines do also indicate when to intervene in
case of pulmonary valve regurgitation (PR) (table 1 and 2)
(4). However, optimal timing for pulmonary revalvulation
remains challenging, but it is generally accepted not to
exceed an end-diastolic volume index > 160 ml/m2 (6).
34
However, long-term follow-up will find out whether PPVI will
improve finally clinical outcome.
References
1. Voet A, Rega F, de Bruaene AV, Troost E, Gewillig M, Van Damme S,
Budts W. Long-term outcome after treatment of isolated pulmonary
valve stenosis. Int J Cardiol. 2012; 156: 11–15.
2. Meyns B, Jashari R, Gewillig M, Mertens L, Komárek A, Lesaffre E,
Budts W, Daenen W. Factors influencing the survival of cryopreserved
homografts. The second homograft performs as well as the first.
Eur J Cardiothorac Surg. 2005; 28: 211–216; discussion 216.
3. Troost E, Meyns B, Daenen W, Van de Werf F, Gewillig M, Van Deyk K,
Moons P, Budts W. Homograft survival after tetralogy of fallot repair:
Determinants of accelerated homograft degeneration. Eur Heart J.
2007; 28: 2503–2509.
4. Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE,
Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P,
Meijboom F, Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A,
Thaulow E, Vouhe PR, Walma E, (ESC) TFotMoG-uCHDotESoC, (AEPC)
AfEPC, (CPG) ECfPG. Esc guidelines for the management of grown-up
congenital heart disease (new version 2010). Eur Heart J. 2010; 31:
2915–2957.
5. Lurz P, Coats L, Khambadkone S, Nordmeyer J, Boudjemline Y, Schievano S, Muthurangu V, Lee TY, Parenzan G, Derrick G, Cullen S, Walker F,
Tsang V, Deanfield J, Taylor AM, Bonhoeffer P. Percutaneous pulmonary
valve implantation: Impact of evolving technology and learning curve
on clinical outcome. Circulation. 2008; 117: 1964–1972.
6. Oosterhof T, van Straten A, Vliegen HW, Meijboom FJ, van Dijk AP,
Spijkerboer AM, Bouma BJ, Zwinderman AH, Hazekamp MG, de Roos A,
Mulder BJ. Preoperative thresholds for pulmonary valve replacement in
patients with corrected tetralogy of fallot using cardiovascular magnetic
resonance. Circulation. 2007; 116: 545–551.
7. Cools B, Brown SC, Heying R, Jansen K, Boshoff DE, Budts W, Gewillig
M. Percutaneous pulmonary valve implantation for free pulmonary regurgitation following conduit-free surgery of the right ventricular outflow tract. Int J Cardiol. 2015; 186: 129–135.
8. Cao QL, Kenny D, Zhou D, Pan W, Guan L, Ge J, Hijazi ZM. Early clinical
experience with a novel self-expanding percutaneous stent-valve in the
native right ventricular outflow tract. Catheter Cardiovasc Interv. 2014;
84: 1131–1137.
9. Haas NA, Moysich A, Neudorf U, Mortezaeian H, Abdel-Wahab M,
Schneider H, De Wolf D, Petit J, Narayanswami S, Laser KT, Sandica E.
Percutaneous implantation of the edwards sapien(™) pulmonic valve:
Initial results in the first 22 patients. Clin Res Cardiol. 2013; 102:
119–128.
35
Failing biological tricuspid valve – percutaneous tricuspid
valve replacement
Peter Ewert
Dept of Pediatric Cardiology and Congenital Heart Diseases
German Heart Center Munich
Technical University Munich
Munich, Germany
While percutaneous pulmonary valve implantation (PPVI)
was the first transcatheter valve replacement which gained
clinical importance with the introduction of the Melody
valve in 2000, there is no such valve developed especially
designed for tricuspid valve replacement.
With increasing experience in valve-in-valve procedures,
however, it became obvious that many degenerated bioprosthesis can be overstented by transcatheter valves. (1–3)
The procedure is analog to the pulmonary valve implantation, and in most cases even technically simpler because
the tricuspid valve location is easier to reach and the bioprosthesis provides a clear landing zone, which is not always the case in PPVI.
36
Coronary compression is not an issue, but pacing leads and
a small ring of the surgically inserted bioprosthesis may be
so. Fortunately, pacing leads may be overstented without
loss in function or can be exchanged across the transcatheter valve later.
In certain surgical bioprosthesis, the valve ring can be cracked with ultra-high pressure balloons in order to implant
larger transcatheter valves. (4)
Special cases are patients with Bjoerk-Fontan circulation. (5)
They have either a patch or a biological conduit across the
right atrial-ventricular junction. Coronary compression may
play a role and pre-stenting is usually necessary, thus the
procedure is more complex.
In patients with atrial switch operation, a tricuspid valvein-valve procedure is possible, replacing the tricuspid valve
in the systemic circulation. A trans-baffle approach is
necessary, otherwise the intervention is comparable to a
percutaneous tricuspid valve or mitral valve implantation,
respectively.
Figure: Patient after atrial Switch Operation with
bioprothesis in tricuspid position. Injection in
the superior caval vein (left). Placement of a transcatheter valve in the bioprothesis via transbaffle
access (middle). Valve after successful placement
(right).
References
1. Roberts PA, Boudjemline Y, Cheatham JP, et al. Percutaneous tricuspid
valve replacement in congenital and acquired heart disease. Journal of
the American College of Cardiology 2011; 58: 117–22.
2. McElhinney DB, Cabalka AK, Aboulhosn JA, et al. Transcatheter Tricuspid Valve-in-Valve Implantation for the Treatment of Dysfunctional Surgical Bioprosthetic Valves: An International Multicenter Registry Study.
Circulation 2016.
3. Eicken A, Schubert S, Hager A, et al. Percutaneous tricuspid valve implantation: two-center experience with midterm results. Circulation
Cardiovascular interventions 2015; 8.
4. Tanase D, Grohmann J, Schubert S, Uhlemann F, Eicken A, Ewert P.
Cracking the ring of Edwards Perimount bioprosthesis with ultrahigh
pressure balloons prior to transcatheter valve in valve implantation.
Int J Cardiol 2014; 176: 1048–9.
5. Eicken A, Fratz S, Hager A, Vogt M, Balling G, Hess J. Transcutaneous
Melody valve implantation in "tricuspid position" after a Fontan Bjork
(RA-RV homograft) operation results in biventricular circulation. Int J
Cardiol 2010; 142: e45–7.
37
Transcatheter Percutaneous Pulmonary Valve-in-Valve
Implantation
Dr Chessa Massimo, MD, PhD, FSCAI, FESC
Pediatric and Adult Congenital Heart Centre
IRCCS-Policlinico San Donato- University Hospital
San Donato M.se – MILAN, Italy
KEY POINTS
Transcatheter PViV can be performed safely, and with
high success rate, low procedure-related morbidity and
excellent medium term results.
The new frontier will be to enlarge the population eligible
to transcatheter implant of pulmonary valve in bioprosthesis, and to identify the best timing and clinical parameters on when to proceed.
The use of 3DRA is helpful defining the implantation site,
and evaluating the relationship between the RVOT and
the coronary arteries (FIGURE 2)
38
Transcatheter percutaneous pulmonary valve-in-valve implantation (TPViV) is an effective and safe treatment for pulmonary bioprosthetic valve (BPV) dysfunction, both using
the Melody or the Edward Sapien valve, improving freedom
from surgical reintervention. Long-term studies will redefine the management of dysfunctional RVOT, either native or
surrogate, including bioprostheses.
Approximately 20 % of newborns with congenital heart
disease (CHD) have anomalies of the pulmonary valve (PV)
or of the right ventricular outflow tract (RVOT) (1), traditionally requiring multiple surgical interventions during their
lifetime due to recurrent RVOT dysfunction (2).
Surgical revision may employ valved conduits, homografts,
mechanical or bioprosthetic valves (BPVs) that can be stented or stentless (Figure 1), which can degenerate, leading to
pulmonary valve stenosis, regurgitation or both (PR) (3–4).
BPVs are currently the most widely used devices for pulmonary valve replacement. They are readily available, easy to
implant, do not need extensive dissection of the pulmonary
arteries, and anticoagulation therapy is not necessary.
Figure 1: Radiographic appearances
of both stented (A) and stentless (B)
bioprosthetic valves
Figure 2: 3DRA
Pre (A, C) and post (B,D) Melody valve implantation.
Within a Sorin Mitraflow 21 mm valve
References
Surgical valves durability is attested at 10 years for more
than 85 % of patients (10).
Percutaneous pulmonary valve implantation has provided
an option for non-surgical management of these bioprosthetic valve failed (5).
The TPViV is feasible, effective, and at a relative low risk.
Gillespie et al. (6), reported the biggest series on TPViV,
in a multicentric North American preliminary experience in
which 104 patients underwent Melody pulmonary implantation within a variety of failed surgical BPVs.
The experience of my Centre confirmed excellent results for
those who received a Melody Valve and for the pts in which
an Edward Sapien was implanted. No differences in terms
of right chamber pressures and output were revealed, neither in terms of symptoms, thus suggesting that Sapien and
Melody could be both equally useful to perform TPViV. The
most significant difference between the two percutaneous
valves (Melody and Sapien), are the larger available diameters and the smaller height of the last one, thus enlarging
the number of patients suitable to TPViV.
1. Ansari MM, Cardoso R, Garcia D, Sandhu S, Horlick E, Brinster D, Martucci G, Piazza N. Percutaneous Pulmonary Valve Implantation: Present
Status and Evolving Future J Am Coll Cardiol. 2015 Nov 17; 66(20):
2246–55. doi: 10.1016/j.jacc.2015.09.055.
2. Lurz P, Coats L, Khambadkone S, Nordmeyer J, Boudjemline Y, Schievano S, Muthurangu V, Lee TY, Parenzan G, Derrick G, Cullen S, Walker F,
Tsang V, Deanfield J, Taylor AM, Bonhoeffer P. Percutaneous pulmonary
valve implantation: impact of evolving technology and learning curve
on clinical outcome. Circulation. 2008 Apr 15; 117(15): 1964–72. doi:
10.1161/CIRCULATIONAHA.107.735779. Epub 2008 Apr 7.
3. Piazza L, Chessa M, Giamberti A, Bussadori CM, Butera G, Negura DG,
Micheletti A, Callus E, Carminati M. Timing of pulmonary valve replacement after tetralogy of Fallot repair. Expert Rev Cardiovasc Ther. 2012
Jul; 10(7): 917–23.
4. Hascoët S, Acar P, Boudjemline Y. Transcatheter pulmonary valvulation:
current indications and available devices. Arch Cardiovasc Dis. 2014
Nov;107(11): 625–34. doi: 10.1016/j.acvd.2014.07.048. Epub 2014 Oct
31. Review.
5. Asoh K, Walsh M, Hickey E, Nagiub M, Chaturvedi R, Lee KJ, Benson LN.
Percutaneous pulmonary valve implantation within bioprosthetic valves. Eur Heart J. 2010 Jun; 31(11): 1404–9. doi:
10.1093/eurheartj/ehq056.
6. Gillespie MJ, Rome JJ, Levi DS, Williams RJ, Rhodes JF, Cheatham JP, Hellenbrand WE, Jones TK, Vincent JA, Zahn EM, McElhinney DB. Melody
valve implant within failed bioprosthetic valves in the pulmonary position: a multicenter experience. Circ Cardiovasc Interv. 2012 Dec; 5(6):
862–70.
39
When treatment fails – indication for and results of
transplantation for failing hearts in Congenital Heart Disease (CHD)
Harald Gabriel, Ass. Prof., MD
Medical University of Vienna
Dept. of Cardiology
Vienna, Austria
KEY POINTS
Remarkable progresses in pediatric cardiac surgery and
interventional procedures have led to the fact that more
patients with moderate to complex congenital heart
disease (CHD) are surviving into adulthood. Heart failure
and progressive cardiopulmonary dysfunction occurs late
after interventions, palliative and corrective surgery.
Therefore heart, lung or combined heart-lung transplantation becomes a treatment option.
Those patients who survive the first year have better
longterm (5–10 years) outcome compared to non-CHD
transplant patients.
There is a need for international consensus to reconsider
current criteria for urgent cardiac transplantation in
patients with adult CHD (ACHD).
Due to progress in pediatric cardiac surgery on patients
with congenital heart disease (CHD) this has led to a noticeable improvement in the life expectancy of these patients
with CHD (1). Together with advances in surgical techni-
40
ques, anesthesia, and intensive nurse care the mortality
has dramatically decreased and approximately 85% of
children with CHD are surviving to adulthood (2, 3).
The most common cause of morbidity and mortality in adult
congenital heart disease (ACHD) patients is late myocardial
dysfunction that often occurs after palliative or corrective
surgery, and heart failure it is the most common cause of
decline and death in patients with CHD (1, 3, 4).
Consequently, a growing number of patients with CHD
presents with a progressive decline in cardiopulmonary
function as an adult, at which point transplantation becomes the only treatment option. The outstanding surgical
and medical challenges in adults with CHD (ACHD) who are
in evaluation to heart transplantation (HT), lung transplantation (LT) or heart-lung transplantation (HLT) owing to their
complex anatomy, multiple prior palliative and corrective
procedures, frequently increased pulmonary vascular resistance (PVR) from longstanding congestive heart failure
or cyanosis, and overall debilitated condition.
ACHD may also require interventional procedures such as
coil embolization of aortopulmonary shunts and collateral
vessels, pulmonary artery angioplasty or stents for stenotic
pulmonary arteries, stenting of atrial baffle obstruction
prior to the transplantation or additional reconstructive
surgery during the transplantation (5).
For these reasons and others, CHD is a significant risk
factor for increased 1-year mortality in heart transplant recipients (6). The statistics vary, ranging from 16 % to as high
as a 50 % 30-day to 3-month early mortality (7–12). But after
the first year of transplantation, ACHD patients have improved survival: 5-year survival ranges from 69 % to 80 % compared with approximately 72 % in non-CHD patients (6, 7, 13,
14), whereas 10-year survival is even better, ranging from
52.8 % to 57.4 % compared with 50.9 % to 53.6 % in non-CHD
transplant recipients ( 7, 8, 11, 15). These findings may be
related to lower recipient age, variable CHD diagnoses and
fewer comorbidities at the time of transplantation (7).
To optimize the outcomes of ACHD transplantation there
is a need of international consensus to reconsider current
criteria for urgent cardiac transplantation rating those who
require mechanical cardiac support (MCS) and inotrope
support. But ACHD patients may be not appropriate candidates for MCS due to restrictive anatomy, limited venous
access, abundant collateral vessels and the presence of
scar tissue (16). At the time of listing ACHD patients are less
likely to be dependent on inotropes but they are presenting
with severe comorbidities like protein losing enteropathy,
hepatic and renal dysfunction or coagulopathies (8).
As pointed out in a recent publication by Goldenberg S. and
colleagues some steps are necessary to redefine the listing
criteria for ACHD (17). The definition of ACHD need to be
standardized, with defined sub-groups, so that research
will expand the understanding of prognostic characteristics
and survival in this population.
Furthermore the characteristics of ACHD that increase
waiting list and post-operative mortality need to be subsequent explored to determine whether they should be
considered when determining listing status.
In addition to it the effect of bystander organ dysfunction
on waiting list and post-operative mortality need to be
further researched and potentially incorporated in listing
status criteria.
Finally a separate scoring system for United Network for
Organ Sharing (UNOS) listing of ACHD transplant candidates, created by international consensus, is needed because
current criteria do not always meet the needs of ACHD patients. If that happens we should be able to identify better
transplant recipients, determine the appropriate time to
list these patients, and optimize post-operative care and
transplantation outcomes.
References
1. McGlothlin D, De Marco T, Transplantation in adults with congenital
heart disease. Prog Cardiovasc Dis 2011; 53: 312–323.
2. Warnes CA, Williams RG, Bashore TM et al. ACC/AHA 2008 Guidelines
for the Management of Adults with Congenital Heart Disease: Executive
Summary: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (writing committee
to develop guidelines for the management of adults with congenital
heart disease). Circulation 2008; 118: 2395–2451.
3. Thorne S, Deanfield J, Long-term outlook in treated congenital heart
disease, Arch Dis Child 1996; 75: 6–8.
4. Budts W, Roos-Hesselink J, Rädle-Hurst T et al. Treatment of heart failure in adult congenital heart disease: a position paper of the Working
Group of Grown-Up Congenital Heart Disease and the Heart Failure
Association of the European Society of Cardiology. Eur Heart J. 2016 Jan
18. [Epub ahead of print]
5. Lamour JM, Addonizio LJ, Galantowicz ME et al. Outcome after orthotopic cardiac transplantation in adults with congenital heart disease.
Circulation, 100 (19 Suppl) (1999), pp. II200–II205.
6. Stehlik J, Edwards LB, Kucheryavaya AY et al.The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report J Heart Lung Transplant, 29 (2010),
pp. 1089–1103.
7. Patel ND, Weiss ES, Allen JG, et al. Heart transplantation for adults
with congenital heart disease: analysis of the United Network for Organ
Sharing database. Ann Thorac Surg, 88 (2009), pp. 814–822.
8. Davies RR, Russo MJ, Yan J, et al. Listing and transplanting adults with
congenital heart disease. Circulation, 123 (2011), pp. 759–767.
9. Izquierdo MT, Almenar L, Martinez-Dolz L, et al. Mortality after heart
transplantation in adults with congenital heart disease: a single-center
experience. Transplant Proc, 39 (2007), pp. 2357–2359.
10. Irving C, Parry G, O’Sullivan J, et al. Cardiac transplantation in adults
with congenital heart disease. Heart, 96 (2010), pp. 1217–1222.
11. McGlothlin D, De Marco T Transplantation in adults with congenital
heart disease. Prog Cardiovasc Dis, 53 (2011), pp. 312–323.
12. Pigula FA, Gandhi SK, Ristich J, et al. Cardiopulmonary transplantation
for congenital heart disease in the adult. J Heart Lung Transplant, 20
(2001), pp. 297–303.
13. Lamour JM, Kanter KR, Naftel DV, et al. The effect of age, diagnosis,
and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol, 54 (2009),
pp. 160–165.
14. Chen JM, Davies RR, Mital SR, et al. Trends and outcomes in transplantation for complex congenital heart disease: 1984 to 2004. Ann Thorac
Surg 2004; 78: 1352–1361.
15. A.R. Hosseinpour, S. Cullen, V.T. Tsang Transplantation for adults with
congenital heart disease. Eur J Cardiothorac Surg 2006;, 30 (2006), pp.
508–514.
16. Everitt MD, Donaldson AE, Stehlik J, et al. Would access to device therapies improve transplant outcomes for adults with congenital heart
disease? Analysis of the United Network for Organ Sharing (UNOS). J
Heart Lung Transplant 2011; 30: 395–401.
17. Goldberg SW, Fisher SA, Wehman B et al. Adults with congenital heart
disease and heart transplantation: optimizing outcomes. J Heart Lung
Transplant 2014; 33: 873–877.
41
The John Hess Lecture – How to optimize ACHD patient care
and future directions in physician education
Gary Webb, M.D.
Director
Cincinnati Adolescent and Adult Congenital Heart Center
Cincinnati Children’s Hospital
Cincinnati, USA
•
•
•
•
•
•
•
KEY POINTS
• Deliver the lifelong care message -repeatedly.
• Keep children and adolescents in care.
• Have methods to track and help prevent loss to care
during childhood and adolescence.
• Work continuously with pediatric cardiologists as
respected care partners.
• Encourage some pediatric cardiologists to take a career
interest in ACHD care.
• Agree on a defined age of transfer to ACHD care.
• Minimize health insurance barriers to care.
• Educate and empower adolescents and young adults to
become competent managing their own lives and health
care - the so-called transition process.
• Provide such good patient care that patients know and
respect its value.
• Commit yourself and your program to excellent patient
care.
• The program's mission should be to be able to address
the needs of any patient that comes through the door.
42
•
You may not be able to do everything in your own institution. If not, you need to make sure that services of high
quality are available to your patients, and you should
refer them to the best available resources.
Care must be 24/7.
Provide patient care as conveniently as possible (Satellite
clinics? Evening clinics? Telemedicine?)
Make sure that ACHD team members are well-qualified
or become well-qualified.
Work to solidify sources of patients, whether from pediatric cardiologists, adult cardiologists, or primary care
physicians.
I believe you need a base of at least 1500 patients to
develop and maintain team skills, to train fellows,
and to drive adequate volumes in both diagnostic and
interventional arenas.
Make “following the guidelines” part of your team culture.
Use the ACHA clinical accreditation criteria as the basis
for your planning clinic accreditation and construction
in your own jurisdiction.
Encourage other and younger colleagues, especially
in subspecialty areas, to make a career commitment
to ACHD care. Build the future.
The future of ACHD professional education
• One-on-one instruction will always be valuable.
• If you make teaching in a digital environment, you can
use it repeatedly, and share it endlessly.
• ACHD colleague should collaborate to create high-quality
educational material that can be used by professional
members of many teams.
• This material should be reused and repurposed as
frequently as possible.
• Don’t just put in one place - put in lots of places repeatedly so people have a chance to see and use it.
• Get regular feedback, and replace or improve or update
material on a continuing basis.
Prognostic Value of Brain Natriuretic Peptides in ACHD
Olga Hajnalka Balint, MD, PhD
Gottsegen György, Hungarian Institute of Cardiology
Budapest, Hungary
Given the heterogeneity of the underlying conditions (eg. univentricular heart,
right ventricular type of systemic ventricle, residual lesions with predominance
of the stenotic and regurgitation component, pulmonary hypertension and
cyanosis) heart failure in adult congenital heart disease (ACHD) differs from that
of acquired heart disease.
KEY POINTS
Brain natriuretic peptide (BNP) value
is one piece of information which
may reflect the actual condition of
a patient with congenital heart
disease. The importance in predicting major cardiac events depends
on the underlying cardiac disease,
however, in many complex diseases
its usefulness remains questionable.
It seems that, also natriuretic peptides, as markers of volume and pressure overload behave differently in these clinical conditions. Patients with ACHD have higher
levels of natriuretic peptides when compared with normal controls, however,
their overall values do not reach such high levels as in acquired heart disease (1).
The most commonly used natriuretic peptides in clinical practice is brain natriuretic peptide (BNP), or his N-terminal pro-hormone (NT-proBNP). These markers
are considered to have greatly equivalent value, although some authors highlight
important differences, showing that BNP might be a better indicator of a chronic
clinical condition compared with NT-proBNP, which might be more useful in
registering acute changes in the disease (2, 3, 9).
43
An important percentage of adult patients with ACHD are in
heart failure, without being aware of it (4). In the presence
of a chronic condition, a “slow” clinical deterioration may
be subjectively missed by the patient. BNP may help in
identifying ACHD patients at risk to deteriorate, and to adjust a therapeutic plan for them. Besides the BNP values as
cross sectional data, limited data are available regarding
longitudinal measurements and their role in predicting
cardiac events, timing of a therapeutic intervention or heart
transplant (1). In this short overview the most important
clinical conditions where BNP has been extendedly studied
will be highlighted.
Tetralogy of Fallot post repair
BNP elevation is determined mostly by the pulmonary
regurgitation (PR) and right ventricular (RV) dilatation.
Nevertheless the presence of left ventricular dysfunction
or aortic regurgitation should be also considered. Higher
NYHA class correlates with higher BNP values (there being a
significant difference between BNP values in asymptomatic
vs. mildly symptomatic patients), and an inverse correlation
exists between BNP and peak oxygen uptake during exercise (5). In patients with a good clinical condition BNP does
44
not seem to present correlations with RV size and PR (6),
although in general there is a significant correlation among
them.
Heng at al. (7) found that 70 % of the asymptomatic patients
had abnormal BNP values, and demonstrated that in stable
patients BNP can be used as mortality predictor. In their
median 10 year follow-up study a BNP above 52 pg/ml predicted a 5 fold increase in risk of death, and each 35 pg/ml
increment resulted in 2 fold increase in risk of arrhythmia.
The role of BNP in timing pulmonary valve replacement
remains questionable, because most studies present only
cross sectional data. There are some exceptions, where
longitudinal studies found elevated BNP levels before
pulmonary valve replacement (PVR), which decreased
afterwards, though the BNP values differed so widely,
that they were unable to conclude which cut-off value
predicts a good timing for intervention (8).
Transposition of the great arteries after atrial
switch operation (TGA-ASO)
Increases in BNP levels might be related to systemic RVdysfunction, severity of tricuspid regurgitation, and abnor-
mal ventricular filling (the latter being seen more often after
the Mustard type surgery).
BNP in TGA-ASO is higher than in normal controls even in
asymptomatic patients (5). Positive correlation with NYHA
class (9) or negative correlation with peak oxygen uptake
has been demonstrated (5), although, there are studies
questioning these facts (5, 10). In most of the studies BNP
has a negative correlation with systemic RV ejection fraction
(by CMR or echocardiography measurements) and a positive correlation with severity of tricuspid regurgitation (5).
Haberger et al. (9) in a study of 83 patients with TGA-ASO,
showed that the BNP cut-off value for discriminating the
risk for a major cardiac event was 85 pg/ml, with a sensitivity of 88 %, and specificity of 85 %. After Mustard type surgery there was a higher risk for a critical event compared
with Senning type of surgery, but in this particular study
there was no difference between simple or complex TGA.
who had undergone the TCPC procedure (total cavo pulmonary connection). Moreover, after completion of the Fontan
procedure by TCPC, the BNP values of asymptomatic patients are comparable with healthy age-matched controls (11).
In some studies ventricular morphology, namely the presence of an anatomically RV in systemic position has been
showed to have a higher BNP compared with LV morphology
(12); but others did not find this correlation.
Overall, in Fontan patients strong positive correlations were
found between BNP and NYHA class when all functional
classes were studied (11).
Data are not convincing regarding the correlation between
BNP and oxygen saturation during rest, though a possible
cause of increased BNP in single ventricle physiology has
been attributed to the presence of cyanosis (5, 13). The relation between BNP and peak oxygen consumption during
exercise was not conclusive as well (5). Prognostic value of
BNP in these patients also remains questionable (1).
Single ventricle
Pulmonary arterial hypertension (PAH)
In Classic Fontan there is an increased wall stretch in the
systemic venous atria which explain why these patients
have significantly higher levels of BNP compared with those
Changes in BNP reflect the degree of increased RV wall
stretching and subsequent deterioration in RV function
caused by pulmonary vascular disease (14). Conflicting data
45
concerning the relationship between BNP and functional
capacity exist (eg. NYHA functional class, 6-minute walk
distance). This might be explained by the different oxygen
carrying capacity of the blood and the degree of desaturation during exercise.
RV volume overload may be a stronger trigger of BNP production than chronic pressure overload, as stable patients
with Eisenmenger syndrome (ES) had lower BNP values (14).
BNP has been demonstrated to have prognostic value in
predicting right heart failure or death in PAH patients.
Serial BNP predicts survival and/or hospitalization in ES,
values >104pg/ml are associated with increased risk of
death (15,16) and values <50pg/ml with better survival (17).
A good response to specific PAH therapy can be demonstrated by decrease in BNP, as well.
Based on 2015 the ESC PAH guideline (18), generally speaking of PAH (not specified for ES) patients, BNP should
be used at the first assessment for risk evaluation and
further on for monitoring the effect of specific therapy.
References
1. Ohuchi H and Diller GP. Biomarkers in Adult Congenital Heart Disease
Heart Failure. Heart Failure Clinics: Heart Failure in Congenital heart
Disease. January 2014. p. 43–56.
2. Giannakoulas G, Dimopoulos K, Bolger AP, et al. Usefulness of natriuretic peptide levels in predicting mortality in adults with congenital heart
disease. Am J Cardiol 2010; 105: 869–73.
3. Clerico A, Recchia FA, Passino C, Emdin M. Cardiac endocrine function
is an essential component of the homeostatic regulation network: Physiological and clinical implications. Am J Physiol Heart Circ Physiol
2006; 290: H17–H29.
4. Diller GP, Dimopoulos K., Okonko D et al. Exercise Intolerance in Adult
Congenital Heart Disease. Comparative Severity, Correlates, and prognostic Implication. Circulation 2005; 112: 828–835.
5. Eindhoven JA, Van den Bosch AE, Jansen PR, et al. The Usefulness of
Brain Natriuretic Peptide In Complex Congenital Heart Disease. JACC
Vol. 60, No. 21, 2012.
6. Giannakoulas G, Mouratoglou SA, and Karvounis H. B-type natriuretic
peptide: another brick in the wall towards better risk stratification in
repaired tetralogy of Fallot. Editorial. Heart March 2015 Vol 101 No 6.
7. Heng EL, Bolger AP, Kempny A, et al. Neurohormonal activation and its
relation to outcomes late after repair of Tetralogy of Fallot. Heart 2015;
101: 447–54.
8. Giannakoulas G, Mouratoglou SA, Karvounis H. B-type natriuretic
peptide: another brick in the wall towards better risk stratification in
repaired tetralogy of Fallot. Heart 2015;101:416–417.
9. Haberger S, Hauser M, Braun SL, et al. Circ J 2015; 79: 2677–2681.
Prognostic Value of Plasma B-Type Natriuretic Peptide in the Long-term
Follow-up of Patients With Transposition of the Great Arteries With
Morphologic Right Systemic Ventricle After Atrial Switch Operation.
46
10. Koch AM, Zink S, Singer H. B-type natriuretic peptide in patients with
systemic right ventricle. Cardiology 2008; 110: 1–7.
11. Koch AM, Zink S, Singer H, Dittrich S. B-type natriuretic peptide levels
in patients with functionally univentricular hearts after total cavopulmonary connection. Eur J Heart Fail 2008; 10: 60–2.
12. Holmgren D, Westerlind A, Berggren H, Lundberg PA, Wahlander H. Increased natriuretic peptide type B level after the second palliative step
in children with univentricular hearts with right ventricular morphology
but not left ventricular morphology. Pediatr Cardiol 2008; 29: 786 –92.
13. Hopkins WE, Chen Z, Fukagawa NK, et al. Increased atrial and brain natriuretic peptides in adults with cyanotic congenital heart disease: enhanced understanding of the relationship between hypoxia and natriuretic peptide secretion. Circulation 2004; 109: 2872–7.
14. Giannakoulas G, Mouratoglou SA, Gatzoulis MA, and Karvounis H. Int J
of Cardiol.Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease . A systematic review. 174 (2014) 618–623.
15. Diller G-P, Alonso-Gonzalez R, Kempny A, et al. B-type natriuretic peptide concentrations in contemporary Eisenmenger syndrome patients:
predictive value and response to disease targeting therapy. Heart 2012;
98: 736–42.
16. Reardon LC, Williams RJ, Houser LS et al. Usefulness of serum brain
natriuretic peptide to predict adverse events in patients with the Eisenmenger syndrome. Am J Cardiol 2012;110:1523–6.
17. Barst RJ, Ivy DD, Foreman AJ, McGoon MD, Rosenzweig EB. Four- and
seven-year outcomes of patients with congenital heart disease — associated pulmonary arterial hypertension (from the REVEAL registry). Am J
Cardiol 2014; 113: 147–55.
18. Galie N., Humbert M., Vachiery JL et. al. ESC/ERS Guidelines for the
diagnosis and treatment of pulmonary hypertension. Eur Hear J. Sept.
2015.
Heart failure in ACHD: What is different from acquired
heart disease?
Pedro Trigo Trindade, MD, FESC
Clinique Générale Beaulieu
Geneva, Switzerland
KEY POINTS
• The incidence of first heart failure admission has been
reported at 1.2 per 1000 patient-years (CONCOR registry).
• Mortality amounted to 2.8% during a follow-up period
of 24865 patient-years.
• Median-age at death from heart failure was 51 years
(range: 20.3–91.2 years).
• Aetiology, pathophysiology and triggers of impaired
ventricular function in ACHD patients are complex and
diverse (Fig. 1, Table 1).
• Patients may not report symptoms even though
systemic pump function is often reduced.
• As opposed to acquired heart disease different scenarios have to be envisaged: systolic failure of the morphological systemic left ventricle, - of the morphological systemic right ventricle, - of the morphological
sub-pulmonary right ventricle, - of the single ventricle.
• There is a lack of randomized controlled trials to guide
therapy in heart failure in adult congenital heart
disease (Table 2).
– The value of ACE-inhibitors, ARB’s and beta-blockers
remains to be defined, and these drugs can even be
harmful in certain patients.
– Pulmonary arterial vasodilators may be helpful
in certain conditions.
– The role of CRT remains unknown.
– Heart transplantation can be a therapeutic option.
47
Figure 1: Diagnosis-treatment algorithm
in congenital heart anomalies with heart failure
(from: Budts W et al. Treatment of heart failure in
adult congenital heart disease: a position paper
of the Working Group of Grown-Up Congenital
Heart Disease and the Heart Failure Association
of the European Society of Cardiology. Eur Heart
J. 2016 Jan 18. doi:10.1093/eurheartj/ehv741
Eur Heart J.)
1. Systolic dysfunction of the systemic morphological left ventricle
Pressure overload (sub-, supravalvular or valvular aortic stenosis, coarctation of the aorta)
Volume overload (aortic valve regurgitation, VSD, patent ductus arteriosus, or mitral regurgitation)
Myocardial injury (limited myocardial protection during bypass, ventriculotomy)
Altered myocardial architecture (non-compaction)
Altered geometry of the sub-pulmonary ventricle interfering with diastolic filling of the systemic ventricle
(severe pulmonary regurgitation in ToF)
2. Systolic dysfunction of the sub-pulmonary morphological right ventricle
Volume overload (severe pulmonary regurgitation in ToF, atrial septal defect with large left-to-right shunt)
Pressure overload (severe RV outflow tract obstruction)
3. Systolic dysfunction of the morphological systemic right ventricle
Pressure overload (congenitally corrected transposition of the great arteries, dextro-transposition of the great arteries after atrial
switch repair [Mustard or Senning])
Myocardial injury by functional ischaemia (single right coronary artery)
4. Systolic dysfunction of the systemic single ventricle
Volume under-load after initial volume overload (Fontan repair)
Myocardial injury (limited myocardial protection during bypass, ventriculotomy)
Myocardial architecture
5. Systolic dysfunction of the cyanotic systemic and/or sub-pulmonary ventricle with or without pulmonary hypertension
Myocardial injury by chronic hypoxia (VSD with pulmonary stenosis)
Pressure overload (Eisenmenger syndrome)
6. Acquired ischaemic heart disease and ventricular dysfunction
Cardiovascular risk factors (hypertension, hyperlipidaemia, diabetes mellitus, smoking)
Congenital coronary artery abnormalities (anomalous origin and/or course, extrinsic compression by a dilated pulmonary artery,
coronary kinking after re-implantation of coronary arteries)
7. Systolic dysfunction of the systemic ventricle due to tachyarrhythmias
Table 1: Trigger factors of heart failure with impaired systolic function
(modified after: Budts W et al. Treatment of heart failure in adult congenital heart disease: a position paper of the Working Group of Grown-Up Congenital
Heart Disease and the Heart Failure Association of the European Society of Cardiology. Eur Heart J. 2016 Jan 18. doi:10.1093/eurheartj/ehv741 Eur Heart J.)
48
Systolic Heart Failure
Systemic ventricle • Morphological
left ventricle
(EF 40 %)
Asymptomatic
or
Symptomatic
• Morphological
right ventricle
(EF 40 %)
Asymptomatic
Symptomatic
• RAAS blocker
• Beta-blocker
• Mineralocorticoid
receptor antagonist
• Diuretics
(loop and thiazide)
• Digoxin
• Morphological
left or right
ventricle
(EF 40 %)
Asymptomatic
No medical treatment
Symptomatic
• Diuretics
(loop and thiazide)
• Mineralocorticoid
receptor antagonist
• Pulmonary vasodilator
(pulmonary arterial
hypertension)
• Fontan circulation
(EF 40 %)
• Morphological
left ventricle
Asymptomatic
• RAAS blocker
• Beta-Blocker
• Mineralocorticoid
receptor antagonist
• Digoxin
• Morphological
right ventricle
• Morphological
left and right
ventricle
Asymptomatic
No medical treatment
Symptomatic
• RAAS blocker
• Beta-Blocker
• Mineralocorticoid
receptor antagonist
• Diuretics
(loop and thiazide)
• Digoxin
• Persistent
right-to-left
shunt
Asymptomatic
No medical treatment
Symptomatic
• Diuretics
(loop and thiazide)
• Agents reducing
afterload
Sub-pulmonary
ventricle
Single ventricle
• RAAS blocker
• Beta-Blocker
• Mineralocorticoid
receptor antagonist
• Diuretics
(loop and thiazide)
• Digoxin
No medical treatment
Heart Failure with preserved EF
Asymptomatic
Symptomatic
No medical treatment
• Diuretics
(loop and thiazide)
• Beta-Blocker
• Rate-limiting calcium
channel blocker
Table 2: Medical treatment for heart failure in Congenital Heart Disease
(modified after: Budts W et al. Treatment of heart failure in adult congenital heart disease: a position
paper of the Working Group of Grown-Up Congenital Heart Disease and the Heart Failure Association
of the European Society of Cardiology. Eur Heart J. 2016 Jan 18. doi:10.1093/eurheartj/ehv741 Eur
Heart J.)
References
1. Budts W et al. Treatment of heart failure in
adult congenital heart disease: a position
paper of the Working Group of Grown-Up
Congenital Heart Disease and the Heart Failure Association of the European Society of
Cardiology. Eur Heart J. doi:10.1093/eurheartj/ehv741.
2. Karen K. Stout, Craig S. Broberg, Wendy M.
Book, Frank Cecchin, Jonathan M. Chen, Konstantinos Dimopoulos, Melanie D. Everitt,
Michael Gatzoulis, Louise Harris, Daphne T.
Hsu, Jeffrey T. Kuvin, Yuk Law, Cindy M. Martin, Anne M. Murphy, Heather J. Ross, Gautam Singh, Thomas L. Spray, on behalf of the
American Heart Association Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology, and Council on
Cardiovascular Radiology and Imaging. Chronic Heart Failure in Congenital Heart Disease:
A Scientific Statement From the American
Heart Association. Circulation. 2016; 133:
770–801. Originally published January 19,
2016. doi: 10.1161/CIR.0000000000000352.
3. Heather J. Ross, Yuk Law, Wendy M. Book,
Craig S. Broberg, Luke Burchill, Frank
Cecchin, Jonathan M. Chen, Diego Delgado,
Konstantinos Dimopoulos, Melanie D. Everitt, Michael Gatzoulis, Louise Harris, Daphne
T. Hsu, Jeffrey T. Kuvin, Cindy M. Martin, Anne
M. Murphy, Gautam Singh, Thomas L. Spray,
Karen K. Stout, on behalf of the American
Heart Association Adults With Congenital
Heart Disease Committee of the Council on
Clinical Cardiology and Council on Cardiovascular Disease in the Young, the Council on
Cardiovascular Radiology and Intervention,
and the Council on Functional Genomics and
Translational Biology. Transplantation and
Mechanical Circulatory Support in Congenital
Heart Disease: A Scientific Statement From
the American Heart Association. Circulation.
2016; 133: 802–820. Originally
published January 21, 2016. doi:
10.1161/CIR.0000000000000353.
49
Hyponatremia in ACHD: From prognosis to treatment
Oktay Tutarel, MD
Department of Cardiology & Angiology
Hannover Medical School
Hannover, Germany
Hyponatremia in heart failure of
non-congenital origin
KEY POINTS
Heart failure is a leading cause of death in adult congenital heart disease (ACHD) patients. Therefore, the identification of possible prognostic predictors is of interest.
Hyponatremia is an important prognostic predictor of
mortality in heart failure of non-congenital origin. Recent
studies indicate a role for hyponatremia as a predictor
of morbidity and mortality in ACHD patients. While treatment aimed solely on correcting sodium levels probably
does not improve the clinical outcome, a closer clinical
surveillance of ACHD patients with hyponatremia is warranted.
Heart failure has important prognostic implications for
adult congenital heart disease (ACHD) patients, and is a
leading cause of death (1). Therefore, the identification of
possible prognostic predictors is of interest. Hyponatremia
(HN) is one promising candidate.
50
Despite increased plasma and extracellular fluid volumes
in heart failure of non-congenital origin, reduced cardiac
output and systemic blood pressure lead to neurohumoral
activation and increased release of antidiuretic hormone,
also known as vasopressin, resulting in reduced excretion
of water and sodium, increased water and sodium reabsorption in the glomeruli, and increased thirst (2). The consequence is HN, which is encountered in 20–25% of patients with heart failure.(3) In several studies, HN has been
established as an important prognostic predictor of mortality in a variety of heart failure patients, ranging from hospitalized to ambulatory patients.(3)
Hyponatremia in ACHD
In a study of 1004 ACHD patients with a variety of underlying CHD, HN was present in 15.5 % (4). The prevalence was
Conclusion
higher in patients with more complex CHD. Furthermore, HN
was a strong predictor of mortality (Figure 1A), independent
of functional class, ventricular function, creatinine levels,
or the use of diuretics (4). The hazard of death decreased
with increasing sodium levels up to a value of 136 mmol/l
and appeared to be constant thereafter (Figure 1B) (4).
Hyponatremia is an independent predictor of mortality in
ACHD patients. While treatment aimed solely on correcting
sodium levels does probably not improve the clinical outcome, a closer clinical surveillance of patients with HN is
warranted.
Figure 1A: Cumulative mortality curves according to the presence of
hyponatremia. Patients with hyponatremia (sodium concentration
<136 mmol/L) had a three-fold increased mortality risk in this study.
B: Functional form of the unadjusted relationship between sodium
concentration and the hazard of death (on a logarithmic scale) using
smoothing splines with 4 degrees of freedom. The fitted spline function
is plotted with pointwise standard errors.
From Dimopoulos et al (4), European Heart Journal – an official Journal of
the European Society of Cardiology, by permission of Oxford University Press
In a study of 91 adult patients after the Fontan operation, HN
was present in 28.6% (5). Plasma sodium level was the only
independent predictor for unscheduled rehospitalizations
in this study (5). Interestingly, levels of plasma norepinephrine, vasopressin, and plasma renin activity were higher in
the hyponatremic group compared to the normonatremic
group, indicating neurohumoral activation (5).
Treatment of hyponatremia in heart failure
There is currently no evidence that correction of HN improves the clinical outcome of patients with heart failure. Restricting fluid intake is still an important measure. Furthermore, based on pathophysiological rationale, it is best to
avoid thiazide-type diuretic agents and mineralocorticoid
receptor antagonists, as these interfere directly with the
kidneys’ capacity to produce hypotonic urine, and instead
prefer loop diuretics (2). However, clinical evidence for this
approach is lacking. Vasopressin receptor blockers like
Tolvaptan increase free water clearance (6). Tolvaptan was
studied in patients hospitalized with heart failure (7). While
it increased serum sodium levels in patients with HN significantly, it had no effect on long-term mortality or heart failure-related morbidity. Studies in ACHD patients addressing
these questions are lacking.
References
1. Budts W, Roos-Hesselink J, Radle-Hurst T, Eicken A, McDonagh TA, Lambrinou E, Crespo-Leiro MG, Walker F, Frogoudaki AA. Treatment of heart
failure in adult congenital heart disease: a position paper of the Working Group of Grown-Up Congenital Heart Disease and the Heart Failure
Association of the European Society of Cardiology. Eur Heart J 2016; doi:
10.1093/eurheartj/ehv741.
2. Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WH, Mullens W. Hyponatremia in acute decompensated heart failure: depletion versus dilution. J Am Coll Cardiol 2015; 65: 480–92.
3. Bettari L, Fiuzat M, Felker GM, O'Connor CM. Significance of hyponatremia in heart failure. Heart Fail Rev 2012; 17: 17–26.
4. Dimopoulos K, Diller GP, Petraco R, Koltsida E, Giannakoulas G, Tay EL,
Best N, Piepoli MF, Francis DP, Poole-Wilson PA, Gatzoulis MA. Hyponatraemia: A strong predictor of mortality in adults with congenital heart
disease. Eur Heart J 2010; 31: 595–601.
5. Ohuchi H, Negishi J, Ono S, Miyake A, Toyota N, Tamaki W, Miyazaki A,
Yamada O. Hyponatremia and its association with the neurohormonal
activity and adverse clinical events in children and young adult patients after the Fontan operation. Congenit Heart Dis 2011; 6: 304–12.
6. Finley JJt, Konstam MA, Udelson JE. Arginine vasopressin antagonists
for the treatment of heart failure and hyponatremia. Circulation 2008;
118: 410–21.
7. Konstam MA, Gheorghiade M, Burnett JC, Jr., Grinfeld L, Maggioni AP,
Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi
C, ; doi: 10.1093/eurheartj/ehv741. Effects of oral tolvaptan in patients
hospitalized for worsening heart failure: the EVEREST Outcome Trial.
JAMA 2007; 297: 1319–31.
51
Can we prevent the development of heart failure in ACHD?
Helmut Baumgartner
Division of Adult Congenital and Valvular Heart Disease
Department of Cardiovascular Medicine
University Hospital Muenster
Muenster, Germany
KEY POINTS
Prevention of the development of
heart failure in ACHD remains challenging. No evidence is available for
medical treatment of asymptomatic
ventricle dysfunction. Early intervention with optimization of hemodynamics remains key but requires careful weighing of risks and benefits of
intervention.
Late development of heart failure remains one of the main long-term problems in ACHD and one of the most
frequent causes of late death.
As soon as the heart failure syndrome
becomes obvious in a patient, the search for hemodynamic disorders that
can eventually be repaired, surgically
52
or interventionally, and in this way at
best resolve heart failure symptoms is
key. However, treatable hemodynamic
disorders may not be present or heart
failure not resolve despite successful
improvement of hemodynamics due to
irreversible damage of ventricular
myocardium or the vascular system.
The challenges of treating heart failure
in adult patients with congenital lesions gives little evidence and frequent
conditions that may not allow the application of the treatment standards
established for acquired – mainly left
heart – disease, will be covered by
other presentations. The present contribution is supposed to deal with the
patient who is still asymptomatic but
at the risk of developing heart failure.
The ultimate goal in the management
of congenital heart disease is obviously to prevent the development of
heart failure in the first place. In this
context two issues need to be addressed:
• How early is surgical or catheter intervention required to avoid irreversible
damage and optimize long-term outcome ?
• Can early medical treatment of still
asymptomatic ventricular dysfunction
prevent or at least delay development
of overt heart failure when repairable
hemodynamics is not present ?
To start with the latter: For acquired
heart disease, large randomized trials
are available that could demonstrate
the benefit of treating asymptomatic
left ventricular (LV) dysfunction with
ß-blockers and ACE inhibitors.
Although ACHD patients were rarely
included in such studies it may still be
justified to apply such results to asymptomatic LV dysfunction. However, in the
ACHD population we are more commonly faced with failing right ventricles
in settings such as transposition of the
great arteries with atrial switch operation or repaired tetralogy and univentricular hearts, nowadays typically
with Fontan circulation. Application of
the data gathered in LV dysfunction
can hardly be applied to such conditions differing markedly in pathophysiology. Thus, medical treatment of
asymptomatic ventricular function
remains controversial and based on
mostly non-conclusive small studies.
Early intervention with the goal to relieve the ventricles from the burden of
pressure and/or volume overload with
eventual development of ventricular
failure is a very logical concept. However, no intervention is without risk and
careful weighing of this risk against
the possible benefits is requested.
While recommendations are relatively
easy when patients suffer from symptoms and interventions are available
that are likely to improve them, current
guidelines frequently struggle with the
recommendations for asymptomatic
patients in whom solid data to support
the treatment benefit are commonly
lacking.
In this context the question arises –
what means asymptomatic?
Studies using cardiopulmonary exercise testing (CPET) demonstrated that
exercise limitations and quite abnormal test parameters are relatively common in ACHD patients even when they
report themselves to be asymptomatic.
In addition, elevated plasma levels of
brain natriuretic peptides (BNP, NTproBNP) – accepted markers of heart
failure - have been reported in a significant number of asymptomatic ACHD
patients.
Both, CPET and BNP have been reported to be important predictors of outcome and it has therefore been suggested to include them in the decision
making to improve timing of early
intervention.
High interest exists in the early detection of interstitial fibrosis by MRT
in this context but more data are
required to define its role in asymptomatic patients.
The threshold for intervening in
asymptomatic patients with significant
lesions will obviously be highly dependent on acute and long-term risks of
the intervention.
While recommendations can be more
liberal for interventions where these
risks are very low, such as interventional atrial septal defect closure, balloon dilation of pulmonary stenosis or
very low risk surgical procedures, the
weighing of risk and benefits becomes
more difficult when operative risk rises
– particularly multiple re-operations –
or if an intervention already implies a
future re-intervention as in the case of
implantation of biological valve substitutes.
53
Endstage heart failure in ACHD: Medical and surgical
treatment concepts
Felix Berger1,2
1
Dept. of Congenital Heart Disease / Pediatric Cardiology
Deutsches Herzzentrum Berlin and Charité – Universitätsmedizin Berlin, Germany
2
DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany
With the expected continuous increase in the number of
adults with congenital heart disease (ACHD), the problem
of the choice of the appropriate therapy will also increase.
It is also to be expected that rising numbers will make
randomized multicentric studies possible, which it is
hoped will provide clear evidence validating the different
therapy algorithms for the ACHD population. This is certainly an urgent need, to underpin the treatment of our
patients with the necessary knowledge and guidelines.
A unified treatment concept for these heart defects is unfortunately not available (1).
On the contrary, the wide variety of defects, the differing
etiology of the patients’ heart failure, inadequate predictive
data concerning the progression of the disease and the lack
of validation of the different treatment possibilities make
it necessary, in most cases, to develop an individually tailored treatment concept (2).
It is not so much acute heart failure with sudden emergency
situations but chronic, progressive heart failure, which
develops inexorably but with great age differences, that
requires a highly complex treatment strategy.
In the past 50 years enormous progress has been made in
the treatment of congenital heart disease (CHD), so that
nowadays not only do children born alive with CHD have an
almost 90 % chance of surviving to adulthood but also the
majority of them will have good quality of life and good physical capacity. Nevertheless, many of the procedures performed today are still more palliative than curative. This
means complications, especially for the group of patients
with highly complex heart defects, during the long-term
course, and often the development of chronic heart failure.
Nowadays it is clear that structural cardiac causes of heart
failure, such as valve degeneration and volume or pressure
overload, should be specifically addressed by interventional or surgical procedures to ensure a balanced load on
the myocardium (3).
Despite this, the development of heart failure in adults
with congenital heart disease (ACHD) is multifactorial and
results in systolic and/or diastolic heart failure, which is
often exacerbated by acute or chronic arrhythmia. The aim
of all treatment must be to avoid adverse remodeling and
KEY POINTS
54
the formation of fibrosis, which both cause irreversible
changes in the myocardium that can no longer be influenced (1, 2, 4, 5).
Currently it is common practice to assume that the basic
mechanisms of heart failure in most patients with CHD are
the same as those in adults with acquired heart disease,
and to extrapolate and apply to them heart failure data and
guidelines relating to adults with acquired disease. However, this does not really work in cases of specific anatomical
preconditions such as systemic right ventricle, right-heartbased heart failure or univentricular defects.
Further, the interaction between the two ventricles is of key
importance in the development of additional left ventricular
heart failure following right ventricular failure.
Nevertheless at present there are no better guides than extrapolating the effects of the different pharmacological
treatment strategies for chronic heart failure from the existing therapy algorithms.
In addition to pharmacological treatment options, electrophysiological diagnostic procedures and ablation therapy
and antiarrhythmic treatment with implantable defibrillators (ICD) are gaining increasing importance, especially
since acute arrhythmia is one of the most frequent causes
of death in patients with CHD, although as yet we have no
data on the survival advantage provided by ablation and
ICD treatment in this patient group (6–9).
Often pharmacological treatment remains unsuccessful and
heart transplantation has to be considered as the ultima
ratio option. Closely related is also the question of mechanical circulatory support (MCS) as destination therapy,
when transplantation is not possible or not likely to succeed or when no donor organ becomes available in time.
Although the use of MCS in the treatment of terminal heart
failure on the whole is growing, this is not the case in ACHD
patients. This is no doubt due to the complexity of the underlying diseases and the patients’ comorbidity, where
MCS no longer represents a real therapy option.
Since not only the therapy algorithm for chronic heart failure in ACHD is based on little data, but also the indication
for heart transplantation has no individually applicable
basis in data, and especially in view of the multiple comorbidity of chronically ill ACHD patients, the decision to list
a patient for organ transplantation is mainly based on the
specific experience of the individual transplant center
(10–15). In any case it is clear that ACHD with terminal heart
failure will remain on the transplantation waiting list for
longer than patients without structural heart disease and
have less chance of being allocated an organ, which in turn
means a comparable increase in the incidence of death on
the waiting list.
References
1. Stout KK, Broberg CS, Book WM, Cecchin F, Chen JM, Dimopoulos K, et
al. Chronic Heart Failure in Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circulation. 2016; 133(8):
770–801.
2. Budts W, Roos-Hesselink J, Radle-Hurst T, Eicken A, McDonagh TA,
Lambrinou E, et al. Treatment of heart failure in adult congenital heart
disease: a position paper of the Working Group of Grown-Up Congenital
Heart Disease and the Heart Failure Association of the European Society of Cardiology. Eur Heart J. 2016.
3. Ministeri M, Alonso-Gonzalez R, Swan L, Dimopoulos K. Common longterm complications of adult congenital heart disease: avoid falling in
a H.E.A.P. Expert Rev Cardiovasc Ther. 2016: 1–18.
4. Ryan TD, Jefferies JL, Wilmot I. Managing heart failure in adults with
congenital heart disease. Curr Treat Options Cardiovasc Med. 2015;
17(2): 376.
5. LeMond L, Mai T, Broberg CS, Muralidaran A, Burchill LJ. Heart Failure in
Adult Congenital Heart Disease: Nonpharmacologic Treatment Strategies. Cardiol Clin. 2015; 33(4): 589–98, viii–ix.
6. Sakaguchi H, Miyazaki A, Yamada O, Kagisaki K, Hoashi T, Ichikawa H,
et al. Cardiac resynchronization therapy for various systemic ventricular
morphologies in patients with congenital heart disease. Circ J. 2015;
79(3): 649–55.
7. Diller GP, Kempny A, Alonso-Gonzalez R, Swan L, Uebing A, Li W, et al.
Survival Prospects and Circumstances of Death in Contemporary Adult
Congenital Heart Disease Patients Under Follow-Up at a Large Tertiary
Centre. Circulation. 2015; 132(22): 2118–25.
8. Motonaga KS, Khairy P, Dubin AM. Electrophysiologic therapeutics in
heart failure in adult congenital heart disease. Heart Fail Clin. 2014;
10(1): 69–89.
9. Mondesert B, Dubin AM, Khairy P. Diagnostic tools for arrhythmia detection in adults with congenital heart disease and heart failure. Heart
Fail Clin. 2014; 10(1): 57–67.
10. Ross HJ, Law Y, Book WM, Broberg CS, Burchill L, Cecchin F, et al. Transplantation and Mechanical Circulatory Support in Congenital Heart
Disease: A Scientific Statement From the American Heart Association.
Circulation. 2016; 133(8): 802–20.
11. Ryan TD, Jefferies JL, Zafar F, Lorts A, Morales DL. The evolving role of
the total artificial heart in the management of end-stage congenital
heart disease and adolescents. ASAIO J. 2015; 61(1): 8–14.
12. Stewart GC, Mayer JE, Jr. Heart transplantation in adults with congenital
heart disease. Heart Fail Clin. 2014; 10(1): 207–18.
13. Robinson JA, Driscoll DJ, O'Leary PW, Burkhart HM, Dearani JA, Daly RC,
et al. Cardiac and multiorgan transplantation for end-stage congenital
heart disease. Mayo Clin Proc. 2014; 89(4): 478–83.
14. Mulukutla V, Franklin WJ, Villa CR, Morales DL. Surgical device therapy
for heart failure in the adult with congenital heart disease. Heart Fail
Clin. 2014; 10(1): 197–206.
15. Miller JR, Eghtesady P. Ventricular assist device use in congenital heart
disease with a comparison to heart transplant. J Comp Eff Res. 2014;
3(5): 533–46.
55
Aortic root dilatation in adults with congenital heart disease
and effects of pharmacotherapy on aortic growth
Julie De Backer
University Hospital Ghent
Department of Cardiology and Medical Genetics
Ghent, Belgium
Aortic root dilatation in Congenital Heart Disease
KEY POINTS
Major subgroups of patients with congenital heart
disease include those with Marfan syndrome and related
Heritable Thoracic Aortic Disorders and patients with
Bicuspid Aortic Valves. Phenotypic differences and differences in outcome should be recognized and may help
us to guide management.
Molecular genetic testing plays an important role in
correct diagnosis and may be used in the future for
personalized management.
At present, β-blockers should be considered as first-line
therapy to slow down progressive aortic growth in these
disorders.
56
Aortic root dilatation (ARD) is defined as enlargement of
the proximal ascending part of the aorta. Depending on the
underlying cause, maximal dilatation may be located at the
sinuses of Valsalva or at the tubular ascending part of the
aorta. Care should be taken when assessing the diameters
of the aorta and comparison with the correct reference
values is crucial (1–3).
In patients with structural congenital heart disease (CHD),
ARD is not infrequent. Primary aortic dilatation is mainly
associated with bicuspid aortic valve, coarctation of the
aorta, and conotruncal abnormalities such as tetralogy
of Fallot, pulmonary atresia with ventricular septal defect,
or truncus arteriosus. The evolution of the aortic diameter
results from a combination of intrinsic pathology, associated malformations, surgical or catheter interventions, and
control of risk factors later in life.
Secondary aortic dilatation may occur after arterial switch
operation or systemic outflow tract reconstruction in patients with a single ventricle (4).
An important proportion of ARD encountered in CHD patients is in the setting of underlying heritable thoracic aortic disorders (H-TAD), with Marfan syndrome (MFS) being
the paradigm disorder. Many aspects related to management and treatment of patients with ARD is based on the
insights obtained in MFS and this brief overview will therefor have an important focus on this disorder.
Marfan syndrome
Marfan syndrome is caused by mutations in the fibrillin1
gene (FBN1).
ARD at the level of the sinuses of Valsalva, leading to aneurysm and dissection is the main determinant of morbidity
and mortality in MFS. It is estimated that aortic root dilatation is present in > 80% of adult MFS patients (5).
Aortic root growth rate in untreated MFS patients is estimated at 0.2 mm/y – the rate in treated patients varies between 0.3 and 0.9 mm/y across different studies with a higher rate in men than in women in some studies (6, 7). This
growth rate is significantly increased when compared to the
average of 1 mm/10 y in the general population (3).
Despite the availability of prophylactic replacement of the
aortic root, even current surgical series document that up to
one third of MFS patients present with aortic dissection,
mainly Stanford type A dissection (8). Such high numbers of
acute aortic emergencies indicate the persisting deficiency
of timely diagnosis and adequate risk estimation (9).
Both structural and local hemodynamic factors interact
in the process of ARD in MFS – a complex process known
as mechanobiology (10, 11). Structural abnormalities in the
ascending aorta arise from the complex and not fully unravelled interplay between embryologic factors, abnormalities in the elastic fibre formation and homeostasis and
altered signalling pathways, including the TGFβ pathway.
Hemodynamic factors in the aortic root are characterized
by its exposure to the repetitive stress of left ventricular
ejection, eventually contributing to progressive dilatation.
Other Heritable-Thoracic Aortic Disorders
Clinical recognition of both distinct syndromic entities as
of patients and families presenting nonsyndromic thoracic
aortic disease is established for many decades.
The recent advances in molecular genetic diagnostics have
already unraveled part of the genetic background of these
disorders.
An example of a distinct syndromic TAD entity is the LoeysDietz syndrome (LDS) caused by mutations in the TGFBR1
or 2 gene and characterized by dysmorphic features including hypertelorism and cleft bifid uvula (12).
57
More widespread vascular disease and a tendency for a
more aggressive course of ARD in LDS may indicate perspectives for genotype-based treatment and management
with extended vascular imaging and a lower threshold for
prophylactic aortic root surgery. More recent studies have
however revealed that at least some patients with TGFBR1/2
mutations show a less aggressive course with an aortic
phenotype indistinguishable from classic MFS with an estimated growth rate of 0.67mm/y (13–15).
Not labeling all TGFBR1/2 mutation carriers as “LDS”, distinguishing a subcategory of nonsyndromic TAD may be a
solution. Multicenter registries analyzing the clinical evolution in these patients are underway and will definitely help
defining improved guidelines.
affected segment. The prevalence of aneurysms in BAV
ranges from 20 to 84 % in different reports (20).
Both hemodynamic factors and abnormal intrinsic wall
properties, similar to those found in MFS, are the underlying pathophysiological mechanism of BAV-associated aneurysms (21). Although the incidence of dissection in patients
with BAV is lower than in MFS (4%), the higher prevalence
of BAV makes it a more common problem (18).
Very similar observations are also true for genes identified
later, including the SMAD3 gene, the TGFβ2 gene and the
TGFβ3 gene with some patients presenting a severe phenotype reminiscent of LDS and others presenting much milder
phenotypes with “Isolated Thoracic Aortic Disease”. A useful common denominator for these conditions is “Heritable-Thoracic Aortic Disease or H-TAD”, covering all genetic
entities, both syndromic and nonsyndromic and offering
the possibility to include those patients/entities in whom
the underlying genetic defect has not been identified
yet(16).
Currently established genes in H-TAD (17), grouped according to their main function and with their corresponding
phenotype are listed in table 1.
Medical treatment
Bicuspid aortic valve
BAV is the most common congenital cardiac disease with
an estimated prevalence of 0.5–2 % (18).
BAV associates with different forms of syndromic H-TAD,
such as MFS and LDS (19), as well as with Turner syndrome
and aortic coarctation, but in the majority of cases, it presents as an isolated feature.
Thoracic aneurysm formation is a well-known association
with BAV and the ascending aorta is usually the most
58
A recent prospective study comparing mortality and dissection rates in MFS, nonsyndromic TAD and BAV indicates
that clinical outcome in nonsyndromic TAD and MFS is
similar but worse than in BAV(22).
The ultimate goal of medical treatment in ARD would be
to arrest aortic root growth but, realistically, postponing
the need for aortic root surgery and avoiding dissection are
the outcomes that have conventionally been aimed at.
So far, unfortunately no study proving this goal has emerged, partly due to the low prevalence of these disorders
and the inherently low occurrence of events.
Decreasing aortic growth has been used a surrogate outcome parameter in most studies. Slowing down aortic root
growth may be achieved through reducing hemodynamic
stress on the proximal aorta.
The first report on the use of β-blockers in MFS dates from
1971 indicating that reduction in the rate of increase in aortic pressure over time (dP/dt) was more effective than could
be explained by reduction of blood pressure alone (23).
Since then, no less than 2022 MFS patients have been included in at least 20 different trials with β-blockers. The
only placebo-controlled randomized trial showed a significant reduction in aortic root growth with propranolol (24).
The beneficial effect of β-blockers has not been consistent
in all studies (25, 26). Differences in the populations studied, in the drug types and dosage and in the study design
render the interpretation and comparison of these trials
particularly challenging.
H-TAD related to genes encoding components of the extracellular matrix
FBN1
Neonatal MFS
COL3A1
vEDS
Isolated/Nonsyndromic TAD
MFAP5
MFS features
Isolated/Nonsyndromic TAD
Classic MFS/MFS features
Isolated/Nonsyndromic TAD (37, 38)
H-TAD related to genes encoding components of the TGFβ pathway
TGFBR1
LDS; vEDS
Classic MFS/MFS features
Isolated/Nonsyndromic TAD
TGFBR2
LDS; vEDS
Classic MFS/MFS features
Isolated/Nonsyndromic TAD
SMAD3
LDS
AOS, classic MFS/MFS features
Isolated/Nonsyndromic TAD
TGFβ2
LDS
Classic MFS/MFS features
Isolated/Nonsyndromic TAD
TGFβ3
LDS, syndrome presenting at MFS features
birth with distal arthrogryposis, hypotonia, bifid uvula, a
failure of normal post-natal
muscle development
H-TAD related to genes encoding proteins involved in the contractile apparatus of vascular smooth muscle cells
ACTA2
TAD with multisystemic
SMC dysfunction
TAD with mild associated skin/ocu- Isolated/Nonsyndromic TAD
lar/vascular lesions
MYLK
Isolated/Nonsyndromic TAD
PRKG1
Isolated/Nonsyndromic TAD (39)
MYH11
TAD with Patent ductus arteriosus
Isolated/Nonsyndromic TAD
Table 1: Schematic overview of Heritable Thoracic Aortic Disease (H-TAD) entities, according to the underlying gene defects and according to degree
of manifestations outside the aorta (Syndromic Gradient, from left to right). Two major groups of gene mutations associated with H-TAD can be
distinguished, namely those affecting structure (i.e. the ECM) and those that affect the ability to modify structure in response to changes in mechanical
load imposed on the aortic wall (i.e. cell-signaling pathways and the contractile apparatus).
AOS: Aneurysm-Osteoarthritis syndrome; MFS: Marfan syndrome; LDS: Loeys-Dietz syndrome; SMC: smooth muscle cell; vEDS: vascular Ehlers-Danlos
syndrome.
Alternatives for β-blockers including Calcium channel
blockers and ACE-inhibitors have been suggested and
studied in small series (27, 28).
A seemingly major breakthrough in the search for improved
medical treatment in MFS patients was achieved with the
documentation of involvement of the TGFβ pathway in the
process of aneurysm formation.
This led to the insight that interference with TGFβ signaling
using Losartan, an angiotensin receptor blocker with known
TGFβ inhibiting potential may have a beneficial impact on
aortic growth. Aortic growth and architecture were restored
in MFS mice treated Losartan (29). An initial small cohort
study in severely affected children with MFS treated with
losartan on top of β-blocker treatment showed hopeful
results (30). At least 10 randomized trials ensued, recruiting
>2000 patients in total, spanning all age ranges. Four large
trials have been reported so far, and overall, these studies
fail to confirm the initial positive results. Neither head-tohead comparison of β-blockers versus losartan nor the
combined treatment of both drugs shows a significant
benefit of losartan (31–34).
More research is needed to explore whether specific subgroups can be identified for whom medical treatment can
be personalized. A large meta-analysis addressing these
issues is underway (35).
With regards to medical treatment in the other H-TAD
entities and BAV, very little – if any - data are available.
Management is often adopted from the evidence obtained
in MFS. The ESC guidelines on Aortic Disease on medical
treatment in BAV is to consider β-blockers in in patients
with BAV and a dilated aortic root >40 mm (ClassIIb indication – level C) (36).
59
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61
Oral Anticoagulants in Adult Congenital Heart Disease
Harald Kaemmerer, Claudia Pujol, Anne-Charlotte Niesert, Andrea Engelhardt, Ekatharina Kusmenkov, Alexey Trepakov, Peter Ewert
Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich, Technical University Munich
Siegmund L. Braun
Department of Laboratory Medicine, Munich, Germany, German Heart Center Munich, Technical University Munich
David Pittrow
Institute for Clinical Pharmacology, Medical Faculty, Technical University, Dresden, Germany
KEY POINTS
Thromboembolic disease in ACHD is currently managed
similar to other heart disease. Until recently, direct
oral anticoagulants (DOAC s) have not been specifically
studied in ACHD.
For the first time the current data on the use of DOAC in
ACHD, show that DOAC s are increasingly used and well
tolerated in this very heterogeneous population.
As the experience with DOACs in ACHD is still limited,
the potential for as yet unrecognized adverse events
exists. Therefore, further studies are necessary in these
vulnerable and unique patients to evaluate and improve
treatment efficacy and safety.
Thromboembolic events (TEE) are common in adults with
congenital heart disease (ACHD) and morbidity and mortality from these complications are high. Therefore, adequate
oral anticoagulation (OAC) for prophylaxis or treatment of
TEE is of outstanding importance.
A recent study, including more than 800 adults with a
broad spectrum of CHD, has proven that 22 % of the inclu-
62
ded patients were on oral anticoagulation, nearly always
with vitamin K antagonists (VKA) (1).
Main indications for OAC in ACHD is prevention of TEE caused by supraventricular arrhythmias, venous thrombosis,
replaced mechanical or biological heart valves and also
specific situations like Fontan-Circulation, Eisenmenger
Syndrome, or after implantation of conduits, stents, or closure devices.
VKA, however, come along with considerable disadvantages, including interactions with food and drugs, a narrow
therapeutic window, inter- and intra-individual variability in
dose response, a delayed onset of action, a long half-life
and the need for regular blood tests. All these factors may
increase the risk of under- or over-anticoagulation (2).
Meanwhile, however, also Direct Oral Anticoagulants
(DOAC) have been introduced for prevention and/or treatment of venous and arterial TEE (Figure 1):
• Direct thrombin-inhibitor dabigatran (Pradaxa®,
Boehringer Ingelheim)
• Factor Xa-inhibitors (Rivaroxaban, Xarelto®, Bayer HealthCare; Apixaban Eliquis®, Bristol-Myers Squibb; Edoxaban
Lixiana®, Daiichi Sankyo).
Figure 1
Disclosures
There is an increasing interest in these substances as
DOACs have major pharmacologic advantages compared
with VKA, including fast begin and offset of action, fewer
drug and food interactions, and a more predictable pharmacokinetic, removing the requirement for routine coagulation monitoring. This is counterbalanced by concerns, particularly regarding dosing in some populations (e. g. renal
dysfunction) and superior drug costs compared with VKA.
Although so many ACHD need OAC, scientific data regarding
the adequate choice and use of DOACs for preventing TEE
are lacking. Neither guidelines nor evidence based treatment algorithms exist for this heterogeneous and unique
population with own pathophysiology, pathobiochemistry
and hemodynamic. Therefore, the existing treatment recommendations cannot be transferred directly to ACHD.
In any case, neither ACHD nor not-ACHD patients a with
mechanical heart valve prosthesis can be treated with
DOAC’s (3).
First real-world experiences regarding the coagulation management of ACHD using DOACs have been published from
our institution recently (4).These data, from a very heterogeneous cohort of ACHD, indicate for the first time that DOACs
are an alternative to VKA for primary and secondary prophylaxis in ACHD. In a cohort of 75 ACHD there were during a
follow-up up to 61 months (Median: 12 ± 11 months) neither
clinically relevant thrombotic or major bleeding events nor
major side effects.
Nevertheless, as the experience with DOACs in ACHD is
still limited, the potential for as yet unrecognized adverse
events exists, and therefore, further studies are necessary
in these vulnerable and unique patients to evaluate and
improve treatment efficacy and safety.
This study was supported by a grant from „Deutsche Stiftung für Herzforschung“ („German Heart Research Foundation“). The views expressed in this publication are those
of the authors and do not necessarily represent those of the
funder.
Bibliography
1. Lummert E. Beitrag zur Problematik nicht-kardialer Comorbiditaeten
bei Erwachsenen mit angeborenen Herzfehlern. Univ Diss.Munich:
Technical University Munich; 2016 (submitted)
2. Riva N, Lip GYH. A new era for anticoagulation in atrial fibrillation.
Polish Arch Intern Med 2012; 122: 45–53.
3. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP,
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Y, Lobmeyer MT, Maas H, Voigt J-U, Simoons ML, Werf F Van de. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J
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4. Pujol C, Niesert A, Engelhardt A, Schoen P, Kusmenkov E, Pittrow D,
Ewert P, Kaemmerer H. Usefulness of Direct Oral Anticoagulants in
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References for figure
1. Stambler BS. A new era of stroke prevention in atrial fibrillation:
comparing a new generation of oral anticoagulants with warfarin.
Int Arch Med. 2013 Oct 31; 6(1): 46.
2. De Caterina R1, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, Baigent C, Huber K, Jespersen J, Kristensen SD, Lip GY, Morais
J, Rasmussen LH, Siegbahn A, Verheugt FW, Weitz JI; European Society
of Cardiology Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. General mechanisms of coagulation and targets
of anticoagulants (Section I). Position Paper of the ESC Working Group
on Thrombosis-Task Force on Anticoagulants in Heart Disease. 2013
Apr; 109(4): 569–79.
63
Morbus Fabry: Too often overlooked?
Tomas Palecek, Ales Linhart
2nd Department of Medicine – Department of Cardiovascular Medicine
First Faculty of Medicine, Charles University in Prague
General University Hospital in Prague
Prague, Czech Republic
KEY POINTS
Fabry disease is an inborn error of metabolism with
X-linked inheritance pattern characterized by a deficiency
in the activity of the lysosomal enzyme a-galactosidase A
leading to progressive lysosomal accumulation of glycosphingolipids, mainly globotriaosylceramide. Due to random X-chromosome inactivation in females, both genders may be affected. Cardiac manifestation is common
with left ventricular hypertrophy being the major cardiac
manifestation. Fabry disease related cardiomyopathy
represents a non-sarcomeric form of hypertrophic cardiomyopathy and shall be included in the differential
diagnosis of unexplained left ventricular hypertrophy in
adults. The effect of enzyme replacement therapy is
related to the extent of left ventricular wall thickening
as well as replacement myocardial fibrosis.
64
Fabry disease is an X-linked genetic disorder of glycosphingolipid metabolism caused by deficient activity of lysosomal enzyme α-galactosidase A.
The disease is characterized by progressive intracellular
accumulation of neutral glycosphingolipids, mainly globotriaosylceramide, within lysosomes of different tissues
throughout the body. The intracellular deposition of the
substrate starts already before birth and most likely represents an initial trigger that causes a cascade of pathophysiological cellular processes leading to structural cellular
change, followed by tissue defects and finally – over some
time – to organ failure.
Reported estimates of the incidence of Fabry disease range
from 1 in 40.000 males to 1 in 117.000 in the general population (1).
As an exception among lysosomal storage disorders, most
patients are clinically asymptomatic during the very first
years of life.
Figure 1
Figure 2
The first symptoms appear typically between the ages of
3 and 10 years in boys, and few later in girls. Typical symptoms in childhood and adolescence are acroparesthesia,
pain crises, hypohidrosis, angiokeratomas and several
gastrointestinal symptoms.
Cardiac as well as renal and cerebrovascular manifestations
appear in adulthood. Life-threatening cardiovascular complications and end-stage renal disease limit life-expectancy
of untreated patients (2).
clinical phenotypes, ranging from asymptomatic disease
course occasionally seen in some females to severe multisystemic involvement in males (3).
For a long time, Fabry disease was considered as a disease
of affected males who developed severe “classic” phenotype consisting of numerous multiorgan manifestations,
some of them mentioned above. With increasing knowledge
about natural course of the disease, so called cardiac as
well as renal variants were introduced for individuals with
predominant or exclusive cardiac or renal involvement due
to residual α-galactosidase A activity. Furthermore, female
heterozygotes were originally incorrectly labeled as asymptomatic carriers. However, virtually all disease manifestations including vital organ involvement may also develop
in females as a consequence of random X-chromosome
inactivation (a process called lyonization), about a decade
later than in males.
Fabry disease is thus associated with a wide spectrum of
The diagnosis of Fabry disease in males is based on analysis of α-galactosidase A activity in leukocytes and plasma
(absent or low activity in positive cases). Molecular analysis
of the GLA gene is necessary to diagnose female heterozygotes because of the significant levels of enzyme activity
that may be present in blood samples due to random
X-inactivation (4).
Cardiac involvement is associated with pathologic substrate accumulation in all cellular components of the heart,
including cardiomyocytes, conduction system cells, valvular
fibroblasts, endothelial cells and vascular smooth muscle
cells.
Left ventricular hypertrophy is the hallmark of cardiac manifestations in Fabry disease, present in more than 50% of
adult patients. The pathogenesis of this hypertrophy is not
clearly understood as globotriaosylceramide accumulation
represents only 1-2% of the total cardiac mass. The disturbance in myocardial energy metabolism together with activation of other signaling pathways, including increase of
trophic factors like globotriaosylsphingosine and sphingo-
65
sine-1-phosphate, lead to evolvement of “true” myocardial
hypertrophy with subsequent interstitial remodeling (5).
In most Fabry disease patients, a concentric left ventricular
hypertrophy with prominent papillary muscles is present
(Figure 1); however, asymmetric septal hypertrophy as well
as dynamic left ventricular obstruction may also be detected, though rarely.
Of note, Fabry disease related left ventricular hypertrophy is
regarded as a non-sarcomeric phenocopy of hypertrophic
cardiomyopathy and shall always be included in differential
diagnosis of unexplained hypertrophic cardiomyopathy in
adults. Indeed, several studies have shown that Fabry
disease may be found in 1–5 % of males with unexplained
left ventricular hypertrophy/hypertrophic cardiomyopathy
(6).
Global left ventricular systolic function as assessed by
ejection fraction is preserved for a long time in Fabry
disease related cardiomyopathy; however, strain imaging
confirms subclinical abnormalities of myocardial deformation properties even in mild forms of cardiac disease. Left
ventricular diastolic function is logically impaired; however,
restrictive filling pattern is present only in advanced stages
of this cardiomyopathy.
With age, progressive myocardial replacement fibrosis
develops. Based on magnetic resonance studies, this replacement fibrosis almost invariably starts in midmyocardial region of the basal posterolateral left ventricular wall.
With progression to transmural fibrosis in end-stage
patients, regional and then global left ventricular systolic
function worsens (Figure 2).
Progressive congestive heart failure and malignant arrhythmias represent important causes of death in patients affected with Fabry disease (5, 6).
Enzyme replacement therapy, which is available since
2001, allows a causal treatment of Fabry disease and is
based on lifelong administration of intravenous infusions
with recombinant α-galactosidase A. The success of enzyme replacement therapy on Fabry disease related cardio-
66
myopathy is heavily determined by the extent of left ventricular hypertrophy and replacement myocardial fibrosis.
The highest effect of this treatment is seen in individuals
with no or only mild ventricular hypertrophy and no fibrosis.
Nevertheless, even in patients with advanced cardiomyopathy enzyme replacement therapy has a potential to prevent
or slow down further progression of the disease.
Early diagnosis of Fabry disease is thus the most important
prerequisite for successful treatment (7).
References
1. Martins AM, D'Almeida V, Kyosen SO, Takata ET, Delgado AG, Gonçalves
AM, Benetti Filho CC, Martini Filho D, Biagini G, Pimentel H, Abensur H,
Guimarães HC, Gomes JG, Sobral Neto J, D'Almeida LO, Carvalho LR,
Harouche MB, Maldonado MC, Nascimento OJ, Montoril PS, Bastos RV.
Guidelines to diagnosis and monitoring of Fabry disease and review of
treatment experiences. J Pediatr. 2009 Oct; 155(4 Suppl): S19–31.
2. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010 Nov 22; 5: 30.
3. Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP;
Fabry Registry. Females with Fabry disease frequently have major organ
involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008
Feb; 93(2): 112–28.
4. Gal A, Hughes DA, Winchester B. Toward a consensus in the laboratory
diagnostics of Fabry disease - recommendations of a European expert
group. J Inherit Metab Dis. 2011 Apr; 34(2): 509–14.
5. Seydelmann N, Wanner C, Störk S, Ertl G, Weidemann F. Fabry disease
and the heart. Best Pract Res Clin Endocrinol Metab. 2015 Mar; 29(2):
195–204.
6. Yousef Z, Elliott PM, Cecchi F, Escoubet B, Linhart A, Monserrat L, Namdar M, Weidemann F. Left ventricular hypertrophy in Fabry disease: a
practical approach to diagnosis. Eur Heart J. 2013 Mar; 34(11): 802–8.
7. Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Störk S,
Voelker W, Ertl G, Wanner C, Strotmann J. Long-term effects of enzyme
replacement therapy on fabry cardiomyopathy: evidence for a better
outcome with early treatment. Circulation. 2009 Feb 3; 119(4): 524–9.
Hypertrophic Cardiomyopathy: the renewed ESC-guidelines
Hubert Seggewiss, FESC
Leopoldina Krankenhaus,
Medizinische Klinik 1
Schweinfurt, Germany
Hypertrophic cardiomyopathy (HCM)
occurs in 0.02 % of adults with much
lower rates of diagnosis in patients
< 25 years of age. HCM is defined by
the presence of increased left ventricular (LV) wall thickness – ≥ 15 mm in
one or more LV myocardial segments –
that is not solely explained by abnormal loading conditions. In up to 60 %
of patients with HCM, the disease is
an autosomal dominant trait caused
by mutations in cardiac sarcomere
protein genes.
Two-thirds of patients with HCM have
dynamic intracavitary obstructions at
rest or during exercise – mainly of the
left ventricular outflow tract (LVOTO)
caused by contact between the mitral
valve and the interventricular septum
during systole.
Bedside physiological provocation
with Valsalva manoeuvre and standing
should be routinely performed during
echocardiography to determine if LV
outflow obstruction can be provoked.
Diagnostic cascade of HCM considers
clinical and non-invasive evaluation
and search of diagnostic red flags of
systemic disease. Careful individual
risk stratification of each individual
patient includes history (age, unexplained syncope, premature familial
HCM-related cardiac death), echo measurements (maximal gradient, LA diameter, maximal LV wall thickness),
and 24–48 hours holter (nsVT (≥3 VB’s)
≥ 120 bpm) and resulted in development of a new risk calculator
(HCMRisk-SCD)
(http://doc2do.com/hcm/webHCM.html)
for prediction of 5 years risk of SCD.
The calculated risk should guide the
use of implantable cardioverter defibrillators (ICD).
Treatment of symptomatic patients
with left ventricular obstruction consists of medical treatment, septal
ablation, and surgical myectomy.
Two decades after introduction of ablation it turned out to be the preferred
method in most clinical situations.
Total heart block with need of pacemaker implantation is the most observed
complication. Long-term observational
studies showed excellent clinical follow-up without increased morbidity
and mortality.
Nevertheless, sufficient clinical and
hemodynamic results can not be
achieved in 5–10 % of the patients
mainly due to anatomic reasons.
Therefore, surgical myectomy is necessary for symptom relief.
Both, surgical myectomy and interventional septal ablation are complementary treatment options and require
special expertise in the diagnosis, genetics, risk stratification and management of myocardial disease.
References
Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F,
Charron P, Hagege AA, Lafont A, Limongelli G,
Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014
ESC Guidelines on diagnosis and management
of hypertrophic cardiomyopathy: the Task Force
for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of
Cardiology (ESC). Eur Heart J. 2014 Oct 14;
35(39): 2733–79.
67
Modern survival analysis in Eisenmenger-Syndrome
Gerhard-Paul Diller
Division of Adult Congenital and Valvular Heart Disease
Department of Cardiovascular Medicine
University Hospital Muenster
Muenster, Germany
KEY POINTS
Eisenmenger syndrome (ES) is a multisystem disorder
placing a high burden on those affected by entailing a
multitude of complications and poor exercise capacity.
In two recent studies, we found an immortal time bias
to be present in almost all ES studies contradicting the
reported relatively beneficial survival outcome in these
patients. Furthermore, we could confirm the benefits of
disease targeted treatment in ES patients and a positive
effect of these patients’ receiving care at larger specialized centers.
These results point to the need of appropriate treatment
in ES patients which seems to be best delivered by a
specialized tertiary center.
Since its discovery in the late 19th century, Eisenmenger
syndrome (ES) has been recognized as a detrimental condition with a high symptom burden and generally increased
morbidity in those affected. Although it was identified as
a multisystem disorder entailing a multitude of complica-
68
tions, several studies have suggested a relatively benign
survival outcome in these patients, which has been the
general assumption until recently.
A single center study by Dimopoulos et al. (1) to investigate
the effects of recently available disease targeting treatment
(DTT) in ES patients was among the first to question the
idea of benign survival in these patients. A poor outcome
was identified especially for treatment naïve patients, for
whom a mortality rate of approximately 25 % at five years’
follow-up was calculated. Besides pointing to the importance of appropriate treatment, the study results suggested
that the survival prospects of ES patients had been overestimated previously.
Based on the results of mentioned study, we hypothesized
an immortal time bias to be present in previous studies,
that is, a bias resulting from only patients being included
who survived up to the point of the first clinical follow-up.
In a systematic review of available literature, combined
with own data from a cohort of 219 untreated ES patients,
we could confirm this hypothesis (2). The review revealed
all but one of the surveyed studies to be prone to immortal
time bias. Furthermore, 10 year mortality rates between
30% and 40% were found in this meta-analytic study.
In addition, the results of this study once more emphasized
the importance of effective DTT.
We could further confirm these findings recently by means
of an analysis of nationwide data, which were derived from
the Germany-wide and representative National Register for
Congenital Heart Defects (3). The analysis identified alarmingly poor survival rates among all surveyed ES patients
and especially among those not receiving any DTT. Regarding the latter, mortality rates as high as 60 % to 70 % at
10 years’ follow-up were calculated. Interestingly, the study
results also support the notion that patients receiving care
in a larger center fare much better compared with the remaining patients.
In summary, one can conclude that a worse outcome than
previously suggested has to be anticipated for ES patients
and that, in fact, survival does not seem to have improved
after the 1960s (in treatment naïve patients). Furthermore,
the available results point to the benefits of DTT and
healthcare being delivered by larger specialized centers.
Accordingly, to ensure the best possible outcome for
ES patients, referring patients to specialized tertiary
centers where a proactive approach of treatment with
DTT is possible should be considered.
References
1. Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ,
Gatzoulis MA. Improved survival among patients with Eisenmenger
syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation. 2010 Jan 5; 121(1): 20–5.
2. Diller GP, Kempny A, Inuzuka R, Radke R, Wort SJ, Baumgartner H,
Gatzoulis MA, Dimopoulos K. Survival prospects of treatment naïve
patients with Eisenmenger: a systematic review of the literature and
report of own experience. Heart. 2014 Sep; 100(17): 1366–72.
3. Diller GP, Körten MA, Bauer UM, Miera O, Tutarel O, Kaemmerer H, Berger F, Baumgartner H; and German Competence Network for Congenital
Heart Defects Investigators. Current therapy and outcome of Eisenmenger syndrome: data of the German National Register for congenital
heart defects. Eur Heart J. 2016 Feb 2. pii: ehv743. [Epub ahead of print]
69
Pulmonary vasoactive medication in adults
with Fontan circulation
Jamil Aboulhosn, M.D.
Director, Ahmanson/UCLA Adult Congenital Heart Disease Center
David Geffen School of Medicine at UCLA, Los Angeles
KEY POINTS
Immediate and short-term improvement in functional
capacity has been reported in Fontan patients receiving
pulmonary vasodilator therapies. The existing data suggests greater benefit of the phospodiesterase-5 inhibition over endothelin blockade. There are as yet no longterm studies that have assessed the impact of pulmonary
vasomodulation on survival, arrhythmias, Fontan failure,
hepatic dysfunction, or arrhythmias. Hence, there is a
need for further studies, that are sufficiently powered
and of sufficient duration to evaluate the long-term
benefits and side-effects of pulmonary vasodilators in
the Fontan population.
70
The prevalence of single ventricle patients palliated with
the Fontan operation continues to grow worldwide (1–4).
Fontan patients’ long-term survival and exercise capacity
is largely dependent upon their pulmonary vascular resistance (PVR). Normal or low pulmonary arterial resistance
is integral to the adequate function of the cavo-pulmonary
circulation (5). With age, the pulmonary arterial resistance
is known to gradually increase in Fontan patients and that
elevated pulmonary resistance is associated with worse clinical outcomes. Pulmonary vascular constriction has been
linked to the surface endothelin-1 receptors on the pulmonary vascular bed (6). It stands to reason that therapies
that decrease pulmonary arterial resistance may improve
pulmonary blood flow and functional capacity in patients
with Fontan physiology. With the understanding that the
pulmonary vascular bed is reactive to nitric oxide, safety
and at least limited efficacy of sildenafil in non-failing
Fontan patients has been demonstrated, including ~ 30 %
improvement in resting and exercise pulmonary blood flow,
myocardial performance indices and estimates of cardiac
output, and respiratory rate and minute ventilation at peak
exercise as well as decreased ventilatory equivalents of
carbon dioxide at the anaerobic threshold, though not peak
oxygen consumption (12–15). Furthermore, elevated endothelin-1 levels in Fontan patients suggest that endothelin
blockade may be efficacious.
While endothelin receptor antagonists have been shown to
increase exercise capacity, improve functional class, and
hemodynamics in patients with pulmonary arterial hypertension, their efficacy has yet to be fully proven in patients
with Fontan physiology.
In a small prospective but non-randomized study of bosentan in patients with failing Fontan physiology there were
non-significant improvements in resting and ambulatory
oxygen saturation but no improvements in maximum oxygen consumption, 6 minute walk distance, or quality of life
measures (7). Another prospective randomized control trial
also failed to demonstrate improvements in exercise, quality of life, or pro-BNP (10). A larger prospective randomized
trial (TEMPO) out of Denmark did demonstrate an improvement in maximal oxygen consumption in patients randomized to Bosentan (11). Given the mixed results of these early
studies, endothelin receptor blockers are still not widely
used in this population.
References
1. Ávila P, Mercier L-A, Dore A, Marcotte F, Mongeon F-P, Ibrahim R, et al.
Adult Congenital Heart Disease: A Growing Epidemic. Canadian Journal
of Cardiology. 2014; 30 (12, Supplement).
2. Coats L, O'Connor S, Wren C, O'Sullivan J. The single-ventricle patient
population: a current and future concern a population-based study in
the North of England. Heart (British Cardiac Society). 2014; 100(17):
1348-53. Epub 2014/05/06. doi: 10.1136/heartjnl-2013–305336.
PubMed PMID: 24794141.
3. Dabal RJ, Kirklin JK, Kukreja M, Brown RN, Cleveland DC, Eddins MC,
et al. The modern Fontan operation shows no increase in mortality out
to 20 years: a new paradigm. The Journal of thoracic and cardiovascular
surgery. 2014; 148(6): 2517–23 e1. Epub 2014/10/04. doi:
10.1016/j.jtcvs.2014.07.075. PubMed PMID: 25277471.
4. d'Udekem Y, Iyengar AJ, Galati JC, Forsdick V, Weintraub RG, Wheaton
GR, et al. Redefining expectations of long-term survival after the Fontan
procedure: twenty-five years of follow-up from the entire population of
Australia and New Zealand. Circulation. 2014; 130(11 Suppl 1): S32–8.
Epub 2014/09/10. doi: 10.1161/circulationaha.113.007764. PubMed
PMID: 25200053.
5. Asagai S, Inai K, Tomimatsu H, Shinohara T, Nakanishi T. Abstract
11430: Clinical Significance of Impaired Vascular Endothelial Function
in Patients After Fontan Procedure. Circulation. 2014; 130(Suppl 2):
A11430.
6. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et
al. Expression of endothelin-1 in the lungs of patients with pulmonary
hypertension. New England Journal of Medicine. 1993; 328(24): 1732–9.
71
7. Ovaert C, Thijs D, Dewolf D, Ottenkamp J, Dessy H, Moons P, et al. The
effect of bosentan in patients with a failing Fontan circulation. Cardiology in the young. 2009;19(4):331–9. Epub 2009/06/13. doi:
10.1017/s1047951109990023. PubMed PMID: 19519964.
8. Bowater SE, Weaver RA, Thorne SA, Clift PF. The safety and effects of
bosentan in patients with a Fontan circulation. Congenital heart
disease. 2012; 7(3): 243–9. Epub 2012/02/22. doi:
10.1111/j.1747–0803.2012.00635.x. PubMed PMID: 22348734.
9. Derk G, Houser L, Miner P, Williams R, Moriarty J, Finn P, et al. Efficacy
of endothelin blockade in adults with Fontan physiology. Congenital
heart disease. 2015; 10(1): E11–6. Epub 2014/06/04. doi:
10.1111/chd.12189. PubMed PMID: 24890846.
10. Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG,
et al. Impact of bosentan on exercise capacity in adults after the Fontan
procedure: a randomized controlled trial. European journal of heart
failure. 2013; 15(6): 690–8. Epub 2013/01/31. doi:
10.1093/eurjhf/hft017. PubMed PMID: 23361871.
11. Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, et al.
Bosentan improves exercise capacity in adolescents and adults after
Fontan operation: the TEMPO (Treatment With Endothelin Receptor
Antagonist in Fontan Patients, a Randomized, Placebo-Controlled,
Double-Blind Study Measuring Peak Oxygen Consumption) study.
Circulation. 2014; 130(23): 2021-30. Epub 2014/12/03. doi: 10.1161/circulationaha.113.008441. PubMed PMID: 25446057.
12. Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, Redington
AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation. 2003 Jul 1; 107(25):
3204–8.
72
13. Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, Picchio FM.
Effect of sildenafil on haemodynamic response to exercise and exercise
capacity in Fontan patients. Eur Heart J. [Randomized Controlled Trial].
2008 Jul; 29(13): 1681–7.
14. Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirarchi N,
et al. Impact of sildenafil on echocardiographic indices of myocardial
performance after the fontan operation. Pediatric cardiology. 2012 Jun;
33(5): 689–96.
15. Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD,
et al. Impact of oral sildenafil on exercise performance in children and
young adults after the fontan operation: a randomized, double-blind,
placebo-controlled, crossover trial. Circulation. 2011 Mar 22; 123(11):
1185– 93.
16. Ovaert C, Thijs D, Dewolf D, Ottenkamp J, Dessy H, Moons P, et al. The
effect of bosentan in patients with a failing Fontan circulation. Cardiology in the young. 2009 Aug;19(4):331-9.
17. Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG,
et al. Impact of bosentan on exercise capacity in adults after the Fontan
procedure: a randomized controlled trial. European journal of heart failure. 2013 Jun;15(6):690-8.
Diagnosis and management of iron deficiency and
hyperuricemia in cyanotic ACHD
Koichiro Niwa, MD, PhD, FACC, FAHA
Cardiovascular Center
St Luke’s International Hospital
Tokyo, Japan
KEY POINTS
• Indication of phlebotomy is moderate to severe hyperviscosity symptoms due to secondary erythrocytosis,
or preoperative in patients with Ht > 65 %.
• Iron supplementation if clinical symptoms of ID are
present.
• Prophylactic administration of iron in the absence
of evident ID is controversial.
• Asymptomatic hyperuricemia in cyanotic ACHD is not
routinely treated.
• From mechanism of hyperuricemia in cyanotic ACHD,
uricosuric agents (URAT1 inhibitor) may be effective for
prevention and treatment of hyperuricemia and gout.
• Hyperuricemia may be the trigger of various cardiovascular diseases and metabolic syndromes, therefore,
possibly better to treat hyperuricemia in cyanotic CHD.
But no positive data exist.
Causes of iron deficiency anemia (ID) in cyanotic CHD
(CCHD) include excessive erythropoiesis, chronic kidney
disease, pregnancy, menorrhagia, gastrointestinal bleeding
especially in patients with chronic use of aspirin and/or
anticoagulants, etc. Consumption of iron stores from recurrent phlebotomies can induce iron deficiency anemia that
results in iron-depleted RBC, which are less deformable. Induced microcytosis increases blood viscosity, impairs oxygen delivery, increases anaerobic metabolism and lactate
production in skeletal muscle worsening hyperviscosity
symptoms.
Therefore, indications for phlebotomy are either moderate
to severe hyperviscosity symptoms due to secondary erythrocytosis or preoperative phlebotomy for autologous
blood donation if the hematocrit level is above 65 %.
Secondary hyperuricemia exerts little effect on renal
function. Urate deposits seldom cause overt renal disease.
Acute gouty arthritis is less common than would be expected
from the relatively high prevalence of elevated UA levels.
Asymptomatic hyperuricemia in CCHD is not routinely treated.
Cause of hyperuricemia is muscular, renal, hepatic, and
overproduction (erythrocytosis). Hyperuricemia possibly
results from increased production and decreased renal
clearance of uric acid.
Uricosuric agents (URAT1 inhibitor, benzbromarone, probenecid) and UA synthesis inhibitors (alloprinol, febuxostat)
are effective.
73
Treat and repair strategies for adults with septal defects and
pulmonary arterial hypertension
Dietmar Schranz
Pediatric Heart Center Giessen
Zentrum für angeborene Herzfehler
Giessen, Germany
“Treat-and-repair” strategies might be a viable approach
if individualized risk-benefit stratification is performed.
An isolated, non-restrictive ASD leads to a PAH only in context of genetic disposition for a pulmonary vascular disease
in context of high flow shear stress of the pulmonary vascular bed.
Significant cardiac shunts associated with pulmonary
hypertension might be positioned on the systemic/pulmonary vein, atrial and ventricular level as well as between
the great arteries.
A non-restrictive ventricular septal defect (VSD) causes after
postnatal adaption an intracardiac left to right shunt, which
leads to increased pulmonary vascular resistance (PVR) and
pulmonary hypertension because of a high shear stress
combined with an increased hydrostatic pressure.
The shunt direction of a non-restrictive atrial septal defect
without any other cardiac lesions is defined by the relationship of the compliance of both, the right (RV) and left (LV)
ventricle.
Considering serial circulation with a normal wall thickness
of the RV to LV, a non-restrictive ASD leads usually to a Qp : Qs
ratio of 3 : 1, if any higher shunt ratio is detected an additional reason has to be evaluated or excluded, in particular
an increased LVEDP. The same is true if the shunt amount
correlates not really with defect diameter.
The combination of an increased LVEDP with non-restrictive
ASD is mostly associated with a precapillary pulmonary
hypertension (PAH).
Therefore, children with an un-restrictive VSD develop in
almost 90 % a nearly fixed PAH already after an age of 2
years. The question rises, why such a pathophysiology does
not induce a 100 % irreversibility of PAH. A protective genetic disposition has to be postulated, which is not discovered
yet.
In the past, unrestrictive VSD’s were the main reason for
an Eisenmenger syndrome with a generalized full body
cyanosis caused by an intracardiac right-to-left shunt with
all the well-known long-term consequences.
The prognosis of such patients is limited, but better than
an idiopathic PAH without any atrial, ventricular or even
arterial communication.
74
Entirely different seems to be the situation of an adult
patient with PAH with systemic or even supra-systemic
pulmonary artery pressure, if primarily a restrictive, leftright shunting VSD was persistent. The question raises,
repair or no repair, and if repair by which technique and
perioperative strategy and if a so-called targeted drug therapy – as “treat and repair” strategy -– should be initialized.
whole, in particular on the atrial level, has to be closed;
patient’s survival might depend on persistence or
re-opening of such an atrial communication.
• Fourth, in case of PH with severe right-to-left ventricular
shunt and generalized cyanosis including coronary and
cerebral vessels, a surgical or percutaneous modification
of a VSD-type Eisenmenger-circulation to a PDA-type
might be postulated as beneficial for the patients.
Strategies
References
• At first, an exact diagnosis has to be performed by history, clinical examination, imaging and hemodynamic assessment.
• The most important hemodynamic assessments have to
be focused on the pulmonary to systemic diastolic artery
pressures (PAd/SAPd) ratio and the oxygen transport parameters.
• Second, the best pre-conditioning strategy has to be analyzed and applicated before and after repair surgery by
utilizing the mentioned “targeted therapy” with the goal
to influence the pulmonary vasculature or even the left
ventricular compliance, if restrictive.
• Third, it has to be carefully considered that not any
• Gorenflo M, Apitz C, Miera O, Stiller B, Schranz D, Berger F, Hager A,
Kaemmerer H. [Pulmonary hypertension/pulmonary arterial hypertension in congenital heart disease and therapy of pulmonary arterial
hypertension in children]. Dtsch Med Wochenschr. 2014 Dec; 139
Suppl 4: S166–70. doi: 10.1055/s-0034-1387491. Epub 2014 Dec 9.
• Latus H, Delhaas T, Schranz D, Apitz C. Treatment of pulmonary arterial
hypertension in children. Nat Rev Cardiol. 2015 Apr; 12(4): 244–54. doi:
10.1038/nrcardio.2015.6. Epub 2015 Feb 3
• Zimmermann R, Schranz D, Ewert P, Kaemmerer H. [Pulmonary arterial
hypertension in congenital heart defects with shunt: a heterogeneous
and complex constellation]. Dtsch Med Wochenschr. 2013 Jun; 138(23):
1244–6. doi: 10.1055/s-0033–1343187. Epub 2013 May 29.
75
The future of PAH treatment on the horizon
Prof. Dr. med. Stephan Rosenkranz
Dept. of Cardiology, Pulmonology, and Intensive Care Medicine
Center for Molecular Medicine Cologne (CMMC)
Cologne Cardiovascular Research Center (CCRC)
Heart Center at the University of Cologne
Cologne, Germany
Key points
Depite recent improvements, the treatment options for
pulmonary arterial hypertension (PAH) remain limited.
Recent advancements were mainly achieved by optimizing
and combining the currently established drug classes,
i.e. endothelin receptor antagonists, phosphodiesterase
type 5 inhibitors, and prostanoids. Current research aims
at identifying novel targets particularly attempting to
reverse pulmonary vascular remodeling, which include
FoxO transcrption factors and PI-3 kinase subunits such
as p110.
76
Although the establishment of current therapies for pulmonary arterial hypertension (PAH) such as prostanoids,
endothelin receptor antagonists (ERA), and phosphodiesterase type 5 inhibitors (PDE5i) has substantially improved
morbidity and mortality in affected patients, PAH remains a
devastating disease with reduced life expectancy, for which
there is no cure. At present, the main achievable treatment
goals include proper disease control, which involves stabilization at a reasonable hemodynamic and performance
level, ideally without or with only mild symptoms, and with
no signs of right heart failure or disease progression (1, 2).
Nevertheless, the majority of the patients remain symptomatic, disease progression is only delayed, and mortality
remains unacceptibly high, so that there is a high need to
further improve the treatment modalities in PAH.
Recent progress was mainly achieved by improving the current treatment strategies which are based on targeting the
prostacyclin, endothelin, and nitric oxide pathways,
Figure 1: Evolution of pulmonary arterial hypertension (PAH) trial design
respectively. To this end, novel compounds have been introduced such as the ERA macitentan (SERAPHIN study [3]),
the soluble guanylate cyclase (sGC) stimulator riociguat
(PATENT study [4]), and the prostacyclin receptor agonist
selexipag (GRIPHON study [5]), the latter awaiting regulatory approval. Collectively, the above studies have also demonstrated additive effects, when drugs targeting the three
pathways were applied in combination. In parallel with the
development of the above drugs, an evolution in trial design enabled investigators to capture the efficacy of PAH
therapies on composite morbidity and mortality endpoints, demonstrating a substantial reduction of such
events (3,5) (Figure 1). The AMBITION study particularly provided evidence that upfront combination therapy with an
ERA (ambrisentan) and a PDE5i (tadalafil) in patients with
newly diagnosed PAH was superior to either treatment
alone in preventing morbidity and mortality events (6).
Accordingly, current guidelines recommend the use of early
or even upfront combination therapy in patients with PAH
(1,2), but proper diagnosis and distinction of PAH from
other forms of PH, particularly PH due to heart failure with
preserved ejection fraction (HFpEF), are important (8).
A recent meta-analysis that included data from 4.095
patients enrolled in 17 trials provided reassurance that
disease control can be achieved in an increasing number
of patients and over longer periods of time, when combination therapies are utilized in PAH (7). Further studies
are needed to evaluate whether even more aggressive
approaches, i.e. triple combination, may be more efficient
than dual combination therapy, as suggested e.g. by a subgroup analysis from the GRIPHON study (5). In this context,
the TRITON study (clinicaltrials.gov identifier NCT02558231),
investigating the impact of selexipag versus placebo on
pulmonary vascular resistance in patients on dual combination therapy with macitentan and tadalafil, is currently
under way.
77
Figure 2: Catalytic class IA PI-3 kinase isoform p110α as a central target in pulmonary hypertension.
In addition to optimize the utilization of existing treatment
concepts either by developing novel compounds belonging
to the current three drug classes or by combining these
approaches, current research aims at identifying novel targets particularly attempting to reverse pulmonary vascular
remodeling. Currently, the efficacy and safety of an apoptosis-regulating kinase-1 (ASK-1) inhibitor are investigated
in a phase II study (ARROW; clinicaltrials.gov identifier
NCT02234141), which has already completed enrolement.
Pre-clinical studies have identified peptide growth factors
such as platelet-derived growh factor (PDGF) as important
contributors to pulmonary vascular remodeling in PH, and
PDGF inhibition by either pharmacological or genetic approaches was highly effective in reversing pulmonary vascular remodeling and PH (9,10). Consistently, the tyrosine
kinase inhibitor imatinib has proven effective at least in a
78
subset of patients with PAH in the phase III IMPRES study
(11), but will not be approved for this indication due to
safety concerns. Innovative new concepts focus on targets
acting downstream of multiple growth factors, including
Forkhead box O transcription factor-1 (FoxO1) and PI-3
kinase isoforms such as p110 (Figure 2) (12,13). However,
these concepts await further evaluation and transition to
human disease.
References
1. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62(Suppl D):
D60–D72.
2. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the
diagnosis and treatment of pulmonary hypertension: The Joint Task
Force for the Diagnosis and Treatment of Pulmonary Hypertension of
the European Society of Cardiology (ESC) and the European Respiratory
Society (ERS). Endorsed by: Association for European Paediatric and
Congenital Cardiology (AEPC), International Society for Heart and Lung
Transplantation (ISHLT). Eur Heart J 2016; 37: 67–119.
3. Pulido T, Adzerikho I, Channick RN, et al., for the SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. New Engl J Med 2013; 369: 809–818.
4. Ghofrani HA, Galiè N, Grimminger F, et al., for the PATENT Investigators.
Riociguat for the treatment of pulmonary arterial hypertension. N Engl J
Med 2013; 369: 330–340.
5. Sitbon O, Channick R, Chin KM, et al. GRIPHON Investigators. Selexipag
for the treatment of pulmonary arterial hypertension. N Engl J Med
2015; 373: 2522–2533.
6. Galiè N, Barbera JA, Frost A, et al. Initial use of Ambrisentan plus Tadalafil in pulmonary arterial hypertension. New Engl J Med 2015; 379:
834–844.
7. Lajoie AC, Lauzière G, Lega J-C, et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. Lancet
Respir Med 2016; [Epub ahead of print], published online Feb 26.
8. Rosenkranz S, Gibbs JSR, Wachter R, De Marco T, Vonk-Noordegraaf A,
Vachiéry JL. Left ventricular heart failure and pulmonary hypertension.
Eur Heart J 2016; 37: 942–954.
9. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental
pulmonary hypertension by PDGF inhibition. J Clin Invest 2005; 115:
2811–2821.
10. Ten Freyhaus H, Berghausen EM, Janssen W, et al. Genetic ablation of
PDGF-dependent signaling pathways abolishes vascular remodeling
and experimental pulmonary hypertension. Arterioscler Thromb Vasc
Biol 2015; 35: 1236–1245.
11. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on
therapy for pulmonary arterial hypertension: results of the randomized
IMPRES study. Circulation 2013; 127: 1128–1138.
12. Savai R, Al-Tamari HM, Sedding D, et al. Pro-proliferative and inflammatory signalling converge on FoxO1 transcription factor in pulmonary
hypertension. Nature Med 2014; 20: 1289–1299.
13. Berghausen EM, Janssen W, Vantler M, et al. p110 is a central target in
pulmonary hypertension. J Am Coll Cardiol 2014 (Abstract).
79
Electrophysiologic considerations in ACHD with heart failure
Prof. Dr. Dr. Karl-Heinz Kuck
Dept. of cardiology
Asklepios-Klinik St. Georg
Hamburg, Germany
Impact of ablation of ventricular tachycardia
in patients with congenital heart disease
Key points
• Ventricular tachycardia (VT) is the dominant cause for
morbidity and mortality in patients with congenital
heart disease (CHD) and repaired CHD.
• Treatment of these VTs by catheter ablation is highly
effective.
• Whether effective ablation of VTs in patients with CHD
and preserved right- and left-ventricular function can
be considered as an alternative to ICD-implantation
needs further evaluation.
80
In Europe as well as in the United States sudden cardiac
death is responsible for about 15 % of the total mortality
and 6 % of the annual mortality. Similar to patients with
an underlying ischemic or non-ischemic cardiomyopathy,
sudden cardiac death is also the dominant cause of mortality in patients with congenital heart disease (CHD) with an
incidence of 19–26 %. (1, 2) The life expectancy of patients
with CHD continuously increased over the last decades due
to improved surgical as well as interventional strategies
and techniques. Therefore, the majority of patients with
CHD reaches higher ages and consequently the prevalence
of SCD continuously increases. Ventricular tachycardia (VT)
is one of the major causes for morbidity and mortality in
patients with repaired and non-repaired CHD. The underlying substrate is mostly formed by anatomical or iatrogenic
post-surgical isthmuses. Ablation of those isthmuses using
three-dimensional mapping systems in conjunction with
radio-frequency catheters allows for effective treatment and
significant reduction of the VT-incidence or even complete
long-term suppression of the clinical VT. In a recently published study focusing on patients with VT after surgically
repaired CHD VT non-inducibility was achieved in 74 % of
patients after ablation and block of the identified isthmus. (3)
In addition, these patients were also free of recurrence of
the clinical VT during long-term follow-up. These encouraging results raise the question, if successful ablation of VTs
in patients with CHD and preserved right and left ventricular function might be considered as an alternative to ICD
implantation. However, in the future this question needs to
be answered by prospective, randomized studies.
References
1. Basso C, Frescura C, Corrado D, Muriago M, Angelini A, Daliento L,
Thiene G. Congenital heart disease and sudden death in the young.
Hum Pathol. 1995; 26: 1065–1072.
2. Verheugt CL, Uiterwaal CS, van der Velde ET, Meijboom FJ, Pieper PG,
van Dijk AP, Vliegen HW, Grobbee DE, Mulder BJ. Mortality in adult
congenital heart disease. Eur Heart J. 2010; 31: 1220–1229.
3. Kapel GF, Reichlin T, Wijnmaalen AP, Piers SR, Holman ER, Tedrow UB,
Schalij MJ, Stevenson WG, Zeppenfeld K. Re-entry using anatomically
determined isthmuses: a curable ventricular tachycardia in repaired
congenital heart disease. Circ Arrhythm Electrophysiol. 2015; 8: 102–9.
81
Efficacy of Antiarrhythmic Pharmacotherapy in ACHD
Dr. med. Joachim Hebe
Center f. Electrophysiology Bremen
Im Klinikum Links der Weser
Bremen, Germany
KEY POINTS
Antiarrhythmic medications represent an essential tool
in the acute and long-term treatment of tachyarrhythmias in adults with CHD, even in times of catheter interventions and antitachycardia devices. Application of
antiarrhythmic agents requires careful adaption to
pronounced limitations in hemodynamic tolerance and
cardiac function, which are frequently found in patients
with CHD. Antiarrhythmic drugs may be inserted as an
exclusive antiarrhythmic strategy or as an adjunct to
lower the arrhythmia burden in patients with ICD- or
incomplete ablative treatment.
Arrhythmias represent the most frequent cause for emergency unit admissions in adults with congenital heart
disease (CHD) (11, 12). Their prevalence increases with
aging and dominates morbidity and mortality of this population next to heart failure (19, 23, 27).
82
An extraordinary and burdensome variety of potential substrates are apparent.: they range from congenitally given
malformations of the sinus node or parts of the specific
conduction system, accessory atrioventricular connections,
to primary myocardial disease and injuries on myocardial
or cellular level as a result of hypoxaemia, dilatation, hypertrophy, as well as any type of postoperative sequelae and
genetics.
In the long-term course different subtypes of brady- and
tachyarrhythmias may coexist in patients with congenital
heart disease and mutually support arrhythmogenesis.
Approximately 50% of the patients with CHD older than
20 years will develop atrial tachycardia, essentially based
on alterations in intra-myocardial conduction, the most
common type of arrhythmia in adults with CHD (4). But the
initiation of such re-entry type tachycardia will be triggered
i.e. by focal atrial automaticity, as a result of inadaequate
sinus bradycardia. By aging of the population, atrial fibrillation already represents an increasingly demanding focus
for antiarrhythmic treatment. Furthermore in the future the
prevalence of atrial fibrillation will grow as expected (17).
Fig. 1: Schematic view to antiarrhythmic
options with regard to substrates and
therapeutical targets
Fig. 2: Schematic view to different timespan of antiarrhythmic medication i.e. in
a patient with surgery for CHD, dividing
acute (< 48 hrs), mid-term (< 6 mths) and
long-term treatment (> 6 mths) as a basis
for adaequate selection of the treatment
option.
Fig. 3: Different roles of antiarrhythmic
drug treatment with regard to prognostic
relevance of the arrhythmia and “teamplay” with device- or interventional treatment options
Despite of relatively rare absolute
numbers, ventricular arrhythmias
provide another demanding objective
for treatment, as hemodynamic consequences are known to be high and are
likewise recognized for being the leading cause of sudden death in diverse
types of CHD (19).
Antiarrhythmic treatment in general
is needed for most patients with CHD,
mainly due to a lower hemodynamic
compensation, but selecting of a proper strategy is often challenging as it
needs to be individualized since
conflictive arrhythmia problems may
coexist.
Amongst all available strategies, antiarrhythmic medications still represent the primary treatment for most
tachyarrhythmias, however, the acute
and especially the long term use of
such drugs may lead to severe and
intolerable adverse effects due to both
inherent abnormalities of the conduction system and an impaired systemic ventricular function.
Despite such limitations, antiarrhythmic drugs still represent an essential
role for the termination of tachycardias
or for rate control in the acute setting.
Not any less frequent they are also applied as an adjunct therapy for interventional electrophysiology or device
treatment, to corporately minimize
the risk for arrhythmia recurrences.
While in recent years catheter ablation
is superior in eliminating circumscribed substrates and ICDs sufficiently
terminate devastating ventricular tachycardia, antiarrhythmic agents carry
83
the potential of a global stabilizing impact on the myocardium
and hence potentially lowering the arrhythmia burden.
For systematic reasons, the use of antiarrhythmic medications must be assorted according to its timing, i.e. acute
setting, mid-, long-term administration and according to
the targeted substrate, mechanism and arrhythmia type,
i.e. atrial or ventricular level, AV-nodal or atrioventricular
tachycardia, focal automaticity, re-entry or fibrillation.
Last but not least, distinction between symptoms related
to treatment or targeting prognostic relevant arrhythmias
is pathbreaking for the selection of a proper antiarrhythmic
strategy.
The role of pharmacologic treatment of tachyarrhythmias
in conjunction with other treatment options has recently
been summarized in the “PACES/HRS Expert Consensus
Statement on the Recognition and Management of
Arrhythmias in Adults Congenital Heart Disease” (14).
is unpredictably high, especially when treating a long lasting
or permanent tachycardia.
There is few data about the use of ibutilide in children and
adults with CHD for the conversion of atrial tachycardia and
atrial fibrillation, showing a high success rate of 71 % and a
low rate of complication but of severe quality. One patient
of a series with 74 patients developed torsades de pointes
tachycardias while another patient developed non-sustained ventricular tachycardias (10).
Sotalol had a 84 % conversion rate of IART and focal atrial
tachycardia in another series, but with some patients
requiring acute pacing for severe sinus bradycardia (22).
In comparison to ibutilide, sotalol causes more hypotension and bradycardia, but the risk for torsade des pointes
was seen as high as 4.3 % in a series investigating the
efficacy of ibutilide in patients without CHD (17). Data in
patients with CHD are missing about the efficacy and safety
for the use of Class IA, IC or other Class III agents like i. e.
amiodarone in the acute setting aiming to convert IART or
atrial fibrillation.
Supraventricular/Atrial tachyarrhythmia
Acute termination
AV-node-dependant supraventricular tachycardia, if a vagal
manoeuver fails, can be terminated by i.v. administration
of adenosine or nondihidropyridine calcium channel
anatgonists (verapamil, diltiazem) (3). For pharmacologic
conversion of atrial reentrytachycardias or fibrillation data
and recommendations from literature are rare. General concerns are about risks for pro-arrhythmia, such as torsades
de pointes with the use of Class III agents and ventricular
tachycardia with the use of Class IA and IC drugs. For adults
predisposed to sinus node dysfunction, the risk for significant sinus bradycardia following drug-mediated conversion
84
Long-term medication
It is well recognized, that for patients with CHD, pharmacologic antiarrhythmic treatment is discouraging on the longterm perspective, regarding declining efficacy by time and
the increasing risk of side effects. Nevertheless, its longterm use is inevitable for arrhythmias/substrates, which
are not amenable for catheter ablation or just at the price of
an unpredictable but high risk.
Targets of such antiarrhythmics can be divided into controlling the ventricular rate (“rate control”) or stabilizing sinus
rhythm and preventing arrhythmia recurrences (“rhythm
control”).
Rate control
Whenever conversion into or stabilization of sinus rhythm
fails, the control of the ventricular heart rate aims to
prevent aggravation of pre-existing heart failure or even
sudden cardiac death as a potential consequence of fast
conducted atrial tachycardia/fibrillation. In less complex
forms of CHD, tachycardia related symptoms can be attenuated, exercise capacity might be improved and cardiac
function can be preserved.
For long-term prevention of arrhythmia recurrences flecainide, propafenone and sotalol are considered to be
favourable, but increased mortality has been shown in
normal heart patients with heart failure or with ventricular
scarring following infarction (6, 25).
Analogue to this an increased all cause mortality has been
observed while treating atrial fibrillation with the use of
Class IA drugs (quinidine, disopyramide), which led to the
recommendation to avoid Class I drugs in patients with co-
Management guidelines from normal heart patient cohorts
suggest a maximum heart rate at rest of 100 bpm, but data
from patients with CHD, especially from complex CHD, like
i.e. univentricular hearts, are missing (24).
ronary artery disease and heart failure (1, 18). Despite the
lack of data from adults with CHD, such experiences need to
be transcribed with all appropriate caution to this patients
cohort, as adults with CHD frequently have a long lasting
hemodynamic disturbance as well as myocardial scarring
and fibrosis resulting from cyanosis or surgery, thereby
presumably increasing the risk for potentially fatal proarrhythmia with the use of Class I agents.
Recommended drugs in general for rate control are ß-blockers
as well as nondihhydropyridine calcium channel antagonists (verapamil, diltiazem). Digoxin is controversal
for its potential for lethal complications. In patients with
atrial redirection surgery of the Mustard or Senning-type for
d-transposition of the great arteries, the use of ß-blockers
is recommended, as additionally a decrease of ventricular
arrhythmias could be shown (15).
In case of preexcitation, administration of digoxin or verapamil/diltiazem needs to be avoided, as it increases the
risk for fatal ventricular arrhythmia due to accelerated atrioventricular conduction in case of fast atrial arrhythmias,
like atrial fibrillation.
Rhythm control
Maintenance of sinus rhythm represents the preferred management target in contrast to rate control, but prospective
data about the outcome of both strategies in patients with
CHD are missing.
One of the few existing studies regarding this purpose in
adult CHD patients showed a nearly two-fold increased
risk for ventricular arrhythmias in patients with tetralogy
of Fallot under Class I antiarrhythmic drug therapy (16).
There is conflictive data about the use of sotalol in children
and adults with CHD and atrial tachycardia. The range goes
from reasonable efficacy and safety in some series towards
low efficacy and high rates of proarrhythmia in others,
presumed involvement of generally accepted exclusion
criteria for the use of Class III agents, like a prolonged
QT-interval (2, 21).
Amongst all antiarrhythmic agents, amiodarone has the
highest potential for rhythm control in patients with many
types of tachyarrhythmias like focal atrial automaticity,
atrial reentrytachycardia, atrial fibrillation and various
arrhythmias on the ventricular level. But well-known time-
85
and dose-related side effects, especially in young adults
are limiting its broad use. Young women with cyanotic heart
disease or univentricular hearts with Fontan palliation are
prone to amiodarone-induced thyreotoxicosis (26).
Despite these limitations, amiodarone still may be considered as a first line therapy in adults with CHD in the
presence of impaired ventricular function, ventricular
hypertrophy or coronary artery disease as alternative drugs
with reliable efficacy are missing.
More modern Class III agents like dronedarone, an amiodarone analog without iodine elements or dofetilide, a selective inhibitor of the delayed rectifier potassium current,
are less effective i.e. in the suppression of atrial fibrillation
recurrences and carry an increased risk for stroke and
cardiovascular mortality, especially in patients with heart
failure or after myocardial infarction (5). Further limitations
are related to the need of unrestrained functions of liver
(dronedarone) and kidneys, to minimize the drug induced
risk for torsades de pointes tachycardia (dofetilide) (20).
Recent data suggest a relatively safe and effective use of
dofetilide in adults with CHD for the treatment of atrial
tachycardias, when initiation of therapy is controlled by
close monitoring of the QTc-interval and an according
adapted dosage (1).
86
Ventricular tachyarrhythmia
(prognostic relevant)
Acute termination
In case of a hemodynamic stable ventricular tachycardia
and if the primary use of an electrical cardioversion might
not be favoured, i.v. application of amiodarone, lidocaine
and procainamide is recommended. Significant hypotension can be a severe side effect with the use of amiodarone
and procainamide. Lidocaine is known to be more effective
in ventricular arrhythmias originating from ischaemic myocardium, whereas procainamide is superior in monomorphic macro-reentry tachycardias as seen in repaired tetralogy of Fallot.
In case of augmented automaticity or triggered activity
adenosine or calcium antagonists might be of help,
especially as electrical cardioversion is expected to be
ineffective in terminating such autonomous mechanism.
Long-term management
For ventricular arrhythmias, classified as prognostic irrelevant, indication for antiarrhythmic drug treatment with all
its inert limitations should be carefully outweighed against
the potential benefits. If treatment is targeting disturbing
symptoms or is aiming to reduce the risk for an arrhythmia-
References
induced impairment of the systemic ventricular function,
the use of ß-blockers is widely accepted due to its universal effects on myocardial function and electrical stability.
For prognostic relevant ventricular arrhythmias or for
the secondary prevention of sudden cardiac death in
adults with CHD, the ICD represents the first-line therapy,
analogous to normal heart patients. In such such case
antiarrhythmic drugs are used aiming to reduce the risk of
arrhythmia recurrences and subsequent ICD discharges.
There are only a few small series existing with this regard
in patients with CHD showing favourable outcomes with
mexiletine and phenytoin (9), sotalol and amiodarone (7).
In patients with drug-refractory ventricular tachycardia
mexiletine might be added to amiodarone according a
retrospective study for the reduction of ICD shocks (8).
The prognostic beneficial impact of ß-blocking agents and
amiodarone, as a general therapeutic aspect, was not
shown in prospective data in adults with CHD so far, but is
conjectural analogous to adults with ischemic cardiomyopathy or those with severely reduced cardiac function resulting from primarily dilated cardiomyopathy.
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2. Beaufort-Krol GC, et al. Sotalol for atrial tachycardias after surgery for
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7. Furushima Het al. J Electro- cardiol 2006; 39: 219–224
8. Gao D, et al. J Cardiovasc Pharmacol 2013; 62: 199–204.
9. Garson A Jr, et al. Control of late postoperative ventricular arrhythmias
with phenytoin in young patients. Am J Cardiol 1980;46:290–294.
10. Hoyer AWet al. The safety and efficacy of ibutilide in children and in
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11. Kaemmerer H, et al. Emergency hospital admissions and three- year
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12. Kaemmerer H, et al. Management of emergencies in adults with congenital cardiac disease. Am J Cardiol 2008; 101: 521–525.
13. Khairy P, et al. Arrhythmia burden in adults with surgically repaired
tetralogy of Fallot: a multi-institutional study. Circulation 2010; 122:
868–875.
14. Khairy P, et al. Heart Rhythm 2014; 11: e102-e165
15. Khairy P, et al. Sudden death and defibrillators in transposition of
the great arteries with intra-atrial baflles: a multicenter study. Circ Arrhythm Electrophysiol 2008; 1: 250–257.
16. Khairy P, et al. Implantable cardioverter-defibrillators in tetralogy of Fallot. Circu- lation 2008; 117: 363–370.
17. Kowey PR, et al. Safety and risk/benefit analysis of ibutilide for acute
conversion of atrial fibrillation/flutter. Am J Cardiol 1996; 78: 46–52.
18. Lafuente-Lafuente C, et al. Antiarrhythmics for maintaining sinus
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disease. Am J Cardiol 2000; 86: 1111–1116.
20.Pedersen OD et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish
investigations of arrhythmia and mortality on dofetilide (DIAMOND)
substudy. Circulation 2001; 104: 292–296.
21. Pfammatter JP, et al. Efficacy and proarrhythmia of oral sotalol in pediatric patients. J Am Coll Cardiol 1995; 26: 1002–1007.
22.Rao SO, et al. Atrial tachycardias in young adults and adolescents with
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24.Skanes AC, et al. Focused 2012 update of the Canadian Cardiovascular
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87
Sudden death in ACHD: Risk stratification
Johan Holm MD, PhD
Associate professor
Skane University Hospital
Department of Heart failure and valvular heart disease
Lund University
Lund, Sweden
Introduction to the population
KEY POINTS
• Survival into adulthood after surgery for congenital
heart disease is increasing over the years, and today
90 % of the patients reach adult age. As the ACHD
population age increase, we have to deal with late
complications such as heart failure, arrhythmia and
sudden death.
• Sudden death (SD) is a very small part of total mortality (7–19 %), but still higher than in the ordinary population. Several mortality studies have been published,
but also studies trying to identify risk markers for SD.
• In 2014 an expert consensus document was published
by PACES/HRS (4) with recommendations for management of arrhythmias in congenital heart disease.
• Correct selection of high-risk patients for ICD is crucial,
as ICD in young ACHD patients is problematic with
more inappropriate shocks.
88
Median age of adults with congenital heart disease (ACHD)
in a tertiary centre in the Swedish SWEDCON registry is
37.5 years with a majority between 20 and 30 years. The
number of adult patients increases with roughly 10 % per
year. The incidence of arrhythmia increases in the third
decade of life.
Factors leading to arrhythmia in ACHD
Surgery for congenital heart disease is often palliative with
residual lesions. This provides an arrhythmia substrate
with decreased myocardial function from volume or pressure overload, early cyanosis before correction, and not the
least myocardial scarring from surgery that may provide reentry circuits.
A combination of ventricular dysfunction, arrhythmia substrate and residual lesions contribute to the risk of sudden death (SD). The complexity of lesions makes it hard to
pinpoint single risk markers. The earliest studies have
been made on tetralogy of Fallot where QRS duration is associated with risk of SD. Coronary problems may be part of
a congenital heart defect, but also superimposed by ischemic heart disease over time.
Risk factors after repair of tetralogy of Fallot
Older age at at time of repair
Longer duration of follow-up since repair
History of syncope
Severe pulmonary regurgitation
Severe RV enlargement
Moderate to severe RV dysfunction
Extensive RV fibrosis/scarring
Moderate to severe LV dysfunction
QRS duration < 180 ms
Non-sustained VT on Holter monitoring
History of atrial tachycardia
Inducible VT at EP study
Table 2 (Walsh E P Heart Rhytm 2014; 11: 1735–1742)
Risk factors after Mustard Senning atrial correction
Longer duration of follow-up
History of syncope or palpitations
Atrial tachycardia
Depressed systemic ventricular function
Table 1 (Walsh E P Heart Rhytm 2014; 11: 1735–1742)
Risk factors in LV outflow obstruction
Longer duration of follow-up
History of repeated syncope
Outflow gradient > 50 mmHg
Aortic regurgitation
High LV end-diastolic pressure
Depressed LV function
Severe LV hypertrophy
Risk factors for SD in ACHD
Not surprisingly, the risk of SD is highest in patients with
systemic right ventricle after Senning- or Mustard-type operation for transposition of the great arteries; left ventricular
outflow obstruction (aortic stenosis or coarctation); and
tetralogy of Fallot. It should however be kept in mind that
any heart defect with residual lesions or poor myocardial
function may have high risk of SD. Symptoms, hemodynamic evaluation, and cardiac function by echo or MRI are key
parameters in every patient.
Tetralogy of Fallot
Risk factors for SD are listed below (5). It is important to remember that individual risk factors are indeed common,
e.g. non-sustained VT, and do not alone predict SD, and
they should rather be used in combination.
TGA – after Mustard- / Senning-type operation
The patients with atrial correction suffer from a right ventricle
in systemic position with increasing risk of ventricular dysfunction, AV valve regurgitation and heart failure with age.
There is also a risk of atrial arrhythmias from extensive scarring that may trigger ventricular arrhythmia. Finally, sick
sinus bradycardia is common and should not be overlooked.
Left sided outflow obstruction
Many of these patients have reduced LV function after multiple
surgeries for aortic stenosis during childhood or residual
stenosis. There is often diastolic dysfunction with elevated
pulmonary pressures from myocardial fibrosis. Systemic
hypertension is common in patients with operated coarctation and may rise to dangerous levels during exercise.
Table 3 (Walsh E P Heart Rhytm 2014; 11: 1735–1742)
Mortality and survival in ACHD
Overall mortality in ACHD is 0,75 % yearly and in a Swedish
material median age at death 61 years. In a recent single
centre retrospective study (1) 6969 ACHD patients had increased mortality (524 deaths) compared to controls, with
chronic heart failure as a leading cause of death (40 %). SD
comprised 7 %, which is lower than in previous studies with
a yearly incidence of 0.1 %. Highest mortality was among
patients with complex ACHD, Fontan physiology and Eisenmenger syndrome. In an earlier multicentre study (2), 19 %
of the patients died suddenly.
Risk factors for SD in a multivariate analysis were supraventricular tachycardia, systemic ventricular dysfunction,
subpulmonary ventricular dysfunction, increased QRS duration and QT dispersion. Interestingly, only 10 % of those
who suffered SD died during physical exercise, which therefore should not be discouraged at an individualised level.
Even in simple heart defects operated in the sixties such as
ASD, PDA and VSD there is an increased risk of SD after the
age of 35 as shown in a Danish cohort study (3).
Conclusion
The risk of SD increases with age in ACHD patients.
Risk stratification involves thorough investigation of haemodynamic and myocardial function. Several risk factors
have been identified in large trials, but must be used in
combination and individualized. Ventricular function
stands out as a major risk factor, but surgical history and
presence of any arrhythmia is important
References
1. Diller G-P et al Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up
at a large tertiary centre. Circulation 2015; 132: 2118–2125.
2. Koyak Z et al Sudden cardiac death in adult congenital heart disease.
Circulation 2012; 126: 1944–1954.
3. Videbaek J et al Long-term nationwide follow-up study of simple congenital heart disease diagnosed in otherwise healthy children. Circulation 2016; 133: 474–483.
4. Khairy P et al PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease.
Can J of Cardiol 2014; 30: e1–e63.
5. Walsh E P Sudden death in adult congenital heart disease:
Risk stratification in 2014. Heart Rhytm 2014; 11: 1735–1742.
89
Device Therapy: Indications and Future Aspects in Primary
Prevention of Cardiac Death
Prof. Dr. med. Christof Kolb
Deutsches Herzzentrum München
Klinik für Herz- und Kreislauferkrankungen
Abteilung für Elektrophysiologie
Munich, Germany
KEY POINTS
Secondary prevention of sudden cardiac death and ICD
implantation in ACHD focuses on patients after aborted
cardiac arrest or symptomatic ventricular tachycardia.
In primary prevention of sudden cardiac death major
criteria for ICD placement are a reduced ejection fraction
of the systemic ventricle or the presence of multiple,
specific risk factors in patients with tetralogy of Fallot.
Conventional, transvenous ICD therapy is burdened by an
increased risk for lead complications and inappropriate
therapies in ACHD.
Whether new technologies such as the entirely subcutaneous ICD or leadless pacemakers reduce device associated morbidity in ACHD still needs to be assessed.
90
Sudden cardiac death is prevalent in adults with congenital
heart disease (ACHD) (1).
Risk stratification, however, is complex and hampered by
limited numbers of patients available for clinical trials and
a variety of sometimes rare entities required to be covered.
Available data are usually derived from prospective registries or retrospective analyses lacking randomization. Therefore, ICD implantation in ACHD for many years has been
limited to indications related to secondary prevention of
sudden cardiac death. These patients have early been perceived as high risk patients and the effectiveness of ICD
has been shown (2-4).
The current guidelines recommend the placement of an ICD
in survivors of aborted cardiac arrest in the absence of a reversible cause or in patients having experienced symptomatic sustained VT if hemodynamic and electrophysiological evaluation and optimization has been performed (5).
ICD placement for primary prevention of sudden cardiac
death in ACHD previously has been directed in many instances by individual considerations and beliefs. Recently published data, however, provide evidence for the usefulness
of ICD in ACHD presenting with a systemic ejection fraction
<35%, biventricular physiology and symptomatic heart failure (NYHA II or III) despite optimal medical therapy notably
References
in patients with transposition complexes (5,6).
In patients with tetralogy of Fallot an ICD should be considered for primary prevention of sudden cardiac death if
multiple risk factors such as left ventricular dysfunction,
non-sustained VT, QRS duration >180 ms or inducible ventricular tachycardias are present (2,5,7).
Despite of the potential benefits of ICD downsides of the
therapy need to be considered when recommendations are
made to the patient. Children and young adults are at an
increased risk for lead failure and insulation breaks, vascular problems and infections (5,8) and inappropriate therapies due to sinus tachycardia, supraventricular arrhythmias
and oversensing are not uncommon (8,9).
New technologies such as the entirely subcutaneous defibrillator are expected to alleviate problems associated with
intravascular leads and for the first time offer a minimal invasive approach to the protection of patients with Eisenmenger syndrome.
The recently introduced leadless pacemakers offer new options in antibradycardia pacing and may be combined with
the subcutaneous ICD in the future.
It remains to be determined, however, which of the available pacing and defibrillator systems is the most suitable for
each of the individual patients.
1. Diller GP, Kempny A, Alonso-Gonzalez R et al. Survival prospects and
circumstances of death in contemporary adult congenital heart disease
patients under follow-up at a large tertiary centre. Circulation 2015; 132:
2118–25.
2. Khairy P, Harris L, Landzberg MJ, et al. Implantable cardioverter-defibrillators in tetralogy of Fallot. Circulation 2008; 117: 363–70.
3. Khairy P, Harris L, Landzberg MJ et al. Sudden death and defibrillators
in transposition of the great arteries with intra-atrial baffles: a multicenter study. Circ Arrhythm Electrophysiol 2008; 1: 250–7.
4. Berul CI, Van Hare GF, Kertesz NJ et al. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and
congenital heart disease patients. J Am Coll Cardiol 2008; 51: 1685–1691.
5. Priori SG, Blomström-Lundqvist C, Mazzanti A et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and
the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of
Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36: 2793–867.
6. Gallego P, Gonzalez AE, Sanchez-Recalde A et al. Incidence and predictors of sudden cardiac arrest in adults with congenital heart defects
repaired before adult life. Am J Cardiol 2012; 110: 109–117.
7. Gatzoulis MA, Balaji S, Webber SA et al. Risk factors for arrhythmia and
sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet 2000; 356: 975–981.
8. Vehmeijer JT, Brouwer TF, Limpens J et al. Implantable cardioverter-defibrillators in adults with congenital heart disease: a systematic review
and meta-analysis. Eur Heart J 2016 Feb 11. pii: ehv735. [Epub ahead
of print]
9. Eicken A, Kolb C, Lange S et al. Implantable cardioverter defibrillator
(ICD) in children. Int J Cardiol 2006; 107: 30–5.
91
Imprint
Herausgeber
Deutsches Herzzentrum München
Klinik für angeborene Herzfehler
und Kinderkardiologie
Klinik an der Technischen
Universität München
Lazarettstraße 36 · 80636 München
92
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