ACC/ESC EXPERT CONSENSUS DOCUMENT
American College of Cardiology/
European Society of Cardiology Clinical Expert
Consensus Document on Hypertrophic Cardiomyopathy
A Report of the American College of Cardiology Foundation
Task Force on Clinical Expert Consensus Documents and the
European Society of Cardiology Committee for Practice Guidelines
WRITING COMMITTEE MEMBERS
BARRY J. MARON, MD, FACC, FESC, Co-Chair
WILLIAM J. MCKENNA, MD, FACC, FESC,* Co-Chair
GORDON K. DANIELSON, MD, FACC
LUKAS J. KAPPENBERGER, MD, FACC, FESC*
HORST J. KUHN, MD, FESC*
CHRISTINE E. SEIDMAN, MD
*Official representatives of the European Society of Cardiology
PRAVIN M. SHAH, MD, MACC
WILLIAM H. SPENCER, III, MD, FACC
PAOLO SPIRITO, MD, FACC, FESC*
FOLKERT J. TEN CATE, MD, PHD, FACC, FESC*
E. DOUGLAS WIGLE, MD, FACC
ACCF TASK FORCE ON CLINICAL EXPERT CONSENSUS DOCUMENTS MEMBERS
ROBERT A. VOGEL, MD, FACC, Chair
JONATHAN ABRAMS, MD, FACC
ERIC R. BATES, MD, FACC
BRUCE R. BRODIE, MD, FACC*
PETER G. DANIAS, MD, PHD, FACC*
GABRIEL GREGORATOS, MD, FACC
MARK A. HLATKY, MD, FACC
JUDITH S. HOCHMAN, MD, FACC
*Former members of Task Force; †Former Chair of Task Force
SANJIV KAUL, MBBS, FACC
ROBERT C. LICHTENBERG, MD, FACC
JONATHAN R. LINDNER, MD, FACC
ROBERT A. O’ROURKE, MD, FACC†
GERALD M. POHOST, MD, FACC
RICHARD S. SCHOFIELD, MD, FACC
CYNTHIA M. TRACY, MD, FACC*
WILLIAM L. WINTERS, JR, MD, MACC*
ESC COMMITTEE FOR PRACTICE GUIDELINES MEMBERS
WERNER W. KLEIN, MD, FACC, FESC, Chair
SILVIA G. PRIORI, MD, PHD, FESC, Co-Chair
ANGELES ALONSO-GARCIA, MD, FACC, FESC
CARINA BLOMSTRO¨M-LUNDQVIST, MD, PHD,
FESC
GUY DE BACKER, MD, PHD, FACC, FESC
JAAP DECKERS, MD, FESC
MARKUS FLATHER, MD, FESC
JAROMIR HRADEC, MD, FESC
ALI OTO, MD, FACC, FESC
ALEXANDER PARKHOMENKO, MD, FESC
SIGMUND SILBER, MD, PHD, FESC
ADAM TORBICKI, MD, FESC
TABLE OF CONTENTS
Preamble........................................................................................2
Introduction ..................................................................................2
General Considerations and Perspectives .....................................2
Nomenclature, Definitions, and Clinical Diagnosis.....................3
Obstruction to LV Outflow..........................................................3
Genetics and Molecular Diagnosis ...............................................4
General Considerations for Natural History
and Clinical Course ......................................................................6
When citing this document, the American College of Cardiology Foundation and the
European Society of Cardiology would appreciate the following citation format:
Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE,
Shah PM, Spencer WH, Spirito P, Ten Cate FJ, Wigle ED. ACC/ESC clinical
expert consensus document on hypertrophic cardiomyopathy: a report of the Amer-
ican College of Cardiology Task Force on Clinical Expert Consensus Documents and
the European Society of Cardiology Committee for Practice Guidelines (Committee
to Develop an Expert Consensus Document on Hypertrophic Cardiomyopathy).
J Am Coll Cardiol 2003;42:page-page.
Copies: This document is available on the Web sites of the ACC at www.acc.org
and ESC at www.escardio.org. Single copies of this document are available by calling
800-253-4636 (US only) or writing the American College of Cardiology Foundation,
Resource Center, 9111 Old Georgetown Road, Bethesda, MD 20814-1699 as well as
by calling or writing ESC Guidelines–Reprints, Elsevier Publishers Ltd., 32 James-
town Road, London, NW17BY, United Kingdom (Tel: �44.207.424.4422; Fax:
�44.207.424.4433; Email: gr.davies@elsevier.com.
Journal of the American College of Cardiology Vol. 42, No. 9, 2003
© 2003 by the American College of Cardiology Foundation and the European Society of Cardiology ISSN 0735-1097/03/$30.00
Published by Elsevier Inc. doi:10.1016/S0735-1097(03)00941-0
Symptoms and Pharmacological Management Strategies ............7
Treatment Options for Drug-Refractory Patients .....................11
Additional Approaches to Relieve Outflow Obstruction
and Symptoms.............................................................................12
Sudden Cardiac Death................................................................16
Atrial Fibrillation ........................................................................20
PREAMBLE
This document has been developed as a Clinical Expert
Consensus Document (CECD), combining the resources of
the American College of Cardiology Foundation (ACCF)
and the European Society of Cardiology (ESC). It is
intended to provide a perspective on the current state of
management of patients with hypertrophic cardiomyopathy.
Clinical Expert Consensus Documents are intended to
inform practitioners, payers, and other interested parties of
the opinion of the ACCF and the ESC concerning evolving
areas of clinical practice and/or technologies that are widely
available or new to the practice community. Topics chosen
for coverage by expert consensus documents are so designed
because the evidence base, the experience with technology,
and/or the clinical practice are not considered sufficiently
well developed to be evaluated by the formal American
College of Cardiology/American Heart Association (ACC/
AHA) Practice Guidelines process. Often the topic is the
subject of considerable ongoing investigation. Thus, the
reader should view the CECD as the best attempt of the
ACC and the ESC to inform and guide clinical practice in
areas where rigorous evidence may not yet be available or the
evidence to date is not widely accepted. When feasible,
CECDs include indications or contraindications. Some
topics covered by CECDs will be addressed subsequently by
the ACC/AHA Practice Guidelines Committee.
The Task Force on Clinical Expert Consensus Docu-
ments makes every effort to avoid any actual or potential
conflicts of interest that might arise as a result of an outside
relationship or personal interest of a member of the writing
panel. Specifically, all members of the writing panel are
asked to provide disclosure statements of all such relation-
ships that might be perceived as real or potential conflicts of
interest to inform the writing effort. These statements are
reviewed by the parent task force, reported orally to all
members of the writing panel at the first meeting, and
updated as changes occur.
Robert A. Vogel, MD, FACC
Chair, ACCF Task Force on Clinical Expert
Consensus Documents
Werner W. Klein, MD, FACC, FESC
Chair, ESC Committee for Practice Guidelines
INTRODUCTION
Organization of committee and evidence review. The
Writing Committee consisted of acknowledged experts in
hypertrophic cardiomyopathy (HCM) representing the
American College of Cardiology Foundation and the Eu-
ropean Society of Cardiology. Both the academic and
private practice sectors were represented. The document was
reviewed by 2 official reviewers nominated by the ACCF, 3
official reviewers nominated by the ESC, 12 members of the
ACCF Clinical Electrophysiology Committee, and 4 addi-
tional content reviewers nominated by the Writing Com-
mittee. The document was approved for publication by the
ACCF Board of Trustees in August 2003 and the Board of
ESC in July 2003. This document will be considered current
until the Task Force on Clinical Expert Consensus Docu-
ments revises or withdraws it from distribution. In addition
to the references cited as part of this document, a compre-
hensive bibliography including relevant, supplementary ref-
erences is available on the ACCF and ESC websites.
Purpose of this Expert Consensus Document. Hypertro-
phic cardiomyopathy is a complex and relatively common
genetic cardiac disorder (about 1:500 in the general adult
population) (1) that has been the subject of intense scrutiny
and investigation for over 40 years (2–15). Hypertrophic
cardiomyopathy affects men and women equally and occurs
in many races and countries, although it appears to be
under-diagnosed in women, minorities, and under-served
populations (16–20).
Hypertrophic cardiomyopathy is a particularly common
cause of sudden cardiac death (SCD) in young people
(including trained athletes) (21–29) and may cause death
and disability in patients of all ages, although it is also
frequently compatible with normal longevity (30–35). Be-
cause of its heterogeneous clinical course and expression
(7,36–42), HCM frequently presents uncertainty and rep-
resents a management dilemma to cardiovascular specialists
and other practitioners, particularly those infrequently en-
gaged in the evaluation of patients with this disease.
Furthermore, with the recent introduction of novel treat-
ment strategies targeting subgroups of patients with HCM
(7,43–49), controversy is predictable, and difficult questions
periodically arise. Consequently, it is now particularly timely
to clarify and place into perspective those clinical issues
relevant to the rapidly evolving management for HCM.
GENERAL CONSIDERATIONS AND PERSPECTIVES
This clinical scientific statement represents the consensus of
a panel of experts appointed by the ACC and ESC. The
writing group is comprised of cardiovascular specialists and
molecular biologists, each having extensive experience with
HCM. The panel focused largely on the management of
this complex disease and derived prudent, practical, and
contemporary treatment strategies for the many subgroups
of patients comprising the broad HCM disease spectrum.
Because of the relatively low prevalence of HCM in general
cardiologic practice (50), its diverse presentation, and mech-
anisms of death and disability and skewed patterns of
patient referral (7,11,13,36–38,42,51–59), the level of evi-
2 Maron and McKenna et al. JACC Vol. 42, No. 9, 2003
ACC/ESC Expert Consensus Document on Hypertrophic Cardiomyopathy November 5, 2003:000–000
dence governing management decisions for drugs or devices
has often been derived from non-randomized and retrospec-
tive investigations. Large-scale controlled and randomized
study designs, such as those that have provided important
answers regarding the management of coronary artery dis-
ease (CAD) and congestive heart failure (60–62), have
generally not been available in HCM as a result of these
factors. Therefore, treatment strategies have necessarily
evolved based on available data that have frequently been
observational in design, sometimes obtained in relatively
small patient groups, or derived from the accumulated
clinical experience of individual investigators, and reason-
able inferences drawn from other cardiac diseases. Conse-
quently, the construction of strict clinical algorithms de-
signed to assess prognosis and dictate treatment decisions
for all patients has been challenging and has not yet
achieved general agreement. In some clinical situations,
management decisions and strategies unavoidably must be
individualized to the particular patient.
Understanding of the molecular basis, clinical course, and
treatment of HCM has increased substantially in the last
decade. In particular, there has been a growing awareness of
the clinical and molecular heterogeneity characteristic of
this disorder and the many patient subgroups that inevitably
influence considerations for treatment. Some of these man-
agement strategies are novel and evolving, and this docu-
ment cannot, in all instances, convey definitive assessments
of their role in the treatment armamentarium. Also, for
some uncommon subsets within the broad disease spectrum,
there are little data currently available to definitively guide
therapy. With these considerations in mind, the panel has
aspired to create a document that is not only current and
pertinent but also has the potential to remain relevant for
many years.
NOMENCLATURE,
DEFINITIONS, AND CLINICAL DIAGNOSIS
The clinical diagnosis of HCM is established most easily
and reliably with two-dimensional echocardiography by
demonstrating left ventricular hypertrophy (LVH) (typically
asymmetric in distribution, and showing virtually any diffuse
or segmental pattern of left ventricular [LV] wall thicken-
ing) (36). Left ventricular wall thickening is associated with
a nondilated and hyperdynamic chamber (often with systolic
cavity obliteration) in the absence of another cardiac or
systemic disease (e.g., hypertension or aortic stenosis) capa-
ble of producing the magnitude of hypertrophy evident, and
independent of whether or not LV outflow obstruction is
present (1,5,7,36). Although the usual clinical diagnostic
criteria for HCM is a maximal LV wall thickness greater
than or equal to 15 mm, genotype-phenotype correlations
have shown that virtually any wall thickness (including those
within normal range) are compatible with the presence of a
HCM mutant gene (6,17,19,63–65). Mildly increased LV
wall thicknesses of 13 to 14 mm potentially due to HCM
should be distinguished from certain extreme expressions of
the physiologically-based athlete’s heart (66–68). The ad-
vent of contemporary magnetic resonance imaging that
provides high-resolution tomographic images of the entire
LV may represent an additional diagnostic modality (69)
particularly in the presence of technically suboptimal echo-
cardiographic studies or when segmental hypertrophy is
confined to unusual locations within the LV wall.
Since the modern description by Teare in 1958 (12),
HCM has been known by a confusing array of names that
largely reflect its clinical heterogeneity, relatively uncom-
mon occurrence in cardiologic practice, and the skewed
experience of early investigators. This problem in nomen-
clature has been an obstacle to general recognition of the
disease within the medical and non-medical community.
Hypertrophic cardiomyopathy (or HCM) is now widely
accepted as the preferred term (7) because it describes the
overall disease spectrum without introducing misleading
inferences that LV outflow tract obstruction is an invariable
feature of the disease, such as is the case with hypertrophic
obstructive cardiomyopathy (70), muscular subaortic steno-
sis (71), or idiopathic hypertrophic subaortic stenosis (72).
Indeed, most patients with HCM do not demonstrate
outflow obstruction under resting (basal) conditions, al-
though many may develop dynamic subaortic gradients of
varying magnitude with provocative maneuvers or agents
(7,13,41,72–77). Of note, even though the absence of
obstruction (at rest) is common, both in patients with and
without symptoms, most treatment modalities have targeted
those symptomatic HCM patients with outflow obstruction
(41,43–49,78–108).
OBSTRUCTION TO LV OUTFLOW
It is of clinical importance to distinguish between the
obstructive or nonobstructive forms of HCM, based on the
presence or absence of a LV outflow gradient under resting
and/or provocable conditions (5,7,11,13,41,109,110). In-
deed, in most patients, management strategies have tradi-
tionally been tailored to the hemodynamic state. Outflow
gradients are responsible for a loud apical systolic ejection
murmur associated with a constellation of unique clinical
signs (14,72,111), hypertrophy of the basal portion of
ventricular septum and small outflow tract, and an enlarged
and elongated mitral valve in many patients (39,112–114).
Obstruction may either be subaortic (13,71,72) or mid-
cavity (13,115) in location. Subaortic obstruction is caused
by systolic anterior motion (SAM) of the mitral valve
leaflets and mid-systolic contact with the ventricular septum
(13,71,113,116–119). This mechanical impedance to out-
flow occurs in the presence of high velocity ejection in
which a variable proportion of the forward blood flow may
be ejected early in systole (120,121). Systolic anterior
motion is probably attributable to a drag effect (117,122) or
possibly a Venturi phenomenon (13,118) and is responsible
not only for subaortic obstruction, but also the concomitant
3JACC Vol. 42, No. 9, 2003 Maron and McKenna et al.
November 5, 2003:000–000 ACC/ESC Expert Consensus Document on Hypertrophic Cardiomyopathy
mitral regurgitation (usually mild-to-moderate in degree)
due to incomplete leaflet apposition, which is typically
directed posteriorly into the left atrium (111,123). When
the mitral regurgitation jet is directed centrally or anteriorly
into the left atrium, or if multiple jets are present, indepen-
dent abnormalities intrinsic to the mitral valve should be
suspected (e.g., myxomatous degeneration, mitral leaflet
fibrosis, or anomalous papillary muscle insertion)
(13,91,115,124). Occasionally (perhaps in 5% of cases),
gradients and impeded outflow are caused predominately by
muscular apposition in the mid-cavity region—usually in
the absence of mitral-septal contact—involving anomalous
direct insertion of anterolateral papillary muscle into the
anterior mitral leaflet, or excessive mid-ventricular or pap-
illary muscle hypertrophy and malalignment (13,91,115).
Although it has previously been subject to periodic
controversy (72,120,125,126), there is now widespread rec-
ognition that the subaortic gradient (30 mm Hg or more)
and associated elevations in intra-cavity LV pressure reflect
true mechanical impedance to outflow and are of patho-
physiologic and prognostic importance to patients with
HCM (127,128). Indeed, outflow obstruction is a strong,
independent predictor of disease progression to HCM-
related death (relative risk vs. nonobstructed patients, 2.0),
to severe symptoms of New York Heart Association
(NYHA) class III or IV, and to death due specifically to
heart failure and stroke (relative risk vs. nonobstructed
patients, 4.4) (127). However, the likelihood of severe
symptoms and death from outflow tract obstruction was not
greater when the gradient was increased in magnitude above
the threshold of 30 mm Hg (127).
Disease consequences related to chronic outflow gradi-
ents are likely to be mediated by the resultant increase in LV
wall stress, myocardial ischemia and eventually cell death
and replacement fibrosis (7,127,129). Therefore, the pres-
ence of LV outflow obstruction justifies intervention to
reduce or abolish significant subaortic gradients in severely
symptomatic patients who are refractory to maximum med-
ical management (11,14,41,127).
Obstruction in HCM is characteristically dynamic (i.e.,
not fixed): the magnitude (or even presence) of an outflow
gradient may be spontaneously labile and vary considerably
with a number of physiologic alterations as diverse as a
heavy meal or ingestion of a small amount of alcohol
(72,73,109). Different gradient cut-offs have been proposed
for segregating individual patients into hemodynamic sub-
groups, but rigorous partitioning into such hemodynamic
categories according to gradient can be difficult because of
the unpredictable dynamic changes that may occur in
individual patients (72,73).
Nevertheless, it is reasonable to divide the overall HCM
disease spectrum into hemodynamic subgroups, based on
the representative peak instantaneous gradient as assessed
with continuous wave Doppler: 1) obstructive gradient
under basal (resting) conditions equal to or greater than 30
mm Hg (2.7 m/s by Doppler), 2) latent (provocable)
obstructive—gradient less than 30 mm Hg under basal
conditions and equal to or greater than 30 mm Hg with
provocation, and 3) nonobstructive—less than 30 mm Hg
under both basal and (provocable) conditions. By current
clinical convention, LV outflow gradients are routinely
measured noninvasively with continuous wave Doppler
echocardiography, generally obviating the need for serial
cardiac catheterizations in this disease (except when athero-
sclerotic CAD or other associated anomalies such as intrin-
sic valvular disease are suspected).
It is important to underscore that a variety of interven-
tions have been traditionally employed to elicit latent
(inducible) gradients in the echocardiography, cardiac cath-
eterization, and exercise laboratories (i.e