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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

Barry J. Maron, William J. McKenna, Gordon K. Danielson, Lukas J. Kappenberger, Horst J. Kuhn, Christine E. Seidman, Pravin M. Shah, William H. Spencer, Paolo Spirito, Folkert J. Ten Cate, E. Douglas Wigle, Robert A. Vogel, Jonathan Abrams, Eric R. Bates, Bruce R. Brodie, Peter G. Danias, Gabriel Gregoratos, Mark A. Hlatky, Judith S. Hochman, Sanjiv Kaul, Robert C. Lichtenberg, Jonathan R. Lindner, Robert A. O’Rourke, Gerald M. Pohost, Richard S. Schofield, Cynthia M. Tracy, William L. Winters, Werner W. Klein, Silvia G. Priori, Angeles Alonso-Garcia, Carina Blomström-Lundqvist, Guy De Backer, Jaap Deckers, Markus Flather, Jaromir Hradec, Ali Oto, Alexander Parkhomenko, Sigmund Silber, Adam Torbicki
DOI: http://dx.doi.org/10.1016/S0195-668X(03)00479-2 1965-1991 First published online: 1 November 2003

Table of contents

  • Preamble

  • Introduction

  •     Organization of committee and evidence review

  •     Purpose of this Expert Consensus Document

  • General considerations and perspectives

  • Nomenclature, definitions, and clinical diagnosis

  • Obstruction to LV Outflow

  • Genetics and molecular diagnosis

  • General considerations for natural history, and clinical course

  • Symptoms and pharmacological managementstrategies

  •     Beta-adrenergic blocking agents

  •     Verapamil

  •     Disopyramide

  •     Drugs in end-stage phase

  •     Asymptomatic patients

  •     Infective endocarditis prophylaxis

  •     Pregnancy

  • Treatment options for drug-refractory patients

  • Additional approaches to relieve outflowobstruction and symptoms

  •     Dual-chamber pacing

  •     Percutaneous alcohol septal ablation

  • Sudden Cardiac Death

  •     Risk stratification

  •     Prevention

  •     Athlete recommendations

  • Atrial Fibrillation

  • References

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 Documents 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 relationships 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 DocumentsWerner 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 European Society of Cardiology. Both theacademic and private practice sectors were represented. The document was reviewed by 2 official reviewers nominated by the ACCF, 3 official reviewers were nominated by the ESC, 12 members of the ACCF Clinical Electrophysiology Committee, and 4 additional content reviewers nominated by the Writing Committee. 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 Documents revises or withdraws it from distribution. In addition to the references cited as part of this document, a comprehensive bibliography including relevant, supplementary references is available on the ACCF and ESC websites.

Purpose of this Expert Consensus Document

Hypertrophic cardiomyopathy is a complex and relatively common genetic cardiac disorder (about 1:500 in the general adult population)1that has been the subject of intense scrutiny and investigation for over 40 years.2–15Hypertrophic 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)21–29and may cause death and disability in patients of all ages, although it is also frequently compatible with normal longevity.30–35Because of its heterogeneous clinical course and expression,7,36–42HCM frequently presents uncertainty and represents a management dilemma to cardiovascular specialists and other practitioners, particularly those infrequently engaged in the evaluation of patients with this disease.

Furthermore, with the recent introduction of novel treatment strategies targeting subgroups of patients with HCM,7,43–49controversy 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 havingextensive 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 cardiologicpractice,50its diverse presentation, and mechanisms of death and disability and skewed patterns of patient referral,7,11,13,36–38,42,51–59the level of evidence governing management decisions for drugs or devices has often been derived from non-randomized and retrospective investigations. Large-scale controlled and randomized study designs, such as those that have provided important answers regarding the management of coronaryartery disease (CAD) and congestive heart failure,60–62have 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, sometimesobtained in relatively small patient groups, or derived from the accumulated clinical experience of individual investigators, and reasonable inferences drawn from other cardiac diseases. Consequently, the construction of strict clinical algorithms designed 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 management strategies are novel and evolving, and this document 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 thickening).36Left 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) capable of producing the magnitude of hypertrophy evident, and independent of whether or not LV outflow obstruction is present.1,5,7,36Although the usual clinical diagnostic criteria for HCM is a maximal 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.6,17,19,63–65Mildly increased LV wall thicknesses of 13 mm to 14 mm potentially due to HCM should be distinguished from certain extreme expressions of the physiologically-based athlete's heart.66–68The advent of contemporary magnetic resonance imaging that provides high-resolution tomographic images of the entire LV may represent an additional diagnosticmodality69particularly in the presence of technically suboptimal echocardiographic studies or when segmental hypertrophy is confined to unusual locations within the LV wall.

Since the modern description by Teare in 1958,12HCM has been known by a confusing array of names that largely reflect its clinical heterogeneity, relatively uncommon occurrence in cardiologic practice, and the skewed experience of early investigators. This problem in nomenclature 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 term7because 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,70muscular subaortic stenosis,71or idiopathic hypertrophic subaortic stenosis.72Indeed, most patients with HCM do not demonstrate outflow obstruction under resting (basal) conditions, although many may develop dynamic subaortic gradients of varying magnitude with provocative maneuvers or agents.7,13,41,72–77Of 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.5,7,11,13,41,109,110Indeed, in most patients, management strategies have traditionally 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,14,72,111hypertrophy of the basal portion of ventricular septum and small outflow tract, and an enlarged and elongated mitral valve in many patients.39,112–114Obstruction may either be subaortic13,71,72or mid-cavity13,115in location. Subaortic obstruction is caused by systolic anterior motion (SAM) of the mitral valve leaflets and mid-systolic contact with the ventricular septum.13,71,113,116–119This mechanical impedance to outflow occurs in the presence of high velocity ejection in which a variable proportion of the forward blood flow may be ejected early in systole.120,121Systolic anterior motion is probably attributable to a drag effect117,122or possibly a Venturi phenomenon13,118and is responsible not only for subaortic obstruction, but also the concomitant mitral regurgitation (usually mild-to-moderate in degree) due to incomplete leaflet apposition, which is typically directed posteriorly into the left atrium.111,123When the mitral regurgitation jet is directed centrally or anteriorly into the left atrium, or if multiple jets are present, independent abnormalities intrinsic to the mitral valve should be suspected (e.g., myxomatous degeneration, mitral leaflet fibrosis, or anomalous papillary muscle insertion).13,91,115,124Occasionally (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 papillary muscle hypertrophy and malalignment.13,91,115

Although it has previously been subject to periodic controversy,72,120,125,126there is now widespread recognition 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 pathophysiologic and prognostic importance to patients with HCM.127,128Indeed, 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).127However, 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 gradients are likely to be mediated by the resultant increase in LV wall stress, myocardial ischemia and eventually cell death and replacement fibrosis.7,127,129Therefore, the presence of LV outflow obstruction justifies intervention to reduce or abolish significant subaortic gradients in severely symptomatic patients who are refractory to maximum medical 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.72,73,109Different gradient cut-offs have been proposed for segregating individual patients into hemodynamic subgroups, but rigorous partitioning into such hemodynamic categories according to gradient can be difficult because 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 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 atherosclerotic CAD or other associated anomalies such as intrinsic valvular disease are suspected).

It is important to underscore that a variety of interventions have been traditionally employed to elicit latent (inducible) gradients in the echocardiography, cardiac catheterization, and exercise laboratories (i.e., amyl nitrite inhalation, Valsalva maneuver, post-PVC response, isoproterenol or dobutamine infusion, standing posture, and physiologic exercise),3,72,73however, rigorous standardization for these maneuvers has beenlacking, and many have come to be regarded as non-physiologic. To define latent gradients during and/or immediately following exercise for the purpose of major management decisions, treadmill or bicycle exercise testing in association with Doppler echocardiography is probably the most physiologic and preferred provocative maneuver, given that HCM-related symptoms are typically elicited with exertion. Intravenous administration of dobutamine is undesirable,130,131as discussed under the section on alcohol septal ablation.

Genetics and molecular diagnosis

Hypertrophic cardiomyopathy is inherited as a Mendelian autosomal dominant trait and is caused by mutations in any one of 10 genes, each encoding protein components of the cardiac sarcomere composed of thick or thin filaments with contractile, structural, or regulatory functions.6,9,17–19,64,65,132–139It is possible to regard the diverse clinical spectrum as a single, unified disease entity and primary disorder of the sarcomere.18,63Three of the HCM-causing mutant genes predominate in frequency—i.e., beta-myosin heavy chain (the firstidentified), myosin-binding protein C and cardiac troponin-T probably comprise more than one-half of the genotyped patients to date. Seven other genes each account for fewer cases: regulatory and essential myosin light chains, titin, alpha-tropomyosin, alpha-actin,cardiac troponin-I, and alpha-myosin heavy chain. This genetic diversity is compounded by intragenic heterogeneity, with about 200 mutations now identified (seehttp://genetics.med.harvard.edu/∼seidman/cg3), mostof which are missense, with a single amino acid residue substituted with another.63Indeed, molecular defects responsible for HCM are usually different in unrelated individuals, and many other mutations in previously identified genes (and even in additional genes, each probably accounting for a small proportion of familial HCM) undoubtedly remain to be identified.

Phenotypic expression of HCM (i.e., LVH) is the product not only of the causal mutation, but also of modifier genes and environmental factors.140,141The magnitude of effect that modifier genes have onmorphologic expression has not yet been systematically explored, but it can be inferred from the phenotypic variability of affected individuals in the same family carrying identical disease-causing mutations. As a result of the complexity of the molecular biology of hypertrophy, a large number of genes may influence theexpression of the phenotype. There is also increasing recognition of the role of genetics in the genesis of electrophysiological abnormalities associated with LVH. For example, an increased risk for atrial fibrillation (AF) in HCM has been identified with a beta-myosin heavy chain Arg663 His mutation.136

Missense mutations in the gene encoding the gamma-2-regulatory subunit of the AMP-activated protein kinase (PRKAG2), a regulator of cellular energy homeostasis, have been reported to cause familial LVH associated with ventricular pre-excitation.134,142Absence of classical histopathology such as myocyte disarray, a distinct molecular cause for LVH (in part, reflecting glycogen accumulation in myocytes), and progressive conduction system disease and heart block distinguish PRKAG2 from sarcomere protein gene mutations typical of HCM.142Indeed, this syndrome is probably most appropriately regarded as a metabolic storage disease distinct from true HCM. Therefore, it may not be optimal to base management and clinical risk assessment of patients with cardiac hypertrophy and WPW on the data derived from patients with HCM. Also, thickening of the LV wall resembling HCM occurs in children (and some adults) with other disease states—e.g., Noonan's syndrome, mitochondrial myopathies, Friedreich's ataxia,metabolic disorders, Anderson-Fabry disease (X-linked deficiency of the lysosomal enzyme alpha-galactosidase),143,144LV non-compaction,145and cardiac amyloidosis.110

Molecular genetic studies over the past decade have underscored and provided important insights into the profound clinical and genetic heterogeneity of HCM, including the power to achieve preclinical diagnosis of individuals who are affected by a mutant gene but who show no evidence of the disease phenotype on a two-dimensional echocardiogram (or ECG).6,17,57,64,65,146,147Indeed, HCM may be even more common in the general population than the cited prevalence of 1:500 (based on recognition of the established phenotype by echocardiography)1because of incomplete, time-dependent, variable expression of the disease phenotype and because many affected individuals have not been clinically recognized and are not represented in general cardiologic practice, where the disease is relativelyuncommon.50In the clinical assessment of individual pedigrees, it is obligatory for the proband to be informed of the familial nature and autosomal dominant transmission of HCM.

Not all individuals harboring a genetic defect will express the clinical features of HCM (e.g., LVH on echocardiogram, abnormal ECG pattern or disease-related symptoms) at all times during life, and 12-lead ECG abnormalities or evidence of diastolic dysfunction assessed by Doppler tissue imaging may even precede the appearance of the phenotype on echocardiogram especially in the young.148–151Indeed, clinical and molecular genetic studies have demonstrated that there is in fact no minimum LV wall thickness required to be consistent with the presence of an HCM-causing mutant gene.17,65,146–148,152For example, it is common for children less than 13 years old to be affected “silent” mutation carriers without evidence of LVH on an echocardiogram. Most commonly, substantial LV remodeling with the spontaneous appearance of LVH occurs associated with accelerated body growth and maturation during the adolescent years and with morphologic expression usually completed at the time physical maturity is achieved (about 17 to 18 years).150,152,153

Furthermore, novel diagnostic criteria for HCM have recently emerged, based on genotype-phenotype studies showing that incomplete penetrance and disease expression with absence of (or minimal) LVH may occur in adult individuals (most commonly due to cardiac myosin-binding protein-C or troponin-T mutations).17,19,65,135,149,151In both cross-sectional17and serial echocardiographic studies,65mutations in myosin-binding protein C gene have demonstrated age-related penetrance and late-onset of the phenotype in which delayed and de novo appearance of LVH on echocardiogram occurs in mid-life and even later. Therefore, the traditional tenet that held that a normal echocardiogram (and ECG) obtained after full growth has been achieved defined a genetically unaffected relative has been revised. Such late-onset adult morphologic conversions dictate that it is no longer possible, based solely on a normal echocardiogram and ECG, to issue definitive reassurance to asymptomatic family members at maturity (or even in middle-age) that they are free of a disease-causing mutant HCM gene.

Clinical screening of first-degree relatives and other family members should be encouraged. Therefore, when a DNA-based diagnosis is not feasible, the recommended clinical strategies for screening family members employ history and physical examination, 12-lead ECG, and two-dimensional echocardiography at annual evaluations during adolescence (12 to18 years of age). Due to the possibility of delayed adult-onset LVH, it is reasonable and prudent to recommend that adult relatives with normal echocardiograms at or beyond age 18 have subsequent clinical studies performed about every five years. Screening in relatives younger than age 12 is not usually pursued systematically unless the child has a high-risk family history or is involved in particularly intense competitive sports programs. Affected patients identified through family screening (or otherwise) are conventionally evaluated on approximately 12- to 18-month basis, as described under Risk Stratification and SCD heading.

Laboratory DNA-analysis for mutant genes is the most definitive method for establishing the diagnosis of HCM. At present, however, there are several obstacles to the translation of genetic research into practical clinical applications and routine clinical strategy. These include the substantial genetic heterogeneity, the low frequency with which each causal mutation occurs in the general HCM population, and the important methodologic difficulties associated with identifying a single disease-causing mutation among 10 different genes in view of the complex, time-consuming, and expensive laboratory techniques involved. Mutation analysis is presently confined to a few research-oriented laboratories. The current development of better methodologies for automated, direct DNA-sequencing and indirect approaches for sequence profiling now provides sensitive techniques that can accurately define the molecular cause for HCM in a single proband, without involving family members or complex linkage analysis in large pedigrees. However, the large number and size of the genes that may need to be examined in each proband continue to limit the efficiency of a gene-based diagnosis. However, once a mutation is defined in a proband, an accurate definition of genetic status in all family members is both efficient and inexpensive.

Although there is interest in the application of gene therapy to a variety of inheritable human conditions, at this time the clinical utilization of this technology in HCM is extremely problematic. Hypertrophic cardiomyopathy is transmitted as an autosomal dominant trait, and affected persons possess one mutated and one normal allele. Because most mutations in this disease cause substitution of a single amino acid within the encoded protein, gene therapy would theoretically have the daunting task of selectively targeting and inactivating the mutated gene, the encoded protein, or both. Furthermore, selection of patients for gene therapy would be particularly complex given that some forms of the disease are compatible with normal longevity and absence of symptoms. Also, such therapeutic interventions would presumably be applicable only to a small patient subset consisting of very young affected members from high-risk families identified prior to the development of LVH. Spontaneous animal models of HCM,154or model organisms including mice and rabbits, may foster the development of pharmacologic therapies that reduce disease manifestations, including hypertrophy and interstitial (matrix) fibrosis.155–158

General considerations for natural history, and clinical course

Hypertrophic cardiomyopathy is a unique cardiovascular disease with the potential for clinical presentation during any phase of life from infancy to old age (day one to over 90 years). The clinical course is typically variable, and patients may remain stable over long periods of time with up to 25% of a HCM cohort achieving normal longevity (75 years of age or older).7,30,31,34,159However, the course of many patients may be punctuated by adverse clinical events, largely related to sudden, unexpected death, embolic stroke, and the consequences of heart failure.5,7,29,30,38Hypertrophic cardiomyopathy is also a rare cause of severe heart failure in infants and very young children, and presentation in this age group itself constitutes an unfavorable prognostic sign.53,58

In general, adverse clinical course proceeds along one or more of several of the following pathways, which ultimately dictate treatment strategies (Figs 1 and2):5,7,11,14,261) high risk for premature sudden and unexpected death; 2) progressive symptoms largely of exertional dyspnea, chest pain (either typical of angina or atypical in nature), and impaired consciousness, including syncope, near-syncope or presyncope (i.e., dizziness/lightheadedness), in the presence of preserved LV systolic function; 3) progression to advanced congestive heart failure (the “end-stage phase”) with LV remodeling and systolic dysfunction;37,160and 4) complications attributable to AF, including embolic stroke.38,161–163

Fig. 1

Clinical presentation and treatment strategies for patient subgroups within the broad clinical spectrum of hypertrophic cardiomyopathy (HCM). See text for details. AF = atrial fibrillation; DDD = dual-chamber; ICD = implantable cardioverter-defibrillator; SD = sudden death; and Rx = treatment. Adapted with permission.11*No specific treatment or intervention indicated, except under exceptional circumstances.

Fig. 2

The principal pathways of disease progression in hypertrophic cardiomyopathy (HCM). Widths of the respective arrows approximate the frequency with which the pathway occurs in HCM populations. AF = atrial fibrillation.

However, full appreciation of the clinical implications of HCM (and its treatment strategies) requires an awareness of the unique patterns of patient referral and selection biases that have had an important impact on our perceptions of this disease.5,7,11,59,164Perhaps to a far greater extent than other cardiovascular diseases, much of the published clinical data assembled over four decades have emanated largely from a fewselected tertiary centers in North America and Europe, disproportionately comprised of patients referred because of their high-risk status or severe symptoms requiring highly specialized care (such as surgery).59,164On the other hand, clinically stable, asymptomatic, or elderly patients were often under-represented.

Over-dependence on frequently cited, ominous mortality rates of 3% to 6% per year for HCM-related premature death from tertiary centers may have led to an exaggeration of the overall risk and impact of this disease on patients and, thereby, contributed to a misguided perception that HCM is invariably an unfavorable disorder with inevitable, adverse consequences frequently requiring major therapeutic intervention.7,59,165However, more recent reports from non-tertiary centers with fewer selected, regional, and community-based cohorts not subject to tertiary center referral bias are probably more representative of the overall disease state, citing annual mortality rates in a much lower range of about 1%, with the survival of patients not dissimilarto that of the general adult U.S. population.7,30,31Nevertheless, of note, there are subgroups of patients within the broad HCM spectrum with annual mortality rates far exceeding 1% and conform to the rates of up to 6% per year previously attributed to the overalldisease.7,11,41,165,166

Hypertrophic cardiomyopathy attributable to sarcomere protein mutations also occurs in the elderly139and should be distinguished from non-genetic hypertensive heart disease or age-related changes in persons of advanced age. The determinants of extended survival in some patients with HCM are largely unresolved. It is possible that benign genetic substrates may convey favorable prognosis and normal life expectancy. However, at present, genotype data are available for only a limited number of elderly patients, with mutations in the cardiac myosin-binding protein C gene being most common.139Older patients with HCM characteristically show relatively mild degrees of LVH and may not experience severe symptoms. Some even have large resting subaortic gradients that are often caused by the SAM-septal contact associated with normal-sized mitralleaflets greatly displaced anteriorly, seemingly by calcium accumulation posteriorly in the mitral annulus, within a particularly small LV outflow tract.167Definitive clinical diagnosis of HCM in older patients with LVH and systemic hypertension is often difficult to resolve, particularly when LV wall thickness is less than 20 mm and SAM is absent. In the absence of genotyping, marked LVH disproportionate to the level of blood pressure elevation, unusual patterns of LVH unique to HCM,36or an obstruction to LV outflow at rest represents presumptiveevidence for HCM.127

Not uncommonly, HCM coexists with other cardiac conditions such as systemic hypertension and/or CAD. In such patients, the management of HCM should be considered independent of any co-morbidity, and each of the disease entities should be treated on its own merit. For example, specific concerns that may arise include avoidance of angiotensin-converting enzyme (ACE) inhibitors to control hypertension in the presence of HCM-related resting or provocable LV outflow tract obstruction and failure to exclude the diagnosis of CAD in those HCM patients with angina pectoris.

In summary, it is probably most appropriate to regard HCM as a complex disease capable of producing important clinical consequences and premature death in some patients, while many other patients reach normal longevity and life expectancy with mild or no disability and without major therapeutic interventions. Many individuals affected by HCM may not require treatment for most or all of their natural lives, and they therefore deserve reassurance with regard to their prognosis.

Symptoms and pharmacological management strategies

A fundamental goal of treatment in HCM is the alleviation of symptoms related to heart failure (Fig. 1). Pharmacological therapy has traditionally been the initial therapeutic approach for relieving disabling symptoms of exertional dyspnea (with or without associated chest pain) and improving exercise capacity for more than 35 years, since the introduction of beta-blockers in the mid-1960s.3,10,14,168–179Also, drugs are often the sole therapeutic option available to the many patients without obstruction to LV outflow, under resting or provocable conditions, who constitute a substantial proportion of the HCM population. Indeed, it is the convention to empirically initiate pharmacologic therapy when symptoms of exercise intolerance intervene, although there have been few randomized trials to compare the effect of drugs in HCM5,7,11,179(Fig. 1).

Exertional dyspnea and disability (often associated chest pain), dizziness, presyncope and syncope usually occur in the presence of preserved systolic function and a nondilated LV.5,7,11,14,180Symptoms appear to be caused in large measure by diastolic dysfunction with impaired filling due to abnormal relaxation and increased chamber stiffness, leading in turn to elevated left atrial and LV end-diastolic pressures (with reduced stroke volume and cardiac output),181–188pulmonary congestion, and impaired exercise performance with reduced oxygen consumption at peak exercise.189

The pathophysiology of such symptoms, due to this form of diastolic heart failure, may also be intertwined with other important pathophysiologic mechanisms such as myocardial ischemia,190–201outflow obstruction associated with mitral regurgitation,13,127and AF.163Indeed, many patients may experience symptoms largely from diastolic dysfunction or myocardial ischemia in the absence of outflow obstruction (or severe hypertrophy). Other patients (i.e., those with LV outflow obstruction) are more disabled by elevated LV pressures and concomitant mitral regurgitation than by diastolic dysfunction, as is evidenced by the often dramatic symptomatic benefit derived from major therapeutic interventions that reduce or obliterate outflow gradient (most frequently myectomy or alcohol ablation).7,13–15,49,81,83–88,90–95,102–106,202

Chest pain in the absence of atherosclerotic CAD may be typical of angina pectoris or atypical in character. Most chest discomfort is probably due by bursts of myocardial ischemia, evidenced by the findings of scars at autopsy,51,195,199,203fixed or reversible myocardial perfusion defects and the suggestion of scarring by magnetic resonance imaging,129net lactate release during atrial pacing, and impaired coronary vasodilatorcapacity.190,192,193,198,201,204Myocardial ischemia is probably a consequence of abnormal microvasculature, consisting of intramural coronary arterioles with thickened walls (from medial hypertrophy) and narrowed lumen,195–201and/or a mismatch between the greatly increased LV mass and coronary flow. Because typical anginal chest pain may be part of the HCM symptom-complex, associated atherosclerotic CAD (which may complicate clinical course) is often overlooked in these patients. Therefore, coronary arteriography is indicated in patients with HCM and persistent angina who are over 40 years of age or who have risk factors for CAD, or when CAD is judged possible prior to any invasive treatmentfor HCM such as septal myectomy (or alcohol septal ablation).

Beta-adrenergic blocking agents

Beta-blockers are negative inotropic drugs that have traditionally been administered to HCM patients withor without obstruction, usually relying on the patient's own subjective and historical perception of benefit.11,14,168,169,172,179However, judgments regarding treatment strategies in HCM with beta-blockers are often difficult, taking into account the frequent day-to-day variability in magnitude of symptoms. Treadmill or bicycle exercise—with or without measurement of peak oxygen consumption189—have proved helpful in targeting patients for therapy or determining when changes in dosage or drugs are appropriate. If limiting symptoms progress, drug dosage may be increased within the accepted therapeutic range. Patient responses to drugs are highly variable in terms of magnitude and duration of benefit, and the selection of medications has not achieved widespread standardization and has been dependent, in part, on the experiences of individual practitioners, investigators, and centers.

Propranolol was the first drug used in the medical management of HCM, and long-acting preparations of propranolol or more cardioselective agents such as atenolol, metoprolol, or nadolol have been employed more recently. There are many reports of subjective symptomatic improvement and enhanced exercise capacity in a dose range of up to 480 mg per day for propranolol (2 mg/kg in children), both in patients with and without outflow obstruction. Although some investigators have administered massive doses of propranolol (up to 1,000 mg per day), claiming symptomatic benefit and long-term survival without major side effects,172this is not generally accepted practice. However, even moderate doses of beta-blockers may affect growth in young children or impair school performance, or trigger depression in children and adolescents, and should be closely monitored in such patients.

Substantial experience suggests that standard dosages of these drugs can mitigate disabling symptoms and limit the latent outflow gradient provoked during exercise when sympathetic tone is high and heart failure symptoms occur. However, there is little evidence that beta-blocking agents consistently reduce outflow obstruction under resting conditions. Consequently, beta-blockers are a preferred drug treatment strategy for symptomatic patients with outflow gradients present only with exertion.

The beneficial effects of beta-blockers on symptoms of exertional dyspnea and exercise intolerance appear to be attributable largely to a decrease in the heart rate with a consequent prolongation of diastole and relaxation and an increase in passive ventricular filling. These agents lessen LV contractility and myocardial oxygen demand and possibly reduce microvascular myocardial ischemia. Potential side effects include fatigue, impotence, sleep disturbances, and chronotropicincompetence.

Verapamil

In 1979, the calcium antagonist verapamil was introduced as another negative inotropic agent for the treatment of HCM,170and has been widely used empirically in both the nonobstructive and obstructive forms, with a reported benefit for many patients, including those with a component of chest pain.176,205,206Verapamil in doses up to 480 mg per day (usually in a sustained release preparation) has favorable effects on symptoms, probably by virtue of improving ventricular relaxation and filling as well as relieving myocardial ischemia and decreasing LV contractility.181,182,206However, aside from the mild side-effects of constipation and hair loss, verapamil may also occasionally harbor a potential for clinically important adverse consequences and has been reported to cause death in a few HCM patients with severe disabling symptoms (orthopnea and paroxysmal nocturnal dyspnea) and markedly-elevated pulmonary arterial pressure in combination with marked outflow obstruction.14Adverse hemodynamic effects of verapamil are presumably the result of the vasodilating properties predominating over negative inotropic effects, resulting in augmented outflow obstruction, pulmonary edema, and cardiogenic shock. Because of these concerns, caution should be exercised in administering verapamil to patients with resting outflow obstruction and severe limiting symptoms. Some investigators discourage the use of calcium antagonists in the management of obstructive HCM and instead favors disopyramide (often with a beta-blocker) for such patients with severesymptoms.14,173Verapamil is not indicated in infants due to the risk for sudden death that has been reported with intravenous administration. Dosages of oral verapamil have not been established for infants and preadolescent children.

Most clinicians favor using beta-blockers over verapamil for the initial medical treatment of exertional dyspnea, although it does not appear to be of crucial importance which drug is administered first. It has been common practice, however, to administer verapamil to those patients who do not experience a benefit from beta-blockers or who have a history of asthma. Improvement with verapamil may be due to the primary actions of the drug, and in some instances, partially attributable to withdrawal of beta-blockers and the abolition of side effects that evolved insidiously over time. At present, there is no evidence that combined medical therapy with administration of beta-blockers and verapamil is more advantageous than the use of either drug alone.

Disopyramide

The negative inotropic and Type I-A antiarrhythmic agent disopyramide was introduced into the treatment regimen for patients with obstructive HCM in 1982. There are reports of disopyramide producing symptomatic benefit (at 300 mg to 600 mg per day with a dose-response effect) in severely limited patients with resting obstruction, because of a decrease in SAM, outflow obstruction, and mitral regurgitant volume.168,171,173,174,177Anti-cholinergic side effects such as dry mouth and eyes, constipation, indigestion, and difficulty in micturation may be reduced by long-acting preparations through which cardioactive benefits are more sustained. Because disopyramide may cause accelerated atrioventricular (A-V) nodal conduction and thus increase ventricular rate during AF, supplemental therapy with beta-blockers in low doses to achieve normal resting heart rate has been advised.

Although disopyramide incorporates antiarrhythmic properties, there is little evidence that proarrhythmic effects have intervened in HCM patients. Nevertheless, this issue remains of some concern in a disease associated with an arrhythmogenic LV substrate; prolongation of the QT interval should be monitored while administering the drug. Furthermore, disopyramide administration may be deleterious in nonobstructive HCM by decreasing cardiac output, causing most investigators to limit its useto patients with outflow obstruction who have not responded to beta-blockers or verapamil.

At present, the information regarding drugs such as sotalol and other calcium antagonists (such as diltiazem) is insufficient to recommend their use in HCM. Diuretic agents may be added to the cardioactive drug regimen prudently—preferably in the absence of marked outflow obstruction. Because many patients have diastolic dysfunction and require relatively high filling pressures to achieve adequate ventricular filling, it may be advisable to administer diuretics cautiously. Nifedipine, because of its particularly potent vasodilating properties, may be deleterious, particularly for patients with outflow obstruction. Combined therapy with disopyramide and amiodarone (or disopyramide and sotalol), or quinidine and verapamil (or quinidine and procainamide), should also be avoided due to concern over proarrhythmia; also, administration of nitroglycerine, ACE inhibitors or digitalis are generally contraindicated or discouraged in the presence of resting or provocable outflow obstruction. In patients with severe heart failure refractory to other medications, caution is advised in administrating amiodarone in a high dosage (greater than or equal to 400 mg per day). In patients with erectile dysfunction, PDE inhibitors should be used with the awareness that a mild afterload reducing effect may be deleterious in patients with resting or provocable obstruction.

Drugs in end-stage phase

A small but important subgroup of patients with nonobstructive HCM develops systolic ventricular dysfunction and severe heart failure, usually associated with LV remodeling demonstrable as wall thinning and chamber enlargement. This particular evolution of HCM occurs in only about 5% of patients and has been variously known as the “end-stage”, “burnt-out”, or “dilated” phase.7,37,160Drug treatment strategies in such patients with systolic failure differ substantially strategies for in HCM patients with typical LVH, nondilated chambers, and preserved systolic function (i.e., involving conversion to after load-reducing agents such as ACE inhibitors or angiotensin II-receptor blockers or diuretics, digitalis, beta-blockers or spironolactone) (Fig. 1). There is no evidence, however, that beta-blockers prevent or convey a benefit to congestive heart failure and ventricular systolic dysfunction of the “end-of-stage” (by contrast with the experience in dilated cardiomyopathy and CAD). Ultimately, patients with end-stage heart failure may become candidates for heart transplantation, and they represent the primary subgroup within the broad disease spectrum of HCM for when this treatment option is considered207(Fig. 1).

Asymptomatic patients

Data from largely unselected cohorts and genotyping studies in families suggest that most HCM patients,including many who are not even aware of their disease, probably have no symptoms or only mild symptoms.5–7,17–19,30,50,55,59,64,65,164While most of the asymptomatic patients do not require treatment, some represent therapeutic dilemmas because of their youthful age and the consideration for prophylactic therapy to prevent SCD or disease progression.21,27,127,208,209

Prophylactic drug therapy in asymptomatic (or mildly symptomatic) patients to prevent or delay development of symptoms and improve prognosis has been the subject of debate for many years, but it remains on an entirely empiric basis without controlled data to either support or contradict its potential efficacy.11This issue is unresolved due to the relatively small patient populations previously available for study, as well as theinfrequency with which adverse end-points occur prematurely in this disease. Additionally, there is a growing awareness that an important proportion of HCM patients achieve normal life expectancy.30–32,34,55In general, treatments to delay or prevent progression of the disease due to heart failure-related symptoms are most appropriately directed toward relieving LV outflow tract obstruction and controlling or abolishing AF through pharmacologic or intervention-based strategies. Indeed, treatments targeted at aborting the disease progression are now confined to those patients judged to be at high-risk for SCD (as discussed under Risk Stratification and SCD). The efficacy of empiric, prophylactic drug treatment with beta-blockers, verapamil or disopyramide for delaying the onset of symptoms and favorably altering the clinical course or outcome in asymptomatic young patients with particularly marked LV outflow tract gradients (about 75 mm Hg to 100 mm Hg or more) is unresolved.

Infective endocarditis prophylaxis

In HCM there is a small risk for bacterial endocarditis, which appears largely confined to those patients with LV outflow tract obstruction under resting conditions or with intrinsic mitral valve disease.210The site of the valvular vegetation is usually the thickened anterior mitral leaflet, although cases have been reported with lesions on the outflow tract endocardial contact plaque (at the point of mitral-septal contact) or on the aortic valve.210,211Therefore, the AHA recommendation212should be applied to HCM patients with evidence of outflow obstruction under resting or exercise conditions at the time of dental or selected surgical procedures that create a risk for blood-borne bacteremia.

Pregnancy

There is no evidence that patients with HCM are generally at increased risk during pregnancy and delivery. Absolute maternal mortality is very low (although possibly higher in patients with HCM than in the general population) and appears to be confined principally to women with high-risk clinical profiles.213Such patients should be afforded highly specialized preventive obstetrical care during pregnancy. Otherwise, most pregnant HCM patients undergo normal vaginal delivery without the necessity for cesarean section.

Treatment options for drug-refractory patients

In some patients, medical therapy ultimately proves insufficient to control symptoms, and the quality of life becomes unacceptable to the patient. At this point in the clinical course, after a trial administration of maximum drug treatment, the subsequent therapeutic strategies are dictated largely by whether LV outflow obstruction is present (Fig. 1).

Surgery. Patients in a small but important subgroup comprising only about 5% of all HCM patients in non-referral settings (but up to 30% in tertiary referral populations), are generally regarded as candidates for surgery. These patients have particularly marked outflow gradients (peak instantaneous usually greater than or equal to 50 mm Hg), as measured with continuous wave Doppler echocardiography either under resting/basal conditions and/or with provocation preferably utilizing physiologic exercise. In addition, these patients have severe limiting symptoms, usually of exertional dyspnea and chest pain that are regarded in adults as NYHA functional classes III and IV, refractory to maximum medical therapy.7,8,11,14,41,90,92,102,103Over the past 40 years, based on the experience of a number of centers throughout the world, the ventricular septal myectomy operation (also known as the Morrow procedure)8has become established as a proven approach for amelioration of outflow obstruction and the standard therapeutic option, and the gold standard, for both adults and children with obstructive HCM and severe drug-refractory symptoms.7,11,14,15,41,70,78,81,84,85,90–95,102–106,214The myectomy operation should be confined to centersexperienced in this procedure.

Myectomy is performed through an aortotomy and involves the resection of a carefully defined relatively small amount of muscle from the proximal septum (about 5 to 10 g), extending from near the base of the aortic valve to beyond the distal margins of mitral leaflets (about 3 to 4 cm), thereby enlarging the LV outflow tract215and, as a consequence in the vast majority of patients, abolishing any significant mechanical impedance to ejection and mitral valve SAM immediately normalizing LV systolic pressures, abolishing mitral regurgitation, and ultimately, reducing LV end-diastolic pressures. Such an abrupt relief of the gradient with surgery (in contrast to slower reduction with alcohol septal ablation in many cases) is particularly advantageous in patients with severe functional limitations.

Some surgeons have utilized a more extensive myectomy procedure for obstructive HCM, with the septal resection widened and extended far more distally than in the classic Morrow procedure (i.e., 7 to 8 cm from the aortic valve to below the level of papillary muscles).70,91In addition, the anterolateral papillary muscle may be dissected partially free from its attachment with the lateral LV free wall to enhance papillary muscle mobility and reduce anterior tethering of the mitral apparatus.91Alternatively, mitral valve replacement or repair has been employed in selected patients judged to have severe mitral regurgitation due to intrinsic abnormalities of the valve apparatus (such as myxomatous mitral valve).124

Previously, some surgeons found it advantageous in selected patients to perform mitral valve replacement216,217when the basal anterior septum in the area of resection is relatively thin (e.g., less than 18 mm) and muscular resection was judged to present an unacceptable risk of septal perforation or inadequate hemodynamic result.93However, currently, some surgical centers experienced with myectomy do not advocate mitral valve replacement (in the absence of intrinsic mitral valve disease), even in the presence of a relatively thin ventricular septum; carefully performed surgical septal reduction is the preferred method.

Mitral valvuloplasty (plication) in combination with myectomy has been proposed for some patients with particularly deformed or elongated mitral leaflets.84Muscular mid-cavity obstruction due to an anomalous papillary muscle requires an extended distal myectomy91or alternatively mitral valve replacement.115Occasionally, patients, usually children, may demonstrate anobstruction to right ventricular outflow due to excessive muscular hypertrophy of trabeculae or crista supraventricularis muscle;218resection of the right ventricular outflow tract muscle, with or without an outflow tract patch, has abolished the gradient.

Published reports of over 2,000 patients from North American and European centers show remarkably consistent results with the ventricular septal myectomy operation. Isolated myectomy (without concomitant cardiac procedures such as valve replacement or coronary artery bypass grafting) is now performed with low operative mortality in patients of all ages, including children, at those centers having the most experience with this procedure (reported as 1% to 3%, and even less in the most recent cases).7,11,15,81,92–95,101–107Surgical risk may be higher among very elderly patients (particularly those with severe disabling symptoms associated with pulmonary hypertension), patients with prior myectomy, or those undergoing additional cardiac surgical procedures. Complications such as complete heart block (requiring permanent pacemaker) and iatrogenic ventricular septal perforation have become uncommon (equal to or less than 1% to 2%), while partial or complete left bundle-branch block is an inevitable consequence of the muscular resection and is not associated with adverse sequelae.15,81,85,90–93,102–106Intraoperative guidance with echocardiography (transesophageal or with the transducer applied directly to the right ventricular surface) is standard at centers performing surgery for HCM and is useful in assessing the site and extent of the proposed myectomy, structural features of the mitral valve, and the effect of muscular resection on SAM and mitral regurgitation.93,123,219

Septal myectomy is associated with persistent, long-lasting improvement in disabling symptoms and exercise capacity (i.e., increase by one or more NYHA classes and demonstrable increase in peak oxygen consumption with exercise) and decreased frequency of syncope five or more years after surgery.7,11,13–15,81,90–95,102–106,220Symptomatic benefit following myectomy appears to be largely the consequence of abolishing or substantially reducing the basal outflow gradient and mitral regurgitation, and restoring normal LV systolic and end-diastolic pressures (in more than 90% of patients), which may also favorably influence LV diastolic filling and myocardial ischemia.204Because myectomy may result in a decrease in left atrial size,221the likelihood of AF occurring after surgery may be mitigated (and sinus rhythm restored with greater ease), especially in patients younger than 45 years.

Selected patients in whom severe refractory symptoms are indisputably linked to marked outflow gradients elicited by exercise (when resting obstruction is absent or mild) usually also benefit from myectomy. Reacquisition of SAM and a large resting LV outflow gradient is exceedingly uncommon after successful myectomy in either adults or children, and the need for reoperation to reduce recurrent outflow gradient is extremely uncommon at centers having the most experience with the septal myectomy operation.15,81,95,103,105

By convention, surgery has not been recommended or performed in asymptomatic or mildly symptomatic patients with obstructive HCM for a number of reasons: 1) the effect of surgery per se on longevity is unresolved, although several surgical series have reported improved late survival after myectomy compared with the clinical course of nonoperated medically treated patients with severe symptoms; 2) operative mortality is now very low, but in some patients the risk of surgery may exceed the ultimate risks from the disease; 3) outflow obstruction is often compatible with normal longevity; 4) there is little or no evidence that surgical relief of outflow obstruction abolishes the risk for progression to the end-stage phase, which is an independent disease consequence.

Although definitive evidence is lacking, there is some suggestion in retrospective non-randomized studies that surgical relief of outflow obstruction in severely sympotomatic patients may reduce long-term mortality and possibly SCD.10,95,105It should be emphasized that surgery is not regarded as curative but is performed to achieve an improved quality of life and functional(exercise) capacity. One possible exception to this tenet may be young asymptomatic or mildly symptomatic patients with particularly marked outflow obstruction (e.g., 75 mm to 100 mm Hg or more at rest). There is a paucity of data in this subset, but it is not unreasonable to at least consider surgical intervention for young patients, even if they are not severely symptomatic, in the presence of particularly marked obstruction to LV outflow.

Additional approaches to relieve outflow obstruction and symptoms

Ventricular septal myectomy has generally been confined to selected major centers having substantial experience with this procedure. However, some patients may not have ready access to such specialized surgical care because of geographical factors; or they may not be favorable operative candidates, because of concomitant medical conditions—particularly advanced age, prior cardiac surgery, or insufficient personal motivation. Two techniques can be considered as potential alternatives to surgery for selected patients who otherwise meet the same clinical criteria as candidates for surgery.

Dual-chamber pacing

Several groups had investigated the effects of permanent dual-chamber pacing on severe outflow obstructionand refractory symptoms within observational and uncontrolled study designs.80,100,222Data in these studies were necessarily based on the subjective perception of symptom level by patients over relatively short periods of time. Such investigations reported dual-chamber pacing to be associated with a substantial decrease in outflow gradient, as well as amelioration of symptoms in most patients. These observations inferred that a reduction of gradient with pacing in turn consistently relieved symptoms. However, other catheterization laboratory studies showed that a decrease in the outflow gradient produced by temporary A-V sequential pacing could be associated with detrimental effects on ventricular filling and cardiac output.97,223

Subsequently, dual-chamber pacing in HCM was subjected to scrutiny in three randomized, cross-over studies (double-blind in two) in which patients received 2 to 3 months each of pacing and also back-up AAI mode (no pacing) as a control, by activating and deactivating the pacemaker accordingly.43,47,98,99Two randomized, cross-over, double-blind studies (one multi-center and one from the Mayo Clinic) reported the effects of pacing in HCM patients to be less favorable than the observational data had suggested.43,98For example, the average decrease in outflow gradient with pacing, while statistically significant, was nevertheless much more modest (about 25% to 40%) than the in the uncontrolled studies and varied substantially among individual patients. In one study, the average subaortic gradient, even after nine months of pacing, remained in the preoperative range (e.g., average 48 mm Hg).

In these controlled studies, subjective symptomatic improvement assessed by quality-of-life score was reported with similar frequency by patients both after periods of pacing and after the same time period without pacing (AAI-backup).43,98Objective measures of exercise capacity (e.g., treadmill exercise time and maximal oxygen consumption) did not differ significantly during pacing and without pacing. These observations demonstrate that subjectively reported symptomatic benefit during pacing frequently occurs without objective evidence of improved exercise capacity and can be regarded in part as a placebo effect.43,89,98Furthermore, no correlation has been demonstrated for gradient reduction between short- and long-term pacing, suggesting that testing the gradient response to short-term pacing in the catheterization laboratory has limited practical clinical value in judging long-term efficacy.43However, the failure to achieve gradient reduction with temporary pacing suggests that permanent pacing is probably not indicated.

As part of its design, the randomized, cross-over, single-blind European multi-center HCM pacing trial, PIC (Pacing in Cardiomyopathy),47,48,89,107excluded from chronic pacing those patients without significant gradient reduction during temporary pacing. With data very similar to the other two randomized studies, (but also with a large proportion of patients who elected to continue pacing based on their own subjective assessment of treatment), the PIC investigators concluded that pacemaker therapy was an option for most severely symptomatic patients with obstructive HCM refractory to drug treatment. Nevertheless, taken together the available data do not support dual-chamber pacing as a primary treatment for most severely symptomatic patients with obstructive HCM. In a nonrandomized study comparing pacing and the myectomy operation, hemodynamic and symptomatic outcome proved to be superior with surgery.99

Although it is not a primary treatment for the disease, there is nevertheless evidence to support utilizing a trial of dual-chamber pacing in selected patient subgroups that may benefit in terms of gradient relief and improvement in symptoms and exercise tolerance. For example, there may be both subjective and objective symptomatic benefit with pacing in some patients of advanced age (over 65 years),43for whom alternatives to surgery are often desirable. Otherwise, there are few predictive data upon which to specifically target those patients who are most likely to potentially benefit from pacing therapy; for example, there is little relationship between the magnitude of gradient reduction with chronic pacing and the symptomatic benefit ultimately achieved. Pacing-induced LV remodeling with thinning of the wall was claimed in one uncontrolled study80but could not be confirmed in a randomized investigation.43Furthermore, there is no evidence that pacing reduces the risk of SCD in HCM,43,80alters or aborts underlying progression of the disease state, or conveys favorable hemodynamic or symptomatic benefit for patients with the nonobstructive form.224

Of potential advantage, pacing therapy permits more aggressive drug treatment by obviating the concern for drug-induced bradycardia.82Some patients receiving an implantable cardioverter defibrillator (ICD) for high-risk status, in which obstruction to LV outflow is also present, may benefit from use of the dual-chamber pacingcomponent of the ICD to effect a reduction in outflow gradient. The ACC/AHA/NASPE 2002 guidelines have designated pacing for severely symptomatic and medically refractory HCM patients with LV outflow obstruction as a class IIB indication.225

However, it should be underscored that maintenance of pacing therapy (directed toward alleviating obstruction and symptoms) may be substantially more complex in HCM than in other cardiac conditions; therefore, for optimal results this procedure should be performed in centers highly experienced in both pacemaker therapy and HCM. Producing and maintaining a reduction in gradient (and presumably in symptoms) requires that pre-excitation of the right ventricular apex and distal septum be established and that complete ventricular capture—both at rest and during exercise—without compromising ventricular filling and cardiac output. Hence, ascertaining the optimal A-V interval for dual-chamber pacing is a crucial element of pacing management in HCM. Programming of the pacemaker A-V interval to ensure complete ventricular capture may require slowing of intrinsic A-V nodal conduction with a beta-blocker or verapamil, or possibly ablation of the A-V node in selected cases (thereby rendering the patient pacemaker dependent), has been suggested. It is also understood that no other treatment modality in HCM (including surgery and alcohol septal ablation) has undergone such rigorous randomized testing in order to validate its efficacy. At present, there are no data concerning the role of biventricular pacing in HCM patients with severe heart disease.

Percutaneous alcohol septal ablation

A second option to surgery is the more recently developed alcohol septal ablation technique (Table1).44–46,49,79,83,86–88,101,226–234First reported in 1995, this catheter interventional treatment involves the introduction of absolute alcohol into a target septal perforator branch of the left anterior descending coronary artery for the purpose of producing a myocardial infarction within the proximal ventricular septum. Septal ablation mimics the hemodynamic consequences of myectomy by reducing the basal septal thickness and excursion (producing akinetic or hypokinetic septal motion), enlarging the LV outflow tract and, thereby, lessening the SAM of the mitral valve and mitral regurgitation.44–46,49,88,227

View this table:
Table 1

Comparison of Septal Myectomy and Percutaneous Alcohol Septal Ablation*

ParameterMyectomyAblation
Operative mortality1% to 2%1% to 2%
Gradient reduction (at rest)to less than 10 mm Hgto less than 25 mm Hg
Symptoms (subjective)decreaseddecreased
Symptoms (objective)decreaseddecreased
Effective with anatomic variability in septumusuallyuncertain
Pacemaker (high grade A-V block)1% to 2%5% to 10%
Estimated patient selection×15 to 20×
Sudden death risk (long-term)very lowuncertain
Available follow-upmore than 40 yearsabout 6 years
Intramyocardial scarabsentpresent
  • * Data represents best estimates based on the assimilation of published data, and with emphasis placed on the most recent clinical experience.

This technique utilizes conventional methods and technology currently available for atherosclerotic CAD. After standard coronary arteriograms are performed, a coronary balloon is placed into a proximal major septal perforator artery with the aid of flexible coronary guide wires. A temporary pacing catheter is positioned in the right ventricular apex in the event that high-grade A-V block occurs. After the balloon is inflated, an arteriogram is performed through the lumen to verify that the balloon is located in the desired anatomic position and to ensure that leakage of alcohol into the left anterior descending coronary artery or coronary venous system does notoccur.

Myocardial contrast echocardiography guidance (with injection of echo contrast or radio-opaque medium) is important in selecting the appropriate septal perforator branch. This technique is useful for determining the precise area of septum targeted for alcohol and infarction and whether the selected septal perforator also perfuses other distant and unwanted areas of left or right ventricular myocardium or papillary muscles.79,230Some groups prefer a pressure-angiographic and fluoroscopy guided technique.226,227,233The targeted septal perforator and area for infarction are identified by an immediate fall in outflow gradient following balloon occlusion and/or contrast injection.

The amount of ethanol to be injected is estimated by the angiographic visualization of septal anatomy and whether contrast wash-out is slow or rapid.46,79,86,226,233Usually, about 1 to 3 cc (average 1.5 to 2 cc) of desiccated ethanol (of at least 95% concentration) is slowly infused into the septal perforator and septum via the balloon catheter, inducing a myocardial infarction demonstrable by 400 to 2,500 units of creatinine phosphokinase release, equivalent to an area of necrosis estimated to be 3% to 10% of the LV mass (20% of the septum). However, centers performing a large number of alcohol septal ablation procedures today are using smaller amounts of ethanol, leading to less creatinine phosphokinase release and smaller septal infarcts, and also reducing the incidence of complete heart block.44,233

Successful alcohol septal ablation may trigger a rapid reduction in resting outflow gradient evident in the catheterization laboratory. More frequently, a progressive decrease in the gradient occurs after 6 to 12 months, usually achieving levels in a range equivalent to thatwith myectomy, and resulting from remodeling of the septum without significant impairment in global LV ejection.46,49,229–234This has been reported for patients with large resting gradients at baseline as well as those with outflow obstruction present only under provocable conditions.234Often a biphasic response of the gradient is observed with alcohol septal ablation in which an acute response with striking reduction (probably due to stunning of the myocardium) is followed by a rise to about 50% of its pre-procedure level the next day, but within several months may reach greatly reduced levels. Results of myectomy and alcohol ablation compared at two institutions showed similar gradient reductions with the two techniques.96Another comparative analysis from a single institution showed both surgery and ablation to substantially reduce resting and provocable gradients, but to a significantly greater degree with surgery.101

A number of other favorable structural and functional effects following ablation have been reported,231representing the expected consequences of reduced outflow gradient, normalization of LV pressures, and reduced systolic overload. Echocardiographic analyses from two groups have reported ablation to be associated with widespread regression of LVH beyond the alcohol target area,229,233but the extent to which remodeling occurs with time secondary to this procedure is unpredictable and not fully understood. Also, there is concern that extensive wall thinning could lead to arrhythmogenic susceptibility or even the end-stage phase.

A large proportion of ablation patients from several centers have been reported to demonstrate subjective improvement in limiting symptoms and in quality of life in observational studies over relatively short-term follow-up periods of 2 to 5 years. As with surgery, the decrease in symptoms associated with ablation is often dramatic.44,46,49,88,101,108,232,234In addition, improved exercise performance has been shown objectively in terms of total treadmill exercise time and peak oxygen consumption in some studies.46,96,101,232However, alcohol septal ablation has yet to be subjected to the scrutiny of randomized or controlled studies or long-term follow-up. A recent study found that both septal myectomy and ablation led to improved exercise testing parameters, but surgery was superior in thisregard.232

The mortality and morbidity associated with alcohol ablation in experienced centers have proved to be relatively low, although they are similar in surgical myectomy. Procedure-related mortality has been reported to be from 1% to 4% but is probably reduced in the more recent cases. Reports of permanent pacemaker implantation for induced high-grade A-V block have ranged from 5% to as high as 30%,46,88,101,228but this complication appears to be decreasing substantially with the use of smaller amounts of alcohol. In contrast to septalmyectomy, which usually produces left bundle branch block, alcohol ablation commonly results in right bundle branch block.45,46It is also possible for coronary artery dissection to occur, as well as backward extravasation of alcohol, producing occlusion or abrupt coronaryno-flow87and a large anteroseptal myocardial infarction.

Proper selection of patients for alcohol septal ablation remains a crucial issue.228Similar to patients recommended for septal myectomy,5,7,8,11,13,41all candidates for alcohol septal ablation should have severe heart failure symptoms (NYHA classes III or IV) refractory to all medications utilized in HCM as well as a subaortic gradient of 50 mm Hg or more measured with Doppler echocardiography either under basal conditions and/or with physiologic provocative maneuvers during exercise.228Caution should be exercised so that in patients selected for alcohol septal ablation, outflow gradients are documented to be due to SAM and proximal mitral valve-septal contact,119exclusive of congenital abnormalities of the mitral apparatus such as anomalous papillary muscle insertion into mitral valve, which produces more distal muscular obstruction in the mid-cavity.91,115

Nevertheless, the number of alcohol ablations performed world-wide now approaches an estimated 3,000 over only about a six-year period, exceeding the number of surgical myectomies performed over the 40 years since this operation was introduced.228In some instances, the frequency with which myectomy surgery has been performed for obstructive HCM has now been reducedby more than 90%103,228due to the recent accelerated enthusiasm for ablation.

Disproportionality in the frequency with which alcohol septal ablation is performed relative to myectomy (ablations are estimated to be at least 15 to 20 times more common than surgery at present) has raised concerns that there may have an insidious and unjustifiable lowering of the symptom and gradient-level threshold in the selection of patients for ablation, with less symptomatic NYHA class II, less obstructed, and younger patients now undergoing the procedure.228This circumstance has evolved in part because of the relative ease with which ablation can be performed (compared to surgery), with substantially less discomfort during a much shorter postoperative hospitalization and recovery period in the absence of a sternotomy. However, this fact does not justify less strict criteria for alcohol septal ablation.

Another factor that has affected patient selection for alcohol septal ablation is the practice of determining eligibility based solely on a subaortic gradient provoked by non-physiologic interventions such as dobutamine infusion (rather than exercise, for example).88,230Dobutamine is an inotropic and catecholamine-inducing drug that is a powerful stimulant of subaortic gradients in normal hearts or in cardiac diseases other than HCM130,131,235of questionable physiologic and clinical significance,235and occasionally results in adverse consequences to patients with obstruction; dependence on dobutamine to induce gradients can expose some patients to septal ablation in the absence of true impedance to LV outflow. Therefore, dobutamine is generally not recommended for the purpose of provoking outflow gradients in severely symptomatic HCM patients who are regarded as possible candidates for major interventions.

A predominate concern raised with respect to alcohol septal ablation is the potential long-term risk for arrhythmia-related cardiac events (including SCD) directly attributable to the procedure. Unlike myectomy, alcohol septal ablation potentially creates a permanent arrhythmogenic substrate in the form of a healed intramyocardial septal scar that could increase the risk of lethal re-entrant arrhythmias.226This is particularly relevant because many patients with HCM already possess an unstable electrophysiologic substrate as part of their underlying disease.2,208,236,237However, since HCM patients are at increased risk for SCD over particularly long periods, possibly through much of their lifetimes, it will require many years (and probably decades) to determine the likelihood that risk for arrhythmia-related events and SCD is increased as a consequence of the healed intramyocardial scar produced by alcohol septal ablation. Indeed, this is particularly relevant for young patients in whom even a modest annual increase in the risk of SCD would have the likelihood of shortening life considerably. Reports of the non-inducibility of re-entrant ventricular tachyarrhythmia in small numbers of patients in the short term after septal ablation46do not appear sufficient at this juncture to exclude the possibility of late-onset ventricular tachyarrhythmias and SCD over the long risk period characteristic of HCM.26,208

Therefore, at present, the impact of alcohol ablation on the incidence of SCD is unresolved. Until more is known regarding the natural history of patients undergoing alcohol septal ablation and there is less uncertainty regarding the consequences of the intramyocardial scar, particularly careful selection of patients seems advisable and prudent (by largely confining the procedure to older adults), particularly when the option for surgical myectomy is feasible. There would not appear to be a primary role for alcohol ablation in children, and such procedures are not advised.

Due to morphologic heterogeneity, not all HCM patients with obstruction are ideal candidates for septal ablation. This therapy relies on the fixed anatomic distribution and size of the septal perforator coronary arteries. Therefore, the ablation technique cannot make adjustments for variability in the distribution and size of these arterial vessels in relation to the distribution of septal hypertrophy, or for other complexities of LV outflow tract morphology such as greatly elongated mitral leaflets and anomalous papillary muscle. The direct operative approach provides greater flexibility for relieving obstruction and also allows surgical treatment for associated cardiac abnormalities such as primary valvular disease (e.g., myxomatous mitral valve prolapse or aortic stenosis),124atherosclerotic CAD, or segmental myocardial bridging of the left anterior descending coronary artery,238as well as anomalies of the mitral valve and apparatus. Also, relief of obstruction with surgery is immediate (but is often delayed with alcohol septal ablation), which may be crucial in some patients with particularly severe symptoms of heart failure.

The “learning curve” for expertise with the alcohol septal ablation technique is steep (due, in part, to the relatively small number of eligible HCM patients), particularly regarding selection of the optimal septal perforator branch; therefore, ablation should not be regarded as a routine technique to be employed by any expert interventional cardiologist. It is advisable that alcohol ablation (as well as myectomy) be largely confined to centers having substantial and specific experience with HCM and the procedure in order to assure proper patient selection, the lowest possible rates of morbidity and mortality, and the greatest likelihood of achieving benefits.

While alcohol ablation represents an option available to HCM patients and a selective alternative to surgery, it is not at this time regarded as the standard and primary therapeutic strategy for all severely symptomatic patients refractory to maximal medical management with marked obstruction to LV outflow (Table 1). Septal myectomy remains the gold standard for this HCM patient subset.7,11,14,41,232

Sudden Cardiac Death

Risk stratification

Since the modern description of HCM by Teare in 1958,12sudden and unexpected death (unassociated with severe heart failure) has been recognized as the most devastating and often unpredictable complication and the most frequent mode of premature demise from this disorder. Sudden cardiac death may occur as the initial disease presentation, most frequently in asymptomatic or mildly symptomatic young people.7,10,21–29,42,56,208,209,237–248The high-risk HCM patients constitute only a minority of the overall disease population,5,7,11,21,22,27,249and historically, a major investigative focus has been the isolation of the small but important subset of patients at high-risk among the overall HCM spectrum. Since SCD can be the initial manifestation of HCM,23,25–27,239it often occurs without reliable warning signs or symptoms, and often in the early morning hours after awakening.24Although SCD is most frequent in adolescents and young adults less than 30 to 35 years old, such risk also extends through mid-life and beyond;26the basis for this particular predilection of SCD for the young is unresolved. Therefore, achieving any particular age does not itself confer an immunity to sudden HCM-related catastrophe. Sudden cardiac death occurs most commonly during mild exertion or sedentary activities (or during sleep), but it is not infrequently triggered by vigorous physical exertion.23,25Indeed, HCM is the most common cause of cardiovascular-related SCD in young people, including competitive athletes (most commonly in basketball and football).25

The available data (largely from recorded arrhythmic events that triggered appropriate defibrillator interventions) suggest that complex ventricular tachyarrhythmias emanating from an electrically unstable myocardial substrate are the most common mechanism by which SCD occurs in HCM.2,208,209,236,237Indeed, ventricular arrhythmias are an important clinical feature in adults with HCM. On routine ambulatory (Holter) 24-h ECG monitoring, 90% of adults demonstrate ventricular arrhythmias, which are often frequent or complex, including premature ventricular depolarizations (greater than or equal to 200 in 20% of patients), ventricular couplets (in greater than 40%) or nonsustained bursts of ventricular tachycardia (in 20% to 30%).250Alternatively,it is possible that in some patients supraventricular tachyarrhythmias could trigger ventricular tachyarrhythmias or that bradyarrhythmias occur and require back-up pacing.

It has been suggested that life-threatening tachyarrhythmias could be provoked in HCM by a number of variables either secondary to environmental factors (e.g., intense physical exertion)23,25or, alternatively, intrinsic to the disease process. The latter may involve a vicious cycle of increasing myocardial ischemia190,192–198,238,251and diastolic (or systolic) dysfunction,37,181–188possibly impacted by outflow obstruction,13,127systemic arterial hypotension,29,252,253or supraventricular tachyarrhythmias163,244,254that lead to decreased stroke volume and coronary perfusion.

Although the available data on the stratification of SCD risk are substantial and a large measure of understanding has been achieved, it is important to underscore that precise identification of all individual high-risk patients by clinical risk markers is not completely resolved. This issue remains a challenge due largely to the heteroeneity of HCM disease presentation and expression, its relatively low prevalence in cardiologic practice, and the complexity of potential pathophysiologic mechanisms.1,7,36,41,50,59Nevertheless, it is possible to identify most high-risk patients by noninvasive clinical markers,21,22,255and only a small minority of those HCM patients who die suddenly (about 3%) are without any of the currently acknowledged risk markers.21The highest risk for SCD has been associated with the following (Table 2): 1) prior cardiac arrest or spontaneously occurring and sustained VT;2392) family history of a premature HCM-related SCD particularlyif sudden, in a close relative, or if multiple inoccurrence;5,7,213) identification of a high-risk mutant gene;6,19,63,132,245–2474) unexplained syncope, particularly in young patients or when exertional orrecurrent;7,115) nonsustained VT (of 3 beats or more and of at least 120 beats/min) evident on ambulatory (Holter) ECG recordings;240,242,256–2586) abnormal blood pressure response during upright exercise which is attenuated or hypotensive, indicative of hemodynamic instability, and of greater predictive value in patients less than 50 years old or if hypotensive;29,252,253,259and 7) extreme LVH with maximum wall thickness of 30 mm or more, particularly in adolescents and young adults.21,27,28

View this table:
Table 2

Risk Factors for Sudden Death in HCM*

MajorPossible in Individual Patients
Cardiac arrest (ventricular fibrillation)Atrial fibrillation
Spontaneous sustained ventricular tachycardiaMyocardial ischemia
Family history of premature sudden deathLV outflow obstruction
Unexplained syncopeHigh-risk mutation
LV thickness greater than or equal to 30 mmIntense (competitive) physical exertion
Abnormal exercise blood pressure
Nonsustained ventricular tachycardia (Holter)
  • Symbols:

    Abbreviations: LV = left ventricular.

  • * see text for details.

HCM patients (particularly those less than 60 years old) should undergo comprehensive clinical assessments on an annual basis for risk stratification and evolution of symptoms, including careful personal and family history, noninvasive testing with two-dimensional echocardiography (primarily for assessment of magnitude of LVH and outflow obstruction), 24- or 48-h ambulatory (Holter) ECG recording for VT, and blood pressure response during maximal upright exercise (treadmill or bicycle). Subsequent risk analysis should be performed periodically and when there is a perceived change in clinical status.

Recent attention has focused on the magnitude of LVH (as assessed by conventional two-dimensional echocardiography) as an indicator of risk.27Two independent groups have reported a direct association between magnitude of LV wall thickness and risk of SCD in large HCM populations.21,22,27In one study,27extreme LVH (maximum thickness of 30 mm or more), present in approximately 10% of HCM patients, conveyed substantial long-term risk. Sudden cardiac death was most common in asymptomatic or mildly symptomatic adolescents or young adults and was estimated at 20% over 10 years and 40% over 20 years (i.e., annual mortality about 2%). There is supporting circumstantial evidence from retrospective cross-sectional analyses that extreme hypertrophy represents a risk factor for premature SCD because it is observed less commonly in older than in younger patients;21,22,260this finding could reflect either preferential SCD at a young age, structural remodeling with wall thinning, or both. This relationship of extreme hypertrophy to age is accentuated with wall thicknesses of 35 mm or more, which appear in less than 1% of patients older than 50 years.260Another group, however, has maintained that extreme hypertrophy is a predictor of SCD, only when associated with other risk factors such as unexplained syncope, family history of premature SCDs, nonsustained VT on Holter, or an abnormal blood pressure response during exercise.22At present, although it is not unequivocably resolved as to whether extreme hypertrophy as a sole risk factor is sufficient to justify a recommendation for prevention of SCD with an ICD, serious consideration for such an intervention should be given to young patients.

The concept that risk of SCD is related to the magnitude of hypertrophy does not, however, infer that the risk is necessarily low when LV wall thickness is less than 30 mm, because other risk markers may be present in a given patient; indeed, the majority of patients who die suddenly do, in fact, have wall thicknesses of less than 30 mm.21,22,27,28Furthermore, a small number of high-risk pedigrees with troponin T and I mutations have been reported in whom SCD was associated with particularly mild forms of LVH, including a few individuals with normal LV wall thickness and mass.19,248,261However, such events appear to be uncommon within the overall HCM patient spectrum. Although prognosis is generally not tightly linked to the pattern and distribution of LVH, the preponderance of evidence suggests that segmental wall thickening at the low end of the morphologic spectrum (i.e., less than 20 mm thickness, regardless of its precise location), generally confers a favorable prognosis in the absence of other major risk factors.11,27,28Such localized hypertrophy includes the nonobstructive form of HCM confined to the most distal portion of LV (“apical HCM”).33,40,52

Disorganized cardiac muscle cell arrangement,4,51,236myocardial replacement scarring as a repair process following cell death (possibly resulting from ischemia due to abnormal microvasculature consisting of intramural small vessel disease or muscle mass-to-coronary flow mismatch)129,195,199,200,203and the expanded interstitial (matrix) collagen compartment262probably serve as the primary arrhythmogenic substrate predisposing some susceptible patients to re-entrant, life-threatening ventricular tachyarrhythmias. That extreme degrees of LVH can be linked to sudden events is perhaps not unexpected, considering the potential impact of such wall thickening on myocardial architecture, oxygen demand, coronary vascular resistance, and capillary density, all of which thereby create an electrophysiologically unstable substrate. The degree of hypertrophy does not appear to be directly associated with the severity of diastolic dysfunction and limiting symptoms.188,263Paradoxically, most patients with massive degrees of LVH do not experience marked symptomatic disability,22,27,263LV outflow obstruction, or left atrial enlargement.

It is a clinical perception that the premonitory symptom most associated with the likelihood of SCD in HCM is impaired consciousness (i.e., syncope or near-syncope).128,165However, the sensitivity and specificity of syncope as a predictor of SCD is low, possibly because most such events in this disease are probably not in fact secondary to arrhythmias or related to outflow obstruction. Indeed, there are many potential causes of syncope, some of which are unrelated to the basic disease state and are often neurocardiogenic (i.e., vagal, neurally-mediated syndromes) in origin.5,7,11,264Even when an underlying cause for impaired consciousness cannot be identified, this symptom-complex can be compelling in some HCM patients,128particularly when it is exertional or recurrent, when it occurs in the young, or in the context of a single recent syncopal episode judged to be disease-related. Therefore, syncope may represent the basis of a defibrillator implant to ensure preservation of life should a life-threatening arrhythmia intervene.208

Available data suggest that LV outflow obstruction (gradient 30 mm Hg or more) can only be regarded as a minor risk factor for SCD in HCM.29,30,127The impact of gradient on SCD risk is not sufficiently strong (positive predictive value of only 7%) for obstruction to merit a role as the sole (or predominant) deciding clinical parameter and the primary basis for decisions to intervene prophylactically with an ICD.127

Identification of HCM in young children is exceedingly uncommon and often creates a specific clinical dilemma because such an initial diagnosis occurring so early in life (frequently fortuitously) raises uncertainty regarding future risk over particularly long time periods. One report suggests that short tunneled (bridged) intramyocardial segments of left anterior descending coronary artery independently convey increased risk for cardiac arrest, probably mediated by myocardial ischemia.238However, potential biases in patient selection, the frequency of coronary arterial bridging in surviving adults and those who have died of noncardiac causes, and the need for routine invasive coronary arteriography in order to identify this abnormality prospectively seem to mitigate the potential power of coronary bridging as a risk factor for SCD.

It has been proposed, based on genotype-phenotype correlations, that the genetic defects responsible for HCM could represent the primary determinant and stratifying marker of prognosis and for SCD and heart failure risk, with specific mutations conveying either favorable or adverse prognosis (i.e., high- and low-risk mutations).6,19,132,138,247,265,266For example, it has been suggested that some cardiac beta-myosin heavy chain mutations (such as Arg403Gln and Arg719Gln) and some troponin-T mutations are associated with higher incidence of premature death, decreased life expectancy, and early onset disease manifestations, while other HCM genes such as cardiac myosin-binding protein C (particularly InsG791) or alpha-tropomyosin (Asp175Asn) convey a more favorable prognosis.63However, routine clinical testing for specific mutations believed to be high (or low) risk has been shown to have low yield.265,266Therefore, it is premature to draw definitive conclusions regarding gene-specific clinical outcomes based solely on the presence of a particular mutation, by virtue of extrapolation from available epidemiologic-genetic data which are formulated from relatively small numbers of genotyped families largely skewed toward high-risk status.6Consequently, it is becoming increasingly evident that the presence or absence of a particular mutation does not by itself represent sufficient data to convey clear prognostic implications and that HCM mutations may not possess distinctive clinical signatures.

The particular prognosis attached to adult carriers with a mutant HCM gene but without LVH and clinical expression of HCM,54,245or those individuals who develop hypertrophy de novo in adulthood,6,17,64,65,146is uncertain; however, at this early juncture, this subgroup would not appear to be associated with an adverse prognosis (Fig. 1). An exception to this tenet may be the small number of SCDs in young people with little or no LVH reported in a very few families with troponin-T mutations.19,245,247,248

There is no convincing evidence that invasive markers such as those defined with laboratory electrophysiologic testing (i.e., programmed ventricular stimulation)264,267have an important routine role in identifying those HCM patients who have an unstable electrical substrate and are at high-risk for SCD due to life threatening arrhythmias. Similar to the experience in CAD and dilated cardiomyopathy, polymorphic VT and VF (which are the most commonly provoked arrhythmias) are generally regarded as nonspecific electrophysiologic testing responses to multiple ventricular extra-stimuli,5,11and these specialized laboratory studies are highly dependant on the level of aggression of the protocol.267For example, stimulation with three ventricular premature depolarizations rarely triggers monomorphic VT in HCM (in contrast to CAD), but frequently induces polymorphic VT or VF, even in some patients at low risk for SCD.

It is now the predominant view that the risk stratification strategies involving laboratory induction of such ventricular arrhythmias are neither desirable in HCM patients on a routine basis nor, per se, justify aggressive intervention.5,7,11Electrophysiologic studies with or without programmed ventricular stimulation may, however, have some value in selected patients such as those with otherwise unexplained syncope.

Most of the clinical markers of SCD risk in HCM are limited by relatively low positive predictive values due in part to relatively low-event rates.11,21,27,28,30,242However, the high negative predictive values (at least 90%) of these markers suggest that the absence of risk factors and certain other clinical features can be used to develop a profile of patients having a low likelihood of SCD or other adverse events.11Adult patients can probably be considered low risk if they demonstrate: 1) no or only mild symptoms of chest pain or exertional dyspnea (NYHA functional classes I and II); 2) absence of family history of premature death from HCM; 3) absence of syncope judged to be HCM-related; 4) absence of nonsustained ventricular tachycardia during ambulatory (Holter) ECG; 5) outflow tract gradient at rest of less than 30 mm Hg); 6) normal or relatively mild increase in left atrial size (less than 45 mm); 7) normal blood-pressure response to upright exercise; and 8) mild LVH (wall thickness less than 20 mm).

Patients with an apparently favorable prognosis in the absence of risk factors constitute an important proportion of the overall HCM population. Most such patients probably will not require aggressive major medical treatment and generally deserve a large measure of reassurance regarding their prognoses. Little or no restriction is necessary with regard to recreational activities and employment, although exclusion from intense competitive sports is advised.

Prevention

Efforts at the prevention of SCD have historically targeted only the minority of patients with HCM in whom SCD risk was unacceptably high. Historically, treatment strategies to prophylactically reduce the risk for SCD or delay progression of congestive symptoms have been predicated on the administration of drugs such as beta adrenergic-blockers, verapamil, and type I-A antiarrhythmic agents (i.e., quinidine, procainamide) to those patients perceived to be at high risk. However, there is no evidence that this practice of prophylactically administering such drugs empirically to asymptomatic HCM patients to mitigate the risk for SCD is efficacious, and this strategy now seems out-dated with the current availability of measures that more effectively prevent SCD, such as the ICD. In addition, low dose (less than 300 mg) amiodarone has been associated with improved survival in HCM,243,257but this agent requires careful monitoring and may not be tolerated due to its potential toxicity over the long risk periods incurred by young patients.

When risk level for SCD is judged by contemporary criteria to be unacceptably high and deserving of intervention, the ICD is the most effective and reliable treatment option available, harboring the potential for absolute protection and altering the natural history of this disease in some patients208,209,237,268(Fig. 1). In one multicenter retrospective study, ICDs appropriately sensed and automatically aborted potentially lethal ventricular tachyarrhythmias by restoring sinus rhythm in almost 25% of a high-risk cohort, followed for a relatively brief period of 3 years.208Appropriate device interventions occurred at a rate of 11% per year for secondary prevention (the implant following cardiac arrest or spontaneous and sustained ventricular tachycardia) and at 5% per year for primary prevention (implant based solely on noninvasive risk factors), usually in patients with no or only mild prior symptoms. There was only a 4 to 1 excess of ICDs implanted to lives saved. Patients receiving appropriate defibrillation shocks were generally young (mean age 40 years). ICDs often remained dormant for prolonged periods before discharging (up to 9 years), emphasizing the unpredictable timing of SCD events in this disease, the potentially long risk period, and the requirement for extended follow-up duration to assess survival in HCM studies.26,208Therefore, while the decision to implant a defibrillator for primary prevention cannot reasonably be deferred beyond the time when high-risk status is first judged to be present, it may precede considerably the time at which the device ultimately discharges. There is an ongoing multicenter international study of HCM patients with ICDs208for the purpose of obtaining data on interventional devices in a much larger population over longer periods of time.

The ICD is strongly warranted for secondary prevention of SCD in those patients with prior cardiac arrestor sustained and spontaneously occurring VT.7,208The presence of multiple clinical risk factors conveys increasing risk for SCD of sufficient magnitude to justify aggressive prophylactic treatment with an ICD for primary prevention of SCD.208,268Strong consideration should be afforded for a prophylactic ICD in the presence of one risk factor regarded as major in that patient (e.g., a family history of SCD in close relatives).7,27,268

Because the positive predictive value of any single risk factor is low, such management decisions must often be based on individual judgment for the particular patient, by taking into account the overall clinical profile including age, the strength of the risk factor identified, the level of risk acceptable to the patient and family, and the potential complications largely related to the lead systems and to inappropriate device discharges. It is also worth noting that physician and patient attitudes toward ICDs (and the access to such devices within the respective health care system) can vary considerably among countries and cultures and thereby have an important impact on clinical decision-making and the threshold for implant in HCM.269The ACC/AHA/NASPE 2002 guidelines have designated the ICD for primary prevention of SCD as a class IIb indication and for secondary prevention (after cardiac arrest) as a class I indication.225

There is, at present, an understandable reluctance on the part of pediatric cardiologists to implant such devices chronically in children (particularly for primary prevention) considering the necessary, ongoing commitment required for maintenance and the likelihood that lead or other (ICD-related) complications will occur over very long time periods. However, while adolescence may represent a psychologically difficult age to be encumbered by an ICD, it should also be emphasized that this is coincidently the period of life consistently showing the greatest predilection for SCD in HCM.7,21–23,25–28,208One alternative but empiric strategy proposed for some very young high-risk children is the administration of amiodarone as a bridge to later ICD placement after sufficient growth and maturation has occurred. Some investigators also regard the end-stage phase of HCM as a risk factor for SCD, justifying implantation of a cardioverter-defibrillator during the waiting period prior to the availability of a heart for transplant.

Athlete recommendations

In accord with the recommendations of the Expert Consensus panel of the 26th Bethesda Conference,241young patients with HCM should be restricted from intense competitive sports to reduce the risk for SCD that may be associated with such extreme lifestyle. A linkage has been established between SCD and intense exertion in trained athletes with underlying cardiovascular disease (including HCM) and SCD.25,270

There is indirect and circumstantial evidence that the removal of young athletes from the competitive arena reduces risk for SCD.241,271Not all trained athletes with HCM die suddenly during their competitive phase of life, only some HCM-related SCDs are associated with intense physical activity,25,26and precision in the stratification of risk for athletes with HCM is particularly difficult given the extreme environmental conditions to which they are often exposed (associated with alterations in blood volume hydration and with electrolytes). Nevertheless, the consensus of the general medical community prudently supports avoiding exposure to most competitive sports for young athletes with HCM to reduce SCD risk, and therefore withdrawal from the athletic arena can be regarded as a treatment modality in this disease.241,271However, stringent lifestyle or employment modifications for other HCM patients (who are not participants in organized athletics) do not seem justified or practical, although intense physical activity involving burst exertion (e.g., sprinting) or systematic isometric exercise (e.g., heavy lifting) should be discouraged. Although data are scarce, there is presently no evidence to suggest that genetically affected but phenotypically normal family members are generally at increased risk for SCD.Therefore, there is little basis for subjecting such individuals to the same activity restrictions as many other HCM patients, or excluding them from competitive athletics in the absence of cardiac symptoms, family history of SCD, or a mutant gene regarded as malignant. However, periodic (probably annual) noninvasive clinical evaluation directed toward risk assessment is warranted in this subset of patients.

Atrial Fibrillation

Atrial fibrillation is the most common sustained arrhythmia in HCM and usually justifies aggressive therapeutic strategies30,38,161–163,249(Fig. 1). Paroxysmal episodes or chronic AF ultimately occur in 20% to 25% of HCM patients,30,163,249linked to left atrial enlargement and an increasing incidence with age.163Furthermore, it is possible that subclinical AF (i.e., identified only by Holter recording) may be even more common. Clinical cohort studies show that AF is reasonably well tolerated by about one-third of patients and is not an independent determinant of sudden unexpected death;163however, it is possible that in certain susceptible patients, AF may trigger life-threatening ventricular arrhythmias.244,254Nevertheless, AF is independently associated with heart failure-related death, occurrence of fatal and nonfatal stroke, as well as long-term disease progression with heart failure symptoms;38,161,163transient episodes occur in about 30% of patients immediately following septal myectomy, often in patients with a prior history of AF.202Risk for complications of AF is enhanced when the arrhythmia becomes chronic, onset is before 50 years of age, and outflow obstruction is present.163

Paroxysmal episodes of AF may also be responsible for acute clinical deterioration, with syncope or heart failure resulting from the reduced diastolic filling and cardiac output—as a consequence of increased ventricular rate and with the loss of atrial contraction (and its contribution to ventricular filling) in a hypertrophied LV with pre-existing impaired relaxation and compliance.161–163Atrial fibrillation in HCM should be managed generally in accordance with the ACC/AHA guidelines.272In particular, electrical or pharmacologic cardioversion are indicated in those patients presenting within 48 h of onset, assuming that the presence of atrial thrombi can be excluded with a reasonable degree of certainty. Although comparative data regarding the efficacy of antiarrhythmic drugs are not available for HCM patients, amiodarone is generally regarded as the most effective antiarrhythmic agent for preventing recurrences of AF, based largely on extrapolation from its use in other heart diseases.273

A generally aggressive strategy for maintaining sinus rhythm is warranted in HCM because of the association of AF with progressive heart failure and mortality, as well as stroke.38In chronic AF, beta-blockers, verapamil (and digoxin) have proved effective in controlling heart rate, although A-V node ablation and permanent ventricular pacing may occasionally be necessary in selected patients. Anticoagulant therapy (with warfarin) is indicated in patients with either paroxysmal or chronic AF.7,11,38,163Because even one or two episodes of paroxysmal AF have been associated with increased risk for systemic thromboembolization in HCM, the threshold for initiation of anticoagulant therapy should be low and can include patients after the initial AF paroxysm.7,38,163Since warfarin has proved superior to aspirin in other cardiac conditions associated with AF, it is the recommended anticoagulant agent in HCM patients judged to be at risk for thromboembolism. While anticoagulation reduces the risk of thromboembolic events in patients with AF and HCM, it is also recognized that anticoagulation does not completely abolish the risk of stroke.38,163Such clinical decisions should be tailored to the individual patient after considering the risk for hemorrhagic complications, lifestyle modifications, and expectations for compliance.

The most appropriate management for patients with asymptomatic nonsustained supraventricular tachycardia (detected only on ambulatory [Holter] ECG or exercise-testing), and associated with left atrial enlargement is presently unresolved. Also, at present, there is little experience specifically in HCM patients with emerging and novel alternative treatment strategies for AF such as pulmonary vein radio-frequency ablation, the surgical MAZE procedure, or implantable atrial defibrillators to warrant definitive recommendations at this time.

Footnotes

  • 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 American 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). Eur Heart J 2003; doi:10.1016/S0195-668X(03)00479-2.

    Copies: This document is available on the Web sites of the ACC at www.acc.org and ESC at www.escardio.org. 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 Jamestown Road, London, NW1 7BY, United Kingdom, Tel: +44.207.424.4422; Fax: +44.207.424.4433; Email: gr.davies@elsevier.com

  • a American College of Cardiology

  • b European Society of Cardiology

  • * Official representatives of the European Society of Cardiology

  • Former members of Task Force

  • Former Chair of Task Force

References