Hypertrophic Cardiomyopathy - Gerald Lawrie MD

[Pages:12]CLINICAL CARDIOLOGY

CLINICIAN'S CORNER

Hypertrophic Cardiomyopathy

A Systematic Review

HYPERTROPHIC CARDIOMYOPathy (HCM) is a complex and relatively common genetic cardiac disease that has been the subject of intense scrutiny andpinvestigation for more than 40years.'-loHypertrophic cardiomyopathyis an important cause of disability and death in patients of all ages,although sudden and unexpected death in youngpeople isperhaps the most devastatingcomponent of its natural history. Because of marked heterogeneity in clinical expression, natural history,and p r o g n o ~ i s , ~H"C~M~ often represents a dilemma to primary care clinicians and cardiovascular specialists, even to those for whom this disease is a focus of their investigative careers. Controversyabounds with regard to diagnostic criteria, clinical course, and management for which difficult questionsoftenarise,particularly amongpractitioners infrequently engaged in the evaluation of HCM patients. Consequently, it is timely to place in perspective and clarify many of these relevant clinical issues and profile the rapidly evolving concepts regarding HCM.

Context Throughout the past 40 years, a vast and sometimes contradictory literature has accumulated regarding hypertrophic cardiomyopathy (HCM),a genetic cardiac disease caused by a variety of mutations in genes encoding sarcomeric proteins and characterized by a broad and expanding clinical spectrum.

Objectives To clarify and summarize the relevant clinical issues and to profile rapidly evolving concepts regarding HCM.

Data Sources Systematicanalysis of the relevant HCM literature,accessed through MEDLINE (1966-2000),bibliographies,and interactions with investigators.

Study Selection and Data Extraction Diverse information was assimilated into a rigorous and objective contemporary description of HCM, affording greatest weight to prospective, controlled, and evidence-based studies.

Data Synthesis Hypertrophic cardiomyopathy is a relatively common genetic cardiacdisease (1:500in the general population)that is heterogeneouswith respectto diseasecausing mutations, presentation, prognosis, and treatment strategies. Visibility attached to HCM relates largely to its recognition as the most common cause of sudden death in the young (including competitive athletes). Clinical diagnosis is by 2-dimensional echocardiographicidentificationof otherwise unexplained leftventricularwall thickening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and normal life expectancy. Subsets with higher mortality or morbidity are linked to the complications of sudden death, progressive heart failure, and atrial fibrillation with embolic stroke.Treatment strategiesdepend on appropriate patient selection,includingdrugtreatment forexertionaldyspnea (p-blockers,verapamil,disopyramide)and theseptalmyotomymyectomy operation, which is the standard of care for severe refractory symptoms associated with marked oufflowobstruction;alcohol septalablationand pacing are alternatives to surgery for selected patients. High-risk patients may be treated effectively for sudden death prevention with the implantable cardioverter-defibrillator.

Conclusions Substantial understanding has evolved regardingthe epidemiologyand clinical course of HCM, as well as novel treatment strategiesthat may alter its natural history. An appreciation that HCM, although an important cause of death and disability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients.

METHODS

JAMA. 2002;287:1308-1320



A systematic search of the medical literature involving 968 articles primarily related to English-language HCM publications (1966-2000) from a varied and extensive number of authors and centers was conducted through MEDLINE or bibliographies of published articles. These studies and others before 1966 were analyzed to create a balanced appraisal of HCM.

Published accounts of HCM have come disproportionately from a rela-

tively small group of highly selected centers in theUnited States,Canada,and Europe. In addition,perceptions emanating from the author's more than 25 years of extensive experience with HCM interfaced with the literature analysis. Many clinical HCM studies are observational and retrospective in design because of difficulty in organizing large prospective and randomized clinical trials for a disease with heterogeneous expres-

sion, selective referral patterns, and diverse mechanisms for morbidity and mortality. Therefore,in HCM, the level of evidence governing management

Author Affiliation: MinneapolisHeart InstituteFoundation, Minneapolis, Minn. Corresponding Author and Reprints: Barry J. Maron, MD, Minneapolis Heart lnstitute Foundation, 920 E 28th St, Suite 60, Minneapolis,MN 55407 (e-rnail: hcrn.rnaron@). Clinical CardiologySection Editor: MichaelS. Lauer, MD, ContributingEditor.

1308 JAMA, March 13,2002-Vol287, No. 10

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An important but complex objec- The latter risk factor emanates from

tive has been the identification of such a continuous, direct relationship be-

higher-risk individuals among the vast tween maximum LV wall thickness and

HCM spectrum. For example, sudden sudden death, which supports the mag-

death can be the initial manifestation nitude of LVH as a determinant of prog-

of HCM, and such patients usually have nosis in HCM.6,41,42E,x4c7eptions to that

no or only mild prior symptoms. Al- association are a few highly selected

though sudden death occurs most com- HCM families with multiple sudden

monly in children and young adults, deaths and mild LVH caused by tropo-

risk extends across a wide age range nin T m u t a t i ~ n s . D~ e~s.cr~ip~ti.o~n ~of the

through midlife and beyond'14; there- total HCM risk profile is probably in-

fore, achievinga particular age does not complete, and no single disease fea-

confer immunity to sudden catastro- ture or test is capable of stratifying risk

phe. Sudden death occurs most com- in all patients.

monly during mild exertion or seden- There is only a suggested associa-

tary activities but is not infrequently

but no clinically relevant

related to vigorous physical exer- and independent linkage between

t i ~ n . ~ ~ , I"n~de,e"d~, HCM is the most sudden death and outflow obstruccommon cause of cardiovascular sud- tion,3.7.41.11~.l~4~1200a1l3t7hough data on par-

den death in young people, including ticularly large ( 2 100 mm Hg) gradi-

trained competitiveathletes (most com- ents arelimited.1"~12O7ne report suggests

monly in basketball and football and in that short, tunneled (bridged) seg-

black athletes).43

ments of left anterior descending coro-

The majority of HCM patients (55%) nary artery, mediated by ischemia, in-

do not demonstrate any of the acknowl- dependently convey increased risk for

edged risk factors in this disease, and it cardiac arrest in children with HCM.'38

is exceedingly uncommon for such pa- Presentation of HCM in young chil-

tients to die suddenly47t;he subset at in- dren is exceedingly uncommon and

creased risk appears to comprise about usually creates a clinical dilemma be-

10% to 20% of the HCM p o p ~ l a t i o n . ~c~ause of diagnosis (often fortuitous) so

Highest risk for sudden death in HCM early in life and the uncertainty regard-

has been associated with any of the fol- ing risk over such long

lowingnoninvasiveclinicalmarkers (Fig- Studies of HCM in children report an-

ure 3)11: prior cardiac arrest or sponta- nual mortality rates of 2% (community-

neous sustainedventriculartachycardia; based pop~lations)'~to' 6% (tertiaryre-

family history of premature HCM- ferral cohorts) .98,107-109

related death, particularly if sudden, in It has been proposed, based on geno-

close relatives, or multiple;syncope and type-phenotype correlations, that the

some cases of near-syncope, particu- genetic defects responsible for larly when exertional or recurrent, or in could ~C~3,7,9,11-13,23-27,139 represent the

young patients when documented as ar- primary determinant and stratifying

rhythmia-based or clearly unrelated to marker for sudden death risk, with spe-

neurocardiogenic mechanisms; mul- cific mutations conveying either favor-

tiple and repetitive or prolonged bursts able or adverse prognosis.140For ex-

of nonsustained ventricular tachycar- ample, some P-myosin heavy chain

dia on serial ambulatory (Holter) ECG m u t a t i o n s (eg, Arg403Gln a n d

recordings;hypotensiveblood pressure Arg719Gln) and some troponin T mu-

response to exercise,particularly in pa- tations may be associatedwith a higher

tients younger than 50 years; and ex- frequency of premature death com-

treme LVH with maximum wall thick- pared with other mutations, such as

ness 230 mm, particularly in adolescents those of myosin-binding protein C

and young adults.

(InsG791) or a-tropomyosin (Asp175Asn).3,7.9.11-13.23.24.26.27 H OW-

ever, caution is warranted before strong conclusions are drawn regarding prog-

nosis based solely on the availableepidemiologic genetic data, which are relatively limited and skewed by virtue of selection bias toward high-risk families.9s139Access to the molecular biology of HCM does not yet represent a clinically relevant strategy that routinely affects disease management.

Prognosis attached to adult gene carriers without LVH appears to be mostly benign.13.25.53T,h5e4re is no available evidence to justify routinely precluding genotype positive-phenotype negative individuals of any age from most activities or employment opport~nities.~

The role of invasive strategies such as electrophysiologic testing with programmed ventricularstimulationand the significance of induced arrhythmias in detectingthe substrate for ventricularfibrillation in individual HCM patients are u n r e ~ o l v e d . ' ~Li~mJi~ta~tionsinclude the infrequency with which monomorphic ventricular fibrillation is provoked and the nonspecificity of rapid polymorphic ventricular tachycardia and ventricular fibri1lati0n.l~~

Although attention has understandably focused on high-risk HCM patients,the absenceof risk factorsand certain clinical features can be used to develop a profile of HCM patients at low likelihood for sudden death caused by life-threateningrhythm disturbances,as well as other adverse events (eg, at a rate of 45 mm); and hypotensiveblood pressure response to exercise.? Such patients with favorable prognosis constitute an important proportion of the overall HCM population and generally

1314 JAMA, March 13, 2002-Vol287, No. 10

HYPERTROPHIC CARDIOMYQPATHY

deserve a measure of reassurance regarding their d i ~ e a s e . ~ , ~

Most HCM patients should undergo a risk stratification assessment (probably with the exception of patients older than 60 years) that requires, in addition to carefulhistory taking and physical examination, noninvasive testing with 2-dimensional echocardiography, 24- or 48-hour ambulatory Holter ECGs, and treadmill (or bicycle) exercise testing. Such evaluation and follow-up should be carried out by (or involve) qualified specialists in cardiovascular medicine.

Prevention. In HCM, treatment strategies to reduce risk for sudden death have been historically predicated on drugs such as @-blockers,verapamil, and antiarrhythmic agents (ie, quinidine, procainamide, and amiodarone).4,116,117,143-14N5 evertheless,there is

little evidence144that prophylacticpharmacological strategies and rhythmmodulatingdrugs effectivelyreduce risk for sudden death; furthermore, because of itspotential toxicity,amiodaroneisunlikely to be tolerated throughout the long risk periods characteristicof youngHCM patients. Therefore, there would appear to be little justification for prophylactic drug treatment in asymptomatic HCM patients, whether or not they arejudged to be at high risk.143

At present, the implantable cardioverter-defibrillator (ICD) appears to be the most effective treatment modality for the high-risk HCM patient, with the potential to alter natural history (Figure 3).98-10In0 a large multicenter study, ICDs aborted potentially lethal ventricular tachyarrhythmias and restored sinus rhythm in almost 25% of patients throughout a brief 3-year foll o w - ~ pA.p~pr~opriate device interventions occurred at 11%annually for secondary prevention (implant following cardiac arrest) and 5% annually for primary prevention (implant based on risk factors), usually in patients with no or only mild prior symptoms.98Patientsreceiving appropriate shocks were young (mean, 40 years), and ICDs often remained dormant for prolonged periods before discharging (up to 9 years),

emphasizing the unpredictability of ure, particularly when AF onset occurs

sudden death events in HCM.

before 50 years of age and is associated

Sudden death prevention with the with basal outflow obstru~tion.'~~

ICD is most strongly warranted for pa- ParoxysmalAF may be responsible for

tients with prior cardiac arrest or sus- acute clinical decompensation, requir-

tained spontaneous ventricular tachy- ing electricalor pharmacologicalcardio-

cardia. Although multiple risk factors ver~ion.~A,',lt~hough data in HCM pa-

convey increasingly greater sudden- tientsare limited, amiodaroneisregarded

death risk,47a singlemajor risk factor in as effective for reducing AF recur-

an individual patient may be sufficient rences. In chronic AF, @-blockersand

to justify strong consideration for pri- verapamil effectively control heart rate,

mary prevention with an ICD. Never- although A-V node ablation with per-

theless, uncertainty persists regarding manent ventricular pacing may occa-

precisely which HCM patients with only sionally be necessary. Because of the

1 risk factor should be candidates for potential for clot formation and embo-

prophylactic ICD treatment,41.42s9a8nd lization,anticoagulant therapywith war-

therefore individual clinical judgment farin is indicated in patients with either

taking into account the overall clinical recurrentor chronicAF. Since 1or 2 par-

profile,including age,apparent strength oxysms of AF have been associatedwith

of the risk factor identified,and the level the risk for systemicthromboembolism

of risk acceptable to the patient and fam- in HCM, the threshold for initiation of

ily, may be necessary to definitively re- anticoagulant therapy should be

solve many of these clinical decisions. lo^.'^^,'^^ However, such clinical deci-

Also,physician and patient attitudes to- sions should be tailored to the indi-

ward ICDs (and also access to the de- vidual patient after the obligatory life-

vices) can vary considerably among style modifications,risk of hemorrhagic

countries and cultures and profoundly complications,and expectationsfor com-

affect clinical decision making.42,98J46 pliance have been considered.

Intense physical exertion consti- Heart Failure. Presentation. Symp-

tutes a sudden-death trigger in suscep- toms such as exertional dyspnea, or-

tible individual^.^^ Therefore, to re- thopnea, paroxysmal nocturnal dys-

duce risk, disqualification of athletes p n e a , a n d fatigue a r e common,

with unequivocal evidence of HCM characteristicallyin the presence of nor-

from most competitive sports has been mal or supranormal LV contractilityand

prudently recommended by a na- independent of whether outflow ob-

tional consensus ~ a n e 1 . l ~ ~

struction is present (Figure 3).2-8,148-154

Atrial Fibrillation. Atrial fibrillation Such symptoms of HCM-related heart

is the most common sustained arrhyth- failure are usually deferred until adult-

mia in HCM, accounting for unex- hood but may occur at any age.

pected hospitaladmissionsand unsched- Marked symptom progression (to

uled work loss, and therefore usually New York Heart Association classes 111

justifies aggressive therapeutic strate- and IV) is relatively infrequent, devel-

gies (Figure 3). Paroxysmal episodes or oping in about 15% to 20% of an unse-

chronic AF ultimately occur in 20% to lected population, and such exertional

25% of HCM patients, increase in inci- disability may evolve at varyingrates;de-

dence with age, and are linked to left terioration is often gradual and punctu-

atrial enlargement.111~120'29A-'3tr1ial fi- ated with long periods of stability and

bnllation is reasonably tolerated by about day-to-day variability (Figure 3).2,3,7

one third of patients and is not an in- Congestivesymptoms and exertional

dependent determinant of sudden limitation in HCM appear to be largely

death.I3OHowever,AF is associatedwith the consequence of diastolic dysfunc-

embolicstroke (incidence,about 1%an- tion in which impaired LV relaxation,

nually;prevalence,6%),leadingto death increased chamber stiffness, and com-

and disability most frequently in the el- promised left atrial systolic function

derly,131as well as progressive heart fail- impede filling, leading to elevated left

JAMA. March 13, 2002-Vol 287, No. 10 1315

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