Br Heart 71994;72 (Supplement):S 13-S 18

Risk factors and stratification for sudden cardiacdeath in patients with hypertrophiccardiomyopathy

Barry J Maron, Franco Cecchi, William J McKenna

Hypertrophic cardiomyopathy (HCM) is aprimary cardiac disease characterised by adiverse clinical expression'-6 in which prema-ture sudden unexpected death has beenregarded as a critical feature of its natural his-tory.'-23 However, it is also apparent that notall patients within the disease spectrum are atequal risk of premature death, and indeed insome individuals the disease seems to conveylittle or no risk.'7-'9 24 25

Consequently, intense investigative interestand substantial energy have been directedtoward the identification of "risk factors"-that is, those features of the disease that areperceived to predispose specific patientswith HCM to sudden death or cardiacarrest.7 8 12 14 16-19 26-31 Nevertheless, despitethese exploratory studies in risk stratification,there are few comprehensive and prospec-tively obtained long-term data analysed in amultivariate fashion. Though knowledge israpidly evolving and workable approaches arebeginning to emerge, the definition of preciseapproaches for most patients and clinical situ-ations remains incomplete. Indeed, becausesuch controversy persists regarding the defini-tion of risk it seems justified and timely toreview the available data to summarise what isknown about the risk of sudden death inHCM. We hope to show that prospective trialsare needed and to evolve a practical approachand workable guidelines to aid the develop-ment of diagnostic and therapeutic strategies.

CardiovascularResearch Division,Minneapolis HeartInstitute Foundation,Minneapolis,Minnesota, USAB J MaronCardiologia S Luca,Ospedale di Careggi,Florence, ItalyF CecchiDepartment ofCardiologicalSciences, St George'sHospital MedicalSchool, LondonW J McKennaCorrespondence to:Dr Barry J Maron,Cardiovascular ResearchDivision, Minneapolis HeartInstitute Foundation,920 E 28th Street, Suite 40,Minneapolis, N 55407,USA.

Factors influencing prevalence of suddendeathPublished reports indicate that prematuredeath in patients with HCM is most oftensudden and unexpected.-5 7-22333 (Suddendeath is defined as unexpected, non-traumaticdeath occurring instantaneously or within one

hour after the onset of acute symptoms or

signs of cardiac dysfunction.) Reportedannual mortality ranges from about 1% to6%.2 7811 13 16 1821 3337 Several factors seem to

be responsible for this wide range, which isfound even among comparable referral cen-

tres. First, the demographic characteristics ofvarious study groups with HCM may differsubstantially. For example, annual mortalityreported in studies from the 1970s is stillfrequently cited. These studies, however, pre-dated echocardiography and more widespreadidentification of the disease (particularly thenon-obstructive form). Subsequent wide-spread application of echocardiography

dramatically altered the composition of thepopulation of patients with HCM.Furthermore, the diagnostic criteria for HCMhave evolved and have been clarified and nowthere is greater appreciation of the true fre-quency of the non-obstructive form of HCM.

Another contributing variable is the intrin-sic heterogeneity and diversity of the disease'sgenetic and phenotypic expression, haemody-namic state, and clinical course.2356824 25 36-41Furthermore, various subgroups of patientsmay show different relative risks. For exam-ple, mortality was reported to be highest inchildren8 11 13 16 22 33 38 and may also differ insymptom free untreated patients and thosetreated in various ways.

Limitations in ascertaining riskSeveral factors have limited the ability ofinvestigators to stratify the risk of sudden car-diac death in individual patients with HCM.These include the heterogeneity of phenotypicexpression2 3 5 6824 25 38-41 which made it exceed-ingly difficult to establish principles of riskstratification that apply to all or most sub-groups. Also, HCM is uncommon, occurringin about 02% of the general population,42 sofew centres can easily assemble a patient pop-ulation large enough to define risk factors fora subgroup or minority of these patients.

Consequently, certain inherent biases inpatient selection and referral patterns forHCM have become important determinantsof the apparent risk for sudden death.Distribution of patients among medical cen-tres has been particularly skewed43 and mostprevious studies on clinical course, naturalhistory, or risk stratification have been con-ducted retrospectively in a few selected ter-tiary referral institutions in North Americaand Western Europe.64344 Patients are gener-ally referred to such tertiary centres becausethey are already perceived to be at high riskowing to progressive symptoms; or because ofa propensity to sudden premature death; orthey are referred for investigational drug treat-ment, electrophysiological study, surgicalintervention, or specialised instrumentationand device implantation. Such referral institu-tions may also become immersed in thedetailed analysis of selected high risk pedi-grees from which additional patients withunfavorable prognosis are introduced in dis-proportionate numbers into the overallcohort. In addition, because HCM is a com-plex disease, a multitude of disease variables

S 13

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Figure 1 Clinical profile ofpatients with HCM and sudden cardiac death. (A) Agedistribution of 78 patients who died suddenly or experienced cardiac arrest. (B) Functionalstate before sudden death or cardiac arrest (SVT, supraventricular tachycardia). (C)Activity at time ofsudden death or cardiac arrest. *Includes 4 patients who died duringsleep. (From Maron, et aP; reproduced with permission of the American HeartAssociation).

and potential risk factors have been identified(and continue to be described), further con-

founding risk stratification assessment.Previous efforts at establishing relative risk inpatients with HCM should be viewed in thecontext of these limitations, particularly theutilisation of patients at tertiary centres whowere already largely preselected because theywere perceived to be at increased risk even

before they were referred.643

Clinical profileSudden cardiac death in hypertrophic car-

diomyopathy seems to be most common inchildren and young adults, aged 12-35years'-3 7-16 19 21 23 31-33 (fig 1), though it may alsooccur in older adults, even in those who havepreviously been symptom free.48 Suddendeath seems to be uncommon in the firstdecade of life: currently, however, there are

few data on this subgroup of patients. Mostpatients with HCM who die suddenly havebeen symptom free (or have had only mildsymptoms) and often their disease has notbeen identified clinically2 3 7 9 12 14 (fig 1).Patients with functional limitation can alsodie suddenly and unexpectedly; however, we

regard deaths that occur suddenly in patientswith profound congestive heart failure

(whether or not this is associated with the endstage of HCM) to be outside the context ofthis discussion. Most patients (about 60%)experience sudden death while they are inac-tive or only mildly active. But about 40% dieduring or just after vigorous physical activi-ties, including competitive sports9 (fig 1);indeed, HCM seems to be the most commoncause of sudden death in young competitiveathletes.'04546 Also, although operation (usu-ally septal myotomy/myectomy) relievessymptoms in most patients, such individualscan die suddenly many years after successfulsurgical relief of outflow obstruction.47

Mechanisms ofsudden deathBecause so few sudden deaths have beenfortuitously monitored, earlier descriptions ofmechanisms for sudden death unavoidablyhave been based largely on anecdotal observa-tions or inference.'5 48 49

Therefore, various potential mechanismsthat singly or in combination can lead to sud-den death in patients with HCM have beenstudied in those who have experienced recur-rent syncope,49 have survived cardiac arrest,50or have been considered to be at increasedrisk of such events.2829 51-54 These mechanismsare undoubtedly not identical in all at riskpatients and may differ in youthful and olderpatients. Furthermore, the origins of somemechanisms appear to be primarily haemody-namic whereas others are arrhythmic.

Proposed mechanisms of sudden death(based on such observations) include sponta-neous primary ventricular tachycardia/fibrilla-tion, paroxysmal atrial fibrillation and othersupraventricular tachyarrhythmias (with orwithout accessory atrioventricular pathways)leading to accelerated atrioventricular con-duction and ventricular fibrillation orhypotension, and conduction abnormalitiesinvolving dysfunction of the sinoatrial oratrioventricular nodes or the distal His-Purkinje system (including complete heartblock).2 3 7 19 48 51 54The haemodynamic consequences of such

electrophysiological abnormalities may beexaggerated by the presence of dynamicobstruction to left ventricular outflow, bysevere impairment of diastolic filling, or by theinduction of myocardial ischaemia (possiblyowing to reduced coronary reserve secondaryto abnormalities of the intramural smallvessels) and fibrosis,2 3 19 54-56 which can reducethe threshold for ventricular arrhythmias.Alternatively, the finding of ischaemia or out-flow obstruction in patients with syncope oraborted cardiac arrest, or of severe exercisehypotension despite an appropriate increasein cardiac output262749 suggests that in somepatients these pathophysiological mechanismscan have a primary role in provoking suddencardiac death.2 3 7 15 19 54-59What determines the clinical outcome after

an arrhythmic, ischaemic, or vascular trigger-ing event? Though unproven, the workinghypothesis of many investigators is that thearrhythmogenic substrate is the extent and

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Risk factors and stratification for sudden cardiac death in patients with hypertrophic cardiomyopathy

Table 1 Probable risk factors associated with suddencardiac death in hypertrophic cardiomyopathy

* Youth* "Malignant" family history of sudden death* Gene abnormalities associated with increased prevalence ofsudden death

* Aborted sudden cardiac death* Sustained ventricular or supraventricular tachyarrhythmias* Recurrent syncope in the young* Non-sustained ventricular tachycardia (Holter monitoring)* Bradyarrhythmias (occult conduction disease)

severity of myocardial disarray2 19 52 59 60 andthat this is an important determinant of elec-trical stability and survival. Identification ofthe arrhythmogenic substrate (or measure-

ments that reflect it) remains a major goal inthe characterisation of patients with HCM.

Finally, as in ischaemic heart disease, sud-den death in HCM is common in the mid-morning hours (7am-lpm). The significanceof this circadian pattern is uncertain, althoughit does suggest a possible role for the tempo-rally related physiological changes (possiblyinvolving arrhythmias and the electrical vul-nerability of the myocardium).20

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Figure 2 Comparisons ofprevalence ofsudden death(or cardiac arrest) in 169HCM patients with orwithout ventriculartachycardia (VT) on

ambulatory (Holter)electrocardiography.Shown separately for 83patients studied in theUnited States (Bethesda,MD) with 24 h Holterrecording andfor 86patients studied in theUnited Kingdom(London) with 72 hHolter. 1718

Risk factors for sudden deathTables 1 and 2 summarise the large numberof disease variables that have at one time oranother been regarded as risk factors forpatients with HCM. They underline theinherent complexities of risk factor stratifica-tion strategies in this disease.

CLINICAL FEATURESSome patients with HCM die young,2 3 7 9 11-14 19but the risk declines with increasing age. Inaddition, there is evidence from unusuallyfrequent occurrence (or "clusters") of suddendeath in some pedigrees that such a "malig-nant" family history may itself be a risk factorfor those surviving and for affected relatives inthe same pedigree.'2 Indeed, this view is con-sistent with the recent observation that partic-ular genetic defects involving contractileproteins, troponin T, a tropomyosin,6' andvarious missense mutations in the /3 myosinheavy chain gene25 may be associated withfavourable or unfavourable clinical course incertain families. Among the particular cardiacsymptoms incurred by patients with HCM,only syncope in children and adolescents hasbeen shown to be associated with subsequentsudden death8 "; however, a likely mechanismfor syncope can be identified in only <20% ofpatients.

Table 2 Potential risk factors for sudden cardiac death inhypertrophic cardiomyopathy* Pronounced increase in left ventricular thickness and mass* Tachycardia-induced myocardial ischaemia* Pronounced dynamic left ventricular outflow tract

obstruction* Dispersion and inhomogeneity of intraventricularconduction

* Exercise-induced hypotension* Pronounced physical exertion* Morning hours of the day

ARRHYTHMIASVarious arrhythmias are common in patientswith HCM.23717183159 In many instances ofsudden death the circumstances suggest aprimary ventricular arrhythmia as the cause,and a close relation between ventriculararrhythmias and sudden death has beeninferred.2 7 15 17-20 28 29 31 33 36 52 59 Therefore, under-standably, considerable effort has focused onthe potential significance of ventriculararrhythmias identified on the ambulatory(Holter) electrocardiogram in stratifying riskin this disease. Two tertiary referral centresindependently studied a total of 169 largelymedically treated and predominantly adultpatients with HCM and linked short runs ofasymptomatic ventricular tachycardia onambulatory electrocardiogram (usually 3 to10 consecutive beats) with an enhanced riskof sudden cardiac death.'718 In these studiesventricular tachycardia conferred an 8% peryear risk of sudden death (over the subse-quent 3 years) as compared with less than 1%per year in the absence of ventricular tachy-cardia (fig 2), with a high negative and lowpositive predictive accuracy (96% and 26%,respectively). The low positive predictiveaccuracy indicates significant heterogeneity ofrisk within the subset of patients with non-sustained ventricular tachycardia. It has alsobeen suggested that non-sustained ventriculartachycardia may not have identical signifi-cance as a marker of sudden cardiac death in"stable low-risk" and unselected groups ofpatients with HCM compared with those intowhich higher risk patients have been preferen-tially referred.62

Despite this limitation, the finding of ven-tricular tachycardia on Holter monitoringremains a useful and practical non-invasivescreening test for risk of sudden cardiac deathin adult patients with HCM. The presence ofventricular tachycardia places the patient in ahigh risk group for which further risk evalua-tion or empirical treatment to prevent suddendeath should be considered. In those patientsin whom non-sustained tachycardia is a riskfactor, it may primarily reflect the arrhythmo-genic substrate or more specifically act as atrigger mechanism for sudden cardiacdeath. 2 7 19 38 52 54 57 The absence of ventriculartachycardia on 24 or 48 hour Holter monitor-ing in an adult patient with an otherwise lowrisk clinical profile (that is, no history ofsyncope or familial sudden death) permitsreassurance and limits the necessity forfurther risk factor evaluation. Similarly, non-sustained ventricular tachycardia on treadmillexercise test (although less common than onHolter) also has important prognosticimplications for patients with HCM.

Initially, investigators advocated treatingsuch non-sustained runs of ventricular tachy-cardia with various antiarrhythmic agents.'7 18McKenna et al reported that long-term treat-ment with low doses of amiodarone (mainte-nance dose, 150 mg/day) protected againstsudden death and prolonged survival inpatients with HCM (fig 3); others have usedantiarrhythmic agents such as quinidine and

S 15

Maron, Cecchi, McKenna

Figure 3 Proposed benefitof amiodarone in patientswith HCM. Cumulativesurvival rate was greater in21 mildly symptomaticpatients with HCM andnon-sustained ventriculartachycardia (VT) (onambulatory ECGmonitoring) treated withamiodarone than in asimilar group of 24patients with HCM andnon-sustained ventriculartachycardia treated withconventionalantiarrhythmicmedications. 123 patientswith HCM withoutventricular tachycardia areshown for comparison(adaptedfrom McKennaet a136; reproduced withpermission of the BritishHeart Journal).

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VT + amiodarone association between considerable and diffuse100 hypertrophy and subsequent sudden cardiac

death and also with non-sustained ventricularNo VT (no antiarrhythmics) tachycardia on the ambulatory electrocardio-

gram.303' In one such study, considerably90 - increased left ventricular wall thickness and

VT + conventionaldiffuse distribution of hypertrophy was eight

VnT+arrhnyenticsnal times more common in patients with HCMantiarrhythmics and sudden cardiac death than in surviving

80 - controls with this disease.30 On the otherhand, relatively mild degrees of hypertrophy

118 are not without risk of sudden death3031 and00 6 12 even occasional patients, apparently within061224 30 36 the disease spectrum ofHCM but without left

Months after 48 h ECGmonitoring667ventricular wall thickening have died.6667Though these relations between the extent

of hypertrophy and the predisposition to sud-cainamide, though there is some concern den death may be statistically significant theyut the proarrhythmic potential of these also show substantial overlap. Also, it is oftennts when they are used to treat asympto- difficult to relate the magnitude of left ventric-tic arrhythmias in patients with HCM. ular hypertrophy to the clinical courserrent recommendations are to perform fur- because wall thickness measurements canr risk evaluation to determine the need for change with time and with age.68 69Ltment and to identify potential mechan- Consequently, at present we cannot useLs of sudden death for which targeted echocardiography to predict reliably whichrapy is available. patients with HCM are at the greatest risk of

sudden death.70-MODYNAMICSny patients with HCM show evidence of ELECTROPHYSIOLOGICAL STUDIESmodynamic instability during exercise Electrophysiological investigation andh systemic hypotension owing to a fall in programmed electrical stimulation are oftentemic vascular resistance (and in the pres- performed in patients with HCM who aree of increasing cardiac index).26 The ulti- judged to be at increased risk for suddente clinical significance of this finding is death (for example, history of syncope or.esolved, although the findings of haemo- aborted sudden death). This is because of theLamic instability, youth, and a family his- perception that sudden death in this disease isy of sudden death have been regarded as a most often related to an arrhythmia and alsostellation that may predispose the patient because of an awareness that non-invasive;udden death.26 evaluation may not always reliably identifyn contrast, several other haemodynamic those patients at high risk.2829 527-78Therefore,iables do not seem to be predictable deter- such electrophysiological studies have twoiants of the risk of sudden death in HCM. aims: to target those patients at increased riskexample, patients with outflow obstruc- of sudden death who should be considered for

i and those without may both experience antiarrhythmic intervention and to identify[den death and no relation between the the substrate and trigger mechanisms forgnitude of outflow gradient and likelihood sudden death in HCM in those patientssudden death has ever been established.2 recognised to be at high risk.28295971747778vertheless, it is still possible that in many Intensive ventricular stimulation protocolsients considerable left ventricular outflow (triple extrastimuli administered at rapid driveSt gradients and raised intraventricular sys- rates) in patients with HCM usually inducec (and diastolic) pressures, through several ventricular arrhythmias that require resuscita-hophysiological mechanisms, predispose tion. Most (>80%) of the ventricular arrhyth-ients to potentially lethal arrhythmia and mias provoked by triple ventricular premature[den cardiac death. Furthermore, indices of depolarisations in patients with HCM aretolic or diastolic dysfunction (assessed by either polymorphic ventricular tachycardia orionuclide or contrast angiography or primary ventricular fibrillation-both ofvocardiography) have not been linked which are non-specific or irrelevant conse-.vincingly with sudden cardiac death and quences of intensive programmed electrical,e not contributed measurably to risk stimulation, and which often do not resembletification.63 the clinically relevant ventricular arrhythmias

that are evident in the same patients.RPHOLOGY Conversely, sustained monomorphic ventric-ial necropsy descriptions of patients who ular tachycardia is uncommon in HCM. Lessd suddenly of HCM consistently showed a intensive stimulation protocols717378 are lessking expression of the disease with a sub- likely to induce these ventricular arrhythmias,itial increase in left ventricular wall thick- even in those patients with prior ventriculars and mass.6465 Though the pattern and fibrillation. Also, because most patients withent of left ventricular wall thickening in HCM selected for programmed electrical,M is diverse,40 echocardiographic analyses stimulation have already shown that they areelected patients have shown some statistical at higher risk, inducible ventricular arrhyth-

S 16

S 17Risk factors and stratification for sudden cardiac death in patients with hypertrophic cardiomyopathy

mias can have little remaining discriminatingpower to stratify further the level of risk.

Consequently, most experienced electro-physiologists believe that programmed ven-

tricular stimulation has a limited role inidentifying patients with HCM who are athigher risk and require treatment for the pre-

vention of sudden death.71 7981 This contrasts

with patients with coronary artery disease andmyocardial infarction in whom the repro-

ducible induction of sustained monomorphicventricular tachycardia often identifies a

potential trigger, which usually reflects docu-mented clinical arrhythmias as well as theelectrophysiological substrate for arrhythmo-genic risk.82 Certainly, in symptom freepatients with HCM and non-sustained ven-

tricular tachycardia on Holter monitoring theyield of programmed electrical stimulation istoo low to warrant routine electrophysio-logical testing.

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