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    LINICAL CARDIOLOGY CLINICIAN’S CORNER Hypertrophic Cardiomyopathy A Systematic Review Barry J Maron, MD Context Throughout the past 40 years, avast and sometimes contradictory Itera- ture has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic car- YPERTROPHIC CaRDIOMYoR- diac disease caused by a variety of mutations in genes encoding sarcomerc proteins shy (HCMD isacomplexand and characterized by a broad and expanding clinical spectrum. relatively common genetic Objectives To clafy and summarize the relevant clinical issues and to profil rap~ cardiac disease that hasbeen _ ‘ly evolving concepts regarding HCM. the subject of intense scrutiny and in- Data Sources Systematic analysis of the relevant HCM literature, accessed through vestigation for more than 40 years." Hy. MEDLINE (1966-2000), bibliographies, and interactions with investigators. pertophic cardiomyopathy isan impor- study Selection and Data Extraction Diverse information was assimilated into tant cause of disability and death in rigorous and objective contemporary description of HCM, affording greatest weight paticntsofallages, although suddenand to prospective, controled, and evidence-based stues. unexpected deathin young peoplesper- Data Synthesis Hypertrophic cardiomyopathy isa relatively common genetic car- thaps the most devastating component of — glacdsease (1-500 the general population) thatis heterogeneous with respect to disease- its natural history. Because of marked causing mutations, presentation, prognosis, and treatment strategies. Visbilty at- hheterogeneity in clinical expression, — tached to HCM relates largely to its recognition as the most common cause of sudden natural history,and prognosis," HEM death in the young (reluding competitive athletes). Clinical dagnoss is by 2-dimen- sional echocardiographic identification of otherwise unexplained lef ventricular wall thick- ening inthe presence of anondlated cavity. Overall, HCM confers an annual mortality Care clinicians and cardiovascular spe. €7108 the pr ty. “ " vasculatSPS- rate of about 1% and in most patient's compatible with ite or no disabilty and nor cialists,even to those for whom this dis- al fe expectancy. Subsets with higher mortality or morbidity are linked tothe com- case isa focus of their investigative ci- _pications of sudden death, progressive hear fale, and atria bilation with embolic reers. Controversy abounds with regard Soke, Treatment tategies depend on appropriate patient selection, incuding drug treat. to diagnostic criteria, clinical course,and _ mentor exertional dyspnea (2-bloces, verapamil, dsopyramide) and the septal mystomy- management for which dificult ques- myectomy operation, which isthe standard of care for severe refractory symptoms as- Uionsoften arise. particulaly amongprac- soeated wth marked outfow obstructon, alcohol septal ablation and pacing ae atematives titoncrs infrequently engaged in the. !Su"gety for selected patients. High-risk patients may be treated effecbvely for sudden Cialustion of HEM patleses Conse. death prevention with the implantable cardoverter- deflator. {quently itis timely to place in perspec Conelusions. Substantial understanding has evolved regarding the epidemiology and tive and clarify many of these relevant citical course of HCM, as well as novel treatment strategies that may alter its natural history. An appreciation that HCM, although an important cause of death and dis- ability 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 saa, 20022871306-1320 ‘wa amacom often represents a dilemma to primary clinical issues and profile the rapidly evolving concepts regarding HEM. systematic search ofthe medical li erature involving 968 articles primar- velysiallgroup ofhighlyseletedcen- ston selective referral pattems, and di- ily related to English-language HCM —tersinhe United States, Canada, andEu- verse mechanisms for morbidity and publications (1966-2000) from a var- rope Inadditon,pereeptionsemanating mortality. Therefore, in HCM, the level ied and extensive number of authots from theamthors more han 25 yearsof of evidence governing management and centers was conducted through extensive experience with HCM inter- MEDLINE or bibliographies of pub- faced with the literature analysis. Many — Aarafiaion Naveapas Van mals Foun lished articles. These studies and oth- clinical HCM studies are observational dation, Minneapolis, Minn. es before 1966 were analyzed to cre~ and retrospective indesign because of | GOTUuntng Author nd Beplet:Bary tea balanced appraisal of HCM. difficulty m organizing large prospee- tom SS0€ 20m tse a Hemespats MNSE1OT Published accounts of HEM have tive and randomized clinical tials for Sir yer ae ey, come disproportionaly from atela- a disease with heterogencous expres- MD, Conoune ae 4808 JAMA, Mash 13, 2002—Vol 267, No. 10 (Reprinted) (©2002 American Medical Association, All rights reserved decisions is derived primarily from non- randomized studies, I placed the great- cst reliance on evidence-based investi gational designs and large, statistically powered and controlled studies, when available, RESULTS Prevalence Epidemiological investigations with di- verse study designs have shown simi- lar estimates for prevalence of pheno- typically expressed HCM in the adult general population at about 0.2% (1 500). Therefore, HEM isnot rareand is the most common genetic cardiovas- cular disease, with reports from many countries, Nevertheless, a substantial proportion of individuals harboring a mutant gene for HCM are probably un- detected clinically. Hypertrophic car- diomyopathy is, however, uncommon in routine cardiologte practice, allect- ing no more than 1% of outpatients." This limited exposure of clinicians to HCM understandably accounts for the uncertainty that prevails regarding this disease and its management ‘Nomenclature Since the first modern description in 1958," HCM has been known by a con- fusing array of names, reflecting its clin cal heterogeneity and the skewed expe- rience of early investigators. Hypertrophic carcliomyopathy** isthe preferred name because it describes the overall disease spectrum without introdueing mislead- Ing inferences that left ventricular (LV) ‘outflow tract obstruction is an invari- able feature (hypertrophic obstructive cardiomyopathy [HOCM] or idio- pathic hypertrophic subsortic stenosis, [IHSS)). Indeed, HCM is predom: nantly a nonobstructive disease; 75% of patients donot have asizable resting out- low tract gradient? Genetics Hypertrophic cardiomyopathy is inher ited as a mendelian autosomal domi- nant trait and caused by mutations in any 1 of 10 genes, each encoding pro- teins of the cardiac sarcomere (compo- nents of thick oF thin filaments with (©2002 American Medical Association, All rights reserved, contractile, structural, or regulatory functions).°"*#2" The physical simi- larity of these proteins makes it pos- sible to regard the diverse HEM spec trum as a single disease entity and primary sarcomere disorder. The mecha- nisms by which disease-causing muta- tions cause LV hypertrophy (LVH) and the HCM disease state are unresolved, although several hypotheses have been suggested" Three of the HCM-causing mutant genes predominate, namely, B-myosin heavy chain (the first identified), car- diac troponin T, and myosin-binding protein C. The other genes each ac- count for a minority of HCM cases, namely, cardiac troponin I, regulatory and essential myosin light chains, ttin, ‘e-tropomyosin, a-aclin, and a-myosin heavy chain. This diversity is com- pounded by intragenic heterogeneity With more than 150 mutations ident fied, most of which are missense with a single amino acid residue substituted with another.”*")2527 Molecular de- fects responsible for HCM are usually different in unrelated individuals, and ‘many other genes and mutations, each accounting fora small proportion offa- milial HCM, remain to be identified. Contemporary molecular genetic studies throughout the pastdecade have provided important insights into the considerable clinical heterogeneity of HM, including the preclinical diagno- sis of allected individuals without phe- notypic evidence of disease (ie, LVH by echocardiography oF electrocar- diography [ECG]).* Although DNA analysis for mutant genes isthe defins live method for establishing the diag- nosis of HCM, it isnot yeta routine lini- cal strategy.” Because of complex, ime consuming, and expensive techniques, genotyping is confined to research- oriented investigations of highly se- lected pedigrees. Development of rapid automated screening for genetic abnor- ‘malities will permit more widespread ac- cess to the power of molecular biology for resolving diagnostic ambiguities Recently, missense mutations in the gene that encodes the y-2 regulatory sub- unit of the adenosine monophosphate HYPERTROPHIC CARDIOMYOPATHY activated protein kinase (PRKAG2) have been reported to cause familial Wolll- Parkinson-White syndrome associated with conduction abnormalities and LVH®* (because of glycogen accumu lation in myocytes). This syndrome is most appropriately regarded as a meta bolic storage disease distinct from HCM, which is caused by mutations in genes encoding sarcomerie proteins. Ther fore, management and risk assessment of patients with Wolff-Parkinson- White syndrome and cardiac hypertro- phy should not be predicated on data derived from patients with HM. ‘Of potential importance for unde: standing HCM pathophysiology are gs neticanimal models (ie, transgenic mice and rabbits)’*”” and spontaneously oc- ccurring animal diseases. In particu- lar, domestic cats with heart failure commonly show a disease with clini- cal and morphologte features remark- ably similar to HCM in humans." Diagnosis Clinical diagnosis of HCM is estab- lished most easly and reliably with mensional echocardiography’ by imag- ingthe hypertrophied but nondilsted LV chamber, in the absence of another car- diac oF systemic disease (eg, hyper sion or aortic stenosis) capable of pro- ducing the magnitude of hypertrophy evident (FIGURE Land FIGURE 2A). Hypertrophic cardiomyopathy may be initially suspected because of a heart murmur (occasionally during prepar- Uicipation sports examinations)” post uve family history, new symptoms, oF abnormal ECG paticrn.**" Across the broad disease spectrum of HCM, the physical examination may’ not be a Iiable method for clinical identifica. ton, given that most patients donot have LY outflow tact obstruction and most of the well-documented physical find- ings (eg, loud systolic heart murmurand bid arterial pulse) are limited to pae Lents with outflow gradients ‘With regard to pedigree assessment, itis obligatory for the proband to be informed ofthe fail nature and auto- Rae TT IE TA (Reprnes) JAMA, Mast 13,2002 Vo 297, No, 10.1808 HIVPERTROPHIC CARDIOMYOPATHY somal dominant transmission of HEM, In clinically diagnosed patients Sereeningof istegree relatives include creased LV wall thicknesses range widely ing history aking and physical exami-_ ftom mild (13-15 mm)" to massive 230 mm [normal,=12.mm). "0" ography and ECGshouldbeencouraged, including the most substantial in any particularly if adverse HCM-related cardiac disease, namely, up to 60 min events have occurred in the family. (Figure 2). tn ualned athletes, mod- nations, and 2-dimensional echocardi- Figure 1. Hen lelerogeneity inthe Patter and Extent of Let Verliicuar (LV) Wall Thickening in ‘tocarogaphic parasternal ong stop-ame mages oblaned dase showing A masve a3 rete yperepy of vere sealur (8) wth wal tines =50 mB pate o etl hypertrophy Inn the ital portion consieay hice han he roma gin at mial valve evel, Mypetoty ‘Sarpy confine to baal (poxma) septa ut low aot valve rows D, hypertrophy canted fe LY Spe ase, cnstent with he designation of apalhypertropne ealonjopaty (HEM, rately ‘id hypervopy na cance (ymmet) pater wih each segment of vera septum and LV fee tal show sma or ental icknesses ated avons) ete pale of hyertrptyin which an {enor VS less substantaly thickened han te pester fe wall PW), wach: marked hypetophied Ge 40.) Cabeaton matt eT em apart Aoindates aoa: AML anterior mallet, and LA let aun Reprsiced om ues eta" wih he pemsion of Eker Scenic, ne 4810 JAMA, Mash 13, 2002Vol 267, No. 10 (Reprinted) cst segmental wall thickening (le, 13-15 nom) raises the differential diagnosis be tween extreme physiologic LVH (e,ath- letes heart) and mild morphologic ex- pressions of HEM, which ean usually bye resolved with noninvasive testing. Magnetic resonance imaging may be of diagnostic value when echocardio- graphic studies are technically inad- equate or in enifying segmental LVH undetectable by echocardiography The 12-lead ECG patters is abnor- smal in 75% to 9586 of HEM paticntsaind typically demonstrates a wide variety of patterns: Normal ECGs are most ‘commonly encountered in family mem- bersidentfied as partof pedigree sereen- ing or when associated with mild local- ized LVH."*"* Only a modest relation between ECG voltages and the magni: tude of LVH assessed by echocardiogra: phy isevident. Nevertheless, ECGshave diagnostic vale in raising suspicion of HiCM in family members without LVHL con echocardiogram and in targeting ath- letes for diagnostic echocardiography as part of preparticipation seeening. However, not all individuals harbor- inga genetic defect willexpress the eli cal feanures of HCM, suchas LVH by ech- ‘cardiography, abnormal ECG results, or cardiac symptoms." Moe lecular genetic studies have infact dems- ‘onstrated that there ts no minimum wall thickness required lor HCM ata given Lime in fe, and its not unustal for chile dren younger than 13 years to carry a mutant HEM gene withou LVH, under. scoring the lick of productivity in p adolescent echocardiographic scree ing.t Substantial LV remodeling with spontaneous appearance of hypertro- phy typically occurs with accelerated body growth during adolescence, and morphologic expression s usually com- pleted at physical maturity (about 17-18 Years ofae)°""* Abnormalities on 12- lead ECG and non-preload-dependent measures of diastolic dysfunction with Ussute Doppler ultrasonography may precede the appearance of hypertro- phy, providing clues to impending Pynibasatanae son Rae STE TES, ST TNPERTROPHIC CARDIOMYOPATHY Novel diagnostic criteria for HEM have recently emerged and are based on _genotype-phenotype studies showing in- complete disease expression with ab- sence of LVH in adult individuals, most Figure 2- Morphologic Features of the Myocardial Substrate for Sudden Death Hypertrptic Cardiomyopathy (HCM) commonly due to cardiac myosin- binding protein C oF troponin T muta- lions. In both cross-sectional and. serial echocardiographic studie lions in the myosin-binding protein © ‘gene may demonstrate age-related pen- trance ofthe HCM phenotype in which delayed de novo onset of LVH may ac- ‘eur in midlife and later.52°7" Such adult morphologic conversions dictate that itis no longer possible o use a nor- mal echocardiogram to offer definitive reassurance at maturity (or even in middle age) that asymptomatic family members are free of a disease-causing mutant HM gene"; this obser vation probably necessitates a strategy of postadolescent echocardiographice Paradoxically, a small distinctive sub- set of HM patients (ie, about 5%- 10%) evolve into the end stage (or burned-out” phase) characterized by LV wall thinning, cavity enlargement and systolic dysfunction often resem bling dilated cardiomyopathy and pro- ducing relentlessly progressive and ir- S55 4s also reversible heart failure. possible that other adults experience subtle regression in wall thickness with aging (not linked with clinical deterio- ration), reflecting gradual, wid spread remodeling." Therefore, the HCM phenotype manifestation; LVH can appear at vir~ tually any age and increase or de- crease dynamically throughout life not astatic disease HCM Phenotype and Morphologic Features Left Ventricular Hypertrophy. Struc tural heterogeneity in HCM is consider able, with no single pattern of LVH rpudcdsegpual gue ysonmnet Although at show diffusely the yentrcuar septum (VS) with respect to the lft ventricular (LV) free wal (RV Incates ight venrclar dal hckeninglcaeedtoasngle Heian ates i pre or Speen.™"lnckangibeplailons™ Reeamitceee aon cmmsaun hum te aia nearer ae a FigenenepegiePgure 1D)" Lele, (©2002 American Medical Association. All rights reserved. (Reprints) JAMA, strc 13, No 19 a1 HIVPERTROPHIC CARDIOMYOPATHY tricular hypertrophy is characteristi- cally asymmetric, with the anterior sep- tum usually predominant (Figure 1A-D, F; Figure 2A), although a few patients show a symmetric (concentric) pattern (Figure 1B). Distribution of LV wall thickening shows no direct linkage to ‘outcome, although distal hypertrophy is associated with the absence of obstruc- tion." Young children may present with, LVH resembling HEM as part of other disease states (eg, Noonan syndrome, mitochondrial myopathies, and meta bolic disorders) unrelated to HCM- causing sarcomere protein mutations. Other markers of HCM that are not obligatory prerequisites for diagnosis include a hypercontractile LV and dynamic subaortic obstruction typi- cally produced by mitra valve systolic anterior motion and septal con- tact’*" (caused by drag effect” or pos- sibly the Venturi phenomenon®*""*"), which is responsible for a loud systolic Cellular Components. Cardiomyo- pathicsubstrate in HM is defined ana- tomically by several histological fe tures based on autopsy observations, Left ventricular myocardial archi lure is disorganized, composed of hy pertrophied cardiac muscle cells (rmyo- cytes) with bizarre shapes and multiple intercellular connections often ar ranged in chaotic alignment at ob- lique and perpendicular angles (Fig- ure 2B)."" Cellular disarray may be widely distributed, occupying substan- tial portions of LV wall (average, 33%), and is more extensive in young pa- tients who die of their disease.” Abnormal intramural coronary ar~ leries, characterized by thickened walls ‘with increased intimal and medial col- lagen and narrowed lumen, may be ‘garded as a form of small vessel disease (Figure 2). Such architectural alter- ations of the microvasculature, as well as the mismatch between myocardial massand coronary circulation, are likely responsible for impaired coronary vaso- dilator reserve” and bursts of myocar- dial ischemia” leading to myocyte death and repair in the form of patchy or transmural replacement scarring (Pig- 4812 JAMA sash 13, 2002—Vol 267, No. 10 Reprinted) ture 2). such myocardial sear- ring supports clinical evidence that is- chemia frequently oceurs within the natural history of HEM?*""°"" and ray serve as the substrate for prema- ture hear falure-related death Itisalso evident that the cardiomyopathic pro- cess in HEM is not confined to areas of gross wall thickening and that nonby- pertrophied regions also contribute tois- chemia or impaired diastolic func Disorganized cellular architee- ture," 77) myocardial sear- ring,”*"*"80" and expanded intersti- tial (matrix) collagen””*” probably serve as arrhythmogenic substrates predisposing to life-threatening elec- trical instability, This substrate is Likely the source of primary ventricu- lar tachycardia and ventricular fibril- lation, which appear to be the pre~ dominant mechanisms of sudden death," either primarily or in asso- ciation with triggers intrinsic to the disease process, namely, myocardial ischemia, systemic hypotension, supraventricular tachyarrhythmias, oF environmental variables (eg, intense physical exertion), Penetrance and variability of pheno- \ypicexpression are undoubtedly influ enced by factors other than disease causing mutant genes such as modifier genes (eg, angiotensin-convertingenzyme genotype). coexistent hypertension, or lifestyle. Indeed, several phenotypic manifestations of HCM do not primar- Aly involve sarcomerie proteins, includ Ing increased interstitial collagen," ab- normal intramural arteries,’*" and mi- tralvalvemalformationssuchaselongated leaflets" or direct papillary muscle in- sertion into the mitral valve.” Clinical Course Hypertrophic cardiomyopathy is unique among cardiovascular diseases by vir- tue ofits potential for clinical presenta tion during any phase of life (from in- fancy to >90 years of age).+ Although adverse clinical consequences have been recognized for many years, particularly Tegan TES OST SESE TO 8 sudden cardiac death,!2°"*! balanced perspective regarding progno- sis has evolved recently.!##"202" Historically, misperceptions regard- ing the clinical significance of HCM have prevailed because of its relatively low prevalence in cardiac populations extremeheterogenciy."*andskewed pate terns of patient referral that created important selection biases.!11!2!!* Indeed, much of the data assembled throughout the past 40 years have been dlispropontionately generated by few te liar centers largely composed of patients preferentially referred because of th high-risk status or severe symptoms requiring specialized care such as sur- gery." Hence, the older literature ‘was dominated by the most adverse con- sequencesof HCM, while clinically stable, asymptomatic, and elderly patients were underrepresented.9? 259! Consequently the risks of HM would appear to have been overestimated by de- pendence on frequently cited, ominous mortality rates of 3% to 6% annu- ally." These figures, based largely on skewed tertary-center experience, have contributed greatly tothe misguided pe ception that HCM is a generally untae voruble disorder Recent reports through ‘out the last 7 years [rom less selected regional or community-based HEM pa- tient cohorts eite much lower annual mortality rates, about 1%," not dis- similar to that for the general adult US population." Such data providea more balanced view in which HEM may be as- sociated with important symptomsand premature death but more frequently ‘with no or relatively mild disability and normal life expectancy. 19155 Elderly HEM patients (=75 years) have been reported to compose as auch as 25% of an HCM cohort, with only a minority having severe manifestations of heart failure." Outflow obstruction is commonly evident in patients of advanced age (ie, in about 40%), sug- gesting that subaorti gradients may be ‘well tolerated for long periods without adverse consequences. Indeed, HCM in elderly patients can be a genetic disor- dler caused by dominant sarcomere pro- tein mutations most commonly in ear- (©2002 American Medical Association, All rights reserved. TNPERTROPHIC CARDIOMYOPATHY dine myosin-binding protein C and along certain relatively diserete, consequences of atrial {brillation troponin I genes. adverse pathways: (1) high risk for (AP), including embolic stroke sudden death8: (2) congestive aymp- Sudden Death Risk Straiication Sad Profiles of Prognosis toms of hear fallute with exertional den death ts the most common mode and Treatment Strategies dyspnea and functional disability of demise and the most devastating The clinical course for individual often associated with chest pain and and unpredictable complication of HCM patients is most appropriately usually in the presence of preserved HCM.'*7""' Therefore, within the viewed in terms of specific subgroups LV systolic function’"!""; and (3) _ broad HCM disease spectrum, for which rather than only {rom perceptions ‘overall annual mortality rate ts about 1%, of the overall disease spectrum | ISRaTET ALATA GEST cxist small subsetsata much higher risk (FIGURE 3). Some patients progress 108,14, 116118127 (perhaps at least 5% annually) Figure 3, Primary Treatment Stateses for Subgroups Within the Hypertrophic Cardiomyopathy Clea Spectrum ‘Overall Population With Hypertophic Cardiomyopathy HM) High Fisk ot Sudden Death ‘Antcoagastion Drug-Retactory Heart Fale Symptoms / \ bstte Hom Nonobsrcive HoM (restorProvecaton? (Pestand Provocation Vector Septal Hea Tgp Myatomptjecony omens, Hypertophic cardiomyopathy (HCI) dnl subgroups are nol necesaly mulualy exisive; ova or progression fom ove subgraupfo another may acar in soldand dashed anes). Mast patents wih HCM who ate at igh ako suden cath or who dev ata iblaton aerial nthe "None a Ml Sats” ‘inca subgroup. Aster indcates tal pent tha postive genotype ara negative pentype may ibsequel show mampholope conversion toe HCM phe rope wi verticuar rypertopry (sual nadlescence, bt aso made fate). Dagger ndestes tha ug therapy may induce flocks, clu ‘Chanel blokes (pateuly vrapem,dsopyfaride, aswel as Gur agents Double dagger nates that for major ltventons, obstructive HCM I gereraly ‘egarded at. let vente ution adeno pprosenaty 80 mmHg eto wth provocative maneuver nts context nancbttuchve HCA regarded Set vent outfiow gaint of ls than approximately 30 to 80 mm gat ets wel a wth provocative maneuvers With he rows fom te overal HOM Population represen te spproxsnatereatve poporton of patents wth HEM yt ech mae eel subgroup. Adapted fom Spaeth persion oe Fieschusts Medi Sobety. (©2002 American Medical Association. All rights reserved. (Reprneg) JAMA, Mast 13,2002 Vo 297, No. 10.4898 HIVPERTROPHIC CARDIOMYOPATHY An important but complex objec- tive has been the kentification of sch hhigher-rsk individuals among the vast HCM spectrum. For example, sudden death can be the intial manifestation of FCM, and such patients usally have no oF only mild prior symptoms. Al- though sudden death occurs most com monly in children and young adults, risk extends across a wide age range trough midlife and beyond": there- fore, achieving particularage does not confer immunity to sudden eatastro- phe. Sudden death occurs most com monly during mild exertion oF seden- lary activities but is not infrequently related to vigorous physical exe tion." Indeed, HEM is the most common cause of cardiovascular std- den death in young people, including tesined competitive athletes (most com smonly in basketball and football and in black athletes). The majority of HM patients (55%) do not demonstrateany of the acknowl- ‘edged risk factors inthis disease, and it is exceedingly uncommon for stich pa- tients to die suddenly”: the subset atin- creased tsk appears to comprise about 10% to 20% of the HCM population.” Highest risk for sudden death im HCM thas been associated with any of the fl- loving noninvasive clinical markers (Fig- ure 3) prior cardiac arrest oF sponta neous sustained ventricular tachycardia; family history of premature HCM- related death, particularly if sudden, in close relatives, or muliiple;syncope and some cases of near-syncope, partici laely when exertional or recurrent, oF in young patients when documented as r- rhythmis-based oF clearly unrelated to neurocardiogente mechanisms; mul- Uple and repetitive or prolonged bursts of nonsustained ventricular tachyear dia on serial ambulatory (Holter) ECG recordings; hypotensive blood pressure response to exercise, particulary in pa- lients younger than 50 years: and ex teeme LV sith mama wall tick- = 30mm, particularly in adolescents and young adults, Ramana, 7,3 ORE, TOT TTT 1,127, 132-136 4814 JAMA sash 13,2002—Vol 207, No. 10 Reprinted) ‘The latter risk factor emanates from a continuous, direct relationship be- ‘oven maximum LV wall thickness and sudden death, which supports the mag- nitude of LVHasa determinant of prog- nosis in HEM.**!" Exceptions to that association are a few highly selected HEM families with multiple sudden deaths and mild LV caused by tropo- niin T mutations." Description of the total HEM risk profile is probably in- complete, and no single disease fea- ture or test iseapable of stratifying risk in all patients, There is only a suggested associ tion’ but no clinically relevant and independent linkage between sudden death and outflow obstrue- tion, 2798807 although data on par ticularly large (2100 mm Hg) gradi- entsarellimited."*" One report suggests that short, tunneled (bridged) seg- rents of let anterior descending coro- nary artery, mediated by ischemia, in- dependently convey increased risk for cardiac arrestin children with HEM." Presentation of HICM in young chil- dren is exceedingly uncommon and usually ereates a clinical dilemma be- cause of diagnosis (often fortuitous) so carly in life and the uncertainty regard- ing risk over such long periods.""%* studies of HEM in children report an- nual mortality rates of 2% (community- based populations) to 6% (tertiary re- ferral cohorts).°°!"" Ithas been proposed, based on geno- type-phenotype correlations, that the genetic defects responsible for HeMe788252150 could represent the primary determinant and stratifying marker for sudden death risk, with spe- cific mutations conveying either favor- able or adverse prognosis." For ex- ample, some B-myosin heavy chain mutations (eg, Arg403GIn and Arg719Gln) and some troponin T mu- tations may be associated with a higher frequency of premature death com- pared with other mutations, such as those of myosin-binding protein (nsG791) or a-tropomyosin (Asph75Asn).289!823282827 How. ever, caution is warranted before strong conclusionsare drawn regarding prog- nosis based solely on the available epi- demiologic genetic data, which are rela- Lively limited and skewed by virtue of selection bias toward high-risk fami- lies. 2 Access to the molecular biol- ‘ogy of HCM does not yet represent a clinically relevant strategy that rou- linely alfects disease management Prognosis attached to adult gene car~ riers without LVH appeats tobe mostly benigh.!2595" There isno available evi- dence to justify routinely precluding ‘genotype positive-phenotype negative individuals of any age from most activi- ties or employment opportunities.” The role of invasive strategies such as electrophystologic testing with pro- ‘grammed ventricular stimulation and the significance of induced arrhythmias in detecting the substrate for ventricular brillation in individual HCM patients are unresolved." Limitationsinclude the infrequency with which monomorphic ventricular fibrillation is provoked and the nonspecificity of rapid polymor- phic ventricular tachyeardia and ve tricular brillation. Although attention has understand- ably focused on high-risk HCM pa- tients, the absence of risk factors and ce lain clinical features can be used to developa profile of HCM patients at low likelihood for sudden death caused by life-threatening yt disturbances, as wellas other adverse events (eg at arate of <1% annually), Adult patients most likely at lowest risk are those with no oF only mild congestive symptoms in the absence of the following: family his- tory of HCM-related premature death; syncope (or near-syneope) judged une likely tobe neurocardiogenie in origin; nonsustained ventricular tachycardia dluringambulatory Holter ECGs; marked LY outflow gradient of at least 50 vom Hig; substantial LVH (wall thick- ness =20 mm); left atrial enlargement (45 mm):and hypotensive blood pres sure response to exercise'4 Such pac Uients with favorable prognosis consti- lute aa important proportion of the ‘overall CM population and generally Temes OETA, 136, 84 (©2002 American Medical Association, All rights reserved. deserve a measure of reassurance re- garding their disease.” ‘Most HCM patients should undergo risk stratification assessment (prob- ably with the exception of patients older than 60 years) that requires, in addi- tion to careful history taking and physt- cal examination, noninvasive testing with 2-dimensional echocardiography, 24- or 48-hourambulatory Holter ECGs, and treadmill (or bicycle) exercise test- ing. Such evaluation and follow-up should be carried out by (or involve) qualified specialists in cardiovascular medicine Prevention, tn HCM, treatment strat- cegies to reduce risk for sudden death have been historically predicated on drugs such as -blockers, verapamil, and antiarrhythmic agents (ie, quinidine, procainamide, and amioda- rone) 141 Nevertheless, there is litle evidence'* that prophylactic phar- macological strategies and rhythm- modulating drugs effectively reduce risk forsudden death; furthermore, because ofits potential toxicity, amiodarone is n= likely to be tolerated throughout the long risk periods characteristic of young HCM_ patients. Therefore, there would appear tobe lite justification for prophylactic drug treatment in asymptomatic HCM patients, whether or not they are judged tobe at high risk. At present, the implantable cardio verter-defibrllator (ICD) appears to be the most effective treatment modality forthe high-risk HCM patient, with the potential to alter natural history (Fig ure). Ina large multicenter study, ICDs aborted potentially lethal ven- tricular tachyarrhythmias and r stored sinus rhythm in almost 25% of patients throughout a brief 3-year fol- low-up." Appropriate device interven- lions occurred at 11% annually for sec ondary prevention (implant following cardiac arrest) and 5% annually for pri mary prevention (implant based on risk factors), usually in patients with no or conly mild prior symptoms.” Patients re- ceiving appropriate shocks were young (mean, 40 years), and ICDs often re- mained dormant for prolonged peri ods before discharging (up to 9 years), (©2002 American Medical Association, All rights reserved, emphasizing the unpredictability of sudden death events in HEM. Sudden death prevention with the ICD is most strongly warranted for pa- tients with prior eardiae arrest oF sus- tained spontaneous ventricular tachy- cardia. Although multiple isk faetors convey increasingly greater sudden- death risk," a single major risk factor in an individual patient may be sufficient to justify strong consideration for p rary prevention with an ICD. Never theless, uncertainty persists regarding precisely which HEM patients with only 1 risk factor should be candidates for prophylactic ICD treatment," and therefore individual clinical judgment taking into account the overall clinical profil including age, apparent strength ofthe risk factor identified, and the level ofrisk acceptable o the patient and fam ily, may be necessary to definitively re- solve many of these clinical decisions. Also, physician and patient attitudes to- ward ICDs (and also access to the de- Viees) can vary considerably among counties and cultures and profoundly alfet clinical decision making. 2°" Intense physical exertion consti- tutesa sudden-death trigger in suscep- tible individuals.” Therefore, to re duce risk, disqualification of athletes with unequivocal evidence of HCM from most competitive sports has been prudently recommended by a na- tional consensus panel." Avrial Fibrillation. Atal fibrillation fs the most common sustained arrhyth- mia in HCM, accounting for unex- pected hospital admissions and unsched- tled work loss, and therefore usually justifies aggressive therapeutic strate- gies (Figure 3). Paroxysmal episodes or chronic AF ultimately occur in 20% to 25% of HEM patients, inerease in inei- dence with age, and are linked to left arial enlargement." vial brillation isreasonably tolerated by about fone third of patients and is mot an in- dependent determinant of sudden death. However, AF is associated with temboliestroke (incidence, about I%an- nually; prevalence, 6%), leading to death and disability most frequently in the eb derly, as well as progressive heat fa HYPERTROPHIC CARDIOMYOPATHY ure, particularly when AF onset occurs before 50 years of age and is associated ‘with basal outflow obstruction. = Paroxysmal AF may be responsible for acute clinical decompensation, requ ing electrical or pharmacological cardio version." Although data in HM pa- lientsare limited, amiodarone is regarded as effective for reducing AF recur- rences. In chronic AF, B-blockers and verapamil effectively control heart rate, although A-V node ablation with per= manent ventricular pacing may occa sionally be necessary. Because of the potential for clot formation and embo- lization, anticoagulant therapy with war- farin is indicated in patients with either recurrentor chronic AF. Since 1 or 2 par- coxystns of AP have been associated with the risk for systemic thromboembolism i HM, the threshold for initiation of anticoagulant therapy should be low." However, such clinical decl- sions should be tailored to the indi- vidual patient after the obligatory lif style modifications, risk of hemorrhagic ‘complications, and expectations for com- pliance have been considered. Heart Failure. Presentation. Symp- toms such as exertional dyspnea, or thopnea, paroxysmal nocturnal dy’ pnea, and fatigue are common, characteristically in the presence of nor- mal orsupranormal LV contractility and independent of whether outflow ol struction is present (Figure 3).**"* Such symptoms of HCM-related heart failureare usually deferred untiladult- ‘hood but may occur at any age Marked symptom progression (10 New York Heart Association classes IIL and 1V) is relatively infrequent, devel- ‘oping in about 15% to 20% of an un lected population, and such exertional dlsabilty may evolveat varying rates de- lerioration isoften gradual and panei ated with long periods of stability and day-to-day variability (Figure 3) Congestive symptoms and exertional limitation in HCM appear to be largely the consequence of diastolic dysfunc tion in which impaired LV relaxation, Increased chamber stiffness, and com- promised left atrial systolic function impede filling, leading to elevated left (Repro) JAMA, Mart 13,2002 Vo 297, No. 10.4895 HIVPERTROPHIC CARDIOMYOPATHY atrial and LV end-diastolic pressures with reduced stroke volume and cardiac out- pt. These mechanisins result in pulmo- nary congestion with diminished exer cise performance'’® evidenced by reduced peak oxygen consumption." However, heart failure related to dias- tolic dysfunction may also be inter~ twined with other pathophysiological mechanisms such as myocardial ische- mia, outflow obstruction, and AF?! Chest pain suggestive of myocar dial ischemia (with angiographically normal coronary arteries), either typ cal or atypical of angina, isa symptom commonly associated with exertional dyspnea" Myocardial perfu- sion defects, net lactate release during atrial pacing, and blunted coronary flow reserve constitute evidence of ischemia likely caused at least in part by an abnormal microvascula- ture.222188159.57 The role of ische- mia in risk stratification is unre- solved, in part because the clinical assessment of ischemia (and that of di- astolic dysfunction) have been limited by an inability to noninvasively me: sure these abnormalities with quanti- lative precision, Drug Treatment Strategies. If exes ional symptoms of heart failure inter vene, itis conventional to initiate phar- macological therapy with negative inotropic drugs such as B-adrenergic blockers or verapamil, independent of whether outflow obstruction is present (Figure 3).28 Patients who do not experience improvement of symptoms with one drug may subsequently ben- fit from the other, but combined ad- Ininistration isnot advantageous," How= ever, verapamil may be deleterious to some patients with severe outflow gra- dlicnts and heart faire," and some in- vestigators favor disopyramide (often with a B-blocker) for such severely symptomatic paints with obstruction and verapamil or B-blockers im pa- Uicnts who do not develop obstruc- S06 There are comparatively few data available regarding the use of other calcium channel blockers such as dil ef of symptoms. Patients who develop severe symp- Uiazem in HCM for rel 4846 JAMA Mash 13, 2002Vol 267, No. 10 (Reprinted) toms of heart failure associated with sys- tolic dysfunction and deteriorate into the end stage requite alternative drug treat- ment with diuretics, vasodilators, and digitale #810 B-Blockers may mitigate predomi- nantly provocable gradients (induced with interventions such as physiologic exercise or Valsalva maneuver, isopro- terenol infusion, oF amyl nitrite inbala- tion), and disopyramide may reduce some subaortic gradients at res," mediated by ventricular afterload redue- tion and slowing of the LY ejection ac- celeration."* For patients with outflow obstruction, risk for bacterial endocar- alts (usually involving the mitral valve) dictates prophylactic administration of antimicrobial drugs, primarily to pa- tients with obstruction, before dental procedures or surgery." Surgical Treatment, Should severe heart failure-related symptoms bi come unrelenting and refractory to phar racological treatment, and lifestyle un- acceptable, subsequent therapeutic decisions are determined largely by whether basal obstruction to LV out- flow is present (peak instantaneous gra dient =50 mm Hg) (Figure 3).°°* Throughout the past 40 years, the perience of many centers worldwide has caused the ventricular septal myotoms mycetomy operation (Morrow proce- dure) to become established asthe stan- dard therapeutic option (ie, “gold standard) foradults and children with obstructive HEM and severe drug- refractory symptoms."“"!"""" How- ever, operative candidates represent only a small (5%) although important sub- set of the overall HM population.” Operation requires rescetion ofa small amount of muscle (about 5 g) from the proximal septum extending just be- Yond the distal margins of mitral leaf lets, thereby abolishing any significant impedance to LY outflow." Other sur- eons have used a low-profile mitral valve prosthesis in patients judged to have unfavorable septal morphol- ogy! or with intrinsic mitral valve disease (such as myxomatous degenera- tion) aecounting for sever gurgitation.""" Papillary muse e mitral re sertion directly into the mitral valve, producing muscular mideavity obstruc- tion, requires distally extended septal resection or valve replacement." Myotomy-myectomy performed at experienced surgical centers in the ab- sence of associated conditions has ac- ceptably low operative mortality (=2%) Most patients (about 70%) achieve sub- jective improvement in symptoms and exercise capacity 5 years orlonger after their operation and often for extended periods. Improved metabolic and he- modynamic measures! associated with symptomatic benefit following my- ‘otomy-mycetomy appear to be largely the consequence of abolition oF sul stantial reduction in basal outflow gra 091 and normalization of LV pres- sures (in >90% of patients), 5!" as dient ‘well as alleviation ofthe mild to mod- crate mital regurgitation that is second- ary to obstruction." Patients in whom severe refractory symptoms can be linked to large outlow gradients p sent only under provocable cond tions, such as elicited physiologically with exereise, may also benefit om m= Consistent relief of severe symp- toms following surgery isevidence that marked outflow gradients and in- creased LV systolic pressure are of clini cal significance to many patients However, outflow obstruction snot del ctcriows to all patienls, since sis now evident that large gradients may be tle crated for long periods with no or hile lsat." Consequently, although the couitlow gradient isa highly visible and {quantifiable component of HICM, iis also typically labile and hemodynarni- cally sensitive oallerations in ventric. lar volume and systemie vascular res tance," even alter standing oF a hheavy meal, and should not be re- garded as equivalent to the disease it sell" Although major interven- tions can be advantageous by reducing the outflow gradient when itis judged to be persistent and the cause of se symptoms, the presence per se of sub- aortic obstruction unassociated with marked disability i rarely the soe jus- Lfication for such treatment.” (©2002 American Medical Association, All rights reserved. Alternatives to Surgery. Some opera tive candidates may not have ready ae- cess to major centers experienced with myotomy-myectomy because of e0- graphical factors, or they may not be' garded as favorable operative eandi- dates because of concomitant medical conditions, advanced age, prior cardiac surgery, oF insufficient motivation.” Therefore, 2 treatment options have cemerged.as potential alternatives to sur- gery forselected patients Figure). First, inuncontrolled and observational stud= ies,chroniedual-chamber pacing wasas- sociated withamelioration of symptoms andreduetion of outflow gradientin many HCM patients." However, several an- domized crossoverelinica ialsreported that subjectivesymptomaticbeneit dur- ing pacing frequently occurs with litle objective evidence of improved exercise capacity"? and canbe largely explained asa placebo effect." Although pacing is not a primary treatment for HEM, 1 study showed that elderly pa- tients (older than 65 years), subgroup for which alternatives to surgery are of- ten desirable, experienced objective im provementinsymptoms with pacing.” ‘While myotomy-myectomy providessu- perioresultstopacingin mostpatiens,"! a dual-chamber pacing trial prior to myotomy-myectomy could be of value inselected candidates, given that pacing (Disimmplctly ess invasive thansurgery cor aleohol septal ablation, (2) isa more ‘widely accessible method to the practic- ingeardiologist, (3) can permit moreag- gressive drugtreatmentby obviating con- cer for drug-induced bradycardia, (4) may be withdrawn, and (5) doesnot ob- vate subsequent implementation of in- vasive procedures Pacingdoesnot reduce sudden-death risk significantly" or trigger LV remodeling." ‘A second alternative therapy to sur- gery is the recently developed alcohol seplal ablation technique, which is per- cutaneous coronary artery intervention using methods and technology avail- able for atherosclerotic coronaty artery dlsease *®* Absolute alcohol (about 1-4 mis introduced into the target septal perforator coronary artery branch to pro- duce myocardial infarction, which in (©2002 American Medical Association, All rights reserved, turn reduces basal septal thickness and motion, enlarges the LV outflow tract, and decreases mitral valve systolic ante- rior motion, thereby mimicking the he- rmodynamie consequences of myotomy- ryectomy.**"2" Indeed, reductions in outflow gradient associated with aleo- hol septa ablation have been reported to be similar to those resulting from my- otomy-myectomy,* although a recent comparative analysis showed surgery to be superior to ablation in reducing rest- ing and provocable gradients *” Also, similar proportions of ablation and sur- sical patients have been reported to show subjective" and objective” im provements in congestive symptomsand quality of life over relatively short peri- ods, largely in observational studies; in addition, there are unconfirmed claims of diffuse regression of LVH following ab- lation. However, aleohol septal abla- tion in HEM has not yet been subjected to the scrutiny of randomized oF con- trolled studies." Septal ablation is associated with op- erative morbidity and mortality, simi larto that of myotomy-myeetomy; com plications include permanent pacemaker for high-grade A-V block, coronary dissection, and large anterior infare- tion 280" In contrast to that for sur gery. the postprocedural follow-up for aleohol septal ablation is relatively brief (about 3-5 years compared with 40 years for myotomy-myectomy)."" Furthermore, ablation alone poten- tially ereates a permanent, electrically Unstable substrate for lethal reentrant ventricular tachyarrhythmias by vietwe ofthe healed intramyocardial septal sear in some HEM patients who are already undoubtedly predisposed to arrhyth- rmogenesis; this consideration raises some uncertainty regarding the long- term risks of aleohol septal ablation.” Heart Transplantation. Therapeutic options are considerably limited for pa- tients who have the nonobstructive form of HCM and experience drug- refractory severe symptoms, includ- ing those inthe end-stage phase." This subset of patients, among the broad HEM spectrum, may become candi- dates for heart transplantation." HYPERTROPHIC CARDIOMYOPATHY Fandng/Supprt: This work wassupocted by grants ‘fom the Mnneapl eat Instat Foundaton and au Glen Foundations eR 41. Tewe D, Aymmtrial ypetopy ofthe heat Iyoung adults Br Heart 1 1958.20: 148 2. BraunwalgELanbrew CT, Reka! Da. Io Pathe ypertophie suber stenoss, I 2 deser fn of te seas based upon an nays of 6p theme Creation. 964 30Gupp 3-21, 3. Mazen. Hypertrophic cacomyopathy. Lancet. soras0a27- 483 2 Maron anon RO, Cenpan RO, Leon MB ‘en Hypertrophic earsonyopsthy:erastonof fncal manetatns,palophsigy. an hry engl Med 1967316 720-70, 48352 5. Fark, araunvad [opathichyperopticsub Sate stenosis cnc ana of 126 pats ith fmphass on the natural history. 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