How should hypertrophic cardiomyopathy beclassified?

What’s in a Name? Dilemmas in NomenclatureCharacterizing Hypertrophic Cardiomyopathy and LeftVentricular HypertrophyBarry J. Maron, MD; Christine E. Seidman, MD; Michael J. Ackerman, MD, PhD;Jeffrey A. Towbin, MD; Martin S. Maron, MD; Steve R. Ommen, MD;Rick A. Nishimura, MD; Bernard J. Gersh, ChB, MB, DPhil

Almost 50 years of study have underscored the consider-able heterogeneity in clinical presentation, natural his-

tory, morphology, and the genetic substrates that characterizeinherited hypertrophic cardiomyopathy.1–5 Similarly, the no-menclature applied to this complex cardiac disease haspersistently created a measure of confusion for both patientsand physicians with regard to the definition and perceptionsof the disease. This ambiguity has had, in turn, substantialimpact on accurate diagnosis, full understanding of diseaseexpression, and ultimately, decisions regarding management. Atthis juncture, it would seem appropriate and timely to concep-tually revisit and clarify this important issue of names, consistentwith the evolving knowledge of the cardiomyopathies.6

Response by Elliott and McKenna see p 86

Historical ContextThe historical confusion over the names used to describe theentity of hypertrophic cardiomyopathy has arisen over theyears in 2 fundamental areas. The first of these concerns thenomenclature used in prior efforts to characterize the disease.

For example, at last count there are more than 80 individualnames that have been used over the last 5 decades (most byearly investigators) to describe the disease entity, which is thesubject of this commentary (ie, hypertrophic cardiomyopa-thy)7 (Figure 1). It is likely that the confusing array ofdesignations used to describe hypertrophic cardiomyopathyhas also undoubtedly contributed to its relatively low visibil-ity among the general public despite a prevalence (ie, 1:500),which greatly exceeds that of many other better known butless common cardiac or noncardiac diseases8,9 (Figure 2).

Furthermore, nomenclature that was once popular in the1960s and 1970s, such as idiopathic hypertrophic subaorticstenosis (IHSS) or hypertrophic obstructive cardiomyopathy(HOCM), are potentially confusing by virtue of their infer-ence that obstruction to left ventricular (LV) outflow is aninvariable and obligatory component of the disease, when infact fully one-third of patients have the nonobstructiveform.10 However, this particular issue has now been largelyresolved. Although terms such as idiopathic hypertrophicsubaortic stenosis and hypertrophic obstructive cardiomyop-

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part I of a 2-partarticle. Part II appears on page 87.

From the Hypertrophic Cardiomyopathy Center (B.J.M.), Minneapolis Heart Institute Foundation, Minneapolis, Minn; Department of Genetics(C.E.S.), Harvard Medical School, Boston, Mass; Departments of Medicine and Pediatrics/Divisions of Cardiovascular Diseases and Pediatric Cardiology(M.J.A., S.R.O., R.A.N., B.J.G.), Mayo Clinic, Rochester, Minn; Department of Pediatrics and Cardiology (J.A.T.), Baylor College of Medicine, Houston,Tex; and Hypertrophic Cardiomyopathy Center (M.S.M.), Tufts Medical Center, Boston, Mass.

Correspondence to Barry J. Maron, MD, Director, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E 28th Street,Suite 620, Minneapolis, MN 55407. E-mail hcm.maron@mhif.org

(Circ Cardiovasc Genet. 2009;2:81-86.)© 2009 American Heart Association, Inc.

Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org DOI: 10.1161/CIRCGENETICS.108.788703

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athy persist occasionally in informal usage, they rarely appearany longer in the literature, whereas hypertrophic cardiomy-opathy (which allows for both the obstructive and nonob-structive hemodynamic forms) has predominated as the for-mal designation for this disease since it was initiallypromoted in 1979.7

The ProblemThe second nomenclature issue, and the focus of this discus-sion, relates to the differential diagnosis of hypertrophiccardiomyopathy with other congenital and familial diseases(largely of childhood) in which increased LV wall thicknessis a prominent clinical feature. Some of these diseases harborcardiac phenocopies in which the pattern and magnitude ofLV hypertrophy clinically mimics hypertrophic cardiomyop-athy due to sarcomere protein mutations. Perhaps the mostcommon example is Noonan syndrome, an autosomal domi-nant cardiofacial condition also associated with pulmonaryvalve dysplasia and septal defects, which is caused bymutations in the PTPN11 gene, as well as those that encodeprotein components of tyrosine kinase signal-transductionpathways (RAF1, KRAS, SOS1).6,11

Other rare conditions that fall under this umbrella ofsarcomere-related cardiomyopathies10 are mitochondrial myop-athies caused by mutations encoding mitochondrial DNA (in-cluding Kearns-Sayre syndrome) or mitochondrial proteins as-sociated with ATP electron transport chain enzyme defectsaltering mitochondrial morphology; metabolic myopathies rep-resenting ATP production and utilization defects involvingabnormalities of fatty acid oxidation (acyl CoA dehydrogenase

Figure 1. The multitude of names used to describe hypertrophic cardiomyopathy in the literature. Many of these traditional terms, suchas idiopathic hypertrophic subaortic stenosis, hypertrophic obstructive cardiomyopathy, and muscular subaortic stenosis, emphasizeobstruction to left ventricular outflow to the exclusion of the nonobstructive form of the disease.

Figure 2. The prevalence of hypertrophic cardiomyopathy in thegeneral population substantially exceeds that of several othercardiac and noncardiac diseases, which paradoxically haveachieved greater recognition in the public sphere.

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deficiencies); carnitine deficiency; infiltrative myopathies, ie,glycogen storage diseases (type II; autosomal recessive Pompedisease); as well as Hunter and Hurler diseases, and the transientnonfamilial cardiomyopathy, which is part of a generalizedorganomegaly occurring in infants of insulin-dependent diabeticmothers.6 In addition, disorders such as Danon disease, due toabnormalities of lysosomal membrane, Barth syndrome, and theglycogen storage-like disease caused by AMP-kinase deficiencyhave more recently been described.12,13 In older patients, sys-temic diseases associated with LV hypertrophy include Fried-reich ataxia, pheochromocytoma, neurofibromatosis, lentigino-sis, and tuberous sclerosis, as well as Fabry disease, an X-linkedrecessive disorder of glycosphingolipid metabolism caused by adeficiency in the lysosomal enzyme �-galactosidase A, resultingin intracellular accumulation of glycosphingolipids.14

The Clinical DefinitionThe generally accepted clinical definition of hypertrophic car-diomyopathy, independent of age, is a disease state characterizedby unexplained LV hypertrophy associated with a nondilatedventricular chamber, in the absence of another cardiac orsystemic disease, which itself would be capable of producing themagnitude of hypertrophy evident in a given patient.1,2,6,7 Thediagnosis of hypertrophic cardiomyopathy in the clinical arena

may be buttressed by other characteristic non–morphologicalfeatures1,2 such as family history of the disease, symptoms, andECG abnormalities.

Therefore, use of the term hypertrophic cardiomyopathy todescribe patients with LV hypertrophy in whom the afore-mentioned syndromes or conditions, including the relativelycommon Noonan syndrome, are known to be present (or arestrongly suspected) is inconsistent with this nomenclature.

Impact of GeneticsThis inadvisable practice of assigning the term hypertrophiccardiomyopathy to many diseases associated with LV hypertro-phy, including even systemic hypertension,15 precedes thegenomic era for cardiomyopathies. The advent of moleculardiagnosis has raised the level of complexity regarding the mostappropriate nomenclature for such diseases. In this regard,genetic testing has contributed both valuable insights into themolecular basis of the diverse hypertrophic cardiomyopathydisease spectrum and has now become a powerful diagnostic aidthrough commercially available (ie, non–research-laboratory)DNA-based testing for disease-causing mutations.

Based on available genotype-phenotype data, hypertrophiccardiomyopathy has been generally regarded as a disease entitycaused by dominant mutations in genes encoding protein com-

Figure 3. Summary of nomenclature that distinguishes hypertrophic cardiomyopathy from other genetic diseases associated with LVhypertrophy. *At this time, the overwhelming evidence links the clinical diagnosis of hypertrophic cardiomyopathy with a variety ofgenes encoding protein components of the cardiac sarcomere. However, it is possible that in the future other nonsarcomeric (but alsononmetabolic) genes may prove to cause hypertrophic cardiomyopathy.

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ponents of the sarcomere and its constituent myofilament com-ponents.1–5,16,17 Indeed, at present, the weight of evidence sup-ports the concept that the majority of genes and mutations,which are responsible for clinically diagnosed hypertrophiccardiomyopathy in adult patients, encode proteins of the sarco-mere.1,3,6,16,17 However, it is unresolved as to whether thesesarcomere protein mutations are primarily causative, or alterna-tively act as triggers for a cascade of protein-protein interactionsresulting in the final common pathway of sarcomeric dysfunc-tion18 is unresolved.

Eleven genes of the sacromere have been identified asresponsible for this disease, but with a wide range in frequency,most commonly the �-myosin heavy chain (the first identified)and myosin-binding protein C genes. The other 9 genes appearto account for far fewer cases and include troponin T and I,�-tropomyosin, regulatory and essential myosin light chains,titin, �-actin, �-myosin heavy chain, and muscle LIM protein(MLP). This intergenetic diversity is compounded by consider-able intragenetic heterogeneity, with �400 mutations identifiedamong the 11 genes (http://cardiogenomics.med.harvard.edu).Several other mutant genes have been promoted as disease-causing for hypertrophic cardiomyopathy, although with lowerlevels of evidence.5,19,20

However, the presentation of LV hypertrophy may bebased on very different mechanisms. It is now evident thatmetabolic or storage disorders in older children and youngadults can mimic hypertrophic cardiomyopathy due to sarco-mere protein mutations, eg, conditions involving the geneencoding �-2-regulatory subunit of the AMP-activated pro-tein kinase (PRKAG2) and the X-linked lysosome-associatedmembrane protein gene (LAMP2; Danon disease).10,12,13

In both PRKAG2 and LAMP2, clinical manifestationspredominantly (but not solely) involve the heart, with vari-able degrees of LV hypertrophy, and frequently ventricularpreexcitation. PRKAG2 is an infiltrative glycogen storagedisease of children and young adults, as is Pompe disease,which is a glycogen storage disease of infants due to �-1,4glycosidase (acid maltase) deficiency.13

Penetration of genetic testing into routine cardiovascularpractice, although increasing, is presently incomplete, all muta-tions responsible for unexplained LV hypertrophy are not yetknown, and only a small proportion of patients with clinicallydiagnosed hypertrophic cardiomyopathy have been genotyped.Consequently, it should be underscored that the present discus-sion of nomenclature does not advocate for clinical diagnosisbased solely on genetic analysis. It is also apparent that theperspective presented here is perhaps best regarded as a “snap-shot” in time for a potentially dynamic process that is likely toevolve further. Undoubtedly, patients with both LV hypertrophyand clinical findings consistent with hypertrophic cardiomyop-athy will be identified with other mutant genes that encode eithernon–myofilament sarcomere protein components or proteinsregulating calcium homeostasis, metabolic diseases (other thanLAMP2 or PRKAG2), and mitochondrial cardiomyopathies,12,13

but nevertheless recapitulate the basic underlying pathologycreated by the known disease-causing sarcomeric mutations.

Final Perspectives and RecommendationsIn clinical practice, 2 perspectives on the nomenclature forhypertrophic cardiomyopathy have evolved. The first sce-nario most commonly arises in pediatric cardiology, where asizable proportion of younger patients with cardiomyopathyand LV hypertrophy (including some with a positive familyhistory) do not carry sarcomeric mutations.21 Among thisgroup, a variety of phenotypic expressions (with LV hyper-trophy) have been regarded as examples of hypertrophiccardiomyopathy, even in those circumstances in which pa-tients are clearly afflicted by a variety of other syndromicconditions.22,23 This approach not only splits hypertrophiccardiomyopathy into a multitude of diverse diseases, many ofwhich are presently known to have different genetic sub-strates, but also ignores the voluminous literature publishedover 50 years, which describes the specific disease entityknown as hypertrophic cardiomyopathy in thousands ofpatients (most of whom are adults and likely with sarcomereprotein mutations).1 To abandon that half-century old con-struct would potentially create even more confusion for bothpatients and clinicians.

Consequently, it would seem preferable that the myriad ofclinically diverse genetic syndromes associated with LV cham-ber hypertrophy (most of which are identified in the pediatricage group) should not be designated as part of the hypertrophiccardiomyopathy disease spectrum. For example, nomenclaturethat describes patients with “Noonan hypertrophic cardiomyop-athy,” is discouraged, whereas “Noonan syndrome with cardio-myopathy” or “Noonan cardiomyopathy” seem most prudentand are preferred, enabling clinicians to communicate effectivelyregarding clinical phenotypes.

Therefore, we support an alternative nomenclature that comesclosest to the reality of contemporary clinical practice, byrecognizing the important impact that genetic substrates have onthe names used to describe heart muscle diseases with LVhypertrophy. To minimize confusion, we believe the mostprudent recommendation should be that hypertrophic cardiomy-opathy (and the acronyms HCM or HC) remains a clinicaldiagnosis limited to those patients in whom: (1) overt diseaseexpression with LV hypertrophy, based on careful clinicalexamination, appears to be confined to the heart and (2) thedisease-causing mutation is either known to be sarcomeric or isunresolved (Figure 3).

This definition would exclude systemic, metabolic, or multi-organ syndromes associated with increased LV wall thicknessthat may mimic hypertrophic cardiomyopathy. However, onlywhen the full compliment of genes responsible for LV hyper-trophy is known, and it is possible and clinically convenient touniversally determine the genetic and etiologic basis for other-wise unexplained cardiac hypertrophy, will the uncertaintysurrounding the evolving nomenclature of hypertrophic cardio-myopathy be definitively resolved.

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Sources of FundingThis study was supported by the Howard Hughes Medical Institute(Dr Seidman) and The Hearst Foundations (Dr Maron).

DisclosuresNone.

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Response to Maron et alPerry Elliott, MD; William J. McKenna, MD

The rationale for the definition proposed by Maron et al is that persistent confusion with regard to the definition ofhypertrophic cardiomyopathy has hampered accurate diagnosis and patient management. If this were true, it is difficult tounderstand how several generations of clinical and basic scientists have been able to produce erudite observations onetiology, pathophysiology, clinical outcomes, and treatment of the disease. In essence, the “controversy” can be distilledto a single question—whether heart muscle disease caused by systemic disorders with extracardiac manifestations shouldbe included under the rubric of hypertrophic cardiomyopathy. The position taken by Maron et al is that it is inappropriateto do so. In an attempt to refine the clinical definition of hypertrophic cardiomyopathy, they suggest that the term shouldonly be used in patients with ventricular hypertrophy and a definite disease causing mutation in a cardiac sarcomeric proteingene or in patients in whom the etiology cannot be determined. However, this definition adds very little to that firstproposed 50 years ago in that it simply excludes patients with systemic diseases. The emphasis on sarcomeric protein genemutations gives the semblance of a more precise diagnosis, but as work by some of the authors of this article has shown,the fact that only a minority of patients in the community with unexplained left ventricular hypertrophy have such mutationsmeans that it has little relevance to everyday clinical practice. Our view is that it is far better to abandon the tortuous effortsto constrain hypertrophic cardiomyopathy into a single entity in favor of a concerted effort to develop new methods for theelucidation of the cause of ventricular hypertrophy in individual patients.

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Maron, Steve R. Ommen, Rick A. Nishimura and Bernard J. GershBarry J. Maron, Christine E. Seidman, Michael J. Ackerman, Jeffrey A. Towbin, Martin S.

HypertrophyNomenclature Characterizing Hypertrophic Cardiomyopathy and Left Ventricular

How should hypertrophic cardiomyopathy be classified?: What's in a Name? Dilemmas in

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