AUTORE, Camillo

P. Spirito

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Archivio della ricerca- Università di Roma La Sapienza

EditorialApical hypertrophic cardiomyopathy or left ventricularnon-compaction? A difficult differential diagnosisPaolo Spirito1* and Camillo Autore21Divisione di Cardiologia, Ospedale Galliera, Via Volta 8, 1628 Genoa, Italy and 2Divisione di Cardiologia, OspedaleSant’Andrea, II Facoltà di Medicina, Università ‘La Sapienza’, Rome, ItalyOnline publish-ahead-of-print 10 July 2007This editorial refers to ‘Mutation in the alpha-cardiac actingene associated with apical hypertrophic cardiomyopathy,left ventricular non-compaction, and septal defects’ byL. Monserrat et al., on page 1953Hypertrophic cardiomyopathy (HCM) is a familial cardiacdisease caused by mutations in one or more of 12 genesencoding protein components of the cardiac sarcomere.1,2The disease is transmitted with an autosomal dominanttrait and a variable penetrance. The phenotypic featuresof HCM may develop at any age from infancy to adulthood,and are characterized by a great heterogeneity in theextent, magnitude, and distribution of left ventricular (LV)hypertrophy.1 Apical HCM is a relatively rare morphologicalexpression of the disease (,5% of patients), in which LVwall thickening is confined to the most distal portion ofthe ventricle, below the papillary muscle level.3,4 Thisform of HCM is more frequently sporadic, but may also beencountered in the context of clinical screening of HCMfamilies with more common patterns of distribution of LVhypertrophy.3,4 A few families have also been reportedwith autosomal dominant inheritance of an apical form ofHCM.5 The clinical course of apical HCM appears to be gene-rally benign, without severe symptoms or major cardiacevents. Indeed, a particularly low annual cardiovascularmortality rate (0.1%) was reported during a mean follow-upof 9 years in a survey of the largest available cohort ofpatients with apical HCM (a total of 105 patients).3Non-compaction of LV myocardium is an increasinglyrecognized but apparently uncommon cardiomyopathy,characterized by a hypertrophied left ventricle with mul-tiple trabeculations and deep intertrabecular recessescommunicating with the ventricular cavity.2,6 These mor-phological abnormalities involve predominantly the distal(apical) portion of the left ventricle. Non-compaction canbe an isolated finding, or may be associated with other con-genital heart anomalies.2,6 At present, this disorder isconsidered to be the result of an arrest of the normalprocess of intrauterine endomyocardial morphogenesis.6Non-compaction may first become manifest during infancy,usually in association with severe clinical manifestationsand an unfavourable natural history. In adults, the clinicalcourse appears to be more variable. A minority of adultpatients have mild manifestations of the disease and a rela-tively favourable clinical course. However, the majorityof adults present with LV systolic dysfunction and heartfailure, and some may experience arrhythmias, thromboem-bolic events, or sudden death.2,6 Both familial and sporadiccases of LV non-compaction have been described, with thefamilial forms being reported in 25% of patients.6 Thedisease is more frequently inherited with an autosomaldominant trait, with an X-linked or mitochondrial inheri-tance being less common. Mutations have been identifiedin the genes encoding a-dystrobrevin, G4.5 (a member oftafazzin proteins), and LIM domain-binding protein 3 (2,6).In most patients, however, the genetic cause remainsundetermined.6 The clinical phenotype within families,and amongst unrelated individuals with the same mutation,is highly variable, suggesting that additional factors such asmodifier genes and the environment may influence theclinical expression of the disease.Mutations in the alpha-cardiac actin gene have beenreported as the cause of HCM in a small minority of patientswith heterogeneous clinical presentations, ranging frommild to severe phenotypes.7 In a recent study, Arad et al.5identified a E101K (Glu101Lys) mutation in the alpha-cardiacactin gene as the cause of apical HCM with an autosomaldominant inheritance in two distantly related families, inwhich all of the 16 mutation carriers had an apical distri-bution of hypertrophy. A LOD score of .4.5 confirmed thedisease-causing role of the mutation. Monserrat et al.8have investigated the possibility that the same E101K actingene mutation could cause a variety of cardiomyopathies.The authors initially screened a large and heterogeneouspopulation for this mutation, including a total of .250index patients affected by either HCM, dilated cardiomyopa-thy, or LV non-compaction. The E101K cardiac actin genemutation was found in five patients. Four of these patientshad been previously diagnosed with predominantly apicalHCM and one with LV non-compaction; two of these fivepatients also belonged to the families previously reportedThe opinions expressed in this article are not necessarily those of theEditors of the European Heart Journal or of the European Society ofCardiology.* Corresponding author. Tel: þ39-010-5634170; fax: þ39-010-5634180.E-mail address: paolo.spirito@galliera.it† doi:10.1093/eurheartj/ehm239& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.orgEuropean Heart Journal (2007) 28, 1923–1924doi:10.1093/eurheartj/ehm266 by guest on November 12, 2012http://eurheartj.oxfordjournals.org/Downloaded from by Arad et al.5 Extensive clinical and genetic screening per-formed by Monserrat et al. in the relatives of the five indexpatients with the E101K cardiac actin gene mutation led tothe identification of a total of 46 mutation carriers. Pene-trance was particularly high, since all the mutation carriershad an abnormal LV phenotype, most patients showing LVtrabeculations and intertrabecular recesses. Indeed, 50%of these patients had trabeculations of a magnitude suchas to fulfil standard morphological criteria for LV non-compaction.9 None of the 46 patients showed thickening ofthe basal interventricular septum, and all patients had thethinnest ventricular segment at the level of the posteriorseptum. In addition, five of the 46 mutation carriers hadan associated atrial septal defect, two had an aneurysmof the atrial septum, and one had a ventricular septaldefect. Of note, the family history and/or clinical coursein these pedigrees was unfavourable, including four suddendeaths, two cardiac arrests, one heart failure death, andone heart transplantation.The phenotypic features of the pedigrees with the E101Kcardiac actin gene mutation described by Monserrat et al.would not appear to reflect the clinical characteristics ofapical HCM. Indeed, prominent trabeculations and deepintertrabecular recesses involving predominantly the LVapex appear to be the most common morphologicalfeature in these families, while only eight patients had awall thickness 15 mm (potentially compatible with HCM)in the compact layer of the LV wall, after excluding thethickness of the trabeculations (Table 1, in Monserratet al.). Therefore, in most patients, the LV morphologywould appear to be consistent with a diagnosis of LV non-compaction rather than apical HCM. The unfavourablenatural history in these pedigrees also differs from thebenign clinical course generally associated with apical HCM.Finally, congenital heart anomalies were present in 15% ofthe carriers of themutation, a finding which is not uncommonin LV non-compaction,2,6 but extremely rare in patients withHCM. Of interest, cardiac actin mutations have also beenreported in pedigrees with autosomal dominant inheritanceof atrial septal defects.10Independently of which nomenclature is used for thecardiac disease affecting the five families reported byMonserrat et al., either apical HCM or LV non-compaction,the clinical phenotypes in the affected individuals appearto be similar in their genetically programmed morphologicalabnormalities, and characterized by a uniquely high pene-trance. Therefore, the E101K (Glu101Lys) mutation in thealpha-cardiac actin gene would seem to cause a specificand single clinical entity, possibly expressing a disorder ofcardiac morphogenesis, which requires genetic screeningin order to establish the definitive diagnosis. In recentyears, major advances in our understanding of the molecularpathways leading to cardiomyopathies have also increasedour appreciation of the frequent similarities in clinicalexpression of diseases with different aetiologies. Theobservations of Monserrat et al. show once more that themorphological information derived from cardiac ultrasoundsmay not always be sufficient to classify the cardiomyopathyaffecting some patients. Although the high-resolutionimages of the heart obtained with magnetic resonancemay offer additional help, ever more frequently DNA analy-sis will become the most definitive method for diagnosis inmany patients with cardiomyopathies.References1. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ,Seidman CE, Shah PM, Spencer WH, Spirito P, Ten Cate FJ, Wigle ED.Task Force on Clinical Expert Consensus Documents. American Collegeof Cardiology; Committee for Practice Guidelines. European Society ofCardiology. American College of Cardiology/European Society of Cardiol-ogy Clinical Expert Consensus Document on Hypertrophic Cardiomyopa-thy. A report of the American College of Cardiology Foundation TaskForce on Clinical Expert Consensus Documents and the EuropeanSociety of Cardiology Committee for Practice Guidelines. Eur Heart J2003;24:1965–1991.2. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D,Moss AJ, Seidman CE, Young JB. Contemporary definitions and classifi-cation of the cardiomyopathies: an American Heart Association scientificstatement from the council on clinical cardiology, heart failure and trans-plantation committee; quality of care and outcomes research and func-tional genomics and translational biology interdisciplinary workinggroups; and council on epidemiology and prevention. Circulation 2006;113:1807–1816.3. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Parker TG, Wigle ED,Rakowski H. Long-term outcome in patients with apical hypertrophiccardiomyopathy. J Am Coll Cardiol 2002;39:638–645.4. Kitaoka H, Doi Y, Casey SA, Hitomi N, Furuno T, Maron BJ. Comparison ofprevalence of apical hypertrophic cardiomyopathy in Japan and theUnited States. Am J Cardiol 2003;92:1183–1186.5. Arad M, Penas Lado M, Monserrat L, Maron BJ, Sherrid M, Ho CY, Barr S,Karim A, Olson TM, Kamisago M, Seidman JG, Seidman CE. Genemutations in apical hypertrophic cardiomyopathy. Circulation 2005;112:2805–2811.6. Xing Y, Ichida F, Matsuoka T, Isobe T, Ikemoto Y, Higaki T, Tsuji T,Haneda N, Kuwabara A, Chen R, Futatani T, Tsubata S, Watanabe S,Watanabe K, Hirono K, Uese K, Miyawaki T, Bowles KR, Bowles NE,Towbin JA. Genetic analysis in patients with left ventricular non compac-tion and evidence for genetic heterogeneity. Mol Genet Metab 2006;88:71–77.7. Mogensen J, Klausen IC, Pedersen AK, Egeblad H, Bross P, Kruse TA,Gregersen N, Hansen PS, Baandrup U, Børglum AD. Alpha-cardiac actinis a novel disease gene in familial hypertrophic cardiomyopathy. J ClinInvest 1999;103:R39–R43.8. Monserrat L, Hermida-Prieto M, Fernandez X, Rodrı́guez I, Dumont C,Cazón L, Cuesta MG, Gonzalez-Juanatey C, Peteiro J, Álvarez N,Penas-Lado M, Castro-Beiras A. Mutation in the alpha-cardiac actingene associated with apical hypertrophic cardiomyopathy, left ventri-cular non-compaction, and septal defects. Eur Heart J 2007;28:1953–1961. First published on July 4, 2007, doi:10.1093/eurheartj/ehm239.9. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echo-cardiographic and pathoanatomical characteristics of isolated non-compaction: a step towards classification as a distinct cardiomyopathy.Heart 2001;86:666–671.10. Matsson H, Klar J, Sunnegardh J, Enell H, Jonzon A, Vikkula M,Gutierrez I, Brook D, Newbury-Ecob RA, Dahl N. Alpha cardiac actin(ACTC) is mutated in autosomal dominant atrial septal defect. Eur JHum Genet 2005;13(Suppl 1):p 1172.Editorial1924 by guest on November 12, 2012http://eurheartj.oxfordjournals.org/Downloaded from 

Apical hypertrophic cardiomyopathy or left ventricular non-compaction? A difficult differential diagnosis

This editorial refers to ‘Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects ’ by L. Monserrat et al., on page 1953 Hypertrophic cardiomyopathy (HCM) is a familial cardiac disease caused by mutations in one or more of 12 genes encoding protein components of the cardiac sarcomere.1,2 The disease is transmitted with an autosomal dominant trait and a variable penetrance. The phenotypic features of HCM may develop at any age from infancy to adulthood, and are characterized by a great heterogeneity in the extent, magnitude, and distribution of left ventricular (LV) hypertrophy.1 Apical HCM is a relatively rare morphological expression of the disease (,5 % of patients), in which LV wall thickening is confined to the most distal portion o

Paolo Spirito

Camillo Autore

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Editorial Apical hypertrophic cardiomyopathy or left ventricular non-compaction? A difficult differential diagnosis

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Apical hypertrophic cardiomyopathy or left ventricular non-compaction? A difficult differential diagnosis

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