Cardiovascular Pathology 14 (2005) 165 – 169
Review Article
Twenty years of progress and beckoning frontiers in cardiovascular pathologyB Cardiomyopathies Gaetano Thiene*, Cristina Basso, Fiorella Calabrese, Annalisa Angelini, Marialuisa Valente Institute of Pathological Anatomy, University of Padua Medical School, Padua, Italy Received 23 February 2005; accepted 31 March 2005
Abstract In the last 20 years, with the advent of cardiac transplantation and the availability of molecular biology techniques, major advancements were achieved in the understanding of cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic right ventricular, primary restrictive, and noncompacted myocardium) and added in the update of WHO classification. Myocarditis was also included with the name binflammatory cardiomyopathy.Q Adenoviruses and parvoviruses were found to be frequent cardiotropic viruses in addition to enteroviruses. The extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed to establish hypertrophic and restrictive cardiomyopathies as sarcomeric (bforce generationQ) diseases, dilated cardiomyopathies as cytoskeleton (bforce transmissionQ) disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC) as cell junction disease. If we consider also cardiomyopathy as ion channel disease (long and short QT syndrome, Brugada syndrome, and cathecolaminergic polymorphic ventricular tachycardia), because they are diseases of the myocardium associated with electrical dysfunction, then a genomic/postgenomic classification of inherited cardiomyopathies may be put forward: cytoskeletal cardiomyopathy, sarcomeric cardiomyopathy, cell junction cardiomyopathy, and ion channel cardiomyopathy. D 2005 Elsevier Inc. All rights reserved. Keywords: Cardiomyopathy; Molecular biology; Pathology
1. Introduction The advent of cardiac transplantation and the renewed interest in sudden cardiac death have resulted in exciting opportunities in the study of cardiomyopathies, especially to allow for the discovery of new entities. The availability of sophisticated methods of investigation like molecular biology techniques, other than the traditional tools of morphology, opened extraordinary avenues in understanding the causes other than the substrates of cardiomyopathies.
The major advances were achieved in the last 20 years, just the time span from the foundation of the Society for Cardiovascular Pathology. Pathologists played a major role and assumed key positions in producing new knowledge. We would like to briefly summarize their contributions to this field. We will discuss the discovery of new cardiomyopathies, the update of the classification, and the understanding of etiopathogenesis.
2. Novel cardiomyopathies B This article is based on a presentation at the Society for Cardiovascular Pathology Companion Meeting at the United States and Canadian Academy of Pathology, February 27, 2005, San Antonio, TX. * Corresponding author. Cardiovascular Pathology, University of Padua Medical School, Via A. Gabelli, Padova 61 35121, Italy. Tel.: +39 049 8272283; fax: +39 049 8272284. E-mail address:
[email protected] (G. Thiene).
1054-8807/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2005.03.008
Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly known as right ventricular dysplasia, was found at postmortem to be a major cause of sudden death in the young [1]. The striking feature is the prevalent involvement of the right ventricular myocardium, with fibrofatty replacement and parchment-like thinning, as well
166
G. Thiene et al. / Cardiovascular Pathology 14 (2005) 165–169
Fig. 1. ARVC. (A) Four chamber view of the heart from a young male who died suddenly. Note the massive fibro-fatty replacement in the right ventricular free wall, whereas the left ventricle and interventricular septum are normal. (B) Histology of the right ventricular free wall with transmural fibro-fatty infiltration (Heidenhein stain 2).
as aneurysms of the free wall [2] (Fig. 1). Cardiac dysfunction is mostly characterized by ventricular arrhythmias with left bundle branch block morphology, indicating right ventricular origin [3]. Ventricular arrhythmogenicity is precipitated by effort, thus explaining why this myocardial disorder is reported as the most frequent cause of sudden death in athletes [4]. A similar cardiomyopathy was reported in cats [5] and dogs [6]. The myocardial disappearance is progressive. Genetically determined dystrophy, myocarditis, and myocyte apoptosis have been
postulated to play a role in the cell loss [2,7]. Why healing occurs through fatty tissue replacement remains intriguing. In nearly 50% of cases, the disease is inherited with an autosomal dominant pattern, variable penetrance, and polymorphic phenotype; certainly, ARVC is not a congenital heart disease due to a myocardial maldevelopment (i.e., dysplasia) because the myocardial disappearance occurs late during childhood [8]. Naxos disease is a recessive form of ARVC with high penetrance, associated with palmoplantar keratosis, and wholly hair [9]. A similar
Fig. 2. Primary restrictive cardiomyopathy. (A) Left side view of the heart from a boy who died with congestive heart failure: note the small left ventricle and huge left atrium. (B) Histology of the ventricular myocardium showing myocyte disarray and interstitial fibrosis (Heidenhein stain 120).
G. Thiene et al. / Cardiovascular Pathology 14 (2005) 165–169
phenotype expression is shown by another cardiocutaneous disease named Carvajal syndrome [10]. Another novel disease is primary restrictive cardiomyopathy [11]. Diastolic ventricular filling is impaired, whereas systolic function is usually preserved. Congestive heart failure may be so severe as to require cardiac transplantation [12]. The ventricles are of normal size, whereas the atria are remarkably dilated due to the difficulty of emptying during diastole because of ventricular myocardium stiffness (Fig. 2). The ventricular diastolic impairment is not the consequence of endocardial thickening, like in eosinophilic obliterative cardiomyopathy, nor of amyloid extracellular deposits. Myocardial disarray and interstitial fibrosis are the striking features at histology [13]. A third novel entity is noncompacted myocardium, where the heart is featured by coarse trabeculations of the ventricular myocardium with very deep intrertrabecular spaces that the endocardium almost reaches the epicardium [14]. This human heart resembles the heart of animals without epicardial coronary arteries, where the myocardial blood supply comes directly from the cavities through sinusoids. The defect is ascribable to an arrested development, with lack of compaction following embryonic myocardium undermining [15].
3. Update of WHO classification A new definition of cardiomyopathy was put forward (bdisease of the myocardium associated with cardiac dysfunctionQ), considering that the previous (bheart muscle disease of unknown etiologyQ) did not reflect the new genetic discoveries (Table 1). The discovery of new entities, not contemplated in the 1980 WHO classification, fostered the need to update the classification. Primary restrictive and arrhythmogenic right ventricular cardiomyopathies were added to the list ([16]; Table 2). Noncompacted myocardium was listed among the unclassified cardiomyopathies, together with mitochondrial cardiomyopathies and endocardial fibroelastosis. Specific heart muscle diseases associated with cardiac or systemic disorders, like amyloid and haemochromatosis, are now named specific cardiomyopathies. Myocarditis, mostly ignored in the early 1980 classification [17], is now included within specific cardiomyopathies Table 1 Cardiomyopathy WHO terminology and definitions: 1980 vs. 1995 1980
1995
Cardiomyopathy Heart muscle disease of unknown cause Specific heart muscle disease Heart muscle disease of known cause or associated with disorders of other systems
Cardiomyopathy Disease of the myocardium associated with cardiac dysfunction Specific cardiomyopathy Heart muscle disease associated with specific cardiac or systemic disorders
167
Table 2 Cardiomyopathy WHO classifications: 1980 vs. 1995 1980
1995
Dilated Hypertrophic Restrictive
Dilated Hypertrophic Restrictive Arrhythmogenic right ventricular
with the name binflammatory cardiomyopathy Q. Ischemic, valvular, and hypertensive diseases are also regarded as specific cardiomyopathies, when the severity of myocardial dysfunction largely exceeds the extent of the basic defect. No question that the introduction of a unified terminology and the recognition of new entities are to be considered steps forward. A major concern has been to extend the concept of cardiomyopathies to dysfunctioning myocardium due to coronary artery, valvular, and hypertensive disease, in which the damage to the myocardium traditionally has been considered secondary [18]. 4. Understanding the etiology of cardiomyopathies The extraordinary achievements accomplished in the last two decades in molecular genetics have allowed the identification of the gene defects in many monogenic familiar cardiomyopathies, inherited according to the Mendelian law. Hypertrophic cardiomyopathy was discovered to be a bsarcomericQ disease in so far as most mutations were found in genes encoding sarcomeric proteins (h-myosin heavy chain, a-tropomyosin, myosin binding–protein C, and troponin T, C, I), thus accounting for the impairment of force generation [19]. The same familial idiopathic restrictive cardiomyopathy was found to be a sarcomeric disease due to the mutation of cardiac troponin I [20]. In familial forms of dilated cardiomyopathy, the mutated genes are those coding cytoskeletal proteins related to force transmission: dystrophin, cardiac actin, desmin, and y-sarcoglycan [21]. In ARVC, as well as in cardiocutaneous syndromes, genes encoding cell junction proteins, like plakoglobin [22], desmoplakin [23,24], and plakophilin [25], were found to show causative missense mutations or deletions. A remodelling of gap junctions, presumably because of abnormal linkage between the mechanical junctions and the Table 3 A genomic/postgenomic classification of inherited cardiomyopathies Cytoskeletal cardiomyopathy Cell junction cardiomyopathy
Sarcomeric cardiomyopathy Ion channel cardiomyopathy
Dilated cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy, cardiocutaneous syndromes Hypertrophic and restrictive cardiomyopathies Long and short QT syndromes, Brugada syndrome, catecholaminergic polymorphic VT
168
G. Thiene et al. / Cardiovascular Pathology 14 (2005) 165–169
cytoskeleton, was also demonstrated, probably enhancing the arrhythmogenic risk [26]. As for inflammatory cardiomyopathy, the introduction of molecular biology techniques as routine diagnostic procedures, like PCR and RT-PCR, allowed the identification of viral genome in nearly 50% of biopsy proven myocarditis, as well as the discovery of new cardiotropic viruses, like adeno- and parvoviruses [27]. These findings entail important implications in the choice of pharmacological therapy, whether antiviral or immunosuppressive [28]. 5. Future perspectives The new definition of cardiomyopathy is based on the concept of myocardial disease associated with cardiac dysfunction [16]. If we accept that the term dysfunction should include not only depressed contractility and impaired relaxation, but also conduction and rhythm disturbances, as well as enhanced myocardial arrhythmogenicity, then we have to realize that myocardial electrical diseases do exist in the absence of structural abnormalities: long and short QT syndromes [29,30], Brugada syndrome [31], and cathecolaminergic polymorphic ventricular tachycardia [32], in which the defect is ascribable to ion channel disorders. These defects are invisible even at ultrastructural levels by electron microscopy, nonetheless the function of the myocyte is abnormal. These conditions should be considered cardiomyopathies too [18]. A genomic-postgenomic classification of inherited cardiomyopathies may be proposed by taking into account the underlying gene mutations and the encoded defective proteins and then distinguishing cytoskeleton, sarcomeric, cell junction, and ion channel cardiomyopathies ([33]; Table 3). What was considered for years as idiopathic (bunknownQ), and as such, at the base of the early classification, was largely elucidated by the finding of a genetic background or a viral etiology. Proteomics, with the employment of microarrays for the study of myocyte biology and protein expression, as well as investigation of cytokine overexpression in inflammatory cardiomyopathies [34], will be of great help to understand the pathogenesis of the disease and to pursue other possible therapeutic targets. Molecular biology and genetics are becoming a routine tool for the pathologist and the gold standard for the diagnosis of infective or genetic disease. They should not be limited to in vivo studies, but also used for achieving a definitive diagnosis at autopsy in cases of sudden death bsine materiaQ [35]. Acknowledgments This study was supported by the European Commission, Brussels; Ministry of Health, Rome; and Veneb Region, Venice.
References [1] Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129 – 33. [2] Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhythmogenic right ventricular cardiomyopathy: dysplasia, dystrophy or myocarditis? Circulation 1996;94:983 – 91. [3] Marcus F, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation 1982;65:384 – 98. [4] Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959 – 63. [5] Fox PR, Maron BJ, Basso C, Liu SK, Thiene G. Spontaneously occurring arrhythmogenic right ventricular cardiomyopathy in the domestic cat: a new animal model similar to the human disease. Circulation 2000;102:1863 – 70. [6] Basso C, Fox PR, Meurs KM, Towbin JA, Spier AW, Calabrese F, Maron BJ, Thiene G. Arrhythmogenic right ventricular cardiomyopathy causing sudden cardiac death in boxer dogs. A new animal model of human disease. Circulation 2004;109:1180 – 5. [7] Valente M, Calabrese F, Thiene G, Angelini A, Basso C, Nava A, Rossi L. In vivo evidence of apoptosis in arrhythmogenic right ventricular cardiomyopathy. Am J Pathol 1998;152:479 – 84. [8] Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja GF, Corrado D, Danieli GA, Thiene G. Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2000; 36:2226 – 33. [9] Protonotarios N, Tsatsopoulou A, Patsourakos P, Alexopoulos D, Gezerlis P, Simitsis S, Scampardonis G. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J 1986;56:321 – 6. [10] Kaplan SR, Gard JJ, Carvajal-Huerta L, Ruiz-Cabezas JC, Thiene G, Saffitz JE. Structural and molecular pathology of the heart in Carvajal syndrome. Cardiovasc Pathol 2004;13:26 – 32. [11] Angelini A, Calzolari V, Thiene G, Boffa GM, Valente M, Daliento L, Basso C, Calabrese F, Razzolini R, Livi U, Chioin R. Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol 1997;80:1046 – 50. [12] Thiene G, Angelini A, Basso C, Calabrese F, Valente M. Novel heart disease requiring transplantation. Adv Clin Pathol 1998;2:65 – 73. [13] Thiene G, Valente M, Angelini A, Boffa GM, Razzolini R, Livi U, Faggian G, Gallucci V. Primary restrictive cardiomyopathy: the paradox of a small heart requiring transplantation. Eur Heart J 1989;10:251A. [14] Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001;86:666 – 71. [15] Angelini A, Melacini P, Barbero F, Thiene G. Evolutionary persistence of spongy myocardium in humans. Circulation 1999;99:2475. [16] Richardson P, McKenna WJ, Bristow M, Maisch B, Mautner B, O’Connel J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P. Report of the 1995 WHO/ISFC Task Force on the definition and classification of cardiomyopathies. Circulation 1996;93:841 – 2. [17] Brandenburg RO, Chazov E, Cherian G, False AO, Grosgogeat Y, Kawai C, Loogen F, Marin Judez V, Orinius E, Goodwin JF, Olsen J, Oakley CM, Pisa Z. Report of the WHO/ISFC Task Force on the definition and classification of cardiomyopathies. Br Heart J 1980;44:672 – 3. [18] Thiene G, Corrado D, Basso C. Cardiomyopathies: is it time for a molecular classification? Eur Heart J 2004;25:1772 – 5. [19] Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell 2001;104: 557 – 67.
G. Thiene et al. / Cardiovascular Pathology 14 (2005) 165–169 [20] Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111:209 – 16. [21] Watkins H. Genetic clues to disease pathways in hypertrophic and dilated cardiomyopathies. Circulation 2003;107:1344 – 6. [22] McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, McKenna WJ. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000;355:2119 – 24. [23] Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002;71:1200 – 6. [24] Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP. Recessive mutation in desmoplakin disrupts desmoplakin–intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000;9:2761 – 6. [25] Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr L. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004;36:1162 – 4. [26] Kaplan S, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis A, Prost Squarcioni C, McKenna WJ, Thiene G, Basso C, Brousse N, Fontaine G, Saffitz JE. Remodelling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 2004;1:3 – 11. [27] Calabrese F, Thiene G. Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res 2003;60:11 – 25.
169
[28] Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 2003;107:857 – 63. [29] Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866 – 74. [30] Brugada R, Hong K, Dumane R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov K, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short QT syndrome linked to mutations in HERG. Circulation 2004;109:30 – 5. [31] Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O’Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293 – 6. [32] Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachicardia. Circulation 2001;103:196 – 200. [33] Bowles NE, Bowles KR, Towbin JA. The bfinal common pathwayQ hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy. Herz 2000;25:168 – 75. [34] Calabrese F, Carturan E, Chimenti C, Pieroni M, Agostini C, Angelini A, Crosato M, Valente M, Boffa GM, Frustaci A, Thiene G. Overexpression of tumor necrosis factor (TNF)alpha and TNFalpha receptor I in human viral myocarditis: clinicopathologic correlations. Mod Pathol 2004;17:1108 – 18. [35] Basso C, Calabrese F, Corrado D, Thiene G. Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res 2001;50:290 – 300.