14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-194

Molecular pathology of arrhythmogenic right ventricular cardiomyopathy/dysplasia

Gaetano Thiene, Cristina Basso, Fiorella Calabrese, Marialuisa Valente.
Department of Pathology, University of Padua Medical School, Padua, Italy

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease of unknown origin (“cardiomyopathy”), featured clinically by ventricular tachycardia and arrhythmic death (“arrhythmogenic”) and pathologically by fibro-fatty replacement of the right ventricle (“right ventricular”)^1,2.

The pathobiology of the disease is still obscure and many questions are still pending (Tab. I).

TABLE I – ARVC/D: queries

Partial or complete absence of the right ventricular myocardium is neither the consequence of a myocardial deranged development (“dysplasia”) nor of myocyte fatty metamorphosis (“metaplasia”). It is an acquired, progressive loss of the right ventricular myocardium due to an unknown myocardial injury followed by repair with fibro-fatty tissue³. Three basic mechanisms have been postulated to account for progressive myocyte death⁴.

The familiar occurrence with autosomal dominant transmission as well as the peculiar fatty infiltration is in keeping with a myocardial dystrophy, i.e. a genetically determined atrophy, like in Duchenne’s and Becker’s skeletal myopathies. Six genes for a pure dominant form of ARVC/D have been mapped to chromosome 14, 1, 2, 3 and 10, and a seventh gene has been mapped to chromosome 17 for a recessive variant of ARVC/D associated with palmo-plantar cheratosis and curly hairs (Tab. II)^5-11. In no case, however, has the responsible gene been identified and characterized thus far.

TABLE II – Genetics of ARVC/D

Based on our current understanding of the molecular basis of cardiovascular disorders, we can speculate that a common set of proteins are mutated in this disorder, all encoded by genes of different chromosomes. A variety of possibilities exists as potential candidate genes including cardiac structural proteins of the cytoskeleton, viral receptor proteins and apoptosis-causing genes.

Unlike long QT and Brugada syndromes, which are caused by mutations in ion channel genes^12,13, and unlike hypertrophic and restrictive cardiomyopathies, which are caused by mutation in sarcomeric protein genes¹⁴, it is quite probable that ARVC/D is secondary to cytoskeleton protein abnormalities. X-linked dilated cardiomyopathy is due to mutations in dystrophin^15,16. Autosomal dominant dilated cardiomyopathy has been related to mutation in cardiac actin which links to the N-terminus of dystrophin¹⁷.

The second mechanism is a programmed cell death, namely myocyte apoptosis. Apoptosis is a peculiar mode of death which, at difference from necrosis, starts from the nucleus with activation of endonuclease, disintegration of DNA and formation of apoptotic bodies¹⁸. On the opposite, necrosis is the consequence of lack of oxygen supply with cytoplasm and mytocondrial swelling and cell membrane disruption. Apoptosis has been proven to occur in the myocardium of hearts with ARVC/D, both in postmortem specimens¹⁹ and in vivo endomyocardial biopsies²⁰, using electron microscopy and TUNEL techniques. It is particularly frequent in cases with recent clinical onset and acute symptoms like angina, pyrexia and raised eritrosedimentary rate²⁰.

The third mechanism is myocarditis. Inflammatory infiltrates have been reported to occur in 2/3 of hearts and in 100% of those which fibro-fatty variant of ARVC/D and with biventricular involvement²¹. A metanalysis of 5 pathological investigations in different countries results in a mean rate of 69% (Tab. III)^21-25. The inflammatory phenomenon is usually focal with patchy infiltrates associated with myocyte death. The frequent finding of mononuclear infiltrates lead to consider the disease as a chronic myocarditis²¹. Immunohistochemistry revealed that mononuclear inflammatory cells were mostly cytotoxic T-lymphocytes, activated T-lymphocytes and macrophages whereas B-lymphocytes were almost absent²⁶. Thus, inflammatory cell population is in keeping with a cell mediate immunomechanism. Autoimmunity was ruled out in ARVC/D since cardiac specific and skeletal muscle cross reaction antibodies were as much frequent in ARVC/D patient as in healthy relatives and normal population⁴.

TABLE III – Inflammatory infiltrates in ARVC/D

The hypothesis of a possible viral etiology induced to perform molecular pathology investigations using polymerase chain reaction, which resulted in controversial findings. Some authors were able to amplify enteroviral genomes^27,28, whereas others²⁹ and our group failed to detect Enterovirus from any endomyocardial biopsies of 20 patients with ARVC/D³⁰ (Tab. IV). However, the role of other RNA as well as DNA viruses cannot be excluded and should be investigated. Whatever infective or immune, inflammatory heart disease is a peculiar feature of ARVC/D. Is there any link between apoptosis and myocarditis? Cytotoxic T-lymphocytes, a constant component of inflammatory infiltrates in ARVC/D, may trigger apoptosis through the release of cytochines like tumor necrosis factor and perforin³¹. Immunohistochemistry have revealed that cytotoxic T-lymphocyte are just close to myocytes dying through apoptotic mechanism²⁶. Thus, apoptosis may be a murder by T-lymphocytes.

TABLE IV – Molecular pathology investigation of viral myocarditis in ARVC/D

Myocarditis has been observed to occur in familiar ARVC/D, namely in affected patients belonging to the same family^32-35 (Tab. V).

TABLE V – Familial ARVC/D and myocarditis

Thus, a genetic propensity to viral infection should be taken into consideration. Viral infection may act as exogenous agent in a genetic background. A defect of viral receptor protein has been postulated³⁰, which might act as a genetic substrate to increase susceptibility to viral virulence, myocarditis, myocardial injury and fibro-fatty replacement (Tab. VI).

A final question regards the elective involvement of the right ventricle. It has been proven that the ARVC/D spreads to the septum and the left ventricle with the time, but still in nearly 50% of cases there is an isolated right ventricular disease. Whether this is related to specific propensity of the right ventricular myocardium to infections or to apoptosis is unknown. Matsumori and Kawai were able to induce Coxsackie virus myocarditis in BALB/c mice with selective involvement of the right ventricle and formation of right ventricular aneurysms, thus suggesting a pathogenetic role of viral infection in ARVC/D³⁶. A similar clinico-pathologic picture was recently observed to occur spontaneously in cats and histology revealed myocarditis³⁷.

In conclusion, virus, immunity or genetics, which act as triggers of both apoptosis and myocarditis, fit the concept of injury and repair process in ARVC/D and all account for myocyte death, fibro-fatty tissue replacement and ominous electrical myocardial instability.

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