Introduction

Arrhythmogenic right ventricular cardiomyopathy/ dysplasia (ARVC/D) is a heart muscle disorder associated with the occurrence of ventricular arrhythmias arising from the right ventricle in the presence of subtle or diffuse morphological changes [1-4]. Histologically the condition is characterized by myocyte loss with fatty or fibrofatty replacement [5]. The reclassification of cardiomyopathies by the World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies in 1995 defined ARVC/D as being "characterized by progressive fibrofatty replacement of the right ventricular myocardium, initially with typical regional, and later global, right and some left ventricular involvement, with relative sparing of the septum. Familial disease is common, with autosomal dominant inheritance and incomplete penetrance; a recessive form is described. Presentation with arrhythmias and sudden death is common, particularly in the young" [6].

The original theory that this is a dysplastic process, with partial or complete congenital absence of ventricular myocardium, has been largely disproved by clinical and pathological evidence demonstrating the acquired and progressive nature of the condition [3,5-13]. One case of antenatal detection of right ventricular structural abnormalities associated with ventricular ectopy of right ventricular origin has been reported [14]. This may reflect a different disorder, sometimes known as Uhl's anomaly, characterized by congenital absence, total or subtotal, of right ventricular myocardium [15]. A genetic basis for classical "acquired" ARVC/D has been identified, with predominantly autosomal dominant transmission. The genes identified have demonstrated ARVC/D to be, for the most part, a disease of the desmosome [16-21]. Some autosomal recessive forms of desmosomal disease have been characterized [22,23], as well as some non-desmosomal forms associated with effort-induced polymorphic ventricular tachycardia [24] and tran-

scriptional abnormalities [25]. To date, however, gene mutations are only identified in 40% of cases [21] suggesting that the other 60% of cases may be comprised of incorrect diagnoses, other cell adhesion gene mutations or phenocopies of ARVC/D.

The first case series published in 1982 described clinical findings in 24 adults, the majority of whom presented with symptomatic ventricular tachycardia [1]. There was a high preponderance of male patients (ratio to females 2.7:1) and onset of symptoms was typically in the fourth decade of life although the age range was broad (13-59 years). Those clinical findings reflect the investigations available at the time. On chest x-ray, the cardiothoracic ratio exceeded 50% in 72% of patients. The most frequent finding on ECG was right precordial T-wave inversion (V1 to V4), present in over 85% of those who had documented ventricular tachycardia. Incomplete or complete right bundle branch block was present in over one third of all patients. Postexcitation waves (Epsilon waves) were seen on the resting ECG in almost one third of patients, and confirmed on signal-averaged ECG. An additional one third of patients had late potentials on signal-averaged ECG but no indication of this on the ECG. Over 90% of patients had documented spontaneous ventricular tachycardia, and in all but one of these the morphology was confirmed as left bundle branch block, consistent with a right ventricular origin. Formal electrophysiological studies were performed in most patients, and almost invariably ventricular tachycardia was induced, usually with the same morphology as the spontaneously occurring arrhythmia. Conventional 2D echo only became available towards the latter part of the follow-up in this study, so only one third of patients underwent such evaluation. The patients with arrhythmia who had 2D echo showed increased RV:LV ratios, and most had right ventricular wall motion abnormalities, although one had left posterior wall involvement. At cardiac catheterization, most patients had normal he-modynamics, although in some cases the right atrial a-wave amplitude was increased. Right ventricular angiography demonstrated global enlargement in most, and wall motion abnormality in some. Cardiac morphological abnormalities were confirmed by direct visualization in half of the patients (mostly at the time of surgery for intractable ventricular arrhythmia resistant to medical therapy). The authors first described the high frequency of structural abnormalities at the 3 points of the "triangle of dysplasia" (the pulmonary infundibulum, the apex, and the inferior wall or subtricuspid region). They noted that in two of their patients with ventricular tachycardia, clinical investigations had not confirmed the diagnosis, but subsequent pathology review of tissue removed at surgery identified features typical of ARVC/D.

As one would expect with any newly described condition, the cases presented represent the more severe end of the spectrum of disease expression. Indeed the Authors reviewed available information on an additional 34 adult cases reported in the literature; less than half of these had documented ventricular tachycardia. Their prevalence (90%) is unusually high, and may have reflected referral bias as they have a special interest in arrhythmias. Only one of their 24 patients was thought to have a familial form of the disease.

In the ensuing years, more cases of ARVC/D were reported and a heterogeneous pattern of disease expression emerged. In the Veneto region of Italy ARVC/D emerged as a significant cause of sudden death in the young. In 20% of sudden deaths occurring in people under age 35 years, features of ARVC/D were detected at postmortem evaluation. In almost half of these there were no prior reported symptoms, and despite history of palpitation and/or syncope in the others, the diagnosis had not been suspected prior to their death [3]. Additionally, in a study of sudden deaths in young athletes conducted over a 10-year period, over a quarter of cases had a postmortem diagnosis of ARVC/D [4]. Other milder phenotypes were emerging, with patients initially diagnosed as having idiopathic ventricular arrhythmia with "normal hearts," with subsequent detailed echo or angiographic studies showing evidence of regional or segmental right and/or left ventricular structural or dynamic abnormalities [26]. Familial disease was also being identified at a higher frequency with disease identified in identical and nonidentical twins [27] and up to 30% in one case series [26].

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