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Etiopathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy

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Etiopathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy J Hum Genet (2005) 50:375–381 DOI 10.1007/s10038-005-0273-5 MINIREVIEW Maithili V.N. Dokuparti Æ Pranathi Rao Pamuru Bhavesh Thakkar Æ Reena R. Tanjore Æ Pratibha Nallari Etiopathogenesis of arrhythmogenic right ventricular cardiomyopathy Received: 19 May 2005 / Accepted: 20 June 2005 / Published online: 12 August 2005 Ó The Japan Society of Human Genetics and Springer-Verlag 2005 Abstract Arrhythmogenic right ventricular cardiomy- TGFb-3 for ARVC1 and the role of all these three genes opathy (ARVC) is characterised by progressive fibro- (plakoglobin, desmoplakin and plakophilin) in cardiac fatty replacement of right ventricular myocardium. morphogenesis indicate some kind of signal-transducing Earlier studies described ARVC as non-inflammatory, pathway disruption in the condition. The finding that non-coronary disorder associated with arrhythmias, ARVC as a milder form of Uhl’s anomaly indicates heart failure and sudden death due to functional exclu- similar ontogeny for the condition. Further, discovery of sion of the right ventricle. Molecular genetic studies have apoptotic cells in the autopsy of the right ventricular identified nine different loci associated with ARVC; myocardium of ARVC patients does indicate a common accordingly each locus is implicated for each type of pathway for different types of ARVCs, which is more ARVC (ARVC1–ARVC9). So far five genes have been specific for the right ventricular myocardium involving identified as containing pathogenic mutations for desmosomal plaque proteins, growth factors and Ca2+ ARVC. Though mutations in each of the gene/s indicate receptors. disruption of different pathways leading to the condi- tion, the exact pathogenesis of the condition is still Keywords Etiopathogenesis Æ ARVC Æ Desmosomes Æ obscure. This review tries to understand the pathogenesis Ryanodine receptor Æ TGFb-3 Æ Sudden death Æ of the condition by examining the individual proteins Non-coronary Æ Non-inflammatory implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cel- lular Ca2+ concentration by releasing Ca2+ reserves Introduction from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to Arrhythmogenic right ventricular dysplasia/cardiomy- disrupt coupled gating of RYR-2, causing after-depo- opathy (ARVD/C) is a genetically heterogenous disor- larisation, leading to arrhythmias followed by structural der characterised by progressive fibro-fatty replacement changes due to altered intra-cellular Ca2+ levels. Three of the right ventricular myocardium. The predominant other genes implicated for ARVC, plakoglobin (Naxos presenting symptoms are due to ventricular arrhythmias, disease), desmoplakin (ARVC8) and plakophilin including palpitations, sustained ventricular tachycardia (ARVC9) have prompted the speculation that ARVC is or uncommonly sudden cardiac death. Although ARVC primarily a disease of desmosomes. But identification of is an unusual disorder, it has been described as the most common cause of sudden death in young athletes under the age of 35 years (Corrado et al. 1990). Heart failure is infrequent but may occur due to severe right or bi-ven- M.V.N. Dokuparti Æ P.R. Pamuru Æ B. Thakkar tricular enlargement. & R.R. Tanjore Æ P. Nallari ( ) Ever since the first description of the disease by Department of Genetics, University College of Science, Osmania University, Jamia Osmania Post Office, Fontaine et al. (1977) as the non-inflammatory, non- Hyderabad, 500 007, Andhra Pradesh, India coronary disorder associated with arrhythmias, heart E-mail: [email protected] failure and sudden death due to functional exclusion of Tel.: +91-040-55270403 the right ventricle among young people, extensive clini- B. Thakkar cal and molecular genetic studies have been carried out. King Edward Memorial Hospital, Parel, But the progress in clear understanding of the disorder Mumbai, India has been impeded by the difficulty in diagnosis. 376 Clinical pathology Four clinicopathologic phases have been described based on the long-term follow-up of clinical data. Concealed phase This phase is characterised by subtle right ventricular structural changes with or without ventricular arrhythmias during which sudden death may occasionally be the first manifestation of the disease, mostly in young people during competitive sports or intense physical exercise (Thiene et al. 1988). Overt arrhythmic phase This phase shows symptomatic right ventricular arrhythmias possibly leading to sudden cardiac arrest associated with overt right ventricular Fig. 1 Electrocardiogram of an arrhythmogenic right ventricular functional and structural abnormalities (Corrado et al. cardiomyopathy (ARVC) patient showing right pre-cordial 1990). T–wave inversions Global right ventricular dysfunctional phase This phase Diagnosis results from the progression and extension of muscle disease with relatively preserved left ventricular function Standardised major and minor criteria encompassing (Corrado et al. 1998). structural, histological, electrocardiographic, arrhythmic and genetic factors have been proposed in order to Final phase The final stage of bi-ventricular pump establish diagnosis (Table 1) (McKenna et al. 1994). failure is caused by pronounced left ventricular According to this classification, the presence of two major involvement. At this stage, ARVC mimics biventricular criteria or one major and two minor criteria or four minor dilated cardiomyopathy of other causes, leading to criteria are required in order to confirm ARVC. congestive heart failure and related complications. Table 1 Criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVD arrhythmogenic right ventricular dysplasia, ECG electrocardiogram 1. Family history Major Familial disease confirmed at necropsy or surgery Minor Family history of premature sudden death (< 35 years) caused by suspected ARVD Family history (clinical diagnosis based on present criteria) 2. ECG depolarisation/conduction abnormalities Major Epsilon waves or localised prolongation (‡ 110 ms) of the QRS complex in the right pre-cordial leads (V1–V3) Minor Late potentials seen on signal-averaged ECG 3. ECG repolarization abnormalities Minor Inverted T waves in right pre-cordial leads (V2 and V3) in people >12 years and in the absence of right bundle branch block (Fig.1) 4. Arrhythmias Minor Sustained or non–sustained left bundle branch block type ventricular tachycardia documented on the ECG, Holter monitoring or during exercise testing Frequent ventricular extra-systoles (more than 1,000/24 h on Holter monitoring) 5. Global and/or regional dysfunction and structural alterations Major Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) left ventricular involvement Localised right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulgings) Severe segmental dilatation of the right ventricle Minor Mild global right ventricular dilatation and/or ejection fraction reduction with normal left ventricle Mild segmental dilatation of the right ventricle Regional right ventricular hypokinesia 6. Tissue characteristics of walls Major Fibro-fatty replacement of myocardium on endomyocardial biopsy Detected by echocardiography, angiography, magnetic resonance imaging or radionuclide scintigraphy 377 unstable nature of RYR-2 resulting from lack of proper Molecular genetics binding of FKBP 12.6 may cause massive leakage of Ca2+ from RYR2, even on minor perturbations such as Various pathological and familial studies have described stress (Tiso et al. 2001).Thus, the arrhythmias found in nine types of ARVC, the types being classified based on the ARVC patients could be explained. Structural different loci mapped for the condition (Table 2). Nine changes accompanying the arrhythmias can be explained different loci for the autosomal dominant form of ARVC by the reports that imbalance of intra-cellular Ca2+ indicate the underlying genetic heterogeneity. Among levels can trigger apoptosis, which is identified as a them, five genes have been identified as containing the primary mechanism for cardiac muscle degeneration in causative mutations for ARVC. Other genes implicated ARVC (Mallat et al. 1996; Valente et al. 1998). in ARVC have to be identified in order to elucidate the The four other genes identified in ARVCs are des- pathogenic pathway leading to the condition. moplakin (ARVC8), plakophilin (ARVC9), plakoglobin (Naxos) and TGFb-3 (ARVC1). All the genes except TGFb-3 are involved in formation of desmosomal pla- Genes identified que, leading to the suggestion that ARVC is primarily a disease of desmosomes (Fig. 2) (Gerull et al. 2004). Cardiac ryanodine receptor (RYR-2) The first gene identified is RYR-2, the cardiac ryanodine Desmoplakin receptor, mutations in which cause the characteristic effort-induced arrhythmias associated with ARVC-2 The second gene identified for ARVCs was desmopla- (Nava et al. 1988). The critical region was identified by kin, associated with ARVC8. Rampazzo et al. (2002) the mapping studies carried out by Rampazzo et al. identified S299R in exon 7 of DSP as the pathogenic (1995) and Bauce et al. (2000). Physical mapping of the mutation in a family of 26 members spanning four critical region of ARVC2 elucidated the pathogenic role generations. Desmoplakin is exclusive to desmosomes of mutations in the RYR-2 gene (Tiso et al. 2001). and is a ubiquitous member of all the desmosomal The most important
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