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Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy Expert Rev. Cardiovasc. Ther. 13(6), 653–664 (2015)

Julia Cadrin-Tourigny1, Rafik Tadros1, Mario Talajic1, Lena Rivard1, Sylvia Abadir2 and Paul Khairy*1 1 From the Electrophysiology Service, Montreal Heart Institute and Department of Medicine, Universite de Montreal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8, Canada 2 Sainte-Justine University Hospital Center, Universite de Montreal, Montreal, Quebec, Canada *Author for correspondence: Tel.: +1 514 376 3330; extn. 3652 Fax: +1 514 593 2551 [email protected]

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) is an uncommon but increasingly recognized inherited cardiomyopathy that is associated with malignant ventricular arrhythmias and sudden cardiac death, particularly in young individuals. The implantable cardioverter-defibrillator (ICD) is widely regarded as the only treatment modality with evidence to support improved survival in patients with ARVC and secondary prevention indications. In contrast, there is no universally accepted risk stratification scheme to guide ICD therapy for primary prevention against sudden cardiac death. Potential benefits must be weighed against the considerable risks of complications and inappropriate shocks in this young patient population. This article tackles the challenges of risk stratification for sudden cardiac death in ARVC and critically appraises available evidence for various proposed risk factors. The authors’ over-arching objective is to provide the clinician with evidence-based guidance to inform decisions regarding the selection of appropriate candidates with ARVC for ICD therapy. KEYWORDS: arrhythmogenic right ventricular cardiomyopathy/dysplasia . cardiac genetics . implantable cardioverter-defibrillators


sudden cardiac death



Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disorder that is associated with ventricular arrhythmia and sudden cardiac death in young people and athletes [1]. Its prevalence in the general population is estimated to be 1 in 1000 to 5000 individuals [2–4]. The marked variability in epidemiological data may reflect geographic clustering within high prevalence areas, such as northern Italy, and non-uniform screening criteria and methodology [5]. ARVC is pathologically characterized by fibro-fatty replacement of the myocardium that predominantly affects the right ventricle (RV), with or without left ventricular (LV) involvement. ARVC is a complex genetic disease. In its most common form, inheritance is autosomal dominant with incomplete penetrance and variable expression, even within families sharing the same genetic defect [6]. Most genes linked to ARVC encode for desmosomal proteins responsible for myocyteto-myocyte adhesion [7]. Together with



ventricular arrhythmias

voltage-gated ion channels and gap junctional proteins, the desmosome forms part of the connexome, which ensures structural stability as well as electrical activation and coupling within the working myocardium [8]. Currently, only 30–50% of patients with ARVC have an identified causative mutation [9,10]. Interpretation of genetic testing is further complicated by other factors such as a the relatively high prevalence of abnormal desmosomal mutations in the general population without phenotypic evidence of ARVC [11,12], and the presence of two gene mutations in as many as 48% of affected patients [11,13]. Diagnosing ARVC is challenging. A definitive diagnosis is established by demonstrating transmural fibro-fatty replacement of the RV myocardium at biopsy, surgery or autopsy [14,15]. However, in the vast majority of patients, assessment of transmural myocardium is impossible. The role of biopsy is further limited by the patchy nature of the disease. Since there is currently no other single

 2015 Informa UK Ltd

ISSN 1477-9072


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Cadrin-Tourigny, Tadros, Talajic, Rivard, Abadir & Khairy

sufficiently specific test, diagnosis relies on a scoring system. The International Task Force Criteria (TFC) were initially published in 1994 and later revised in 2010 to include quantitative measurements with improved sensitivity and preserved specificity, especially in the setting of familial disease. The TFC use multiple parameters including RV function and morphology, histopathology, electrocardiography, presence of ventricular arrhythmias and family history of ARVC or presence of a desmosomal mutation to categorize patients as possible, probable or definite ARVC. Other criteria, such as a catecholaminergic challenge test, have been proposed but are not yet integrated into formal diagnostic schemes [16]. Ventricular arrhythmias represent the most common mode of presentation. Sudden cardiac death secondary to ventricular tachycardia (VT) or ventricular fibrillation (VF) is the leading cause of death due to ARVC but it can also be the first manifestation of the disease [1]. Management of ARVC is primarily directed at preventing this catastrophic outcome. Screening of asymptomatic family members and the appropriate selection of patients for implantable cardioverter-defibrillator (ICD) therapy are of paramount importance in efforts to avert sudden cardiac deaths. Estimates of an individual’s risk for sudden cardiac death must be balanced against potential ICD-related drawbacks, including device infection, inappropriate shocks, lead-related complications and psychosocial issues that may impact quality of life. This review focuses on the risk of sudden cardiac death in patients with ARVC and provides a critical overview of available data regarding associated factors in order to guide the clinician in selecting appropriate candidates for ICD implantation. Ventricular arrhythmia & sudden cardiac death

The natural course of ARVC is characterized by a spectrum of ventricular arrhythmias. The mechanism of arrhythmogenesis varies during the time course of the disease. In young and previously asymptomatic patients without visible structural abnormalities, VF is the usual cause of sudden cardiac death. This is likely related to a phase of disease progression that is marked by myocyte death and resulting inflammation [4,17]. Gap junction remodeling giving rise to slow myocardial conduction in the absence of overt cardiomyopathy has also been postulated as predisposing to VF in this population [18–20]. In contrast, older patients with long-standing disease more often experience hemodynamically stable monomorphic VT due to scar-related reentry. Monomorphic ventricular arrhythmias, which range from frequent premature ventricular complexes (PVC) to sustained VT [21], typically have a left bundle branch block morphology consistent with their RV origin. Several different morphologies of VT can occur in the same individual with long-lasting and/or widespread disease. It is worth noting that long episodes of very rapid VT (200–250 bpm) are often well tolerated in patients with ARVC in the setting of preserved LV function [22].

low 0.08% per year rate in a cohort of families [28] to approximately 2.9% per year [31] in symptomatic patients followed at referral centers. Over the past 25 years, numerous studies have attempted to identify clinical, electrocardiographic, genetic and anatomic parameters associated with sudden cardiac death in ARVC. These data will be reviewed here. While each study has its strengths and limitations, it should be emphasized that the best evidence is currently based on predominantly observational studies, most of which are retrospective in nature, with relatively small sample sizes, and without prospective validation. Such studies are limited in their ability to adjust for potential confounders and in their statistical power to assess the independent predictive value of potentially correlated risk factors. Additional common limitations include referral biases, which may overestimate risks for sudden cardiac death. Moreover, limiting inclusion to survivors at study entry (so-called left truncation bias) and incorporating periods of time during which sudden cardiac death could not have occurred (so-called immortal time bias, e.g., limiting inclusion to patients who have not yet had an event yet setting time 0 to date of birth) can result in grossly inaccurate estimates. In addition, most studies rely on appropriate ICD therapy as a proxy for sudden cardiac death. Yet, an appropriate ICD intervention is not equivalent to aborted sudden cardiac death. For example, in patients with non-ischemic cardiomyopathy, appropriate ICD therapy was associated with a two- to threefold overestimation of risk of sudden cardiac death [36]. Notwithstanding these limitations, BOX 1 summarizes reported risk factors for sudden cardiac death in ARVC classified loosely according to the totality of supportive evidence. TABLE 1 reports the estimated annual risk of ventricular arrhythmic events associated with risk factors for which such data are available. A detailed list of studies evaluating risk factors for arrhythmic outcomes in ARVC cited in this review can be found in SUPPLEMENTARY TABLE 1 (supplementary material can be found online at Secondary prevention

As may be expected, a prior aborted sudden cardiac death and unstable VT are well entrenched as major risk factors for subsequent sudden cardiac death in ARVC [26,37,38]. In the Darvin I study [37], a multicenter retrospective analysis of patients with ARVC and ICDs implanted almost exclusively for secondary prevention, those with aborted sudden cardiac death or unstable VT had a 10% annual rate of ICD therapy for what the authors considered life-threatening ventricular arrhythmias, that is, VT faster than 250 bpm or VF. Conversely, patients with ICDs implanted for hemodynamically stable VT had a significantly better outcome, with a much lower (1% per year) incidence of life-threatening ventricular arrhythmias (FIGURE 1) [37].

Risk factors


The overall annual incidence of sudden cardiac death in ARVC varies markedly from series to series [21,23–35], ranging from a

Syncope as a predictor of sudden cardiac death in ARVC was originally reported by Marcus et al. [24,39] and has since been


Expert Rev. Cardiovasc. Ther. 13(6), (2015)

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Risk stratification for sudden death in ARVC


confirmed by numerous other studies [1,21,28,30,37,40]. In the above-mentioned Darvin I study, Corrado et al. [37] reported an 8% annual incidence of life-threatening ventricular arrhythmias in patients with unexplained syncope (FIGURE 1). In the Darvin II study [41], a multicenter cohort of 106 patients with ARVC and primary prevention ICDs, syncope was the strongest predictor of appropriate ICD shocks and life-saving ICD interventions (defined as VT faster than 250 bpm), associated with an annual rate of 9%. A similar event rate was reported by Bhonsale et al. in 84 patients with primary prevention ICDs [42]. In this study, the timing of syncope also appeared to be relevant: patients with recent unexplained syncope (40 ms) as the strongest independent predictor of sudden cardiac death, with a sensitivity and specificity of 90 and 77%, respectively [40]. In this study, QRS duration was associated with sudden death in univariate but not multivariate analyses, perhaps reflecting the strong correlation of QRS duration with QRS dispersion.

Strongest risk factors . . .

Aborted sudden cardiac arrest Unstable sustained VT Unexplained syncope

Risk factors with consistency across studies . . . . . . .

Sustained stable VT RV dysfunction LV dysfunction Proband status Non-sustained VT Extent of T-wave inversion (beyond V3, inferior leads) Physical activity

Other promising risk factors . . . .

. . .

TMEM43 gene mutation (p.S358L) Burden of electroanatomic scar QRS duration or dispersion RV dilation Early onset PVC count Late potential on SAECG VT inducibility by programmed ventricular stimulation

Probably not risk factors . .

Family history of sudden cardiac death Healthy ARVC-associated mutation carriers

ARVC: Arrhythmogenic right ventricular cardiomyopathy; LV: Left ventricular; PVC: Premature ventricular complexes; RV: Right ventricular; SAECG: Signal averaged ECG; VT: Ventricular tachycardia.

Late potentials on a signal-averaged ECG likewise remain controversial as a risk marker in ARVC. Several studies have disputed such an association [30,41,42,46,47]. In contrast, an analysis of 64 patients published by Liao et al. in 2014 [48], of whom 50% had a definite diagnosis of ARVC according to the 2010 revised TFC, suggests that having abnormal values for all three parameters evaluated by signal-averaged ECG as defined by the revised TFC [15] is independently associated with malignant arrhythmias (odds ratio: 30.5; 95% CI: 2.5–373.7; p = 0.008). Link et al. [38] likewise reported a univariate association between the filtered QRS duration and subsequent arrhythmias in their prospective analysis of the North American ARVC registry. The extent of T-wave inversion is a relatively novel and potentially promising predictor of subsequent major arrhythmic events [32,38,44,45,49]. Recent data suggest a positive correlation between the number of precordial leads with inverted T-waves and risk for subsequent arrhythmic events [44]. Inverted T-waves in more than three precordial leads independently predicted arrhythmic outcomes. Moreover, in family members, arrhythmic events were limited to those having this risk factor. 655


Cadrin-Tourigny, Tadros, Talajic, Rivard, Abadir & Khairy

Table 1. Estimated annual risk during follow-up associated with individual risk factors.

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Combined annual arrhythmic outcome (appropriate ICD therapy, sustained VA, SCD) (%)

Annual appropriate ICD therapy for lifethreatening arrhythmia (%)

Aborted SCD/Unstable VT

10 [37]

Hemodynamically stable VT

1 [37]


9 [41]

Proband status

13 [42]–18 [44]†

Symptomatic patients

6 [32]

8 [37]–9 [42]

0.8 [38]

Asymptomatic patients Family members

1 [44]–3 [42]

Asymptomatic family members

0 [41]

RV dysfunction: RVEF

Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) is an uncommon but increasingly recognized inherited cardiomyopathy that is associate...
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