Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members

Abstract

Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals. Methods and Results— Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed. Mutations were identified in 276 index-patients (63%). Index-patients presented predominantly with sustained ventricular arrhythmias (268; 61%). During a median follow-up of 7 years, 301 of the 416 index-patients presenting alive (72%) experienced sustained ventricular arrhythmias. Sudden cardiac death during follow-up occurred more frequently among index-patients without an implantable cardioverter-defibrillator (10/63, 16% versus 2/335, 0.6%). Overall, cardiac mortality and the need for cardiac transplantation were low (6% and 4%, respectively). Clinical characteristics and outcomes were similar in index-patients with and without mutations, as well as in those with familial and nonfamilial ARVD/C. ARVD/C was diagnosed in 207 family members (37%). Symptoms at first evaluation correlated with disease expression. Family members with mutations were more likely to meet Task Force Criteria for ARVD/C (40% versus 18%), experience sustained ventricular arrhythmias (11% versus 1%), and die from a cardiac cause (2% versus 0%) than family members without mutations. Conclusions— Long-term outcome was favorable in diagnosed and treated ARVD/C index-patients and family members. Outcome in index-patients was modulated by implantable cardioverter-defibrillator implantation, but not by mutation status and familial background of disease. One third of family members developed ARVD/C. Outcome in family members was determined by symptoms at first evaluation and mutations.

Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

“…Unfortunately, due to family choice, prospective information on family screening could not be obtained. Negative family history is not unusual in ARVC, as reduced penetrance is well described 3. Additionally, as with most cardiomyopathy variants, functional data are lacking for the majority of the variants identified here.…”

“…Without systematic functional studies or extensive segregation in affected individuals on each of these rare novel variants, however, it is difficult to determine the role these variants play in the ARVC phenotype of individuals. Integration of segregation analysis in families with ARVC is also challenging given the well described reduced penetrance 3. In addition, mounting exome population data over the years have led to systematic reclassification of previously described pathogenic variants in the cardiomyopathies as uncertain, or even benign 17.…”

“…Pathogenic variants in five genes ( DSP , PKP2 , DSG2 , DSC2 , and JUP ) are classically thought to play a large role in ARVC pathogenesis 2, 3. In routine clinical practice, however, even in a well phenotyped population, up to 40% of ARVC cases still elude identification of a genetic root cause 2, 3. Because of the importance of identifying those at risk for sudden death, gene finding efforts have continued.…”

“…PLN has been identified as a causative factor in a significant portion of individuals with ARVC patients 3, 6. Additionally, recent reports have identified SCN5A mutations in a small percentage of ARVC patients 7.…”

Right ventricular dysplasia: management and treatment in light of current evidence

“…He looked at 439 ARVC patients and 562 of their family members with median follow-up of 7 years [58,59]. SCD rate during the follow-up period was higher (16%) among patients without ICD placement compared to ARVC with ICD placement (0.6%).…”