Towards Early Detection and Risk Stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by frequent ventricular arrhythmias and usually slowly progressive ventricular dysfunction. Since its initial description in 1982, sudden cardiac death (SCD) occurring in young and usually asymptomatic ARVD/C patients has been the most visible and devastating, as well as unpredictable complication of this disease. Importantly, recent studies have shown that life-threatening arrhythmias occur early in the disease process with up to half of cases presenting with SCD. As such, improving methods for early detection and risk stratification of ARVD/C is of utmost importance. In the first part of my thesis, I focus on early detection of ARVD/C using different angles. In a first chapter, I describe the clinical characteristics and outcomes of children with ARVD/C. One of my findings is that, in comparison to adult ARVD/C patients, pediatric subjects disproportionately present with sudden cardiac death. In this regard, ARVD/C may be more reminiscent of a channelopathy than of a cardiomyopathy. As such, I next set out to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding the major alpha subunit of the cardiac voltage-gated sodium channel) in ARVD/C. Subsequently, I employ cardiac magnetic resonance imaging (CMR) and electroanatomic mapping to determine the cardiac phenotype of early ARVD/C. While I find that early ARVD/C predominantly affects the RV subtricuspid region, abnormalities in this remain largely undetected by current diagnostic criteria. I therefore use CMR tissue tracking to unmask subtle early changes in ARVD/C. In the second part of this thesis, I change my attention from early detection to risk stratification of ARVD/C. I first describe the incremental value of CMR in arrhythmic risk stratification among ARVD/C mutation carriers. I find that electrical abnormalities on electrocardiogram (ECG) and Holter monitoring precede detectable structural changes in ARVD/C, and that the presence of both electrical and CMR abnormalities identifies patients at high risk of events. However, some ARVD/C patients with ventricular arrhythmias have a normal ECG. I focus on the clinical characteristics of these individuals in the next chapter. While these studies provide information for clinical practice, they were cross-sectional in design, and were largely populated by probands. Therefore, I next describe disease progression among at-risk relatives of ARVD/C patients, and confirm that electrical abnormalities precede structural changes in a longitudinal setting. Using this same cohort of at-risk relatives, the last chapter of this thesis focuses on predictors of ARVD/C diagnosis and an optimal approach to arrhythmic risk stratification among subjects at risk of ARVD/C.