Diagnostic yield of inherited cardiac conditions in first-degree relatives of decedents and survivors with isolated valvular heart disease

Introduction

Bicuspid aortic valve (BAV) and mitral valve prolapse (MVP) are common heart valve abnormalities that affect 1 to 2% of the general population respectively. Both have been associated with sudden cardiac death (SCD), but their causal effect in malignant arrhythmias remain unclear.

Aims

To determine the prevalence and spectrum of inherited cardiac conditions (ICCs) in first-degree relatives of SCD victims and survivors of unexplained cardiac arrest (UCA) who had isolated findings of BAV or MVP at autopsy or at clinical investigations.

Methods

First-degree relatives were investigated with 12-lead and high-lead ECG, echocardiogram, exercise tolerance test, cardiovascular magnetic resonance, 24-hour 12-lead Holter, and Ajmaline provocation test in selected cases. Next-generation genetic sequencing was performed in the probands.

Results

The study included 52 SCD victims and 6 UCA survivors with isolated valvular abnormalities (BAV, n=14; MVP, n=44). Mean age at event was 38 ± 15 years, and 31 (53%) were male. A total of 134 first-degree relatives were evaluated (mean age 44 ± 15 years; 70 [52%] female). ICCs were identified in 23 (40%) families. Of these, 17 families had a single diagnosis, 5 had dual diagnoses, and 1 had three distinct cardiac pathologies among family members. The ICCs identified were dilated cardiomyopathy (n=18), familial MVP (n=8), hypertrophic cardiomyopathy (n=2), arrhythmogenic cardiomyopathy (n=1), and BAV (n=1). No channelopathies were diagnosed. Genetic testing was performed in 42 probands, of which 3 (7%) cases revealed a pathogenic variant associated with cardiomyopathies. These variants segregated with cardiomyopathy in relatives but were not associated with valvular abnormalities.

Among the 8 families in whom familial MVP was diagnosed in relatives, 10 relatives were affected (9 were older than the proband). In 2 cases diagnostic criteria for dilated cardiomyopathy were fulfilled, in 2 myocardial fibrosis on cardiovascular magnetic resonance was detected, and in 1 a short run of non-sustained ventricular tachycardia was found at Holter monitor, with none exhibiting major arrhythmias.

Conclusions

A significant proportion (40%) of families of SCD victims and UCA survivors with isolated BAV or MVP were diagnosed with ICCs, most commonly cardiomyopathies. These findings suggest that isolated valvular abnormalities in this context may represent phenotypic markers of a broader inherited cardiac substrate. Comprehensive clinical evaluation of first-degree relatives should therefore extend beyond valvular assessment to include screening for cardiomyopathies to optimise diagnostic yield and risk stratification.SCD in VHD