Phenotype- and genotype-specific dominance of arrhythmic versus heart failure trajectories in inherited cardiomyopathies
A Antonopoulos, V Gardikioti, T Gossios, A Kasiakogias, D Terentes-Printzios, G Efthimiadis, G Lazaros, K Tsioufis, C VlachopoulosAbstract
Background
Inherited cardiomyopathies demonstrate heterogeneous clinical courses characterised by varying dominance of malignant ventricular arrhythmias (VA) and progressive heart failure (HF). Although phenotype-based and gene-specific risk patterns have been described individually, the relative dominance of arrhythmic versus HF progression has not been systematically compared across cardiomyopathy subtypes.
Purpose
To characterise and quantitatively compare the predominant modes of clinical progression by phenotype and genotype.
Methods
We conducted a quantitative synthesis of published data using aggregated cohort-level event counts and person-years (py) from representative longitudinal studies. Major arrhythmic events (MAE) included sustained VA, appropriate implantable cardioverter-defibrillator (ICD) therapies, aborted sudden cardiac death (SCD), or SCD. Major HF events included HF-related death, heart transplantation, or left ventricular assist device implantation. Annualised event rates (per 100 py) were calculated, and the relative predominance of arrhythmic versus HF events was expressed as the MAE/HF ratio.
Results
A total of 35 representative cohort studies were included (n=31,660 individuals). At the phenotype level, arrhythmogenic right ventricular cardiomyopathy (ARVC) demonstrated marked arrhythmic predominance (MAE 7.46 vs HF 1.17 per 100 py; MAE/HF ratio 6.4). Hypertrophic cardiomyopathy (HCM) showed a dominance of arrhythmic events (MAE 1.02 vs HF 0.42 per 100 py; ratio 2.4), while dilated cardiomyopathy (DCM) exhibited a more balanced profile (MAE 3.0 vs HF 2.41 per 100 py; ratio 1.20) (Figures 1 and 2A). At the genotype level, a marked predominance of VA over HF events was observed in transmembrane protein 43 (TMEM43; MAE 3.50 vs HF 0.64 per 100 py; MAE/HF ratio 5.5) and desmoplakin cohorts (DSP; MAE 3.77 vs HF 0.74 per 100 py; MAE/HF ratio 5.1). Filamin C truncating variants (FLNCtv) also demonstrated a predominance of arrhythmic events (MAE 3.90 vs HF 1.68 per 100 py; MAE/HF ratio 2.3). In contrast, HF–predominant trajectories were observed in BCL2-associated athanogene 3 (BAG3; MAE 1.64 vs HF 6.30 per 100 py; MAE/HF ratio 0.3), and in titin truncating variants (TTNtv; MAE 0.85 vs HF 1.84 per 100 py; MAE/HF ratio 0.5). Lamin A/C (LMNA) variants were characterised by almost equally elevated absolute rates of both MAE (5.17 per 100 py) and HF (4.37 per 100 py) and a near-balanced MAE/HF ratio (1.2). A more balanced distribution between arrhythmic and HF trajectories was observed in phospholamban, RNA-binding protein 20 (RBM20) and desmin cohorts (Figures 1 and 2B) as well.
Conclusions
Inherited cardiomyopathies exhibit distinct phenotype- and gene-specific patterns of arrhythmic vs HF trajectory predominance. Systematic quantification of such potential trajectories may support phenotype- and genotype-tailored surveillance strategies and prioritisation of arrhythmic versus HF–directed interventions.