Truncating Variants in TTN are Associated With Primary Atrial Myopathy

Truncating TTN variants (TTNtv) are the main genetic cause of dilated cardiomyopathy (DCM) and are independently associated with atrial fibrillation (AF). In DCM, AF usually arises from left atrial (LA) remodeling attributable to left ventricular systolic dysfunction. Whether TTNtv are linked to primary LA dysfunction independent of left ventricular systolic dysfunction remains unclear.

This retrospective, multicenter study evaluated atrial function by strain echocardiography in TTNtv carriers across the left ventricular ejection fraction (LVEF) spectrum and its relationship with AF. Individuals with TTNtv and LVEF ≥50% (TTNtv+/DCM-) were compared with matched healthy controls, and those with LVEF <50% (TTNtv+/DCM+) were compared with matched patients with idiopathic, variant-negative DCM (iDCM).

Among 460 participants, 153 carried a TTNtv (87 with LVEF ≥50%, 66 with LVEF <50%). All LA strain parameters were significantly lower in TTNtv+/DCM- than in controls (P<0.001). In TTNtv+/DCM+, only LA contractile strain was reduced compared with iDCM (P<0.001). LA contractile strain correlated with LVEF only when LVEF was <50% (TTNtv+/DCM+, r=0.50, P<0.001; iDCM, r=0.47, P<0.001). In TTNtv+/DCM-, all LA strain parameters except contractile strain correlated with LV strain. AF incidence was higher in TTNtv+/DCM+ (3.15/100 person-years) than in TTNtv+/DCM- (1.48) and iDCM (2.27), though cumulative incidence was not significantly different (P=0.200).

LA myopathy, detected by strain imaging, appears early in TTNtv+/DCM- individuals and may represent an early phenotypic marker independent of left ventricular systolic dysfunction. When LVEF declines below 50%, atrial dysfunction worsens in parallel. AF was more frequent in TTNtv carriers, supporting further research on LA strain for AF risk stratification within this population.