Truncating TTN Variants and Primary Atrial Myopathy

10 Mar 20264 min read0 viewsJournal Feed

GIST

Journal of the American Heart Association, Volume 15, Issue 6 , March 17, 2026. BackgroundTruncating 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.MethodsThis 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).ResultsAmong 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).

Clinical Editorial

Scope and design

A retrospective, multicenter analysis assessed left atrial (LA) function via strain echocardiography in individuals carrying truncating titin variants (TTNtv) across the full spectrum of left ventricular ejection fraction (LVEF).
The study contrasted TTNtv carriers without dilated cardiomyopathy (DCM) and preserved LVEF (TTNtv+/DCM–) against matched healthy controls; TTNtv carriers with reduced LVEF (TTNtv+/DCM+) were compared to patients with idiopathic, variant-negative DCM (iDCM).

Population and grouping

Total participants: 460; TTNtv carriers: 153 (87 with LVEF ≥50%, 66 with LVEF <50%).
TTNtv+/DCM– group represents TTNtv carriers with preserved systolic function.
TTNtv+/DCM+ group comprises TTNtv carriers with LV systolic dysfunction, contrasted with iDCM controls.

Atrial mechanics across LV function strata

no, all LA strain parameters were lower, highlighting LA myopathy independent of LV dysfunction.

In TTNtv+/DCM–, all LA strain measurements were reduced versus controls, with contractile strain the exception?
In TTNtv+/DCM+, LA contractile strain was diminished relative to the iDCM group, indicating additional atrial impairment beyond what is observed in LV-reduced DCM alone.
LA contractile strain demonstrated a relationship with LV performance only when LV function was diminished (LVEF <50%), with correlation coefficients around 0.50 in TTNtv+/DCM+ and 0.47 in iDCM.

Atrial fibrillation signal and interpretation

AF incidence appeared higher in TTNtv carriers with reduced LVEF (3.15 per 100 person-years) compared with TTNtv carriers with preserved LVEF (1.48) and with iDCM (2.27).
However, the cumulative incidence comparison did not reach statistical significance (P = 0.200).

Contextual conclusions and limitations

The findings propose early LA myopathy detectable by strain imaging in TTNtv+/DCM– individuals, suggesting a primary atrial phenotype that may be independent of LV systolic impairment.
As LV function declines (LVEF <50%), atrial dysfunction intensifies in parallel.