Elucidating the reverse remodeling potential of TTNtv in dilated cardiomyopathy: clinical and ultrastructural evidence

Background Titin truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM), typically associated with favorable left ventricular reverse remodeling (LVRR)[1]. However, this recovery is highly unpredictable in clinical practice. The clinical predictors and the distinct ultrastructural features driving this reversibility remain unclear, making early clinical management complicated. Purpose To investigate predictors of LVRR, assess how baseline severity modulates TTNtv-associated recovery, and find the ultrastructural mechanisms driving the reversibility. Methods Dual-center DCM cohorts (2020–2025) comprising a clinical longitudinal cohort and an end-stage transplant cohort. Patients with secondary etiologies (ischemic, hypertensive, valvular, and congenital) were strictly excluded. Whole-exome sequencing variants were classified according to ACGS guidelines. LVRR was defined as an absolute LVEF increase ≥10% (or reaching ≥50%) and an LVEDD decrease ≥10% following ≥6 months of guideline-directed medical therapy. Results Among 376 non-acquired DCM patients (excluding patients with alcoholic, peripartum, infectious, and other acquired etiologies; mean age 44±14 years, 71.5% male), genetic and idiopathic DCM accounted for 24.7% and 75.3%, respectively. In genotype-positive patients, the predominant variants were TTNtv (50.5%), LMNA (7.5%), MYH7 (6.5%), RBM20 (6.5%), FLNC (6.5%), DSP (4.3%), and TNNT2 (4.3%). Longitudinal LVRR analysis was performed on 229 patients with standardized echocardiographic follow-up. Multivariable logistic regression identified TTNtv as an independent positive predictor of LVRR (OR 2.75, 95% CI 1.12-6.76), while NSVT was a negative predictor (OR 0.33, 95% CI 0.15-0.72) (Figure 1). Notably, TTNtv exhibited a significant interaction with baseline LVEF: its LVRR-promoting effect was prominent only in the severe subgroup (LVEF <35%; OR 5.45, 95% CI 1.09-27.23), but absent in patients with LVEF ≥35%. To further explain this phenomenon, ultrastructural analysis of end-stage explanted hearts was performed, including 10 TTNtv cases and 142 non-TTNtv cases. While there were no significant inter-group differences in secondary cellular toxicities (e.g., mitochondrial injury, accumulation of autophagosomes), TTNtv hearts exhibited a higher prevalence of primary mechanical defects, specifically sarcomeric dysplasia (40.0% vs. 11.3%, P=0.028) and Z-line abnormalities (30.0% vs. 5.6%, P=0.026) (Figure 2). Conclusions TTNtv strongly promotes LVRR specifically in DCM patients with severe baseline impairment (LVEF <35%). This severity-dependent "mechanical rebound" is driven by primary sarcomeric dysfunction rather than irreversible cellular damage. These findings reveal a unique pathophysiology for TTNtv-DCM, strongly supporting genotype-guided and severity-stratified management.Figure1Figure2