Titin Cardiomyopathy, Emerging Evidence: More Than A Big Heart

TTN truncating variants (TTNtv) are associated with DCM but are also present in asymptomatic individuals, complicating their interpretation. Emerging evidence suggests that both haploinsufficiency and toxic gain-of-function mechanisms may underlie disease expression, influenced by variant location and expression. Patient-derived iPSC models and advanced imaging studies have elucidated pathophysiological mechanisms and highlighted promising therapeutic targets. Clinically, TTN-CMP shows relatively high rates of left ventricular reverse remodeling and variable arrhythmic burden, with male sex and environmental stressors influencing outcomes. TTN-CMP spans a broad phenotypic spectrum, ranging from asymptomatic carriers to end-stage heart failure. While standard heart failure therapies are often effective, precision management remains limited. Improved clinical, genetics and molecular understanding, together with novel experimental models, provide promising new tools for precise disease assessment and targeted therapeutic interventions.