Clinical correlates and prognostic significance of mechanical dispersion across genotypes in dilated cardiomyopathy

Abstract Background Mechanical dispersion (MD), assessed by myocardial strain, reflects myocardial contraction heterogeneity and is increasingly recognized as a predictor of arrhythmic risk in cardiomyopathies. Desmoplakin (DSP) and filamin C (FLNC) mutations are well-documented to confer a high burden of myocardial fibrosis, detectable as late gadolinium enhancement (LGE) on cardiac MRI, whereas titin (TTN) mutations may exhibit minimal or absent LGE despite arrhythmic risk. Prior studies suggest that elevated MD reflects intraventricular electromechanical delay, potentially preceding structural changes on imaging. However, limited data exist comparing MD across different genetic subtypes. Aim This study aims to evaluate differences in MD between patients with DSP/FLNC mutations and those with TTN mutations and to assess the relationship between MD and clinical variables, including ventricular arrhythmias (VAs), myocardial fibrosis, and left ventricle (LV) function. Methods We prospectively enrolled 48 patients diagnosed with genetic cardiomyopathy harboring pathogenic or likely pathogenic DSP, FLNC or TTN variants evaluated at our center. Patients were grouped based on genotype: TTN (n = 24) and DSP/FLNC (n = 24). VAs were defined as non-sustained and sustained ventricular tachycardia and aborted cardiac arrest. Mechanical dispersion (MD) was calculated as standard deviation (SD) of time from Q/R on ECG to peak longitudinal strain in 16 left ventricular segments. LV function was assessed by diastolic volume index (LV EDVi), ejection fraction (EF) and by global longitudinal strain (GLS) derived by speckle tracking echocardiography. Results There was no significant difference in age at diagnosis or sex distribution between TTN and DSP/FLNC groups (mean age 41.6 vs 44.5 years, p=0.42). Although TTN mutation carriers presented lower prevalence of LGE compared to DSP/FLNC carriers (41.7% vs. 75%, respectively; p= 0.03), MD did not significantly differ between DSP/FLNC and TTN mutation carriers (66.0 ± 16.7 ms vs. 70.8 ± 27.1 ms; p = 0.468). MD was significantly higher in patients with ventricular arrhythmias, those with LGE on MRI, patients who received an ICD, and those in NYHA class III–IV (see Table 1). ROC analysis demonstrated that MD had the highest area under the curve (AUC = 0.728) for predicting arrhythmias, outperforming GLS (AUC = 0.607), LVEF (AUC = 0.344), and LV EDVi (AUC = 0.586). Conclusions Although mechanical dispersion did not differ significantly between genetic etiologies, it was strongly associated with markers of adverse clinical outcomes, including ventricular arrhythmias, myocardial scar, and the need for ICD implantation. These findings support the use of MD as a robust, non-invasive risk stratification tool in patients with inherited cardiomyopathies across different genotypes.