Dilated and ischemic cardiomyopathy share widespread RNA splicing dysregulation compared to controls, with DCM showing pan-cardiac changes and ICM showing localized left ventricular changes.
Observational (n=122)
Does alternative RNA splicing dysregulation differ between genetic dilated cardiomyopathy and ischemic cardiomyopathy across different cardiac regions?
Alternative RNA splicing alterations in end-stage heart failure are largely shared between dilated and ischemic cardiomyopathy, reflecting a general response to cardiac remodeling rather than etiology-specific drivers.
Abstract Background/Introduction Cardiomyopathy encompasses a heterogeneous group of heart diseases characterized by structural remodeling and cardiac dysfunction. Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction associated with a reduction in myocardial force of contraction, representing the most frequent indication for heart transplantation. Genetic DCM represents 30-40% of DCM patients and mutations in more than 50 genes contribute to the profound genetic heterogeneity found in such patients. On the other hand, an ischemic injury due to coronary artery disease may also lead to DCM, giving rise to the so-called ischemic cardiomyopathy (ICM). Alternative RNA splicing dysregulation in key cardiac genes, including TNNT2, LDB3, and TTN, has been documented in heart disease. However, a comprehensive genome-wide alternative splicing characterization of DCM is lacking. Purpose This study aimed to determine whether splicing alterations in different cardiac regions act as disease drivers or arise as a consequence of the pathological environment. Methods We characterized by deep sequencing the RNA splicing profiles of left ventricular biopsies from end-stage heart failure patients with DCM (n=11) and ICM (n=10), as well as non-failing controls (n=5). Selected splicing events in genes with known roles in cardiac physiology were confirmed by quantitative PCR across the left ventricule (LV), right ventricle (RV), and interventricular septum (IVS) in an expanded cohort of 54 DCM, 45 ICM, and 23 control samples. Results RNA sequencing data analysis allowed the identification of a widespread splicing dysregulation shared between heart failure samples and controls, with minimal differences between DCM and ICM (Figure). Validation of six key splicing events by quantitative PCR in the expanded cohort of patients and controls confirmed shared dysregulation in DCM and ICM. Splicing events in CAMK2D and PDLIM3 genes exhibited consistent alterations across all cardiac regions (LV, RV, IVS) in both disease groups. However, splicing events in EYA4, ESSRG, MYL6, and SORBS1 demonstrated dysregulation throughout the heart exclusively in DCM, indicating that these perturbations in ICM predominantly affect the LV. Conclusion The presence of similar RNA splicing alterations in DCM and ICM suggests that these alterations reflect a general response to cardiac dysfunction in end-stage heart failure, regardless of etiology, as a consequence of cardiac remodelling. Furthermore, we identified distinct patterns of splicing alterations across cardiac chambers, with widespread dysregulation observed in DCM and more localized changes in the LV in ICM. Our results emphasize the potential value of alternative splicing as a sensitive indicator of heart failure progression and provide a foundation for future studies to explore the functional consequences of these events.
Martins et al. (Sat,) conducted a observational in Dilated cardiomyopathy and ischemic cardiomyopathy (n=122). Dilated and ischemic cardiomyopathy vs. Non-failing controls was evaluated on RNA splicing dysregulation. Dilated and ischemic cardiomyopathy share widespread RNA splicing dysregulation compared to controls, with DCM showing pan-cardiac changes and ICM showing localized left ventricular changes.