Alternative splicing profiling revealed shared dysregulation in dilated and ischemic cardiomyopathy, with DCM showing broader chamber-wide alterations compared to focal changes in ICM.
Observational (n=148)
How do alternative splicing events differ spatially and etiologically between dilated and ischemic cardiomyopathy in end-stage heart failure?
Splicing dysregulation is a shared molecular response in advanced heart failure, but spatial patterns differ between dilated (diffuse) and ischemic (focal) cardiomyopathy.
Abstract Aims Alternative splicing plays a critical role in cardiac development and function and becomes dysregulated in heart failure. Although splicing defects have been described in both dilated (DCM) and ischemic (ICM) cardiomyopathy, the extent to which these alterations contribute to disease mechanisms and how they are spatially distributed across cardiac regions remains poorly understood. This study aimed to profile alternative splicing events across the left ventricle (LV), right ventricle (RV), and interventricular septum (IVS) in end-stage heart failure patients with DCM and ICM, and to investigate potential regulatory factors driving these changes. Methods and Results RNA-seq was performed on LV tissue from patients with DCM (n=10), ICM (n=11), and non-failing controls (n=5), and analysed using three complementary splicing tools to maximize event detection. This integrative approach consistently revealed widespread splicing alterations in heart failure samples compared to controls, with substantial overlap between DCM and ICM. Motif enrichment analysis implicated the RNA-binding protein QKI as a potential splicing regulator in heart failure. Validation of six selected splicing events by qRT-PCR in a larger cohort (54 DCM, 45 ICM, 23 controls) confirmed shared dysregulation in DCM and ICM. While splicing alterations in CAMK2D and PDLIM3 were detected across the LV, RV, and IVS in both DCM and ICM, other transcripts (MYL6, ESRRG, EYA4, and SORBS1) differed between DCM and ICM, with DCM showing broader chamber-wide splicing alterations.s Conclusions This study presents the first multi-chamber analysis of splicing in human heart failure, revealing a set of splicing events commonly dysregulated in DCM and ICM. These findings support the notion that splicing dysregulation can be a shared molecular response to advanced cardiac remodeling, rather than a driver of etiology-specific pathology. We further uncovered distinct spatial patterns: in DCM, splicing alterations were consistently observed across all cardiac chambers, likely reflecting diffuse myocardial involvement. In contrast, certain splicing changes in ICM were restricted to the left ventricle, consistent with the focal nature of ischemic injury.
Furtado et al. (2026) conducted an observational in Heart failure (dilated and ischemic cardiomyopathy) (n=148). Alternative splicing profiling vs. Non-failing controls was evaluated on Alternative splicing events across cardiac regions. Alternative splicing profiling revealed shared dysregulation in dilated and ischemic cardiomyopathy, with DCM showing broader chamber-wide alterations compared to focal changes in ICM.