Right ventricular transcriptional changes in male DCM patients were primarily associated with pulmonary hypertension severity, with 982 genes positively and 2215 negatively correlated with mPAP.
Observational (n=25)
Single-nuclei transcriptomics of right ventricular tissue in DCM patients reveals that pulmonary hypertension severity drives significant gene expression changes, identifying potential novel biomarkers for RV dysfunction.
Abstract Background Pulmonary hypertension (PH) and subsequent right ventricular (RV) dysfunction are major factors in heart failure pathology, contributing to adverse events and poor prognosis. PH can arise from various causes but is defined by elevated pulmonary artery pressure, which can progressively strain the RV and lead to RV failure with fatal outcome. The most common form of PH is associated with left heart disease, in which left ventricular (LV) dysfunction causes increased pressure in the pulmonary circulation. Purpose This study aims to characterize molecular alterations in RV tissue in patients with heart failure due to dilated cardiomyopathy (DCM), providing insights into how PH exacerbates RV pathology. Methods We performed single-nuclei RNA sequencing (snRNA-seq) on 158012 nuclei from snap-frozen RV tissue of 21 male DCM patients and 4 male healthy controls (HC). Bioinformatic analysis was performed using the Seurat pipeline with differential expression analysis conducted in pseudobulk using edgeR. To model relationships between gene expression and clinical metrics, we incorporated patients' echocardiographic and hemodynamic data, along with age, as continuous variables in a generalized linear model. Results In DCM samples, transcriptional changes were predominantly detected in cardiomyocytes, with most differentially expressed genes (DEGs) associated with the severity of PH, primarily mean pulmonary arterial pressure (mPAP), rather than with LV or RV structural and functional metrics. 982 genes correlated positively with mPAP, while 2215 correlated negatively (Fig. 1). Notably, non-coding transcripts represented 10.1% of the upregulated genes and 64.7% of the downregulated genes. Gene set enrichment analysis showed that higher mPAP levels corresponded with increased expression of genes involved in cardiomyocyte contraction and remodeling, autophagy, adrenergic signaling, endosomal transport, and glucose metabolism. Transcription factor activity inference identified myocyte enhancer factor 2A (MEF2A) and serum response factor (SRF) among most active transcription factors, consistent with their known involvement in cardiac development and pathology (Fig. 2). To explore potential biomarkers for RV dysfunction, we assessed the expression of mPAP-associated DEGs in cardiomyocytes from healthy control RV samples and compared our findings with published snRNA-seq dataset of LV tissue from DCM patients. After selecting genes encoding plasma-secreted proteins, 68 genes positively associated with mPAP (including FLNC, MYL9, ZYX) and 52 genes negatively associated with mPAP emerged as potential candidates for RV dysfunction biomarkers. Conclusions The observed transcriptional changes underscore the crucial impact of PH on shaping the molecular profile of cardiomyocytes in the RV. These findings offer insights into the molecular mechanisms of heart failure, potentially enabling non-invasive monitoring of RV dysfunction in PH patients.Figure 1 Figure 2
Bonazza et al. (Sat,) conducted a observational in Heart failure due to dilated cardiomyopathy with pulmonary hypertension (n=25). Single-nuclei RNA sequencing (snRNA-seq) vs. Healthy controls was evaluated on Transcriptional changes in right ventricular tissue associated with pulmonary hypertension severity (mPAP). Right ventricular transcriptional changes in male DCM patients were primarily associated with pulmonary hypertension severity, with 982 genes positively and 2215 negatively correlated with mPAP.