High Burden of Premature Ventricular Contractions Upregulates Transcriptional Markers of Inflammation and Promotes Adverse Cardiac Remodeling Linked to Cardiomyopathy

BACKGROUND: Premature ventricular contractions (PVCs) are the most prevalent ventricular arrhythmia in adults. High PVC burden can lead to left ventricular systolic dysfunction, eccentric hypertrophy, and an increased risk of heart failure and sudden cardiac death. Inadequate angiogenesis is a key determinant in the transition from adaptive to maladaptive cardiac hypertrophy, and fibrosis is a risk factor for arrhythmia and sudden cardiac death. We quantitatively assessed structural remodeling and transcriptional alterations in PVC-induced cardiomyopathy (PVC-CM). METHODS: Animals were implanted with modified pacemakers to deliver bigeminal PVCs (200–220 ms coupling interval) for 12 weeks. Collagen deposition and interstitial ultrastructure of left ventricular samples were analyzed using light and transmission electron microscopy, respectively. Pericytes, fibroblasts, myocytes, smooth muscle, and endothelial cells were imaged using confocal microscopy, quantified with an artificial intelligence-based segmentation analysis, and compared using hierarchical statistics. Transcriptional changes were assessed via RNAseq, and protein expression was assessed using western blot. RESULTS: Although cardiomyocytes hypertrophied in PVC-CM, capillary rarefaction was overcome by an increase in the capillary-to-myocyte ratio. Additionally, thicker blood vessels were more abundant in PVC-CM. Fibroblast-to-myocyte ratio more than doubled, interstitial collagen fibers increased, and interstitial space thickened in PVC-CM. Transcripts involved in interstitial remodeling, inflammatory response, and alarmins were strongly elevated in PVC-CM, showing enrichment of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) transcriptional signature. These results coincide with elevated levels of the proinflammatory cytokine IL (interleukin)‑1β, the inflammasome component NLRP3 (nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3), and increased expression of NF‑κB p65 (RelA). CONCLUSIONS: Although the angiogenic response meets the metabolic demands of cardiac hypertrophy, upregulated markers of inflammation and cardiomyopathy linked to reactive fibrosis collectively represent an adverse left ventricular remodeling in PVC-CM that could provide the substrate for heart failure, arrhythmias, and sudden cardiac death in PVC-CM.