High burden of premature ventricular contractions upregulates transcriptional markers of inflammation linked with adverse cardiac remodeling and cardiomyopathy.
Premature ventricular contractions (PVCs) are the most prevalent ventricular arrhythmia in adults. High PVC burden can lead to left ventricular (LV) systolic dysfunction, eccentric hypertrophy, and an increased risk of heart failure (HF) and sudden cardiac death (SCD). Deficient angiogenesis is a key determinant in the transition from adaptive to maladaptive cardiac hypertrophy and fibrosis is a risk factor for arrhythmias and SCD. Here,  the primary objective was to quantitatively assess the structural remodeling and transcriptional alterations associated with PVC-induced cardiomyopathy (PVC-CM). Canines were implanted with modified pacemakers to reproduce bigeminal PVCs (200-220 ms coupling interval) for 12 weeks. Collagen deposition and interstitial ultrastructure were visualized using light and transmission electron microscopy, respectively, in LV samples. Morphometric studies of pericytes, fibroblasts, myocytes, smooth muscle and endothelial cells were performed using confocal microscopy and quantified with an artificial intelligence-based segmentation analysis and compared using hierarchical statistics. Transcriptional changes were assessed via RNAseq. Although the cardiomyocytes were hypertrophied in PVC-CM LV samples, capillary rarefaction was not observed due to an increase in 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 the interstitial space thickened in PVC-CM. Transcripts involved in interstitial remodeling, inflammatory response, and alarmins were strongly elevated in PVC-CM. While the angiogenic response meets the metabolic demands of cardiac hypertrophy, upregulated markers of inflammation and cardiomyopathy linked to reactive fibrosis collectively represent an adverse remodeling that heightens the risk of HF and SCD in PVC-CM. Overall design: Female mongrel canines (>10 months old, ~21 Kg) were implanted with a modified dual-chamber epicardial pacemaker. After a 2-week surgical recovery, animals were randomized into 2 groups: 1) PVC-CM group, receiving bigeminal PVCs (50% burden) with a 200-220 ms coupling interval for 12 weeks, and 2) sham group where PVCs were not enabled. Echocardiographic recordings were obtained at baseline and at 12-weeks of chronic PVCs to evaluate the development of cardiomyopathy. Euthanasia was performed at week 12, via exsanguination during final left thoracotomy surgery under general anesthesia. The harvested heart was immediately rinsed with ice-cold phosphate-buffered saline (PBS), which was injected directly through the left main coronary artery to remove blood. Segments of the anterior LV were snap frozen and snap-frozen myocardial tissue from randomly selected regions of the left ventricular (LV) free wall was used for RNA extraction and downstream analysis.