Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction‐induced cardiomyopathy

Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC‐induced cardiomyopathy (PVC‐CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200–220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC‐CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC‐CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store‐operated Ca 2+ entry, calcineurin/NFAT pathway, β‐myosin heavy chain, and skeletal type α‐actin were unaltered in the PVC‐CM group. In contrast, pro‐hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC‐CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti‐hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro‐hypertrophic factor VEGF‐A and its receptor VEGFR2 were significantly elevated in the PVC‐CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy.