Serial and regional assessment of the right ventricular molecular and functional response to pressure loading.

Abstract

Right ventricular (RV) function determines outcomes in RV pressure loading. A better understanding of the time-course and regional distribution of RV remodeling may help optimize targets and timing for therapeutic intervention. We sought to characterize RV remodeling between zero and 6 wk after the initiation of RV pressure loading. Thirty-six rats were randomized to either sham surgery or to pulmonary artery banding (PAB). After echocardiography and conductance catheter studies, groups of rats were euthanized at 1 wk, 3 wk, and 6 wk after sham surgery, or induction of RV pressure loading, for RV histological, RNA, and molecular analysis. A vigorous inflammatory response characterized by increased RV inflammatory cytokines, chemokines, and macrophage markers was observed at 1 wk following PAB. Metabolic changes, transforming growth factor-β (TGF-β)1 canonical signaling, collagenous fibrosis deposition, and apoptosis were already significantly increased by 1 wk after PAB. Genes marking fibroblast activation were upregulated at 1 wk but not at 6 wk post-PAB surgery. Mitochondrial dysfunction was evidenced by increased pyruvate dehydrogenase kinase (PDK) activity and decreased pyruvate dehydrogenase (PDH) phosphorylation significantly at 6-wk post-PAB. These processes preceded the development of overt myocardial hypertrophy and impaired echo parameters of systolic and diastolic function that occurred significantly from 3 wk after PAB. RV myocardial inflammation, metabolic shift, metabolic gene transcription, and profibrotic signaling occur early after initiation of pressure loading when RV pressures are only moderately elevated, before the development of overt myocardial hypertrophy and dysfunction, suggesting that adaptive hypertrophy and maladaptive remodeling occur simultaneously. These results suggest that therapeutic intervention to reduce adverse RV remodeling may be needed earlier and at lower thresholds than currently used.NEW & NOTEWORTHY Exploring the dynamics of right ventricular remodeling: unveiling the intricate interplay between inflammation, metabolic shifts, and fibrotic signaling in response to pressure loading. Through a comprehensive study spanning from initiation to 6 wk post-pressure loading, our research sheds light on the early onset of crucial molecular processes preceding overt hypertrophy and dysfunction. These findings challenge conventional intervention timing, advocating for early, targeted therapeutic strategies to mitigate adverse remodeling in right ventricular pressure loading.