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-weeks after 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-week, 3-weeks and 6-weeks 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-week following PAB. Metabolic changes, TGF-β1 canonical signaling, collagenous fibrosis deposition and apoptosis were already significantly increased by 1-week after PAB. Genes marking fibroblast activation were upregulated at 1-week but not 6-week post-PAB surgery. Mitochondrial dysfunction as evidenced by increased PDK activity and decreased PDH phosphorylation significantly at 6-week post PAB. These processes preceded the development of overt myocardial hypertrophy and impaired echo parameters of systolic and diastolic function which occurred significantly from 3-weeks after PAB. RV myocardial inflammation, metabolic shift, metabolic gene transcription and pro-fibrotic 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 employed.