Rho‐kinase Mediates Biventricular Coronary Arterial Remodeling During Pulmonary Arterial Hypertension in Fischer 344 Rats

Abstract

Rationale: Fischer 344 rats exposed to Sugen‐5416 and hypoxia, then normoxia (Su/Hx/Nx) develop severe pulmonary arterial hypertension (PAH). Unique to this strain, PAH is accompanied by significant death within 8 weeks. Coronary remodeling and acute heart failure is suspected. Here, we test the hypothesis that PAH is accompanied by biventricular Rho‐kinase mediated coronary arterial remodeling, ischemia and heart failure.
 Methods: Rats were injected with Sugen‐5416 followed by 3 weeks of hypoxia (10% O2), then 6 weeks of normoxia (21% O2). Survival was plotted as a Kaplan‐Meier curve. Histology examined biventricular coronary remodeling and matrix deposition. Hypertensive rats were treated with fasudil, a Rho‐kinase inhibitor, added to the drinking water.
 Preliminary Results: 3 out of 4 non‐treated PAH rats died between 5 and 8 weeks of Su/Hx/Nx exposure, while 3 out of 3 fasudil‐treated PAH rats survived to 9 weeks, when sacrificed. Echocardiography at 5 weeks showed right ventricular dilation, septal deviation and decreased cardiac output. RV/(LV+S) confirmed significant hypertrophy of the right ventricular wall regardless of treatment. Histology revealed that Rho‐kinase inhibition normalized biventricular coronary remodeling and perivascular fibrosis (Figure 1).
ConclusionDuring PAH in Fischer rats, Rho‐kinase mediates coronary arterial wall thickening in both ventricles, which primes the heart for ischemia and failure.Funding: NIH‐ HL060024 and HL066299 Figure 1: Coronary arteries during PAH with or without fasudil treatment compared to normotensive. Red arrows‐ smooth muscle medial hypertrophy; yellow star‐ perivascular fibrosis.image