Abstract 17306: Fatty Acid Oxidation Inhibitors Improve RV Function and Cardiac Repolarization in Right Ventricular Hypertrophy Induced by Pulmonary Artery Banding
Introduction: Right ventricular hypertrophy (RVH) and right ventricular failure is major determinants of prognosis and functional state of patients with congenital heart disease or pulmonary artery hypertension (PAH). We previously reported metabolic shift from glucose oxidation to glycolysis accompanied with RV dysfunction in RVH with and without PAH. Dichloroacetate, an inhibitor of mitochondrial pyruvate dehydrogenase kinase improved RV function by increasing impaired glucose oxidation. There is a reciprocal relationship between fatty acid and glucose oxidation such that partial inhibitors of fatty acid oxidation (pFOXi) increase glucose oxidation. We tested the hypothesis that pFOXi, ranolazine (RAN) would restore RV function by improving glucose oxidation in RVH caused by pulmonary artery banding (PAB).
Methods and Results: RVH was induced in Sprague-Dawley rats by PAB (using a 1.3 mm constrictor placed by partial median sternotomy). RAN was given orally for 1 week beginning 3 weeks after PAB surgery. The degree RV/LV+Septum increased from 0.28 ± 0.02 to 0.68 ± 0.04 but was less with RAN (0.53 ± 0.01, P < 0.001). Thermodilution cardiac output (CO) decreased from 126.3 ± 5.1 to 82.9 ± 4.8 ml/min with PAB and was better preserved with RAN (104.6 ± 5.8ml/min, P<0.05). O2 consumption of RV shaving (140mg samples) was measured using high-resolution respirometry. PAB reduced RV oxygen consumption from 652.2 ± 48.1 to 385.6 ± 23.6 pM/(sec*ml) (P<0.005) and was improved by RAN (543.9 ± 25.8 pM/(sec*ml), P<0.005). Treadmill walking distance decreased from 811.0 ± 71.98 to 269.0 ± 21.02 with PAB and was improved with RAN (338.0 ± 21.61 P< 0.05).
Conclusions: pFOXi improve RV function and partially reverse RVH and reverse electrical remodeling in PAB-induced RVH. We speculate this reflects activation of Randle's cycle (i.e. by blocking fatty acid oxidation and glucose oxidation improves. pFOXi are a potential therapeutic treatment for RVH and RV failure.
- © 2010 by American Heart Association, Inc.