Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle

Abstract

Right ventricular hypertrophy (RVH) and RV failure are major determinants of prognosis in pulmonary hypertension and congenital heart disease. In RVH, there is a metabolic shift from glucose oxidation (GO) to glycolysis. Directly increasing GO improves RV function, demonstrating the susceptibility of RVH to metabolic intervention. However, the effects of RVH on fatty acid oxidation (FAO), the main energy source in adult myocardium, are unknown. We hypothesized that partial inhibitors of FAO (pFOXi) would indirectly increase GO and improve RV function by exploiting the reciprocal relationship between FAO and GO (Randle’s cycle). RVH was induced in adult Sprague-Dawley rats by pulmonary artery banding (PAB). pFOXi were administered orally to prevent (trimetazidine, 0.7 g/L for 8 weeks) or regress (ranolazine 20 mg/day or trimetazidine for 1 week, beginning 3 weeks post-PAB) RVH. Metabolic, hemodynamic, molecular, electrophysiologic, and functional comparisons with sham rats were performed 4 or 8 weeks post-PAB. Metabolism was quantified in RV working hearts, using a dual-isotope technique, and in isolated RV myocytes, using a Seahorse Analyzer. PAB-induced RVH did not cause death but reduced cardiac output and treadmill walking distance and elevated plasma epinephrine levels. Increased RV FAO in PAB was accompanied by increased carnitine palmitoyl-transferase expression; conversely, GO and pyruvate dehydrogenase (PDH) activity were decreased. pFOXi decreased FAO and restored PDH activity and GO in PAB, thereby increasing ATP levels. pFOXi reduced the elevated RV glycogen levels in RVH. Trimetazidine and ranolazine increased cardiac output and exercise capacity and attenuated exertional lactic acidemia in PAB. RV monophasic action potential duration and QTc interval prolongation in RVH normalized with trimetazidine. pFOXi also decreased the mild RV fibrosis seen in PAB. Maladaptive increases in FAO reduce RV function in PAB-induced RVH. pFOXi inhibit FAO, which increases GO and enhances RV function. Trimetazidine and ranolazine have therapeutic potential in RVH.

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…Recent human and animal studies show evidence that there is a glycolytic shift in PAH and that these alterations are associated with an activation of glycolytic genes such as GLUT1, PDH and PDK (Oikawa et al, 2005;Fang et al 2012;Archer et al 2013) Our findings support this premise as demonstrated by elevated FDG SUVs in the RV and associated upregulation in glucose transporter GLUT4. There was a strong inverse correlation between increased FDG uptake and RV function suggesting that the glycolytic shift is maladaptive.…”

“…During episodes of ischemia, there is an activation of AMPK and subsequently an increase in FAO. Although overall myocardial oxidative metabolism is reduced, FAs dominate as the main substrate source for residual oxidative phosphorylation (Fang et al, 2012). Myocardial FA metabolism is accelerated (Obrzut et al, 2010) as a compensatory mechanism to generate more fuel and inhibit apoptosis when exposed to ischemic stress however, sustained accelerated FAO rates inhibit glucose oxidation and reduce cardiac efficiency (Dyck et al, 2006).…”

“…Little is known about the adaptive changes in fatty acid metabolism and the cross-talk between glucose-fatty acid cycle in the right ventricle (Fang et al, 2012). The benefit of therapeutically inhibiting FAO on improving RV function has previously been shown (Fang et al, 2012;Archer et al, 2013).…”

“…There exists a pressing demand to better understand the pathophysiology of PAH and the contributing factors leading to the detriment of right ventricular (RV) function, to identify new therapeutic targets and accordingly develop more effective therapies. Recently, studies have revealed that metabolic perturbations may be an important mechanism of RV failure (Fang et al, 2012) and may be implicated in pathogenic pulmonary vascular remodeling Marsboom et al, 2012). Additionally, metabolic modulation has been shown to have beneficial effects on RV function by therapeutically improving metabolic efficiency and enhancing glucose oxidation (GO) Archer et al, 2010;Fang et al, 2012;Marsboom et al, 2012).…”

“…Recently, studies have revealed that metabolic perturbations may be an important mechanism of RV failure (Fang et al, 2012) and may be implicated in pathogenic pulmonary vascular remodeling Marsboom et al, 2012). Additionally, metabolic modulation has been shown to have beneficial effects on RV function by therapeutically improving metabolic efficiency and enhancing glucose oxidation (GO) Archer et al, 2010;Fang et al, 2012;Marsboom et al, 2012). This may provide a new treatment avenue to directly and selectively target the failing RV and improve prognosis in patients with PAH however, there have been limited studies evaluating in-vivo metabolism of the RV Fang et al, 2012).…”