Short-Term Treatment With Ranolazine Improves Mechanical Efficiency in Dogs With Chronic Heart Failure

Abstract

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MV O 2 ) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MV O 2 and LV mechanical efficiency increased (22.4؎2.8% to 30.9؎3.4% (P<0.05). In contrast, dobutamine significantly increased MV O 2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MV O 2 , resulting in an increased myocardial mechanical efficiency in dogs with HF. F ree fatty acids (FFAs) are the primary energy substrate of the myocardium; however, they are not as efficient as glucose and lactate. 1 Studies in isolated rat hearts, 1 dogs, 2 pigs, 3 and humans 4 show that external power is reduced for a given myocardial oxygen consumption (MV O 2 ) when the heart has elevated FFA oxidation. Abnormalities of energy metabolism may contribute to the poor left ventricular (LV) function that characterizes heart failure (HF). 5,6 Patients with HF designated as New York Heart Association (NYHA) class II-III have greater myocardial FFA oxidation and lower carbohydrate oxidation compared with healthy individuals. 7 Impaired carbohydrate oxidation may contribute to mechanical dysfunction in the failing heart, as suggested by improved contractile function and efficiency in HF patients when carbohydrate oxidation is stimulated with dichloroacetate 8 or intracoronary pyruvate. 9 It has been suggested that pharmacological inhibition of myocardial FFA oxidation improves LV function without an increase in MV O 2 , and thus increases LV mechanical efficiency. 5 Ranolazine inhibits FFA ␤-oxidation and significantly improves treadmill time to onset of angina and 1-mm STsegment depression in patients with chronic stable angina. 10,11 The purpose of this investigation was to measure MV O 2 , LV function, and mechanical efficiency during short-term treatment with ranolazine. We used dobutamine, a positive inotropic agent that should not improve the mechanical efficiency, as a comparator. In addition, the net myocardial uptake of FFAs, glucose, and lactate was assessed. Materials and MethodsThe canine model of chronic HF was previously described in detail. 12,13 Chronic LV dysfunction and failure were produced by multiple sequential intracoronary embolizations, which results in loss of viable myocardium. 12 Eight healthy dogs (Hodgins Kennel, Howell, Mich) underwent microembolizations to induce HF. This study was approved by the Henry Ford Health System Institutional Animal Care and Use Committee.Dogs were anesthetized 12,13 and catheters placed in the femoral vein, coronary sinus, and left ventricle under fluoroscopic guidance, and LV pressure was measured. Cardiac function and coronary flow measurements were made 12,13 and arterial and coronary sinus (cs) blood samples drawn at baseline and after 30 minutes of treatment with either ranolazine (0.5 mg/kg bolus, followed by a constant infusion of 1.0 mg ·...

Excitation-contraction coupling and mitochondrial energetics

“…Both approaches were cardioprotective in experimental models of ischemia/ reperfusion, since in this situation, an excessive increase of [Na + ] i contributes to progressive cytosolic and mitochondrial Ca 2+ -overload and thus, the induction of apoptosis through activation of the mitochondrial PTP [78,135,168,189]. Also in animal models of heart failure, both the inhibition of I NHE by cariporide and of late I Na by ranolazine reduced [Na + ] i and improved EC coupling and LV remodeling [6,34,38,62,163,202]. In conditions of cardiac ischemia/reperfusion, inhibition of I NHE preserved mitochondrial energetics (i.e., ATP and PCr content) [111,162].…”

Effects of Ranolazine, a Novel Anti-anginal Drug, on Ion Currents and Membrane Potential in Pituitary Tumor GH3 Cells and NG108-15 Neuronal Cells

“…The inhibitory effect of this drug was also found to be rapidly developing and readily washed out. The concentration of ranolazine required for the inhibition of I K(IR) or I Na is lower than that for the inhibition of fatty acid oxidase (26). The observed effect of ranolazine on these ion currents is thus unlinked to its inhibitory effect on β-oxidation of fatty acids and can be due to the drug acting on the channel itself.…”

Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions

“…The study was limited by the absence of blinding and a placebo control. In subsequent experiments from the same laboratory, Chandler et al 41 reproduced these findings and determined that the improvement in left ventricular performance was not associated with an increase in myocardial oxygen consumption (MV O 2 ) compared with an intravenous infusion of dobutamine that improved left ventricular performance to a similar extent but was associated with a significant increase in MV O 2 requirements. In subsequent studies from the same laboratory in which a chronic canine heart failure model was used, pre/post 3-month comparison of oral ranolazine compared with placebo demonstrated decreased left ventricular end-diastolic pressure, negative LV ϪdP/dt, and left ventricular circumferential wall stress and increased deceleration time of early mitral inflow velocity (H. Sabbah, PhD, written communication, February 16, 2006).…”

“…10 -12 Ranolazine inhibits the late I Na current and significantly improves left ventricular performance in experimental models of heart failure. [41][42][43][44][45] Sabbah et al 43 measured hemodynamics before and 40 minutes after an intravenous dose of 0.5 mg/kg of ranolazine followed by a continuous infusion of 1.0 mg/kg per hour in a canine model of heart failure induced by intracoronary microembolization to produce an average ejection fraction of 27%. Results in 13 experimental dogs were compared with those obtained in 8 normal healthy dogs.…”