Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure

Sabbah, Hani N.; Chandler, Margaret P.; Mishima, Takayuki; Suzuki, George; Chaudhry, Pervaiz A; Nass, Omar; Biesiadecki, Brandon J.; Blackburn, Brent; Wolff, Andrew; Stanley, William C.

doi:10.1054/jcaf.2002.129232

Cited by 129 publications

(81 citation statements)

References 36 publications

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“…Additionally, ranolazine did not modify late I Na in vehicletreated cardiomyocytes, while it markedly reduced the enhanced current measured in cells treated with doxorubicin. These data are supported by several studies showing the neutral effect of ranolazine on healthy animals or cardiomyocytes from normal hearts (Sabbah et al, 2002;Undrovinas et al, 2010;Coppini et al, 2013a;Tocchetti et al, 2014).…”

Section: Bjpsupporting

confidence: 78%

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Cappetta

Esposito

Coppini

et al. 2017

British J Pharmacology

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Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca 2+ and Na + overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na + current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. EXPERIMENTAL APPROACHFischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg À1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg À1 , daily) for the following 4 weeks. KEY RESULTSWhile diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na + /Ca 2+ exchanger 1 and Na v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca 2+ /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. CONCLUSIONS AND IMPLICATIONSRanolazine, by the increased Na + influx, induced by doxorubicin, altered cardiac Ca 2+ and Na + handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. LINKED ARTICLES

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Section: Bjpsupporting

confidence: 78%

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Cappetta

Esposito

Coppini

et al. 2017

British J Pharmacology

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“…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].…”

Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…110 Ranolazine treatment of intracoronary embolization-induced heart failure in dogs was associated with improvement in left ventricular systolic function without alterations in cardiovascular hemodynamics, suggesting that ranolazine primarily targets cardiac metabolism. 111 Currently, a clinical trial investigating the effect of ranolazine on heart failure with preserved ejection fraction is ongoing. 112 Enhancing glucose oxidation Inhibiting PDK (the enzyme that phosphorylates and inhibits PDH) using dichloroacetate (DCA) appears to be beneficial in pressure overload heart failure.…”

Section: Approaches To Treat Left Heart Failure Inhibiting Fat Oxidationmentioning

confidence: 99%

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Sankaralingam

Lopaschuk

2015

Pulm. circ.

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Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

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Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure

Cited by 129 publications

References 36 publications

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Excitation-contraction coupling and mitochondrial energetics

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

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