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

Chaitman, Bernard R.

doi:10.1161/circulationaha.105.597500

Cited by 265 publications

(230 citation statements)

References 49 publications

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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

218

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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Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

218

183

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“…3,11 In addition it is a potent inhibitor of I Kr . 12 Through its effect on the delayed rectifier (I Kr ) ranolazine was found to increase QT interval with a resultant decrease of dose or withdrawing medication in 1% of patients.…”

Section: Discussionmentioning

confidence: 99%

The potential contribution of ranolazine to Torsade de Pointe

Liu

Williams

Rosen

2013

Journal of Cardiovascular Disease Research

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a b s t r a c tRanolazine is a novel anti-anginal agent acting through pharmacologic mechanism of inhibition of the late phase of the inward sodium current. In addition, it is a potent inhibitor of rapid delayed rectifier potassium currents, leading to prolongation of the QT interval. However, ranolazine has not yet described to be associated with Torsade de Pointes despite its QT-prolonging effect. In this case report, we describe a patient on ranolazine who developed Torsade de Pointes and discuss about the potential contribution of ranolazine to the development of Torsade de Pointes.

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“…Ranexa (CV Therapeutics Inc., Palo Alto, CA) is the sustainedrelease ranolazine preparation recently approved. 13 It has maximal plasma concentrations (C max ), typically seen 4-6 h after administration, and a peak/trough difference of 1.6-fold with 500-1,000 mg twice daily dosing. The Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) and subsequent CARISA and ERICA trials enrolled patients with chronic angina for at least 3 months.…”

Section: Ranolazinementioning

confidence: 99%

“…The most common adverse events reported with ranolazine are dizziness, nausea, asthenia, and constipation. 4,5,11,13 The mechanism of action of ranolazine is under investigation. Initially, it was thought to exert its therapeutic effects through partial inhibition of fatty acid oxidation.…”

Section: Ranolazinementioning

confidence: 99%

Novel therapeutic approaches to treating chronic angina in the setting of chronic ischemic heart disease

Chaitman

Sano

2007

Clin Cardiol

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SummaryPharmacologic therapy to alleviate symptoms in chronic angina has been enhanced by the recent approval of several novel compounds that complement the traditional approach using beta-adrenergic blocking drugs, calcium antagonists, and long-acting nitrates. In the United States, ranolazine, a drug that inhibits late I Na , was approved for patients with chronic angina that remain symptomatic on beta-blockers, calcium antagonists, or long-acting nitrates, on the basis of an acceptable safety profile and efficacy in several randomized placebo controlled studies. A slight increase in the QT interval is observed (< 10 ms on average) at the maximum approved dose of 1,000 mg twice daily. Therefore, an ECG should be acquired at baseline and during follow-up, and the drug should not be used in patients with QT prolongation or those who are on QT prolonging drugs unless longer term randomized outcome data demonstrates no excess risk. The MERLIN trial of non-ST-elevation acute coronary syndrome (NSTE ACS) randomized 6,560 patients to assess the potential benefit of ranolazine in reducing the composite endpoint of cardiovascular death, myocardial infarction, and recurrent ischemia, with results expected in 2007. In Europe, ivabradine, a drug that inhibits the hyperpolarizationactivated mixed sodium/potassium inward I f current, which slows the rest and exercise heart rate, was approved in 2005. Ivabradine at a dose of 10 mg twice daily has been shown to have similar efficacy to amlodipine 10 mg once daily or atenolol 100 mg once daily in alleviating chronic angina symptoms. In this review, several other novel investigational approaches are presented and patient selection considerations for the most recent approved drugs for chronic angina are discussed.

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

Cited by 265 publications

References 49 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

The potential contribution of ranolazine to Torsade de Pointe

Novel therapeutic approaches to treating chronic angina in the setting of chronic ischemic heart disease

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