Associate editor: Y.S. ChatzizisisRole of ranolazine in angina, heart failure, arrhythmias, and diabetes
Introduction
Cardiac ischemia is a major risk factor for the development of heart failure and both pathologies are often associated with severe ventricular and atrial arrhythmias. Moreover, a large number of patients with coronary artery disease suffer from diabetes. Common antianginal drugs do not improve glucose metabolism but rather exert adverse glycometabolic effects, e.g. ß-blockers. In addition, antianginal drugs other than ß-blockers and calcium channel blockers (e.g. verapamil) do not have antiarrhythmic effects. Therefore, a compound with antianginal and antiarrhythmic properties, with beneficial effects on contractile dysfunction which also improves glucose metabolism would be desirable for optimal treatment of patients with coronary artery disease. Ranolazine has a unique mode of action and causes its antianginal and antiischemic effects by selective inhibition of the late sodium current (late INa) and additionally exerts promising effects on arrhythmias, heart failure and diabetes. This article focuses on the experimental and clinical importance of ranolazine, and discusses the relevance of an increasing body of promising studies.
Section snippets
The late sodium current (late INa)
In 1979 Coraboeuf and coworkers measured action potentials (AP) in dog Purkinje fibers. They found that tetrodotoxin reduces action potential (AP) duration at concentrations lower than those at which the maximum rate of AP upstroke decreases. This finding led them to the conclusion “that this current, which is more sensitive to tetrodotoxin than the normal rapid (or peak) Na current, flows through a background Na conductance or/and a small proportion of Na channels with no inactivation
Role of ranolazine in myocardial ischemia and angina
Ranolazine (N-(2,6-dimethylphenyl)-4(2-hydroxy-3-[2-methoxyphenoxy]-propyl)-1-piperazine acetamide dihydrochloride) is currently the most potent clinical inhibitor of late INa. Early studies suggested that its main mechanism of action may be through inhibition of fatty acid oxidation (McCormack et al., 1996); however, these effects were measured at very high ranolazine concentrations well in excess of clinical relevant plasma concentrations of 2–8 μM. In multicellular tissue and in cardiac
Experimental studies
Acute infusion of ranolazine in a dog heart failure model caused an increase in LV ejection fraction and stroke volume but not in nonfailing controls (Sabbah et al., 2002). These effects were again observed in the absence of changes in heart rate or blood pressure. In another dog study, ranolazine was investigated as a chronic treatment option, alone and in combination with metoprolol or enalapril (Rastogi et al., 2008). Ranolazine prevented progressive LV dysfunction as well as global and
Role of ranolazine in diastolic dysfunction/heart failure
Diastolic heart failure or heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of heart failure. Ventricles show a decreased compliance and relaxation. Until now there are no evidence-based agents for treating diastolic heart failure. Since late INa is abnormally elevated in heart failure (Maltsev et al., 2007) and inhibition of late INa improves diastolic performance in ischemic myocardium, there is ongoing effort to investigate possible effects of
Experimental studies
An increased late INa can alter cell electrophysiology by two ways and thus increase the propensity for arrhythmias (Table 3):
- 1)
Prolongation of cardiac APs
- 2)
Cellular Na-dependent Ca overload
Early afterdepolarizations (EADs) are more likely to occur during a prolonged AP which can be induced by enhancing late INa (Song et al., 2004). Transmural differences of late INa and hence AP duration might increase transmural dispersion of repolarization and QT interval, which underlies the development of
Role of ranolazine in atrial arrhythmias
Rhythm control remains important in the treatment of atrial fibrillation, but cannot be effectively achieved without the risk of potential side effects e.g. proarrhythmia, hypotension, or severe organ toxicity with current drugs (except for ß-blockers). Thus, there is a huge demand for novel pharmacological strategies to prevent or suppress atrial fibrillation. Ranolazine may achieve antiarrhythmic effects through several pathways (Fig. 5).
Diabetes
The burden of cardiovascular disease among patients with diabetes is extensive. On the one hand, diabetes is a common co-morbidity in angina patients. On the other hand, patients with diabetes have a two- to four-fold increased risk of cardiovascular events. In diabetic patients over the age of 65 years, 68% of deaths are due to coronary artery disease (Centers for Disease Control & Prevention, 2008). The high mortality and risk for cardiovascular events have led to considerable interest in
Conclusions and future perspectives
This article provides evidence that ranolazine may have a therapeutic role for the treatment of systolic and diastolic heart failure in addition to its current antianginal role. Since there is no evidence-based compound for the treatment of diastolic heart failure, appropriate randomized clinical trials are indicated to evaluate the safety and efficacy of ranolazine in patients with diastolic and possibly systolic heart failure.
Ischemia and heart failure are widely associated with atrial
Disclosures
Dr. Maier receives research grants from Gilead and is involved in clinical trials with Gilead and Menarini. Dr. Sossalla and Dr. Maier receive speaker's honoraria from Berlin-Chemie.
Acknowledgments
Dr. Sossalla is funded by the Research Program, Faculty of Medicine, Georg-August-University Göttingen. Dr. Maier is funded by the Deutsche Forschungsgemeinschaft through a Clinical Research group (MA 1982/2-2) and a Heisenberg grant (MA 1982/4-1), as well as by the Leducq Transatlantic Networks of Excellence “Alliance for CaMK Signaling in Heart Disease” and “Redox and Nitrosative Regulation of Cardiac Remodeling: Novel Therapeutic Approaches for Heart Failure”.
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