The use of ranolazine to facilitate electrical cardioversion in cardioversion-resistant patients: a case series

Background: Occasionally atrial fibrillation (AF) is resistant to electrical cardioversion (EC). Ranolazine (RZ) is an antianginal agent, which inhibits abnormal late Na⁺ channel currents in cardiomyocytes and decreases Na⁺/Ca⁺⁺ overload. RZ is a potent inhibitor of after‐depolarizations and triggered activity and prolongs atrial refractory periods. We postulated RZ could facilitate EC in patients resistant to EC. Methods: Over a 3‐year period, we identified 25 EC‐resistant patients who had been administered oral RZ shortly after failing attempted EC. The anterior‐posterior cardioversion approach was used and each patient had failed to be restored to sinus rhythm despite using up to the maximum output of a biphasic cardioversion device. Repeat EC was performed 3.5–4 hours after administration of 2 g of oral RZ using the same device, sedation, and lead placement. Results: Sinus rhythm was successfully restored in 19 (76%) of 25 EC‐resistant patients. Three patients spontaneously converted before the second attempt at EC within 4 hours of the RZ dose. Of the 22 patients undergoing another attempt at EC, 16 were successfully converted to sinus rhythm. Five of the six patients who were refractory to repeat EC despite RZ had AF of unknown duration and each is now in permanent AF. No adverse effects were noted. Conclusion: RZ shows promise as a safe and convenient agent to facilitate EC in EC‐resistant patients. It appears to be most effective in patients whose AF duration is known to be less than 3 months. (PACE 2011;1–6)     

Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease

Summary To assess the effects of ranolazine, a new antiischemic drug, on regional myocardium of the left ventricle, left ventricular (LV) hemodynamic and angiographic data were obtained in 15 patients with previous transmural myocardial infarction before and after intravenous infusion of ranolazine (200 or 500 µg/kg body weight). LV angiogram was analyzed by the area method and was divided into six segments. Regional LV segments were classified as normal (perfused by intact coronary vessels, n=20), ischemic (perfused by stenotic vessels but without ECG evidence suggesting myocardial necrosis, n=25), or infarcted (total coronary occlusion and with the ECG evidence for necrosis, n=45). Regional area fractional shortening, peak filling rate, and segmental wall motion during isovolumic relaxation period were analyzed. After ranolazine, regional area fractional shortening was unchanged in all segments. However, regional peak filling rate was decreased in the normal segments (1499±315 to 1368±303 mm²/sec, p<0.05). In the ischemic segments, by constrast, the administration of ranolazine significantly increased the regional peak filling rate (1050±410 to 1133±439 mm/sec, p<0.05) and regional wall lengthening during the isovolumic relaxation period (0.9±4.1% to 2.8±5.7% of end-diastolic segmental area, p<0.05), which indicates an improvement of regional diastolic function. Infarct segments were little affected by ranolazine. Thus, ranolazine improves diastolic function of the noninfarcted myocardium under chronic ischemic conditions and also may exert a mild negative lusitropic effect on the normal myocardium, although the former beneficial effect appears to be more clinically important. This finding supports the hypothesis that chronic myocardial ischemia impairs myocardial diastolic function and also opens new therapeutic perspectives.     

Diabetogenic effects of cardioprotective drugs

Drugs that protect against cardiovascular events in the patient with diabetes may also positively or negatively affect glycaemic control in the patient with established diabetes and may induce the development of diabetes in the predisposed patient. Mainly through increasing insulin resistance, beta-blockers, statins and high-dose diuretics have the potential to worsen glycaemic control. Dihydropyridine calcium channel blockers, low-dose diuretics, vasodilating beta-blockers, alpha-blockers and pitavastatin have little or no effect on glycaemic control. Blockers of the renin-angiotensin-aldosterone system, colesevelam, ranolazine and verapamil, through slowing breakdown of bradykinin, vasodilation, increasing cholecystokinin levels, blocking sodium channels and decreasing beta cell apoptosis, may improve glycaemic control and avoid the development of diabetes.     

Synthesis of Ranolazine Derivatives Containing the (1S,4S)‐2,5‐Diazabicyclo[2.2.1]Heptane Moiety and Their Evaluation as Vasodilating Agents

Two diazabicyclic analogues of ranolazine, ( S , S , S )‐5 and ( S , S , R )‐5 , and their epimeric mixture were synthesized. Furthermore, their vasomotor effects on rat aorta rings precontracted with phenylephrine were analyzed. These compounds showed vasodilating effects significantly greater than ranolazine. The vasodilating activities of these analogues have two components, one that depends on the endothelium, due to the release of NO, and another one due to a direct effect on the vascular smooth muscle. The compounds [( S , S , S )( S , S , R )]‐5 and ( S , S , R )‐5 induce, in a manner similar to ranolazine, the release of a prostanoid from the cyclooxygenase pathway, whose vasoconstrictor effect is masked by the predominant vasodilation induced by these compounds.     

雷诺嗪对豚鼠在体心肌缺血-再灌注损伤心律失常的预防作用

目的:探讨雷诺嗪对豚鼠在体心肌缺血-再灌注损伤(MIRI)模型的心律失常的影响及其可能作用机制.方法:将40只MIRI模型豚鼠分为4组:假手术组,对照组(MIRI组),雷诺嗪注射组和雷诺嗪持续灌注组,观察各组超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、再灌注心律失常发生情况.结果:与MIRI组比较,雷诺嗪注射组、雷诺嗪持续灌注组SOD活性增高,MDA含量降低,发生心室颤动的只数减少.结论:雷诺嗪可增强SOD活性,降低MAD水平,对抗MIRI过程的作用,减少再灌注心律失常的发生.