Effect of ranolazine on plasma arginine derivatives and urinary isoprostane 8-iso-PGF2α in patients with myocardial infarction in the randomized RIMINI-Trial.

The purpose of the present study was to assess whether 6-week ranolazine application on top of guideline-based treatment impacts on the arginine/NO pathway and urinary isoprostane 8-iso-PGF2α as marker of oxidative stress in patients directly after a myocardial infarction. 20 patients with unstable angina pectoris and proof of acute cardiac ischemia entered the study. 10 subjects received the study drug ranolazine in addition to standard treatment, the others received only standard treatment. Urine and venous blood were collected before and after treatment. At the end of the study and compared to baseline, homoarginine levels had increased in the control group. This was not the case in ranolazine-patients. Interestingly, in ranolazine-treated-patients arginine plasma levels were significantly higher at the end of the study than at baseline (difference +26 µmol/L, 95% CI 8.6 to 44 µmol/L). ADMA and SDMA levels were not different. Urine levels of the oxidative stress marker 8-iso-PGF2α tended to be lower in ranolazine-treated patients (-144 pmol/mg creatinine). Findings of this hypothesis-driven study give evidence that ranolazine treatment enhances arginine plasma levels and lowers oxidative stress.

Effect of Ranolazine on Ischemic Myocardium IN Patients With Acute Cardiac Ischemia (RIMINI-Trial): A Randomized Controlled Pilot Trial.

BACKGROUND: Coronary artery disease is the most prevalent manifestation among cardiovascular diseases. Despite modern treatment, risk of ischemic complications in patients with acute coronary syndrome (ACS) remains important. The late Na+ current blocker ranolazine has shown to reduce the risk of recurrent ischemia and worsening of angina in patients with non-ST-segment elevation ACS by possibly improving myocardial perfusion, but up to now no trial has addressed whether this enhanced perfusion also leads to a decrease in ischemic myocardium of patients with ACS. We designed a pilot trial (Reduction of Ischemic Myocardium with Ranolazine-Treatment IN patients with acute myocardial Infarction, ClinicalTrials.gov Identifier: NCT01797484) for feasibility and proof of concept that a 6-week ranolazine add-on therapy would reduce the area of ischemic myocardium in patients with ACS. METHODS AND RESULTS: The trial was designed in a 2-armed, controlled and randomized way. Twenty participants with unstable angina, proof of acute cardiac ischemia, and myocardial dyskinesia by speckle-tracking echocardiography were included. Ten participants received the study drug ranolazine additionally to standard treatment. The control group received standard treatment without additional study medication. Speckle-tracking echocardiography was performed before coronary intervention, before the first dose of ranolazine, and after 6 weeks of ranolazine treatment. Ranolazine was administered safely during acute myocardial infarction. Speckle-tracking echocardiography proved to be suitable for evaluation of myocardial dyskinesia. Patients receiving ranolazine showed a trend to higher normal fraction of the cumulative global strain than patients in the standard treatment group (15% vs 11%). No major complications relating study medication were observed. CONCLUSION: In conclusion, in this preliminary hypothesis-driven study, 6-week ranolazine therapy was shown to decrease the area of dyskinetic myocardium in patients with ACS by trend. Global strain rate measurement using speckle-tracking echocardiography can be applied measuring those effects and is, compared to other techniques, safe and harmless. Our data provide a sound basis for a follow-up trial.