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Objective: About one-third of patients undergoing percutaneous coronary interventions (PCIs) for flow-limiting coronary stenosis continue to develop signs of myocardial ischemia (MI) during exercise stress test [EST], despite successful coronary revascularization. Coronary microvascular dysfunction is a likely major cause of the persistence of EST-induced MI in these patients., Patients and Methods: We studied 15 patients (14 men, age 67±5 years) fulfilling the following strict inclusion criteria: (1) recent PCI (<6 months), with drug-eluting stent, of coronary artery stenoses for stable angina, with evidence of full success (no residual stenosis >20% in any vessel); (2) persistence of ST-segment depression induction during EST. After a basal investigation, patients received either ranolazine (375 mg bid) or isosorbide-5-mononitrate (ISMN, 20 mg bid) for 3 weeks in a single-blind, randomized crossover study. Clinical assessment, symptom-limited EST, echocardiographic color-Doppler, with tissue-Doppler examination, and coronary microvascular dilator response to adenosine (CFR-ADO) and cold pressor test (CFR-CPT), assessed by transthoracic echo-Doppler, were obtained at baseline and the end of the 3-week therapy with each drug., Results: Compared to both baseline and ISMN, ranolazine showed a longer time to 1 mm ST-segment depression (404±116 s vs. 317±98 and 322±70 s, respectively; p<0.01). No differences were observed in coronary microvascular function and diastolic left ventricular function between the 2 drugs and compared to baseline., Conclusions: Our data show that ranolazine, but not ISMN, improved time to ischemia during EST. This effect, however, was independent of any effects on coronary microvascular and diastolic function.