This is a Phase IIb, multicentric, prospective, randomized (1:1 ratio), open label, and no profit study, with the aim of evaluating the efficacy of late INa current inhibition to improve coronary microcirculation in patients presenting with acute myocardial infarction and multivessel disease.

All consecutive patients presenting with acute MI undergoing primary PCI (pPCI) on a major coronary artery, and with at least one remaining angiographically significant (% diameter stenosis > 50%) non-culprit stenosis will be enrolled.

The primary objective of the study is to evaluate the potential effect of Ranolazine in preserving coronary microcirculation subtended to the culprit vessel as compared with control group. Coronary microcirculation will be assessed both at the time of the culprit lesion revascularization and within 6+/-2 weeks by measuring the Index of Microcirculatory Resistance (IMR) either invasively or derived by the angiography (angioIMR).

In addition, the following secondary endpoints will be assessed: 1. The prevalence of residual CMD downstream to the culprit vessel in all patients (CMDculprit). CMDculprit will be defined as the finding of an IMR/angioIMR value > 25, assessed after successful pPCI.

2. The prevalence of CMD downstream to the non-culprit vessel in the two group of patients (CMDnon-culprit). CMDnon-culprit will be defined as the finding of an IMRnon-culprit or an angioIMRnon-culprit value > 25. IMRnon-culprit or angioIMRnon-culprit will be assessed at the time of staged PCI of the non-culprit stenosis.

3. The incidence of peri-procedural CMD after staged PCI of the non-culprit stenoses, defined as a 20% increase of IMR values assessed before and after elective PCI of the non-culprit vessel (CMDprocedural).

4. The difference between the two groups of patients, in terms of incidence of periprocedural Myocardial Infarction (PMI), eventually occurring during the staged procedure.

5. The effects of INa current inhibition on endothelial function assessed at follow up as compared with control group.

6. The extent of the Infarct Size, as assessed by the CMR, as compared with control group.

7. The incidence of MACE, defined as composite of death, myocardial infarction, periprocedural MI, or any unplanned percutaneous coronary revascularization at short (42+/-7 days) term follow-up.

8. Angina symptoms and quality of life

Ranolazine has already been studied in the setting of the acute coronary syndromes, without any significant advantage in terms of MACE occurrence as compared with control group. However, it was not associated with any significant adverse event, thereby the use of ranolazine is not forbidden in ACS patients, especially in the setting of patients with MVD. Of note, the individual component of recurrent ischemia was significantly reduced by ranolazine, as compared with control group and ranolazine reduced recurrent ischemic events, regardless of whether patients did or did not receive PCI within 30 days of a non-ST-segment ACS.

The aim of the present multicenter, randomized, controlled and open-label study is to evaluate the efficacy of late INa current inhibition to preserve coronary microcirculation after the acute myocardial infarction in patients presenting with STEMI and multivessel disease. Thereby, primary endpoint will be the relative difference in terms of IMR and/or angioIMR will be evaluated. IMR and/or angioIMR will be assessed both at the baseline (after successful coronary revascularization) and at the time of staged revascularization of the non-culprit stenosis (either at 5+/-2 days or within 6+/-2 weeks after pPCI).

In addition, as secondary objectives, It will be assessed whether the late INa current inhibition, as compared with the control group, might be effective at:

1. Reducing the prevalence of CMD after successful pPCI
2. Reducing the extension of the infarct size, as assessed at the cardiac magnetic resonance
3. Reducing the prevalence of CMD downstream to the non-culprit vessel before staged PCI
4. Reducing the incidence of CMD downstream to the non-culprit vessel after staged PCI
5. Reducing the incidence of periprocedural MI eventually occurring after staged procedures
6. Reducing the incidence of endothelial dysfunction
7. Reducing the early incidence of major cardiovascular events (MACE)
8. Improving residual angina symptoms and quality of life

Thereby, the following secondary endpoints will be evaluated:

1. The prevalence of residual CMD downstream to the culprit vessel in the two group of patients. Residual CMD will be defined as the finding of an IMRculprit or angioIMRculprit value > 25
2. The extent of the Infarct Size, as assessed by the CMR, in terms of grams (g) and percentage as compared with control group.
3. The prevalence of CMD downstream to the non-culprit vessel in the two group of patients (CMDnon-culprit). CMDnon-culprit will be defined as the finding of an IMRnon-culprit or angioIMRnon-culprit value > 25
4. The incidence of peri-procedural CMD after staged PCI of the non-culprit stenoses, defined as a 20% increase of IMRnon-culprit or angioIMRnon-culprit values assessed before and after elective PCI of the non-culprit vessel.
5. The difference between the two groups of patients, in terms of incidence of periprocedural Myocardial Infarction (PMI), eventually occurring during the staged procedure. PMI require to satisfy all the criteria of the fourth Universal Definition of Myocardial Infarction
6. The effects of INa current inhibition on endothelial function will be assessed at follow up as compared with control group. Endothelial function will be evaluated with the EndoPAT, measuring both the Endoscore and RHI
7. The incidence of MACE, defined as composite of death, myocardial infarction, or target-vessel revascularization at short (42+/-7 days) term follow-up.
8. Angina symptoms and quality of life will be assessed with SAQ7 and EuroQoL questionnaires and results compared between the two groups. Study Design This will be a prospective, multicenter, randomized (1:1 ratio), open-label, trial to evaluate the relative difference in terms of IMR and/or angioIMR measured both at baseline (after successful pPCI) and at follow-up (during staged PCI procedure).

Patients enrolled in the experimental group will receive ranolazine by oral administration, on top of regular therapy, starting with a dosage of 500mg bid and increased at 750mg bid starting from 7 days after pPCI up to 6 +/-2 weeks. Conversely, patients enrolled in the Control group will be managed, as per standard practice, with regular therapy only.

All comer patients undergoing successful pPCI for ST-segment elevation myocardial infarction (STEMI) will be screened for eligibility for study participation within six hours. STEMI will be defined by symptom onset within 24 hours and ST-segment elevation of ≥ 1 mm in 2 or more contiguous leads, true posterior MI, or new left bundle branch block. Patients who fulfil all inclusion criteria and do not meet any of the exclusion criteria will be eligible for trial inclusion soon after successful pPCI. Patients will be informed on the nature of the trial and of any potential harm or risk that the study may cause and will be assured of confidentiality. Patients will receive a copy of the signed and dated written informed consent form.

Inclusion Criteria

1. Age ≥ 18 years and < 80 years on day of signing informed consent
2. Ability to provide written informed consent in a time window 0 to 1 day after successful pPCI
3. ST-Elevation Myocardial Infarction at the time of the index hospitalization.
4. Successful pPCI (Thrombolysis In Myocardial Infarction [TIMI] flow 3 and residual coronary stenosis <30%)
5. Presence of at least one remaining angiographically significant (% diameter stenosis > 50%) non-culprit stenosis treatable with PCI
6. Evidence of post-menopausal status or negative urinary or serum pregnancy test for child-bearing potential patients (definitions reported in section 10.9)
7. Agreement for child-bearing potential patients who are sexually active to use contraception (definitions reported in section 10.10)

Exclusion Criteria:

1. Hemodynamically unstable patients
2. Previous myocardial infarction
3. Previous coronary artery by-pass graft (CABG)
4. Female patients with a positive pregnancy test at enrollment or prior to administration of study medication.
5. Female patients who are pregnant or breastfeeding or reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of Ranolazine
6. Known hypersensitivity to the active principle (Ranolazine) or any of the excipients
7. Chronic Kidney Disease Stage 4 or 5 (eGFR < 30 mL/min/1.73 m 2)
8. Moderate to severe liver failure (Child Pugh B - C)
9. Simultaneous intake of the following classes of drugs: strong CYP3A4 inhibitors (i.e. clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole); HIV protease inhibitors (i.e. saquinavir, indinavir, ritonavir); class Ia antiarrhythmic drugs (i.e. ajmaline, disopyramide, procainamide, quinidine ) and class III antiarrhythmic drugs except amiodarone (i.e. dofetilide, sotalol)
10. Previous participation in a clinical trial in which an investigational drug was administered within 30 days of screening or within the 5 half-lives of the study drug, whichever is longer.

It will be shared upon request