Please select the eligibility criteria that correspond to the clinical trial below.
Title: Treatment With Ranolazine in Microvascular Coronary Dysfunction (MCD): Impact on Angina Myocardial Ischemia
Brief Summary: This research study is designed to test the use of ranolazine in patients with angina (chest discomfort due to reduced blood supply to the heart) due to microvascular coronary dysfunction (MCD; abnormalities in the small blood vessels of the heart). This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. The FDA has approved this drug based on studies primarily on patients with chronic angina with major blockages of the arteries.


Options:
A: Inclusion Criteria:

1. Men or women age \>18 from diverse racial/ethnic groups;
2. Competent to give informed consent;
3. Patients with chronic angina or its equivalent;
4. Coronary angiogram revealing MCD with no obstructive CAD (epicardial coronary stenosis \<50% luminal diameter stenosis);
5. Left ventricular ejection fraction \> or = 45%;
6. Objective evidence of ischemia by noninvasive methods such as exercise stress test, stress Echo, MRI, or SPECT;
7. Patients with 10% myocardial ischemia by Cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index ≤ 2.0 or abnormal coronary reactivity testing (CFR \< 2.5, or ACH response of no dilation or constriction, determined by local site read).

Exclusion Criteria:

1. Acute coronary syndrome (defined by WHO), cardiogenic shock or requiring inotropic or intra-aortic balloon support;
2. Planned percutaneous coronary intervention or CABG or established obstructive CAD with ischemia eligible for revascularization, acute MI;
3. Prior non-cardiac illness with an estimated life expectancy \<4 years;
4. Unable to give informed consent;
5. Allergy or contra-indication to CMRI testing, including renal failure, claustrophobia, and asthma, uncontrolled moderate hypertension (sitting blood pressure \>160/95mmHg with measurements recorded on at least 2 occasions), conditions likely to influence outcomes: Severe lung, creatinine \>1.8 or CrCl ≤ 50ml/min) or hepatic disease;
6. Surgically uncorrected significant congenital or valvular heart disease and other disease likely to be fatal or require frequent hospitalization within the next six months;
7. Adherence or retention reasons;
8. Unwilling to complete follow-up evaluation including repeat testing, documented obstructive hypertrophic cardiomyopathy;
9. Aortic stenosis (valve area \<1.5cm);
10. LV dysfunction (ejection fraction ≤35%);
11. History of significant cocaine or amphetamine abuse;
12. Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir);
13. Women who are pregnant.
B: Inclusion Criteria:

* Hospitalized with non-ST elevation acute coronary syndrome
* Ischemic symptoms (more than or equal to 5 minutes) at rest within 48 hours of study entry
* At least one additional risk factor (e.g., elevated cardiac enzymes, ST-depression, diabetes)

Exclusion Criteria:

* Persistent acute ST-segment elevation
* Successful revascularization during the qualifying hospitalization, prior to study entry
* Acute pulmonary edema, hypotension, or evidence of cardiogenic shock
* Clinically significant liver disease
* End stage kidney disease requiring dialysis
* Concomitant use of drugs known to prolong the QT interval, or any digitalis drugs
* Use at study entry of drugs that are strong inhibitors of cytochrome P450 3A4
* Pregnant or lactating women, or women of child bearing potential not using an acceptable form of birth control

Additional study entry criteria will be evaluated during initial screening.
C: Inclusion Criteria:

* Written informed consent
* Males and females aged at least 18 years
* At least a 3-month history of chronic stable angina triggered by physical effort and relieved by rest and/or sublingual nitroglycerin
* CAD documented by one or more of the following:

  1. Angiographic evidence of ≥ 50% stenosis of one or more major coronary arteries
  2. History of myocardial infarction (MI) documented by positive myocardial muscle creatine kinase (CK-MB) enzymes, troponins, or electrocardiogram (ECG) changes
  3. Cardiac imaging study or exercise test diagnostic for CAD
* Treatment with up to 2 antianginal therapies at a stable dose for at least 2 weeks prior to the Qualifying Period.
* Documented history of T2DM
* Willing to maintain stable tobacco usage habits throughout the study
* Willing to maintain stable activity levels throughout the study
* Females of childbearing potential must agree to utilize highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug.

Exclusion Criteria:

* New York Heart Association (NYHA) Class III and IV
* Acute coronary syndrome in the prior 2 months or planned coronary revascularization during the study period
* Stroke or transient ischemic attack within 6 months prior to Screening
* QTc \> 500 milliseconds
* Uncontrolled hypertension (seated systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg)
* Systolic blood pressure \< 100 mmHg
* Clinically significant hepatic impairment
* Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine
* Females who are breastfeeding
* Positive serum pregnancy test
* Participation in another investigational drug or device study within 1 month prior to Screening
* Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to the Qualifying Period.
* Current treatment with potent inhibitors of cytochrome (CYP)3A (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
* Current treatment with CYP3A and P glycoprotein (Pgp) inducers (eg, rifampicin/rifampin, carbamazepine, and St. John's wort \[Hypericum perforatum\])
* Current treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, and sirolimus)
* Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin
* Current treatment with Class I or III antiarrhythmic medications
* History of illicit drug use or alcohol abuse within 1 year of Screening
* Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study
D: Inclusion Criteria:

1. Women with signs and symptoms of myocardial ischemia (chest pain, abnormal stress testing, abnormal noninvasive testing) in the absence of obstructive coronary artery disease (epicardial coronary stenosis \<50% luminal diameter stenosis).
2. Women with ≥10% myocardial ischemia by CMR perfusion.

Exclusion Criteria:

1. Contraindications to withholding nitrates, beta-blockers, calcium channel agents, ACE/ARB agents for 48 hours prior to testing.
2. Contraindications in CMR including AICD, pacemaker, untreatable claustrophobia or known angio-edema.
3. Contraindications to ranolazine including hepatic insufficiency, prolonged QT, renal failure.
4. Women taking drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole, macrolides or HIV protease inhibitors.
5. Women less than 18 years of age.
6. Women on drugs that prolong the QT interval such as Class Ia or III antiarrhythmic agents, erythromycin, certain antipsychotics.
7. Pregnancy or breast feeding.
8. Life expectancy less than 6 months.

Answer: A