Impact of Ranolazine on Myocardial Ischemia Detected by High-Field 3T Cardiovascular Magnetic Resonance (CMR) Imaging and P-31 Spectroscopy

Specific Aim:

To determine in patients with stable coronary artery disease with documented inducible
ischemia, if treatment with ranolazine leads to reduced intracellular ischemia as detected
by CMR perfusion imaging and 31P spectroscopy at 3 Tesla.

Abstract:

Despite many advances in cardiovascular medicine for patients with coronary artery disease
(CAD), many patients in the United States continue to have the morbidity and mortality
associated with chronic stable angina. Ranolazine is a novel late sodium current inhibitor
shown to be effective in treating angina in patients with chronic stable coronary artery
disease without affecting the blood pressure heart rate product. It has been shown to reduce
myocardial energy utilization by enhancing diastolic myocardial relaxation and possibly by
increasing myocardial blood flow. While ranolazine has been demonstrated to improve size and
severity of stress-induced myocardial perfusion defects, it's direct effect on myocardial
metabolism and cellular ischemia has not been tested in humans. We propose using cardiac
magnetic resonance imaging (CMRI) and phosphorous-31 magnetic resonance spectroscopy (31P
MRS) to evaluate patients with chronic stable angina before and after 4 weeks of a stable
dose of ranolazine to detect changes in myocardial blood flow, ventricular function,
myocardial scar and metabolic parameters of cellular ischemia.

Inclusion Criteria:

1. Age >18 years of age with stable angina pectoris or an anginal equivalent symptom
(e.g. atypical chest discomfort, dyspnea, easy fatigue) AND

2. Mild, moderate or severe myocardial ischemia detected on nuclear perfusion imaging
(exercise or pharmacologic SPECT or Rubidium PET), exercise stress echocardiography
or stress cardiac MRI OR Documentation of obstructive coronary artery with at least
one major coronary artery (left anterior descending, circumflex or right coronary
artery) of at least 70% by either conventional or CT coronary angiography.

Exclusion Criteria:

1. Acute coronary syndrome including unstable angina or non ST elevation myocardial
infarction within the last 60 days

2. ST-elevation myocardial infarction within 60 days

3. Equivocal myocardial ischemia on non-invasive testing or studies demonstrating
reversible perfusion defects complicated by significant attenuation artifacts.

4. Recent PCI within the last 60 days

5. Recent CABG within the last 60 days

6. Inability to sign informed consent

7. Patients who have taken ranolazine within 30 days of screening

8. Patients taking strong CYP3A inhibitors e.g. ketoconazole, itraconazole,
clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir

9. Patients taking inducers of CYP3A e.g. rifampin, rifabutin, rifapentine,
phenobarbital, phenytoin, carbamazepine, and St. John's wort

10. Patients with liver cirrhosis or liver disease that is Grade B or C by the Child-Pugh
Classification

11. Prior allergic reaction or intolerance to ranolazine

12. Patients with a history of inherited or acquired prolonged QT interval

13. Moderate to severe claustrophobia or previous inability to undergo an MRI exam

14. Patients with implanted pacemaker or internal cardiac defibrillator

15. Patients who have a metallic foreign body implants (metal silver in their eye,
cochlear implants) or have an aneurysm clip in their brain

16. GFR < 30 ml/m2

17. Type 2 second degree heart block (Mobitz II) in the absence of functioning permanent
pacemaker.

18. Sinus node dysfunction in the absence of functioning permanent pacemaker.

19. Patients taking dipyridamole therapy.

20. Active bronchospasm (active asthma or COPD with active wheezing.