RANOLAZINE STUDY: Speckle Tracking Derived Myocardial Strain

Many cardiac patients with severe coronary artery disease have areas of ischemic LV
myocardium that cannot be revascularized (Non-R). The investigators propose to identify such
patients via retrospective case review of CMRI data, as well as identify the exact regions
which specify Non-R coronary anatomy. This selected study group will have a specific
echocardiographic imaging protocol performed, which includes the known ischemic regions. All
segments will be collected and analyzed as a pre-therapeutic baseline using specialized STE
software to derive strain values. Following eight (8) weeks of ranolazine therapy, each
subject will be re-interrogated with the same echocardiographic imaging protocol and have
identical measurements of regional strain performed. Ranolazine will be added to the
patients' usual medical therapy. Each patient will serve as their own control, from baseline
to post therapeutic state.

It is the hypothesis of the investigators, that additional therapeutic dosing of ranolazine
will improve regional and perhaps global myocardial function. Improvement in LV mechanical
function (regional and global) will be quantitated and objectively elucidated by STE derived
myocardial strain as described further in this document.

Inclusion Criteria:

- age > 18 Stable GDMT for 60 days prior to enrollment Normal sinus rhythm Coronary
artery revascularization > 60 days prior to enrollment Non-revascularizable area of
myocardial ischemia as determined by stress MRI Able to perform the bicycle stress
echocardiograms Able to provide written, informed consent Women of childbearing
potential with negative pregnancy test at the index visit, and consent to use
effective contraception throughout the study period and up to at least 14 days
following the last dose of study drug

Exclusion Criteria:

- More than 1+MR, aortic stenosis, aortic insufficiency, mitral stenosis Serious
co-morbidities with predicted life expectancy <1 year Patients not in normal sinus
rhythm (NSR) Patients who have undergone coronary artery revascularization (PCI, CABG)
within 60 days Pregnant or unknown pregnancy status Liver cirrhosis Patients
unwilling/unable to provide written, informed consent Concomitant use of QTc
prolonging drugs, potassium channel variants resulting in a long QT interval, patients
with a family history of (or congenital) long QT syndrome, and patients with known
acquired QT interval prolongation Concomitant use of strong CYP3A inhibitors including
ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir,
indinavir, and saquinavir Concomitant use of CYP3A4 inducers such as rifampin,
rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort
Breast feeding Atrial fibrillation or frequent atrial or ventricular ectopy Moderate
CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) P-gp inhibitors (e.g.,
cyclosporine) which increase ranolazine exposure Renal failure. Patients with
Creatinine clearance less than 30ml/min . Safety Considerations for patients with the
following drugs/conditions CYP3A substrates: Limit simvastatin to 20 mg when used with
ranolazine. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A
substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus)
may need to be reduced with ranolazine OCT2 substrates: Limit the dose of metformin to
1700 mg daily when used with ranolazine 1000 mg twice daily. Doses of other OCT2
substrates may require adjusted doses Drugs transported by P-gp (e.g., digoxin), or
drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses
when used with ranolazine Renal failure: Patients with creatinine clearance less than
30ml/min are excluded from participation in this study. Monitor renal function after
initiation and periodically in patients with moderate to severe renal impairment (CrCL
< 60 mL/min). If acute renal failure develops, discontinue ranolazine.