This study investigates whether symptom-limited exercise capacity in ischemic cardiomyopathy patients with angina is deleteriously affected by treatment with CK-1827452.

The primary objective of this study is to assess the effect of intravenous (i.v.) CK-1827452 on symptom-limited exercise tolerance in patients with ischemic cardiomyopathy and angina. The secondary objectives are to assess the tolerability of CK-1827452 administered three times daily (tid) to steady state in an immediate-release (IR), blend-in-capsule oral formulation to outpatients with ischemic cardiomyopathy and angina and to assess CK-1827452 plasma concentrations at trough and 1 hour after dosing with CK-1827452 administered tid to steady state in an IR, blend-in-capsule oral formulation to outpatients with ischemic cardiomyopathy and angina.

Inclusion Criteria:

1. The patient has signed an Informed Consent Form/Patient Information Sheet for this study approved by the governing Institutional Review Board (IRB) or Independent Ethics Committee (IEC).

2. The patient is at least 18 years old.

3. The patient has ischemic heart disease documented by any one or more of the following:

   • A history of myocardial infarction documented by elevated CPK-MB, troponin I or T, or the presence of electrocardiographic Q waves consistent with myocardial infarction.
   • Coronary angiography demonstrating at least 1 major epicardial coronary artery (i.e., left main, left anterior descending, left circumflex, or right coronary artery) with a stenosis of at least 60% diameter or greater but excluding stenosis of the left main coronary artery unless revascularized by coronary artery bypass grafting.

4. The patient has a history of ≥ 1 episode of exercise induced angina within 2 months prior to the initial screening visit.

5. The patient has been taking a beta blocker and an ACE inhibitor (and/or an ARB) for at least 4 weeks. If prescribed, diuretics must have been administered for at least 4 weeks prior to the initial screening visit.

6. The patient is NYHA Class II-III at the time of enrollment and has been so for ≥ 3 months prior to the initial screening visit.

7. The patient has a history of a left ventricular ejection fraction (LVEF) ≤ 35%.

8. The patient has a history of EITHER a left ventricular end-diastolic diameter ≥ 55 mm, OR a left ventricular end-diastolic diameter index ≥ 32 mm/m2.

9. The patient can be expected to complete at least 4 minutes of a Modified Naughton ETT (see Appendix B).

10. For female patients only: The patient is post-menopausal (≥ 1 year) or sterilized, or if she is of childbearing potential, she is not breastfeeding, her pregnancy test is negative, she has no intention to become pregnant during the course of the study, and she is using contraceptive drugs or devices.

Exclusion Criteria:

1. The patient has acute myocarditis; clinically significant restrictive, constrictive, or hypertrophic obstructive cardiomyopathy; or clinically significant congenital heart disease.
2. The patient has a SBP > 160 mmHg, documented on at least 3 separate occasions, at least 10 minutes apart.
3. The patient has a DBP > 90 mmHg, documented on at least 3 separate occasions, at least 10 minutes apart.
4. The patient has levels of troponin I or T, or CPK-MB > the upper limit of normal at any time from 6 weeks prior to the Initial Screening Visit (Visit 1) and up to randomization.
5. The patient has severe aortic or mitral stenosis.
6. The patient has had an acute coronary syndrome, transient ischemic attack, or revascularization procedure within 6 weeks of the Initial Screening Visit (Visit 1).
7. The patient has significant co-morbid conditions (i.e., lung disease, arthritis, peripheral vascular disease) that may limit his or her treadmill exercise capacity.
8. The patient has renal impairment defined by a calculated creatinine clearance < 30 cc/min or a need for renal replacement therapy.
9. The patient has known hepatic impairment defined by a total bilirubin > 3 mg/dL, or an ALT or AST > 2 times the upper limit of normal.
10. The patient has received an investigational drug or device within 30 days or 5 half-lives, whichever is greater, of randomization.
11. The patient weighs > 120 kg.
12. The patient has a body temperature > 38 ° C, confirmed by at least 2 successive measurements, at least 10 minutes apart.
13. The patient has any laboratory abnormality which, in the opinion of the investigator, should preclude his or her participation in the study.
14. The patient has had any prior treatment with CK-1827452.