Reversing Endothelial and Diastolic Dysfunction and Improving Collagen Turnover in Diastolic Heart Failure

The principle aim is to determine the efficacy of eplerenone in patients with diastolic heart failure to reverse cardiac remodeling and to improve diastolic function.

The study will be a single center, double-blind, randomized, parallel group trial enrolling a minimum of 80 patients designed to determine the efficacy of eplerenone in subjects with diastolic heart failure. Prior to administration of study medication, a medical history, physical exam, blood draw, electrocardiogram, 2D echocardiogram, and cardiomyopathy questionnaire will be performed. Subjects will then be randomized to receive either eplerenone 25 mg once daily or placebo for 2 weeks. At the Week 2 visit all patients will be titrated up to the next dose (50 mg eplerenone once daily or placebo). Each study arm will have 40 subjects who will participate for 9 months. Follow-up assessments will be completed at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 9 months.

Starting at the Month 1 visit, any subjects with uncontrolled blood pressure will be administered add-on therapy of HCTZ (starting dose of 12.5 mg daily, that may titrate up to 25 mg daily) and/or amlodipine (starting dose at 5 mg daily, that may titrate up to 10 mg daily). Any subject who receives add-on therapy must have their blood pressure checked within 2 weeks. Uncontrolled blood pressure may be treated by either increasing the add-on therapy dose or increasing the add-on therapy regimen to include both add-on drugs. Changes in add-on therapy require blood pressure checks within 2 weeks.

Eligibility Criteria:
Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:

1. Male or non-pregnant female (if female, either post-menopausal, or if of child-bearing potential, using adequate contraception e.g. hormonal or barrier methods, or surgically sterile, and not lactating)
2. Age \>/= 18 years of age
3. Present or prior history of symptoms of heart failure (dyspnea, fatigue) consistent with diagnosis of diastolic heart failure, following optimized medical therapy including blood pressure control with ACE inhibitors and/or beta-blockers for 2 weeks or over.
4. Echocardiographic evidence of preserved left ventricular systolic function (LVEF \>/= 45%) and evidence of diastolic dysfunction (by transmitral inflow, pulmonary venous flow, color M-mode and/or tissue Doppler).
5. Signed informed consent

Exclusion Criteria:

The presence of any of the following will exclude a patient from study enrollment:

1. Unwilling to participate for the 9-month duration of the study
2. Significant primary valvular, pulmonary or congenital cardiac disease believed to be the cause of dyspnea
3. Life expectancy or planned cardiac transplantation \<9 months
4. History of hypertrophic obstructive cardiomyopathy
5. Unstable angina or ischemia requiring revascularization
6. Renal insufficiency (Cr \>2.0 mg/dL in males and \>1.8 mg/dl in females, or modified Cockcroft-Gault estimate of creatinine clearance \<30 mL/min) at enrollment
7. Known hypersensitivity to spironolactone or eplerenone
8. Decompensated heart failure or clinical evidence of instability at the time of enrollment 9 History of hyperkalemia (\>6.0 mg/dL) with spironolactone

10. Use of spironolactone or amiloride within 30 days 11. Poorly controlled seating blood pressure at the time of drug initiation:

* Systolic blood pressure \>160 mmHg; and/or
* Diastolic blood pressure \>100 mmHg