CLCNKA (Ka Renal Chloride Channel[ClC-Ka]) Polymorphism Effects on Hypertrophy Regression

This study will consist of middle-aged Caucasian non-failing subjects with high blood pressure who are homozygous for a gene that confers increased risk of developing heart failure, the Glycine 83 variant of the Ka renal chloride channel (ClC-Ka Gly/Gly 83), or middle-aged Caucasian non-failing hypertensive subjects who lack the heart failure risk gene, the wild-type Arginine 83 Ka renal chloride channel (ClC-Ka Arg/Arg 83). Subjects on standard therapy for high blood pressure with an angiotensin converting inhibitor (ACEI) or angiotensin receptor blocker (ARB) will be randomized to additional treatment with eplerenone (an aldosterone antagonist) or placebo, and assessed for changes in echocardiographic left ventricular hypertrophy (LVMI). Secondary endpoints will assess left ventricular remodeling and other echocardiographic variables. The investigators hypothesize that subjects homozygous for the CLCNKA risk allele will have a greater response to eplerenone in terms of reductions in LVMI than those lacking the risk allele.

The screening phase will involve identifying Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 and the ClC-Ka Arg/Arg 83 allele. All patients will be on background therapy with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at least mid range dosing. If patient is not at recommended dose of ACE or ARB they must be titrated up and be stable on a midrange dose of ACEI or ARB for at least 4 weeks before they can be entered into the study. There will be 2 treatment phases. Phase 1 will be up to 4 weeks in duration and will consist of randomization to one table of eplerenone (25 mg) or matching placebo. On week 2 the patient will be up titrated to two tablets of eplerenone (50 mg) or matching placebo, to achieve a target dose of 50 mg of eplerenone. If the patient cannot tolerate two tablets of eplerenone or matching placebo they can be down titrated to one tablet of eplerenone or matching placebo. The target BP on study medication is \< 130/80 mmHg. After the patients have been up titrated to the maximally tolerated dose of study medication, the background hypertension therapy can be adjusted to reach the target BP of \< 130/80 mmHg by the end of week 4. Phase 2 will be 52 weeks in duration to assess the effects of placebo or eplerenone on LV hypertrophy. Serum potassium will be monitored throughout the study, and if necessary, doses of eplerenone will be titrated down as necessary.

Eligibility Criteria:
Inclusion Criteria:

1. Caucasians with hypertension who are homozygous for the ClC-Ka Gly/Gly83 and the ClC-Ka Arg/Arg 83 allele.
2. Male or non-pregnant female aged 40 to 80 years.
3. Hypertension, defined as currently taking high blood pressure medications or not on medications but having SDP \>140 or DBP \>90.
4. Ejection fraction \> 50% by any method within 6 months of the screening visit.
5. The Investigator must obtain written informed consent before the subject is screened for the study.
6. Subject should be on stable dose of ACE or ARB at moderate dosing for at least 4 weeks before randomization.

Exclusion Criteria:

1. History of heart failure with preserved or depressed ejection fraction.
2. Creatinine clearance of \< 45 mL/min based on the Cockcroft-Gault formula (Appendix C).
3. Pregnancy
4. Life expectancy less than 12 months.
5. Planned cardiac surgery or percutaneous cardiac intervention within 3 months.
6. Serum potassium \>5.5 mEq/L.
7. History of hyperkalemia (K\>6.0 mEq/L) with eplerenone or spironolactone.
8. Myocardial infarction or stroke within 3 months of screening.
9. Evidence of clinical instability (hypotension, arrhythmias, unstable angina etc.).
10. Subjects on or requiring K-sparing diuretics or spironolactone.
11. Concomitant use of potent inhibitors of CYP3A4 including ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir or any drug noted in the Contraindications, Warnings or Precautions sections of their labeling to be potent CYP3A4 inhibitors
12. Known hypersensitivity to eplerenone or spironolactone.
13. Evidence of current alcohol or drug abuse Severe organic disorders or surgery or disease of the gastrointestinal tract that in the opinion of the Investigator may interfere in the absorption and elimination of the study drug.
14. Psychoses or behavioral conditions that in the opinion of the Investigator would limit study compliance.
15. Subjects who have received any investigational medication or used any investigational device within 30 days prior to first dose of study drug or subjects actively participating in any investigational drug or device study.