CR Aim #2 - AT1 Receptor Blockade & ACE Inhibition Effect on Humoral Function

To advance our understanding of the mechanisms of human cardiorenal syndrome with emphasis upon the interaction of diuretic therapy and the renal-angiotensin-aldosterone -system and cGMP pathway.

The belief is that the chronic AT1 receptor blockade in subjects with compensated CHF and renal dysfunction will improve renal function with increased sodium excretion, glomerular filtration rate and effective renal plasma flow and renal function reserve as compared to the response of placebo-treated subjects.

IRB # 09-003284, "Specific Aims 2: Define in humans with compensated CHF and renal dysfunction, the modulating action of chronic AT1 receptor blockade in addition to ACE inhibition on cardiorenal and humoral function", involving 12 weeks of study drug (Candesartan or placebo) starting at 4 mg daily and doubling every 2 weeks to 16 mg, if tolerated. Safety labs are performed one week after each dose increase (end of weeks 1, 3 and 5), and in week 10 of the study. Participants are monitoring their blood pressure weekly, and are aware to watch for symptoms of hypotension (lightheadedness, dizziness, blurred vision). Renal clearance testing and ECHO are performed at the start and end of the 12 weeks of study medication in the 5-Domitilla Clinical Research Unit.

Eligibility Criteria:
Inclusion Criteria:

* Left ventricular ejection fraction of equal or less than 40% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 48 months.
* Stable New York Heart Association (NYHA) class II and III symptoms as defined by: no change in NYHA symptoms over the past 3 months, on stable doses of ACE inhibitor, beta blocker, digoxin and furosemide over the last 4 weeks and no episode of decompensated CHF over the past 6 months.
* Calculated creatinine clearance of equal or less than 80 ml/min and greater than 20 ml/min, using the MDRD formula assessed within the past 48 months and a confirmatory calculated creatinine clearance equal or less than 80 ml/min and greater than 20 ml/min at the time of enrollment.

Subjects who are already taking AT1 receptor blocker will be excluded. Aldosterone antagonist, antiarrhythmic medications and other vasodilators will be allowed; however, all medications must be at stable doses 4 weeks prior to enrollment. Subjects taking nonsteroidal anti-inflammatory drugs (NSAIDs) except aspirin will not be able to increase their medication dose for the duration of the study. Subjects will be excluded if they have had a prior diagnosis of intrinsic renal disease, including renal artery stenosis of \> 50%, or if they meet any one of the exclusion criteria listed below.

Exclusion Criteria:

* Prior diagnosis of intrinsic renal diseases including renal artery stenosis of \> 50%
* Peritoneal or hemodialysis within 90 days or anticipation that dialysis or ultrafiltration of any form will be required during the study period
* Hospitalization for decompensated CHF during the past 6 months
* Subjects that are taking AT1 receptor blockers
* Myocardial infarction within 6 months of screening
* Unstable angina within 6 months of screening, or any evidence of myocardial ischemia
* Significant valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis
* Severe congenital heart diseases
* Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening
* Second or third degree heart block without a permanent cardiac pacemaker
* Stroke within 3 months of screening, or other evidence of significantly compromised CNS perfusion
* ALT \>1.5 times the upper limit of normal
* Serum sodium of \< 125 mEq/dL or \> 160 mEq/dL
* Serum potassium of \< 3.5 mEq/dL or \> 5.7 mEq/dL
* Serum digoxin level of \> 2.0 ng/ml
* Hemoglobin \< 9 gm/dl
* Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data
* Received an investigational drug within 1 month prior to dosing
* Patients with an allergy to iodine.
* Female subject who is pregnant or breastfeeding
* In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons