Regression of Fatty Heart by Valsartan Therapy

Condition(s) targeted: Metabolic Syndrome; Lipotoxicity

Intervention: Valsartan (Drug); Hydrochlorothiazide (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: University of Texas Southwestern Medical Center

Official(s) and/or principal investigator(s):
Ronald G Victor, MD, Principal Investigator, Affiliation: University of Texas Southwestern Medical Center
Lidia S Szczepaniak, PhD, Study Director, Affiliation: University of Texas Southwestern Medical Center

Overall contact:
Angela L Price, MD, Phone: 214.648.0335, Email: Angela.Price@UTSouthwestern.edu

Traditionally, obesity is considered an indirect cause of heart disease. Obese individuals typically present with a number of traditional Framingham risk factors (hypertension, dyslipidemia, and type 2 diabetes), predisposing them to heart attacks and subsequent heart failure. However, an emerging body of basic research revisits a hypothesis that fat is a direct cardiotoxin. Under healthy conditions, most triglyceride is stored in fatty tissue (adipocytes) while the amount of triglyceride stored in non-adipocyte tissues (such as the pancreas, the liver, skeletal muscle, and heart) is minimal and very tightly regulated. When this regulation is disrupted, intracellular triglyceride accumulates excessively in these organs ("steatosis") and has been implicated in activating adverse pathways which culminate in irreversible cell death ("lipotoxicity"), leading to several well-recognized clinical syndromes. These include non-alcoholic steatohepatitis (NASH), pancreatic beta-cell failure in type 2 diabetes, and dilated cardiomyopathy. It has been recently observed that angiotensin II receptor blockers (ARBs) in addition to lowering blood pressure improve insulin sensitivity and decrease the risk for type 2 diabetes. This study will test the above theory in two study groups: Valsartan vs. Hydrochlorothiazide. We hypothesize that in obese humans with elevated myocardial triglycerides, blockade of the renin-angiotensin system (Valsartan group) will reduce myocardial fat with improvement of insulin sensitivity and heart function.

Official title: Regression of Fatty Heart by Valsartan Therapy

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Myocardial triglyceride levels

Secondary outcome: Hepatic triglyceride levels, insulin sensitivity, abdominal fat mass

Detailed description: Basic science in animal models of genetic obesity have demonstrated that obese, insulin resistant animals have fatty hearts with reduced functional ability. More importantly, insulin sensitizing treatment of prediabetic rats delayed development of diabetes and improved heart function. A primary aim of our laboratory is to translate basic animal research, suggesting that excessive lipid accumulation in the myocardium is toxic, into the clinical setting using cardiac magnetic resonance imaging/spectroscopy technology. The results of this research may identify new biomarkers and drug targets to prevent cardiac disease in obese humans. We used our novel in vivo magnetic resonance imaging and spectroscopy technique that enables quantification of triglyceride in human myocardium non-invasively, to demonstrate that obese humans like obese animals are characterized by elevated fat in myocardium. We hypothesize that in obese humans with elevated myocardial TG, blockade of the renin-angiotensin system will reduce myocardial fat with improvement of insulin sensitivity and heart function. The aims of this study are to test if in obese people with impaired glucose tolerance (IGT): Aim 1) Valsartan treatment will reduce myocardial fat and will improve heart geometry and function, Aim 2) therapy with thiazide diuretic hydrochlorothiazide (HCTZ) treatment will elevate myocardial fat. We are planning to test the action of Valsartan versus HCTZ as we expect that these drugs cause opposite metabolic effects. The landmark trial ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) has refocused attention to the thiazide-type diuretics as the first-line therapy for most patients with hypertension. Despite proven reduction in cardiovascular outcomes and low costs, there is on-going concern that one of the major side effect of the thiazides—glucose intolerance—may fuel the current U. S. epidemic of type 2 diabetes. Despite of efficacy and low cost thiazide diuretics are long known to cause insulin resistance, impaired glucose tolerance, and precipitation of overt diabetes.

Minimum age: 18 Years. Maximum age: 50 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Prediabetic individuals with impaired glucose tolerance (2 hr postprandial glucose >

140mg/dL) or having 3 of 5 Metabolic Syndrome criteria: 1. Fasting glucose > 100mg/dL; 2. Waist circumference: men > 102cm, women > 88cm (confirmed with abdominal MRI); 3. HDL: men < 40mg/dL, women < 50mg/dL; 4. Triglycerides > 150mg/dL; 5. Blood pressure > 130/80mmHg;

- Elevated hepatic triglycerides (>5. 5%) and myocardial triglycerides (>0. 6%)

- Elevated blood triglycerides >150mg/dL

- Age < 50 years

Exclusion Criteria:

- Type 2 Diabetes mellitus

- Prior exposure to renin system blockers or HCTZ

- BP > 160/100mmHg

- Claustrophobia

- Metallic implants in body

- Pregnant or planning to become pregnant

- Prior exposure to statin medications

Angela L Price, MD, Phone: 214.648.0335, Email: Angela.Price@UTSouthwestern.edu

University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States; Recruiting

Starting date: August 2007
Last updated: August 17, 2009