Metabolic Syndrome Clinical Trial
Official title:
Regression of Fatty Heart by Valsartan Therapy
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.
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.
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