Cardiac Steatosis and Lipotoxicity Clinical Trial
Official title:
Regression of Myocardial Steatosis by Nebivolol
Within large number of patients with obesity, it is crucial to determine who is at the greatest risk for development of chronic heart disease. The investigators previous studies suggest that an excessive accumulation of fat in heart cells precedes the development of obesity-related pathologies and may serve as a biomarker of heart disease in high-risk population. Until now, the evaluation of fat in the human heart was possible postmortem or by biopsy. The investigators novel magnetic resonance spectroscopy technique enables the quantification of intracellular lipid content non-invasively and repeatedly in humans in vivo. It could be used to better screen and treat obese patients at risk for the development of metabolic disease. The investigators hypothesize that in obese humans with elevated myocardial triglycerides, treatment with Nebivolol will reduce myocardial fat and will improve heart function.
Background:
Epidemiological data have provided abundant evidence showing that obesity is a major risk
factor for cardiovascular morbidity and mortality, although the exact mechanisms remain
incompletely understood. Traditionally, obesity is thought to indirectly increase
cardiovascular risk by means of its intermediary effects; obesity increases the risk of
hypertension, dyslipidemia, and diabetes mellitus, thereby increasing one's overall risk for
cardiovascular disease. In contrast to this traditional view, a growing body of research from
our group and others advanced the novel hypothesis that ectopic myocardial fat deposition
directly damages the heart. Lipid deposition and overload in the myocardium, termed "cardiac
steatosis", is directly toxic to cardiac myocytes.
Deposition of lipid droplets in non-adipocytes (Steatosis): Normally, most of the
triglycerides in the body are stored in adipose tissue with little to no lipid accumulation
in non-adipocytes (e.g. parenchymal cells of the liver, pancreas, and muscle) due to a
balance between fatty acid uptake and oxidation. When this mechanism is defective, fat
accumulates in non-adipocytes. This abnormal retention of lipid within non-adipose tissues
such as heart, liver, pancrease, and skeletal muscle is known as "steatosis" and reflects an
impairment of the normal synthesis and elimination of triglyceride. This was first
demonstrated in pancreatic β-cells of obese Zucker rats, a genetic model of obesity.
The intracellular accumulation of long chain free fatty acids (FFA) is hypothesized to engage
an adverse signaling cascade in which conversion to Ceramide stimulates inducible nitric
oxide synthase (iNOS), eventually leading to apoptosis. Progressive apoptosis of lipid-laden
pancreatic β-cells over time eventually leads to insulin deficiency. A combination of β-cell
failure and insulin resistance has produced diabetes in this animal model. More importantly,
the pancreatic steatosis in pre-diabetic Zucker rats and the accompanying metabolic
abnormalities were shown to be effectively reversed by the PPAR-Ƴ antagonist, Troglitazone.
The next logical step was to ask if similar mechanisms lead to deposition of lipid droplets
within cardiomyocytes. Indeed, prediabetic obese Zucker rats deposit fat into cardiomyocytes;
whereas, lean rats do not deposit fat in cardiomyocytes. Furthermore, the obese Zucker rats
have progressive left ventricular systolic dysfunction, presumably due to excessive lipid
deposition and toxicity, as dysfunction occurs before the onset of frank diabetes. In human
studies, MR spectroscopy allows non-invasive evaluation of the number and size of lipid
droplets in cardiomyocytes. Similar to the rodent studies, our group has demonstrated a
strong linear relationship between triglyceride deposition in the myocardium and LV
concentricity and function.
Nebivolol and its role in myocardial steatosis regression: Nebivolol (Bystolic® by
Forest/Mylan)through its various modes of action has an exquisite ability to regress cardiac
steatosis on many different levels. We propose a novel mechanism of Nebivolol action that
results in reduction of myocardial steatosis.
Specific aims: This investigation will study whether: 1) cardiac steatosis plays a pivotal
role in the early pathogenesis of obesity-related adverse cardiac remodeling in humans, 2)
Nebivolol improves cardiac remodeling via its unique metabolic ability to reduce cardiac
steatosis above and beyond its effect on hemodynamic cardiac remodeling due to blood pressure
reduction.
Study Design and Hypotheses: Before and after six months of low dose (10 mg daily) Nebivolol
treatment, localized proton MR spectroscopy (to measure triglyceride content in myocytes, as
well as liver, pancreas and skeletal muscle) and cardiac MRI (for structural and functional
measurements of the left ventricle) will be performed. Additionally, we will study abdominal
subcutaneous fat levels over the six month period (MRI and Bioimpedance).
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