Regression of Myocardial Steatosis by Nebivolol

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.