This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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 myocardial infarction and ischemic cardiomyopathy. In addition to an elevated Framingham risk score, the hemodynamic hallmark of obesity is a hyperdynamic circulation (increased heart rate and stroke volume). It is thought to be a compensatory adaptation to increased adipose mass at the expense of eccentric left ventricular remodeling. In extreme obesity hyperdynamic circulation progresses to non-ischemic dilated cardiomyopathy.In contrast to these rather traditional concepts, an emerging body of basic research revisits a hypothesis that fat is a direct cardiotoxin. Under healthy conditions, most trigylceride is stored in adipocytes while the amount of triglyceride stored in non-adipocyte tissues (such as the pancreas, the liver, skeletal muscle, and the myocardium) is minimal and very tightly regulated. When this regulation is disrupted, cytosolic triglyceride accumulates excessively in these organs ('steatosis') and has been implicated in activating adverse signaling cascades culminating 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.Initial studies in our laboratory revealed that human obesity and type 2 diabetes are characterized by elevated myocardial triglyceride levels; however, the relationship between myocardial triglyceride levels and cardiac performance remains unclear. The primary aim of this proposal is therefore to determine the influence of myocardial triglyceride content on left ventricular performance in humans.
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