The causal relationship between obesity and heart failure is broadly acknowledged; however, the pathophysiological mechanisms involved remain unclear. Besides hemodynamic changes, an alternative mechanism of cardiomyocytes apoptosis secondary to intracellular lipid accumulation has been proposed. However, this seems to be valid only for severe obesity but may not explain the increase in heart failure risk with mild-to-moderate overweight. Since adipocytes secrete a wide variety of factors with autocrine, paracrine and/or endocrine action, we tested whether human adipocytes produce cardioactive substances that directly and acutely affect cardiomyocyte contractility. We cultivated adipocytes obtained from human white adipose tissue, and incubated isolated rat adult cardiomyocytes with adipocyte-conditioned or control medium. The study was approved by the local ethical committee. This is the first report to demonstrate that human adipocytes exhibit cardiodepressant activity with a direct and acute effect on cardiomyocyte contraction. This adipocyte-derived negative inotropic activity directly depressed shortening amplitude as well as intracellular systolic peak Ca2+ in cardiomyocytes within a few minutes. The adipocyte-derived cardiodepressant activity was dose-dependent, and was completely blunted by heating. Filtration of adipocyte-conditioned medium based on molecular mass characterized the cardiodepressant activity at between 10 and 30 kDa. In summary, our data demonstrate that adipocytes exert a hitherto unknown negative inotropic effect, depressing cardiac contraction by reducing intracellular Ca2+. These findings suggest a direct involvement of adipose tissue in the pathogenesis of myocardium dysfunction, thus explaining the tight association between obesity and heart failure.
01 - 05 Apr 2006
European Society of Endocrinology