In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non-ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non-ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non-ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) -regulated genes, myosin heavy chain beta (MHC-beta), and tumor necrosis factor alpha (TNF-alpha). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.

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Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH.

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Background-An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-␣ is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-␣ expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-␣ expression in human failing myocardium. Methods and Results-Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-␣, and quantitative analysis of the stained area was performed. We found that TNF-␣ content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-␣ content were found in patients who were successfully weaned off the LVAD who did not require transplantation. Conclusions-These data show for the first time that chronic mechanical circulatory assistance decreases TNF-␣ content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.