Abstract 16136: High-Fat Diet-Induced Obesity Induces Cardiac Hypertrophy and Augments Adaptive Cardiac ER Stress but does not Exacerbate Post-Infarction Remodeling in Mice
Although obesity increases the risk of developing heart failure (HF), obese subjects with HF have better clinical outcomes than lean subjects (the “obesity paradox”). The importance of metabolic abnormalities to this effect is unclear. We hypothesized that the metabolic changes of diet-induced obesity would not be sufficient to exacerbate post-infarction left ventricular (LV) remodeling. C57BL/6J mice fed a 45% kcal high fat diet (HFD) for 6 wk exhibited (p < 0.05) increased body weight (31.4±2.4 vs 26.9±1.3 g), fasting hyperglycemia (171± 33 vs 110± 21 mg/dl) and impaired glucose tolerance, and hyperinsulinemia as compared to mice fed normal diet (ND, 10% kcal fat). Although LV chamber size and systolic function by echocardiography were unchanged, HFD hearts exhibited myocyte hypertrophy (50% increase in ANF expression, p < 0.05), fibrosis, reduced adiponectin and increased cytokine expression, and augmented expression of endoplasmic reticulum (ER) chaperones Grp94 and calreticulin, but no increase in the pro-apoptotic ER stress protein CHOP. HFD and ND mice underwent sham surgery or coronary ligation to induce HF and were followed for 4 weeks. Compared to ND sham, ND HF hearts exhibited (p < 0.05): 1) LV dilatation (EDV 100±25 vs 47± 13 μL); 2) LV systolic dysfunction (LVEF 26±4 vs 63±3%); 3) interstitial fibrosis (12.0±6.3 vs 1.4±0.8%); 4) hypertrophy (myocyte area 337±61 vs 204±29 μm2); 5) apoptosis (1.8±0.3 vs. 0.3±0.04%), 6) hyperinsulinemia, and 7) increased cytokine gene expression and phosphorylation of JNK1/2. Surprisingly, compared to ND HF mice, HFD HF mice exhibited similar degrees of LV dilatation (EDV 102± 8 μL), dysfunction (LVEF 27±4%), fibrosis, hypertrophy, and apoptosis. However, as compared to HFD sham mice, HFD HF hearts exhibited no augmentation of hypertrophy, apoptosis, or pro-inflammatory cytokines, and showed normalization of adiponectin expression and JNK1 phosphorylation. We concluded that despite the induction of cardiac hypertrophy and inflammation, the metabolic abnormalities of diet-induced obesity are insufficient to exacerbate LV remodeling after infarction in mice. This may relate to the constitutive activation of adaptive ER stress in the heart, and may underlie the obesity paradox noted in human HF.
- © 2010 by American Heart Association, Inc.