title: Obesity-metabolic derangement exacerbates cardiomyocyte loss distal to moderate coronary artery stenosis in pigs without affecting global cardiac function.
abstract: Obesity associated with metabolic derangements (ObM) worsens the prognosis of patients with coronary artery stenosis (CAS), but the underlying cardiac pathophysiologic mechanisms remain elusive. We tested the hypothesis that ObM exacerbates cardiomyocyte loss distal to moderate CAS. Obesity-prone pigs were randomized to four groups (n = 6 each): lean-sham, ObM-sham, lean-CAS, and ObM-CAS. Lean and ObM pigs were maintained on a 12-wk standard or atherogenic diet, respectively, and left circumflex CAS was then induced by placing local-irritant coils. Cardiac structure, function, and myocardial oxygenation were assessed 4 wk later by computed-tomography and blood oxygenation level dependent (BOLD) MRI, the microcirculation with micro-computed-tomography, and injury mechanisms by immunoblotting and histology. ObM pigs showed obesity, dyslipidemia, and insulin resistance. The degree of CAS (range, 50-70%) was similar in lean and ObM pigs, and resting myocardial perfusion and global cardiac function remained unchanged. Increased angiogenesis distal to the moderate CAS observed in lean was attenuated in ObM pigs, which also showed microvascular dysfunction and increased inflammation (M1-macrophages, TNF-α expression), oxidative stress (gp91), hypoxia (BOLD-MRI), and fibrosis (Sirius-red and trichrome). Furthermore, lean-CAS showed increased myocardial autophagy, which was blunted in ObM pigs (downregulated expression of unc-51-like kinase-1 and autophagy-related gene-12; P < 0.05 vs. lean CAS) and associated with marked apoptosis. The interaction diet xstenosis synergistically inhibited angiogenic, autophagic, and fibrogenic activities. ObM exacerbates structural and functional myocardial injury distal to moderate CAS with preserved myocardial perfusion, possibly due to impaired cardiomyocyte turnover.
authors: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors: Zi-Lun
authors: ZL
authors: Li
authors: Behzad
authors: B
authors: Ebrahimi
authors: Xin
authors: X
authors: Zhang
authors: Alfonso
authors: A
authors: Eirin
authors: John R
authors: JR
authors: Woollard
authors: Hui
authors: H
authors: Tang
authors: Amir
authors: A
authors: Lerman
authors: Shen-Ming
authors: SM
authors: Wang
authors: Lilach O
authors: LO
authors: Lerman
mesh_terms: D050154:Adiposity; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D003326:Coronary Circulation; D023921:Coronary Stenosis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005355:Fibrosis; D006439:Hemodynamics; D006949:Hyperlipidemias / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008833:Microcirculation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D013552:Swine; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators
keywords: apoptosis; autophagy; inflammation