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.

The metabolic syndrome induces early changes in the swine renal medullary mitochondria

“…Future studies are needed to test whether MetS-induced renal changes and the renoprotective properties of ELAM are observed in conscious pigs. Despite increased RBF and GFR in MetS pigs, PRA levels remain unchanged in MetS, consistent with our previous findings in swine obesity (51) and renovascular disease (52). ELAM did not affect PRA levels, arguing against regulation of the systemic renin/angiotensin system, consistent with our previous finding that ELAM does not directly regulate vascular tone (13).…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…In a rodent model of obesity associated with metabolic syndrome and hypertension, infiltration of the myocardium with macrophages was observed (57). In a porcine model, obesity associated with metabolic dysfunction induced an increase in infiltration with pro-inflammatory M1 macrophages and accentuated cardiac fibrosis in regions perfused by a stenotic coronary artery (58). Whether increased macrophage infiltration in obesity and diabetes plays a crucial role in mediating the myocardial fibrotic response, or simply represents an epiphenomenon, remains unknown.…”

Ossabaw Pigs With a PCSK9 Gain‐of‐Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies

“…To evaluate cardiac function and microvascular function, MDCT (SomatomFlash‐128; Siemens Medical Solution, Forchheim, Germany) images were acquired and analyzed using Analyze (Biomedical Imaging Resource, Mayo Clinic), as shown previously . A 50‐second flow scan followed a bolus injection of the contrast medium iopamidol (0.33 mL/kg over 2 seconds) into the right atrium to evaluate myocardial perfusion in the lateral left ventricular (LV) wall . Subsequently, the entire LV was scanned 20 times at multilevels throughout the cardiac cycle for measurement of indexes of LV systolic (cardiac output and LV ejection fraction) and diastolic (E/A ratio) function, as well as LV muscle mass.…”

“…Subsequently, the entire LV was scanned 20 times at multilevels throughout the cardiac cycle for measurement of indexes of LV systolic (cardiac output and LV ejection fraction) and diastolic (E/A ratio) function, as well as LV muscle mass. Cardiac volume and pericardial fat (density between −190 and −30 Hounsfield units) were then traced manually at each cross‐section, as shown . Pericardial fat was assessed as adipose tissue enclosed by the visceral pericardium, expressed as a fraction of cardiac volume.…”