BackgroundIn humans there is a positive association between epicardial adipose tissue (EAT) volume and coronary atherosclerosis (CAD) burden. We tested the hypothesis that EAT contributes locally to CAD in a pig model.MethodsOssabaw miniature swine (n = 9) were fed an atherogenic diet for 6 months to produce CAD. A 15 mm length by 3–5 mm width coronary EAT (cEAT) resection was performed over the middle segment of the left anterior descending artery (LAD) 15 mm distal to the left main bifurcation. Pigs recovered for 3 months on atherogenic diet. Intravascular ultrasound (IVUS) was performed in the LAD to quantify atheroma immediately after adipectomy and was repeated after recovery before sacrifice. Coronary wall biopsies were stained immunohistochemically for atherosclerosis markers and cytokines and cEAT was assayed for atherosclerosis-related genes by RT-PCR. Total EAT volume was measured by non-contrast CT before each IVUS.ResultsCircumferential plaque length increased (p < 0.05) in the proximal and distal LAD segments from baseline until sacrifice whereas plaque length in the middle LAD segment underneath the adipectomy site did not increase. T-cadherin, scavenger receptor A and adiponectin were reduced in the intramural middle LAD. Relative to control pigs without CAD, 11β-hydroxysteroid dehydrogenase (11βHSD-1), CCL19, CCL21, prostaglandin D2 synthase, gp91phox [NADPH oxidase], VEGF, VEGFGR1, and angiotensinogen mRNAs were up-regulated in cEAT. EAT volume increased over 3 months.ConclusionIn pigs used as their own controls, resection of cEAT decreased the progression of CAD, suggesting that cEAT may exacerbate coronary atherosclerosis.

Background and Aims Coronary artery disease (CAD) is progressive, classified by stages of severity. Alterations in Ca2+ regulation within coronary smooth muscle (CSM) cells in metabolic syndrome (MetS) have been observed, but there is a lack of data in relatively early (mild) and late (severe) stages of CAD. The current study examined alterations in CSM Ca2+ regulation at several time points during CAD progression. Methods MetS was induced by feeding an excess calorie atherogenic diet for 6, 9, or 12 months and compared to age-matched lean controls. CAD was measured with intravascular ultrasound (IVUS). Intracellular Ca2+ was assessed with fura-2. Results IVUS revealed that the extent of atherosclerotic CAD correlated with the duration on atherogenic diet. Fura-2 imaging of intracellular Ca2+ in CSM cells revealed heightened Ca2+ signaling at 9 months on diet, compared to 6 and 12 months, and to age-matched lean controls. Isolated coronary artery rings from swine fed for 9 months followed the same pattern, developing greater tension to depolarization, compared to 6 and 12 months (6 months= 1.8±0.6 g, 9 months= 5.0±1.0 g, 12 months= 0.7±0.1 g). CSM in severe atherosclerotic plaques showed dampened Ca2+ regulation and decreased proliferation compared to CSM from the wall. Conclusions These CSM Ca2+ regulation data from several time points in CAD progression and severity help to resolve the controversy regarding up- vs. down-regulation of CSM Ca2+ regulation in previous reports. These data are consistent with the hypothesis that alterations in sarcoplasmic reticulum Ca2+ contribute to progression of atherosclerotic CAD in MetS.

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Introduction: Low-energy proximal femur fractures are common in the aging population and the ability to identify patients at increased mortality risk provides surgeons information to improve informed decision-making with patients and families. We evaluated for gender differences in 1-year mortality after sustaining low-energy proximal femur fractures with subgroup analysis to identify the impact of fracture location, age, and comorbidities on mortality. Materials and Methods: Patients ≥40 years of age sustaining a low-energy proximal femur fracture identified at our institution between January 1, 2014, and December 31, 2017. International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes were used to identify comorbidities for calculation of the age-adjusted Charlson comorbidity index (ACCI). The county clerk database was searched to identify mortality within 1 year of injury. One-year mortality rates were calculated and multiple comparisons were made between genders controlling for age, fracture location, and/or ACCI. Results: Women presented with low-energy proximal femur fractures at a rate of almost 3:1 to men at our institution ( P = .001). Men demonstrated a significantly increased ACCI at presentation (5.35 ± 2.55 vs 4.86 ± 1.77, P = .03). Men had an increased 1-year mortality rate for all (31.3% vs 21.5%, P = .004) and intertrochanteric (IT) fractures (36.2% vs 22.9%, P = .008). Controlling for ACCI, gender, and fracture location, men demonstrated increased mortality rate with IT fractures ( P = .002) and trended toward but did not reach significance with femoral neck fractures ( P = .07). Discussion: Men presenting with low-energy femur fractures are at an increased mortality risk compared to women. On average, men present with an overall worse health status as identified by ACCI, which could predispose these patients not only to fractures themselves but also impair their ability to recover from injury. Conclusion: Men are at an increased 1-year mortality risk after sustaining proximal femur fractures.

Metabolic syndrome (MetS) doubles the risk of adverse cardiovascular events. Glucagon-like peptide 1 (GLP-1) receptor agonists induce weight loss, increase insulin secretion, and improve glucose tolerance. Studies in healthy animals suggest cardioprotective properties of GLP-1 receptor agonists, perhaps partially mediated by improved sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) activity. We examined the acute effect of GLP-1 receptor agonists on coronary smooth muscle cells (CSM) enzymatically isolated from lean, healthy Ossabaw miniature swine. Intracellular Ca2+ handling was interrogated with fura-2. The GLP-1 receptor agonist exenatide activated SERCA but did not alter other Ca2+ transporters. Further, we tested the hypothesis that chronic, in vivo treatment with GLP-1 receptor agonist AC3174 would attenuate coronary artery disease (CAD) in swine with MetS. MetS was induced in 20 swine by 6 months' feeding of a hypercaloric, atherogenic diet. Swine were then randomized (n = 10/group) into placebo or AC3174 treatment groups and continued the diet for an additional 6 months. AC3174 treatment attenuated weight gain, increased insulin secretion, and improved glucose tolerance. Intravascular ultrasound and histology showed no effect of AC3174 on CAD. MetS abolished SERCA activation by GLP-1 receptor agonists. We conclude that MetS confers vascular resistance to GLP-1 receptor agonists, partially through impaired cellular signaling steps involving SERCA.