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Objective: To test the efficacy of metformin (MET) during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy. Background: Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether MET pretreatment could ameliorate therapeutic decrements associated with MS. Methods: Yorkshire swine (n = 29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg oral MET or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for 5 weeks before the acquisition of functional and perfusion data immediately before terminal myocardial harvest. Immunoblotting and immuno-fluorescence were performed on the most ischemic tissue from all groups. Results: Regardless of EV administration, animals that received MET exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing, improved perfusion to the most ischemic myocardial region at rest and during pacing, and markedly reduced apoptosis. Conclusions: MET administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and loaddependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and MS. [ABSTRACT FROM AUTHOR]

Objective: Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson's trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors. [ABSTRACT FROM AUTHOR]

Background In Cox's Bazar, Bangladesh, 860 356 Rohingya living in refugee camps have experienced decades of persecution. Little is known about disease burden in this population. Methods A retrospective review of deidentified electronic health records (EHR) of 51 270 Rohingya attending two primary health clinics in Kutupalong and Balukahli from October 2017 to October 2019 was performed. A novel EHR system named NIROG was used for patients' medical records'. Results Females comprised 53.8% of patients. The median age of females was 25 y and for males it was 19 y. Prevalence of adult hypertension and diabetes was 14.1% and 11.0%, respectively. Also, 16.6% of children aged <5 y had moderate or severe acute malnutrition, while 36.6% were at risk of malnutrition. Body mass index (BMI) analysis showed that 34.4% of adults were underweight. Females were more likely to be hypertensive, diabetic, overweight/obese and malnourished. BMI had a statistically significant positive correlation with fasting blood glucose levels and systolic blood pressure. Conclusions The use of a portable EHR system was highly effective at providing longitudinal care in a humanitarian setting. Significant proportions of the adult population appear to have hypertension or diabetes, pointing to a critical need for management of chronic non-communicable diseases (NCDs). The findings of the current study will help stakeholders to plan effective prevention and management of NCDs among displaced Rohingya and other displaced populations. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. In particular, patients who suffer from ischemic heart disease (IHD) that is not amenable to surgical or percutaneous revascularization techniques have limited treatment options. Furthermore, after revascularization is successfully implemented, there are a number of pathophysiological changes to the myocardium, including but not limited to ischemia-reperfusion injury, necrosis, altered inflammation, tissue remodeling, and dyskinetic wall motion. Electrospinning, a nanofiber scaffold fabrication technique, has recently emerged as an attractive option as a potential therapeutic platform for the treatment of cardiovascular disease. Electrospun scaffolds made of biocompatible materials have the ability to mimic the native extracellular matrix and are compatible with drug delivery. These inherent properties, combined with ease of customization and a low cost of production, have made electrospun scaffolds an active area of research for the treatment of cardiovascular disease. In this review, we aim to discuss the current state of electrospinning from the fundamentals of scaffold creation to the current role of electrospun materials as both bioengineered extracellular matrices and drug delivery vehicles in the treatment of CVD, with a special emphasis on the potential clinical applications in myocardial ischemia. [ABSTRACT FROM AUTHOR]

Introduction: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. Methods: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. Results: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all p ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (p = 0.64, p = 0.32) between the groups. Conclusions: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration. [ABSTRACT FROM AUTHOR]

Human bone mesenchymal stem cell‐derived extracellular vesicles (HBMSC‐EV) have been used successfully in animal models of myocardial ischemia, yet have dampened effects in metabolic syndrome through unknown mechanisms. This study demonstrates the basal differences between non‐diabetic human coronary artery endothelial cells (HCAEC) and diabetic HCAEC (DM‐HCAEC), and how these cells respond to the treatment of HBMSC‐EV. HCAEC and DM‐HCAEC were treated with HBMSC‐EV for 6 h. Proteomics, western blot analysis, and tube formation assays were performed. Key metabolic, growth, and stress/starvation cellular responses were significantly altered in DM‐HCAEC in comparison to that of HCAEC at baseline. Proteomics demonstrated increased phosphorus metabolic process and immune pathways and decreased RNA processing and biosynthetic pathways in DM‐HCAEC. Similar to previous in vivo findings, HCAEC responded to the HBMSC‐EV with regenerative and anti‐inflammatory effects through the upregulation of multiple RNA pathways and downregulation of immune cell activation pathways. In contrast, DM‐HCAEC had a significantly diminished response to HBMSC‐EV, likely due to the baseline abnormalities in DM‐HCAEC. To achieve the full benefits of HBMSC‐EV and for a successful transition of this potential therapeutic agent to clinical studies, the abnormalities found in DM‐HCAEC will need to be further studied. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 inhibitors (DPP4i) may be cardioprotective based on several small animal and clinical studies, though randomized control trials have demonstrated limited benefit. Given these discrepant findings, the role of these agents in chronic myocardial disease, particularly in the absence of diabetes, is still poorly understood. The purpose of this study was to determine the effects of sitagliptin, a DPP4i, on myocardial perfusion and microvessel density in a clinically relevant large animal model of chronic myocardial ischemia. Normoglycemic Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (CON, n = 8) or 100 mg oral sitagliptin (SIT) daily (n = 5). Treatment continued for 5 weeks, followed by hemodynamic measurements, euthanasia, and tissue harvest of ischemic myocardium. There were no significant differences in myocardial function between CON and SIT as measured by stroke work (p > 0.5), cardiac output (p = 0.22), and end‐systolic elastance (p = 0.17). SIT was associated with increased absolute blood flow at rest (17% increase, IQR 12–62, p = 0.045) and during pacing (89% increase, IQR 83–105, p = 0.002). SIT was also associated with improved arteriolar density (p = 0.045) compared with CON, without changes in capillary density (p = 0.72). SIT was associated with increased expression of pro‐arteriogenic markers MCP‐1 (p = 0.003), TGFß (p = 0.03), FGFR1 (p = 0.002), and ICAM‐1 (p = 0.03), with a trend toward an increase in the ratio of phosphorylated/active PLCγ1 to total PLCγ1 (p = 0.11) compared with CON. In conclusion, in chronically ischemic myocardium, sitagliptin improves myocardial perfusion and arteriolar collateralization via the activation of pro‐arteriogenic signaling pathways. [ABSTRACT FROM AUTHOR]