Role of bariatric surgery in improving diabetic cardiomyopathy: Molecular mechanisms and therapeutic perspectives (Review).

Diabetic cardiomyopathy (DCM), a significant complication of diabetes mellitus, is marked by myocardial structural and functional alterations due to chronic hyperglycemia. Despite its clinical significance, optimal treatment strategies are still elusive. Bariatric surgery via sleeve gastrectomy and Roux-en-Y gastric bypass have shown promise in treating morbid obesity and associated metabolic disorders including improvements in diabetes mellitus and DCM. The present study reviews the molecular mechanisms by which bariatric surgery improves DCM, offering insights into potential therapeutic targets. Future research should further investigate the mechanistic links between bariatric surgery and DCM, to evaluate the benefits and limitations of these surgical interventions for DCM treatment. The present study aims to provide a foundation for more effective DCM therapies, contributing to the advancement of patient care.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.

BACKGROUND: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment. METHODS: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX. RESULTS: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment. CONCLUSION: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.

Risk factors of in-stent restenosis in patients with diabetes mellitus after percutaneous coronary intervention: A protocol for systematic review and meta-analysis.

BACKGROUND: Percutaneous coronary intervention (PCI) has become one of the effective methods for the treatment of coronary heart disease (CHD). However, it is easy to have in-stent restenosis (ISR), even cardiovascular events after PCI, which affects the therapeutic effects. The incidence of ISR in diabetes mellitus (DM) patients increased by 2 to 4 times. Early identification of the risk factors of ISR in DM patients after PCI may help clinical staff to prevent and intervene as soon as possible, so it is very important to improve the clinical outcomes of DM patients. Although scholars at home and abroad have studied and summarized the risk factors of ISR in DM patients after PCI, the conclusions are different. Therefore, in this study, meta-analysis was used to summarize the risk factors of ISR in DM patients after PCI, and to explore the characteristics of high-risk groups of ISR, thus providing reference for early identification and prevention of ISR. METHODS: We will search related literature from PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang Database. Eligible studies will be screened based on inclusion criteria. Meanwhile, data extraction, risk of bias assessment, publication bias assessment, subgroup analysis, and quality assessment will be performed. Review Manager Version 5.3 software will be applied for data analysis. Each process is independently conducted by 2 researchers. If there is any objection, it will be submitted to a third researcher for resolution. RESULTS: We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals. CONCLUSIONS: The results of this analysis can be used to generate a risk prediction model and provide an intervention strategy for the occurrence of ISR in DM patients after PCI. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/WC87Y.

Metformin impairs homing ability and efficacy of mesenchymal stem cells for cardiac repair in streptozotocin-induced diabetic cardiomyopathy in rats.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) have demonstrated potential in treating diabetic cardiomyopathy. However, patients with diabetes are on multiple drugs and there is a lack of understanding of how transplanted stem cells would respond in presence of such drugs. Metformin is an AMP kinase (AMPK) activator, the widest used antidiabetic drug. In this study, we investigated the effect of metformin on the efficacy of stem cell therapy in a diabetic cardiomyopathy animal model using streptozotocin (STZ) in male Wistar rats. To comprehend the effect of metformin on the efficacy of BM-MSCs, we transplanted BM-MSCs (1 million cells/rat) with or without metformin. Our data demonstrate that transplantation of BM-MSCs prevented cardiac fibrosis and promoted angiogenesis in diabetic hearts. However, metformin supplementation downregulated BM-MSC-mediated cardioprotection. Interestingly, both BM-MSCs and metformin treatment individually improved cardiac function with no synergistic effect of metformin supplementation along with BM-MSCs. Investigating the mechanisms of loss of efficacy of BM-MSCs in the presence of metformin, we found that metformin treatment impairs homing of implanted BM-MSCs in the heart and leads to poor survival of transplanted cells. Furthermore, our data demonstrate that metformin-mediated activation of AMPK is responsible for poor homing and survival of BM-MSCs in the diabetic heart. Hence, the current study confirms that a conflict arises between metformin and BM-MSCs for treating diabetic cardiomyopathy. Approximately 10% of the world population is diabetic to which metformin is prescribed very commonly. Hence, future cell replacement therapies in combination with AMPK inhibitors may be more effective for patients with diabetes.NEW & NOTEWORTHY Metformin treatment reduces the efficacy of mesenchymal stem cell therapy for cardiac repair during diabetic cardiomyopathy. Stem cell therapy in diabetics may be more effective in combination with AMPK inhibitors.

Lipid Accumulation in Hearts Transplanted From Nondiabetic Donors to Diabetic Recipients.

BACKGROUND: Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood. OBJECTIVES: By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup. METHODS: The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase-polymerase chain reaction. RESULTS: There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors. CONCLUSIONS: Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.

Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes.

Chronic heart failure is a common complication in patients with type 2 diabetes mellitus (T2DM). T2DM is associated with disturbed metabolism of fat, which can result in excessive accumulation of lipids in cardiac muscle. In the current study, we assessed mitochondrial oxidation of carbohydrates and fatty acids, lipid accumulation, endoplasmic reticulum (ER) stress, and apoptosis in diabetic left ventricle. Left ventricular myocardium from 37 patients (a group of patients with diabetes and a group of patients without diabetes [ejection fraction >50%]) undergoing coronary artery bypass graft surgery was obtained by subepicardial needle biopsy. The group with diabetes had a significantly decreased rate of mitochondrial respiration fueled by palmitoyl-carnitine that correlated with blood glucose dysregulation, while there was no difference in oxidation of pyruvate. Diabetic myocardium also had significantly decreased activity of hydroxyacyl-CoA dehydrogenase (HADHA) and accumulated more lipid droplets and ceramide. Also, markers of ER stress response (GRP78 and CHOP) and apoptosis (cleaved caspase-3) were elevated in diabetic myocardium. These results show that, even in the absence of contractile failure, diabetic heart exhibits a decreased mitochondrial capacity for ß-oxidation, increased accumulation of intracellular lipids, ER stress, and greater degree of apoptosis. Lower efficiency of mitochondrial fatty acid oxidation may represent a potential target in combating negative effects of diabetes on the heart.

The Exosome: a New Player in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and occurs worldwide. However, the underlying cellular and molecular mechanisms remain poorly understood. Recently, exosomes have attracted considerable interest for their use as efficient, targeted, and non-immunogenic delivery systems for biological molecules or pharmacotherapies. This review will summarize the fast-developing field of the regulation and function of exosomes in DCM, affording valuable insights and therapeutic opportunities in combatting diabetes-related cardiac disorder for modern human health.

SYNTAX Score and Outcomes of Coronary Revascularization in Diabetic Patients.

PURPOSE OF REVIEW: This review describes the dynamic relationship between diabetes mellitus (DM) and coronary artery disease (CAD) with respect to different revascularization strategies and how angiographic tools such as the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score can supplement clinical decision-making. RECENT FINDINGS: The SYNTAX score characterizes the anatomical extent of CAD in terms of the number of lesions, functional importance, and complexity. Studies not limited to patients with DM suggest that percutaneous coronary intervention (PCI) is a reasonable alternative to coronary artery bypass grafting (CABG) in patients with low-medium SYNTAX scores, while patients with high SYNTAX scores should be revascularized with CABG if operable. Similar findings were also observed for diabetes patients with multivessel disease in retrospective pooled analysis. The SYNTAX II score combines anatomical and clinical risk to improve upon the decision regarding the optimal revascularization strategy. The SYNTAX II score can be applied to patients with DM. The SYNTAX scores provide guidance to clinicians faced with determining the optimal revascularization strategy in patients with DM and advanced CAD. Using a heart team approach, the information can be considered along with other factors that influence PCI or CABG risk.

Sex-dependent effects of diabetes mellitus on the revascularization rate in mid-term follow up of young patients with coronary artery disease.

AIMS: We investigated the association between Type-2 diabetes mellitus (DM) and the need for revascularization at a 5-year follow-up of young coronary artery disease patients and the role of sex in this regard. METHODS: Among 1121 young (males≤45, and females≤55years) patients (female: 49.7%) from Tehran Heart Center's Premature Coronary Atherosclerosis Cohort, 371(33.1%) had diabetes prior to angiography. Revascularization was considered as either percutaneous coronary intervention or coronary artery bypass graft surgery. RESULTS: The mean follow-up duration was 57.67±22.43months. In the univariable analysis, diabetics were at a significantly higher risk of revascularization than nondiabetics (Sub-distributional Hazard Ratio [SHR]=1.843, P value<0.001). There was no association between DM and revascularization among men (SHR=1.232, P value=0.508). In contrast, women with DM had threefold more revascularization risk than women without DM (SHR=3.519, P value<0.001). After adjustment for confounding factors, the risk of revascularization in diabetics compared to nondiabetics increased to 2.139 fold (95% CI=1.473, 3.108) among the whole subjects, remained nonsignificant among men, and increased significantly to 3.725 fold (95% CI=2.067, 6.725) in women. CONCLUSIONS: Our data showed that in women with premature CAD, but not in men, DM may have a significant role in emerging revascularization during a mean follow-up of 5years.

Fever, Malaise, and Dyspnea in a Diabetic Heart Transplant Patient: A Case Report.

Patients with solid-organ transplants usually present at the emergency department with nonspecific symptoms. The physician should consider a great variety of syndromes and diseases, given the greater risk that solid-organ transplant patients carry because of immunosuppression and transplant-related conditions. Myocardial infarction caused by cardiac allograft vasculopathy must be always suspected and ruled out, even when initial symptoms do not orientate in that direction. We present a case that conjugates signs that can be present in different pathologies. It shows that fever is not always related to infection or rejection but could also appear in acute cardiac allograft vasculopathy. It emphasizes the need of a multi-disciplinary team led by a heart transplant specialist when dealing with this sort of clinical case.

Hospitalization costs and clinical outcomes in CABG patients treated with intensive insulin therapy.

BACKGROUND: The financial impact of intensive (blood glucose [BG] 100-140mg/dl [5.5-7.8mM] vs. conservative (141-180mg/dl (7.9-10.0mM) glucose control in the ICU in patients, with and without diabetes, undergoing coronary artery bypass graft (CABG) surgery is not known. METHODS: This post-hoc cost analysis determined differences in hospitalization costs, resource utilization and perioperative complications in 288 CABG patients with diabetes (n=143) and without diabetes (n=145), randomized to intensive (n=143) and conservative (n=145) glucose control. RESULTS: Intensive glucose control resulted in lower BG (131.4±14mg/dl-(7.2±0.8mM) vs. 151.6±17mg/dl (8.4±0.8mM, p<0.001), a nonsignificant reduction in the median length of stay (LOS, 7.9 vs. 8.5days, p=0.17) and in a composite of perioperative complications including wound infection, bacteremia, acute renal and respiratory failure, major cardiovascular events (42% vs 52%, p=0.10) compared to conservative control. Median hospitalization costs were lower in the intensive group ($39,366 vs. $42,141, p=0.040), with a total cost savings of $3654 (95% CI: $1780-$3723), than conservative control. Resource utilization for radiology (p=0.008), laboratory (p=0.014), consultation service (p=0.013), and ICU utilization (p=0.007) were also lower in the intensive group. Compared to patients without perioperative complications, those with complications had longer hospital length of stay (10.7days vs. 6.7days, p<0.001), higher total hospitalization cost ($48,299 vs. $32,675, p<0.001), and higher resource utilization units (2745 vs. 1710, p<0.001). CONCLUSION: Intensive glycemic control [BG 100-140mg/dl (5.5-7.8mM)] in patients undergoing CABG resulted in significant reductions in hospitalization costs and resource utilization compared to patients treated with conservative [BG 141-180mg/dl (7.9-10.0mM)] glucose control.

Association Between Glycosylated Hemoglobin Level and Cardiovascular Outcomes in Diabetic Patients After Percutaneous Coronary Intervention.

Glycosylated hemoglobin (HbA1c) is a critical measure of glycemic control, which may be a reliable predictor of complications after percutaneous coronary intervention (PCI). This systematic review and meta-analysis evaluates the association between HbA1c levels and clinical outcomes in diabetic patients after PCI.Pubmed, Embase, and Cochrane Library databases (dated to December 2015) were screened for relevant studies. Appropriate diabetic cases and controls, assessed using blood HbA1c levels, were extracted, and statistical analysis was conducted using RevMan 5.3 software. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the associations between HbA1c levels and clinical outcomes in diabetic patients after PCI. Ethics review and approval was not necessary because this systematic meta-analysis did not involve any direct human trials or animal experiments.Eight studies that reported HbA1c levels for a total of 3290 diabetic subjects after PCI were included in this meta-analysis. Comprehensive integration and analysis revealed a significant correlation between higher HbA1c levels and the risk of target vessel revascularization progression (OR 1.36, 95% CI 1.03-1.82) and nonfatal myocardial infarction after PCI (OR 2.47, 95% CI 1.38-4.44). However, no significant association was found between HbA1c levels and major adverse cardiovascular events (OR 1.02, 95% CI 0.83-1.27), all-cause mortality (OR 0.73, 95% CI 0.52-1.02), cardiac death (OR 1.12, 95% CI 0.62-2.03), or in-stent thrombosis (OR 0.65, 95% CI 0.23-1.87) among diabetic patients after PCI. Sensitivity analysis indicated a statistically robust result and revealed no publication bias.Our meta-analysis demonstrated that blood HbA1c levels might be associated with higher risks of target vessel revascularization progression and nonfatal myocardial infarction among diabetic patients after PCI. However, further studies with larger sample sizes are required to verify the association.

Prognostic significance of glycemic variability after cardiac surgery.

INTRODUCTION: The prognostic significance of acute glycemic variability (GV) after cardiac surgery is not known. This study was therefore planned to analyze the independent prognostic value of GV after cardiac surgery. MATERIALS AND METHODS: This is a single center prospective observational study in 870 consecutive cardiac surgery patients over a 3-month period at a tertiary care institute in India. RESULTS: In linear regression analysis, GV was a significant predictor of length of stay in intensive care unit (LOS-ICU) (beta 0.102, p=0.007) and rise in creatinine after surgery (beta 0.229, p<0.001). Mean POC-BG was a significant positive predictor of length of stay in hospital (LOS-hospital) (beta 0.1, p=0.004). In multivariable logistic regression analysis, GV predicted prolonged LOS-ICU (p=0.006, OR 1.016) and acute kidney injury (p<0.001, OR 1.034). CONCLUSION: This study showed that GV, as measured by standard deviation, was a predictor of LOS-ICU, rise in creatinine and AKI after cardiac surgery. GV is therefore a new dimension in postoperative glycemic management in cardiac surgery patients, which needs to be explored.

Efficacy of CD34+ Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Is Absent in Patients With Diabetes but Preserved in Patients With Insulin Resistance.

UNLABELLED: We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). A total of 45 outpatients with DCM received granulocyte colony-stimulating factor for 5 days. CD34(+) cells were then collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no-IR group). After stimulation, we found higher numbers of CD34(+) cells in the IR group (94 ± 73 × 10(6) cells per liter) than in the no-IR group (54 ± 35 × 10(6) cells per liter) or DM group (31 ± 20 × 10(6) cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34(+) cells in the IR group (IR group, 216 ± 110 × 10(6) cells; no-IR group, 127 ± 82 × 10(6) cells; DM group, 77 ± 83 × 10(6) cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6% ± 6.9%) and the no-IR group (+4.4% ± 7.2%) but not in the DM group (-0.9% ± 5.4%; p = .035). The N-terminal pro-brain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DM group (-606 ± 850 pg/ml; -698 ± 1,105 pg/ml; and +238 ± 963 pg/ml, respectively; p = .034). Transendocardial CD34(+) cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34(+) stem cell mobilization and a preserved clinical response to cell therapy. SIGNIFICANCE: The present study is the first clinical study directly evaluating the effects of altered glucose metabolism on the efficacy of CD34(+) stem cell therapy in patients with nonischemic dilated cardiomyopathy. The results offer critical insights into the physiology of stem cell mobilization in heart failure and possibly an explanation for the often conflicting results obtained with stem cell therapy for heart failure. These results demonstrate that patients with dilated cardiomyopathy and diabetes do not benefit from autologous CD34(+) cell therapy. This finding could serve as a useful tool when selecting heart failure patients for future clinical studies in the field of stem cell therapy.

Weight Loss with Sleeve Gastrectomy in Obese Type 2 Diabetes Mellitus: Impact on Cardiac Function.

BACKGROUND: Diabetic cardiomyopathy is an increasingly prevalent health issue, with no specific management options. We examined the impact of weight loss with sleeve gastrectomy on diabetic cardiomyopathy. METHODS: Eight obese patients with type 2 diabetes undergoing sleeve gastrectomy had left ventricular (LV) systolic and diastolic function assessed by global longitudinal strain (GLS) and septal early diastolic velocity (e') using echocardiography, before and 9 months after surgery. RESULTS: Following surgery, mean weight loss was 28.0 ± 16 kg; body mass index (BMI) decreased from 44 ± 9 to 35 ± 6 kg/m(2) (p < 0.001). Glycaemic control improved with glycated haemoglobin (HbA1c) improving from 9.2% at baseline to 6.7% at follow-up (p = 0.002), with a corresponding improvement in LV GLS from -13.2 ± 3.7 to -19.7 ± 2.2% (p < 0.001), and LV ejection fraction from 60 ± 5 to 70 ± 4% (p < 0.001). Improvement in GLS was associated with the amount of weight lost (ρ = 0.81, p = 0.015). LV septal e' velocities increased, and LV filling pressures decreased after surgery. CONCLUSIONS: Weight loss with sleeve gastrectomy in obese patients with type 2 diabetes is effective in improving glycaemic control in subjects with type 2 diabetes and results in significant improvement in both systolic and diastolic myocardial function.

Diabetes Mellitus Impairs Left Ventricular Mass Regression after Surgical or Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis.

BACKGROUND: It is well-documented that persistent myocardial hypertrophy in patients with aortic stenosis is related to suboptimal postoperative outcomes after aortic valve replacement. Although diabetes is known to potentially exacerbate myocardial hypertrophy, it has yet to be examined if it affects postoperative left ventricular mass regression (LVMR). METHODS: A single-centre, retrospective analysis was performed on 183 consecutive patients who underwent either surgical or transcatheter aortic valve replacement between 2010 and May 2013. Patient demographics, postoperative outcomes and echocardiographic data were obtained preoperatively and a year after surgery. RESULTS: There were 42 diabetic and 141 non-diabetic patients. Preoperative characteristics of diabetic patients were statistically similar to those of non-diabetic patients, except for higher prevalence of hyperlipidaemia (p <0.001) and history of cerebrovascular disorder (p=0.046) in diabetic patients. Median value of postoperative LVMR of all patients was -36.5 g/m(2), and was significantly greater in the non-diabetics compared to the diabetics (-39.1 vs. -22.2 g/m(2), p=0.008). Univariate and multivariate analyses were performed on preoperative variables, and stepwise multiple regression analysis demonstrated that diabetes (standardised partial regression coefficient (SPRC)=-0.187, p=0.018), female gender (SPRC=0.245, p=0.026) and age (SPRC=0.203, p=0.018) were associated with poor postoperative LVMR. CONCLUSIONS: Patients with diabetes showed suboptimal postoperative LVMR, and the disease was a prognostic factor that was associated with poor LVMR. These findings suggest that diabetes may predispose the particular group of patients to worse postoperative outcomes.

Diazoxide preconditioning of endothelial progenitor cells from streptozotocin-induced type 1 diabetic rats improves their ability to repair diabetic cardiomyopathy.

Type 1 diabetes mellitus (DM) is a strong risk factor for the development of diabetic cardiomyopathy (DCM) which is the leading cause of morbidity and mortality in the type 1 diabetic patients. Stem cells may act as a therapeutic agent for the repair of DCM. However, deteriorated functional abilities and survival of stem cells derived from type 1 diabetic subjects need to be overcome for obtaining potential outcome of the stem cell therapy. Diazoxide (DZ) a highly selective mitochondrial ATP-sensitive K(+) channel opener has been previously shown to improve the ability of mesenchymal stem cells for the repair of heart failure. In the present study, we evaluated the effects of DZ preconditioning in improving the ability of streptozotocin-induced type 1 diabetes affected bone marrow-derived endothelial progenitor cells (DM-EPCs) for the repair of DCM in the type 1 diabetic rats. DM-EPCs were characterized by immunocytochemistry, flow cytometry, and reverse transcriptase PCR for endothelial cell-specific markers like vWF, VE cadherin, VEGFR2, PECAM, CD34, and eNOS. In vitro studies included preconditioning of DM-EPCs with 200 µM DZ for 30 min followed by exposure to either 200 µM H2O2 for 2 h (for oxidative stress induction) or 30 mM glucose media (for induction of hyperglycemic stress) for 48 h. Non-preconditioned EPCs with and without exposure to H2O2 and 30 mM high glucose served as controls. These cells were then evaluated for survival (by MTT and XTT cell viability assays), senescence, paracrine potential (by ELISA for VEGF), and alteration in gene expression [VEGF, stromal derived factor-1α (SDF-1α), HGF, bFGF, Bcl2, and Caspase-3]. DZ preconditioned DM-EPCs demonstrated significantly increased survival and VEGF release while reduced cell injury and senescence. Furthermore, DZ preconditioned DM-EPCs exhibited up-regulated expression of prosurvival genes (VEGF, SDF-1α, HGF, bFGF, and Bcl2) on exposure to H2O2, and VEGF and Bcl2 on exposure to hyperglycemia while down regulation of Caspase-3 gene. Eight weeks after type 1 diabetes induction, DZ preconditioned, and non-preconditioned DM-EPCs were transplanted into left ventricle of diabetic rats (at a dose of 2 × 10(6) DM-EPCs/70 µl serum free medium). After 4 weeks, DZ preconditioned DM-EPCs transplantation improved cardiac function as assessed by Millar's apparatus. There was decrease in collagen content estimated by Masson's trichrome and sirius red staining. Furthermore, reduced cell injury was observed as evidenced by decreased expression of Caspase-3 and increased expression of prosurvival genes Bcl2, VEGF, and bFGF by semi-quantitative real-time PCR. In conclusion, the present study demonstrated that DZ preconditioning enhanced EPCs survival under oxidative and hyperglycemic stress and their ability to treat DCM.

Cardiopulmonary Bypass Decreases Activation of the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway in Diabetic Human Myocardium.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with increased myocardial oxidative stress and apoptosis in diabetic patients. A mechanistic understanding of this relationship could have therapeutic value. To establish a possible mechanism, we compared the activation of the cardioprotective signal transducer and activator of transcription 3 (STAT3) pathway between patients with uncontrolled diabetes (UD) and nondiabetic (ND) patients. METHODS: Right atrial tissue and serum were collected before and after CPB from 80 patients, 39 ND and 41 UD (HbA1c ≥ 6.5), undergoing cardiac operations. The samples were evaluated with Western blotting, immunohistochemistry, and microarray. RESULTS: On Western blot, leptin levels were significantly increased in ND post-CPB (p < 0.05). Compared with ND, the expression of Janus kinase 2 and phosphorylation (p-) of STAT3 was significantly decreased in UD (p < 0.05). The apoptotic proteins p-Bc12/Bc12 and caspase 3 were significantly increased (p < 0.05), antiapoptotic proteins Mcl-1, Bcl-2, and p-Akt were significantly decreased (p < 0.05) in UD compared with ND. The microarray data suggested significantly increased expression of interleukin-6 R, proapoptotic p-STAT1, caspase 9, and decreased expression of Bc12 and protein inhibitor of activated STAT1 antiapoptotic genes (p = 0.05) in the UD patients. The oxidative stress marker nuclear factor-κB was significantly higher (p < 0.05) in UD patients post-CPB compared with the pre-CPB value, but was decreased, albeit insignificantly, in ND patients post-CPB. CONCLUSIONS: Compared with ND, UD myocardium demonstrated attenuation of the cardioprotective STAT3 pathway. Identification of this mechanism offers a possible target for therapeutic modulation.

Prevalence of unrecognized diabetes, prediabetes and metabolic syndrome in patients undergoing elective percutaneous coronary intervention.

BACKGROUND: Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention is not well defined. We aimed to analyse the prevalence and characteristics of patients undergoing percutaneous coronary intervention with previously unrecognized prediabetes, diabetes and metabolic syndrome. METHODS: Data were collected from 740 patients undergoing elective percutaneous coronary intervention between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Haemoglobin A1c (A1c ≥ 6.5% for DM, A1c 5.7-6.4% for prediabetes). A modified definition was used for metabolic syndrome [three or more of the following criteria: body mass index ≥30 kg/m2; triglycerides ≥ 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure ≥ 130 mmHg and/or diastolic ≥ 85 mmHg; and A1c ≥ 5.7% or on therapy]. RESULTS: Mean age was 67 years, median body mass index was 28.2 kg/m(2) and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of percutaneous coronary intervention. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM). CONCLUSION: Among patients undergoing elective percutaneous coronary intervention, a substantial number were identified with a new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors.