Non-diabetic Hearts Research Articles

Sodium glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation.

This review focuses on the pathogenic role of sodium glucose cotransporter (SGLT)-2 in the development of renal dysfunction and heart failure in patients with diabetes, by emphasizing the concept of reno-cardiac syndrome (kidney injury worsens cardiac condition) and by substantiating the deleterious effect of sympathetic overdrive in this context. Furthermore, the review proposes a mechanistic hypothesis to explain the benefits of SGLT2 inhibitors, specifically that SGLT-2 inhibitors reduce sympathetic activation at the renal level. To illustrate this point, several examples from both animal experiments and clinical observations are introduced. The bidirectional interaction of the heart and kidney were deeply implicated as an exacerbator of heart failure and renal failure without diabetes. Renal cortical ischemia and abnormal glucose metabolism of tubular epithelial cells are likely to exist as common pathologies in nondiabetic heart failure patients. It is no wonder why SGLT-2 inhibitors are specifically being studied even in the absence of diabetes, both for heart failure and also for renal failure.

Efficacy of Enhanced External Counter Pulsation on Clinical Parameters and Health-Related Quality of Life in Coronary Heart Disease patients with Diabetes Mellitus

To assess the effect of Enhanced External Counter Pulsation (EECP) treatment on clinical parameters and health related quality of life (HRQoL) in Coronary Heart Disease (CHD) patients with Diabetes Mellitus. This was a pretest-posttest designed prospective study among 163 diabetic and non-diabetic coronary heart disease patients enrolled from SAAOL Heart Center, New Delhi, India. Patients were divided into two groups- diabetic CHD group and non-diabetic CHD group. EECP treatment was given to both the groups for 35 day. After EECP treatment physical and clinical profile along with HRQoL of study participants was assessed. The physical profile of study participants was assessed using Cooper’s 12 minutes’ walk test, Canadian Cardiovascular Society (CCS) angina scale and Medical Research Council (MRC) dyspnea scale and HRQoL was assessed through SF-36 (short form) and Seattle Angina Questionnaire (SAQ) scale. The follow-up of both groups was done at 6th and 12th months. Collected data were assessed through IBM, SPSS software v 21. Descriptive analysis with sample t-test for two independent groups and paired sample t-test for EECP effectiveness within the group was done. A significant improvement was observed in blood pressure; heart rate, lipid profile angina and MRC score in both the groups at 6th and 12 month follow-up. A significant reduction was observed in blood sugar fasting, blood sugar postprandial (PP) and glycosylated hemoglobin (HbA1c) in diabetic CHD patients. A significant improvement was also observed in all health domains of SF-36 & SAQ scale HRQoL after EECP treatment. EECP therapy is an effective non-invasive method to treat diabetic and non–diabetic CHD patients. This therapy may improve both physical (physical functional capacity, angina, dyspnea) and clinical profile (lipid profile, lower the blood glucose level) in diabetic CHD patients. EECP may also improve clinical symptoms of CHD patients and lower the blood glucose level in diabetic CHD patients this may directly improve overall HRQoL of CHD patients with DM.

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

• What is the central question of this study? What is the impact of chronic adult-onset diabetes on cardiac ischaemic outcomes and preconditioning? • What is the main finding and its importance? Chronic adult-onset type 2 but not type 1 diabetes significantly impairs myocardial ischaemic tolerance and ischaemic preconditioning. Preconditioning may be detrimental in type 2 diabetes, exaggerating nitrosative stress and apoptotic protein expression. Effects of diabetes on myocardial responses to ischaemia-reperfusion (I-R) and cardioprotective stimuli remain contentious, potentially reflecting influences of disease duration and time of onset. Chronic adult-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) were modelled non-genetically in male C57Bl/6 mice via 5×50mgkg-1 daily streptozotocin (STZ) injections + 12weeks' standard chow or 1×75mgkg-1 STZ injection + 12weeks' obesogenic diet (32% calories as fat, 57% carbohydrate, 11% protein), respectively. Systemic outcomes were assessed and myocardial responses to I-R ± ischaemic preconditioning (IPC; 3×5min I-R) determined in Langendorff perfused hearts. Uncontrolled T1D was characterised by pronounced hyperglycaemia (25mm fasting glucose), glucose intolerance and ∼10% body weight loss, whereas T2D mice exhibited moderate hyperglycaemia (15mm), hyperinsulinaemia, glucose intolerance and 17% weight gain. Circulating ghrelin, resistin and noradrenaline were unchanged with T1D, while leptin increased and noradrenaline declined in T2D mice. Ischaemic tolerance and IPC were preserved in T1D hearts. In contrast, T2D worsened post-ischaemic function (∼40% greater diastolic and contractile dysfunction) and cell death (100% higher troponin efflux), and abolished IPC protection. Whereas IPC reduced post-ischaemic nitrotyrosine and pro-apoptotic Bak and Bax levels in non-diabetic hearts, these effects were reduced in T1D and IPC augmented Bax and nitrosylation in T2D hearts. The data demonstrate chronic T1D does not inhibit myocardial I-R tolerance or IPC, whereas metabolic and endocrine disruption in T2D is associated with ischaemic intolerance and inhibition of IPC. Indeed, normally protective IPC may exaggerate damage mechanisms in T2D hearts.

Ketone body metabolism in diabetic and non-diabetic heart failure.

Heart failure (HF) is one of the most common cardiovascular diseases, causing large disease and economic burden worldwide. Impaired metabolic balance has been confirmed as a significant aspect of HF, and alteration of substrate utilization plays a vital role in the development of HF. Diabetes mellitus is strictly related with HF, and patients with diabetes show a higher mortality and morbidity of HF. Furthermore, HF patients and animals with diabetes behave different characteristics of metabolic pattern and substrate utilization comparing to those without diabetes. Recently, ketone body has been demonstrated as an alternative energy source in HF, which may improve myocardial energy supply and thus be adaptive for HF. Studies measured ketone body oxidation and production of ketone body metabolism in different groups of patients and animal models. This review focuses on the alteration of ketone body metabolism during HF and compares different results between diabetic and non-diabetic HF and the potential mechanism.

P3487Pre-ischemic succinate dehydrogenase inhibition is protective against ischemia-reperfusion injury in rat and human myocardium with and without diabetes mellitus

Abstract Background Ischemia-reperfusion (IR) injury can be attenuated through modulation of mitochondrial metabolism with succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). However, it is unknown whether SDH inhibition yields protection in aged, diabetic individuals and whether protection translate into human cardiac tissue. Purpose We wished to evaluate if SDH inhibition can be protective in aged, diabetic rat hearts and could be translated to the human myocardium. Methods We studied infarct size in aged non-diabetic and diabetic rat hearts subjected to isolated, retrograde perfusion and global ischemia and reperfusion. The hearts were randomized to: Sham hearts, IR injured hearts and IR injured hearts co-perfused with 0.1 mM or 0.6 mM DiMAL. Infarct size and mitochondrial respiratory capacity were evaluated post-ischemic. To translate our findings into human cardiac tissue, we tested the efficacy of DiMAL treatment in human atrial trabeculae from patients with and without diabetes mellitus undergoing cardiac surgery. We randomized atrial trabeculae to: IR injury, IR injury treated with ischemic preconditioning (IPC) and IR injury treated with 5 mM DiMAL. Contractile force recovery and mitochondrial respiratory capacity were evaluated post-ischemic. Results In non-diabetic rat hearts, DiMAL 0.1 mM reduced infarct size/area-at-risk (IS/AAR) compared to IR hearts (53±7% vs. 69±6% of IS/AAR; p<0.05). In diabetic hearts, an increased concentration of 0.6 mM DiMAL was required to confer protection (62±13% vs. 80±8% of IS/AAR; p<0.05). Mitochondrial complex I linked respiratory capacity was higher in both Sham and DiMAL 0.1 mM groups than with DiMAL 0.6 mM in non-diabetic hearts (157.4±26.5 and 140.0±35.3 vs. 81.8±42.4 pmol O2/(s*mg); p<0.01 and p<0.05). In trabeculae from humans without diabetes mellitus, IPC and DiMAL improved contractile force recovery compared to IR (43±12% and 43±13% vs. 23±13%, p<0.05). In trabeculae from patients with diabetes, IPC but not DiMAL administration improved contractile force recovery compared to IR (48±16% and 19±7% vs. 25±13%, p<0.01 and p>0.99). Mitochondrial complex I linked respiration capacity did not improve by IPC or DiMAL compared to IR in non-diabetic trabeculae (p>0.99). Conclusion Inhibition of the SDH by DiMAL protects the aged non-diabetic and diabetic heart from IR injury but the threshold for cardioprotection is increased in diabetic rat hearts. DiMAL provides cardioprotection similar to IPC in non-diabetic trabeculae but does not protect the human diabetic myocardium when given in identical concentrations. SDH inhibition can provide protection in both animal and human tissue and may provide a new target for pharmacologic conditioning in patients.

P4543Steatosis in explanted heart of type 2 diabetic patients with end-stage heart failure: progression of intra-myocytes fat accumulation in non-diabetic heart implanted in diabetic patients

Abstract Background How metabolic impairment leads to cardiac dysfunction in diabetics is unknown. A recent theory, derived mainly from rodent models, involves lipid over-storage to cardiomyocytes. Previous human study demonstrated cardiac steatosis on explanted hearts of diabetics with heart failure. However, this study did not provide any evidence about the effects of diabetes milieu on implanted non-diabetic heart. Purpose We evaluated intramyocyte lipid infiltration in explanted heart of type 2 diabetics with end-stage heart failure. Moreover, we studied the effects of diabetic milieu on myocyte lipid infiltration and cardiac function of non-diabetic implanted hearts in type 2 diabetics one year after heart transplantation (HTx). Methods We conducted a prospective study with a follow-up of 12 months on 88 patients over 18 years of age underwent first HTX. Patients with pre-HTx diabetes duration for at least 6 months were included in the study. Patients with endomyocardial biopsy (EMB) considered positive for rejection, according to International Society for Heart Lung Transplantation (ISHLT), and with post-HTx diabetes were excluded from the study. All patients underwent immunosuppression induction according ISHLT indications. All patients were followed applying internationally accepted patient evaluations (echocardiography and metabolic control) and EMB schedules. EBM from patients without rejection evidences were evaluated for intramyocyte lipid infiltration with oil red-O staining (Or-O). Results The patients were divided in diabetics (44%, age 51.6±7.2 y, diabetes duration 11±3 y) and no-diabetics (56%, 52.1±10.9 y). The patients were matched on the basis of eligibility for a HTx. Seven patients (3 diabetics and 4 no-diabetics) died in hospital. 5 (11%) patients developed post- HTx diabetes. No differences were seen in rejection (12% vs. 10%), infection (9% vs. 10%), renal dysfunction (9% vs. 8%) or mortality (7% vs. 8%). Therefore, the study population included 23 no-diabetics and 22 diabetics. After 1 year, we evidenced an impairment of both sx and dx ventricular function as showed by a significantly reduction of ejection fraction and TAPSE in diabetic patients (Figure-A). Although diastolic function not show significant differences among groups, the E/e' ratio showed lower reduction in diabetics. Or-O evidenced that 91% of diabetic and only 2 of no-diabetic explanted hearts (9%) showed intramyocyte lipid infiltration (Figure-B). Moreover, Or-O of EMB, for monitoring heart transplant during 1 year, evidenced a progressive intramyocyte lipid infiltration in 18 diabetics (81%), whereas none of no-diabetics showed intramyocyte lipid infiltration. Conclusions Our data show that almost all of the explanted diabetic hearts had intramyocyte lipid infiltration. More interesting, we observed that healthy heart transplanted in recipients with pretransplant diabetes were affected early by metabolic disorders leading to intramyocyte lipid infiltration.

P3496Empagliflozin improves cardiac function through the increased production of acetylcarnitine in a murine non-diabetic heart failure model

Abstract Background Empagliflozin is a renal sodium glucose transporter 2 (SGLT2) inhibitor, thereby mediates its anti-diabetic effect via excretion of glucose into urine. EMPA-REG OUTCOME study, the first big randomized control trial of empagliflozin have shown significant reduction of mortality and hospitalization due to heart failure in diabetic patients. This trial hasn't only had a huge impact to cardiovascular field, but also raised a number of questions about underlying mechanisms. It is also uncertain about the efficacy of empagliflozin in non-diabetic heart failure. In this study, we aimed to elucidate the biological effects and its underling mechanism of empagliflozin in a murine non-diabetic heart failure model. Methods We generated a heart failure murine model due to left ventricular (LV) pressure overload by performing transverse aortic constriction (TAC) operation to C57BL/6NCr mice. Two weeks after TAC operation we started empagliflozin administration mixed with diet at the ratio of 0.03% w/w. LV function was measured with echocardiography after administration of empagliflozin for two weeks (four weeks after TAC operation) and compared to a littermate control (no treatment) group. Then, heart samples were collected and subjected to further studies including metabolomic analysis. In-vitro studies including Seahorse Extracellular Flux Analyzer were also conducted with differentiated C2C12 cells and neonatal rat ventricular myocytes (NRVM). Results We found that empagliflozin treatment (Empa) significantly ameliorated LV systolic dysfunction induced by TAC compared to control group (Con) (figure.A) while heart weight/body weight ratio wasn't reduced. To explore key metabolites that can contribute to improvement of LV function, we conducted metabolomic analysis and found that empagliflozin significantly increased plasma acetylcarnitine level both in sham and TAC groups (figure.B). Previous studies have shown that acetylcarnitine acts as a substrate of acetyl CoA to fuel tricarboxylic acid cycle, and we tested the efficacy of acetylcarnitine for mitochondrial respiration capacity in differentiated C2C12 cells with Seahorse Extracellular Flux Analyzer. This analysis revealed that administration of acetylcarnitine resulted in a significant increase of oxygen consumption reflected by enhancing mitochondrial respiration. Similary, acetylcarnitine also markedly ameliorated impairment of mitochondrial respiration induced by isoproterenol in NRVM. Conclusion Our results indicated that empagliflozin has cardioprotective effect in murine heart failure model by enhancing mitochondrial respiration through the increased production of acetylcarnitine. We provide new evidence that empagliflozin would become a promising therapeutic agent to heart failure without diabetes.

The Relationship between Lipoprotein a and Glycosylated Hemoglobin and the Degree of Coronary Artery Stenosis in Non-Diabetic Coronary Heart Disease Patients

Nowadays, with the rapid development of society and economy, people’s living standard is constantly improved, and unhealthy lifestyle is also prevalent..

Abstract 945: A Novel Role of Cardiac DNA Methylation as a Regulator of Fibrosis in Human Diabetic Heart Failure

Human heart failure (HF) is accompanied by changes in cardiac gene expression; however, the impact of diabetes mellitus on this transcriptional regulation remains unclear. Our laboratory studies the role of epigenetics in HF and focuses on DNA methylation, commonly accepted as a negative regulator of gene expression when present in a gene’s promoter. In the current study, we hypothesized that diabetes alters cardiac DNA methylation and the transcriptome. We performed an integrated analysis of RNA-sequencing and DNA methylation using human left ventricle biopsies from HF patients to determine the effect of diabetes on this reprogramming. Our analysis identified global changes in cardiac DNA methylation as well as mRNA expression sufficient to distinguish diabetic from non-diabetic patients. Specifically, we identified significant regulation of 1,133 genes (|1.5| fold-change, P<0.05) and 9,302 methylation sites (|5%| methylation, P<0.05). Within the 391 co-regulated genes, only 174 genes had altered promoter-associated methylation. Consistent with the accepted dogma that promoter methylation inversely regulates gene expression, we found that 119 of those 174 genes displayed this inverse relationship; of these, an overwhelming majority (102) were hypomethylated in diabetic relative to non-diabetic hearts. These findings contrast the cardiac hypermethylation we have reported for ischemic HF. Gene set enrichment of the 119 inversely-regulated genes identified numerous pathways involved in fibrosis, including extracellular matrix organization (FDR<0.05, 3.9% enriched) and collagen biosynthesis (FDR<0.05, 6.3% enriched), which suggest that DNA methylation contributes to the adverse cardiac remodeling associated with diabetic heart failure. To identify putative regulators of these transcriptional and epigenetic differences, a candidate gene approach was used to reveal induction (2.5-fold, Q<0.05) and demethylation (20.5%, P<0.05) of EGR2, a known regulator of fibrosis. Furthermore, we found induction of GADD45beta (2.6-fold, Q < 0.05) a known regulator of DNA demethylation. Taken together, these observations suggest that epigenetic mechanisms underlie an etiology-specific reprogramming of cardiac fibrosis in diabetic HF.

413-P: SIRT1 Overexpression Restores the Protective Effects of Ischemic Post-conditioning in Diabetic Mice via Modulating Akt Signaling Pathway

Ischemic post-conditioning (IPO) activates Akt signaling to confer cardioprotection. The responsiveness of diabetic hearts to IPO is impaired. We hypothesized that decreased cardiac SIRT1, a positive regulator of Akt, may be responsible for the impaired responsiveness of diabetic hearts to IPO-mediated cardioprotection. High-fat diet and streptozotocin-induced diabetic mice were subjected to myocardial ischemia/reperfusion (MI/R, 30 minutes ischemia and 180 minutes reperfusion) or IPO (three cycles of 10 s of reperfusion and ischemia at the onset of reperfusion). Adenoviral vectors encoding GFP or SIRT1 (Ad-SIRT1) were administered by direct injection into the left ventricular. IPO activated the Akt signaling pathway and reduced MI/R injury in nondiabetic hearts but not in diabetic hearts, in which reduced expression of SIRT1 and increased Akt acetylation were observed. Delivery of Ad-SIRT1 into the diabetic hearts reduced Akt acetylation and restored the cardioprotective effects of IPO. In in vitro study, transfection with wild type SIRT1 but not inactive mutant SIRT1 reduced the expression of Akt acetylation and restored the protective effects of hypoxic post-conditioning in high glucose-incubated primary cardiomyocytes. Moreover, the cardiomyocytes transfected with Akt acetylation-defective mutant (K20R) showed increased Akt phosphorylation and enhanced protective effects against hypoxia/reoxygenation injury. These findings demonstrate that SIRT1 up-regulation restores IPO-mediated cardioprotection in diabetic mice via deacetylation-dependent activation of Akt signaling pathway. It is suggested that targeting up-regulation of SIRT1 may be a potential therapeutic strategy to restore myocardial responsiveness to post-conditioning in diabetic patients. Disclosure M. Ding: None. K. Zeng: None. M. Yu: None. C. Liu: None. F. Fu: None. Funding National Natural Science Foundation of China (81600235, 81670354); Natural Science Foundation of Shaanxi (2018JM7061)

Reduction of SIRT1 blunts the protective effects of ischemic post-conditioning in diabetic mice by impairing the Akt signaling pathway

Ischemic post-conditioning (IPO) activates Akt signaling to confer cardioprotection. The responsiveness of diabetic hearts to IPO is impaired. We hypothesized that decreased cardiac SIRT1, a positive regulator of Akt, may be responsible for the impaired responsiveness of diabetic hearts to IPO-mediated cardioprotection. High-fat diet and streptozotocin-induced diabetic mice were subjected to myocardial ischemia/reperfusion (MI/R, 30 min ischemia and 180 min reperfusion) or IPO (three cycles of 10 s of reperfusion and ischemia at the onset of reperfusion). Adenoviral vectors encoding GFP or SIRT1 (Ad-SIRT1) were administered by direct injection into the left ventricular. Our results showed that IPO activated the Akt signaling pathway and reduced MI/R injury in non-diabetic hearts but not in diabetic hearts, in which reduced expression of SIRT1 and increased Akt acetylation were observed. Delivery of Ad-SIRT1 into the diabetic hearts reduced Akt acetylation and restored the cardioprotective effects of IPO by modulating Akt signaling pathway. In contrast, cardiac-specific SIRT1 knockout increased Akt acetylation and blunted the cardioprotective effects of IPO. In in vitro study, transfection with wild-type SIRT1 but not inactive mutant SIRT1 reduced the expression of Akt acetylation and restored the protective effects of hypoxic post-conditioning in high glucose-incubated cardiomyocytes. Moreover, the cardiomyocytes transfected with constitutive Akt acetylation showed repressed Akt phosphorylation and blunted protective effects against hypoxia/reoxygenation injury. These findings demonstrate that the reduction of SIRT1 blunts the protective effects of IPO by impairing Akt signaling pathway and that SIRT1 up-regulation restores IPO-mediated cardioprotection in diabetic mice via deacetylation-dependent activation of Akt signaling pathway.

Let's face the fats: palmitate restores cellular redox state in the diabetic heart.

Let's face the fats: palmitate restores cellular redox state in the diabetic heart.

Abstract 16826: Reversal of TSPO Upregulation in the Diabetic Heart by Chronic TSPO Gene Silencing Causes Metabolic Sink via an Increase in ROMK Expression

Introduction: The mitochondrial translocator protein (TSPO) is an integral component of a macromolecular complex that regulates cell death & survival pathways. Myocardial TSPO levels are markedly increased in diabetes. Objectives: We sought to investigate the electrophysiological effects of TSPO in diabetes using a cardiotropic TSPO gene silencing approach that avoids off-target effects of TSPO ligands. Methods: In a standard model of diabetes mellitus consisting of Zucker Obese rats, AAV9.shTSPO (5E11 gc/mL) was delivered by tail vein injection (N=5). Non-diabetic lean (N=4) and spontaneously hypertensive (N=16) rats served as treatment controls. Untreated diabetic (N=6) and non-diabetic (N=6) hearts were also studied. The TSPO ligand DZP (64μμ) was perfused in additional diabetic hearts to contrast its effects with those of chronic TSPO knockdown. Optical action potential (AP) mapping was performed 2 wks following gene transfer. Hearts were challenged with 12 min ischemia followed by reperfusion. Results: Myocardial TSPO knockdown by AAV9.shTSPO promoted metabolic sink in diabetic hearts. This manifested as rapid and spatially heterogeneous loss of AP amplitude and upstroke velocity in response to ischemia (Figure). Areas of early loss of excitability remained inexcitable upon reperfusion resulting in wide regions of conduction block that supported VT. These findings were specific to diabetes as AAV9.shTSPO did not alter the response of non-diabetic hearts to ischemia. Loss of excitability was not related to irreversible cell death by TUNEL staining. Analysis of the expression of ATP-sensitive channel subunits revealed marked upregulation of ROMK in response to TSPO knockdown exclusively in the diabetic heart. Unlike TSPO knockdown, DZP did not promote metabolic sink but rather prevented post-ischemic VT. Conclusions: Chronic gene silencing of TSPO promotes VT via a metabolic sink mechanism likely arising from compensatory upregulation of ROMK.

Abstract 536: Increased O-linked Glycosylation in Diabetic Myocardium of Mice and Human

Objectives: The modification of serine and threonine residues of nuclear and cytoplasmic proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a highly dynamic post-translational modification that plays a critical role in regulating numerous biological processes. Our focus was to establish the difference of O-linked glycosylation in diabetic (DM) and Non-diabetic (ND) heart of mouse and human in the presence or absence of cardioplegic ischemia and cardiopulmonary bypass (CP/CPB). Methods and results: Right atrial tissue was harvested pre- and post-CP/CPB from the ND patients and patients with type-2 DM undergoing cardiac surgery (n = 4/group).The post-CP/CPB tissue samples were from a atrial tissue segment exposed to cold, hyperkalemic blood cardioplegia (ischemia) and a brief period (10 minutes) of reperfusion. Ventricular tissue samples were also obtained from mice with and without type-2 DM (n =3/group). Thin Layer Chromatography (TLC) was used to measure the contents of acetyl coenzyme A (acetyl-CoA) in the tissue lysates of mouse and human myocardium. Western blotting and immunohistochemistry analysis were employed to determine the expression/localization of O-Linked β-N-acetylglucosamine (O-GlcNAc) in the tissue lysates and paraffin-embedded tissue sections. Diabetes tends to increase the amounts of acetyl-CoA and O-GlcNAc (20% increase vs. ND, P<0.05) in the myocardium compared with ND. Post-CP/CPB further induced more acetyl-CoA and this effect was more pronounced in the diabetic atrial myocardium than that of ND. Immunofluorescence experiments with O-GlcNAc-specific antibody and paraffin-embedded tissue sections from human atria and mouse heart show a significant number of cells stain positively with the antibody in the diabetes sections (3 folds increases in optical density vs. ND, P <0.01). The protein oxidation and ratio of NADH/NAD in the DM myocardium were significantly increased compared with ND (P<0.05). Conclusion: Diabetes and cardioplegic ischemia are associated with an increase in O-linked glycosylation in the mouse and human myocardium, suggesting that diabetes and cardioplegic ischemia affect myocardial metabolism via hexosamine biosynthetic pathway.

Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

SGLT 2 inhibitor, Canagliflozin attenuates myocardial infarction in the diabetic and non-diabetic heart

SGLT 2 inhibitor, Canagliflozin attenuates myocardial infarction in the diabetic and non-diabetic heart

Diabetes mellitus and heart failure: insights from a toxic relationship

Diabetes mellitus and heart failure: insights from a toxic relationship

Downregulation of allograft inflammatory factor-1 prevents B cell infiltration to cardiac tissue during the development of diabetic cardiomyopathy (DCM)

Abstract An emerging concept is that inflammation might be linked to alteration of immune system, thus leading to adverse cardiac function, remodeling in DCM. However, the role of inflammatory pathways during development of DCM is poorly understood and controversial, as both positive/negative effects of inflammation have been observed. 8 weeks wild type male mice were injected with streptozotocin (50 mg/kg, 5 days intraperitoneally) and studied 8 weeks after induction of diabetes mellitus having elevated blood glucose levels (>300 mg/dL) and DCM was confirmed through ECG. We found a significant decrease in B cell infiltration into left ventricular heart, but not in other organs, during DCM. Interestingly, downregulation of B cell infiltration correlates with downregulation of a B cell inflammatory molecule expression, Allograft Inflammatory Factor-1 (AIF-1), which has been reported to enhance lymphocyte activation. Our in vitro study showed that B cell migration is regulated by AIF-1 expression. We observed significant migration of B cells to hyperglycemic AIF-1 transfected H9C2cells compared to control cells transfected with an empty vector. In vivo studies showed strong co-localization of AIF-1 and CD19 B-cell marker in nondiabetic heart tissue compared with diabetic heart tissue. Interestingly, AdAIF-1 overexpression promoted B cell migration into diabetic hearts, reduced inflammation and pathological remodeling. These data suggest that AIF-1 downregulation in cardiac myocytes is caused by diabetes that prevents B cell infiltration into hearts, and increase cardiac inflammation that leads to cardiomyocyte death and that overexpression of AIF-1 could be a novel treatment for this condition.

Comparison of Cardiac miRNA Transcriptomes Induced by Diabetes and Rapamycin Treatment and Identification of a Rapamycin-Associated Cardiac MicroRNA Signature.

Rapamycin (Rap), an inhibitor of mTORC1, reduces obesity and improves lifespan in mice. However, hyperglycemia and lipid disorders are adverse side effects in patients receiving Rap treatment. We previously reported that diabetes induces pansuppression of cardiac cytokines in Zucker obese rats (ZO-C). Rap treatment (750 μg/kg/day for 12 weeks) reduced their obesity and cardiac fibrosis significantly; however, it increased their hyperglycemia and did not improve their cardiac diastolic parameters. Moreover, Rap treatment of healthy Zucker lean rats (ZL-C) induced cardiac fibrosis. Rap-induced changes in ZL-C's cardiac cytokine profile shared similarities with that of diabetes-induced ZO-C. Therefore, we hypothesized that the cardiac microRNA transcriptome induced by diabetes and Rap treatment could share similarities. Here, we compared the cardiac miRNA transcriptome of ZL-C to ZO-C, Rap-treated ZL (ZL-Rap), and ZO (ZO-Rap). We report that 80% of diabetes-induced miRNA transcriptome (40 differentially expressed miRNAs by minimum 1.5-fold in ZO-C versus ZL-C; p ≤ 0.05) is similar to 47% of Rap-induced miRNA transcriptome in ZL (68 differentially expressed miRNAs by minimum 1.5-fold in ZL-Rap versus ZL-C; p ≤ 0.05). This remarkable similarity between diabetes-induced and Rap-induced cardiac microRNA transcriptome underscores the role of miRNAs in Rap-induced insulin resistance. We also show that Rap treatment altered the expression of the same 17 miRNAs in ZL and ZO hearts indicating that these 17 miRNAs comprise a unique Rap-induced cardiac miRNA signature. Interestingly, only four miRNAs were significantly differentially expressed between ZO-C and ZO-Rap, indicating that, unlike the nondiabetic heart, Rap did not substantially change the miRNA transcriptome in the diabetic heart. In silico analyses showed that (a) mRNA-miRNA interactions exist between differentially expressed cardiac cytokines and miRNAs, (b) human orthologs of rat miRNAs that are strongly correlated with cardiac fibrosis may modulate profibrotic TGF-β signaling, and (c) changes in miRNA transcriptome caused by diabetes or Rap treatment include cardioprotective miRNAs indicating a concurrent activation of an adaptive mechanism to protect the heart in conditions that exacerbate diabetes.

Combined postconditioning with ischemia and cyclosporine-A restore oxidative stress and histopathological changes in reperfusion injury of diabetic myocardium.

Objective(s):Chronic diabetes impedes cardioprotection in reperfusion injury and hence protecting the diabetic heart would have important outcomes. In this study, we evaluated whether combined postconditioning with ischemia and cyclosporine-A can restore oxidative stress and histopathological changes in reperfusion injury of the diabetic myocardium.Materials and Methods:Streptozocin-induced diabetic hearts and nondiabetic controls in eight subgroups (with or without receiving ischemic-postconditioning (IPostC), cyclosporine-A, an inhibitor of mitochondrial permeability transition, or both of them) suffered from 30 min regional ischemia followed by 45 min reperfusion on an isolated-heart Langendorff system. The levels of lactate dehydrogenase (LDH) in the coronary effluent, and the levels of oxidative stress markers including 8-isoprostane, superoxide dismutase (SOD), glutathione peroxidase (GPX), and total antioxidant capacity (TAC) in myocardial supernatant prepared from the ischemic zone were measured using specific kits, spectrophotometrically. Histopathological studies were performed -eosin staining method.Results:Administration of IPostC and cyclosporine-A (alone or together) in nondiabetic hearts potentially reduced the severity of histological changes and level of LDH release as compared with untreated-controls (P<0.05). of any procedures in diabetic hearts did not show significant cardioprotective effects (P>0.1). However, the combined postconditioning with ischemia and CsA exerted significant protective effects in diabetic hearts (P<0.05).Conclusion:By augmenting the protective effects of IPostC and CsA through their combined application, reperfusion injury and related oxidative stress are reduced in diabetic hearts similar to non-diabetics.