Phenolics Extracted from Jasminum sambac Mitigates Diabetic Cardiomyopathy by Modulating Oxidative Stress, Apoptotic Mediators and the Nfr-2/HO-1 Pathway in Alloxan-Induced Diabetic Rats.

Diabetes mellitus is a chronic metabolic disorder defined as hyperglycemia and pancreatic ß-cell deterioration, leading to other complications such as cardiomyopathy. The current study assessed the therapeutic effects of phenolic acids extracted from Jasminum sambac phenols of leaves (JSP) against diabetes-induced cardiomyopathy in rats. The rats were divided into four groups, with each group consisting of 20 rats. The rats were given intraperitoneal injections of alloxan monohydrate (150 mg/kg) to induce diabetes. The diabetes-induced groups (III and IV) received treatment for six weeks that included 250 and 500 mg/kg of JSP extract, respectively. In the treated rats, the results demonstrated that JSP extract restored fasting glucose, serum glucose, and hyperlipidemia. Alloxan induced cardiomyopathy, promoted oxidative stress, and altered cardiac function biomarkers, including cardiac troponin I, proBNP, CK-MB, LDH, and IMA. The JSP extract-treated rats showed improved cardiac function indicators, apoptosis, and oxidative stress. In diabetic rats, the mRNA expression of caspase-3, BAX, and Bcl-2 was significantly higher, while Bcl-2, Nrf-2, and HO-,1 was significantly lower. In the treated groups, the expression levels of the BAX, Nrf-2, HO-1, Caspase-3, and Bcl-2 genes were dramatically returned to normal level. According to our findings, the JSP extract prevented cardiomyopathy and heart failure in the hyperglycemic rats by improving cardiac biomarkers and lowering the levels of hyperlipidemia, oxidative stress, apoptosis, hyperglycemia, and hyperlipidemia.

NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity; its nature is insidious, complex and difficult to treat. NLRP3 inflammasome triggers the maturation and release of pro-inflammatory cytokines, participates in pathophysiological processes such as insulin resistance and myocardial fibrosis, in addition to being closely related to the development and progression of diabetic cardiomyopathy. The development of inhibitors targeting specific aspects of inflammation suggests that NLRP3 inflammasome can be used to treat diabetic cardiomyopathy. This paper aims to summarize NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy, and to provide new suggestions for the treatment of this disease.

La cardiomiopatía diabética es una complicación grave de la diabetes causada por estrés oxidativo, inflamación, resistencia a la insulina, fibrosis miocárdica y lipotoxicidad. Se trata de un padecimiento insidioso, complejo y difícil de tratar. El inflamasoma NLRP3 desencadena la maduración y liberación de citoquinas proinflamatorias, participa en procesos fisiopatológicos como la resistencia a la insulina y la fibrosis miocárdica, además de estar estrechamente relacionado con la aparición y progresión de la cardiomiopatía diabética. El desarrollo de inhibidores dirigidos a aspectos específicos de la inflamación sugiere que el inflamasoma NLRP3 puede utilizarse para tratar la cardiomiopatía diabética. Este artículo pretende resumir el mecanismo y las dianas terapéuticas del inflamasoma NLRP3 en la cardiomiopatía diabética, así como aportar nuevas sugerencias para el tratamiento de esta enfermedad.

Guidelines on models of diabetic heart disease.

Diabetes is a major risk factor for cardiovascular diseases, including diabetic cardiomyopathy, atherosclerosis, myocardial infarction, and heart failure. As cardiovascular disease represents the number one cause of death in people with diabetes, there has been a major emphasis on understanding the mechanisms by which diabetes promotes cardiovascular disease, and how antidiabetic therapies impact diabetic heart disease. With a wide array of models to study diabetes (both type 1 and type 2), the field has made major progress in answering these questions. However, each model has its own inherent limitations. Therefore, the purpose of this guidelines document is to provide the field with information on which aspects of cardiovascular disease in the human diabetic population are most accurately reproduced by the available models. This review aims to emphasize the advantages and disadvantages of each model, and to highlight the practical challenges and technical considerations involved. We will review the preclinical animal models of diabetes (based on their method of induction), appraise models of diabetes-related atherosclerosis and heart failure, and discuss in vitro models of diabetic heart disease. These guidelines will allow researchers to select the appropriate model of diabetic heart disease, depending on the specific research question being addressed.

Biochanin A Attenuates Cardiomyopathy in Type 2 Diabetic Rats by Increasing SIRT1 Expression and Reducing Oxidative Stress.

Diabetic cardiomyopathy is one of the major complications in type 2 diabetes associated with myocardial structure abnormality and major cause of morbidity in type 2 diabetic patients. Biochanin A is a methylated isoflavone present in flowering tops of Trifolium pratense reported for anti-inflammatory, anti-oxidant, anti-infective, anti-cancer and anti-diabetic activity. The study was designed to assess the efficacy of Biochanin A in type 2 diabetic cardiomyopathy. Type 2 diabetes was induced in rats feeding high fat diet for two weeks and administration of single low dose of streptozotocin. Biochanin A was administered for 16 weeks orally once in a day (10, 20 and 40 mg/kg of body weight). Various parameters such as blood glucose, cardiac markers, oxidative stress and hemodynamic parameters, immunohistochemical, histopathological investigation and SIRT1 expression were measured at the end of the study. Biochanin A treatment resulted into reduction in plasma concentration of cardiac markers along with reduction in hyperglycemia, hyperlipidemia and oxidative stress in cardiac tissue. Biochanin A treated animals also demonstrated improvement in hemodynamic parameters. Diabetic animals treated with different doses of Biochanin A shown increased SIRT1 expression in cardiac tissue, and also confirmed reduced cardiac hypertrophy and cardiac protection in histopathological study. Outcome of the study indicates that Biochanin A is the potential candidate to control hyperglycemia, oxidative stress and improve SIRT1 expression in cardiac tissue. Biochanin A might be considered as potential candidate to control progression of cardiomyopathy in type 2 diabetes mellitus.

Prostaglandin E receptor subtype 4 protects against diabetic cardiomyopathy by modulating cardiac fatty acid metabolism via FOXO1/CD36 signalling.

BACKGROUND: Cardiac fatty acid metabolism is essential for maintaining normal cardiac function at baseline and in response to various disease stress, like diabetes. EP4 is widely expressed in cardiomyocytes and has been demonstrated to play a role in cardio function. However, its function in regulating cardiac fatty acid metabolism is remained unknown. METHODS: Mice were fed with standard chow or high-fat for eight weeks. The effects of EP4 deficiency on cardiac function, cardiomyocytes hypertrophy and myocardial fibrosis were studied. The possible regulatory mechanisms were further investigated. RESULTS: EP4-/- mice exhibited concentric hypertrophy and myocardial fibrosis with cardiac energy deprivation due to reduction of fatty acid uptake and inhibition of ATP generation mediated by FOXO1/CD36 signalling. Moreover, pharmacologically activated EP4 alleviated impaired fatty acid transport and insufficient ATP generation in cardiomyocytes. CONCLUSION: EP4 tightly coordinates the rates of cardiac fatty acid uptake and ATP generation via FOXO1/CD36 signalling axis. Our study provides evidences for the link between EP4 and cardiac fatty acid transport and further pointed out that EP4 could be a potential target for modulating fatty acid metabolism and curbing cardiac tissue-specific impairment of function following diabetes.

Engineered cardiac tissues: a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy.

Rodent diabetic models, used to understand the pathophysiology of diabetic cardiomyopathy (DCM), remain several limitations. Engineered cardiac tissues (ECTs) have emerged as robust 3D in vitro models to investigate structure-function relationships as well as cardiac injury and repair. Advanced glycation end-products (AGEs), produced through glycation of proteins or lipids in response to hyperglycemia, are important pathogenic factor for the development of DCM. In the current study, we developed a murine-based ECT model to investigate cardiac injury produced by AGEs. We treated ECTs composed of neonatal murine cardiac cells with AGEs and observed AGE-related functional, cellular, and molecular alterations: (1) AGEs (150 µg/mL) did not cause acute cytotoxicity, which displayed as necrosis detected by medium LDH release or apoptosis detected by cleaved caspase 3 and TUNEL staining, but negatively impacted ECT function on treatment day 9; (2) AGEs treatment significantly increased the markers of fibrosis (TGF-ß, α-SMA, Ctgf, Collagen I-α1, Collagen III-α1, and Fn1) and hypertrophy (Nppa and Myh7); (3) AGEs treatment significantly increased ECT oxidative stress markers (3-NT, 4-HNE, HO-1, CAT, and SOD2) and inflammation response markers (PAI-1, TNF-α, NF-κB, and ICAM-1); and (4) AGE-induced pathogenic responses were all attenuated by pre-application of AGE receptor antagonist FPS-ZM1 (20 µM) or the antioxidant glutathione precursor N-acetylcysteine (5 mM). Therefore, AGEs-treated murine ECTs recapitulate the key features of DCM's functional, cellular and molecular pathogenesis, and may serve as a robust in vitro model to investigate cellular structure-function relationships, signaling pathways relevant to DCM and pharmaceutical intervention strategies.

N-Acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators.

Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.

In vitro and in vivo cardioprotective and metabolic efficacy of vitamin E TPGS/Apelin.

AIMS: Apelin and vitamin E have been proposed as signaling molecules, but their synergistic role is unknown. The aim of this work was to develop vitamin E TPGS/Apelin system to test their cardioprotective and metabolic efficacy in vitro and in vivo. METHODS: FDA-approved surfactant D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-1000) and Apelin complex were characterized by physico-chemical methods (CMC determination, dynamic light scattering and circular dichroism). In vitro studies were carried out on H9C2 cardiomyoblasts and isolated murine cardiomyocytes. In vivo studies were performed in isoproterenol- and high-fat diet-induced cardiac remodeling models in mice. RESULTS: We found that vitamin E TPGS/Apelin provide cardioprotective and metabolic efficacy in vitro and in vivo. In vitro studies revealed that vitamin E TPGS/Apelin reduces hypoxia-induced mitochondrial ROS production in cultured cardiomyocytes and H9C2 cardiomyoblasts. In addition, vitamin E TPGS/Apelin confers apoptotic response to hypoxic stress in cells. In a mouse model of isoproterenol-induced cardiac injury, TPGS is not able to affect cardiac remodeling, however combination of vitamin E TPGS and Apelin counteracts myocardial apoptosis, oxidative stress, hypertrophy and fibrosis. Furthermore, combination treatment attenuated obesity-induced cardiometabolic and fibrotic remodeling in mice. CONCLUSION: Together, our data demonstrated the therapeutic benefits of vitamin E TPGS/Apelin complex to combat cardiovascular and metabolic disorders.

Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats.

Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) following the disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over-activation and consequently attenuate DCM. Streptozotocin-induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure-volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15-F2t-Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme-linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT-PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end-systolic volume (LVVs) as compared to non-diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P < .05). Hearts of diabetic rats displayed excessive oxidative stress manifested as increased levels of 15-F2t-Isoprostane and superoxide anion production, increased apoptotic cell death and cardiomyocytes autophagy that were concomitant with reduced expressions of Nrf2, heme oxygenase-1 (HO-1) and Keap1. ALP reverted all the above-mentioned diabetes-induced biochemical changes except that it did not affect the levels of Keap1. In vitro, ALP increased Nrf2 and reduced the hyperglycaemia-induced increases of H9C2 cardiomyocyte hypertrophy, oxidative stress, apoptosis and autophagy, and enhanced cellular viability. Nrf2 gene silence cancelled these protective effects of ALP in H9C2 cells. Activation of Nrf2 subsequent to the suppression of Keap1 and the mitigation of autophagy over-activation may represent major mechanisms whereby ALP attenuates DCM.

The association between bacterial infections and the risk of coronary heart disease in type 1 diabetes.

BACKGROUND: Diabetes increases the risk of infections and coronary heart disease (CHD). Whether infections increase the risk of CHD and how this applies to individuals with diabetes is unclear. OBJECTIVES: To investigate the association between bacterial infections and the risk of CHD in type 1 diabetes. METHODS: Individuals with type 1 diabetes (n = 3781) were recruited from the Finnish Diabetic Nephropathy Study (FinnDiane), a prospective follow-up study. CHD was defined as incident events: fatal or nonfatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, identified through national hospital discharge register data. Infections were identified through national register data on all antibiotic purchases from outpatient care. Register data were available from 1 January 1995 to 31 December 2015. Bacterial lipopolysaccharide (LPS) activity was measured from serum samples at baseline. Data on traditional risk factors for CHD were collected during baseline and consecutive visits. RESULTS: Individuals with an incident CHD event (n = 370) had a higher mean number of antibiotic purchases per follow-up year compared to those without incident CHD (1.34 [95% CI: 1.16-1.52], versus 0.79 [0.76-0.82], P < 0.001), as well as higher levels of LPS activity (0.64 [0.60-0.67], versus 0.58 EU mL-1 [0.57-0.59], P < 0.001). In multivariable-adjusted Cox proportional hazards models, the mean number of antibiotic purchases per follow-up year was an independent risk factor for incident CHD (HR 1.21, 95% CI: 1.14-1.29, P < 0.0001). High LPS activity was a risk factor for incident CHD (HR 1.93 [1.34-2.78], P < 0.001) after adjusting for static confounders. CONCLUSION: Bacterial infections are associated with an increased risk of incident CHD in individuals with type 1 diabetes.

The metabolic syndrome in heart failure: insights to specific mechanisms.

The presence of comorbidities significantly influences long-term morbidity and mortality of symptomatic and asymptomatic heart failure (HF) patients. Metabolic syndrome and diabetic cardiomyopathy are two clinical conditions that share multiple pathophysiological mechanisms and that might be both responsible for cardiac dysfunction. However, it is argued whether metabolic syndrome (MS) independently increases HF risk or the association between MS and HF merely reflects the impact of individual risk factors included in its definition on HF development. Similarly, in the context of diabetic cardiomyopathy, many aspects are still challenging starting from the definition up to the therapeutic management. In this clinical review, we focused the attention on molecular pathways, myocyte alterations, and specific patterns of metabolic syndrome and diabetic cardiomyopathy in order to better define the potential diagnostic and therapeutic approaches of these two pathological conditions.

Impact of Cardio-Renal-Metabolic Comorbidities on Cardiovascular Outcomes and Mortality in Type 2 Diabetes Mellitus.

BACKGROUND: We evaluated the incremental contribution of chronic kidney disease (CKD) to the risk of major adverse cardiovascular (CV) events (MACE), heart failure (HF), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients and its importance relative to the presence of other cardio-renal-metabolic (CaReMe) comorbidities. METHODS: Patients (≥40 years) were identified at the time of T2DM diagnosis from US (Humedica/Optum) and UK (Clinical Practice Research Datalink) databases. Patients were monitored post-diagnosis for modified MACE (myocardial infarction, stroke, ACM), HF, and ACM. Adjusted hazard ratios were obtained using Cox proportional-hazards regression to evaluate the relative risk of modified MACE, HF, and ACM due to CKD. Patients were stratified by the presence or absence of atherosclerotic CV disease (ASCVD) and age. RESULTS: Between 2011 and 2015, of 227,224 patients identified with incident T2DM, 40,063 (17.64%) had CKD. Regardless of prior ASCVD, CKD was associated with higher risk of modified MACE, HF, and ACM; this excess hazard was more pronounced in older patients with prior ASCVD. In time-to-event analyses in the overall cohort, patients with T2DM + CKD or T2DM + CKD + hypertension + hyperlipidemia had increased risks for modified MACE, HF, and ACM versus patients with T2DM and no CaReMe comorbidities. Patients with CKD had higher risks for and shorter times to modified MACE, HF, and ACM than those without CKD. CONCLUSION: In T2DM patients, CKD presence was associated with higher risk of modified MACE, HF, and ACM. This may have risk-stratification implications for T2DM patients based on background CKD and highlights the potential importance of novel renoprotective strategies.

The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity-mediated diabetic cardiomyopathy.

Sirtuins (Sirts) are implicated in regulating a myriad of biologic functions ranging from cell growth and metabolism to longevity. Here, we show that nuclear Sirt, Sirt6, and mitochondrial Sirt, Sirt3, regulate each other's activity and protect the heart from developing diabetic cardiomyopathy. We found that expression of both Sirt6 and Sirt3 was reduced in cardiomyocytes treated with palmitate and in hearts of mice fed with a high-fat, high-sucrose (HF-HS) diet to develop obesity and diabetes. Conversely, whole-body overexpressing Sirt6 transgenic (Tg.Sirt6) mice were protected from developing obesity and insulin resistance when fed with the same HF-HS diet. The hearts of Tg.Sirt6 mice were also protected from mitochondrial fragmentation and decline of Sirt3, resulting otherwise from HF-HS diet feeding. Mechanistic studies showed that Sirt3 preserves Sirt6 levels by reducing oxidative stress, whereas Sirt6 maintains Sirt3 levels by up-regulating nuclear respiratory factor 2 (Nrf2)-dependent Sirt3 gene transcription. We found that Sirt6 regulates Nrf2-mediated cardiac gene expression in 2 ways; first, Sirt6 suppresses expression of Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, and second, Sirt6 binds to Nrf2 and antagonizes its interaction with Keap1, thereby stabilizing Nrf2 levels in cardiomyocytes. Together, these studies demonstrate that Sirt6 and Sirt3 maintain each other's activity and protect the heart from developing diabetic cardiomyopathy.-Kanwal, A., Pillai, V. B., Samant, S., Gupta, M., Gupta, M. P. The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity-mediated diabetic cardiomyopathy.

Myocardial Function Assessed by Multi-Layered Two-Dimensional Speckle Tracking Analysis in Asymptomatic Young Subjects with Diabetes Mellitus Type 1.

BACKGROUND: Diabetes mellitus type 1 (DM1) is associated with a high risk for cardiovascular disease, and early detection of myocardial dysfunction is crucial for the prevention of cardiac complications. OBJECTIVES: The aim of this study was to evaluate left ventricular (LV) and right ventricular (RV) function by using both conventional echocardiography as well as multi-layered speckle tracking echocardiography (STE) in young adults with DM1. METHODS: We included 50 young asymptomatic adults diagnosed with DM1 (mean interval from diagnosis 9 ± 6 years) and 80 healthy controls. STE was acquired using the GE Vivid S60 equipment. The LV longitudinal strain (LS), layer-specific strains of the endocardium, myocardium, and epicardium (global longitudinal strain [GLS]endo, GLSmyo, GLSepi) as well as RV strain were obtained using the EchoPAC BT13 workstation. RESULTS: No significant intergroup differences in LV ejection fraction were noted. GLSendo and GLSmyo were reduced in the DM1 group (-20.6 ± 2.7 vs. -22.0 ± 2.3 and -18.0 ± 2.4 vs. -19.1 ± 1.9, respectively, p < 0.05) compared to controls. Mechanical dispersion was higher in the diabetes group (34 ± 11 vs. 29 ± 7, p < 0.05). RV strain measurements showed no significant difference between the groups. CONCLUSIONS: Young adults with DM1 and without known heart disease have subclinical myocardial dysfunction with lower LV endocardium and myocardium LS and higher mechanical dispersion demonstrated by multi-layered STE.

Sex-specific prevalence of coronary heart disease among Tehranian adult population across different glycemic status: Tehran lipid and glucose study, 2008-2011.

BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of death. Alarmingly Iranian populations had a high rank of CHD worldwide. The current study aimed to assess the prevalence of CHD across different glycemic categories. METHODS: This study was conducted on 7718 Tehranian participants (Men = 3427) aged ≥30 years from 2008 to 2011. They were categorized based on glycemic status. The prevalence of CHD was calculated in each group separately. CHD was defined as hospital records adjudicated by an outcome committee. The association of different glycemic categories with CHD was calculated using multivariate logistic regression, compared with normal fasting glucose /normal glucose tolerance (NFG/NGT) group as reference. RESULTS: The age-standardized prevalence of isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT), both impaired fasting glucose and impaired glucose tolerance (IFG/IGT), newly diagnosed diabetes mellitus (NDM), and known diabetes mellitus (KDM) were 14.30% [95% confidence interval (CI): 13.50-15.09], 4.81% [4.32-5.29], 5.19% [4.71-5.67], 5.79% [5.29-6.28] and 7.72% [7.17-8.27], respectively. Among a total of 750 individuals diagnosed as cases of CHD (398 in men), 117 (15.6%), 453 (60.4%), and 317 (42.3%) individuals had a history of myocardial infarction (MI), cardiac procedure, and unstable angina, respectively. The age-standardized prevalence of CHD for the Tehranian population was 7.71% [7.18-8.24] in the total population, 8.62 [7.81-9.44] in men and 7.19 [6.46-7.93] in women. Moreover, among diabetic participants, the age-standardized prevalence of CHD was 13.10 [9.83-16.38] in men and 10.67 [8.90-12.44] in women, significantly higher than corresponding values for NFG/NGT and prediabetic groups. Across six levels of glycemic status, CHD was associated with IFG/IGT [odds ratio (OR) and 95% CI: 1.38 (1.01-1.89)], NDM [1.83 (1.40-2.41)], and KDM [2.83 (2.26-3.55)] groups, in the age- and sex-adjusted model. Furthermore, in the full-adjusted model, only NDM and KDM status remained to be associated with the presence of CHD by ORs of 1.40 (1.06-1.86) for NDM and 1.91 (1.51-2.43) for KDM. CONCLUSION: The high prevalence of CHD, especially among diabetic populations, necessitates the urgent implementation of behavioral interventions in the Tehranian population, according to evidence-based guidelines for the clinical management of diabetic patients.

4-O-methylhonokiol protects against diabetic cardiomyopathy in type 2 diabetic mice by activation of AMPK-mediated cardiac lipid metabolism improvement.

Diabetic cardiomyopathy (DCM) is characterized by increased left ventricular mass and wall thickness, decreased systolic function, reduced ejection fraction (EF) and ultimately heart failure. The 4-O-methylhonokiol (MH) has been isolated mainly from the bark of the root and stem of Magnolia species. In this study, we aimed to elucidate whether MH can effectively prevent DCM in type 2 diabetic (T2D) mice and, if so, whether the protective response of MH is associated with its activation of AMPK-mediated inhibition of lipid accumulation and inflammation. A total number of 40 mice were divided into four groups: Ctrl, Ctrl + MH, T2D, T2D + MH. Five mice from each group were sacrificed after 3-month MH treatment. The remaining animals in each group were kept for additional 3 months without further MH treatment. In T2D mice, the typical DCM symptoms were induced as expected, reflected by decreased ejection fraction and lipotoxic effects inducing lipid accumulation, oxidative stress, inflammatory reactions, and final fibrosis. However, these typical DCM changes were significantly prevented by the MH treatment immediately or 3 months after the 3-month MH treatment, suggesting MH-induced cardiac protection from T2D had a memory effect. Mechanistically, MH cardiac protection from DCM may be associated with its lipid metabolism improvement by the activation of AMPK/CPT1-mediated fatty acid oxidation. In addition, the MH treatment of DCM mice significantly improved their insulin resistance levels by activation of GSK-3ß. These results indicate that the treatment of T2D with MH effectively prevents DCM probably via AMPK-dependent improvement of the lipid metabolism.

Right ventricular dysfunction and remodeling in diabetic cardiomyopathy.

The increasing prevalence of diabetic cardiomyopathy (DCM) is an important threat to health worldwide. While left ventricular (LV) dysfunction in DCM is well recognized, the accurate detection, diagnosis, and treatment of changes in right ventricular (RV) structure and function have not been well characterized. The pathophysiology of RV dysfunction in DCM may share features with LV diastolic and systolic dysfunction, including pathways related to insulin resistance and oxidant injury, although the RV has a unique cellular origin and composition and unique biomechanical properties and is coupled to the lower-impedance pulmonary vascular bed. In this review, we discuss potential mechanisms responsible for RV dysfunction in DCM and review the imaging approaches useful for early detection, protection, and intervention strategies. Additional data are required from animal models and clinical trials to better identify the onset and features of altered RV and pulmonary vascular structure and function during the onset and progression of DCM and to determine the efficacy of early detection and treatment of RV dysfunction on clinical symptoms and outcomes.

Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation.

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after ß-sympathetic blockade.

Overexpression of scavenger receptor and infiltration of macrophage in epicardial adipose tissue of patients with ischemic heart disease and diabetes.

BACKGROUND: Oxidized low-density lipoproteins and scavenger receptors (SRs) play an important role in the formation and development of atherosclerotic plaques. However, little is known about their presence in epicardial adipose tissue (EAT). The objective of the study was to evaluate the mRNA expression of different SRs in EAT of patients with ischemic heart disease (IHD), stratifying by diabetes status and its association with clinical and biochemical variables. METHODS: We analyzed the mRNA expression of SRs (LOX-1, MSR1, CXCL16, CD36 and CL-P1) and macrophage markers (CD68, CD11c and CD206) in EAT from 45 patients with IHD (23 with type 2 diabetes mellitus (T2DM) and 22 without T2DM) and 23 controls without IHD or T2DM. RESULTS: LOX-1, CL-P1, CD68 and CD11c mRNA expression were significantly higher in diabetic patients with IHD when compared with those without T2DM and control patients. MSR1, CXCL16, CD36 and CD206 showed no significant differences. In IHD patients, LOX-1 (OR 2.9; 95% CI 1.6-6.7; P = 0.019) and CD68 mRNA expression (OR 1.7; 95% CI 0.98-4.5; P = 0.049) were identified as independent risk factors associated with T2DM. Glucose and glycated hemoglobin were also shown to be risk factors. CONCLUSIONS: SRs mRNA expression is found in EAT. LOX-1 and CD68 and were higher in IHD patients with T2DM and were identified as a cardiovascular risk factor of T2DM. This study suggests the importance of EAT in coronary atherosclerosis among patients with T2DM.

Diabetic Cardiomyopathy: Definition, Diagnosis, and Therapeutic Implications.

A strict bidirectional relationship exists between diabetes mellitus and heart failure. Diabetic cardiomyopathy is a specific cardiac manifestation of patients with diabetes characterized by left ventricular hypertrophy and diastolic dysfunction in the early phase up to overt heart failure with reduced systolic function in the advanced stages. The pathogenesis of this condition is multifactorial and recognizes as main promoting factors the presence of insulin resistance and hyperglycemia. Diabetic cardiomyopathy exerts a negative prognostic impact in affected patients and no target treatments are currently available. More efforts are needed to better define the diagnostic and therapeutic approach in this specific setting.