This study aimed to explore metabolic reprogramming in diabetic myocardium subjected to ischemia-reperfusion injury (I/RI) and potential mechanisms.

Increased vulnerability after I/RI in diabetic myocardium is a major cause of the high prevalence of perioperative adverse cardiac events, and the specific alterations in energy metabolism after I/RI in diabetic myocardium and the impact on increased vulnerability are not fully understood.

Metabolomic methods were used to explore the differences and characteristics of metabolites in the heart tissues of four groups, and then, single-cell RNA sequencing (ScRNA-seq) was used to explore the potential mechanism of metabolic reprogramming.

It was found that the fatty acid metabolism of db/db mouse I/RI (DMI) showed a significant upward trend, especially the metabolites of ultra-long and medium-long-chain fatty acids; the metabolic flow analysis found that the U-13C glucose M + 6 was significantly higher in the C57BL mouse sham operation (NM) group than in the db/db mouse sham operation (DM) group, and in the C57BL mouse I/RI (NMI) than in the DMI group. Compared with the NMI group, the intermediate metabolites of glycolysis and tricarboxylic acid (TCA) cycle were significantly reduced in the DMI group; all comparisons were statistically significant (p < 0.05), indicating that the glucose uptake of diabetic myocardetis, the ability of glucose glycolysis after I/RI, and the contribution of glucose to TCA were significantly reduced. The results of ScRNA-seq revealed that the number of Cluster 0 myocardial isoforms was significantly increased in diabetic myocardium, and the differential genes were mainly enriched in fatty acid metabolism, and the PPARA signaling pathway was found to be over-activated and involved in the regulation of metabolic reprogramming of diabetic myocardial I/RI.

Metabolic reprogramming of diabetic myocardial I/RI may be the main cause of increased myocardial vulnerability. The number of myocardial subtype Cluster 0 increased significantly, and PPARA PPARA is a ligand-activated receptor of the nuclear hormone receptor family that plays a central regulatory role in lipid metabolism. signaling pathway activation may be a potential mechanism for reprogramming metabolism in diabetic myocardium.

This educational review provides information about the epidemiology of diabetes and heart failure (diabetic cardiomyopathy) and the challenges in diagnosis and screening. Details on how to investigate patients with imaging and other modalities are discussed, as well as an update regarding the efficacy and safety of novel agents for treatment of diabetic cardiomyopathy.

The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1 diabetes mellitus (DM) and 52% of deaths in type 2 DM. Diabetes elicits cardiovascular dysfunction through 2 major mechanisms: ischemic and non-ischemic. Non-ischemic injury is usually under-recognized although common in DM patients, and also a pathogenic factor of heart failure in those diabetic individuals complicated with ischemic heart disease. Diabetic cardiomyopathy (DCM) is defined as a heart disease in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertensive, valvular, or congenital heart disorders in diabetic patients, theoretically caused by non-ischemic injury solely. Current therapeutic strategies targeting DCM mainly address the increased blood glucose levels, however, the effects on heart function are disappointed. Accumulating data indicate endothelial dysfunction plays a critical role in the initiation and development of DCM. Hyperglycemia, hyperinsulinemia, and insulin resistance cause the damages of endothelial function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory dysregulation. In turn, endothelial dysfunction promotes impaired myocardial metabolism, intracellular Ca²⁺ mishandling, endoplasmic reticulum (ER) stress, mitochondrial defect, accumulation of advanced glycation end products, and extracellular matrix (ECM) deposit, leads to cardiac stiffness, fibrosis, and remodeling, eventually results in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. While endothelial dysfunction is closely related to cardiac dysfunction and heart failure seen in DCM, clinical strategies for restoring endothelial function are still missing. This review summarizes the timely findings related to the effects of endothelial dysfunction on the disorder of myocardium as well as cardiac function, provides mechanical insights in pathogenesis and pathophysiology of DCM developing, and highlights potential therapeutic targets.

Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.

Due to the multiple biological activities of polysaccharides, their great potential as "natural drugs" for many diseases has been the subject of continuous exploration in the field of food and nutrition. Apoptosis and autophagy play a key role in mammalian growth, development and maintenance of cellular homeostasis. Recent studies suggest that apoptosis/autophagy may be the key regulatory target for the beneficial effects of polysaccharides. However, the regulation of apoptosis and autophagy by polysaccharides is not consistent in different disease models. Therefore, this review outlined the relationship between apoptosis/autophagy and some common human diseases, then discussed the role of apoptosis/autophagy pathway in the regulation of human health by polysaccharides, Furthermore, the application of visualization, imaging and multi-omics techniques was proposed in the future trend. The present review may be beneficial to accelerate our understanding of the anti-disease mechanisms of polysaccharides, and promote the development and utilization of polysaccharides.

Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. Fibroblast growth factor 21 (FGF21) has been proved to have cardioprotective effect in DCM. However, the insufficient cardiac delivery effect of FGF21 limits its application in DCM. Therefore, to improve the therapeutic efficacy of FGF21 in DCM, an effective drug delivery system is urgently required. In this study, perfluoropropane (C₃F₈) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles (CPPNBs) were synthesized via double-emulsion evaporation and FGF21 was efficiently absorbed (CPPNBs@FGF21) via the electrostatic incorporation effect. CPPNBs@FGF21 could effectively deliver FGF21 to the myocardial tissue through the cavitation effect under low-frequency ultrasound (LFUS). The as-prepared CPPNBs@FGF21 could efficiently load FGF21 after doping with the cationic polymer PEI, and displayed uniform dispersion and favorable biosafety. After filling with C₃F₈, CPPNBs@FGF21 could be used for distribution monitoring through ultrasound imaging. Moreover, CPPNBs@FGF21 significantly downregulated the expression of ANP, CTGF, and caspase-3 mRNA via the action of LFUS owing to increased FGF21 release, therefore exhibiting enhanced inhibition of myocardial hypertrophy, apoptosis, and interstitial fibrosis in DCM mice. In conclusion, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM. STATEMENT OF SIGNIFICANCE: Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks effective clinical treatments. Fibroblast growth factor 21 (FGF21) can protect cardiomyocytes from diabetic damage, but insufficient cardiac drug delivery limits the application of FGF21 in DCM. In this study, perfluoropropane (C3F8) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles loaded with FGF21 (CPPNBs@FGF21) were developed for the prophylactic treatment of DCM. CPPNBs@FGF21 could effectively deliver the FGF21 to the myocardial tissue through the cavitation effect of low-frequency ultrasound (LFUS). Our results indicated that CPPNBs@FGF21 combined with LFUS could significantly down-regulate the expressions of ANP, CTGF, and caspase-3 mRNA, and as a result, it prevented the myocardial hypertrophy, apoptosis, and interstitial fibrosis of DCM mice. Overall, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM.

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a "snapshot" showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy.

Insulin promotes glucose consumption as the main cardiac energy source, while increasing myocardial efficiency. The short-term effects of insulin on cardiac function and its potential curative role in an acute diabetological cardiology setting remain unknown. Our study evaluated the role of acute insulin administration in the diabetic heart, its corresponding effective blood insulin level, and the time-course applicability of insulin treatment in a routine clinical setting.

We evaluated a case series of six male (48.1 ± 4.9 y/o) patients with controlled diabetes (HbA1c of 6.6 ± 0.3%) and disease duration of 14.4 ± 6.7 yr. Each subject was evaluated for glucose homeostasis, as well as hemodynamic and echocardiographic (systolic and diastolic) parameters at three points: baseline followed by two successive insulin loads in euglycemic hyperinsulinemic clamp study. Results were analysed using Student's t-test.

The first insulin load led to a physiologic blood insulin level of 145 ± 36 μU/ml, and both systolic (7 mmHg) blood pressure and diastolic (4 mmHg) blood pressure decreased significantly. Left ventricular fractional shortening (LVFS) increased significantly by 11.8%. Diastolic function parameters of mitral annulus movement of the A' wave increased relative to baseline by 20.0% (27.8% under the second insulin load), A' medial increased relative to baseline by 30%, and A' lateral increased relative to baseline by 17%, displayed by tissue Doppler imaging.

Insulin acutely affected the diabetic heart at a physiologic level within a 2 h time course. Insulin mainly increased left ventricular systolic function and, to a second degree, improved left ventricular diastolic functions and atrial systole in diabetic subjects. These results may facilitate the development of insulin-based acute treatment in diabetic patients with cardiac morbidity. This trial is registered with NCT02962921.

This study investigated if calcineurin/nuclear factor of activated T cells (NFAT) axis mediates the cardiac apoptosis in rats with type 1 diabetes mellitus (T1DM)-induced rats or administered chronically high-fat diet rich in corn oil (CO-HFD). Also, it investigated the impact of chronic administration of CO-HFD on Fas/Fas ligand (Fas/FasL)-induced apoptosis in the hearts of T1DM-induced rats. Adult male Wistar rats (140-160 g) were classified as control: (10% fat) CO-HFD: (40% fat), T1DM, and T1DM + CO-HFD (n=20/each). In vitro, cardiomyocytes were cultured in either low glucose (LG) or high glucose (HG) media in the presence or absence of linoleic acid (LA) and other inhibitors. Compared to the control, increased reactive oxygen species (ROS), protein levels of cytochrome C, cleaved caspase-8 and caspase-3, myocardial damage and impeded left ventricular (LV) function were observed in the hearts of all treated groups and maximally in T1DM + CO-HFD-treated rats. mRNA of all NFAT members (NFAT1-4) were not affected by any treatment. CO-HFD or LA significantly up-regulated Fas levels in both LVs and cultured cardiomyocytes in a ROS dependent mechanism and independent of modulating intracellular Ca²⁺ levels or calcineurin activity. T1DM or hyperglycemia significant up-regulated mRNA and protein levels of Fas and FasL by activating Ca²⁺/calcineurin/NFAT-4 axis. Furthermore, Fas/FasL cell death induced by recombinant FasL (rFasL) or HG media was enhanced by pre-incubating the cells with LA. In conclusion, activation of the Ca²⁺/calcineurin/NFAT4 axis is indispensable for hyperglycemia-induced Fas/FasL cell death in the cardiomyocytes and CO-HFD sensitizes this by up-regulation of Fas.

The aim of this study was to assess the dynamics of epicardiac adipose tissue (EAT) thickness and total volume as well as that of systolic and diastolic dysfunction in a group of patients with type 2 diabetes (T2D) after initiation of sodium glucose co-transporter 2 (SGLT 2) inhibitors therapy.

This prospective, observational study included 53 patients with T2D who received SGLT-2 inhibitors for 24 weeks. In all patients, echocardiographic screening for EAT, systolic and diastolic dysfunction and non-contrast computed tomography scans were performed, both before and after 24 weeks of SGLT-2 inhibition. Imagistic evaluation was followed by the association's analysis between the dynamics of EAT and heart function, as well as the patient's clinical and biological parameters. We considered a decrease or increase of more than 10% in EAT as being clinically significant.

The mean volume of EAT decreased significantly after SGLT 2 inhibition (37.8±17.2 vs. 20.7±7 cm³; p<0.001). Median values of EAT thickness also decreased significantly (5.95 vs. 3.01 mm; p<0.001). Most patients, 75.4% (40/53), presented more than 10% decrease in EAT volume, 9.5% (5/53) had stable EAT volume values, while in 15.1% (8/53) the means of EAT volume increased. 73.5% of the patients had diastolic dysfunction type 1 (DD 1) at baseline. No significant change was observed in the left ventricular ejection fraction or diastolic dysfunction after 24 weeks of treatment. Although not statistically significant, an improvement in cardiac function has been noticed throughout the duration of 1 year of treatment with SGLT 2 inhibitors.

This study showed the beneficial effect of SGLT 2 inhibitors on EAT after a short period of treatment, but there were no significant changes in the systolic function during the 1st year of study. However, reducing epicardial fat has led to remission of diastolic dysfunction.

Despite the burden of pre-clinical heart failure (HF) among diabetes mellitus (DM) patients, routine screening echocardiography is not currently recommended. We prospectively assessed risk prediction for HF/death of a screening strategy combining clinical data, electrocardiogram, NTproBNP, and echocardiogram, aiming to identify DM patients more suitable for selective echocardiography.

Among 4047 screened subjects aged≥55/≤80years, the DAVID-Berg Study prospectively enrolled 623 outpatients with DM, or hypertension, or known cardiovascular disease but with no HF history/symptoms. The present analysis focuses on data obtained during a longitudinal follow-up of the 219 patients with DM.

Mean age was 68years, 61% were men, and median DM duration was 4.9years. During a median follow-up of 5.2years, 50 subjects developed HF or died. A predictive model using clinical data demonstrated moderate predictive power, which significantly improved by adding electrocardiogram (C-statistic 0.75 versus 0.70; p<0.05), but not NTproBNP (C-statistic 0.72, p=0.20). Subjects with normal clinical variables or abnormal clinical variables but normal electrocardiogram had low events rate (1.3 versus 2.4events/100-person-years, p=NS). Conversely, subjects with both clinical and electrocardiogram abnormalities (47%) carried higher risk (9.0events/100-person-years, p<0.001). The predictive power for mortality/HF development increased when echocardiography was added (13.6events/100-person-years, C-statistic 0.80, p<0.05).

Our prospective study found that a selective echocardiographic screening strategy guided by abnormal clinical/electrocardiogram data can reliably identify DM subjects at higher risk for incident HF and death. This screening approach may hold promise in guiding HF prevention efforts among DM patients.

To investigate the possible protective effect of elevated undercarboxylated osteocalcin on diabetic cardiomyopathy mechanisms and risk factors.

In all, 32 male rats were divided into four groups: control, diabetic, diabetic warfarin and normal warfarin-treated groups. Isolated heart functions were assessed; fasting serum insulin, glucose and glycosylated haemoglobin, homeostasis model assessment insulin resistance and lipid profile were investigated. Serum undercarboxylated osteocalcin and adiponectin were also measured. In cardiac tissue, malondialdehyde content, acyl-CoA dehydrogenase gene expression, Bax/Bcl2 ratio, sarcoendoplasmic reticulum calcium ATPase and osteocalcin receptor (G protein-coupled receptor family C group 6 member A) genes expression were investigated.

Prophylactic elevation of undercarboxylated osteocalcin was accompanied by improved insulin sensitivity and lipid profile, increased serum adiponectin, upregulated myocardial osteocalcin receptor with preserved left ventricular function, decreased cardiac malondialdehyde content, acyl-CoA dehydrogenase and Bax/Bcl2 ratio.

Undercarboxylated osteocalcin was suggested to have protective effects against diabetic cardiomyopathy, possibly through direct action on upregulated G protein-coupled receptor family C group 6 member A and indirectly via adiponectin. These effects may be mediated through antagonizing oxidative stress and apoptosis.

In type I diabetes (T1DM), alterations in LV function may occur due to changes in innervation, metabolism, and efficiency.

We evaluated the association between sympathetic nerve function, oxidative metabolism, resting blood flow, LV efficiency and function in healthy diabetics, and assessed gender differences.

Cross-sectional study of 45 subjects with T1DM, 60% females, age 34 ± 13 years, and 10 age-matched controls. Positron emission tomography (PET) imaging with [(11)C]acetate and [(11)C]meta-hydroxyephedrine was performed, in addition to cardiac magnetic resonance imaging.

There were no significant differences in LV function, innervation, or oxidative metabolism between T1DM and controls. Cardiac oxidative metabolism was positively associated with higher levels of sympathetic activation, particularly in women. Diabetic women had significantly lower efficiency compared with diabetic men. Resting flow was significantly higher in diabetic women compared with diabetic men, and tended to be higher in female controls as well.

Measures of myocardial function, metabolism, blood flow, and sympathetic activation were preserved in young, otherwise healthy, T1DM patients. However, T1DM women presented with greater myocardial oxidative metabolism requirements than men. Ongoing studies are evaluating changes over time.

Mitochondrial oxidative stress has emerged as a key contributor towards the development of diabetic cardiomyopathy. Peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, scavenges H2O2 and offers protection against ROS related pathologies. We observed a decrease in the expression of Prx-3 in the hearts of streptozotocin (STZ) induced diabetic rats, and also high glucose treated H9c2 cardiac cells, which may augment oxidative stress mediated damage. Hence we hypothesized that overexpression of Prx-3 could prevent the cardiac damage associated with diabetes. In this study we used quercetin (QUE) to achieve Prx-3 induction in vivo, while a Prx-3 overexpressing H9c2 cell line was employed for carrying out in vitro studies. Diabetes was induced in Wistar rats by a single intraperitoneal injection of STZ. Quercetin (50mg/kg body weight) was delivered orally to hyperglycemic and age matched control rats for 2 months. Quercetin treatment induced the myocardial expression of Prx-3 but not Prx-5 both in control and STZ rats. Prx-3 induction by quercetin prevented diabetes induced oxidative stress as confirmed by decrease in expression of markers such as 4-HNE and mitochondrial uncoupling protein, UCP-3. It was also successful in reducing cardiac cell apoptosis, hypertrophy and fibrosis leading to amelioration of cardiac contractility defects. Overexpression of Prx-3 in cultured H9c2 cardiac cells could significantly diminish high glucose inflicted mitochondrial oxidative damage and apoptosis, thus strengthening our hypothesis. These results suggest that diabetes induced cardiomyopathy can be prevented by elevating Prx-3 levels thereby providing extensive protection to the diabetic heart.

The incidence of diabetes is increasing globally, with cardiovascular disease accounting for a substantial number of diabetes-related deaths. Although atherosclerotic vascular disease is a primary reason for this cardiovascular dysfunction, heart failure in patients with diabetes might also be an outcome of an intrinsic heart muscle malfunction, labelled diabetic cardiomyopathy. Changes in cardiomyocyte metabolism, which encompasses a shift to exclusive fatty acid utilization, are considered a leading stimulus for this cardiomyopathy. In addition to cardiomyocytes, endothelial cells (ECs) make up a significant proportion of the heart, with the majority of ATP generation in these cells provided by glucose. In this review, we will discuss the metabolic machinery that drives energy metabolism in the cardiomyocyte and EC, its breakdown following diabetes, and the research direction necessary to assist in devising novel therapeutic strategies to prevent or delay diabetic heart disease.

Patients with type 2 diabetes have increased cardiovascular disease risk compared with those without diabetes. Hyperglycemia can induce reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. Our previous study has demonstrated that the total saponins of Aralia taibaiensis (sAT), a frequently-used antidiabetic medicine in traditional Chinese medicine (TCM), can scavenge free radicals in vitro and have good anti-oxidant ability on lipid peroxidation of rat liver microsomes. This work was designed to investigate whether sAT could protect the heart while it was used in the treatment of diabetes. Oxidative stress was induced in H9c2 cells by high glucose (33 mM) and glucose oxidase (15 mU, G/GO) and the protective effects of sAT were evaluated. Treatment of H9c2 cells with G/GO resulted in an increase in cell death, intracellular ROS level and cell oxidative injury, which were markedly reduced by sAT treatment. Further study revealed that sAT induced the nuclear translocation of Nrf2 and expression of its downstream targets. Moreover, Nrf2 siRNA markedly abolished the cytoprotective effects of sAT. sAT exerted cytoprotective effects against oxidative stress induced by hyperglycemia and the cardioprotective effects of sAT might be through the Nrf2/ARE pathway. Thus, sAT might be a promising candidate for the treatment of diabetic cardiomyopathy.

Higher cellular reactive oxygen species (ROS) levels is important in reducing cellular energy charge (EC) by increasing the levels of key metabolic protein, and nitrosative modifications, and have been shown to damage the cardiac tissue of diabetic mice. However, the relation between energy production and heart function is unclear.

Streptozotocin (STZ, 150 mg/kg body weight) was injected intraperitoneally once to mice that had been fasted overnight for induction of diabetes. After diabetic induction, mice received citrate (5 µg/kg) through intraperitoneal injection every other day for 5 weeks. The caspase-3, plasminogen activator inhibitor 1 (PAI1), protein kinase B (PKB), commonly known as AKT and phosphorylated-AKT (p-AKT) proteins were examined to elucidate inflammation and apoptosis in the heart. For histological analysis, heart samples were fixed with 10% formalin and stained with hematoxylin-eosin (HE) and Sirius red to assess pathological changes and fibrosis. The expression levels[AGA1] of marker proteins, tyrosine nitration, activity of ATP synthase and succinyl-CoA3-ketoacid coenzyme A transferase-1 (SCOT), and EC were measured.

Intraperitoneal injection of citrate significantly reduced caspase-3 and PAI-1 protein levels and increased p-AKT level on the 5(th) week; EC in the heart was found to be increased as well. Further, the expression level, activity, and tyrosine nitration of ATP synthase and SCOT were not affected after induction of diabetes.

Results indicate that application of citrate, a tricarboxylic acid (TCA) cycle intermediate, might alleviate cardiac dysfunction by reducing cardiac inflammation, apoptosis, and increasing cardiac EC.

The pathogenesis of diabetic cardiomyopathy (DCM) is partially understood and is likely to be multifactorial, involving metabolic disturbances, hypertension and cardiovascular autonomic neuropathy (CAN). Therefore, an important need remains to further delineate the basic mechanisms of diabetic cardiomyopathy and to apply them to daily clinical practice. We attempt to detail some of these underlying mechanisms, focusing in the clinical features and management. The novelty of this review is the role of CAN and reduction of blood pressure descent during sleep in the development of DCM. Evidence has suggested that CAN might precede left ventricular hypertrophy and diastolic dysfunction in normotensive patients with type 2 diabetes, serving as an early marker for the evaluation of preclinical cardiac abnormalities. Additionally, a prospective study demonstrated that an elevation of nocturnal systolic blood pressure and a loss of nocturnal blood pressure fall might precede the onset of abnormal albuminuria and cardiovascular events in hypertensive normoalbuminuric patients with type 2 diabetes. Therefore, existing microalbuminuria could imply the presence of myocardium abnormalities. Considering that DCM could be asymptomatic for a long period and progress to irreversible cardiac damage, early recognition and treatment of the preclinical cardiac abnormalities are essential to avoid severe cardiovascular outcomes. In this sense, we recommend that all type 2 diabetic patients, especially those with microalbuminuria, should be regularly submitted to CAN tests, Ambulatory Blood Pressure Monitoring and echocardiography, and treated for any abnormalities in these tests in the attempt of reducing cardiovascular morbidity and mortality.

Diabetic cardiomyopathy as an important threat to health occurs with or without coexistence of vascular diseases. The exact mechanisms underlying the disease remain incompletely clear. Although several pathological mechanisms responsible for diabetic cardiomyopathy have been proposed, oxidative stress is widely considered as one of the major causes for the pathogenesis of the disease. Hyperglycemia-, hyperlipidemia-, hypertension- and inflammation-induced oxidative stress are major risk factors for the development of microvascular pathogenesis in the diabetic myocardium, which results in abnormal gene expression, altered signal transduction and the activation of pathways leading to programmed myocardial cell deaths. In the present article, we aim to provide an extensive review of the role of oxidative stress and anti-oxidants in diabetic cardiomyopathy based on our own works and literature information available.

Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.

The potential mechanism of high glucose-induced cardiomyocyte apoptosis and selenium's protective effects were investigated in this study. Myocytes isolated from neonate rats were cultured in high-glucose medium (25.5 mmol/L glucose) to mimic sustained hyperglycemia. Before high-glucose incubation, myocytes were pretreated by sodium selenite solution. Cell apoptosis was evaluated by annexin V/propidium iodide (PI) staining and caspase activation. Expression of Toll-like receptor 4 (TLR-4) and myeloid differentiation factor 88 (MyD-88) was examined at both mRNA and protein levels. The intracellular reactive oxygen species (ROS) production and glutathione peroxidase (GPx) activity in myocytes were also detected. We found high glucose-induced cell apoptosis and activation of TLR-4/MyD-88/caspase-8/caspase-3 signaling, accompanied by increased production of ROS. Selenium pretreatment attenuated apoptosis in high glucose-incubated myocytes, and mechanically, this protective effect was found to be associated with attenuating oxidative status by increasing activity of GPx, decreasing the generation of ROS, as well as inhibition of the activation of TLR-4/MyD-88/caspase-8/caspase-3 signaling in myocytes. These results suggest that activation of TLR-4/MyD-88 signaling pathway plays an important role in high glucose-induced cardiomyocyte apoptosis. Additionally, by modulating TLR-4/MyD-88 signaling pathway, which is linked to ROS formation, selenium exerts its antioxidative and antiapoptotic effects in high glucose-incubated myocytes.

Diabetic cardiomyopathy is characterized by ventricular dysfunction that occurs in diabetic patients independent of coronary artery disease, hypertension, and any other cardiovascular diseases. Diabetic cardiomyopathy has become a major cause of diabetes-related mortality. Thus, an urgent need exists to clarify the mechanism of pathogenesis. Emerging evidence demonstrates that diabetes induces cardiomyocyte apoptosis and suppresses cardiac autophagy, indicating that the interplay between the autophagy and apoptotic cell death pathways is important in the pathogenesis of diabetic cardiomyopathy. This review highlights recent advances in the crosstalk between autophagy and apoptosis and its importance in the development of diabetic cardiomyopathy. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

The aim of the study is to evaluate the prevalence and incidence of myocardial dysfunction (MD) and heart failure (HF) in long-lasting (≥10 years) type 1 diabetes without cardiovascular disorders or with hypertension or coronary heart disease (CHD). The study included 1,685 patients with type 1 diabetes (mean baseline age, 51 years; diabetes duration, 36 years). In all patients, echocardiography was performed, NT-proBNP levels were measured, and clinical symptoms were evaluated. A 7-year follow-up was conducted to monitor systolic and diastolic manifestations of MD and HF. At the end of the follow-up period, the prevalence of HF in the entire group was 3.7 %, and the incidence was 0.02 % per year. The prevalence of MD was 14.5 % and the incidence -0.1 % per year. MD and HF were observed only in hypertensive or CHD patients. At baseline, subjects with diastolic HF constituted 85 % of the HF population and those with systolic HF the remaining 15 %. Baseline HF predictors included age, diabetes duration, HbA1c levels, CHD, systolic blood pressure >140 mmHg, and GFR <60 mL/min/1.73 m(2). In patients with type 1 diabetes, MD and HF occurred only when diabetes coexisted with cardiovascular disorders affecting myocardial function. The prevalence and incidence of HF in patients with hypertension and CHD were relatively low. While the cause of this observation remains uncertain, it could probably be explained, at least partially, by the cardioprotective effect of concomitant treatment.

Hyperglycemia is a risk factor for the development of diabetic cardiovascular complications, which are associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we demonstrate the inhibitory effects of exogenous hydrogen sulfide (H₂S) on the activation of the MAPK pathway. The aim of the present study was to determine whether exogenous H₂S prevents high glucose (HG)-induced injury by inhibiting the activation of the p38 MAPK and extracellular signal-regulated kinase (ERK)1/2 (members of MAPK) pathways in cardiomyoblasts (H9c2 cells). The findings of the present study demonstrated that the treatment of H9c2 cells with HG (35 mM glucose) for 24 h not only significantly induced injury, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (MMP), but also upregulated the expression levels of phosphorylated (p)-p38 MAPK and p-ERK1/2. The increased expression levels of p-p38 MAPK and p-ERK1/2 were markedly reduced by pre-treatment of the H9c2 cells with 400 µM sodium hydrogen sulfide (NaHS; a donor of H2S) prior to exposure to 35 mM glucose. Importantly, pre-treatment of the cells with 400 µM NaHS or 3 µM SB203580 (a selective inhibitor of p38 MAPK) or 15 µM U0126 (a selective inhibitor of ERK1/2) attenuated the HG-induced cardiomyocyte injury, leading to an increase in cell viability and a decrease in the number of apoptotic cells, preventing ROS generation, as well as the loss of MMP. In addition, pre-treatment of the cells with 1,000 µM N‑acetyl‑L‑cysteine (a ROS scavenger) prior to exposure to HG ameliorated the HG-induced cytotoxicity. Taken together, the data from the present study demonstrate for the first time, to our knowledge, that exogenous H2S exerts a protective effect against HG‑induced injury by inhibiting the activation of the p38 MAPK and ERK1/2 pathways and preventing oxidative stress in H9c2 cells.

Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose-treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal kinase 1 (JNK1)-B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated JNK1-Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high glucose-induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of metformin in diabetic mice restored cardiac autophagy by activating JNK1-Bcl-2 pathways and dissociating Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis.

To compare magnetic resonance imaging-derived right ventricular (RV) dimensions and function between men with type 2 diabetes and healthy subjects, and to relate these parameters to left ventricular (LV) dimensions and function.

RV and LV volumes and functions were assessed in 78 men with uncomplicated type 2 diabetes and 28 healthy men within the same range of age using magnetic resonance imaging. Steady-state free precession sequences were used to assess ventricular dimensions. Flow velocity mapping across the pulmonary valve and tricuspid valve was used to assess RV outflow and diastolic filling patterns, respectively. Univariate general linear models were used for statistical analyses.

RV end-diastolic volume was significantly decreased in patients compared with healthy subjects after adjustment for BMI and pulse pressure (177 ± 28 mL vs. 197 ± 47 mL, P < 0.01). RV systolic function was impaired: peak ejection rate across the pulmonary valve was decreased (433 ± 54 mL/s vs. 463 ± 71 mL/s, P < 0.01) and pulmonary flow acceleration time was longer (124 ± 17 ms vs. 115 ± 25 ms, P < 0.05). Indexes of RV diastolic function were impaired: peak filling rate and peak deceleration gradient of the early filling phase were 315 ± 63 mL/s vs. 356 ± 90 mL/s (P < 0.01) and 2.3 ± 0.8 mL/s(2) × 10(-3) vs. 2.8 ± 0.8 mL/s(2) × 10(-3) (P < 0.01), respectively. All RV parameters were strongly associated with its corresponding LV parameter (P < 0.001).

Diabetic cardiomyopathy affects the right ventricle, as demonstrated by RV remodeling and impaired systolic and diastolic functions in men with type 2 diabetes, in a similar manner as changes in LV dimensions and functions. These observations suggest that RV impairment might be a component of the diabetic cardiomyopathy phenotype.

Both diabetic cardiomyopathy (DCM) and baroreflex dysfunction independently contribute to sudden cardiac death (SCD), however the inherent connections between them under diabetic state remains unclear. As microRNAs (miRNAs) have been reported to participate in various physiological and pathological processes, we presume they may also be involved in DCM and DM-induced impairment of baroreflex sensitivity. Two sets of gene expression profiles data from streptozotocin (STZ)-induced diabetic heart and diabetic dorsal root ganglia (DDRG) were retrieved from GEO and ArrayExpress. Co-differentially-expressed genes in diabetic heart and DDRG were identified by t test and intersection analysis. Human Protein Reference Database (HPRD) was applied to find direct interacting proteins of Gadd45α. Differentially-expressed miRNAs in left ventricle from 4-week STZ-induced diabetic rats were screened by miRNA microarray. Expression of miR-499 and its regulating effect on Gadd45α were then verified by quantitative real-time PCR (qRT-PCR), western blot, computational predication, and dual-luciferase reporter analysis. Four co-differentially-expressed genes in DCM and DDRG were identified. Among these genes, Gadd45α has 16 direct interacting proteins and 11 of them are documentedly associated with DM. Accompanied with significantly increased miR-499 expression, Gadd45α expression was increased at mRNA level but decreased at protein level in both diabetic heart and nucleus ambiguous. Furthermore, miR-499 was confirmed negatively regulating Gadd45α by targeting its 3'UTR. Collectively, reduced Gadd45α protein expression by forced miR-499 expression indicated it's a diabetes-associated gene which might potentially be involved in both DCM and DM-induced baroreflex dysfunction.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor activated by a range of oxidants and electrophiles. The transcriptional response to endogenous oxidative cues by Nrf2 plays an important role in mammalian redox physiology and oxidative pathology. Hyperglycemia induces oxidative stress in the heart where it leads to apoptosis and ultimately cardiomyopathy. Here we investigated the mechanism by which Nrf2 suppresses oxidative stress in diabetic mouse heart. Knockout (KO) of Nrf2 induced oxidative stress and apoptosis in KO heart; diabetes further increased oxidative damage. A pathway-focused gene array revealed that Nrf2 controls the expression of 24 genes in the heart, including the gene encoding thioredoxin-interacting protein (TXNIP). Nrf2 suppressed the basal expression of Txnip in the heart and blocked induction of Txnip by high glucose by binding to an antioxidant response element (ARE) (-1286 to -1276) of the Txnip promoter. Binding of Nrf2 to ARE also suppressed the binding of MondoA to the carbohydrate response element with or without high glucose. TXNIP promoted reactive oxygen species production and apoptosis by inhibiting thioredoxin. On the other hand, Nrf2 boosted thioredoxin activity by inhibiting Txnip. The findings revealed, for the first time, that Nrf2 is a key gatekeeper of Txnip transcription, suppressing both its basal expression and MondoA-driven induction to control the thioredoxin redox signaling in diabetes.

Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.

High glucose-induced oxidative stress is a major contributing mechanism to the development of diabetic cardiomyopathy. Nrf2 is an emerging critical regulator of cellular defense against oxidative damage. The role of Nrf2 in diabetic cardiomyopathy was investigated in vivo. Streptozotocin (STZ) induced diabetes in Nrf2 knockout (KO) mice that rapidly progressed to severe conditions with high mortality within two weeks of injection; whereas, in wild type (WT) mice, diabetes was less severe with no death. Severe myocardial lesions were observed in diabetic KO mice that had high, sublethal levels of blood glucose including: (a) irregular myocardial arrangements, myofibrillar discontinuation, and cell death; (b) reduced electron density, discontinuation of myocardial fibers, and mitochondrial damage; and (c) markedly reduced contractility of the cardiomyocytes to β-agonist stimulation. Parallel to severe cardiomyopathy, the diabetic KO hearts showed: (a) increased apoptosis as revealed by TUNEL and PARP1 cleavage assays; (b) infiltration of granulocytes and macrophages as well as fibrosis indicating robust inflammatory response; and (c) heightened oxidative stress as evidenced by increased levels of 8-hydroxydeoxyquanine, free malondialdehyde, and 3-nitrotyrosine. Increased oxidative stress in the KO hearts was attributed to decrease or loss of the basal and induced expression of Nrf2-dependent cytoprotective genes. Our findings demonstrate that loss of Nrf2 function synergizes with high glucose to cause heightened oxidative stress in the heart leading to severe diabetic cardiomyopathy.

Diabetic autonomic neuropathies are a heterogeneous and progressive disease entity and commonly complicate both type 1 and type 2 diabetes mellitus. Although the aetiology is not entirely understood, hyperglycaemia, insulin deficiency, metabolic derangements and potentially autoimmune mechanisms are thought to play an important role. A subgroup of diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN), is one of the most common diabetes-associated complications and is ultimately clinically important because of its correlation with increased mortality. The natural history of CAN is unclear, but is thought to progress from a subclinical stage characterized by impaired baroreflex sensitivity and abnormalities of spectral analysis of heart rate variability to a clinically apparent stage with diverse and disabling symptoms. Early diagnosis of CAN, using spectral analysis of heart rate variability or scintigraphic imaging techniques, might enable identification of patients at highest risk for the development of clinical CAN and, thereby, enable the targeting of intensive therapeutic approaches. This Review discusses methods for diagnosis, epidemiology, natural history and potential causes and consequences of CAN.

We hypothesized that oxidative stress may contribute to the development of hypertrophy observed in mice with cardiac specific ablation of the insulin sensitive glucose transporter 4 gene (GLUT4, G4H(-/-) ). Measurements of oxidized glutathione (GSSG) in isolated mitochondria and whole heart homogenates were increased resulting in a lower ratio of reduced glutathione (GSH) to GSSG. Membrane translocation of the p67(phox) subunit of cardiac NADPH oxidase 2 (NOX2) was markedly increased in G4H(-/-) mice, suggesting elevated activity. To determine if oxidative stress was contributing to cardiac hypertrophy, 4-week-old control (Con) and G4H(-/-) mice were treated with either tempol (T, 1 mm, drinking water), a whole cell antioxidant, or Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP, 10 mg·kg(-1) , intraperitoneally), a mitochondrial targeted antioxidant, for 28 days. Tempol attenuated cardiac hypertrophy in G4H(-/-) mice (heart : tibia, Con 6.82 ± 0.35, G4H(-/-) 8.83 ± 0.34, Con + T 6.82 ± 0.46, G4H(-/-) + T 7.57 ± 0.3), without changing GSH : GSSG, glutathione peroxidase 4 or membrane translocation of the p67(phox) . Tempol did not modify phosphorylation of glycogen synthase kinase 3β or thioredoxin-2. In contrast, MnTBAP lowered mitochondrial GSSG and improved GSH : GSSG, but did not prevent hypertrophy, indicating that mitochondrial oxidative stress may not be critical for hypertrophy in this model. The ability of tempol to attenuate cardiac hypertrophy suggests that a cytosolic source of reactive oxygen species, probably NOX2, may contribute to the hypertrophic phenotype in G4H(-/-) mice.

Diabetic cardiomyopathy (DCM) is an increasingly recognized cause of chronic heart failure amongst diabetic patients. Both increased reactive oxygen species (ROS) generation and impaired ROS scavenging have been implicated in the pathogenesis of hyperglycemia-induced left ventricular dysfunction, cardiac fibrosis, apoptosis and hypertrophy. We hypothesized that 3',4'-dihydroxyflavonol (DiOHF), a small highly lipid soluble synthetic flavonol, may prevent DCM by scavenging ROS, thus preventing ROS-induced cardiac damage.

Six week old homozygous Ren-2 rats were randomized to receive either streptozotocin or citrate buffer, then further randomized to receive either DiOHF (1 mg/kg/day) by oral gavage or vehicle for six weeks. Cardiac function was assessed via echocardiography and left ventricular cardiac catheterization before the animals were sacrificed and hearts removed for histological and molecular analyses. Diabetic Ren-2 rats showed evidence of diastolic dysfunction with prolonged deceleration time, reduced E/A ratio, and increased slope of end-diastolic pressure volume relationship (EDPVR) in association with marked interstitial fibrosis and oxidative stress (all P<0.05 vs control Ren-2). Treatment with DiOHF prevented the development of diastolic dysfunction and was associated with reduced oxidative stress and interstitial fibrosis (all P<0.05 vs untreated diabetic Ren-2 rats). In contrast, few changes were seen in non-diabetic treated animals compared to untreated counterparts.

Inhibition of ROS production and action by DiOHF improved diastolic function and reduced myocyte hypertrophy as well as collagen deposition. These findings suggest the potential clinical utility of antioxidative compounds such as flavonols in the prevention of diabetes-associated cardiac dysfunction.

Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice.

OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.

Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice.

Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy.

Oxidative stress plays a dominant role in the pathogenesis of cardiac cell apoptosis in diabetic patients. Sildenafil has been demonstrated to have antioxidant effects. In this study, the effects of sildenafil on diabetes-induced cardiac cell apoptosis and the antioxidant status of diabetic mouse hearts were investigated. Diabetic mice showed lower body weight gains and heart weights compared with control mice, and sildenafil treatment did not increase these parameters in diabetic mice. Although apoptotic rates, caspase-3 enzyme activity, and malondialdehyde levels were significantly higher in diabetic mouse hearts than in controls, they were reduced in diabetic mice after sildenafil treatment. At the end of the first week, we observed no significant differences in antioxidant enzyme activities (CAT, GSH-Px, and SOD) in diabetic and control groups, whereas at the end of the second week of sildenafil treatment, antioxidant enzyme activities were higher in the diabetic group. In conclusion, our study indicated that sildenafil was beneficial to hearts of diabetic mice by reducing cardiac cell apoptosis, partially because of its antioxidant effects in the heart.

The aim of this study was to investigate the relations between the P-wave dispersion and diastolic functions in type 1 diabetic children.

A total of 33 diabetic patients without any cardiovascular disease, with a mean age of 12.3 plus or minus 4.2 years, and 29 healthy controls, with a mean age of 10.4 plus or minus 3.9 years were enrolled for this study. Left and right ventricular functions were assessed by using standard pulsed-wave Doppler echocardiography. P-wave dispersion was calculated by measuring minimum and maximum P-wave duration values on the surface electrocardiogram.

For the diabetic patients, P-wave maximum duration and dispersion was found to be significantly increased compared with healthy controls. Likewise, mitral A velocity and A velocity time integral was significantly increased while the isovolumic contraction time was significantly higher in the diabetics. In tricuspid valve measurements, however, A velocity time integral was found to be significantly higher, whereas the deceleration time was significantly lower in the diabetics. No relation was found between the left ventricle diastolic functions and duration of diabetes, HbA1c levels and P-wave dispersion in the diabetic children. No correlation was found between the diastolic functions and P-wave minimum, maximum duration, and dispersion for all the participants.

In type-1 diabetic children, the diastolic functions of both the ventricles were observed to be affected negatively together. Diabetes might be causing the prolongation of P-wave dispersion, but there was no relationship between the diastolic functions and P-wave dispersion in the diabetic children.

The aim of the current study was to address the issue of cardiomyocyte apoptosis as a possible contributor in the development of diabetic cardiomyopathy and whether it would be possible to suppress this apoptosis by the use of a peroxisome proliferator-activated receptor (PPAR)-alpha agonist (fenofibrate) or a PPAR-gamma agonist (rosiglitazone).

Ten normal male albino rats (group I) were injected intraperitoneally (IP) by a single dose of saline and served as a control for group II. Thirty male albino rats were made diabetic by IP streptozotocin (STZ) injection and were divided into 3 groups: group II (nontreated diabetic rats), groups III and IV (diabetic rats treated with PPAR-gamma agonist (rosiglitazone), and PPAR-alpha agonist (fenofibrate) respectively, for 12 weeks starting 1 week following STZ injection.

The studied drugs decreased left ventricular to body weight ratio and cardiac: caspase-3, tumor necrosis factor-alpha, hydroxyproline, free fatty acids (FFAs) as well as triglycerides (TGs) and improved oxidative stress parameters as well as left ventricular papillary muscle developed tension (DT).

The results of the current study support the hypothesis that apoptosis plays a key role in the pathophysiology of diabetic cardiomyopathy and demonstrate that the use of PPAR-alpha and -gamma agonists might have a protective role against diabetic cardiomyopathy.

Cardiovascular disease is a leading cause of death worldwide. Diabetes mellitus is a well-known and important risk factor for cardiovascular diseases. The occurrence of diabetic cardiomyopathy is independent of hypertension, coronary artery disease, or any other known cardiac diseases. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. Myocardial apoptosis, hypertrophy and fibrosis are the most frequently proposed mechanisms to explain cardiac changes in diabetic cardiomyopathy. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. 14-3-3 protein regulates diabetic cardiomyopathy via multiple signaling pathways. This review focuses on emerging evidence suggesting that 14-3-3 protein plays a key role in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.

Diabetes mellitus is a powerful risk factor for cardiovascular disease associated with high morbidity and mortality rates. Diabetic patients also have an increased incidence of heart failure which has been traditionally attributed to the concurrent presence of ischemic or hypertensive heart disease. Yet, nowadays, according to recent scientific evidence, diabetic myocardial disease (DMD) is more and more being considered as a distinct nosologic entity, independent of the co-existence of coronary artery disease, arterial hypertension or other risk factors, with the potential to lead to a self-existent progressive development of heart failure. In this article, we review the possible pathophysiologic mechanisms involved in the development of DMD as well as the structural and functional changes in the diabetic heart. We emphasize the importance of early detection of the syndrome, especially by novel echocardiographic techniques. Finally, we refer to the various therapeutic options for the optimal management of DMD according to the recent literature.

Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) in cardiomyocytes that may contribute to the development of cardiomyopathy in diabetes. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the antioxidant response element (ARE)-dependent gene regulation in response to oxidative stress. The role of Nrf2 in defense against high glucose-induced oxidative damage in cardiomyocytes was investigated. Glucose at high concentrations induced ROS production in both primary neonatal and adult cardiomyocytes from the Nrf2 wild type (WT) mouse heart, whereas, in Nrf2 knockout (KO) cells, ROS was significantly higher under basal conditions and high glucose markedly further increased ROS production in concentration and time-dependent manners. Concomitantly, high glucose induced significantly higher levels of apoptosis at lower concentrations and in shorter time in Nrf2 KO cells than in WT cells. Primary adult cardiomyocytes from control and diabetic mice also showed dependence on Nrf2 function for isoproterenol-stimulated contraction. Additionally, cardiomyocytes from Nrf2 KO mice exhibited increased sensitivity to 3-nitropropionic acid, an inhibitor of mitochondrial respiratory complex II, for both ROS production and apoptosis compared with Nrf2 WT cells, further emphasizing the role of Nrf2 in ROS defense in the cells. Mechanistically, Nrf2 was shown to mediate the basal expression and induction of ARE-controlled cytoprotective genes, Nqo1 and Ho1, at both mRNA and protein levels in cardiomyocytes, as both the basal and inducible expressions of the genes were lost in Nrf2 KO cells or largely reduced by Nrf2 SiRNA. The findings, for the first time, established Nrf2 as a critical regulator of defense against ROS in normal and diabetic hearts.

Glucose-mediated oxidative stress and the upregulation of cyclooxygenase (COX)-2 pathway activity have been implicated in the pathogenesis of several vascular complications of diabetes including diabetic neuropathy. However, in nondiabetic subjects, the cardiovascular safety of selective COX-2 inhibition is controversial. The aim of this study was to explore the links between hyperglycemia, oxidative stress, activation of the COX-2 pathway, cardiac sympathetic integrity, and the development of left ventricular (LV) dysfunction in experimental diabetes. R wave-to-R wave interval (R-R interval) and parameters of LV function measured by echocardiography using 1% isoflurane, LV sympathetic nerve fiber density, LV collagen content, and markers of myocardial oxidative stress, inflammation, and PG content were assessed after 6 mo in control and diabetic COX-2-deficient (COX-2(-/-)) and littermate, wild-type (COX-2(+/+)) mice. There were no differences in blood glucose, LV echocardiographic measures, collagen content, sympathetic nerve fiber density, and markers of oxidative stress and inflammation between nondiabetic (ND) COX-2(+/+) and COX-2(-/-) mice at baseline and thereafter. After 6 mo, diabetic COX-2(+/+) mice developed significant deteriorations in the R-R interval and signs of LV dysfunction. These were associated with a loss of LV sympathetic nerve fiber density, increased LV collagen content, and a significant increase in myocardial oxidative stress and inflammation compared with those of ND mice. Diabetic COX-2(-/-) mice were protected against all these biochemical, structural, and functional deficits. These data suggest that in experimental diabetes, selective COX-2 inactivation confers protection against sympathetic denervation and LV dysfunction by reducing intramyocardial oxidative stress, inflammation, and myocardial fibrosis.