cardiovascular-agents and Diabetic-Cardiomyopathies

Heart failure (HF) and diabetes mellitus (DM) confer considerable burden on the health care system. Although these often occur together, DM can increase risk of HF, whereas HF can accelerate complications of DM. HF is a clinical syndrome resulting from systolic or diastolic impairment caused by ischemic, nonischemic (eg, DM), or other etiologies. HF exists along a spectrum from stage A (ie, persons at risk of DM) to stage D (ie, refractory HF from end-stage DM cardiomyopathy [DMCM]). HF is further categorized by reduced, midrange, and preserved ejection fraction (EF). In type 2 DM, the most prevalent form of DM, several pathophysiological mechanisms (eg, insulin resistance and hyperglycemia) can contribute to myocardial damage, leading to DMCM. Management of HF and DM and patient outcomes are guided by EF and drug efficacy. In this review, we focus on the interplay between HF and DM on disease pathophysiology, management, and patient outcomes. Specifically, we highlight the role of novel antihyperglycemic (eg, sodium glucose cotransporter 2 inhibitors) and HF therapies (eg, renin-angiotensin-aldosterone system inhibitors) on HF outcomes in patients with DM and HF.

Topics: Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Health Behavior; Heart Failure; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Phenotype; Risk Factors; Ventricular Remodeling

We performed this meta-analysis to determine which stent among everolimus eluting stents (EES), sirolimus eluting stents (SES) and paclitaxel eluting stents (PES) should be preferred for the treatment of DM patients.. A systematic search of publications about randomized controlled trials (RCTs) focused on diabetic patients received EES, SES or PES was conducted. We evaluated the following indicators: target vessel revascularization (TVR), target lesion revascularization (TLR), late luminal loss (LLL), stent thrombosis (ST), myocardial infarction (MI), all-cause mortality and cardiac mortality.. EES showed obvious advantages over SES for DM patients, as it induced the lowest rate of target vessel revascularization and target lesion revascularization (TLR) (p = 0.04). In addition, EES induced lower in-segment LLL than PSE and SES and lower in-stent LLL than PES in DM patients (all p < 0.05). Moreover, EES effectively reduced all-cause mortality compared to SES (RR = 0.71, 95% CI: 0.52-0.99, p = 0.04) and MI rates compared to PES (RR = 0.44, 95% CI: 0.26-0.73, p = 0.0002). Furthermore, EES could reduce the ST rate compared with both SES (RR = 0.53, 95% CI: 0.28-0.98, p = 0.04) and PES (RR = 0.18, 95% CI: 0.07-0.51, p = 0.001).. Among those three types of stents, EES should be the first recommended stent for DM patients.

Topics: Cardiovascular Agents; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug-Eluting Stents; Everolimus; Humans; Paclitaxel; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome

Melatonin is a pineal-produced indole known for its anti-aging, antiapoptotic and antioxidant properties. In past decades, the protective potentials of melatonin for cardiovascular diseases, such as atherosclerosis and myocardial infarction, have been widely revealed, triggering more investigations focused on other cardioprotective effects of melatonin. Recently, the roles of melatonin in diabetic cardiomyopathy (DCM) have attracted increased attention. In this regard, researchers found that melatonin attenuated cardiac fibrosis and hypertrophy, thus interrupting the development of DCM. Retinoid-related orphan receptor α is a key melatonin receptor that contributed to the cardioprotective effect of melatonin in hearts with DCM. For the downstream mechanisms, the inhibition of mammalian STE20-like kinase 1 plays a pivotal role, which exerts antiapoptotic and proautophagic effects, thus enhancing cardiac tolerance in high-glucose conditions. In addition, other signalling mechanisms, such as sirtuin-1/peroxisome proliferator-activated receptor gamma-coactivator alpha and endoplasmic reticulum-related signalling, are also involved in the protective effects of melatonin on cardiomyocytes under diabetic conditions. This review will focus on the protective signalling mechanisms regulated by melatonin and provide a better understanding of the therapeutic applications of melatonin signalling in DCM.

Topics: Animals; Cardiovascular Agents; Diabetic Cardiomyopathies; Heart; Humans; Melatonin; Myocardium; Signal Transduction

Heart failure (HF) is one of the major challenges in the management of diabetes patients. Among subjects with diabetes, up to 20% could have HF. Conversely, diabetes prevalence in HF patients varies greatly from more than 10% up to 50%. When it is present, the risk of mortality and rehospitalization increases substantially. In addition, current evidence points to an increased risk of atrial fibrillation and sudden cardiac death in patients with diabetes. The inter-relation between diabetes cardiomyopathy, left ventricular hypertrophy, coronary artery disease and renal dysfunction indicates complex and intricate pathways. Despite the great value of clinical assessment and echocardiography, there is insufficient data to suggest systematic screening for HF in asymptomatic patients with diabetes. There is little evidence to indicate that improved glycaemic control improves HF outcome in this population. In the case of established HF, the general guidelines apply in diabetes patients. However, recent advances concerning glucose-lowering treatment in patients with cardiovascular disease suggest that the choice of glucose-lowering agent is of crucial interest and should be based on the patient's phenotype. New drug classes, such as SGLT2 inhibitors, seem to be of particular benefit in these patients. In the future, new personalized strategies should aim at not only good control of the glycaemic level but also the reduction and possibly the prevention of HF onset.

Topics: Atrial Fibrillation; Cardiovascular Agents; Death, Sudden, Cardiac; Diabetes Complications; Diabetic Cardiomyopathies; Heart Failure; Humans; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Prevalence; Risk; Sodium-Glucose Transporter 2 Inhibitors

The death of cardiomyocytes is a precursor for the cascade of hypertrophic and fibrotic remodeling that leads to cardiomyopathy. In diabetes mellitus (DM), the metabolic environment of hyperglycemia, hyperlipidemia, and oxidative stress causes cardiomyocyte cell death, leading to diabetic cardiomyopathy (DMCM), an independent cause of heart failure. Understanding the roles of the cell death signaling pathways involved in the development of cardiomyopathies is crucial to the discovery of novel targeted therapeutics and biomarkers for DMCM. Recent evidence suggests that hydrogen sulfide (H

Topics: Animals; Apoptosis; Autophagy; Cardiovascular Agents; Diabetic Cardiomyopathies; Humans; Hydrogen Sulfide; Myocardium; Necroptosis; Pyroptosis; Signal Transduction; Ventricular Remodeling

Various signaling pathways have been identified in the heart as important players during development, physiological adaptation or pathological processes. This includes the MAPK families, particularly p38MAPK, which is involved in several key cellular processes, including differentiation, proliferation, apoptosis, inflammation, metabolism and survival. Disrupted p38MAPK signaling has been associated with several diseases, including cardiovascular diseases (CVD) as well as diabetes and its related complications. Despite efforts to translate this knowledge into therapeutic avenues, p38 inhibitors have failed in clinical trials due to adverse effects. Inhibition of MK2, a downstream target of p38, appears to be a promising alternative strategy. Targeting MK2 activity may avoid the adverse effects linked to p38 inhibition, while maintaining its beneficial effects. MK2 was first considered as a therapeutic target in inflammatory diseases such as rheumatoid polyarthritis. A growing body of evidence now supports a key role of MK2 signaling in the pathogenesis of CVD, particularly ischemia/reperfusion injury, hypertrophy, and hypertension and that its inhibition or inactivation is associated with improved heart and vascular functions. More recently, MK2 was shown to be a potential player in diabetes and related complications, particularly in liver and heart, and perturbations in calcium handling and lipid metabolism. In this review, we will discuss recent advances in our knowledge of the role of MK2 in p38MAPK-mediated signaling and the benefits of its loss of function in CVD and diabetes, with an emphasis on the roles of MK2 in calcium handling and lipid metabolism. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

Topics: Animals; Calcium; Calcium Signaling; Cardiovascular Agents; Diabetic Cardiomyopathies; Energy Metabolism; Humans; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Molecular Targeted Therapy; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Signal Transduction

Despite being first described 45 years ago, the existence of a distinct diabetic cardiomyopathy remains controversial. Nonetheless, it is widely accepted that the diabetic heart undergoes characteristic structural and functional changes in the absence of ischaemia and hypertension, which are independently linked to heart failure progression and are likely to underlie enhanced susceptibility to stress. A prominent feature is marked collagen accumulation linked with inflammation and extensive extracellular matrix changes, which appears to be the main factor underlying cardiac stiffness and subclinical diastolic dysfunction, estimated to occur in as many as 75% of optimally controlled diabetics. Whether this characteristic remodelling phenotype is primarily driven by microvascular dysfunction or alterations in cardiomyocyte metabolism remains unclear. Although hyperglycaemia regulates multiple pathways in the diabetic heart, increased reactive oxygen species (ROS) generation is thought to represent a central mechanism underlying associated adverse remodelling. Indeed, experimental and clinical diabetes are linked with oxidative stress which plays a key role in cardiomyopathy, while key processes underlying diabetic cardiac remodelling, such as inflammation, angiogenesis, cardiomyocyte hypertrophy and apoptosis, fibrosis and contractile dysfunction, are redox sensitive. This review will explore the relative contributions of the major ROS sources (dysfunctional nitric oxide synthase, mitochondria, xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases) in the diabetic heart and the potential for therapeutic targeting of ROS signalling using novel pharmacological and non-pharmacological approaches to modify specific aspects of the remodelling phenotype in order to prevent and/or delay heart failure development and progression.

Topics: Cardiovascular Agents; Diabetic Cardiomyopathies; Disease Progression; Drug Discovery; Heart Failure; Humans; Reactive Oxygen Species; Signal Transduction

Ischaemic heart diseases are one of the major causes of death in the world. In most patients, ischaemic heart disease is coincident with other risk factors such as diabetes. Patients with diabetes are more prone to cardiac ischaemic dysfunctions including ischaemia-reperfusion injury. Ischaemic preconditioning, postconditioning and remote conditionings are reliable interventions to protect the myocardium against ischaemia-reperfusion injuries through activating various signaling pathways and intracellular mediators. Diabetes can disrupt the intracellular signaling cascades involved in these myocardial protections, and studies have revealed that cardioprotective effects of the conditioning interventions are diminished in the diabetic condition. The complex pathophysiology and poor prognosis of ischaemic heart disease among people with diabetes necessitate the investigation of the interaction of diabetes with ischaemia-reperfusion injury and cardioprotective mechanisms. Reducing the outcomes of ischaemia-reperfusion injury using targeted strategies would be particularly helpful in this population. In this study, we review the protective interventional signaling pathways and mediators which are activated by ischaemic conditioning strategies in healthy and diabetic myocardium with ischaemia-reperfusion injury.

Topics: Animals; Cardiovascular Agents; Diabetic Cardiomyopathies; Humans; Ischemic Postconditioning; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Myocardium; Risk Factors; Signal Transduction; Treatment Outcome

The prevalence of patients with concomitant diabetes mellitus (DM) and heart failure (HF) is growing exponentially. Patients with HF and DM show specific metabolic, neurohormonal, and structural heart abnormalities, which potentially contribute to worse HF outcomes than seen in patients without comorbid DM. Subgroup analysis of recent trials suggest that patients with HF and DM may respond differently to standard therapy, and data are emerging on the possible increase in the risk of hospitalizations for HF in patients with DM treated with specific class of antidiabetic agents, pointing to the need of developing specific medications to be tested in dedicated future studies to address the unique metabolic and hemodynamic alterations seen in these patients.

Topics: Cardiovascular Agents; Comorbidity; Diabetes Complications; Diabetic Cardiomyopathies; Disease Progression; Heart Failure; Humans; Phenotype; Prevalence; Prognosis

Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.

Topics: Administration, Topical; Animals; Apolipoprotein A-I; Cardiovascular Agents; Cardiovascular Diseases; CD36 Antigens; Diabetic Cardiomyopathies; Endothelial Cells; Genetic Therapy; Humans; Lipoproteins, HDL; Myocardial Reperfusion Injury; Myocytes, Cardiac; Regeneration; Skin; Stem Cells; Treatment Outcome; Wound Healing

Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and hypertension. Although the pathogenesis of diabetic cardiomyopathy has yet to be fully elucidated, aberrations in cardiac substrate metabolism and energetics are thought to be key drivers. These aberrations include excessive fatty acid utilisation and storage, suppressed glucose oxidation and impaired mitochondrial oxidative phosphorylation. An appreciation of how these abnormalities arise and synergise to promote adverse cardiac remodelling is critical to their effective amelioration. This review focuses on disturbances in myocardial fuel (fatty acids and glucose) flux and energetics in type 2 diabetes, how these disturbances relate to the development of diabetic cardiomyopathy and the potential therapeutic agents that could be used to correct them.

Topics: Antioxidants; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Energy Metabolism; Fatty Acids; Glucose; Humans; Mitochondria, Heart; Myocardium; Organophosphorus Compounds; Oxidative Phosphorylation; Oxidative Stress; Perhexiline; Ranolazine; Trimetazidine; Ubiquinone

In this prospective study, we examined the effect of atorvastatin treatment on baroreflex sensitivity (BRS) in subjects with type 2 diabetes. A total of 79 patients with type 2 diabetes with dyslipidaemia were recruited. A total of 46 subjects were enrolled to atorvastatin 10 mg daily and low-fat diet and 33 patients to low-fat diet only. BRS was assessed non-invasively using the sequence method at baseline, 3, 6 and 12 months. Treatment with atorvastatin increased BRS after 12 months (from 6.46 ± 2.79 ms/mmHg to 8.05 ± 4.28 ms/mmHg, p = 0.03), while no effect was seen with low-fat diet. Further sub-analysis according to obesity status showed that BRS increased significantly only in the non-obese group (p = 0.036). A low dose of atorvastatin increased BRS in non-obese subjects with type 2 diabetes and dyslipidaemia after 1-year treatment. This finding emphasizes the beneficial effect of atorvastatin on cardiovascular system, beyond the lipid-lowering effects.

Topics: Aged; Atorvastatin; Baroreflex; Body Mass Index; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Diet, Fat-Restricted; Dyslipidemias; Female; Greece; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myalgia; Obesity; Patient Dropouts; Prospective Studies; Pyrroles; Risk Factors

Development of a cardiomyopathy in diabetes mellitus is independent of traditional risk factors, with no clinical trials targeting specific therapeutic interventions. Myocardial fibrosis is one of the key mechanisms and aldosterone is a key mediator of myocardial fibrosis. We propose that aldosterone antagonism will improve cardiac function. We aim to evaluate the efficacy of selective aldosterone receptor antagonism with eplerenone added to optimal medical treatment in improving cardiac structure and function in diabetic cardiomyopathy. We will randomize 130 patients with type 2 diabetes mellitus, stable metabolic control and impaired left ventricular (LV) systolic or diastolic function, to either eplerenone (target dose 50mg) or matching placebo, in addition to optimal medical therapy for 12 months. The primary endpoints are changes in LV systolic and diastolic function, measured by echocardiographic 2-dimensional speckle tracking strain and strain rate and tissue Doppler imaging. The secondary endpoints include changes in echocardiographic markers and plasma biomarkers of collagen turnover; left atrial dimensions and function, incidence of atrial fibrillation and changes in exercise capacity and dyspnea score. The present study will assess whether specific aldosterone antagonism with eplerenone in addition to standard therapy will prevent progression or reverse cardiac dysfunction in diabetic cardiomyopathy using sensitive, robust and quantifiable echocardiographic measures that allow early detection of change. The study may offer a new direction in the management of this condition.. ACTRN12610001063000.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Clinical Protocols; Collagen; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diastole; Double-Blind Method; Drug Therapy, Combination; Echocardiography, Doppler; Eplerenone; Fibrosis; Humans; Mineralocorticoid Receptor Antagonists; Myocardium; New South Wales; Prospective Studies; Recovery of Function; Research Design; Spironolactone; Systole; Time Factors; Treatment Outcome; Ventricular Function, Left

We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size.. The ASPIRE trial enrolled 820 patients 2-8 weeks after MI with ejection fraction ≤ 45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01-2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E' 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (-4.9 ± 17.9 vs. -5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08).. Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.

Topics: Aged; Amides; Cardiovascular Agents; Diabetic Cardiomyopathies; Diastole; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Myocardial Infarction; Renin; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Topics: Acyclic Monoterpenes; Aldehydes; Animals; Cardiovascular Agents; Diabetic Cardiomyopathies; Fibrosis; Heart Failure; Male; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor Receptor-1; Ventricular Dysfunction, Left

The incidence of heart failure was significantly increased in patients with diabetic cardiomyopathy (DCM). The therapeutic effect of triptolide on DCM has been reported, but the underlying mechanisms remain to be elucidated. This study is aimed at investigating the potential targets of triptolide as a therapeutic strategy for DCM using a network pharmacology approach. Triptolide and its targets were identified by the Traditional Chinese Medicine Systems Pharmacology database. DCM-associated protein targets were identified using the comparative toxicogenomics database and the GeneCards database. The networks of triptolide-target genes and DCM-associated target genes were created by Cytoscape. The common targets and enriched pathways were identified by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The gene-gene interaction network was analyzed by the GeneMANIA database. The drug-target-pathway network was constructed by Cytoscape. Six candidate protein targets were identified in both triptolide target network and DCM-associated network: STAT3, VEGFA, FOS, TNF, TP53, and TGFB1. The gene-gene interaction based on the targets of triptolide in DCM revealed the interaction of these targets. Additionally, five key targets that were linked to more than three genes were determined as crucial genes. The GO analysis identified 10 biological processes, 2 cellular components, and 10 molecular functions. The KEGG analysis identified 10 signaling pathways. The docking analysis showed that triptolide fits in the binding pockets of all six candidate targets. In conclusion, the present study explored the potential targets and signaling pathways of triptolide as a treatment for DCM. These results illustrate the mechanism of action of triptolide as an anti-DCM agent and contribute to a better understanding of triptolide as a transcriptional regulator of cytokine mRNA expression.

Topics: Caco-2 Cells; Cardiovascular Agents; Databases, Genetic; Diabetic Cardiomyopathies; Diterpenes; Epoxy Compounds; Gene Regulatory Networks; Humans; Molecular Docking Simulation; Molecular Structure; Molecular Targeted Therapy; Myocytes, Cardiac; Network Pharmacology; Phenanthrenes; Protein Interaction Maps; Signal Transduction; Structure-Activity Relationship

Topics: Animals; Cardiovascular Agents; Diabetic Cardiomyopathies; Drug Delivery Systems; Humans; Mice; rho-Associated Kinases

Diabetic cardiomyopathy (DCM) is a common diabetes complication that can cause arrhythmia, heart failure, and even sudden death. Ranolazine is an antianginal agent used to treat chronic stable angina and has been demonstrated as an effective treatment for many cardiovascular diseases. However, the mechanism by which ranolazine alleviates DCM is unclear, motivating this study investigating the effects of ranolazine in DCM.. DCM rats were treated with one of three doses of ranolazine (10, 30, and 90 mg/kg/day) for 12 weeks. B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), Notch homolog 1 (NOTCH1), and Neuregulin 1 (NRG1) expression was assayed using western blot and qRT-PCR. Cardiac changes were assayed using echocardiography, CT, HE staining, and Masson's trichrome staining. TUNEL staining and flow cytometry were used to detect cell apoptosis. NOTCH1 inhibitor (DAPT) was used to explore the mechanism of ranolazine.. Compared with the DCM group, the ranolazine groups had no obvious weight loss and significantly decreased blood glucose levels. Ranolazine prevented diabetes-caused cardiac injury. Ranolazine also decreased the number of apoptotic cells and altered the expression of apoptosis-related mRNAs and proteins. Ranolazine-induced NOTCH1 activated NRG1 and inhibited the downstream apoptosis-related pathway, while DAPT partially inhibited ranolazine-induced NOTCH1 and NRG1 expression.. To our knowledge, this study is the first to demonstrate that ranolazine protects against DCM-induced apoptosis by activating the NOTCH1/NRG1 signaling pathway. Moreover, our study identified new mechanisms involved in DCM.

Topics: Animals; Apoptosis; Blood Glucose; Cardiovascular Agents; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dose-Response Relationship, Drug; Male; Neuregulin-1; Ranolazine; Rats; Rats, Sprague-Dawley; Receptor, Notch1; Signal Transduction

HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide.. A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group.. Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.

Topics: Animals; Benzamides; Cardiovascular Agents; Diabetic Cardiomyopathies; Disease Models, Animal; Glycation End Products, Advanced; Heart Failure; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondria, Heart; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Inflammation and oxidative stress play a crucial role in the development of diabetic cardiomyopathy (DCM). We previously had synthesized an Aza resveratrol-chalcone derivative 6b, of which effectively suppressing lipopolysaccharide (LPS)-induced inflammatory response in macrophages. This study aimed to investigate the potential protective effect of 6b on DCM and underlying mechanism. In H9c2 myocardial cells, 6b potently decreased high glucose (HG)-induced cell fibrosis, hypertrophy and apoptosis, alleviating inflammatory response and oxidant stress. In STZ-induced type 1 diabetic mice (STZ-DM1), orally administration with 6b for 16 weeks significantly attenuated cardiac hypertrophy, apoptosis and fibrosis. The expression of inflammatory cytokines and oxidative stress biomarkers was also suppressed by 6b distinctly, without affecting blood glucose and body weight. The anti-inflammatory and antioxidative activities of 6b were mechanistic associated with nuclear factor-kappa B (NF-κB) nucleus entry blockage and Nrf2 activation both in vitro and in vivo. The results indicated that 6b can be a promising cardioprotective agent in treatment of DCM via inhibiting inflammation and alleviating oxidative stress. This study also validated the important role of NF-κB and Nrf2 taken in the pathogenesis of DCM, which could be therapeutic targets for diabetic comorbidities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Cardiovascular Agents; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Gene Expression Regulation; Glucose; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Resveratrol; Signal Transduction; Streptozocin

Visceral adipose tissue-derived serine protease inhibitor (Vaspin) is an adipocytokine that has been shown to exert anti-inflammatory effects and inhibits apoptosis under diabetic conditions. This study was designed to investigate the impact of vaspin on autophagy in tumor necrosis factor (TNF)-α-induced injury in cardiomyocytes and its cardioprotective effects in the pathogenesis of diabetic cardiomyopathy (DCM). H9C2 cells were treated with TNF-α with or without vaspin in vitro. Tumor necrosis factor-α treatment inhibited autophagy and promoted apoptosis in H9C2 cells after stimulating for 24 hours. Pretreatment with vaspin significantly mitigated apoptosis induced by TNF-α partly because of augment effects of vaspin on autophagy as demonstrated by a higher ratio of LC3-II/LC3-I, higher expression of Beclin-1, and increased autophagosomes formation. Furthermore, the AKT agonist IGF-1 significantly reversed the effect of vaspin on autophagy. In vivo DCM model was also developed by treating rats with streptozotocin followed by intraperitoneal injection with vaspin. In DCM rats, upregulation of vaspin reversed cardiac dysfunction, as identified by increased left ventricular ejection fractions and fractional shortening levels, a higher Em/Am ratio, and lower levels of TNF-α, lactate dehydrogenase, creatine kinase, and creatine kinase-myocardial isoenzyme. In conclusion, vaspin attenuated the TNF-α-induced apoptosis by promoting autophagy probably through inhibiting the PI3K/AKT/mTOR pathway and further ameliorated the cardiac dysfunction in DCM rats.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagosomes; Autophagy; Autophagy-Related Proteins; Cardiovascular Agents; Cell Line; Diabetic Cardiomyopathies; Disease Models, Animal; Male; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Serpins; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Preclinical and clinical studies have demonstrated that berberine (BBR) improves diabetic complications and reduces mortality of patients with congestive heart failure. The therapeutic effects of BBR have been reported to be mediated by its regulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We previously reported that BBR protects against ischemia-reperfusion injury via regulating AMPK activity in both ischemic and nonischemic areas of the rat heart. Since diabetic hearts are more sensitive to ischemia-reperfusion injury, we examined whether BBR treatment exhibited cardioprotective effects in the diabetic heart. Type 2 diabetic rats were pretreated plus or minus BBR for 7 days and subjected to 30-minute ischemia followed by 120-minute reperfusion. Pretreatment of type 2 diabetic rats with BBR reduced ischemia-reperfusion injury infarct size and attenuated arrhythmia compared to untreated diabetic controls. Subsequent to ischemia-reperfusion, serum triglyceride, total cholesterol, and malondialdehyde levels were reduced by pretreatment of type 2 diabetic rats with BBR compared to untreated diabetic controls. In contrast, serum glucose and superoxide dismutase levels were unaltered. The mechanism for the BBR-mediated cardioprotective effect was examined. Pretreatment with BBR did not alter AMPK activity in ischemic areas at risk but increased AMPK activity in nonischemic areas compared to untreated diabetic controls. The increased AMPK activity in nonischemic areas was due an elevated ratio of AMP to adenosine triphosphate (ATP) and adenosine diphosphate to ATP. In addition, pretreatment with BBR increased protein kinase B (AKT) phosphorylation and reduced glycogen synthase kinase 3β (GSK3β) activity in nonischemic areas compared to untreated diabetic controls. These findings indicate that BBR protects the diabetic heart from ischemia-reperfusion injury. In addition, BBR may mediate this cardioprotective effect through AMPK activation, AKT phosphorylation, and GSK3β inhibition in the nonischemic areas of the diabetic heart.

Topics: AMP-Activated Protein Kinases; Animals; Arrhythmias, Cardiac; Berberine; Biomarkers; Blood Glucose; Cardiovascular Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Energy Metabolism; Enzyme Activation; Glycogen Synthase Kinase 3 beta; Lipids; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction

Ginsenoside Rg1 has been demonstrated to have cardiovascular protective effects. However, whether the cardioprotective effects of ginsenoside Rg1 are mediated by endoplasmic reticulum (ER) stress-induced apoptosis remain unclear. In this study, among 80 male Wistar rats, 15 rats were randomly selected as controls; the remaining 65 rats received a diet rich in fat and sugar content for 4 weeks, followed by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) to establish a diabetes model. Seven days after STZ injection, 10 rats were randomly selected as diabetic model (DM) controls, 45 eligible diabetic rats were randomized to three treatment groups and administered ginsenoside Rg1 in a dosage of 10, 15 or 20 mg/kg/day, respectively. After 12 weeks of treatment, rats were killed and serum samples obtained to determine cardiac troponin (cTn)-I. Myocardial tissues were harvested for morphological analysis to detect myocardial cell apoptosis, and to analyse protein expression of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Caspase-12. Treatment with ginsenoside Rg1 (10-20 mg/kg) significantly reduced serum cTnI levels compared with DM control group (all P < 0.01). Ginsenoside Rg1 (15 and 20 mg/kg) significantly reduced the percentage of apoptotic myocardial cells and improved the parameters of cardiac function. Haematoxylin and eosin and Masson staining indicated that ginsenoside Rg1 could attenuate myocardial lesions and myocardial collagen volume fraction. Additionally, ginsenoside Rg1 significantly reduced GRP78, CHOP, and cleaved Caspase-12 protein expression in a dose-dependent manner. These findings suggest that ginsenoside Rg1 appeared to ameliorate diabetic cardiomyopathy by inhibiting ER stress-induced apoptosis in diabetic rats.

Topics: Animals; Apoptosis; Cardiovascular Agents; Caspase 12; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diet, High-Fat; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Gene Expression Regulation; Ginsenosides; Heat-Shock Proteins; Male; Myocardium; Myocytes, Cardiac; Rats; Rats, Wistar; Signal Transduction; Streptozocin; Transcription Factor CHOP; Troponin I

Topics: Cardiovascular Agents; Contraceptive Agents; Contraindications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Humans; Pregnancy

To describe contraception use and the prescription of drugs that are either not recommended in pregnancy or are potentially teratogenic by diabetes type in women of child-bearing age.. Retrospective, cross-sectional chart review undertaken in 22 general practices in Warwickshire, UK. Demographic, anthropometric, medical history, medication and contraception data were extracted from women aged 14 to 49 years with pre-existing diabetes. Independent sample t-test, Mann-Whitney test and χ(2) -test were used to test for univariable associations and multiple logistic regression was used to adjust for confounders.. Four hundred and seventy eligible women were identified; the majority had a diagnosis of Type 2 diabetes (67%). Thirty-six per cent and 64% of women with Type 1 and Type 2 diabetes, respectively, were prescribed drugs not recommended for use in pregnancy (P < 0.001). Less than half were using concomitant contraception (P < 0.001). No significant difference of contraception use was observed between women who were and were not taking drugs not recommended for use in pregnancy (40 vs. 41%, P = 0.4).. Use of drugs not recommended during pregnancy in women with diabetes of child-bearing age is common but is not associated with increased use of contraception. There is need to identify and overcome barriers to effective contraception use for this population group in order to facilitate optimal management of cardiovascular risk.

Topics: Adolescent; Adult; Cardiovascular Agents; Contraceptive Agents; Contraindications; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Humans; Middle Aged; Pregnancy; Prescription Drugs; Retrospective Studies; Risk Factors; Teratogens; Young Adult

Diabetes mellitus has been associated with changes in the structure and function of the myocardium manifesting in the early stages of the disease as subtle systolic and diastolic dysfunction; the role of dobutamine stress echocardiography (DSE) in this setting remains unclear. We sought to evaluate the prevalence of dobutamine-induced systolic dysfunction amongst diabetic patients with normal at rest left ventricular ejection fraction and no coronary artery disease and to investigate whether an optimized therapeutic approach can reverse these abnormalities. 1,363 patients with DM referred to our echocardiography laboratory for DSE between January 2008 and June 2010 were prospectively investigated. Patients with normal left ventricular ejection fraction (LVEF) at rest and significant deterioration during peak dobutamine infusion (defined as a ≥10% decrease) in the absence of coronary artery disease or vasospasm were enrolled. They received on top of their usual treatment 5 mg perindopril and had their glycemic control intensified. At 60 days, all of them were controlled for clinical status and underwent a control DSE. 18 patients were included, there were 9 males and 9 females, mean age was 66.1 ± 10.2 years. All the patients had type II DM with a mean duration of 12.7 ± 6.6 years. They all had normal at rest echocardiographic findings with no wall motion abnormalities; mean LVEF was 62 ± 6%. At peak dobutamine, LVEF significantly deteriorated in all the patients with a mean 15 ± 5% decrease compared to baseline. After therapeutic optimization, Glycated haemoglobin improved from 8.53 ± 2.05% to 6.8 ± 0.6% (δ HbA1C = 1.73%, P = 0.001), mean LVEF at peak dobutamine infusion evolved from 47.17 ± 4.2% pre-optimization to 58 ± 4.8% at control (10.83% improvement; P < 0.001). In patients with DM and normal at rest LVEF, Dobutamine infusion during DSE can induce a significant deterioration in LVEF in the absence of coronary artery disease or vasospasm. This specific condition could be largely reversed through an optimized therapy based on a tighter metabolic control and a more stringent renin-angiotensin-aldosterone system inhibition.

Topics: Adrenergic Agonists; Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dobutamine; Echocardiography, Stress; Female; France; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Predictive Value of Tests; Prevalence; Prospective Studies; Stroke Volume; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Amides; Animals; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Fumarates; Humans; Male; Myocardial Infarction; Renin; Ventricular Dysfunction, Left; Ventricular Remodeling