Diabetes Mellitus Cardiomyopathy Research Articles

The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy.

Papel do Strain no Diagnóstico Precoce da Cardiomiopatia Diabética

Background: Advanced echocardiography using two- and three-dimensional myocardial strain proposes to identify subclinical systolic dysfunction in different clinical conditions. Strain assessment plays an important role in the early diagnosis of diabetic cardiomyopathy in diabetes mellitus (DM). However, the findings of published articles are heterogeneous. Here we conducted a systematic review to analyze the current role of strain assessment in patients with DM. Methods: This systematic review of five databases identified 19 studies that used twodimensional strain and 8 studies that used three-dimensional strain. Results: The studies of two-dimensional strain included 1,774 DM patients (mean age, 57.1 years; median age, 55 years; 47.5% women), while those of three-dimensional strain included 488 DM patients (mean age, 55.7 years; median age, 63 years; 51% women). Global longitudinal strain was the myocardial deformation marker that differed most frequently between the DM and control groups. Conclusion: Myocardial strain imaging by two- and three-dimensional speckle tracking echocardiography allows the identification of subclinical systolic dysfunction in DM patients, and differences become more marked when associated with risk factors and ventricular remodeling.

An Emerging Role of Defective Copper Metabolism in Heart Disease.

Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.

Trehalose Ameliorates Diabetic Cardiomyopathy: Role of the PK2/PKR Pathway.

Ample clinical case reports suggest a high incidence of cardiomyopathy in diabetes mellitus (DM). Recent evidence supports an essential role of trehalose (TLS) in cardiomyocyte survival signaling. Our previous study found that prokineticin2 (PK2) was involved in the process of diabetic cardiomyopathy (DCM). The present study examined the protective effects and mechanisms of TLS on DM-induced cardiomyocyte injury in mice and H9c2 cardiomyocytes. C57BL/6J mice were intraperitoneally injected with 50 mg·kg−1·d−1 streptozotocin for five consecutive days to establish an experimental diabetic model and then administered TLS (1 mg·g−1·d−1, i.p.) for two days every 4 weeks and given 2% TLS in drinking water for 24 weeks. Echocardiography, myocardial structure, apoptosis, pyroptosis, autophagy, and the PK2/PKR pathway were assessed. Cardiomyocytes exposed to high glucose (HG) were treated with TLS in the absence or presence of the PK2 antagonist PKRA7, and proteins involved in apoptosis, autophagy, and pyroptosis and the PK2/PKR pathways were evaluated using Western blot analysis. Diabetic mice demonstrated metabolic disorder, abnormal myocardial zymograms, and aberrant myocardial systolic and diastolic function, which were accompanied by pronounced apoptosis, pyroptosis, and dampened autophagy. TLS treatment relieved these effects. PK2 and receptor expressions were downregulated in diabetic mice, and TLS nullified this effect. PKRA7 eliminated the impact of TLS on cardiomyocytes. This evidence suggests that TLS rescues DM-induced myocardial function, pyroptosis, and apoptosis, likely via the PK2/PKR pathway.

Apelin/APJ relieve diabetic cardiomyopathy by reducing microvascular dysfunction

Microcirculatory injuries had been reported to be involved in diabetic cardiomyopathy, which was mainly related to endothelial cell dysfunction. Apelin, an adipokine that is upregulated in diabetes mellitus, was reported to improve endothelial cell dysfunction and attenuate cardiac insufficiency induced by ischemia and reperfusion. Therefore, it is hypothesized that apelin might be involved in alleviating endothelial cell dysfunction and followed cardiomyopathy in diabetes mellitus. The results showed that apelin improved endothelial cell dysfunction via decreasing apoptosis and expression of adhesion molecules and increasing proliferation, angiogenesis, and expression of E-cadherin, VEGFR 2 and Tie-2 in endothelial cells, which resulted in the attenuation of the capillary permeability in cardiac tissues and following diabetic cardiomyopathy. Meanwhile, the results from endothelial cell-specific APJ knockout mice and cultured endothelial cells confirmed that the effects of apelin on endothelial cells were dependent on APJ and the downstream NFκB pathways. In conclusion, apelin might reduce microvascular dysfunction induced by diabetes mellitus via improving endothelial dysfunction dependent on APJ activated NFκB pathways.

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids.

As the powerhouse of the cells, mitochondria play a very important role in ensuring that cells continue to function. Mitochondrial dysfunction is one of the main factors contributing to the development of cardiomyopathy in diabetes mellitus. In early development of diabetic cardiomyopathy (DCM), patients present with myocardial fibrosis, dysfunctional remodeling and diastolic dysfunction, which later develop into systolic dysfunction and eventually heart failure. Cardiac mitochondrial dysfunction has been implicated in the development and progression of DCM. Thus, it is important to develop novel therapeutics in order to prevent the progression of DCM, especially by targeting mitochondrial dysfunction. To date, a number of studies have reported the potential of phenolic acids in exerting the cardioprotective effect by combating mitochondrial dysfunction, implicating its potential to be adopted in DCM therapies. Therefore, the aim of this review is to provide a concise overview of mitochondrial dysfunction in the development of DCM and the potential role of phenolic acids in combating cardiac mitochondrial dysfunction. Such information can be used for future development of phenolic acids as means of treating DCM by alleviating the cardiac mitochondrial dysfunction.

Diabetes Mellitus Is an Independent Predictor for the Development of Heart Failure: A Population Study

ObjectivesTo delineate the impact of diabetes mellitus (DM) on the development of cardiovascular diseases in a community population. Patients & MethodsCross-sectional survey of residents randomly selected through the Rochester Epidemiology Project, 45 years or older, of Olmsted County as of June 1, 1997, through September 30, 2000. Responders (2042) underwent assessment of systolic and diastolic function using echocardiography. The current analyses included all participants with DM and were compared with a group of participants without DM matched 1:2 for age, sex, hypertension, and coronary artery disease. Baseline characteristics and laboratory and echocardiography findings between groups were compared along with rates of mortality due to various cardiovascular conditions. ResultsWe identified 116 participants with DM and 232 matched participants without DM. Those with DM had a higher body mass index and plasma insulin and serum glucose levels. Although left ventricular ejection fractions were similar, E/e' ratio (9.7 vs 8.5; P=.001) was higher in DM vs non-DM. During a follow-up of 10.8 (interquartile range, 7.8-11.7) years, participants with DM had a higher incidence of heart failure (HF); hazard ratio, 2.1; 95% confidence limits, 1.2-3.6; P=.01) and 10-year Kaplan-Meier rate of 21% (22 of 116) vs 12% (24 of 232) compared with those without DM. We also examined the subgroup of participants without diastolic dysfunction. In this subgroup, those with DM had an increased risk for HF; hazard ratio, 2.5; 95% confidence limits, 1.0-6.3; P=.04). ConclusionIn this cohort, participants with DM have an increased incidence of HF over a 10-year follow-up period even in the absence of underlying diastolic dysfunction. These findings suggest that DM is an independent risk factor for the development of HF and supports the concept of DM cardiomyopathy.

Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca2+/Na+ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca2+ contents, intracellular Ca2+ transients, L-type Ca2+, reverse mode Na+-Ca2+exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca2+ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na+ current and Na+/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca2+ regulation, late Na+ and Na+/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.

Diabetes Mellitus is Associated with Increased Incidence of CHF Independent of Hypertension and Coronary Artery Disease: A Population Based Study

Background Diabetes mellitus (DM) is known to be associated with hypertension, coronary artery disease and poor cardiovascular outcomes. However, it is unclear what impact DM has on cardiovascular outcomes independent of coronary artery disease and hypertension. This study focuses on the impact of DM on cardiovascular disease and survival in a community population independent of hypertension and coronary artery disease. Objectives To further delineate the longitudinal impact of Diabetes Mellitus on the development of cardiovascular diseases and mortality secondary to cardiovascular disease in a community population. Methods Cross-sectional survey of 2,042 randomly selected residents of Olmsted County, aged 45 years or older from June 1997 through September 2000. All patients underwent Doppler echocardiographic assessment of systolic and diastolic function. The current analyses included all subjects with DM and were compared to a group of non DM subjects matched 1:2 for age, gender, hypertension and coronary artery disease. Baseline characteristics, laboratory findings and transthoracic echocardiogram findings between both groups were compared along with rates of mortality due to various cardiovascular conditions. Results We identified 116 subjects with DM and compared to the 232 matched non-DM subjects. Subjects with DM had higher BMI (29 ± 5vs 31±5, kg/m2; p=0.001), plasma insulin (5.8 [4,9]vs 8.5 [5,15], uU/ml; p Conclusions In this community based cohort matched for age, gender, hypertension and coronary artery disease, subjects with diabetes have elevated LV filling pressures and increased incidence of CHF over a 10 year follow-up period. These findings suggest that DM is an independent risk factor for development of heart failure and supports the concept of DM cardiomyopathy.

Histone deacetylase inhibition of cardiac autophagy in rats on a high‑fat diet with low‑dose streptozotocin-induced type 2 diabetes mellitus.

Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1 (PARP1), insulin signaling, advanced glycosylation end product‑specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high‑fat diet (60% fat) and low‑dose streptozotocin (35mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50mg/kg/rat daily for 7days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end‑diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)‑5' adenosine monophosphate‑activated protein kinase α 2, light chain 3‑II, Beclin‑1, glucose transporter 4, p‑protein kinase B, and insulin receptor substrate‑1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p‑mTOR‑S2448, p‑P70S6K‑Thr‑389, RAGE, tumor necrosis factor‑α, and interleukin‑6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.

A Study of cardiac functions in type-2 diabetic patients

Introduction: The cardiomyopathy in diabetes mellitus (DM) is the disorders in cardiac muscle due to prolonged exposure of vascular tissues to hyperglycemia in DM; and is termed as diabetic cardiomyopathy (DC). The early pre-clinical features of DC are the left ventricular diastolic dysfunction (LVDD), preceding the systolic dysfunction and being able to evolve to symptomatic heart failure. Methods: A cross-sectional study was done including 50 DM-2 patients without any feature of cardiovascular involvement and blood pressure less than 130/80 mmHg. Doppler echocardiography was done to evaluate LVDD. Results: In this study results showed diastolic dysfunction was more common among female than male. The prevalence of diastolic dysfunction is more in cases of longer duration of DM. Conclusion: Our study supports other studies that myocardial damage in DM-2 affects diastolic dysfunction before systolic dysfunction. As Doppler echocardiography is a simple non-invasive procedure to assess cardiac function, so in diabetes it should be done routinely in DM for early diagnosis and prevention of further complications.

HDAC Inhibition Modulates Cardiac PPARs and Fatty Acid Metabolism in Diabetic Cardiomyopathy.

Peroxisome proliferator-activated receptors (PPARs) regulate cardiac glucose and lipid homeostasis. Histone deacetylase (HDAC) inhibitor has anti-inflammatory effects which may play a key role in modulating PPARs and fatty acid metabolism. The aim of this study was to investigate whether HDAC inhibitor, MPT0E014, can modulate myocardial PPARs, inflammation, and fatty acid metabolism in diabetes mellitus (DM) cardiomyopathy. Electrocardiography, echocardiography, and western blotting were used to evaluate the electrophysiological activity, cardiac structure, fatty acid metabolism, inflammation, and PPAR isoform expressions in the control and streptozotocin-nicotinamide-induced DM rats with or without MPT0E014. Compared to control, DM and MPT0E014-treated DM rats had elevated blood glucose levels and lower body weights. However, MPT0E014-treated DM and control rats had smaller left ventricular end-diastolic diameter and shorter QT interval than DM rats. The control and MPT0E014-treated DM rats had greater cardiac PPAR-α and PPAR-δ protein expressions, but less cardiac PPAR-γ than DM rats. Moreover, control and MPT0E014-treated DM rats had lower concentrations of 5′ adenosine monophosphate-activated protein kinase 2α, PPAR-γ coactivator 1α, phosphorylated acetyl CoA carboxylase, cluster of differentiation 36, diacylglycerol acyltransferase 1 (DGAT1), DGAT2, tumor necrosis factor-α, and interleukin-6 protein than DM rats. HDAC inhibition significantly attenuated DM cardiomyopathy through modulation of cardiac PPARS, fatty acid metabolism, and proinflammatory cytokines.

A study of prevalence of cardiomyopathy in diabetes mellitus as evidenced by electrocardiography and 2-D echo

Background: Diabetic cardiomyopathy is characterized by diastolic dysfunction, which is rarely clinically apparent unless associated with hypertension and/or with myocardial ischemia. The aim of the study was to determine the prevalence of cardiomyopathy in diabetes mellitus. Methods: This study was carried out on patients coming as out patients (100) to Dr. D.Y.Patil Hospital & Research Centre, Nerul Navi Mumbai from June 2006 to December 2008. Results: In this study maximum number of diabetics are between the age group of 41-50. Males (65) are more common than female (35). Main complaints of the patients coming to OPD was chest pain (59%), followed by giddiness (48%), breathlessness (47%), sweating (33%). ECG changes does not have any correlation with duration of DM. ECG changes related to cardiomyopathy were present in 38 out of 65 males and 25 out of 35 females i.e. total number of 63 subjects had ECG changes related to diabetic cardiomyopathy. 28 males and 16 females had diastolic dysfunction in 2 D Echo. Maximum numbers of patients with diastolic dysfunction were between the age group of 51-60 years in male and females i.e. 11 and 08 respectively. 46 patients had mild systolic dysfunction. 40 patients had normal systolic function but 13 patients had moderate systolic dysfunction while only 01 patient had severe systolic dysfunction. Conclusions: Prevalence of cardiomyopathy in diabetes in present study as evidenced by ECG is 63% and by 2 D Echo it is 62%. Patient with DM of 5 years of duration, should be properly screened & put on proper inotropic drugs to prevent the worsening of diabetic cardiomyopathy.

Quantitative proteomics study of protective effects of grape seed procyanidin B2 on diabetic cardiomyopathy in db/db mice.

Diabetic cardiomyopathy is one of the major complications of diabetes mellitus. Oxidative stress appears to play a substantial role in cardiomyopathy. Grape seed procyanidin B2 (GSPB2) has been known as an anti-oxidant in treating diabetes mellitus; however, little is known about its effects and underlying mechanisms on diabetic cardiomyopathy. The present study is to explore the molecular targets of GSPB2 responsible for the anti-oxidative effects in db/db mice by quantitative proteomics. GSPB2 (30 mg/kg body weight/day) were intragastric administrated to db/db mice for 10 weeks. Proteomics of the heart tissue extracts by isobaric tags for relative and absolute quantification analysis was obtained from db/db mice. Our study provides important evidence that GSPB2 protect against cardiomyopathy in diabetes mellitus, which are believed to result from regulating the expression of key proteins involving cardiac fibrosis and proliferation. GSPB2 could be expected to become novel clinical application in fighting against diabetic cardiomyopathy.

Rationale and design of a randomized trial on the impact of aldosterone antagonism on cardiac structure and function in diabetic cardiomyopathy

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.Trial registrationACTRN12610001063000