Management Of Diabetic Cardiomyopathy Research Articles

Cardioprotective Effects of 'Vasant Kusumakar Rasa,' a Herbo-metallic Formulation, in Type 2 Diabetic Cardiomyopathy in Rats.

Diabetic cardiomyopathy (DCM) is one of the serious complications of type 2 diabetes mellitus. Vasant Kusumakar Rasa (VKR) is a Herbo-metallic formulation reported in Ayurveda, an Indian system of medicine. The present work was designed to study the effect of VKR in cardiomyopathy in type 2 diabetic rats. Diabetes was induced by feeding a high-fat diet (HFD) for 2weeks followed by streptozotocin (STZ) administration (35mg/kg i.p.). VKR was administered orally at dose of28 and 56mg/kg once a day for 16weeks. The results of the study indicated that VKR treatment significantly improved the glycemic and lipid profile, serum insulin, CK-MB, LDH, and cardiac troponin-I when compared to diabetic control animals. VKR treatment in rats significantly improvedthe hemodynamic parameters and cardiac tissue levels of TNF-α, IL-1β, and IL- 6 were also reduced. Antioxidant enzymes such as GSH, SOD, and catalase were improved in all treatment groups. Heart sections stained with H & E and Masson's trichome showed decreased damage to histoarchitecture of the myocardium. Expression of PI3K, Akt, and GLUT4 in the myocardium was upregulated after 16weeks of VKR treatment. The study data suggested the cardioprotective capability of VKR in the management of diabetic cardiomyopathy in rats.

Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.

Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.

Diallyl trisulfide (DATS) ameliorates cardiac fibrosis in a rat model of diabetes

Cardiac fibrosis is a prevalent pathological complication observed in individuals with diabetes. Diallyl trisulfide (DATS), a bioactive compound found in garlic oil, has been reported to exhibit anti-inflammatory and anti-apoptotic effects in various cardiovascular diseases. However, its potential impact on cardiac fibrosis, particularly in the context of diabetes, remains unknown. In the neonatal rat ventricular fibroblasts (NRVFs) model, our results demonstrated that DATS effectively attenuated advanced glycation end products (AGEs)-induced activation of Nuclear factor kappa B (NF-κB) and Smad2/3 signaling pathways, leading to a reduction in the downstream secretion of pro-inflammatory cytokines and collagen synthesis. In the in vivo study using echocardiographic assessment, administration of DATS significantly ameliorated cardiac dysfunction induced by streptozotocin (STZ). Taken together, our findings highlight the potential of DATS as a promising therapeutic agent for mitigating cardiac fibrosis associated with diabetes, emphasizing its potential clinical relevance in the prevention and management of diabetic cardiomyopathy.

Chinese herbal medicine and active ingredients for diabetic cardiomyopathy: molecular mechanisms regulating endoplasmic reticulum stress.

Background: Diabetic cardiomyopathy (DCM) is one of the serious microvascular complications of diabetes mellitus. It is often associated with clinical manifestations such as arrhythmias and heart failure, and significantly reduces the quality of life and years of survival of patients. Endoplasmic reticulum stress (ERS) is the removal of unfolded and misfolded proteins and is an important mechanism for the maintenance of cellular homeostasis. ERS plays an important role in the pathogenesis of DCM by causing cardiomyocyte apoptosis, insulin resistance, calcium imbalance, myocardial hypertrophy and fibrosis. Targeting ERS is a new direction in the treatment of DCM. A large number of studies have shown that Chinese herbal medicine and active ingredients can significantly improve the clinical outcome of DCM patients through intervention in ERS and effects on myocardial structure and function, which has become one of the hot research directions. Purpose: The aim of this review is to elucidate and summarize the roles and mechanisms of Chinese herbal medicine and active ingredients that have the potential to modulate endoplasmic reticulum stress, thereby contributing to better management of DCM. Methods: Databases such as PubMed, Web of Science, China National Knowledge Internet, and Wanfang Data Knowledge Service Platform were used to search, analyze, and collect literature, in order to review the mechanisms by which phytochemicals inhibit the progression of DCM by targeting the ERS and its key signaling pathways. Keywords used included "diabetic cardiomyopathy" and "endoplasmic reticulum stress." Results: This review found that Chinese herbs and their active ingredients can regulate ERS through IRE1, ATF6, and PERK pathways to reduce cardiomyocyte apoptosis, ameliorate myocardial fibrosis, and attenuate myocardial hypertrophy for the treatment of DCM. Conclusion: A comprehensive source of information on potential ERS inhibitors is provided in this review. The analysis of the literature suggests that Chinese herbal medicine and its active ingredients can be used as potential drug candidates for the treatment of DCM. In short, we cannot ignore the role of traditional Chinese medicine in regulating ERS and treating DCM, and look forward to more research and new drugs to come.

Cardioprotection by Citrus grandis (L.) Peel Ethanolic Extract in Alloxan-Induced Cardiotoxicity in Diabetic Rats.

Diabetic cardiomyopathy (DCM) pathogenesis is multifarious, and there are insufficient therapeutic options to treat DCM. The present research explored the effects of Citrus grandis peel ethanolic extract (CGPE) in alloxan-induced DCM in rats. Diabetes was triggered by intraperitoneal (i.p.) injection of alloxan (150 mg/kg) in Wistar rats (200-250 g). CGPE (100, 200, and 400 mg/kg) or glibenclamide (Glib, 10 mg/kg) were administered orally for 2 weeks. After the treatment schedule, prooxidants (thiobarbituric acid reactive substances), antioxidants (glutathione, catalase, and superoxide dismutase), and inflammatory markers (tumor necrosis factor-α) were determined in cardiac tissues. Biomarkers of cell death, viz., lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) activity, glucose levels, total cholesterol (TC), and high-density lipoproteins (HDL), were assessed in the blood. Rats administered with alloxan showed a consistent increase in blood glucose level (days 7 and 14) that was lowered considerably (p < 0.001) by CGPE or Glib. Alloxan-induced increase in LDH, CK-MB, TC, and decline in HDL was attenuated (p < 0.001) in rats that were treated with CGPE or Glib. Alloxan significantly (p < 0.001) elevated oxidative stress, inflammation, and reduced antioxidants in the cardiac tissue of rats, and these pathogenic abnormalities were ameliorated (p < 0.001) by CGPE. Histopathological studies showed a decrease in morphological disruptions by alloxan in CGPE-treated rats. CGPE (400 mg/kg) significantly ameliorated biochemical parameters in comparison to the lower doses against alloxan cardiotoxicity. Citrus grandis peel extract can be an alternative in the management of DCM.

Abrogation of cardiomyopathy in diabetic rats by escin – possible role of NF-κβ and MCP-1

Objective Diabetic cardiomyopathy is one of the most common complications of diabetes. Escin may significantly inhibit myocardial damage through its NF-κβ inhibitory, antidiabetic, neuroprotective, and potent anti-inflammatory activity. Hence, the study was carried out to evaluate the effect of escin in diabetic cardiomyopathy. Methods Diabetes induction was done in rats with streptozotocin. After six weeks of induction, diabetic animals were administered with escin (5, 10, and 20 mg/kg) for the next four weeks. Results Escin prevented the progression of abnormalities in the biochemical, hemodynamic parameters and electrocardiogram. Escin also prevented the progression of abnormality in the oxidative stress parameters. The expression of NF-κβ and MCP-1 was significantly reduced with escin treatment. Furthermore, escin also prevented damage to myocardial cells and reduced collagen deposition in the cardiomyocytes. Conclusion Escin prevented the progression of cardiomyopathy in diabetic rats. Hence escin can be an alternative option for the management of diabetic cardiomyopathy.

Role of novel biomarkers in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is commonly defined as cardiomyopathy in patients with diabetes mellitus in the absence of coronary artery disease and hypertension. As DCM is now recognized as a cause of substantial morbidity and mortality among patients with diabetes mellitus and clinical diagnosis is still inappropriate, various expert groups struggled to identify a suitable biomarker that will help in the recognition and management of DCM, with little success so far. Hence, we thought it important to address the role of biomarkers that have shown potential in either human or animal studies and which could eventually result in mitigating the poor outcomes of DCM. Among the array of biomarkers we thoroughly analyzed, long noncoding ribonucleic acids, soluble form of suppression of tumorigenicity 2 and galectin-3 seem to be most beneficial for DCM detection, as their plasma/serum levels accurately correlate with the early stages of DCM. The combination of relatively inexpensive and accurate speckle tracking echocardiography with some of the highlighted biomarkers may be a promising screening method for newly diagnosed diabetes mellitus type 2 patients. The purpose of the screening test would be to direct affected patients to more specific confirmation tests. This perspective is in concordance with current guidelines that accentuate the importance of an interdisciplinary team-based approach.

Assessment of subclinical diabetic cardiomyopathy by speckle-tracking imaging.

Diastolic dysfunction is traditionally believed to be the first subclinical manifestation of diabetic cardiomyopathy (DCM), leading to systolic dysfunction and then overt heart failure. However, in the last few years, several studies suggested that systolic subclinical dysfunction measured by speckle-tracking echocardiography (STE) may appear ahead of diastolic dysfunction. In this review, the main endpoint is to show whether subclinical myocardial systolic dysfunction appears ahead of diastolic dysfunction and the implication this may have on the evolution and management of DCM. We performed a search in PubMed for all relevant publications on the assessment of DCM by STE from 1 June 2015 to 1 June 2020. The results illustrate that subclinical systolic dysfunction assessed by STE is present in early DCM stages, with or without the association of diastolic dysfunction. This could be a promising perspective for the early management of patients with DCM leading to the prevention of the overt form of disease.

Bauhinia variegata leaf extract: An effective management option for diabetic cardiomyopathy

Hyperglycemia, hyperlipidemia, and oxidative stress are an important pathological conditions in diabetes which are linked with the progression of diabetic cardiomyopathy. Cardiomyopathy is considered as one of the major cause of mortality in diabetic patients. The present study focuses on the effect of Bauhinia variegata Linn leaves in the management of diabetic cardiomyopathy. Alcoholic extract of Bauhinia variegata Linn leaves (AlcE) was prepared and standardized using liquid chromatography-mass spectroscopy (LC-MS) analysis. Male Sprague Dawley rats received a single intraperitoneal injection of streptozotocin (55 mg/kg) for induction of diabetes. After 6 weeks of diabetes induction, animals were treated with AlcE at the dose of 250, 500 and 1000 mg/kg by oral route for next 28 days. Diabetic control animals showed a significant increased level of blood glucose (P<0.001) when compared with normal control. Treatment with AlcE at dose 500 and 1000 mg/kg significantly reduced the elevated blood glucose (521.0 ± 8.40 and 459.3 ± 49.42, respectively) after 28 days of treatment (p<0.05 and p<0.001). Diabetic control group also showed significant increased level of cardiac marker enzyme-like aspartate transaminase (299.7 ± 17.0), lactate dehydrogenase (1235±40.39), creatinine kinase- MB (1081±42.49) in plasma. Treatment with AlcE at dose 1000 mg/kg significantly reduced the elevated level of aspartate transaminase (194.4 ± 12.27), lactate dehydrogenase (872.3 ± 28.58) and creatinine kinase- MB (735.5 ± 38.35) (p<0.001, p<0.001 and p<0.001, respectively). Elevated lipid markers like total cholesterol and triglyceride were found to be significantly attenuated after AlcE treatment at dose 1000 mg/kg (p<0.001 and p<0.05, respectively). AlcE treatment also significantly prevented the loss of antioxidant enzymes like superoxide dismutase, catalase and glutathione and reduced formation of lipid malondialdehyde in cardiac tissue (p<0.01, p<0.00, p<0.001 and P<0.001). Restoration of altered electrocardiogram pattern and hemodynamic parameters were also observed after AlcE treatment. Histopathological findings indicated that AlcE treatment prevented cardiac tissue from necrotic damage and collagen deposition.Form the results, it can be concluded that Bauhinia variegata extract is having significant effect in the management of diabetic cardiomyopathy.

Effect of Bauhinia variegata Leaf Extract in Diabetic Cardiomyopathy

Diabetes mellitus is a chronic metabolic disorder associated with development of micro and macro vascular diabetic complications. According to World Health Organization cardiovascular disease causes up to 65% of deaths among diabetic population. The present work was designed to study effect of Bauhinia variegata, a medicinal plant described in Ayurveda for its medicinal benefits in diabetic cardiomyopathy. Alcoholic extract of Bauhinia variegata leaf (AlcE) was prepared by Soxhlet extraction technique and was standardized using HPTLC. Male Sprague Dawley rats were injected with streptozotocin (55 mg/kg, i.p.) for induction of diabetes. After 42 days of diabetes induction, the animals were grouped and treated with alcoholic extract at dose of 250, 500 and 1000 mg/kg by oral route for next 28 days. At the end of treatment, plasma and heart tissue were collected for evaluation of various parameters. AlcE at 1000 mg/kg significantly reduced plasma glucose as compared to diabetic control animals. AlcE at dose of 500 and 1000 mg/kg significantly (P&lt;0.001) reduced elevated level of creatine kinase‐MB, lactate dehydrogenase and aspartate transaminase in plasma as compared to diabetic animals. AlcE treatment prevented cardiac tissue from oxidative damage, it significantly reduced the elevated level of malonyl dialdehyde at dose of 500 and 1000 mg/kg whereas it significantly increased the level of antioxidant enzymes at dose of 1000 mg/kg (P&lt;0.001). Present study showed that Bauhinia variegata leaf extract has significant effect in management of diabetic cardiomyopathy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK.

Chlorogenic acid attenuates glucotoxicity in H9c2 cells via inhibition of glycation and PKC α upregulation and safeguarding innate antioxidant status

A series of cardiovascular complications associated with hyperglycemia is a critical threat to the diabetic population. Here we elucidate the link between hyperglycemia and cardiovascular diseases onset, focusing on oxidative stress and associated cardiac dysfunctions. The contribution of advanced glycation end products (AGE) and protein kinase C (PKC) signaling is extensively studied. For induction of hyperglycemia, H9c2 cells were incubated with 33 mM glucose for 48 h to simulate the diabetic condition in in vitro system. Development of cardiac dysfunction was confirmed with the significant increase of lactate dehydrogenase (LDH) release to the medium and associated decrease in cell viability. Various parameters like free radical generation, alteration in innate antioxidant system, lipid peroxidation, AGE production and PKC α -ERK axis were investigated during hyperglycemia and with chlorogenic acid. Hyperglycemia has significantly enhanced reactive oxygen species (ROS- 4 fold) generation, depleted SOD activity (1.3 fold) and expression of enzymes particularly CuZnSOD (SOD1) and MnSOD (SOD2), increased production of AGE (2.18 fold). Besides, PKC α dependent ERK signaling pathway was found activated (1.43 fold) leading to cardiac dysfunction during hyperglycemia. Chlorogenic acid (CA) was found beneficial against hyperglycemia most probably through its antioxidant mediated activity. The outcome of this preliminary study reveals the importance of integrated approach emphasizing redox status, glycation and signaling pathways like PKC α - ERK axis for control and management of diabetic cardiomyopathy (DCM) and potential of bioactives like CA.

Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2

Oxidative stress and inflammation play key roles in the development of diabetic cardiomyopathy (DCM). Dimethyl fumarate (DMF), an FDA approved medicine for relapsing multiple sclerosis, has manifested its antioxidant and anti-inflammatory function mostly in the central nervous system. In this study, we investigated whether DMF could attenuate the development of DCM. Type 1 diabetes mouse model was established using multiple low-dose streptozotocin, and the diabetic mice were treated with DMF (10 mg/kg body weight) for 3 months. Cardiac functions were determined using echocardiography. Oxidative stress, pro-inflammatory cytokines and pro-fibrotic markers were determined with commercially available kits, real-time quantitative PCR or western blot techniques. DCM was characterized by diminished cardiac function, accompanied by oxidative stress and enhanced expression of pro-inflammatory cytokines. Diabetic cardiac tissue exhibited marked fibrosis, revealed by extracellular matrix deposition as determined by Sirius red staining of the myocardial tissues. Furthermore, Nrf2 and its downstream effectors were repressed in diabetic myocardium. On the contrary, diabetic animals treated with DMF exhibited blunted oxidative stress, inflammation, fibrosis and this correlated with Nrf2 activation. Our findings suggest that DMF could potentially thwart diabetes-induced myocardial tissue injury, likely via activation of Nrf2 function, providing firm impetus for future repurposing of DMF in the management of DCM.

Argatroban Attenuates Diabetic Cardiomyopathy in Rats by Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression.

Chronic diabetes is associated with cardiovascular dysfunctions. Diabetic cardiomyopathy (DCM) is one of the serious cardiovascular complications associated with diabetes. Despite significant efforts in understanding the pathophysiology of DCM, management of DCM is not adequate due to its complex pathophysiology. Recently, involvement of protease-activated receptors (PARs) has been postulated in cardiovascular diseases. These receptors are activated by thrombin, trypsin, or other serine proteases. Expression of PAR has been shown to be increased in cardiac diseases such as myocardial infarction, viral myocarditis, and pulmonary arterial hypertension. However, the role of PAR in DCM has not been elucidated yet. Therefore, in the present study, we have investigated the role of PAR in the condition of DCM using a pharmacological approach. We used argatroban, a direct thrombin inhibitor for targeting PAR. Type-2 diabetes mellitus (T2DM) was induced by high-fat feeding along with low dose streptozotocin (STZ 35mg/kg, i.p. single dose) in male Sprague-Dawley rats. After 16weeks of diabetes induction, animals were treated with argatroban at 0.3 and 1mg/kg dose daily for 4weeks. After 20weeks, ventricular functions were measured using ventricular catheterization. Cardiac histology, TUNEL staining, and immunoblotting were performed to evaluate cardiac fibrosis, DNA fragmentation, and expression level of different proteins, respectively. T2DM was associated with cardiac structural and functional disturbances as evidenced from impaired cardiac functional parameters and increased fibrosis. There was a significant increase in PAR expression after 20weeks of diabetes induction. Four weeks argatroban treatment ameliorated metabolic alterations (reduced plasma glucose and cholesterol), ventricular dysfunctions (improved systolic and diastolic functions), cardiac fibrosis (reduced percentage area of collagen in picro-sirius red staining), and apoptosis (reduced TUNEL positive nuclei). Reduced expression of PAR1 and PAR4 in the argatroban-treated group indicates a response towards inhibition of thrombin. In addition, AKT (Ser-473), GSK-3β (Ser-9), p-65 NFĸB phosphorylation, TGF-β, COX-2, and caspase-3 expression were reduced significantly along with an increase in SERCA expression in argatroban-treated diabetic rats which indicated the anti-fibrotic, anti-inflammatory, and anti-apoptotic potential of argatroban in DCM. This study suggests the ameliorative effects of argatroban in diabetic cardiomyopathy by improving ventricular functions and reducing fibrosis, inflammation, apoptosis, and PAR expression.

Antioxidative Effects of Natural Products on Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes and results in high mortality. It is therefore imperative to develop novel therapeutics for the prevention or inhibition of the progression of DCM. Oxidative stress is a key mechanism by which diabetes induces DCM. Hence, targeting of oxidative stress-related processes in DCM could be a promising therapeutic strategy. To date, a number of studies have shown beneficial effects of several natural products on the attenuation of DCM via an antioxidative mechanism of action. The aim of the present review is to provide a comprehensive and concise overview of the previously reported antioxidant natural products in the inhibition of DCM progression. Clinical trials of the antioxidative natural products in the management of DCM are included. In addition, discussion and perspectives are further provided in the present review.

Role of the Cathepsin K/Calcineurin/Nuclear Factor of Activated T-Cells Axis in the Pathogenesis and Management of Diabetic Cardiomyopathy

Diabetes mellitus has become a devastating global epidemic. Patients with diabetes suffer a high prevalence of diabetic cardiomyopathy (DCM). DCM is a type of cardiac problem independent of any preexisting macro- and micro-vascular diseases. The pathophysiological basis underlying diabetes-induced cardiac damage is rather complex and multifactorial. Although a number of risk factors including oxidative stress, apoptosis, and aberrant intracellular Ca2+ metabolism have been postulated to play a role in the onset and development of cardiac anomalies within diabetes, the precise mechanisms responsible for DCM remain elusive. This mini-review discusses the latest findings of mechanisms involved in the progression of cardiomyopathy in diabetes. We emphasize the role of the lysosomal cysteine protease, cathepsin K, and its downstream calcineurin/nuclear factor of activated T-cells signaling in the prevention and treatment of DCM.

Myocardial metabolism in diabetic cardiomyopathy: potential therapeutic targets.

Cardiovascular complications in diabetes are particularly serious and represent the primary cause of morbidity and mortality in diabetic patients. Despite early observations of cardiac dysfunction in diabetic humans, cardiomyopathy unique to diabetes has only recently been recognized. Research has focused on understanding the pathogenic mechanisms underlying the initiation and development of diabetic cardiomyopathy. Emerging data highlight the importance of altered mitochondrial function as a major contributor to cardiac dysfunction in diabetes. Mitochondrial dysfunction occurs by several mechanisms involving altered cardiac substrate metabolism, lipotoxicity, impaired cardiac insulin and glucose homeostasis, impaired cellular and mitochondrial calcium handling, oxidative stress, and mitochondrial uncoupling. Currently, treatment is not specifically tailored for diabetic patients with cardiac dysfunction. Given the multifactorial development and progression of diabetic cardiomyopathy, traditional treatments such as anti-diabetic agents, as well as cellular and mitochondrial fatty acid uptake inhibitors aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose may not adequately target all aspects of this condition. Thus, an alternative treatment such as resveratrol, which targets multiple facets of diabetes, may represent a safe and promising supplement to currently recommended clinical therapy and lifestyle changes. Elucidation of the mechanisms underlying the initiation and progression of diabetic cardiomyopathy is essential for development of effective and targeted treatment strategies. Of particular interest is the investigation of alternative therapies such as resveratrol, which can function as both preventative and mitigating agents in the management of diabetic cardiomyopathy.

Application of a novel curcumin analog in the management of diabetic cardiomyopathy.

Diabetes mellitus is becoming an epidemic health threat and represents one of the most prevalent chronic noncommunicable disorders. Cardiovascular complications are considered the leading cause of death for diabetic patients. Diabetes leads to undesired changes in cardiac structure and function, a condition commonly known as diabetic cardiomyopathy, which occurs independent of macro- and microvascular comorbidities in diabetes (1,2). Both systolic and diastolic dysfunctions have been demonstrated in diabetic hearts including prolonged duration of contraction and relaxation, reduced velocity of contraction and relaxation, and depressed myocardial contractility (1,3). In particular, clinical evaluation using electrocardiogram and echocardiography has revealed substantial functional changes in diabetic hearts, including shorter left ventricular ejection time, prolonged pre-ejection duration, increased wall stiffness, decreased fractional shortening, decreased rate of left ventricular filling, and increased action potential duration (4,5). To date, a plethora of cellular and molecular mechanisms have been postulated for the onset and development of diabetic cardiomyopathy, including reduced energy production due to decreases in mitochondrial respiration and pyruvate dehydrogenase activity, accumulation of reactive oxygen species, oxidative stress, apoptosis, impaired autophagy, and malfunction of cardiac contractile and intracellular Ca2+ regulatory proteins such as myosin, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), and Na+-Ca2+ exchanger (1–3,5,6). The high morbidity and mortality for diabetic cardiomyopathy warrant aggressive clinical management involving lifestyle modification, control of glucose and lipid abnormalities, and treatment of hypertension and …

Multiple Antioxidants Improve Cardiac Complications and Inhibit Cardiac Cell Death in Streptozotocin-Induced Diabetic Rats

Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. Since diabetic cardiomyopathy is now known to have a high prevalence in the asymptomatic diabetic patient, prevention at the earliest stage of development by existing molecules would be appropriate in order to prevent the progression of heart failure. In this study, we investigated the protective role of multiple antioxidants (MA), on cardiac dysfunction and cardiac cell apoptosis in streptozotocin (STZ)-induced diabetic rat. Diabetic cardiomyopathy in STZ-treated animals was characterized by declined systolic, diastolic myocardial performance, oxidative stress and apoptosis in cardiac cells. Diabetic rats on supplementation with MA showed decreased oxidative stress evaluated by the content of reduced levels of lipid per-oxidation and decreased activity of catalase with down-regulation of heme-oxygenase-1 mRNA. Supplementation with MA also resulted in a normalized lipid profile and decreased levels of pro-inflammatory transcription factor NF-kappaB as well as cytokines such as TNF-α, IFN-γ, TGF-β, and IL-10. MA was found to decrease the expression of ROS-generating enzymes like xanthine oxidase, monoamine oxidase-A along with 5-Lipoxygenase mRNA and/or protein expression. Further, left ventricular function, measured by a microtip pressure transducer, was re-established as evidenced by increase in ±dp/dtmax, heart rate, decreased blood pressure, systolic and diastolic pressure as well as decrease in the TUNEL positive cardiac cells with increased Bcl-2/Bax ratio. In addition, MA supplementation decreased cell death and activation of NF-kappaB in cardiac H9c2 cells. Based on our results, we conclude that MA supplementation significantly attenuated cardiac dysfunction in diabetic rats; hence MA supplementation may have important clinical implications in terms of prevention and management of diabetic cardiomyopathy.

Diabetic cardiomyopathy

Diabetic individuals are at significantly greater risk of developing heart failure (HF) independent from other risk factors such as coronary artery disease (CAD) and hypertension. Diabetic cardiomyopathy (DCP) is defined as ventricular dysfunction in the absence of hypertension, coronary artery and valvular heart disease, which increases the risk of HF. Due to better understanding of its pathophysiology and clinical importance, DCP is more frequently recognized in daily practice. The most important mechanisms of DCP are hyperglycemia, insulin resistance/hyperinsulinemia, abnormal fatty acid metabolism, increased apoptosis, cardiac autonomic neuropathy and local renin-angiotensin-aldosterone system (RAAS) overactivation. Echocardiography is the most frequently used diagnostic method for the detection of this pathology. Currently, although there is no specific treatment for DCP, strict glycemic and concomitant risk factor controls seems to be the most important target strategy for prevention of the progression and treatment of DCP. In this article, we aim to provide an extensive review on the pathophysiology, diagnosis, management of DCP.