OBJECTIVE: We aim to explore the potential of diverse treatments, including perhexiline, calcium channel blockers, anti-hypertensives, PDE5 inhibitors, anti-anginal drugs, aldose reductase inhibitors, and SGLT-2 inhibitors, supported by clinical evidence. Additionally, this review seeks to identify novel therapeutic targets and future avenues for improving cardiovascular outcomes in diabetic populations.
METHODS: We performed a comprehensive literature review of English-language studies across multiple electronic databases, such as PubMed, ScienceDirect, Scopus, and Google Scholar, focusing on clinical trials. The search utilized keywords including \'Anti-hyperglycaemic drug,\' \'Diabetic cardiomyopathy,\' \'DPP-4 inhibitors,\' \'GLP-1 receptor agonists,\' \'Heart failure,\' and \'SGLT-2 inhibitors.\'
RESULTS: We assessed clinical investigations in the treatment of cardiomyopathy and diabetes mellitus (DM) that are enhancing our understanding through trials evaluating the Polypill, Perhexiline, Eplerenone, IMB-1018972, AT-001, tadalafil, and dapagliflozin inhibitors. The development of new targeted interventions is of paramount importance due to the overlooked early symptoms, the complexity of the cellular and molecular pathways involved, and the absence of effective drug therapies.
CONCLUSIONS: Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety.

OBJECTIVE: To assess the role of Cardiotrophin-1 (CT-1) and echocardiography in early detection of subclinical Diabetic Cardiomyopathy (DCM) in children with type 1 Diabetes Mellitus (T1D).
METHODS: This case-control study included two groups of children and adolescents aged between 7 and 18. Group (1) included forty patients with T1D (duration > 5 years) regularly followed at the children\'s hospital of Cairo University, and Group (2) included forty age and sex-matched healthy subjects as a control group. The serum level of CT-1 was measured, and conventional echocardiography, tissue Doppler imaging (TDI), and 2D speckle tracking echocardiography were performed.
RESULTS: The level of CT-1 in the cases ranged from 11 to 1039.4 pg/ml with a median (IQR) of 19.4 (16.60-25.7) pg/ml, while its level in the control group ranged from 10.8 to 162.6 pg/ml with a median (IQR) of 20.2 (16.2-24.8) pg/ml. CT-1 levels showed no statistically significant difference between cases and controls. Patients had significantly higher mean left ventricle E/E\' ratio (p<0.001), lower mean 2D global longitudinal strain (GLS) of the left ventricle (LV) (p<0.001), and lower mean GLS of the right ventricle (RV) (p<0.001) compared to controls. Ofpatients with diabetes, 75 % had LV diastolic dysfunction, 85 % had RV diastolic dysfunction, 97.5 % had LV systolic dysfunction, and 100 % had RV systolic dysfunction.
CONCLUSIONS: Non-conventional echocardiography is important for early perception of subclinical DCM in patients with T1D. Cardiotrophin-1 was not specific for early detection of DCM.

OBJECTIVE: Abnormalities in specific echocardiographic parameters and cardiac biomarkers have been reported among individuals with diabetes. However, a comprehensive characterization of diabetic cardiomyopathy (DbCM), a subclinical stage of myocardial abnormalities that precede the development of clinical heart failure (HF), is lacking. In this study, we developed and validated a machine learning-based clustering approach to identify the high-risk DbCM phenotype based on echocardiographic and cardiac biomarker parameters.
RESULTS: Among individuals with diabetes from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of cardiovascular disease and other potential aetiologies of cardiomyopathy (training, n = 1199), unsupervised hierarchical clustering was performed using echocardiographic parameters and cardiac biomarkers of neurohormonal stress and chronic myocardial injury (total 25 variables). The high-risk DbCM phenotype was identified based on the incidence of HF on follow-up. A deep neural network (DeepNN) classifier was developed to predict DbCM in the ARIC training cohort and validated in an external community-based cohort (Cardiovascular Health Study [CHS]; n = 802) and an electronic health record (EHR) cohort (n = 5071). Clustering identified three phenogroups in the derivation cohort. Phenogroup-3 (n = 324, 27% of the cohort) had significantly higher 5-year HF incidence than other phenogroups (12.1% vs. 4.6% [phenogroup 2] vs. 3.1% [phenogroup 1]) and was identified as the high-risk DbCM phenotype. The key echocardiographic predictors of high-risk DbCM phenotype were higher NT-proBNP levels, increased left ventricular mass and left atrial size, and worse diastolic function. In the CHS and University of Texas (UT) Southwestern EHR validation cohorts, the DeepNN classifier identified 16% and 29% of participants with DbCM, respectively. Participants with (vs. without) high-risk DbCM phenotype in the external validation cohorts had a significantly higher incidence of HF (hazard ratio [95% confidence interval] 1.61 [1.18-2.19] in CHS and 1.34 [1.08-1.65] in the UT Southwestern EHR cohort).
CONCLUSIONS: Machine learning-based techniques may identify 16% to 29% of individuals with diabetes as having a high-risk DbCM phenotype who may benefit from more aggressive implementation of HF preventive strategies.

Diabetic cardiomyopathy (DCM), a significant complication of diabetes mellitus, is marked by myocardial structural and functional alterations due to chronic hyperglycemia. Despite its clinical significance, optimal treatment strategies are still elusive. Bariatric surgery via sleeve gastrectomy and Roux-en-Y gastric bypass have shown promise in treating morbid obesity and associated metabolic disorders including improvements in diabetes mellitus and DCM. The present study reviews the molecular mechanisms by which bariatric surgery improves DCM, offering insights into potential therapeutic targets. Future research should further investigate the mechanistic links between bariatric surgery and DCM, to evaluate the benefits and limitations of these surgical interventions for DCM treatment. The present study aims to provide a foundation for more effective DCM therapies, contributing to the advancement of patient care.

Absent in melanoma 2(AIM2) exacerbates atherosclerosis by inflammasome assembly. However, AIM2-mediated inflammation in diabetic cardiomyopathy remains incompletely understood. Here we investigate the role of AIM2 in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. By RNA-seq, we found that AIM2 were significantly upregulated in HG-induced macrophages, upregulation of AIM2 in cardiac infiltrating macrophages was confirmed in a high-fat diet (HFD)/streptozotocin (STZ)-induceddiabetic mouse model . Therefore, AIM2 knockout mice were constructed. Compared to WT mice, HFD/STZ-induced cardiac hypertrophy and dysfunction were significantly improved in AIM2-/- mice, despite no changes in blood glucose and body weight. Further, AIM2 deficiency inhibited cardiac recruitment of M1-macrophages and cytokine production. Mechanistically, AIM2-deficient macrophgaes reduced IL-1β and TNF-α secretion, which impaired the NLRC4/IRF1 signaling in cardiomyocytes, and reduced further recruitment of macrophages, attenuated cardiac inflammation and hypertrophy, these effects were confirmed by silencing IRF1 in WT mice, and significantly reversed by overexpression of IRF1 in AIM2-/- mice. Taken together, our findings suggest that AIM2 serves as a novel target for the treatment of diabetic cardiomyopathy.

BACKGROUND: Sodium-dependent glucose transporter 2 inhibitors (SGLT2i) have shown efficacy in reducing heart failure (HF) burden in a very heterogeneous groups of patients, raising doubts about some contemporary assumptions of their mechanism of action. We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy. Two groups of patients were included in the study: the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.
OBJECTIVE: To evaluate the outcomes regarding natriuretic peptide, oxidative stress, inflammation, blood pressure, heart rate, cardiac function, and body weight.
METHODS: The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain (GLS), N-terminal pro-brain natriuretic peptide, myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), and systolic and diastolic blood pressure. To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up, a rise in stroke volume index, body mass index (BMI) decrease, and lack of heart rate increase, linear regression analysis was performed.
RESULTS: There was a greater reduction of MPO, hsCRP, GLS, and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up. Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI, while the predictor of stroke volume index increase was SGLT2i therapy itself.
CONCLUSIONS: SGLT2i affect body composition, reduce cardiac load, improve diastolic/systolic function, and attenuate the sympathetic response. Glycemic control contributes to the improvement of heart function, blood pressure control, oxidative stress, and reduction in inflammation.

Cardiovascular disease including diabetic cardiomyopathy (DbCM) represents the leading cause of death in people with diabetes. DbCM is defined as ventricular dysfunction in the absence of underlying vascular diseases and/or hypertension. The known molecular mediators of DbCM are multifactorial, including but not limited to insulin resistance, altered energy metabolism, lipotoxicity, endothelial dysfunction, oxidative stress, apoptosis, and autophagy. FoxO1, a prominent member of forkhead box O transcription factors, is involved in regulating various cellular processes in different tissues. Altered FoxO1 expression and activity have been associated with cardiovascular diseases in diabetic subjects. Herein we provide an overview of the role of FoxO1 in various molecular mediators related to DbCM, such as altered energy metabolism, lipotoxicity, oxidative stress, and cell death. Furthermore, we provide valuable insights into its therapeutic potential by targeting these perturbations to alleviate cardiomyopathy in settings of type 1 and type 2 diabetes.

Diabetic cardiomyopathy, a severe diabetic complication, impairs heart function, leading to heart failure. Treatment that effectively addresses this condition without causing side effects is urgently needed. Current anti-hyperglycemic therapies are expensive, has side effects and do not effectively prevent cardiac remodeling. Therefore, it is important to explore natural products that may have the potential to reverse cardiac remodeling. That is why the aim of the current study was to determine the left ventricular remodeling potential of the methanolic extract of Artemisia vulgaris in a diabetic cardiomyopathy rat model. Following the initial comprehensive phytochemical evaluation of plant phenolic and flavonoid content, which showed strong anti-hyperglycemic and antioxidant activities, an extract of Artemisia vulgaris was administered in an in vivo experiment. Diabetic cardiomyopathy was induced in Wistar albino rats according to previously described protocols in the literature, and the effect of treatment was checked by serum and histopathological analysis after 45 days. Artemisia vulgaris treatment significantly (p ≤ 0.05) reduced fasting blood glucose (108.5 ± 1.75 mg/dL), glycated hemoglobin (4.03 ± 0.12 %), serum glucose (116.66 ± 3.28 mg/dL), insulin (15.66 ± 0.66 ng/mL), total oxidant status (54.66 ± 3.22 µmol H2O2Equiv.L-1), Malondialdehyde (0.20 ± 0.01 mmol/L), total cholesterol (91.16 ± 3.35 mg/dL), triglycerides (130.66 ± 3.15 mg/dL), low-density lipids (36.57 ± 1.02 mg/dL), sodium (140 ± 3.21 mmol/L), calcium (10.44 ± 0.24 mmol/L), creatine kinase MB (1227.5 ± 17.89 IU/L), lactate dehydrogenase (1300 ± 34.64 IU/L), C-reactive protein (30 ± 0.57 pg/mL), tumor necrosis factor-α (58.66 ± 1.76 pg/mL), atrial natriuretic peptide (2.53 ± 0.04 pg/mL), B-type natriuretic peptide (10.66 ± 0.44 pg/mL), aspartate aminotransferase (86.5 ± 4.99 U/L), Alanine Transaminase (55.33 ± 2.90 U/L), urea (25.33 ± 1.15 mg/dL) and creatinine (0.64 ± 0.02 mg/dL) but significantly increased (p ≤ 0.05) total antioxidant capacity (1.73 ± 0.07 mmol Trolox Equil./L), high-density lipids (40 ± 1.59 mg/dL) and potassium (3.82 ± 0.04 mmol/L) levels. ECG and histopathology confirmed the significant improvement in remodeling and the reversal of structural changes in the heart and pancreas. In conclusion, Artemisia vulgaris possesses significant left ventricular remodeling potential in course of diabetes-induced cardiomyopathy.

Background: Diabetic cardiomyopathy (DCM) poses a significant risk for heart failure in individuals with diabetes, yet its underlying mechanisms remain incompletely understood. Elevated blood sugar levels initiate harmful processes, including apoptosis, collagen accumulation, and fibrosis in the heart. Vinpocetine, a derivative of Vinca minor L., has demonstrated diverse pharmacological effects, including vasodilation, anti-inflammatory properties, and enhanced cellular metabolism. This study aims to investigate Vinpocetine\'s protective and remodeling effects in diabetic cardiomyopathy by evaluating biochemical and histopathological parameters. Methods: Twenty-one adult male Wistar rats were induced with diabetes using streptozocin and divided into Diabetes and Diabetes + Vinpocetine groups. Histopathological analyses, TGF-β1 immunoexpression, and measurements of plasma markers (TGF-β, pro-BNP, Troponin T) were performed. Biochemical analyses included HIF-1 alpha and neuregulin-1β quantification and evaluation of lipid peroxidation. Results: Vinpocetine significantly reduced cardiac muscle thickness, TGF-β1 expression, and plasma in diabetic rats. HIF-1 alpha and neuregulin-1β levels increased with Vinpocetine treatment. Histopathological observations confirmed reduced fibrosis and structural abnormalities in Vinpocetine-treated hearts. Conclusions: This study provides comprehensive evidence supporting the protective effects of Vinpocetine against diabetic cardiomyopathy. Vinpocetine treatment improved cardiac morphology, immunohistochemistry, and modulation of biochemical markers, suggesting its potential as a therapeutic intervention to attenuate the negative impact of diabetes on heart function.

Recently, the roles of pyroptosis, a form of cell death induced by activated NOD-like receptor protein 3 (NLRP3) inflammasome, in the pathogenesis of diabetic cardiomyopathy (DCM) have been extensively investigated. However, most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models, and whether various medications and natural products prevent the development of DCM, associated with decreased levels of cardiac NLRP3 inflammasome and pyroptosis. The direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies, with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific inhibitors. We thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link, given that several studies have provided both direct and indirect evidence under specific conditions. This editorial emphasizes that the current investigation should be circumspect in its conclusion, i.e., not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent models. Only clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM, targeting these biomarkers.