This investigation seeks to elucidate the contribution of leptin to the pathogenesis of diabetic cardiomyopathy (DCM).

Mice were rendered diabetic through the administration of streptozotocin (STZ). Leptin was delivered via subcutaneously implanted osmotic pumps. Assessments of cardiac performance, hypertrophy, and fibrosis were conducted using echocardiography, Hematoxylin and Eosin (H&E), Wheat Germ Agglutinin (WGA), and Masson trichrome staining. Myocardial apoptosis and oxidative stress were quantified through TUNEL assay and biochemical markers of oxidative stress, including Malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), and 3-Nitrotyrosine (3NT). Mitochondrial structure was examined using Transmission Electron Microscopy (TEM). Primary neonatal cardiomyocytes were subjected to high glucose (HG) conditions. The fluorescent indicators MitoTracker Green and MitoSOX Red were employed to evaluate mitochondrial morphology and function within the cardiomyocytes.

Mice with diabetes displayed marked cardiac hypertrophy and fibrosis, as indicated by H&E, WGA, and Masson staining. The administration of leptin significantly mitigated the cardiac pathological manifestations in diabetic mice. Leptin increased the expression of Opa1 and enhanced mitochondrial fusion and function in cardiomyocytes exposed to HG. The cGAS/STING signaling pathway may serve as a pivotal intermediary for leptin to facilitate Opa1-driven mitochondrial fusion.

Leptin appears to safeguard against hyperglycemia-induced mitochondrial oxidative damage and DCM by modulating the cGAS/STING signaling cascade and Opa1-mediated mitochondrial fusion. These results propose that leptin could be a promising agent for promoting mitochondrial fusion and preventing diabetes-associated cardiac pathologies.

Diabetic cardiomyopathy (DCM) is a common complication of type 2 diabetes mellitus (T2DM). The effects of methylophiopogonanone A (MO-A), a natural homoisoflavonoid with anti-inflammatory effects, on DCM and its underlying mechanisms were investigated in this study.

The T2DM mouse model was induced by intraperitoneal injection of 30 mg/kg streptozotocin for 7 consecutive days and fed with a high-fat diet for 12 weeks. T2DM mice received MO-A (2.5, 5, or 10 mg/kg) treatment for two weeks. Cardiac function, hypertrophy, fibrosis, and inflammation were evaluated. The binding energy between MO-A and JNK1 was analyzed using molecular docking. The underlying mechanism was further investigated in high glucose (HG)-induced H9C2 cells. The cytotoxic effects, cardiomyocyte hypertrophy, fibrosis, inflammation, and relevant signaling proteins were assessed.

MO-A treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, MO-A treatment significantly decreased COLI, TGF-β1, MYH7, and ANP expression levels in DCM mice. Furthermore, TNF-α, IL-6, and IL-1β expression levels were notably downregulated after treatment with MO-A in DCM mice. Similar results were also observed in vitro. Mechanistically, MO-A targets JNK1 and downregulates its phosphorylation levels in DCM mice. The protective properties of MO-A were reversed by JNK1 overexpression in HG-induced H9C2 cells.

Our results revealed that MO-A could alleviate cardiac function, hypertrophy, fibrosis, and inflammation in DCM via inhibiting JNK1 signaling.

Diabetic cardiomyopathy (DCM) is a significant cardiovascular complication in diabetic patients, and treatment regimens are limited. Rhein, a compound extracted from the herb rhubarb, was investigated in this study for its efficacy on DCM and the potential mechanism.

Streptozotocin-induced DCM mice, high-glucose (HG)-treated neonatal rat cardiomyocytes (NRCMs), and H9c2 cells with ClpP knockdown were used for the study. We performed phenotypic and molecular mechanistic studies using immunoblotting, quantitative polymerase chain reaction, transmission electron microscopy, cardiac echocardiography, and histopathological analysis.

Rhein improved the cardiac function and myocardial fibrosis, and decreased the cross-sectional area of cardiomyocytes in the DCM mice. It also improved mitochondrial dynamic disorder as evidenced by a decreased ratio of mitochondrial fission-related proteins p-Drp1S616/ Drp1 and increased expression of mitochondrial fusion proteins (Opa1, Mfn1 and Mfn2). Rhein mitigated apoptosis as indicated by decreased apoptosis-related proteins (caspase 9, cleaved-caspase 3 and Bax) and increased anti-apoptosis protein Bcl2 in the heart tissue of DCM mice. Upregulations of cardiac hypertrophy associated genes (ANP, BNP and β-MHC) were significantly inhibited by Rhein treatment. In addition, the level of ClpP, a mitochondrial protease, was increased in DCM, but was normalized by Rhein treatment. However, ClpP knockdown exacerbated cardiomyocyte injury in the presence or absence of HG in H9c2 cells, indicating that a normal level of ClpP is essential for cardiomyocytes to survive.

Our results suggest that Rhein protects DCM by ameliorating mitochondrial dynamics disorder, inhibiting cardiomyocyte apoptosis, and myocardial hypertrophy. These protective effects of Rhein may be mediated by preventing ClpP upregulation.

Diabetic cardiomyopathy (DC) refers to the abnormal myocardial structure and performance induced by diabetes. Although numerous studies have been carried out, the pathophysiological mechanisms of cardiovascular disorders during diabetes have not been fully clarified. Here, we compared the cardiomyopathy of healthy rhesus monkeys and rhesus monkeys with a history of streptozocin induced type 1 diabetes (T1D) over 7 years. Through comparing the cardiac function using echocardiography, and detecting the serum biochemical indexes, and changes of left ventricle (LV), we found that decreased systolic function, higher blood glycosylated hemoglobin A1c (HbA1C) level, hyperglycemia, and hyperlipidemia were early events in diabetic rhesus monkeys. In addition, cardiac histological analysis showed mildly fibrosis and early myocardial hypertrophy, as evidenced by increased Sirius red stained area and cross-sectional area of left ventricle. Transcriptome results revealed that the nutrients metabolism and extracellular matrix related pathways were markedly changed in the left ventricle of diabetic monkeys. Targeted metabolomics and targeted lipid metabolomics further revealed that disturbed amino acid metabolism and lipid accumulation in the LV of diabetic monkeys manifested by accumulated branched chain amino acids (BCAAs) and triglycerides (TAGs), and reduced contents of sphingolipids, glycerophospholipids, cholesteryl esters and carnitines. In conclusion, we reported here for the first time that diabetes lasting for more than 7 years leads to some early pathological changes of myocardium in rhesus monkeys. The cardiac function is mildly compromised and the reprogramming of lipids and amino acids metabolism might play important roles in the progression of DC.

The renin-angiotensin system (RAS) plays a pivotal role in regulating vascular homeostasis, while angiotensin 1-8 (Ang 1-8) traditionally dominates as a vasoconstrictor factor. However, the discovery of angiotensin 1-7 (Ang 1-7) and Ang 1-8 has revealed counter-regulatory mechanisms mediated through endothelial-derived relaxing factors (EDRFs) and endothelial-derived hyperpolarizing factors (EDHFs). This review delves into the vascular actions of Ang 1-7 and Ang 1-8 in both non-diabetes mellitus (non-DM) and diabetes mellitus (DM) conditions, highlighting their effects on vascular endothelial cell (VECs) function as well. In a non-DM vasculature context, Ang 1-8 demonstrate dual effect including vasoconstriction and vasodilation, respectively. Additionally, Ang 1-7 induces vasodilation upon nitric oxide (NO) production as a prominent EDRFs in distinct mechanisms. Further research elucidating the precise mechanisms underlying the vascular actions of Ang 1-7 and Ang 1-8 in DM will facilitate the development of tailored therapeutic interventions aimed at preserving vascular health and preventing cardiovascular complications.

The present study aimed to explore the role of mitochondria‑associated membranes (MAMs) as a key interface between mitochondria and the endoplasmic reticulum (ER) and to evaluate their importance in maintaining the physiological functions of these two organelles. MAMs not only act as a structural bridge between mitochondria and the ER but also widely participate in the regulation of mitochondrial biosynthesis and function, Ca2+ signal transduction, lipid metabolism, oxidative stress response and autophagy. In addition, the specific protein composition of MAMs is increasingly being recognized as having a profound impact on their function, and these proteins play a central role in regulating intercellular communication. Recently, the scientific community has accumulated a large amount of evidence supporting MAMs as potential targets for cardiovascular disease treatment. The present review focuses on the fine structure and multifunctional properties of MAMs and their mechanisms in the occurrence and development of cardiovascular diseases. The goal is to explore the mechanism of MAMs, therapeutic intervention points directly related to cardiovascular diseases, and feasibility of incorporating MAMs into the diagnostic strategy and treatment plan of cardiovascular diseases to provide novel insights and theoretical support for clinical practice in this field. MAMs have great potential as therapeutic targets for various cardiovascular diseases. This finding not only deepens the understanding of the interaction between organelles but also opens up a promising research path for the development of new therapeutic strategies for cardiovascular diseases.

Patients with diabetes are at an increased risk of diabetic cardiomyopathy (DCM) and acute myocardial infarction (AMI). Protecting the heart against AMI is more challenging in DCM than in nondiabetic hearts. We investigated whether intravenous (i.v.) atorvastatin administration during AMI exerts cardioprotection in DCM as seen in nondiabetic hearts. Sprague-Dawley rats were divided into streptozotocin-induced DCM and normoglycemic control groups. Our model of DCM rats exhibited interstitial fibrosis and cardiac dysfunction at 5 weeks. At this time point, all animals underwent AMI induction (coronary ligation for 45 min), receiving i.v. atorvastatin or vehicle during ischemia. Animals were reperfused and sacrificed 24 h later for myocardial infarct size analysis and cardiac tissue sampling. Echocardiography was performed. DCM vehicle rats had larger infarcts than normoglycemic vehicle-treated animals at a comparable area-at-risk. Intravenous atorvastatin reduced infarct size and preserved systolic function in both groups. Compared with vehicle animals, i.v. atorvastatin inhibited RhoA membrane translocation, induced AMPK phosphorylation, prevented apoptosis execution, and improved cardiac remodelling in the infarcted heart of both groups, whereas innate immune cell infiltration was further reduced in i.v. atorvastatin-treated DCM animals. The proven cardioprotective effectiveness of this i.v. statin formulation in the presence of DCM warrants its further development into a clinically therapeutic option.

Diabetic cardiomyopathy (DCM) significantly increases the risk of acute myocardial infarction and attenuates or abolishes the cardioprotective effects of several therapeutic approaches. Whether intravenous atorvastatin administration during ongoing acute myocardial infarction retains its cardioprotective potential in the presence of DCM was investigated. Intravenous atorvastatin during ischemia reduces infarct size and preserves cardiac function in DCM rats. The efficacy of this intravenous statin formulation in DCM supports its development as a viable therapeutic option for clinical use.

Hyperuricemia and diabetes mellitus (DM) are prevalent metabolic disorders with high comorbidity, imposing a substantial global public health burden. Their coexistence is not merely additive but synergistic, exacerbating metabolic dysregulation through mechanisms such as insulin resistance and β-cell apoptosis, ultimately establishing a vicious cycle. Both disorders induce acute and chronic damage to vital organs, particularly the cardiovascular, renal systems. Hyperuricemia aggravates diabetic complications, notably diabetic cardiomyopathy, nephropathy and retinopathy via oxidative stress, inflammation, and metabolic dysregulation.Current urate-lowering therapies (ULTs), such as xanthine oxidase inhibitors and urate transporter 1 (URAT1, also known as SLC22A12) antagonists, demonstrate potential benefits in ameliorating diabetic complications but face challenges including safety concerns and dose adjustments. Similarly, several glucose-lowering drugs also exhibit the benefits of improving hyperuricemia. This review summarizes the metabolic crosstalk and therapeutic interplay between hyperuricemia and DM, examines the pathogenic role of uric acid in diabetic complications, and discusses the benefits and challenges of existing ULTs and glucose-lowering drugs in disrupting this cycle of metabolic dysregulation and concurrent organ damage. We hope our findings deepen the comprehension of the intricate metabolic crosstalk between glucose and urate homeostasis, providing novel therapeutic insights for patients with comorbid DM and hyperuricemia.

Diabetic cardiomyopathy (DbCM) is increasingly prevalent, but intervention targets remain unclear due to the lack of appropriate models and the complexity of risk factors. Here, this work establishes an in vitro assessment system for DbCM function using cardiomyocytes derived from human pluripotent stem cells and engineered heart tissue. This work finds high-fat status in complex diabetes risk factors majorly contributes most to cardiomyocyte death and contractile dysfunction. Notably, PA induced early electrophysiological abnormalities, and lately is associated with cardiac fibrosis, mitochondrial fission, and systolic and diastolic dysfunction at tissue level. Using this in vitro assessment system, this work finds that empagliflozin (EMPA), a first-line glucose-lowering drug, effectively alleviated early PA-induced cardiomyocyte injury. Treatment with EMPA enhanced abnormal diastolic and electrophysiological functions in the PA-hEHT model and significantly reduced endoplasmic reticulum stress, and apoptosis. Furthermore, these promising results are confirmed in a type 2 diabetes mellitus mouse model, reinforcing the potential of EMPA as a therapeutic option to alleviate cardiomyocyte injury under diabetic conditions. These findings suggest that this work has developed an engineered model of diabetic cardiomyopathy that mimics the various stages of lipotoxic myocardial injury and support the use of EMPA as a potential therapeutic option for diabetic or lipotoxic cardiomyopathy.

Among the multitude of pressing global health concerns, diabetes mellitus stands out as a significant issue. An alarming consequence of this condition is diabetic cardiomyopathy (DCM), which represents a critical contributor to mortality in individuals with diabetes. Recently, research has unveiled the pivotal role that pyroptosis plays in the progression of myocardial fibrosis associated with DCM. An epimedial flavonoid monomer, Icariin (ICA), primarily sourced from Epimedium genus plants, has shown a safeguarding influence on cardiac health through various means, encompassing anti-inflammatory actions and its capacity against oxidative stress. Our research endeavor focuses on elucidating the beneficial impacts alongside the underlying physiological processes triggered by ICA within the context of DCM. An animal model representative of DCM was developed through intraperitoneal administration of streptozotocin (STZ). In parallel, in vitro experiments utilized H9C2 cardiomyocytes to mimic hyperglycemic environments relevant to disease states. In vivo experiments found that ICA improved cardiac function, alleviated myocardial fibrosis, and reduced NLRP3-mediated pyroptosis in heart tissue of DCM mice. Under in vitro settings characterized by elevated glucose concentrations, there was a notable elevation in both NLRP3 pyroptosis-associated proteins and oxidative stress markers within the heart muscle cells. ICA treatment attenuated pyroptosis and oxidative stress caused by high glucose in cardiomyocytes. Further studies revealed that when treated with an AMPK inhibitor, the shielding benefits conferred by ICA on cardiomyocytes were negated, suggesting that the regulatory effects of ICA on cardiomyocyte pyroptosis may be achieved through the AMPK-NLRP3 pathway. In conclusion, ICA exerts protective effects in DCM by inhibiting cardiomyocyte pyroptosis, alleviating myocardial fibrosis, and improving cardiac function via the AMPK-NLRP3 pathway.

Diabetic cardiomyopathy (DCM) is a significant cardiovascular complication of diabetes, characterized by structural and functional heart muscle dysfunction. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are pivotal in the pathogenesis of DCM. Ranolazine, primarily used for angina, has demonstrated potential cardioprotective effects. This study investigates the effects of ranolazine on oxidative stress, ER stress, and inflammation in the heart tissue of type 2 diabetic rats.

Diabetes was induced in male Wistar rats using Nicotinamide (110 mg/kg) and Streptozotocin (60 mg/kg). The rats were then divided into control and diabetic groups, with further subdivision into ranolazine-treated and untreated subgroups. Ranolazine was administered via gavage for eight weeks. Various parameters, including body weight, heart weight, serum glucose, troponin-I levels, oxidative stress markers, ER stress markers, and inflammatory markers, were assessed.

Diabetic rats showed increased heart weight and decreased body weight over eight weeks. Ranolazine treatment improved body weight but didn't affect serum glucose levels. The treatment significantly lowered serum troponin-I and oxidative stress markers, increased superoxide dismutase (SOD) and glutathione (GSH) levels, and decreased malondialdehyde (MDA) concentrations. Additionally, ranolazine reduced the expression of stress-related genes (GRP78, XBP1, and NLRP3) and lowered serum IL1β levels.

The results indicate that ranolazine protects against DCM by attenuating oxidative stress, ER stress, and inflammation. Its potential as a therapeutic agent for DCM warrants further investigation.

Diabetes mellitus is a significant public health issue. Despite the emergence of promising anti-hyperglycemic drugs, treatment outcomes for diabetic patients continue to be inadequate. Gypenosides are the major bioactive compounds isolated from Gynostemma pentaphyllum (Thunb.) Makino. Gynostemma pentaphyllum has longstanding history of usage in traditional oriental medicine, particularly for the treatment of diabetes mellitus. Gypenosides were found to exhibit antidiabetic effects. This review outlined the advancements in the preclinical studies of gypenosides' pharmacological properties on diabetes mellitus and their potential mechanism of action, while also noting the lack of clinical evidence for gypenosides' efficacy.

Literatures search was done using scientific databases PubMed, Web of Science, Scopus and Google Scholar up to November 2024 utilizing keywords such as "Gynostemma pentaphyllum", "gypenoside*", and "diabet*".

Research has shown that gypenosides possess therapeutic properties in mitigating diabetes mellitus by regulating blood glucose levels and insulin production. Gypenosides can modulate various key pathways associated with diabetes pathogenesis, including PI3K/Akt, PPARγ, NF-κB, AMPK and PDX1, hence contributing to their antidiabetic properties. Nevertheless, there is a paucity of research on gypenosides in clinical settings, with existing studies being mainly conducted on animal models and in vitro. Future studies with the focus on the isolation and purification of specific gypenosides, as well as the exploration on the probable pharmacological effect and molecular mechanisms behind the biological actions are necessary.

The findings presented may establish a foundation for subsequent clinical trials for the development of specific gypenosides as antidiabetic therapies for the betterment of human health.

STRA13, a basic helix-loop-helix protein superfamily member, is a CLOCK gene. Previous studies have reported the role of STRA13 in regulating blood pressure. However, the role of STRA13 in diabetic cardiomyopathy (DCM) has not been fully elucidated. In this study, STRA13 full knockout mice were subjected to a high-fat diet (HFD) to induce DCM. We found that STRA13 was upregulated in both heart tissue and cardiomyocytes undergoing metabolic disorders. STRA13 knockout ameliorated HFD-induced cardiac dysfunction, fibrosis, mitochondrial dysfunction and cell apoptosis. STRA13 deficiency also protected against HFD-induced glucose and lipid metabolism disorders. STRA13 overexpression in mice worsened HFD-induced cardiac dysfunction, fibrosis, and injury. STRA13 overexpression in cardiomyocytes worsened high glucose-induced cell injury, mitochondrial dysfunction and oxidative stress. STRA13 silencing in cardiomyocytes protected against the high glucose (HG)-induced alterations described above. Moreover, STRA13 was found to downregulate retinoid X receptor alpha (RXRα), resulting in reduced expression of uncoupling protein 1 (UCP-1). Co-IP confirmed that STRA13 interacted with RXRα. A luciferase assay confirmed that RXRα regulated the transcription of UCP-1. Silencing of STRA13 did not protect cardiomyocytes from HG-induced injury caused by RXRα or UCP-1 knockdown. Cardiac overexpression of UCP-1 also blunted the deteriorating effects of STRA13. However, STRA13 inhibited RXRα nuclear expression, which hampered the protective effects of RXRα overexpression in vivo. Taken together, our findings demonstrate that STRA13 exacerbates diabetic cardiomyopathy by impairing mitochondrial function through the disruption of RXRα-UCP-1 signaling. Therefore, targeting the STRA13-RXRα-UCP-1 axis may represent a promising therapeutic strategy for mitigating mitochondrial dysfunction and cardiac injury in the context of DCM.

Exosome-like nanoparticles mediate intercellular communication and regulate gene expression. In this study, we isolated and purified exosome-like nanoparticles from Salvia miltiorrhiza (SM-ELNs), a traditional Chinese medicinal herb, and investigated their therapeutic effects on diabetic cardiomyopathy (DCM).

To investigate the effect of SM-ELNs on DCM, we established a mouse model via HFD/STZ treatment. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was assessed by measuring the heart weight/body weight ratio and HE staining, while myocardial fibrosis was evaluated using Masson's trichrome staining. The role of SM-ELNs on NLRP3 inflammasome inhibition and macrophage pyroptosis were evaluated both in vivo and in vitro. The interaction between NEDD4 and SGK1 was analyzed by Co-IP and ubiquitination assays.

SM-ELNs treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, SM-ELNs suppressed NLRP3 inflammasome activation and subsequent macrophage pyroptosis in both in vivo and in vitro models. Mechanistically, NEDD4 facilitated the ubiquitination and degradation of SGK1 in macrophages. Both NEDD4 depletion and SGK1 addition could counteract the SM-ELNs-induced suppression of NLRP3 inflammasome-triggered macrophage pyroptosis in LPS/ATP-treated RAW264.7 cells.

Our study provides the first evidence that SM-ELNs inhibit NLRP3 inflammasome-mediated macrophage pyroptosis in DCM by modulating the NEDD4/SGK1 axis.

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, is widely used in polymers, plasticizers, and food packaging, raising significant concerns for human health. Growing evidence links BPA exposure to cardiovascular diseases, including diabetic cardiomyopathy (DCM), a severe complication of diabetes characterized by myocardial dysfunction. This study employs an integrative approach combining network toxicology and molecular docking to elucidate the molecular mechanisms underlying BPA-induced DCM. Using computational tools such as ADMETlab2.0, ProTox3.0, GeneCards, OMIM, Swiss Target Prediction, and ChEMBL databases, we systematically predicted BPA's potential to induce DCM and constructed comprehensive disease and BPA target libraries. Venn diagram analysis identified 93 potential targets associated with BPA-induced DCM, and a robust BPA regulatory network was established using Cytoscape. Functional enrichment analyses revealed significant involvement of oxidative stress, insulin signaling, and metabolic pathways in BPA toxicity. Molecular docking simulations demonstrated stable binding interactions between BPA and core targets (INS, AKT1, PPARG, STAT3, PPARA, MMP9), with binding energies ranging from -5.3 to -7.5 kcal/mol. Our findings indicate that BPA may induce DCM through key genes and pathways, including cGMP-PKG signaling pathway, insulin signaling pathway, AMPK signaling pathway, and HIF-1 signaling pathway. This study provides a novel theoretical framework for understanding the molecular pathogenesis of BPA-induced DCM and highlights the potential of network toxicology in identifying toxic pathways for uncharacterized environmental compounds. These insights offer potential targets for preventive and therapeutic strategies against BPA-associated cardiovascular complications.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists positively affect diabetic cardiac complications.

To evaluate and compare the impact of liraglutide, dapagliflozin, and their combination on cardiac biomarkers of inflammation, oxidative stress, and fibrosis in a rat model of streptozotocin (STZ)-induced diabetes.

Adult male Wistar rats were assigned into five groups (15-17 rats/group): control rats, diabetic rats (DM, single 50 mg/kg STZ intraperitoneally (IP)), diabetic rats treated with dapagliflozin (Dapa, 1 mg/kg by oral gavage), diabetic rats treated with liraglutide (Lira), 0.4 mg/kg subcutaneously (SC), and diabetic rats treated with both medications (Dapa+Lira) for 8 weeks. Cardiac biomarkers of inflammation, oxidative stress, and fibrosis were evaluated.

Dapagliflozin and/or liraglutide treatment lowered glucose levels, mostly in the combination group. Diabetes increased heart/body weight ratio, which was normalized by all treatments. DM increased cardiac inflammatory and oxidant markers, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), endothelin-1 (ET-1), myeloperoxidase (1), plasminogen activator inhibitor-2 (PAI-2), total nitrite, and thiobarbituric acid reactive substances (TBARS). Dapagliflozin normalized inflammatory markers levels, but combination with Lira added no benefit, except for PAI-2. Dapagliflozin normalized total nitrite and TBARS levels. Combining treatments further decreased nitrite and TBARS levels and normalized cardiac SOD activity. Both dapagliflozin and the combination normalized cardiac fibrosis and platelet-derived growth factor-BB (PDGF-BB) levels.

Dapagliflozin reduced cardiac fibrosis, and attenuated oxidative stress, and inflammation more effectively than liraglutide. Combining treatments improved oxidative status. Our findings support using dapagliflozin to prevent cardiovascular diseases more than liraglutide.

The protective effect of cruciferae-derived sulforaphane (SFN) on diabetic cardiomyopathy (DCM) has garnered increasing attention. However, no studies have specifically explored its mechanistic involvement in cardiac substrate metabolism and mitochondrial function. To address this gap, Type 2 diabetes mellitus (T2DM) db/db mice were orally gavaged with vehicle or 10 mg/kg body weight SFN every other day for 16 weeks, with vehicle-treated wild-type mice as controls. SFN intervention (SFN-I) alleviated hyperglycemia, dyslipidemia, HOMA-IR, serum MDA levels, and liver inflammation. Furthermore, SFN-I improved the lipotoxicity-related phenotype of T2DM cardiomyopathy, manifested as attenuation of diastolic dysfunction, cardiac injury, fibrosis, lipid accumulation and peroxidation, ROS generation, and decreased mitochondrial complex I and II activities and ATP content, despite having no effect on ceramide abnormalities. Protein expression data revealed that the model mice exhibited upregulated cardiac CD36, H-FABP, FATP4, CPT1B, PPARα, and PDK4 but downregulated GLUT4, with unchanged MPC1 and MPC2. Notably, SFN-I significantly attenuated the increase in CD36, H-FABP, CPT1B, and PPARα. These results suggest that chronic oral SFN-I protects against DCM by mitigating overall metabolic dysregulation and inhibiting cardiolipotoxicity. The latter might involve controlling cardiac fatty acid metabolism and improving mitochondrial function, rather than promoting glucose metabolism.

Diabetic cardiomyopathy (DbCM) is recognised as a key mediator and determinant of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Improved understanding of mechanisms underlying transition from early-stage DbCM to HFpEF will inform innovative evidence-based treatment approaches, which are urgently required to alleviate increasing disease burden. This study aimed to determine whether inhibition of neprilysin activity by Sacubitril/Valsartan in both experimental and clinical DbCM attenuates adverse remodelling through promotion of cardioprotective signalling.

Sacubitril/Valsartan effectively reduced plasma neprilysin activity in both diabetic patients with pre-clinical HFpEF from the PARABLE trial (baseline (Val n = 25; Sac/Val n = 35) and 3 months after treatment (Val n = 21/25; Sac/Val n = 33/35)) and DbCM (high-fat diet and streptozotocin) mice. Plasma neprilysin activity at baseline was correlated with worsening cardiac performance at 18 months indicated by left atrial stiffness index in patients (n = 44/60), whilst diastolic dysfunction and pathological remodelling in DbCM mice were improved by Sacubitril/Valsartan, but not Valsartan. snRNA-sequencing showed that progressive experimental DbCM is characterised by chronic low-grade inflammation, reflected by increased infiltration of pro-inflammatory monocytes (Ccr2+ Ly6chi) and reduction in MHC-II macrophages, which was prevented by Sacubitril/Valsartan. Informatics analysis implicated IRF7 as a central mediator of Sacubitril/Valsartan-induced immunomodulation in DbCM, whilst treatment of M2-like pro-repair macrophages with the neprilysin inhibitor, LBQ657 and Valsartan suppressed glucose-induced IRF7 expression and paracrine activation of cardiac fibroblast differentiation in vitro.

Immune cells are significantly involved in DbCM progression, impacting myocardial homeostasis and HF progression. Neprilysin inhibition by Sacubitril/Valsartan improved adverse cardiac remodelling in experimental DbCM through direct regulation of inflammation, highlighting immunomodulation as a novel mechanism underlying established its cardioprotective actions.

Fumonisin B1 (FB1) is considered the most toxic fumonisin produced by fungi and is commonly found in contaminated feed and crops. Fumonisin and its metabolites extensively exist in feed and crops, where FB1-polluted crop ingestion can do harm to livestock and poultry, causing poultry intestinal toxicity in the latter. For investigating FB1-mediated intestinal toxicity, we assessed the function of FB1 exposure in quail intestines and explored its possible molecular mechanisms. In total, 120 quail pups were classified into two groups, where those in the control group were given a typical control diet, and those in the experimental group were given a typical diet that contained 30 mg/kg FB1. We evaluated the histopathological and ultrastructural changes in quails' intestines on days 14, 28, and 42, and studied the molecular mechanisms by assessing oxidative stress, inflammation, and nuclear xenobiotic receptors (NXRs). Our results suggest that FB1 exposure causes intestinal inflammation by triggering oxidative stress pathways and modulating NXRs to induce Cytochrome P450 proteins (CYP) isoforms, leading to intestinal histopathological damage. The results of this study shed novel light on the molecular mechanism underlying FB1-induced intestinal injury in juvenile quails.

Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.

Cardiomyopathies comprise a heterogeneous group of cardiac disorders characterized by structural and functional abnormalities in the absence of significant coronary artery disease, hypertension, valvular disease, or congenital defects. Major subtypes include hypertrophic, dilated, arrhythmogenic, and stress-induced cardiomyopathies. Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has emerged as a key contributor to the pathogenesis of these conditions. ROS-mediated injury drives inflammation, protease activation, mitochondrial dysfunction, and cardiomyocyte damage, thereby promoting cardiac remodeling and functional decline. Although numerous studies implicate OS in cardiomyopathy progression, the precise molecular mechanisms remain incompletely defined. This review provides an updated synthesis of current findings on OS-related signaling pathways across cardiomyopathy subtypes, emphasizing emerging therapeutic targets within redox-regulatory networks. A deeper understanding of these mechanisms may guide the development of targeted antioxidant strategies to improve clinical outcomes in affected patients.

Diabetes is a metabolic disease in which tissues and organs are exposed to a hyperglycemic environment for a prolonged period. Long-term hyperglycemia can cause dysfunction of multiple organs and tissues in the body, leading to diabetic complications such as diabetic cardiomyopathy and diabetic nephropathy. Diabetes and its complications have become one of the key issues that seriously threaten the health of people worldwide. Farnesoid X receptor (FXR), as a metabolic regulator, has multiple functions in regulating insulin synthesis and secretion, insulin resistance, lipid metabolism, oxidative stress, inflammatory response, and fibrosis. It plays a key role in alleviating diabetes and its complications. In this review, we discuss the latest findings of FXR related to diabetes and its complications, focusing on its role in diabetes, diabetic nephropathy, diabetic cardiomyopathy, and diabetic liver injury. The aim is to better understand the role of FXR in diabetes and its complications and to provide new perspectives on the treatment of diabetes and its complications.

Diabetic cardiomyopathy (DCM) is a leading cause of heart failure (HF) among individuals with diabetes, presenting a significant medical challenge due to its complex pathophysiology and the lack of targeted therapies. Pyroptosis, a pro-inflammatory form of programmed cell death (PCD), is the predominant mode of cell death in the primary resident cells involved in DCM. It has been reported to be critical in DCM's onset, progression, and pathogenesis. Non-coding RNAs (ncRNAs), diverse transcripts lacking protein-coding potential, are essential for cellular physiology and the progression of various diseases. Increasing evidence indicates that ncRNAs are pivotal in the pathogenesis of DCM by regulating pyroptosis. This observation suggests that targeting the regulation of pyroptosis by ncRNAs may offer a novel therapeutic approach for DCM. However, a comprehensive review of this topic is currently lacking. Our objective is to elucidate the regulatory role of ncRNAs in pyroptosis associated with DCM and to elucidate the relationships among these factors. Additionally, we explored how ncRNAs influence pyroptosis and contribute to the pathophysiology of DCM. By doing so, we aim to identify new research targets for the clinical diagnosis and treatment of DCM.

Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients. Current therapies do not adequately resolve this problem and focus only on the optimal level of blood glucose for patients. Ferroptosis plays an important role in diabetes mellitus and cardiovascular diseases. However, the role of ferroptosis in DCM remains unclear. Differentially expressed ferroptosis-related genes (DE-FRGs) were identified by intersection of the GSE26887 dataset and the Ferroptosis Database. The associations between the DE-FRGs and immune cells in DCM, estimated via the CIBERSORTx algorithm, were analysed. Flow cytometry (FCM) was used to evaluate the infiltration of immune cells in myocardial tissues. The expression of DE-FRGs, glutathione peroxidase 4 and solute carrier family 7 member 11 was examined via real-time quantitative PCR and Western blotting. Three DE-FRGs were identified: heat shock protein family B (small) member 1 (HSPB1), microsomal glutathione S-transferase 1 (MGST1) and solute carrier family 40 member 1 (SLC40A1), which are closely linked to immune cells in DCM. In vivo, the levels of CD8 + T cells, B cells and regulatory T (Treg) cells were significantly decreased in the DCM group, whereas the levels of CD4 + T cells, M1 cells, M2 cells and monocytes were increased. Diabetes significantly decreased HSPB1 and MGST1 levels and increased ferroptosis compared with the Normal group. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) alleviated high-fat diet (HFD)-induced cardiomyocyte injury and rescued ferroptosis. These findings suggest that the ferroptosis-related genes HSPB1 and MGST1 are closely related to immune cell infiltration and may be therapeutic targets for DCM.

Type 2 diabetes mellitus (T2DM) has led to a considerable increase in morbidity and mortality worldwide. Current treatments control blood glucose but cannot reverse the disease, making it important to identify biomarkers that predict T2DM onset and progression. This study explores heme oxygenase 1(HMOX1) as a novel biomarker for T2DM through bioinformatics and experimental validation. Core differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus database, with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis analyses revealing notable pathways, including Toll-like receptor signaling and cytokine receptor interactions. A Nomogram model and receiver operating characteristic curves demonstrated strong diagnostic effectiveness for these core DEGs. The CIBERSORT algorithm assessed the relation between core DEGs and immune cell infiltration, showing substantial associations with several immune cell types, particularly highlighting HMOX1's correlation with eight immune cells (p < 0.05). In a mouse model, db/db mice displayed typical diabetic characteristics and lower serum HMOX1 levels compared to db/m controls (p < 0.01). Histological analysis confirmed liver damage and decreased expression of NFE2L2 and HMOX1 in diabetic mice tissues (p < 0.05). HMOX1 is identified as a promising biomarker for T2DM, with its downregulation confirmed through bioinformatics and experimental methods.

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

Diabetic cardiomyopathy (DCM) is a common and fatal cardiac complication caused by diabetes, with its pathogenesis involving various forms of cell death and mitochondrial dysfunction, particularly ferroptosis and mitochondrial injury. Recent studies have indicated that ferroptosis and mitochondrial damage play crucial roles in the onset and progression of DCM, though their precise regulatory mechanisms remain unclear. Of particular interest is the interaction between ferroptosis and mitochondrial damage, as well as their synergistic effects, which are not fully understood. This review summarizes the roles of ferroptosis and mitochondrial injury in the progression of DCM and explores the molecular mechanisms involved, with an emphasis on the interplay between these two processes. Additionally, the article offers an overview of targeted drugs shown to be effective in cellular experiments, animal models, and clinical trials, analyzing their mechanisms of action and potential side effects. The goal is to provide insights for future drug development and clinical applications. Moreover, the review explores the challenges and prospects of multi-target combination therapies and personalized medicine interventions in clinical practice to offer strategic guidance for the comprehensive prevention and management of DCM.

Isoliquiritigenin (ISL), a major chalcone-type flavonoid produced predominantly from liquorice roots (Glycyrrhiza species), has exceptional therapeutic potential across a wide range of pharmacological activities. ISL has numerous benefits including antioxidant, anti-inflammatory, antidiabetic, cardioprotective, hepatoprotective, neuroprotective, and anticancer activities. This review gathers the pharmacological effects of ISL remarking into its mechanism of actions such as how it modulates oxidative stress, inflammatory pathways, glucose metabolism, and cancer growth, demonstrating its pharmacological versatility. The review emphasizes new advances in the field, allowing for more rational development and clinical use of ISL in medicine. However, further research is required to confirm the target-organ toxicity or side-effect investigations.

The global prevalence of diabetes is rapidly increasing, significantly raising the risk of various cardiovascular diseases. Among these, diabetic cardiomyopathy (DCM) is a distinct and critical complication characterized by ventricular hypertrophy and impaired myocardial contractility, ultimately progressing to heart failure and making it a leading cause of mortality among diabetic patients. Despite advances in pharmacological therapies, the effectiveness of managing cardiac dysfunction in DCM remains challenging. Consequently, exploring additional therapeutic strategies for the prevention and treatment of DCM is urgently needed. Beyond pharmacological approaches, lifestyle modifications, particularly exercise and dietary interventions, play a fundamental role in managing DCM due to their significant cardiovascular benefits in diabetic patients. This review synthesizes recent advancements in the field, elucidating the underlying mechanisms through which exercise and dietary interventions influence DCM pathophysiology. By integrating these strategies, we aim to facilitate the development of personalized exercise and dietary regimens that effectively mitigate or prevent DCM progression.

Hyperlipidemia and myocardial apoptosis caused by myocardial ischemia are the main causes of high mortality rates in cardiovascular diseases. Previous studies have indicated that Krüppel-like factor 4 (KLF4) is involved in the induction of cardiac myocyte apoptosis under various stress conditions. In current study, we discovered that KLF4 also participates in palmitic acid (PA)-induced cardiac myocyte apoptosis. However, the specific mechanisms by which KLF4 regulates cardiac myocyte apoptosis remain unclear. Cardiac myosin light-chain kinase (cMLCK) is a crucial enzyme involved in regulating cardiac myocyte contraction and is closely associated with the regulation of apoptosis. Here, we employed the lipotoxicity in vitro and in vivo models to explore the potential synergistic role of KLF4 and cMLCK in cardiac myocyte apoptosis. Our findings demonstrate that under the influence of PA, upregulation of KLF4 expression accompanied by downregulation of cMLCK expression leads to cardiomyocyte apoptosis and cell proliferation inhibition. Selective knockdown and overexpression of KLF4 in cardiomyocytes further confirmed the involvement of KLF4 in PA-induced cardiomyocyte apoptosis. Likewise, overexpression of cMLCK alleviated PA-induced cardiac myocyte apoptosis. Our study reveals the pro-apoptotic effect of KLF4 and elucidates the specific mechanism by which the KLF4/cMLCK signaling pathway is involved in PA-induced cardiac myocyte apoptosis, providing new therapeutic targets for cardiovascular disease treatment.

To investigate the association between chronic inflammation and subclinical left ventricular dysfunction in type 1 diabetes (T1D).

In a cross-sectional study of individuals with T1D without known heart disease, interleukin-6 (IL-6), soluble-urokinase-plasminogen-activator-receptor (suPAR), and high-sensitivity C-reactive-protein (hsCRP) were examined for associations with echocardiographic E/e' (primary outcome) and global longitudinal strain (GLS) (secondary outcome). We adjusted for several clinical variables in linear regression analysis, including N-terminal pro-B-type natriuretic peptide (NT-proBNP). The biomarkers were categorized as elevated/non-elevated based on their upper quartiles.

Of 962 individuals (52 % male, mean age 49 ± 14 years), mean E/e' was 7 ± 3 and GLS 18 ± 3. In fully adjusted models, all biomarkers were each associated with increased E/e': beta coefficients for IL-6 0.2 (95 % confidence intervals: 0.1-0.3, P = 0.001), suPAR 0.5 (0.1-0.7, P = 0.011), and hsCRP 0.1 (0.0-0.2, P = 0.023). Combining biomarkers showed stronger associations: elevated IL-6 and suPAR 1.3 (0.7-2.0, P < 0.001), elevated all three 1.9 (1.1-2.7, P < 0.001). Results were similar for decreased GLS with IL-6-0.4 (-0.7 to 0.0, P = 0.039), IL-6 and hsCRP -1.0 (-1.7 to -0.4, P = 0.007), all three -1.1 (-2.0 to -0.3, P = 0.009).

Inflammatory biomarkers are independently associated with subclinical left ventricular dysfunction. Chronic inflammation may contribute to the development of myocardial dysfunction in T1D.

The present study aimed to investigate the effects and underling mechanisms of cardiomyocyte-specific STING knockout on cardiac function and wound healing in diabetes.

In this study, type 2 diabetes was induced in cardiomyocyte-specific STING knockout mice using a combination of a high-fat diet and streptozotocin. Cardiac function and remodeling were assessed by echocardiography and histopathological analysis. Glucose homeostasis was evaluated through insulin sensitivity tests and intraperitoneal glucose tolerance tests. Wound healing was quantified by measuring the wound area in diabetic mice.

The results demonstrated that STING deletion in cardiomyocytes improved cardiac function in diabetic mice, which was accompanied by enhanced insulin sensitivity and improved glucose tolerance. Furthermore, the deletion of STING partially mitigated mitochondrial dysfunction in the myocardium. STING knockout in cardiomyocytes also facilitated angiogenesis and wound healing in diabetic mice.

Our findings suggest that cardiomyocyte-specific STING deletion enhances cardiac function, glucose homeostasis, and wound healing, indicating that targeting STING in the heart may serve as a promising therapeutic strategy for managing diabetes mellitus.

A significant increase in mitochondrial fatty acid oxidation (FAO) is now increasingly recognized as one of the metabolic alterations in diabetic cardiomyopathy (DCM). However, the molecular mechanisms underlying mitochondrial FAO impairment in DCM remain to be fully elucidated.

A type 2 diabetes (T2D) mouse model was established by a combination of high-fat diet (HFD) and streptozotocin (STZ) injection. Neonatal rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (HP) to simulate diabetic cardiac injury. Gain- and loss-of-function approaches and RNA sequencing were utilized to investigate the role and mechanism of 2,4-dienoyl-CoA reductase 1 (Decr1) in DCM.

By integrating the genomic data available in the Gene Expression Omnibus (GEO) with DCM rodents, we found that the transcriptional level of Decr1 was consistently upregulated in DCM (+255% for diabetic heart, p < 0.0001; +281% for diabetic cells, p < 0.0001). Cardiomyocytes-specific knockdown of Decr1 preserved cardiac function (+41% for EF, p < 0.0001; +24% for FS, p = 0.0052), inhibited cardiac hypertrophy (-34%, p < 0.0001), fibrosis (-69%, p < 0.0001), apoptosis (-56%, p < 0.0001) and oxidative damage (-59%, p < 0.0001) in DCM mice, while cardiomyocytes-specific overexpression of Decr1 aggravated DCM (-28% for EF, p = 0.0347; -17% for FS, p = 0.0014). Deletion of Decr1 prevented high glucose/palmitate (HG/HP)-induced hypertrophy (-22%, p = 0.0006), mitochondrial dysfunction and apoptosis (-74%, p < 0.0001) in cultured cardiomyocytes. Furthermore, RNA sequencing and functional analysis showed that Decr1 interacted with and upregulated pyruvate dehydrogenase kinase 4 (PDK4) in injured cardiomyocytes, and overexpression of PDK4 eliminated the benefits of Decr1 downregulation in DCM (-20% for EF, p = 0.0071; -28% for FS, p = 0.0022). Mechanistically, PDK4 acted as a kinase that induced phosphorylation and mitochondrial translocation of HDAC3. In the mitochondria, HDAC3 mediated the deacetylation of dehydrogenase trifunctional multienzyme complex α subunit (HADHA), contributing to excessive mitochondrial FAO and subsequent cardiac injury. From a screening of 256 natural products, we identified Atranorin and Kurarinone as potential inhibitors of Decr1, both demonstrating protective effects against DCM (Atranorin, +21% for EF, p = 0.0134; +24% for FS, p = 0.0006; Kurarinone, +20% for EF, p = 0.0183; +27% for FS, p = 0.0001).

Our study delineates a molecular mechanism by which Decr1 potentiated higher mitochondrial lipid oxidation and cardiac damage by enhancing HADHA deacetylation through the PDK4/HDAC3 signalling pathway.

Cardiac lipotoxicity, characterized by excessive lipid accumulation in the cardiac tissue, is a critical contributor to the pathogenesis of diabetic heart. Recent research has highlighted the key mechanisms underlying lipotoxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and cell apoptosis, which ultimately impair the cardiac function. Various therapeutic interventions have been developed to target these pathways, mitigate lipotoxicity, and improve cardiovascular outcomes in diabetic patients. Given the global escalation in the prevalence of diabetes and the urgent demand for effective therapeutic approaches, this review focuses on how targeting cardiac lipotoxicity may be a promising avenue for treating diabetes.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide, posing significant challenges to healthcare systems. Despite advances in medical interventions, the molecular mechanisms underlying CVDs are not yet fully understood. For decades, protein-coding genes have been the focus of CVD research. However, recent advances in genomics have highlighted the importance of long non-coding RNAs (lncRNAs) in cardiovascular health and disease. Changes in lncRNA expression specific to tissues may result from various internal or external factors, leading to tissue damage, organ dysfunction, and disease. In this review, we provide a comprehensive discussion of the regulatory mechanisms underlying lncRNAs and their roles in the pathogenesis and progression of CVDs, such as coronary heart disease, atherosclerosis, heart failure, arrhythmias, cardiomyopathies, and diabetic cardiomyopathy, to explore their potential as therapeutic targets and diagnostic biomarkers.

Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing.