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Circulation Research Apr 2019Diabetic cardiomyopathy was initially described as a human pathophysiological condition in which heart failure occurred in the absence of coronary artery disease,... (Review)
Review
Diabetic cardiomyopathy was initially described as a human pathophysiological condition in which heart failure occurred in the absence of coronary artery disease, hypertension, and valvular heart disease. Recent studies in diabetic animal models identify decreased cardiomyocyte function as an important mediating mechanism for heart failure. Decreased cardiomyocyte function is in part mediated by abnormal mitochondrial calcium handling and a decreased level of free matrix calcium levels which could be a good target for new therapeutic interventions.
Topics: Animals; Calcium; Calcium Channels; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Extracellular Matrix; Heart Failure; Humans; Hyperglycemia; Mice; Mitochondria, Heart; Myocardial Contraction; Myocytes, Cardiac; Nuclear Matrix; Rats; Risk Factors; Sarcoplasmic Reticulum Calcium-Transporting ATPases
PubMed: 30973809
DOI: 10.1161/CIRCRESAHA.118.314665 -
Nature Reviews. Endocrinology Mar 2016Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of... (Review)
Review
Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Humans; Hyperinsulinism; Insulin Resistance
PubMed: 26678809
DOI: 10.1038/nrendo.2015.216 -
Circulation Research May 2020Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart... (Review)
Review
Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
Topics: Animals; Diabetic Cardiomyopathies; Heart; Humans; Myocardium
PubMed: 32437308
DOI: 10.1161/CIRCRESAHA.120.315913 -
International Journal of Molecular... Mar 2022There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are... (Review)
Review
There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Heart Failure; Humans; Hypertrophy; Insulin Resistance; Myocardium
PubMed: 35408946
DOI: 10.3390/ijms23073587 -
Diabetologia Jan 2018Diabetic cardiomyopathy is characterised in its early stages by diastolic relaxation abnormalities and later by clinical heart failure in the absence of dyslipidaemia,... (Review)
Review
Diabetic cardiomyopathy is characterised in its early stages by diastolic relaxation abnormalities and later by clinical heart failure in the absence of dyslipidaemia, hypertension and coronary artery disease. Insulin resistance, hyperinsulinaemia and hyperglycaemia are each independent risk factors for the development of diabetic cardiomyopathy. The pathophysiological factors in diabetes that drive the development of cardiomyopathy include systemic metabolic disorders, inappropriate activation of the renin-angiotensin-aldosterone system, subcellular component abnormalities, oxidative stress, inflammation and dysfunctional immune modulation. These abnormalities collectively promote cardiac tissue interstitial fibrosis, cardiac stiffness/diastolic dysfunction and, later, systolic dysfunction, precipitating the syndrome of clinical heart failure. Recent evidence has revealed that dysregulation of coronary endothelial cells and exosomes also contributes to the pathology behind diabetic cardiomyopathy. Herein, we review the relationships among insulin resistance/hyperinsulinaemia, hyperglycaemia and the development of cardiac dysfunction. We summarise the current understanding of the pathophysiological mechanisms in diabetic cardiomyopathy and explore potential preventative and therapeutic strategies.
Topics: Animals; Diabetic Cardiomyopathies; Heart Diseases; Humans; Hyperglycemia; Insulin Resistance
PubMed: 28776083
DOI: 10.1007/s00125-017-4390-4 -
International Journal of Molecular... Jan 2023Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by...
Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl or elesclomol-CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe-S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.
Topics: Animals; Mice; Cardiotoxicity; Copper; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Glycation End Products, Advanced; Glycosylation; Myocytes, Cardiac; Apoptosis
PubMed: 36675183
DOI: 10.3390/ijms24021667 -
Circulation Research Jan 2019Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction).... (Review)
Review
Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction). Cardiovascular outcomes, hospitalization, and prognosis are worse for patients with diabetes mellitus relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes mellitus the high prevalence of HF persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. This review summarizes the state of knowledge about the impact of existing antihyperglycemic therapies on HF and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for HF and review evidence that addresses their efficacy in the context of diabetes mellitus. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity, and altered signal transduction such as GRK (g-protein receptor kinase) signaling, renin angiotensin aldosterone signaling and β-2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of HF in the context of type 2 diabetes mellitus. Successful targeting of these pathways could alter the prognosis and risk of HF beyond what is currently achieved using existing antihyperglycemic and HF therapeutics.
Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Hypoglycemic Agents; Myocytes, Cardiac; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome; Ventricular Function
PubMed: 30605420
DOI: 10.1161/CIRCRESAHA.118.311371 -
Frontiers in Endocrinology 2022Diabetic cardiomyopathy (DCM) is a pathophysiological condition of cardiac structure and function changes in diabetic patients without coronary artery disease,... (Review)
Review
Diabetic cardiomyopathy (DCM) is a pathophysiological condition of cardiac structure and function changes in diabetic patients without coronary artery disease, hypertension, and other types of heart diseases. DCM is not uncommon in people with diabetes, which increases the risk of heart failure. However, the treatment is scarce, and the prognosis is poor. Since 1972, one clinical study after another on DCM has been conducted. However, the complex phenotype of DCM still has not been fully revealed. This dilemma hinders the pace of understanding the essence of DCM and makes it difficult to carry out penetrating clinical or basic research. This review summarizes the literature on DCM over the last 40 years and discusses the overall perspective of DCM, phase of progression, potential clinical indicators, diagnostic and screening criteria, and related randomized controlled trials to understand DCM better.
Topics: Humans; Diabetic Cardiomyopathies; Heart; Heart Failure; Phenotype; Prognosis; Diabetes Mellitus
PubMed: 36568097
DOI: 10.3389/fendo.2022.1032268 -
Diabetologia Apr 2014In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Cardiovascular complications are the major cause of... (Review)
Review
In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. While ischaemic events dominate the cardiac complications of diabetes, it is widely recognised that the risk for developing heart failure is also increased in the absence of overt myocardial ischaemia and hypertension or is accelerated in the presence of these comorbidities. These diabetes-associated changes in myocardial structure and function have been called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed to contribute to the development of diabetic cardiomyopathy following analysis of various animal models of type 1 or type 2 diabetes and in genetically modified mouse models. The steady increase in reports presenting novel mechanistic data on this subject expands the list of potential underlying mechanisms. The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans
PubMed: 24477973
DOI: 10.1007/s00125-014-3171-6 -
Metabolism: Clinical and Experimental Dec 2021Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms... (Review)
Review
Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.
Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans
PubMed: 34627874
DOI: 10.1016/j.metabol.2021.154910