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      Cellular and molecular mechanisms, genetic predisposition and treatment of diabetes-induced cardiomyopathy

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          Abstract

          Diabetes mellitus is a common disease affecting millions of people worldwide. This disease is not limited to metabolic disorders but also affects several vital organs in the body and can lead to major complications. People with diabetes mellitus are subjected to cardiovascular complications, such as cardiac myopathy, which can further result in major complications such as diabetes-induced cardiac failure. The mechanism underlying diabetes-induced cardiac failure requires further research; however, several contributing factors have been identified to function in tandem, such as reactive oxygen species production, inflammation, formation of advanced glycation end-products, altered substrate utilisation by mitochondria, activation of the renin–angiotensin–aldosterone system and lipotoxicity. Genetic factors such as microRNAs, long noncoding RNAs and circular RNAs, as well as epigenetic processes such as DNA methylation and histone modifications, also contribute to complications. These factors are potential targets for developing effective new therapies. This review article aims to facilitate in depth understanding of these contributing factors and provide insights into the correlation between diabetes mellitus and cardiovascular complications. Some alternative targets with therapeutic potential are discussed to indicate favourable targets for the management of diabetic cardiomyopathy.

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          Highlights

          • Molecular and Cellular mechanisms of diabetes-induced cardiomyopathy.

          • Pathophysiology of diabetic Cardiomyopathy.

          • Genetic involvement in the diabetic cardiomyopathy.

          • Emerging approaches in the treatment of diabetic cardiomyopathy.

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          Most cited references59

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          COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

          Abstract The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
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            Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.

            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.
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              Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways.

              Cardiovascular disease is the primary cause of morbidity and mortality among the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. 'Diabetic cardiomyopathy' is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress as a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin-angiotensin-aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Curr Res Pharmacol Drug Discov
                Curr Res Pharmacol Drug Discov
                Current Research in Pharmacology and Drug Discovery
                Elsevier
                2590-2571
                03 September 2022
                2022
                03 September 2022
                : 3
                : 100126
                Affiliations
                [1]Himalayan Pharmacy Institute Majhitar, Rangpo, Sikkim, 737132, India
                Author notes
                []Corresponding author. manodeep.chakraborty@ 123456gmail.com
                Article
                S2590-2571(22)00046-3 100126
                10.1016/j.crphar.2022.100126
                9780063
                36568261
                76dc3a9b-d747-4f92-9f3e-d894876453be
                © 2022 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 March 2022
                : 13 August 2022
                : 18 August 2022
                Categories
                Review Article

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