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Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment
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Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 47179

Special Issue Editor

Prof. Dr. Vincenzo Mollace

E-Mail Website
Guest Editor
Institute of Research for Food Safety & Health (IRC-FSH), University of Catanzaro “Magna Graecia”, Catanzaro, Italy
Interests: neurological diseases; neurodegeneration; natural compounds; poliphenols; reactive oxygen species; apoptosis; autophagy; mitochondria; endoplasmic reticulum; blood brain barrier; endothelium involvement
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Type 2 diabetes (T2D) represents the major risk factor for developing myocardial dysfunction and, at the late stage, heart failure (HF). The occurrence of Diabetic Cardiomyopathy (DCM) seems to occur independently of coronary artery disease. Indeed, although the number of cases of myocardial infarction in the T2D population has been reduced by 25% over the last 10 years, the incidence of HF is continuously increasing, making it the most worrying diabetes complication. This strongly reinforces the urgent need for better characterization of pathophysiological mechanisms underlying DCM and for identifying innovative therapeutic interventions to prevent cardiac dysfunction in T2D patients. To this end, epidemiological, imaging, and animal studies have aimed to highlight the mechanisms involved in the development of diabetic cardiomyopathy. Epidemiological observations clearly show that hyperglycaemia correlates with severity of cardiac dysfunction and mortality in T2D patients. Both animal and cellular studies have demonstrated that, in the context of diabetes, the heart loses its ability to utilize glucose, therefore leading to glucose overload in cardiomyocytes that, in turn, promotes oxidative stress. This has been shown to reduce protective authophagy and to activate apoptosis, thus altering heart contractility, calcium signaling, and mitochondrial function, leading to fibrosis and compromised diastolic function. This seems to correlate with early changes in cardiomyocyte metabolic function, mostly occurring in the presence of microvascular complicances. On the other hand, although tight glycaemic control has failed to improve cardiac function in T2D patients, recent clinical trials have reported cardiovascular benefit with hypoglycaemic antidiabetic drugs of the SGLT2-inhibitor family. This Special Issue aims to cover some recent advances in basic science studies addressed to better characterize the pathophysiology of early stages of DCM. Moreover, the correlation between biomolecular changes occurring in T2D with recent advances in the development of better therapeutic interventions will be taken into account for identifying better solutions to prevent and treat HF associated to T2D.

Prof. Vincenzo Mollace
Guest Editor

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Keywords

  • diabetes mellitus
  • myocardial dysfunction
  • microvascular coronary artery disease
  • oxidative stress
  • cardiomyocyte apoptosis
  • fibrosis
  • food supplementation
  • mitochondrial-targeted therapy

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Published Papers (6 papers)

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Review

16 pages, 790 KiB  
Review
Review of Single-Cell RNA Sequencing in the Heart
by Shintaro Yamada and Seitaro Nomura
Int. J. Mol. Sci. 2020, 21(21), 8345; https://doi.org/10.3390/ijms21218345 - 6 Nov 2020
Cited by 55 | Viewed by 17678
Abstract
Single-cell RNA sequencing (scRNA-seq) technology is a powerful, rapidly developing tool for characterizing individual cells and elucidating biological mechanisms at the cellular level. Cardiovascular disease is one of the major causes of death worldwide and its precise pathology remains unclear. scRNA-seq has provided [...] Read more.
Single-cell RNA sequencing (scRNA-seq) technology is a powerful, rapidly developing tool for characterizing individual cells and elucidating biological mechanisms at the cellular level. Cardiovascular disease is one of the major causes of death worldwide and its precise pathology remains unclear. scRNA-seq has provided many novel insights into both healthy and pathological hearts. In this review, we summarize the various scRNA-seq platforms and describe the molecular mechanisms of cardiovascular development and disease revealed by scRNA-seq analysis. We then describe the latest technological advances in scRNA-seq. Finally, we discuss how to translate basic research into clinical medicine using scRNA-seq technology. Full article
(This article belongs to the Special Issue Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment)
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Graphical abstract

22 pages, 2072 KiB  
Review
Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning
by Antonio Crisafulli, Pasquale Pagliaro, Silvana Roberto, Lucia Cugusi, Giuseppe Mercuro, Antigone Lazou, Christophe Beauloye, Luc Bertrand, Derek J. Hausenloy, Manuela Aragno and Claudia Penna
Int. J. Mol. Sci. 2020, 21(8), 2896; https://doi.org/10.3390/ijms21082896 - 21 Apr 2020
Cited by 45 | Viewed by 7279
Abstract
Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. [...] Read more.
Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review. Full article
(This article belongs to the Special Issue Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment)
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14 pages, 1130 KiB  
Review
Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy
by Naranjan S. Dhalla, Anureet K. Shah and Paramjit S. Tappia
Int. J. Mol. Sci. 2020, 21(7), 2413; https://doi.org/10.3390/ijms21072413 - 31 Mar 2020
Cited by 46 | Viewed by 3845
Abstract
Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes [...] Read more.
Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin–angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy. Full article
(This article belongs to the Special Issue Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment)
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Figure 1

21 pages, 1139 KiB  
Review
Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms
by Dae Yun Seo, Jeong Rim Ko, Jung Eun Jang, Tae Nyun Kim, Jae Boum Youm, Hyo-Bum Kwak, Jun Hyun Bae, Amy Hyein Kim, Kyung Soo Ko, Byoung Doo Rhee and Jin Han
Int. J. Mol. Sci. 2019, 20(24), 6284; https://doi.org/10.3390/ijms20246284 - 12 Dec 2019
Cited by 23 | Viewed by 4609
Abstract
Diabetes mellitus is associated with cardiovascular, ophthalmic, and renal comorbidities. Among these, diabetic cardiomyopathy (DCM) causes the most severe symptoms and is considered to be a major health problem worldwide. Exercise is widely known as an effective strategy for the prevention and treatment [...] Read more.
Diabetes mellitus is associated with cardiovascular, ophthalmic, and renal comorbidities. Among these, diabetic cardiomyopathy (DCM) causes the most severe symptoms and is considered to be a major health problem worldwide. Exercise is widely known as an effective strategy for the prevention and treatment of many chronic diseases. Importantly, the onset of complications arising due to diabetes can be delayed or even prevented by exercise. Regular exercise is reported to have positive effects on diabetes mellitus and the development of DCM. The protective effects of exercise include prevention of cardiac apoptosis, fibrosis, oxidative stress, and microvascular diseases, as well as improvement in cardiac mitochondrial function and calcium regulation. This review summarizes the recent scientific findings to describe the potential mechanisms by which exercise may prevent DCM and heart failure. Full article
(This article belongs to the Special Issue Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment)
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19 pages, 889 KiB  
Review
Cardiomyopathy Associated with Diabetes: The Central Role of the Cardiomyocyte
by Tiziana Filardi, Barbara Ghinassi, Angela Di Baldassarre, Gaetano Tanzilli, Susanna Morano, Andrea Lenzi, Stefania Basili and Clara Crescioli
Int. J. Mol. Sci. 2019, 20(13), 3299; https://doi.org/10.3390/ijms20133299 - 5 Jul 2019
Cited by 79 | Viewed by 5721
Abstract
The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%–80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal [...] Read more.
The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%–80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as “passive” targets but as “active” units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted. Full article
(This article belongs to the Special Issue Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment)
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Graphical abstract

15 pages, 1814 KiB  
Review
Molecular Dysfunction and Phenotypic Derangement in Diabetic Cardiomyopathy
by Isabella Evangelista, Ranuccio Nuti, Tommaso Picchioni, Francesco Dotta and Alberto Palazzuoli
Int. J. Mol. Sci. 2019, 20(13), 3264; https://doi.org/10.3390/ijms20133264 - 2 Jul 2019
Cited by 109 | Viewed by 7528
Abstract
The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) [...] Read more.
The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) and it can account for 15–20% of the total diabetic population. The pathogenesis of DCM remains controversial, and several molecular and cellular alterations including myocardial hypertrophy, interstitial fibrosis, oxidative stress and vascular inflammation, have been postulated. The main cardio-vascular alterations associated with hyperglycemia comprise endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation. High glucose concentrations lead to a loss of mitochondrial networks, increased reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) activation and a reduction in cGMP production related to protein kinase G (PKG) activity. Current mechanisms enhance the collagen deposition with subsequent increased myocardial stiffness. Several concerns regarding the exact role of DCM in HF development such as having an appearance as either dilated or as a concentric phenotype and whether diabetes could be considered a causal factor or a comorbidity in HF, remain to be clarified. In this review, we sought to explain the different DCM subtypes and the underlying pathophysiological mechanisms. Therefore, the traditional and new molecular and signal alterations and their relationship with macroscopic structural abnormalities are described. Full article
(This article belongs to the Special Issue Diabetic Cardiomyopathy: Biomolecular Mechanisms and Treatment)
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