Introduction
Diabetic cardiomyopathy is a specific form of heart disease, promoted by resistance to the metabolic actions of insulin in heart tissue (e.g. insulin resistance), compensatory hyperinsulinaemia and the progression of hyperglycaemia, which occurs independent of other cardiac risk factors such as coronary artery disease (CAD) and hypertension. Diabetic cardiomyopathy as a distinct entity was first described in 1972 in four individuals with diabetes who manifested heart failure symptoms [1]. This was confirmed in a secondary analysis of the Framingham Heart Study in 1974, which found that the risk of heart failure was increased 2.4-fold in men and fivefold in women with diabetes compared with individuals without diabetes after adjustment for other risk factors including age, hypertension, obesity, dyslipidaemia and CAD [2].
In this context, the clinical course of cardiac dysfunction in diabetes progresses from subclinical cardiac abnormalities, such as left ventricular fibrosis and diastolic dysfunction, to severe diastolic heart failure with normal ejection fraction and eventually to systolic dysfunction accompanied by heart failure with reduced ejection fraction [4, 5].
The prevalence of diabetic cardiomyopathy associated with type 1 and type 2 diabetes
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The risk for development of cardiac stiffness/diastolic dysfunction is also high in those with type 2 diabetes [10]. For example, observations from the Framingham Heart Study indicated that persons with type 2 diabetes had a two- to eightfold increased risk for development of heart failure and that 19% developed symptoms of heart failure [2].
Changes in cardiac structure and function in diabetic cardiomyopathy
In the early stages of diabetic cardiomyopathy, the cardiac structural and functional adaptations are promoted by metabolic disturbances including impaired insulin metabolic signalling, excess ambient insulin, impaired glucose uptake, increases in myocardial NEFA uptake and mitochondrial dysfunction [4, 14]. These collective metabolic disturbances promote cardiac remodelling, fibrotic diastolic dysfunction and, ultimately, decreased ejection fraction in those with diabetes [14, 15]. In this regard, the pathophysiological changes, including impaired cardiomyocyte autophagy, increased cardiomyocyte death, inappropriate renin–angiotensin–aldosterone system (RAAS) activation despite salt and water excess, oxidative stress and maladaptive immune responses, result in fibrosis and substantial cardiac stiffness/diastolic dysfunction [14, 15].
Pathophysiological mechanisms involved in the development of diabetic cardiomyopathy
Abnormal insulin metabolic signalling
Impaired insulin metabolic signalling in the heart is a key pathophysiological abnormality associated with diabetic cardiomyopathy (Fig. 1).
Under normal physiological conditions in cardiomyocytes, the PI3K/Akt signalling pathway stimulates GLUT4 recruitment to the plasma membrane, resulting in glucose uptake into the heart [4] (Fig. 2). The reduction of glucose uptake resulting from PI3K/Akt impairment decreases Ca2+ ATPase activity and moves Ca2+ back into the sarcoplasmic reticulum, thus increasing intracellular Ca2+ [4]. In addition, impairment of insulin metabolic signalling inhibits cardiac insulin-stimulated coronary endothelial NO synthase activity and NO production, which further increases intracellular Ca2+ levels and Ca2+ sensitisation in cardiomyocytes via the cGMP/PKG signalling pathway [4]. These abnormalities cause cardiac stiffness and diastolic dysfunction (Fig. 2).
Hyperglycaemia and glucotoxicity
Hyperglycaemia and glucotoxicity can induce a protein glycation reaction leading to increases in AGEs, which are produced from non-enzymatic glycosylation of lipids, lipoproteins and amino acids. AGE deposition contributes to increased connective tissue crosslinking, fibrosis, cardiac stiffness and impaired diastolic relaxation [4] (Fig. 1). For example, elevated serum levels of AGEs are associated with a prolongation of left ventricular relaxation time in individuals with early diabetic heart failure [19].
Cardiac lipotoxity
Abnormal lipid metabolism often accentuates the process of diabetic cardiomyopathy (Fig. 1). Increased circulating triacylglycerol levels lead to increased fatty acid delivery to cardiomyocytes and, thus, enhanced fatty acid β-oxidation and impaired insulin metabolic signalling in diabetic hearts.
Mitochondrial dysfunction and oxidative stress
The increased mitochondrial fatty acid uptake and β-oxidation in diabetic hearts may exceed the capacity of mitochondrial respiration and induce an accumulation of toxic lipid metabolites, resulting in cardiac lipotoxicity and mitochondrial dysfunction [4] (Fig. 1). Adenosine monophosphate-activated protein kinase (AMPK) usually improves mitochondrial biogenesis through activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1α (PGC-1α), which is a master metabolic regulator of mitochondrial biogenesis and respiratory function [4]. However, the PGC-1α/AMPK signalling pathways involved in β-oxidation are impaired during the advanced stage of diabetic cardiomyopathy, thereby further contributing to mitochondrial dysfunction [4].
Endoplasmic reticulum stress, impaired calcium handling and cardiomyocyte death
The endoplasmic reticulum (ER) has an integral role in lipid synthesis, Ca2+ handling and protein folding and modification [28]. In diabetes, hyperglycaemia and insulin resistance induce ER stress, involving impaired Ca2+ handling and accumulation of unfolded proteins [29] (Fig. 1).
Inappropriate activation of RAAS
Activation of both the systemic and cardiac tissue RAAS despite a state of salt and volume excess in states of insulin resistance and hyperglycaemia plays an important role in the development of diabetic cardiomyopathy (Fig. 1). One study found that hyperglycaemia induced systemic RAAS activation, associated with increased vascular resistance and arterial pressure [32].
Maladaptive immune modulation
Activation of proinflammatory immune cells, including macrophages, dendritic cells and activated T lymphocytes, is also involved in diabetic cardiomyopathy [4]. Proinflammatory cytokines, such as TNF-α, IL-6 and monocyte chemotactic protein 1 (MCP-1), contribute to cardiac oxidative stress and coronary artery dysfunction, ultimately leading to cardiac remodelling, fibrosis and diastolic dysfunction [4].
Coronary endothelial dysfunction and dysregulation of exosomes
The notion that dysfunctional coronary endothelial cells drive abnormal cardiac function has recently gained momentum [36, 37] (Figs 1, ,2).2). Normally, NO, prostacyclin (prostaglandin I2) and endothelium-derived hyperpolarising factors (EDHFs) are released from coronary endothelial cells and exert beneficial effects including vasodilatation and reduced cardiac tissue inflammation [38]. In the early stages of insulin resistance and early diabetic cardiomyopathy, NO-induced vasodilatation is impaired whereas EDHF-mediated vasodilatation is generally preserved or even enhanced to maintain normal vascular tone [38]. However, in the later stages, both NO- and EDHF-induced vasodilatation may eventually become impaired, thereby promoting microvascular dysfunction and inflammation [38].
Exosomes are regarded as important mediators in intercellular communication and regulate normal physiological and pathophysiological effects [39]. These extracellular vesicles have a diameter of 30–90 nm and possess a variety of biological components including microRNAs (miRNAs), proteins and lipids [24]. Recent data suggest that dysregulation of exosomes is involved in diabetic cardiomyopathy (Fig. 1). For example, hypoxia, inflammation and hyperglycaemia-induced endothelial cell stress increase protein and messenger RNA content in endothelial cell-derived exosomes [40, 41].
Potential preventative and therapeutic strategies for diabetic cardiomyopathy
It is clear that aerobic exercise and restriction of fat and refined carbohydrate intake are efficacious therapeutic methods for preventing and treating diabetic cardiomyopathy in individuals with the metabolic syndrome [4]. It is also clear that improving glycaemic control is a key factor in the prevention of diabetic cardiomyopathy and cardiovascular morbidity and mortality. For example, thiazolidinediones and metformin improve systemic and tissue insulin sensitivity, thus improving cardiomyocyte glucose uptake and cardiac function by activation of PPAR-γ and AMPK, respectively [4].
Recently, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes and associated cardiovascular disease. For example, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycaemic disorders and reduce weight and are thus both regarded as among the best therapeutic options for type 2 diabetes [4]. One study further found that infusion of GLP-1 for 5 week improved left ventricular ejection fraction and functional status in diabetes patients who had chronic heart failure [43].
Conclusions
Diabetic cardiomyopathy is manifested as abnormal cardiac structure and function in the absence of ischaemic or hypertensive heart disease in individuals with diabetes. Insulin resistance, hyperinsulinaemia and hyperglycaemia are independently associated with the development of cardiac dysfunction and heart failure. Pathophysiological abnormalities underlying diabetic cardiomyopathy include cardiac insulin resistance, glucotoxicity, mitochondrial dysfunction, oxidative stress, ER stress, impaired calcium handling, activation of systemic and tissue RAAS, impaired mitophagy and autophagy, coronary microvascular dysfunction and dysregulation of exosomes. However, there are still gaps in our knowledge of the different mechanisms involved in type 1/type2 diabetes-induced cardiac dysfunction that remain to be investigated. There are no prospective clinical trials currently underway to confirm that type 1 diabetes or type 2 diabetes alone increases the risk of cardiac dysfunction and heart failure in the complete absence of other risk factors such as CAD, obesity and hypertension. Further studies are needed to understand the molecular mechanisms behind diabetic cardiomyopathy and to develop new preventative and therapeutic approaches.
Referência :
(1) Diabetologia. 2018;61(1):21-28.