The increase in cardiovascular mortality among patients with diabetes mellitus is not fully attributable to accelerated atherosclerosis. Epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors such as coronary artery disease (CAD) and hypertension. Being first described in the early 1970s, diabetic cardiomyopathy has become a well-characterized clinical disease directly affecting the structure and the function of the myocardium. Abnormalities in diabetic cardiomyopathy include myocardial hypertrophy, impairment of contractile proteins, accumulation of extracellular matrix proteins, formation of advanced glycation end products and decreased left ventricular compliance.
Phenotype
Diabetes is associated with hyperglycemia-specific microvascular and macrovascular complications. CAD, stroke and peripheral vascular disease are especially increased by two- to four-fold in Type 2 diabetes. Cardiovascular disease (CVD) is the most important long-term complication and is by far the greatest cause of death in people with diabetes Citation[1]. Evidence from large cohort studies clearly suggest that hyperglycemia is a key risk factor not only for diabetes-related disease, but also for cardiovascular and all-cause mortality. On the basis of these long-term observations, one can assume an increment of cardiovascular disease per increase of 1% HbA1c of approximately 18%.
The early myocardial alterations that progress with other diabetes-associated complications lead to the development of more clinically recognized conditions, with left ventricular hypertrophy and heart failure being end points Citation[2]. The earliest finding is diastolic dysfunction, which is characterized by impairment of relaxation and passive filling of the left ventricle. Therefore, diabetes is an independent contributor to left ventricular hypertrophy (LVH) and myocardial stiffness Citation[3]. Hyperglycemia seems to be central in the pathogenesis of diabetic cardiomyopathy and triggers a series of maladaptive stimuli that result in myocardial fibrosis and collagen deposition. By using echocardiography, a significant increase in left ventricular wall thickness – especially in women with diabetes – was reported in the Framingham study and confirmed in the Framingham offspring study Citation[4]. The Strong Heart study did not show this gender specificity – both men and women with diabetes presented with greater left ventricular mass and wall thickness. Not only hyperglycemia, but also hyperlipidemia contributes to the phenotype of the diabetic heart. Increased deposition of intramyocardial lipids, which contribute to cell death and cardiac dysfunction, are obvious Citation[5]. A significant increase in myocardial triglyceride and cholesterol content was found in left ventricular transmural biopsies of diabetic patients. Oil Red O staining of heart sections of nonischemic failing hearts revealed an increased deposition of lipid that was pronounced by diabetes.
In addition to the intracardiac deposition of triglycerides and glycogen granules, which indicate metabolic derangement in diabetic heart failure, irregularly distributed capillaries and perivascular plaques of collagen are frequent. Myocytolysis and deterioration as well as myofilament fragmentation are common structural findings. Areas of focal necrosis and contraction can also be found regularly. Mechanisms leading to increased diastolic stiffness of the diabetic heart are different in heart failure with reduced and normal left ventricular ejection fraction (LVEF). In cases of reduced LVEF, fibrosis occurs and advanced glycation end products (AGEs) are detectable, whereas in hearts with normal LVEF cardiomyocyte resting tension is more relevant Citation[6]. Diabetic heart failure patients without symptoms of CAD showed higher diastolic left ventricular stiffness independently of LVEF. Myocardial collagen volume fraction as well as myocardial AGE deposition was increased in patients with diabetes and reduced LVEF Citation[6].
Metabolism
The flexibility in myocardial substrate metabolism for energy production is fundamental to cardiac health. Cardiac energy metabolism comprises of three components. Besides the use of substrates derived from glucose and free fatty acids (FFAs) via the Krebs cycle, the oxidative phosphorylation for the generation of ATP and finally the use of ATP are main parts of the cardiac energy cycle. Myocardial energy and lipid metabolism are essential for heart structure and function. Energy surplus as well as energy starvation may lead to disarrangement in myocardial tissue. In total, 70% of cardiac ATP are derived from fatty acid oxidation; glucose and lactate account for 30% of the energy Citation[7]. Glucose is the preferred substrate under hypoxic conditions such as ischemia and increased workload, because the glycolytic ATP production through conversion of glucose to lactate is independent from oxygen; ATP production under aerobic conditions is much more efficient.
The loss in variability leads to fixation on special substrates. Predominance in fatty acid metabolism is characteristic of diabetic heart disease and is associated with pressure-overload left ventricular hypertrophy. This is the process in which the heart loses its ability to use different substrates, becoming dependent primarily on the metabolism of a single substrate for energy production.
Lipotoxicity results from decreased cardiac uptake of glucose, which is caused by either insulin resistance or decreased availability of glucose transporters (GLUTs). GLUT4 is downregulated in failing hearts of patients with diabetes as opposed to failing hearts in those without diabetes Citation[8]. Lipotoxicity results in impaired β-oxidation, which generates even more FFAs Citation[9].
Hypertriglyceridemia contributes to cardiac lipotoxicity and affects insulin-stimulated cardiac uptake of glucose. Cardiac efficiency is inversely associated with insulin resistance, glucose intolerance and obesity Citation[10]. The mechanism for increased fatty acid oxidation in the myocardium of diabetic humans is not fully understood, but may involve the transcriptional regulation of key components of this pathway. Peroxisome proliferator activator receptors and their regulated genes are of importance in this clinical setting.
Metabolic and morphologic defects affect myocardial energy metabolism, reduced flow reserve, the formation of AGEs and structural alterations that impair cardiac function. In animal models of diabetes, cardiac dysfunction coexists with increased myocardial nonesterified fatty acid use, triglyceride accumulation and the subsequent increased production of toxic intermediates, which, in the presence of hyperglycemia, contribute to the increased formation of reactive oxygen species, mitochondrial uncoupling, decreased ATP synthesis, mitochondrial dysfunction and, finally, apoptosis. These deleterious processes are commonly referred to as lipotoxicity.
Not only is hyperglycemia a risk factor, but glucose fluctuations, defined as mean average glucose excursions, also contribute to the generation of oxidative stress Citation[11], as well as to vascular risk. Glucose fluctuations and hyperglycemia trigger inflammatory responses via increased mitochondrial superoxide production Citation[12] and endoplasmic reticulum stress Citation[13].
Inflammation results in insulin resistance and β-cell dysfunction, which trigger hyperglycemia Citation[14]. Endothelial dysfunction as a first step of atherogenesis best describes the pathways that integrate hyperglycemia, oxidative stress and diabetic vascular complications Citation[15]. Impaired insulin action (insulin resistance) is characterized by compensatory hyperinsulinemia, which is the major metabolic dysfunction associated with the early stages of Type 2 diabetes. Elevated plasma insulin levels lead to numerous metabolic and pathological derangements in various tissues, including the heart.
Inflammation
Inflammation represents another diabetes-related mechanism for macrovascular disease. Inflammatory cells (e.g., monocytes and T cells) enter damaged endothelial cells and migrate into the intima media, ingesting oxidized LDL and – as a consequence – forming foam cells. Foam cells are the main components of atherosclerotic fatty streaks and represent an early marker of macrovascular disease. In individuals with diabetes, the levels of adhesion molecules are elevated, facilitating the process of foam cell formation.
Among the inflammatory biomarkers that contribute to insulin resistance – C-reactive protein, IL-6 and TNF-α – the latter is one of the key inflammatory mediators expressed during a variety of inflammatory conditions and is capable of initiating the expression of an entire spectrum of inflammatory cytokines ranging from interleukins to interferons Citation[16]. Mechanisms by which TNF-α induces insulin resistance comprise direct inhibitory effects on the glucose transporter protein GLUT4, the insulin receptor and insulin receptor substrates. Intracellular insulin signaling in fat, skeletal muscle and other insulin-responsive tissues is altered by inhibiting kinase activity in the proximal part of the insulin-signaling pathway. A similar signaling pathway in the vascular endothelium results in the production of NO, which is necessary for insulin-stimulated vasodilation Citation[17]. Endothelial dysfunction occurring in obesity relies on the inflammatory cytokine TNF-α and the subsequent production of superoxide (O2•-) Citation[18]. TNF-α affects endothelial function through increased O2•- production by NAD(P)H oxidases, which in turn leads to a reduced NO bioactivity by direct scavenging.
Oxidative stress
According to the unifying hypothesis, all pathogenic mechanisms (increased polyol pathway flux, increased hexosamine pathway flux and modification of proteins, increased formation of AGEs, increased protein kinase C isoform expression) are linked by a single, unifying, hyperglycemia-induced process: the overproduction of superoxide by the mitochondrial electron transport chain resulting in oxidative stress, which is regarded as the pathomechanism underlying insulin resistance, CVD, diabetes and diabetes complications Citation[12].
Multiple intracellular sources for the formation of oxygen free radicals, such as NAD(P)H-dependent oxidases, xanthine oxidase, lipoxygenase, mitochondrial oxidase and NOS, exist. The primary proximate route to radical production in Type 2 diabetes is through NAD(P)H oxidase activation and link oxidative stress closely to inflammatory processes, characterized by an increase in TNF-α. Hyperglycemia promotes glycation and the inactivation of antioxidant proteins such as Cu/Zn superoxide dismutase, leading to inactivation and reduction in antioxidant defense for these proteins. Hyperglycemia increases oxidative stress through reactive oxygen species overproduction at the mitochondrial transport chain level.
Conclusion
Although there is an overflow of substrates, the heart resembles an engine running out of fuel; mainly disturbances in the key signal pathways account for the imbalance between energy demand and cardiac efficiency. Thus, direct effects of gluco- and lipo-toxicity, oxidative stress and low-grade inflammation act in a vicious circle that impairs insulin sensitivity, accelerates and escalates loss of β-cells, impairs endothelial function and leads to microvascular and macrovascular disease. The fact that in diabetes oxidative stress is increased through the higher amount of reactive oxygen species and a lower antioxidative capacity further potentiates this disease.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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