The complexities of diabetic cardiomyopathy: Lessons from patients and animal models

Cardiovascular diseases are foreseeable complications of diabetes mellitus; heart failure is a prominent complication among these. Diabetic cardiomyopathy is a distinct entity independent of coronary artery disease and hypertension. Most of our knowledge on diabetic cardiomyopathy’s pathogenesis comes from studies performed on various animal models. The recent advances in the domain confirm that the disease is above all a maladaptation of the heart mostly driven by the metabolic derangements that accompany diabetes mellitus.     

Rationale for a metabolic approach in diabetic coronary patients

The incidence of ischaemic heart disease and acute myocardial infarction are greater in people with diabetes than in nondiabetic individuals. Heart disease patients with diabetes have a higher incidence of mortality during and following an acute myocardial infarction and a high risk for progression to heart failure post-infarction. The greater occurrence of ischaemic heart disease is partially due to a poorer coronary artery disease risk factor profile in diabetic patients, and, importantly, due to diabetes-induced abnormalities in the myocardium, termed 'diabetic cardiomyopathy'. The main metabolic abnormalities in the diabetic myocardium are impaired carbohydrate metabolism, specifically reduced pyruvate oxidation in the mitochondria and a greater reliance on fatty acids and ketone bodies as fuels. The healthy heart takes up glucose and lactate and converts them to pyruvate; however, in the diabetic heart there is a reduced capacity to oxidize pyruvate, and thus less glucose and lactate uptake. The defective metabolism is due to high circulating free fatty acids and ketone body concentrations in the plasma, resulting in greater acetyl-Co-enzyme A/Co-enzyme A and reduced nicotinamide adenonine dinucleotide/nicotinamide adenonine dinucleotide+ ratios in the mitochondria, and the subsequent inhibition of pyruvate dehydrogenase. Pharmacological inhibition of fatty acid oxidation during ischaemia increases myocardial pyruvate oxidation and provides clinical benefit to patients with stable angina or ischaemic left ventricular dysfunction. Recent clinical trials with trimetazidine, an inhibitor of the fatty acid beta-oxidation enzyme long chain 3-ketoacylthiolase, showed improvement in cardiac function and exercise performance in diabetic patients with ischaemic heart disease, illustrating the effectiveness of this approach in diabetes.     

Non-invasive diagnostic imaging techniques as a window into the diabetic heart: a review of experimental and clinical data.

Epidemiological and clinical studies show a clear association of diabetes mellitus with congestive heart failure and cardiovascular events independent of blood pressure and ischemic heart disease. The definition of 'diabetic cardiomyopathy' as a clinical entity, however, relies on distinct myocellular and interstitial alterations found in the myocardium of patients with diabetes. The histological findings comprise myocellular hypertrophy, thickening of capillary basement membranes, interstitial fibrosis and rarification of mitochondria on the ultrastructural level. For clinical routine, early detection of diabetic cardiomyopathy seems crucial for identification of patients at cardiovascular risk since the prevalence of heart failure in individuals with diabetes is markedly increased. Recent technical developments in cardiac magnetic resonance imaging (MRI), echocardiography as well as nuclear scintigraphy have advanced the diagnostic applications for the detection of diabetic heart disease. This review aims to present distinct aspects of diabetic cardiomyopathy that were identified using non- invasive imaging techniques. Due to the wide availability and the low costs of echocardiography, it is the most frequently used imaging technique to detect left ventricular dysfunction in patients with diabetes. MRI on the other hand can provide assessment of myocardial structure with higher spatial resolution and allows objective assessment of left ventricular function. This makes MRI an attractive alternative for the detection of discrete alterations, particularly in patients with poor echogenic windows. Finally, nuclear scintigraphy can provide information on cardiac autonomic integrity and accurately detect defects in autonomic control, which are considered a major cardiovascular risk factor in patients with diabetes.     

Diabetic cardiomyopathy,causes and effects

Diabetes is associated with increased incidence of heart failure even after controlling for coronary artery disease and hypertension. Thus, as diabetic cardiomyopathy has become an increasingly recognized entity among clinicians, a better understanding of its pathophysiology is necessary for early diagnosis and the development of treatment strategies for diabetes-associated cardiovascular dysfunction. We will review recent basic and clinical research into the manifestations and the pathophysiological mechanisms of diabetic cardiomyopathy. The discussion will be focused on the structural, functional and metabolic changes that occur in the myocardium in diabetes and how these changes may contribute to the development of diabetic cardiomyopathy in affected humans and relevant animal models.     

PPARγ activator,rosiglitazone: Is it beneficial or harmful to the cardiovascular system?

Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with typeⅡdiabetes.Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity.Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction,inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation,and the protection of myocardial injury during ischemic/reperfusion in different animal models.Previous clinical studies in typeⅡdiabetes patients demonstrated that rosiglitazone played an important role in protectingagainst arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system.Despite these benefits,inconsistent findings have been reported,and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system,including increased risk of acute myocardial infarction,heart failure and chronic heart failure.As a result,rosiglitazone has been recently withdrawn from EU countries.Nevertheless,the effect of rosiglitazone on ischemic heart disease has not yet been firmly established.Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.     

Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction

In the heart, collagens are the major extracellular matrix (ECM) protein. The fibrillar collagens of the heart surround and interconnect myocytes and muscle fibers to provide for muscle fiber and myocyte alignment which imparts mechanical support to the myocardium and governs tissue stiffness. Loss of collagen fibrils and struts are said to lead to myocyte slippage, ventricular dilation, and progressive contractile dysfunction. Failed human hearts examined either at autopsy or explantation invariably exhibit alterations of the ECM primarily due to changes in collagen. Modulation of the balance between matrix synthesis and degradation is important in the process of ventricular remodeling and in the pathophysiology of chronic heart failure. Support for the importance of the ECM and activity of matrix metalloproteinases (MMP) in the development of chronic heart failure has been demonstrated both in animal models of heart disease and in humans. A causative role for the ECM in this process was recently revealed in experiments using a transgenic mouse model that expresses the specific collagen-degrading enzyme, MMP-1, in the heart. These studies demonstrated that chronic expression of MMP-1 leads to dynamic changes in the heart and ultimately results in systolic dysfunction. Multiple studies in animal models have also shown that inhibition of MMP activity in animal models of heart failure have attenuated the onset of left ventricular dilatation. Future studies will determine whether inhibition of MMP activity improves morbidity and mortality in patients with heart failure.     

Diabetic cardiomyopathy revisited

Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. This review discusses the latest findings in diabetic humans and in animal models and reviews emerging new mechanisms that may be involved in the development and progression of cardiac dysfunction in diabetes.     

Glycemic control and treatment patterns in patients with heart failure

Patients with diabetes mellitus are more likely to develop heart failure and cardiac dysfunction (with or without coronary artery disease), and the combination portends a poorer prognosis. Although the majority of treatment options in heart failure appear to be as effective in those with diabetes as in those without, less is known about the safety and effectiveness of different antidiabetic medications in the setting of heart failure. Nevertheless, it is well recognized that many patients with diabetes mellitus may develop subclinical structural heart disease prior to overt clinical presentations. Therefore, the potential of early detection (or screening) is very important to prevent the significant disease burden of heart failure in the diabetic population. In-depth investigations of the role of current and emerging strategies of metabolic modulation are promising, although the precise therapeutic targets remain elusive.     

Murine Models of Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction

Left ventricular diastolic dysfunction leads to heart failure with preserved ejection fraction, an increasingly prevalent condition largely driven by modern day lifestyle risk factors. As heart failure with preserved ejection fraction accounts for almost one-half of all patients with heart failure, appropriate nonhuman animal models are required to improve our understanding of the pathophysiology of this syndrome and to provide a platform for preclinical investigation of potential therapies. Hypertension, obesity, and diabetes are major risk factors for diastolic dysfunction and heart failure with preserved ejection fraction. This review focuses on murine models reflecting this disease continuum driven by the aforementioned common risk factors. We describe various models of diastolic dysfunction and highlight models of heart failure with preserved ejection fraction reported in the literature. Strengths and weaknesses of the different models are discussed to provide an aid to translational scientists when selecting an appropriate model. We also bring attention to the fact that heart failure with preserved ejection fraction is difficult to diagnose in animal models and that, therefore, there is a paucity of well described animal models of this increasingly important condition.     

Role of exercise and metabolism in heart failure with normal ejection fraction

Left ventricular dysfunction associated with metabolic disorders has a number of features that might shed light on the integrity of heart failure with normal ejection fraction. First, although these patients may be dyspneic and have a normal ejection fraction, their diastolic dysfunction is not isolated. Both experimental models and sensitive new parameters in humans have shown abnormal systolic function, even though the less sensitive parameters (such as ejection fraction) become abnormal only with stress. Moreover, the mechanistic contributors to myocardial dysfunction, including structural changes and metabolic influences on the cardiac myocyte, interstitial fibrosis, vascular disease, and altered loading, are likely to influence systolic as much as diastolic function. The responses of systolic and diastolic heart failure to exercise training show analogies, particularly with respect to the importance of peripheral adaptation, as well as a similar training response. Together, these features are more supportive of a continuum of pathophysiology between systolic and diastolic heart failure, rather than the 2 representing discreet phenomena.     

Diastolic dysfunction in the elderly--the interstitial issue

Diastolic dysfunction is increasingly recognized as a cause of congestive heart failure. Meta-analyses of earlier studies of this disorder suggest that 40%–50% of patients with the congestive heart failure syndrome have preserved left ventricular systolic function, with current estimates ranging up to 74%. Among patients ≥65 years of age with congestive heart failure, 55% of all subjects and 67% of women had normal systolic function. Histopathologic evaluation reveals a maladaptive remodeling of the interstitium associated with aging, resulting in an increase in interstitial collagen content. The interstitium normally plays a critical role in the generation of early diastolic suction. When there is a significant enough increase in myocardial collagen volume fraction, with its increased viscoelastic burden, this normal early diastolic suction is compromised and diastolic pressures increase. Left ventricular diastolic dysfunction ensues. Neurohumoral abnormalities associated with diastolic dysfunction include activation of the renin-angiotensin-aldosterone system, including increased elaboration of myocardial aldosterone. This excess of aldosterone appears to play a major role in the development of myocardial fibrosis. Recent observations in animal models and humans have demonstrated regression of interstitial collagen volume fraction in response to inhibition of the renin-angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors and aldosterone inhibition, with improvement in diastolic function. Therapeutic implications of these observations suggest targeting the maladaptive remodeling of the interstitium via inhibition of the renin-angiotensin-aldosterone system.     

Adiposity of the heart, revisited

Obesity is a major risk factor for heart disease. In the face of obesity's growing prevalence, it is important for physicians to be aware of emerging research of novel mechanisms through which adiposity adversely affects the heart. Conventional wisdom suggests that either hemodynamic (that is, increased cardiac output and hypertension) or metabolic (that is, dyslipidemic) derangements associated with obesity may predispose individuals to coronary artery disease and heart failure. The purpose of this review is to highlight a novel mechanism for heart disease in obesity whereby excessive lipid accumulation within the myocardium is directly cardiotoxic and causes left ventricular remodeling and dilated cardiomyopathy. Studies in animal models of obesity reveal that intracellular accumulation of triglyceride renders organs dysfunctional, which leads to several well-recognized clinical syndromes related to obesity (including type 2 diabetes). In these rodent models, excessive lipid accumulation in the myocardium causes left ventricular hypertrophy and nonischemic, dilated cardiomyopathy. Novel magnetic resonance spectroscopy techniques are now available to quantify intracellular lipid content in the myocardium and various other human tissues, which has made it possible to translate these studies into a clinical setting. By using this technology, we have recently begun to study the role of myocardial steatosis in the development of obesity-specific cardiomyopathy in humans. Recent studies in healthy individuals and patients with heart failure reveal that myocardial lipid content increases with the degree of adiposity and may contribute to the adverse structural and functional cardiac adaptations seen in obese persons. These studies parallel the observations in obese animals and provide evidence that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in obese patients.     

Digitalis and neurohormonal abnormalities in heart failure and implications for therapy.

A pathophysiologic hallmark of heart failure is neurohormonal excitation, a prominent feature of which is activation of the sympathetic nervous system. Studies from our laboratories demonstrate that clinical heart failure is characterized by marked increases in efferent sympathetic neural outflow to muscle; the magnitude of this sympatho-excitation parallels the degree of cardiac dysfunction. Impairments of cardiopulmonary and arterial baroreflex sensory mechanisms appear to be responsible to a significant degree for this sympatho-excitation, consistent with findings in animal models of heart failure. Digitalis glycosides exert modest inotropic actions when administered to patients with heart failure. Digitalis also has potent autonomic effects that can potentiate impaired arterial and cardiopulmonary baroreflex mechanisms in experimental models of cardiac dysfunction. Acute digitalis administration to patients with moderate-to-severe heart failure produces profound and sustained sympatho-inhibition, which precedes any observed hemodynamic action of the agent. Further, acute digitalization of such patients rapidly normalizes impaired baroreflex-mediated mechanisms. Data now suggest that the mechanism of action of digitalis in humans is an acute potentiation of baroreceptor-mediated afferent regulation of sympathetic neural mechanisms. Prospective, randomized and controlled studies now are required to test the hypothesis that the acute effects of digitalis on autonomic mechanisms also are observed during chronic administration. In theory, the chronic sympatho-inhibitory action of digitalis, combined with its chronic potentiation of impaired baroreflex mechanisms, may offer beneficial effects independent of its inotropic actions in patients with heart failure.     

Diabetes-related cardiomyopathy: The sweet story of glucose overload from epidemiology to cellular pathways

Type 2 diabetes (T2D) is a major risk factor for heart failure (HF). 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 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, accumulation of advanced glycation end-products (AGEs) and chronic activation of the hexosamine pathway. These have all been found to activate apoptosis and to alter heart contractility, calcium signalling and mitochondrial function. Although, in the past, 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 review, based on clinical evidence from mechanistic studies as well as several large clinical trials, covers 15 years of research, and strongly supports the idea that hyperglycaemia and glucose overload play a central role in the pathophysiology of diabetic cardiomyopathy.     

Glucagon-Like Peptide-1 and its Cardiovascular Effects

Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested by both preclinical and clinical studies. In vivo and in vitro studies have demonstrated cardio-protective effects of GLP-1 by activating cell survival signal pathways, which have greatly reduced ischemia/reperfusion injury and also cardiac dysfunction in various congestive heart failure animal models. Clinically, beneficial effects of GLP-1 have been shown in patients with myocardial infarction, hypertension, and heart failure, and 2 classes of incretin enhancers, GLP-1 receptor agonists and DPP-4 inhibitors, are currently available for the treatment of type 2 diabetes mellitus. In this review, we will summarize the role of incretins in various cardiovascular events such as hypertension and heart failure and postprandial lipoprotein secretion, and discuss their molecular mechanisms and potentials as a new therapeutic as well as preventive drug type for reducing cardiovascular events in both diabetic and nondiabetic patients.     

Increased prevalence of concentric left ventricular hypertrophy in African-Americans: Will an epidemic of heart failure follow?

Left ventricular hypertrophy (LVH), used in this review to denote abnormally increased left ventricular (LV) mass, is an important cardiac trait because of its association with numerous adverse cardiovascular outcomes including myocardial infarction and heart failure. LV mass is typically assessed by noninvasive cardiac imaging (echocardiography or MRI); electrocardiography is an insensitive measure. There are two predominant types of hypertrophy: concentric, where LV wall thickness is increased relative to cavity dimensions, and eccentric, where LV wall thickness is not increased relative to cavity dimensions. Several large studies indicate that the prevalence of concentric LVH is higher in African-Americans versus whites. Although there are data to suggest that concentric LVH results in systolic heart failure in animal models, such data are lacking in humans. How concentric LVH affects the prevalence of systolic and diastolic heart failure in African-Americans needs further study. Given the large burden of LVH among African-Americans, such data are needed to estimate the expected burden and type of heart failure which will occur in the future in this population.     

Myocardial metabolism and cardiac performance in obesity and insulin resistance

Obesity, insulin resistance, and their frequent complication of type 2 diabetes are risk factors for left ventricular diastolic dysfunction, systolic dysfunction, and clinical heart failure. Although obesity, insulin resistance, and diabetes are risk factors for coronary artery disease, and hence ischemic cardiomyopathy-related heart failure, there is increasing evidence that these three risk factors are implicated in the development of cardiac dysfunction not related to epicardial coronary disease. There are several mechanisms by which this triad may cause cardiac dysfunction, including alterations in myocardial metabolism, which may initially be adaptations but evolve into maladaptive responses over time. Recent advances in our understanding of these mechanisms will aid in the development of novel therapies, including metabolic manipulations that could prevent and treat cardiac dysfunction in patients with obesity, insulin resistance, and diabetes.     

Quantitation and distribution of beta-tubulin in human cardiac myocytes

Increasing evidence suggests that derangements of cytoskeletal proteins contribute to alterations in intracellular signaling, myocyte function, and the coupling of myocytes to the extracellular matrix during cardiac hypertrophy and failure. Data from animal studies have shown an increased density of beta-tubulin protein in the right or left ventricle subjected to pressure overload, and have demonstrated that interfering with excess polymerization of beta-tubulin improves contractility. We tested the hypothesis that beta-tubulin is increased in human left ventricular hypertrophy and end-stage heart failure. Confocal microscopy of fluorescently labeled beta-tubulin protein revealed an increased density of the beta-tubulin network in cardiomyocytes from both hypertrophied and failing human hearts as compared to cells from nonfailing hearts. Western blot analysis on total heart homogenate showed no change in beta-tubulin when data were normalized to either actin or calsequestrin, although there was a significant increase in failing human hearts when data were normalized only for a constant amount of protein per heart. The mRNA for beta-tubulin was not changed in hypertrophied hearts, but was significantly decreased in failing human hearts. Thus, similar to animal models, we have shown that the density of the microtubular network within the cardiomyocyte is increased in end-stage failing human hearts. We have also shown for the first time that beta-tubulin density is increased in cells from hypertrophied human hearts. Although the functional implications of this finding in the human heart remain to be explored, data from animal studies suggest that increased beta-tubulin protein contributes to cardiac dysfunction.     

The diabetic myocardium

Heart failure and diabetes mellitus are frequently associated, with diabetes potentiating the development of heart failure after other myocardial insults. This review documents the evidence in support of a specific primary myocardial disease in diabetes. The strongest clinical evidence relates to the detection of otherwise unexplained diastolic dysfunction in apparently healthy diabetic subjects, but recent studies with sensitive echocardiographic markers have shown systolic disturbances as well. The mechanism of this myocardial disease is multifactorial, with contributions from metabolic effects on the myocyte, structural changes in the myocardium and interstitium, autonomic neuropathy, and perhaps coronary vascular disease. The common pathway appears to be related to glycemic control and new evidence suggests better metabolic control to be beneficial, as well as angiotensinconverting enzyme inhibition and cross-link breakers.     

Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer's disease: studies in animal models

A growing body of animal and epidemiological studies suggest that metabolic diseases such as obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus are associated with the development of cognitive impairment, dementia and Alzheimer's disease, particularly in aging. Several lines of evidence suggest that insulin signalling dysfunction produces these metabolic alterations and underlie the development of these neurodegenerative diseases. In this article, we address normal insulin function in the synapse; we review and discuss the physiopathological hallmarks of synaptic insulin signalling dysfunction associated with metabolic alterations. Additionally, we describe and review the major animal models of obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The comprehensive knowledge of the molecular mechanisms behind the association of metabolic alterations and cognitive impairment could facilitate the early detection of neurodegenerative diseases in patients with metabolic alterations, with treatment that focus on neuroprotection. It could also help in the development of metabolic‐based therapies and drugs for using in dementia and Alzheimer's disease patients to alleviate their symptoms in a more efficient and comprehensive way. Copyright © 2014 John Wiley & Sons, Ltd.