Diabetic cardiomyopathy: pathophysiology and clinical features.
TL;DR: Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients, but a strategy for prevention or treatment to improve its prognosis has not yet been established.
Abstract: Since diabetic cardiomyopathy was first reported four decades ago, substantial information on its pathogenesis and clinical features has accumulated. In the heart, diabetes enhances fatty acid metabolism, suppresses glucose oxidation, and modifies intracellular signaling, leading to impairments in multiple steps of excitation–contraction coupling, inefficient energy production, and increased susceptibility to ischemia/reperfusion injury. Loss of normal microvessels and remodeling of the extracellular matrix are also involved in contractile dysfunction of diabetic hearts. Use of sensitive echocardiographic techniques (tissue Doppler imaging and strain rate imaging) and magnetic resonance spectroscopy enables detection of diabetic cardiomyopathy at an early stage, and a combination of the modalities allows differentiation of this type of cardiomyopathy from other organic heart diseases. Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients. However, a strategy for prevention or treatment of diabetic cardiomyopathy to improve its prognosis has not yet been established. Here, we review both basic and clinical studies on diabetic cardiomyopathy and summarize problems remaining to be solved for improving management of this type of cardiomyopathy.
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30 Mar 2017
TL;DR: A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development.
Abstract: Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in β-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.
753 citations
TL;DR: Recent observations of potential differences in the pathophysiology of T1DM compared with T2DM are summarized and the implications for treatment of CVD risk factors in patients with diabetes mellitus are explored.
Abstract: Despite the known higher risk of cardiovascular disease (CVD) in individuals with type 1 diabetes mellitus (T1DM), the pathophysiology underlying the relationship between cardiovascular events, CVD risk factors, and T1DM is not well understood. Management approaches to CVD reduction have been extrapolated in large part from experience in type 2 diabetes mellitus (T2DM), despite the longer duration of disease in T1DM than in T2DM and the important differences in the underlying pathophysiology. Furthermore, the phenotype of T1DM is changing. As a result of the findings of the Diabetes Control and Complications Trial (DCCT), which compared intensive glycemic control with usual care, and its follow-up observational study, Epidemiology of Diabetes Interventions and Complications (EDIC), intensive management of diabetes mellitus (DM) has become the standard of care and has led to increasing longevity. However, our understanding of CVD in T1DM comes in large part from the previous era of less intensive glycemic control. More intensive glycemic control is associated with significant risk of weight gain, which may be magnified by the obesity epidemic. There is growing interest in better understanding the adverse effects of glycemia, the prevalence and type of lipid abnormalities in T1DM, the prognostic role of albuminuria and renal insufficiency, and the role of blood pressure (BP) in CVD. Obesity-associated metabolic abnormalities such as the proinflammatory state likely modify CVD risk in T1DM; however, the effect may be different from what is seen in T2DM. These concepts, and how they may affect management, have not been fully explored.
The present review will focus on the importance of CVD in patients with T1DM. We will summarize recent observations of potential differences in the pathophysiology of T1DM compared with T2DM, particularly with regard to atherosclerosis. We will explore the implications of these concepts for treatment of CVD risk factors in patients with …
447 citations
Cites background from "Diabetic cardiomyopathy: pathophysi..."
...Heart failure and cardiomyopathy have also been described in T1DM (6,7), although informa-...
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TL;DR: Evidence gathered over the last decade has shown GLS to be more sensitive to left ventricular dysfunction than LVEF and to provide additional prognostic information, and there is a strong case for incorporation of GLS into clinical decision making.
Abstract: Left ventricular (LV) ejection fraction (LVEF) is a simple measure of global systolic function that pervades the risk evaluation and management of many cardiovascular diseases. However, this parameter is limited not only by technical challenges, but also by pathophysiological entities where the ratio of stroke volume to LV cavity size is preserved. The assessment of global longitudinal strain (GLS) from speckle-tracking analysis of 2-dimensional echocardiography has become a clinically feasible alternative to LVEF for the measurement of myocardial function. Evidence gathered over the last decade has shown GLS to be more sensitive to left ventricular dysfunction (LVD) than LVEF and to provide additional prognostic information. The technology is validated, reproducible within an acceptable range, and widely available. GLS has been proposed as the test of choice in guidelines for monitoring of asymptomatic cardiotoxicity related to chemotherapy. It also has the potential to improve risk stratification, redefine criteria for disease classification, and determine treatment in asymptomatic LVD resulting from a variety of etiologies. GLS provides utility across the spectrum of heart failure (and LVEF) as well as in the evaluation of valvular heart disease. There is a strong case for incorporation of GLS into clinical decision making. This review appraises the evidence addressing the utility of GLS as a complementary metric to LVEF for incorporation into mainstream clinical practice.
375 citations
Cites background from "Diabetic cardiomyopathy: pathophysi..."
...In the absence of ischemic heart disease (IHD) and hypertension, this entity has been termed diabetic cardiomyopathy (39), and its phenotype is commonly considered one of early diastolic dysfunction....
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TL;DR: Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis.
248 citations
Cites background from "Diabetic cardiomyopathy: pathophysi..."
...Accumulating recent evidence suggests that the complex interplay of oxidative, nitrosative and nitrative stress [10–12] with major proinflammatory,metabolic [13] and cell death pathways [14–17] play an essential role in the development of complex biochemical [18,19], mechanical, and structural alterations associated with diabetic cardiomyopathy [8,20,21], which will be overviewed in this brief synopsis....
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TL;DR: The need for continued interrogation of these mechanisms is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
Abstract: Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
215 citations
References
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TL;DR: A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.
Abstract: From the Steno Diabetes Center, Copenhagen (P.G., P.V., N.L., H.-H.P., O.P.); Herlev County Hospital, Herlev (N.L.); Amtssygehuset Roskilde, Roskilde (G.V.H.J.); and the Faculty of Health Science, Aarhus University, Aarhus (H.-H.P., O.P.) — all in Denmark. Address reprint requests to Dr. Pedersen at the Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark, or at oluf@steno.dk. N Engl J Med 2003;348:383-93. Copyright © 2003 Massachusetts Medical Society. background Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. methods The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. results The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). conclusions A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.
4,111 citations
"Diabetic cardiomyopathy: pathophysi..." refers background in this paper
...Second, the Steno-2 trial [199] showed that simultaneous control of glycemia, hypertension, and dyslipidemia significantly reduced cardiovascular events and mortality in T2DM patients....
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TL;DR: Glycaemia and diabetes are rising globally, driven both by population growth and ageing and by increasing age-specific prevalences, and effective preventive interventions are needed, and health systems should prepare to detect and manage diabetes and its sequelae.
3,410 citations
TL;DR: In the community, systolic dysfunction is frequently present in individuals without recognized CHF and diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognizedCHF, and associated with marked increases in all-cause mortality.
Abstract: Context Approximately half of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Yet, the prevalence of diastolic dysfunction and its relation to systolic dysfunction and CHF in the community remain undefined. Objectives To determine the prevalence of CHF and preclinical diastolic dysfunction and systolic dysfunction in the community and determine if diastolic dysfunction is predictive of all-cause mortality. Design, Setting, Participants Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000. Main Outcome Measures Doppler echocardiographic assessment of systolic and diastolic function. Presence of CHF diagnosis by review of medical records with designation as validated CHF if Framingham criteria are satisfied. Subjects without a CHF diagnosis but with diastolic or systolic dysfunction were considered as having either preclinical diastolic or preclinical systolic dysfunction. Results The prevalence of validated CHF was 2.2% (95% confidence interval [CI], 1.6%-2.8%) with 44% having an EF higher than 50%. Overall, 20.8% (95% CI, 19.0%-22.7%) of the population had mild diastolic dysfunction, 6.6% (95% CI, 5.5%-7.8%) had moderate diastolic dysfunction, and 0.7% (95% CI, 0.3%-1.1%) had severe diastolic dysfunction with 5.6% (95% CI, 4.5%-6.7%) of the population having moderate or severe diastolic dysfunction with normal EF. The prevalence of any systolic dysfunction (EF ≤50%) was 6.0% (95% CI, 5.0%-7.1%) with moderate or severe systolic dysfunction (EF ≤40%) being present in 2.0% (95% CI, 1.4%-2.5%). CHF was much more common among those with systolic or diastolic dysfunction than in those with normal ventricular function. However, even among those with moderate or severe diastolic or systolic dysfunction, less than half had recognized CHF. In multivariate analysis, controlling for age, sex, and EF, mild diastolic dysfunction (hazard ratio, 8.31 [95% CI, 3.00-23.1],P Conclusions In the community, systolic dysfunction is frequently present in individuals without recognized CHF. Furthermore, diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognized CHF, and associated with marked increases in all-cause mortality.
2,822 citations
TL;DR: Because of the emerging evidence about the adverse effects of AGEs on the vasculature of patients with diabetes, a number of different therapies to inhibit A GEs are under investigation.
Abstract: Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. AGEs are prevalent in the diabetic vasculature and contribute to the development of athe...
2,054 citations
"Diabetic cardiomyopathy: pathophysi..." refers background in this paper
...addition to the increase in collagen deposition, cross-linking of collagen fibers may be increased by diabetes, contributing to reduction in ventricular compliance [16]....
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...Activation of the receptor for AGE (RAGE) in the endothelium by AGE inhibits production of nitric oxide (NO) and up-regulates expression of cell adhesion molecules [16]....
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TL;DR: It is postulated that the myocardial disease seen in these cases is probably secondary to diabetic mjcroangiopathy although the direct effects of the abnormalMyocardial metabolism in diabetes could not be excluded.
Abstract: The postmortem findings and clinical records of 27 patients with proved diabetic glomerulosclerosis were examined and reviewed for evidence of primary myocardial disease. Twenty-three cases were excluded because of complicating conditions such as hypertension, significant obstruction of the major coronary arteries or valvular disease. Four patients demonstrated cardiomegaly and congestive heart failure of no known cause. The autopsy findings consisted of left ventricular hypertrophy and, in 1 case, right ventricular hypertrophy as well, in the absence of major coronary artery disease. Histopathologic study revealed diffuse fibrotic strands extending between bundles of muscle fibers and myofibrillar hypertrophy. In 1 case, the small intramural coronary arterioles demonstrated thickening of the wall and narrowing of the lumen due primarily to the deposition of acid mucopolysaccharide material in the subendothelial layers and subsequent subintimal thickening and medial hypertrophy. It is postulated that the myocardial disease seen in these cases is probably secondary to diabetic mjcroangiopathy although the direct effects of the abnormal myocardial metabolism in diabetes could not be excluded.
1,591 citations
"Diabetic cardiomyopathy: pathophysi..." refers background in this paper
...Thickening of the capillary basement membrane, medial thickening of the arteriole, and perivascular fibrosis were observed in autopsy samples of the ventricular myocardium by conventional histology [12, 14, 21, 22]....
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...[12], who examined pathology of four autopsy cases with diabetic glomerulosclerosis and no known cause of heart failure....
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...hallmark of diabetic cardiomyopathy [12, 14, 15], and the extent of fibrosis correlates with heart weight [15]....
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...‘‘Microangiopathy’’ has been demonstrated in the myocardium of diabetic patients, and it was reproducible in a rat model of diabetes [12, 14, 21, 22, 122, 123]....
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...Photographs of the histology of autopsy cases presented in earlier reports [12, 14, 15] show hypertrophic cardiomyocytes mixed with atrophic ones in diabetic cardiomyopathy....
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