Vascular Endothelial Dysfunction In Diabetic Cardiomyopathy: Pathogenesis and Potential Treatment Targets (original) (raw)

Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy

Acta Pharmacologica Sinica, 2018

Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as "diabetic cardiomyopathy". However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.

Diabetic Cardiomyopathy: Intersection of Macrovascular and Microvascular Disease, or Much More?

Macedonian Medical Review

Cardiovascular disease is responsible for over 75% of deaths in diabetic patients, the majority caused by coronary artery disease (CAD) and heart failure. Cardiovascular morbidity and mortality in diabetic patients might be independently associated with other pathophysiologic mechanisms than coronary artery disease, epicardial and microvascular disease. There is an increasing notion that diabetic patients suffer from an additional cardiac condition named “diabetic cardiomyopathy”. There are several clinical, experimental, pathological and epidemiological researches that support the existence of a specific “diabetic cardiomyopathy”. This is assumed to be influenced by complex interaction of several metabolic changes that leads to both functional and structural alterations of the diabetic myocardium. In this review epidemiological aspects and clinical implications of this condition are presented.

Endothelial Function in Pre-diabetes, Diabetes and Diabetic Cardiomyopathy: A Review

Journal of Diabetes & Metabolism, 2014

Diabetes mellitus worsens cardiovascular risk profile of affected individuals. Its worldwide increasing prevalence and its negative influences on vascular walls morphology and function are able to induce the expression of several morbidities which worsen the clinical conditions of the patients getting them running towards a reduced survival curve. Although overt diabetes increases the mortality rate of individuals due to its pathogenesis, poor information are in literature about the role of pre-diabetes and family history of diabetes mellitus in the outcome of general population. This emphasizes the importance of early detection of vascular impairment in subjects at risk of developing diabetes. The identification of early stages of atherosclerotic diseases in diabetic persons is a fundamental step in the risk stratification protocols followed-up by physicians in order to have a complete overview about the clinical status of such individuals. Common carotid intima-media thickness, flow-mediated vasodilatation, pulse wave velocity are instrumental tools able to detect the early impairment in cardiovascular system and stratify cardiovascular risk of individuals. The aim of this review is to get a general perspective on the complex relationship between cardiovascular diseases onset, pre-diabetes and family history of diabetes. Furthermore, it points out the influence of diabetes on heart function till the expression of the so-called diabetic cardiomyopathy.

Endothelial dysfunction in diabetes mellitus

Vascular health and risk management, 2007

Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. A number of trials have demonstrated that statins therapy as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes. In the present review we provide the up to date details on this subject.

Diabetic Cardiovascular Disease: Getting to the Heart of the Matter

Journal of Cardiovascular Translational Research, 2012

Diabetes is a major risk factor for heart disease, and heart disease is responsible for substantial morbidity and mortality among people living with diabetes. The diabetic metabolic milieu predisposes to aggressive obstructive coronary artery disease that causes heart attacks, heart failure and death. Furthermore, diabetes can be associated with heart failure, independent of underlying coronary artery disease, hypertension or valve abnormalities. The pathogenesis of the vascular and myocardial complications of diabetes is, as yet, incompletely understood. Although a number of medical and surgical approaches can improve outcomes in diabetic patients with cardiovascular disease, much remains to be learned in order to optimize approaches to these critical complications.

Coronary microvascular dysfunction in diabetes mellitus: A review

World Journal of Cardiology, 2010

The exploration of coronary microcirculatory dysfunction in diabetes has accelerated in recent years. Cardiac function is compromised in diabetes. Diabetic patients manifest accelerated atherosclerosis in coronary arteries. These data are confirmed in diabetic animal mod-els, where lesions of small coronary arteries have been described. These concepts are epitomized in the classic microvascular complications of diabetes, i.e. blindness, kidney failure and distal dry gangrene. Most importantly, accumulating data indicate that insights gained from the link between inflammation and diabetes can yield predictive and prognostic information of considerable clinical utility. This review summarizes the evidence for the predisposing factors and the mechanisms involved in diabetes, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We evaluate the roles of hyperglycemia, oxidative stress, polyol pathway, protein kinase C, advanced glycation end products, insulin resistance, peroxisome proliferator-activated receptor-γ, inflammation, and diabetic cardiomyopathy as a "stem cell disease". Furthermore, we discuss the mechanisms responsible for impaired coronary arteriole function. Finally, we consider how new insights in diabetes may provide innovative therapeutic strategies. . Coronary microvascular dysfunction in diabetes mellitus: A review. 55: 480-486 19 Weidig P, McMaster D, Bayraktutan U. High glucose mediates pro-oxidant and antioxidant enzyme activities in coronary endothelial cells. Diabetes Obes Metab 2004; 6: 432-441 20 Enderle MD, Benda N, Schmuelling RM, Haering HU, Pfohl M. Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects. Diabetes Care 1998; 21: 271-277 21 Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992; 90: 2548-2554 22 Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94: 1172-1179 23 Baron AD. Hemodynamic actions of insulin. Am J Physiol 1994; 267: E187-E202 24 Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L. Ischemia-reperfusion selectively impairs nitric oxidemediated dilation in coronary arterioles: counteracting role of arginase. FASEB J 2003; 17: 2328-2330 25 Fossum E, Høieggen A, Moan A, Rostrup M, Nordby G, Kjeldsen SE. Relationship between insulin sensitivity and maximal forearm blood flow in young men. Hypertension 1998; 32: 838-843 26 Ferri C, Bellini C, Desideri G, Di Francesco L, Baldoncini R, Santucci A, De Mattia G. Plasma endothelin-1 levels in obese hypertensive and normotensive men. Diabetes 1995; 44: 431-436 27 Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, Supiano MA. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity.

Endothelial Dysfunction and Diabetes: Effects on

2012

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia due to lack of or resistance to insulin. Patients with DM are frequently afflicted with ischemic vascular disease or wound healing defect. It is well known that type 2 DM causes amplification of the atherosclerotic process, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. These complications ultimately lead to impairment of neovascularization and diabetic wound healing. Therapeutic angiogenesis remains an attractive treatment modality for chronic ischemic disorders including PAD and/or diabetic wound healing. Many experimental studies have identified better approaches for diabetic cardiovascular complications, however, successful clinical translation has been limited possibly due to the narrow therapeutic targets of these agents or the lack of rigorous evaluation of pathology and therapeutic mechanisms in experimental models of disease. This paper discusses the current body of evidence identifying endothelial dysfunction and impaired angiogenesis during diabetes.