Managing Cardiovascular Complications in Diabetes

D. John Betteridge, Stephen Nicholls, D. John Betteridge, Stephen Nicholls

• Publisher: Wiley-Blackwell
• Year: 2014
• Print ISBN: 9780470659496
• eBook ISBN: 9781118337943
• Edition: 1
• Topic: Medizin
• Subtopic: Endokrinologie & Stoffwechsel

Of all the complications which arise from diabetes, cardiovascular complications are by far the most prevalent and the most deadly.

Authored by some of the world's leading names in this area, this outstanding book provides all those managing diabetic patients with clinical, practical and succinct guidance to the diagnosis and management of cardiovascular complications in diabetes.

With a joint endocrinology and cardiology focus, and with the very latest in clinical guidelines from the ADA, EASD, AHA, ASC and ESC, selected highlights include:

• The role of new biomarkers of cardiovascular disease in diabetes
• The latest on diagnosis of cardiovascular problems via vascular imaging
• Hypertension and cardiovascular disease in the diabetic patient
• Dyslipidaemia and its management  in type 2 diabetes
• Management of thrombosis, acute coronary syndrome and peripheral arterial disease in diabetes

Key points, case studies and self-assessment questions allow for rapid-reference, quick understanding of all topics, thus ensuring that this is perfect reading for endocrinologists, diabetes specialists and cardiologists of all levels managing patients with diabetes and associated cardiovascular problems.

Chapter 1
The Vascular Endothelium in Diabetes

Andrew Lansdown¹, Elizabeth Ellins² and Julian Halcox²

¹ Cardiff University School of Medicine, Cardiff, UK

² Swansea University College of Medicine, Swansea, UK

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Key Points

• The endothelium is a key participant in the homeostasis of the vessel wall.
• Nitric oxide (NO) plays a key role in regulating healthy vascular function.
• Reduced local NO bioavailability is a characteristic hallmark of vascular endothelial dysfunction.
• Endothelial dysfunction is chiefly driven by oxidative stress and inflammation.
• A number of techniques for assessing endothelial function are available; flow-mediated dilatation (FMD) is the current noninvasive ‘gold-standard’ methodology.
• A number of circulating markers are also helpful in assessment of endothelial dysfunction.
• Hyperglycemia, insulin resistance, and dyslipidemia are all important contributors to endothelial dysfunction.
• Endothelial dysfunction in diabetes is associated with adverse micro- and macrovascular complications.
• Drug therapies, including statins, insulin sensitizers, and ACE inhibitors, have been shown to improve endothelial dysfunction in diabetes.

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Introduction

The vascular endothelium, the monolayer of thin cells lining the arteries and veins, serves as the key regulator of arterial homeostasis. It plays a vital role in regulating vascular tone, cellular adhesion, platelet activity, vessel wall inflammation, angiogenesis, and vascular smooth muscle cell proliferation. In order to regulate these functions, a number of important vasoactive molecules, including nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin (PGI2), and endothelin (ET-1), are produced and released by the endothelial cells [1, 2].

Normal Endothelial Cell Function

The arterial endothelium is composed of a layer of spindle-shaped endothelial cells that are bound together by tight junctions and communicate directly with each other and the underlying smooth muscle cells via gap junctions. This forms a protective barrier between the blood and the rest of the vessel wall that is relatively impermeable to low-density lipoprotein (the core component of atherosclerotic lesions), able to sense molecular cues and interact with cellular components of the circulating blood.

Furchgott and Zawadzki first demonstrated in 1980 that endothelial cells are essential in order for underlying smooth muscle relaxation to occur in response to acetylcholine administration in the rabbit aorta [3] and NO was subsequently identified as this endothelium-derived relaxing factor [4]. A healthy endothelium is able to secrete NO, a diatomic molecule generated from L-arginine, by the action of the enzyme endothelial NO synthase (eNOS) in the presence of cofactors such as tetrahydrobiopterin [5]. NO exerts its action by diffusing into vascular smooth muscle cells where it activates G-protein-bound guanylate cyclase, resulting in c-GMP generation, smooth muscle relaxation, and vasodilatation [1] (Figure 1.1). eNOS, in normal physiology, is activated by shear stress from blood flow through the vessels and also by molecules such as adenosine, bradykinin, serotonin (in response to platelet aggregation), and vascular endothelial growth factor (induced by hypoxia; Figure 1.1) [6–8].

Figure 1.1 Illustration of the stimulation of endothelial NO synthase by acetylcholine and shear stress leading to increased nitric oxide (NO) production in endothelial cells by receptor and nonreceptor and calcium-dependent and noncalcium-dependent pathways. (Source: Herrmann J et al. 2010 [8]. Reproduced with permission of Oxford University Press.)

In addition, NO has antiplatelet effects and can down-regulate inflammatory pathways and also decrease the generation of ET-1, a potent vasoconstrictor polypeptide, which also possesses pro-inflammatory, pro-oxidant, and pro-proliferative activity [9].

Other endothelial-derived vasodilators exist and act independently of NO to maintain vasodilator tone. PGI2, produced from the cyclooxygenase system, and EDHF are such molecules, with the latter able to compensate for the loss of NO-mediated vasodilator tone when NO bioavailability is reduced [10, 11]. Normal health and physiological functioning of the vascular endothelium are maintained by a balanced release of endothelial-derived relaxing factors, such as NO and prostacyclin (PGI2), and vasoconstricting factors like ET-1 and angiotensin II. The dysequilibrium of their production, release, and action is the chief characteristic of endothelial dysfunction [12].

Beyond its function in regulating vessel tone, the vascular endothelium also serves to play an important role in both mediating and responding to inflammatory pathways. In addition to its constrictor effects, angiotensin II generated by the endothelium has effects on vascular smooth muscle cell contraction, growth, proliferation, and differentiation. A range of selectins and adhesion molecules are produced, resulting in the binding and transendothelial migration of inflammatory cells [13, 14]. Furthermore, the endothelium is directly involved in the balance between coagulation and fibrinolysis, which is mediated by its synthesis of both tissue-type plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1) [12, 15].

Measuring Endothelial Function

Following the in vitro work of Furchgott and Zawadzki, Ludmer et al. demonstrated for the first time in humans that locally administered acetylcholine caused vasoconstriction of atherosclerotic coronary arteries and vasodilatation in normal coronary vessels in subjects undergoing cardiac catheterization [16]. Subsequently, a noninvasive method was developed for assessing endothelial function in the conduit arteries of the peripheral circulation. This method used a period of forearm ischemia followed by reactive hyperemia to increase blood flow through the brachial artery, increasing local shear stress, mediating NO release and brachial artery dilatation [17]. Peripheral endothelial vasodilator function correlates with coronary endothelial function and cardiovascular risk factors, including smoking, dyslipidemia, and diabetes, and can predict incident cardiovascular events in older adults [18–21].

Various techniques have been developed that use pharmacologic agents to act on the endothelium or that measure the vasodilator response to increased shear stress. No one test has been shown to be ideal and indeed a combination may be required to evaluate fully the various aspects of vascular endothelial biology (Figure 1.2).

Figure 1.2 Methods for assessing human endothelial function.

Invasive methods for assessing endothelial function include venous occlusion plethysmography and quantitative coronary angiography with Doppler flow wire to assess coronary diameter and blood flow.

The original tests of endothelial function used the latter techniques to assess coronary circulatory physiology. Pharmacologic agents, such as acetylcholine, are used to induce an endothelium-dependent vasomotor response, measuring changes in the epicardial and microvascular circulation. At the doses traditionally used, a vasodilator response is usually observed in normal coronary vessels, but in the presence of endot...

Table of contents

• Cover
• Title Page
• Copyright
• List of Contributors
• Introduction
• Chapter 1: The Vascular Endothelium in Diabetes
• Chapter 2: New Biomarkers of Cardiovascular Disease in Diabetes
• Chapter 3: Kidney Disease in Diabetes
• Chapter 4: Vascular Imaging
• Chapter 5: Glycemia and CVD and Its Management
• Chapter 6: Hypertension and Cardiovascular Disease and Its Management
• Chapter 7: Dyslipidemia and Its Management in Type 2 Diabetes
• Chapter 8: Thrombosis in Diabetes and Its Clinical Management
• Chapter 9: Diet and Lifestyle in CVD Prevention and Treatment
• Chapter 10: Management of Acute Coronary Syndrome
• Chapter 11: Management of Peripheral Arterial Disease
• Index
• End User License Agreement