Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease
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Increased arterial stiffness associated with diabetes and the metabolic syndrome may in part explain the increased cardiovascular disease risk observed in these conditions. Arterial stiffness can be estimated by quantifying pulse pressure but is better described by distensibility and compliance coefficients, pulse wave velocity and wave reflection. The most common non-invasive methodologies used to quantify these estimates of arterial stiffness (e.g. ultrasonography and applanation tonometry) are also described. We then review and summarise the current data on the associations between diabetes, the metabolic syndrome and insulin resistance on the one hand and greater arterial stiffness on the other, and identify and discuss some unresolved issues such as differential stiffening of central vs peripheral arterial segments, the impact of sex, and the pathobiology of increased arterial stiffness in diabetes and the metabolic syndrome. Finally, some considerations with regard to treatment options are presented. At present the most powerful therapy available for reducing arterial stiffness is to vigorously treat hypertension using pharmacological agents. New pharmacological strategies to reduce arterial stiffness are likely to be especially relevant to individuals with diabetes.
KeywordsArterial stiffness Cardiovascular disease Diabetes Insulin resistance Metabolic syndrome Pathophysiology
advanced glycation end-products
Cardiovascular disease is the main cause of death in both type 1 and type 2 diabetes mellitus . The pathophysiological mechanisms underlying these associations are incompletely understood. Increased arterial stiffness may be one important pathway linking diabetes to the increased cardiovascular risk, as it commonly occurs in these conditions . Indeed, increased arterial stiffness predicts the development of cardiovascular disease and mortality in the general population  and in type 2 diabetes .
Arterial stiffness—why is it important?
Systolic blood pressure increases progressively with increasing age, whereas a decrease in diastolic blood pressure is observed particularly from the 5th decade onwards . Because ventricular ejection decreases with age, arterial stiffness assumes a critical role in the explanation of the age-related increases in systolic and pulse pressure and related mortality, and this therefore explains why brachial pulse pressure is commonly used as a marker of arterial stiffness .
Estimates of arterial stiffness
The stiffness of an arterial site or segment is dependent on its background level of distending pressure, i.e. mean arterial pressure—a greater recruitment of relatively inelastic collagen fibres occurs with increasing distending pressures, enhancing stiffness. Therefore, to fully appreciate arterial stiffness estimates in clinical studies, adjustment for mean arterial pressure levels is imperative so that the distending pressure effects can be differentiated from true differences in viscoelastic properties of the arterial wall .
Arterial stiffness in diabetes and the metabolic syndrome: the evidence
As the literature up to 1999 has been extensively reviewed , we shall focus on recent developments. In addition, and in the context of type 2 diabetes, we also review the evidence with regard to the association between the metabolic syndrome and arterial stiffness, as clustering of cardiovascular risk factors precedes the development of diabetes [14, 15], and understanding their impact on arterial stiffness may be critical for the primary prevention of diabetes-related macrovascular disease. Finally, we discuss the evidence with regard to the role of insulin resistance.
Type 1 diabetes mellitus
Type 2 diabetes mellitus
Taken together, these data support the concept of increased arterial stiffness in the metabolic syndrome, which may explain, at least in part, the increased cardiovascular risk in these individuals, and emphasise the importance of primary prevention. It is important to stress that the association between (traits of) the metabolic syndrome and arterial stiffness is not only related to higher blood pressure; in addition to (and independently of) blood pressure, (central) obesity and increased fasting glucose levels were the traits consistently associated with arterial stiffness, whereas dyslipidaemia was less so. These are the three traits that are most often observed in combination, and this clustering is associated with the greatest mortality risk . Analyses of the metabolic syndrome traits and their clustering expressed as a continuous score and the close examination of each trait (and/or combination of traits) in relation to increased arterial stiffness may therefore be a more appropriate approach in aetiological studies (for an example, see ).
The role of insulin resistance
Unresolved issues in diabetes- and metabolic syndrome-related arterial stiffening
Preferential stiffening of peripheral over central arteries?
One important issue is whether the association between diabetes (or the metabolic syndrome) and arterial stiffening differs between central and peripheral arteries. This question has been raised by the conflicting results published by the relatively few studies examining arterial stiffness in several arterial territories within the same individual. Discrepancies detected may be due to the use of different methods (i.e. regionally or locally) in the assessment of estimates of arterial stiffness and/or the different histological features (i.e. the elastin to collagen ratio that decreases from proximal to distal sites) of the arterial tree, which may have different susceptibilities to risk factors.
Studies in which regional stiffness estimates have been compared in different arterial segments have shown diabetes or the metabolic syndrome to preferentially affect the central rather than the peripheral part of the arterial tree [43, 50, 73] or to have a similar impact on the stiffness of central and peripheral segments [47, 51, 84]. In contrast, in studies where stiffness estimates have been assessed locally at different (mainly peripheral) arterial sites, the deleterious effects of diabetes or the metabolic syndrome were stronger at the more muscular (i.e. radial, brachial and femoral) rather than the more elastic (i.e. the carotid) arteries [17, 42, 48, 70, 90]. However, preferential stiffness of elastic over muscular arteries has also been shown [21, 97]. Because most of the studies reviewed herein have investigated one particular vascular territory only (see ESM Tables 1, 2, 3), no consistent picture has as yet emerged with regard to preferential central or peripheral stiffening in either diabetes or the metabolic syndrome, which hampers pathophysiological interpretation of these data. Preferential stiffness of peripheral arterial segments or sites would suggest that the cushioning function of the central circulatory system would be relatively preserved over the peripheral conduit function, which would facilitate cardiac stroke volume expulsion into a circulatory system that increasingly stiffens with age.
Central vs peripheral stiffness as cardiovascular risk factor
Studies demonstrating the prognostic value of arterial stiffness in the prediction of cardiovascular events have been almost all confined to estimates of stiffness of elastic arterial segments or sites (i.e. aortic pulse wave velocity and carotid distensibility) . Whether stiffness of muscular segments or sites has the same predictive value is largely unknown. So far, this has been investigated in one study only, where central but not peripheral arterial stiffness was an independent predictor of death in a cohort of haemodialysis patients . Similarly, a recent study showed that central rather than peripheral arterial stiffness was elevated in type 2 diabetes patients with ischaemic heart disease ; however, its cross-sectional design does not allow the conclusion of a greater prognostic value of central over peripheral stiffness in the diabetic population. Nevertheless, peripheral arterial stiffness may be clinically relevant as it has been shown to be closely associated with prevalent peripheral vascular disease [100, 101], which is a clinically important outcome in the (pre-)diabetic population. Additional studies to clarify these issues are needed.
The impact of sex
The pathobiology of increased arterial stiffness in diabetes and the metabolic syndrome
Increased arterial stiffness is primarily determined by the properties of the extracellular matrix (elastin, collagen) and vascular smooth muscular cell function [107, 108]. These variables are strongly affected by aging and blood pressure, which cause repetitive pulsatile stress upon the arterial wall, leading to both structural and functional disruption of the arterial pressure load-bearing elastin–collagen network within the media (e.g. fracturing of elastin fibres resulting from mechanical fatigue and altered pressure-dependent recruitment of [excessive] collagen fibres) . How arterial stiffness is increased in diabetes and the metabolic syndrome is largely unknown [11, 34, 108, 109]. One of the main mechanisms thought to be involved, particularly in diabetic individuals, is the formation of advanced glycation end-products (AGEs) on the arterial wall, causing cross-linking of collagen molecules, which may lead to loss of collagen elasticity and a subsequent increase in arterial stiffness . Indeed, AGEs have been associated with greater stiffness in diabetic patients [111, 112], and cross-link breakers have been demonstrated to decrease arterial stiffness in humans . Chronic hyperglycaemia and hyperinsulinaemia also increase the local activity of the renin–angiotensin–aldosterone system and expression of angiotensin type I receptor in vascular tissue, promoting development of wall hypertrophy and fibrosis . In addition, low-grade inflammation and endothelial dysfunction, which are inter-related, may also explain, at least in part, the increases in arterial stiffness related to diabetes and the metabolic syndrome [75, 84, 114]. Indeed, low-grade inflammation and endothelial dysfunction are common in diabetes and the metabolic syndrome [34, 35, 109] and partially explain the increased cardiovascular risk in these conditions [115, 116]. Endothelial dysfunction may lead to functional stiffening of large arteries as the reduced availability of nitric oxide and increased activity of vasoconstrictors such as endothelin-1 affect vascular smooth muscle cell tone [117, 118, 119]. In addition, endothelial dysfunction may lead to smooth muscle cell proliferation and increased synthesis of structural proteins such as collagen. Low-grade inflammation impairs endothelial function, which may therefore result in increased arterial stiffness . However, prospective data to test the mediating role of endothelial dysfunction and/or inflammation on the metabolic syndrome and diabetes-related arterial stiffening are still lacking.
At present the most powerful therapy to reduce arterial stiffness is vigorous treatment of hypertension with pharmacological agents. Indeed, many, but not all, of the current pharmacological strategies reduce arterial stiffness, but this is an indirect effect resulting from lowering of mean arterial pressure (for review see ). In fact, because anti-hypertensive drugs were primarily designed to reduce peripheral resistance, they may not alter the pathological process of arterial stiffening itself or electively reduce systolic blood pressure. This may explain why isolated systolic hypertension is so often resistant to pharmacological intervention. Whether some anti-hypertensives are more effective than others in this respect constitutes a current important area of investigation (cf. the Conduit Artery Function Evaluation [CAFÉ] study  and Regression of Arterial Stiffness in a Controlled Double-Blind Study [REASON] ). In addition, new strategies to reduce arterial stiffness [e.g. so-called AGE breakers such as Alagebrium (ALT 711)] are in development and are likely to be especially relevant to individuals with diabetes . These pharmacological agents break down established AGE cross-links between proteins within the arterial wall, thereby reducing arterial stiffness , but more evidence is necessary to establish the clinical relevance of such drugs. Alternative strategies to reduce arterial stiffness may involve enhancing NO release from endothelial cells (e.g. by the use of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors), and/or changes in lifestyle patterns with the aim of increasing dietary intake of n-3 fatty acids and decreasing salt intake, increasing aerobic physical activity levels, and reducing body fatness [108, 125]. None of these strategies, however, has unequivocally been shown to reduce arterial stiffness in diabetes or the metabolic syndrome, and more study of these issues is needed.
There is convincing evidence that diabetes and the metabolic syndrome are associated with greater arterial stiffness. The underlying pathobiology is complex and remains to be fully elucidated. However, greater arterial stiffness may, at least in part, explain the increased cardiovascular risk in individuals with diabetes and the metabolic syndrome. For the clinician, it is important to realise that greater brachial pulse pressure, particularly in middle-aged and older individuals but even in relatively young type 1 diabetic individuals, is a marker of greater arterial stiffening and thus a marker of greater cardiovascular risk. However, whether other estimates of arterial stiffness (e.g. aortic pulse wave velocity) can improve risk stratification in diabetes or the metabolic syndrome remains to be shown.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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