Mechanisms Linking Stiffness and Cholesterol

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A number of potential mechanisms may explain the link between serum lipids and arterial stiffness. As already noted, one of the more obvious is the development of atherosclerotic plaques. Atherosclerosis in the coronary arteries, and at other sites, has been consistently associated with increased arterial stiffness (see Section II). This has led some to suggest that stiffening of the large arteries is simply a measure of the amount or degree of atherosclerosis.

However, arterial stiffening occurs in populations with a low prevalence of atherosclerosis, and also affects vessels such as the brachial artery which are not normally a site of plaque development.

Cholesterol and oxidized LDL cholesterol, in particular, have a number of direct, non-atheromatous, effects on the arterial wall, which may lead to arterial stiffening. Oxidized LDL cholesterol also leads to peroxynitrite formation and a generalized state of increased oxidative stress, both of which can damage elastin directly [37, 38], Oxidized LDL cholesterol is also pro-inflammatory. Several groups, including our own, have recently shown an association between measures of acute inflammation, such as C-reactive protein and arterial stiffness in otherwise healthy individuals [39, 40], Moreover, Pirro et al. recently found a significant, positive relationship between aortic pulse wave velocity and C-reactive protein in subjects with hypercholesterolaemia. Interestingly, when both C-reactive protein and HDL cholesterol were entered into a multivariate model, only C-reactive protein remained an independent predictor of aortic stiffness.

Systemic and local inflammation may lead to arterial stiffening by a variety of different mechanisms. Cytokines lead to increased expression of a number of inducible enzymes that may damage the structural components of the arterial wall. One enzyme of particular interest is matrix metalloproteinase-9 (MMP-9), which is a gelatinase capable of digesting arterial elastin - the main 'elastic element' of the large arteries. We have recently demonstrated a positive relationship between serum MMP-9 levels and aortic pulse wave velocity in a large cohort of apparently healthy subjects [41]. A pro-inflammatory environment also leads to an influx of inflammatory cells into the arterial wall. This in itself may lead to arterial stiffening possibly due to changes in the ground substance, secretion of destructive enzymes such as MMP-9 and remodelling of the wall. An interesting novel hypothesis is that inflammation, and inflammatory lipids in particular, may promote deposition of calcium within the arterial wall [42], In animal models, arterial calcification leads to stiffening of the arterial wall [43], and in humans with end-stage renal failure excessive calcification is associated with aortic stiffening and increased mortality [44, 45].

It is unlikely that structural changes in the arterial wall are solely responsible for the relationship between stiffness and cholesterol. As already noted, a fatty meal is associated with an acute increase in arterial stiffness, and statin therapy can lead to a reduction in stiffness with a matter of weeks. These observations suggest that lipid abnormalities may lead to functional arterial stiffening.

Endothelial Function

Mounting evidence suggests that there is a degree of functional regulation of stiffness by the vascular endothelium [46-48]. We and others have recently demonstrated that endothelium-derived nitric oxide, in part, regulates the stiffness of the large arteries [47]. Inhibiting endogenous nitric oxide production leads to arterial stiffening [49, 50].

Hypercholesterolaemia is strongly associated with endothelial dysfunction and reduced nitric oxide bioavailability [51, 52]. Indeed, acute elevation of plasma lipids, achieved by either a fatty meal [53] or intravenous infusion [54], leads to a rapid onset of endothelial dysfunction, which can be equally rapidly corrected by interventions such as plasmapheresis [55]. Hypercholesterolaemia may impair the L-arginine/nitric oxide pathway at a number of sites. Endothelial damage may lead to a decrease in either basal or stimulated release of nitric oxide or, alternatively, there may be an increased breakdown of nitric oxide. The vascular smooth muscle may also exhibit a decreased sensitivity to the actions of nitric oxide. Finally, the buildup of endogenous inhibitors of nitric oxide synthase, such as asymmetric dimethyl arginine (ADMA), may decrease the biological activity of the endothelial isoform of nitric oxide synthase (eNOS) and hence the production of nitric oxide.

Oxidized LDL cholesterol is the major molecule mediating both atherosclerosis and endothelial dysfunction [56]. Indeed, oxidized LDL cholesterol impairs endothelial function to a greater extent than native LDL cholesterol

[57]. Furthermore, oxidized LDL cholesterol downregulates eNOS expression

[58], and reduces the uptake of L-arginine into endothelial cells [59], both of which lead to decreased nitric oxide production. In addition, LDL cholesterol has recently been shown to increase the synthesis of ADMA [60].

Interestingly, many of the above deleterious effects of LDL cholesterol can be reversed by statins, providing a potential explanation for the beneficial effects of these agents on both endothelial function and arterial stiffness. In addition to decreased nitric oxide production, abnormal vascular function may also be caused by overproduction of constrictors such as endothelin-1 which, in contrast to nitric oxide, is an atherogenic molecule. LDL cholesterol increases production of endothelin-1 [61], an effect that can also be inhibited by statins [62]. We have also recently demonstrated that endothelin-1 is involved in the functional regulation of large artery stiffness [63], providing yet another link between stiffness and hypercholesterolaemia, and one further explanation for the beneficial effects of cholesterol reduction on arterial stiffness. Other agents with therapeutic potential in hypercholesterolaemia include angiotensin-con-verting enzyme (ACE) inhibitors. These drugs increase the bioavailability of nitric oxide, possibly via increasing circulating levels of bradykinin, upregulat-ing expression of eNOS or decreasing superoxide production. ACE inhibitors improve endothelial function in patients with hypercholesterolaemia, independently of cholesterol reduction [64]. Although ACE inhibition has been shown to decrease arterial stiffness in other disease states, as yet, its effect on arterial stiffness in patients with hypercholesterolaemia has not been studied.

To summarize: The majority of the available evidence suggests a positive relationship between plasma cholesterol and the stiffness of the large arteries. Lipid-lowering agents appear to significantly reduce arterial stiffness. However, a number of important questions remain unanswered. It is unclear which of various lipid subfractions best correlate with arterial stiffness, and the strength, or indeed, pathophysiological importance of any independent associations. It is important to remember that associations, even if independent, do not necessarily imply causality. Stiffening may reflect atherosclerosis rather than a direct effect of cholesterol on the mechanical properties of the large arteries themselves. Likewise, it is unclear whether the beneficial effect of statins results from lipid-lowering per se, or the much talked about pleiotropic effect of this drug class. Greater evidence of causality is likely to come from studying much larger cohorts of younger subjects - free for the confounding effects of atherosclerosis, and other cardiovascular risk factors - and examining the longitudinal relationship between different lipid fractions and arterial stiffening. Longitudinal studies also need to be undertaken in populations with different prevalences of atherosclerosis and average cholesterol levels. Finally, carefully designed studies are required to separate the cholesterol-lowering effect of statins from their potential pleiotropic effects on large arteries.

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