Aortic and large artery stiffening, hallmarks of vascular aging, 1 are predictive of cardiovascular events, particularly in subjects with hypertension and components of the metabolic syndrome. 2, 3 One hypothesis is that stiffening is a consequence of the combined insult of risk factors on the vascular wall. 3 However, cross-sectional studies show little association of arterial stiffness with conventional risk factors other than blood pressure. 4 The interrelationship of arterial stiffness with blood pressure makes it fascinating for the hypertensionologist. An elevation in mean arterial pressure stretches the arterial wall, leading to a functional increase in stiffness. Stiffening associated with a chronic elevation of blood pressure (ie, hypertension) may be because of distention of the arterial wall but could also be explained by structural changes of the arterial wall. The degree to which the latter explains hypertension-associated stiffening is still disputed. 5 Finally, the effect of increased stiffening is to increase pulse pressure and systolic blood pressure. Disentangling these interrelationships is challenging, and the causal link between blood pressure and arterial stiffness has not been elucidated. Longitudinal studies that provide insight into the role of blood pressure and novel risk factors on arterial stiffening are, thus, particularly useful. In this issue of Hypertension, McEniery et al6 present an analysis of prospective risk factors for aortic stiffness in men from the Caerphilly Prospective Study. In a cohort of 825 men of mean age 74 years, aortic pulse wave velocity (PWV), regarded by many as the gold-standard measure of arterial stiffness, was measured during the most recent follow-up phase of the Caerphilly Prospective Study. The relationship of PWV to blood pressure and risk factors at the time of its measurement and over an average follow-up of 20 years was examined. PWV (adjusted for “current risk factors”) was closely correlated with the pulse pressureheart rate product over the 20-year follow-up. There was also a highly significant correlation of PWV with baseline and subsequent measures of C-reactive protein. Aside from weak correlations with blood glucose, triglycerides, and waist diameter, PWV was not correlated with any other risk factor. A limitation of the study, which the authors were keen to point out, is that they did not have longitudinal measures of PWV. Thus the association of PWV with longitudinal measures of pulse pressure could be explained by pulse pressure acting as a surrogate for PWV. Similarly, the contribution of heart rate could be explained in part by the functional increase in PWV that accompanies an acute elevation in heart rate and that is probably attributable to visco-elastic properties of the arterial wall. Nonetheless, the finding of a relationship between PWV and repetitive cyclic stress is appealing, because such stress is thought to result in stress fracturing of elastin and consequent stiffening. 1

How does the other major finding of this study, the association of PWV with CRP, fit with our understanding of the pathophysiology of arterial stiffening? CRP is a recognized biomarker of atherosclerosis. Could atherosclerosis cause arterial stiffening? Lack of association of PWV with conventional risk factors for atherosclerosis in this and other studies makes this seem unlikely. Furthermore, in animal studies, atherosclerosis, at least in its early stages, is not associated with increased stiffness. An alternative possibility is that inflammation is directly or indirectly related to increased aortic stiffness through mechanisms that are, at least in part, distinct from atherosclerosis. Vascular calcification is a process thought to be driven by inflammation. Animal models …