Arteriosclerosis: inevitable or self-inflicted?

Over the last 20 years, aortic stiffness has emerged as an important, independent predictor of cardiovascular outcome. Recent data suggest that it may add to existing risk prediction models and improve patient stratification. However, the precise biological pathways and processes underlying aortic stiffening remain unclear. A better understanding of these is an important prerequisite for the rational design of novel antistiffening drugs, which may prove valuable in reducing cardiovascular risk, particularly in those individuals with stiff arteries. In almost all populations, aortic stiffness is positively correlated with age, and in multiple regression analyses age is invariably the dominant determinant of stiffness. Consequently, age-related aortic stiffening (arteriosclerosis) is often considered to be inevitable. The process underlying arteriosclerosis is generally believed to be fatigue fracture of elastic fibers within the arterial wall. As such, age is actually a surrogate for cycle number (ie, number of heart beats), which, together with the level of cyclic stress (pulse pressure), determines the rate of elastic fiber degeneration. To a limited extent, this view has been substantiated by animal studies, and our own recent observations in the Caerphilly Heart Study. We found that the heart rate pulse pressure product, integrated over a 20-year follow-up period, was independently correlated with current aortic pulse wave velocity (aPWV). However, this cannot be the whole story, not least because the correlation that we observed was quite modest, and several other lines of evidence strongly suggest that arteriosclerosis is more pathological than inevitable. More than 20 years ago, Avolio et al published a seminal article describing the relationship between age and aPWV in 2 different Chinese populations. They noted that individuals living in a rural province appeared to exhibit much less age-related stiffening than those in an urban setting. They speculated that differences in sodium intake may have been responsible for this effect, and to some extent the findings mirror those reported previously for blood pressure itself. Nevertheless, the observations of Avolio et al indicate that, although some degree of biological aging may be inevitable, a substantial proportion of arteriosclerosis is attributed to pathological processes (Figure 1). This may explain why the population variability in aPWV increases significantly with age. Data published in this issue of Hypertension extend the observations of Avolio et al into a completely different ethnic population. Lemogoum et al assessed aPWV in 2 groups of Cameroonian pygmies, one living a traditional hunter-gatherer existence in a rural setting and one in a more Westernized, semiurban environment. On average, aortic stiffness was 20% lower in the rural individuals but did not differ between the semiurban pygmies and other ethnically unrelated individuals in the same environment. Interestingly, wave reflection, as assessed by augmentation index, did not differ significantly among the 3 groups. Although aPWV correlated positively with age in the semiurban dwellers, there was no association in the rural cohort. However, the sample size was very modest, and much smaller than that of Avolio et al, so some degree of the age-related stiffening could not be robustly excluded. Nevertheless, the observations of Lemogoum et al do appear to substantiate those of Avolio et al, although both were cross-sectional, and longitudinal studies in indigenous populations have not been undertaken. Lemogoum et al speculate that their findings concerning aortic stiffness provide evidence that the hunter-gatherer lifestyle of the traditional pygmies is associated with a lower risk of atherosclerosis. However, they overlook the important point made by Avolio et al, that it is actually arteriosclerosis and not atherosclerosis that underlies age-related aortic stiffening. Indeed, the 2 processes are pathologically distinct and largely driven by different mechanisms (Figure 2). Moreover, the correlation between atherosclerotic load, assessed at postmortem, and in-life aPWV is very modest. More recently, Cecelja et al reported no association between aPWV and noncalcified plaque load assessed by ultrasound. Furthermore, atherosclerotic risk factors, other than blood pressure, per se, appear to play a relatively minor role in arterial stiffening, as highlighted by a recent systematic review and longitudinal observations. If arteriosclerosis is not entirely inevitable, then what might be responsible for the seeming inextricable rise in aPWV in Westernized societies? Blood pressure early on in life would seem an attractive explanation, because this would increase cyclic stress, theoretically accelerating elastic fiber degeneration. Indigenous populations are known to have lower blood pressures, in part because of lower average sodium intake. Data from the Framingham Heart Study suggest that pulse pressure, frequently regarded as a surrogate The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom. Correspondence to Ian B. Wilkinson, University of Cambridge, Clinical Pharmacology Unit, Addenbrooke’s Hospital, Cambridge CB20QQ, United Kingdom. E-mail [email protected] (Hypertension. 2012;60:3-5.) © 2012 American Heart Association, Inc.