Bronwyn A. Kingwell Anna A. Ahimastos Baker Heart Research Institute, Melbourne, Australia
Large artery stiffening may be both a cause and a consequence of atherosclerosis and is independently related to coronary outcome. This relationship is likely to be causal given the unfavourable effect of large artery stiffening on coronary hemodynamics. There is clear experimental and clinical evidence that large artery stiffening promotes myocar-dial ischemia secondary to central pulse pressure elevation. Many agents commonly used to treat ischemic heart disease symptoms also reduce large artery stiffness, through both functional and structural mechanisms. Such effects likely contribute to the anti-ischemic actions of these drugs. However, it remains to be elucidated whether agents specifically targeted to reduce large artery stiffness provide ischemic protection in the setting of coronary disease.
Copyright © 2007 S. Karger AG, Basel
Stiff large arteries are associated with coronary artery disease [1-7], myocardial ischemia [8, 9] and coronary mortality . The inter-relationships between large artery stiffness and coronary artery disease are not straightforward and are likely bidirectional (fig. 1). That is, arterial stiffness may be both a cause and a consequence of atherosclerosis. However, regardless of mechanism, it is clear that large artery stiffening exacerbates the ischemic symptoms of coronary disease  (fig. 1). The relationship between arterial stiffness and death from coronary artery disease is thus likely to be causal. This chapter will
discuss the mechanisms linking large artery stiffness and coronary artery disease. It will further examine the consequences for symptoms and outcome. The effect on arterial stiffness of conventional therapies for treatment of coronary disease symptoms will be discussed with regard to mechanisms of benefit. Finally, the therapeutic potential of therapies specifically targeting the large arteries will be discussed with regard to ischemic coronary disease.
Arterial Stiffness as a Risk Factor for Ischemic Heart Disease
Strong relationships between pulse pressure and coronary outcomes provided some of the first definitive evidence that large artery stiffness may be a risk factor for coronary disease [11-13]. In 2002, Boutouyrie et al.  published the first study directly relating a measure of large artery stiffness (pulse wave velocity) to coronary outcome during a 15-year follow-up in a hypertensive French cohort. Certainly, indices of arterial stiffness including pulse wave velocity are higher in patients with angiographically determined coronary disease than those without [1-7]. Several studies have also reported a positive correlation between arterial stiffness and the severity of coronary disease. Waddell et al.  showed that both systemic arterial compliance and central blood pressure were independently related to the maximum coronary stenosis determined angiographically. Similarly, both augmentation index and augmentation pressure have been associated with an increased risk of angiographically determined coronary disease . Small artery compliance also relates to diffuse, but not focal coronary disease . Interestingly, coronary disease severity and pulse pressure, which is significantly influenced by large artery stiffness, track together in post-menopausal women. In the Estrogen Replacement in Atherosclerosis trial, pulse pressure related closely to standardized measures of minimum angiographically determined coronary lumen diameter during 3.2 years' follow-up . The tight association between stiffness of the large arteries and coronary disease severity suggest that these two phenomena are closely inter-related.
Large artery stiffness may be either a marker or a cause of coronary atherosclerosis or may contribute to coronary ischemia independently of any relationship with coronary atherosclerosis. The first possibility is that atherosclerosis in the coronaries and the aorta develops in parallel, and that large artery stiffness is simply a surrogate measure of atherosclerosis in both regions . That atherosclerosis promotes arterial stiffening is certainly well established. For example in monkeys, development of aortic atherosclerosis on an atherogenic diet has been associated with elevation in pulse wave velocity . Of greater interest is the possibility that intrinsic stiffening of the large arteries independently of atherosclerosis, and perhaps related to age or genetic factors, could actually promote atherosclerosis in the coronaries. Certainly large artery stiffness has been shown to be heritable  and a number of genes regulating arterial structure have been associated with arterial stiffness in various contexts [21-26]. It would be expected that individuals with intrinsically stiff large vessels would have elevated pulse pressure and that this could contribute to an unfavorable hemodynamic profile promoting atherosclerosis. In vitro studies of rabbit carotid arteries show that elevated pressure pulsatility
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