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  1. 1. Predictive value for fatal stroke of pulse wave velocity (PWV) in essential hypertensive patients [from 36].
  2. 1. Predictive value for fatal stroke of pulse wave velocity (PWV) in essential hypertensive patients [from 36].

Brachial pulse pressure (instead of carotid pulse pressure) is used for the calculation of all these parameters and this may reduce their precision. Despite this limitation, all these parameters are well accepted as indices of arterial stiffness [35].

Cross-sectional studies have shown a significant correlation between arterial stiffness and CV risk factors for atherosclerotic lesions, such as aging, hypertension, hypercholesterolemia, type 2 diabetes mellitus or glucose intolerance, metabolic syndrome, and several inflammation parameters, suggesting that arterial stiffness may be considered a marker of CV risk [3].

In addition, longitudinal studies have evaluated the incidence of cardiovascular events, including stroke, during follow-up, and have demonstrated the predictive value of arterial stiffness as an intermediate endpoint.

Longitudinal Studies

Longitudinal studies directly demonstrated that arterial stiffness, measured through carotid-femoral PWV, was an independent predictor of stroke [36] in patients with uncomplicated essential hypertension. In a population of 1,715 essential hypertensive patients, Laurent et al. [36] have found that after a mean follow-up of 7.9 years, for each SD increase in PWV (4 m/s) the relative risk for fatal stroke increased by 1.72 (95% CI 1.48-1.96; p > 0.0001). The predictive value of PWV remained significant (RR = 1.39; 95% CI 1.08-1.72; p > 0.02) after full adjustment for classic cardiovascular risk factors, including age, cholesterol, diabetes, smoking, mean arterial pressure, and pulse pressure (fig. 1).

Additional evidence of the predictive value of aortic stiffness was provided in patients with end-stage renal disease, although cardiovascular events, i.e. stroke or coronary disease, were not analyzed separately [37].

I n 2,488 older subjects participating into the Health, Aging and Body Composition (Health ABC) study [38], aortic PWV was measured at baseline and during the follow-up (over 4.6 years) and 94 stroke events were recorded. The higher quartiles of aortic PWV were significantly associated with an increased risk of stroke, and the association remained statistically significant also after adjustment for age, gender, race, systolic blood pressure, known CV disease, and other variables related to events.

In summary, a significant association between the increase in aortic stiffness and the incidence of cerebrovascular (and cardiovascular) events has been demonstrated, independently from other traditional risk factors. In patients with end-stage renal disease it has also been reported that the lack of decrease in PWV during antihypertensive treatment was associated with a higher cardiovascular mortality, while the improvement of PWV was associated with a lower incidence of cardiovascular events [39].

In addition to aortic stiffness, it may be also important to assess the prognostic significance of carotid stiffness. In stiff carotid arteries the local pulse pressure is increased, and this may influence structural and functional changes of intracranial vessels. Higher local pulse pressure may increase the carotid wall thickness and favor the development of plaques and stenosis, as well as the rupture of unstable plaque.

In patients with end-stage renal disease and with kidney transplantation [38, 40], but not in patients at elevated cardiovascular risk [41], carotid stiffness had a high predictive power for future cardiovascular fatal events, and for ischemic stroke as well.

The pathophysiological mechanisms relating aortic and carotid stiffness to stroke include the association with similar risk factors [42], and the alterations in the vascular wall of aorta that may reflect those in cerebral vessels; in addition, both the carotid arteries and the aorta may be exposed to other pathological mechanisms, such as thrombosis and inflammation [43].

Future trials should provide measurements of both aortic and carotid stiffness in low or moderate CV risk populations, in order to better evaluate their relative prognostic value for cerebrovascular and coronary events.

Effect of Drug Treatment

It is conceivable that the reduction of arterial stiffness may become a therapeutic goal in treating patients at high risk of CV complications [44, 45]. In this regard, an important issue is represented by the ability of different drugs to prevent cardiovascular events by improving arterial distensibility, even independently of the effect on other risk factors.

Organic nitrates, and in particular nitroglycerin, reduce systolic blood pressure, pulse pressure and augmentation index, but have a small effect on peripheral arterial resistance, or on aortic PWV. In fact, organic nitrates may improve symptoms, without modifying mortality or cardiovascular events.

It is generally accepted that ACE inhibitors, calcium antagonists and diuretics may similarly affect large artery stiffness in hypertensive patients, while P-blockers are less effective in this regard [46]. ^-Blockers do not reduce central arterial waveform reflection amplitude, while a reduction of the augmentation index has been documented during treatment with P- and a-block-ers. The effect of drugs that interfere with the renin-angiotensin system (ACE inhibitors, aldosterone antagonists and angiotensin II antagonists) seems to be, at least in part, independent of blood pressure reduction, since they modify the composition of the vascular wall, including the spatial arrangement of wall material and the collagen content [46-51].

The augmentation index can be reduced by vasodilating drugs and by an-giotensin-converting enzyme (ACE) inhibitors in both essential hypertensive patients and in patients with end-stage renal failure. The low-dose combination of the ACE inhibitor perindopril and the diuretic indapamide, in comparison with atenolol, induced a more pronounced effect on central arterial pressure and was associated to a greater decrease in LV mass [50].

The observed effect of ACE inhibitors (and possibly of angiotensin II antagonists) is to some degree influenced by genetic factors [52, 53], since ACE ID and A1166C angiotensin II type 1 receptor polymorphisms are related to carotid-femoral PWV, while M235T angiotensinogen gene and ACE ID polymorphisms are related to carotid stiffness.

In patients with familiar hypercholesterolemia, pravastatin was able to improve arterial stiffness after 13 months of treatment [54], while atorvastatin had no significant effect on carotid stiffness. In non-familiar hypercholester-olemia, short-term treatment with simvastatin did not change aorto-femoral PWV.

In addition, treatment for 2 months with a new compound, that acts as an advanced glycation product cross-link breaker, has been beneficial in ameliorating PWV [55].


Carotid atherosclerosis and arterial stiffness are both related to risk factors associated with the occurrence of stroke. These two markers of 'preclinical' vascular disease are related to the occurrence of stroke independently of other cardiovascular risk factors. Assessment of IMT or of measures of large arteries compliance may therefore identify patients at increased risk for stroke.

Interventional studies have demonstrated that treatment with statins, calcium antagonists, ACE inhibitors, and insulin sensitizers may be particularly effective on slowing the progression or favoring the regression of atherosclerotic changes, and may reduce large artery stiffness. It remains to be demonstrated in large prospective studies whether the regression of increased arterial stiffness or of carotid IMT and plaque have a prognostic significance, i.e. are associated with a reduction of the risk of cerebrovascular events.


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Prof. Enrico Agabiti-Rosei, Chair of Internal Medicine

Department of Medical and Surgical Sciences, University of Brescia c/o 2a Medicina Spedali Civili di Brescia, Piazza Spedali Civili 1, IT-25100 Brescia (Italy)

Tel. +39 030 396 044, Fax +39 030 338 8147, E-Mail [email protected]

Section II - Arterial Stiffness, Atherosclerosis and End-Organ Damage

Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 187-198

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