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Fig. 2. Population of subjects with PAD: double-blind study evaluating the effect of the converting enzyme inhibitor ramipril vs. placebo. Change in brachial and central SBP (upper panel) and systemic arterial compliance (SAC lower left) and central pulse wave velocity (PWVc, lower right) in the placebo (white bars) and ramipril groups (black bars). The two populations had the same MAP [41]. Data are presented as mean ± SEM. * p < 0.001 compared with control.

vascular resistance is observed [38]. Similar effects on SBP reduction have been observed in elderly subjects with isolated systolic hypertension, and confirm that nitrate compounds improve arterial stiffness in such patients in conjunction with delayed wave reflections [13, 24].

Several lines of evidence suggest that the autonomic nervous system is affected in patients with PAD. A slight but significant decrease in baseline heart rate has been reported [8, 9, 21]. Since age or previous treatment could not explain this relative bradycardia, two possible mechanisms have been explored: an alteration in the intrinsic pacing function of the heart and a baroreflex-me-diated mechanism related to the increased arterial stiffness. To test this latter hypothesis, baroreflex mechanisms were evaluated according to the method of Smyth et al. [39]. The curve relating SBP to the RR interval of EKG after phen-ylephrine was clearly reset, so that a higher stretch was required in patients with PAD to obtain the same heart rate as in controls [21]. Furthermore, the expected enhancement of baroreflex sensitivity usually observed in normal subjects following administration of cardiotonic substances [40] was not observed in patients with PAD [21]. This latter result suggests a complex disturbance of baroreflex mechanisms involving sodium pumps. Finally, acute administration of propranolol in patients with PAD showed that the abnormalities of the autonomic nervous system affected not only the heart but also blood vessels [ 8]. Indeed, following propranolol administration, arterial stiffness was significantly increased despite the lack of BP change. On the opposite, in subjects with PAD, converting enzyme inhibition reduces arterial stiffness and delays wave reflections independently of MAP [41] (fig. 2).

The alterations of the autonomic nervous system in patients with PAD are difficult to interpret. They may be involved in the development of the overall atherosclerotic process, or take place within the context of disease of the lower limbs. In a previous study in patients with PAD and unilateral intermittent claudication, Lorensten [42] observed that both systemic SBP and DBP increased to significantly higher levels during exercise with the diseased limb than during exercise with the healthy limb. Furthermore, after the first minutes of recovery following exercise, the systemic SBP (but not the DBP) in the diseased limb stayed higher than the pressure measured at rest immediately before exercise. Such results suggested that active contraction of muscle cells under ischemic conditions might cause stimulation of local receptors involving generalized circulatory pressor reflexes, with a predominant influence on SBP [43].

Relevance of Systolic Hypertension and Systemic Hemodynamics for the Interpretation of Intermittent Claudication

The hemodynamic changes of the diseased lower limbs of patients with PAD are usually analyzed in terms of a linear mathematical model resulting from the association of two major resistances coupled in series (the stenotic and the arteriolar resistances), rather than predominantly in terms of the downstream arteriolar resistance as it is normally the case [44]. Under these conditions, mean blood flow is determined by the driving pressure across these two resistances, the mean systemic BP being an important component. However, studies of human atherosclerotic femoral arteries have shown that non-linear models are more relevant to describe the hemodynamic changes. In that condition, vascular impedance is a more reliable index of the severity of large vessel atherosclerotic stenosis than is resistance [45]. Therefore, the oscillatory component of blood flow and BP is important to consider with regard to the mechanisms of the disease of the lower limbs. In clinical studies, both MAP and PP should be considered separately in evaluating the role of systemic hemodynamics in the severity of intermittent claudication.

Under resting conditions, calf blood flow is known to remain within the normal range in patients with PAD [46, 47]. Furthermore, calf blood flow is positively correlated with BP in patients with PAD, but not in normal subjects [10]. The results suggest that systemic BP in patients with PAD contributes to maintain an adequate perfusion of the lower limbs. Interestingly, in such patients, baseline calf blood flow is positively correlated with both systemic MAP and PP [10]. Despite the interest of hemodynamic determinations at rest, it is clear that the limiting influence of the PAD disease will occur rather at elevated flow rates, i.e. during exercise and post-occlusive reactive hyperemia. Indeed the pressure drop caused by the stenosis increases with increasing flow [45-48]. Under such conditions, it is interesting to observe that walking distance and post-occlusive reactive hyperemia are strongly correlated with baseline PP, and not with baseline MAP: the higher the PP, the greater the reduction in walking distance and the greater the alteration in vascular reserve, as evaluated from post-occlusive reactive hyperemia [10]. Such results emphasize the role of the oscillatory component of BP (i.e. PP) in the mechanism of the intermittent claudication. In that regard, it is important to note that exercise in man produces not only arteriolar vasodilatation, but also increase in PWV and arterial stiffness [49]. This observation is important to consider in patients with increased baseline arterial stiffness, as those with PAD, and suggests that stiffness abnormalities may play a major role in the severity of intermittent claudication.

Concluding Remarks

For the study of contribution of PAD in CV risk, several previous reports have drawn attention to the strong association between PAD and stenosis of the internal carotid artery, PAD and coronary heart disease [50]. Given such associations, the value of the symptomatic expression of PAD, intermittent claudication, as a predictive factor of CV mortality has been widely investigated. It has been suggested that claudication is not an independent marker of mortality, once adjustments have been made for other risk factors, and mainly signs and symptoms of coexisting coronary heart disease [51]. On the other hand, more recent studies using highly reliable non-invasive hemodynamic tests of large vessel disease have indicated a more than fourfold excess risk of subjects with PAD, independent of other CV risk factors or disease [52]. In our opinion, discrepancies in assessment of the validity of intermittent claudication as a CV risk factor may be better understood in the light of the pathophysiological mechanisms of PAD as described in this chapter. Indeed, SBP and PP are the most important CV risk factor in individuals of around 50 years of age [53]. and increased SBP is also an important feature in patients with PAD, in whom it plays a significant part in the systemic hemodynamic modifications.

Accepting the hemodynamic changes observed in patients with PAD, the possible links between PAD and mortality due to coronary heart disease may be better understood. As far as the cardiac muscle is concerned, it is known that the metabolic needs of the left ventricle are greatly influenced by the level of SBP, and therefore by the increase in systemic arterial stiffness and the modification of the timing and amplitude of reflected waves initiated and/or favored by PAD [12, 23]. On the other hand, the coronary circulation is primarily dependent on mean DBP, due to the predominant diastolic perfusion of coronary arteries [12]. Since DBP tends to be reduced in patients with PAD, the supply/demand ratio may be altered under various circumstances, such as the development of cardiac hypertrophy, or exercise, or both. For these reasons alone, the alterations of systemic hemodynamics which characterize patients with PAD (i.e. increase SBP and decrease in DBP due to increased arterial stiffness) may by themselves be detrimental to the heart. Clearly, these are important fields for further clinical research in patients with PAD and atherosclerotic disease.

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Prof. Michel Safar

Centre de Diagnostic, Hôtel-Dieu, 1, place du Parvis Notre-Dame FR-75181 Paris Cedex 04 (France) Tel. +33 1 4234 8025, Fax +33 1 4234 8632 E-Mail [email protected]

Section III - Arterial Stiffness, Atherosclerosis and Cardiovascular Risk Factors

Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 212-222

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