Quintiles of pulse pressure
Quintiles of systolic pressure i i u p = 0.13
Quintiles of mean arterial pressure
Quintiles of diastolic pressure
Fig. 2. Relationship between different blood pressure variables and presence of angiographic ulceration at the symptomatic carotid bifurcation [from 25].
sclerosis in a population-based cohort of 855 women. The women were examined radiographically for calcified deposits in the abdominal aorta. The age-adjusted relation risk of substantial atherosclerotic progression in women with a decrease in diastolic blood pressure of 610 mm Hg was 2.5 (95% confidence interval 1.3-3.5) compared with the reference group of women who had a smaller decrease or no change. The excess risk in this group was confined to women whose increase in pulse pressure was above the median. Therefore, this prospective study suggests that the progression of atherosclerosis is accompanied by an increase in pulse pressure.
Hypertension is a risk factor for the development of atherosclerosis. In this respect, pulse pressure is well established as an important independent predictor of cardiovascular events whereas more recently, large artery stiffness has been linked to total mortality. Of interest to note that in an observational study, brachial pulse pressure is a predictor of coronary heart disease mortality, whereas its predictive value is not significant for cerebrovascular mortality . In line with these observations, in therapeutic trials, coronary morbidity is more substantially reduced in populations of subjects with isolated systolic hypertension (i.e. in patients with high pulse pressure) than in populations involving subjects with systolic-diastolic hypertension  whereas it was consistently shown that antihypertensive drug therapy prevented 40% of strokes both in patients with isolated systolic hypertension and systolic-diastolic hypertension.
Relation between Pulse Pressure and Other Cardiovascular Risk Factors
It is unlikely that pulse pressure per se influences glucose or lipid metabolism. Conversely, there are several lines of evidence suggesting that glucose or lipid metabolism impairment results in changes in pulse pressure via changes in endothelial function and the development of atheroma. Also, the role of inflammation as a link between pulse pressure, glucose and lipid metabolisms may be evoked.
Major mechanisms by which cholesterol, glucose metabolism and smoking impairment might affect via arterial stiffness pulse pressure are through alteration in endothelial function and the development of atheroma. Many of the traditional coronary risk factors that enhance the development of athero sclerosis, such as hypercholesterolemia, hypertension, smoking, diabetes are also associated with endothelial dysfunction . The total number of risk factors in a given patient has been found to be a potent independent predictor of endothelial dysfunction as measured by the acetylcholine test.
Effects of circulating lipoproteins on endothelial function are well recognized. There is evidence that the presence of high serum LDL levels impairs endothelium-dependent vasodilation possibly reversed by short-term removal of LDL particles. Also, endothelium-derived relaxing factor is rapidly inactivated by oxidized LDL particles. Improvement in endothelium-dependent va-sodilation has been achieved with cholestyramine and LDL apheresis, implicating LDL cholesterol reduction as an important mechanism.
Several molecular mechanisms have been implicated  in hyperglyce-mia-induced endothelial damage: activation of protein kinase C isoforms via de novo synthesis of the lipid second messenger diacylglycerol, increased hex-osamine pathway flux, increased advanced glycation end product formation, increased polyol pathway flux, and activation of the proinflammatory nuclear transcription factor nuclear factor-kB. All of these mechanisms are independently associated with overproduction of superoxide by the mitochondrial electron transport chain. As a result, hyperglycemia-induced formation of reactive oxygen species may lead to endothelial dysfunction. Since endothelial function plays a key role on arterial compliance, particularly via the constitutive release of nitric oxide (NO) as shown in young healthy humans , it is likely that the deleterious influence of most cardiovascular risk factors on endothelial function may result in increasing pulse pressure. On the other hand, it has been found in spontaneously hypertensive rats  that pulse pressure changes disproportionately with age, together with an enhanced isobaric arterial stiffness. The endothelial NO response to norepinephrine is abolished in association with endothelium-dependent heightened norepinephrine reactivity and enhanced accumulation of vessel extracellular matrix. Thus, during aging in spontaneously hypertensive rats, a negative feedback may be observed between NO bioactivity and pulse pressure through changes in arterial structure.
In summary, it is likely that endothelial dysfunction associated with cardiovascular risk factors negatively influences pulse pressure via arterial stiffening and also it could be speculated that increasing pulse pressure in turn may impair endothelial function through changes in arterial structure.
Lipid or glucose metabolism impairment as well as smoking are associated with the development of atheroma. As described above, the development of atheroma results in stiffening of large arteries. Also, the development of plaques may produce reflection sites closer to the heart, as shown in the presence of calcified plaques, particularly at the site of arterial bifurcations (aorta, carotid and femoral arteries, origin of renal arteries). Both the stiffening of large arteries and the development of reflection sites closer to the heart result in increasing pulse pressure, particularly central pulse pressure.
Potential Role of Inflammation
Population-based studies have shown that the C-reactive protein (CRP) level correlates with pulse pressure and predicts the development of hypertension . Supporting a causal relationship leading from pulse pressure to CRP production, it has been reported that perindopril-indapamide combination therapy is more effective than (3-blockade in lowering elevated CRP in hypertensive subjects and that this effect is significantly associated with a more effective pulse pressure reduction .
Subclinical inflammation was associated with most of other cardiovascular risk factors. Indeed, IL-6 plays a key role in the development of the metabolic syndrome . Histologically, there is evidence of significant infiltration of macrophages into white adipose tissue and of the release of IL-6 by the adipose tissue before the development of insulin resistance. In addition, IL-6 is correlated with obesity, glucose intolerance and insulin resistance, and decreases with weight loss. In line with this result, the CRP level where the hepatic synthesis is predominantly controlled by IL-6 levels is also highly correlated with body mass index, waist-hip ratio and insulin resistance. Furthermore, many cross-sectional population-based studies have shown a positive association between CRP and current smoking.
In the light of these data, it could be suggested that pulse pressure and other major traditional risk factors may be linked through inflammation. Also, with respect to the role played by inflammation on cardiovascular events, it is possible that inflammation may contribute to the association between pulse pressure and atherosclerotic diseases.
Pulse pressure is linked with glucose metabolism, smoking and the progression of atherosclerosis. More controversial data have been reported for blood lipids. Collectively, these relations may contribute to the predictive role of pulse pressure on cardiovascular prognosis. The deleterious influence of risk factors on large artery stiffness via endothelial dysfunction and progression of atheroma and the role played by subclinical inflammation are likely to underlie these connections.
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Prof. Jacques Amar
Service de Médecine Interne et d'hypertension artérielle Hôpital Rangueil, Allées Jean Pouilhes FR- 31059 Toulouse (France)
Tel. +33 5 61 32 30 72, Fax +33 5 61 32 27 10, 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 223-233
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