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.

Atherosclerotic Diseases

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 [27]. 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 [28] whereas it was consistently shown that antihypertensive drug therapy prevented 40% of strokes both in patients with isolated systolic hypertension and systolic-diastolic hypertension.

Pathophysiological Aspects

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.

Endothelial Dysfunction

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 [29]. 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 [30] 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 [31], 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 [32] 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.

Development of Atheroma

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

Pulse Pressure

Population-based studies have shown that the C-reactive protein (CRP) level correlates with pulse pressure and predicts the development of hypertension [33]. 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 [34].

Cardiovascular Risk Factors

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 [35]. 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.


1 Newman WP 3rd, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, Williamson GD, Webber LS, Berenson GS: Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The Bogalusa Heart Study. N Engl J Med 1986;314:138-144.

2 Reaven GM, Lithell H, Landsberg L: Hypertension and associated metabolic abnormalities - the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-381.

3 Safar ME, London GM, Asmar R, Frohlich ED: Recent advances on large arteries in hypertension. Hypertension 1998;32:156-161.

4 Cameron JD, Jennings GL, Dart AM: The relationship between arterial compliance, age, blood pressure and serum lipid levels. J Hypertens 1995;13:1718-1723.

5 Dart AM, Lacombe F, Yeoh JK, Cameron JD, Jennings GL, Laufer E, Esmore DS: Aortic disten-sibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant. Lancet 1991;338:270-273.

6 Tanaka H, DeSouza CA, Seals DR: Absence of age-related increase in central arterial stiffness in physically active women. Arterioscler Thromb Vasc Biol 1998; 18:127-132.

7 Giral P, Atger V, Amar J, Cambillau M, Del Pino M, Megnien JL, Levenson J, Moatti N, Simon A: A relationship between aortic stiffness and serum HDL3 cholesterol concentrations in hyper-cholesterolaemic, symptom-free men. The PCVMETRA Group (Groupe de Prévention Cardio-vasculaire en Médecine du Travail). J Cardiovasc Risk 1994;1:53-58.

8 Dart AM, Gatzka CD, Cameron JD, Kingwell BA, Liang YL, Berry KL, Reid CM, Jennings GL: Large artery stiffness is not related to plasma cholesterol in older subjects with hypertension. Arterioscler Thromb Vasc Biol 2004;24:962-968.

9 Marques-Vidal P, Amar J, Cambou JP, Chamontin B: Relationships between blood pressure components, lipids and lipoproteins in normotensive men. J Hum Hypertens 1996;10:239-244.

10 Darne B, Girerd X, Safar M, Cambien F, Guize L: Pulsatile versus steady component of blood pressure: a cross-sectional analysis and a prospective analysis on cardiovascular mortality. Hypertension 1989;13:392-400.

11 Madhavan S, Ooi WL, Cohen H, Alderman MH: Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994;23:395-401.

12 Dyer AR, Stamler J, Shekelle RB, Schoenberger JA, Stamler R, Shekelle S, Berkson DM, Paul O, Lepper MH, Lindberg HA: Pulse pressure. I. Level and associated factors in four Chicago epidemiologic studies. J Chronic Dis 1982;35:259-273.

13 Ferrier KE, Muhlmann MH, Baguet JP, Cameron JD, Jennings GL, Dart AM, Kingwell BA: Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol 2002;39:1020-1025.

14 Matthews PG, Wahlqvist ML, Marks SJ, Myers KA, Hodgson JM: Improvement in arterial stiffness during hypolipidaemic therapy is offset by weight gain. Int J Obes Relat Metab Disord 1993; 17:579-583.

15 O'Callaghan CJ, Krum H, Conway EL, Lam W, Skiba MA, Howes LG, Louis WJ: Short-term effects of pravastatin on blood pressure in hypercholesterolaemic hypertensive patients. Blood Press 1994;3:404-406.

16 Foss OP, Graff-Iversen S, Istad H, Soyland E, Tjeldflaat L, Graving B: Treatment of hypertensive and hypercholesterolaemic patients in general practice: The effect of captopril, atenolol and pravastatin combined with lifestyle intervention. Scand J Prim Health Care 1999;17:122-127.

17 Sposito AC, Mansur AP, Coelho OR, Nicolau JC, Ramires JA: Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercho-lesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril). Am J Cardiol 1999;83:1497-1499, A8.

18 Benetos A, Topouchian J, Ricard S, Gautier S, Bonnardeaux A, Asmar R, Poirier O, Soubrier F, Safar M, Cambien F: Influence of angiotensin II type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension 1995;26:44-47.

19 Schram MT, Henry RM, van Dijk RA, Kostense PJ, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Westerhof N, Stehouwer CD: Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes: the Hoorn Study. Hypertension 2004;43:176-181.

20 Amar J, Ruidavets JB, Chamontin B, Drouet L, Ferrieres J: Arterial stiffness and cardiovascular risk factors in a population-based study. J Hypertens 2001;19:381-387.

21 Schram MT, Schalkwijk CG, Bootsma AH, Fuller JH, Chaturvedi N, Stehouwer CD, EURODIAB Prospective Complications Study Group: Advanced glycation end products are associated with pulse pressure in type 1 diabetes: the EURODIAB Prospective Complications Study. Hypertension 2005;46:232-237.

22 Vlachopoulos C, Kosmopoulou F, Panagiotakos D, Ioakeimidis N, Alexopoulos N, Pitsavos C, Stefanadis C: Smoking and caffeine have a synergistic detrimental effect on aortic stiffness and wave reflections. J Am Coll Cardiol 2004;44:1911-1917.

23 Zureik M, Bureau JM, Temmar M, Adamopoulos C, Courbon D, Bean K, Touboul PJ, Benetos A, Ducimetiere P: Echogenic carotid plaques are associated with aortic arterial stiffness in subjects with subclinical carotid atherosclerosis. Hypertension 2003;41:519-527.

24 McLeod AL, Uren NG, Wilkinson IB, Webb DJ, Maxwell SR, Northridge DB, Newby DE: Noninvasive measures of pulse wave velocity correlate with coronary arterial plaque load in humans. J Hypertens 2004;22:363-368.

25 Lovett JK, Howard SC, Rothwell PM: Pulse pressure is independently associated with carotid plaque ulceration. J Hypertens 2003;21:1669-1676.

26 Witteman JC, Grobbee DE, Valkenburg HA, van Hemert AM, Stijnen T, Burger H, Hofman A: J-shaped relation between change in diastolic blood pressure and progression of aortic atherosclerosis. Lancet 1994;343:504-507.

27 Benetos A, Rudnichi A, Safar M, Guize L: Pulse pressure and cardiovascular mortality in nor-motensive and hypertensive subjects. Hypertension 1998;32:560-564.

28 SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-3326.

29 Davignon J, Ganz P: Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109(suppl 1):III27-32.

30 Moreno PR, Fuster V: New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol 2004;44:2293-2300.

31 Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P: Endothelium-de-rived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 2001;38: 1049-1053.

32 Safar M, Chamiot-Clerc P, Dagher G, Renaud JF: Pulse pressure, endothelium function, and arterial stiffness in spontaneously hypertensive rats. Hypertension 2001;38:1416-1421.

33 Abramson JL, Weintraub WS, Vaccarino V: Association between pulse pressure and C-reactive protein among apparently healthy US adults. Hypertension 2002;39:197-202.

34 Amar J, Ruidavets JB, Peyrieux JC, Mallion JM, Ferrieres J, Safar ME, Chamontin B: C-reactive protein elevation predicts pulse pressure reduction in hypertensive subjects. Hypertension 2005; 46:151-155.

35 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-1830.

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

Was this article helpful?

0 0

Post a comment