Central Pulse Pressure and Atherosclerotic Alterations of Coronary Arteries

Nicolas Danchina Jean-Jacques Mouradb aDepartment of Cardiology, Hôpital Européen Georges Pompidou, Paris, and bDepartment oflnternal Medicine, Hôpital Avicenne, Bobigny, France

Abstract

Central pulse pressure is more likely to reflect the haemodynamic conditions to which the heart and coronary arteries are subjected than is peripheral pulse. We reviewed the data currently available on the correlations between central pulse pressure and both the presence and extent of coronary artery disease, as well as clinical outcomes. Five clinical studies have reported an association between central pulse pressure and the presence of coronary artery disease documented by coronary angiography. Four studies, including three of the previous ones, also found a correlation between central pulse pressure and the extent of coronary artery disease. In one of these studies, however, the correlation was present only in men, whereas no link was found between pulse pressure and coronary artery disease in women. After coronary angioplasty, increased central pulse pressure has been found correlated with the occurrence of restenosis after balloon angioplasty, but not after stent implantation. Finally, the ASCOT-CAFE trial found a positive correlation between pulse pressure and the occurrence of cardiovascular events, confirming the prognostic significance of this parameter.

Copyright © 2007 S. Karger AG, Basel

Although there is epidemiologic evidence of a relationship between brachial pulse pressure and cardiovascular events, including coronary events, conflicting data have also been reported [1-4]; This may be because brachial pulse pressure is likely to be a less reliable index of the condition of the coronary arteries than central pulse pressure. In the present article, we will review the data currently available on the links between central and peripheral pulse pressure, as well as the data on the correlations between central pulse pressure and the presence and extent of coronary artery disease.

Central versus Peripheral Pulse Pressure

Differences between central and peripheral arterial pressures have been described in detail elsewhere [5-8] (Chapter 1). Schematically, the arterial tree can be divided into two compartments (central and peripheral). Brachial pressure represents blood pressure in the peripheral compartment, while aortic (or carotid) pressure represents blood pressure in the central compartment. While diastolic and mean arterial pressures remain more or less constant throughout the arterial tree, the level of systolic blood pressure varies according to the nature of the arteries where it is measured. Thus, systolic blood pressure (and consequently pulse pressure) is notably higher in peripheral than in central arteries (by approximately 14 mm Hg in humans). This difference results from a difference in the summation of the forward and backward pressure waves along the arterial tree, as detailed in Chapter 1. Under physiologic conditions in younger subjects, the backward pressure wave returns to the central arteries during diastole, which explains why pulse pressure is higher in the peripheral than in the central arteries (pulse pressure amplification). However, when reflection occurs earlier, the backward (reflected) wave will reach the central compartment at an earlier stage, during systole. The consequence of this altered timing is an increase in systolic blood pressure and a decrease in dia-stolic blood pressure, resulting in an increased pulse pressure. Earlier reflection of the pressure wave may be the consequence of increased pulse wave velocity, such as is observed with stiffer and/or calcified arteries, but also of changes in the more peripheral arteries, that will affect their capacity to reflect the pressure wave. Arteriolar constriction, remodeling, and rarefaction can thus increase systolic blood pressure and pulse pressure. In addition, more proximal reflection sites, which have limited impact under normal conditions, may influence wave reflection in certain pathological conditions, such as extensive atherosclerotic disease of the arteries; in particular, the presence of calcifications at the bifurcation of the main branches of the aorta may constitute reflection sites which are more proximal to the ascending aorta and therefore increase pulse pressure. These will influence central pulse pressure whereas peripheral pulse pressure will not be directly affected.

Interpreting the significance of elevated pulse pressure is difficult. Indeed, increased pulse pressure per se is likely to have untoward effects on the coronary circulation because an elevated systolic blood pressure increases vascular load, while a lower diastolic blood pressure will reduce coronary perfusion; but in addition, an increased pulse pressure may correspond to the presence of vascular disease (and in particular, atherosclerosis of the aorta). Therefore, whereas hypertension is a well-known cardiovascular risk factor, pulse pressure might represent more of a marker of preclinical disease [9], as the correla-

Table 1. Central pulse pressure in patients with or without coronary artery disease (CAD) demonstrated by coronary angiography

Study (first author)

Pulse pressure in Pulse pressure in p value patients without patients with CAD, mm Hg CAD, mm Hg

<0.0001

Nishijima [14] Hayashi [15] Waddell [16]1 Danchin [17]

1 Central blood pressure measured non-invasively using carotid blood pressure.

2 Two groups with CAD of increasing severity.

tions between the presence of atheroma of the thoracic aorta and the presence of coronary artery disease have been well documented. Whatever the case, however, it is obvious that central pulse pressure is more likely to reflect the hemodynamic conditions to which the heart and coronary arteries are subjected than is peripheral pulse.

Central Pulse Pressure and Presence and Extent of Coronary Artery

Disease (tables 1, 2)

Over the past 10 years, several studies in different types of populations have shown that central pulse pressure could be related to the presence and extent of coronary artery disease.

Experimental studies have shown that increases in pulse pressure resulted in impaired acetylcholine-induced vascular relaxation [10], suggesting that increased pulse pressure might be involved in the first steps of the process of atherosclerosis. More recently, it has been shown that high pulse pressure on ambulatory recordings was associated with increases in biological markers of thrombogenesis and altered flow-mediated vasodilation in patients with coronary artery disease [11].

To the best of our knowledge, Lee et al. [12], who studied a population of patients undergoing left heart catheterization before intervention for mitral valve stenosis, were the first, in 1998, to show an association between the presence of coronary artery disease and high pulse pressure, measured either at the

Table 2. Central pulse pressure in relation to severity of coronary artery disease (CAD)

Study (first author)

Definition of the groups studied

Central pulse pressure mm Hg

p value

Waddell [16]1

No CAD, 50-89% stenosis, >90% stenosis

38 ±1/45 ±2/53 ±3

<0.01

Danchin [17]2

No CAD, 1-2 stenoses, > 3 stenoses

51 ±16/54 ±18/64 ±20

<0.001

Philippe [18]

1-, 2-, and 3-vessel disease

55 ±18/64 ±19/66 ±19

<0.03

Jankowski [19]

1-, 2-, and 3-vessel disease

63 ±16/65 ±18/72 ±19

<0.001

1 Central blood pressure measured non-invasively using carotid blood pressure.

2 Male population.

1 Central blood pressure measured non-invasively using carotid blood pressure.

2 Male population.

aortic or brachial levels. Central pulse pressure was 81 8 15 mm Hg in the 48 patients with coronary disease versus 51 8 16 mm Hg in those with no coronary stenosis. Brachial pulse pressure was also significantly higher in patients with coronary artery disease.

Nearly simultaneously, Gatzka et al. [13] showed that aortic stiffness was higher in patients with chest pain and positive exercise tests, compared with controls.

Nishijima et al. [14] included 293 patients who had undergone coronary angiography for suspected coronary artery disease, and without history of myocardial infarction or presence of local asynergy on left ventriculography. Aortic pressures were recorded in the ascending aorta by means of fluid-filled catheters. There was no significant difference between the group of 102 patients with and the one without coronary artery disease as regards systolic, diastolic and mean blood pressure in the ascending aorta. However, central pulse pressure and fractional pulse pressure, defined as the ratio of pulse pressure to mean blood pressure, were significantly higher, while just a trend was noted for peripheral pulse pressure. When pulsatility was analyzed by tertiles, the odds ratio (OR) for the presence of coronary artery disease, after adjustment for potential confounders, was 2.90 (95% confidence interval (CI): 1.435.89) for the second tertile, and 3.47 (95% CI: 1.52-7.95) for the third tertile. Conversely, no significant relationship was found between peripheral pulsatil-ity and the presence of coronary artery disease.

In another Japanese population of 190 patients undergoing coronary angiography, Hayashi et al. [15] analyzed aortic pressures and waveform in relation to coronary heart disease. Central pulse pressure was higher in patients with coronary artery disease (74 ± 20 vs. 66.5 ± 23 mm Hg, p < 0.03). In addition, the inflection time of the aortic pressure waveform, an indicator of large artery function and reflection in the arterial system, was a strong correlate of the presence of coronary atherosclerosis, even after multivariable adjustment.

Concordant findings were reported by Waddell et al. [16] in a cohort of 114 men with coronary artery disease (defined as the presence of at least one >50% stenosis on one of the main coronary arteries), compared with 57 age-matched men controls. In addition, coronary artery disease patients were further subdivided into those with moderate disease (n = 57; stenosis severity 50-89%) and those with severe (>90%) stenoses (n = 57). Central pressure was recorded non-invasively by measuring carotid pressure. Brachial pulse pressure was higher in patients than in controls, but there was no significant difference between the two groups of coronary patients according to the severity of the disease. In contrast, carotid pulse pressure was significantly different in all three groups, and highest in the group with the most severe stenoses. In this study, however, coronary artery disease severity was defined in a rather unusual way, by taking into account the degree of stenosis, but not the extent of coronary disease.

In a larger, multicenter study involving 1,337 patients with suspected coronary artery disease and referred for a first diagnostic angiogram, we analyzed the correlations between the presence and extent of coronary artery disease and aortic pulse pressure in the subset of280 patients receiving no medications with antihypertensive properties [17]. Blood pressure was measured by fluid-filled catheters in the ascending aorta. Coronary artery disease was defined by the presence of at least one >50% stenosis on any of the coronary arteries or their main branches. The extent of coronary artery disease was further characterized by the number of >50% stenoses for each patient. In the whole population, brachial pulse pressure was only slightly and not significantly higher in patients with coronary artery disease. In contrast, aortic pulse pressure was 5 mm Hg higher in the population with coronary artery disease (p < 0.03). The size of the population allowed analyzing separately the data according to gender. Interestingly, the correlation between increased central pulse pressure and presence of coronary artery disease was present only in men. Moreover, the extent of coronary disease was also correlated with pulse pressure in men, but not in women: men with no disease, 51 ± 16 mm Hg; 1 or 2 coronary stenoses, 54 ± 18 mm Hg; >2 stenoses, 64 ± 20 mm Hg (p < 0.001). Because several baseline variables were different between patients with or without coronary artery disease, a multiple regression analysis was performed to determine whether aortic pulse pressure was an independent correlate of coronary artery disease. In women, there was no significant association between pulse pressure and coronary artery disease. In contrast, in men, a 1-mm Hg increase in central pulse pressure was associated with an OR of 1.02 for the presence of coronary artery disease (p < 0.05). The association between pulse pressure and coronary artery disease in men persisted even after the other components of blood pressure (systolic, diastolic or mean blood pressure) were forced into the multivariable model.

Philippe et al. [18] also analyzed the correlations between pulse pressure and extent of coronary disease, in 99 patients with documented coronary stenoses that were scheduled for percutaneous transluminal coronary interventions. Most of the patients were men. The extent of coronary artery disease was categorized by the number of major vessels involved (one, two or three diseased vessels). Aortic, but not brachial pulse pressure was significantly related to the extent of coronary disease: one-vessel disease, 55 8 18 mm Hg; two-vessel disease, 64 8 19 mm Hg; three-vessel disease, 66 8 19 mm Hg (p < 0.03). Using multiple regression analysis, only male gender and the level of aortic pulse pressure were significant correlates of the extent of coronary artery disease. Conversely, using aortic pulse pressure as a dependent variable, higher mean aortic pressure, lower heart rate, female gender, and number of diseased vessels were independent correlates of pulse pressure in a multiple linear regression model. Of note, 11 patients had subsequent restenosis; no association was found between restenosis and either brachial or central pulse pressure.

Jankowski et al. [19] studied a group of 445 patients (including 95 women) with angiographically documented coronary artery disease and a left ventricular ejection fraction >55%. The extent of coronary artery disease was also defined as the number of diseased major coronary vessels. A strong association was found between aortic pulse pressure and extent of coronary artery disease: one-vessel disease, 63 8 16 mm Hg; two-vessel disease, 65 8 18 mm Hg; three-vessel disease, 72 8 19 mm Hg (p < 0.001). Fractional systolic and diastolic pressures were also associated with the number of diseased vessels. By multivariable analyses, a 10-mm Hg increase in aortic pulse pressure was associated with an OR of 1.15 (95% CI: 1.01-1.30) for the presence of triple vessel disease. Brachial pulse pressure was significantly associated with the number of diseased vessels by univariate analysis (p < 0.05), but not by multivariate analysis. The male and female populations were not analyzed separately.

Finally, the findings linking the presence and extent of coronary artery disease with central pulse pressure are corroborated by a study showing increased central pulse pressure in hypercholesterolemic patients compared with controls, suggesting that a relationship between central pulse pressure and coronary artery disease might already exist at a very early stage of the atherosclerotic disease [20].

Central Pulse Pressure and Clinical Outcomes

In coronary patients, only a few studies have assessed the prognostic value of brachial or central pulse pressure in terms of clinical outcomes [21-26]; In the Balloon Angioplasty Revascularization Investigation (BARI) trial [ 21]. brachial pulse pressure was shown to be an important prognostic indicator in patients with known coronary artery disease undergoing myocardial revascularization. Likewise, investigators of the Survival and Ventricular Enlargement (SAVE) trial also found a strong prognostic significance for brachial pulse pressure measured before hospital discharge in patients having sustained large myocardial infarctions [22].

As regards central pulse pressure, several studies [23-25] found an association between high pulse pressure and restenosis after coronary angioplasty. Nakayama et al. [23] studied 53 patients with preserved left ventricular function undergoing balloon angioplasty; 23 of them subsequently had restenosis at the angioplasty site. Fractional pulse pressure in the ascending aorta was significantly associated with the risk of restenosis; restenosis rates were 18, 33 and 78%, respectively, for tertiles 1-3 of aortic pulsatility. Lu et al. [24] also analyzed a population of 87 patients >60 years of age and with preserved left ventricular function, undergoing balloon angioplasty. Restenosis was found in 39 patients and was associated with higher levels of central pulse pressure (78 8 12 mm Hg vs. 66 8 15 mm Hg, p < 0.001). The ORs for restenosis were 5.88 (95% CI: 2.17-15.93) for a pulse pressure >66 mm Hg and 13.72 (95% CI: 4.8139.05) for a fractional pulse pressure >0.72. In addition to the two previously described studies, another one [25] analyzed the correlation between the inflection time on the aortic waveform, a marker of arterial stiffness, and the risk of restenosis in 74 patients having undergone balloon coronary angioplasty. Restenosis was observed in 26, 33 and 74% according to the tertiles of inflection time and a shorter inflection time was an independent correlate of restenosis after multivariable analysis. Overall, there is concordant evidence of a link between central pulse pressure and the risk of restenosis after balloon an-gioplasty. After stent implantation, which is the currently used angioplasty technique, however, no such relationship was evidenced in the small cohort of patients with restenosis in the study by Philippe et al. [18].

More relevant to current clinical practice are the results from Chirinos et al. [26]; who followed a cohort of 324 men having undergone coronary angiography for an average of 3 years. All patients had coronary artery disease defined by the presence of at least one >10% stenosis. Patients with concomitant valvular disease were excluded. During the follow-up period, 20% of the patients died and 43% had at least one major adverse cardiac event (death, myo-cardial infarction, unstable angina, unscheduled myocardial revasculariza-

Time (years)

Fig. 1. Peripheral and central SBP on amlodipine and atenolol-based therapy in the ASCOT-CAFE substudy [27].

Time (years)

Fig. 1. Peripheral and central SBP on amlodipine and atenolol-based therapy in the ASCOT-CAFE substudy [27].

tion or stroke). Central pulse pressure correlated with the risk of both death and major cardiac events. After adjustment on left ventricular function and mean aortic pressure, the OR for all-cause mortality was 1.18 (95% CI: 1.051.33, p < 0.005), and the OR for any major cardiac event was 1.09 (95% CI: 1.00-1.17, p < 0.05) for each 10 mm Hg increment in pulse pressure. In addition, an inverse correlation was found between adverse events and diastolic blood pressure, and this particularly for patients with three-vessel disease. When adjusted for each other, both aortic mean blood pressure and aortic pulse pressure were independent correlates of mortality. Brachial pulse pressure was not a predictor of major adverse cardiac events.

The importance of integrating central pressure in a comprehensive approach of recent trials findings has been highlighted by the ASCOT-CAFE trial [27]: A total of 2,199 patients were recruited for this substudy from the main ASCOT patient population, and were well-matched. The difference in peripheral SBP between the amlodipine-based regimen and atenolol-based regimen in ASCOT CAFE was only 0.7 mm Hg (NS) compared with 2.7 mm Hg in the full study. The central arterial SBP was shown to be 4.3 mm Hg lower (fig. 1) for the amlodipine-based regimen (solid line in fig. 1) than for the atenolol-based regimen (dotted line in fig. 1). While peripheral PP was 0.9 mm Hg greater in the amlodipine-based regimen, it was found to be 3.0 mm Hg lower centrally. Unadjusted for patient characteristics, both peripheral PP and central PP predicted ASCOT CAFE study outcomes with a p value of <0.0001. Since the pressures are dependent on risk factors, the results were adjusted for baseline differences in these parameters. When corrected this way, central PP remained significantly related to outcome (p = 0.048).

The most solid result of the ASCOT CAFE trial was the demonstration of the amlodipine-based regimen's greater central arterial pressure-lowering effect versus the atenolol-based regimen. Since central PP was correlated with long-term outcomes, this may help explain the benefit of the amlodipine-based regimen. Other demonstrations of superiority, based on the results of similar trials, such as the LIFE study [28], should be reconsidered in terms of underlying explicative mechanisms.

Conclusion

Overall, there are concordant data showing an association between aortic or central pulse pressure and both the presence and extent of coronary artery disease. Whether this association is found only, or mainly, in men, as suggested by one study, will need further research, as most of the studies so far have involved only small populations of women. Several studies also indicate that, in patients with documented coronary artery disease, an increased pulse pressure is a correlate of worse clinical outcomes. In patients undergoing balloon coronary angioplasty, the risk of restenosis may be increased when pulse pressure is higher. More importantly, in men with coronary artery disease the risk of death increases at higher levels of central pulse pressure. These data suggest that high pulse pressure is not only a marker of preclinical cardiovascular disease, but possibly also a true risk factor for adverse clinical events in patients with coronary artery disease.

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Nicolas Danchin

Service de Cardiologie, Hôpital Européen Georges Pompidou 20, rue Leblanc, FR-75015 Paris (France) Tel. +33 156 09 25 71, Fax +33 156 09 25 72 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 150-159

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