Does Arterial Stiffness Predict Atherosclerotic Coronary Events

Carmel M. McEnierya John R. Cockcroftb aClinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, and b Wales Heart Research Institute, CardiffUniversity, University Hospital, Cardiff, UK

Abstract

Coronary heart disease is a major cause of death and morbidity. Due to the increased longevity of most developed societies, there is an increasing overlap between arteriosclerosis associated with normal vascular ageing and atherosclerosis associated with cardiovascular risk factors. There is therefore a need for improvements, both in the early identification of individuals at risk, and in cardiovascular risk stratification. Arterial stiffness is an important determinant of cardiovascular risk and can now be measured simply and non-invasively in large populations. This review will therefore focus on the current evidence as to the predictive value of arterial stiffness in relation to coronary events and also on the possible pathophysiological mechanisms linking arterial stiffness and atherosclerosis.

Copyright © 2007 S. Karger AG, Basel

Introduction

Atherosclerotic coronary heart disease (CHD) is one of the leading causes of death worldwide. Therefore, the early detection of occult atheroma, or those individuals who are at significantly increased risk, is necessary for successful primary prevention of myocardial infarction and angina. Moreover, significant CHD can exist without overt clinical signs or symptoms. Indeed, a significant number of first myocardial infarctions occur in individuals in whom traditional cardiovascular risk factors are only slightly elevated [1, 2], Therefore, early identification of novel cardiovascular risk markers and more accurate risk stratification is required. As described in previous chapters, arterial stiffness is considered a key risk factor for cardiovascular disease, and can be assessed in large populations, using relatively simple, non-invasive methods. This chapter will review the evidence surrounding the predictive value of arterial stiffness in relation to atherosclerotic coronary events.

Cross-Sectional Studies

A logical first step in defining the value of arterial stiffness as a predictor of atherosclerotic coronary events is to determine whether large artery stiffness is increased in subjects who have already experienced a coronary event compared to healthy individuals. Hirai et al. [3] were amongst the first to examine this question. They assessed P stiffness index (a measure of aortic stiffness) in 49 patients who had suffered a myocardial infarction and 19 controls, and demonstrated that aortic stiffness was significantly higher in patients relative to controls.

Two further studies have examined the relationship between arterial stiffness and restenosis post-angioplasty [4, 5]: Both were invasive and demonstrated a significant relationship between restenosis and aortic pulsatility [4], and with aortic augmentation index [5]: Nishijima et al. [4] studied 53 consecutive patients admitted for revascularization who had had successful coronary balloon angioplasty and coronary angiography 3 months after angioplasty. They evaluated the morphology of the invasively measured ascending aortic pressure wave. In order to quantify the relative magnitude of the pulsatile aortic pressure they normalized it to mean pressure and defined this value as the fractional pulse pressure. This surrogate measure of aortic stiffness was a powerful predictor of restenosis, even after adjustments for age, sex, cardiovascular risk factors, vessel size and previous myocardial infarction. The odds ratio for restenosis was 33.5% in the highest tertile of fractional pulse pressure compared to the lowest tertile and the authors calculated that for each 0.1 increase in fractional pulse pressure, the odds ratio of restenosis rose by 88%.

In a similar study, Ueda et al. [5] investigated the predictive value of the invasively measured aortic augmentation index in 74 consecutive patients undergoing revascularization using similar inclusion criteria as the study of Nishijima et al. [4]. They assessed aortic stiffness by measuring time to the inflection point on the aortic pressure wave form - so-called 'TR', which provides a surrogate measure of aortic pulse wave velocity (TR falls as pulse wave velocity increases). The odds ratio of restenosis was ~7 in the lowest tertile relative to the highest, and a 20-ms increase in inflection time increased the odds ratio of restenosis by 70%. One potential limitation of these studies is that they used fluid-filled pressure catheters which are less accurate than high-fidelity pres sure transducers due to a poorer frequency response. Nevertheless, they do emphasize the value of surrogate measures of aortic stiffness in predicting the risk of restenosis post-angioplasty.

Arterial stiffness also appears to be increased in subjects with microvascular CHD. In a more recent study, Arroyo-Espliguero et al. [6] assessed carotid artery stiffness using Doppler ultrasound in a cohort of 30 patients with syndrome X. Carotid stiffness was significantly increased in those with syndrome X compared with control subjects. Although distensibility also tended to be lower in the syndrome X group, this did not reach statistical significance.

The risk of myocardial infarction is greatest in individuals with pre-existing coronary artery disease and a number of small studies have demonstrated significant relationships between invasive [4, 7, 8] and non-invasive [ 9, 10] measurements of arterial stiffness and the extent and severity of coronary atheromatous disease. Jankowski et al. [8] studied 445 patients with angiograph-ically confirmed coronary artery disease and measured ascending aortic pressure during catheterization. They used fractional aortic diastolic and systolic pressure derived from the invasively acquired aortic waveforms. Fractional systolic and fractional diastolic pressure differentiated patients with one-, two-, and three-vessel coronary artery disease. Interestingly, none of the brachial pressure indices was independently related to the extent of coronary atherosclerosis.

A recent large multi-centre study involving 1,337 patients at high risk of coronary artery disease from 75 centres demonstrated a significant relationship between invasively measured central aortic pulse pressure and both the presence and severity of angiographically determined coronary artery disease

[11]. McLeod et al. [9] assessed pulse wave velocity and augmentation index in a group of patients undergoing intravascular ultrasound of their coronary arteries. They demonstrated a significant relationship between carotid-radial pulse wave velocity and plaque load. Interestingly, aortic augmentation index measured non-invasively did not correlate with plaque load, which is in contrast to an earlier study using invasive measurements of augmentation index

[12]. Moreover, in a large non-invasive study performed in 465 consecutive male patients undergoing coronary angiography for symptoms of suspected coronary artery disease, Weber et al. [10] found a significant association between the presence and severity of coronary artery disease and central aortic augmentation index. Taken together, the results from the studies to date are consistent with the hypothesis that central aortic stiffness may promote the development of coronary artery disease and that therapeutic intervention targeted at reducing arterial stiffness may be of benefit in patients with coronary artery disease.

Table 1. Prospective longitudinal studies examining the relationship between aortic pulse wave velocity and outcome o o

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