Patients with coronary artery disease (CAD) have impaired endothelial function. Arterial elasticity is modulated by endothelial function. The association between arterial elasticity and endothelial function has not been reported in patients with CAD. The present study was designed to investigate whether endothelial dysfunction contributes to impaired arterial elasticity. Thirty patients with CAD and 30 control subjects were recruited. Large and small artery elasticity indices were non-invasively assessed using pulse wave analysis. Brachial artery endothelium-dependent and -independent function were assessed by vascular response to flow-mediated vasodilation (FMD) and sublingual nitroglyceride (NTG), respectively. C1 large artery elasticity index was not different in the CAD group compared with the control group. However, C2 small artery elasticity index was significantly reduced in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) was also impaired in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) in the brachial artery correlated with C2 small arterial elasticity index. But NTG-mediated brachial artery vasodilation was similar between the two groups. The present findings suggest that the patients with CAD have reduced C2 small arterial elasticity index and impaired FMD. Endothelial dysfunction is involved in diminished arterial elasticity, suggesting that C2 small arterial elasticity index is a novel surrogate measure for the clinical evaluation of endothelial function.
Endothelial function is recognized as a sensitive marker of the integrity of arterial wall. Accumulating evidence indicates that endothelial function plays a pivotal role in the maintenance of vascular structural and functional homeostasis.1, 2, 3 Coronary artery disease (CAD) is characterized by endothelial dysfunction and endothelial function in coronary arteries can be evaluated by measuring vasomotor function after intra-coronary infusion of biological agents which increase the release of endothelial nitric oxide (NO).4, 5 Impaired endothelium-dependent vasodilation has been demonstrated in various phases of CAD.6, 7, 8 However, assessment of this response is invasive, which makes it unsuitable for clinical applications in large populations or in studies involving asymptomatic patients in the early phase of CAD. Therefore, recent interest has been focused on the feasibility and application of non-invasive measures of endothelial function. Endothelial function can non-invasively be assessed by using flow-mediated vasodilation (FMD) in the brachial artery, an endothelium-dependent response that is largely mediated by NO.9, 10 Accumulating evidence demonstrated that FMD in the brachial artery is impaired in patients with CAD.11, 12
Arterial elasticity is also a non-invasive measure for the determination of cardiovascular risk. It has been shown that arterial elasticity assessment reflects the extent of vascular injury owing to cardiovascular risk factors, provides risk stratification and determines prognostic value.13 Several methodologies have become available for the non-invasive assessment of arterial elasticity. Studies have shown that endothelium-derived NO production contributes to the regulation of arterial elasticity and arterial elasticity is reduced in the presence of endothelial dysfunction.15, 16 The pulse wave analysis of diastolic pressure contour can be used to derive information on the arterial elasticity of both proximal and distal arteries.14 Our study and previous investigation also showed that impaired arterial elasticity measured by pulse wave analysis represents an abnormality in vascular endothelial function.17, 18 Less is known, however, about the relationship between endothelial function and arterial elasticity in patients with CAD. We hypothesized that reduced arterial elasticity is related to impaired endothelial function in patients with CAD. To test this assumption, the present study was performed to measure endothelial function and arterial elasticity in patients with CAD compared to age- and gender-matched normal subjects, by using non-invasive pulse wave analysis and FMD in the brachial artery.
Thirty patients with angina pectoris who were admitted for invasive evaluation of their coronary atherosclerosis and 30 control subjects with no hypertension, diabetes mellitus and other cardiovascular abnormalities entered this study Selective coronary angiography was performed according the Judkin technique. All the patients showed the presence of maximum coronary diameter stenosis of at least 50% in the left anterior descending, left circumflex or right coronary artery. Following angiography, patients underwent ultrasound examination of the brachial artery and measurement of arterial elasticity identified by pulse counter analysis after withdrawal of all vasoactive medications for at least 24 h. This clinical investigation was approved by the Ethical Committee of our hospital.
Arterial elasticity measurement
The investigation was performed in a controlled environment maintained at 23°C after the participants had rested for at least 15 min in a supine position. The subjects refrained from consuming alcohol and caffeine for 12 h before the study.
Radial arterial pulse waves were recorded with an acoustic transducer using the CVProfilor DO-2020 CardioVascular System (Hypertension Diagnostics Inc., Eagan, MN, USA.) as reported previously.4 A wrist stabilizer was positioned on the right wrist using two hook and loop straps in order to immobilize gently the wrist and stabilize the radial artery, making it readily accessible for placement of the arterial pulsewave sensor. The sensor electronically adjusts itself automatically in order to obtain an acceptable waveform. Then, a 30-s-long collection of the radial artery waveform, digitized at 200 samples per second, is stored in an onboard computer for analysis. To obtain arterial elasticity data, a model was used that divides the total systemic arterial compliance into C1 large artery and C2 small artery elasticity indices. The model describes diastolic pressure contours by the following equation:
where P2(t) is the diastolic pressure at time t relative to aortic value closure. A parameter-estimating algorithm was applied for determination of the best set of Ai values for matching the diastolic portion of the measured beats to this equation. These Ai parameters, together with an estimate of systemic vascular resistance, determine the large or capacitive compliance and the small or oscillatory compliance. The compliance values for each beat were weighted inversely with respect to an estimate of error and then averaged. The estimate of error was the predicted variance in the compliance divided by a measure of the goodness-of-fit of the model to the data. This approach ensures that individual compliance values with high estimated variance will contribute proportionally less to the overall compliance value. Additionally, end-diastolic distortions were eliminated by defining end-diastole as the point where diastolic pressure is no longer monotonically decreasing.
Assessment of brachial artery endothelial function
Arterial endothelial function of the brachial artery was assessed non-invasively by ultrasound examination of the vasodilation response to endothelium-dependent and -independent stimuli described by Celermajer et al.9 Using high-resolution ultrasound (Acuson 128XP/10, mountain View, CA, USA, with a 7.0 MHz linear-array transducer), the right brachial artery proximal to the antecubital fossa was imaged longitudinally using the linear-array transducer. Flow-mediated endothelium-dependent vasodilation was assessed by measuring the brachial artery diameter at baseline and during reactive hyperaemia. Reactive hyperaemia was induced by deflating a cuff previously inflated 300 mm Hg for 5 min in the forearm. Lumen diameter in the brachial artery was measured from one media-adventitia interface to the other. After 15 min, the endothelium-independent response was assessed by the change in artery diameter after 400 μg dose of sublingual nitroglyceride (NTG). All scans were recorded on super-VHS videotapes for analysis. The maximum FMD and NTG diameters were taken as the average of the three consecutive maximum diameter measurements following hyperaemia and NTG, respectively. Vasodilation was then calculated as the percent change in diameter compared to baseline.
Results were expressed as means±s.d. Our data were normally distributed. Data were analyzed with unpaired Student's t-test between the two means. Single linear regression was used to correlate the association between endothelial function and arterial elasticity indices. Values of P<0.05 were considered statistically significant.
Baseline characteristics for both the control group and CAD group are shown in Table 1. As shown in Figure 1, C1 large artery elasticity index was not different in the CAD group compared with the control group. However, C2 small artery elasticity index was significantly reduced in the CHD group compared with the control group (P<0.05; Figure 1). FMD was impaired in the CAD group compared with the control group (P<0.05; Figure 2). NTG-mediated brachial artery vasodilation (NMD) was similar in the CAD group compared with the control group (Figure 2). Figure 3 shows the association between C2 small artery elasticity index and FMD and NMD in the brachial artery. There was a significant linear regression relationship between C2 small artery elasticity index and FMD in the brachial artery dilation (r=0.34, P<.05).
The major findings of the present study are that in patients with CAD compared with control subjects, C2 small artery index is reduced, but C1 large artery elasticity index not further decreased. The FMD in the brachial artery is also diminished but NMD remains unchanged in patients with CAD compared with control subjects. These results suggest that in patients with CAD, there is presence of systemic arterial endothelial dysfunction and impaired C2 small artery elasticity index. There is a close relationship between FMD and C2 small artery elasticity index, which suggests that C2 small artery elasticity index may be used as a novel non-invasive surrogate parameter for the determination of endothelial function.
The measurement of brachial artery FMD as a non-invasive measure of endothelial function was first reported by Celermajer et al.9 It has been demonstrated that there is a close relation between endothelial function in the coronary and peripheral artery.11 Numerous studies have shown that the presence of coronary atherosclerotic lesion is associated with impaired endothelium-dependent vasodilation.4, 6, 9 Endothelial dysfunction predicts disease progression and cardiovascular event rates in patients with coronary artery disease.7, 8 In patients with traditional cardiovascular risk factors without evidence for atherosclerotic lesion, endothelial dysfunction is also observed, which suggests that early functional abnormality of the arterial system is present in the preclinical phase of vascular disease.19 Our present results are in accordance with previous studies to show that the functional response of the brachial artery not only reflects the number and intensity of risk factor, but also the presence of coronary disease when angiographically detectable. However, vasodilation to NTG is similar in CAD patients compared to controls, suggesting the endothelium-independent vasodilation is preserved.
Measurement of the arterial elasticity identified by pulse wave analysis is a recently developed method to non-invasively assess vascular function. It has been demonstrated that the arterial elasticity is determined by both structural elements in the vessel wall and functional regulation by the endothelium-derived NO. Our present study showed that C2 small artery elasticity index is reduced in patients with coronary artery disease compared with control subjects. However, C1 large artery elasticity index was apparently not affected by CAD. The potential explanation for the discrepancy between the large and small artery elasticity alterations identified by pulse wave analysis may be related to structure and function of the arteries examined. Windkessel theory treats the large arteries as a central elastic reservoir, storing blood during cardiac ejection and releasing it during diastole, thus enabling the pulsatile cardiac output to be converted to a steady flow in the capillaries. The elasticity of the proximal large arteries is the result of the high elastin to collagen ratio in their walls, which progressively declines towards the periphery. The fall in large artery elasticity that occurs with age is mainly the result of progressive elastic fibre degeneration. Therefore, the age as a major factor, together with transmural pressure, contributes to large arterial elasticity changes.20, 21 In the present studies, the age and arterial blood pressure between the two groups was comparable. Based on the factors affecting the large arterial elasticity mentioned above, it appears logical that C1 large artery elasticity index is not reduced in CAD patients compared with control subjects. Indeed, recently Syeda et al.22 reported that in the early stage of CAD, C1 large artery elasticity index is normal, although C2 small artery elasticity index is low, in patients with CAD compared with non-CAD subjects, supporting our present observation.
The alteration of arterial elasticity identified by pulse wave analysis could reflect either functional or structural alterations in the artery wall. Endothelial dysfunction may result in an increase in tone of the small arteries that would reduce oscillatory compliance or C2 elasticity index. Indeed, the results of the present studies showed that impaired FMD is associated with reduced C2 elasticity index, supporting this notion. In the large arteries, however, endothelial dysfunction may more likely facilitate the development of structural abnormalities that reduce large artery compliance or C1 elasticity index. Because age- and pressure-related structural changes in the arterial wall are the major determinants of proximal large artery elasticity,20, 21 therefore, it is not surprising that the C1 large artery elasticity index is not reduced in patients with CAD compared to control subjects. Indeed, previous investigation also provided data to demonstrate that inhibition of endogenous NO production in humans leads to the fall in C2 artery elasticity index but C1 remains unchanged, a finding similar to our present results.18
In summary, the present studies provide data to show that patients with CAD have impaired FMD in the brachial artery and reduced C2 small artery elasticity index. The fall in C2 small artery elasticity index is, at least in part, related to endothelial dysfunction. The C2 small artery elasticity may serve as a surrogate measure for the clinical evaluation of endothelial function in humans.
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