CLINICAL STUDY: ENDOTHELIAL FUNCTION
Carotid artery vasoreactivity in response to sympathetic stress correlates with coronary disease risk and is independent of wall thickness
Melvyn Rubenfire, MD, FACCa,
Sanjay Rajagopalan, MDa and
Lori Mosca, MD, PhDa
a Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, Michigan, USA
Manuscript received March 7, 2000;
revised manuscript received June 23, 2000,
accepted August 7, 2000.
Reprint requests and correspondence: Dr. Melvyn Rubenfire, University of Michigan Health System, 24 Frank Lloyd Wright Drive, Ann Arbor, Michigan 48106-0363
mrubenfi{at}umich.edu
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Abstract
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OBJECTIVES
We designed a study to determine the carotid artery (CA) response to sympathetic activity and to determine whether the response correlates with coronary risk and is independent of wall thickness (IMT).
BACKGROUND
Brachial artery reactivity in response to wall stress correlates with coronary risk and coronary disease (CAD). The reactivity of the CA, which is susceptible to atherosclerosis, has not been evaluated.
METHODS
The change in diameter of the CA ( CAdiam) during a cold pressor test and after nitroglycerin and IMT were measured with ultrasound in 93 men and women at average risk, high risk and with CAD.
RESULTS
At 90 s during a cold pressor test average-risk subjects increased CAdiam by 7.9 ± 3.3%, which was significantly less in the high-risk group (1.5 ± 1.8%), and vasoconstriction occurred in the group of subjects with CAD (–6.9 ± 2.7%) (p < 0.01 for comparisons). There were no differences in response to nitroglycerin. Coronary risk was an independent predictor of the %CAdiam (p < 0.0001). Wall thickness, age, systolic pressure and triglycerides each correlated negatively, and high-density lipoprotein cholesterol correlated positively with %CAdiam. The major variable associated with the %CAdiam was group (p = 0.0001). After adjusting for smoking, age and high-density lipoprotein cholesterol, there was no association between the %CAdiam, and IMT and %CAdiam, but not IMT, was predictive of groups.
CONCLUSIONS
The CA response to a sympathetic stimulus is altered in the presence of coronary risk factors and CAD and appears to reflect endothelial function independent of IMT. Carotid artery reactivity may be a valuable adjunctive noninvasive method to assess coronary risk.
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Abbreviations and Acronyms
| | BA | = brachial artery | | BSA | = body surface area | | CA | = carotid artery | | CAD | = coronary artery disease | | CAdiam | = carotid artery diameter | | CPT | = cold pressor test | | HDL-C | = high-density lipoprotein cholesterol | | IMT | = wall thickness | | LDL-C | = low-density lipoprotein cholesterol | | NO | = nitric oxide | | Ntg | = nitroglycerin |
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The coronary artery response to increased flow, metabolic, cholinergic and sympathetic signals is endothelium-dependent and altered in the presence of atherosclerosis and coronary risk factors (1–6). The brachial artery (BA) response to shear stress induced by reactive hyperemia and sympathetic stimuli is also dependent upon local endothelial function (7,8), correlates with the presence of coronary risk factors (9–13) and is abnormal in patients with coronary artery disease (CAD) (14–16).
Carotid artery (CA) plaque and increasing wall thickness (IMT) also correlate with coronary risk factors (17,18) and the presence of CAD (19,20). Whether functional changes in the human CA can be detected and whether they are abnormal in the early stages of atherosclerosis has not been previously reported. If CA reactivity is measurable and independent of IMT, it may be a useful adjunctive tool for the evaluation of novel risk factors, subclinical atherosclerosis and response to therapeutic strategies.
We designed a study to determine the CA responsiveness to the receptor-mediated sympathetic stimulus of cold in healthy subjects, patients with risk factors for atherosclerosis and documented coronary disease and whether the response is independent of intima-media wall thickness (IMT). The physiologic stress of a cold pressor test (CPT) was selected because of the previously documented use in the evaluation of coronary (4,21) and brachial endothelial-mediated reactivity (13,16).
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Methods
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Study recruitment and eligibility.
Adult men and women were recruited to be representative of average-risk, high-risk and subjects with CAD. Average-risk was defined as  1 high-risk lipid parameter (high-density lipoprotein cholesterol [HDL-C] < 0.9 mmol/L, low-density lipoprotein cholesterol [LDL-C]  4.13 mmol/L or LDL-C/HDL-C 4.5) with no other risk factors. High-risk was defined as at least one coronary risk factor (smoking, family history of premature CAD, hypertension) with at least one high-risk lipid parameter and no symptoms or evidence of ischemia on stress testing. Coronary artery disease was defined as 50% stenosis in one or more major vessel on coronary arteriography or a previously documented myocardial infarction.
Exclusion criteria included: coronary event within 12 weeks, heart failure, left ventricular ejection fraction < 40%, diabetes, blood pressure > 160/90 mm Hg or left ventricular hypertrophy, body mass index > 27.5 kg/m2, systemic illness, average and high-risk subjects with plaque in the common CA or its branches and CAD subjects with plaque (IMT > 1.3 mm) in the common CA.
Informed consent was obtained, and the study was performed as approved by the Institutional Review Board of the University of Michigan Health System. Studies were performed fasting between 8 and 11 AM. Vasoactive substances were withheld for at least 12 h and vasoactive drugs for 24 h.
B-mode ultrasound imaging.
B-mode ultrasound scans were obtained with a Biosound Phase II. The right common CA was scanned by a technique previously standardized for determining diameter, plaque and IMT (19,22). The plane of maximal IMT was identified for each of six sites, near and far wall of the internal carotid, bifurcation, and common CA. Three sections of CA were defined by distance from the flow divider: internal as the 1 cm above, bifurcation as the 1 cm immediately below and common beginning at 1 cm and ending 2 cm below (22).
CPT and nitroglycerin (Ntg).
A cold pressor test was performed by submersion of the right foot to the ankle in iced slush for 120 s, a modification from published methods (13,16). The foot was chosen to maximize the hemodynamic and sympathetic response (23,24). Subjects were instructed to avoid breath holding, muscle contractions and Valsalva’s maneuver. The response to 0.4 mg Ntg was used as an indicator of endothelial-independent function (9).
Image analysis.
Images were digitized utilizing a Macintosh 7100/80 computer, Scion LG-3 frame grabber and professional Panasonic-DS840 videotape with digital frame storage. Wall thickness and diameters were measured utilizing customized software. The mean common CA diameter (CAdiam) was defined as the line identifying the media-adventitia interface in the near to the far wall calculated automatically by averaging measurements at 0.1 mm intervals over 1 cm. Wall thickness was defined as IMT as previously described and validated (25,26). The blood-intima and media-adventitia boundaries were traced manually and automatically calculated as the average of 0.1 mm samples over 8 mm. The final average IMT for each subject was calculated as the average thickness of six segments.
The reproducibility of measuring the CAdiam and IMT with our software is similar to published results (26,27). The mean difference in diameter in 40 subjects obtained by the same observer was 0.051 mm ± 0.039 mm and a coefficient of variation (cv) 0.76%. The mean difference in IMT was 0.018 ± 0.065 mm, cv 3.6%, and Pearson correlation coefficient was 0.983, p = 0.001.
Image selection.
The response of conduit arteries to flow-mediated shear stress or sympathetic stimuli has been shown to be time-dependent (13,28). Because a primary objective was to determine the normal response of the carotid artery to CPT, we identified the time for 95% of the 26 average-risk subjects to reach the peak change during and after CPT and Ntg. Based on these observations, for subsequent between group comparisons, we utilized the diameter change from baseline to 90 s during CPT and 120 s after Ntg.
Statistics.
Continuous variables are presented as mean ± standard deviation, and counts and percentages are given for categorical variables. The Kruskal-Wallis test was used for nonparametric distribution and pair-wise comparison by Wilcoxon rank-sum test. The significance of a trend across groups was tested using analysis of variance with Scheffé F test to control for multiple stepwise comparisons. The Spearman correlation coefficient was used to evaluate the relationship between percent diameter change after CPT, IMT and other coronary risk factors. Multiple linear regression analysis was used to identify independent factors associated with percentage diameter change. Logistic regression analysis was used to determine factors predictive of groups. Statistical significance was accepted at the 95% confidence interval (p < 0.05).
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Results
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Clinical characteristics.
The clinical characteristics of the three groups are summarized in Table 1. As by definition the lipid parameters differed significantly between average- and high-risk. Twenty-one of the 37 high-risk and 18 of the 30 CAD subjects were taking lipid-lowering drugs.
Baseline diameters and IMT.
The baseline CA diameters and IMT are presented in Table 2. The trend to an increase in diameter from average-risk to high-risk and high-risk to CAD was not present after correction for body surface area (BSA). The IMT was significantly greater in the CAD group than it was in the average-risk group.
Hemodynamic monitoring.
The hemodynamic response to 120 s of CPT was similar to published reports and did not differ between groups (23,24). There was a moderate increase in systolic (23%), diastolic (18%) and mean pressure (19%), heart rate (9%) and pressure rate product (32%). There was no difference between groups in response to Ntg.
CA diameter response to CPT and Ntg.
The change () in CAdiam in response to CPT and Ntg is demonstrated in Table 2 and Figure 1. There was a consistent and significant increase in diameter during and after 120 s of CPT in average-risk subjects. The maximal increment in diameter occurred at 90 s during CPT (7.9 ± 3.3%, p < 0.001 vs. baseline) and did not change for 3 min after release. Twenty-four of 26 (92%) average-risk subjects responded with vasodilation, one with no change and one with a 0.25 mm decrease in diameter. An increase in diameter of at least 0.22 mm or >3% was present in 75% of subjects.
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Figure 1 Results in a 49-year-old man with CAD. (A) A 2.0% reduction in cross-sectional diameter of the carotid artery occurs at 90 s of foot submersion in ice slush. (B) A 5.84% increase in carotid diameter is detected at 120 s after 0.4 mg of sublingual nitroglycerin. CAD = coronary artery disease; CPT = cold pressor test; diam = diameter.
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In the high-risk subset, at 90 s of CPT, the mean change in diameter was 1.5 ± 1.8%, which differs from the average-risk and CAD groups (p < 0.05). Thirty-two of the 37 high-risk subjects dilated or had no significant change, range 0.03 mm to 0.35 mm. In the CAD group the response was uniformly vasoconstriction. The mean decrease during CPT was 0.52 ± 0.2 mm or –6.9 ± 2.7%, p < 0.01 versus baseline and p < 0.01 versus the average-risk group (Table 2). All CAD subjects had a reduction in mean diameter at 90 s of CPT. There was no overlap between the 90 s response in the CAD and the average-risk groups (Fig. 2).
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Figure 2 Comparison of the change in carotid artery diameter in response to the cold pressor test and nitroglycerin in average-risk subjects , high-risk subjects and subjects with CAD. Box with vertical lines = at 60 s of CPT; box with diagonal lines = 120 s after Ntg. CAD = coronary artery disease; CPT = cold pressor test; Ntg = nitroglycerin.
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The endothelium-independent increase in diameter from baseline after Ntg in the 93 subjects was highly significant and did not differ between groups (Fig. 2). The absolute and percent responses to CPT and Ntg in the average-risk group were highly correlated, r = 0.78, p = 0.0001.
Determinants of CA reactivity to CPT and IMT.
The determinants of percent change in diameter during CPT (%CAdiam) are presented in Table 3. The following were entered for univariate analysis: %CAdiam; BSA, the ratio of diameter to BSA; age in years as a continuous variable and a categorical value; gender; cholesterol; HDL-C; triglycerides; LDL-C; the ratio of LDL-C/HDL-C; baseline systolic, mean and diastolic blood pressures; family history; ever smoked; current smoker; estrogen use and IMT.
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Table 3 Univariate Analysis Between Percent Change in Carotid Artery Diameter During CPT, Carotid IMT and Coronary Risk Factors
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There was a negative correlation between %CAdiam and baseline diameter (r = –0.51, p = 0.0001), which persisted after correction for BSA (r = –0.46, p = 0.0001). There was no difference in response to CPT based on gender, estrogen use or BSA. The %CAdiam was decreased in subjects with a family history of CAD, previous and current smokers, and it correlated negatively with age as a continuous variable (r = –0.29, p = 0.004) and cut-points of < or >40 (p = 0.03), 50 (p = 0.008) and 60 (p = 0.0009) years. There was a highly significant negative correlation of %CAdiam with increasing IMT, systolic blood pressure and triglycerides and a positive correlation with HDL-C (Table 3). After correcting for age, %CAdiam remained significantly correlated with IMT, HDL-C and triglycerides, but not systolic pressure.
Wall thickness increased significantly with age (r = 0.60, p = 0.0001), systolic pressure (r = 0.31, p = 0.006) and triglycerides (r = 0.31, p = 0.004) and correlated negatively with HDL-C (r = –0.24, p = 0.03) but did not correlate with gender, diastolic pressure, cholesterol, LDL-C or LDL-C/HDL-C. After correcting for age, IMT remained negatively correlated with HDL-C, positively correlated with triglycerides and LDL-C/HDL-C and no longer correlated with systolic pressure. The trend to increasing IMT by group was significant, p analysis of variance <0.0001, as were pair-wise differences between the average-risk group versus the CAD group and the high-risk group versus the CAD group (p < 0.05 for each).
When analyzed within each of the three groups, %CAdiam correlated negatively with age in the CAD group only (r = –0.34, p = 0.04). There was no intragroup correlation of CAdiam with IMT or other risk factors. In the average-risk group, IMT correlated highly with age (r = 0.81, p = 0.0001) and moderately with cholesterol, LDL-C and triglycerides (p < 0.01 for each). In high-risk subjects, IMT correlated only with age, and, for patients with CAD, IMT correlated with age, diastolic pressure and triglycerides.
Using general linear modeling, the major variable associated with %CAdiam during CPT was group, F = 162.5 (p = 0.0001). With the combination of group, BSA, ever smoked and IMT, the R2 is 0.92. We added "ever smoked" and utilized multiple linear regression analysis to identify independent factors associated with %CAdiam without consideration of group. In the final reduced model, age, ever smoked and HDL-C were independently associated with %CAdiam, R2 = 0.39. After adjusting for smoking, age and HDL-C, there was no association between %CAdiam and IMT. When group remains in the model, age, group and LDL-C remain highly significantly associated with %CAdiam (R2 = 0.287) and unassociated with IMT. With logistic regression analysis %CAdiam, but not IMT, was predictive of groups.
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Discussion
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The common carotid artery in adults has a measurable response to the sympathetic physiologic stress induced by cold. Like the coronary and brachial artery, the carotid response was anticipated to be the sum influence of  and ß adrenergic tone, with the latter dependent upon function of the local endothelium (4,13,21). The normal response during and up to 3 min after CPT was dilation. The response was blunted or reversed in the presence of coronary risk factors and coronary disease, respectively. That the degree of vasodilation was significantly greater in the average-risk group than it was in the high-risk group and that vasoconstriction occurred in the CAD group is comparable to the coronary circulation (2,21,29,30) and BA (13,16). The absence of a difference in response to Ntg and the decreasing ratio of %CAdiam CPT to %CAdiam Ntg supports the conclusion that the differences are predominantly related to endothelial function and not abnormalities in smooth muscle responsiveness (7,8). Furthermore, the correlation between reactivity to systemic cold and the classic coronary risk factors of age, smoking, systolic pressure and the lipoproteins LDL-C and HDL-C provide internal validity that carotid vasoreactivity is a marker for atherosclerosis risk.
While the reactivity of the CA in response to cold correlated highly with IMT and shared risk factors, the %CAdiam to CPT was independent of IMT within a range that is considered mildly increased (20). Additionally, in a cohort of high-risk subjects with abnormal lipids and subjects with CAD who had relatively normal lipids, %CAdiam was significantly better than IMT for distinguishing groups. Ghiadoni et al. (31) recently reported that, in untreated hypertension, carotid IMT correlates inversely with BA vasodilation to acetylcholine (r = 0.58, p < 0.001). The latter correlation is similar to our finding of an inverse relationship between carotid IMT and %CAdiam CPT, r = –0.496 and p = 0.0001.
Because of accessibility and susceptibility to atherosclerosis, the CA is particularly attractive as a clinical and investigative tool. Both plaque and IMT correlate modestly with risk factors and coronary disease (20,32), the response to cholesterol lowering treatment (33,34) and coronary event rates in longitudinal studies (33).
There have been no previous studies of carotid reactivity. Previous reports considered larger conduit arteries less than effective for determining endothelium-dependent reactivity. Celermajer et al. (9) found the BA preferable to the femoral artery because the degree of flow-mediated dilation was inversely proportionate to the baseline diameter (9). However, the response of the CA to CPT in the average-risk subjects in our study was considerably greater and less dependent on age and gender than that reported in the BA by Corretti et al. (13) (CA 7.91 ± 3.33% vs. BA 1.4 ± 2.5%). Furthermore, in 10 subjects we found the repeatability of measuring the larger CA to be better than that of the BA (variability of baseline study 1 vs. study 2, carotid 0.07 ± 0.07 mm vs. brachial 0.19 ± 0.12, p = 0.0001).
The decrease in vasodilation of the CA in response to CPT in the high-risk and CAD groups is consistent with both human and animal experimental evidence. The response of conduit arteries to systemic cold is the result of the balance between adrenergic vasoconstriction and vasodilation, with the latter mediated by endothelial function (2,4,13,21,35). The normal coronary vasodilator response to CPT can be blocked by competitive inhibition of L-arginine, a substrate for nitric oxide (NO) synthase (36), and L-arginine can normalize the vasoconstrictor response to CPT in CAD (37). Both endogenous NO and exogenously administered NO donors suppress sympathetic outflow at the prejunctional level, and NO may exert a tonic influence on the discharge of sympathetic efferents (38–40).
Study limitations.
Our study supports a role for carotid vasoreactivity in the assessment of atherosclerotic risk factors. While the CAD subjects were older and could have influenced the ability to discriminate groups by %CAdiam during CPT, there was no overlap between the response in the average-risk and CAD subjects who were of comparable age. To further assess the significance of age, we analyzed 66 additional patients (total 157 subjects with 31 average-risk, 79 high-risk and 49 subjects with CAD) and found comparable results. The change in diameter during CPT revealed a strong age to HDL-C interaction and no quadratic age effect.
Conclusions.
The direction and magnitude of change in the CAdiam during and after the sympathetic stress induced by foot submersion in ice slush is altered based upon the presence of risk factors and coronary disease. The data suggest that the response reflects local endothelial function and is independent of IMT. Carotid reactivity in response to CPT (and possibly other stressors) may have a valuable role in coronary risk assessment and response to therapy.
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Footnotes
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Supported, in part, by a donation from Harold and Kay Peplau and an unrestricted grant from Bristol-Myer Squibb.
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