1Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Huispostnummer Str. 6.131, PO Box 85060, 3508 BA Utrecht, The Netherlands
2Department of Neurology, Rudolph Magnus Institute for Neuroscience, University Medical Center Utrecht,Utrecht, The Netherlands
3Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Received 15 December 2004; revised 24 February 2005; accepted 3 March 2005; online publish-ahead-of-print 11 April 2005.
* Corresponding author. Tel: +31 30 2509352; fax: +31 30 2505485. E-mail address: m.l.bots@jc.azu.nl
See page 1152 for the editorial comment on this article (doi:10.1093/eurheartj/ehi280)
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Abstract |
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Methods and results The study was performed in the first consecutive 2183 patients with manifest arterial disease enrolled in the SMART study (Second Manifestations of ARTerial disease), a cohort study among patients with manifest arterial disease or cardiovascular risk factors. Common carotid distension (i.e. the change in carotid diameter in systole relative to diastole) was measured at baseline by ultrasonography. With the distension, several stiffness parameters were determined. In the entire cohort, none of the carotid artery stiffness parameters was related to the occurrence of vascular events. However, decreased stiffness was related to decreased vascular risk in subjects with low baseline SBP. The relation of carotid stiffness with vascular events did not differ between tertiles of baseline risk and carotid stiffness.
Conclusion Carotid artery stiffness is no independent risk factor for vascular events in patients with manifest arterial disease. However, in patients with low SBP, decreased carotid stiffness may indicate a decreased risk of vascular events.
Key Words: Elasticity Cardiovascular diseases Risk factors Mortality Carotid arteries
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Introduction |
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In this study, we prospectively examined whether carotid artery stiffness is related to the occurrence of cardiovascular events and cardiovascular death in a large cohort of patients with manifest arterial disease, which are referred as part of routine care. Furthermore, we evaluated whether baseline vascular risk, arterial stiffness, and blood pressure modified the relation of arterial stiffness to vascular disease.
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Methods |
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For the current study, the data of the 2476 participants with manifest cardiovascular disease [cerebral, coronary or peripheral artery disease, renal artery stenosis, or aneurysm of the abdominal aorta (AAA)] who were included in SMART before March 1, 2003, were considered. Of 193 participants, stiffness measurements were missing due to equipment failure or logistical problems. Measurements of 94 participants were excluded from the analysis because the intra-individual variance between stiffness measurements was considered out of range. Of six patients, no follow-up information was available. Finally, the data of 2183 participants were used in the analysis.
Vascular screening
Vascular screening was conducted on a single day at the UMCU. Blood samples were collected after an overnight fast. Glucose, total cholesterol, triglycerides, and HDL-cholesterol were measured. LDL-cholesterol was calculated by use of Friedewald's formula. Height and weight were measured without shoes and heavy clothing. Blood pressure was measured in supine position at the right brachial artery every 4 min during the arterial stiffness measurement with a semiautomatic oscillometric device (Omega 1400, Invivo Research Laboratories Inc., Broken Arrow, OK, USA). Medical history, use of current medication, and packyears smoked were derived from a questionnaire described elsewhere.12 Common carotid intima-media thickness (CIMT) was measured at the left and right common carotid arteries with an ATL Ultramark 9 (Advanced Technology Laboratories, Bethel, WA, USA) equipped with a 10 MHz linear array transducer as previously described elsewhere.12 The mean CIMT was calculated in each patient. Duplex scanning of the carotid arteries was performed for assessment of presence of an internal carotid artery stenosis.12,13
Carotid artery stiffness
Stiffness was assessed by measurement of distension of the left and right common carotid arteries. The distension of an artery is the change in diameter in systole relative to the diastolic diameter during the cardiac cycle. The displacement of the walls of the left and right common carotid artery was measured with a Wall Track System (Scanner 200, Pie Medical, Maastricht, The Netherlands) equipped with a 7.5 MHz linear array transducer and vessel wall moving detector system. After a rest of at least 5 min in supine position, patients were examined in supine position with the head turned 45° away from the side examined. The left and right carotid arteries were examined separately. Measurements were performed in the distal common carotid artery 2 cm proximal to the origin of the carotid bulb as described elsewhere.14 In short, at the right carotid artery, five measurements were performed. Each assessment lasted 4 s and comprised several cardiac cycles. First, the distension of the cardiac cycles within a single measurement was averaged. Next, the results of the five assessments were averaged. A similar procedure was used for the left carotid artery. The mean of the left and right carotid artery measurements was taken as distension measurement for one individual. The same procedure was followed for lumen diameter measurements. An intra-observer variability study on distension and end-diastolic lumen diameter measurements showed a coefficient of variation of 6.2 and 2.1%, respectively. Between observers, the coefficient was 7.3 and 3.5%, respectively.14
Adjusted carotid distension was the primary stiffness measure,15,16 using blood pressure simultaneously measured at the brachial artery at 4 min intervals. In addition, traditional indexes of arterial stiffness were used for comparison. ß stiffness index was determined as ln(SBP/DBP)/(D/Dd) with SBP indicating systolic blood pressure, DBP indicating diastolic blood pressure,
D indicating the mean carotid distension, and Dd indicating end-diastolic diameter. Cross-sectional compliance coefficient (CC) in mm2 kPa1 was given as (
xDdx
D)/(2xPP) with PP indicating pulse pressure (SBPDBP). Distensibility coefficient (DC) in 103 kPa1 was (2x
D/Dd)/PP. Peterson's modulus (EP) in kPa 102 was defined as (PPxDd)/
D. Young's elastic modulus (YEM) in kPa was (PPxDd2)/(
Dx2xIMT). Increasing distension, CC, and DC imply decreasing stiffness. Distensibility is the relative change in diameter and compliance is the absolute change in diameter with pressure. Peterson's (elastic) modulus is the pressure change required for (theoretic) 100% increase in diameter, and Young's modulus is the pressure per square millimetre required for (theoretic) 100% extension.17
SMART risk score
To obtain information on baseline vascular risk, the previously developed SMART risk score, which has been previously described, was used.14 The SMART risk score is based on baseline data of pre-existing disease and risk factors. Patients receive points for gender, age, body mass index, smoking behaviour, hyperlipidaemia, hyperglycaemia, hypertension, medication use, medical history, and prevalent vascular disease at baseline.
Follow-up
Patients were biannually asked to fill in a questionnaire on hospitalizations and outpatient clinic visits in the preceding 6 months. Events of interest for this study were vascular death, ischaemic stroke, coronary ischaemic disease, and the composite of these vascular events. Definitions have been described previously.12 When a possible event was recorded by the participant, hospital discharge letters and results of relevant laboratory and radiology examinations were collected. With this information, all events were audited by three members of the SMART study Endpoint Committee comprising physicians from different departments.12
Data analysis
Cox proportional hazards analysis was performed to estimate hazard ratios and 95% confidence intervals (CI) for the association of arterial stiffness and the occurrence of cardiovascular events. If a patient had multiple events, the first was used in the analyses. Three models were used. In model I, the unadjusted association of carotid stiffness and cardiovascular events was examined. In model II, age was added. Additional adjustment for the confounders mean arterial pressure (MAP) [(2xDBP+SBP)/3], sex, packyears smoked, and use of antihypertensive medication at baseline was performed in model III, because these variables altered the regression coefficient>10% after entering the model. The variables diabetes mellitus, body mass index, triglycerides, HDL-cholesterol, LDL-cholesterol, use of lipid-lowering medication, and a carotid artery stenosis of 5069 or 70% were not included in the model because these variables did not change the magnitude or the direction of the association. Quadratic terms were entered for continuous variables and remained in the model if statistically significant to adjust optimally and thus reduce residual confounding. The proportional hazards assumption was satisfied based on logminlog plots for tertiles of the stiffness parameters. The linearity assumption was assessed by comparing the estimates of the stiffness parameters in models including the continuous variables as such and models in which the percentile dummies of the continuous variables were included. The linearity assumptions were satisfied.
The primary measure of carotid stiffness was distension divided by the standard deviation of the mean population (147 µm), adjusted for MAP.16 Additionally, analyses were performed for the other indexes of arterial stiffness. First, analyses were conducted for all patients with manifest arterial disease and secondly, for patients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease separately. The number of patients with an AAA was too small for separate analysis. To determine whether the relation between arterial stiffness and vascular disease in all patients was influenced by inclusion of AAA patients, the analysis was additionally performed in patients without an AAA.
To evaluate whether baseline risk (with the SMART score) and SBP were effect modifiers, interaction terms were computed and stratified analyses were performed in tertiles of baseline risk and SBP with a model with all vascular events as outcome in all patients with manifest arterial disease. To examine whether the relation of arterial stiffness with the occurrence of vascular events varies between patients with different levels of arterial stiffness, the relation was studied in tertiles of the stiffness parameters distension and DC.
Finally, for interpretation of the results of the stratified analysis, a linear regression model was constructed to study the distension as a function of SBP. Quadratic terms were entered if statistically significant. To describe the association of SBP and carotid distension independently, adjustments were made for the confounders in model III. The association was graphically displayed, with mean values for the other variables in the SBP model. P-values were two-sided and P<0.05 was considered statistically significant.
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Results |
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Discussion |
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Before discussing these results in more detail, some methodological aspects need to be addressed. First, we used several parameters of carotid stiffness, most of them ratios of distension, blood pressure, and end-diastolic carotid diameter. As a ratio in a statistical model may obscure the impact of the separate variables, we used carotid distension with adjustment for MAP and end-diastolic carotid diameter separately in the linear regression model as primary measure of carotid stiffness. To determine whether our results could be explained by this approach, the associations of other stiffness parameters and vascular events were evaluated as well, which showed similar results. Secondly, blood pressure was measured at the brachial artery, whereas stiffness measurements were performed at the carotid artery. It is known that the brachial SBP may overestimate the carotid SBP because of changes in amplitude and timing of wave reflections along the arterial tree.18,19 Adjusting for a blood pressure that is higher than the true carotid blood pressure might lead to an underestimation of the relation of arterial stiffness with vascular disease. However, due to decreasing arterial stiffness with increasing age, SPB-amplification is reduced in patients of 50 years.19,20 As all patients with manifest arterial disease probably had relatively stiff arteries and as the majority of the studied population aged
50, SBP-amplification is not likely to play an important role. Moreover, we adjusted for MAP and amplification of MAP is less than amplification of SBP.21 Thirdly, blood pressure was determined at 4 min intervals during the assessment of distension. Possibly, carotid stiffness parameters might have been more precise with simultaneous blood pressure and distension waveforms.21 Yet, we do not think this would have resulted in materially different findings because blood pressure was measured during the assessment of distension and because assessment of both blood pressure and distension started after a rest of at least 5 min to reduce variability. Furthermore, it was previously shown that timing of blood pressure measurement did not materially influence arterial stiffness values.22 Finally, results of a study adjusting for both brachial intermittent blood pressure measurement and waveform calibrated PP were similar.23
Arterial distension is largely determined by SBP, with the distension increasing as SBP increases.24 Figure 1 shows that at high SBP levels, further increase in carotid distension appears to be limited. This may explain our finding that in patients with high SBP no association between carotid stiffness and vascular events is present (Table 4). We found no evidence for the hypothesis that the relation of carotid stiffness with vascular events is different according to baseline vascular risk or carotid stiffness.
Up till now, mainly positive relations between arterial stiffness measurements and vascular disease on follow-up were reported, although the magnitude varied considerably (Table 1). In our overall patient group, we found no relation between arterial stiffness and vascular events. As published data mainly reported on subjects with risk factors for vascular disease who generally can be considered to have a lower risk than the patients with manifest arterial disease in our study, the different reported relations between arterial stiffness and vascular disease may be explained by an association between arterial stiffness and vascular events in low-risk patients only. However, the observation in studies on patients with ESRD who are known to be at high vascular risk,25 that arterial stiffness was associated with vascular events,2,3,11 is not in accordance with this explanation. Moreover, our finding that the association of arterial stiffness and vascular events is not modified by baseline risk does not support this hypothesis either, although opposite findings were observed in a study relating stiffness measured as PWV to vascular events in patients without manifest arterial disease.5 A second explanation for the differences in reported relative risks may be that different methods of stiffness assessment were used. In most other studies, arterial stiffness was measured as aortic stiffness (Table 1), whereas we used carotid distension. Previously, we showed that in patients with manifest arterial disease carotid stiffness is mainly associated with cerebrovascular disease, whereas aortic stiffness may be more closely related to coronary artery disease.26 As the majority of events in the current study were due to coronary ischaemic disease, this may partly explain the absence of an association with carotid stiffness.
In this study, no relation of arterial stiffness was observed at relatively high levels of SBP. Because in hypertensive patients in the general population, a relation of PWV with vascular events was observed,4 this may be explained by a different population or by a different technique of assessing arterial stiffness as well. In another study in hypertensive patients, increased arterial stiffness assessed as PWV was associated with vascular events in patients at low vascular risk only;5 this may imply that effect modification of SBP is only present in patients at high vascular risk.
In conclusion, the findings in this study do not show an association between carotid stiffness and risk of vascular events in patients with manifest arterial disease at large. In patients with low SBP, less stiff arteries may indicate a lower risk of vascular events.
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Acknowledgements |
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Appendix |
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These are departments in the University Medical Centre Utrecht, The Netherlands.
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References |
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