An increased brachial artery intima media thickness (BA-IMT) has been shown to be of prognostic value. Conflicting prognostic data have been reported for brachial artery flow–mediated vasodilation (BA-FMD), and the longest evaluated follow-up period to date is 5.5 years. We sought to investigate the very late prognostic value of BA-IMT and BA-FMD in 396 consecutive patients (age 54 ± 9 years) admitted for invasive evaluation of chest pain. BA-IMT and BA-FMD were measured using high-resolution ultrasonography. The patients were divided according to the median BA-IMT (0.37 mm) and median BA-FMD (7.6%). After a mean follow-up of 141 ± 12 months, cardiovascular events were documented. More cardiovascular events were found in patients with an increased BA-IMT (50 vs 78 events, p = 0.003). When the groups were compared according to the median BA-FMD, no differences in the number of events were documented (70 vs 75 events, p = 0.60). On multivariate Cox regression analysis, including age, number of risk factors, BA diameter, presence of coronary artery disease, BA-FMD, and BA-IMT, only the presence of coronary artery disease and BA-IMT remained significantly associated with outcome. In conclusion, BA-IMT, but not BA-FMD, predicted cardiovascular events and cardiovascular death with ≤12 years of follow-up in patients undergoing an invasive evaluation of chest pain. Our results represent, by far, the longest follow-up of BA-IMT and peripheral endothelial function testing compared with previously reported data.
The carotid intima media thickness (IMT) is thought to be a marker of atherosclerosis and is frequently used for cardiovascular risk assessment in asymptomatic adults in routine clinical practice. Measurements of the brachial artery IMT (BA-IMT) have not been established in daily clinical practice, although atherosclerosis also occurs in this vessel. An increased BA-IMT was associated with a greater risk of cardiovascular events in patients with chest pain. In addition to the BA-IMT measurements, the peripheral endothelial function can also be assessed in the brachial artery by calculating the BA flow-mediated vasodilation (BA-FMD). The prognostic data of BA-FMD have been conflicting, especially in those with established cardiovascular disease. We have demonstrated that BA-IMT, but not BA-FMD, has a prognostic value after a mean follow-up of 39 months in patients undergoing coronary angiography for evaluation of chest pain. BA-IMT has increasingly been used as a surrogate end point parameter, and the longest follow-up duration for BA-FMD reported to date is 67 months. Therefore, the aim of the present analysis was to evaluate the prognostic value of BA-IMT and BA-FMD in a previously investigated patient cohort >10 years after study initiation.
Methods
A total of 396 male patients (mean age 54 ± 9 years) who underwent coronary angiography to evaluate chest pain and positive exercise stress test findings were consecutively enrolled. The exclusion criteria were age >70 years and the presence of acute coronary syndrome, congestive heart failure, left ventricular ejection fraction <40%, and significant valvular disease. Coronary artery disease (CAD) was defined as ≥30% diameter stenosis in ≥1 major coronary vessels. All patients provided written informed consent, and the local ethical committee approved the present study. We have certified that we complied with the “Principles of Ethical Publishing” in the International Journal of Cardiology.
After inclusion, fasting blood samples were obtained, and the coronary risk factors were assessed, as previously described. On the day after coronary angiography, high-resolution ultrasonography (13 MHz, Acuson Sequoia C256, Mountain View, California) was used for the assessment of BA-IMT and BA-FMD. After a mean follow-up of 141 ± 12 months, cardiovascular events were assessed by a review of the hospital records and included coronary revascularization either by coronary artery bypass grafting or percutaneous coronary intervention, acute coronary syndrome (either ST-segment elevation myocardial infarction or non–ST-segment elevation acute coronary syndrome according to the common definition), ischemic stroke, and cardiovascular death (death from myocardial infarction, stroke, or other atherosclerotic disease). An official death registry, recording the deaths occurring in Austria, was reviewed at the beginning of 2012, including deaths to the end of 2011. The power analysis, performed for the earlier published results at 36 months of follow-up, calculated a sample size of 150 patients in each group with a power of 80% to detect a 10% difference in events (α = 0.05).
BA-IMT was measured as the distance between the lumen–intima and the media–adventitia border using a regional expansion system in addition to 13-MHz ultrasonography, as previously described.
BA-FMD measurements were performed by scanning the right brachial artery, as previously described, between 9 a.m . and 12 a.m. by an observer who was unaware of the patient diagnosis. To induce hyperemia, a cuff was placed on the upper arm and inflated to suprasystolic levels for 5 minutes. For 120 seconds after deflation of the cuff, serial scans were stored on a hard disk. Finally, 0.8 mg nitroglycerin was given sublingually. The maximum diameter after cuff release and nitroglycerin application were used to calculate the BA-FMD and BA-NMD. Measurements were obtained at 2 sites per image on 4 different images per patient. The interobserver variability of BA-IMT and BA-FMD in our laboratory have been previously published.
All analyses were conducted using statistical software, SPSS Statistics, version 20 (IBM, Armonk, New York). Data are expressed as the mean ± SD or frequencies and percentages. A normal distribution of variables was tested using the Kolmogorov-Smirnov test. The patient characteristics between groups were compared using the Student t test or Mann-Whitney U test for continuous variables and the chi-square test for categorical variables, as appropriate. Cumulative event rates were calculated using the Kaplan-Meier method and log-rank test. Cox regression analyses were performed to determine the variables independently associated with the occurrence of cardiovascular events. p Values <0.05 were considered statistically significant.
Results
The clinical characteristics and rate of antihypertensive and lipid-lowering medications for the overall patient cohort and the analyzed subgroups are summarized in Table 1 . BA-IMT measurements were feasible in 359 patients. The patients were divided into 2 groups according to the median BA-IMT (0.37 mm in the overall cohort and in patients with CAD). To analyze the prognostic value of BA-FMD, the study population was also divided according to the median BA-FMD (7.6%). No differences in the use of antihypertensive medication or statin treatment was found according to the median BA-FMD.
| Variable | Overall | Overall by BA-IMT Median | CAD by BA-IMT Median | ||||
|---|---|---|---|---|---|---|---|
| <0.37 (n = 178) | ≥0.37 (n = 181) | p Value | <0.37 (n = 130) | ≥0.37 (n = 156) | p Value | ||
| Age (yrs) | 54 ± 9 | 50 ± 9 | 58 ± 8 | <0.001 | 51 ± 9 | 58 ± 6 | <0.001 |
| Number of risk factors | 1.95 ± 0.98 | 1.86 ± 0.95 | 2.04 ± 0.96 | 0.15 | 2.02 ± 0.93 | 2.09 ± 0.95 | 0.80 |
| Coronary artery disease | 79% | 73% | 86% | 0.002 | |||
| Arterial hypertension | 54% | 43% | 69% | <0.001 | 42% | 70% | <0.001 |
| Smoker | 33% | 32% | 34% | 0.71 | 36% | 36% | 0.93 |
| Diabetes mellitus | 8% | 4% | 11% | 0.02 | 5% | 11% | 0.10 |
| Positive family history | 23% | 28% | 17% | 0.01 | 35% | 17% | <0.001 |
| Hypercholesterolemia ∗ | 77% | 79% | 75% | 0.30 | 82% | 76% | 0.12 |
| Total cholesterol (mg/dl) | 218 ± 49 | 218 ± 43 | 217 ± 55 | 0.92 | 218 ± 45 | 217 ± 57 | 0.85 |
| Low-density lipoprotein cholesterol (mg/dl) | 143 ± 41 | 142 ± 39 | 144 ± 44 | 0.66 | 144 ± 40 | 145 ± 44 | 0.76 |
| High-density lipoprotein cholesterol (mg/dl) | 47 ± 14 | 47 ± 14 | 48 ± 13 | 0.21 | 46 ± 12 | 47 ± 12 | 0.57 |
| Triglycerides (mg/dl) | 171 ± 124 | 171 ± 102 | 159 ± 96 | 0.43 | 176 ± 110 | 161 ± 98 | 0.37 |
| Body mass index (kg/m 2 ) | 27.0 ± 3.5 | 26.4 ± 3.2 | 27.5 ± 3.6 | 0.003 | 26.8 ± 3.3 | 27.4 ± 3.5 | 0.09 |
| Brachial artery flow-mediated vasodilation (%) | 8.1 ± 4.2 | 8.4 ± 4.3 | 8.0 ± 3.9 | 0.34 | 8.4 ± 4.5 | 8.1 ± 4.1 | 0.49 |
| Brachial artery nitroglycerin-mediated vasodilation (%) | 17.6 ± 7.1 | 17.7 ± 7.4 | 17.5 ± 7.0 | 0.83 | 17.7 ± 7.7 | 17.6 ± 7.2 | 0.86 |
| Brachial artery intima media thickness (mm) | 0.36 ± 0.07 | 0.31 ± 0.04 | 0.42 ± 0.04 | <0.001 | 0.31 ± 0.04 | 0.42 ± 0.04 | <0.001 |
| Angiotensin-converting enzyme inhibitors | 23% | 22% | 24% | 0.65 | 29% | 24% | 0.41 |
| Angiotensin receptor blockers | 4% | 2% | 4% | 0.36 | 2% | 5% | 0.21 |
| β Blocker | 50% | 48% | 56% | 0.05 | 61% | 60% | 0.95 |
| Calcium antagonist | 13% | 10% | 14% | 0.04 | 10% | 15% | 0.21 |
| Statin | 24% | 24% | 25% | 0.54 | 30% | 26% | 0.53 |
∗ Low-density lipoprotein cholesterol >130 mg/dl and/or statin therapy.
During a mean follow-up of 141 ± 12 months (range 122 to 168), 216 events (coronary revascularization in 101, acute coronary syndrome in 59, stroke in 28, and cardiovascular death in 28) were documented. For statistical analysis, whichever of the events occurred first was included in the combined end point (n = 145). The combined end point occurred in 135 patients with CAD (43%) and in 10 patients with non-CAD (12%). Separate analyses were performed for cardiovascular death. From the initially included and analyzed 398 patients, 2 patients were excluded from the recent analysis because they had moved abroad.
In the overall study cohort, the combined end point (50 vs 78 events, p = 0.003) and cardiovascular death (3 vs 20 events, p <0.001) occurred less often in those with BA-IMT less than the median of 0.37 mm. Classifying patients according to the median BA-FMD, neither the combined end point (70 vs 75 events, p = 0.60) nor the rate of cardiovascular death (18 vs 10 events, p = 0.12) was significantly different. The results of Cox regression analyses for the combined end point and cardiovascular death are listed in Table 2 .
| Covariate | OR (95% CI) | p Value |
|---|---|---|
| Combined end point ∗ | ||
| Age (per yr) | 0.99 (0.98–1.01) | 0.77 |
| Number of risk factors | 1.09 (0.90–1.32) | 0.36 |
| Brachial artery diameter | 0.80 (0.55–1.16) | 0.23 |
| Presence of coronary artery disease | 6.23 (2.28–14.34) | <0.001 |
| Brachial artery intima media thickness greater than median | 1.52 (1.04–2.24) | 0.03 |
| Brachial artery flow mediated vasodilation greater than median | 1.05 (0.72–1.54) | 0.79 |
| Cardiovascular death | ||
| Covariate | ||
| Age (per yr) | 1.06 (1.00–1.12) | 0.04 |
| Number of risk factors | 1.68 (1.10–2.56) | 0.02 |
| Brachial artery diameter | 1.22 (0.55–2.71) | 0.62 |
| Presence of coronary artery disease | 1.28 (0.37–4.40) | 0.70 |
| Brachial artery intima media thickness greater than median | 4.16 (1.17–14.71) | 0.03 |
| Brachial artery flow mediated vasodilation greater than median | 2.0 (0.76–5.23) | 0.16 |
∗ Revascularization, acute coronary syndrome, stroke, and cardiovascular death.
When only patients with CAD were analyzed, more combined end points (47 vs 75 events, p = 0.04) and cardiovascular deaths (2 vs 18 events, p = 0.001) occurred in those with a BA-IMT greater than the median ( Figure 1 ). For BA-FMD, no differences in the event rates for the combined end point were found between those with a BA-FMD value less than versus greater than median (69 vs 66 events, p = 0.70; Figure 1 ). A trend toward more cardiovascular deaths in those with a decreased BA-FMD was found in patients with CAD (17 vs 8, p = 0.06; Figure 1 ). Cox regression analyses revealed BA-IMT was associated with the combined end point, and BA-IMT and the number of risk factors present were associated with cardiovascular death. For BA-FMD, a trend toward an association with cardiovascular death was found ( Table 3 ).
| Covariate | OR (95% CI) | P Value |
|---|---|---|
| Combined end point ∗ | ||
| Age (per yr) | 0.99 (0.98–1.02) | 0.75 |
| Number of risk factors | 1.09 (0.90–1.33) | 0.39 |
| Brachial artery diameter | 0.72 (0.49–1.06) | 0.10 |
| Brachial artery intima media thickness greater than median | 1.52 (1.03–2.26) | 0.04 |
| Brachial artery flow-mediated vasodilation greater than median | 1.22 (0.82–1.80) | 0.32 |
| Cardiovascular death | ||
| Age (per yr) | 1.04 (0.99–1.10) | 0.13 |
| Number of risk factors | 1.80 (1.15–2.81) | 0.01 |
| Brachial artery diameter | 1.14 (0.48–2.71) | 0.77 |
| Brachial artery intima media thickness greater than median | 5.76 (1.28–25.92) | 0.02 |
| Brachial artery flow-mediated vasodilation greater than median | 2.91 (0.98–8.68) | 0.06 |
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