Arterial diameter is an underutilized indicator of vascular health. We hypothesized that interadventitial and lumen diameter of the common carotid artery would be better indicators of vascular health than carotid plaque or intima media thickness (IMT). Participants were 491 overweight or obese, postmenopausal women who were former or current hormone therapy (HT) users, 52–62 years, with waist circumference
Until recently, the adventitia has been largely neglected [
The results from one of these studies, an ancillary of the Study of Women’s Health Across the Nation (SWAN) called SWAN Heart, suggest that declining endogenous estrogen that accompanies the menopausal transition has a direct effect on the peripheral vasculature [
The strong association between IAD and endogenous estrogen suggests that a similar association may exist with the use of exogenous estrogen. The purpose of this study was to determine whether postmenopausal current HT users had significantly different IAD than those who were former users of HT in the Women on the Move through Activity and Nutrition (WOMAN) randomized trial. We also wanted to determine if there were differences between other measures of vascular health.
This study evaluates cross-sectional associations using measurements from the baseline visit of the clinical trial (clinical trials registry number: NCT 00023543). The WOMAN trial tested the ability of nonpharmacological lifestyle intervention to modify cardiovascular risk factors in postmenopausal women. The study recruited 508 eligible African American and Caucasian women from Allegheny County, PA, between April 2002 and October 2003 through direct mailings. Eligible women were postmenopausal, between 52 and 62 years of age, able to walk, currently using HT, and willing to participate in either intervention group regardless of assignment and had a waist circumference ≥80 cm, a body mass index (BMI) between 25.0 and 39.9 kg/m2, blood pressure <160/95 mmHg, and low density lipoprotein (LDL) cholesterol between 100 and 160 mg/dL. Women were ineligible if they were taking medication for cholesterol, diagnosed with or on medication for diabetes, diagnosed with a psychotic disorder, or suffering from depression [
Common carotid artery intima media thickness (IMT), IAD, lumen diameter (LD), and plaque were assessed by B-mode ultrasound using a Toshiba SSA-270A duplex scanner (Toshiba American Medical Systems, Tustin, CA, USA) with a 5 MHz-linear array transducer. Right and left carotid images were taken of the near and far walls of the distal common carotid artery 1 cm proximal to the carotid bulb [
Measurement of the common carotid artery lumen diameter (LD), intima media thickness (IMT), and interadventitial diameter (IAD) also known as adventitial diameter.
The presence of plaque was determined for each of the 5 segments of the left and right carotid artery (distal and proximal CCA, carotid bulb, and proximal internal and external carotid artery). Plaque was defined as a distinct area protruding into the vessel lumen at least 50% thicker than the adjacent IMT. This analysis categorized plaque as either absent or present.
The first of two prerandomization screening visits included a 12-hour fasting blood draw, physical measures of height, weight, waist circumference, blood pressure, the long distance corridor walk, medical, physical activity, and weight history. Conventional enzymatic methods were used to obtain total cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride concentrations from the blood samples [
Five hundred eight women were randomized into the WOMAN study. Seventeen women had incomplete data for the calculation of IAD or IMT and were excluded leaving 491 women for analysis. All analyses were completed using SAS v9.1 or v9.2 (SAS Institute Inc., Cary, NC, USA). A
Descriptive statistics and normality of continuous measures were assessed for the cohort. Means and standard deviations are presented for normally distributed variables and medians and 25th and 75th percentiles are provided for nonparametric variables; dichotomous variables are presented as percents. Differences between the current HT users and the former HT users were determined using chi-square analyses for categorical variables and
Simple linear regression was used to assess univariate associations between IAD and LD with HT and the following cardiovascular risk factors: age, race, systolic blood pressure, diastolic blood pressure, pulse pressure, BMI, weight, height, waist circumference, total cholesterol, LDL and HDL cholesterol, triglycerides, glucose, insulin, smoking status, and antihypertensive medication use. When collinearity between covariates was suspected (
The median (25th, 75th percentiles) age of the women was 57 (55, 60) years, median BMI was 30 (28, 34) kg/m2; 11% were African American and 6% were current smokers. There were 197 former HT users and 294 current HT users at the time of the baseline carotid ultrasound scan. Former HT users were older and had a higher percent of African Americans (Table
Demographic, anthropometric and health characteristics by hormone therapy use.
Former users ( |
Current users ( |
|
|
---|---|---|---|
Age, years | 57.2 (55.2, 60.0) | 56.5 (54.1, 59.2) | 0.006 |
African American Race, % | 16.9 | 7.2 | 0.008 |
Systolic blood pressure, mmHg | 123.6 ± 13.0 | 123.7 ± 13.4 | 0.899 |
Diastolic blood pressure, mmHg | 76.7 ± 7.6 | 76.1 ± 8.0 | 0.349 |
Pulse pressure, mmHg | 46.8 ± 10.5 | 47.7 ± 10.8 | 0.400 |
Body mass index, kg/m2 | 29.9 (27.6, 33.5) | 30.0 (27.5, 33.4) | 0.793 |
Weight, kg | 79.4 (72.8, 9.0) | 80.7 (72.6, 89.8) | 0.849 |
Height, cm | 163.3 ± 5.6 | 162.9 ± 5.9 | 0.493 |
Waist circumference, cm | 105.5 ± 11.8 | 105.9 ± 10.7 | 0.520 |
Cholesterol, mg/dL | 223.1 ± 29.0 | 212.5 ± 26.7 | <0.0001 |
High density lipoprotein, mg/dL | 56.8 (49.7, 67.0) | 59.8 (51.8, 69.0) | 0.052 |
Low density lipoprotein, mg/dL | 137.1 ± 26.0 | 122.1 ± 22.8 | <0.0001 |
Triglycerides, mg/dL | 119.0 (94.5, 159.0) | 130.5 (96.0, 173.5) | 0.222 |
Glucose, mg/dL | 97.3 ± 9.0 | 93.8 ± 9.0 | <0.0001 |
Insulin, mg/dL | 13.0 (9.9, 17.2) | 11.6 (8.8, 15.8) | 0.004 |
Current cigarette smoker, % | 8.1 | 5.1 | 0.181 |
Antihypertensive medications, % | 25.9 | 21.4 | 0.251 |
achi-square for categorical variables,
The mean IAD was 6.94 mm for former HT users and 6.79 mm for current HT users (
Subclinical measures of cardiovascular disease by hormone therapy use.
Former users ( |
Current users ( |
|
|
---|---|---|---|
Inter-adventitial diameter, mm | 6.94 ± 0.54 | 6.79 ± 0.52 | 0.001 |
Lumen diameter, mm | 5.44 ± 0.48 | 5.31 ± 0.46 | 0.002 |
Intima media thickness, mm | 0.70 (0.65, 0.77) | 0.71 (0.65, 0.77) | 0.900 |
Presence of plaque, % | 30.5 | 29.6 | 0.838 |
achi-square for categorical,
Simple linear regression showed that in addition to former HT use, larger IAD was significantly associated with greater systolic blood pressure, pulse pressure, BMI, weight, height, waist circumference (all
Univariate linear regression showing the association of demographic and cardiovascular risk factors with common carotid artery diameter.
Interadventitial diameter | Lumen diameter | |||
---|---|---|---|---|
|
|
|
|
|
Current HT use | −0.157 (0.048) | 0.001 | −0.132 (0.043) | 0.002 |
Age, years | 0.017 (0.008) | 0.037 | 0.005 (0.007) | 0.460 |
African American race | −0.187 (0.076) | 0.014 | −0.067 (0.068) | 0.326 |
Systolic blood pressure, mmHg | 0.007 (0.002) | <0.0001 | 0.003 (0.002) | 0.049 |
Diastolic blood pressure, mmHg | 0.003 (0.003) | 0.410 | 0.001 (0.003) | 0.796 |
Pulse pressure, mmHg | 0.010 (0.002) | <0.0001 | 0.004 (0.002) | 0.025 |
Body mass index, kg/m2 | 0.031 (0.006) | <0.0001 | 0.021 (0.006) | 0.0001 |
Weight, kg | 0.013 (0.002) | <0.0001 | 0.009 (0.002) | <0.0001 |
Height, cm | 0.016 (0.004) | <0.0001 | 0.012 (0.004) | 0.001 |
Waist circumference, cm | 0.009 (0.002) | <0.0001 | 0.007 (0.002) | 0.001 |
Cholesterol, mg/dL | 0.001 (0.001) | 0.435 | 0.000 (0.001) | 0.532 |
HDL cholesterol, mg/dL | −0.000 (0.002) | 0.991 | 0.000 (0.002) | 0.830 |
LDL cholesterol, mg/dL | 0.001 (0.001) | 0.338 | 0.001 (0.001) | 0.396 |
Triglycerides, mg/dL | −0.000 (0.000) | 0.631 | −0.000 (0.000) | 0.406 |
Glucose, mg/dL | 0.009 (0.003) | 0.001 | 0.006 (0.002) | 0.013 |
Insulin, mg/dL | 0.012 (0.004) | 0.001 | 0.009 (0.003) | 0.006 |
Current cigarette smoker | −0.205 (0.098) | 0.037 | −0.116 (0.088) | 0.184 |
Antihypertensive medication use | 0.132 (0.057) | 0.020 | 0.088 (0.050) | 0.083 |
Std: standard. HDL: high density lipoprotein. LDL: low density lipoprotein.
Multivariable linear regression of factors associated with common carotid artery diameter.
Interadventitial diameter | Lumen diameter | |||
---|---|---|---|---|
|
|
|
|
|
Current HT use | −0.137 (0.047) | 0.004 | −0.125 (0.043) | 0.004 |
Age, years | 0.013 (0.008) | 0.106 | 0.003 (0.007) | 0.630 |
African American race | −0.049 (0.074) | 0.503 | 0.033 (0.068) | 0.623 |
Pulse pressure, mmHg | 0.008 (0.002) | 0.0002 | 0.003 (0.002) | 0.081 |
Weight, kg | 0.012 (0.002) | <0.0001 | 0.009 (0.002) | <0.0001 |
Current cigarette smoker | −0.180 (0.093) | 0.052 | −0.106 (0.085) | 0.214 |
Std: standard.
Current HT use was associated with a 0.14 mm smaller IAD (Table
Former HT use, greater BMI, weight, height, waist circumference, insulin (all
Current HT use was associated with a 0.13 mm smaller LD (Table
Postmenopausal current HT users had statistically significant smaller IAD than the former HT users; this relationship remained significant after adjustment for known cardiovascular risk factors. The current HT users also had statistically significant smaller LD than the former HT users. In contrast, IMT and plaque were not statistically different between current HT users and former HT users. This suggests that HT may be associated with preserved vascular geometry in postmenopausal women. It also demonstrates the value of measuring IAD and LD in this type of study.
The adventitia, the most outer layer of the artery, is composed of supportive connective tissue, fibroblasts, collagen, and elastin fibers [
The results of the current study, specifically the association of current exogenous estrogen use with smaller IAD, is in line with the SWAN Heart study [
Current HT use was associated with smaller LD. These findings agree with the results of a cross-sectional study that found smaller LD among non-oral (percutaneous gel or transdermal patch) HT users compared to HT non-users [
Both the current study and the SWAN Heart study found that larger diameter was associated with older age, higher systolic blood pressure, higher glucose, and higher insulin: all risk factors for CVD. Additional supporting evidence that enlarged diameter is an indicator of poor vascular health come from several studies showing enlarged IAD is associated with cardiovascular disease risk factors [
Arterial diameter differences in current HT users and former HT users were observed in this study but differences in IMT were not. Consistent with our findings, a cross-sectional study of an American cohort from the Atherosclerosis Risk in Communities (ARIC) study [
Three studies evaluated differences in IMT by HT and age [
A limitation of this study is that the HT regimen was varied since the dose, hormone composition (estrogen only or estrogen plus progestin), and form were chosen prior to the study by the participant and her health care provider. The main type of HT was oral. One study observed that transdermal HT had greater effects on IMT than oral HT [
Strengths of this study are that it fills a gap in the literature, the methods used are valid and reliable, the lab that performed the ultrasound measures has high quality control, and it is one of the first to evaluate IAD and HT. The contribution of the adventitia to vascular function has been largely ignored [
In conclusion, these data suggest that current HT use is associated with vascular geometry in the postmenopausal women independent of cardiovascular risk factors. It also demonstrates the importance of measuring IAD and LD in postmenopausal women with differing HT use. These measures should be included in addition to IMT to provide a more complete story of vascular response and health.
The authors declare no conflict of interests.
Dr. Lloyd would like to thank the Woman On the Move through Activity and Nutrition participants and staff for their commitment to the study, Theresa Fanelli for her assistance with dataset preparation and Dr. Jack Guralnik for his assistance on the revision. This research was funded by the National Institutes of Health, National Heart, Lung and Blood Institute contract R01-HL-66468. K. D. Lloyd was supported by National Institute on Aging Training Grants T32 AG000181 and T32 AG000262 during the creation and preparation of this paper.