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Non-invasive evaluation of endothelial function in hypertensive elderly patients
Archives of Gerontology and Geriatrics 40 (2005) 61–71
Non-invasive evaluation of endothelial function in hypertensive elderly patients Bulent Saka a,∗ , Huseyin Oflaz b , Nilgun Erten a , Gulistan Bahat a , Memduh Dursun c , Burak Pamukcu b , Fehmi Mercanoglu b , Mehmet Meric b , M. Akif Karan d a
Department of Internal Medicine, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey b Department of Cardiology, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey c Department of Radiology, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey d Department of Geriatrics, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey Received 24 November 2003; received in revised form 7 May 2004; accepted 20 May 2004 Available online 28 July 2004
Abstract Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium. The aim of the present study was to investigate the effects of aging and hypertension on endothelial function. Sixty-six geriatric subjects with ages over 60 (48 hypertensive and 18 healthy) and 40 middle-aged subjects (16 hypertensive and 24 healthy) were included in the study. Systemic vascular endothelial function was evaluated through measuring brachial arterial vasodilation, a physiologic answer to reactive hyperemia occured with increased blood flow in the vessel after transient ischemia (flow-mediated dilation, FMD%), and with carotid artery intima-media thickness (IMT) measurement, using high-resolution ultrasonography. Endothelial independent vasodilation was also measured after administration of sublingual isosorbide dinitrate (isosorbide dinitrate mediated dilation, IDNMD%). FMD% was significantly decreased in elderly and/or hypertensive (HT) patients (geriatric HT: 9.5 ± 4.7%, geriatric non-HT: 12.7 ± 5.5%, middle-aged HT: 12.9 ± 4.3% and middle-aged non-HT: 18.9 ± 8.1%) (geriatric HT versus geriatric non-HT (P = 0.02), geriatric HT versus middle-aged HT (P = 0.01), geriatric non-HT versus middle-aged non-HT (P = 0.008)). Both FMD% and IDNMD% were inversely correlated with age, baseline vessel diameter and carotid artery intima-media thickness. FMD% was also inversely correlated with diastolic blood pressure. No correlation was found between FMD% and systolic blood pressure, serum cholesterol and triglyceride levels. Endothelium dependent (EDD) and independent dilatation of large arteries decreased with aging even in the healthy elderly,
∗ Corresponding author. Tel.: +90 212 414 20 00x31478; fax: +90 212 532 42 08. E-mail address: [email protected] (B. Saka).
0167-4943/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2004.05.008
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and FMD further declined in HT elderly patients, indicating that age and hypertension independently impair endothelial function. Positive correlations with age and hypertension, and significant inverse correlation with FMD, makes carotid artery IMT a possible indicator of endothelial function. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Flow-mediated dilation; Elderly; Hypertension
1. Introduction Healthy endothelium regulates vascular tone through powerful vasodilating substances such as endothelium-derived relaxing factor and nitric oxide and vasoconstrictors such as endothelin in response to physical and chemical stimuli (Drexler, 1999). Endothelial dysfunction (ED) in large arteries is an important early event in the atherogenic process. Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium (Celermajer, 1997) and impaired peripheral endothelial function may also be a marker of increased future cardiovascular disease risk (Fathi and Marwick, 2001). During the 1990s, a technique measuring brachial artery flow-mediated vasodilation (FMD) with high-resolution ultrasound was developed and found to be a reliable marker for systemic endothelial function. Ischemia occured after brachial artery occlusion provokes the endothelium to release nitric oxide, with subsequent vasodilation that can be imaged and quantitated as an index of vasomotor function (Celermajer et al., 1992). There are evidences about association of both aging and hypertension (HT) with progressive endothelial dysfunction (Panza et al., 1990; Celermajer et al., 1994; Deng et al., 1999). However aging was found independent of endothelial function in other studies (Schroeder et al., 2000) and reports about HT were mostly confined to the middle aged group. The aim of the present study was to investigate the endothelial function in normotensive and hypertensive geriatric patients with well-preserved renal function. 2. Materials and methods 2.1. Study population In this prospective study, we included 66 geriatric subjects (48 hypertensive [mean age 71.8 ± 10.9] and 18 healthy [mean age 69.3 ± 7.2]) and 40 middle-aged subjects (16 hypertensive [mean age 40.8 ± 4.9] and 24 healthy [mean age 38.2 ± 8.2]). Subjects with chronic heart failure, renal insufficiency, chronic hemodialysis, significant valvular heart disease or ischemic heart disease were excluded from both geriatric and middle-aged populations. All subjects gave their informed consent to participate in the study. Smoking was outlined as having smoked at least five cigarettes per day within the last 3 months. Venous blood samples were taken after an overnight fasting between 8 and 9 a.m. All biochemical analyses including glucose, total cholesterol, triglyceride concentrations, blood–urea–nitrogen and creatinine were performed at the Technicon DAX-72 auto-analyzer (Technicon, Bayer Corporation, Tarrytown, New York, USA). High-density lipoprotein (HDL)-cholesterol concentrations were also measured at the RA-XT auto-analyzer
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after phosphotungstic acid and magnesium chloride precipitation. Low-density lipoprotein (LDL)-cholesterol was calculated by Friedewald formula. Hyperlipidemia was defined as a serum total cholesterol ≥200 mg/dl or LDL-cholesterol ≥130 mg/dl and/or serum triglyceride ≥200 mg/dl or being on a lipid lowering diet (Brewer, 2003). Hypertension was defined as having a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg (Chobanian et al., 2003) or being on a anti-HT medication. All patients in HT groups were on an anti-HT regimen. Body mass index (BMI) was determined in all subjects. None of the subjects in two groups had taken any vitamins in the past year. 2.2. Assessment of flow-mediated and nitroglycerin-induced vasodilations of the brachial artery FMD of the brachial artery following transient ischemia was measured according to a noninvasive method for assessing endothelial function defined by Celermajer (Celermajer et al., 1992) using an ultrasound system with a high-resolution (10 MHz) linear array transducer (Vingmed System Five, Norway). All groups were abstained from smoking and caffeine containing drinks for at least 12 h. They were kept in supine position in the stable room temperature between 20 and 25 ◦ C during the ultrasonographic examination. In order to best visualize the brachial artery (BA), the arm was comfortably immobilized in the extended position and BA was scanned in the longitudinal section 3–5 cm above the antecubital fossa. After optimal transducer positioning, the skin was marked for reference for later measurements and arm was kept in the same position throughout the study. All measurements of the BA lumen diameter were assessed at the end-diastole (timed by the QRS complex) and were calculated as the average of the measurements obtained during three consecutive cardiac cycles. After baseline measurements of the BA were recorded, the cuff was inflated to 200 mmHg (or 50 mmHg higher than systolic blood pressure) for 5 min to create a transient forearm ischemia. Subsequently, the cuff was deflated and the arterial diameter was measured at 60 s after deflation. In addition, endothelium independent vasodilatation (EID), a surrogate marker for vascular smooth muscle function, was assessed by measuring changes in BA diameter following sublingual isosorbide dinitrate (IDN) administration in all groups. Ten minutes after the first measurement, 5 mg of IDN was administered sublingually and measurements were repeated 3 min later. All measurements were performed by single investigator blinded to clinical details and echocardiographic results of the study groups and were recorded on VHS videotape for subsequent off-line analysis. Endothelium dependent (EDD) and independent dilatations were determined according to the percentage changes in the BA diameter following reactive hyperemia (FMD%) and sublingual isosorbide dinitrate (sublingual isosorbide dinitrate mediated dilation, IDNMD%) administration calculated by dividing the difference from baseline diameter by the baseline value multiplied by 100. The interobserver and intraobserver variability for measurements of brachial artery diameter were 3%. 2.3. Carotid intima-media thickness measurements Bilateral common carotid arteries of the subjects were scanned longitudinally with an ultrasonographic method through high resolution 10 MHz linear array transducer (attached
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to standart Vingmed System Five, Norway). The bulb dilation served as a landmark to indicate the border between distal common carotid artery and the carotid bulb. Images were obtained from the distal portion of the common carotid artery, 1–2 cm proximal to the carotid bulb. Images were saved and stored on S-VHS videotape. The two bright echogenic lines in the arterial wall were identified as the intima and media lines. The intimal plus medial thickness (intima-media thickness, IMT) was measured as the distance from the main edge of the first to main edge of the second echogenic line. Each measurements were repeated three times and the mean of the left and right common carotid arteries was taken and used for further analysis. All scans were made by the same observer. None of the subjects had atheroma, localized lesion of thickness >2.0 mm or stenosis in this region. 2.4. Statistical analysis Continuous variables were described by the use of statistical characteristics (means, standard deviations, median). Discrete variables were described as counts and percentages. Using chi-square test, homogeneity of the groups were identified according to the non-numeric variables such as gender, smoking, number of diabetic patients and drug usages. Unpaired Student t-tests were used to compare the test results. Relationship between FMD and IDNMD with other variables were assessed by Unpaired Student t-test and Spearman’s rho correlation test. A P value of <0.05 was taken to define statistical significance. 3. Results No significant difference was found between the groups when gender, smoking habbits, diabetic population and the usage of certain drugs (anti-HT drugs, acetylsalicylic acid and statins) were taken into consideration (Table 1). Numeric variables such as; age, serum glucose, cholesterol, triglycerides, creatinine, BA basal diameter, diastolic and systolic blood pressure and BMI were also matched between groups (Tables 2A and 2B). Table 1 Matching of the groups for non-parametric variables Geriatric HT (n = 48) Gender (female/male) DM Smoking ACE-I Diuretics ARB BB CCB ASA Statin
13/35 8/40 10/38 18/30 16/32 12/36 12/36 9/39 9/39 5/43
Total
48
Middle-aged HT (n = 16) 4/12 3/13 4/12 6/10 5/11 4/12 4/12 3/13 3/13 2/14 16
Geriatric non-HT (n = 18) 4/14 3/15 4/14
18
Middle-aged non-HT (n = 24) 6/18 4/20 5/19
P value 0.9 0.9 0.9 0.6 0.6 0.6 0.6 0.6 0.6 0.6
24
ACE-I: angiotensin converting enzyme inhibitors, ARB: angiotensin-1 receptor blockers, ASA: acetylsalicylic acid, BB: beta-blocker, CCB: calcium channel blocker, DM: diabetes mellitus.
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Table 2 Unpaired Student t-test: group statistics of the parametric variables
Age Glucose (mg/dl) Creatinine (mg/dl) Cholesterol (mg/dl) Triglyceride (mg/dl) BMI (kg/m2 ) Systolic BP (mmHg) Diastolic BP (mmHg) BA baseline diameter (mm) FMD (%) IDNMD (%) CA IMT (mm) Total
Geriatric HT (n = 48)
Middle-aged HT (n = 16)
Geriatric non-HT (n = 18)
Middle-aged non-HT (n = 24)
71.8 ± 10.9 113 ± 31 0.93 ± 0.20 194 ± 29 143 ± 48 27.4 ± 4.9 128 ± 9 73 ± 6 3.8 ± 0.5 9.5 ± 4.7 12.5 ± 9.5 0.74 ± 0.17
40.8 ± 4.8 103 ± 15 0.91 ± 0.10 180 ± 31 151 ± 22 26.0 ± 3.2 134 ± 14 77 ± 13 3.7 ± 0.4 12.9 ± 4.3 19.3 ± 6.8 0.58 ± 0.13
69.3 ± 7.2 102 ± 23 0.81 ± 0.12 197 ± 21 145 ± 54 25.9 ± 4.1 113 ± 14 71 ± 7 3.4 ± 0.5 12.7 ± 5.5 12.1 ± 6.6 0.60 ± 0.10
38.1 ± 8.8 101 ± 16 0.78 ± 0.10 187 ± 25 148 ± 28 24.5 ± 3.5 119 ± 14 71 ± 7 3.4 ± 0.6 18.9 ± 8.1 25.0 ± 9.9 0.45 ± 0.10
48
16
18
24
BP: blood pressure.
Table 3 Unpaired Student t-test: independent samples test for matching of the parametric variables between groups
Age Glucose Creatinine Cholesterol Triglyceride BMI Systolic BP Diastolic BP BA baseline diameter FMD (%) IDNMD (%) CA IMT
Geriatric HT with middle-aged HT (P value)
Geriatric HT with geriatric non-HT (P value)
Geriatric non-HT with middle-aged Non-HT (P value)
<0.0001 NS NS 0.1 NS NS NS NS NS 0.01 0.01 0.002
NS NS 0.03 NS NS NS <0.001 NS 0.004 0.02 NS 0.004
0.0001 NS NS 0.2 NS NS NS NS NS 0.008 <0.0001 <0.0001
NS: non-significant.
Mean ages of the geriatric groups were significantly higher than middle-aged populations, as can be predicted (Table 2A, P < 0.0001). Differences between the mean serum creatinine level and baseline BA diameter of geriatric HT and geriatric non-HT groups were statistically significant (P = 0.03 and 0.004), and renovascular changes due to HT can be involved in the elevated serum creatinine levels in geriatric HT group. Normal mean blood pressures of the HT patients were related with effective anti-HT regimens. No significant difference was found between the groups, when BMI and diastolic blood pressure of the subjects were taken into consideration.
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Table 4 Spearman’s rho correlation to study the influence of age and cardiovascular risk factors on the test results FMD%
Age Glucose Creatinine Cholesterol Triglyceride BMI Systolic BP Diastolic BP CA IMT BA baseline diameter
IDNMD%
P value
rs
P value
rs
<0.001 0.462 0.280 0.252 0.168 0.975 0.06 0.002 <0.001 <0.001
−0.410 −0.073 −0.107 −0.113 0.136 −0.03 −0.185 −0.307 −0.463 −0.341
<0.001 0.702 0.858 0.428 0.451 0.208 0.857 0.085 0.001 0.002
−0.490 −0.041 0.019 −0.086 0.081 −0.135 0.019 −0.185 −0.367 −0.321
rs : correlation coefficient.
FMD and IDNMD of the BA in all groups are shown in Table 2A. The change in the diameter of BA induced by reactive hyperemia in the geriatric HT group was significantly lower than both the geriatric non-HT group and the middle-aged HT group (P = 0.02 and 0.01). FMD% change in geriatric non-HT group is significantly lower than the middle-aged non-HT group (P = 0.008). IDNMD% change in geriatric HT group was significantly lower than the middle-aged HT group (P = 0.01), and it was also significantly low in geriatric non-HT group when compared with middle-aged non-HT group (P < 0.0001). Both FMD% and the dilatation of the BA in response to IDN were inversely correlated with age, baseline vessel diameter and carotid artery IMT (P < 0.0001, P < 0.001; P < 0.001, P = 0.002; P < 0.001, P = 0.001). FMD% was also inversely correlated with diastolic blood pressure (P = 0.002). There were no significant correlation between FMD and systolic blood pressure, serum cholesterol and triglyceride levels (Table 3). No significant relation was found between FMD% and anti-HT drugs and smoking while FMD% decreases with male gender (Table 4). In our study, 51 of 79 females were postmenapousal women (64%) and FMD% decrease in postmenapousal women was distinct statistically when compared with women on normal menses (11.29 ± 5.08% versus 18.62 ± 8.05%, P < 0.001).
4. Discussion The most important findings of the present study are: (a) endothelial dysfunction is associated with aging; (b) endothelial function further declines in hypertensive elderly people; (c) FMD% was inversely correlated with basal lumen diameter of the BA and carotid artery IMT; (d) FMD% was found to be rather independent of the BMI, and (e) endothelial independent vasodilatation was also inversely correlated with age.
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Table 5 Unpaired Student t-test: independent samples test for matching FMD% and IDNMD% with gender, diabetes, smoking and medications FMD%
Gender DM Smoking ACE-I ARB Diuretics BB CCB Statins ASA
IDNMD%
P value
t-ratio
%95-CI
P value
t-ratio
%95-CI
0.014 0.626 0.500 0.302 0.485 0.456 0.785 0.709 0.595 0.896
−2.498 0.488 0.677 −1.040 −0.703 0.750 −0.274 −0.375 −0.534 0.131
−6.626–0.760 −2.636–4.358 −2.097–4.272 −3.772–1.189 −3.964–1.901 −1.607–3.538 −3.264–2.475 −3.702–2.531 −5.254–3.026 −3.269–3.733
0.261 0.705 0.641 0.265 0.347 0.396 0.352 0.919 0.139 0.947
−1.131 0.380 −0.468 −1.128 0.949 −0.857 0.939 −0.102 1.494 −0.067
−7.670–2.107 −4.845–7.138 −6.250–3.867 −8.093–2.270 −3.018–8.429 −7.666–3.080 −3.352–9.239 −6.951–6.280 −1.777–12.516 −6.028–5.637
ACE-I: angiotensin converting enzyme inhibitors, ARB: angiotensin-1 receptor blockers, ASA: acetylsalicylic acid, BB: beta-blocker, CCB: calcium channel blocker, CI: confidence interval, DM: diabetes mellitus.
4.1. Age and FMD% There are evidences for positive correlation between aging and progressive endothelial dysfunction (Deng et al., 1999; Kimura et al., 1999), however, FMD% was found independent of age in some recent trials as well (Schroeder et al., 2000). On multivariate analysis in our study, FMD% was found inversely correlated with age which was an independent factor (P < 0.001, rs = −0.410). Aging is associated with an increasing prevalence of diabetes, HT and hyperlipidemia in the population, and these risk factors for coronary endothelial dysfunction have an important confounding effect. However, in our study, homogeneity of the groups was achieved according to these risk factors, and hypertension was evaluated as an independent risk factor. 4.2. Hypertension and FMD% Mean systolic and diastolic blood pressures of the HT patients in our study were in normal ranges and that was related with the effective anti-HT treatment. FMD% was found inversely correlated with diastolic blood pressure and this dysfunction was further increased with advancing age, however, was independent of the serum concentrations of total cholesterol and triglyceride. Increased systolic blood pressure leads to increased pulse pressure that indicates increased arterial stiffness and hence is commonly seen in older subjects. As patients age and vessels stiffen, there is a resulting loss of arterial compliance, the ability of the vessel to store blood volume temporarily as it is ejected with each systole. Endothelial dysfunction can increase stiffness, raising blood pressure and pulse pressure, and ultimately leading to atherosclerosis, plaque formation, and attendant clinical events (Glasser, 2000). Only a weak inverse relationship was found between systolic blood pressure and FMD% in this study (P = 0.06), and for our opinion, a significant correlation would be evident in a larger sample size.
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4.3. Baseline lumen diameter of the brachial artery and FMD% Some studies showed inverse correlation between the baseline diameter of the BA and FMD% (Celermajer et al., 1992, 1994; Chobanian et al., 2003), other studies did not (Iiyama et al., 1996; Deng et al., 1999). In our study, FMD% showed an inverse correlation with the increasing lumen diameter (P < 0.001). Correlation was distinct in female patients when compared with male patients (respectively, P = 0.002 and 0.350). Due to the low male patient number (27/106, 25%), the clinical implication of this finding remains uncertain. Mean BA baseline diameters were found increased in both HT groups, indeed significant difference was shown between geriatric HT and non-HT groups (P = 0.004). Hemodynamically, increased vascular resistance is the most important component of HT especially in elderly. Increased angiotensin, endothelin-1, sympathetic activity, platelet derived growth factor are involved in vascular hypertrophy and increased media/lumen diameter ratio (Schiffrin and Deng, 1999; Julius et al., 2001). However, increased BA basal lumen diameters were found in our HT patients according to non-HT groups, and that may be due to treatment with calcium channel blockers and angiotensin converting enzyme inhibitors. Although FMD was inversely correlated with the vessel lumen diameter in the whole population, statistical significance in lumen diameter was only found between geriatric HT and non-HT groups in our study. In geriatric HT group, certain patients were under treatment with calcium channel blockers and angiotensin converting enzyme inhibitors, those can cause vasodilatation. On the other hand, FMD was inversely correlated with diastolic HT. So FMD might be influenced by medications and HT, instead of lumen diameter in these subjects. 4.4. Gender and FMD% Mean FMD% change in BA was more intense in female subjects (13.76 ± 7.10% for females versus 10.07 ± 4.87% for males, P = 0.014), however, this was not valid for EID (mean IDNMD%, 17.94 ± 10.89% versus 15.16 ± 8.33%, P = 0.261). Mean FMD% change was also significant in elderly female subjects when compared to elderly male subjects, those were all postmenopausal (11.24 ± 5.14% versus 8.36 ± 4.65%, P = 0.024). However, a more valid analysis will be available in a larger sample size with more male subjects included. Mean basal lumen diameter of BA was significantly smaller in female subjects (3.56 ± 0.54 mm versus 3.93 ± 0.53 mm, P = 0.005) and this might support the hypothesis that larger arteries show less distinct vasodilatations. The absolute risk of coronary disease is greater for men than for pre-menopausal women. Following the menopause gender differences in coronary risk are thought to diminish. Oestrogen deficiency in postmenopausal women may contribute to endothelial dysfunction (Sanada et al., 2003; Walters et al., 2003). Reactive hyperemia is impaired in forearm resistance arteries of postmenopausal women in our study. 4.5. Body mass index and FMD% BMI was ranged from 16.0 to 40.0 (26.35 ± 4.34 kg/m2 ). No significant influence of BMI could be seen on FMD% both in our whole study group (P = 0.733) and in obese
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subjects (BMI > 30 kg/m2 , n = 16) as well (P = 0.488). Thus, BMI cannot be taken into consideration in FMD% measurements. 4.6. Carotid artery intima-media thickness and FMD% Intima-media thickness of the common carotid artery (CA IMT) has been used as a non-invasive end point in epidemiological studies and clinical trials to assess the progression and regression of atherosclerosis in the body, and it is used as a surrogate end point for atherosclerosis of the coronary arteries (Hodis et al., 1998). Early atherosclerosis can be evaluated morphologically through IMT measurement of carotid arteries by ultrasonography (Furumoto et al., 2002). On the other hand, FMD of BA is a functional marker of endothelial function in the body and a significant negative correlation between the CA IMT and percent FMD change of BA was proposed in the past (Hashimoto et al., 1999). In our study, inverse correlation was found between CA IMT and FMD% (P < 0.001). Positive correlation was found between CA IMT and age (elderly versus middle-aged subjects; 0.71 ± 0.17 mm versus 0.50 ± 0.12 mm, P < 0.001). There was also positive correlation between CA IMT and HT (geriatric HT versus geriatric non-HT groups; P = 0.004). No significance was found between CA IMT and gender (P = 0.242). Mean CA IMT was significantly increased in postmenapousal women when compared with other female subjects with normal menses (0.66 ± 0.16 versus 0.52 ± 0.13, P < 0.001). 4.7. IDNMD% Sublingual IDN induces vasodilatation by direct action on the smooth muscles of the vessel, then its effect is endothelium independent. In our study, IDNMD% was inversely correlated with age, basal lumen diameter and CA IMT. Only a weak inverse relationship was found with diastolic HT (P = 0.085), although it was not valid in elderly population (P = 0.875). 4.8. Study limitations Population (n = 106) included in this study was small, especially, when male subjects (n = 27) were taken into consideration, and this might lead to weak relation of FMD% with systolic HT and even no relation with serum lipid levels as well. However, most of the trials in the literature were performed with similar or even less number of patients (Deng et al., 1999; Hashimoto et al., 1999; Schroeder et al., 2000). Further investigations with larger populations are needed for confirmation of the data. Although we could investigate atherosclerosis with ultrasonographic imaging of carotid arteries in the whole population, coronary angiographic data for excluding coronary artery disease was unavailable. Meanwhile, absence of clinical symptoms and demonstrable wall motion abnormalities on echocardiography decreased the possibility of coronary artery disease. Additionally, because of ethical considerations, patients were studied under concurrent medications, and this might have had an influence on the precision of the measurements of FMD%.
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5. Conclusions Endothelium dependent and independent dilatation of large arteries decreased with aging even in the healthy elderly, and FMD further declined in HT elderly patients, indicating that age and HT independently impair endothelial function. Significant inverse correlation between FMD and vessel lumen diameter must be investigated with further studies in larger populations, excluding other factors which can effect the interpretation of FMD change. Positive correlations with age and HT, and significant inverse correlation with FMD, makes CA IMT a possible indicator of endothelial function.
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Non-invasive evaluation of endothelial function in hypertensive elderly patients Bulent Saka a,∗ , Huseyin Oflaz b , Nilgun Erten a , Gulistan Bahat a , Memduh Dursun c , Burak Pamukcu b , Fehmi Mercanoglu b , Mehmet Meric b , M. Akif Karan d a
Department of Internal Medicine, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey b Department of Cardiology, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey c Department of Radiology, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey d Department of Geriatrics, Istanbul Medical School, Istanbul University, 34270 Capa, Istanbul, Turkey Received 24 November 2003; received in revised form 7 May 2004; accepted 20 May 2004 Available online 28 July 2004
Abstract Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium. The aim of the present study was to investigate the effects of aging and hypertension on endothelial function. Sixty-six geriatric subjects with ages over 60 (48 hypertensive and 18 healthy) and 40 middle-aged subjects (16 hypertensive and 24 healthy) were included in the study. Systemic vascular endothelial function was evaluated through measuring brachial arterial vasodilation, a physiologic answer to reactive hyperemia occured with increased blood flow in the vessel after transient ischemia (flow-mediated dilation, FMD%), and with carotid artery intima-media thickness (IMT) measurement, using high-resolution ultrasonography. Endothelial independent vasodilation was also measured after administration of sublingual isosorbide dinitrate (isosorbide dinitrate mediated dilation, IDNMD%). FMD% was significantly decreased in elderly and/or hypertensive (HT) patients (geriatric HT: 9.5 ± 4.7%, geriatric non-HT: 12.7 ± 5.5%, middle-aged HT: 12.9 ± 4.3% and middle-aged non-HT: 18.9 ± 8.1%) (geriatric HT versus geriatric non-HT (P = 0.02), geriatric HT versus middle-aged HT (P = 0.01), geriatric non-HT versus middle-aged non-HT (P = 0.008)). Both FMD% and IDNMD% were inversely correlated with age, baseline vessel diameter and carotid artery intima-media thickness. FMD% was also inversely correlated with diastolic blood pressure. No correlation was found between FMD% and systolic blood pressure, serum cholesterol and triglyceride levels. Endothelium dependent (EDD) and independent dilatation of large arteries decreased with aging even in the healthy elderly,
∗ Corresponding author. Tel.: +90 212 414 20 00x31478; fax: +90 212 532 42 08. E-mail address: [email protected] (B. Saka).
0167-4943/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2004.05.008
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and FMD further declined in HT elderly patients, indicating that age and hypertension independently impair endothelial function. Positive correlations with age and hypertension, and significant inverse correlation with FMD, makes carotid artery IMT a possible indicator of endothelial function. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Flow-mediated dilation; Elderly; Hypertension
1. Introduction Healthy endothelium regulates vascular tone through powerful vasodilating substances such as endothelium-derived relaxing factor and nitric oxide and vasoconstrictors such as endothelin in response to physical and chemical stimuli (Drexler, 1999). Endothelial dysfunction (ED) in large arteries is an important early event in the atherogenic process. Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium (Celermajer, 1997) and impaired peripheral endothelial function may also be a marker of increased future cardiovascular disease risk (Fathi and Marwick, 2001). During the 1990s, a technique measuring brachial artery flow-mediated vasodilation (FMD) with high-resolution ultrasound was developed and found to be a reliable marker for systemic endothelial function. Ischemia occured after brachial artery occlusion provokes the endothelium to release nitric oxide, with subsequent vasodilation that can be imaged and quantitated as an index of vasomotor function (Celermajer et al., 1992). There are evidences about association of both aging and hypertension (HT) with progressive endothelial dysfunction (Panza et al., 1990; Celermajer et al., 1994; Deng et al., 1999). However aging was found independent of endothelial function in other studies (Schroeder et al., 2000) and reports about HT were mostly confined to the middle aged group. The aim of the present study was to investigate the endothelial function in normotensive and hypertensive geriatric patients with well-preserved renal function. 2. Materials and methods 2.1. Study population In this prospective study, we included 66 geriatric subjects (48 hypertensive [mean age 71.8 ± 10.9] and 18 healthy [mean age 69.3 ± 7.2]) and 40 middle-aged subjects (16 hypertensive [mean age 40.8 ± 4.9] and 24 healthy [mean age 38.2 ± 8.2]). Subjects with chronic heart failure, renal insufficiency, chronic hemodialysis, significant valvular heart disease or ischemic heart disease were excluded from both geriatric and middle-aged populations. All subjects gave their informed consent to participate in the study. Smoking was outlined as having smoked at least five cigarettes per day within the last 3 months. Venous blood samples were taken after an overnight fasting between 8 and 9 a.m. All biochemical analyses including glucose, total cholesterol, triglyceride concentrations, blood–urea–nitrogen and creatinine were performed at the Technicon DAX-72 auto-analyzer (Technicon, Bayer Corporation, Tarrytown, New York, USA). High-density lipoprotein (HDL)-cholesterol concentrations were also measured at the RA-XT auto-analyzer
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after phosphotungstic acid and magnesium chloride precipitation. Low-density lipoprotein (LDL)-cholesterol was calculated by Friedewald formula. Hyperlipidemia was defined as a serum total cholesterol ≥200 mg/dl or LDL-cholesterol ≥130 mg/dl and/or serum triglyceride ≥200 mg/dl or being on a lipid lowering diet (Brewer, 2003). Hypertension was defined as having a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg (Chobanian et al., 2003) or being on a anti-HT medication. All patients in HT groups were on an anti-HT regimen. Body mass index (BMI) was determined in all subjects. None of the subjects in two groups had taken any vitamins in the past year. 2.2. Assessment of flow-mediated and nitroglycerin-induced vasodilations of the brachial artery FMD of the brachial artery following transient ischemia was measured according to a noninvasive method for assessing endothelial function defined by Celermajer (Celermajer et al., 1992) using an ultrasound system with a high-resolution (10 MHz) linear array transducer (Vingmed System Five, Norway). All groups were abstained from smoking and caffeine containing drinks for at least 12 h. They were kept in supine position in the stable room temperature between 20 and 25 ◦ C during the ultrasonographic examination. In order to best visualize the brachial artery (BA), the arm was comfortably immobilized in the extended position and BA was scanned in the longitudinal section 3–5 cm above the antecubital fossa. After optimal transducer positioning, the skin was marked for reference for later measurements and arm was kept in the same position throughout the study. All measurements of the BA lumen diameter were assessed at the end-diastole (timed by the QRS complex) and were calculated as the average of the measurements obtained during three consecutive cardiac cycles. After baseline measurements of the BA were recorded, the cuff was inflated to 200 mmHg (or 50 mmHg higher than systolic blood pressure) for 5 min to create a transient forearm ischemia. Subsequently, the cuff was deflated and the arterial diameter was measured at 60 s after deflation. In addition, endothelium independent vasodilatation (EID), a surrogate marker for vascular smooth muscle function, was assessed by measuring changes in BA diameter following sublingual isosorbide dinitrate (IDN) administration in all groups. Ten minutes after the first measurement, 5 mg of IDN was administered sublingually and measurements were repeated 3 min later. All measurements were performed by single investigator blinded to clinical details and echocardiographic results of the study groups and were recorded on VHS videotape for subsequent off-line analysis. Endothelium dependent (EDD) and independent dilatations were determined according to the percentage changes in the BA diameter following reactive hyperemia (FMD%) and sublingual isosorbide dinitrate (sublingual isosorbide dinitrate mediated dilation, IDNMD%) administration calculated by dividing the difference from baseline diameter by the baseline value multiplied by 100. The interobserver and intraobserver variability for measurements of brachial artery diameter were 3%. 2.3. Carotid intima-media thickness measurements Bilateral common carotid arteries of the subjects were scanned longitudinally with an ultrasonographic method through high resolution 10 MHz linear array transducer (attached
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to standart Vingmed System Five, Norway). The bulb dilation served as a landmark to indicate the border between distal common carotid artery and the carotid bulb. Images were obtained from the distal portion of the common carotid artery, 1–2 cm proximal to the carotid bulb. Images were saved and stored on S-VHS videotape. The two bright echogenic lines in the arterial wall were identified as the intima and media lines. The intimal plus medial thickness (intima-media thickness, IMT) was measured as the distance from the main edge of the first to main edge of the second echogenic line. Each measurements were repeated three times and the mean of the left and right common carotid arteries was taken and used for further analysis. All scans were made by the same observer. None of the subjects had atheroma, localized lesion of thickness >2.0 mm or stenosis in this region. 2.4. Statistical analysis Continuous variables were described by the use of statistical characteristics (means, standard deviations, median). Discrete variables were described as counts and percentages. Using chi-square test, homogeneity of the groups were identified according to the non-numeric variables such as gender, smoking, number of diabetic patients and drug usages. Unpaired Student t-tests were used to compare the test results. Relationship between FMD and IDNMD with other variables were assessed by Unpaired Student t-test and Spearman’s rho correlation test. A P value of <0.05 was taken to define statistical significance. 3. Results No significant difference was found between the groups when gender, smoking habbits, diabetic population and the usage of certain drugs (anti-HT drugs, acetylsalicylic acid and statins) were taken into consideration (Table 1). Numeric variables such as; age, serum glucose, cholesterol, triglycerides, creatinine, BA basal diameter, diastolic and systolic blood pressure and BMI were also matched between groups (Tables 2A and 2B). Table 1 Matching of the groups for non-parametric variables Geriatric HT (n = 48) Gender (female/male) DM Smoking ACE-I Diuretics ARB BB CCB ASA Statin
13/35 8/40 10/38 18/30 16/32 12/36 12/36 9/39 9/39 5/43
Total
48
Middle-aged HT (n = 16) 4/12 3/13 4/12 6/10 5/11 4/12 4/12 3/13 3/13 2/14 16
Geriatric non-HT (n = 18) 4/14 3/15 4/14
18
Middle-aged non-HT (n = 24) 6/18 4/20 5/19
P value 0.9 0.9 0.9 0.6 0.6 0.6 0.6 0.6 0.6 0.6
24
ACE-I: angiotensin converting enzyme inhibitors, ARB: angiotensin-1 receptor blockers, ASA: acetylsalicylic acid, BB: beta-blocker, CCB: calcium channel blocker, DM: diabetes mellitus.
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Table 2 Unpaired Student t-test: group statistics of the parametric variables
Age Glucose (mg/dl) Creatinine (mg/dl) Cholesterol (mg/dl) Triglyceride (mg/dl) BMI (kg/m2 ) Systolic BP (mmHg) Diastolic BP (mmHg) BA baseline diameter (mm) FMD (%) IDNMD (%) CA IMT (mm) Total
Geriatric HT (n = 48)
Middle-aged HT (n = 16)
Geriatric non-HT (n = 18)
Middle-aged non-HT (n = 24)
71.8 ± 10.9 113 ± 31 0.93 ± 0.20 194 ± 29 143 ± 48 27.4 ± 4.9 128 ± 9 73 ± 6 3.8 ± 0.5 9.5 ± 4.7 12.5 ± 9.5 0.74 ± 0.17
40.8 ± 4.8 103 ± 15 0.91 ± 0.10 180 ± 31 151 ± 22 26.0 ± 3.2 134 ± 14 77 ± 13 3.7 ± 0.4 12.9 ± 4.3 19.3 ± 6.8 0.58 ± 0.13
69.3 ± 7.2 102 ± 23 0.81 ± 0.12 197 ± 21 145 ± 54 25.9 ± 4.1 113 ± 14 71 ± 7 3.4 ± 0.5 12.7 ± 5.5 12.1 ± 6.6 0.60 ± 0.10
38.1 ± 8.8 101 ± 16 0.78 ± 0.10 187 ± 25 148 ± 28 24.5 ± 3.5 119 ± 14 71 ± 7 3.4 ± 0.6 18.9 ± 8.1 25.0 ± 9.9 0.45 ± 0.10
48
16
18
24
BP: blood pressure.
Table 3 Unpaired Student t-test: independent samples test for matching of the parametric variables between groups
Age Glucose Creatinine Cholesterol Triglyceride BMI Systolic BP Diastolic BP BA baseline diameter FMD (%) IDNMD (%) CA IMT
Geriatric HT with middle-aged HT (P value)
Geriatric HT with geriatric non-HT (P value)
Geriatric non-HT with middle-aged Non-HT (P value)
<0.0001 NS NS 0.1 NS NS NS NS NS 0.01 0.01 0.002
NS NS 0.03 NS NS NS <0.001 NS 0.004 0.02 NS 0.004
0.0001 NS NS 0.2 NS NS NS NS NS 0.008 <0.0001 <0.0001
NS: non-significant.
Mean ages of the geriatric groups were significantly higher than middle-aged populations, as can be predicted (Table 2A, P < 0.0001). Differences between the mean serum creatinine level and baseline BA diameter of geriatric HT and geriatric non-HT groups were statistically significant (P = 0.03 and 0.004), and renovascular changes due to HT can be involved in the elevated serum creatinine levels in geriatric HT group. Normal mean blood pressures of the HT patients were related with effective anti-HT regimens. No significant difference was found between the groups, when BMI and diastolic blood pressure of the subjects were taken into consideration.
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Table 4 Spearman’s rho correlation to study the influence of age and cardiovascular risk factors on the test results FMD%
Age Glucose Creatinine Cholesterol Triglyceride BMI Systolic BP Diastolic BP CA IMT BA baseline diameter
IDNMD%
P value
rs
P value
rs
<0.001 0.462 0.280 0.252 0.168 0.975 0.06 0.002 <0.001 <0.001
−0.410 −0.073 −0.107 −0.113 0.136 −0.03 −0.185 −0.307 −0.463 −0.341
<0.001 0.702 0.858 0.428 0.451 0.208 0.857 0.085 0.001 0.002
−0.490 −0.041 0.019 −0.086 0.081 −0.135 0.019 −0.185 −0.367 −0.321
rs : correlation coefficient.
FMD and IDNMD of the BA in all groups are shown in Table 2A. The change in the diameter of BA induced by reactive hyperemia in the geriatric HT group was significantly lower than both the geriatric non-HT group and the middle-aged HT group (P = 0.02 and 0.01). FMD% change in geriatric non-HT group is significantly lower than the middle-aged non-HT group (P = 0.008). IDNMD% change in geriatric HT group was significantly lower than the middle-aged HT group (P = 0.01), and it was also significantly low in geriatric non-HT group when compared with middle-aged non-HT group (P < 0.0001). Both FMD% and the dilatation of the BA in response to IDN were inversely correlated with age, baseline vessel diameter and carotid artery IMT (P < 0.0001, P < 0.001; P < 0.001, P = 0.002; P < 0.001, P = 0.001). FMD% was also inversely correlated with diastolic blood pressure (P = 0.002). There were no significant correlation between FMD and systolic blood pressure, serum cholesterol and triglyceride levels (Table 3). No significant relation was found between FMD% and anti-HT drugs and smoking while FMD% decreases with male gender (Table 4). In our study, 51 of 79 females were postmenapousal women (64%) and FMD% decrease in postmenapousal women was distinct statistically when compared with women on normal menses (11.29 ± 5.08% versus 18.62 ± 8.05%, P < 0.001).
4. Discussion The most important findings of the present study are: (a) endothelial dysfunction is associated with aging; (b) endothelial function further declines in hypertensive elderly people; (c) FMD% was inversely correlated with basal lumen diameter of the BA and carotid artery IMT; (d) FMD% was found to be rather independent of the BMI, and (e) endothelial independent vasodilatation was also inversely correlated with age.
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Table 5 Unpaired Student t-test: independent samples test for matching FMD% and IDNMD% with gender, diabetes, smoking and medications FMD%
Gender DM Smoking ACE-I ARB Diuretics BB CCB Statins ASA
IDNMD%
P value
t-ratio
%95-CI
P value
t-ratio
%95-CI
0.014 0.626 0.500 0.302 0.485 0.456 0.785 0.709 0.595 0.896
−2.498 0.488 0.677 −1.040 −0.703 0.750 −0.274 −0.375 −0.534 0.131
−6.626–0.760 −2.636–4.358 −2.097–4.272 −3.772–1.189 −3.964–1.901 −1.607–3.538 −3.264–2.475 −3.702–2.531 −5.254–3.026 −3.269–3.733
0.261 0.705 0.641 0.265 0.347 0.396 0.352 0.919 0.139 0.947
−1.131 0.380 −0.468 −1.128 0.949 −0.857 0.939 −0.102 1.494 −0.067
−7.670–2.107 −4.845–7.138 −6.250–3.867 −8.093–2.270 −3.018–8.429 −7.666–3.080 −3.352–9.239 −6.951–6.280 −1.777–12.516 −6.028–5.637
ACE-I: angiotensin converting enzyme inhibitors, ARB: angiotensin-1 receptor blockers, ASA: acetylsalicylic acid, BB: beta-blocker, CCB: calcium channel blocker, CI: confidence interval, DM: diabetes mellitus.
4.1. Age and FMD% There are evidences for positive correlation between aging and progressive endothelial dysfunction (Deng et al., 1999; Kimura et al., 1999), however, FMD% was found independent of age in some recent trials as well (Schroeder et al., 2000). On multivariate analysis in our study, FMD% was found inversely correlated with age which was an independent factor (P < 0.001, rs = −0.410). Aging is associated with an increasing prevalence of diabetes, HT and hyperlipidemia in the population, and these risk factors for coronary endothelial dysfunction have an important confounding effect. However, in our study, homogeneity of the groups was achieved according to these risk factors, and hypertension was evaluated as an independent risk factor. 4.2. Hypertension and FMD% Mean systolic and diastolic blood pressures of the HT patients in our study were in normal ranges and that was related with the effective anti-HT treatment. FMD% was found inversely correlated with diastolic blood pressure and this dysfunction was further increased with advancing age, however, was independent of the serum concentrations of total cholesterol and triglyceride. Increased systolic blood pressure leads to increased pulse pressure that indicates increased arterial stiffness and hence is commonly seen in older subjects. As patients age and vessels stiffen, there is a resulting loss of arterial compliance, the ability of the vessel to store blood volume temporarily as it is ejected with each systole. Endothelial dysfunction can increase stiffness, raising blood pressure and pulse pressure, and ultimately leading to atherosclerosis, plaque formation, and attendant clinical events (Glasser, 2000). Only a weak inverse relationship was found between systolic blood pressure and FMD% in this study (P = 0.06), and for our opinion, a significant correlation would be evident in a larger sample size.
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4.3. Baseline lumen diameter of the brachial artery and FMD% Some studies showed inverse correlation between the baseline diameter of the BA and FMD% (Celermajer et al., 1992, 1994; Chobanian et al., 2003), other studies did not (Iiyama et al., 1996; Deng et al., 1999). In our study, FMD% showed an inverse correlation with the increasing lumen diameter (P < 0.001). Correlation was distinct in female patients when compared with male patients (respectively, P = 0.002 and 0.350). Due to the low male patient number (27/106, 25%), the clinical implication of this finding remains uncertain. Mean BA baseline diameters were found increased in both HT groups, indeed significant difference was shown between geriatric HT and non-HT groups (P = 0.004). Hemodynamically, increased vascular resistance is the most important component of HT especially in elderly. Increased angiotensin, endothelin-1, sympathetic activity, platelet derived growth factor are involved in vascular hypertrophy and increased media/lumen diameter ratio (Schiffrin and Deng, 1999; Julius et al., 2001). However, increased BA basal lumen diameters were found in our HT patients according to non-HT groups, and that may be due to treatment with calcium channel blockers and angiotensin converting enzyme inhibitors. Although FMD was inversely correlated with the vessel lumen diameter in the whole population, statistical significance in lumen diameter was only found between geriatric HT and non-HT groups in our study. In geriatric HT group, certain patients were under treatment with calcium channel blockers and angiotensin converting enzyme inhibitors, those can cause vasodilatation. On the other hand, FMD was inversely correlated with diastolic HT. So FMD might be influenced by medications and HT, instead of lumen diameter in these subjects. 4.4. Gender and FMD% Mean FMD% change in BA was more intense in female subjects (13.76 ± 7.10% for females versus 10.07 ± 4.87% for males, P = 0.014), however, this was not valid for EID (mean IDNMD%, 17.94 ± 10.89% versus 15.16 ± 8.33%, P = 0.261). Mean FMD% change was also significant in elderly female subjects when compared to elderly male subjects, those were all postmenopausal (11.24 ± 5.14% versus 8.36 ± 4.65%, P = 0.024). However, a more valid analysis will be available in a larger sample size with more male subjects included. Mean basal lumen diameter of BA was significantly smaller in female subjects (3.56 ± 0.54 mm versus 3.93 ± 0.53 mm, P = 0.005) and this might support the hypothesis that larger arteries show less distinct vasodilatations. The absolute risk of coronary disease is greater for men than for pre-menopausal women. Following the menopause gender differences in coronary risk are thought to diminish. Oestrogen deficiency in postmenopausal women may contribute to endothelial dysfunction (Sanada et al., 2003; Walters et al., 2003). Reactive hyperemia is impaired in forearm resistance arteries of postmenopausal women in our study. 4.5. Body mass index and FMD% BMI was ranged from 16.0 to 40.0 (26.35 ± 4.34 kg/m2 ). No significant influence of BMI could be seen on FMD% both in our whole study group (P = 0.733) and in obese
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subjects (BMI > 30 kg/m2 , n = 16) as well (P = 0.488). Thus, BMI cannot be taken into consideration in FMD% measurements. 4.6. Carotid artery intima-media thickness and FMD% Intima-media thickness of the common carotid artery (CA IMT) has been used as a non-invasive end point in epidemiological studies and clinical trials to assess the progression and regression of atherosclerosis in the body, and it is used as a surrogate end point for atherosclerosis of the coronary arteries (Hodis et al., 1998). Early atherosclerosis can be evaluated morphologically through IMT measurement of carotid arteries by ultrasonography (Furumoto et al., 2002). On the other hand, FMD of BA is a functional marker of endothelial function in the body and a significant negative correlation between the CA IMT and percent FMD change of BA was proposed in the past (Hashimoto et al., 1999). In our study, inverse correlation was found between CA IMT and FMD% (P < 0.001). Positive correlation was found between CA IMT and age (elderly versus middle-aged subjects; 0.71 ± 0.17 mm versus 0.50 ± 0.12 mm, P < 0.001). There was also positive correlation between CA IMT and HT (geriatric HT versus geriatric non-HT groups; P = 0.004). No significance was found between CA IMT and gender (P = 0.242). Mean CA IMT was significantly increased in postmenapousal women when compared with other female subjects with normal menses (0.66 ± 0.16 versus 0.52 ± 0.13, P < 0.001). 4.7. IDNMD% Sublingual IDN induces vasodilatation by direct action on the smooth muscles of the vessel, then its effect is endothelium independent. In our study, IDNMD% was inversely correlated with age, basal lumen diameter and CA IMT. Only a weak inverse relationship was found with diastolic HT (P = 0.085), although it was not valid in elderly population (P = 0.875). 4.8. Study limitations Population (n = 106) included in this study was small, especially, when male subjects (n = 27) were taken into consideration, and this might lead to weak relation of FMD% with systolic HT and even no relation with serum lipid levels as well. However, most of the trials in the literature were performed with similar or even less number of patients (Deng et al., 1999; Hashimoto et al., 1999; Schroeder et al., 2000). Further investigations with larger populations are needed for confirmation of the data. Although we could investigate atherosclerosis with ultrasonographic imaging of carotid arteries in the whole population, coronary angiographic data for excluding coronary artery disease was unavailable. Meanwhile, absence of clinical symptoms and demonstrable wall motion abnormalities on echocardiography decreased the possibility of coronary artery disease. Additionally, because of ethical considerations, patients were studied under concurrent medications, and this might have had an influence on the precision of the measurements of FMD%.
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5. Conclusions Endothelium dependent and independent dilatation of large arteries decreased with aging even in the healthy elderly, and FMD further declined in HT elderly patients, indicating that age and HT independently impair endothelial function. Significant inverse correlation between FMD and vessel lumen diameter must be investigated with further studies in larger populations, excluding other factors which can effect the interpretation of FMD change. Positive correlations with age and HT, and significant inverse correlation with FMD, makes CA IMT a possible indicator of endothelial function.
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