& Wilkins. Received 20 February 2008 Revised 11 April 2008 Accepted 14 April 2008

Transcription

1 Clinical methods and pathophysiology 245 Endothelium-dependent vasodilation in relation to different measurements of blood pressure in the elderly: the prospective investigation of the Vasculature in Uppsala Seniors study Lars Lind Objectives We have earlier showed endotheliumdependent vasodilation (EDV) in forearm resistance arteries to be mainly related to diastolic blood pressure (DBP), whereas flow-mediated vasodilation (FMD) was mainly related to systolic blood pressure (SBP) when measured with a mercury sphygmomanometer in the brachial artery. Here, we investigated whether these relationships were more powerful if blood pressure was measured invasively or by transformation to central aortic blood pressure. Methods In the prospective study of the Vasculature in Uppsala Seniors, 1016 patients aged 70 years were evaluated by the invasive forearm technique with acetylcholine (EDV), and brachial artery ultrasound to assess FMD. Blood pressure was measured with a mercury sphygmomanometer, invasively in the brachial artery and transformed to aortic blood pressure by pulse wave analysis. Results EDV was related to DBP with a similar strength regardless of whether DBP was measured traditionally, invasively or as calculated aortic pressure. Similarly, FMD was related to SBP with similar strength regardless of whether SBP was measured traditionally, invasively or as calculated aortic pressure. Only FMD was significantly related to pulse pressure. Conclusion Measurements of blood pressure invasively or by calculation of aortic blood pressure did not increase the power of the associations between blood pressure and EDV in the elderly, when compared with traditional blood pressure measurements. Blood Press Monit 13: c 2008 Wolters Kluwer Health Lippincott Williams & Wilkins. Blood Pressure Monitoring 2008, 13: Keywords: aorta, blood pressure, endothelium, invasive, vasodilation Department of Medicine, Uppsala University Hospital, Sweden Correspondence to Lars Lind, MD, Department of Medicine, University Hospital, Uppsala, Sweden lars.lind@medsci.uu.se Received 20 February 2008 Revised 11 April 2008 Accepted 14 April 2008 Introduction Hypertension is one of the major cardiovascular risk factors increasing the risk for myocardial infarction and stroke [1,2]. During the past two decades much attention has also been paid to the function of the endothelium as endothelial dysfunction early was shown to induce atherosclerosis in animal models [3], and later was shown to predict cardiovascular events in human patient populations [4,5]. Today, two different methods to assess peripheral artery endothelium-dependent vasodilation (EDV) are widely used in clinical research; the invasive forearm model using acetylcholine infusion in the brachial artery (EDV), which mainly evaluates vasodilation in resistance arteries, and the brachial artery ultrasound technique using hyperaemia to induce flow-mediated dilatation (FMD) in a conduit artery. Both of these techniques have been reported to be related to the major cardiovascular risk factors [6 15], but the techniques in themselves do not seem to be closely related at the individual level [16,17]. A third noninvasive technique based on pulse wave analysis and vasodilation with a b-2 agonist has recently been validated by different groups [18 21]. This technique mainly induces vasodilation in resistance vessels. The impaired EDV evaluated with this technique has been described in patients with coronary heart disease, hypercholesterolaemia or diabetes [18 20]. A number of studies using both EDV and FMD have shown impairment in EDV in patients with essential hypertension [6,7,22 34], although some investigators could not show any impairment [35 37]. The majority of these investigations has been performed in middle-aged hypertensives and only a few studies have addressed endothelial function in the elderly, an age group in which isolated systolic hypertension is the most common form of hypertension. Furthermore, although it has been reported that EDV and FMD are not related and might c 2008 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MBP.0b013e328305d286

2 246 Blood Pressure Monitoring 2008, Vol 13 No 5 therefore contain different information of endothelial function [16,17], few studies have used more than one technique to assess EDV in the same study. The Prospective Investigation of the Vasculature in Uppsala Seniors (the PIVUS study) was initiated with the primary aim to evaluate the predictive power of three different tests of EDV described above to predict future cardiovascular events in more than 1000 participants aged 70 years living in the community of Uppsala, Sweden. Using data from this cohort we have recently shown that systolic blood pressure (SBP) mainly is related to EDV in a conduit vessel (FMD), whereas diastolic blood pressure (DBP) mainly was related to EDV in the forearm resistance vessels. In that report, blood pressure was conventionally measured [38]. The aim of this study is to evaluate whether two alternative measurements of blood pressure are more closely related to EDV than conventionally measured blood pressure. Thus, we hypothesized that, intraarterially measured blood pressure and central aortic blood pressure calculated from tonometry recordings, both are more closely related to EDV compared with conventionally measured blood pressure. Intra-arterially measured blood pressure is the gold standard for blood pressure measurements, and central blood pressure calculated from tonometry has been recently shown to be more predictive regarding cardiovascular events than conventionally measured blood pressure [39]. Materials Patients All participants aged 70 years and living in the community of Uppsala, Sweden were eligible. The patients were chosen from the register of community living and were invited in a randomized order from the start of the study in April 2001 to the last included patient in June The participants received an invitation by letter within 1 month of their 70th birthday to standardize for age. Of the 2025 participants invited, 1016 participants were investigated giving a participation rate of 50.1% [40]. This study was approved by the Ethics Committee of the University of Uppsala and the participants gave informed consent. Baseline investigation The participants were asked to answer a questionnaire about their medical history, smoking habits, and regular medication. All participants were investigated in the morning after an overnight fast. No medication or smoking was allowed after midnight. During the investigation, the participants were in supine position in a quiet room maintained at a constant temperature. After recordings of height, weight, abdominal and hip circumference, an arterial cannula was inserted in the brachial artery for blood sampling and later regional infusions of vasodilators. Lipid variables and fasting blood glucose were measured by standard laboratory techniques. Ofthetotalsample,32%oftheparticipantswereonregular antihypertensive treatment (median duration of hypertension 10 years, range years) and another 38% showed blood pressure greater than 139/89 mmhg. Thus, 70% of the sample was considered to be hypertensive. As different hypertensive regiments may, however, affect EDV in different ways [41 44], only participants not treated with antihypertensive drugs were analysed in this study (n = 647), in accordance with our earlier report [38]. Characteristics of the sample are given in Table 1. Approximately 10% of the cohort reported a history of coronary heart disease, 4% reported stroke, and 9% diabetes mellitus. Almost half of the cohort reported any cardiovascular medication (45%), with antihypertensive medication being the most prevalent (32%). Fifteen percent reported use of statins, whereas insulin and oral antiglycemic drugs were reported in 2 and 6%, respectively (for details, see ref. [40]). As the participation rate in this cohort was only 50%, we carried out an evaluation of cardiovascular disorders and medications in 100 consecutive participants who were invited to the study, but denied participation. The prevalences of cardiovascular drug intake, history of myocardial infarction, coronary revascularization, antihypertensive medication, statin use, and insulin treatment were similar to those in the investigated sample, whereas the Table 1 Basic characteristics, major cardiovascular risk factors, and measures of endothelium-dependent vasodilation in the total sample Total sample Present subsample n Females (%) Height (cm) 169 ± ± 9.2 Weight (kg) 77 ± ± 14 Waist circumference (cm) 91 ± ± 11 BMI (kg/m 2 ) 27.0 ± ± 4.2 Waist/hip ratio 0.90 ± ± SBP (mmhg) 150 ± ± 21 DBP (mmhg) 79 ± ± 10 Heart rate (beats/min) 62 ± ± 8.5 Serum cholesterol (mmol/l) 5.4 ± ± 1.0 LDL-cholesterol (mmol/l) 3.3 ± ± 0.84 HDL-cholesterol (mmol/l) 1.5 ± ± 0.42 Serum triglycerides (mmol/l) 1.3 ± ± 0.57 Fasting blood glucose (mmol/l) 5.3 ± ± 1.1 Current smoking (%) Means are given ± SD or as median and 10th and 90th percentiles in parenthesis. BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure.

3 Vasodilation and blood pressure Lind 247 prevalences of diabetes, congestive heart failure, and stroke tended to be higher among the nonparticipants [40]. Methods Blood pressure recordings Blood pressure was measured intra-arterially by a standard pressure transducer placed at heart level. The pressure given is the mean of all continuous sampled recordings during 5 min of controlled breathing (12 breaths/min). The intra-arterial blood pressure recordings were obtained by a catheter (20 G/ mm) connected to a pressure tube (150 mm) and a transducer (DTX Plus Transducer DT-XX, Franklin Lakes, New Jersey, USA). The signals were registered by GE Marquette Eagle 4000 (Stockholm, Sweden) sampled with a frequency of 200 Hz and stored digitally for later analyses in the custom-made program package Pharmlab 3.0 (Axenborg J, Hirsch I, AstraZeneca R&D Mölndal, Sweden). Blood pressure was also measured by a calibrated mercury sphygmomanometer in the noncannulated arm to nearest mmhg after at least 30 min of rest and the average of three recordings was used. These data were then also used for calculations of central blood pressure. The invasive forearm technique Forearm blood flow (FBF) was measured by venous occlusion plethysmography (Elektromedicin, Kullavik, Sweden). A mercury in silastic strain gauge was placed at the upper third of the forearm, which rested comfortably slightly above the level of the heart. The strain gauge was connected to a calibrated plethysmograph. Venous occlusion was achieved by a blood pressure cuff applied proximal to the elbow and inflated to 50 mmhg by a rapid cuff inflator. Evaluations of FBF were made by calculations of the mean of at least five consecutive recordings. An arterial cannula was placed in the brachial artery. No more than one attempt to insert the cannula in each arm was allowed. Resting FBF was measured 30 min after cannula insertion. After evaluation of resting FBF, local intra-arterial drug infusions were given during 5 min for each dose with a 20 min washout period between the drugs. The infused dosages were 25 and 50 mg/min for acetylcholine (Clin-Alpha, Laufelfingen, Switzerland) to evaluate EDV and 5 and 10 mg/min for sodium nitroprusside (SNP) (Nitropress, Abbot, UK) to evaluate endothelium-independent vasodilation (EIDV). The dosages of these drugs have been chosen to result in FBFs on the steep part of the dose response curve without giving systemic effects. The drugs were given in a random order at a maximal rate of 1 ml/min. In this study only data from the highest doses of acetylcholine and SNP were used. EDV was defined as FBF during infusion of 50 mg/min of acetylcholine minus resting FBF divided by resting FBF. EIDV was defined as FBF during infusion of 10 mg/min of SNP minus resting FBF divided by resting FBF. EDV and EIDV were successfully evaluated in 87% of the participants of this study. Cannulation of the artery was not performed in the 3% of the patients who were on regular treatment with warfarin and in another 10% cannulation failed. We have previously shown the reproducibility (coefficient of variation) for EDV and EIDV to be 8 10% [45]. The brachial artery ultrasound technique The brachial artery was assessed by external B-mode ultrasound imaging 2 3 cm above the elbow (Acuson XP128 with a 10 MHz linear transducer, Acuson Mountain View, California, USA), according to the recommendations of the International Brachial Artery Task Force [46]. Depths and gains settings were optimized to identify the lumen-to-vessel wall interface. The patient rested in the supine position for at least 30 min before the first scan and remained supine during the evaluation. Blood flow increase was induced by inflation of a pneumatic cuff placed around the forearm to a pressure at least 50 mmhg above SBP. When the cuff was rapidly deflated 5 min later, the artery was scanned continuously for 90 s and recorded on a super-vhs videotape for later analysis of the diameter in end-diastole. FMD was defined as the maximal brachial artery diameter recorded between 30 and 90 s after cuff release minus diameter at rest divided by the diameter at rest. FMD was successfully evaluated in 97% of the participants. In the remaining 3%, only suboptimal images not allowing proper analysis were obtained. We have previously shown the reproducibility (coefficient of variation) to be 3% for baseline brachial artery diameter and 29% for FMD [16]. Pulse wave analysis A micromanometer tipped probe (Sphygmocor, Pulse Wave Medical Ltd, West Ride, Australia) was applied to the surface of the skin overlying the radial artery and the peripheral radial pulse wave was continuously recorded. The mean values of 10 pulse waves were used for analyses. Recordings were regarded as satisfactory if the variations in the systolic peak and the diastolic peak were 5% or below. Only three attempts to achieve a satisfactory recording were allowed. The maximal systolic peak and the reflected waves were identified by the calculations of the first and second derivative of the pulse curve. From these data, the central blood pressure was calculated by validated transfer functions included in the equipment software.

4 248 Blood Pressure Monitoring 2008, Vol 13 No 5 After a baseline recording, terbutaline was subcutaneously administered (0.25 mg in the upper part of the arm) and a reevaluation of the pulse wave was performed after 15 and 20 min. We had found earlier that the maximal alterations in the pulse waveform occurred after 15 min in young healthy patients [21], but we also performed a measurement after 20 min in this sample of elderly patients. Thus, the maximal change occurring at either 15 or 20 min was used for calculations. In earlier studies, the augmentation index derived from the first reflected wave in systole was used [18,19]. We and others have earlier validated change in the relative height of the first diastolic reflected wave (the reflection index, RI) [20,21] and found this index to be closely related to the change in the augmentation index following terbutaline. Here, we report the change in RI as relative changes from baseline following terbutaline. Thus, a large reduction of the pulse wave indices indicates a good response. The change in the RI could successfully be evaluated in 86% of the sample. In 5% of the patients, the pulse waves showed too high variability because of atrial fibrillation or frequent ectopic beats, and in 9% of the patients the reflected waves could not be detected in a reproducible way. We have earlier shown the reproducibility (coefficient of variation) for the changes in RI to be 9.4% [21]. The three different techniques to evaluate EDV were performed in the order described above. Three technicians were employed at the laboratory, but each vasodilatory technique was performed and evaluated by one unique technician throughout the study; he was not aware of the results of the other techniques or any clinical data. Statistics Non-normally distributed variables, such as EDV and FMD, were log-transformed to achieve a normal distribution. Linear regression analysis was applied to evaluate relationships between pairs of variables with adjustment for sex. Two-tailed significance values were given with P value of less than 0.05 regarded as significant. The statistical programme StatView (SAS Inc., Cary, North Carolina, USA) was used for calculations. Results Means and SD for the studied variables are given in Table 2. EDV was related to DBP with a similar strength regardless of whether DBP was measured traditionally, invasively or as calculated aortic pressure. Similarly, FMD was related to SBP with a similar strength regardless of whether SBP was measured traditionally, Table 2 Studied variables in the subsample without antihypertensive treatment (n = 647) Variable Mean ± SD or median (10th to 90th percentile) EDV (%) 478 ( ) FMD (%) 4.7 ( ) Change in RI (%) 33 ± 14 Office SBP (mmhg) 145 ± 21 Office DBP (mmhg) 77 ± 9.8 Office PP (mmhg) 68 ± 17 Invasive SBP (mmhg) 143 ± 19 Invasive DBP (mmhg) 68 ± 8.8 Invasive PP (mmhg) 76 ± 14 Central SBP (mmhg) 137 ± 20 Central DBP (mmhg) 78 ± 10 Central PP (mmhg) 59 ± 16 DBP, diastolic blood pressure; EDV, endothelium-dependent vasodilation (invasive forearm technique); FMD, flow-mediated dilatation; PP, pulse pressure; RI, reflectance index; SBP, systolic blood pressure. Table 3 Relationships between systolic, diastolic, and pulse pressure measured either manually in the brachial artery (office), invasively in the contra-lateral brachial artery or calculated central blood pressure by pulse wave analysis and three different measures of endothelium-dependent vasodilation, the invasive forearm technique, flow-mediated vasodilation, and by means of pulse wave analysis (change in RI) EDV FMD Change in RI Office SBP 0.07 (0.033) 0.09 (0.010) 0.06 (0.074) Office DBP 0.15 (0.0001) 0.07 (0.061) 0.18 (0.0001) Office PP 0.01 (0.87) 0.07 (0.034) 0.05 (0.15) Invasive SBP 0.04 (0.23) 0.10 (0.0077) 0.04 (0.26) Invasive DBP 0.11 (0.0015) 0.08 (0.035) 0.18 (0.0001) Invasive PP 0.01 (0.73) 0.08 (0.028) 0.02 (0.50) Central SBP 0.06 (0.076) 0.09 (0.015) 0.05 (0.12) Central DBP 0.14 (0.0001) 0.08 (0.032) 0.15 (0.0001) Central PP 0.01 (0.89) 0.06 (0.076) 0.02 (0.47) Linear correlation coefficients are given with P values in parenthesis in genderadjusted analysis. DBP, diastolic blood pressure; EDV, endothelium-dependent vasodilation; FMD, flow-mediated dilatation; PP, pulse pressure; RI, reflectance index; SBP, systolic blood pressure. invasively or as calculated aortic pressure. Only FMD was significantly related to the pulse pressure (Table 3). Discussion This study showed that intra-arterially measured blood pressure or central blood pressure derived from tonometry measurements was not more closely related to indices of EDV in the elderly, when compared with traditional blood pressure measurements. Central blood pressure Central aortic blood pressure can nowadays be reliably determined by aplanation tonometry and validated transfer functions [47]. A better prognostic value regarding cardiovascular events has been shown both in hypertensive patients and in a general population, when compared with conventional brachial pressure recordings [39,48]. Furthermore, the Conduit Artery Function Evaluation study recently showed that different

5 Vasodilation and blood pressure Lind 249 antihypertensive regiments might affect central blood pressure differently despite having a similar effect on conventional brachial pressure recordings [48]. Despite these promising features of central blood pressure, we could not demonstrate its superiority over traditional blood pressure measurements regarding its relation to EDV. Intra-arterially blood pressure Invasively measured blood pressure is the gold standard for blood pressure recordings. In this study, we tried to obtain this recording as accurately as possible by sampling the pressure wave during 5 min of controlled breathing to minimize errors because of the breathing pattern. The invasive SBP was very closely related to traditional SBP (r = 0.92), whereas a greater discrepancy was seen for DBP (r = 0.77). Thus, we believe that especially invasive DBP might contain different information than traditional DBP and may be more accurate. Despite the fact that invasive blood pressure is the gold standard, we could not demonstrate its superiority over traditional blood pressure measurements regarding its relation to EDV. Pulse pressure Especially in the elderly, pulse pressure, rather than SBP or DBP alone, is predictive of cardiovascular events [49 51]. Pulse pressure has also been related to EDV in different vascular beds [52 54]. We therefore found it worthwhile to investigate whether pulse pressure is more closely related to EDV than SBP or DBP alone. Of the three methods used to measure EDV, however, pulse pressure was only related to FMD, and was not superior to SBP alone. Systolic blood pressure versus diastolic blood pressure Systolic hypertension is mainly because of vascular stiffening in conduit arteries and FMD is measured in a conduit artery. DBP, on the other hand, is mainly governed by the tone of the smaller resistance arteries. These smaller arteries are the basis for the measurement of EDV. 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