Journal of Hypertension 2006, 24: a Department of Medicine, Uppsala University Hospital and b AstraZeneca R&D.

Transcription

1 Original article 1075 A comparison of three different methods to determine arterial compliance in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study Lars Lind a,b, Nilla Fors a, Jan Hall a, Kerstin Marttala a and Anna Stenborg a Background Several different techniques to evaluate arterial compliance have been described but have not been simultaneously tested in a large-scale, population-based setting. This study aimed to evaluate the feasibility and relation to cardiac risk of three of these techniques in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. Methods and results In the population-based PIVUS study (1016 participants aged 70), assessment of arterial distensibility by ultrasound in the carotid artery, by pulse wave analysis (augmentation index) and the stroke volume to pulse pressure ratio by echocardiography were successfully employed in 86, 92, 91 and 77% of the sample, respectively. All three indices of arterial compliance were inter-related (r U , P < for all). Although all three indices were significantly related to the Framingham risk score (r U , P U ), only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently associated with the Framingham score in multiple regression analysis (P < for both). Conclusions All three indices to evaluate arterial compliance were feasible to obtain in a general elderly population and were inter-related. Although all of the techniques were correlated to Framingham risk score, only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently related to coronary risk, suggesting complementary use of these two indices of arterial compliance in the future. J Hypertens 24: Q 2006 Lippincott Williams & Wilkins. Journal of Hypertension 2006, 24: Keywords: artery, compliance, cardiovascular, risk, elderly a Department of Medicine, Uppsala University Hospital and b AstraZeneca R&D Mölndal, Sweden Correspondence and requests for reprints to Lars Lind, MD, Department of Medicine, University Hospital, Uppsala, Sweden Tel: ; lars.lind@medsci.uu.se Received 28 October 2005 Revised 2 January 2006 Accepted 6 February 2006 Introduction Arterial compliance is a characteristic feature of the conduit arteries being gradually reduced by age also in healthy individuals due to a gradual loss of elastin fibers in the vascular wall [1]. The vascular smooth muscle cells in the larger arteries also participate in the regulation of the compliance of the arteries, however, and it has recently been shown that nitric oxide release from the endothelium is involved in this process [2,3]. No standard method exists to evaluate arterial compliance in humans. On the contrary, three different noninvasive techniques are widely used; assessment of pulse wave velocity in the aorta, analysis of the pulse wave contour and the distensibility of an arterial segment evaluated by ultrasound (for a recent review, see [4]). Arterial compliance evaluated by all three of these techniques is known to decline with age and to be impaired by the existence of major cardiovascular risk factors, such as hypertension, diabetes and smoking [5 12], and have all been shown to predict future cardiovascular events in different populations [13 17]. Another measure of arterial compliance, the stoke volume to pulse pressure ratio (SV/PP ratio), has also been related to the main cardiovascular risk factors and to predict cardiovascular events in prospective studies [18,19]. Although all of these techniques to measure arterial compliance have been evaluated in different studies, only a few investigations have used more than one technique in the same study [20 23]. It would therefore be of great value to evaluate whether the major methods are closely inter-related or whether they carry different information, justifying the use of more than one technology. In the present study we have used three indices that are easy to obtain by non-invasive techniques and thereby could be used in large-scale studies; carotid artery distensibility obtained by ultrasound, the SV/PP ratio measured by echocardiography and the augmentation index obtained by pulse wave analysis. We conducted the Prospective Investigation of the Vasculature in Uppsala Seniors (the PIVUS study) with the primary aim to evaluate the power of endotheliumdependent vasodilation measurements to predict future cardiovascular events in more than 0 individuals aged 70 living in the community of Uppsala, Sweden [24]. We report here four secondary aims of the study related to measurements of arterial compliance. First, to evaluate the feasibility to perform the aforementioned three ß 2006 Lippincott Williams & Wilkins

2 1076 Journal of Hypertension 2006, Vol 24 No 6 Table 1 Basic characteristics and major cardiovascular risk factors in the total sample and in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cardiovascular healthy reference groups Total sample PIVUS healthy reference group Young healthy reference group n Women (%) Height (cm) 169 (9.1) 171 (10) 174 (8.7) Weight (kg) 77 (14) 72 (12) 67 (9.4) Waist circumference (cm) 91 (12) 86 (9.0) 77 (5.2) Body mass index (kg/m 2 ) 27.0 (4.3) 24.6 (2.8) 22.2 (1.7) Waist/hip ratio 0.90 (0.075) 0.88 (0.066) 0.81 (0.042) Brachial SBP (mmhg) 150 (23) 125 (9.8) 113 (13) Brachial DBP (mmhg) 79 (10) 72 (7.2) 68 (12) Central SBP (mmhg) 142 (22) 118 (10) 97 (12) Central DBP (mmhg) 80 (10) 73 (7.3) 69 (12) Central pulse pressure (mmhg) 62 (17) 46 (9.3) 28 (7.5) Heart rate (beats/min) 62 (8.7) 61 (9.0) 64 (13) Serum cholesterol (mmol/l) 5.4 (1.0) 5.2 (0.74) 3.8 (0.7) LDL-cholesterol (mmol/l) 3.3 (0.88) 3.1 (0.60) 2.1(0.5) HDL-cholesterol (mmol/l) 1.5 (0.42) 1.6 (0.48) 1.4 (0.3) Serum triglycerides (mmol/l) 1.3 (0.60) 1.0 (0.42) 0.8 (0.3) Fasting blood glucose (mmol/l) 5.3 (1.6) 4.8 (0.5) 4.9 (0.4) Current smoking (%) Data presented as mean (SD). SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein. techniques of arterial compliance in a large group of unselected elderly individuals. Second, to obtain reference values for the three methods in this age group. Third, to evaluate the relationships between the three different techniques in a large sample. Finally, to investigate whether these three techniques of arterial compliance were related to the Framingham risk score [25], a widely used score to quantify risk for coronary heart disease. Materials and methods Participants Eligible were all individuals aged 70 living in the community of Uppsala, Sweden. The participants 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 participant in June The participants received an invitation by letter within 1 month of their 70th birthday in order to standardize for age. Of the 2025 individuals invited, 1016 participants were investigated giving a participation rate of 50.1%. The study was approved by the Ethics Committee of the University of Uppsala and the participants gave informed consent. Basic investigation The participants were asked to answer a questionnaire about their medical history, smoking habits and regular medication. These data were only used to describe the sample. All participants were investigated in the morning after an overnight fast. No medication or smoking was allowed after midnight. After recordings of height, weight, abdominal and hip circumference, an arterial cannula was inserted into the brachial artery for blood sampling and later regional infusions of vasodilators. During the investigation, the participants were supine in a quiet room maintained at a constant temperature. Blood pressure was measured by a calibrated mercury sphygmomanometer in the non-cannulated arm (to the nearest mmhg) after at least 30 min of rest and the average of three recordings was used. Lipid variables and fasting blood glucose were measured by standard laboratory techniques. Basic risk factor characteristics, medical history and regular medication are presented in Tables 1 and 2. Healthy reference groups A group with no cardiovascular diagnosis or major risk factors was identified. The exclusion criteria were: history of any cardiovascular diagnosis or medication, obesity (body mass index > 30 kg/m 2 ), hypertension (antihypertensive treatment or blood pressure > /90 mmhg), diabetes (antidiabetic treatment including diet or fasting blood glucose > 6.1 mmol/l), hyperlipidemia (antihyperlipidemic treatment, low-density lipoprotein-cholesterol > 3.5 mmol/l or serum triglycerides > 1.7 mmol/l) and current smoking. This group was denoted the PIVUS cardiovascular healthy reference group. To give a descriptive young reference group, 10 young men and 10 young women (age years) with the same exclusion criteria were investigated with an identical protocol. This group was denoted the young cardiovascular healthy reference group. As the participation rate in this cohort was only 50%, we carried out an evaluation of cardiovascular disorders and

3 Arterial compliance in the elderly Lind et al Table 2 Self-reported history of cardiovascular disorders and regular drug intake given as the percentage in the investigated sample and in non-attendees Total investigated sample Not attending n 1016 Myocardial infarction Stroke Angina pectoris CABG/PTCA Congestive heart failure Diabetes Any regular drug Any cardiovascular drug Any antihypertensive medication Beta-blockers Calcium antagonists Diuretics Angiotensin-converting enzyme inhibitors Angiotensin II-blockers Any nitroglycerine preparation Digoxin Statins Other antihyperlipidemic drugs Insulin Oral antidiabetic drugs Warfarin Aspirin/clopidogrel Other antiarrhythmic drugs CABG/PTCA, coronary artery bypass graft/percutaneous coronary angioplasty. medications in consecutive non-participants. 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, while the prevalences of diabetes, congestive heart failure and stroke tended to be higher among the non-participants (see Table 2). Pulse wave analysis A micromanometer tipped probe (Sphygmocor; Pulse Wave Medical Ltd, Sydney, 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 around 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. Based on transfer functions, the aortic systolic and diastolic blood pressure were calculated from the radial recordings with the Sphygmocor software [26]. The central pulse pressure was calculated by central systolic blood pressure minus central diastolic blood pressure. The aortic augmentation index is calculated as the ratio between the amplitude of the first reflected wave divided by the amplitude of the first systolic peak. Echocardiography and Doppler A comprehensive two-dimensional Doppler echocardiography was performed with an Acuson XP124 cardiac ultrasound unit (Acuson, Los Angeles, California, USA) A 2.5-MHz transducer was used for the majority of the twodimensional, M-mode and Doppler examinations. This investigation was carried out in 97% of the participants. The presence of stenosis or regurgitations in the mitral and aortic valves was recorded by use of color and continuous Doppler. Left ventricular dimensions were measured with the M-mode online from the parasternal projections, using the leading-edge to leading-edge convention. Measurements included left ventricular diameters in end-diastole and end-systole. The left ventricular volumes in end-diastole and endsystole were calculated according to the Teichholz formula (7 D 3 / (2.4 þ D)) and from that the ejection fraction and stroke volume were calculated. The SV/PP ratio was calculated as the stroke volume divided by the central pulse pressure (achieved by pulse wave analysis) [27]. Carotid artery compliance The diameter of the common carotid artery (CCA) of the right-side 1 2 cm proximal of the bifurcation was measured at its maximal diameter in systole and the minimal diameter in diastole by an Acuson XP124 cardiac ultrasound unit (Acuson) with a 7.5-MHz transducer. The distensibility of the CCA was calculated as the percentage change in the diameter maximum to minimum in relation to the minimal diameter in diastole divided by the central pulse pressure obtained by pulse wave analysis. The three different techniques to evaluate arterial compliance were evaluated by three different persons not aware of the results of the other techniques or any clinical data. Based on two repeated measurements performed in 12 subjects 4 weeks apart, the coefficients of variation were for CCA distensibility 20%, for SV/PP ratio 16% and for the augmentation index 12%. Statistics Non-normally distributed variables were transformed to achieve a normal distribution. Relationships between pairs of variables were evaluated by Pearson s correlation coefficient. Multiple regression analysis was applied to relate several independent variables to a dependent variable. Two-tailed significance values were given, with P less than 0.05 regarded as significant. The statistical programme package StatView (SAS Inc., Cary, North Carolina, USA) was used.

4 1078 Journal of Hypertension 2006, Vol 24 No 6 Fig. 1 Count Count Count CCA distensibility (%/mmhg) SV/PP (ml/mmhg) Aorta AIx (%) Frequency distribution for the three indices of arterial compliance evaluated; distensibility of the common carotid artery (CCA distensibility), stroke volume to pulse pressure ratio (SV/PP), and the pulse-wave-based aortic augmentation index (AIx). Results Feasibility to perform the methods The augmentation index was successfully obtained in 91% of the sample, respectively. The main reasons for not obtaining reliable values were atrial fibrillation (2.5% of the sample) and frequent ectopic beats (3.7%). This was also true for the derivation of central blood pressure used for calculations of CCA distensibility and SV/PP. Central pulse pressure was derived in 93% of the sample. Successful measurements of the diameter of the CCA in systole and diastole were obtained in 93% of the sample, resulting in 86% of the sample with reliable measurements of CCA distensibility. As the SV/PP ratio was not calculated in those with an ejection fraction less than 50% (3.5% of the sample), and as an appropriate M-mode recording was not obtained in 14%, the stroke volume was obtained in 82% of the investigated participants, resulting in 77% of the sample with reliable measurements of the SV/PP ratio. Distribution The frequency distributions of the three indices of arterial compliance are given in Fig. 1. The augmentation index was normally distributed, while the distributions of the two other tests were skewed. In the further analysis, these latter tests were ln-transformed to achieve a normal distribution. Reference values Table 3 presents the mean (or median) and variance for the different vascular variables in the total sample, the PIVUS cardiovascular healthy reference group and the young healthy reference group. As gender differences were seen in the augmentation index and the SV/PP ratio in the PIVUS cardiovascular healthy reference group, gender-specific reference values are given for the major compliance variables in the table. Relationships between the methods All other indices of arterial compliance were related to each other (r ¼ , P ¼ for all), as could be seen in Table 4 and Fig. 2. Similar correlation coefficients were found when only the PIVUS cardiovascular healthy reference group was studied. Relationships with the Framingham risk score All of the three indices of arterial compliance were correlated with the Framingham risk score, as could be seen in Fig. 3 (r ¼ 0.12, P ¼ for augmentation index, r ¼ 0.13, P ¼ for reflection time, r ¼ 0.32, P < for CCA distensibility, and r ¼ 0.27, P < for the SV/PP ratio). When the Framingham risk score was used as the dependent variable in a multiple regression model with the three indices of arterial compliance as independent variables, only CCA distensibility and the SV/PP ratio were independently related to the Framingham risk score (P < for both, see Table 5). CCA distensibility and the SV/PP ratio were independently related to the

5 Arterial compliance in the elderly Lind et al Table 3 Means W SD or median (10th 90th percentiles) for vascular variables in the total sample (n U 1016), the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cardiovascular healthy reference group (n U 131), and in the young cardiovascular healthy reference group (n U 20) Method Variable Total sample PIVUS healthy reference group Young healthy reference group CCA Change in diameter (mm) CCA Change in diameter/diastolic diameter (%) CCA CCA distensibility (%/mmhg) ( ) 0.12 ( ) (median 0.11 in 0.51 ( ) woman and 0.13 in men) Echocardiography Stroke volume (ml) 77 (55 104) 77 (55 101) 86 (70 125) Echocardiography Stroke volume/pulse pressure 1.3 ( ) 1.6 ( ) (median 1.37 in 3.3 ( ) (ml/mmhg) woman and 1.86 in men) Pulse wave analysis Aorta augmentation index (%) ( in women and in men) CCA, common carotid artery measured by ultrasound. CCA distensibility, change in the diameter/diastolic diameter divided by the central pulse pressure. Framingham risk score also after adjustment for gender and central pulse pressure. When the three indices of arterial compliance were related to the different components included in the Framingham risk score, univariate analysis showed the major determinant of all of the three markers of arterial compliance to be systolic blood pressure (see Table 6 for details). Current smoking was not significantly related to any of the markers of arterial compliance. Although systolic blood pressure was the only significant independent variable to explain CCA distensibility in multiple regression analysis, also high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol (P < and P < 0.05, respectively) were, together with SBP, related to the SV/PP ratio, while SBP, high-density lipoprotein-cholesterol and fasting blood glucose all were significantly related to augmentation index (P < , P < 0.01 and P < 0.05, respectively). Discussion Four findings were disclosed in the present study corresponding to the four aims of the study. First, it was feasible to perform all technologies in a general population of elderly individuals. Second, reference values are presented in a healthy subsample of the population. Third, all of the evaluated indices of arterial compliance were inter-related. Finally, all of the indices evaluated were related to coronary risk, as assessed by the Framingham risk score, but multiple regression analysis showed that only CCA distensibility and the SV/PP ratio were independently related to coronary risk. Table 4 Univariate correlations between the three indices of arterial compliance; the pulse-wave-based aortic augmentation index (AIx), distensibility of the common carotid artery (CCA) and stroke volume to pulse pressure ratio (SV/PP) AIx CCA CCA 0.19 (0.0001) SV/PP 0.26 (0.0001) 0.34 (0.0001) Common carotid artery distensibility Using measurement of the carotid artery diameter by ultrasound and relating the change in diameter over the Fig. 2 ln CCA distensibility Aorta AIx (%) ln SV/PP ln SV/PP Relationships between the stroke volume to pulse pressure ratio (SV/ PP) (ln-transformed) and the other two indices of arterial compliance: distensibility in the common carotid artery (CCA distensibility) (upper panel, ln-transformed, r ¼ 0.34, P < ) and the pulse-wave-based aortic augmentation index (AIx) (middle panel, r ¼ 0.26, P ¼ ).

6 1080 Journal of Hypertension 2006, Vol 24 No 6 Fig. 3 ln CCA distensibility ln SV/PP Aorta AIx (%) Framingham score Framingham score Framingham score Relationships between the Framingham risk score and three indices of arterial compliance; distensibility in the common carotid artery (CCA distensibility) (ln-transformed, r ¼ 0.32, P < ), stroke volume to pulse pressure ratio (SV/PP) (ln-transformed, r ¼ 0.27, P < ) and the pulse-wave-based aortic augmentation index (AIx) (r ¼ 0.12, P ¼ ). cardiac cycle to the pulse pressure is a commonly used technique to evaluate the distensibility of an arterial segment [5,8,15]. Although this technology could result in many different indices of elasticity, we chose to use Table 5 Multiple regression model with the Framingham risk score as the dependent variable and the three different indices of arterial compliance as independent variables; the pulse-wave-based aortic augmentation index (AIx), distensibility of the common carotid artery (CCA) and the stroke volume to pulse pressure ratio (SV/PP) Independent variable Correlation coefficient P value AIx SV/PP CCA distensibility CCA distensibility as this index minimized the difference between men and women. Of the techniques used to evaluate arterial compliance in the present study, the CCA distensibility was most closely related to coronary risk, assessed by the Framingham risk score. This was also seen in multiple regression analysis, in which the relationship to coronary risk was independent of the other markers of arterial compliance, as well as of pulse pressure and gender. Thus, in accordance with the study showing CCA distensibility to be a predictor of future cardiovascular events [15], we found this measure of arterial compliance to be related to coronary risk. None of the other commonly used indices of arterial compliance that could be obtained by this technology, such as compliance, the stiffness beta index or the elastic modulus, were superior to distensibility in the association with coronary risk. Stroke volume/pulse pressure ratio Of the techniques to evaluate arterial compliance in the present study, this technique is the least commonly used. It is regarded as a measure of total arterial compliance and has been validated against invasive measurements [27]. In the present study we used the derived central pulse pressure for the calculation of the SV/PP ratio in accordance with other investigators [18]. This reduced the number of observations, however, since a reliable central blood pressure was not obtained in those with arrhythmias. Furthermore, appropriate echocardiographic M- mode recordings to calculate the stroke volume was not obtained in a number of participants. This, together with the fact that this technique should not be employed in individuals with an impaired systolic function, limited the feasibility to perform an adequate evaluation of the SV/PP ratio to 77%. The SV/PP ratio was found to be related to the more commonly used marker of arterial compliance, CCA distensibility. Despite this, the SV/PP ratio was together with the CCA distensibility independently related to coronary risk also after adjustment for pulse pressure and gender. This observation together with previous findings that the SV/PP ratio could predict future cardiovascular disorders also in the general population [19] therefore suggest this index to be of value for the evaluation of general arterial compliance.

7 Arterial compliance in the elderly Lind et al Table 6 Univariate relationships between the different methods to evaluate arterial compliance [aortic augmentation index, distensibility of the common carotid artery (CCA) and the stroke volume to pulse pressure ratio (SV/PP)] and the different cardiovascular risk factors included in the Framingham risk score Low-density lipoprotein-cholesterol High-density lipoprotein-cholesterol Systolic blood pressure Diastolic blood pressure Fasting glucose CCA distensibility SV/PP ratio Aortic augmentation index Pearson s correlation coefficient is presented. P < 0.05, P < 0.01, P < Augmentation index The augmentation index obtained by analysis of the systolic part of the pulse wave has gained in popularity during recent years. This is probably mainly due to easy assess to the technique now being commercially available by the Sphygmocor equipment. The augmentation index is technically easy to obtain also in the elderly population, with arrhythmias being the major reason for not obtaining excellent recordings. The augmentation index was related to the other established method used to evaluate arterial compliance in the present study, the CCA compliance method, and also the SV/PP ratio. It should be emphasized, however, that the augmentation index is not only affected by arterial compliance, but also by the resistance in the arteriole causing the wave reflection. This was clearly shown in a study in which augmentation index was reduced to a major extent after administration by any nitroglycerine preparation, while aortic pulse wave velocity was not [28]. In accordance with previous studies showing a relationship between the augmentation index and major cardiovascular risk factors [11,12], we showed the augmentation index to be related to the Framingham risk score, a composite score of several coronary risk factors. Blood pressure and arterial compliance It is well documented that hypertension is a major determinant of arterial compliance [8 10]. Of the traditional risk factors included in the Framingham risk score, a high systolic blood pressure was the most powerful determinant of arterial compliance, whether measured by indices that included pulse pressure in the calculation, such as CCA distensibility and the SV/PP ratio, or not, such as the augmentation index. Limitation of the study The present sample is limited to Caucasians aged 70. Caution should therefore be made to draw conclusions to other ethnic and age groups. The present study had a moderate participation rate. An analysis of non-participants, however, showed the present sample to be fairly representative of the total population regarding most cardiovascular disorders and drug intake. In the present study we only used indices of arterial compliance that easily could be obtained by non-invasive techniques suitable for large-scale epidemiological research. These indices all have limitations as compared with the traditional definition of compliance. A correct definition of the latter should consider, at the very least, a simultaneous measurement of pressure, diameter and flow (obtained at the same point). Compliance is then typically evaluated with rather more complex mathematical techniques. In the present used indices, the pulse pressure is directly or indirectly used in the calculations of the data, which could induce erroneous relationships. Pulse wave velocity was not measured directly in the present study. This is the best validated variable in terms of risk assessment [13,14], and might thereby be better related to the Framingham risk score than the other three variables evaluated in the present study. In the present study the three measurements of arterial compliance were not related to cardiovascular events, as it will take some 8 10 years to collect the amount of prospective events needed to evaluate the arterial compliance measurements as prospective risk factors. We only analyzed the relationships to the Framingham risk score in a cross-sectional way. The Framingham risk equation is based on data from United States. However, we have found this scoring system to be a highly significant predictor for myocardial infarction in another population from Uppsala, Sweden [29]. In conclusion, all three indices to evaluate arterial compliance were feasible to obtain in a general elderly population and were inter-related. Although all of the techniques were correlated to the Framingham risk score, only CCA distensibility and the SV/PP ratio were independently related to coronary risk, suggesting complementary use of these two indices of arterial compliance in the future. 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