Validation of a New Index for Estimating Arterial Stiffness: Measurement of the QPV Interval by Doppler Ultrasound

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1 Clin. Cardiol. 29, (6) Validation of a New Index for Estimating Arterial Stiffness: Measurement of the QPV Interval by Doppler Ultrasound MIN-YI LEE, M.D., CHIH-SHENG CHU, M.D.,* KUN-TAI LEE, M.D.,* CHAN-MING WU, M.D., HO-MIN SU, M.D.,* SHIN-JING LIN, M.D.,* SHENG-HSIUNG SHEU, M.D.,* WEN-TER LAI, M.D.* Division of Cardiology, Department of Internal Medicine, Kaohsiung Municipal United Hospital; *Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Summary This study was supported in part by a grant from Kaohsiung Municipal United Hospital Medicine Foundation. Address for reprints: Wen-Ter Lai, M.D. Division of Cardiology Department of Internal Medicine Kaohsiung Medical University 100 Shih-Chuan 1st Road Kaohsiung 807, Taiwan wtlai@cc.kmu.edu.tw Received: February 9, 6 Accepted with revision: April 4, 6 Background: Pulse wave velocity (PWV), a relevant indicator of arterial stiffness, can be measured noninvasively with a variety of automatic devices, but most are complexly equipped. We developed a novel index for estimating arterial stiffness as QPV interval, which was determined by means of surface electrocardiogram and Doppler ultrasound of the brachial artery simultaneously. Hypothesis: This study aimed to validate the QPV interval as an exact and convenient index for estimation of arterial stiffness. Methods: Forty-seven patients with untreated essential hypertension and 19 normotensive subjects were enrolled. Brachial-ankle PWV (bapwv) was measured using an automatic volume-plethysmographic apparatus, and Doppler ultrasound was implemented sequentially to measure the QPV interval in each subject. Clinical biochemistry and echocardiography were performed on the same day. Results: Mean bapwv was significantly higher in hypertensive patients than in normotensive subjects (p = 0.002), whereas mean QPV interval was significantly shorter in hypertensive patients than in the normotensive group (p = 0.019). A simple regression analysis demonstrated an inverse correlation between the QPV interval and bapwv (r = 0.671, p < 0.001) in all enrolled subjects. In a stepwise regression model that adjusted for age, systolic blood pressure, and other determinants of bapwv, the negative association remained between the QPV interval and bapwv (p < 0.001). Conclusion: The QPV interval correlates inversely with bapwv, independent of age and other determinants of bapwv; hence, the QPV interval can serve as a simple and convenient index for assessing arterial stiffness in clinical practice. Key words: arterial stiffness, pulse wave velocity, QPV interval, Doppler ultrasound Introduction Arterial stiffness is known to be associated with target organ damage and is a relevant predictor of future cardiovascular morbidity and mortality in hypertensive patients. 1 Previous studies have reported that arterial stiffness increases with age 2 and is also enhanced in patients with hypertension, 3 hypercholesterolaemia, 4 diabetes mellitus, 5 atherosclerosis, 6 and end-stage renal disease. 7 The consequence of arterial stiffening is the increase in pulsatile blood pressure (BP) caused by higher systolic and lower diastolic BP. 8 It is desirable to measure the elastic properties of the vascular wall in the arterial system, which may reflect the degree of arterial atherosclerotic changes. 9 Arterial stiffness can be assessed noninvasively by measuring pulse wave velocity (PWV), that is, the velocity of the propagating pulse wave to travel a given distance between two sites of the arterial system. 10 Pulse wave velocity is a well-recognized independent predictor of cardiovascular events in patients with risk factors and is applicable as a marker for the severity of atherosclerosis. Conventionally, arterial stiffness was measured noninvasively with carotid-femoral PWV using Doppler velocimetry or arterial tonometry; 11 however, the data obtained from carotid-femoral PWV are highly variable and operator dependent. Recently, a more convenient method, brachial-ankle PWV (bapwv), performing pulse

2 346 Clin. Cardiol. Vol. 29, August 6 volume recording simultaneously over upper and lower extremities, is available in clinical practice. 12, 13 Although the measurements of PWV either using carotid-femoral or brachial-ankle PWV as reference points are clinically feasible, the costs of these complex equipments are too high for easy access and the procedures are time consuming for large-scaled screen examination. Another method for estimating arterial stiffness, the QKD interval, recording the time interval between the onset of depolarization on the electrocardiogram (ECG) and detection of the last Korotkoff sound at the level of the brachial artery during cuff deflation, is not feasible, as it necessitates 24-h ECG-gated ambulatory BP monitoring to determine the interval. 14 Compared with the Doppler ultrasonic spectra of other superficial arteries, such as carotid, radial, or femoral arteries, the brachial artery offers a definite and uniform ultrasonic signal for the measurement of time interval either in healthy subjects or in patients with atherosclerotic risk factors. Therefore, we developed a novel method, which was defined as QPV interval, utilizing the easily accessible Doppler ultrasound to estimate the severity of arterial stiffness. The accuracy and applicability of this new index were evaluated in patients with untreated essential hypertension and normotensive control and compared with bapwv measured with a new commercial device. 13 Methods Subjects and Study Protocol Forty-seven patients with untreated essential hypertension and 19 healthy subjects without hypertension were enrolled in this cross-sectional study. Informed consent was obtained from all participants. The protocol for this study was approved by the institutional review board of Kaohsiung Medical University. Patients with chronic congestive heart failure, established cerebrovascular disease, chronic renal insufficiency, or peripheral arterial disease were excluded. No patient had a history of diabetes mellitus before inclusion. The values of BP were obtained automatically by the oscillometric method (Terumo ES-P110, Tokyo, Japan) on at least two occasions. The diagnostic criteria of hypertension were according to the JNC-7 report. 15 No subject had previously used antihypertensive or vasoactive medication. All subjects were asked to refrain from smoking and drinking coffee or tea on the day of assessment. Blood samples were drawn on the day of examination after a fasting period of 8 h. Complete blood cell counts, serum electrolytes, serum glucose level, and thyroid function test were all within the normal range of our standardized values. Normal sinus rhythm with a rate of within 60 to 100 beats/min was also required on rest ECG. All subjects rested for at least 10 min in supine position before bapwv measurements and ultrasound examination were undertaken. The following parameters were obtained with standard techniques on the day of examination: total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and body mass index (BMI). Left ventricular ejection fraction was estimated according to the recommendations of the American Society of Echocardiography. 16 Assessment of Arterial Stiffness Arterial stiffness was assessed by means of bapwv. The bapwv was measured automatically using a volume plethysmographic apparatus (form PWV/ABI, Colin Co., Ltd., Aichi, Japan). This instrument can record bapwv, BP of both upper and lower extremities (and hence, right-sided and left-sided ankle-brachial index), ECG, and phonocardiogram simultaneously. Four pneumatic pressure cuffs were placed around both upper arms and both ankles. The recorded pressure signals of the four extremities by oscillometric principle, known as pulse volume traces, were processed instantaneously to provide the pulse transit time (foot to foot time intervals, T) from the right upper arm to the right ankle and from the right upper arm to the left ankle. The distance between the arm and ankle (D) was calculated based on the regression equation: D = height The right brachial-to-right ankle bapwv and the right brachial-to-left ankle bapwv were calculated as D/ T, respectively. The mean value of right brachial-to-right ankle bapwv and right brachial-to-left ankle bapwv, and the right-sided and left-sided ankle-brachial index (ABI) of each patient were obtained for data analysis. The validation and reproducibility of this method has been reported previously. 13 Measurement of the QPV Interval With a 7.5-MHz linear array transducer, ECG-gated Doppler spectral flow of the brachial artery was assessed using a carrier frequency of 3.75 MHz and an insonation angle of 60 at baseline and after sublingual administration of 400 µg nitroglycerin while patients were in supine position. All Doppler flow signals were captured digitally with customized equipment. The QPV interval, expressed in ms, was measured during the time interval between the ECG QRS initiation and the peak flow velocity of the brachial artery at baseline and 4 min after sublingual administration of nitroglycerin. The mean QPV interval was obtained by measuring the time interval at two consecutive velocity waveforms (Fig. 1). Assessments of Inter- and Intraobserver Reproducibility Thirty subjects (aged 30 to 73 years; mean age 51 ± 17.5 years; 22 males; 15 controls and 15 patients with hypertension) were recruited for the assessment of interobserver reproducibility. For each subject, the QPV interval was measured by two observers (an experienced observer: measurement 1, and an inexperienced observer: measurement 2) in a random order with a minimum of 5 min between the two measurements. Twenty-five subjects (aged 33 to 70 years; mean age 50 ± 16.5 years; 15 males; 10 controls and 15 patients with untreated hypertension) were recruited for assessment of intraobserver reproducibility. The experienced ob-

3 M.Y. Lee et al.: New index for estimating arterial stiffness 347 FIG. 1 Measurement of the QPV interval (QPVI, ms) obtained by Doppler ultrasound. The sample volume was positioned centrally in the lumen of brachial artery and the mean QPV interval was obtained by measuring the time interval at two consecutive pulsatile velocity waveforms using in-built electronic caliber. The mean QPV interval was ms in this patient. server measured the QPV interval twice for each participant with an interval of at least 1 day between the two measurements. Repeated analysis of QPV interval measurements was highly reproducible at baseline and after sublingual administration of nitroglycerin with a correlation of > 0.86 for all paired comparisons in our laboratory. Statistical Analysis All values are expressed as mean ± standard deviation (SD) except as noted. Univariate associations between the study variables were analyzed by calculating Pearson s correlation coefficients. Multivariate analyses were performed using stepwise regression to examine whether associations exist between bapwv and QPV interval, age, BMI, total cholesterol, systolic BP, mean arterial pressure, pulse pressure, heart rate, and ankle-brachial index. Regression coefficients were expressed per SD increase of the independent variables. Partial R 2 values represent the change in R 2 as each variable entered the model. All statistical analyses were achieved using the Statistical Package for Social Sciences 11.0 software (SPSS Inc., Chicago, Ill., USA). A probability value of p < 0.05 was considered to be statistically significant. Results As listed in Table I, the intra- and interobserver variation of coefficients for measurements of the QPV interval were 5.3 and 7.1% at baseline and 6.7 and 7.5% after sublingual admin- TABLE I Intra- and interobservational reproducibility data of QPV interval at baseline and 4 min after sublingual administration of nitroglycerin (post-ntg) Measurement 1 Measurement 2 r p Value CV, % Intraobservational Baseline ± ± < Post-NTG ± ± < Interobservational Baseline ± ± < Post-NTG ± ± < All values are expressed as mean ± standard deviation. Abbreviations: r = Pearson s correlation coefficient, CV = coefficient of variation, NTG = nitroglycerin.

4 348 Clin. Cardiol. Vol. 29, August 6 TABLE II Clinical characteristics of all enrolled subjects Normotensive Hypertensive (n = 19) (n = 47) p Value Age, years 48.1 ± ± Male, % Smoking, % BMI, kg/m ± ± Height, cm ± ± Total cholesterol, mg/dl ± ± LDL cholesterol, mg/dl ± ± HDL cholesterol, mg/dl 36.8 ± ± Triglyceride, mg/dl ± ± Systolic BP, mmhg ± ± 13.6 < Diastolic BP, mmhg 80.6 ± ± 10.9 < Mean arterial pressure, mmhg 99.2 ± ± 11.9 < Pulse pressure, mmhg 49.6 ± ± 10.1 < Heart rate, beats/min 72.4 ± ± LVEF, % 68.4 ± ± bapwv, cm/s ± ± QPV interval, ms ± ± ABI 1.11 ± ± All values are expressed as mean ± standard deviation or percent. Abbreviations: BMI = body mass index, LDL cholesterol = low-density lipoprotein cholesterol, HDL cholesterol = high-density lipoprotein cholesterol, BP = blood pressure, LVEF = left ventricular ejection fraction, bapwv = brachial ankle pulse-wave velocity, ABI = ankle-brachial index. istration of nitroglycerin, respectively. The clinical characteristics of all enrolled subjects are shown in Table II. The mean bapwv was significantly higher in hypertensive patients than in normotensive control ( ± vs ± cm/s, p = 0.002), whereas the mean QPV interval was significantly shorter in hypertensive patients than in normotensive subjects (192.9 ± 19.1 vs ± 16.2 ms, p = 0.019). There was no difference in age, smoking status, lipid profile, and ankle-brachial index between the two groups. A simple regression analysis demonstrated there was an inverse correlation between baseline QPV interval and bapwv (r = 0.671, p < 0.001) in all enrolled subjects (Fig. 2). Furthermore, age, systolic BP, mean arterial pressure, and pulse pressure all correlated negatively with the QPV interval, as shown in Figure 3. No association could be found between height and QPV interval (r = 0.128, p = 0.304). Resting heart rate was also shown to have no association with the QPV interval (r = 0.203, p = 0.103). Body mass index, total cholesterol, LDL cholesterol, HDL cholesterol, and ankle-brachial index showed no correlation with either bapwv or QPV interval in this study. Except for a marginally positive correlation between the QPV interval and left ventricular end-diastolic diameter in the hypertensive group (r = 0.296, p = 0.046), no other correlation existed between the QPV interval and parameters of ventricular geometry in either hypertensive or normotensive groups. The results of unadjusted linear regression models assessing the ability of the QPV interval and other factors to predict bapwv are shown in Table III. Age showed to be a strong and significant predictor of bapwv level among all subjects. For each SD increase in age, the bapwv value increased by (95% confidence interval [CI] , p = 0.001). The QPV interval was also demonstrated to be an independent contributor to bapwv. For each SD increase in the QPV interval, the bapwv value decreased by (95% CI , p = 0.004). The R 2 of this unadjusted model was 0.469, indicating that the QPV interval explained 46.9% of the variance in bapwv, which was greater than the variance in bapwv explained by age (26.4%). Multivariate stepwise regression analysis assessing the QPV interval as a predictor of bapwv is shown in Table IV. After adjustment for systolic BP bapwv (cm/s) 2,600 2,400 2, 2,000 1,800 1,600 1,400 1, 1,000 r = 0.671, p < FIG. 2 Relation between brachial-ankle pulse wave velocity (bapwv) and QPV interval in all subjects. Scatter plot illustrates the inverse association between the QPV interval and bapwv.

5 M.Y. Lee et al.: New index for estimating arterial stiffness 349 (A) 20 r= 0.310, p = Age (years) (B) 100 r = 0.424, p< SBP (mmhg) (C) 60 r= 0.380, p = MAP (mmhg) (D) r = 0.496, p< PP (mmhg) FIG. 3 Relations between QPV interval and known PWV determinants: age (years) (A), systolic blood pressure (SBP, mmhg) (B), mean arterial pressure (MAP, mmhg) (C), and pulse pressure (PP, mmhg) (D). The QPV interval correlated inversely to the four PWV determinants. TABLE III Unadjusted linear regression analysis of predictors for brachial ankle pulse-wave velocity (bapwv) among all subjects Predictors (per SD increase) Change (95% CI) in bapwv p Value R 2 Age ( ) QPV interval ( ) BMI ( ) Height 3.04 ( ) Heart rate ( ) Systolic BP ( ) Mean arterial pressure ( ) Pulse pressure ( ) ABI ( ) Total cholesterol ( ) Abbreviations: SD = standard deviation, BMI = body mass index, CI = confidence interval. Other abbreviations as in Table II. TABLE IV Stepwise linear regression model assessing the QPV interval as a predictor of brachial ankle pulse-wave velocity (bapwv) Change (95% CI) in bapwv Models (per SD increase in the QPV interval) p Value Partial R 2 Model 1 QPV interval ( ) < Model 2 QPV interval and systolic BP ( ) < Model 3 QPV interval, systolic BP and age ( ) < Abbreviations as in Table III.

6 350 Clin. Cardiol. Vol. 29, August 6 (model 2), the QPV interval still had a significantly negative association with bapwv and explained 18.1% of the variance in bapwv. Although further adjustment for systolic BP and age did attenuate the relationship between QPV interval and bapwv, the association remained statistically significant, and the QPV interval explained 10.5% of the variance in bapwv (model 3). All p values were < Discussion The present study has examined the feasibility of measuring the QPV interval for assessment of arterial stiffness in subjects with and without untreated essential hypertension. We demonstrated that the QPV interval correlated inversely with bapwv and with known determinants of bapwv such as age, systolic BP, mean arterial pressure, and pulse pressure. After adjusting for several established factors that affect arterial stiffness, the QPV interval still had a significantly inverse association with bapwv. This result provided an acceptable validation of the convenient and simple measurement for estimation of arterial stiffness. Until now, there has been no standard of reference for the measurement of arterial stiffness in clinical practice. Since the pulse waves expelled from the left ventricle are transmitted faster in stiffer than in more elastic arteries, PWV may serve as a relevant indicator for assessing arterial stiffness. 11 A conventionally used indicator, the carotid-femoral PWV, may not reflect critical changes in the proximal aortic stiffness and needs to be corrected by heart rate. 17 In addition, when the femoral artery is used as a reference point, a transducer must be attached to the inguinal region, which may have a strong psychological impact on the subject and an influence on the sympathetic tone. These disadvantages make the technique for PWV measurement unsuitable for screening a large population. However, bapwv using extremity arteries for estimating arterial stiffness has been widely accepted as a simpler method with less psychological stress. 18 The validity and reliability of bapwv have been defined and were proven to correlate well with the invasive aortic PWV (r = 0.87, p < 0.01). 13 Therefore, we chose bapwv as a comparable index of arterial stiffness in this study and found a strongly inverse association between the QPV interval and bapwv. Our results also indicated that the QPV interval was age dependent and could be used as a reliable indicator for vascular aging. Many noninvasive methods are used for estimating arterial stiffness, such as pulse transit time, analysis of arterial pressure pulse and wave contour, and estimation of changes in vascular diameter and distending pressure. 10 Devices for measuring pulse transit time include the Complior system (Artech Medical, Pantin, France) and the QKD interval. 11, 14 Unfortunately, their clinical applications have been limited by technical difficulties, high costs, and the need for simultaneous measurements at different vascular sites. In the present study, our results demonstrated that the QPV interval was not related to the height of each subject. Since the QPV interval was determined by the pulse transit time across a certain length of the arterial tree from the aortic valve to the brachial artery, height may not have a significant influence on such a short distance for the pulse wave to travel. This result also suggested that the QPV interval is a simpler method without correction for body length. Because the arteriosclerotic process was ubiquitous within the entire vasculature, the QPV interval can represent the severity of arterial stiffness across the vascular beds. The reproducibility of QPV interval measurement is acceptable either at baseline or under the effect of vasodilatory medication. Although the QPV interval does not reveal the locus of arteriosclerosis, it affords repeated measurements easily and makes chronological estimations of arterial stiffness possible in an individual subject. Limitations There are several limitations to this study. First, we could not determine whether the QPV interval was sufficient for assessing the atherosclerotic burden, which could be evaluated noninvasively with transesophageal echocardiography or magnetic resonance imaging. Second, acquisition of the QPV interval and pulse waveform analysis for calculating the transit time from brachium to ankle were implemented in different cardiac cycles; hence, the beat-to-beat variability might affect the difference between QPV interval and bapwv. Third, the study was limited by its relatively small sample size. A large number of study subjects is required if the aim is to establish the normal range of QPV interval in a healthy population. Conclusion The QPV interval of the brachial artery measured by Doppler ultrasound is easy to obtain and was closely associated with bapwv as well as with age, systolic BP, and pulse pressure. The results suggest that this new index can reflect age-related changes in vascular stiffness. Furthermore, the QPV interval can be determined simultaneously with the noninvasive evaluation of endothelial function by brachial artery ultrasound examination. Hence, measurement of the QPV interval may become a promising and relevant index for estimation of arterial stiffness and vascular aging. Acknowledgments The authors are grateful to Hui-Fen Lin and Jen-Hui Yen for technical assistance. References 1. Stéphane L, Pierre B, Roland A, Isabelle G, Brigitte L, Louis G, Pierre D, Athanase B: Aortic stiffness is an independent predictor of all cause and cardiovascular mortality in hypertensive patients. Hypertension 1;37: Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O'Rourke MF: Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 1983;68:50 58

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