Clinical usefulness of the second peak of radial systolic blood pressure for estimation of aortic systolic blood pressure

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1 (2009) 23, & 2009 Macmillan Publishers Limited All rights reserved /09 $ ORIGINAL ARTICLE Clinical usefulness of the second peak of radial systolic blood pressure for estimation of aortic systolic blood pressure K Kohara 1, Y Tabara 2, H Tomita 1, T Nagai 1, M Igase 1 and T Miki 1 1 Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan and 2 Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Ehime, Japan Central aortic blood pressure (BP), obtained from radial arterial waveform using the transfer function method (TFM), has been shown to have prognostic value independently of brachial BP. In this study, the relationship between peripheral systolic BP (SBP) and aortic SBP was evaluated. We further investigated whether TFMderived aortic SBP can be estimated by information obtained from the radial waveform. The radial waveform was analysed to obtain the first peak of radial SBP (SBP1), second peak of radial SBP (SBP2), radial augmentation index (AI) (radial (SBP2 DBP)/(SBP1 DBP) and aortic SBP and AI using TFM in 233 subjects in the supine position. Measurements were repeated after changing position to the prone position. The constructed equation was validated in 149 community residents with different backgrounds. Radial SBP2 was closer to TFMderived aortic SBP compared with brachial SBP. TFMderived aortic SBP was approximated by the equation: aortic SBP ¼ 18.9 radial SBP HR radial AI (r 2 ¼ 0.992). The equation was also applicable to predicting aortic SBP in the prone position as well as in different populations (mean difference between predicted aortic SBP and TFM-derived aortic SBP: 0.01±1.34 and 1.05±1.47 mm Hg, respectively). Radial arterial waveform analysis can be used for estimation of TFM-derived aortic SBP. (2009) 23, ; doi: /jhh ; published online 8 January 2009 Keywords: augmentation index; transfer function method; radial artery; central blood pressure; waveform analysis Introduction The clinical usefulness of central arterial blood pressure (BP), especially aortic BP, has been reported with an emphasis that changes in aortic BP are not always reflected by those in peripheral BP such as brachial BP. 1 3 Recently, it has been shown that change in aortic BP was an independent predictor of a composite outcome in hypertensive patients with risk factors in the ASCOT-CAFE study. 4 Non-invasively, aortic BP is measured from the radial arterial waveform using the transfer function method (TFM). 5,6 Using a generalized TFM, haemodynamic parameters including aortic BP and augmentation index (AI) can be obtained. The accuracy and reproducibility of TFM have made it possible to be used in clinical studies. 4 Correspondence: Dr K Kohara, Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon city, Ehime , Japan. koharak@m.ehime-u.ac.jp Received 8 August 2008; revised 5 November 2008; accepted 8 November 2008; published online 8 January 2009 Although the definition is different, AI can also be obtained directly from the radial arterial waveform. 7 It has been shown in several studies that radial AI is close enough to aortic AI, obtained by either direct measurement or TFM, to be used as a surrogate index for aortic AI. 8,9 It has also been shown that the second peak of systolic BP (SBP2) of the radial artery is very close to aortic SBP in studies with hypertensive patients, 10 and patients undergoing diagnostic coronary angiography. 11,12 As the reflected wave from the lower body is a major determinant of both later part of aortic SBP and the second peak of SBP in the radial artery, 3 aortic SBP and radial SBP2 may share common features of the reflected waves. However, whether there is close association between aortic SBP and radial SBP2 in a general population needs to be further determined. In this study, we investigated the relationship between TFM-derived aortic BP and peripheral BP, including brachial SBP and SBP2 in a random sample of 233 employees obtained from a large manufacturing enterprise. Second, we investigated whether TFM-derived aortic SBP can be estimated

2 from peripheral haemodynamic parameters. Third, the same measurements were repeated after postural change from the supine to the prone position, which is known to change both AI and BP, to examine the association between aortic SBP and peripheral parameters persisting even after acute changes in these parameters. Lastly, the reproducibility of the findings was examined in 149 community-dwelling subjects. Methods and subjects Study subjects The study subjects were participants in the Shimanami Health Promoting Program (J-SHIPP), which was designed as a longitudinal epidemiological study evaluating factors related to cardiovascular disease, dementia and death. 13,14 The first population was a random sample of 233 employees obtained from a large manufacturing enterprise in Ehime Prefecture, Japan. The second population was 149 community residents in Ehime. Both populations were from the study cohort of the J-SHIPP study. The present and past medical history was obtained by interview from each subject, and those who had no history or symptoms of cardiovascular disease except for hypertension were enrolled in the study. Informed consent for the procedure was obtained from each subject. All procedures were approved by the ethical committee of Ehime University School of Medicine. Haemodynamic measurements First population. After a more than 5-min rest in a sitting position, the subjects were asked to lie in a supine position, and brachial BP and the radial waveform were measured. Brachial BP was measured using an automatic cuff-oscillometric device (HEM-907; OMRON HEALTHCARE Co. Ltd, Kyoto, Japan). The validity and reproducibility of this device have been confirmed in a previous report. 15 The radial arterial waveform was recorded using a SphygmoCor system (AtCor Medical Pty. Ltd, Sydney, Australia). The aortic pressure waveform was derived from a radial waveform by using a previously validated TFM. 16,17 Radial BP was obtained by calibrating brachial BP to the radial arterial waveform. The following parameters were obtained from the radial arterial waveform and the TFM-derived aortic waveform (Figure 1): the first peak of SBP in radial BP (SBP1), radial SBP2, aortic SBP. Aortic AI was obtained as the percent ratio of augmented SBP by the reflected pressure wave to the pulse pressure ((DSBP)/(SBP DBP) (%)), and radial AI was defined as (SBP2 DBP)/ (SBP1 DBP) (%). The measurements were repeated on the same arm 1 min after the posture was changed from supine to prone. Second population. In the second population, the measurements were performed in the sitting position after a more than 5-min rest, with otherwise the same protocol as that for the first population. All measurements were carried out between 0900 hours and 0 hours under a fasting condition. Subjects were not permitted to drink water or smoke for at least 30 min before the measurements. Statistical analysis All values are expressed as mean±s.d. unless otherwise specified. The association between two parameters was evaluated by Spearman s correlation coefficient. The difference between two correlation coefficients was evaluated by Z-statistics. Comparisons among three groups were performed by analysis of variance with post hoc comparison. Stepwise regression analysis was used to determine the factors independently associated with aortic SBP. All statistical analysis was performed using a commercially available statistical package (JMP, SAS Institute Inc., Cary, NC, USA). A P-value less than 0.05 was defined as statistically significant. 539 Peripheral SBP Aortic SBP SBP SBP1 SBP2 Aortic DBP DBP Aortic AI (%)= SBP/(Aortic SBP-DBP) x Aortic waveform Radial AI (%)= SBP2/SBP1 x Radial arterial waveform Figure 1 Parameters measured in the study. Augmentation index is defined as DSBP/(aortic SBP DBP) in the aorta, and (SBP2 DBP)/ (SBP1 DBP) in the radial artery. SBP; systolic blood pressure, DBP; diastolic blood pressure, SBP1; first peak of SBP, SBP2; second peak of SBP.

3 540 Results Difference between peripheral SBP and aortic SBP in resting supine position in the first population Table 1 summarizes the clinical characteristics of the study population. In the first population, 39 subjects were taking antihypertensive drugs. The relationships between peripheral SBPs, brachial SBP and radial SBP2, and aortic SBP are depicted in Figure 2. Although both peripheral SBPs showed a highly significant association with aortic SBP, correlation strength between radial SBP2 and TMFderived aortic SBP was significantly higher than that between brachial SBP and TMF-derived aortic SBP (r ¼ and 0.957, Po0.0001). The mean difference from aortic SBP was significantly smaller for radial SBP2 compared with brachial SBP ( 1.62±3.05 and 12.62±4.72 mm Hg, Po0.001). The difference between radial SBP2 and TFMderived aortic SBP was significantly associated with radial AI (Figure 3). There was significant difference between subjects with (n ¼ 39) and without (n ¼ 194) antihypertensive medication in the association between brachial SBP and TFM-derived aortic SBP (r ¼ and 0.936, respectively, P ¼ 0.008) as well as the association between radial SBP2 and TFM-derived aortic SBP (r ¼ and 0.982, respectively, P ¼ 0.02). Table 1 Clinical characteristics of study subjects First population Second population N Male (%) Age (years old) 46.3± ±10.9 Body height (cm) 168.4± ±8.0 Body weight (kg) 66.2± ±9.7 Body mass index (kg m 2 ) 23.3± ±3.3 Brachial SBP (mm Hg) 124.6± ±16.4 Brachial DBP (mm Hg 73.1± ±12.3 Heart rate, beats (min 1 ) 64.5± ±9.8 Radial AI (%) 72.4± ±10.4 Radial SBP1 (mm Hg) 124.6± ±16.5 Radial SBP2 (mm Hg) 110.3± ±16.8 Aortic AI (%) 27.6± ±11.5 Aortic SBP (mm Hg) 119.8± ±15.6 Aortic DBP (mm Hg) 74.1± ±12.4 Total cholesterol (mg per 199.5±36.0 NA ml) HDL-cholesterol (mg per 58.8±13.4 NA ml) Triglyceride (mg per ml) 113.2±74.6 NA Fasting glucose (mg per ml).2±22.0 NA Current smoker (%) 35 NA Antihypertensive drugs (%) Abbreviations: AI, augmentation index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; NA; not available; SBP, systolic blood pressure; SBP1, the first peak of SBP; SBP2, the second peak of SBP. Values are mean±s.d. Effect of postural change on difference between peripheral SBPs and aortic SBP in the first population Changing position from supine to prone significantly decreased BP and AI (Table 2). The relationships between peripheral SBPs and aortic SBP in the prone position are also illustrated in Figure 2. Correlation strength between radial SBP2 and TFM-derived aortic SBP was significantly higher than that between brachial SBP and TFM-derived aortic SBP (r ¼ and 0.927, Po0.0001). The postural change in radial SBP2 was more closely associated with the change in aortic SBP than that in brachial SBP (r ¼ vs 0.926, Po0.0001) (Figure 4). However, the mean change in SBP in response to the postural change was not different among brachial SBP, radial SBP2 and aortic SBP (Table 2). Estimate of aortic SBP from peripheral SBP As the difference between radial SBP2 and TFMderived aortic SBP was significantly related to radial AI (Figure 3), incorporating other factors may further improve to predict TFM-derived aortic SBP. Stepwise regression analyses for TFM-derived aortic SBP in the supine position were performed with three models with radial SBP2, in subjects without antihypertensive medication in the first population (Table 3). By the regression obtained from the data in the supine position, aortic SBP can best be estimated with the equation: aortic SBP ¼ 18.9 radial SBP HR radial AI (r 2 ¼ 0.992). The mean difference from central SBP for estimated aortic SBP was significantly smaller than that for radial SBP2 ( 0.15±1.12 vs 1.62±3.06 mm Hg, Po0.0001). Similar findings were observed with prone position. Correlation coefficient for estimated aortic SBP and TFM-derived aortic SBP was significantly higher than that for radial SBP2 and TFM-derived aortic SBP (r ¼ and 0.984, Po0.001). The mean difference between estimated SBP and TFM-derived SBP was significantly smaller than the difference between radial SBP2 and TFM-derived SBP ( 0.01±1.34 vs 1.49±3.45 mm Hg, Po0.0001). The reproducibility of the equation was further confirmed in an independent second population. In community residents, an elderly and female dominant population, radial SBP2 also showed a significant association with TFM-derived aortic SBP measured in the sitting position (Figure 5). However, estimated aortic SBP showed a closer association with TMF-derived aortic SBP that radial SBP2 (r ¼ and 0.988, respectively, Po0.0001) (Figure 5). The mean difference between estimated SBP and TFM-derived SBP was also significantly smaller than the difference between radial SBP2 and TFMderived SBP in the second population (1.05±1.47 vs 2.48±2.73 mm Hg, Po0.0001). Estimate of aortic SBP in hypertensive patients and elderly subjects The association was further evaluated in hypertensive patients and elderly subjects. In the combined

4 Supine Aortic SBP (mmhg) r 2 =0.917 r 2 = Brachial SBP (mmhg) Radial SBP2 (mmhg) Aortic SBP (mmhg) 541 Prone Aortic SBP (mmhg) Brachial SBP (mmhg) r 2 =0.907 Aortic SBP (mmhg) Radial SBP2 (mmhg) r 2 =0.969 Figure 2 Relationship between transfer function method-derived aortic systolic blood pressure (SBP) and two peripheral SBPs; brachial SBP and second peak of radial SBP (SBP2) in supine position (upper panels) and in prone position (bottom panels). White circles are subjects not taking antihypertensive drugs, and black circles are subjects taking antihypertensive drugs. Radial SBP2-TFM-derived aortic SBP r=0.922 p< Peripheral augmentation index Figure 3 Relationship between the difference between the second peak of radial systolic blood pressure (SBP2) and transfer function method (TFM)-derived aortic SBP and radial augmentation index (AI). population (n ¼ 382), correlation coefficient for TFM-derived aortic SBP and estimated aortic SBP was significantly higher than that for TFM-derived aortic SBP and radial SBP2 in normotensive subjects (n ¼ 264, r ¼ vs r ¼ 0.966, Po0.0001), hypertensive patients (n ¼ 118, r ¼ vs r ¼ 0.981, Po0.0001), subjects aged o65 years (n ¼ 273, r ¼ vs r ¼ 0.984, Po0.0001) and elderly subjects aged 465 years (n ¼ 109, r ¼ vs r ¼ 0.987, Po0.0001). Discussion Aortic BP estimated from radial arterial waveform using TFM was initially reported by Karamanoglu et al. 16 TMF has now become common practice and has been used in many clinical studies including large clinical trials. 4 An extremely close association between radial AI and aortic AI has also been reported, 9,10 suggesting that radial AI can be used clinically as an approximate value of aortic AI.

5 542 Table 2 Postural change in blood pressure and augmentation index (n ¼ 233) Supine Prone Change P-value Brachial SBP (mm Hg) 124.6± ± ±7.8 o Brachial DBP (mm Hg) 73.1± ± ± Heart rate (beats min 1 ) 64.5± ± ±6.0 o Radial AI (%) 72.4± ± ± Radial SBP1 (mm Hg) 124.6± ± ±7.8 o Radial SBP2 (mm Hg) 110.3± ± ±8.6 o Aortic AI (%) 27.6± ± ± Aortic SBP (mm Hg) 112.0± ± ±7.6 o Aortic DBP (mm Hg) 74.1± ± ± Abbreviations: AI, augmentation index; DBP, diastolic blood pressure; SBP, systolic blood pressure; SBP1, the first peak of SBP; SBP2, the second peak of SBP. Values are mean±s.d. P-values are for the postural changes Aortic SBP Aortic SBP r 2 =0.859 r 2 = Brachial SBP Radial SBP2 Figure 4 Change in peripheral systolic blood pressure (SBP) and transfer function-derived aortic SBP in response to postural change from supine to prone position. White circles are subjects not taking antihypertensive drugs, black circles are subjects taking antihypertensive drugs. Table 3 Stepwise regression analysis for aortic SBP in subjects not taking antihypertensive drugs in the first population (n ¼ 194) Parameters Model 1 Model 2 Model 3 b P-value b P-value b P-value Sex (female) Not entered Age 0.09 o Not entered Body height Not entered Heart rate Radial AI 0.21 o0.001 Radial SBP o o o0.001 Total r *,w Abbreviations: AI, augmentation index; SBP, systolic blood pressure; SBP2, the second peak of SBP. Stepwise regression analyses for transfer function method-derived aortic SBP with three models including radial SBP2 with age, sex, body height and radial AI were performed. Based on model 3, aortic SBP can best be estimated by the equation: aortic SBP ¼ 18.9 radial SBP HR radial AI. *Po vs model 1. w Po vs model 2. The close association between peripheral BP and TFM-derived aortic BP was first reported by Cameron et al. 18 in subjects with treated hypertension. Recently, Munir et al. 12 reported a close association between radial SBP2 and aortic SBP in 391 subjects undergoing coronary angiography. We reconfirmed their findings in the two independent general populations predominant with middle-aged men and elderly women with short statue. We further showed that TFM-derived aortic SBP could be approximated by the equation in the supine position: aortic SBP ¼ 18.9 radial SBP HR radial AI. This equation was also applicable in predicting aortic SBP after a change in posture from the supine to the prone position, which significantly decreased both central and peripheral SBP as well as AI. Furthermore, the findings were reconfirmed in an independent population of community residents who were older and female dominant compared with the first population. Does this equation have any physiological meaning? To answer this question, we need to consider the possible mechanisms why is radial SBP2 closer to aortic SBP? Physiologically, central aortic SBP is lower than SBP in peripheral arteries for a similar mean BP. 19 This is due to the phenomenon known as peripheral amplification of pulse pressure, which results from propagation of the pressure wave along

6 TFM-derived aortic SBP (mmhg) n=149 n=149 r 2 =0.978 r 2 =0.992 TFM-derived aortic SBP (mmhg) Radial SBP2 (mmhg) Estimated aortic SBP (mmhg) 543 Difference between TFM-derived aortic SBP and estimated aortic SBP (mmhg) 10 8 n= Average of TFM-derived aortic SBP and estimated aortic SBP (mmhg) Figure 5 Upper left: Relationship between the second peak of radial systolic blood pressure (SBP2) and transfer function method (TFM)-derived aortic SBP. Upper right: Relationship between predicted aortic SBP obtained by applying the formula in subjects in the second population and TFM-derived aortic SBP. Lower: Bland Altman plot of estimated aortic SBP and TFM-derived aortic SBP. the vascular bed, the progressive narrowing of arterial and arteriolar vessels with subsequent increase of arterial stiffness and mostly the summation of wave reflections. 1,20 The systolic pressure wave in the radial artery is the composite of three waves: forward travelling incident wave, backward reflection wave from the periphery (hand) and forward travelling reflection wave from the lower body. 3 As the distance from the reflection point of the periphery (hand) is so short in the radial artery, the incident wave and reflection wave merge into the one systolic wave, making the first peak of systolic pressure in the radial artery. 3 The second peak of systolic pressure in the radial artery is made by the arrival of the reflected wave from the lower body. 1,3 The height of the second peak of the radial artery is determined by the timing and the magnitude of the reflected wave from the lower body. In the central aorta, the systolic pressure wave is the composite of two waves; the forward incident wave and backward reflected wave, mainly from the lower body. 1,3 If the reflected wave arrives after the peak of the incident wave (AI o0), the reflection wave has no influence on aortic SBP. On the contrary, if the reflected wave arrives early in systole (AI 40), it augments SBP to form the late systolic peak of aortic SBP. In this study, the change in aortic AI by postural change was significantly associated with the change in radial SBP2 (r ¼ 0.454, Po0.0001) but not associated with the change in brachial SBP (r ¼ 0.112, P ¼ 0.087). Accordingly, the late peak of SBP in the aorta shares information with radial SBP2 about propagation speed and magnitude of the reflected wave from the lower body. The difference between radial SBP2 and TFMderived aortic SBP was, however, significantly associated with radial AI in the supine position (Figure 3). Similar findings were also observed in the second population (data not shown). This is the major reason of the fact that incorporation of radial AI further improved the prediction of TMF-derived aortic SBP from radial SBP2. Although it is beyond the scope of this study to identify the underlying mechanisms for this phenomenon, it may relate to TMF itself, as the association was so close. We and others have shown that posture significantly changes AI In this study, peripheral SBP and aortic SBP significantly decreased after changing to a prone position in association with AI. Surprisingly, the relationship between aortic SBP and radial SBP2 was not changed in the prone

7 544 position. There was a highly significant association between TFM-derived aortic SBP and estimated aortic SBP in the prone position using the equation obtained from the supine data (r ¼ 0.996). These findings indicate that a close association between radial SBP2 and aortic SBP exists even after an acute change in AI. The findings were reconfirmed in the second population characterized by elderly and female dominant population. Furthermore, the similar findings were also observed in elderly subjects as well as hypertensive patients. As both conditions are known to be associated with higher AI, these findings also support that the correction of radial SBP2 by radial AI further improve the prediction of aortic SBP. There are several limitations, however, in estimating aortic SBP from radial SBP2. Use of potentially inaccurate brachial BP measures to calibrate the radial waveform to estimate central SBP is one of the limitations of the method. BP measurements were performed in the prone position in the first population, and in the sitting position in the second population. Although the estimate equation also showed a higher correlation with TMF-derived aortic SBP than radial SBP2 in both postures, data obtained from these positions may violate transfer function estimation of aortic SBP, as SphygmoCor system validates BP in the supine position. The limitation of radial waveform analyses also exists in cases where radial late systolic pressure cannot be identified due to very early or very late return of reflected wave. In summary, radial SBP2 is close to TFM-derived aortic SBP. Further incorporation of radial AI and heart rate can predict aortic SBP after an acute change in AI. This was also reconfirmed in a different older population. These findings indicate further usefulness of peripheral arterial waveform analysis, which can be used for estimation of TFMderived aortic BP. What is known about the topic K Central aortic BP has been shown to have prognostic value independently of brachial BP. 1 4 K Central aortic BP can be estimated noninvasively from radial arterial waveform using the transfer function method (TFM). 4 7 What this study adds K Second peak of radial SBP (SBP2) is close to aortic SBP in a general population. K TFM-derived aortic SBP can be accurately estimated with radial SBP2, heart rate and radial augmentation index (AI) (r 2 ¼ 0.992). Acknowledgements Part of the study was supported by a grant-in-aid from Mitsubishi Pharma Research Foundation. References 1 Nichols WW, O Rourke MF. McDonald s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, 4th edn. Edward Arnold: London, UK, Sharman JE, Stowasser M, Fassett RG, Marwick TH, Franklin SS. Central blood pressure measurement may improve risk stratification. J Hum Hypertens 2008; 22(12): Nichols WW. 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