The effects of pressure wave reflection have been incompletely described by the central augmentation index (cAI) and augmented pressure (Pa). We therefore investigated the determinants of amplitude of the reflected wave (Pb), which is independent of the reflected wave transit time (RWTT) and has been shown to predict cardiovascular mortality in the general population. A total of 180 (117 men, mean age 68 years old) patients were recruited. Carotid pressure waveforms derived by tonometry at baseline and 3 min after administration of sublingual nitroglycerin (NTG) were calibrated and then decomposed into the forward and backward waves to yield Pb. The ratio of pre-ejection period/ejection time (PEP/ET) was measured. By stepwise multivariate analysis, independent determinants of Pb included brachial mean blood pressure (β=0.56, P<0.001), heart rate (β=−0.29, P<0.001), age (β=0.20, P<0.001), PEP/ET (β=−0.16, P=0.004) and height (β=−0.13, P=0.018). RWTT, body mass index and sex were significant independent determinants of Pa and cAI but did not contribute to Pb. Change of Pb but not Pa or cAI significantly predicted the changes of carotid systolic (r=0.550, P<0.001) and pulse pressure (r=0.618, P<0.001) after NTG. In conclusion, determinants of Pb differ from those of cAI and Pa. Pb is independent of sex and RWTT.
Pressure wave generated by the left ventricle propagates along the arterial tree with manifested phenomena of reflection, dispersion and attenuation.1, 2 The backward traveling reflection waves from peripheral reflection sites superimpose on the forward traveling wave to form the varying pressure waveforms recorded at central and peripheral arteries.1, 3 Thus, wave reflection dominates age-related change in aortic blood pressure throughout the human life span, and increased wave reflection contributes significantly to left ventricular afterload, coronary perfusion and cardiovascular risk.1, 4
The intensity of global wave reflection has conventionally been estimated from the analysis of central aortic or carotid pressure waveforms and from the calculation of the augmentation index (cAI), based on the concept of augmentation of central aortic systolic pressure (SBP) by a summated reflected wave.1, 3 However, the impacts of wave reflection on central pulse pressure (PP),5 central aortic pressure waveform,2 target organ damages and cardiovascular events may have been underestimated when cAI or augmented pressure (Pa) is used as a surrogate of the wave reflection intensity,6 probably because cAI is dependent of the reflected wave transit time (RWTT) and sex,3, 7, 8 and is principally determined by aortic reservoir function, other elastic arteries and only to a minor extent by reflected waves,9 and may be dissociated with arterial stiffness measured by the aortic pulse wave velocity.10, 11
The absolute amplitude (Pb) of the reflected pressure wave decomposed from a central aortic or carotid pressure waveform is independent of RWTT and may be a better measure of wave reflection intensity than cAI or Pa.6, 8 Because of the limitations of cAI and Pa, our current understanding about the determinants of wave reflection has been incomplete.3, 10 Furthermore, it remains to be determined whether cAI and Pa adequately quantify the change of wave reflection intensity after pharmacological intervention such as nitroglycerin (NTG). This is important because cAI has long been used as a surrogate end point in the evaluation of antihypertensive therapy.12, 13 The effect of NTG on wave reflection has long been recognized, and any indices of wave reflection intensity should demonstrate adequate responses to NTG.14, 15 Therefore, the purpose of this study was to investigate the determinants of Pb and the response of Pb to the administration of a sublingual NTG.
Subjects and methods
Subjects were recruited from an outpatient department of cardiovascular division at the Taipei Veteran General Hospital between September 2007 and November 2009. All subjects had signed a consent form approved by our institutional review board. Anthropometric measures, including height, body weight, waist circumference and body mass index (BMI), as well as other conventional cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia and smoking with related medication were collected. Patients who had brachial blood pressure lower than 90 mm Hg or intolerant to NTG were excluded. For patients’ safety, medications were not adjusted before the study and were continued on the day of the study.
Subjects were studied under supine resting position in a quiet, temperature-controlled room. Measurements were carried out after at least 15-min supine rest. We used a commercially available device (VP-2000, Colin Corporation, Komaki, Japan) that was customized to output all physiological signals, including electrocardiogram, phonocardiogram, oscillometric signals from arms and ankles, and tonometric signals from right common carotid and femoral artery. All signals were recorded and digitized simultaneously for off-line analysis. The validity and reproducibility of the device have been documented before.16 Brachial blood pressure was obtained by oscillometric technique in the supine position (means of two measurements). Carotid arterial pressure waveforms were stored for 30 s from applanation tonometric sensors. Bilateral brachial and posterior–tibial arterial pulse volume recording waveforms were stored for 10 s by extremities cuffs connected to a plethysmographic sensor and an oscillometric pressure sensor wrapped on both arms and ankles. Brachial–ankle pulse wave velocity was calculated by the simultaneously digitized tonometric and pulse volume recording waveforms with customized software. Details of the measurement have been reported previously.17 The higher between right and left brachial–ankle pulse wave velocity was selected as the representative brachial–ankle pulse wave velocity. The carotid ejection time (ET) was automatically measured from the foot to the dicrotic notch (incisura, produced by the closure of aortic valve) of carotid waveform. Electromechanical systolic interval was measured from the onset of the QRS complex on the electrocardiogram to the first high-frequency vibrations of the aortic component of the second heart sound on the phonocardiogram. The carotid pre-ejection period (PEP) was automatically calculated by subtracting the ET from the systolic interval.
Sublingual NTG administration
After baseline measurements, 0.4 mg sublingual NTG was given. The same process was repeated 3 min after sublingual NTG.
Carotid pressure waveform analysis
The digitized carotid pressure waveform signals were analyzed using the custom-designed software on a commercial software package (Matlab, version 4.2, The MathWorks Inc., Natick, MA, USA). All of the processed individual signals were subjected to fully automatic batch analysis to avoid inter- and intraobserver variations. A total of 5–10 consecutive carotid pressure waves were ensemble averaged to 1 wave. The averaged carotid pressure waveform was then calibrated using mean and diastolic brachial pressure levels measured in the supine position. Carotid SBP, PP, RWTT, Pa (the difference between early and late pressure peaks) and cAI (Pa divided by carotid pulse pressure) were calculated automatically by waveform analysis. Then the pressure waveform was decomposed into forward pressure wave and reflected pressure wave using the triangulation flow method, and the absolute amplitudes of the forward (Pf) and the backward (Pb) were measured, respectively (Figure 1). Details of the waveform decomposition process have been described elsewhere.6, 18 Pf and Pb (before and after NTG) calculated by using the triangular-shaped flow wave have been compared with those calculated by using the true aortic flow wave derived from Doppler echocardiography in another 20 subjects in our laboratory. The mean differences and standard deviations between Pf and the reference were -0.8±2.0 mm Hg and 1.7±2.4, before and after NTG, respectively. The mean differences and s.d.s between Pb and the reference were -0.1±1.1 mm Hg and −0.9±1.1, before and after NTG, respectively. (See Supplementary Figure S1)
Statistical analysis was performed using SPSS software (Version 16.0, SPSS Inc., Chicago, IL, USA). All data were expressed as proportions or means and s.d.s. Pearson correlation coefficients were calculated. Simple and multiple linear regression analyses were used to assess the determinants for Pb, Pa and cAI. Statistical significance was established at two-tailed P<0.05.
A total of 180 study subjects (117 men, mean age 68±14 years old) were recruited. Their clinical characteristics and hemodynamic parameters are given in Table 1.
Table 2 shows the correlation of demographic and hemodynamic parameters with Pb, Pa and cAI. In summary, Pb, Pa and cAI correlated significantly with age, all blood pressure variables, heart rate, height and PEP/ET. In contrast, Pa and cAI but not Pb correlated significantly with sex, BMI and waist circumference. In addition, Pb and Pa but not cAI correlated significantly with brachial–ankle pulse wave velocity.
Table 3 displays the independent determinants of Pb, Pa and cAI, which were obtained by forward stepwise multiple linear regression. The independent determinants of Pb included brachial mean blood pressure (β=0.56, P<0.001), heart rate (β=−0.29, P<0.001), age (β=0.20, P<0.001), PEP/ET (β=−0.16, P=0.004) and height (β=−0.13, P=0.018). RWTT, BMI and sex were significant determinants of Pa and cAI but did not contribute to Pb. Body height was a significant correlate of Pb, Pa and cAI. However, the contribution of height to the total model variance was small for Pb (R2 increment with the addition of the variable to the model: Pb, 2%; Pa, 5%; and cAI, 6%).
After the administration of a sublingual NTG, change of Pb significantly predicted the change of carotid SBP (r=0.550, P<0.001) and carotid PP (r=0.618, P<0.001) (Figures 2a and d). By contrast, change of Pa did not correlate with change of carotid SBP (r=0.075, P=0.317) or carotid PP (r=0.027, P=0.717) (Figures 2b and e). There was no correlation between changes in carotid SBP and cAI (Figure 2c).
In the present study, we demonstrated that Pb was independent of RWTT. In contrast, RWTT had a great influence on Pa and cAI. The significant independent determinants of Pb were mean blood pressure, heart rate, age, PEP/ET and height. In comparison with Pa and cAI, Pb had no gender difference and was less influenced by body size (BMI, height and waist circumstance). Furthermore, only change of Pb correlated with changes of central SBP and PP after NTG. These findings support that Pb is a better measure of wave reflection intensity than Pa and cAI.
Determinants of cAI and Pa
The factors influencing cAI and Pa identified by using multiple regression analysis usually include age, sex, mean blood pressure, height, heart rate and RWTT.7, 19, 20 The association of age and cAI is non-linear.6, 7, 20 cAI increases little after the age of 60 years and may thus underestimate the change of vascular property due to aging.3 Females generally have higher cAI than males even after accounting for height.7, 19, 20 It has been recognized that RWTT does not correspond with the timing obtained by wave separation analysis, based on measurement of pressure and flow.8 Although the association of age and Pa may be linear,6, 7 we have shown that it remains non-linear in females.6 On the other hand, the effect of left ventricular contractility on cAI remains controversial.3
Determinants of Pb
Myogenic tone is an intrinsic property of vascular smooth muscle cells and a crucial component of autoregulation of the coronary and peripheral microcirculations. An increase in intraluminal pressure may induce vasoconstriction in muscular arteries and arterioles, a phenomenon called the myogenic response.21 Elevated mean blood pressure enhances wave reflection probably through the increased myogenic tone and the impedance mismatch at the major reflecting sites due to reduction of lumen diameter and stiffening of arterial wall.22
Heart rate was inversely related to Pb, Pa and cAI with similar partial R2 changes (Pb: 13%, Pa: 12% and cAI: 10%). These findings support that pressure wave reflection is significantly influenced by heart rate.23, 24 With increasing heart rate, less reflected waves may arrive in systole. The strong and significant inverse relationship between heart rate and Pb suggests that the major impact of heart rate on central hemodynamics is through its effect on the reflected pressure wave, rather than on the incident pressure wave.23
The systolic time interval, including PEP, ET and their ratio (PEP/ET), is one of the established non-invasive techniques for the quantitative assessment of cardiac performance.25 We have shown that PEP/ET is useful in the assessment of ventriculo–arterial coupling in patients with heart failure.26 Low PEP/ET indicates good left ventricular function and optimal status of ventricular–arterial coupling, and is associated with increased forward and the corresponding backward (Pb) pressure wave amplitudes. However, the associations of PEP/ET with Pa and cAI were not significant in the multivariate analyses.
Aging causes degeneration of the arterial medial wall and progressive stiffening of large elastic arteries, whereas peripheral muscular arteries and arterioles are only minimally affected. However, aging may impair the vasomotor function of the peripheral small arteries, which would change the impendence properties and increase the intensity of wave reflection.27 Our study showed that age may contribute more to the transit time-independent Pb than to the transit time-dependent Pa and cAI, suggesting that aging predominately increases the intensity of wave reflection instead of facilitating the early return of the reflected wave.
Height is explained up to 5% of Pa variance and 6% of cAI variance, and only 2% of Pb variance in the multivariate analysis. The contribution of height to Pa and cAI in the multivariate models was probably underestimated because RWTT was included. RWTT was influenced by wave speed, distance of travel and the time shift at the reflection site.28 Decreased height is associated with decreased wave traveling distance and results in early return of the reflected wave in systole. Because the transit time-independent Pb also correlated with height and other mechanisms, such as more dispersion of the reflection sites in taller people, may be involved in the relations between height and wave reflection.2
Sublingual NTG dilates peripheral muscular arteries and prearterioles with the reduction of the myogenic tone and wave reflection, which leads to decreased aortic and left ventricular SBP levels.29, 30, 31 In our study, only the change of Pb significantly predicted the change of central SBP and PP after sublingual NTG. The changes of Pa and cAI after NTG would be influenced by changes other than the magnitude of reflected pressure wave, such as decreased large artery stiffness and increased RWTT. These results further support the advantage of Pb over Pa or cAI as a measure of wave reflection intensity.
Sex dependency of wave reflection
cAI has consistently been higher in women than in men, even after adjustment for differences in height.19, 32, 33 However, because central aortic SBP and PP increase linearly with age,7 and the reflected wave dominates age-related changes in aortic SBP and PP across the human lifespan in men and women,4 an absolute amplitude of wave reflection intensity would be expected to show a linear relationship with age without a sex difference.6 In fact, cAI was only modestly correlated with the reflection coefficient calculated from the input impedance, which was shown to be independent of sex.32 Furthermore, we have shown that Pb but not cAI or Pa was independently associated with long-term cardiovascular mortality, regardless of sex.6 Therefore, although only 35% were female in the present study, the results that cAI and Pa but not Pb were significantly dependent upon sex in both the univariate and multivariate analyses support that wave reflection is not higher in women than in men.32
Pb was estimated by the triangulation method in the present study. The triangular wave shape assumed for the flow may differ from the actual flow wave shape. Most of our study subjects were hypertensive patients. Therefore, the findings in this present study may not be generalizable to the general population. Although our patients continued their medications on the day of the study that might have exerted an influence on wave reflections, the conclusion may still be valid because the determinants of cAI demonstrated in the present study were consistent with previous studies.
Endothelial dysfunction plays a crucial role in the process of atherosclerosis and may be a possible mechanism for an increased wave reflection.34 Endothelial function was shown to be inversely associated with cAI and, therefore, cAI may be considered as an indicator of endothelial function.35 However, the relationship between endothelial function and Pb was not assessed in the present study. It remains to be demonstrated in the future studies that whether Pb is a better indicator of endothelial function than cAI.
Avolio AP, Van Bortel LM, Boutouyrie P, Cockcroft JR, McEniery CM, Protogerou AD et al. Role of pulse pressure amplification in arterial hypertension. Experts’ opinion and review of the data. Hypertension 2009; 54: 375–383.
Hope SA, Tay DB, Meredith IT, Cameron JD . Waveform dispersion, not reflection, may be the major determinant of aortic pressure wave morphology. Am J Physiol Heart Circ Physiol 2005; 289: H2497–H2502.
Shimizu M, Kario K . Role of the augmentation index in hypertension. Ther Adv Cardiovasc Dis 2008; 2: 25–35.
Namasivayam M, McDonnell BJ, McEniery CM, O’Rourke MF . Does wave reflection dominate age-related change in aortic blood pressure across the human life span? Hypertension 2009; 53: 979–985.
Mitchell GF, Conlin PR, Dunlap ME, Lacourciere Y, Arnold JM, Ogilvie RI et al. Aortic diameter, wall stiffness, and wave reflection in systolic hypertension. Hypertension 2008; 51: 105–111.
Wang KL, Cheng HM, Sung SH, Chuang SY, Li CH, Spurgeon HA et al. Wave reflection and arterial stiffness in the prediction of 15-Year all-cause and cardiovascular mortalities. a community-based study. Hypertension 2010; 55: 799–805.
McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR . Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 2005; 46: 1753–1760.
Segers P, Rietzschel ER, De Buyzere ML, De Bacquer D, Van Bortel LM, De Backer G et al. Assessment of pressure wave reflection: getting the timing right!. Physiol Meas 2007; 28: 1045–1056.
Davies JE, Baksi J, Francis DP, Hadjiloizou N, Whinnett ZI, Manisty CH et al. The arterial reservoir pressure increases with aging and is the major determinant of the aortic augmentation index. Am J Physiol Heart Circ Physiol 2010; 298: H580–H586.
Sakurai M, Yamakado T, Kurachi H, Kato T, Kuroda K, Ishisu R et al. The relationship between aortic augmentation index and pulse wave velocity: an invasive study. J Hypertens 2007; 25: 391–397.
Vyas M, Izzo Jr JL, Lacourciere Y, Arnold JM, Dunlap ME, Amato JL et al. Augmentation index and central aortic stiffness in middle-aged to elderly individuals. Am J Hypertens 2007; 20: 642–647.
Chen CH, Ting CT, Lin SJ, Hsu TL, Yin FCP, Siu CO et al. Different effects of fosinopril and atenolol on wave reflections in hypertensive patients. Hypertension 1995; 25: 1034–1041.
Mahmud A, Feely J . Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection. Am J Hypertens 2008; 21: 663–667.
Fitchett DH, Simkus GJ, Beaudry JP, Marpole DGF . Reflected waves in the ascending aorta: effect of glyceryl trinitrate. Cardiovasc Res 1988; 22: 494–500.
Panca AL, Wallenhaupt SL, Kon ND, Tucker WY . Does radial artery pressure accurately reflect aortic pressure? Chest 1992; 102: 1193–1198.
Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K et al. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 2002; 25: 359–364.
Yu WC, Chuang SY, Lin YP, Chen CH . Brachial-ankle vs carotid-femoral pulse wave velocity as a determinant of cardiovascular structure and function. J Hum Hypertens 2008; 22: 24–31.
Westerhof BE, Guelen I, Westerhof N, Karemaker JM, Avolio A . Quantification of wave reflection in the human aorta from pressure alone: a proof of principle. Hypertension 2006; 48: 595–601.
Fantin F, Mattocks A, Bulpitt CJ, Banya W, Rajkumar C . Is augmentation index a good measure of vascular stiffness in the elderly? Age Ageing 2007; 36: 43–48.
Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 2004; 43: 1239–1245.
Bayliss WM . On the local reactions of the arterial wall to changes of internal pressure. J Physiol 1902; 28: 220–231.
Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27: 2588–2605.
Williams B, Lacy PS . Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation) study: CAFE-heart rate. J Am Coll Cardiol 2009; 54: 705–713.
Laurent P, Albaladejo P, Blacher J, Rudnichi A, Smulyan H, Safar ME . Heart rate and pulse pressure amplification in hypertensive subjects. Am J Hypertens 2003; 16: 363–370.
Lewis RP, Rittogers SE, Froester WF, Boudoulas H . A critical review of the systolic time intervals. Circulation 1977; 56: 146–158.
Cheng HM, Yu WC, Sung SH, Wang KL, Chuang SY, Chen CH . Usefulness of systolic time intervals in the identification of abnormal ventriculo-arterial coupling in stable heart failure patients. Eur J Heart Fail 2008; 10: 1200.
Hashimoto J, Ito S . Some mechanical aspects of arterial aging: physiological overview based on pulse wave analysis. Ther Adv Cardiovasc Dis 2009; 3: 367–378.
Westerhof BE, van den Wijngaard JP, Murgo JP, Westerhof N . Location of a reflection site is elusive: consequences for the calculation of aortic pulse wave velocity. Hypertension 2008; 52: 478–483.
Jiang XJ, O’Rourke MF, Jin WQ, Liu LS, Li CW, Tai PC et al. Quantification of glyceryl trinitrate effect through analysis of the synthesised ascending aortic pressure waveform. Heart 2002; 88: 143–148.
Bank AJ, Kaiser DR . Smooth muscle relaxation: effects on arterial compliance, distensibility, elastic modulus, and pulse wave velocity. Hypertension 1998; 32: 356–359.
Stokes GS, Barin ES, Gilfillan KL . Effects of isosorbide mononitrate and AII inhibition on pulse wave reflection in hypertension. Hypertension 2003; 41: 297–301.
Segers P, Rietzschel ER, De Buyzere ML, Vermeersch SJ, De Bacquer D, Van Bortel LM et al. Noninvasive (input) impedance, pulse wave velocity, and wave reflection in healthy middle-aged men and women. Hypertension 2007; 49: 1248–1255.
Hayward CS, Kelly RP . Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol 1997; 30: 1863–1871.
Laurent S, Boutouyrie P . Recent advances in arterial stiffness and wave reflection in human hypertension. Hypertension 2007; 49: 1202–1206.
McEniery CM, Wallace S, Mackenzie IS, McDonnell B, Yasmin, Newby DE et al. Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans. Hypertension 2006; 48: 602–608.
This work was supported by the intramural grants (V97C1-101, V98C1-028 and V99C1-091) from Taipei Veterans General Hospital, Taiwan, Republic of China.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Journal of Human Hypertension website
About this article
Cite this article
Liao, CF., Cheng, HM., Sung, SH. et al. Determinants of pressure wave reflection: characterization by the transit time-independent reflected wave amplitude. J Hum Hypertens 25, 665–671 (2011). https://doi.org/10.1038/jhh.2010.106
- pressure wave reflection
Frontiers in Pediatrics (2020)
Computers in Biology and Medicine (2019)
Hemodynamic Determinants of the Short-Term Blood Pressure Variability: Differential Roles of Arterial Stiffness and Wave Reflection
American Journal of Hypertension (2017)
American Journal of Hypertension (2017)
Nutrition, Metabolism and Cardiovascular Diseases (2015)