- Email: [email protected]
B-Type Natriuretic Peptide and Arterial Stiffness in Healthy Japanese Men
AJH
ORIGINAL CONTRIBUTIONS
2006; 19:443– 447
Epidemiology
B-Type Natriuretic Peptide and Arterial Stiffness in Healthy Japanese Men Minoru Yambe, Hirofumi Tomiyama, Yutaka Koji, Kohki Motobe, Kazuki Shiina, Zaydun Gulnisia, Yoshio Yamamoto, and Akira Yamashina Background: Recent evidence suggests that even a slight increase in the plasma level of B-type natriuretic peptide (BNP) may be a marker of cardiovascular risk; however, the mechanisms underlying the association are currently unclear. Because increased arterial stiffness, as reflected by an increase of the pulse wave velocity (PWV) or pulse pressure (PP), may contribute to increasing plasma BNP levels, in the present study we investigated the relationships between the plasma BNP level and the PWV and PP, all of which are known markers of cardiovascular risk, in a healthy male Japanese cohort. Methods: This was a cross-sectional study of 725 healthy Japanese men (age, 54 ⫾ 4 years). The PWV was assessed by the volume-rendering method. Plasma BNP levels were determined with a high-sensitivity noncompetitive immunoradiometric assay.
Results: A univariate linear regression analysis demonstrated that the plasma BNP level was significantly correlated with age (r ⫽ 0.20, P ⬍ .01), PWV (r ⫽ 0.12, P ⬍ .01), and PP (r ⫽ 0.17, P ⬍ .01). A stepwise multivariate linear regression analysis demonstrated that both the PWV and PP were significantly associated with the plasma BNP level, independent of age. Conclusion: In healthy Japanese men, stiffening of large arteries, as evidenced by an increase of the PWV or PP, may account at least in part for elevated plasma BNP levels, even within the so-called normal range. Am J Hypertens 2006; 19:443– 447 © 2006 American Journal of Hypertension, Ltd. Key Words: Atherosclerosis, cardiovascular diseases, natriuretic peptide, pulse wave velocity.
recent study suggested that even a slight increase in plasma B-type natriuretic peptide (BNP) level, within the high normal range (below the current cutoff values used to diagnose heart failure), may be a marker of increased cardiovascular risk,1 althought the mechanisms underlying this association are still unclear. On the other hand, increased cardiac afterload elevates the plasma BNP level,2 and arterial stiffness contributes to cardiac afterload.3,4 Arterial stiffening is a known cardiovascular risk factor,5–9 but whether the two factors—BNP and arterial stiffness—are related or independent markers of atherosclerotic cardiovascular risk remains uncertain. In the present cross-sectional study, the relationships between the plasma BNP level and both pulse pressure (PP) and pulse wave velocity (PWV), which are known markers of arterial stiffness,5–10 were examined in a healthy male Japanese cohort to determine whether the two factors, BNP and arterial stiffness, are related or independent markers of cardiovascular risk.
A
Methods
Received January 30, 2005. First decision August 18, 2005. Accepted August 23, 2005.
This study was supported in part by a grant-in-aid awarded from the Japanese Atherosclerosis Prevention Fund (to A.Y.). Address correspondence and reprint requests to Dr. Hirofumi Tomiyama, Second Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan 160-0023; e-mail: [email protected]
From the Second Department of Internal Medicine (MY, HT, YK, KM, KS, ZG, AY), Tokyo Medical University, Tokyo, Japan; and Health Care Center (YY), Kajima Corporation, Tokyo, Japan. © 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Subjects Among the individuals undergoing an annual physical health check at a clinic affiliated with Tokyo Medical University, 945 were screened for the present study. All of the examinees were office workers at a construction company and ranged in age from 49 to 76 years. Examinees with atrial fibrillation (n ⫽ 4) or an abnormal ankle/ brachial pressure index (ankle-brachial index ⬍0.95) (n ⫽ 3) were excluded from the study, because measurements of brachial–ankle PWV in persons with atrial fibrillation or an abnormal ankle/brachial pressure index are not accurate. In addition, individuals being treated for hypertension, dyslipidemia, or diabetes mellitus (n ⫽ 183) and those being treated for heart disease or stroke (n ⫽ 25) were excluded. Of the 945 persons examined, 725 were ultimately enrolled as subjects in this study. Informed consent was obtained from all subjects. The study protocol
0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2005.08.004
444
AJH–May 2006 –VOL. 19, NO. 5
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
Table 1. Clinical characteristics of the study subjects Age (y) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) MBP (mm Hg) PP (mm Hg) HR (beats/min) baPWV (cm/sec) FBG (mmol/L) TC (mmol/L) HDL (mmol/L) TG (mmol/L) BNP (pg/ml) Smoking (%)
54 ⫾ 4 24 ⫾ 3 128 ⫾ 15 79 ⫾ 10 95 ⫾ 11 49 ⫾ 9 66 ⫾ 10 1378 ⫾ 209 5.4 ⫾ 1.1 5.5 ⫾ 0.9 1.5 ⫾ 0.3 1.6 ⫾ 1.1 11.6 ⫾ 9.9 266 (37)
baPWV ⫽ brachial–ankle pulse wave velocity; BMI ⫽ body mass index; BNP ⫽ plasma B-type natriuretic peptide; DBP ⫽ diastolic blood pressure; FBG ⫽ fasting blood glucose; HDL ⫽ high-density lipoprotein cholesterol; HR ⫽ heart rate; MBP ⫽ mean blood pressure; PP ⫽ pulse pressure; SBP ⫽ systolic blood pressure; TC ⫽ total cholesterol; TG ⫽ triglycerides.
was approved by the Ethics Committee of Tokyo Medical University. Measurement of PWV and Blood Pressure Brachial–ankle PWV was measured with a volume-plethysmographic apparatus (Form/ABI, Colin Co. Ltd., Komaki, Japan) with the subjects in the supine position. The methodology used has been described in detail.11,12 Cuffs were tied around both arms and both the legs, and the pulse-volume waveforms in all four limbs were recorded with a semiconductor pressure sensor. The brachial–ankle PWV measurements were made after the subject had rested for at least 5 min. Validation of this method, with a reported interobserver coefficient of variation of 8.4% and intraobserver coefficient of variation of 10.0%,11 has been reported.
the brachial–ankle PWV or the PP as a covariate was then performed to assess the associations between the plasma BNP level and age, heart rate, and conventional atherosclerotic risk factors identified by the univariate linear regression analysis as independent variables significantly correlated with the plasma BNP level. All analyses were performed with SPSS software for Windows, version 11.0J (SPSS Inc., Chicago, IL). P values ⬍.05 were considered to indicate statistical significance.
Results The clinical characteristics of the 725 subjects screened for the study are summarized in Table 1. Their plasma BNP levels ranged from 1.0 to 98.0 pg/mL. The results of the linear regression analyses revealed that the plasma BNP level was significantly correlated with brachial–ankle PWV (r ⫽ 0.12, P ⬍ .001) and PP (r ⫽ 0.17, P ⬍ .001). Table 2 shows the regression coefficients obtained in the univariate linear regression analysis between the plasma level of BNP and other cardiovascular risk factors, including the heart rate. The variables of age, body mass index, mean blood pressure, heart rate, and total cholesterol level showed significant correlations with the plasma BNP level. The results of stepwise multivariate linear regression analysis revealed that the brachial–ankle PWV and PP were significantly correlated with the plasma BNP level independent of age, heart rate, or other parameters identified by univariate linear regression analysis (Table 3).
Discussion This is the first study to examine the association between brachial–ankle PWV and the plasma BNP level within the so-called normal range. In recent years plasma BNP levels ⬎100 pg/mL have come to be widely regarded as an adverse prognostic biomarkers in patients with heart fail-
Laboratory Measurements Plasma total cholesterol, high-density lipoprotein cholesterol, triglyceride, and blood glucose levels were measured by enzymatic means. Plasma BNP was measured by a high-sensitivity noncompetitive immunoradiometric assay (Shiono RIA BNP Assay kit; Shionogi Co., Osaka, Japan). The detection threshold of the BNP assay was ⬍1.0 pg/ mL, and in the range ⬍25.0 pg/mL the interassay coefficient of variation was 2.1% and intra-assay coefficient of variation was 4.5%. All blood samples were obtained in the morning after an overnight fast. Statistical Analysis All data are expressed as means ⫾ SD.A univariate linear regression analysis was performed to assess the correlations between the plasma BNP level and established cardiovascular risk factors, including the heart rate. A stepwise multivariate linear regression analysis including
Table 2. Regression coefficients in the univariate linear regression analysis between the plasma Btype natriuretic peptide level and other atherosclerosis related variables Covariate
Coefficient
P Value
baPWV PP Age BMI MBP HR FBG TC HDL TG Smoking habit
0.12 0.17 0.20 ⫺0.08 0.07 ⫺0.12 0.02 0.10 0.06 0.05 0.05
⬍0.001 ⬍0.001 ⬍0.001 0.04 0.05 ⬍0.001 0.56 0.06 0.11 0.13 0.17
Abbreviations as in Table 1.
AJH–May 2006 –VOL. 19, NO. 5
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
445
Table 3. Results of a stepwise multivariate linear regression analysis including either the brachial–ankle pulse wave velocity or pulse pressure as a covariate to assess the correlation of the plasma B-type natriuretic peptide with variables identified by univariate regression analysis Including brachial–ankle pulse wave velocity as a covariate (total R2 ⴝ 0.09) Covariate Age HR baPWV TC Not significant variables MBP BMI
 0.16 ⫺0.17 0.18 ⫺0.12 — —
t Value
P Value
4.46 ⫺4.41 4.45 ⫺3.19
⬍.001 ⬍.001 ⬍.001 .001
1.06 ⫺1.49
.29 .14
Including pulse pressure as a covariate (total R2 ⴝ 0.09) Covariate Age PP HR TC Not significant variables MBP BMI
 0.18 0.17 ⫺0.12 ⫺0.10 — —
t Value
P Value
5.00 4.68 ⫺3.27 ⫺2.81
⬍.001 ⬍.001 .001 .005
1.57 ⫺1.76
.12 .08
Abbreviations as Table 1.
ure or acute myocardial infarction.13–15 Wang et al. reported that a plasma BNP level ⬎20 pg/mL in men in a general population double the risk of a future cardiovascular event (intial cardiovascular event, stroke, or atrial fibrillation),1 and Nielsen et al. suggested that even a level of ⬎8 pg/mL may be a marker of asymptomatic cardiac systolic dysfunction.16 However, the pathophysiologic basis for considering a slight increase in the plasma BNP level, within the so-called normal range, as a marker of cardiovascular risk has not yet been clearly elucidated. The present study showed that the brachial–ankle PWV may indeed bear a weak but significant correlation with the plasma BNP level in healthy Japanese men. Although aging is an important determinant of arterial stiffness,7,10,12,17 in as much as brachial–ankle PWV and PP were associated with plasma BNP levels independent of age, arterial stiffness may be associated with plasma BNP levels independent of the aging process. Brachial– ankle PWV reflects both arterial stiffness at peripheral sites in the upper and lower limbs and central arterial stiffness; it is strongly correlated with aortic PWV.11 An increase in central arterial stiffness leads to earlier arrival of the reflected pulse waves, causing increased ventricular afterload with concomitant decreased coronary perfusion but increased myocardial oxygen demand.3,4,18,19 These alterations related to increased arterial stiffness can stimulate the synthesis and release of BNP.2,20 On the other hand, PP is presented as the formula 10: PP ⫽ cardiac stroke volume/arterial compliance. Thus, cardiac performance is also an important determinant of PP. Ventricular–arterial coupling maintains cardiac stroke volume in the presence of increased arterial stiffening,3,21
and it has been demonstrated that ventricular–arterial uncoupling increases the production of BNP.22 In addition, our previous study demonstrated a significant association between the brachial–ankle PWV and the cardiac diastolic function, which is a known marker of cardiac stiffness.12 Therefore we speculated that in our study cohort also, this adaptive coupling may explain the increase in the plasma level of BNP. The present study suggested that increased brachial– ankle PWV and PP are equally reliable markers of elevated plasma BNP level in a general population. However, compared with PP, the PWV is a more robust marker of arterial stiffness6,8 and also of the severity of atherosclerosis 6,7,8,23 Furthermore, increased arterial stiffness acts as an atherogenic factor by itself, apart from its unfavorable effect on the cardiovascular system via elevation of the plasma BNP level.6,8 Therefore, a longitudinal study must be conducted in the future to confirm whether the plasma level of BNP and markers of arterial stiffness (PWV and PP) are related or independent markers of increased cardiovascular risk in a general population. In addition to BNP, plasma C-reactive protein and matrix metalloproteinase–9 levels have also been reported to be predictors of future cardiovascular events.24,25 These parameters have also been shown to be significantly associated with PWV, and their significant associations may be related to the finding that vascular inflammation or vascular connective tissue metabolism may be involved in the arterial stiffening process.26 –28 Both of these parameters were even more closely associated with PWV than the association between brachial–ankle PWV and plasma
446
AJH–May 2006 –VOL. 19, NO. 5
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
BNP level.26 –28 However, the results of our study suggest that slight increases in arterial stiffness observed in a general population may not be a major determinant of increases in plasma BNP level within the high normal range. This significant but weak association between brachial–ankle PWV and plasma BNP level can be explained by the finding that BNP directly reduces arterial stiffness through its favorable effects on arterial properties,29 and the effects of BNP that counter the arterial stiffness may blunt the positive association between arterial stiffness and plasma BNP level. There are three major limitations of the present study. The first is that the possibility of asymptomatic cardiac dysfunction was not fully evaluated. Another study that would examine the association between cardiac systolic or diastolic function and plasma BNP level within the high normal range is proposed. The second limitation of our study is that the brachial–ankle PWV is a surrogate of the carotid–femoral PWV, which is an established marker of aortic stiffness. As mentioned earlier here, although the brachial–ankle PWV bears a close correlation with the aortic PWV, the possibility that the carotid–femoral PWV may show a closer association with the plasma BNP level cannot be neglected. Therefore, confirmation of the present results using the carotid–femoral PWV is proposed. The third limitation was that the study was conducted in Japanese men,and the results may not be applicable to women or to other ethnic groups. In conclusion, the brachial–ankle PWV and PP were found to be significantly associated with the plasma BNP level, independent of age. In healthy Japanese men, stiffening of the large arteries, as evidenced by an increased PVW or PP, may account at least in part for elevated BNP plasma levels, even within the so-called normal range.
8.
9.
10. 11.
12.
13.
14. 15.
16.
17.
18.
19.
References 1.
2.
3.
4.
5.
6. 7.
Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS: Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655– 663. Magga J, Vuolteenaho O, Tokola H, Marttila M, Ruskoaho H: Involvement of transcriptional and posttranscriptional mechanisms in cardiac overload-induced increase of B-type natriuretic peptide gene expression. Circ Res 1997;81:694 –702. Nichols WW, O’Rourke MF: Wave reflections, in Nichols WW, O’Rourke MF (eds): McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, Fourth Edition. Edward Arnold, London, 1998, pp 203–222. Kingwell BA, Waddell TK, Medley TL, Cameron JD, Dart AM: Large artery stiffness predicts ischemic threshold in patients with coronary artery disease. J Am Coll Cardiol 2002;40:773–779. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236 –1241. London GM, Cohn JN: Prognostic application of arterial stiffness: task forces. Am J Hypertens 2002;15:754 –758. Benetos A, Waeber B, Izzo J, Mitchell G, Resnick L, Asmar R, Safar M: Influence of age, risk factors, and cardiovascular and renal
20.
21. 22.
23.
24.
25.
disease on arterial stiffness: clinical applications. Am J Hypertens 2002;15:1101–1108. Oliver JJ, Webb DJ: Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003; 23:554 –566. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D: Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham Heart Study. Circulation 1999;100:354 –360. Dart AM, Kingwell BA: Pulse pressure—a review of mechanisms and clinical relevance. J Am Coll Cardiol 2001;37:975–984. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y: Validity, reproducibility, and clinical significance of noninvasive brachial–ankle pulse wave velocity measurement. Hypertens Res 2002;25:359 –364. Yambe M, Tomiyama H, Hirayama Y, Gulniza Z, Takata Y, Koji Y, Motobe K, Yamashina A: Arterial stiffening as a possible risk factor for both atherosclerosis and diastolic heart failure. Hypertens Res 2004;27:625– 631. Cowie MR, Jourdain P, Maisel A, Dahlstrom U, Follath F, Isnard R, Luchner A, McDonagh T, Mair J, Nieminen M, Francis G: Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J 2003;24:1710 –1718. Ruskoaho H: Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 2003;24:341–356. Heeschen C, Hamm CW, Mitrovic V, Lantelme NH, White HD, Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators: N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes. Circulation 2004;110:3206 –3212. Nielsen OW, McDonagh TA, Robb SD, Dargie HJ: Retrospective analysis of the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic dysfunction in the general population. J Am Coll Cardiol 2003;41:113–120. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D: Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 2004;43:1239 –1245. Buckberg GD, Fixler DE, Archie JP, Hoffman JI: Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ Res 1972;30:67– 81. Nichols WW, O’Rourke MF: Coupling the left ventricle with systemic circulation: implications to cardiac failure, in Nichols WW, O’Rourke MF (eds): McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, Fourth Edition. Edward Arnold, London, 1998, pp 294 –316. Ruck A, Gustafsson T, Norrbom J, Nowak J, Kallner G, Soderberg M, Sylven C, Drvota V: ANP and BNP but not VEGF are regionally overexpressed in ischemic human myocardium. Biochem Biophys Res Commun 2004;322:287–291. Kass DA: Age-related changes in venticular-arterial coupling: pathophysiologic implications. Heart Fail Rev 2002;7:51– 62. Mehra MR, Milani RV, Richie MB, Uber PA, Park MH, Ventura HO, Scott RL, Lavie CJ: Ventricular-vascular uncoupling increases expression of B-type natriuretic peptide in heart transplantation. Transplant Proc 2004;36:3149 –3151. van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman RS, Hoeks AP, van der Kuip DA, Hofman A, Witteman JC: Association between arterial stiffness and atherosclerosis: the Rotterdam Study. Stroke 2001;32:454 – 460. Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391–397. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L, AtheroGene Investigators: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579 –1585.
AJH–May 2006 –VOL. 19, NO. 5
26. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB: C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969 –974. 27. Tomiyama H, Arai T, Koji Y, Yambe M, Hirayama Y, Yamamoto Y, Yamashina A: The relationship between high-sensitive C-reactive protein and pulse wave velocity in healthy Japanese men. Atherosclerosis 2004;174:373–377. 28. Yasmin, Wallace S, McEniery CM, Dakham Z, Pusalkar P, Maki-
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
447
Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB: Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25:372–378. 29. Schmitt M, Qasem A, McEniery C, Wilkinson IB, Tatarinoff V, Noble K, Klemes J, Payne N, Frenneaux MP, Cockcroft J, Avolio A: Role of natriuretic peptides in regulation of conduit artery distensibility. Am J Physiol Heart Circ Physiol 2004;287:H1167– H1171.
ORIGINAL CONTRIBUTIONS
2006; 19:443– 447
Epidemiology
B-Type Natriuretic Peptide and Arterial Stiffness in Healthy Japanese Men Minoru Yambe, Hirofumi Tomiyama, Yutaka Koji, Kohki Motobe, Kazuki Shiina, Zaydun Gulnisia, Yoshio Yamamoto, and Akira Yamashina Background: Recent evidence suggests that even a slight increase in the plasma level of B-type natriuretic peptide (BNP) may be a marker of cardiovascular risk; however, the mechanisms underlying the association are currently unclear. Because increased arterial stiffness, as reflected by an increase of the pulse wave velocity (PWV) or pulse pressure (PP), may contribute to increasing plasma BNP levels, in the present study we investigated the relationships between the plasma BNP level and the PWV and PP, all of which are known markers of cardiovascular risk, in a healthy male Japanese cohort. Methods: This was a cross-sectional study of 725 healthy Japanese men (age, 54 ⫾ 4 years). The PWV was assessed by the volume-rendering method. Plasma BNP levels were determined with a high-sensitivity noncompetitive immunoradiometric assay.
Results: A univariate linear regression analysis demonstrated that the plasma BNP level was significantly correlated with age (r ⫽ 0.20, P ⬍ .01), PWV (r ⫽ 0.12, P ⬍ .01), and PP (r ⫽ 0.17, P ⬍ .01). A stepwise multivariate linear regression analysis demonstrated that both the PWV and PP were significantly associated with the plasma BNP level, independent of age. Conclusion: In healthy Japanese men, stiffening of large arteries, as evidenced by an increase of the PWV or PP, may account at least in part for elevated plasma BNP levels, even within the so-called normal range. Am J Hypertens 2006; 19:443– 447 © 2006 American Journal of Hypertension, Ltd. Key Words: Atherosclerosis, cardiovascular diseases, natriuretic peptide, pulse wave velocity.
recent study suggested that even a slight increase in plasma B-type natriuretic peptide (BNP) level, within the high normal range (below the current cutoff values used to diagnose heart failure), may be a marker of increased cardiovascular risk,1 althought the mechanisms underlying this association are still unclear. On the other hand, increased cardiac afterload elevates the plasma BNP level,2 and arterial stiffness contributes to cardiac afterload.3,4 Arterial stiffening is a known cardiovascular risk factor,5–9 but whether the two factors—BNP and arterial stiffness—are related or independent markers of atherosclerotic cardiovascular risk remains uncertain. In the present cross-sectional study, the relationships between the plasma BNP level and both pulse pressure (PP) and pulse wave velocity (PWV), which are known markers of arterial stiffness,5–10 were examined in a healthy male Japanese cohort to determine whether the two factors, BNP and arterial stiffness, are related or independent markers of cardiovascular risk.
A
Methods
Received January 30, 2005. First decision August 18, 2005. Accepted August 23, 2005.
This study was supported in part by a grant-in-aid awarded from the Japanese Atherosclerosis Prevention Fund (to A.Y.). Address correspondence and reprint requests to Dr. Hirofumi Tomiyama, Second Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan 160-0023; e-mail: [email protected]
From the Second Department of Internal Medicine (MY, HT, YK, KM, KS, ZG, AY), Tokyo Medical University, Tokyo, Japan; and Health Care Center (YY), Kajima Corporation, Tokyo, Japan. © 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Subjects Among the individuals undergoing an annual physical health check at a clinic affiliated with Tokyo Medical University, 945 were screened for the present study. All of the examinees were office workers at a construction company and ranged in age from 49 to 76 years. Examinees with atrial fibrillation (n ⫽ 4) or an abnormal ankle/ brachial pressure index (ankle-brachial index ⬍0.95) (n ⫽ 3) were excluded from the study, because measurements of brachial–ankle PWV in persons with atrial fibrillation or an abnormal ankle/brachial pressure index are not accurate. In addition, individuals being treated for hypertension, dyslipidemia, or diabetes mellitus (n ⫽ 183) and those being treated for heart disease or stroke (n ⫽ 25) were excluded. Of the 945 persons examined, 725 were ultimately enrolled as subjects in this study. Informed consent was obtained from all subjects. The study protocol
0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2005.08.004
444
AJH–May 2006 –VOL. 19, NO. 5
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
Table 1. Clinical characteristics of the study subjects Age (y) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) MBP (mm Hg) PP (mm Hg) HR (beats/min) baPWV (cm/sec) FBG (mmol/L) TC (mmol/L) HDL (mmol/L) TG (mmol/L) BNP (pg/ml) Smoking (%)
54 ⫾ 4 24 ⫾ 3 128 ⫾ 15 79 ⫾ 10 95 ⫾ 11 49 ⫾ 9 66 ⫾ 10 1378 ⫾ 209 5.4 ⫾ 1.1 5.5 ⫾ 0.9 1.5 ⫾ 0.3 1.6 ⫾ 1.1 11.6 ⫾ 9.9 266 (37)
baPWV ⫽ brachial–ankle pulse wave velocity; BMI ⫽ body mass index; BNP ⫽ plasma B-type natriuretic peptide; DBP ⫽ diastolic blood pressure; FBG ⫽ fasting blood glucose; HDL ⫽ high-density lipoprotein cholesterol; HR ⫽ heart rate; MBP ⫽ mean blood pressure; PP ⫽ pulse pressure; SBP ⫽ systolic blood pressure; TC ⫽ total cholesterol; TG ⫽ triglycerides.
was approved by the Ethics Committee of Tokyo Medical University. Measurement of PWV and Blood Pressure Brachial–ankle PWV was measured with a volume-plethysmographic apparatus (Form/ABI, Colin Co. Ltd., Komaki, Japan) with the subjects in the supine position. The methodology used has been described in detail.11,12 Cuffs were tied around both arms and both the legs, and the pulse-volume waveforms in all four limbs were recorded with a semiconductor pressure sensor. The brachial–ankle PWV measurements were made after the subject had rested for at least 5 min. Validation of this method, with a reported interobserver coefficient of variation of 8.4% and intraobserver coefficient of variation of 10.0%,11 has been reported.
the brachial–ankle PWV or the PP as a covariate was then performed to assess the associations between the plasma BNP level and age, heart rate, and conventional atherosclerotic risk factors identified by the univariate linear regression analysis as independent variables significantly correlated with the plasma BNP level. All analyses were performed with SPSS software for Windows, version 11.0J (SPSS Inc., Chicago, IL). P values ⬍.05 were considered to indicate statistical significance.
Results The clinical characteristics of the 725 subjects screened for the study are summarized in Table 1. Their plasma BNP levels ranged from 1.0 to 98.0 pg/mL. The results of the linear regression analyses revealed that the plasma BNP level was significantly correlated with brachial–ankle PWV (r ⫽ 0.12, P ⬍ .001) and PP (r ⫽ 0.17, P ⬍ .001). Table 2 shows the regression coefficients obtained in the univariate linear regression analysis between the plasma level of BNP and other cardiovascular risk factors, including the heart rate. The variables of age, body mass index, mean blood pressure, heart rate, and total cholesterol level showed significant correlations with the plasma BNP level. The results of stepwise multivariate linear regression analysis revealed that the brachial–ankle PWV and PP were significantly correlated with the plasma BNP level independent of age, heart rate, or other parameters identified by univariate linear regression analysis (Table 3).
Discussion This is the first study to examine the association between brachial–ankle PWV and the plasma BNP level within the so-called normal range. In recent years plasma BNP levels ⬎100 pg/mL have come to be widely regarded as an adverse prognostic biomarkers in patients with heart fail-
Laboratory Measurements Plasma total cholesterol, high-density lipoprotein cholesterol, triglyceride, and blood glucose levels were measured by enzymatic means. Plasma BNP was measured by a high-sensitivity noncompetitive immunoradiometric assay (Shiono RIA BNP Assay kit; Shionogi Co., Osaka, Japan). The detection threshold of the BNP assay was ⬍1.0 pg/ mL, and in the range ⬍25.0 pg/mL the interassay coefficient of variation was 2.1% and intra-assay coefficient of variation was 4.5%. All blood samples were obtained in the morning after an overnight fast. Statistical Analysis All data are expressed as means ⫾ SD.A univariate linear regression analysis was performed to assess the correlations between the plasma BNP level and established cardiovascular risk factors, including the heart rate. A stepwise multivariate linear regression analysis including
Table 2. Regression coefficients in the univariate linear regression analysis between the plasma Btype natriuretic peptide level and other atherosclerosis related variables Covariate
Coefficient
P Value
baPWV PP Age BMI MBP HR FBG TC HDL TG Smoking habit
0.12 0.17 0.20 ⫺0.08 0.07 ⫺0.12 0.02 0.10 0.06 0.05 0.05
⬍0.001 ⬍0.001 ⬍0.001 0.04 0.05 ⬍0.001 0.56 0.06 0.11 0.13 0.17
Abbreviations as in Table 1.
AJH–May 2006 –VOL. 19, NO. 5
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
445
Table 3. Results of a stepwise multivariate linear regression analysis including either the brachial–ankle pulse wave velocity or pulse pressure as a covariate to assess the correlation of the plasma B-type natriuretic peptide with variables identified by univariate regression analysis Including brachial–ankle pulse wave velocity as a covariate (total R2 ⴝ 0.09) Covariate Age HR baPWV TC Not significant variables MBP BMI
 0.16 ⫺0.17 0.18 ⫺0.12 — —
t Value
P Value
4.46 ⫺4.41 4.45 ⫺3.19
⬍.001 ⬍.001 ⬍.001 .001
1.06 ⫺1.49
.29 .14
Including pulse pressure as a covariate (total R2 ⴝ 0.09) Covariate Age PP HR TC Not significant variables MBP BMI
 0.18 0.17 ⫺0.12 ⫺0.10 — —
t Value
P Value
5.00 4.68 ⫺3.27 ⫺2.81
⬍.001 ⬍.001 .001 .005
1.57 ⫺1.76
.12 .08
Abbreviations as Table 1.
ure or acute myocardial infarction.13–15 Wang et al. reported that a plasma BNP level ⬎20 pg/mL in men in a general population double the risk of a future cardiovascular event (intial cardiovascular event, stroke, or atrial fibrillation),1 and Nielsen et al. suggested that even a level of ⬎8 pg/mL may be a marker of asymptomatic cardiac systolic dysfunction.16 However, the pathophysiologic basis for considering a slight increase in the plasma BNP level, within the so-called normal range, as a marker of cardiovascular risk has not yet been clearly elucidated. The present study showed that the brachial–ankle PWV may indeed bear a weak but significant correlation with the plasma BNP level in healthy Japanese men. Although aging is an important determinant of arterial stiffness,7,10,12,17 in as much as brachial–ankle PWV and PP were associated with plasma BNP levels independent of age, arterial stiffness may be associated with plasma BNP levels independent of the aging process. Brachial– ankle PWV reflects both arterial stiffness at peripheral sites in the upper and lower limbs and central arterial stiffness; it is strongly correlated with aortic PWV.11 An increase in central arterial stiffness leads to earlier arrival of the reflected pulse waves, causing increased ventricular afterload with concomitant decreased coronary perfusion but increased myocardial oxygen demand.3,4,18,19 These alterations related to increased arterial stiffness can stimulate the synthesis and release of BNP.2,20 On the other hand, PP is presented as the formula 10: PP ⫽ cardiac stroke volume/arterial compliance. Thus, cardiac performance is also an important determinant of PP. Ventricular–arterial coupling maintains cardiac stroke volume in the presence of increased arterial stiffening,3,21
and it has been demonstrated that ventricular–arterial uncoupling increases the production of BNP.22 In addition, our previous study demonstrated a significant association between the brachial–ankle PWV and the cardiac diastolic function, which is a known marker of cardiac stiffness.12 Therefore we speculated that in our study cohort also, this adaptive coupling may explain the increase in the plasma level of BNP. The present study suggested that increased brachial– ankle PWV and PP are equally reliable markers of elevated plasma BNP level in a general population. However, compared with PP, the PWV is a more robust marker of arterial stiffness6,8 and also of the severity of atherosclerosis 6,7,8,23 Furthermore, increased arterial stiffness acts as an atherogenic factor by itself, apart from its unfavorable effect on the cardiovascular system via elevation of the plasma BNP level.6,8 Therefore, a longitudinal study must be conducted in the future to confirm whether the plasma level of BNP and markers of arterial stiffness (PWV and PP) are related or independent markers of increased cardiovascular risk in a general population. In addition to BNP, plasma C-reactive protein and matrix metalloproteinase–9 levels have also been reported to be predictors of future cardiovascular events.24,25 These parameters have also been shown to be significantly associated with PWV, and their significant associations may be related to the finding that vascular inflammation or vascular connective tissue metabolism may be involved in the arterial stiffening process.26 –28 Both of these parameters were even more closely associated with PWV than the association between brachial–ankle PWV and plasma
446
AJH–May 2006 –VOL. 19, NO. 5
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
BNP level.26 –28 However, the results of our study suggest that slight increases in arterial stiffness observed in a general population may not be a major determinant of increases in plasma BNP level within the high normal range. This significant but weak association between brachial–ankle PWV and plasma BNP level can be explained by the finding that BNP directly reduces arterial stiffness through its favorable effects on arterial properties,29 and the effects of BNP that counter the arterial stiffness may blunt the positive association between arterial stiffness and plasma BNP level. There are three major limitations of the present study. The first is that the possibility of asymptomatic cardiac dysfunction was not fully evaluated. Another study that would examine the association between cardiac systolic or diastolic function and plasma BNP level within the high normal range is proposed. The second limitation of our study is that the brachial–ankle PWV is a surrogate of the carotid–femoral PWV, which is an established marker of aortic stiffness. As mentioned earlier here, although the brachial–ankle PWV bears a close correlation with the aortic PWV, the possibility that the carotid–femoral PWV may show a closer association with the plasma BNP level cannot be neglected. Therefore, confirmation of the present results using the carotid–femoral PWV is proposed. The third limitation was that the study was conducted in Japanese men,and the results may not be applicable to women or to other ethnic groups. In conclusion, the brachial–ankle PWV and PP were found to be significantly associated with the plasma BNP level, independent of age. In healthy Japanese men, stiffening of the large arteries, as evidenced by an increased PVW or PP, may account at least in part for elevated BNP plasma levels, even within the so-called normal range.
8.
9.
10. 11.
12.
13.
14. 15.
16.
17.
18.
19.
References 1.
2.
3.
4.
5.
6. 7.
Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS: Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655– 663. Magga J, Vuolteenaho O, Tokola H, Marttila M, Ruskoaho H: Involvement of transcriptional and posttranscriptional mechanisms in cardiac overload-induced increase of B-type natriuretic peptide gene expression. Circ Res 1997;81:694 –702. Nichols WW, O’Rourke MF: Wave reflections, in Nichols WW, O’Rourke MF (eds): McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, Fourth Edition. Edward Arnold, London, 1998, pp 203–222. Kingwell BA, Waddell TK, Medley TL, Cameron JD, Dart AM: Large artery stiffness predicts ischemic threshold in patients with coronary artery disease. J Am Coll Cardiol 2002;40:773–779. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236 –1241. London GM, Cohn JN: Prognostic application of arterial stiffness: task forces. Am J Hypertens 2002;15:754 –758. Benetos A, Waeber B, Izzo J, Mitchell G, Resnick L, Asmar R, Safar M: Influence of age, risk factors, and cardiovascular and renal
20.
21. 22.
23.
24.
25.
disease on arterial stiffness: clinical applications. Am J Hypertens 2002;15:1101–1108. Oliver JJ, Webb DJ: Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003; 23:554 –566. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D: Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham Heart Study. Circulation 1999;100:354 –360. Dart AM, Kingwell BA: Pulse pressure—a review of mechanisms and clinical relevance. J Am Coll Cardiol 2001;37:975–984. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y: Validity, reproducibility, and clinical significance of noninvasive brachial–ankle pulse wave velocity measurement. Hypertens Res 2002;25:359 –364. Yambe M, Tomiyama H, Hirayama Y, Gulniza Z, Takata Y, Koji Y, Motobe K, Yamashina A: Arterial stiffening as a possible risk factor for both atherosclerosis and diastolic heart failure. Hypertens Res 2004;27:625– 631. Cowie MR, Jourdain P, Maisel A, Dahlstrom U, Follath F, Isnard R, Luchner A, McDonagh T, Mair J, Nieminen M, Francis G: Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J 2003;24:1710 –1718. Ruskoaho H: Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 2003;24:341–356. Heeschen C, Hamm CW, Mitrovic V, Lantelme NH, White HD, Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators: N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes. Circulation 2004;110:3206 –3212. Nielsen OW, McDonagh TA, Robb SD, Dargie HJ: Retrospective analysis of the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic dysfunction in the general population. J Am Coll Cardiol 2003;41:113–120. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D: Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 2004;43:1239 –1245. Buckberg GD, Fixler DE, Archie JP, Hoffman JI: Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ Res 1972;30:67– 81. Nichols WW, O’Rourke MF: Coupling the left ventricle with systemic circulation: implications to cardiac failure, in Nichols WW, O’Rourke MF (eds): McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, Fourth Edition. Edward Arnold, London, 1998, pp 294 –316. Ruck A, Gustafsson T, Norrbom J, Nowak J, Kallner G, Soderberg M, Sylven C, Drvota V: ANP and BNP but not VEGF are regionally overexpressed in ischemic human myocardium. Biochem Biophys Res Commun 2004;322:287–291. Kass DA: Age-related changes in venticular-arterial coupling: pathophysiologic implications. Heart Fail Rev 2002;7:51– 62. Mehra MR, Milani RV, Richie MB, Uber PA, Park MH, Ventura HO, Scott RL, Lavie CJ: Ventricular-vascular uncoupling increases expression of B-type natriuretic peptide in heart transplantation. Transplant Proc 2004;36:3149 –3151. van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman RS, Hoeks AP, van der Kuip DA, Hofman A, Witteman JC: Association between arterial stiffness and atherosclerosis: the Rotterdam Study. Stroke 2001;32:454 – 460. Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391–397. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L, AtheroGene Investigators: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579 –1585.
AJH–May 2006 –VOL. 19, NO. 5
26. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB: C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969 –974. 27. Tomiyama H, Arai T, Koji Y, Yambe M, Hirayama Y, Yamamoto Y, Yamashina A: The relationship between high-sensitive C-reactive protein and pulse wave velocity in healthy Japanese men. Atherosclerosis 2004;174:373–377. 28. Yasmin, Wallace S, McEniery CM, Dakham Z, Pusalkar P, Maki-
ARTERIAL STIFFNESS AND NATRIURETIC PEPTIDE
447
Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB: Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25:372–378. 29. Schmitt M, Qasem A, McEniery C, Wilkinson IB, Tatarinoff V, Noble K, Klemes J, Payne N, Frenneaux MP, Cockcroft J, Avolio A: Role of natriuretic peptides in regulation of conduit artery distensibility. Am J Physiol Heart Circ Physiol 2004;287:H1167– H1171.