Blood Pressure, 2014; Early Online: 1–7
ORIGINAL ARTICLE
Central blood pressure reflects left ventricular load, while brachial blood pressure reflects arterial damage
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SUMIYO YAMASHITA1, YASUAKI DOHI1, HIROYUKI TAKASE2, TOMONORI SUGIURA1 & NOBUYUKI OHTE1 1Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and 2Department of Internal Medicine, Enshu Hospital, Hamamatsu, Japan
Abstract Objectives. The present study investigated whether brachial and central blood pressures have differential impact on the cardiovascular system in the general population. Methods. The study included 706 subjects (59 ⫾ 10 years) who visited our hospital for a physical check-up. Brachial blood pressure and radial artery pressure waveforms were recorded using an automated device, and the pressure corresponding to the radial late systolic peak (SBP2) was taken as central blood pressure. The concentration of B-type natriuretic peptide and the intima-media thickness of the carotid artery were measured and a cross-sectional analysis was performed. Results. Brachial blood pressure was 128 ⫾ 18/74 ⫾ 12 (mean blood pressure, 92 ⫾ 13) mmHg and SBP2 was 120 ⫾ 19 mmHg. Although both brachial systolic blood pressure and SBP2 correlated with B-type natriuretic peptide in a univariate analysis, only SBP2 independently correlated with B-type natriuretic peptide after adjustment for possible factors. In contrast, brachial systolic blood pressure, but not SBP2, independently correlated with carotid artery intima-media thickness. Conclusions. Central blood pressure is more closely associated with left ventricular load than brachial blood pressure, while brachial blood pressure is more strongly associated with vascular damage than central blood pressure. Key Words: B-type natriuretic peptide, carotid arteries, intima-media thickness, target organ damage, ventricular load
Introduction A chronic increase in blood pressure is a major risk factor for cardiovascular disease and reduction of blood pressure reduces cardiovascular events in the population at large (1,2). Although brachial blood pressure is a powerful predictor of cardiovascular damage, morbidity and mortality (3), several recent studies argue the importance of central blood pressure in the management of hypertension (4–8). Left ventricular load is determined not only by cardiac output and peripheral vascular resistance but also by the stiffness of conduit arteries and the timing and magnitude of pressure wave reflections (9–11). Thus, left ventricular load may be more accurately estimated by the measurement of central blood pressure than brachial blood pressure. A chronic increase in left ventricular load leads to left ventricular hypertrophy and related cardiac dysfunction. On the other hand, atherosclerotic status also
has a significant impact on the development of cardiovascular complications in patients with hypertension, though left ventricular load is not totally independent of the progression of atherosclerosis. Thus, heart failure may be better predicted by central blood pressure than brachial blood pressure, but in atherothrombotic disease this may not be the case. Indeed, the relationship between brachial blood pressure and the incidence of heart failure is somewhat weak when compared with the relationship between brachial blood pressure and other cardiovascular events such as stroke (1). Thus, our fundamental hypothesis is that central blood pressure predicts left ventricular load and brachial blood pressure predicts vascular damage. Practically central blood pressure measurement requires invasive catheterization. However, the possibility of simultaneously measuring brachial blood pressure and radial arterial pulse waves to evaluate
Correspondence: Tomonori Sugiura, Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel: ⫹81 52 853 8221. Fax: ⫹81 52 852 3796. E-mail: [email protected] (Received 22 November 2013 ; accepted 14 April 2014 ) ISSN 0803-7051 print/ISSN 1651-1999 online © 2014 Scandinavian Foundation for Cardiovascular Research DOI: 10.3109/08037051.2014.923250
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central blood pressure has been recently reported (12–16). The observation of late systolic blood pressure in the radial artery by the measurement of brachial blood pressure and radial artery pulse wave activity enables an accurate evaluation of central blood pressure (17). Thus, the present study was designed to investigate whether brachial and central blood pressures have differential impact on left ventricular load and vascular damage in the general population using late systolic blood pressure in the radial artery to estimate central blood pressure.
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Study design The present study was a cross-sectional evaluation of the relationships between central blood pressure and brachial blood pressure and cardiovascular variables. We undertook the study in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Enshu Hospital. All participants gave written informed consent prior to taking part in the study. Study participants and procedures Seven hundred and six Japanese participants who visited our hospital for a yearly physical check-up (men, 63.9%; mean age, 59 ⫾ 10 years) were enrolled in the present study. Those with cardiovascular diseases, such as coronary artery disease, arrhythmia, peripheral artery disease and congestive heart failure were excluded from the study. Besides the routine check-up program (which included a routine physical examination, chest X-ray, electrocardiography and laboratory assessment of cardiovascular risk factors), the participants underwent carotid ultrasound scans for the measurement of intima-media thickness (IMT), examination of radial artery pressure waveforms for the estimation of central blood pressure and measurement of plasma concentrations of B-type natriuretic peptide (BNP). The medical history and current cigarette-smoking habit of each participant were obtained using a self-administered questionnaire. Measurement of IMT The carotid artery was imaged with an ultrasound system (ProSound SSD-3500SV; Aloka Co., Ltd., Tokyo, Japan). On a longitudinal, two-dimensional ultrasound image of the common carotid artery, the left common carotid artery was examined 1–2 cm proximal to the carotid bifurcation. The IMT of the posterior wall of the common carotid artery was measured as the distance from the leading edge of the first echogenic line (lumen–intima interface) to the leading edge of the second line (media–adventitia
interface). Six measurements were averaged, and this value was then used in further calculations. The IMT was measured by a single expert technician who was unaware of the case status of each participant.
Estimation of central blood pressure Brachial blood pressure was measured after participants were seated in a chair for 5 min with their backs supported and their arms supported at heart level. Brachial blood pressure (oscillometer) and radial artery pressure waveforms (tonometer) were recorded using an automated device (HEM-9000AI; Omron Healthcare, Kyoto, Japan), and the systolic pressure corresponding to the second systolic peak of the radial artery pressure waveform (SBP2) was calculated (17,18). The non-invasive radial pulse wave measurement system consists of a tonometry sensor unit, radial pulse measurement unit and laptop personal computer. The sensor unit has a pressure sensor consisting of an array of 40 microtransducer elements. As one of these 40 sensor elements is automatically selected to obtain the optimal radial arterial pressure waveform, this method is thought to be a more objective approach. Signals of the radial arterial pressure wave were low-pass filtered at a cut-off frequency of about 105 Hz. The radial arterial waveform obtained with this device is reported to be identical to the simultaneously and invasively measured intra-arterial pulse waveform of the opposite radial artery (17). Inflection points or peaks that corresponded to early and late systolic blood pressure were obtained by multidimensional derivatives of the original pulse pressure waveforms. The maximal systolic pressure and diastolic pressure in the radial artery were corrected to the brachial systolic (SBP) and diastolic blood pressure (DBP), respectively. SBP2 was calculated by the following equation: SBP2 ⫽ (P2/PP) ⫻(SBP⫺ DBP)⫹ DBP where P2 and PP indicate the height of the late systolic shoulder/peak pressure and the pulse pressure of the radial arterial pressure contour, respectively. In the present study, we took the SBP2 reading as a central blood pressure, because this value is independent of technique used for the estimation of central blood pressure and very close to the central blood pressure value estimated by the SphygmoCor technique (13,15,19,20).
Measurement of BNP concentration To measure BNP, 3 ml blood was transferred to a plastic tube containing 4.5 mg 2Na-EDTA. Plasma samples were prepared within 30 min using a precooled centrifuge, frozen immediately and stored at ⫺ 70°C until analysis. BNP concentration was
Central blood pressure and organ damage Table I. Characteristics of the study participants.
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Variable Age (years) Male sex (n [%]) Waist circumference (cm) Current smoking (%) Brachial systolic blood pressure (mmHg) Brachial diastolic blood pressure (mmHg) Brachial mean blood pressure (mmHg) SBP2 (mmHg) Heart rate (beats/min) Creatinine (mg/dl) Uric Acid (mg/dl) Fasting plasma glucose (mg/dl) Triglycerides (mg/dl) High-density lipoprotein-cholesterol (mg/dl) Low-density lipoprotein-cholesterol (mg/dl) Hemoglobin (g/dl) BNP (ng/l) IMT (mm)
59.3 ⫾ 9.9 451 [63.9] 84.2 ⫾ 8.8 27.8 128.3 ⫾ 18.3 73.8 ⫾ 12.2 92.0 ⫾ 13.2 119.7 ⫾ 18.9 63 ⫾ 10 0.76 ⫾ 0.33 5.3 ⫾ 1.3 100 ⫾ 17 112 ⫾ 68 63 ⫾ 14 131 ⫾ 33 14.6 ⫾ 1.4 10.1 ⫾ 5.7 0.82 ⫾ 0.16
Values are mean⫾ standard deviation for continuous variables or percentages for categorical variables. SBP2 indicates systolic pressure corresponding to the second systolic peak of the radial pressure waveform; BNP, B-type natriuretic peptide; IMT, intimamedia thickness of the carotid artery.
determined using a commercially available chemiluminescence enzyme immunoassay (MI02 Shionogi BNP kit; Shionogi, Osaka, Japan). The intra- and interassay coefficients of variation of the BNP assay were 4.0% and 4.7%, respectively. The lower limit of detection of the assay was 2.0 ng/l BNP. Statistical analysis All analyses were performed using StatView 5.0 (SAS Institute Inc., Cary, NC). Data in the text and tables are expressed as the mean⫾ standard deviation except for BNP, which is expressed as the median⫾ median absolute deviation.
Univariate and multivariate linear regression analyses were performed after log transformation of the BNP value in order to investigate the relationship between BNP or IMT and other variables. The dichotomous variables (sex, smoking status) were assigned values of 0 (female, non-smoking) and 1 (male, smoking). In another series of analyses, the number of variables that were included in the multivariate linear regression analysis was limited using stepwise regression analysis. A p-value less than 0.05 was considered statistically significant.
Results Table I summarizes the characteristics of the study participants. Hypertension, dyslipidemia and diabetes mellitus were present in 40.2%, 62.0% and 9.8% of the participants, respectively, and among these subjects 51.1%, 11.1% and 81.2% were under medication, respectively. The metabolic syndrome was detected in 26.2% of participants. A significant correlation was observed between BNP and several variables (Table II and Figure 1), but multivariate regression analysis revealed that only SBP2, but not brachial systolic blood pressure, remained independently correlated with BNP after adjustment for possible risk factors (Table III, Model I). Although brachial systolic blood pressure seemed to be correlated with SBP2, multicolinearity may not have affected the result of Model I (variance inflation factor 6.58). In order to further confirm the independent correlation between BNP and SBP2, we performed another series of analyses. First, the number of variables to be included in the multivariate regression analysis was limited using stepwise regression analysis. This analysis included age, gender, waist circumference, current smoking, brachial systolic blood pressure, SBP2, creatinine,
Table II. Univariate correlation analyses of factors associated with B-type natriuretic peptide (BNP) and intima-media thickness of the carotid artery (IMT). Correlation with BNP Parameter Age Male sex Waist circumference Current smoking Brachial SBP SBP2 Creatinine Uric acid Fasting plasma glucose Triglycerides HDL-cholesterol LDL-cholesterol Hemoglobin
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Correlation with IMT
Coefficient
p
Coefficient
p
0.443 ⫺ 0.182 ⫺ 0.021 ⫺ 0.168 0.107 0.168 0.047 ⫺ 0.22 0.018 ⫺ 0.150 0.068 ⫺ 0.126 ⫺ 0.325
⬍ 0.0001 ⬍ 0.0001 0.60 ⬍ 0.0001 ⬍ 0.01 ⬍ 0.0001 0.21 ⬍ 0.0001 0.63 ⬍ 0.0001 0.072 ⬍ 0.001 ⬍ 0.0001
0.193 ⫺ 0.012 0.135 0.046 0.260 0.251 0.012 0.042 0.025 0.031 ⫺ 0.035 0.114 ⫺ 0.017
⬍ 0.001 0.83 ⬍ 0.05 0.47 ⬍ 0.0001 ⬍ 0.0001 0.83 0.44 0.65 0.57 0.52 ⬍ 0.05 0.76
SBP indicates systolic blood pressure; SBP2, systolic pressure corresponding to the second systolic peak of the radial pressure waveform; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
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Figure 1. Correlations between B-type natriuretic peptide (BNP) concentration (log transformed) and brachial systolic blood pressure (BP; left panel) and BNP concentration (log transformed) and blood pressure corresponding to the radial late systolic peak (SBP2; right panel).
uric acid, fasting plasma glucose, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)cholesterol and hemoglobin as independent variables, and BNP as a dependent variable. The result indicated that age (standardized coefficient 0.348), gender (⫺ 0.117), SBP2 (0.127), creatinine (0.148), uric acid (⫺ 0.126) and hemoglobin (⫺ 0.164) should be adopted as significant variables (p ⬍ 0.0001). Multivariate regression analysis was then performed including age, gender, SBP2, creatinine, uric acid and hemoglobin as independent variables, and BNP as a dependent variable (Table III, Model II). The result demonstrated that BNP was independently correlated with SBP2 after adjustment for age, gender, creatinine, uric acid and hemoglobin. Table III. Multivariate regression analysis of factors showing association with B-type natriuretic peptide. Variables Model I Age Male sex Brachial systolic blood pressure SBP2 Creatinine Fasting plasma glucose Low-density lipoprotein-cholesterol Hemoglobin Current smoking Model II Age Male sex SBP2 Creatinine Uric acid Hemoglobin
Standardized coefficient
p
0.380 ⫺ 0.123 ⫺ 0.057 0.179 0.132 ⫺ 0.042 ⫺ 0.087 ⫺ 0.203 ⫺ 0.037
⬍ 0.0001 ⬍ 0.05 0.54 ⬍ 0.05 ⬍ 0.001 0.24 ⬍ 0.05 ⬍ 0.0001 0.32
0.375 ⫺ 0.079 0.128 0.136 ⫺ 0.107 ⫺ 0.212
⬍ 0.0001 0.10 ⬍ 0.001 ⬍ 0.001 ⬍ 0.01 ⬍ 0.0001
Although IMT was positively correlated with brachial systolic blood pressure and SBP2 in the univariate analysis (Table II and Figure 2), neither of them was independently correlated with IMT after adjustment for possible risk factors (Table IV, Model I). Then, we limited variables to be included in the multivariate regression analysis using stepwise regression analysis (independent variables: age, gender, waist circumference, current smoking, brachial systolic blood pressure, SBP2, creatinine, uric acid, fasting plasma glucose, high-density lipoproteincholesterol, LDL-cholesterol and hemoglobin; dependent variable: IMT). As a result, age (standardized coefficient 0.276), waist circumference (0.140), brachial systolic blood pressure (0.181) and LDLcholesterol (0.177) were adopted (p ⬍ 0.0001). Multivariate regression analysis (Table IV, Model II) demonstrated that IMT was independently correlated with brachial systolic blood pressure after adjustment for age, LDL-cholesterol and waist circumference. Discussion
Model I, possible risk factors were included in the analysis; Model II, in the exploratory phase, variables included in the analysis were selected using stepwise regression analysis. SBP2 indicates systolic pressure corresponding to the second systolic peak of the radial pressure waveform.
This is, to the best of our knowledge, the first study to generate the hypothesis that central blood pressure predicts left ventricular load and brachial blood pressure predicts vascular damage. The present study not only confirmed but also further developed previous studies reporting that central blood pressure and brachial blood pressure are differentially regulated and have different characteristics (4–7,21–23). BNP is secreted from ventricular myocytes in response to an increased ventricular filling pressure or volume, and hence is a sensitive and significant marker of left ventricular overload (24–26). BNP is also elevated in subjects with hypertension (27–30). Since BNP levels were independently associated with blood pressure after adjustment for left ventricular mass index in patients with hypertension (30), an increase in blood pressure per se may stimulate the secretion of BNP through an increase in left
Central blood pressure and organ damage
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Figure 2. Correlations between the intima-media thickness of the carotid artery (IMT) and brachial systolic blood pressure (BP; left panel) and IMT and blood pressure corresponding to the radial late systolic peak (SBP2; right panel).
ventricular wall stress. This concept leads to the hypothesis that BNP is better predicted by central blood pressure than by brachial blood pressure. The present study proved this hypothesis, suggesting that central blood pressure may more accurately reflect loading conditions of the left ventricular myocardium than brachial blood pressure. The result is compatible with a previous investigation that reported changes in left ventricular mass were associated with changes in central, but not brachial, blood pressure after antihypertensive treatment with a combination of perindopril and indapamide (31). The pressure waveform at any site of the arterial tree is the sum of the forward traveling waveform generated by left ventricular ejection and the backward traveling wave reflected at peripheral sites. Stiffening of large conduit arteries increases pulse wave velocity and the reflected wave augments central blood pressure (32). This indicates that an increase in central blood Table IV. Multivariate regression analysis of factors showing association with intima-media thickness of the carotid artery. Variables Model I Age Male sex Waist circumference Current smoking Brachial systolic blood pressure SBP2 Creatinine Fasting plasma glucose Low-density lipoprotein-cholesterol Model II Age Waist circumference Brachial systolic blood pressure Low-density lipoprotein-cholesterol
Standardized coefficient
p
0.266 ⫺ 0.074 0.142 0.105 0.098 0.124 ⫺ 0.006 0.020 0.175
⬍ 0.0001 0.24 0.02 0.09 0.20 0.09 0.93 0.74 ⬍ 0.01
0.274 0.138 0.182 0.177
⬍ 0.0001 ⬍ 0.05 ⬍ 0.01 ⬍ 0.01
Model I, possible risk factors were included in the analysis; Model II, in the exploratory phase, variables included in the analysis were selected using stepwise regression analysis. SBP2 indicates systolic pressure corresponding to the second systolic peak of the radial pressure waveform.
pressure also reflects advanced atherosclerotic process in large conduit arteries (33). Thus, central blood pressure may be a good marker of aortic stiffness and left ventricular load (6,7). The present study suggests that brachial blood pressure closely relates to atherosclerotic vascular damage assessed by IMT. Mechanisms underlying the close association between brachial blood pressure and IMT are not clear. However, it is possible that stiffening of large conduit arteries may not always reflect the atherosclerotic status of the arterial tree and an increase in IMT may predict a progression of atherosclerotic process rather than sclerotic changes in the aorta. Arterial pressure at small arteries where peripheral resistance is mainly regulated may be a good index of arterial damage. Alternatively, the development of atherosclerosis may, in a large part, be attributable to mechanisms other than mechanical stress on the arterial wall produced by pulsating transmural pressure, and developed atherosclerosis may be one of the most important determinants of brachial blood pressure. Indeed, a different result from the CAFE trial was reported in the ANBP2 trial where a better prognosis for patients randomly assigned to an angiotensin converting enzyme inhibitor was not related to the disproportionate lowering of central blood pressure (34). Also, the central aortic augmentation index was not associated with the extent or severity of coronary artery disease (35). Recent meta-analysis (36) demonstrated that central pulse pressure had marginally but not significantly better predictive ability for cardiovascular events than peripheral pulse pressure. Although the outcomes of interest in the meta-analysis were total cardiovascular events and all-cause mortality and were, thus, quite different from those in the present study, the results of the meta-analysis may imply that central blood pressure has great impact on the progression of atherosclerosis. The apparent discrepancy between the above-mentioned meta-analysis and our present study may be derived from the difference in characteristics of subjects studied. Indeed,
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most subjects studied in the meta-analysis were patients at high risk (coronary artery disease, endstage renal disease, elderly) with high mortality during the follow-up period, whereas we performed crosssectional investigation in the general population. The potential limitations of the present study include the small number of participants studied. However, the present result raises the concern that central blood pressure is not an ideal index of vascular damage in the general population. This should be further studied with a larger number of patients. Lack of longitudinal follow-up of participants during antihypertensive treatment also limits the interpretation. Second, the use of SBP2 as a surrogate of central systolic blood pressure is not sufficiently validated, though SBP2 obtained in the Omron device shows significant correlation with central systolic blood pressure estimated by the SphygmoCor device with a minimal difference between absolute values (37). Third, medication in some subjects might have affected the results. Finally, observed correlations between blood pressure values and other variables do not necessarily indicate causal relationships considering the cross-sectional nature of the present study. In conclusion, central blood pressure and brachial blood pressure have different impacts on the cardiovascular system. Central blood pressure is closely associated with left ventricular load, whereas brachial blood pressure is closely associated with arterial damage. Measurement of these two indices may enable a more accurate evaluation of hypertensive patients. Declaration of interest: No conflict of interest exists. References 1. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials. Lancet. 2003;362: 1527–1535. 2. Schmieder RE, Lehmann MV, Schmidt S. Optimizing blood pressure control in hypertension: The need to use ABPM. Blood Press. 2013;22:65–72. 3. Prospective Studies Collaboration. Age-specific relevance of usual BP to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913. 4. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al.; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113: 1213–1225. 5. Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T, et al. Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: The Strong Heart Study. Hypertension. 2007;50:197–203. 6. Wang KL, Cheng HM, Chuang SY, Spurgeon HA, Ting CT, Lakatta EG, et al. Central or peripheral systolic or pulse pres-
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ORIGINAL ARTICLE
Central blood pressure reflects left ventricular load, while brachial blood pressure reflects arterial damage
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SUMIYO YAMASHITA1, YASUAKI DOHI1, HIROYUKI TAKASE2, TOMONORI SUGIURA1 & NOBUYUKI OHTE1 1Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and 2Department of Internal Medicine, Enshu Hospital, Hamamatsu, Japan
Abstract Objectives. The present study investigated whether brachial and central blood pressures have differential impact on the cardiovascular system in the general population. Methods. The study included 706 subjects (59 ⫾ 10 years) who visited our hospital for a physical check-up. Brachial blood pressure and radial artery pressure waveforms were recorded using an automated device, and the pressure corresponding to the radial late systolic peak (SBP2) was taken as central blood pressure. The concentration of B-type natriuretic peptide and the intima-media thickness of the carotid artery were measured and a cross-sectional analysis was performed. Results. Brachial blood pressure was 128 ⫾ 18/74 ⫾ 12 (mean blood pressure, 92 ⫾ 13) mmHg and SBP2 was 120 ⫾ 19 mmHg. Although both brachial systolic blood pressure and SBP2 correlated with B-type natriuretic peptide in a univariate analysis, only SBP2 independently correlated with B-type natriuretic peptide after adjustment for possible factors. In contrast, brachial systolic blood pressure, but not SBP2, independently correlated with carotid artery intima-media thickness. Conclusions. Central blood pressure is more closely associated with left ventricular load than brachial blood pressure, while brachial blood pressure is more strongly associated with vascular damage than central blood pressure. Key Words: B-type natriuretic peptide, carotid arteries, intima-media thickness, target organ damage, ventricular load
Introduction A chronic increase in blood pressure is a major risk factor for cardiovascular disease and reduction of blood pressure reduces cardiovascular events in the population at large (1,2). Although brachial blood pressure is a powerful predictor of cardiovascular damage, morbidity and mortality (3), several recent studies argue the importance of central blood pressure in the management of hypertension (4–8). Left ventricular load is determined not only by cardiac output and peripheral vascular resistance but also by the stiffness of conduit arteries and the timing and magnitude of pressure wave reflections (9–11). Thus, left ventricular load may be more accurately estimated by the measurement of central blood pressure than brachial blood pressure. A chronic increase in left ventricular load leads to left ventricular hypertrophy and related cardiac dysfunction. On the other hand, atherosclerotic status also
has a significant impact on the development of cardiovascular complications in patients with hypertension, though left ventricular load is not totally independent of the progression of atherosclerosis. Thus, heart failure may be better predicted by central blood pressure than brachial blood pressure, but in atherothrombotic disease this may not be the case. Indeed, the relationship between brachial blood pressure and the incidence of heart failure is somewhat weak when compared with the relationship between brachial blood pressure and other cardiovascular events such as stroke (1). Thus, our fundamental hypothesis is that central blood pressure predicts left ventricular load and brachial blood pressure predicts vascular damage. Practically central blood pressure measurement requires invasive catheterization. However, the possibility of simultaneously measuring brachial blood pressure and radial arterial pulse waves to evaluate
Correspondence: Tomonori Sugiura, Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel: ⫹81 52 853 8221. Fax: ⫹81 52 852 3796. E-mail: [email protected] (Received 22 November 2013 ; accepted 14 April 2014 ) ISSN 0803-7051 print/ISSN 1651-1999 online © 2014 Scandinavian Foundation for Cardiovascular Research DOI: 10.3109/08037051.2014.923250
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central blood pressure has been recently reported (12–16). The observation of late systolic blood pressure in the radial artery by the measurement of brachial blood pressure and radial artery pulse wave activity enables an accurate evaluation of central blood pressure (17). Thus, the present study was designed to investigate whether brachial and central blood pressures have differential impact on left ventricular load and vascular damage in the general population using late systolic blood pressure in the radial artery to estimate central blood pressure.
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Study design The present study was a cross-sectional evaluation of the relationships between central blood pressure and brachial blood pressure and cardiovascular variables. We undertook the study in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Enshu Hospital. All participants gave written informed consent prior to taking part in the study. Study participants and procedures Seven hundred and six Japanese participants who visited our hospital for a yearly physical check-up (men, 63.9%; mean age, 59 ⫾ 10 years) were enrolled in the present study. Those with cardiovascular diseases, such as coronary artery disease, arrhythmia, peripheral artery disease and congestive heart failure were excluded from the study. Besides the routine check-up program (which included a routine physical examination, chest X-ray, electrocardiography and laboratory assessment of cardiovascular risk factors), the participants underwent carotid ultrasound scans for the measurement of intima-media thickness (IMT), examination of radial artery pressure waveforms for the estimation of central blood pressure and measurement of plasma concentrations of B-type natriuretic peptide (BNP). The medical history and current cigarette-smoking habit of each participant were obtained using a self-administered questionnaire. Measurement of IMT The carotid artery was imaged with an ultrasound system (ProSound SSD-3500SV; Aloka Co., Ltd., Tokyo, Japan). On a longitudinal, two-dimensional ultrasound image of the common carotid artery, the left common carotid artery was examined 1–2 cm proximal to the carotid bifurcation. The IMT of the posterior wall of the common carotid artery was measured as the distance from the leading edge of the first echogenic line (lumen–intima interface) to the leading edge of the second line (media–adventitia
interface). Six measurements were averaged, and this value was then used in further calculations. The IMT was measured by a single expert technician who was unaware of the case status of each participant.
Estimation of central blood pressure Brachial blood pressure was measured after participants were seated in a chair for 5 min with their backs supported and their arms supported at heart level. Brachial blood pressure (oscillometer) and radial artery pressure waveforms (tonometer) were recorded using an automated device (HEM-9000AI; Omron Healthcare, Kyoto, Japan), and the systolic pressure corresponding to the second systolic peak of the radial artery pressure waveform (SBP2) was calculated (17,18). The non-invasive radial pulse wave measurement system consists of a tonometry sensor unit, radial pulse measurement unit and laptop personal computer. The sensor unit has a pressure sensor consisting of an array of 40 microtransducer elements. As one of these 40 sensor elements is automatically selected to obtain the optimal radial arterial pressure waveform, this method is thought to be a more objective approach. Signals of the radial arterial pressure wave were low-pass filtered at a cut-off frequency of about 105 Hz. The radial arterial waveform obtained with this device is reported to be identical to the simultaneously and invasively measured intra-arterial pulse waveform of the opposite radial artery (17). Inflection points or peaks that corresponded to early and late systolic blood pressure were obtained by multidimensional derivatives of the original pulse pressure waveforms. The maximal systolic pressure and diastolic pressure in the radial artery were corrected to the brachial systolic (SBP) and diastolic blood pressure (DBP), respectively. SBP2 was calculated by the following equation: SBP2 ⫽ (P2/PP) ⫻(SBP⫺ DBP)⫹ DBP where P2 and PP indicate the height of the late systolic shoulder/peak pressure and the pulse pressure of the radial arterial pressure contour, respectively. In the present study, we took the SBP2 reading as a central blood pressure, because this value is independent of technique used for the estimation of central blood pressure and very close to the central blood pressure value estimated by the SphygmoCor technique (13,15,19,20).
Measurement of BNP concentration To measure BNP, 3 ml blood was transferred to a plastic tube containing 4.5 mg 2Na-EDTA. Plasma samples were prepared within 30 min using a precooled centrifuge, frozen immediately and stored at ⫺ 70°C until analysis. BNP concentration was
Central blood pressure and organ damage Table I. Characteristics of the study participants.
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Variable Age (years) Male sex (n [%]) Waist circumference (cm) Current smoking (%) Brachial systolic blood pressure (mmHg) Brachial diastolic blood pressure (mmHg) Brachial mean blood pressure (mmHg) SBP2 (mmHg) Heart rate (beats/min) Creatinine (mg/dl) Uric Acid (mg/dl) Fasting plasma glucose (mg/dl) Triglycerides (mg/dl) High-density lipoprotein-cholesterol (mg/dl) Low-density lipoprotein-cholesterol (mg/dl) Hemoglobin (g/dl) BNP (ng/l) IMT (mm)
59.3 ⫾ 9.9 451 [63.9] 84.2 ⫾ 8.8 27.8 128.3 ⫾ 18.3 73.8 ⫾ 12.2 92.0 ⫾ 13.2 119.7 ⫾ 18.9 63 ⫾ 10 0.76 ⫾ 0.33 5.3 ⫾ 1.3 100 ⫾ 17 112 ⫾ 68 63 ⫾ 14 131 ⫾ 33 14.6 ⫾ 1.4 10.1 ⫾ 5.7 0.82 ⫾ 0.16
Values are mean⫾ standard deviation for continuous variables or percentages for categorical variables. SBP2 indicates systolic pressure corresponding to the second systolic peak of the radial pressure waveform; BNP, B-type natriuretic peptide; IMT, intimamedia thickness of the carotid artery.
determined using a commercially available chemiluminescence enzyme immunoassay (MI02 Shionogi BNP kit; Shionogi, Osaka, Japan). The intra- and interassay coefficients of variation of the BNP assay were 4.0% and 4.7%, respectively. The lower limit of detection of the assay was 2.0 ng/l BNP. Statistical analysis All analyses were performed using StatView 5.0 (SAS Institute Inc., Cary, NC). Data in the text and tables are expressed as the mean⫾ standard deviation except for BNP, which is expressed as the median⫾ median absolute deviation.
Univariate and multivariate linear regression analyses were performed after log transformation of the BNP value in order to investigate the relationship between BNP or IMT and other variables. The dichotomous variables (sex, smoking status) were assigned values of 0 (female, non-smoking) and 1 (male, smoking). In another series of analyses, the number of variables that were included in the multivariate linear regression analysis was limited using stepwise regression analysis. A p-value less than 0.05 was considered statistically significant.
Results Table I summarizes the characteristics of the study participants. Hypertension, dyslipidemia and diabetes mellitus were present in 40.2%, 62.0% and 9.8% of the participants, respectively, and among these subjects 51.1%, 11.1% and 81.2% were under medication, respectively. The metabolic syndrome was detected in 26.2% of participants. A significant correlation was observed between BNP and several variables (Table II and Figure 1), but multivariate regression analysis revealed that only SBP2, but not brachial systolic blood pressure, remained independently correlated with BNP after adjustment for possible risk factors (Table III, Model I). Although brachial systolic blood pressure seemed to be correlated with SBP2, multicolinearity may not have affected the result of Model I (variance inflation factor 6.58). In order to further confirm the independent correlation between BNP and SBP2, we performed another series of analyses. First, the number of variables to be included in the multivariate regression analysis was limited using stepwise regression analysis. This analysis included age, gender, waist circumference, current smoking, brachial systolic blood pressure, SBP2, creatinine,
Table II. Univariate correlation analyses of factors associated with B-type natriuretic peptide (BNP) and intima-media thickness of the carotid artery (IMT). Correlation with BNP Parameter Age Male sex Waist circumference Current smoking Brachial SBP SBP2 Creatinine Uric acid Fasting plasma glucose Triglycerides HDL-cholesterol LDL-cholesterol Hemoglobin
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Correlation with IMT
Coefficient
p
Coefficient
p
0.443 ⫺ 0.182 ⫺ 0.021 ⫺ 0.168 0.107 0.168 0.047 ⫺ 0.22 0.018 ⫺ 0.150 0.068 ⫺ 0.126 ⫺ 0.325
⬍ 0.0001 ⬍ 0.0001 0.60 ⬍ 0.0001 ⬍ 0.01 ⬍ 0.0001 0.21 ⬍ 0.0001 0.63 ⬍ 0.0001 0.072 ⬍ 0.001 ⬍ 0.0001
0.193 ⫺ 0.012 0.135 0.046 0.260 0.251 0.012 0.042 0.025 0.031 ⫺ 0.035 0.114 ⫺ 0.017
⬍ 0.001 0.83 ⬍ 0.05 0.47 ⬍ 0.0001 ⬍ 0.0001 0.83 0.44 0.65 0.57 0.52 ⬍ 0.05 0.76
SBP indicates systolic blood pressure; SBP2, systolic pressure corresponding to the second systolic peak of the radial pressure waveform; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
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Figure 1. Correlations between B-type natriuretic peptide (BNP) concentration (log transformed) and brachial systolic blood pressure (BP; left panel) and BNP concentration (log transformed) and blood pressure corresponding to the radial late systolic peak (SBP2; right panel).
uric acid, fasting plasma glucose, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)cholesterol and hemoglobin as independent variables, and BNP as a dependent variable. The result indicated that age (standardized coefficient 0.348), gender (⫺ 0.117), SBP2 (0.127), creatinine (0.148), uric acid (⫺ 0.126) and hemoglobin (⫺ 0.164) should be adopted as significant variables (p ⬍ 0.0001). Multivariate regression analysis was then performed including age, gender, SBP2, creatinine, uric acid and hemoglobin as independent variables, and BNP as a dependent variable (Table III, Model II). The result demonstrated that BNP was independently correlated with SBP2 after adjustment for age, gender, creatinine, uric acid and hemoglobin. Table III. Multivariate regression analysis of factors showing association with B-type natriuretic peptide. Variables Model I Age Male sex Brachial systolic blood pressure SBP2 Creatinine Fasting plasma glucose Low-density lipoprotein-cholesterol Hemoglobin Current smoking Model II Age Male sex SBP2 Creatinine Uric acid Hemoglobin
Standardized coefficient
p
0.380 ⫺ 0.123 ⫺ 0.057 0.179 0.132 ⫺ 0.042 ⫺ 0.087 ⫺ 0.203 ⫺ 0.037
⬍ 0.0001 ⬍ 0.05 0.54 ⬍ 0.05 ⬍ 0.001 0.24 ⬍ 0.05 ⬍ 0.0001 0.32
0.375 ⫺ 0.079 0.128 0.136 ⫺ 0.107 ⫺ 0.212
⬍ 0.0001 0.10 ⬍ 0.001 ⬍ 0.001 ⬍ 0.01 ⬍ 0.0001
Although IMT was positively correlated with brachial systolic blood pressure and SBP2 in the univariate analysis (Table II and Figure 2), neither of them was independently correlated with IMT after adjustment for possible risk factors (Table IV, Model I). Then, we limited variables to be included in the multivariate regression analysis using stepwise regression analysis (independent variables: age, gender, waist circumference, current smoking, brachial systolic blood pressure, SBP2, creatinine, uric acid, fasting plasma glucose, high-density lipoproteincholesterol, LDL-cholesterol and hemoglobin; dependent variable: IMT). As a result, age (standardized coefficient 0.276), waist circumference (0.140), brachial systolic blood pressure (0.181) and LDLcholesterol (0.177) were adopted (p ⬍ 0.0001). Multivariate regression analysis (Table IV, Model II) demonstrated that IMT was independently correlated with brachial systolic blood pressure after adjustment for age, LDL-cholesterol and waist circumference. Discussion
Model I, possible risk factors were included in the analysis; Model II, in the exploratory phase, variables included in the analysis were selected using stepwise regression analysis. SBP2 indicates systolic pressure corresponding to the second systolic peak of the radial pressure waveform.
This is, to the best of our knowledge, the first study to generate the hypothesis that central blood pressure predicts left ventricular load and brachial blood pressure predicts vascular damage. The present study not only confirmed but also further developed previous studies reporting that central blood pressure and brachial blood pressure are differentially regulated and have different characteristics (4–7,21–23). BNP is secreted from ventricular myocytes in response to an increased ventricular filling pressure or volume, and hence is a sensitive and significant marker of left ventricular overload (24–26). BNP is also elevated in subjects with hypertension (27–30). Since BNP levels were independently associated with blood pressure after adjustment for left ventricular mass index in patients with hypertension (30), an increase in blood pressure per se may stimulate the secretion of BNP through an increase in left
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Figure 2. Correlations between the intima-media thickness of the carotid artery (IMT) and brachial systolic blood pressure (BP; left panel) and IMT and blood pressure corresponding to the radial late systolic peak (SBP2; right panel).
ventricular wall stress. This concept leads to the hypothesis that BNP is better predicted by central blood pressure than by brachial blood pressure. The present study proved this hypothesis, suggesting that central blood pressure may more accurately reflect loading conditions of the left ventricular myocardium than brachial blood pressure. The result is compatible with a previous investigation that reported changes in left ventricular mass were associated with changes in central, but not brachial, blood pressure after antihypertensive treatment with a combination of perindopril and indapamide (31). The pressure waveform at any site of the arterial tree is the sum of the forward traveling waveform generated by left ventricular ejection and the backward traveling wave reflected at peripheral sites. Stiffening of large conduit arteries increases pulse wave velocity and the reflected wave augments central blood pressure (32). This indicates that an increase in central blood Table IV. Multivariate regression analysis of factors showing association with intima-media thickness of the carotid artery. Variables Model I Age Male sex Waist circumference Current smoking Brachial systolic blood pressure SBP2 Creatinine Fasting plasma glucose Low-density lipoprotein-cholesterol Model II Age Waist circumference Brachial systolic blood pressure Low-density lipoprotein-cholesterol
Standardized coefficient
p
0.266 ⫺ 0.074 0.142 0.105 0.098 0.124 ⫺ 0.006 0.020 0.175
⬍ 0.0001 0.24 0.02 0.09 0.20 0.09 0.93 0.74 ⬍ 0.01
0.274 0.138 0.182 0.177
⬍ 0.0001 ⬍ 0.05 ⬍ 0.01 ⬍ 0.01
Model I, possible risk factors were included in the analysis; Model II, in the exploratory phase, variables included in the analysis were selected using stepwise regression analysis. SBP2 indicates systolic pressure corresponding to the second systolic peak of the radial pressure waveform.
pressure also reflects advanced atherosclerotic process in large conduit arteries (33). Thus, central blood pressure may be a good marker of aortic stiffness and left ventricular load (6,7). The present study suggests that brachial blood pressure closely relates to atherosclerotic vascular damage assessed by IMT. Mechanisms underlying the close association between brachial blood pressure and IMT are not clear. However, it is possible that stiffening of large conduit arteries may not always reflect the atherosclerotic status of the arterial tree and an increase in IMT may predict a progression of atherosclerotic process rather than sclerotic changes in the aorta. Arterial pressure at small arteries where peripheral resistance is mainly regulated may be a good index of arterial damage. Alternatively, the development of atherosclerosis may, in a large part, be attributable to mechanisms other than mechanical stress on the arterial wall produced by pulsating transmural pressure, and developed atherosclerosis may be one of the most important determinants of brachial blood pressure. Indeed, a different result from the CAFE trial was reported in the ANBP2 trial where a better prognosis for patients randomly assigned to an angiotensin converting enzyme inhibitor was not related to the disproportionate lowering of central blood pressure (34). Also, the central aortic augmentation index was not associated with the extent or severity of coronary artery disease (35). Recent meta-analysis (36) demonstrated that central pulse pressure had marginally but not significantly better predictive ability for cardiovascular events than peripheral pulse pressure. Although the outcomes of interest in the meta-analysis were total cardiovascular events and all-cause mortality and were, thus, quite different from those in the present study, the results of the meta-analysis may imply that central blood pressure has great impact on the progression of atherosclerosis. The apparent discrepancy between the above-mentioned meta-analysis and our present study may be derived from the difference in characteristics of subjects studied. Indeed,
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most subjects studied in the meta-analysis were patients at high risk (coronary artery disease, endstage renal disease, elderly) with high mortality during the follow-up period, whereas we performed crosssectional investigation in the general population. The potential limitations of the present study include the small number of participants studied. However, the present result raises the concern that central blood pressure is not an ideal index of vascular damage in the general population. This should be further studied with a larger number of patients. Lack of longitudinal follow-up of participants during antihypertensive treatment also limits the interpretation. Second, the use of SBP2 as a surrogate of central systolic blood pressure is not sufficiently validated, though SBP2 obtained in the Omron device shows significant correlation with central systolic blood pressure estimated by the SphygmoCor device with a minimal difference between absolute values (37). Third, medication in some subjects might have affected the results. Finally, observed correlations between blood pressure values and other variables do not necessarily indicate causal relationships considering the cross-sectional nature of the present study. In conclusion, central blood pressure and brachial blood pressure have different impacts on the cardiovascular system. Central blood pressure is closely associated with left ventricular load, whereas brachial blood pressure is closely associated with arterial damage. Measurement of these two indices may enable a more accurate evaluation of hypertensive patients. Declaration of interest: No conflict of interest exists. References 1. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials. Lancet. 2003;362: 1527–1535. 2. Schmieder RE, Lehmann MV, Schmidt S. Optimizing blood pressure control in hypertension: The need to use ABPM. Blood Press. 2013;22:65–72. 3. Prospective Studies Collaboration. Age-specific relevance of usual BP to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913. 4. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al.; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113: 1213–1225. 5. Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T, et al. Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: The Strong Heart Study. Hypertension. 2007;50:197–203. 6. Wang KL, Cheng HM, Chuang SY, Spurgeon HA, Ting CT, Lakatta EG, et al. Central or peripheral systolic or pulse pres-
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