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An association between central aortic pressure and subclinical organ damage of the heart among a general Japanese cohort: Circulatory Risk in Communities Study (CIRCS)

      Highlights

      • We examine the relation between central aortic pressure and subclinical organ damage of the heart.
      • CAP levels are positively associated with the prevalence of subclinical organ damage of the heart.
      • The positive associations with LHAR were observed primarily among non-hypertensive subjects.
      • The measurement of CAP levels may be a useful screening tool to identify high-risk individuals.

      Abstract

      Background

      This study aimed to investigate associations between central aortic pressure (CAP) and subclinical organ damage of the heart amongst the general population.

      Methods

      We conducted a cross-sectional study in a community-based population, consisting of 3002 men and women aged between 40 and 79 years. The CAP was measured using the HEM-9000AI device, an automated tonometer. Electrocardiograms (ECG) were read according to the Minnesota Code. Subclinical organ damage in the heart was defined as measurable left high amplitude R waves (LHAR), major and minor ST-T abnormalities, and left ventricular hypertrophy (LVH).

      Results

      Age- and sex-adjusted prevalence of LHAR, major and minor ST-T abnormalities, and LVH was higher for subjects in the highest tertile of CAP levels than those in the lowest tertile. After further adjustments for other cardiovascular risk factors, these associations did not change substantially. The multivariable odds ratios (ORs) (95% CI) of LHAR, major and minor ST-T abnormalities, and LVH for the highest tertile of CAP levels compared to the lowest tertile were 2.7(1.9–3.9), 1.8(1.1–2.9), 1.7(1.3–2.3) and 3.2(1.3–8.1), respectively. The positive associations with LHAR and minor ST-T abnormalities were observed primarily among non-hypertensive subjects. The respective corresponding ORs were 2.8(1.7–4.6) and 1.7(1.2–2.4) for non-hypertensive subjects, and 1.7(0.9–3.3) and 1.1(0.7–1.8) for hypertensive subjects.

      Conclusion

      CAP levels were associated with subclinical organ damage of the heart independent of cardiovascular risk factors, and these associations were primarily seen in non-hypertensive subjects.

      Keywords

      1. Introduction

      Minor and major ST-T abnormalities, left high amplitude R waves (LHAR) and left ventricular hypertrophy (LVH), as estimated by electrocardiogram (ECG) measurements, are signs of subclinical organ damage of the heart, which increase the risk of cardiovascular disease morbidity and mortality [
      • Ohira T.
      • Maruyama M.
      • Imano H.
      • et al.
      Risk factors for sudden cardiac death among Japanese: the Circulatory Risk in Communities Study.
      ,
      • Ohira T.
      • Iso H.
      • Imano H.
      • et al.
      Prospective study of major and minor ST-T abnormalities and risk of stroke among Japanese.
      ,
      • Daviglus M.L.
      • Liao Y.
      • Greenland P.
      • et al.
      Association of nonspecific minor ST-T abnormalities with cardiovascular mortality: the Chicago Western Electric Study.
      ,
      • Sundström J.
      • Lind L.
      • Arnlöv J.
      • et al.
      Echocardiographic and electrocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men.
      ]. Furthermore, echocardiographic studies have indicated that patients with LVH have an increased risk of cardiovascular disease [
      • Sundström J.
      • Lind L.
      • Arnlöv J.
      • et al.
      Echocardiographic and electrocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men.
      ,
      • Nunez E.
      • Arnett D.K.
      • Benjamin E.J.
      • et al.
      Comparison of the prognostic value of left ventricular hypertrophy in African-American men versus women.
      ,
      • Levy D.
      • Garrison R.J.
      • Savage D.D.
      • et al.
      Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study.
      ]. Several prospective studies have also reported that central aortic pressure (CAP) levels are strongly related to carotid artery intimal–medial thickness and plaque score [
      • Roman M.J.
      • Devereux R.B.
      • Kizer J.R.
      • et al.
      Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study.
      ], and are related to risk of mortality from cardiovascular disease compared to brachial systolic blood pressure levels [
      • Wang K.L.
      • Cheng H.M.
      • Chuang S.Y.
      • et al.
      Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality?.
      ].
      Recently, CAP has been estimated non-invasively using the HEM-9000AI device (Omron Healthcare Co., Ltd., Kyoto, Japan), an automated tonometer, which showed good validity for determining CAP levels as evaluated by the catheter method [
      • Takazawa K.
      • Kobayashi H.
      • Shindo N.
      • et al.
      Relationship between radial and central arterial pulse wave and evaluation of central aortic pressure using the radial arterial pulse wave.
      ]. This non-invasive method is widely used in clinical and epidemiological studies [
      • Sako H.
      • Miura S.
      • Kumagai K.
      • et al.
      Associations between augmentation index and severity of atheroma or aortic stiffness of the descending thoracic aorta by transesophageal echocardiography.
      ,
      • Funada J.
      • Takata Y.
      • Hashida H.
      • et al.
      Dysfunctional central hemodynamic regulation after daily meal intake in metabolic syndrome.
      ,
      • Kohara K.
      • Tabara Y.
      • Oshiumi A.
      • et al.
      Radial augmentation index: a useful and easily obtainable parameter for vascular aging.
      ,
      • Tabara Y.
      • Saito I.
      • Nishida W.
      • et al.
      Relatively lower central aortic pressure in patients with impaired insulin sensitivity and resistance: the Toon Health Study.
      ]. However, to date, no studies have investigated the relationships between CAP and subclinical organ damage of the heart in the general population.
      Therefore, the present study was undertaken to examine the relationship between CAP levels and subclinical organ damage of the heart, estimated by determining resting ECG in a community-based cohort study, the Circulatory Risk in Communities Study (CIRCS).

      2. Methods

      2.1 Subjects

      The CIRCS is a dynamic community cohort study of the Japanese population covering five communities in Japan [
      • Imano H.
      • Kitamura A.
      • Sato S.
      • et al.
      Trends for blood pressure and its contribution to stroke incidence in the middle-aged Japanese population: the circulatory risk in communities study (CIRCS).
      ]. The CIRCS measured CAP in three communities: Yao City, Osaka Prefecture; Ikawa town, Akita Prefecture; and, Kyowa town, Ibaraki Prefecture. This was conducted between January 2010 and June 2011. A total of 3002 subjects (1507 men and 1495 women) aged 40–79 years, participated in a cardiovascular risk survey and measurement of CAP. For each subject, physician epidemiologists and trained staff members explained the protocol in detail, and the study protocol was approved by the Ethics Committee of the Osaka University.

      2.2 Measurement of CAP and cardiovascular risk factors

      The measurement of CAP was conducted by trained observers using the automated tonometer, HEM-9000AI (Omron, Healthcare Co., Kyoto, Japan), at the same time for all participants in a sitting position after 5 min of rest, using a standard protocol [
      • Kohara K.
      • Tabara Y.
      • Oshiumi A.
      • et al.
      Radial augmentation index: a useful and easily obtainable parameter for vascular aging.
      ,
      • Tabara Y.
      • Saito I.
      • Nishida W.
      • et al.
      Relatively lower central aortic pressure in patients with impaired insulin sensitivity and resistance: the Toon Health Study.
      ]. The late systolic peak in the radial artery was obtained by calibrating the radial waveform with brachial systolic pressure, and an additional linear equation was used to calculate the CAP. A previous clinical study examined the validity and reproducibility of CAP levels using both HEM-9000AI and standard cardiac catheterisation among 18 hypertension patients aged 47–78 years [
      • Takazawa K.
      • Kobayashi H.
      • Shindo N.
      • et al.
      Relationship between radial and central arterial pulse wave and evaluation of central aortic pressure using the radial arterial pulse wave.
      ]. There was a strong correlation between the two measurement systems: the correlation coefficient = 0.95 (p < 0.001). The correlation coefficient between repeated of CAP measurement by HEM-9000AI was 0.93 (p < 0.001) [
      • Takazawa K.
      • Kobayashi H.
      • Shindo N.
      • et al.
      Relationship between radial and central arterial pulse wave and evaluation of central aortic pressure using the radial arterial pulse wave.
      ].
      Protocols for the measurement of height, weight, blood pressure, serum lipids and glucose, assessment of smoking and drinking habits, interviews on history of stroke and coronary heart disease and medication use for hypertension and diabetes mellitus, and quality-control procedures for this study have been reported previously [
      • Imano H.
      • Kitamura A.
      • Sato S.
      • et al.
      Trends for blood pressure and its contribution to stroke incidence in the middle-aged Japanese population: the circulatory risk in communities study (CIRCS).
      ,
      • Cui R.
      • Iso H.
      • Yamagishi K.
      • et al.
      Ankle-arm blood pressure index and cardiovascular risk factors in elderly Japanese men.
      ]. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2). Seated brachial systolic blood pressure and diastolic blood pressure were measured on the right arm of participants who had rested for 5 min by trained observers using standard mercury sphygmomanometers [
      • Kirkendall W.M.
      • Feinlieb M.
      • Freis E.D.
      • et al.
      Recommendations: subcommittee of the AHA Postgraduate Education Committee.
      ]. A resting ECG was obtained with subjects in the supine position and was classified according to the Minnesota code [
      • De Bacquer D.
      • De Backer G.
      • Kornitzer M.
      • et al.
      Prognostic value of ECG findings for total, cardiovascular disease, and coronary heart disease death in men and women.
      ] by 2 trained physicians. Left high amplitude R waves (LHAR) were defined as Minnesota code 3-1, that is, an R amplitude greater than 26 mm in either lead V5 or V6; an R amplitude greater than 20 mm in any of leads I, II, III, or aVF; or an R amplitude greater than 12 mm in lead aVL [
      • Ohira T.
      • Maruyama M.
      • Imano H.
      • et al.
      Risk factors for sudden cardiac death among Japanese: the Circulatory Risk in Communities Study.
      ,
      • De Bacquer D.
      • De Backer G.
      • Kornitzer M.
      • et al.
      Prognostic value of ECG findings for total, cardiovascular disease, and coronary heart disease death in men and women.
      ]. Left ventricular hypertrophy (LVH) was defined as Minnesota code 3-1 plus 4-1 to 4-3 or 5-1 to 5-3 [
      • Ohira T.
      • Iso H.
      • Imano H.
      • et al.
      Prospective study of major and minor ST-T abnormalities and risk of stroke among Japanese.
      ,
      • De Bacquer D.
      • De Backer G.
      • Kornitzer M.
      • et al.
      Prognostic value of ECG findings for total, cardiovascular disease, and coronary heart disease death in men and women.
      ]. The LVH was based on these ECG abnormalities was correlated well with LVH estimated by an ultrasound among Japanese men [
      • Nakanishi N.
      • Konishi M.
      • Akiyama M.
      • et al.
      Examination of the electrocardiogram left ventricle hypertrophy with the Minnesota code using the ultrasound cardiography.
      ]. The criteria for minor ST-segment depression were either of the followings: i) Minnesota code 4-3 to 4-4; ii) modified Minnesota code 4-5, i.e., no ST-J depression as much as 0.5 mm but downward or horizontally sloping ST segment, and a segment or T-wave nadir at least 0.25 mm below P-R baseline in any of leads I, II, aVL, or V2 to V6. The criteria for minor T-wave abnormality were either of the followings: i) Minnesota code 5-3 to 5-4; ii) modified Minnesota code 5-5, i.e., T-wave amplitude positive and T- to R-wave ratio of <1:10 when R-wave amplitude in the corresponding leads was ≥10.0 mm. The criteria for major ST-T abnormalities were either of the followings: i) Minnesota code 4-1 to 4-2 or 5-1 to 5-2; ii) LVH (Minnesota code 3-1 plus 4-1 to 4-3 or 5-1 to 5-3) [
      • Ohira T.
      • Iso H.
      • Imano H.
      • et al.
      Prospective study of major and minor ST-T abnormalities and risk of stroke among Japanese.
      ]. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive medication. Diabetes mellitus was defined as a fasting glucose level of ≥7.8 mmol/L, a non-fasting glucose level of ≥11.1 mmol/L, or use of medication for diabetes mellitus.
      For measurement of serum lipids and glucose, non-fasting blood was drawn from seated participants into a plain, siliconised glass tube, and the serum was separated within 30 min. Serum total and HDL-cholesterol and triglycerides were measured using enzymatic methods by an automatic analyser (Hitachi 7250, Hitachi Medical Corp., Ibaraki, Japan) at the Osaka Medical Centre for Health Science and Promotion, an international member of the US National Cholesterol Reference Method Laboratory Network (CRMLN) [
      • Nakamura M.
      • Sato S.
      • Shimamoto T.
      Improvement in Japanese clinical laboratory measurements of total cholesterol and HDL-cholesterol by the US cholesterol reference method laboratory network.
      ]. Serum glucose was measured by the hexokinase method using the same instrument.
      Persons who smoked ≥1 cigarette per day were defined as current smokers, and those who had not smoked for ≥3 months were defined as ex-smokers. An interviewer assessed the usual weekly intake of alcohol in units of “go”, a traditional Japanese unit of volume corresponding to 23 g of ethanol, and converted to grams of ethanol per day.

      2.3 Statistical analysis

      We analysed the association between CAP levels and ECG abnormalities for all subjects, adjusting for sex because the association between two variables did not vary by sex (p for interaction > 0.05). Differences in age-, sex-, and multivariate-adjusted odds ratios (ORs) and 95% confidence interval (CI) of LHAR, minor and major ST-T abnormalities, LVH, and history of stroke and coronary heart disease were calculated by using logistic regression analysis according to tertile of CAP levels. We used the lowest tertile of CAP levels as the reference. We also conducted stratified analysis by hypertensive status. The significance of the interaction by hypertensives was tested using cross-product terms of CAP levels and ECG abnormalities in multivariable models. The predictive powers of CAP and brachial systolic blood pressure were compared by testing the difference between areas under the curve (AUC) of receiver operating characteristic (ROC) curves.
      In this study, the potential confounding factors included age (year), sex, BMI (kg/cm2), serum total and HDL-cholesterol levels (mmol/L), triglycerides (mmol/L), smoking and drinking status (never, ex- and current), use of antihypertensive medication (yes or no), diabetes mellitus (yes or no) and communities. All analyses were conducted using the SAS statistical package version 9.3 (SAS Institute Inc., Cary, CA). All p values for statistical tests were two-tailed, and values of p < 0.05 were regarded as indicative of statistical significance.

      3Results

      Table 1 shows age-adjusted sex-specific characteristics of the population in this study. Mean values of age, total and HDL-cholesterol levels, and the proportions of antihypertensive medication use and minor ST-T abnormalities were lower, while mean values of BMI, systolic and diastolic blood pressure levels and triglycerides, and the proportions of smoker, hypertension and LHAR were higher in men than in women. However, there were no sex differences in means of CAP or proportions of diabetes mellitus, major ST-T abnormalities, LVH, and history of stroke and coronary heart disease.
      Table 1Age-adjusted mean values ± standard errors and proportions of selected cardiovascular risk factors.
      Total subjectsMenWomenp for Sex difference
      Number300215071495
      Age, year64.1 ± 8.563.4 ± 0.2264.8 ± 0.22<0.001
      Central aortic pressure, mmHg143.9 ± 20.3143.8 ± 0.51144.0 ± 0.510.80
      Systolic blood pressure, mmHg126.4 ± 15.8128.2 ± 0.40124.6 ± 0.40<0.001
      Diastolic blood pressure, mmHg77.9 ± 10.277.5 ± 0.2674.3 ± 0.26<0.001
      BMI, kg/m223.6 ± 3.223.8 ± 0.0823.4 ± 0.08<0.001
      Total cholesterol, mmol/L5.43 ± 0.95.26 ± 0.025.61 ± 0.02<0.001
      HDL-cholesterol, mmol/L1.62 ± 0.41.54 ± 0.011.70 ± 0.01<0.001
      Triglycerides, mmol/L1.27 ± 0.91.38 ± 0.021.16 ± 0.02<0.001
      Alcohol intake, g/day20.1 ± 22.324.8 ± 0.726.9 ± 1.20<0.001
      Current smoker, %15.927.73.9<0.001
      Hypertension, %36.639.334.00.003
      Use of antihypertensive medication, %18.716.121.3<0.001
      Diabetes mellitus, %7.98.77.10.11
      Left high amplitude R waves, %8.813.64.0<0.001
      Major ST-T abnormalities, %3.83.54.00.39
      Minor ST-T abnormalities, %16.411.121.8<0.001
      Left ventricular hypertrophy, %1.41.81.10.10
      History of stroke, %2.22.12.20.88
      History of coronary heart disease, %1.31.51.00.30
      For ‘Total subjects’ shows the mean values ± standard deviation. BMI; body mass index, HDL-cholesterol: high density lipoprotein-cholesterol. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, and/or use of antihypertensive medication.
      The ORs and 95% CIs of ECG abnormalities according to tertile of CAP levels are shown in Table 2. The age- and sex-adjusted prevalence of LHAR, major and minor ST-T abnormalities, and LVH was higher for subjects in the highest tertile of CAP levels than those in the lowest tertile. After further adjustment for other cardiovascular risk factors, these associations did not change substantially. The multivariable ORs (95% CI) of LHAR, major and minor ST-T abnormalities, and LVH for the highest vs. lowest tertile of CAP levels were 2.7(1.9–3.9), 1.8(1.1–2.9), 1.7(1.3–2.3), and 3.2(1.3–8.1), respectively. The prevalence of coronary heart disease but not for stroke tended to be higher for subjects in the highest tertile of CAP levels than in the lowest tertile, although the trend did not reach statistical significance.
      Table 2Odds ratios and 95% confidence intervals of ECG abnormalities according to the tertiles of CAP in total, non-hypertensive and hypertensive subjects.
      Tertile of CAPTotal subjectsNon-hypertensivesHypertensives
      LowMiddleHighLowMiddleHighLowMiddleHigh
      Total number9999981005863667372136331633
      Mean, central aortic pressure, mmHg123142166123142161126143169
      Mean, systolic blood pressure, mmHg115127138114123127122134144
      Mean, diastolic blood pressure, mmHg717680707576748083
      Left high amplitude R waves, n4884132365140123392
      Age-, sex-adjusted OR1.01.7(1.1–2.4)†2.7(1.9–3.8)‡1.01.8(1.1–2.8)*2.7(1.6–4.4)‡1.01.2(0.6–2.4)1.8(0.9–3.4)
      Multivariable OR1.01.7(1.2–2.5)†2.7(1.9–3.9)‡1.01.8(1.1–2.9)†2.8(1.7–4.6)‡1.01.2(0.6–2.4)1.7(0.9–3.3)
      Major ST-T abnormalities, n27305724202131036
      Age-, sex-adjusted OR1.01.0(0.6–1.7)1.8(1.1–2.9)*1.01.0(0.5–1.8)1.7(0.9–3.1)1.01.5(0.4–5.4)2.7(0.8–8.9)
      Multivariable OR1.01.0(0.6–1.8)1.8(1.1–2.9)*1.01.0(0.5–1.8)1.7(0.9–3.1)1.01.3(0.4–5.0)2.6(0.8–8.7)
      Minor ST-T abnormalities, n1131552268486772969149
      Age-, sex-adjusted OR1.01.4(1.0–1.8)*2.0(1.5–2.7)‡1.01.3(0.9–1.8)1.9(1.3–2.7)‡1.01.0(0.6–1.7)1.2(0.7–1.8)
      Multivariable OR1.01.3(1.0–1.7)1.7(1.3–2.3)‡1.01.2(0.9–1.7)1.7(1.2–2.4)†1.01.0(0.6–1.7)1.1(0.7–1.8)
      Left ventricular hypertrophy, n613245791615
      Age-, sex-adjusted OR1.01.9(0.7–5.0)3.1(1.3–7.8)*1.01.5(0.5–4.9)3.1(1.0–9.5)*1.02.6(0.3–22)3.3(0.4–25)
      Multivariable OR1.02.0(0.7–5.2)3.2(1.3–8.1)*1.01.7(0.5–5.6)3.2(1.0–10)*1.02.4(0.2–21)3.0(0.4–24)
      History of stroke, n2322201410491216
      Age-, sex-adjusted OR1.00.9(0.5–1.5)0.7(0.4–1.3)1.00.8(0.4–1.9)0.5(0.2–1.7)1.00.6(0.2–1.4)0.4(0.2–0.9)*
      Multivariable OR1.00.7(0.4–1.4)0.5(0.3–1.0)1.00.9(0.4–2.3)0.6(0.2–1.9)1.00.6(0.2–1.6)0.4(0.1–1.2)
      History of coronary heart disease, n916147732911
      Age-, sex-adjusted OR1.01.6(0.7–3.5)1.2(0.5–2.8)1.01.0(0.4–2.9)0.6(0.1–2.3)1.01.9(0.4–8.9)1.2(0.3–5.4)
      Multivariable OR1.01.4(0.6–3.5)1.3(0.5–3.5)1.01.3(0.4–4.2)0.6(0.1–2.5)1.02.2(0.4–11)2.5(0.5–14)
      *p < 0.05, †p < 0.01, ‡p < 0.001 compared to subjects with lower tertile category. OR: odds ratio; ECG: electrocardiogram. Multivariable variable includes age, sex, BMI, smoking and drinking status, serum total and HDL-cholesterol, triglycerides, diabetes mellitus, and communities. Further adjustment of use of antihypertensive medication for total subjects.
      When these associations were examined by hypertension status, the positive associations of CAP with LHAR and minor ST-T abnormalities were observed primarily in non-hypertensive subjects. The corresponding multivariable ORs (95% CI) of LHAR and minor ST-T abnormalities for the highest vs. lowest tertiles of CAP levels were 2.8(1.7–4.6) and 1.7(1.2–2.4), respectively. The similar but non-significant trends were observed for hypertensive subjects: 1.7(0.9–3.3) and 1.1(0.7–1.8), respectively.
      Furthermore, the CAP levels were correlated better with minor ST-T abnormalities, as compared to brachial systolic blood pressure levels, which were confirmed in the ROC analysis. For each indicator of ECG abnormality, the AUC values as based on CAP levels vs. brachial systolic blood pressure levels were calculated for non-hypertensives, hypertensives, and all subjects. For LHAR, these values were 0.61 vs. 0.59 (p = 0.32), 0.58 vs. 0.59 (p = 0.99), and 0.63 vs. 0.62 (p = 0.76), respectively, and for minor ST-T abnormalities, these values were 0.62 vs. 0.56 (p = 0.004), 0.55 vs. 0.50 (p = 0.02), and 0.62 vs. 0.58 (p = 0.002), respectively. For major ST-T abnormalities, these AUC values were 0.59 vs. 0.55 (p = 0.26), 0.63 vs. 0.65 (p = 0.57), and 0.61 vs. 0.59 (p = 0.29), respectively, and for LVH, the values were 0.66 vs. 0.54 (p = 0.06), 0.62 vs. 0.66 (p = 0.60), and 0.67 vs. 0.63 (p = 0.27), respectively (not shown in Table).

      4. Discussion

      In this community population-based study in Japanese subjects aged 40–79 years, we found that high levels of CAP had a 1.8-fold to 3.2-fold higher prevalence of LHAR, major and minor ST-T abnormalities, and LVH. The positive association with LHAR and minor ST-T abnormalities was more evident in non-hypertensive than in hypertensive subjects.
      Our findings that associate high CAP levels with a higher prevalence of LHAR and LVH have been suggested in previous reports from population-based studies, where high levels of CAP were associated with higher mean values of left ventricular mass and higher prevalence of LVH [
      • Wohlfahrt P.
      • Wichterle D.
      • Seidlerová J.
      • et al.
      Relation of central and brachial blood pressure to left ventricular hypertrophy. The Czech Post-MONICA Study.
      ,
      • Roman M.J.
      • Okin P.M.
      • Kizer J.R.
      • et al.
      Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study.
      ]. The Czech Post-MONICA Study of 728 men and women aged over 25 years showed that a 1 mmHg increment of CAP levels was associated with a 1.1-fold higher prevalence of LVH for subjects aged over 45 years [
      • Wohlfahrt P.
      • Wichterle D.
      • Seidlerová J.
      • et al.
      Relation of central and brachial blood pressure to left ventricular hypertrophy. The Czech Post-MONICA Study.
      ]. Further, the Strong Heart Study of 2585 subjects aged 15–93 years reported that the mean values of left ventricular mass became progressively higher from the first to fourth quartiles of CAP levels [
      • Roman M.J.
      • Okin P.M.
      • Kizer J.R.
      • et al.
      Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study.
      ].
      In the present study, the AUC of LVH tended to be large when analysed by CAP rather than by brachial systolic blood pressure among non-hypertensive subjects: 0.66 vs. 0.54 (p = 0.06) although the number of subjects with LVH was small. The Czech Post-MONICA Study reported that LVH was better predicted by the AUC for CAP than for brachial systolic blood pressure (AUC = 0.90 vs. 0.83, p < 0.05) among subjects aged ≥45 years [
      • Wohlfahrt P.
      • Wichterle D.
      • Seidlerová J.
      • et al.
      Relation of central and brachial blood pressure to left ventricular hypertrophy. The Czech Post-MONICA Study.
      ]. The Strong Heart Study also showed that the left ventricular mass was more strongly correlated with CAP levels than brachial systolic blood pressure levels (correlation coefficients = 0.396 vs. 0.374, p < 0.001) [
      • Roman M.J.
      • Okin P.M.
      • Kizer J.R.
      • et al.
      Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study.
      ].
      We also found that CAP levels were positively associated with the prevalence of LHAR and minor ST-T abnormalities for total subjects, primarily non-hypertensive subjects, independent of cardiovascular risk factors. Our result supports the finding from previous studies that CAP is strongly correlated with left ventricular mass and is an independent predictor of cardiovascular mortality [
      • Wang K.L.
      • Cheng H.M.
      • Chuang S.Y.
      • et al.
      Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality?.
      ]. In other cohort studies, subjects with LHAR, or major or minor ST-T abnormalities had 1.5- to 3.5-fold higher risk of sudden cardiac death [
      • Ohira T.
      • Maruyama M.
      • Imano H.
      • et al.
      Risk factors for sudden cardiac death among Japanese: the Circulatory Risk in Communities Study.
      ], and those with major or minor ST-T abnormalities had an approximately 2.0-fold higher risk of stroke incidence [
      • Ohira T.
      • Iso H.
      • Imano H.
      • et al.
      Prospective study of major and minor ST-T abnormalities and risk of stroke among Japanese.
      ]. In addition, CAP was strongly correlated with carotid atherosclerosis [
      • Roman M.J.
      • Devereux R.B.
      • Kizer J.R.
      • et al.
      Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study.
      ] and was a robust predictor of cardiovascular disease incidence and mortality [
      • Roman M.J.
      • Devereux R.B.
      • Kizer J.R.
      • et al.
      Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study.
      ,
      • Wang K.L.
      • Cheng H.M.
      • Chuang S.Y.
      • et al.
      Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality?.
      ]. On the other hand, the effect of blood pressure lowering drugs [
      • Williams B.
      • Lacy P.S.
      • Thom S.M.
      • et al.
      CAFE InvestigatorsAnglo-Scandinavian Cardiac Outcomes Trial Investigators
      Differential impact of blood pressure lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) Study.
      ] was greater on CAP levels compared with brachial systolic blood pressure levels. CAP levels were correlated more strongly with intimal–medial thickness of carotid arteries than brachial systolic blood pressure among Americans (r = 0.257 vs. 0.196, p < 0.001) [
      • Roman M.J.
      • Devereux R.B.
      • Kizer J.R.
      • et al.
      Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study.
      ] and among Taiwanese subjects (r = 0.252 vs. 0.225, p < 0.05) [
      • Wohlfahrt P.
      • Wichterle D.
      • Seidlerová J.
      • et al.
      Relation of central and brachial blood pressure to left ventricular hypertrophy. The Czech Post-MONICA Study.
      ]. A 10 mmHg increment of CAP was more strongly associated with risk of cardiovascular disease compared to brachial systolic blood pressure, the multivariable HR(95% CI) being 1.34(1.10–1.49) and 0.96(0.79–1.16), respectively [
      • Wang K.L.
      • Cheng H.M.
      • Chuang S.Y.
      • et al.
      Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality?.
      ]. In a 4-year randomised controlled trial of 2199 hypertension patients with similar brachial systolic blood pressure levels between treatment groups using different blood pressure lowering drugs, i.e., a calcium channel blocker regimen vs. a β-blocker-based regimen, [Δ0.7 mmHg (95% CI, −0.4 to 1.7; p = 0.20)], there was substantial reduction in CAP between the groups, i.e., Δ3.0 mmHg (95% CI, 2.1–3.9; p < 0.001) [
      • Williams B.
      • Lacy P.S.
      • Thom S.M.
      • et al.
      CAFE InvestigatorsAnglo-Scandinavian Cardiac Outcomes Trial Investigators
      Differential impact of blood pressure lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) Study.
      ]. Therefore, the present study suggests that the measurement of CAP in the general population may be a useful screening tool to identify high-risk individuals and to prevent cardiovascular disease.
      The strengths of the present study include the use of a non-invasive technique for measurement of CAP, the estimation of subclinical organ damage of the heart, and the standardised measurement of other cardiovascular risk factors in community population-based samples [
      • Ohira T.
      • Maruyama M.
      • Imano H.
      • et al.
      Risk factors for sudden cardiac death among Japanese: the Circulatory Risk in Communities Study.
      ,
      • Imano H.
      • Kitamura A.
      • Sato S.
      • et al.
      Trends for blood pressure and its contribution to stroke incidence in the middle-aged Japanese population: the circulatory risk in communities study (CIRCS).
      ]. As for the study limitations, we are unable to draw a causal relationship in this study due to its cross-sectional design.
      In conclusion, we have identified that CAP levels were associated with subclinical organ damage of the heart, which was independent of cardiovascular risk factors and primarily seen in non-hypertensive subjects.

      Conflict of interest

      The authors declared no conflict of interest.

      Acknowledgements

      This study was supported by Grants-in-Aid research C (No. 21590691 in 2009–2011) from the Ministry of Health, Welfare and Labour , Japan.
      The authors are grateful to Wen Zhang, Ehab Salah Eshak Farag, and Keyang Liu, Osaka University, for their excellent technical assistance and help with data collection.

      Appendix. CIRCS collaborators

      The Circulatory Risk in Communities Study (CIRCS) is a collaborative study managed by the Osaka Medical Centre for Health Science and Promotion, University of Tsukuba, Osaka University, and Ehime University. The CIRCS investigators who contributed to this study are as follows: Masamitsu Konishi, Yoshinori Ishikawa, Akihiko Kitamura, Masahiko Kiyama, Masakazu Nakamura MD, Takeo Okada, Kenji Maeda, Masatoshi Ido, Masakazu Nakamura (PhD), Mitsumasa Umesawa, Takashi Shimamoto, Minoru Iida, and Yoshio Komachi, Osaka Medical Centre for Health Science and Promotion, Osaka; Shinichi Sato, Chiba Prefectural Institute of Public Health, Chiba; Tomonori Okamura, National Cardiovascular Centre, Osaka; Yoshihiko Naito, Mukogawa Women's University, Nishinomiya; Tomoko Sankai, Kazumasa Yamagishi, Kimiko Yokota, and Minako Tabata, University of Tsukuba, Tsukuba; Hiroyasu Iso, Tetsuya Ohira, Hironori Imano, Renzhe Cui, Ai Ikeda, Hiroyuki Noda, Satoyo Ikehara, Kotatsu Maruyama, Yoshimi Kubota, and Isao Muraki, Osaka University, Suita; Takeshi Tanigawa, Isao Saito, Katsutoshi Okada, and Susumu Sakurai, Ehime University, Tōon; Masayuki Yao, Ranryoen Hospital, Ibaraki.

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