Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.

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ORIGINAL ARTICLE
VascularMedicine

Acute and Chronic Effects of Smoking on Arterial Stiffness

Takuro Kubozono, MD; Masaaki Miyata, MD; Kiyo Ueyama, MD; Shuichi Hamasaki, MD; Ken Kusano, MD; Osamu Kubozono, MD; Chuwa Tei, MD

Background: The brachialankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) are usedtoevaluatearterialdistensibility.Thepurposeofthisstudywastoelucidatetheacuteandchroniceffectsof smokingonarterialstiffnessasmeasuredbybaPWVandCAVI. Methods and Results: Tenmalesmokerswerestudiedtoevaluatetheacuteeffectofsmokingonarterialstiffness.Toelucidatethechroniceffectofsmokingonarterialstiffness,160maleactivesmokerswereanalyzed. CAVI and baPWV were calculated by measuring the pulse volume record, blood pressure (BP), and vascular length from heart to ankle. CAVI and baPWV were measured using a VaSera VS-1000. In the acute study, baPWVandCAVIincreasedimmediatelyaftersmoking1cigarette.Inthechronicstudy,baPWVandCAVIsignificantlycorrelatedwithmeanBP(MBP)andtheBrinkmanindex.Inmultipleregressionanalysis,baPWVindependentlycorrelatedwithMBP,andCAVIindependentlycorrelatedwiththeBrinkmanindex,butnotwithMBP. Receiver-operating characteristics (ROC) curves of baPWV and CAVI to predict Brinkman index 500 demonstratedthattheareaundertheROCcurveofCAVIwashigherthanthatofbaPWV. Conclusions: Smoking causes a significant increase in arterial stiffness as measured by baPWV and CAVI. CAVIcorrelatedwiththeBrinkmanindex,whichsuggeststhatCAVIisausefulindexofthedegreeofarterialstiffnesscausedbysmoking. (Circ J 2011;75:698702) Key Words: Arterialstiffness;Brachialanklepulsewavevelocity(baPWV);Cardio-anklevascularindex(CAVI); Smoking

igarette smoking is a major risk factor for cardiovascular disease.15 Smoking alters arterial function through several mechanisms, including endothelial dysfunction, unfavorable changes in the lipid profile, and abnormal thrombohemostasis.6 Flow-mediated dilatation in subjects with systolic blood pressure (SBP) <120 mmHg appears to be impaired by cigarette smoking.7 Smoking has been reported to reduce arterial distensibility in both medium and large arteries.8 Carotidfemoral pulse wave velocity (PWV) has been used as a noninvasive clinical index of aortic stiffness9,10 and smoking causes a significant increase in this index.11,12 Cigarette smoking induces global changes in both peripheral and central vascular function, even in young smokers.13

Editorial p 548
A simple, noninvasive, and automatic method of measuring brachialankle PWV (baPWV) has been developed, and a close correlation between baPWV and aortic PWV has been reported.14 We previously reported that baPWV corre-

lated with age in healthy subjects, suggesting that it reflects age-related changes in vascular stiffness.15 Although baPWV is a useful index of arterial stiffness, the drawback is that the result is affected by changes in blood pressure (BP) during measurement of PWV.1517 Recently, an atherosclerotic index, the cardio-ankle vascular index (CAVI), was developed for measuring PWV and BP.1719 CAVI is adjusted for BP based on the stiffness parameter and measures arterial stiffness independent of BP. We have previously reported that the correlation of CAVI with SBP was weaker than the correlation of baPWV with SBP, and CAVI was not affected by changes in BP during measurement.19 CAVI has been associated with the presence and severity of coronary atherosclerosis.20 Furthermore, high CAVI implies progression of carotid and coronary arteriosclerosis, and CAVI may be more closely linked with arteriosclerosis than baPWV.21 It has been reported that active smokers, as confirmed by cotinine levels, have worse arterial stiffness than nonsmokers, and long-term smoking can markedly increase arterial stiffness.22 However, to the best of our knowledge, there

Received June 8, 2010; revised manuscript received October 5, 2010; accepted October 28, 2010; released online December 24, 2010 Time for primary review: 34 days Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima (T.K., M.M., K.U., S.H., C.T.); JA Kagoshima Kouseiren Medical Health Care Center, Kagoshima (K.K., O.K.), Japan Mailing address: Masaaki Miyata, MD, Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: miyatam@m3.kufm.kagoshima-u.ac.jp ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0552 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
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Table 1. Changes in BP and Heart Rate After Smoking 1 Cigarette Before smoking SystolicBP(mmHg) DiastolicBP(mmHg) MeanBP(mmHg) Heartrate(beats/min) BP,bloodpressure. 1209 759 929 639 After smoking 12411 779 9410 748 P value
0.09

<0.05
0.30

<0.0001

Figure 1. Changein(A)brachialanklepulsewavevelocity(baPWV)and(B)cardio-anklevascularindex(CAVI)immediately aftercigarettesmoking.Bothmeasuressignificantlyincreasedaftersmokingjust1cigarette.n=10,*P<0.01vs.beforesmoking.

have been no reports on the comparative effect of smoking on baPWV and CAVI. Thus, the purpose of this study was to elucidate the acute and chronic effects of smoking on arterial stiffness as measured by baPWV and CAVI.

Methods
AcuteEffectofSmoking We studied 10 male active smokers (mean age, 356 years) to evaluate the acute effect of smoking on arterial stiffness. None of the participants had hypertension, diabetes mellitus, hypercholesterolemia or cardiac disease, and they were not taking any medications. First, baPWV and CAVI were measured using a Vasera VS-1000 (Fukuda Denshi, Tokyo, Japan) after a 5-min rest. Next, all subjects smoked 1 cigarette for 5 min while supine, and baPWV and CAVI were measured after smoking. ChronicEffectofSmoking We enrolled 160 male active smokers undergoing routine health checkups at JA Kagoshima Kouseiren Medical Health Care Center. From the personal interviews it was ascertained that 8 subjects were receiving treatment for hypertension, 4 for diabetes mellitus, and one for hyperlipidemia. One subject had a history of ischemic heart disease, and one had a history of stroke. Information on smoking history was obtained from a self-administered questionnaire. This study

included 5 subjects with low estimated glomerular filtration rate (eGFR <60 ml min1 1.73 m2). eGFR was calculated by the equation of the Japanese Society of Nephrology: eGFR = 194 Cr1.094age0.287 (ml min1 1.73 m2). Blood samples were collected after the subjects fasted overnight. The serum concentrations of total cholesterol, triglycerides (TG) and high-density lipoprotein-cholesterol were measured by standard laboratory procedures, and that of low density lipoprotein-cholesterol (LDL-C) was calculated by the Friedewald equation. Eight subjects with a serum TG concentration of 400 mg/dl or higher did not have their LDL-C calculated because the Friedewald equation is unsuitable for TG values above this level. All subjects underwent measurements of baPWV and CAVI using a Vasera VS-1000 after 5 min at rest. CAVIandbaPWVMeasurements CAVI and baPWV were measured using a Vasera VS-1000 (Fukuda Denshi, Tokyo, Japan) as reported previously.1723 In brief, cuffs were applied to the 4 extremities and electrocardiographic electrodes attached to the upper arm. A microphone was placed on the sternal angle for phonocardiography. The subjects then rested supine for 5 min. PWV was calculated by dividing the distance from the aortic valve to the ankle artery by the sum of the difference between the time the pulse waves were transmitted to the brachium and the time the same waves were transmitted to the ankle, and

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KUBOZONO T et al.

Table 2. Characteristics of the Male Smokers n=160 Age(years) Triglycerides(mg/dl) HDL-cholesterol(mg/dl) LDL-cholesterol(mg/dl) Fastingbloodsugar(mg/dl) Bloodureanitrogen(mg/dl) Creatinine(mg/dl) Uricacid(mg/dl) Heartrate(beats/min) MeanBP(mmHg) Pulsepressure(mmHg) Brinkmanindex baPWV(cm/s) CAVI 4612 13684 5213 12131 10320 15.13.8 0.80.1 5.91.0 7012 9913 458 586365 1,327239 8.31.3

Table 3. Coefficients of Correlation From Linear Regression Analysis Between baPWV or CAVI and Other Variables in Smokers (n=160) baPWV Age Triglycerides HDL-cholesterol LDL-cholesterol Fastingbloodsugar Bloodureanitrogen Creatinine Uricacid MeanBP Pulsepressure Brinkmanindex *P<0.0001,**P<0.05. AbbreviationsseeinTables1,2. 0.498* 0.208** 0.064 0.064 0.225** 0.122 0.118 0.203** 0.568* 0.103 0.352* CAVI 0.563* 0.172* 0.017 0.051 0.121 0.162** 0.149 0.162** 0.279** 0.115* 0.447*

HDL, high-density lipoprotein; LDL, low-density lipoprotein; baPWV, brachial-ankle pulse wave velocity; CAVI, cardio-ankle vascularindex.OtherabbreviationseeinTable1.

Table 4. Multiple Regression Analysis Between baPWV or CAVI and Other Variables in Smokers (n=160) baPWV Coefficient Age Triglycerides Fastingbloodsugar Uricacid MeanBP Brinkmanindex AbbreviationsseeinTables1,2. 30.663 7.971 7.872 0.425 P value <0.0001 <0.01
0.4037

CAVI Coefficient 0.052 0.002 0.172 0.001 P value <0.0001 <0.05

0.4359

<0.05 <0.0001
0.4319

<0.05
0.0813

<0.05

the time difference between the second heart sound on the phonocardiogram and the notch of the brachial pulse wave.17,19,23 To minimize cuff inflation effects on blood flow dynamics, pulse waves were measured with the cuffs inflated to less than the diastolic BP (DBP) (50 mmHg). The extremity BP was then measured by oscillometry. SBP, DBP and pulse pressure (PP) were obtained by measuring BP at the right brachial artery. CAVI was calculated by the following equation: CAVI = a [{2 1/(SBP DBP)} {In (SBP/DBP) PWV2}] + b ( den sity of blood, a and b: constants).18,19,23 In this study, there were no subjects with peripheral artery disease as documented by an anklebrachial index less than 0.9. The protocol used for the present study was approved by the institutional review board of Kagoshima University. Informed consent was given by all the volunteers. StatisticalAnalysis Data are expressed as the mean SD. Differences between the mean values at 2 time points of measurement were analyzed by a paired t-test. The relationship between continuous variables was analyzed by linear regression analysis. The independence of the association between variables was tested with multiple regression analysis. Statistical analyses were performed with Stat View, version 5.0, and receiveroperating characteristics (ROC) curve analysis was performed with JMP version 5.1.1. P values less than 0.05 were considered statistically significant.

Results
AcuteEffectofSmokingonbaPWVandCAVI We analyzed the acute effect of smoking on baPWV and CAVI in 10 male active smokers. The mean age was 356 years, mean height was 1725 cm and mean body weight was 688 kg. Table 1 demonstrates the changes in BP and heart rate (HR) after smoking 1 cigarette. HR and DBP significantly increased immediately after smoking 1 cigarette (HR: 638 to 748 beats/min, P<0.001; DBP: 759 to 779 mmHg, P<0.05), and SBP tended to increase immediately after smoking. Figure 1 shows the changes of baPWV and CAVI immediately after smoking 1 cigarette. Both baPWV and CAVI significantly increased after smoking (baPWV: 1,171 115 to 1,222112 cm/s; CAVI: 7.00.9 to 7.30.7, P<0.01). ChronicEffectofSmokingonbaPWVandCAVI The clinical characteristics of the 160 male smokers are summarized in Table 2. The mean age was 4612 years, and the mean BP (MBP) was 9913 mmHg. The mean baPWV value was 1,327239 cm/s and the mean CAVI value was 8.31.3. Table 3 shows the relationship between baPWV or CAVI and the other clinical variables. baPWV significantly correlated with age, TG, fasting blood sugar, uric acid (UA), MBP and the Brinkman index. In contrast, CAVI significantly correlated with age, TG, blood urea nitrogen, UA, MBP and the Brinkman index. Multiple regression analysis was performed using baPWV

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Figure 2. Receiver-operatingcharacteristics(ROC)curvesoftheabilityof(A)brachialanklepulsewavevelocityand(B)cardio-anklevascularindextopredictthemedianvalueoftheBrinkmanindex(500).AUC,areaunderROCcurve.

or CAVI as an objective variable, and conventional atherosclerotic risk factors, such as age, TG, fasting blood sugar, UA, MBP and Brinkman index, as explanatory variables. This analysis revealed that baPWV independently correlated with age, UA and MBP. In contrast, CAVI independently correlated with age, TG, UA and the Brinkman index, but not with MBP (Table 4). Figure 2 demonstrates the ROC curves of baPWV and CAVI to predict the median value of the Brinkman index (500). The area under the ROC curve (AUC) for baPWV was 0.63, with the highest discriminating sensitivity and specificity being 0.59 and 0.65, respectively at baPWV =1,276 cm/s. In contrast, the AUC for CAVI was 0.69 and the highest discriminating sensitivity and specificity were 0.60 and 0.72, respectively at CAVI =8.2. The AUC, sensitivity and specificity of CAVI were demonstrably higher than the values for baPWV.

AcuteEffectofSmokingonArterialStiffness Previous studies have reported that smoking 1 cigarette increased carotidfemoral PWV.11,12 Similarly, we showed in this study that baPWV and CAVI significantly increased after smoking 1 cigarette. Acute cigarette smoking reduces distensibility not only in medium-sized but also in large elastic arteries.8 There are several mechanisms for the acute increase in arterial stiffness, including an increase in both circulating and local catecholamine levels caused by nicotine stimulating the sympathetic ganglia and increasing the central nervous system sympathetic neural discharge, and impaired nitric oxide (NO) production resulting in endothelial dysfunction.11 Plasma catecholamines are maximal at the end of a 10-min period of smoking and return to baseline levels 30 min after the start of smoking.24 Lekakis et al showed that endothelial dysfunction persisted for 90 min after smoking.25 These are possible mechanisms for the acute effects of smoking on the baPWV and CAVI. ChronicEffectofSmokingonArterialStiffness In the present study, baPWV and CAVI correlated with the Brinkman index in our linear regression analysis. Vascular dysfunction has been implicated as an early event in atherogenesis. A particularly important aspect of vascular function is the integrity of the L-arginine-NOcyclic guanosine monophosphate pathway.26 Cigarette smoking is shown to be associated with reduced endothelial-dependent vasodilation, NO generation, and endothelial NO synthase activity.27 Flowmediated dilatation (FMD) of the brachial artery has been demonstrated to reflect endothelium-dependent vasodilation. Yufu et al28 reported that FMD was independently predicted by baPWV in their smoking group, but not in their non-smoking group, and they suggested that the increased baPWV in the smokers was associated with a reduction in endotheliumdependent vasodilation. In addition, it has been reported that smoking status relates to CAVI and that smoking cessation might improve CAVI.29

Discussion
We have shown acute and chronic effects of smoking on arterial stiffness as measured by baPWV and CAVI. In the acute study, HR, DBP, baPWV and CAVI significantly increased after smoking just 1 cigarette. In the chronic study, baPWV and CAVI significantly correlated with age, the Brinkman index and MBP. In multiple regression analysis, baPWV independently correlated with age and MBP, but not with the Brinkman index, whereas CAVI independently correlated with age and the Brinkman index, but not with MBP. Furthermore, the ROC curves of baPWV and CAVI to predict the median value of the Brinkman index (500) demonstrated that AUC of CAVI was higher than that of baPWV. These results suggest that CAVI is a useful index that is independent of BP for evaluating the degree of arterial stiffness caused by smoking. Therefore, our message for clinicians is that CAVI is a useful index of the arterial stiffness caused by smoking. We recommend measuring CAVI in current smokers and using the result to advise smoking cessation.

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702 ComparisonofbaPWVandCAVI Although linear regression analysis demonstrated that both baPWV and CAVI correlated with the Brinkman index, multiple regression analysis showed that only CAVI independently correlated with the Brinkman index. We have already reported that the correlation between baPWV and SBP is closer than the correlation between CAVI and SBP,19 which is why baPWV correlated with SBP, but not with the Brinkman index, in multiple regression analysis in the present study. In addition, the ROC curves of baPWV and CAVI to predict the Brinkman index 500 demonstrated that the AUC of CAVI was higher than that of baPWV. These results suggest that CAVI is superior than baPWV in evaluating the hemodynamic effect of smoking. StudyLimitations Some limitations of this study should be considered when interpreting the results. First, we analyzed the effect of smoking on baPWV and CAVI in almost healthy subjects. Although we could evaluate the pure effect of smoking in these subjects, our results should be useful in relation to patients with atherosclerotic risk factors. Second, a small number of subjects was used to evaluate the acute effect of smoking. Additional studies in a larger population should be conducted. Third, the subjects included in the present study were only men, because the rate of women smokers was very low (4%). For this reason, the results of this analysis may not be applicable to women.

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Conclusion
Smoking caused a significant increase in arterial stiffness as measured by baPWV and CAVI. Because it is independent of BP, CAVI may be a useful clinical method of evaluating the degree of the arterial stiffness caused by smoking.
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