Vascular abnormalities in asymptomatic, healthy young adult smokers without other major cardiovascular risk factors: The Bogalusa Heart Study

Vascular abnormalities in asymptomatic, healthy young adult smokers without other major cardiovascular risk factors: The Bogalusa Heart Study

AJH 2005; 18:319 –324 Vascular Abnormalities in Asymptomatic, Healthy Young Adult Smokers Without Other Major Cardiovascular Risk Factors: The Bogal...

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AJH

2005; 18:319 –324

Vascular Abnormalities in Asymptomatic, Healthy Young Adult Smokers Without Other Major Cardiovascular Risk Factors: The Bogalusa Heart Study Hong Li, Sathanur R. Srinivasan, Wei Chen, Ji-Hua Xu, Shengxu Li, and Gerald S. Berenson Cigarette smoking, an established cardiovascular (CV) disease risk factor, is known to impair pulsatile arterial function in middle-aged and older adults. However, information is scant in healthy young adults for whom smoking is the only CV risk factor, at current guidelines. Nonsmokers (n ⫽ 145) and smokers (n ⫽ 142) aged on average 36 years were selected for not having obesity, hypertension, dyslipidemia, diabetes, or clinically manifest CV disease. Pulsatile arterial function was measured in terms of large artery compliance (C1), small artery compliance (C2), and systemic vascular resistance (SVR) by noninvasively recorded radial artery waveforms. Smokers versus nonsmokers had significantly lower measures of adiposity and LDL-cholesterol; and higher systolic blood pressure and triglycerides. In addition, smokers versus nonsmokers had lower C2 (5.09 v 6.63 mL/mm Hg ⫻ 100, P ⫽ .0009) and higher SVR (1399.0 v 1325.5 dyn · sec · cm⫺5, P ⫽ .006), after adjustment for race, sex, and age. Decreases in C2 (P

for trend ⫽ .001) and increases in SVR (P for trend ⫽ .01) were noted with increasing years of smoking. Multivariate analysis revealed that duration of smoking was associated adversely with C2 (P ⫽ .004), independent of race, sex, age, systolic and diastolic blood pressures, HDL-cholesterol, triglycerides, glucose, and insulin. The odds of having adverse C2 (bottom 10 percentile) and SVR (top 10 percentile) were, respectively, 2.9 (P ⫽ .01) and 2.6 (P ⫽ .07) times higher in smokers versus nonsmokers. The observed deleterious effects of cigarette smoking on arterial wall dynamics in otherwise healthy young adults underscore the need for aggressive early prevention and intervention strategies to control smoking behavior. Am J Hypertens 2005;18:319 –324 © 2005 American Journal of Hypertension, Ltd.

igarette smoking has been established as a major risk factor for cardiovascular (CV) disease, and it contributes to as much as 30% of all CV disease mortality in the US each year.1,2 Risk factors for CV disease, including smoking, mediate their effects by adversely altering the structure, endothelial function, and dynamic properties of the arterial wall.3 Smoking, either acute or chronic, is known to decrease vascular compliance.4 –10 Recent studies have shown that alterations in the pulsatile behavior of the vasculature may be a sensitive marker to detect arterial injury related to CV risk factors.11–13 In this regard, arterial pressure pulse contour,

C

which can be obtained noninvasively, provides assessments of large artery (capacitive) compliance, small artery (oscillatory or reflective) compliance, and systemic vascular resistance.11,14,15 Most studies on the effect of smoking on the arterial wall properties were performed on heterogeneous groups of subjects with confounding factors such as varying ages, CV risk factors, and clinical manifestations of CV disease that could bias the outcome. Furthermore, information concerning the effect of smoking on the measures of pulsatile arterial function in otherwise healthy young adult smokers is sparse. As part of the Bogalusa Heart Study, a community-based investigation of early natural history of

Received June 16, 2004. First decision August 19, 2004. Accepted October 4, 2004. From the Tulane Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana. This study was supported by National Institutes of Health grants AG-16592 from the National Institute of Aging, HL-38844 from the

National Heart, Lung, and Blood Institute, and HD-043820 from the National Institute of Child Health and Human Development. Address correspondence and reprint requests to Dr. Gerald S. Berenson, Tulane Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, 1440 Canal St., Suite 1829, New Orleans, LA 70112-2824; e-mail: [email protected]

© 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.

Key Words: Cigarette smoking, arterial compliance, vascular resistance, pulse contour analysis, young healthy adults.

0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2004.10.005

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CV disease,16 this study examines the effect of smoking on the compliance of large artery versus small artery and systemic vascular resistance in healthy young adults for whom smoking was the only major traditional CV risk factor.

Methods Study Population The screenings for the CV risk factors of the young adults, who participated earlier as children and remained accessible, were conducted periodically since 1979 as part of the longitudinal cohort survey in the biracial (65% white, 35% black), semirural community of Bogalusa, LA. During the 2000 –2002 survey of young adults aged 18 to 45 years (n ⫽ 1203; mean age 36.3 years; 70% white, 43% men; 31.7% smokers), radial arterial pulse pressure waveforms were recorded on 815 participants (mean age 36.4 years; 70% white, 43% men; 33.9% smokers). Of these, 145 nonsmokers (mean age 35.4 years; 51% white, 45% men) and 142 smokers (mean age 35.6 years; 49% white, 55% men) without obesity (body mass index [BMI] ⱖ30 kg/m2), hypertension (ⱖ140/90 mm Hg), diabetes (fasting glucose ⬎125 mg/dL), dyslipidemia (total cholesterol/ HDL-cholesterol ratio ⬎5.8 for men and ⬎5.3 for women), CV events (heart attack, bypass surgery, angioplasty, and angina), or on medication for these conditions, were selected for this study. Healthy (n ⫽ 114) former smokers and passive smokers without these conditions were not included for this study. Written informed consent was obtained from the study precipitants, and study protocols were approved by the Institutional Review Board of the Tulane University Health Science Center. Examinations Data on risk factors were collected according to previously defined protocols.17 Participants were instructed to fast 12 hours before screening with compliance ascertained by interview on the morning of the examination. All examinations were preformed after venipuncture and a light breakfast. Replicate measures of height, weight, subscapular and triceps skin fold thicknesses were made and the mean values used. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Systolic and diastolic blood pressures were measured three times by each of two randomly assigned trained observers on the right arm of participants in a relaxed, sitting position. Information on health, medication history, and behavioral lifestyle were obtained by questionnaires. With respect to smoking behavior, subjects were asked about the age of initiation, the length (years) of use, the number of cigarettes smoked per week, and information on passive smoking (exposure to smoking in working and living environments).18 The questionnaire on smoking was val-

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idated by measuring plasma thiocyanate as an independent measure of smoking.19 Those subjects who never tried cigarettes and were not exposed to passive smoking were classified as nonsmokers. Current smokers were identified as smoking at least one cigarette per week during the past year. Laboratory Analyses Cholesterol and triglycerides levels in serum were determined by enzymatic procedures on the Hitachi 902 Automatic Analyzer (Roche Diagnostics, Indianapolis, IN). Serum very-low density lipoprotein (VLDL), LDL-, and HDL-cholesterol levels were analyzed using a combination of heparin– calcium precipitation and agar–agarose gel electrophoresis procedures.20 The laboratory has been monitored for precision and accuracy of lipid measurements by the surveillance program of the Centers for Disease Control and Prevention (Atlanta, GA). Plasma immunoreactive insulin levels were measured by a commercial radioimmunoassay kit (Phadebas, Pharmacia Diagnostics, Piscataway, NJ). Plasma glucose levels were measured by an enzymatic procedure as part of a multichemistry (SMA20) profile. Arterial Compliance Measurements Radial arterial pulse pressure waveforms were recorded by an acoustic transducer using the HDI/Pulsewave CR 2000 Research Cardiovascular Profiling System (Hypertension Diagnostic Inc., Egan, MN).21 A wrist stabilizer was used to gently immobilize the right wrist and stabilize the radial artery during measurements. From each subject in the supine position, pressure waveforms were recorded for 30 sec, digitized at 200 samples per second, and stored in a computer. A modified Windkessel model of the circulation was used to match the diastolic pressure decay of the waveforms and to quantify changes in arterial waveform morphology in terms of large artery (capacitive) compliance, representative of the aorta and major branches, small artery (oscillatory) compliance, representative of the distal part of the circulation including small arteries and arterioles, and systemic vascular resistance (mean arterial pressure divided by cardiac output).21–23 Four measurements were taken for each subject: two continuous measurements followed by separation of sensor from the tonometer for 5 min of rest and then an additional two continuous measurements. The mean values of four measurements were used in the analyses. The reproducibility in terms of intraclass correlation coefficients between first two and second two measurements on 815 subjects was 0.74 for large artery compliance, 0.87 for small artery compliance, and 0.95 for systemic vascular resistance. To examine the reproducibility further, 60 randomly selected subjects were reexamined 1 to 3 h later, after the initial examination. The intraclass correlation coefficient between these two examinations was 0.63 for large artery compliance, 0.75 for small artery compliance,

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Table 1. Characteristics of healthy young adult nonsmokers and smokers. The Bogalusa Heart Study Parameters*

Nonsmokers (n ⴝ 145)

Smokers (n ⴝ 142)

Comparison P‡

Age (y) White (%)/ male (%) Height (cm) BMI (kg/m2) Skin folds (mm)† Systolic BP (mm Hg) Diastolic BP (mm Hg) HDL-chlesterol (mg/dL) LDL-cholesterol (mg/dL) Triglycerides (mg/dL) Glucose (mg/dL) Insulin (␮U/mL)

35.4 ⫾ 0.5 51 / 45 169.3 ⫾ 0.8 24.9 ⫾ 0.3 46.8 ⫾ 0.7 116.2 ⫾ 0.8 69.0 ⫾ 0.6 53.6 ⫾ 1.3 120.5 ⫾ 2.4 90.5 ⫾ 3.9 82.3 ⫾ 0.7 1.76 ⫾ 0.1

35.6 ⫾ 0.4 49 / 55 170.8 ⫾ 0.8 23.6 ⫾ 0.3 37.0 ⫾ 0.8 119.2 ⫾ 0.8 70.8 ⫾ 0.7 54.2 ⫾ 1.3 111.9 ⫾ 2.4 103.1 ⫾ 4.0 80.2 ⫾ 0.7 1.56 ⫾ 0.1

NS NS / NS NS ⬍.001 ⬍.0001 .01 NS NS .02 .004 NS NS

BMI ⫽ body mass index; BP ⫽ blood pressure. * Raw mean ⫾ standard error for continuous variable, percentage for categorical variable. † Sum of triceps and subscapular. ‡ Height, BMI, and skin folds were adjusted by race, sex, and age; blood pressure and metabolic parameters were adjusted by race, sex, age, and BMI.

and 0.89 for systemic vascular resistance. The reproducibility of the measured variables was comparable to previous studies.21,24,25 Statistical Analyses All data analyses were performed using SAS version 8.2 (SAS, Cary, NC). Continuous variables were tested for normality using a Kolmogorov-Smirnov test. Variables were compared between smoking and nonsmoking samples using t test, ␹2 test, or analysis of covariance. Predictors of measures of pulsatile arterial function were identified by a stepwise multivariate regression analysis. Furthermore, multiple logistic regression analysis based on maximum-likelihood method was used to calculate adjusted odds ratio (OR) and 95% confidence interval (CI) for smokers versus nonsmokers having adverse levels (bottom or top 10 percentile of the distribution for the entire 815 subjects examined) of measures of pulsatile arterial function.

Results Characteristics of selected groups of healthy, asymptomatic nonsmokers and smokers are presented in Table 1. Race, sex, age, and height were similar between the two

groups. Smokers versus nonsmokers displayed significantly lower BMI and sum of subscapular and triceps skin folds. Despite relatively lower adiposity, smokers had significantly higher systolic blood pressure (BP) and triglycerides than nonsmokers, after adjustment of race, sex, age, and BMI. Also, the covariate-adjusted LDL-cholesterol level was significantly lower in smokers. Measures of pulsatile arterial function by smoking status are listed in Table 2. Race-, sex-, and age-adjusted small artery compliance was lower (P ⫽ .0009) and systemic vascular resistance was higher (P ⫽ .006) among smokers versus nonsmokers; whereas large artery compliance remained similar between the two groups. The significant adverse effect of smoking on small artery compliance and systemic vascular resistance was noted in both men and women (data not shown). The impact of duration (years) of smoking on small artery compliance and systemic vascular resistance is illustrated in Fig. 1. After adjustment for race, sex, and age, individuals who smoked 0, 1 to 19, and 20 or more years displayed significant decreases in small artery compliance (P for trend ⫽ .001) and increases in systemic vascular resistance (P for trend ⫽ .01). No significant relationship was noted between duration of smoking and large artery compliance (data not shown).

Table 2. Measures of pulsatile arterial function in healthy nonsmokers and smokers. The Bogalusa Heart Study Parameters

Nonsmokers

Smokers

Large arterial compliance (mL/mm Hg ⫻ 10) Small arterial compliance (mL/mm Hg ⫻ 100) Systemic vascular resistance (dyn · sec · cm⫺5)

15.8 ⫾ 0.4 6.6 ⫾ 0.2 1325.5 ⫾ 18.6

15.6 ⫾ 0.4 5.9 ⫾ 0.2 1399.0 ⫾ 18.9

* Adjusted by race, sex, and age.

P* NS ⬍.001 .006

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butions of the entire (unselected) study population (n ⫽ 815), after adjustment for the predictor variables other than smoking retained in the multivariate model, as listed in Table 3, for each dependent parameter.

Discussion

FIG. 1. The impact of duration of smoking on measures of pulsatile arterial function in asymptomatic, healthy young adults. The Bogalusa Heart Study.

Results of multivariate analysis, given in Table 3, showed that duration in years of smoking was associated adversely with small artery compliance (P ⫽ .004), independent of age, race, sex, systolic and diastolic BP, HDLcholesterol, triglycerides, glucose, and insulin. Body mass index and LDL-cholesterol were not included in the multivariate model because of their favorite (inverse) association with smoking, which might confound the prediction model, as noted previously.26 When the multivariate analysis was repeated on the entire unselected sample (N ⫽ 815) to improve the statistical power, duration of smoking was independently and adversely associated with small artery compliance (P ⬍ .0001) and systemic vascular resistance (P ⫽ .0009), but not with large artery compliance (data not shown). Furthermore, as shown in Table 4, smokers versus nonsmokers were, respectively, 2.9-fold (P ⫽ .01) and 2.6-fold (P ⫽ .07) more likely to have small artery compliance in the bottom 10th percentile and systemic vascular resistance in the top 10th percentile distri-

The ability to identify alterations in structure and function of the vasculature due to adverse hemodynamic, metabolic, and inflammatory factors is crucial to CV risk assessment at a preclinical stage. Using a noninvasive diastolic pulse contour analysis, the present communitybased study demonstrates that habitual cigarette smoking in healthy young adults is independently associated with decreased small artery compliance and increased systemic vascular resistance. In addition, smokers versus nonsmokers displayed higher systolic BP and triglycerides, and lower body fatness, assessed by BMI and sum of triceps and subscapular skin fold thickness, and LDL-cholesterol. These findings are noteworthy in that the young study subjects were chosen by design to be free of major CV risk factors to minimize the confounding effects of advancing age, obesity, hypertension, dyslipidemia, diabetes, and CV disease on arterial wall properties. The observed decreases in small artery compliance in smokers compared with nonsmokers are in agreement with earlier studies.4,27–29 However, the lack of significant difference in large artery compliance between groups in this study is consistent with some,4,7 but not all studies.5,9,10,30,31 It should be mentioned that our recent study showed smoking as an independent correlate of large artery compliance as measured by brachial-ankle pulse wave velocity.32 The reason for this discrepancy is not readily apparent, and may be due to differences in approaches to different CV methodologies (diastolic pulse contour analysis versus arterial pulse wave velocity) that provide information on the status of different segments of the arterial wall.

Table 3. Predictors of measures of pulsatile arterial function in healthy young adults. The Bogalusa Heart Study Large Arterial Compliance Predictors* Systolic BP Sex Diastolic BP Age Insulin

B†

P

⫺0.34 ⫺3.92 ⫺0.18 ⫺0.10 0.07

⬍.0001 ⬍.0001 ⬍.001 .01 .14

R2 ⫽ 0.37

Small Arterial Compliance Predictors*

B†

P

Sex ⫺2.60 ⬍.0001 Diastolic BP ⫺0.08 ⬍.0001 Years of smoking ⫺0.03 .004 Age ⫺0.07 .05 Systolic BP ⫺0.05 .03 Insulin 0.06 .09 Race ⫺0.54 .07 R2 ⫽ 0.38

Systemic Vascular Resistance Predictors* Diastolic BP Sex Insulin Systolic BP Age

B†

P

15.78 ⬍.0001 135.28 ⬍.0001 ⫺12.25 ⬍.0001 5.21 .009 4.02 .035

R2 ⫽ 0.54

Abbreviation as in Table 1. * Stepwise regression model include race, sex, age, systolic BP, diastolic BP, HDL-cholesterol, triglycerides, glucose, insulin, and years of smoking. Predictor variables met 0.15 significant level for entry model, and they are listed in order of entry. † Regression coefficient; sex: male ⫽ 1, female ⫽ 2; race: white ⫽ 1, black ⫽ 2.

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Table 4. Odds ratios for healthy young adult smokers versus nonsmokers having adverse measures of pulsatile arterial function. The Bogalusa Heart Study Parameters

Adjusted OR‡

95% CI

P

Large arterial compliance (mL/mm Hg ⫻ 10)* Small arterial compliance (mL/mm Hg ⫻ 100)* Systemic vascular resistance (dyn.sec.cm⫺5)†

1.1 2.9 2.6

(0.4, 2.7) (1.3, 7.0) (1.0, 7.7)

NS .01 .07

OR ⫽ odds ratio; CI ⫽ confidence interval. * Bottom 10 percentile. † Top 10 percentile. ‡ Adjusted for predictor variables (other than smoking) retained in Table 3 for each parameter of pulsatile arterial function.

Deleterious effects of smoking on small arteries and arterioles, unlike large arteries, are relatively independent of the confounding effects of atherosclerotic process mediated by other CV risk factors.4,15,27 It is suggested that changes in vascular reactivity, as reflected by impaired basal production of nitric oxide, may contribute to the smoking-related pathologic changes in the small arteries.33,34 Of interest, an earlier study found a decrease in small artery compliance and an increase in systemic vascular resistance with no change in large artery compliance in response to nitric oxide synthase inhibition, strongly implicating nitric oxide-mediated alteration in arterial smooth muscle tone.35 Furthermore, impairment of flowmediated endothelium-dependent arterial dilatation, which is in large part due to the release of nitric oxide, has been found in healthy young smokers.36 Nicotine in cigarette smoke is known to contribute to sympathetic neural stimulation, systemic catecholamine release, impaired nitric oxide production, and endothelial dysfunction.37 However, because cigarette smoke also contains many other vasoactive substances including carbon monoxide and reactive oxygen species, the mechanisms underlying the impaired pulsatile arterial function due to smoking may be several and complex. As in previous reports,5,12,38 – 40 smokers, despite having lower body fatness, displayed relatively higher levels of serum triglycerides and systolic BP in this study. Although these variables could contribute to vascular injuries, changes in measures of arterial pulsatile function remained significant after adjustment for BP. Therefore, smoking may have a direct adverse effect on arterial wall properties. With respect to the value of diastolic pulse contour analysis in the assessment of future CV outcomes, the temporal relationship between arterial pulsatile characteristics of the arterial circulation and the development of CV disease remains unsolved.41 Longitudinal studies are needed to establish the prognostic value of large versus small artery compliance measurements for CV morbidity and mortality. In summary, habitual cigarette smoking is associated with impaired pulsatile function of the vasculature in asymptomatic, healthy young adults. Current findings in conjunction with other studies on this subject underscore

the need for aggressive prevention and intervention strategies to control smoking behavior early in life, regardless of the absence or presence of other CV risk factors. The ability to detect vascular abnormalities by a simpler noninvasive technique may be helpful in motivating smokers to quit smoking.

Acknowledgments The Bogalusa Heart Study is a joint effort of many investigators and staff members, whose contributions are gratefully acknowledged. We especially thank the participants in this study.

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