Smoking and atherosclerotic cardiovascular disease in women with lower levels of serum cholesterol

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1 Atherosclerosis 190 (2007) Smoking and atherosclerotic cardiovascular disease in women with lower levels of serum cholesterol Sun Ha Jee a,b,c,, Jungyong Park b, Inho Jo d, Jakyoung Lee a,b, Soojin Yun a, Ji-Eun Yun a, Yangsu Jang e a Department of Epidemiology, Graduate School of Public Health, Yonsei University, Seoul, Republic of Korea b Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Republic of Korea c Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA d Center for Biomedical Sciences, Republic of Korea e Cardiovascular Genome Center, Yonsei University College of Medicine, Seoul, Republic of Korea Received 23 October 2005; received in revised form 8 February 2006; accepted 14 March 2006 Available online 4 May 2006 Abstract This cohort study of Koreans examines the relationship between smoking on atherosclerotic cardiovascular disease (ASCVD) and whether serum levels of total cholesterol modify the impact of smoking on ASCVD. A 10-year prospective cohort study was carried out on 234,399 Korean women, ranging years of age who received health insurance from the National Health Insurance Corporation and had a medical evaluation in The main outcome measures were hospital admissions and deaths from ischemic heart disease (IHD), cerebrovascular disease (CVD), and total ASCVD. At baseline, 13,696 (5.8%) were current smokers and 105,755 (45.1%) had a total cholesterol <200 mg/dl. Between 1994 and 2003, 4534 IHD (176/100,000 person year), 7961 CVD (310/100,000 person year), and 2418 other ASCVD events (94/100,000 person year) occurred. In multivariate Cox proportional hazard models controlling for age, hypertension, hypercholesterolemia, diabetes and alcohol drinking, current smoking increased the risk of IHD [hazard ratio (HR) = 1.7 (95% CI: )], CVD [HR = 1.6 (95% CI: )], and total ASCVD events [HR = 1.6 (95% CI: )]. Throughout the range of serum cholesterol levels, current smoking significantly increased the risk of myocardial infarction and CVD, but not angina pectoris. There was no evidence of an interaction between smoking and serum cholesterol (p for interaction = 0.469, 0.612, and for IHD, CVD, and total ASCVD, respectively). This study demonstrated that smoking was a major independent risk factor for IHD, CVD and ASCVD in Korean women. A low cholesterol level confers no protective benefit against smoking-related ASCVD Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiovascular disease; Smoking; Low serum cholesterol 1. Introduction Morbidity and mortality from cardiovascular disease is rapidly escalating in economically developing countries, including those in South East Asia. In Korea, proportionate morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD) has increased markedly between 1981 and 2003 [1]. Between 1981 and 2003, age-adjusted Corresponding author. Tel.: ; fax: address: jsunha@yumc.yonsei.ac.kr (S.H. Jee). IHD mortality increased from 1.8 deaths/100,000 to 16.6 deaths/100,000 in Korean men and from 1.0 deaths/100,000 to 13.6 deaths/100,000 in Korean women [1]. Cigarette smoking is widely recognized as a major risk factor for IHD in Western countries [2 8]. Nonetheless, few studies have examined the relationship between cigarette smoking and IHD in South East Asian countries [9 12], where the prevalence of women s smoking is rapidly increasing among young generation. In Korea, the prevalence of smoking in adult women aged 40 or older was decreased 13.2% in 1989 to 6.4% in 1999 [13], while increased 2.5% /$ see front matter 2006 Elsevier Ireland Ltd. All rights reserved. doi: /j.atherosclerosis

2 S.H. Jee et al. / Atherosclerosis 190 (2007) in 1989 to 5.0% in 1999 among young women aged In several respects, the populations of South East Asia differ from Western populations. On average, individuals from South East Asia are leaner and have lower cholesterol levels than their Western counterparts [11]. Such differences, particularly the lower levels of cholesterol, have led to speculation that smoking is a less important risk factor for ischemic heart disease in South East Asian populations [14]. Jee et al. reported that a low cholesterol level had no protective benefit against smoking-related ASCVD in men [12]. However, studies on the independent effects of women s smoking as a risk factor for ASCVD in South East Asia were sparse and particularly data that address the impact of cholesterol levels on the relationship between smoking and ASCVD in women have not been studied much. In the view of the escalating morbidity and mortality from ASCVD in Korea and the paucity of data on smoking as an ASCVD risk factor in Korea and other South East Asian countries, we examined prospectively the impact of smoking as an independent risk factor for ASCVD in Korean women. 2. Materials and methods The National Health Insurance Corporation (NHIC), previously the Korea Medical Insurance Corporation, provides health insurance to government employees, teachers, and their dependents. Of the Korean population approximately 43.7 million in ,662,438 (10.7%) were insured by this organization, including 1,297,833 workers and 3,364,605 dependents. This study population was 789,396 dependents over aged 40 years old. Of these eligible women people, 341,183 subjects were actually enrolled with the participation rate of 43.22%. Among 341,183 women, 271,894 women (79.7%) were selected for this study. All workers were required to participate in biennial medical examinations [15]. This examination included a lifestyle and medical questionnaire, along with measurement of blood chemistries in a fasting blood sample. The present cohort includes 271,894 women from 40 to 69 years of age who received health insurance from the NHIC and who had biennial medical evaluations during the period Of the 271,894 female participants, 9090 subjects (3.9%) with incomplete data on smoking, weight and height and 3767 subjects (1.6%) with missing information on fasting serum cholesterol level were excluded. A total of 24,607 (10.5%) people reporting a history of any form of chronic diseases including cancer, cardiovascular disease, respiratory disease, and other illness and 31 who died in the interval between questionnaire completion and start of follow-up on 1 January of the subsequent year were also excluded, leaving a final sample size of 234, Data collection The NHIC biennial examinations, conducted by medical staff at local hospitals, follow a standard procedure. In the 1993 questionnaires, participants were asked to describe their smoking habits, along with some other health habits including alcohol consumption. The 1993 medical examination included measurements of weight, height, and blood pressure. Blood pressure was measured in the seated position by a registered nurse or blood pressure technician using a standard mercury sphygmomanometer or automatic manometer. In the case of manual manometers, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured as the first and fifth Korotkoff sounds, respectively. One measurement was taken. A fasting blood specimen was drawn and analyzed for total cholesterol and blood sugar levels. Each hospital had internal and external quality control procedures directed by the Korean Association of Laboratory Quality Control. In the 1993 examination, people were asked about the status of smoking. Using the data collected in the 1993 examination, the study population were classified as current smokers if they smoked currently for at least 1 year, non-smokers if they never smoked, and ex-smokers if they smoked but quit. Current smokers were further classified by the average number of cigarettes smoked per day (1 9, and 20 cigarettes/day) and duration of smoking (1 19, 20 29, and 30 years). Body mass index (BMI) was calculated as weight/height 2 (kg/m 2 ). Hypertension was defined as a systolic BP 140 or diastolic BP 90 mmhg; stages of hypertension were further classified according to the Sixth Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) criteria [16]. Using National Cholesterol Education Program (NCEP) guidelines [17], serum total cholesterol was classified as desirable (blood cholesterol <200 mg/dl), borderline-high (blood cholesterol mg/dl) and high (blood cholesterol 240 mg/dl). Using National Diabetes Data Group s diagnostic criteria [18], diabetes was defined by a fasting blood sugar 126 mg/dl. Categories of average alcohol consumption were 0, 1 20, and 20 g/day, as used in previous studies [10]. The principal outcome variables were morbidity and mortality from: (1) ischemic heart disease (IHD) alone (ICD 9 codes ), along with acute myocardial infarction (AMI) alone (ICD 9 codes 410) and angina pectoris (AP) alone (ICD 9 codes 413), (2) cerebrovascular disease (CVD) alone (ICD codes ), and (3) total ASCVD. The latter category included hypertensive disease (ICD 9 codes ), ischemic heart disease ( ), hemorrhagic stroke ( ), thrombotic stroke ( ), other stroke ( ), other heart disease likely related to ASCVD ( ), sudden death (798) and other vascular disease ( ). For those individuals with more than one event, we used just the first event in our analyses. Outcomes were ascertained from diagnoses on hospital discharge summaries and from causes of death on death certificates. In Korea, professionally trained and certified medical chart recorders abstracted charts and assigned discharge diagnoses in a standardized fashion using WHO codes

3 308 S.H. Jee et al. / Atherosclerosis 190 (2007) for common diseases such as stroke and myocardial infarction. Likewise, these recorders completed death certificates using information provided by doctors. In terms of mortality, follow-up was 100% completed, because we could perform computerized searches of death certificate data from the National Statistical Office in Korea on each of the NHIC enrollees. For morbidity, which was defined exclusive by hospital discharge diagnoses, follow-up was likely to be quite high, if not close to 100%, because hospitals cannot receive payments until the bill with the discharge diagnoses was submitted to NHIC. The follow-up period was up to 10 years, through 31 December The exact dates of completion of the survey form were not recorded. Consequently, follow-up accrual began on 1 January of the calendar year (1994) following the year (1993) in which the survey form was completed. Persons who completed a survey but died within the calendar year of the survey were excluded Statistical analysis In bivariate analyses, we examined the relationship between smoking status and traditional ASCVD risk factors, adjusting for age using the age distribution of the 1995 Korean Census population. In these bivariate analyses, we tested for trends across categories of amount of current smoking, using non-smokers as the reference. For ASCVD risk factors with a continuous distribution, we used simple linear regression and entered an ordinal variable for the categories of current smoking ( 0 for non-smokers, 1 for 1 9 cigarettes/day, 2 for cigarettes/day, and 3 for 20+ cigarettes/day). For dichotomous variables, we used the method of Mantel Haenszel [19]. In these models, ex-smokers were excluded. Cox proportional hazards models were used to assess the independent effects of smoking (both current cigarette smoking and ex-smoking) on IHD, CVD, and ASCVD events, controlling for age and traditional risk factors (hypertension, hypercholesterolemia, diabetes and alcohol drinking). For the CVD analyses, we assessed the impact of smoking with and without adjustment for alcohol consumption. After excluding ex-smokers, tests of interaction were performed in Cox proportional hazard models adding terms for current smoking (yes/no), cholesterol status (<200 mg/dl versus 200 mg/dl) and a corresponding interaction term. To calculate the population attributable risk (PAR) from cigarette smoking and other ASCVD risk factors, we used Levins formula [20]; separate PAR analyses were performed in those with a total cholesterol <200 mg/dl. In all analyses, a two-sided α level of 0.05 was considered statistically significant. 3. Results The mean (S.D.) age of study participants was 51.8 (8.1) years. Among the 234,399 women, 13,696 (5.8%) were current smokers and 5753 (2.5%) were ex-smokers; 51,337 (21.9%) had stage I, 18,237 (7.8%) stage II, and 8690 (3.7%) stage III hypertension. With respect to total cholesterol, 128,644 (54.9%) had a total cholesterol <200 mg/dl, 72,493 (30.9%) had a borderline level of mg/dl and 33,262 (14.2%) had a level 240 mg/dl. Among current smokers, 44.4% smoked for over 20 years; 54.0%, 33.5% and 12.5% of current smokers smoked 1 9, 10 19, and 20 cigarettes/day, respectively. Characteristics of non-smokers, ex-smokers and current smokers are presented in Table 1. After adjustment for age, current smokers compared to non-smokers had significantly higher fasting blood sugar (p-trend = 0.044), consumed more alcohol (p-trend = 0.046) and had a higher prevalence of hypertension, hypercholesterolemia, diabetes, and alcohol use (each p-trend < 0.001). Table 1 Baseline characteristics of 234,399 women in 1993, according to smoking status a Non-smokers (n = 214,950) Ex-smokers (n = 5753) Current smokers (cigarettes/day) 1 9 (n = 7394) (n = 4595) 20 (n = 1707) p-trend b Age (year) 51.2 ± ± ± ± ± Systolic blood pressure (mmhg) ± ± ± ± ± Diastolic blood pressure (mmhg) 79.5 ± ± ± ± ± Total cholesterol (mg/dl) ± ± ± ± ± Body mass index (kg/m 2 ) 23.8 ± ± ± ± ± Fasting blood sugar (mg/dl) 90.6 ± ± ± ± ± Alcohol consumption (drinks/day) 0.1 ± ± ± ± ± Conditions (%) Hypertension c <0.001 Hypercholesterolemia d <0.001 Diabetes e <0.001 Alcohol use f <0.001 a Except for age, all values were age-adjusted. b Testing for trend across non-smokers and current smokers; ex-smokers excluded. c Systolic blood pressure 140 mmhg and/or diastolic blood pressure 90 mmhg. d Total cholesterol 240 mg/dl. e Fasting blood sugar 126 mg/dl. f Consumption of any alcohol.

4 S.H. Jee et al. / Atherosclerosis 190 (2007) Table 2 Age-adjusted incidence of atherosclerotic cardiovascular disease in Korean women Non-smokers Ex-smokers Current smokers (cigarettes/day) Event Person year (PY) Age-adjusted rate a a Per 100,000 PY. During 10 years of follow-up (2,546,880 person year), 14,913 women (6.4%) were either hospitalized or died from ASCVD. Of these, 4534 IHD (176/100,000 person year), 7961 CVD (310/100,000 person year) and 2418 other ASCVD events occurred, including 475 deaths (19/100,000 person year) from IHD, 1928 deaths (76/100,000 person year) from CVD and 302 deaths from other ASCVD. These 2705 deaths from ASCVD were 24.5% of all deaths that occurred during follow-up. Compared with non-smokers, age-adjusted incidence rates for ASCVD for ex- or current smokers was increased (Table 2). The independent effects of smoking on IHD, CVD and total ASCVD were examined in Cox proportional hazards models that simultaneously controlled for age, hypertension, hypercholesterolemia, diabetes and alcohol drinking (Table 3). Compared to non-smokers, the hazard ratio (HR) (95% confidence interval) for IHD was 1.7 ( ) in smokers (p < 0.001) and 1.2 ( ) in ex-smokers (p < 0.001). For CVD, the corresponding HRs were 1.6 ( ) in smokers (p < 0.001) and 1.1 ( ) in ex-smokers (p = 0.082). Compared to non-smokers, the HRs for any ASCVD event was 1.6 ( ) (p < 0.001) in smokers and 1.2 ( ) (p < 0.001) in ex-smokers. In these models, hypertension status was associated with cardiovascular events in a progressive, dose response fashion. Borderline and high total cholesterol were associated with IHD and total ASCVD; high cholesterol but not borderline cholesterol was associated with CVD alone. In separate Cox proportional models, current smoking was significantly associated with the occurrence of hemorrhagic stroke (HR = 1.9, p < 0.001) and thrombotic stroke (HR = 1.6, p < 0.001). After additional adjustment for alcohol intake, the corresponding HR were 1.8 (p = 0.001) and 1.6 (p < 0.001). To assess the relationship between smoking and ASCVD by level of total cholesterol, we divided the cohort into quartiles of total cholesterol (<166, , , 217 mg/dl). In these quartiles, the number of IHD events was 669, 824, 1147, 1894, respectively, while the number of CVD events was 1312, 1722, 2117, and 2810, respectively. In each quartile of serum cholesterol, current smoking was Table 3 Risk of morbidity and mortality from ischemic heart disease, cerebrovascular disease, and total atherosclerotic cardiovascular disease in Korean women, Cox proportional hazards model Variable Category Ischemic heart disease Cerebrovascular disease Total atherosclerotic cardiovascular disease HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value Age (5 years) < < <0.001 Cigarette smoking Ex-smoker = =0.001 Amount 1 9 cigarettes/day < < < cigarettes/day < < < cigarettes/day < < <0.001 Blood pressure a High normal blood pressure < < <0.001 Stage 1 hypertension < < <0.001 Stage 2 hypertension < < <0.001 Stage 3 hypertension < < <0.001 Total cholesterol b Borderline high cholesterol < = <0.001 High cholesterol < = <0.001 Fasting blood sugar c Diabetes < < <0.001 Alcohol drinking Drinker < HRs were estimated adjusted for age, cigarette smoking, blood pressure, fasting blood sugar, and alcohol drinking. a The reference category is normal (SBP < 130 and DBP < 85 mmhg); other categories were high normal (130 SBP < 140 or 85 DBP < 90 mmhg), stage 1 hypertension (140 SBP < 160 or 90 DBP < 100 mmhg), stage 2 hypertension (160 SBP < 180 or 100 DBP < 110 mmhg), and stage 3 hypertension (SBP 180 or DBP 110 mmhg). b The reference category is desirable (blood cholesterol <200 mg/dl); other categories were borderline-high (blood cholesterol mg/dl) and high (blood cholesterol 240 mg/dl). c The reference category is a fasting blood sugar <126 mg/dl; diabetes is defined as a fasting blood sugar 126 mg/dl.

5 310 S.H. Jee et al. / Atherosclerosis 190 (2007) Fig. 1. Hazard ratio with 95% confidence interval of morbidity and mortality from ischemic heart disease (IHD) and cerebrovascular disease (CVD) in quartiles of total cholesterol of smokers compared with non-smokers. HRs were estimated adjusted for age, cigarette smoking, blood pressure, fasting blood sugar, and alcohol drinking. Fig. 2. Hazard ratio with 95% confidence interval of morbidity and mortality from myocardial infarction (MI) and angina pectoris (AP) in quartiles of total cholesterol of smokers compared with non-smokers. HRs were estimated adjusted for age, cigarette smoking, blood pressure, fasting blood sugar, and alcohol drinking. significantly associated with CVD but not IHD (Fig. 1) in lowest quartile. In further analysis of IHD, we found that current smoking was significantly associated with AMI but not AP (Fig. 2) in lowest quartile. For current smoking and other traditional risk factors, we estimated the population attributable risks for IHD alone, and CVD alone using risk factor prevalence estimates from this study. For IHD, current smoking accounted for approximately 3.9% of events and hypertension for 16.2% of events. For CVD, corresponding estimates were 3.3% from smoking and 24.7% from hypertension. 4. Discussion In this large prospective, observational study of Korean women, we documented that current cigarette smoking was a strong, independent risk factor for IHD, CVD, and total ASCVD events. These risk relationships were present throughout the range of total serum cholesterol, including the lowest quartile (<166 mg/dl) for AMI and CVD events, but not AP. To date, few studies have examined the independent effects of cigarette smoking on IHD in South East Asian countries. In one observational study conducted in China, cigarette smoking was significantly associated with IHD mortality [10]. However, the IHD analyses were only adjusted for age and alcohol intake, not for traditional ASCVD risk factors. In an initial and subsequent report from Nippon, Honolulu, and San Francisco (NI HON SAN) study, cigarette smoking was a significant, independent risk factor for coronary heart disease in Japanese men living in Hawaii but not in those living in Japan, where serum cholesterol levels were relatively low [11,21]. In the Hisayama, Japan, cohort study, smoking was significantly associated with coronary heart disease in persons with a total cholesterol level of 180 mg/dl or higher but not in persons with a cholesterol level of less than 180 mg/dl [9]. In autopsy series from same study, smoking was not a risk factor for coronary atherosclerosis [22]. In the Puerto Rico Heart Health Program, where the mean total cholesterol level was 202 mg/dl, smoking did not predict the occurrence of IHD [23]. However, in one recent observational study conducted in Korea, a low cholesterol level had no protective benefit against smoking-related ASCVD in men (12). To our knowledge, no study had been done among women. In the context of these equivocal results, our previous (12) and present study provides unambiguous evidence that current cigarette smoking is a risk factor for IHD and CVD, even among persons with low serum cholesterol levels. Only exception was that smoking was not associated with the risk of AP in lowest quartile of total cholesterol in our study. These results, along with the unchanged findings with exclusion of the first 5 years of follow-up, weigh against the possibility that the presence of AP increases smoking cessation; i.e., reverse causality. The present study also demonstrated that cigarette smoking was a significant risk factor for CVD events and stroke subtypes, both thrombotic and hemorrhagic. In this respect, our data are consistent with observational data from the United States [6,24], and Japan (2004) [25], but not with recent data from China [10]. In the latter study, cigarette smoking did not predict the occurrence of stroke mortality in analyses adjusting for age and alcohol use. This inconsistency may have resulted from differences in study power, i.e. 197 events in the Yuan study versus 10,606 events in the NHIC study. In our analyses, ex-smokers had a lower risk of IHD than current smokers. In contrast, the risk of CVD disease in ex-smokers was not significantly different from that of nonsmokers. This pattern of findings suggests that the high risk of CVD disease subsides after cessation of smoking, while the risk of IHD persists for a longer, albeit unknown, period of time. Unfortunately, the present data does not have information on quit dates in ex-smokers. Among the strengths of the NHIC study are high follow-up rates, its large, national sample. The sufficient sample size of

6 S.H. Jee et al. / Atherosclerosis 190 (2007) our cohort allowed us to evaluate the effect of smoking with various level of serum cholesterol level. There, however, may be some concern on selection bias since the final sample of 234,399 women (68.7%) out of 341,183 subjects was selected for our study, we interpreted carefully our study results for the general population. Other potential limitations of our study include the relatively brief duration of follow-up, inclusion of individuals with prevalent ASCVD in the cohort, and reliance on diagnoses from discharge summaries and death certificates. The inclusion of persons with antecedent ASCVD events could potentially lead to biased estimates. The bias, however, is likely to be conservative, because such individuals tend to adopt desirable habits after clinical ASCVD events; hence, the category of non-smokers may be differentially enriched with persons who stopped smoking after a heart attack or stroke. The impact of prevalent ASCVD is also diminished because individuals who experienced ASCVD events between 1/93 and 12/93, the years of baseline data collection, were excluded. Reliance on diagnoses from hospitalizations and death certificates may introduce random and systematic errors. Random error would tend to diminish the study s power to detect associations. Systematic error could alter the distribution of events and perhaps risk factor disease relationships if the errors were related to exposure status. However, the consistency of our findings, i.e. significant relationships of current smoking with the broad category of ASCVD events as well as the component categories of IHD and CVD events, suggest that major systematic errors related to the coding of ASCVD events was unlikely. The information on medical treatment for dyslipidemia was not available for this study population. However, in 1993 at baseline of this study, medical treatment for dyslipidemia in Korea was not common. The average level of total serum cholesterol among the participants from the health examination in 1993 was (S.D., 39.7) [26]. In summary, smoking is a major, independent risk factor for ASCVD in Korean women, a South East Asian country with a increasing prevalence of women s smoking and an escalating burden of ASCVD. Furthermore, a low total cholesterol level confers no protective benefit against smoking-related ASCVD. Acknowledgments The authors thank the staff of the Korean National Insurance Corporation. This study was partially supported by a grant of Ministry of Health and Welfare, Republic of Korea (00-PJ6-PG ) and Seoul City R&BD project. References [1] National Statistical Office. Annual report on the cause of death statistics. Republic of Korea; [2] Kannel WB, McGee DL, Castelli WP. Latest perspective on cigarette smoking and cardiovascular disease: the Framingham study. J Cardiac Rehab 1984;4: [3] The Pooling Project Research Group. 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