Smoking and Smoking Cessation in Relation to All-Cause Mortality and Cardiovascular Events in 25,464 Healthy Male Japanese Workers

Circulation Journal Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp ORIGINAL ARTICLE Preventive Medicine Smoking and Smoking Cessation in Relation to All-Cause Mortality and Cardiovascular Events in 25,464 Healthy Male Japanese Workers Takahisa Kondo, MD, PhD; Shigeki Osugi, MD, PhD; Keiko Shimokata MD, PhD; Haruo Honjo, MD, PhD; Yasuhiro Morita, MD; Kengo Maeda, MD, PhD; Kentaro Yamashita, MD; Takashi Muramatsu, MD; Satoshi Shintani, MD, PhD; Kunihiro Matsushita, MD, PhD; Toyoaki Murohara, MD, PhD Background: Smoking is still a major health problem among males in Japan. The effects of smoking and quitting on mortality and cardiovascular disease (CVD) need updating. Methods and Results: This was a prospective cohort study with a median follow-up of 7.5 years of a total of 25,464 healthy male Japanese workers aged 20 61 years who were not on any medication. The adjusted hazard ratios (HR; 95% confidence interval) for all-cause death were 1.51 (0.73, 2.94), 1.68 (1.07, 2.70), 1.30 (0.70, 2.34), and those for total CVD events 1.91 (0.72, 4.67), 2.94 (1.65, 5.63), and 3.25 (1.69, 6.54) for light smokers (1 10 cigarettes/day), moderate smokers (11 20/day), and heavy smokers ( 21/day) compared to never-smokers, respectively. Total CVD events increased dose-dependently as the number of cigarettes/day increased. Acute myocardial infarction was increased at any level of smoking. Stroke was increased at a moderate level of smoking. Quitting for 4 years, compared with continuing smokers, reduced the HR for all-cause death to 0.64 (0.38, 1.01), and total CVD events to 0.34 (0.17, 0.62). Conclusions: In healthy young- and middle-aged Japanese males, a significant increase in HR for total CVD events was confirmed for a smoking level of 11 20 cigarettes/day. Quitting reduced the HR for total CVD events, with quitting for 4 years being statistically significant. A similar trend was observed for all-cause mortality. (Circ J 2011; 75: 2885 2892) Key Words: Cardiovascular event; Longitudinal cohort study; Mortality; Smoking cessation Smoking is still a major public health concern in Japan, as well as other Asian countries, where over 40 60% of men are smokers. 1 6 Smoking increases mortality and the risk of ischemic heart disease by 1.4 to 3-fold. 4,6 10 Conversely, cessation of smoking begins to reduce the risk of total cardiovascular disease (CVD) events within 2 4 years and that of all-cause mortality after 10 20 years. 9,11 19 However, the effects of smoking and smoking cessation on individual health, especially depending on the duration and smoking status, are still not well enough known among Asians, and these effects may differ among the types of CVD event. In fact, a reduction in the incidence of stroke by smoking cessation was not observed in a meta-analysis of Asian populations. 18 Because Asians such as Japanese and Chinese have a higher prevalence of smoking and a lower prevalence of obesity-related conditions compared with Caucasians, 1,5,10,20,21 the effects of smoking and smoking cessation in Asians may be different from those in Caucasians, and should be investigated. Editorial p 2763 Therefore, we conducted a survey of 25,464 Japanese men aged 20 61 years without any diseases who were not taking any medication, to (1) clarify the relationship between cigarette smoking and all-cause mortality and CVD events including acute myocardial infarction (MI) and stroke, and (2) investigate how smoking cessation influences all-cause death and CVD events, depending on the duration, past smoking status, and systemic inflammatory state. Received April 18, 2011; accepted August 29, 2011; released online October 6, 2011 Time for primary review: 34 days Department of Cardiology, Nagoya University Graduate School of Medicine (T.K., S.O., K.S., Y.M., K. Maeda, K.Y., T. Muramatsu, S.S., K. Matsushita, T. Murohara); Research Institute of Environmental Medicine (H.H.), Nagoya University, Nagoya, Japan Mailing address: Takahisa Kondo, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: takahisa@med.nagoya-u.ac.jp ISSN-1346-9843 doi: 10.1253/circj.CJ-11-0416 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

2886 KONDO T et al. 30,636 men 25,464 men 5,165 excluded (1) History of Cancer CVD (2) Medication for Diabetes Mellitus Hypertension Dyslipidemia (3) Frequent change in smoking status before baseline examination Current nonsmokers (N=11,250) Current smokers (N=14,214) Never smoked (N=6,338) Ex-smokers (N=4,912) Light smokers (N=2,240) Moderate smokers (N=9,180) Heavy smokers (N=2,794) Long-term quitters (off smoking 4 years) (N=3,917) Short-term quitters (off smoking 2-4 years) (N=425) Short-term quitters (off smoking <2 years) (N=563) Figure 1. Disposition of subjects. CVD, cardiovascular disease. Methods Study Population We performed a prospective cohort study of 30,636 youngand middle-aged male Japanese workers who underwent physical check-ups annually at seven workplaces between 2000 and 2008. In Japan, the law stipulates that employers must provide employees with mandatory physical check-ups at least once a year as normal policy. To examine the effect of smoking per se by excluding the potential influence of diseases and medications that might ameliorate endothelial function in smokers, 22,23 we only enrolled healthy subjects who had no known diseases (including cancer or any CVD) and who were not taking medications for hypertension, diabetes or dyslipidemia. Seven subjects whose smoking status had frequently changed during the 4 years before the baseline examination were also excluded. As a result, a total of 25,464 men were suitable for analysis. Informed consent was given by every subject and the study was approved by the Ethics Review Committee of Nagoya University School of Medicine (Institutional No. 714). Baseline Examination Trained nurses assessed all participants to determine their smoking status and medical history in face-to-face interviews lasting 15 30 min at the time of the annual physical check-up. The anthropometric and laboratory data (complete blood cell count, serum lipid levels, and plasma glucose level) obtained in 2000 from the subjects after an overnight fast were used for baseline assessment. Analyses were performed by standard methods at a single laboratory. Baseline blood pressure was measured in a seated position 3 times after a 10-min rest, and the average value was calculated. Current smokers in the year 2000 were classified as light (1 10 cigarettes/day), moderate (11 20 cigarettes/day) or heavy smokers ( 21 cigarettes/day). Ex-smokers in the year 2000 were further divided into 3 groups according to the duration of cessation of smoking: (1) <2 years (short-term quitters), (2) 2 4 years (middle-term quitters) or (3) 4 years (long-term quitters) (Figure 1). In some of the analyses, because there were too few events to analyze, short-term and middle-term quitters were combined and analyzed as quitters for <4 years. Follow-up All subjects were followed from January 1, 2001 to July 10, 2008. Their health status and use of medications were checked in face-to-face interviews at annual physical check-ups. All deaths and all CVD events that occurred in the cohort were ascertained by death certificates issued by the municipal office, or from medical certificates issued by the attending physician, except for subjects whose events occurred after they resigned from their workplaces; those persons were treated as censored. Deaths from any cause were included in the analyses. The causes of death were identified by clinical course or autopsy. An unwitnessed death in connection with which an autopsy was not performed was included in allcause death. Total CVD events, which included both fatal and non-fatal events, were defined as events of MI, stroke, aortic dissection, and acute limb ischemia because of arterial occlusion. The situation at the onset and the diagnosis of CVD events was confirmed by hospital records. MI events were

Death and CVD With Smoking and Quitting 2887 Table. Baseline Characteristics of Never-Smokers,, and Light, Moderate, and Heavy Smokers Never-smokers (n=6,338) Ex-smokers (n=4,912) Light smokers (n=2,240) Moderate smokers (n=9,180) Heavy smokers (n=2,794) Person-years of follow-up 45,633 34,649 16,104 66,428 19,667 No. of events All-cause death 26 27 12 64 19 Total CVD 13 16 7 53 26 Myocardial infarction 3 3 5 15 11 Stroke 10 11 2 37 13 Age (years) 36.2 (0.1) 39.7 (0.1) 35.2 (0.2) 36.8 (0.1) 40 (0.2) Body mass index (kg/m 2 ) 22.7 (0.0) 22.8 (0.0) 22.2 (0.1) 22.4 (0.0) 22.9 (0.1) Systolic BP (mmhg) 116 (0.2) 117 (0.2) 115 (0.3) 116 (0.1) 116 (0.2) Diastolic BP (mmhg) 70.3 (0.1) 71.6 (0.1) 68.9 (0.2) 69.4 (0.1) 70.6 (0.2) White blood cells ( 10 3 /μl) 5.67 (0.02) 5.66 (0.02) 5.95 (0.03) 6.62 (0.02) 7.25 (0.03) Total cholesterol (mmol/l) 4.93 (0.01) 5.00 (0.01) 4.81 (0.02) 4.84 (0.01) 5.01 (0.01) Triglyceride (mmol/l) 1.05 (0.74 1.51) 1.08 (0.77 1.58) 1.05 (0.75 1.53) 1.13 (0.80 1.65) 1.27 (0.87 1.83) HDL cholesterol (mmol/l) 1.51 (0.00) 1.51 (0.01) 1.51 (0.01) 1.44 (0.00) 1.4 (0.01) FPG (mmol/l) 5.02 (0.01) 5.1 (0.01) 4.97 (0.02) 5.01 (0.01) 5.09 (0.01) Data are presented as the mean (standard deviation) or median (25 75%). CVD, cardiovascular disease; BP, blood pressure; HDL, high-density lipoprotein; FPG, fasting plasma glucose. Event-Free Survival (%) 100% All-cause death Log rank test P=0.2084 98% 0 1 2 3 4 5 6 7 8 Number at risk Time to event (years) 6,338 6,203 6,047 5,894 5,811 4,912 4,757 4,600 4,403 4,302 Light Smokers 2,240 2,179 2,132 2,087 2,056 Moderate Smokers9,180 9,014 8,811 8,592 8,451 Heavy Smokers 2,794 2,707 2,619 2,488 2,414 Event-Free Survival (%) 100% MI Log rank test P=0.0006 98% 0 1 2 3 4 5 6 7 8 Number at risk Time to event (years) 6,338 6,201 6,046 5,894 5,811 4,912 4,754 4,597 4,403 4,302 Light Smokers 2,240 2,179 2,131 2,087 2,056 Moderate Smokers 9,180 9,008 8,810 8,592 8,451 Heavy Smokers 2,794 2,703 2,616 2,488 2,414 Light Smokers (1-10 cigarettes per day) Event-Free Survival (%) 100% Total CVD events Log rank test P=<0.0001 98% 0 1 2 3 4 5 6 7 8 Number at risk Time to event (years) 6,338 6,201 6,043 5,886 5,804 4,912 4,751 4,589 4,394 4,293 Light Smokers 2,240 2,178 2,130 2,086 2,055 Moderate Smokers 9,180 8,993 8,794 8,575 8,432 Heavy Smokers 2,794 2,702 2,608 2,482 2,405 Event-Free Survival (%) 100% Stroke Log rank test P=0.0051 98% 0 1 2 3 4 5 6 7 8 Number at risk Time to event (years) 6,338 6,201 6,043 5,886 5,804 4,912 4,751 4,590 4,395 4,293 Light Smokers 2,240 2,178 2,130 2,086 2,055 Moderate Smokers9,180 8,994 8,795 8,576 8,433 Heavy Smokers 2,794 2,703 2,608 2,482 2,405 Moderate Smokers (11-20 cigarettes per day) Heavy Smokers ( 21 cigarettes per day) Figure 2. Kaplan-Meier curves for all-cause death, total CVD events, MI, and stroke in Japanese men depending on smoking status. MI, myocardial infarction; CVD, cardiovascular disease.

2888 KONDO T et al. Hazard Ratios All-cause death (N=148) Light Smokers Moderate Smokers Heavy Smokers 8 16 32 (0.58 1.73) HR (95% CI), 1.51 (0.73 2.94) HR (95% CI), 1.68 (1.07 2.70) HR (95% CI), 1.30 (0.70 2.31) Total CVD events (N=115) Light Smokers Moderate Smokers Heavy Smokers 8 16 32 HR (95% CI), 1.06 (0.51 2.24) HR (95% CI), 1.91 (0.72 4.67) HR (95% CI), 2.94 (1.65 5.63) HR (95% CI), 3.25 (1.69 6.54) MI (N=37) Light Smokers Moderate Smokers Heavy Smokers 8 16 32 HR (95% CI), 0.83 (0.15 4.50) HR (95% CI), 6.80 (1.66 33.3) HR (95% CI), 3.93 (1.29 17.0) HR (95% CI), 5.82 (1.80 25.9) Stroke (N=73) Light Smokers Moderate Smokers Heavy Smokers 8 16 32 (0.42 2.41) HR (95% CI), 0.67 (0.10 2.55) HR (95% CI), 2.46 (1.26 5.25) HR (95% CI), 2.21 (0.97 5.19) Figure 3. HR for all-cause death, total CVD events, MI, and stroke adjusted for age, systolic blood pressure, total cholesterol, and fasting plasma glucose level depending on the status of smoking. Closed squares indicate HR and bars indicate 95%CI. MI, myocardial infarction; CVD, cardiovascular disease; HR, hazard ratios; CI, confidence interval. defined as fatal and non-fatal acute coronary syndrome, the onset of which was confirmed by electrocardiogram change, elevation of cardiac enzymes, and a culprit lesion detected by coronary angiography. Stroke was defined as an event in which a neurological deficit persisted for more than 24 h and relevant findings on CT or MRI were confirmed. Being a cohort study in worksites, there was no follow-up after a worker s retirement. Effect of Smoking or Smoking Cessation on All-Cause Death, IHD, Stroke, and Total CVD Events We examined the effect of smoking and smoking cessation on all-cause death and CVD events (total, MI, and stroke), based on the number of cigarettes smoked per day. We further examined the effects of smoking cessation according to the previous cigarette consumption per day. To further investigate whether systemic inflammatory status influences the effects of quitting, we compared the effects of quitting on total CVD events based on white blood cell (WBC) levels. Quitters were stratified according to the median value of WBC count (5,900/μl) and the effects of quitting were assessed. Statistical Analysis Statistical analyses were based on mortality and CVD events during the follow-up period. For each subject, person-years of follow-up were calculated from the date of observation (January 1, 2001) to the occurrence of each endpoint, resignation from the workplace, or July 10, 2008, whichever occurred first. Data are presented as the mean ± standard deviation or as the median (25 75 interquartile range) for continuous variables, and as percentages for categorical variables. Each event-free survival rate was determined by Kaplan-Meier analysis. The association between each variable and the target events was investigated with the Cox proportional hazards models after adjustment for age, systolic blood pressure, total cholesterol, fasting plasma glucose, and alcohol consumption (non-drinkers vs. drinkers). The hazard ratio (HR) and 95% confidence interval (CI) for light, moderate, and heavy smokers were calculated by comparison with never-smokers. The HRs and 95% CIs for individual ex-smoking categories were also calculated relative to those for continuing smokers. Statistical significance was accepted at P<0.05. All analyses were performed with JMP 7.0 J software (SAS Institute Japan, Tokyo, Japan). Results The median observation period was 7.5 years. Figure 1 illustrates the disposition of subjects. During the follow-up, a total of 2,323 cases were dropouts because of retirement due to age (n=1,893) or resignation due to changing jobs (n=430). Table summarizes the baseline characteristics of the subjects. Compared with never-smokers, ex-smokers and heavy smokers were approximately 3 years older. WBCs and triglyceride became higher and high-density lipoprotein (HDL) cholesterol became lower as the number of cigarettes smoked increased. Total cholesterol and fasting plasma glucose were highest among heavy smokers.

Death and CVD With Smoking and Quitting 2889 All-cause death (N=122) Hazard Ratios Short-term quitters (<2 years) Moderate-term quitters (2-4 years) HR (95% CI), 1.12 (0.34 2.65) HR (95% CI), 1.09 (0.27 2.87) HR (95% CI), 0.57 (0.38 1.01) Total CVD events (N=103) Short-term quitters (<2 years) Moderate-term quitters (2-4 years) HR (95% CI), 1.25 (0.38 3.00) HR (95% CI), 0.81 (0.13 2.55) HR (95% CI), 0.34 (0.17 0.62) Stroke (N=62) Smoker Quitters for <4 years* HR (95% CI), 0.60 (0.10 1.94) HR (95% CI), 0.54 (0.25 1.03) (*Due to the few events, the number of events of <2 years and 2-4 years were combined.) Figure 4. HR for all-cause death, total CVD events, and stroke adjusted for age, systolic blood pressure, total cholesterol, and fasting plasma glucose level among smokers and various levels of quitters. Closed squares indicate HR and bars indicate 95%CI. CVD, cardiovascular disease; HR, hazard ratios; CI, confidence interval. a. b. Hazard Ratios All-cause death (N=122) Quitters <4 years (ex moderate or ex heavy smokers) Quitters <4 years (ex light smokers) Total CVD events (N=103) Quitters <4 years (ex moderate or ex heavy smokers) Quitters <4 years (ex light smokers) Total CVD events (N=103) WBC count ( < 5900/mL) Quitters for <4 years WBC count ( 5900/mL) Quitters for <4 years HR (95% CI), 1.03 (0.32 2.45) HR (95% CI), 1.22 (0.30 3.23) HR (95% CI), 0.64 (0.38 1.01) HR (95% CI), 1.36 (0.48 3.01) HR (95% CI), 0.50 (0.03 2.27) HR (95% CI), 0.34 (0.17 0.62) HR (95% CI), 1.60 (0.38 4.59) HR (95% CI), 0.68 (0.27 1.51) HR (95% CI), 0.93 (0.23 2.49) HR (95% CI), 0.19 (0.05 0.51) Figure 5. (a) HR for all-cause death and total CVD events adjusted for age, systolic blood pressure, total cholesterol, and fasting plasma glucose level among smokers and quitters depending on former smoking status. (b) HR for total CVD events adjusted for age, systolic blood pressure, total cholesterol, and fasting plasma glucose level among smokers and quitters depending on WBC count levels. CVD, cardiovascular disease; WBC, white blood cell; HR, hazard ratios; CI, confidence interval.

2890 KONDO T et al. Number of Respective Endpoints There were 148 all-cause deaths observed. As for total CVD events, which included fatal and non-fatal events, 115 cases were observed, among which 37 were IHD events, 73 stroke events (cerebrovascular infarction: 36 cases; subarachnoid hemorrhage: 25 cases; intracranial hemorrhage: 12 cases), and 5 other CVD events. The crude incidence of rates per 1,000 person-years for all-cause deaths and total CVD events were 0.81 and 0.63, respectively. Relationship Between Smoking Status and All-Cause Mortality and CVD Events Figure 2 shows the event-free survival rate of all-cause mortality and CVD events. The event-free rate of total CVD events decreased as the number of cigarettes smoked per day increased. Figure 3 shows the adjusted HRs for respective endpoints. Smoking was associated with a 1.3 to 1.7-fold increase in mortality, with moderate smokers being statistically significant. As for total CVD events, the risk increased in a dose-dependent fashion. The risks of moderate to heavy smokers were approximately 3-fold or more compared with never-smokers, being statistically significant. Compared with stroke, smokers seem more susceptible to MI. Any level of smoking was associated with an elevated risk for MI. All-Cause Mortality and CVD Events After Smoking Cessation Compared with continuing smokers, long-term quitters were associated with reduced mortality (Figure 4), but it did not reach statistical significance (HR: 0.57; 0.38 1.01). As for total CVD events, the longer the duration of quitting, the less events there were, with long-term quitters being statistically significant (HR: 0.34; 0.17 0.62). The number of MI events among quitters was small (n=3). Therefore, we did not calculate HRs for MI. As for stroke, quitters were associated with reduced events, with only long-term quitting having borderline statistical significance. For reference, the HRs of all-cause mortality and total CVD events of never-smokers compared with continuing smokers were 0.65 (0.41 0.99) and 0.35 (0.19 0.61), respectively. Relationship Between Previous Smoking Status Among Quitters and All-Cause Mortality and Total CVD Events Quitters 4 years, not being associated with decreased HRs for all-cause mortality and total CVD events, were further analyzed based on the previous level of smoking: quitters 4 years who had been light smokers had HR for total CVD events of 0.40 (0.02 1.80), whereas those who had been moderate to heavy smokers had HR of 1.09 (0.38 2.42) (Figure 5a). Effects of Quitting on Total CVD Events According to WBC Count Among quitters 4 years and long-term quitters with lower WBC counts, the HR for total CVD events was not reduced. Among quitters 4 years and long-term quitters with higher WBC counts, the HR for total CVD events was 0.91 (0.22 2.45) and 0.19 (0.04 0.51), respectively. Only long-term quitters with higher WBC counts were significantly associated with a low HR for total CVD events (Figure 5b). Discussion The present new finding is that HRs for CVD events were significantly elevated, even from lower levels of cigarette smoking in young- and middle-aged Japanese men, than previously alleged. Another feature is that HRs for death tended to be elevated from a smoking level of 11 cigarettes per day. On the other hand, quitting smoking was associated with lower HRs for death and total CVD events, with a duration of smoking cessation 4 years being statistically significant for total CVD events. HRs of long-term quitters became almost similar to those for never-smokers. Other findings are: (1) quitters who used to smoke 10 cigarettes per day were associated with decreased but not significant total CVD events within 4 years, and (2) decrease in total CVD events by long-term quitting was greater among quitters with higher WBC count than for those with lower WBC count. Smoking is still prevalent in Asian countries, including Japan, and the chief cause of CVD among Japanese and Chinese. 1,4,18,19,21,24 28 Therefore, the relationship between smoking or smoking cessation, and CVD events, including MI and stroke, requires updating in Asian populations. In our study, overall, a clear dose response relationship was observed between the number of cigarettes smoked per day and the risk of total CVD events. Compared with other cohort studies for general populations, high HRs were observed in the present study. One of the reasons for the high HR may be the focus of the present study on only relatively young workers compared with other population studies that included elderly people. It is well known that HRs for all CVD risk factors in younger generations are larger than those in older ones. 29,30 As for the breakdown of CVD events, an increased risk of MI was observed even among light smokers, although the cardiovascular risk burden was less severe in light smokers than in moderate or heavy smokers (Table). It is well known that smoking increases the risk of MI dose-dependently. 4,10,19,31 The lack of dose-dependency between MI and smoking in our study may be related to the occurrence of small MI events, which presumably led to random variation. Nonetheless, the strong influence of smoking on the occurrence of MI observed in the present study may partly be related to the ready occurrence of coronary vasospasm in Japanese. 32 The present study also highlights the influence of smoking on stroke at a lower level of smoking (11 20 cigarettes/day) than previously acknowledged. In the present study, the incidence of subarachnoid hemorrhage was 34.7%, which is greater than in other population studies: Mannami reported 73 cases among 619 total strokes, 33 and Kubo reported 42 cases among 529 total strokes. 24 The effects of smoking on subarachnoid hemorrhage are known to be large compared with other types of stroke. 4,8,30,34 The high HRs for stroke among 11 20 cigarettes/day smokers could be related to our enrolment of younger subjects, because subarachnoid hemorrhage tends to occur at a younger age than other types of stroke. A decrease in mortality after cessation of smoking ( 4 years) was borderline significant. Previous study demonstrated that the risk reduction of lung cancer occurred approximately 5 9 years after quitting, 11 and the reduction of death by CVD events was observed approximately 5 years after quitting. Considering that the subjects of the present study were followed for only 7.5 years as a median value, a change in mortality could be attributed to a reduction in CVD deaths. In line with this finding, a decrease in the total CVD events was evident among subjects who had quit smoking for 4 years. Furthermore, even among quitters <4 years, ex-light smokers tended to be associated with a decreased HR of total CVD events. Again, this finding may indicate the dose-dependent effects of smoking on CVD events. All previous reports did not relate the effects of smoking cessation to WBC count, which reflects the systemic inflam-

Death and CVD With Smoking and Quitting 2891 matory status and is often elevated among smokers. 35 In the present study, quitters with a higher WBC count had greater benefits in terms of CVD events. This finding would indicate that smokers with a high inflammatory state are at risk for the occurrence of CVD events. The strengths of this study were (1) analysis of hard endpoints, and (2) confirmation of the smoking status of each subject by face-to-face interview (15 30 min) at each annual health check. In turn, the limitations should be addressed. First, there was no follow-up after worker retirements, and events that happened after retirements were not taken into consideration. Therefore, the number of events occurring were not enough to sub-analyze the component of CVD events. Second, the effects of quitting smoking on the reduction in all-cause death and CVD events would be overestimated, because the duration of smoking cessation would increase during the follow-up. Last, but not least, subjects who quit smoking tend to lead a healthier lifestyle. In fact, the percentage of subjects who exercise regularly was higher among long-term quitters (30.7%) compared with continuing smokers (17.2%). Conclusions A significant increase in total CVD events was observed with the number of cigarettes smoked per day in healthy young- and middle-aged Japanese males, with smoking 11 cigarettes/day considered as statistically significant. The smoking level that increases CVD events was lower in Japanese than previously alleged in Caucasians. However, quitting smoking was associated with a substantial reduction in the risk of mortality and total CVD events, with quitting for 4 years being statistically significant for total CVD events. The influence of quitting was greater among smokers with a higher WBC count. Acknowledgments We thank all of the healthcare providers who worked with us for the benefit of the subjects. Disclosures Funding: This work was supported by grants from Nagoya University Graduate School of Medicine (Nagoya, Japan). Authors Contribution: Kondo, Maeda, Yamashita, Muramatsu, Shintani, Matsushita, and Murohara contributed to the conception and design of this study and analyzed and interpreted the data. Osugi, Shimokata, Honjo, and Morita contributed to the data acquisition and interpretation. All of the authors contributed to the drafting of the manuscript, and approved this paper. Competing Interests: All authors declare that they have no conflict of interest in connection with this paper. References 1. World Lung Foundation/the American Cancer Society. The Tobacco Atlas, Third Edition. http://www.tobaccoatlas.org/males.html (accessed July 7, 2011). 2. Kinjo K, Sato H, Shiotani I, Kurotobi T, Ohnishi Y, Hishida E, et al. Circadian variation of the onset of acute myocardial infarction in the Osaka area, 1998 1999: Characterization of morning and nighttime peaks. 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