The Trend and Age-Period-Cohort Analysis on the Burden of Cardiovascular Disease attributable to Tobacco Exposure in China, Japan, USA and World

Background Tobacco exposure is the major contributor of CVD mortality, but none of the published studies on CVD mortality attributable to tobacco exposure analyzed the possible reasons underlying the long-term trends and the differences between age-groups in China. Methods The mortality data in China, Japan, USA and World were obtained from GBD 2017. The joinpoint regression analysis was used to assess the magnitude and direction of trends over time for CVD morality, and the age-period-cohort method was used to analyze the temporal trends of CVD mortality by age, period, and cohort. The smoking prevalence was acquired from WHO. Results There was a significant downward trend in ASMR of CVD attributable to smoking in four regions, but China has the smallest decline and the ASMR of CVD attributable to smoking in China rose to the first place in 2017 (41.41 per 100,000). All the net drifts per year in four regions were negative, and the local drift values were below zero in all age groups. The longitudinal age curves of the CVD mortality attributable to smoking increased in four regions and China had the largest increase. The period/cohort RRs indicated a decline, and China has the smallest decline. All the cohort/period RRs and net drifts per year in female had more quickly declining trends than that in male. All the results of secondhand smoke were similar to that of smoking. For Stroke and IHD, their results were similar to those of CVD. Conclusions Although CVD mortality attributable to tobacco exposure had declined in four regions, CVD mortality attributable to tobacco exposure in China was at a high level, and the high CVD mortality attributable to secondhand smoke caused by high smoking prevalence. China should strengthen tobacco control measures to reduce the burden of CVD.


Introduction
Accompanying economic development and urbanization, the patterns of disease has shifted from infectious diseases to noncommunicable diseases. As one of noncommunicable diseases, cardiovascular disease (CVD) is the leading cause of premature morbidity and mortality in the world.
In 2017, the estimated 17.8 million people died of CVD, which was the cause of 30% of deaths all over the world [1]. In China, CVD mortality had increased from 187.58 per 100,000 in 1990 to 309.95 per 100,000 in 2017, and the burden of CVD was also very high, the estimated number of CVD death had almost doubled, from 2.25 million in 1990 to 4.38 million in 2017 [2]. In the world, China has the highest burden of CVD, China is facing enormous challenges in tackling the burden of CVD [3].
Tobacco exposure mainly included active smoking and secondhand smoke (SHS). In the world, nearly 7 million people died from tobacco exposure, including approximately 6 million among tobacco users and an estimated 890,000 among nonsmokers exposed to SHS [4]. Long-term smokers lost at least 10 years of life on average. In the world, over 22000 people die from tobacco exposure every day (one person dies every 4 seconds). Smoking is a widely recognized risk factor for premature morbidity and mortality, but adequate monitoring of smoking levels and trends throughout the world has been challenging. Nearly two-thirds of smokers in the world were mainly in ten countries, and China accounted for about 30%. In 2017, active smoking had become the first leading risk factor for DALYs and the second risk factor for death in China [5].
Tobacco exposure is a major modifiable risk factor for CVD. Several epidemiological studies concluded that smoking is a major cause of CVD and causes one of every four deaths from CVD [6]. SHS also can cause CVD, including heart attack and stroke. Nonsmokers who breathe SHS at home or at work increase their risk of developing heart disease by 25-30%. SHS increases the risk for stroke by 20−30% [7]. The World Health Organization (WHO) considered that Tobacco exposure was the totally avoidable risk factor of CVD [8]. The probability of tobacco exposure varied by different age and gender, and the different regions had different tobacco control strategies, so the disease burden attributable to tobacco exposure varied among age, sex and regions [9]. Currently, none of the published studies on CVD mortality attributable to tobacco exposure had analyzed the possible reasons underlying the long-term trends and the differences between age-groups. Therefore, we used CVD mortality attributable to tobacco exposure in China, Japan, United States (USA) and the world during the period between 1990 and 2017, and analyzed the changes in long-term trends and the independent effects of chronological age, time period, and birth cohort, and provided evidences for tobacco control strategies.

Data Source
Data are available at the GBD Data Tool repository and can be accessed at http://ghdx.healthdata.org/gbd-results-tool. To analyze the status on CVD mortality attributable to tobacco exposure in China, we extract the relevant data on CVD mortality, and compared to Japan, USA and the world. In 2017, ischemic heart disease (IHD) and stroke were top two in mortality rate of all the causes of death in China [2], so we not only analyzed the changes of CVD attributable to tobacco exposure by the temporal trend and Age-Period-Cohort methods, but also analyzed the changes of IHD and stroke, in order to reflect the impact of tobacco exposure on CVD systematically and comprehensively. CVD, IHD and stroke were diagnosed and defined based on the WHO clinical criteria and ICD 9. The smoking prevalence in four regions was collected from WHO[10]. The dataset provided the summarized smoking prevalence for each country in four year points (2000,2005,2010 and 2015). Please see the detailed data in Additional file 1- Table S1.

Statistical Analysis
In order to assess the magnitude and direction of trends over time for morality rate, we used JoinPoint software (Version 4.7.0.0) to calculate the average annual percentage change (AAPC) and the corresponding 95% CIs by joinpoint regression analysis. We used three joinpoints to detect four different trends uniformly, to investigate the trend of mortality rate of CVD attributable to tobacco exposure in different periods.
In order to assess death risks experienced by the population in a particular year and the accumulation of health risks since birth, we used the age-period-cohort (APC) model to analyze the temporal trends by age, period, and cohort and after adjustment for age, period, and cohort on smoke-attributable CVD mortality. The APC model could provide a useful parametric framework that complements standard nonparametric descriptive methods. In our APC model, we needed to convert the collected data to successive 5-year age groups and consecutive 5-year periods. Because the GBD dataset did not provide successive 5-year age groups under 29 or over 80 years in smoking, the mortality rates of CVD attributable to smoking were recoded into successive 5-year age groups (30-34 years to 75-79 years) and consecutive 5-year periods (1990 to 2017). Because the GBD dataset did not provide successive 5-year age groups under 25 or over 80 years in SHS, the mortality rates of CVD attributable to SHS were recoded into successive 5-year age groups (25-29 years to 75-79 years) and consecutive 5-year periods (1990 to 2017). The general linear model was used to analyze the slope of the period/cohort RRs. The statistical analysis was performed by R statistical software (R version 3.5.1), and p<0.05 was considered significant.
For male, the rank in 1990 and 2017 were similar to both sexes. There was a significant downward trend in USA, world and Japan, but there was no significant downward trend in China. For female, in 1990, the rank was USA, world, Japan and China. In 2017, the rank was USA, China, world and Japan.
There was a significant downward trend in USA, China, world and Japan. Figure 1 and Table 1 showed the temporal trend in ASMR of CVD attributable to smoking in China, Japan, USA and the world from 1990 to 2017. Secondhand smoke: For both sexes, from 1990 to 2017, there was no change in the rank for the ASMR of CVD attributable to SHS with China on top followed by world, USA and Japan. The ASMR of CVD attributable to SHS in China, Japan, the USA and the world significantly decreased by 1.2% (95%CI: 0.7%-1.7%), 3.8% (95%CI: 3.5%-4.1%), 3.9% (95%CI: 3.6%-4.2%) and 1.8% (95%CI: 1.5%-2.0%) per year, respectively. For male, the rank in 1990 was world, China, USA and Japan. In 2017, the rank in the ASMR of CVD attributable to SHS was China, world, USA and Japan. There was a significant downward trend in USA, world and Japan, but there was no significant downward trend in China. For female, the rank from 1990 to 2017 was similar to both sexes. There was a significant downward trend in USA, China, world and Japan. Figure 2 and Table 2 showed the temporal trend in ASMR of CVD attributable to SHS in China, Japan, USA and the world from 1990 to 2017.  (2) The APC analysis in the mortality rate of CVD attributable to Tobacco Exposure from 1990 to 2017 Smoking: For both sexes, in the same birth cohort, the mortality rate of CVD attributable to smoking rapidly increased 7.38 (95%CI: 6.34, 8.58) per 100,000 in age group 30-34 to 360.15 (95%CI: 338.97, 382.67) per 100,000 in age group 75-79 in China. The similar changes can be observed in world, USA and Japan. Figure 3(A) showed the longitudinal age curves of the mortality rate of CVD attributable to smoking. All the cohort and period RRs showed a decreasing trend in four regions. For male and female, the changes in mortality rate were similar to both sexes. All the cohort and period RRs were statistically significant (P<0.001 for all) and so were the net drifts. Figure 3(B, C) showed the estimated cohort and period RRs of the mortality rate of CVD attributable to smoking. Figure 4(A) and Table 3 showed the detailed results of net drifts.
Secondhand smoke: All the results were similar to that of smoking. Figure 5(A) showed the longitudinal age curves of the mortality rate of CVD attributable to SHS. Figure 5(B, C) showed the estimated cohort and period RRs of the mortality rate of CVD attributable to SHS. Figure 4(B) and Table 3 showed the detailed results of net drifts.   (3) The temporal trend in the age-standardized mortality rate (ASMR) of stroke attributable to Tobacco Exposure from 1990 to 2017 Smoking: The rank in stroke was slightly different from CVD from 1990 to 2017. For both sexes, the rank in the ASMR of stroke attributable to smoking was China, world, Japan and USA all the time.
There was a significant downward trend in four regions. The temporal trends in male and female were similar to both sexes. Additional file 2- Figure S1 and Additional file 1- Table S2 showed the temporal trend in ASMR of stroke attributable to smoking in China, Japan, USA and the world from 1990 to 2017.
Secondhand smoke: All the results were similar to that of smoking. Additional file 2- Figure S2 and Additional file 1- Table S3 showed the temporal trend in ASMR of stroke attributable to SHS in China, Japan, USA and the world from 1990 to 2017.
(4) The APC analysis in the mortality rate of stroke attributable to Tobacco Exposure from 1990 to 2017 Smoking: For both sexes, in the same birth cohort, the mortality rate of stroke attributable to smoking rapidly increased in China. The similar changes can be observed in other three regions. Additional file 2- Figure S3(A) showed the longitudinal age curves of the mortality rate of stroke attributable to smoking. All the cohort and period RRs showed a decreasing trend in four regions. For male and female, the changes in mortality rate were similar to both sexes. All the cohort and period RRs were statistically significant (P<0.001 for all) and so were the net drifts. Additional file 2- Figure S3(B, C) showed the estimated cohort and period RRs of the mortality rate of stroke attributable to smoking.
Additional file 2- Figure S4(A) and Additional file 1- Table S4 showed the detailed results of net drifts.
Secondhand smoke: All the results were similar to that of smoking. Additional file 2- Figure S5(A) showed the longitudinal age curves of the mortality rate of stroke attributable to SHS. Additional file 2- Figure S5(B, C) showed the estimated cohort and period RRs of the mortality rate of stroke attributable to SHS. Additional file 2- Figure S4(B) and Additional file 1- Table S4 showed the detailed results of net drifts.
(5) The temporal trend in the age-standardized mortality rate (ASMR) of IHD attributable to Tobacco Exposure from 1990 to 2017 Smoking: The rank in IHD was similar to CVD from 1990 to 2017. For both sexes, in1990, the rank in the ASMR of IHD attributable to smoking was USA, world, Japan and China. In 2017, the rank was China, world, USA and Japan. There was a significant downward trend in world, USA and Japan, but there was a significant upward trend in China, especially in 1999-2015. For male, the temporal trend was similar to both sexes. Although the mortality rate in China is rising, it is not significant. For female, there was a significant downward trend in world, USA and Japan. Additional file 2- Figure S6 and Additional file 1- Table S5 showed the temporal trend in ASMR of IHD attributable to smoking in China, Japan, USA and the world from 1990 to 2017.
Secondhand smoke: For both sexes, in 1990, the rank in the ASMR of IHD attributable to second smoke was world, China, USA and Japan. In 2017, the rank was China, world, USA and Japan. There was a significant downward trend in world, USA and Japan, but there was no significant trend change in China. The temporal trends in male and female were similar to both sexes. Additional file 2- Figure   S7 and Additional file 1- Table S6 showed the temporal trend in ASMR of IHD attributable to SHS in China, Japan, USA and the world from 1990 to 2017.  Figure S8(A) showed the longitudinal age curves of the mortality rate of stroke attributable to smoking. All the cohort and period RRs showed a decreasing trend in four regions. For male and female, the changes in mortality rate were similar to both sexes. The cohort and period RRs were statistically significant in world, USA and Japan (P<0.001 for all) and so were the net drifts. Additional file 2- Figure S8(B, C) showed the estimated cohort and period RRs of the mortality rate of CVD attributable to smoking. Additional file 2- Figure S9(A) and Additional file 1- Table   S7 showed the detailed results of net drifts.
Secondhand smoke: All the results were similar to that of smoking. Additional file 2- Figure S10(A) showed the longitudinal age curves of the mortality rate of IHD attributable to SHS. Additional file 2- Figure S10(B, C) showed the estimated cohort and period RRs of the mortality rate of CVD attributable to SHS. Additional file 2- Figure S9(B) and Additional file 1- Table S7 showed the detailed results of net drifts.

Discussion
Our results show that for CVD, there was a significant downward trend in ASMR of CVD attributable to smoking from 1990 to 2017 in four regions, but China has the smallest decline. Therefore, the rank in the ASMR of CVD attributable to smoking had changed, China rose to the first place in 2017. The ASMR of CVD attributable to smoking in Japan was at the lowest level in four regions. We found that the longitudinal age curves of the mortality rate of CVD attributable to smoking increased in four regions, and China had the largest increasing extent. Regardless of age and birth cohort effects, the period RRs indicated a decline in the mortality rate of CVD attributable to smoking in recent years.
Similarly, regardless of the age and period effects, the cohort RRs also indicated a decline in CVD mortality among younger generations. All the net drifts were significant. China has the smallest decline in the cohort and period RRs, and all the cohort and period RRs in female has more quickly declining trends than that in male. All the results of SHS were similar to that of smoking.
Because stroke and IHD were important components of CVD, we further analyzed the trend of their ASMR attributable to tobacco exposure and the impact of age, cohort and period on mortality rate.
For stroke, the rank in the ASMR of stroke attributable to smoking had no change, China remained the first place from 1990 to 2017. The downward trend in ASMR, the change of the cohort and period RRs and the net drifts of stroke were similar to those of CVD. For IHD, we found that the downward trends in ASMR, the change of the cohort and period RRs and the net drifts of IHD were similar to those of CVD in the world, USA and Japan. In China, the significant upward trend in both sexes and male were observed, but all the cohort and period RRs in female has more quickly declining trends.
Tobacco exposure can damage blood vessels very quickly, but the blood vessels can repair themselves naturally when smokers stop smoking, heart attack risk drops dramatically in one year, and risk of stroke can reduce to the level of nonsmoker [11]. Tobacco exposure caused CVD by atherosclerosis and thrombosis. The mechanism of smoking-induced atherosclerosis and thrombosis was that oxidative stress mediated by cigarette smoke and/or endogenous oxygen free radicals, Eventually, tobacco exposure can lead to plaque and blood clots, restrict blood flow, and lead to heart attack and stroke. Stroke, like heart disease, has a high risk of death, and survivors of stroke may experience disastrous disabling conditions, such as paralysis or loss of vision or speech [16].
One in three deaths is attributed to CVD in the world, and tobacco exposure is the major contributor, From the report, we found that compared with other three regions, the smoking prevalence in China had been at highest level, and the decline of smoking prevalence in China was the smallest, the exposure of second-hand smoke would also be at a high level, so the ASMR of stroke, IHD and CVD caused by tobacco exposure would also be higher, and the decline of ASMR would be smaller. These were concluded by our results, and tobacco exposure had caused a great burden on CVD mortality in China. Smoking increased the risk of CVD, and so did SHS, but the hazards of SHS were often ignored.
In our study, from 1990 to 2017, the ratio of second-hand smoke to smoking in the ASMR of CVD ranged from 1/3 to 1/4 in China. Compared with other three regions, the ratio of China was highest, SHS exposure caused a serious burden of CVD in China. A study on SHS found that an almost 40% increase in mortality risk among non-smoking women whose husbands smoked, and the incidence of heart disease increased [18]. A national population-based case-control study found that SHS could increase the risk of death by 10% for all strokes by adjustment for related variables [19].
In age effect, we found that the CVD (including stroke and IHD) mortality attributable to tobacco exposure increased with age. This might be mainly caused by two reasons: On the one hand, longterm tobacco exposure led to vascular damage; on the other hand, physical resistance declined with age [20]. Due to the possibility of tobacco exposure, sex was one of important demographic risk factor for CVD [21]. In four regions, the smoking prevalencein male was higher than that in female, the difference in smoking rates between men and women in China was the largest, and so was the difference in ASMR attributable to smoking. In our study, we found that the changes of ASMR attributable to smoking for both sexes were similar to those for male, and the changes of ASMR attributable to SHS for both sexes were similar to those for female. In the cohort effect, we found that the later the year of birth, the lower the mortality rates. In the period effect, we also found that the mortality rates gradually decreased overtime. By the development of the economy, social propaganda, and policy constraints, people had a certain level of understanding of the dangers of tobacco exposure, resulting in lower smoking prevalence, and lower exposure to second-hand smoke in public areas, resulting in reduced the mortality rate of CVD attributable to tobacco exposure [22].
Our study is the first study to show the temporal trends of CVD mortality attributable to tobacco exposure, to analyze the effects of age-cohort-period, and to focus on a comprehensive comparison in China, Japan, USA and the world. The ASMRs, period effects and cohort effects of CVD mortality attributable to tobacco exposure in four regions have been declining in both sexes and all age groups from 1990 to 2017. Comparing with the differences between their results, we found the gap between different regions: the USA and Japan had greatly reduced the CVD mortality attributable to tobacco exposure from 1990 to 2017, which were lower than the world average levels, and should continue to maintain the status. The CVD mortality attributable to tobacco exposure in China was higher than that in the world. Based on the above findings, China should try its best to implement tobacco control strategies to reduce the effect of tobacco exposure on CVD mortality in the next few years, to achieve the goal of reducing the burden of CVD.

Consent for publication
Not applicable Availability of data and materials All our research data are obtained from GBD 2017, the website was http://ghdx.healthdata.org/ gbdresults-tool.

Conflict of interest
The authors declare that they have no competing interests.    Figure 1 The ASMR of CVD attributable to smoking in China, Japan, USA and the world from 1990 to 2017 Figure 2 The ASMR of CVD attributable to Secondhand smoke in China, Japan, USA and the world from 1990 to 2017 The APC results of CVD attributable to smoking in China, Japan, USA and the world from 1990 to 2017.

Figure 4
The local drift with net drift values of the mortality rate of CVD attributable to tobacco exposure in China, Japan, USA and the world from 1990 to 2017