Stroke in young adults is relatively uncommon (1–4). Although the prognosis of young stroke is generally considered benign, young adults with stroke are at a higher risk of recurrent stroke and mortality than their healthy peers. Most survivors between 20 and 50 years may have emotional, social, or physical sequelae that impair their quality of life (4, 5). In addition, young stroke victims are often responsible for providing child care or generating income for their families. Therefore, young stroke is a major health and socioeconomic problem.

Smoking is one of the biggest public health threats associated with many chronic diseases, such as cardiovascular disease and cancer (6–8). More importantly, smoking is also aggregated with other adverse behaviors, such as chewing bet-but and drinking alcohol. However, several recent studies observed an improved outcome in smokers with antithrombotic therapy after an index cardiovascular event, a phenomenon called “smoker's paradox” (9–13). Sample sizes in these studies are small (10, 11). Moreover, no study has examined the effects of pre-stroke smoking on post-stroke long-term outcome.

In Taiwan, about 24,000 smokers die of smoking and nearly 2,600 non-smokers die of second-hand smoke each year. Since the enactment of the Tobacco Hazards Prevention Act (THPA) in 1997, smoking prevalence has decreased. However, Taiwan still records a 15% adult smoking rate. The purpose of this study was to evaluate the effect of smoking status on stroke outcome in young stroke.

In our community-based longitudinal study in young stroke, a total of 9,087 strokes were identified among patients aged ≤ 50 years. We observed a gender difference between smokers and non-smokers. Smokers were associated with the higher severity of the initial stroke (NIHSS score upon admission) and more ischemic stroke. In addition, modifiable risk factors are prevalent in smokers, including hypertension (66.41%), diabetes (23.59%), hypercholesterolemia (31.52%), previous stroke (11.50%), and alcohol consumption (42.35%). According to the stratified analysis, smoking has detrimental effects on post-stroke outcomes. However, only lower crude ratios for mortality, not adjusted HRs, were observed in the smoker group. Smoking cessation is recommended to improve post-stroke functional outcome.

Approximately 10% of strokes occur at ages ≤ 50 years, and the proportion of strokes in young adults has increased over time (3, 4). Despite their more favorable stroke outcomes, younger adult patients still have an obvious socioeconomic consequence because a large proportion of them are at a higher risk of future cardiovascular events and labor productivity loss. Besides this, the burden of disease is heavier in the case of recurrent events. Stroke is far more common in the geriatric population, and associations between risk factors for acute stroke and the clinical outcomes are stronger among older adults (1–4). However, the knowledge gleaned from research on older adults cannot always be applied to younger adults. Lutski et al. show that young adults have a high prevalence of modifiable vascular risk factors and, in particular, a high rate of smoking (17). In our study, we found that most strokes in young smokers were related to the existence of traditional stroke risk factors. There are several reasons why smokers may have a higher risk of developing stroke. Smoking increases the risk of complex atherosclerotic cardiovascular events, including deleterious effects on the endothelial function, inflammation, lipids, and thrombosis (9, 10). Nicotine exposure could also induce a reduction in insulin release, and negatively affect insulin action, suggesting that nicotine could be a cause for the development of insulin resistance. Therefore, young stroke patients who smoked are more likely to have those comorbidities.

Initially, the term “smoker's paradox” was an observational phenomenon of an unexpected favorable outcome in smokers who experienced acute myocardial infarction and had a smoking duration of over 25 years (9). Recent studies in stroke indicate a strong positive correlation between recanalization and smokers, indicating that thrombolytic therapy acts more effectively in smokers (11, 12). However, they had some shortcomings, including short observation durations or their patients' low clinical risk profiles and low NIHSS scores on admission. In addition, those studies ignore that smoking is associated with a younger age of stroke. The risk of recurrent stroke after the first stroke is about 10% at 1 year, 25% at 5 years, and 40% at 10 years, and about 40% of stroke survivors become disabled after stroke (18). Recurrent strokes often have a higher rate of death and disability. In our present study, we only investigated young stroke patients, and the data suggest that smoking is associated with higher severity of the initial stroke, more modifiable risk factors, and poor functional outcome recorded at 3 months after stroke. Therefore, the smoker's paradox is misleading.

The difference in the incidence of stroke between the two sexes are well-established. Several epidemiological studies report higher age-specific stroke rates in men (19–21). However, women still experience more frequent stroke events because of their increased longevity and high stroke incidence at older ages. The higher prevalence of traditional vascular risk factors, including hypertension, diabetes mellitus, and hyperlipidemia in middle-aged men may contribute to this result (22, 23). Our findings are consistent with those of a meta-analysis and certain community-based reports on the relationship between stroke and sex. More interestingly, age-specific stroke rates are higher in men, and the higher prevalence of traditional vascular risk factors is associated with smoking.

Patients who cease smoking are expected to live longer and be less likely to develop tobacco-related diseases, including coronary heart disease, stroke, cancer, and pulmonary disease (24–27). In 1997, Taiwan established its first comprehensive policy package for tobacco control, the THPA, to include pictorial health warnings, smoke-free worksites and restaurants, and a ban on most tobacco advertising (24, 25). In 2018, Taiwan recorded an adult smoking rate of 13%—its lowest rate since 1990. This resulted from the efforts of the government to discourage smoking since the enactment of the THPA in 1997. Taiwan was the second Asian country after Bhutan to institute an indoor smoking ban. However, Taiwan's tobacco price still remains too low, and now, the Taiwan government only levies one package of 20 cigarettes at NT$10 (US$0.3). According to a World Bank study, a 10% rise in the cigarette price leads to a 4–8% reduction in cigarette consumption. Therefore, it is imperative to raise the price of tobacco.

The TSR provides the opportunity to investigate these issues owing to its large sample size, the homogeneous demographic characteristics and clinical phenotypes of the study subjects, and the standard diagnostic workup (16, 28, 29).

However, the present study has a number of limitations that need to be addressed. First, the baseline characteristics of the study groups were only obtained in the hospitals; hence, certain unadjusted potential confounders may still exist. Second, the sample sizes were sufficiently large, representing 3% of the total adult population in Taiwan. However, our cohort consisted of participants with an above-average socioeconomic status engaging in a medical screening program. This may affect the generalizability of our findings. Third, the smoking paradox refers to a better outcome following intravenous thrombolysis as well as endovascular therapy in smokers. However, TSR does not include data on patients who accepted endovascular therapy, leading to the possible underestimation of the reperfusion rate. Fourth, our body begins a series of positive changes that continue for years after quitting smoking. Being smoke-free not only adds years to your life, but also greatly improves your chances of a disease-free old age. Our data included patients who stopped smoking more than 2 years before stroke defined as past smokers, leading to the possible underestimation of the benefit of smoking cessation.

In conclusion, this study uncovers an intriguing relation between smoking and young stroke. High smoking rates are found among male young stroke patients, compared with much lower rates among females. Smoking is associated with higher comorbidities and poor long-term function outcomes. Smoking cessation would substantially reduce those effects. This implies that physicians should put more efforts into reducing cigarette smoking in Taiwan.

Publicly available datasets were analyzed in this study. This data can be found here: The TSR raw data in this study are managed by the Management Office for Health Data (Dry Lab), China Medical University Hospital (http://stroke.cmuh.org.tw/). All researchers can submit their proposals to the research committee of the TSR (taiwanstrokeregistry@gmail.com). After study proposals are accepted, the results will be sent back to investigators.

The studies involving human participants were reviewed and approved by the China Medical University Hospital Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

P-LC, W-LC, P-YY, C-YW, M-JT, YS, C-HL, J-TL, T-CL, L-ML, M-CL, C-LLin, and H-KW: designed research. C-LLia, H-JC, Y-CL, C-CW, C-HT, and H-KW: analyzed data. H-KW and CH wrote the paper. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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