An intracranial aneurysm (IA) is a partial expansion of cerebral blood vessels caused by the local abnormalities of blood vessels. The incidence of IA is 3–5% in the general population (1), and 85% of subarachnoid hemorrhage (SAH) is due to the rupture of IA, which could be seriously hazardous to health (2). Since most IAs are diagnosed after its rupture, it is of great importance to screen its risk factors.

At present, the diagnosis of IA in clinical settings mainly relies on neuroimaging technology (3). In addition, the use of MRI and CT as diagnostic tools has increased over the past 20 years as the quality of intracranial imaging techniques improved, and unruptured aneurysms have been detected with increasing frequency (4). Although the annual risk of ruptured incidental IA is relatively low (5), the prognosis of SAH caused by IA rupture is poor, with the 1 month case fatality rate still as high as 35% (6). About one-third of survivors require lifelong care, and another one-third have residual cognitive impairment that affects functional status and quality of life (7). Thus, preventing rupture of IA is vital. However, surgical clipping and endovascular intervention to prevent aneurysm rupture also have associated hemorrhagic and ischemic risks, which may exceed the natural risk of rupture (estimated total morbidity and mortality in the first month is 10–14%) (8, 9). Therefore, the prevention of IA by identifying and managing the modifiable risk factors, rather than surgical clipping and intravascular intervention, has a significant clinical and social value (10).

Many pieces of literature have reported that risk factors for the formation and rupture of IA include age, female sex, hypertension, and smoking. Among them, smoking is the most easily controlled risk factor (11). A previous studies has documented that cigarette smoking was significantly associated with the growth and rupture of IA (12). However, the mechanisms by which smoking causes the formation and rupture of IA are unclear. In the present meta-analysis, we aimed to determine the relationship between current smoking, former smoking (smoking cessation), and non-smoking and the risk of ruptured IA. Further, we summarized the potential biological effects of smoking on the formation, growth, and rupture of IA, which could be helpful in studying the pathophysiological mechanism of smoking and IA formation and rupture.

Previous studies have documented that smoking is one of the most important risk factors for the formation of IA. However, there are still several studies with controversial results. We have presented an integrated overview and a systematic review of recent studies on the relationship between the current smoking, the former smoking (smoking cessation), and the non-smoking groups and the risk of ruptured IA. Further, we discussed the underlying mechanism of smoking on IA formation and rupture.

The global decline in the incidence of SAH parallels the decline in smoking prevalence. For every 1% point decrease in the smoking rate, the overall age- and gender-adjusted SAH incidence decreases by 2.4% (26), which clearly illustrates that the smoking is related to ruptured aneurysms. Moreover, genetic susceptibility to smoking leads to an increased risk of IA and drives most of the genetic association between IA and other cerebrovascular traits (27, 28). To better understand the relationship between smoking and ruptured IA, scholars analyzed the relationship between smoking time, smoking intensity, smoking index, and smoking status and ruptured IA. One case-control study showed that current smoking, smoking intensity, and smoking duration are significantly related to ruptured IA (25). There is also a dose-response relationship between the intensity, duration of smoking, and the incidence of ruptured IA (10). As the number of cigarettes smoked per day (CPD) and the number of years of smoking increased, the risk of IA also increased accordingly (25). Moreover, a positive correlation between the smoking index (CPD × years of tobacco use) and the risk of ruptured aneurysms were also reported (10). According to published data, current smokers are 2.5 times more likely to have a rupture than non-smokers, while former smokers are nearly 2 times more likely to have a rupture than non-smokers (25, 29). Compared with former smokers and non-smokers, current smokers are more likely to develop ruptured aneurysms, which is consistent with our results. Prospective studies showed that the risk of ruptured aneurysms will be reduced when patients quit smoking (12, 30). However, the study of Anil and his colleagues reported that the longer the smoking cessation period, the lower the risk of ruptured aneurysms in former smokers, but this association disappeared after adjusting for other confounding factors in the multivariate analysis (25). This indicates that the risk of ruptured IA caused by smoking could still exist even after smoking cessation. The reason for this phenomenon might be that smoking has caused irreversible damage. For example, the nicotine in cigarettes damages elastin, which has a low repair potential (31). Therefore, the elastin damage caused by long-term smoking may be permanent, even after smoking cessation. In addition, for a long time after quitting smoking, quitters showed persistent low-grade inflammation (32). These results obtained from Can et al. showed that smoking cessation only reduces the cumulative dose of tobacco in the body and that early quitting does not reduce the risk of SAH. This view has sparked debate about the relationship between smoking cessation and the risk of ruptured IA. Then, we further evaluated the association between smoking cessation (Former smoking) and the risk of ruptured IA. The results showed that there was no significant difference in the risk of ruptured IA between the former smoking (smoking cessation) group and the non-smoking group, suggesting that quitting smoking may be beneficial for patients with unruptured IA. Moreover, smoking cessation can also reduce the damage of delayed cerebral ischemia after SAH. Delayed cerebral ischemia is the leading cause of death and disability after ruptured IA (33). Therefore, smoking cessation is still indispensable in the treatment of IA. Moreover, those results emphasized the importance of quitting smoking in patients with unruptured IA.

The majority of previous research has focused on the effects of active smoking on IA. In contrast, people's understanding of the effects of passive smoking on IA is still incomplete. The two primary sources of exposure to passive smoking are the workplace and the home (such as a smoking spouse), and passive smoking is common among women. Previous studies have shown that, in non-smoking women with IA, passive smoking is not an independent risk factor for ruptured IA (10). However, passive smoking reduces eNOS activity and increases vascular endothelial inflammation similar to active smoking, which indicates that passive smoking has direct damage to the vascular system (34). There seems to be no harm in avoiding passive smoking in one's everyday life, although the association between passive smoking and the formation and rupture of IA remains indistinct. Further, we summarized the differences in aneurysm morphology between smokers and non-smokers (Table 3), and some aneurysm morphology parameters were significantly correlated with smoking status, such as larger daughter vessel diameters, larger size ratio, and the location at the basilar apex (19). Compared with non-smokers, current smokers may have larger daughter vessel diameters and size ratio, and smokers are more likely to develop basilar apex aneurysms (19). The size ratio is the ratio of the maximum aneurysm height to the mean diameter of the artery bearing the aneurysm (37). The larger size ratio means that large aneurysms formed by small blood vessels are more likely to rupture than small aneurysms formed by large blood vessels. Aneurysms at the Basilar apex have a higher risk of rupture, morbidity, and mortality (38, 39). Of course, the mechanism of smoking-induced changes in morphological parameters of these IA is indistinct, which requires further study. The morphological changes of the IA can reflect the process of its occurrence, growth, and rupture. The relationship between smoking and these specific morphological changes could provide a morphological basis for how smoking increases in aneurysm formation and rupture. However, not all morphological parameters of IA are related to smoking. The study by Juchler et al. found no association between the luminal shape of the IA and the patient's sex, age, smoking, or history of hypertension, even though these factors were strongly associated with aneurysm incidence (28, 40).

It is well-known that IA formation is associated with hemodynamics, chronic inflammation, vascular endothelial dysfunction, and vascular remodeling (41–43) (Figure 10). Pieces of evidence have shown that smoking could induce an inflammatory response in blood vessels, hemodynamic stress, endothelial dysfunction, and eventually cause weakened blood vessel walls and rupture of blood vessel walls (25, 34, 44) (Figure 11). Smoke mainly contains chemicals such as tar, carbon monoxide, nicotine, nitrosamines, volatile organic compounds, and polycyclic aromatic hydrocarbons, which are characteristic of tobacco (46). Nicotine is a major biologically active constituent of tobacco products, which has deleterious effects on IA formation, and rupture (Table 4). Nicotine is also one of the most significant components that cause vascular inflammation (59). The early and key step of cigarette smoke-induced vascular inflammation is the activation of the NF-κB pathway (52), which might be related to nicotine (46). Nicotine also directly stimulates macrophages to secrete high levels of inflammatory factors such as TNF-α, IL-1β, and other chemokines (53). Moreover, the nicotine-induced endothelial dysfunction and inflammatory microenvironment also promote vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation and vascular wall calcification. Experiments have shown that chronic nicotine exposure induces the expression of MMPs in the arterial wall and the destruction of the arterial wall structure (elastin damage) (54). Long-term smoking can impair vascular endothelial function (60), which may be also related to nicotine and oxidants in cigarette smoke. Nicotine promotes oxidative stress in VSMCs and endothelial cells by downregulating superoxide dismutase (SOD), catalase, and glutathione reductase (45). Together, smoking exposure could cause endothelial dysfunction, increase oxidative stress, and increase morbidity and mortality of cardiovascular diseases, which promotes the formation and rupture of IA. Therefore, to prevent the growth and rupture of IA, we underline that patients necessarily cease smoking, which is a valuable measure.

There are some limitations to this study. First, all the included studies are observational, and inevitably, there is an observational bias. Second, different studies use different criteria to define current smoking and former smoking. In addition, we did not consider gender, age, race, hypertension, and other factors in the study. Subgroup analyses were not performed because we could not extract relevant data for some factors from the included literature, which may increase heterogeneity among the included studies. These unspecified factors and other unmeasured or unknown confounding factors can also affect the reliability of these findings. We divided tobacco exposure into current smoking, former smoking, and non-smoking. To some extent, this may reduce heterogeneity between included studies. Finally, due to the relatively small number of studies included, the statistical power of these results is limited.

A larger and prospective cohort study should be conducted to validate our results in the future.

In conclusion, there is a dose-response relationship between the intensity and duration of smoking and the increased risk of ruptured IA. In terms of the morphology of IA, smoking causes IA to form morphologies that are more prone to rupture. The risk of ruptured IA was not statistically different between the former smoking (smoking cessation) group and the non-smoking group. To summarize, smoking is involved in the formation and rupture of IA, and it is indispensable for patients with IA to quit smoking. Despite numerous related studies on the formation and rupture of IA, the mechanism of IA formation and rupture is still inaccurate, which requires further investigation in our future.

CL and LZ: conception, design, and critically revising the article. HW, LW, and JW: acquisition of data. HW and LW: drafting the article. All authors reviewed submitted version of manuscript.

This work was supported by the Scientific Research Starting Foundation of Affiliated Hospital of Hebei University [Grant Number 31010413]; the Provincial Medical Talents Project funded of Hebei Province [Grant Number 361007]; the Key Scientific Research Projects of the Affiliated Hospital of Hebei University [Grant Number 2021Z001].

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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