Tobacco smoking prevalence remains high worldwide and causes over 7 million deaths annually from smoking-related diseases [1,2]. Chronic tobacco smoking has significant cardiovascular effects impacting vascular function, leading to increased risk of cardiovascular disease and sudden cardiac death [3-5]. Conversely, stopping smoking has been shown to significantly reduce the risks of cardiovascular events [6,7], and guidelines strongly recommend smoking cessation for primary and secondary prevention of cardiovascular disease [8-10]. Efforts to promote smoking cessation have intensified, with research showing that success rates can double or triple when counseling is combined with pharmacotherapy such as varenicline [11], cytisine [12], bupropion [13], and nicotine replacement therapy [14]. Additionally, Cochrane systematic reviews, meta-analyses, and umbrella reviews suggest that electronic cigarettes (ECs) may also be effective for smoking cessation [15,16]. The US Food and Drug Administration and UK’s National Institute for Health and Care Excellence (NICE) recognize ECs as less harmful than conventional smoking and a useful adjunct for smoking cessation [17,18].

Most evidence linking smoking cessation to improved cardiovascular outcomes and vascular function comes from cross-sectional studies, which cannot establish causality. In addition, prior reviews often aggregate studies with highly heterogeneous designs, populations, and outcome measures, and many focus only on short-term or acute effects following limited EC or nicotine exposure. These limitations hinder our understanding of the long-term vascular consequences of smoking cessation or switching to exclusive EC use. Furthermore, a key limitation in evaluating smoking cessation and harm reduction strategies is the lack of early, sensitive, and clinically meaningful end points. This gap has slowed progress in understanding the full health impact of cessation therapies and reduced-risk nicotine or tobacco products. Advancing regulatory science and clinical research in this area requires identifying early indicators of biological and physiological recovery. Yet, this search remains challenging. Our understanding of early smoking–induced pathophysiological changes is incomplete, and sensitive, clinically relevant end points for early health impact assessment are still poorly defined. Although functional vascular end points are widely used, they often lack the sensitivity to capture subtle, early-stage changes in recent quitters. Specifically, no systematic review to date has synthesized prospective evidence focused on key vascular and cardiovascular end points and incident cardiovascular events among adult smokers who either quit or switch to ECs in order to detect early and clinically significant end points of vascular damage reversal.

To address these limitations, this systematic review aims to synthesize prospective evidence on the vascular and cardiovascular outcomes associated with smoking cessation and switching to exclusive EC use in order to identify early and clinically relevant indicators of vascular recovery. The review will examine changes in vascular function—including pulse wave velocity (PWV), intima-media thickness (IMT), and flow-mediated dilatation (FMD)—as well as cardiovascular indicators such as blood pressure and heart rate, and the incidence of major events, including nonfatal myocardial infarction, nonfatal stroke, sudden cardiovascular death, and acute heart failure. In addition, it will explore methodological patterns, assess the quality of available studies, and highlight areas for future research.

A thorough literature review was performed in January 12, 2025, by using PubMed and Scopus databases. Search queries have been designed to identify relevant studies in each database. Details of the search strings for each database are provided in Table 1. To identify additional literature, 2 reviewers will examine the reference lists of the included studies. Medical experts will also be consulted to ensure that no recent relevant studies have been overlooked. The search will be conducted without any restrictions on publication date. Only studies published in English will be considered.

The studies will be selected based on the following inclusion and exclusion criteria.

Data extraction will be performed using a standardized form specifically designed for this purpose. The relevant data, including the lead author's name (surname, first name), publication year, country, study design, mean age of the cohort(s), percentage of male and female participants, sample size, study population, comorbidities (if applicable), prior smoking history (minimum cigarettes per day), prior smoking history (pack years), whether dual use of e-cigarettes and smoking is allowed (yes/no), whether other concomitant nicotine products are allowed (yes/no), follow-up duration (in weeks), vascular and cardiovascular end point, and main findings (focused solely on the effects of abstinence from cigarette smoking on vascular outcomes, with quantitative data provided where available or summarized narratively), will be systematically recorded and organized in a table. Potential limitations and conclusions of the studies will also be noted. In the qualitative synthesis, emphasis will be placed on the clinical impact of smoking abstinence on vascular outcomes.

If sufficient and comparable data are available, a meta-analysis will be performed. The primary measures of effect will be the odds ratio with a corresponding 95% CI for dichotomous outcomes and the mean difference with a 95% CI for continuous outcomes. Due to potential variations in study populations, interventions, and outcome definitions across trials, a random-effects model will be employed to account for potential heterogeneity among studies. The meta-analysis will be conducted using the STATA/BE (version 17; StataCorp LT) statistical package. Heterogeneity among the included studies will be assessed using the I² statistic, with an I² value >50% considered indicative of substantial heterogeneity. Potential publication bias will be assessed visually using funnel plots. If a meta-analysis is not feasible due to substantial heterogeneity among studies, a narrative synthesis will be conducted.

Two authors will independently assess the methodological quality of the included studies, using the Joanna Briggs Institute’s critical appraisal tools tailored to each specific study design [20]. Each checklist includes a set of items covering core domains such as participant selection, exposure and outcome measurement, control of confounding, and the appropriateness of statistical analysis. Any disagreements will be resolved through discussion to reach a consensus or by consulting a third author if necessary. Risk of bias assessments will be presented in a tabular or graphical format, with responses recorded for each item per study. A narrative synthesis will accompany the tables, summarizing methodological quality across studies grouped by study design. The risk of bias assessments will inform the synthesis and interpretation of results. In particular, sensitivity analyses will be conducted—quantitative or narrative—by excluding studies presenting multiple methodological limitations as identified through the Joanna Briggs Institute’s checklists. Additionally, we will transparently report how the quality of the included studies influences the level of confidence in the findings, especially in the narrative synthesis. This approach will help highlight areas of greater methodological robustness versus vulnerability.

To ensure a focused and comprehensive analysis, each major end point category (ie, vascular function, heart rate/blood pressure, and major cardiovascular outcomes) will be addressed in separate publications. These domains are methodologically and clinically distinct, often involving different measures, statistical models, and implications for harm reduction. Rather than merging all the findings into a single, overly complex manuscript, this approach is intended to enhance clarity, support in-depth interpretation, and serve both clinical and research audiences more effectively. To prevent fragmentation, each paper will include a concise overview of the full systematic review protocol and clearly explain the rationale behind the separate reporting. Publications will be cross-referenced to allow readers to easily access related findings. A final synthesis manuscript will integrate all the results and discuss their broader clinical and public health implications.