Cardiovascular disease (CVD) remains a major cause of premature mortality and disability worldwide. Although coronary artery disease (CAD) is more common in older adults, acute coronary syndrome (ACS) and myocardial infarction also occur in younger individuals. Premature CAD is a particular concern in South Asian populations, which experience cardiovascular events at younger ages

than several other ethnic groups. This pattern reflects a combination of conventional cardiovascular risk factors, genetic susceptibility, and environmental and lifestyle influences. In Pakistan, ACS among younger adults presents a challenge for prevention because affected individuals may develop disease during their most productive years [1,2].

Evidence from Pakistan supports the need to investigate cardiovascular risk factors in young adults. Peerwani et al. analysed 23,560 patients with ACS at a cardiac centre in Karachi and reported that 12.2% of patients were aged 45 years or younger. Smoking was more prevalent in younger patients than in older patients, whereas hypertension, diabetes and dyslipidemia were more common in the older group [1]. A separate study conducted at the National Institute of Cardiovascular Diseases, Karachi, identified 466 patients aged 40 years or younger among 4,686 patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction. The mean age of the younger group was 36.5 ± 4.4 years, and the findings highlighted the contribution of smoking and family history to premature ACS [2]. These observations suggest that cardiovascular disease in young adults cannot be explained by age-related metabolic risk factors alone.

Smoking is an established modifiable risk factor for CAD, myocardial infarction and stroke. Tobacco smoke contains nicotine, carbon monoxide and numerous oxidant compounds that affect vascular function and cardiovascular homeostasis. Nicotine stimulates the sympathetic nervous system, increasing heart rate, blood pressure and myocardial oxygen demand. Carbon monoxide reduces the oxygen-carrying capacity of blood, while oxidant compounds contribute to vascular injury. Smoking also reduces nitric oxide bioavailability, promotes endothelial dysfunction, increases inflammatory activity and enhances platelet activation and thrombosis. These processes contribute to atherosclerotic plaque development and may increase the likelihood of an acute coronary event [3,4]. The World Health Organization and the World Heart Federation have identified tobacco exposure as an important preventable cause of coronary heart disease, including events occurring at younger ages [5].

The association between smoking and premature coronary disease may be particularly relevant in South Asian populations. Evidence from Pakistani patients with ACS indicates that smoking is more prevalent among younger patients, while studies of South Asian populations have documented an increased burden of premature CAD [1,6]. However, smoking behaviour varies according to age, sex, socioeconomic status, duration of exposure and type of tobacco product. Cigarette smoking, waterpipe use and smokeless tobacco should therefore be assessed separately where relevant. Recording only a history of smoking without considering frequency, duration and cumulative exposure may not adequately characterise its relationship with early-onset cardiac disease.

Substance use other than tobacco may also contribute to cardiovascular disease through several physiological mechanisms. Cocaine and amphetamine-type stimulants can increase sympathetic activity, blood pressure and myocardial oxygen demand. They may also produce coronary vasoconstriction, arrhythmias and myocardial injury. Cannabis has been associated with cardiovascular events in observational studies, although the strength of evidence varies by outcome and exposure pattern. In a large longitudinal study involving more than 23 million adults in California, the use of methamphetamine, cocaine, opiates and cannabis was associated with an increased incidence of atrial fibrillation after adjustment for potential confounders. The adjusted hazard ratios were 1.86 for methamphetamine, 1.61 for cocaine, 1.74 for opiates and 1.35 for cannabis [7]. These findings support further investigation of substance-related cardiovascular risks, although atrial fibrillation is a distinct outcome from premature CAD.

A review of early-onset cardiovascular disease associated with cocaine, amphetamines, alcohol and marijuana described potential links between recreational substance use and coronary disease, arrhythmias and other cardiovascular complications [8]. The American Heart Association has similarly highlighted potential cardiovascular concerns associated with cannabis use, while acknowledging limitations in the available evidence [9]. The cardiovascular effects of these substances differ according to their pharmacological properties, dose, route of administration, frequency of use and concurrent exposure to tobacco. For this reason, substance use should not be treated as a single uniform exposure. Studies should identify the substances involved and distinguish occasional use from regular or heavy consumption whenever possible.

Concurrent smoking and substance use warrant particular attention because individuals may be exposed to several cardiovascular stressors simultaneously. Tobacco-related endothelial dysfunction and thrombosis may coexist with substance-induced sympathetic stimulation, vasoconstriction or electrical instability. These mechanisms provide a biological basis for examining combined exposure; however, a greater risk from combined use should not be assumed without appropriate statistical analysis. Age, sex, hypertension, diabetes, dyslipidemia, obesity, family history of premature CAD, physical inactivity and other behavioural factors may confound the observed associations. Careful adjustment for these variables is necessary to distinguish the independent association of smoking and substance use from the effects of other cardiovascular risk factors [3,4,7,10].

Despite evidence linking tobacco and several recreational substances with cardiovascular complications, the relationship between these exposures and early-onset cardiac disease in young Pakistani adults requires further investigation. Local evidence is particularly relevant because substance-use patterns, tobacco products, healthcare access and socioeconomic circumstances may differ from those in populations studied internationally. Evaluating smoking and substance use together may help identify potentially modifiable exposures among young patients presenting with premature CAD or other defined cardiac conditions.

Therefore, this study aimed to assess the association of smoking and substance abuse with early-onset cardiac disease among young Pakistani adults. It examined the prevalence of these exposures, compared their distribution between participants with and without cardiac disease, and evaluated their associations after adjustment for relevant demographic and clinical confounders. The findings may help inform targeted cardiovascular risk assessment and preventive interventions for young adults in Pakistan.

A hospital-based analytical case-control study was conducted to assess the association of smoking and substance abuse with early-onset cardiac disease among young Pakistani adults. The study included 200 participants aged 18–40 years, comprising 100 cases with confirmed premature coronary artery disease (CAD) and 100 controls without a clinical diagnosis of CAD. Participants were recruited from relevant clinical departments of participating healthcare institutions in Pakistan. Cases were defined as individuals with documented CAD established through clinical assessment and appropriate investigations, including electrocardiography, cardiac biomarkers and coronary angiography, where indicated. Controls were individuals without documented CAD, selected from a comparable age group. Written informed consent was obtained from all participants before data collection. Demographic and clinical information was collected using a structured questionnaire and review of medical records. Variables included age, sex, residence, occupation, smoking status, duration and frequency of smoking, and history of substance use. Tobacco exposure was classified according to current, former or never-smoking status. Where available, duration of smoking and number of cigarettes consumed per day were recorded to estimate cumulative exposure. Substance use was documented separately for each reported substance, including cannabis, opioids, cocaine, amphetamine-type stimulants and other locally relevant psychoactive substances. Information on frequency, duration and route of administration was recorded where participants provided these details. Tobacco and other substance exposures were analysed separately to avoid treating substances with different pharmacological effects as a single exposure category. Potential confounding variables were assessed, including hypertension, diabetes mellitus, dyslipidemia, obesity, family history of premature CAD, physical activity and relevant dietary habits. Clinical diagnoses and laboratory findings were extracted from available medical records. Data were coded and entered into IBM SPSS Statistics for analysis. Continuous variables were expressed as mean and standard deviation or median and interquartile range, depending on their distribution. Categorical variables were presented as frequencies and percentages. Differences between cases and controls were assessed using the independent-samples t-test or Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables, as appropriate. Logistic regression was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the associations of smoking and substance use with premature CAD. The multivariable model included relevant demographic and clinical confounders identified before analysis. Combined exposure to smoking and other substances was assessed separately where the sample size permitted reliable estimation. A two-sided p-value of less than 0.05 was considered statistically significant. Ethical approval was obtained from the relevant institutional review committee before recruitment. Participant confidentiality was maintained by using coded study identifiers and restricting access to identifiable information. Participation was voluntary, and participants were informed of their right to withdraw without affecting their clinical care.

total of 200 participants were included, comprising 100 cases with premature CAD and 100 controls without diagnosed CAD. The mean age of participants was 33.1 ± 5.2 years, and 154 (77.0%) were male.

Table 1. General characteristics of study participants

Smoking was reported by 64 (64.0%) cases and 32 (32.0%) controls. The difference between groups was statistically significant (p < 0.001).

Table 2. Smoking status among cases and controls

Figure 1. Smoking prevalence among cases and controls.

Other substance use was reported by 27 (27.0%) cases and 12 (12.0%) controls (p = 0.009).

Table 3. Other substance use among cases and controls

Figure 2. Other substance use among cases and controls.

Combined exposure to smoking and other substances was reported by 20 (20.0%) cases and 6 (6.0%) controls (p = 0.004).

Table 4. Combined exposure among cases and controls

In multivariable analysis, smoking and other substance use were associated with higher odds of premature CAD after adjustment for selected demographic and clinical risk factors.

Table 5. Adjusted associations with premature CAD

Figure 3. Adjusted odds ratios and 95% confidence intervals for premature CAD.

In this analysis, smoking was associated with 2.85 times the adjusted odds of premature CAD, while other substance use was associated with 2.21 times the adjusted odds. These estimates describe odds and should not be interpreted as direct estimates of relative risk.

The findings suggest that smoking and other substance use may be associated with premature coronary artery disease among young Pakistani adults. Smoking was reported by 64% of cases compared with 32% of controls, while other substance use was reported by 27% and 12%, respectively. In the multivariable analysis, smoking was associated with an adjusted odds ratio of 2.85 (95% CI 1.49–5.45), whereas other substance use had an adjusted odds ratio of 2.21 (95% CI 1.01–4.84). These findings suggest that both exposures may be relevant to premature CAD. The higher prevalence of smoking among cases is consistent with the established relationship between tobacco exposure and cardiovascular disease. A 2025 analysis of Global Burden of Disease data estimated that approximately 2.15 million cardiovascular deaths worldwide were attributable to tobacco in 2021, including a substantial burden from ischemic heart disease. The analysis also identified considerable differences in tobacco-attributable cardiovascular mortality across sociodemographic groups [11]. These findings provide context for investigating smoking among younger populations in countries where cardiovascular risk factors remain common. However, global burden estimates cannot establish the magnitude of smoking-associated risk among young Pakistani patients specifically. The association observed in this analysis may reflect several biological pathways. Smoking can contribute to endothelial dysfunction, platelet activation, inflammation and atherothrombotic events. These effects may accelerate coronary atherosclerosis and increase the likelihood of acute coronary events in susceptible individuals. The findings also support assessing smoking duration and intensity rather than recording smoking status alone. Differences in cumulative tobacco exposure may help explain variation in cardiovascular risk between individuals of similar age. However, the present analysis does not establish whether smoking duration, cigarette consumption or age at smoking initiation was associated with CAD severity. The association between other substance use and premature CAD also warrants consideration. In this study, 27% of cases reported substance use compared with 12% of controls. Gagnon et al. reviewed cardiovascular complications of commonly misused substances and described associations with acute coronary syndrome, myocardial injury, arrhythmias and cardiomyopathy [10]. The clinical effects differ between substances, and the findings from one drug cannot be applied directly to all forms of substance use. Consequently, future analyses should identify individual substances and examine their frequency, duration and concurrent use with tobacco. Stimulant use provides a plausible explanation for some of the observed association. Cocaine and amphetamine-type stimulants can increase sympathetic activity, alter cardiac ion-channel function and promote coronary vasoconstriction. These effects may increase myocardial oxygen demand and contribute to ischemia or arrhythmias. Dominic et al. reviewed the electrophysiological effects of stimulant drugs and described their potential to cause atrial and ventricular arrhythmias [12]. A 2024 review of recreational drug-related cardiopulmonary complications also described a range of cardiovascular manifestations associated with cocaine, amphetamine-type stimulants, opioids and cannabis [14]. Because the present analysis does not provide substance-specific frequencies, it cannot establish which substances contributed most strongly to the observed association. The combined-exposure findings require cautious interpretation. In this study, 20% of cases and 6% of controls reported both smoking and other substance use. This difference may indicate that combined exposure deserves further investigation, but it does not demonstrate a synergistic effect. A formal interaction analysis would be needed to determine whether the joint association exceeds what would be expected from the individual exposures. The analysis should also account for alcohol use, socioeconomic circumstances, mental health conditions and other behavioural factors where these variables are relevant and reliably measured. The adjusted association between smoking and premature CAD was stronger than that observed for other substance use. This difference should not be interpreted as proof that smoking is more harmful than every other substance. The substance-use category combines exposures with different cardiovascular effects, and its estimated association may be influenced by the types of substances used and the accuracy of self-reporting. In addition, the confidence interval for other substance use was relatively wide, suggesting uncertainty in the estimated association. Larger studies with substance-specific exposure categories may provide more precise estimates. The findings should also be interpreted in the context of the Pakistani population. A 2023 study of patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention at a cardiac centre in Karachi examined clinical characteristics and outcomes among younger and older patients [13]. Hospital-based studies help describe premature coronary disease in Pakistan, but differences in recruitment criteria, age thresholds and clinical settings limit direct comparisons between studies. A case-control design focused on smoking and substance use may provide complementary evidence, particularly if it includes controls selected from an appropriate source population. Several limitations should be considered. The hospital-based case-control design may be affected by selection bias if cases and controls differ in ways related to substance exposure. Self-reported smoking and substance use may be affected by recall and social-desirability bias. Residual confounding may persist even after adjustment for recognised cardiovascular risk factors. The sample size may also provide limited statistical power for evaluating individual substances or interactions between exposures. These issues should be addressed in future studies using clearly defined exposure categories, validated data-collection procedures and larger samples. Despite these limitations, the research question has practical relevance. Recording tobacco exposure and substance use during cardiovascular assessment may help clinicians identify modifiable risk factors in young adults. Prevention strategies could combine smoking cessation support, confidential screening for substance use and management of conventional cardiovascular risk factors. The effectiveness of these measures in the study population would require further evaluation. In summary, smoking and other substance use were associated with premature CAD among young adults in this study. The findings are consistent with published evidence on tobacco-related cardiovascular burden and the potential cardiac effects of psychoactive substances [10–14].

Smoking and other substance use were associated with premature coronary artery disease among young Pakistani adults. Smoking showed the stronger adjusted association in the analysis, while the prevalence of combined exposure was higher among cases than controls. Cardiovascular assessment in young adults should include a detailed tobacco history, confidential screening for other substance use and evaluation of conventional cardiovascular risk factors. Further studies with larger samples and substance-specific exposure data are needed to clarify the independent and combined associations of these exposures with premature cardiac disease.