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Background: Although physical activity is associated with cardiovascular health benefits and reduced all-cause mortality, vigorous exertion is also recognized as a trigger for sudden cardiac death (SCD). This study investigated vigorous exertion as a trigger for SCD resulting from myocardial infarction (MI) and the potential modifying effect of habitual vigorous exercise training among Swedish men who subsequently experienced SCD due to MI.

Methods: This prospective nested case-crossover study was performed within the Västerbotten Intervention Programme cohort from 1985 to 2006 and included male participants who later experienced SCD caused by MI. The risk of SCD during and within 30 min of vigorous exertion was compared with the risk during periods of non-exertion. Participants were categorized into three groups according to baseline frequency of habitual vigorous exercise training to assess effect modification.

Results: We included 192 men with SCD caused by MI, with a mean time from screening to event of 6.5 years. A majority of cases reported physical inactivity, with 161 cases reporting no exercise or <1 exercise event per week. 24 men suffered SCD in relation to vigorous exertion, yielding a relative risk of 43.6 (95% CI: 27.1-70.3) compared to non-exertion. The highest relative risk (107.7 [95% CI: 63.4-182.9]) was found among physically inactive men and was mitigated by a higher frequency of habitual exercise training at baseline.

Conclusion: Among Swedish men who experienced SCD caused by MI, vigorous exertion was associated with a transiently increased risk, which was mitigated by higher levels of habitual vigorous exercise training.

Patients at a high risk for sudden cardiac death (SCD) without previous history of cardiovascular disease remain a challenge to identify. Atherosclerosis and prothrombotic states involve inflammation and non-cardiac tissue damage that may play active roles in SCD development. Therefore, we hypothesized that circulating proteins implicated in inflammation and tissue damage are linked to the future risk of SCD. We conducted a prospective nested case–control study of SCD cases with verified myocardial infarction (N = 224) and matched controls without myocardial infarction (N = 224), aged 60 ± 10 years time and median time to event was 8 years. Protein concentrations (N = 122) were measured using a proximity extension immunoassay. The analyses revealed 14 proteins significantly associated with an increased risk of SCD, from which two remained significant after adjusting for smoking status, systolic blood pressure, BMI, cholesterol, and glucose levels. We identified leukotriene A4 hydrolase (LTA4H, odds ratio 1.80, corrected confidence interval (CI_corr) 1.02–3.17) and hepatocyte growth factor (HGF; odds ratio 1.81, CI_corr 1.06–3.11) as independent risk markers of SCD. Elevated LTA4H may reflect increased systemic and pulmonary neutrophilic inflammatory processes that can contribute to atherosclerotic plaque instability. Increased HGF levels are linked to obesity-related metabolic disturbances that are more prevalent in SCD cases than the controls.