Multisite Pain and Myocardial Infarction and Stroke: A Prospective Cohort and Mendelian Randomization Analysis

Background: Whether individuals with multisite pain had a higher risk of cardiovascular diseases is unclear. Objectives: The purpose of this study was to investigate the longitudinal association of pain in multiple sites with incident myocardial infarction (MI) and stroke, and to disentangle the genetic causality of these associations. Methods: A total of 281,760 participants (mean age: 56.3 years) who had no MI and stroke at baseline from UK Biobank study were included. Data on pain in the hip, knee, back and neck/shoulder, or ‘all over the body’ were collected. Chronic pain was defined if pain had lasted for ≥3 months. MI and stroke events were determined from hospital admission records and death registries. Cox regression and 2-sample Mendelian randomization were used for the analyses. Results: During a median follow-up of 11.9 years, 4,854 had a first MI and 2,827 had a first stroke. In multivariable analyses, greater number of painful sites was dose-responsively associated with higher risks of incident MI and stroke, with a higher risk among participants with pain ‘all over the body’ (MI: HR: 1.65, 95% CI: 1.32-2.07; stroke: HR: 1.44, 95% CI: 1.13-1.85). Similar trends and associations were observed in those with chronic pain. Two-sample Mendelian randomization results supported a causal effect of multisite pain on MI risk, but not vice versa. No causal association was found between multisite pain and stroke risk. Conclusions: Pain in multiple sites causally increases the risk of MI, highlighting that pain should be considered when assessing individuals’ MI risk, and pain treatment and management may prevent MI risk.