OBJECTIVE: Individuals with bipolar disorder are at greater risk of developing cardiovascular disease. However, the mechanisms underlying this association remain poorly understood. This study aimed to (1) determine the risk of major adverse cardiovascular events (MACE) after adjusting for important confounders and (2) evaluate the neural, autonomic, and immune mechanisms underlying the link between bipolar disorder and cardiovascular disease. METHODS: Leveraging the Mass General Brigham Biobank, bipolar disorder and incident MACE were identified using the International Classification of Disease (ICD) codes. Incident MACE events were assessed from enrollment to the date of data lock (December 2020)
or to the 10-year period. Health behavior data were derived from optional surveys. Cox regression hazard models were applied. RESULTS: Of 118,827 Biobank participants, 6009 were diagnosed with bipolar disorder. Those with bipolar disorder (vs. without) demonstrated a higher risk of MACE after adjusting for cardiovascular risk factors (hazard ratio [95% confidence interval] = 1.29 [1.10-1.51], p = 0.002). The relationship remained significant over 10 years after adjustment for unhealthy lifestyle behaviors (1.29 [1.03, 1.61], p = 0.025). Furthermore, SNA, autonomic nervous system, and inflammatory markers each significantly associated with both bipolar disorder and MACE risk. Each of these measures mediated the association between bipolar disorder and MACE (accounting for 3.8%-17.8% of the relationship). CONCLUSION: This study demonstrates that bipolar disorder associates with heightened cardiovascular risk, even after accounting for cardiovascular risk. Moreover, the findings suggest that neurobiological pathways and perturbations in autonomic and inflammatory pathways may confer cardiovascular risk in bipolar disorder.