The Relationship between Depression, Stress-Related Neurobiology, and Incident Heart Failure: Understanding the Neurobiological Mechanisms Underlying Exercise as a Preventive Measure

Abstract

Background: Numerous evidence underscores the link between high metabolic activity in the brain related to stress (stress-related neural network activity, SNA) and increased risk of cardiovascular disease (CVD) events, including heart failure (HF). Our recent study has demonstrated that physical activity (PA) can effectively decrease SNA levels in a dose-dependent manner. Based on this compelling evidence, we hypothesize that PA may decrease the risk of incident HF in part through a reduction in SNA.

Method: Self-reported PA data were acquired from Mass General Brigham (MGB) Biobank participants. The metabolic equivalent of task minutes per week (MET*minutes/week) was calculated and categorized according to current PA recommendations ( 500 and ≥ 500 METmin/wk). In a subset with 18F-fluorodeoxyglucose positron emission tomography imaging (n=679), SNA was measured as a ratio of amygdalar to ventromedial prefrontal cortical activity (vmPFC). Subsequent HF and baseline CVD risk factor data were obtained using ICD Codes. Linear and Cox regression models were employed to evaluate the relationship between PA vs. HF risk. Mediation analysis was used to test whether PA’s impact on SNA significantly mediated the association between PA and HF.

Results: Among 48,673 participants (median age 60 years [IQR 44 - 70], 39.5% male). PA within recommended level associated with a lower risk of subsequent HF (hazard ratio (HR) [95% confidence interval (CI)]: 0.829 [ 0.743, 0.926], p 0.001). Mediation analysis showed that PA reduces HF risk in part via reductions in SNA, accounting for 9.1% of the total relationship between PA and HF risk (p 0.05). Moreover, among individuals with pre-existing depression and/or anxiety, PA was associated with greater reductions in ten-year HF risk compared to those 28 without depression and/or anxiety (HR [95% CI]: 0.836 [0.785, 0.891] vs. 0.882 [0.858, 0.907], p- interaction=0.048).

Conclusion: PA associates with reductions in SNA activity and subsequent HF risk. Notably, this reduction is greater among those with pre-existing depression and/or anxiety. Moreover, the mechanism by which PA reduces HF risk may involve salutary effects on stress-related neural pathways.