Effect of Stress-Related Neural Pathways on the Cardiovascular Benefit of Physical Activity

Hadil Zureigat, Michael T. Osborne, Shady Abohashem, Kenechukwu Mezue, Charbel Gharios, Simran Grewal, Alex Cardeiro, Nicki Naddaf, Giovanni Civieri, Taimur Abbasi, Azar Radfar, Wesam Aldosoky, Antonia V. Seligowski, Meagan M. Wasfy, James Sawalla Guseh, Timothy W. Churchill, Rachel P. Rosovsky, Zahi Fayad, Anthony Rosenzweig, Aaron BaggishRoger K. Pitman, Karmel W. Choi, Jordan Smoller, Lisa M. Shin, Ahmed Tawakol

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood. Objectives: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression. Methods: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC). CVD events were ascertained from electronic health records. Results: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygAC (standardized β: −0.245; 95% CI: −0.444 to −0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). Conclusions: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression.

Original languageEnglish
Pages (from-to)1543-1553
Number of pages11
JournalJournal of the American College of Cardiology
Issue number16
StatePublished - 23 Apr 2024


  • brain
  • cardiovascular disease
  • depression
  • imaging
  • stress


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