Higher Activation of the Rostromedial Prefrontal Cortex During Mental Stress Predicts Major Cardiovascular Disease Events in Individuals With Coronary Artery Disease

Circulation. 2020 Aug 4;142(5):455-465. doi: 10.1161/CIRCULATIONAHA.119.044442. Epub 2020 Jun 11.

Abstract

Background: Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease. Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE.

Methods: Participants with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high-resolution positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 levels 90 minutes after stress, and high-frequency heart rate variability during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure hospitalization.

Results: We studied 148 subjects (69% male) with mean±SD age of 62±8 years. After adjustment for baseline demographics, risk factors, and baseline levels of interleukin-6 and high-frequency heart rate variability, higher rmPFC stress reactivity was independently associated with higher interleukin-6 and lower high-frequency heart rate variability with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each increase of 1 SD in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (hazard ratio, 1.21 [95% CI, 1.08-1.37]). Stress-induced interleukin-6 and high-frequency heart rate variability explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (P=0.03).

Conclusions: Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.

Keywords: coronary artery disease; heart rate; inflammation; prefrontal cortex; stress, psychological; treatment outcome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Angina, Unstable / etiology*
  • Angina, Unstable / surgery
  • Comorbidity
  • Coronary Artery Disease / complications
  • Coronary Artery Disease / physiopathology*
  • Default Mode Network / physiology*
  • Emotions / physiology
  • Female
  • Heart Disease Risk Factors
  • Heart Failure / etiology*
  • Heart Rate
  • Hospitalization / statistics & numerical data
  • Humans
  • Inflammation
  • Interleukin-6 / blood
  • Male
  • Mathematics
  • Middle Aged
  • Myocardial Infarction / etiology*
  • Myocardial Revascularization / statistics & numerical data
  • Neuroimaging*
  • Positron-Emission Tomography*
  • Prefrontal Cortex / physiopathology*
  • Prognosis
  • Speech / physiology
  • Stress, Psychological / diagnostic imaging
  • Stress, Psychological / physiopathology*

Substances

  • IL6 protein, human
  • Interleukin-6