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Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization
Andrew A Crawford1,2,3, Stefan Soderberg4, Clemens Kirschbaum5
1BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Insights
Elevated morning cortisol is a causal risk factor for cardiovascular disease (CVD). This finding suggests potential new strategies for CVD prevention and treatment by targeting cortisol levels.
Area of Science:
- Endocrinology
- Cardiovascular Medicine
- Genetics
Background:
- Cardiovascular disease (CVD) remains a leading cause of death globally.
- Identifying novel causal risk factors is crucial for improving CVD risk prediction and developing effective treatments.
- Cortisol, a stress hormone, has been investigated for its potential role in CVD pathogenesis.
Purpose of the Study:
- To investigate whether cortisol is a causal risk factor for cardiovascular disease (CVD) and coronary heart disease (CHD) in the general population.
- To assess the association between morning plasma cortisol levels and incident CVD/CHD.
- To explore the utility of cortisol as a target for CVD prevention strategies.
Main Methods:
- Utilized multivariable regression in two prospective nested case-control studies (n=798).
- Performed a random-effects meta-analysis of existing prospective studies and the nested case-control data (total 6680 controls, 696 incident CVD/CHD).
- Conducted one- and two-sample Mendelian randomization analyses using large-scale genetic data (122,737 CHD cases, 547,261 controls).
Main Results:
- Prospective studies showed a positive association between morning plasma cortisol and incident CVD (OR: 1.28, 95% CI: 1.06-1.54).
- Meta-analysis confirmed this association (OR: 1.18, 95% CI: 1.06-1.31).
- Mendelian randomization analyses were consistent, suggesting a causal link (OR: 1.06, 95% CI: 0.98-1.15).
Conclusions:
- All three analytical approaches consistently indicated a positive association between elevated morning plasma cortisol and incident CVD.
- These findings strongly suggest that higher morning cortisol levels represent a causal risk factor for CVD.
- Further research evaluating interventions targeting cortisol action is warranted for CVD prevention.
Objective:
The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD).
Design And Methods:
Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses).
Results:
In the two prospective nested case-control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06-1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98-1.15.
Conclusions:
All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.
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