Inhibition of Cortisol Production With Metyrapone Prevents Mental Stress-Induced Endothelial Dysfunction and Baroreflex Impairment

Broadley, Andrew; Korszun, Ania; Abdelaal, Eltigani; Moskvina, Valentina; Jones, Christopher J.; Nash, Gerard B.; Ray, Clare J.; Deanfield, John; Frenneaux, Michael

doi:10.1016/j.jacc.2005.03.068

Cited by 125 publications

(112 citation statements)

References 35 publications

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“…FMD is not impaired by elevations in plasma epinephrine in experimental settings (37). Intravenous administration of acetylcholine and cortisol antagonists do affect FMD (38); however, the doses of inhaled anticholinergics that are absorbed and circulate to the brachial artery are low. Additional adjustment of COPD medications did not explain associations of FMD and lung measures, and associations were present in patients without COPD who were not administered these medications.…”

Section: Discussionmentioning

confidence: 99%

Impaired Flow-mediated Dilation Is Associated with Low Pulmonary Function and Emphysema in Ex-smokers

Barr¹,

Mesía-Vela²,

Austin³

et al. 2007

Am J Respir Crit Care Med

222

228

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Rationale: Basic science research suggests a causal role for endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Clinical studies examining endothelial function are lacking, particularly early in the disease. Flow-mediated dilation (FMD) is a physiologic measure of endothelial reactivity to endogenous nitric oxide. Objectives: We hypothesized that lower FMD among former smokers would be associated with lower post-bronchodilator FEV 1 , higher percentage of emphysema using computed tomography (CT) and lower diffusing capacity. Methods: We measured FMD, pulmonary function, and CT percentage of emphysema in a random sample of 107 cotinine-confirmed former smokers in the ongoing EMCAP study. FMD was defined as percentage change in the brachial artery diameter with reactive hyperemia. Generalized additive models were used to adjust for potential confounders and assess linearity. Measurements and Main Results: Mean age of participants was 71 6 5 years, 46% were female, and pack-years averaged 48 6 26. Mean FMD was 3.8 6 3.1%; mean post-bronchodilator FEV 1 , 2.3 6 0.8 L; and mean CT percentage of emphysema, 26 6 10%. A 1 SD decrease in FMD was associated with a 132-ml (95% confidence interval, 16-248 ml; P 5 0.03) decrement in post-bronchodilator FEV 1 and a 2.6% (95% confidence interval, 0.5-4.7%; P 5 0.02) increase in CT percentage of emphysema in fully adjusted models. These associations were linear across the spectrum from normality to disease, independent of smoking history, and also significant among participants without COPD. Associations with diffusing capacity were consistent but nonsignificant (P 5 0.09). The FMD-FEV 1 association was entirely attributable to percentage of emphysema. Conclusions: Impaired endothelial function, as measured by FMD, was associated with lower FEV 1 and higher CT percentage of emphysema in former smokers early in COPD.Keywords: pulmonary disease, chronic obstructive; bronchitis, chronic; pulmonary emphysema; endothelial dysfunction Recent research on the pathogenesis of chronic obstructive pulmonary disease (COPD) suggests that perturbations in the vasculature and, specifically, endothelial health may occur early in COPD (1). Decreased expression of vascular endothelial growth factor (VEGF) causes endothelial apoptosis, epithelial apoptosis, and emphysema (2-4). The second messenger lipid ceramide mediates VEGF blockade-induced apoptosis in COPD and ceramide instillation acutely triggers apoptosis in pulmonary endothelial cells, causing emphysema in mice (5).Apoptotic endothelial cells are present in the lungs of smokers with COPD (6, 7), and there are significant morphologic differences in the endothelium of smokers with mild, moderate, and severe COPD compared with smokers without COPD (8). Furthermore, nitric oxide (NO)-mediated, endotheliumdependent relaxation provoked by adenosine diphosphate and acetylcholine is attenuated in the excised pulmonary arteries of patients with COPD compared with those of smoking and nonsmoking control subjects (9, 10). Publ...

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Section: Discussionmentioning

confidence: 99%

Impaired Flow-mediated Dilation Is Associated with Low Pulmonary Function and Emphysema in Ex-smokers

Barr¹,

Mesía-Vela²,

Austin³

et al. 2007

Am J Respir Crit Care Med

222

228

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“…There is widespread agreement for a key role of endothelial dysfunction in the adverse effects of stress on the cardiovascular system (44,114,198,313). Social interactions in monkeys accelerate atherosclerosis, possibly through activation of the sympathetic nervous system (317).…”

Section: A Central Role For the Endotheliummentioning

confidence: 99%

Chronic stress impacts the cardiovascular system: animal models and clinical outcomes

Golbidi

Frisbee

Laher

2015

American Journal of Physiology-Heart and Circulatory Physiology

178

132

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“…The experience of a severe cardiac event such as an ACS is a strong emotional stressor, but the fact that elevated cortisol output was not related to depressed mood or diagnosed depression 3 weeks after an ACS suggests that the phenomenon is not specifically associated with experience of ACS. Nonetheless, the observation that these individuals have raised cortisol output over the day may increase their risk of cardiac sequelae through the impact of HPA function on inflammatory responses, endothelial dysfunction and insulin resistance (Girod & Brotman, 2004 ;Broadley et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Cortisol levels and history of depression in acute coronary syndrome patients

et al. 2012

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BackgroundDepressed mood following an acute coronary syndrome (ACS) is a risk factor for future cardiac morbidity. Hypothalamic–pituitary–adrenal (HPA) axis dysregulation is associated with depression, and may be a process through which depressive symptoms influence later cardiac health. Additionally, a history of depression predicts depressive symptoms in the weeks following ACS. The purpose of this study was to determine whether a history of depression and/or current depression are associated with the HPA axis dysregulation following ACS.MethodA total of 152 cardiac patients completed a structured diagnostic interview, a standardized depression questionnaire and a cortisol profile over the day, 3 weeks after an ACS. Cortisol was analysed using: the cortisol awakening response (CAR), total cortisol output estimated using the area under the curve method, and the slope of cortisol decline over the day.ResultsTotal cortisol output was positively associated with history of depression, after adjustment for age, gender, marital status, ethnicity, smoking status, body mass index (BMI), Global Registry of Acute Cardiac Events (GRACE) risk score, days in hospital, medication with statins and antiplatelet compounds, and current depression score. Men with clinically diagnosed depression after ACS showed a blunted CAR, but the CAR was not related to a history of depression.ConclusionsPatients with a history of depression showed increased total cortisol output, but this is unlikely to be responsible for associations between depression after ACS and later cardiac morbidity. However, the blunted CAR in patients with severe depression following ACS indicates that HPA dysregulation is present.

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Inhibition of Cortisol Production With Metyrapone Prevents Mental Stress-Induced Endothelial Dysfunction and Baroreflex Impairment

Abstract: Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.

Cited by 125 publications

References 35 publications

Impaired Flow-mediated Dilation Is Associated with Low Pulmonary Function and Emphysema in Ex-smokers

Impaired Flow-mediated Dilation Is Associated with Low Pulmonary Function and Emphysema in Ex-smokers

Chronic stress impacts the cardiovascular system: animal models and clinical outcomes

Cortisol levels and history of depression in acute coronary syndrome patients

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