Cushing’s syndrome increased risk for coronary arterial atherosclerosis

Neary NM. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2012-3754.

In a recent study supported by the NIH, researchers determined that patients with Cushing’s syndrome have a greater risk for developing coronary arterial atherosclerosis, increasing their rate of cardiovascular morbidity. These findings were published in the Journal of Clinical Endocrinology & Metabolism.

The researchers conducted a prospective case-control study of 15 consecutive patients with adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome who were matched with 15 controls (aged 32 to 66 years) with at least one risk factor for cardiac disease (ie, diabetes, hypertension, hyperlipidemia, family history of early-onset coronary artery disease and previous or current smoking).

Researchers used a multidetector CT (MDCT) coronary angiogram scan to measure calcified and noncalcified coronary plaque volume and Agatston scores. Additional variables included fasting lipids, BP, history of hypertension or diabetes and 24-hour urine free cortisol excretion.

According to data, patients with Cushing’s syndrome had significantly greater noncalcified plaque volume and Agatston scores compared with controls (noncalcified plaque volume median [interquartile ranges]: 49.5 vs. 17.9,P<.001; Agatston score: 70.6 vs. 0, P<.05).

Patients with Cushing’s syndrome also demonstrated higher systolic (143 mm Hg) and diastolic (86 mm Hg) BP compared with controls (systolic: 134 mm Hg, diastolic: 76 mm Hg).

The limitations of the study include the small cohort of patients and potential selection bias due to ectopic ACTH secretion. However, the researchers wrote that these findings demonstrate a significant difference between the two groups included in the study.

“Overall, the findings point to the possible causes of cardiovascular morbidity in patients treated with exogenous steroids and indicate the need for further studies of that population,” they wrote.

Disclosure: The researchers report no relevant financial disclosures.

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PERSPECTIVE

 Alice C. Levine

• It has long been recognized that endogenous hypercortisolism (Cushing's syndrome) and administration of supraphysiologic doses of glucocorticoids are associated with increased mortality, primarily due to cardiovascular disease. Excess glucocorticoids induce all of the features of the metabolic syndrome including obesity with central weight gain, hypertension, impaired glucose tolerance/diabetes mellitus and dyslipidemia, all of which increase cardiovascular risk. In this small but well-designed study, the authors attempt to determine whether excess glucocorticoids have a direct adverse effect on the coronary vasculature. Utilizing multidetector computerized tomographic (MDCT) coronary angiography, a validated noninvasive method of assessing calcified and noncalcified coronary plaques, they compared measurements of coronary plaques (Agatston score) in 15 patients with ACTH-dependent Cushing's syndrome (CS) vs. 15 age-, sex- and body weight-matched controls with at least one risk factor for cardiac disease. They found significantly greater coronary calcifications and noncalcified coronary plaque volumes in patients with active or previous hypercortisolism.There are obvious limitations to the study; most notably the small sample size, the predominance of patients with CS due to ectopic ACTH (14/15) and significantly more hypertension in the CS vs. the control group. However, other than the HTN, the groups were well-matched and there was no statistical difference in the Framingham risk scores between groups. This is the first study to demonstrate direct effects of CS on coronary plaque burden.
  
  The findings, while unsurprising, underscore several important features of CS which endocrinologists need to consider. Firstly, as there were no statistical differences in plaque burden in patients with CS who were eucortisolemic (4/15) vs. those who were hypercortisolemic (11/15) at the time of study, the effects of CS on the coronary vasculature may persist even after biochemical cure. Many previous studies in larger cohorts have similarly demonstrated that the adverse effects of high glucocorticoids on cardiovascular, metabolic, psychiatric and neurocognitive function may be only partially reversible with disease remission. Secondly, even adjusting for all the confounding variables, hypercortisolism seems to be an independent risk factor for the development of coronary artery disease. The possible mechanisms underlying this observation are discussed and include increases in prothrombotic factors, circulating levels of vascular endothelial growth factor (VEGF) and angiogenesis. It is also plausible that cortisol increases atherosclerosis through the mineralocorticoid rather than the glucocorticoid receptor, suggesting the possibility of treating this particular deleterious effect of hypercortisolism with a mineralocorticoid-receptor blocker such as spironolactone.
  
  Within the CS group, no significant correlations were observed between the coronary plaque volumes and the duration of CS or urinary free cortisol (UFC) either at presentation or at the time of MDCT. Although this lack of correlation may also be attributable to the small sample size, it is well known that the onset of Cushing's syndrome is often insidious and it is impossible to pinpoint the exact duration of the abnormality in most patients. This study's finding of direct, adverse and possibly irreversible effects of hypercortisolism on the coronary vasculature should make endocrinologists even more vigilant in diagnosing and treating the disease as early as possible in its course.
• • Alice C. Levine, MD
  • Professor of medicine, division of endocrinology, diabetes and bone diseases
    Co-Director of The Adrenal Center
    Icahn School of Medicine
    Mount Sinai, New York, NY
• Disclosures: Levine reports no relevant financial disclosures.

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