ACTH Infusion Impairs Baroreflex Sensitivity-Implications for Cardiovascular Hypoglycemia-Associated Autonomic Failure

Abstract

Context: Hypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality.

Objective: The objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1-24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day.

Design: A double-blind, placebo-controlled, random-order, cross-over study was conducted.

Setting: This study took place in a clinical research center.

Participants: Participants included healthy men and women.

Interventions: Interventions included an intravenous infusion of cosyntropin (70 μg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo.

Main outcome measures: Outcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions.

Results: Cosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ± 1.38 vs 17.0 ± 2.07; during 14.4 ± 1.43 vs 17.3 ± 1.65; and next day 14.8 ± 1.42 vs 18.9 ± 2.04; P < .05, time by treatment, analysis of variance). BRS was decreased during the final 30 minutes of the morning cosyntropin infusion as compared to baseline (P < .01) and remained suppressed the next day (16 hours after afternoon infusion) (P < .025). Placebo infusion did not significantly change BRS. Corrected QT interval was not affected.

Conclusions: ACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

Trial registration: ClinicalTrials.gov NCT02339506.

Keywords: ACTH; autonomic failure; baroreflex; cortisol; hypoglycemia.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Experimental design. Participants completed 2 study conditions (two 2.5-hour infusions of placebo [0.9% saline] and synthetic adrenocorticotropin [1-24] [cosyntropin] 70 µg/hour) in random order with 1 to 3 months between study visits. MO refers to the modified Oxford test for assessing baroreflex sensitivity performed at baseline (before morning infusion), during the morning infusion (between 2 and 2.5 hours after start of morning infusion), and the following day (24 hours after baseline measures on day 1 and 16 hours after completion of the second infusion on day 1).

Figure 2.

Participant flow diagram.

Figure 3.

Cortisol levels during cosyntropin and placebo infusions. Cosyntropin infusion significantly increased serum cortisol levels compared to placebo infusion, P less than .001 time × treatment interaction (analysis of variance, ANOVA). Mean ± SEM are displayed, n = 16. Circles denote placebo and squares cosyntropin infusion. MO refers to the modified Oxford technique.

Figure 4.

Effect of cosyntropin and placebo infusion on baroreflex sensitivity. Baroreflex sensitivity (BRS) was measured by the modified Oxford method at baseline (preinfusion), during the morning infusion (between 2 and 2.5 hours after start of morning infusion) and the following day (24 hours after baseline measures on day 1). Cosyntropin infusion significantly decreased BRS as compared to placebo, P less than .05 time × treatment interaction (analysis of variance, ANOVA). Cosyntropin infusion decreased BRS during morning infusion and the next day compared to baseline (preinfusion), *P less than .05. Placebo infusion did not alter BRS. Mean ± SEM are displayed, n = 17. Circles denote placebo and squares denote cosyntropin infusion.

Figure 5.

Baroreflex sensitivity of representative participant during modified Oxford technique. Baroreflex sensitivity is represented by the slope of the relationship between systolic blood pressure (SBP) and R-R interval. Data from a single individual displays a decrease in the linear relationship during the morning cosyntropin infusion compared to baseline (preinfusion) the same day. Solid squares denote cosyntropin and open squares denote baseline (preinfusion).