The effects of carotid chemoreceptor inhibition on exercise tolerance in health and chronic heart failure

• Author / Creator

  Collins, Sophie É

• Background and Rationale: Chronic heart failure (CHF) is a condition where heart function is insufficient to meet metabolic demand and is caused by anatomical or physiological abnormalities of the heart. In 2009, one in nine deaths included heart failure as a contributing cause, and the five-year survival rate following a diagnosis of CHF was 51.5% in 2017. CHF is characterized by heightened sympathetic nervous activity, peripheral chemosensitivity (both predictive of mortality in CHF), marked exercise intolerance and an increased ventilatory response to exercise. Amplified carotid chemoreceptor (CC) activity increases sympathetic nervous activity, which may lead to deterioration of cardiac function. Dopamine is known to suppress the CC, and previous work has shown that CC inhibition increases peripheral blood flow both at rest and during exercise in HF animals, suggesting that dopamine administration is a potential therapy to normalize CC activity/sensitivity and improve exercise tolerance in patients with CHF. However, this has not yet been examined in humans with CHF during full-body exercise.

  Purpose and Hypothesis: The purpose of this study was to determine the effect of CC inhibition on cardiovascular and ventilatory function, and exercise tolerance in health and CHF. It was hypothesized that CC inhibition with low-dose dopamine (2μg∙kg-1∙min-1) would result in improvements in exercise tolerance in participants with CHF but not in controls, secondary to reduced ventilation, and improved cardiac output, vascular conductance and muscle oxygenation during whole-body exercise.

  Methods: Nine clinically stable, optimally medicated patients (treated with β-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists and diuretics) with CHF (mean ejection fraction: 44 ± 3.3%) and nine age- and sex-matched controls were recruited. Participants completed 4 testing days: 1) pulmonary function and cardiopulmonary exercise tests; 2) basal chemoreflex testing (hypoxic ventilatory response test, transient hyperoxia, and progressive hypercapnic hyperoxic rebreathe); and 3/4) two time-to-symptom-limitation (TLIM) constant load cycling exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2μg·kg-1·min-1; order randomized). Ventilation was measured using expired gas data and operating lung volume data were determined during exercise by inspiratory capacity maneuvers. Dyspnea and leg discomfort ratings were obtained using a modified Borg scale. Cardiac output was estimated using impedance cardiography, and vascular conductance was calculated as cardiac output/mean arterial pressure. Tissue oxygenation was estimated using near infrared spectroscopy at the vastus lateralis and the 7th intercostal space.

  Results: CHF patients had significantly greater resting CC sensitivity as demonstrated by a higher hypoxic ventilatory response than controls (CHF: 0.74 ± 0.20; Control: 0.28 ± 0.07, p=0.046), while ventilatory responses to transient hyperoxia and CO2 rebreathe tests were not different between groups. There was no change in TLIM in either group with dopamine (CHF: saline 13.5 ± 3.0 vs dopamine 14.0 ± 1.9 min, p=0.81; Control: saline 10.9 ± 1.3 vs dopamine 13.4 ± 1.6 min, p=0.14). Dopamine had no significant effect on exercise cardiac output, ventilation, operating lung volumes, or dyspnea in CHF and controls. Dopamine had no effect on vascular conductance in patients with CHF, however there was a statistically significant increase in conductance at TLIM in controls (saline: 120 ± 8.6 vs dopamine: 139 ± 13 L·min-1·mmHg-1, p=0.027).

  Discussion and Significance: CC inhibition with dopamine does not improve exercise tolerance in chemosensitive CHF patients, suggesting that the enhanced CC sensitivity observed in CHF does not contribute to exercise intolerance. This work highlights the importance of further understanding the mechanisms of exercise intolerance in CHF, and its role in secondary prevention and management as part of the core components of cardiac rehabilitation of patients with CHF.

• Subjects / Keywords

  • carotid chemoreceptor inhibition
  • carotid chemoreceptor sensitivity
  • exercise tolerance
  • dopamine
  • carotid chemoreceptor activity
  • carotid chemoreceptor
  • cardiovascular function
  • chronic heart failure
  • ventilation

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3804Z16S

• License

  Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.