Cardiovascular and Ventilatory Regulation in Chronic Obstructive Pulmonary Disease

• Author / Creator

  Phillips, Devin B

• The purpose of this dissertation was to investigate cardiovascular function and ventilatory regulation at rest and during exercise in patients with chronic obstructive pulmonary disease (COPD). This dissertation consisted of three separate experiments that aimed to provide insight into the pathophysiology of COPD and examine potential therapeutic interventions to improve dyspnea and exercise capacity in patients with COPD.
  The first study examined the effect of carotid chemoreceptor (CC) inhibition on cardiovascular and ventilatory regulation at rest in patients with mild to moderate COPD. Thirteen mild-moderate COPD patients and thirteen age- and risk-matched controls completed resting cardiovascular function measurements with either intravenous saline or dopamine (2 mcg·kg-1·min-1) while breathing normoxia or hyperoxia (100% O2). On a separate day, a subset of seven COPD patients and seven controls completed muscle sympathetic nervous activity (MSNA) measurements while breathing normoxia or hyperoxia (100% O2). Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). Carotid chemoreceptor inhibition with dopamine decreased PWV, and MAP (p<0.05) while increasing vascular conductance in COPD. No change in cardiovascular function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (p<0.05) in COPD but not controls.
  The second study examined the effect of CC on ventilatory and cardiovascular regulation, dyspnea and exercise tolerance in patients with mild to moderate COPD. Twelve COPD patients and twelve age- and risk-matched healthy controls completed two time-to-symptom limitation (TLIM) constant load exercise tests at 75% peak power output with the order randomized to either intravenous saline or low-dose dopamine (2 mcg·kg-1·min-1) to inhibit the CC. Ventilatory responses were evaluated using expired gas data and dyspnea was evaluated using a modified Borg scale. Inspiratory capacity maneuvers were performed to determine operating lung volumes. Cardiac output was estimated using impedance cardiography and vascular conductance was calculated as cardiac output/MAP. At a standardized exercise time of 4-minutes and at TLIM, ventilation, operating volumes and dyspnea were not different between saline and dopamine conditions in COPD or controls. Mean arterial blood pressure was decreased with dopamine, secondary to increased vascular conductance, in COPD, while no change was observed in controls. There was no change in time to exhaustion in either group with dopamine.
  The third study examined the effect of inhaled nitric oxide (iNO) on ventilation, dyspnea and exercise capacity in patients with mild COPD. In a randomized-control crossover study, fifteen patients with mild COPD and fifteen healthy age- and risk-matched controls completed symptom-limited cardiopulmonary exercise tests (CPET) while breathing either normoxia (placebo) or 40 parts per million iNO. During the CPET, detailed ventilatory, hemodynamic and perceptual response data were obtained. Inhaled NO increased peak oxygen uptake (p<0.05) in COPD, compared to placebo, while no effect was observed in controls. At the highest equivalent work rate of 60 Watts, iNO reduced ventilation and dyspnea (both p=0.05) in COPD, while no effect was observed in controls.
  When combined, the experimental results suggest three major findings. First, CC inhibition decreased PWV, MSNA and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in mild to moderate COPD. Second, CC inhibition with low-dose dopamine improved exercise vascular conductance in COPD, however, ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in mild to moderate COPD patients. The results suggest that the CC appears to be a modulator of vasoconstrictor outflow during exercise in COPD patients, however, the exaggerated ventilatory response typically observed in COPD was not explained by heightened activity and sensitivity of the CC (i.e. autonomic dysfunction). Lastly, iNO increased exercise capacity in mild COPD, secondary to reduced ventilation and dyspnea. These data suggest that mild COPD patients demonstrated pulmonary vascular dysfunction that contributed to exercise intolerance, secondary to inefficiencies in gas exchange. Further, these data help to explain why patients with mild COPD demonstrate disproportionately greater dyspnea relative to the degree of airway obstruction. The results of this dissertation help to identify therapeutic targets to lower cardiovascular risk, reduce dyspnea and increase exercise capacity in patients with COPD.

• Subjects / Keywords

  • Dyspnea
  • Ventilatory Regulation
  • Cardiovascular Function
  • Chronic Obstructive Pulmonary Disease

• Graduation date

  Spring 2020

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-4m8q-8938

• License

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