Publications by authors named "Sandra G Vincent"

14 Publications

  • Page 1 of 1

Qualitative Components of Dyspnea during Incremental Exercise across the COPD Continuum.

Med Sci Sports Exerc 2021 Dec;53(12):2467-2476

Respiratory Investigation Unit, Department of Medicine, Queen's University and Kingston Health Sciences Centre, Kingston General Hospital Campus, Kingston, Ontario, CANADA.

Introduction: Evaluation of the intensity and quality of activity-related dyspnea is potentially useful in people with chronic obstructive pulmonary disease (COPD). The present study sought to examine associations between qualitative dyspnea descriptors, dyspnea intensity ratings, dynamic respiratory mechanics, and exercise capacity during cardiopulmonary exercise testing (CPET) in COPD and healthy controls.

Methods: In this cross-sectional study, 261 patients with mild-to-very severe COPD (forced expiratory volume in 1 s, 62 ± 25%pred) and 94 age-matched controls (forced expiratory volume in 1 s, 114 ± 14%pred) completed an incremental cycle CPET to determine peak oxygen uptake (V˙O2peak). Throughout exercise, expired gases, operating lung volumes, and dyspnea intensity were assessed. At peak exercise, dyspnea quality was assessed using a modified 15-item questionnaire.

Results: Logistic regression analysis revealed that among 15 dyspnea descriptors, only those alluding to the cluster "unsatisfied inspiration" were consistently associated with an increased likelihood for both critical inspiratory mechanical constraint (end-inspiratory lung volume/total lung capacity ratio ≥0.9) during exercise and reduced exercise capacity (V˙O2peak < lower limit of normal) in COPD (odds ratio (95% confidence interval), 3.26 (1.40-7.60) and 3.04 (1.24-7.45), respectively; both, P < 0.05). Thus, patients reporting "unsatisfied inspiration" (n = 177 (68%)) had an increased relative frequency of critical inspiratory mechanical constraint and low exercise capacity compared with those who did not select this descriptor, regardless of COPD severity or peak dyspnea intensity scores.

Conclusions: In patients with COPD, regardless of disease severity, reporting descriptors in the unsatisfied inspiration cluster complemented traditional assessments of dyspnea during CPET and helped identify patients with critical mechanical abnormalities germane to exercise intolerance.
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http://dx.doi.org/10.1249/MSS.0000000000002741DOI Listing
December 2021

Mechanisms of Exertional Dyspnea in Patients with Mild COPD and a Low Resting DL.

COPD 2021 10 8;18(5):501-510. Epub 2021 Sep 8.

Respiratory Investigation Unit, Department of Medicine, Queen's University, and Kingston Health Sciences Centre, Kingston, Ontario, Canada.

Patients with mild chronic obstructive pulmonary disease (COPD) and lower resting diffusing capacity for carbon monoxide (DL) often report troublesome dyspnea during exercise although the mechanisms are not clear. We postulated that in such individuals, exertional dyspnea is linked to relatively high inspiratory neural drive (IND) due, in part, to the effects of reduced ventilatory efficiency. This cross-sectional study included 28 patients with GOLD I COPD stratified into two groups with ( = 15) and without ( = 13) DL less than the lower limit of normal (
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http://dx.doi.org/10.1080/15412555.2021.1932782DOI Listing
October 2021

In vivo cardiopulmonary impact of skeletal MDq DREADD expression: a pilot study.

J Comp Physiol B 2021 Nov 16;191(6):1059-1070. Epub 2021 Jul 16.

Department of Biomedical and Molecular Sciences and Division of Respirology, Department of Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.

The muscarinic M receptor (MR) is implicated in cardiopulmonary control and many other peripheral physiologic functions. Previous observations report mortality in mice expressing a Gq-linked designer G-protein coupled receptor (Dq) selectively in striated muscle, while MDq DREADD (Designer Receptor Exclusively Activated by Designer Drug), selectively expressed in skeletal muscle (SKM) impacts glucose metabolism. We investigated whether activation of SKM MDq impacts cardiopulmonary function. Heart rate (HR), body temperature (Tb) and locomotor activity (ACT) were measured in 4 conscious, chronically instrumented MDq DREADD mice and 4 wildtype controls. Circadian values of HR, BT and ACT were not different between genotypes (p > 0.05). Activation of the MDq DREADD by clozapine N-oxide (CNO; 0.1 mg/kg) resulted in: a significant drop in heart rate, 2 h after injection, compared with a time-matched baseline control period from the same animals (460 ± 28 vs. 532 ± 6, p < 0.05), significantly lower ACT compared to the baseline control (p < 0.05) and reduced pulmonary minute ventilation compared to pre-CNO control (p < 0.05). MDq DREADD activation did not cause bronchoconstriction (separate protocol), however, there was a concomitant reduction in HR, Tb and ventilation, accompanied by cardiac arrhythmias. We speculate that reductions in Tb, HR and ventilation reflect a mechanistic link between SKM Gq signaling and the metabolic responses associated with the initiation of torpor. Supported by the Canadian Institutes of Health Research (CIHR MOP-81211).
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http://dx.doi.org/10.1007/s00360-021-01387-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572194PMC
November 2021

Reduced exercise tolerance in mild chronic obstructive pulmonary disease: The contribution of combined abnormalities of diffusing capacity for carbon monoxide and ventilatory efficiency.

Respirology 2021 08 7;26(8):786-795. Epub 2021 Apr 7.

Respiratory Investigation Unit, Department of Medicine, Queen's University and Kingston Health Sciences Centre, Kingston General Hospital Campus, Kingston, Ontario, Canada.

Background And Objective: The combination of both reduced resting diffusing capacity of the lung for carbon monoxide (DL ) and ventilatory efficiency (increased ventilatory requirement for CO clearance [V˙ /V˙CO ]) has been linked to exertional dyspnoea and exercise intolerance in chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are poorly understood. The current study examined if low resting DL and higher exercise ventilatory requirements were associated with earlier critical dynamic mechanical constraints, dyspnoea and exercise limitation in patients with mild COPD.

Methods: In this retrospective analysis, we compared V˙ /V˙CO , dynamic inspiratory reserve volume (IRV), dyspnoea and exercise capacity in groups of patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 COPD with (1) a resting DL at or greater than the lower limit of normal (≥LLN; Global Lung Function Initiative reference equations [n = 44]) or (2) below the
Results: Spirometry and resting lung volumes were similar in the two COPD groups. During exercise, V˙ /V˙CO (nadir and slope) was consistently higher in the DL  < LLN compared with the other groups (all p < 0.05). The DL  < LLN group had lower IRV and greater dyspnoea intensity at standardized submaximal work rates and lower peak work rate and oxygen uptake than the other two groups (all p < 0.05).

Conclusion: Reduced exercise capacity in patients with DL  < LLN was related to higher ventilatory requirements, a faster rate of decline in dynamic IRV and greater dyspnoea during exercise. These simple measurements should be considered for the clinical evaluation of unexplained exercise intolerance in individuals with ostensibly mild COPD.
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http://dx.doi.org/10.1111/resp.14045DOI Listing
August 2021

Elevated exercise ventilation in mild COPD is not linked to enhanced central chemosensitivity.

Respir Physiol Neurobiol 2021 02 5;284:103571. Epub 2020 Nov 5.

Respiratory Investigation Unit, Department of Medicine, Queen's University and Kingston Health Sciences Centre Kingston General Hospital Campus, Kingston, Ontario, Canada. Electronic address:

Background: The purpose of this study was to determine if altered central chemoreceptor characteristics contributed to the elevated ventilation relative to carbon dioxide production (V̇/V̇CO) response during exercise in mild chronic obstructive pulmonary disease (COPD).

Methods: Twenty-nine mild COPD and 19 healthy age-matched control participants undertook lung function testing followed by symptom-limited incremental cardiopulmonary exercise testing . On a separate day, basal (non-chemoreflex) ventilation (V̇), the central chemoreflex ventilatory recruitment threshold for CO (VRTCO), and central chemoreflex sensitivity (V̇) were assessed using the modified Duffin's CO rebreathing method. Resting arterialized blood gas data were also obtained.

Results: At standardized exercise intensities, absolute V̇ and V̇/V̇CO were consistently elevated and the end-tidal partial pressure of CO was relatively decreased in mild COPD versus controls (all p < 0.05). There were no between-group differences in resting arterialized blood gas parameters, basal V̇, VRTCO, or V̇ (all p > 0.05).

Conclusion: These data have established that excessive exercise ventilation in mild COPD is not explained by altered central chemosensitivity.
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http://dx.doi.org/10.1016/j.resp.2020.103571DOI Listing
February 2021

Evaluation of Dynamic Respiratory Mechanical Abnormalities During Conventional CPET.

Front Med (Lausanne) 2020 10;7:548. Epub 2020 Sep 10.

Respiratory Investigation Unit, Division of Respirology, Department of Medicine, Kingston Health Sciences Centre & Queen's University, Kingston, ON, Canada.

Assessment of the ventilatory response to exercise is important in evaluating mechanisms of dyspnea and exercise intolerance in chronic cardiopulmonary diseases. The characteristic mechanical derangements that occur during exercise in chronic respiratory conditions have previously been determined in seminal studies using esophageal catheter pressure-derived measurements. In this brief review, we examine the emerging role and clinical utility of conventional assessment of dynamic respiratory mechanics during exercise testing. Thus, we provide a physiologic rationale for measuring operating lung volumes, breathing pattern, and flow-volume loops during exercise. We consider standardization of inspiratory capacity-derived measurements and their practical implementation in clinical laboratories. We examine the evidence that this iterative approach allows greater refinement in evaluation of ventilatory limitation during exercise than traditional assessments of breathing reserve. We appraise the available data on the reproducibility and responsiveness of this methodology. In particular, we review inspiratory capacity measurement and derived operating lung volumes during exercise. We demonstrate, using recent published data, how systematic evaluation of dynamic mechanical constraints, together with breathing pattern analysis, can provide valuable insights into the nature and extent of physiological impairment contributing to exercise intolerance in individuals with common chronic obstructive and restrictive respiratory disorders.
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http://dx.doi.org/10.3389/fmed.2020.00548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533639PMC
September 2020

Deterioration of Nighttime Respiratory Mechanics in COPD: Impact of Bronchodilator Therapy.

Chest 2021 01 27;159(1):116-127. Epub 2020 Jun 27.

Department of Medicine, Queen's University, Kingston, Canada; Division of Respiratory Medicine, Queen's University, Kingston, Canada. Electronic address:

Background: COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV have been documented previously. However, the precise nature of this deterioration and mechanisms by which evening bronchodilation may mitigate this occurrence have not been studied.

Research Question: What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)?

Study Design And Methods: A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 μg) or placebo on morning trough IC (12 h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12 h after the dose and compared with sleeping IND.

Results: Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12 h after the dose (P = .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12 h after the dose, and IC for 10 h after the dose were improved (P < .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P < .05) with no change in ventilation or breathing pattern.

Interpretation: Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765.
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http://dx.doi.org/10.1016/j.chest.2020.06.033DOI Listing
January 2021

Low resting diffusion capacity, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease.

J Appl Physiol (1985) 2019 10 1;127(4):1107-1116. Epub 2019 Aug 1.

Department of Medicine and Queen's University and Kingston Health Sciences Centre, Kingston, Ontario, Canada.

The mechanisms linking reduced diffusing capacity of the lung for carbon monoxide (Dl) to dyspnea and exercise intolerance across the chronic obstructive pulmonary disease (COPD) continuum are poorly understood. COPD progression generally involves both Dl decline and worsening respiratory mechanics, and their relative contribution to dyspnea has not been determined. In a retrospective analysis of 300 COPD patients who completed symptom-limited incremental cardiopulmonary exercise tests, we tested the association between peak oxygen-uptake (V̇o), Dl, and other resting physiological measures. Then, we stratified the sample into tertiles of forced expiratory volume in 1 s (FEV) and inspiratory capacity (IC) and compared dyspnea ratings, pulmonary gas exchange, and respiratory mechanics during exercise in groups with normal and low Dl [i.e.,
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http://dx.doi.org/10.1152/japplphysiol.00341.2019DOI Listing
October 2019

Unraveling the Causes of Unexplained Dyspnea: The Value of Exercise Testing.

Clin Chest Med 2019 06;40(2):471-499

Department of Medicine, Queen's University, Kingston Health Sciences Centre, 102 Stuart Street, Kingston, Ontario K7L 2V6, Canada.

Unexplained dyspnea presents a significant diagnostic challenge. Dyspnea arises when inspiratory neural drive (IND) to the respiratory muscles is increased and the respiratory system fails to meet this increased demand. Cardiopulmonary exercise testing (CPET) is a valuable tool to unravel the causes of exertional dyspnea in the individual. Moreover, analysis of breathing pattern, operating lung volumes and flow-volume loops allows characterization of abnormal dynamic mechanical response to increased IND - an important source of breathing discomfort. We illustrate the clinical utility of this approach which examines respiratory sensation, ventilatory control, respiratory mechanics and cardio-circulatory responses in cases of unexplained dyspnea.
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http://dx.doi.org/10.1016/j.ccm.2019.02.014DOI Listing
June 2019

Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists.

Proc Natl Acad Sci U S A 2018 11 7;115(47):12046-12050. Epub 2018 Nov 7.

Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany;

Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.
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http://dx.doi.org/10.1073/pnas.1813988115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255194PMC
November 2018

Interaction of hypoxia and core temperature: potential role of TRPV1.

Adv Exp Med Biol 2012 ;758:173-8

Department of Biomedical and Molecular Sciences, Queen's University, Ontario, Kingston, Canada.

Hypoxia exposure in small mammals elicits an initial rise in ventilation followed by a reduction to levels that are often less than the normoxic value. The fall in ventilation is matched by a decrease in metabolism rate and a reduction in core body temperature (Tb). The transient receptor potential vanilloid 1 (TRPV1) ion channel has been implicated in thermoregulation (Caterina et al., Science 288:306-313, 2000) and recently shown to exert a tonic effect on Tb in human subjects (Gavva et al., Pain 136:202-210, 2008). We review herein the hypothesis that TRPV1 modulates the Tb response to hypoxia. We provide preliminary evidence that a 24 h hypoxia (FIO(2)=0.1) exposure caused an enhanced decrease in Tb in mutant TRPV1(-/-) mice compared to the TRPV1(+/+) genotype (Tb was » 1°C lower than TRPV1(+/+)). Further investigation is warranted to determine the extent of TRPV1 ion channel involvement in acute and adaptive responses to hypoxia.
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http://dx.doi.org/10.1007/978-94-007-4584-1_24DOI Listing
April 2013

A murine model of hyperdopaminergic state displays altered respiratory control.

FASEB J 2007 May 25;21(7):1463-71. Epub 2007 Jan 25.

Department of Physiology, Queen's University, Kingston, ON K7L 3N6, Canada.

The dopamine transporter (DAT) protein plays an important role in the termination of dopamine signaling. We addressed the hypothesis that loss of DAT function would result in a distinctive cardiorespiratory phenotype due to the significant role of dopamine in the control of breathing, especially with respect to chemical control, metabolism, and thermoregulation. The DAT knockout mouse (DAT-/-) displays a state of functional hyperdopaminergia characterized by marked novelty driven hyperactivity. Certain behavioral and drug responses in these mice are reminiscent of endophenotypes of individuals with attention deficit hyperactivity disorders (ADHD). We performed experiments on conscious, unrestrained DAT-/- mice (KO) and littermate DAT+/+ wild-type (WT) controls. Ventilation was measured by the barometric technique during normoxia, hypoxia, or hypercapnia. We measured core body temperature and CO2 production as an index of metabolism. DAT-/- mice displayed a significantly lower respiratory frequency than WT mice, reflecting a prolonged inspiratory time. DAT-/- mice exhibited a reduced ventilatory response to hypoxia characterized by an attenuation of both the respiratory frequency and tidal volume responses. Both groups showed similar metabolic responses to hypoxia. Circadian measurements of body temperature were significantly lower in DAT-/- mice than WT mice during inactive periods. We conclude that loss of the DAT protein in this murine model of altered dopaminergic neurotransmission results in a significant respiratory and thermal phenotype that has possible implications for understanding of conditions associated with altered dopamine regulation.
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http://dx.doi.org/10.1096/fj.06-7248comDOI Listing
May 2007

Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors.

FASEB J 2004 Apr 20;18(6):711-3. Epub 2004 Feb 20.

Department of Physiology, Queen's University, Kingston, Ontario, Canada K7L 3N6.

The presence of multiple muscarinic acetylcholine receptor (mAChR) subtypes in the heart and lung, combined with the lack of mAChR subtype-selective ligands, have complicated the task of identifying the mAChR subtypes mediating cardiac slowing (bradycardia) and airway narrowing (bronchoconstriction) due to vagal innervation. To determine which of the five mAChRs are responsible for the cholinergic control of heart rate and airway caliber in vivo, we performed experiments on mutant mice lacking the two prime candidates for such control, the M2 or M3 mAChR. Here, we report that in vivo, bradycardia caused by vagal stimulation or administration of the muscarinic agonist methacholine (MCh) was abolished in mice lacking functional M2 mAChRs (M2-/- mice). In contrast, heart rate responses remained unchanged in M3 receptor-deficient mice (M3-/- mice). The reduced hypotensive response of M3-/- mice to MCh suggests M3 mAChRs contribute to peripheral vasodilation. The M2-/- mice showed significantly enhanced in vivo bronchoconstrictor responses to vagal stimulation or MCh administration. In contrast, bronchoconstrictor responses were totally abolished in M3-/- mice. Because altered cardiac or pulmonary vagal tone is involved in a number of pathophysiological conditions, including cardiac arrhythmias, chronic obstructive pulmonary disease and asthma, these results should be of considerable therapeutic relevance.
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http://dx.doi.org/10.1096/fj.03-0648fjeDOI Listing
April 2004
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