Genetic Variation of SCNN1A Influences Lung Diffusing Capacity in Cystic Fibrosis

Baker, Sarah E.; Wong, Eric C.; Wheatley, Courtney M.; Foxx-Lupo, William T.; Martínez, Melissa A.; Morgan, Mary; Sprissler, Ryan; Morgan, Wayne J.; Snyder, Eric M.

doi:10.1249/mss.0b013e318266ebc3

Cited by 8 publications

(11 citation statements)

References 41 publications

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“…NPD is a validated measure of ion channel activity and the fact that there was a relationship between EBC and NPD helps to validate EBC as a measure of changes in ASL ion concentration and as such an indirect measure of ion channel activity. Also we have previously found that 1)there is a relationship between EBC Na + and epithelial sodium channel genotypes, where the less active ENaC genotype demonstrated lower EBC Na + values 50 ; 2) CF subjects have lower EBC Cl − at baseline than healthy subjects as would be expected and ENaC genotype influences lung diffusion capacity 51 . Collectively, these findings strengthen the claim that EBC can be utilized as a measure of ion channel activity.…”

Section: Discussionmentioning

confidence: 76%

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis

Wheatley

Baker

Morgan

et al. 2015

Respiratory Medicine

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Rationale Despite the demonstrated advantageous systemic changes in response to regular exercise for individuals with cystic fibrosis (CF), exercise is still viewed as an elective rather than a vital component of therapy, and it is likely that these benefits extend to and are partially mediated by exercise-induced changes in ion regulation. Objective We sought to determine if exercise could provide comparable improvements in ion regulation in the CF lung as albuterol, measured using exhaled breath condensate (EBC) collection and nasal potential difference (NPD). Methods Fourteen CF (13-42yrs.) and sixteen healthy (18-42yrs.) subjects completed a randomized crossover study of albuterol and submaximal exercise. EBC was collected at baseline, 30- and 60-min post-albuterol administration, and at baseline and during three separate 15 min cycling exercise bouts at low, moderate, and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). NPD was performed at 30- and 80-min post albuterol or following moderate and vigorous intensity exercise. Results CF subjects had lower EBC Cl−, but no difference in EBC Na+ at baseline when compared to healthy subjects. EBC Cl− increased four-fold with moderate exercise which was similar to that seen 60-min post albuterol administration for CF subjects. Neither exercise nor albuterol altered EBC Na+. The change in NPD voltage with amiloride (ΔAmil) was greater and there was minimal Cl− secretion (ΔTCC) seen at baseline in the CF compared to the healthy subjects. ΔAmil was greater with both albuterol and exercise when compared to baseline within both CF and healthy groups, but there was no significant difference in the ΔTCC response with either treatment. Conclusion Both exercise and albuterol can alter ion regulation increasing Cl− secretion to a significant and similar degree in individuals with CF.

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Section: Discussionmentioning

confidence: 76%

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis

Wheatley

Baker

Morgan

et al. 2015

Respiratory Medicine

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“…Although not a primary aim of this study, to assess overall functional capacity ( i.e. peak VO 2 ), participants performed a seated upright peak cycle ergometry test to volitional fatigue (symptom limited) as described and reported previously by our group [ 8 ]. This assessment occurred on a separate study visit that was separated by at least 48 h but no greater than 1 week prior to participation in the present study.…”

Section: Methodsmentioning

confidence: 99%

“…Structural and physiological abnormalities of the pulmonary system in CF disease readily transgress to functional impairments as assessed by airway and gas-transfer tests. Low forced expiratory volume in one second (FEV 1 ), attenuated capacity of gas transfer within lungs, and reduced oxygen uptake (VO 2 ) at rest and during exercise are leading pulmonary system abnormalities in CF [ 4 , 6 , 8 , 9 , 11 , 12 ]; which, more importantly, strongly relate with morbidity and mortality in this population [ 1 – 3 , 5 , 6 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In this context and taking into account that β 2 AR are found in abundant concentrations in pulmonary as well as cardiac and systemic vascular tissue [ 13 – 20 ]; observations relating pulmonary airway dysfunction to impaired airway β 2 AR in CF are noteworthy and may have critical clinical implications in this population [ 13 , 14 , 19 ]. As such, our group and others have shown that individuals with CF demonstrate attenuated cardiac output (Q), large arterial dysfunction, abnormal ventilatory mechanics, and attenuated lung gas-transfer [ 8 , 9 , 11 , 12 , 21 ]. Cumulatively, these observations suggest that there is global cardiovascular system impairment in individuals with CF; and, that the hallmark clinical phenotype of this disease is not isolated to pulmonary system dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Impaired cardiac and peripheral hemodynamic responses to inhaled β2-agonist in cystic fibrosis

et al. 2015

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BackgroundPulmonary system dysfunction is a hallmark of cystic fibrosis (CF) disease. In addition to impaired cystic fibrosis transmembrane conductance regulator protein, dysfunctional β2-adrenergic receptors (β2AR) contribute to low airway function in CF. Recent observations suggest CF may also be associated with impaired cardiac function that is demonstrated by attenuated cardiac output (Q), stroke volume (SV), and cardiac power (CP) at both rest and during exercise. However, β2AR regulation of cardiac and peripheral vascular tissue, in-vivo, is unknown in CF. We have previously demonstrated that the administration of an inhaled β-agonist increases SV and Q while also decreasing SVR in healthy individuals. Therefore, we aimed to assess cardiac and peripheral hemodynamic responses to the selective β2AR agonist albuterol in individuals with CF.Methods18 CF and 30 control (CTL) subjects participated (ages 22 ± 2 versus 27 ± 2 and BSA = 1.7 ± 0.1 versus 1.8 ± 0.0 m2, both p < 0.05). We assessed the following at baseline and at 30- and 60-minutes following nebulized albuterol (2.5mg diluted in 3.0mL of normal saline) inhalation: 12-lead ECG for HR, manual sphygmomanometry for systolic and diastolic blood pressure (SBP and DBP, respectively), acetylene rebreathe for Q and SV. We calculated MAP = DBP + 1/3(SBP–DBP); systemic vascular resistance (SVR) = (MAP/Q)•80; CP = Q•MAP; stroke work (SW) = SV•MAP; reserve (%change baseline to 30- or 60-minutes). Hemodynamics were indexed to BSA (QI, SVI, SWI, CPI, SVRI).ResultsAt baseline, CF demonstrated lower SV, SVI, SW, and SWI but higher HR than CTL (p < 0.05); other measures did not differ. At 30-minutes, CF demonstrated higher HR and SVRI, but lower Q, SV, SVI, CP, CPI, SW, and SWI versus CTL (p < 0.05). At 60-minutes, CF demonstrated higher HR, SVR, and SVRI, whereas all cardiac hemodynamics were lower than CTL (p < 0.05). Reserves of CP, SW, and SVR were lower in CF versus CTL at both 30 and 60-minutes (p < 0.05).ConclusionsCardiac and peripheral hemodynamic responsiveness to acute β2AR stimulation via albuterol is attenuated in individuals with CF, suggesting β2AR located in cardiac and peripheral vascular tissue may be dysfunctional in this population.

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“…The result of this is an increased viscosity and decreased depth of the airway surface fluid in the lung, leading to the development of thick, sticky mucus which is the characteristic of CF. 4 , 5 Cystic fibrosis patients may express a homozygous deletion of F508 ( homo-F508del ), a heterozygous deletion of F508 ( hetero-F508del ), or no deletion of F508 3 and have a diagnosis of CF.…”

Section: Introductionmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis

Bisch

Wheatley

Baker

et al. 2019

Clin Med Insights Circ Respir Pulm Med

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Background: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. Methods: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C 2 H 2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). Results: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m 2 vs healthy = 1.84 ± 0.04 m 2 , P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m 2 vs healthy = 39.9 ± 2.5 mL/beat/m 2 , P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm −5 vs healthy = 1616 ± 74 dynes*s/cm −5 , P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV ( P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F (2,14) = 7.982, ...

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Genetic Variation of SCNN1A Influences Lung Diffusing Capacity in Cystic Fibrosis

Cited by 8 publications

References 41 publications

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis

Impaired cardiac and peripheral hemodynamic responses to inhaled β2-agonist in cystic fibrosis

Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis

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