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

Abstract

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.

The Coupling of Peripheral Blood Pressure and Ventilatory Responses during Exercise in Young Adults with Cystic Fibrosis

“…For example, whereas observations of Hull et al [20] (ergometry) or Schrage et al [35] (handgrip) do not suggest overt exacerbation of blood pressure during exercise in mild- to- moderate severity adult CF, it is both novel and relevant in understanding peripheral hemodynamic function in CF that Hull et al [20] demonstrated increased augmentation index in these individuals, suggesting the presence of increased arterial stiffness. Further, and consistent with Hull et al [20, 36], our group has demonstrated that mild- to- moderate severity adult CF have blunted reductions in resting systemic vascular resistance in response to inhalation of the β 2 -selective agonist albuterol [19]. Thus, if increased blood pressure, underpinned by impaired peripheral vascular function [19–21, 24, 35, 36], does indeed parallel exaggerated slope during exercise in adult CF, demonstrating this calibration in the laboratory setting should help add to our understanding that the clinical implications of CF may extend to the entire cardiovascular system.…”

“…Further, and consistent with Hull et al [20, 36], our group has demonstrated that mild- to- moderate severity adult CF have blunted reductions in resting systemic vascular resistance in response to inhalation of the β 2 -selective agonist albuterol [19]. Thus, if increased blood pressure, underpinned by impaired peripheral vascular function [19–21, 24, 35, 36], does indeed parallel exaggerated slope during exercise in adult CF, demonstrating this calibration in the laboratory setting should help add to our understanding that the clinical implications of CF may extend to the entire cardiovascular system.…”

“…Neither CF nor controls used bronchodilators (e.g., albuterol) <8 hours prior to airway testing, lung volume testing, or CPET. Individuals with CF were on standard pharmacologic therapy as recommended for CF [19]. No participant required use of therapy during testing procedures.…”

“…Although observations in adolescent or adult CF suggest in addition to impaired cardiac function [14, 22, 25, 32–34], these individuals may demonstrate abnormal peripheral function including skeletal muscle weakness or slowed muscle oxygenation kinetics [12, 18, 22, 23], which may cumulatively contribute to impaired aerobic exercise capacity coupled with ventilatory inefficiency, limited studies in adult CF have focused on describing the role of peripheral blood pressure [20, 35] in the context of questioning whether pulmonary dysfunction is accompanied by gross peripheral vascular abnormalities in these individuals [19, 21, 24, 36]. For example, whereas observations of Hull et al [20] (ergometry) or Schrage et al [35] (handgrip) do not suggest overt exacerbation of blood pressure during exercise in mild- to- moderate severity adult CF, it is both novel and relevant in understanding peripheral hemodynamic function in CF that Hull et al [20] demonstrated increased augmentation index in these individuals, suggesting the presence of increased arterial stiffness.…”

Evidence of microvascular dysfunction in patients with cystic fibrosis

“…Patients with CF were instructed to adhere to the timing of their daily treatments and come to the laboratory following their morning airway clearance technique and inhaled medicines. It is worth noting that the use of inhaled ␤-agonists as part of routine treatment of CF does not affect cardiac or peripheral hemodynamics in these patients (52). Microvascular function was assessed; then a pulmonary function test was performed and a blood sample was collected for assessment of standard laboratory values.…”