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

Abstract

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, ...

CFTR plays an important role in the regulation of vascular resistance and high-fructose/salt-diet induced hypertension in mice

“…1 B and 4 A) and a decreased aortic compliance ( Figs. 1 C and 4 A,c) are consistent with the findings from Bisch et al [4] and also with the results from previous in vitro studies by Robert et al that arteries from cftr −/ − mice became significantly more constricted than that from cftr + / + mice in response to vasoactive agents [ 3 , 19 ]. For our in vivo experiments we did not examine whether the endothelial function of aorta or mesenteric arteries from cftr −/ − mice remains normal or not since Robert et al reported that arteries with or without endothelium from cftr −/ − mice became significantly more constricted than that from cftr + / + mice in response to vasoactive agents and thus CFTR activation contributed to an endothelium-independent vasorelaxation [ 3 , 19 ].…”

“…Disruption of CFTR not only affects the response of VSMCs to vasoactive agents but also prevents the cAMP-dependent vasorelaxasion [3] . Consistent with these in vitro findings, it has been recently reported that the most common mutation ( F508) of CFTR is associated with an increased systemic vascular resistance (SVR) at rest in CF patients when compared with healthy subjects [4] . In contrast to these findings, however, Peotta et al reported that in a mouse model of heterozygous CFTR F508 mutation the aortic contractility was decreased and the arterial pressures were significantly lower than the wild-type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg) [7] .…”

“…The F508del mutation of CFTR results in cystic fibrosis (CF). More recently, it has been reported CF patients demonstrated significantly higher HR and systemic vascular resistance (SVR) at rest when compared with healthy subjects [4] . A single dose of β-agonist lowered SVR in healthy subjects but there was an attenuated response in SVR to acute β2-adrenergic receptor stimulation in CF patients [20] .…”

“…However, the mutant protein still exhibits some residual Cl − channel activity and display partial function [23] . Very recently, however, Bisch et al reported that F508 CFTR is associated with an increased systemic vascular resistance (SVR) at rest in CF patients when compared with healthy subjects [4] . They provided compelling evidence that CFTR genotypes, not circulating catecholamines, influences cardiovascular function in CF patients.…”

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review

“…Whether these changes were clinically significant cannot be determined from the information available, but the single case of bradycardia reported was asymptomatic [ 45 ]. In one study, people with CF were found to have a higher baseline heart rate when compared to healthy controls [ 119 ]; therefore, correction of CFTR function may theoretically reduce heart rate. However, again, this heart rate-lowering effect is seemingly unique to LUM/IVA.…”