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(Chest. 2006;130:1527-1534.)
© 2006 American College of Chest Physicians

ß2-Adrenergic Receptor Genotype and Pulmonary Function in Patients With Heart Failure*

Eric M. Snyder, PhD; Stephen T. Turner, MD and Bruce D. Johnson, PhD

* From the Divisions of Cardiovascular Diseases (Drs. Snyder and Johnson) and Nephrology and Hypertension (Dr. Turner), Department of Internal Medicine, Mayo Clinic, Rochester, MN.

Correspondence to: Bruce D. Johnson, PhD, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, 200 First St, SW, Rochester, MN 55905; e-mail: johnson.bruce{at}mayo.edu

Abstract

Objective: Chronic heart failure (CHF) is associated with neurohumoral activation and decrements in pulmonary function (PF). The ß2-adrenergic receptor (ADRB2) modulates airway smooth muscle tone and influences lung fluid clearance. Common polymorphisms of the ADRB2 are associated with differences in ADRB2 function and therefore could differentially influence PF in patients with CHF.

Methods: We studied baseline PF according to genetic variations of the ADRB2 at amino acid 16 (ie, arginine [Arg] or glycine [Gly]) in 126 CHF patients (mean [± SEM] age, 56 ± 1 years; left ventricular ejection fraction [LVEF], 29 ± 1%; body mass index [BMI], 28 ± 0.4 kg/m2) and in 100 healthy control subjects (mean age, 50 ± 2 years; LVEF, 63 ± 0.7%; BMI, 25 ± 0.3 kg/m2).

Results: Venous epinephrine levels did not differ between CHF patients and control subjects or across genotype groups; however, norepinephrine levels were higher in CHF patients and was greater in ArgArg patients compared to GlyGly patients (p < 0.05). PF did not differ according to genotype in control subjects; however, CHF patients who were homozygous for Arg had reduced PF relative to heterozygotes or those subjects who were homozygous for Gly (vital capacity: ArgArg group, 82 ± 3% predicted; ArgGly group, 92 ± 2% predicted; GlyGly group, 93 ± 2% predicted; FVC: ArgArg group, 77 ± 3% predicted; ArgGly group, 89 ± 2% predicted; GlyGly group, 90 ± 2% predicted; FEV1: ArgArg group, 75 ± 4% predicted; ArgGly group, 86 ± 3% predicted; GlyGly group, 87 ± 2% predicted; diffusing capacity of the lung for carbon monoxide: ArgArg group, 76 ± 4% predicted; ArgGly group, 83 ± 2% predicted; GlyGly group, 85 ± 2% predicted; p < 0.05). In addition, there was a modest correlation between mitral valve inflow deceleration time and PF in CHF patients (r = 0.42; p < 0.01), but not in control subjects.

Conclusions: These data suggest that genetic variation of the ADRB2 is associated with differences in PF in CHF patients but not in healthy subjects, which may be related to an increased susceptibility of the homozygous Arg subjects to agonist-mediated desensitization of ADRB2s in the lungs, or related to an influence of this polymorphism on cardiac diastolic properties.

Key Words: airway • congestive heart failure • echocardiography • receptors

Pulmonary function (PF) is often reduced in patients with chronic heart failure (CHF) when compared to age-matched and gender-matched healthy control subjects.12 Patients with CHF not only have reductions in maximal lung volumes and expiratory flow rates, but also exhibit reductions in the diffusing capacity of the lung for carbon monoxide (DLCO).3 Maximal lung volumes and expiratory flow rates may be reduced in CHF patients because of an increase in thoracic blood volume occurring as a result of the impaired left ventricular function that is a hallmark of CHF, or because of decreased airway smooth muscle relaxation or impaired lung fluid clearance, due to chronic desensitization of airway ß2-adrenergic receptors (ADRB2s).4 The reduction in DLCO in CHF patients is likely a result of impaired alveolar-capillary conductance due to subclinical interstitial edema but may also be a result of decreased pulmonary capillary blood volume.45 Regardless of the mechanism for the decrease in maximal lung volumes and expiratory flow rates in CHF patients, the administration of an inhaled ß2-agonist appears to improve PF, suggesting involvement of the ADRB2s.6

The ADRB2 plays a key role in both the regulation of airway smooth muscle tone and lung fluid clearance.78 The ADRB2 is a G-protein-coupled receptor that is found in airway smooth muscle from the trachea to the alveoli.78 With catecholamine stimulation, the ADRB2 goes through a conformational change that leads to an increase in levels of adenosine 3',5'-monophosphate (cAMP), which in turn activates protein kinase A, leading to airway smooth muscle relaxation.9 The increase in cAMP levels with ADRB2 stimulation induces alveolar fluid clearance through the activation of apical epithelial sodium channels on type-II alveolar cells.1011 In addition, the increase in cAMP levels may relax the smooth muscle of the pulmonary lymphatics, which would also increase lung fluid clearance.1213

There are several common polymorphisms of the ADRB2 including an adenine or guanine at nucleotide 46 (leading to an arginine [Arg] or glycine [Gly] at amino acid 16). While the most functionally significant variant of the ADRB2 appears to be a substitution of threonine to isoleucine (Ile) at amino acid 164, the heterozygous condition occurs in < 3% of the population.1415 We have found that young healthy subjects who are homozygous for adenine at nucleotide 46 (ie, ArgArg at amino acid 16) have reduced cardiac function at rest and during exercise, and reduced airway function following several minutes of high-intensity exercise when compared to subjects who are homozygous for guanine at this nucleotide (ie, GlyGly at amino acid 16).1617 Other studies18 have suggested that the Gln polymorphism at amino acid 27 has attenuated receptor function in response to the administration of a ß-agonist in healthy subjects. Collectively, previous studies1617192021 have suggested that the Arg16 group has reduced receptor function when compared to the Gly16 group in vivo.

Heart failure is associated with elevated adrenergic drive when compared to healthy subjects.2223 It is possible, therefore, that this increased adrenergic drive results in desensitization of the ADRB2s, particularly in polymorphisms that have been shown to be susceptible to desensitization in vivo. Thus, for the present study, we sought to determine the effect of variation at amino acid 16 of the ADRB2 on maximal lung volumes, expiratory flow rates, and DLCO in healthy subjects, and in patients with CHF. We hypothesized that there would be no differences in PF among genotype groups in the healthy subjects; however, in CHF patients, those who are homozygous for Arg at amino acid 16 would have reduced PF when compared to CHF patients who are homozygous for Gly at this amino acid.

Materials and Methods

Subjects
Healthy white subjects (n = 100) and white subjects with CHF (n = 125) [New York Heart Association class II-III] with a history of ischemic or idiopathic dilated cardiomyopathy were recruited at the Mayo Clinic in Rochester, MN, from 1999 to 2004. Inclusion criteria included stable CHF of > 1 year duration with a left ventricular ejection fraction (LVEF) of ≤ 40%. Patients with conditions likely to affect PF (ie, primary lung disease, obesity, and musculoskeletal diseases) or with a > 15 pack-year smoking history were excluded from the study. Healthy subjects matched for age and gender, who were not receiving cardiovascular or pulmonary medications, were also recruited. The study was approved by the Mayo Clinic Institutional Review Board, each subject provided informed consent prior to study, and all aspects of the study were performed according to the Declaration of Helsinki.

Neurohormones
All measurements were performed following 10 min of quiet rest. Levels of plasma catecholamines (ie, epinephrine [EPI] and norepinephrine [NE]) were measured using high-performance liquid chromatography. For our laboratory, the intraassay coefficients of variation are as follows: NE: 224 pg/mL, 4.5%; 429 pg/mL, 3.3%; EPI: 13.8 pg/mL, 12.2%; 242 pg/mL, 3.6%. The interassay coefficients of variation are as follows: NE: 337 pg/mL, 8.2%; 533 pg/mL, 6.3%; EPI: 179 pg/mL, 8.5%; 390 pg/mL, 6.3%.

ADRB2 Genotyping
ADRB2 genotyping was performed as described previously according to the methods of Bray et al.24 In brief, buffy coat was obtained from whole blood anticoagulated with ethylenediaminetetraacetic acid and DNA was extracted using a DNA isolation kit (Pure gene DNA Isolation Kit; Gentra Systems; Minneapolis, MN). Following extraction, DNA was treated with a proteinase K solution in preparation for polymerase chain reaction (PCR). The PCR reaction was conducted according to standard methods, using the following primer sequences (Arg16Gly): (forward) 5'-AGC CAG TGC GCT TAC CTG CCA GAC-3' (at –32); and (reverse) 3'-CA TGG GTA CGC GGC CTG GTG CTG CAG TGC –5'. These resulted in a PCR product that was 107 base pairs (bps) in length. The reaction included 30 ng of DNA, 1.5 mmol/L magnesium chloride, 0.5 U of taq polymerase (Invitrogen; Carlsbad, CA), 8.5% dimethylsulfoxide, and standard concentrations of nucleotides and buffer in a 20-µL reaction volume. After initial denaturation at 94°C for 4 min, the fragments were amplified by 35 cycles of denaturation for 1 min at 94°C, 1 min at 61°C, 1 min at 72°C, followed by 5 min at 72°C and 5 min at 98°C. The amplicons were then digested by exposure to 5 U of the restriction enzyme KpnI, followed by electrophoretic separation on 3% aragose gels, staining with ethidium bromide, and visualization using ultraviolet light. The Arg16 homozygous genotype is represented by a single 107-bp band, and the Gly16 homozygous group by 82-bp and 25-bp bands.

Echocardiographic Methods
LVEF and ventricular filling pattern were measured with the subject at rest by two-dimensional echocardiography according to recommendations of the American Society of Echocardiography,25 and by pulsed-wave Doppler flow of the mitral valve as previously described by Oh et al.26

PF Measurements
PF measurements were performed with the subject at rest according to American Thoracic Society standards,27 and included assessments of lung volumes (ie, slow vital capacity [VC], FVC, and FEV1), and expiratory flows (ie, mean forced expiratory flow at 25 to 75% of the FVC [FEF25–75]). Single-breath DLCO was also measured.

Statistical Analysis
All statistical comparisons were made using a statistical software package (SPSS; SPSS Inc; Chicago, IL). Group demographics were compared with a one-way analysis of variance (ANOVA) using an {alpha} level of 0.05 to determine significance. The difference in PF between the healthy group and the group containing CHF patients was compared using an independent-samples t test with an {alpha} level of 0.05 for significance. Genotype differences in PF within groups were compared with an ANOVA using a post hoc Student t test to detect differences among the genotype groups. An {alpha} level of 0.05 was used for the ANOVA and post hoc analyses. Prior to each ANOVA, a Levene test was performed to determine homogeneity of variance. A Pearson correlation was performed between mitral valve inflow deceleration time and PF, also with an {alpha} of 0.05. The values presented are the mean ± SEM.

Results

Subjects
For both populations (ie, healthy subjects and patients with CHF), the genotype groups were within Hardy-Weinberg equilibrium. The majority of the subjects in both groups were either heterozygous at amino acid 16 or homozygous for Gly at this amino acid (ArgArg: healthy subjects, 22; CHF patients, 18; ArgGly: healthy subjects, 41; CHF patients, 53; GlyGly: healthy subjects, 37; CHF patients, 54). Patients with CHF tended to be slightly older and heavier than the healthy subjects, although these variables did not reach significance across genotype groups (Table 1 ).


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  		Table 1. Subject Characteristics According to Genetic Variation at Amino Acid 16 of the ADRB2*

 
By design, LVEF was lower in CHF patients when compared to healthy subjects, but there were no differences among the genotype groups in healthy subjects or patients with CHF (healthy subjects: ArgArg, 61.7 ± 2%; ArgGly, 62.4 ± 1%; GlyGly, 64 ± 3%; CHF patients: ArgArg, 26.0 ± 2%; ArgGly, 30.9 ± 2%; GlyGly, 28.9 ± 1%) at amino acid 16. In healthy subjects, there were no differences among genotype groups at amino acid 16 in mitral valve inflow deceleration time; in contrast, in CHF patients, the ArgArg group had a lower deceleration time compared to the GlyGly group (healthy subjects: ArgArg, 195 ± 8 ms; ArgGly, 208 ± 9 ms; GlyGly, 201 ± 8 ms; CHF patients: ArgArg, 180 ± 12 ms; ArgGly, 189 ± 9 ms; 219 ± 12 ms; p < 0.05). There were also no differences in ß-blocker therapy or CHF type according to the variation at amino acid 16 in the heart failure group; however, more subjects with the Gly allele were receiving angiotensin-II receptor blockers (Table 2 ).


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  		Table 2. Heart Failure Type and Medication Use According to Genotype Variation at Amino Acid 16 of the ADRB2*

 
Neurohormones
Venous EPI was not different between healthy subjects and patients with CHF; however, venous NE levels were higher in patients with CHF (EPI level: healthy subjects, 22.8 ± 3 pg/mL; CHF patients, 22.7 ± 3 pg/mL; NE level: healthy subjects, 254 ± 40 pg/mL; CHF patients, 417 ± 60 pg/mL). There were no differences in EPI or NE according to genotype in healthy subjects (EPI: ArgArg, 19.0 ± 2 pg/mL; ArgGly, 26.8 ± 3 pg/mL; GlyGly, 22.2 ± 3 pg/mL; NE: ArgArg, 244 ± 42 pg/mL; ArgGly, 232 ± 32 pg/mL; GlyGly, 287 ± 45 pg/mL). In CHF patients, there were no differences in EPI levels among the genotype groups, but the ArgArg and ArgGly groups had higher NE levels when compared to the GlyGly group (EPI: ArgArg, 21.7 ± 2 pg/mL; ArgGly, 22.0 ± 3 pg/mL; GlyGly, 24.3 pg/mL; NE: ArgArg, 547 ± 100 pg/mL; ArgGly, 409 ± 46 pg/mL; GlyGly, 294 ± 30 pg/mL; p < 0.05).

PF
Compared to healthy subjects, CHF patients had lower maximal lung volumes, expiratory flow rates, and DLCO (VC, 108 ± 1.4% vs 91 ± 1.5% predicted, respectively; FVC, 106 ± 1.4% vs 87 ± 1.5% predicted, respectively; FEV1, 105 ± 1.5% vs 85 ± 1.6% predicted, respectively; FEF25–75, 99 ± 2.7% vs 82 ± 2.8% predicted, respectively; and DLCO, 97 ± 1.4% vs 83 ± 1.4% predicted, respectively; p < 0.05). There were no differences in maximal lung volumes or DLCO according to genotype in healthy subjects; however, the ArgArg group had a greater FEF25–75 when compared to the GlyGly group (Fig 1 , top). In the CHF patients, the ArgArg group had lower VC, FVC, and FEV1 levels when compared to ArgGly and GlyGly subjects, and lower FEF25–75 and DLCO when compared to GlyGly subjects (p < 0.05) [Fig 1, bottom].


Figure 1
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  		Figure 1. PF in healthy subjects and in patients with CHF according to genotype variation at amino acid 16 of the ADRB2. Top: the PF for healthy subjects. Bottom: the PF in patients with CHF. The x-axis represents the PF measure, and the y-axis represents the percentage of predicted for the PF measures. Predicted values are from Knudson et al46 and Miller and Thornton.47 • = subjects homozygous for Arg at amino acid 16; {circ} = subjects heterozygous at amino acid 16; {blacktriangleup} = subjects homozygous for Gly at amino acid 16; * = p < 0.05 [ANOVA]; {dagger} = p < 0.05 (ArgArg vs GlyGly).

 
Discussion

We found that CHF subjects homozygous for Arg at amino acid 16 of the ADRB2 had reduced maximal lung volumes, expiratory flow rates, and DLCO when compared to CHF patients homozygous for Gly at this amino acid. There were no differences in maximal lung volumes, expiratory flow rates, or DLCO in healthy subjects according to variation at this amino acid. These data suggest that the decrease in PF in the ArgArg subjects may be due to an increased susceptibility to desensitization of the ADRB2s in CHF patients as a result of the increased neurohumoral activation.

The ADRB2s in the lungs are found to be densely distributed over the airway epithelium and alveolar walls.7 The ADRB2s are G-protein-coupled receptors, which have been shown to lead to bronchodilation in response to an agonist.28 On binding with an agonist, the receptor undergoes a conformational change, which, through a number of pathways, leads to smooth muscle relaxation. The ADRB2s are also involved in lung fluid regulation. Stimulation of the ADRB2s leads to an increase in cAMP, stimulates epithelial sodium channel activity on type-II alveolar cells, and results in smooth muscle relaxation of the pulmonary lymphatics, both of which can increase lung fluid clearance.121329

The coding region of the ADRB2 demonstrates multiple sites of polymorphic variation such as amino acids 16, 27, and 164.30 Amino acids 16 and 27 (nucleotides 46 and 79, respectively) have been studied extensively both in vitro and in vivo with controversial findings.16171819202131 The most impaired single site polymorphism of the ADRB2 appears to be due to a threonine to Ile change at amino acid 164; however, the heterozygous condition at amino acid 164 occurs in < 3% of the healthy population, and subjects homozygous for Ile164 have not been observed in large samples from the general population. In the present study, we chose to examine the influence of variation at amino acid 16 because the Arg16Gly polymorphism is common in the white population and because previous research has suggested that ArgArg subjects may have reduced receptor function in vivo. Although some studies30 have suggested that comparison using haplotypes may provide additional information over single-nucleotide polymorphisms, we observed differences in PF in patients with CHF when comparing groups according to the Arg16Gly polymorphism, suggesting that either the variation at amino acid 16 has a functional effect or it is in linkage with another site that influences receptor function.

These data suggest that the ADRB2s likely play a role in the loss of airway function and the decrease in DLCO in patients with CHF (because the genotype group that is thought to have attenuated ADRB2 function in vivo exhibited lower PF and DLCO). Interestingly, Pavia et al32 have demonstrated that ß-blockade (selective and nonselective) results in a small but significant drop in PF, even in healthy subjects, which seems to support the findings in the present study. It is also possible that genotype differences in cardiac function, particularly differences in diastolic function, could have contributed to the observed differences. Previous work3334 has suggested that the decrease in maximal lung volumes, expiratory flow rates, and DLCO in patients with heart failure may be due to the attenuation in left ventricular function, which leads to an increase in thoracic blood volume because of an inability of the heart to move blood away from the lungs, resulting in a backup of blood, pulmonary congestion, and, perhaps, interstitial edema. Other studies635 have suggested that there is a chronic desensitization of the ADRB2s, which leads to a reduction in ß2-agonist-mediated airway smooth muscle relaxation in CHF patients. While there is evidence for a significant improvement in lung volumes and expiratory flow rates following heart transplantation, previous work3637 has shown minimal improvement in DLCO with transplantation. This would suggest that cardiac function plays a significant role in the loss of maximal lung volumes and expiratory flow rates, and likely influences the reduction in DLCO in CHF patients; however, there appears to be some chronic remodeling of the alveolar-capillary membrane with worsening heart failure that may be irreversible.

Previous studies1, 2, 4 have demonstrated both obstructive and restrictive changes in PF associated with CHF. In the present study, the FEV1/FVC ratio (an index of the degree of obstruction) averaged 81% in the healthy subjects (ArgArg group, 81%; ArgGly group, 80%; GlyGly group, 82%) and 77% in the CHF group (ArgArg group, 77%; ArgGly, 76%; GlyGly group, 77%). This suggests that CHF is only associated with very mild obstructive changes relative to the healthy subjects (but not clinically significant obstruction) and that this does not explain the genotype-related differences in lung function in the CHF subjects. Thus, the primary deficit in CHF appears to be restrictive changes that are accentuated in the ArgArg group. These changes are likely related to alterations in lung fluid balance or cardiac abnormalities (size or function), both of which may be influenced by the ADRB2s.

Our laboratory has previously found38 that CHF patients who are homozygous for Arg at amino acid 16 of the ADRB2 have poorer left ventricular diastolic function when compared to subjects homozygous for Gly at this amino acid. To determine the influence of diastolic function on maximal lung volumes in the present study, we performed a correlation between mitral valve inflow deceleration time and vital capacity (Fig 2 ). In healthy subjects, there was no association between this index of diastolic function and vital capacity; however, in CHF patients there was a significant modest correlation between these two variables. This suggests that diastolic function does not play a role in PF in healthy subjects with normal cardiac function, likely because of normal lung blood and fluid volumes. In contrast, these data suggest that diastolic function may play a role in the loss of PF in patients with CHF. Because the ADRB2s are found in the cardiac tissue and influence the contractility of the ventricular walls, it is possible that some of the genotype effect on PF is a result of the genetic influence on cardiac function; however, it is also possible that this polymorphism of the ADRB2 has a separate effect on the heart and the lungs.


Figure 2
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  		Figure 2. Relationship between diastolic function (assessed with mitral valve inflow deceleration time) and PF in healthy subjects (top) and in patients with CHF (bottom). • = subjects homozygous for Arg at amino acid 16; {circ} = subjects heterozygous at amino acid 16; {blacktriangleup} = subjects homozygous for Gly at amino acid 16.

 
An interesting finding of the present study is an observed genotype difference in NE in the CHF group. Although no previous studies have examined the effect of genotypes of the ADRB2 on NE synthesis or release, the ADRB2s have been implicated in EPI-stimulated NE release at the nerve endings.3940 Interestingly, previous work414243 has demonstrated that ß-blockade increases in NE release at rest and during exercise, which is possibly related to a decrease in cardiac output. It is possible that the elevated NE levels in the ArgArg subjects in the present study are related to an attenuation in cardiac function. Further study is needed, however, to determine the exact mechanisms for the genotype-related difference in NE levels.

Limitations
In the present study, we found that the CHF patients had higher NE levels, but similar EPI levels when compared to healthy subjects. The EPI results in the present study may have been influenced by differences in catecholamine uptake because of differences in the removal of EPI from tissues44; however, at least one study45 has found a strong relationship between baseline values of arterial and venous catecholamines in healthy subjects. Based on these findings, it is possible that there were differences in catecholamine uptake between the group of CHF patients and the group of healthy subjects (because of the use of venous rather than arterial blood samples) and/or among the genotype groups within a population.

We observed differences in the use of angiotensin-II receptor blockers and digitalis in the present study as well as small differences in the use of ß-blockade. To determine the influence of the differences among genotype groups in pharmacotherapy, we ran a post hoc analysis on the relationship between genotype and PF while controlling for medication. We found that there remained significant genotype differences in FVC, FEV1, and FEF25–75 (p < 0.01); however, the effect of genotype on DLCO was only marginally significant (p = 0.06).

Conclusions

We have found that genetic variation of the ADRB2s influences resting PF in patients with CHF, but not in healthy subjects. We found that CHF patients homozygous for Arg at amino acid 16 had reduced maximal lung volumes, flow rates, and DLCO when compared to CHF patients homozygous for Gly. Because this occurred in patients with CHF, but not in healthy subjects, our findings may suggest that the elevated adrenergic drive that is associated with CHF may play a role in modulating differences in receptor function among genotype groups. Furthermore, we found a significant association between an index of diastolic function and PF, suggesting that a heart-lung interaction that may be genotype-dependent could influence the genotype differences in PF.

Acknowledgements

We thank Kathy O’Malley and Angela Heydman for their help with data collection; Minelle L. Hulsebus for her help with manuscript preparation; as well as the efforts of the study participants. We would also like to thank the staff of the General Clinical Research Center for their assistance throughout this study.

Footnotes

Abbreviations: ADRB2 = ß2-adrenergic receptor; ANOVA = analysis of variance; Arg = arginine; bp = base pair; cAMP = 3',5'-monophosphate; CHF = chronic heart failure; DLCO = diffusing capacity of the lung for carbon monoxide; EPI = epinephrine; FEF25–75 = forced expiratory flow at 25 to 75% of the FVC; Gly = glycine; Ile = isoleucine; LVEF = left ventricular ejection fraction; NE = norepinephrine; PCR = polymerase chain reaction; PF = pulmonary function; VC = slow vital capacity

This work was supported by National Institutes of Health grants HL71478 and HL54464, and American Heart Association grants 56051Z and 0410073Z. The Mayo Clinic General Clinical Research Center is supported by US Public Health Service grant M01-RR00585.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication January 9, 2006. Accepted for publication April 21, 2006.

References

  1. Collins, JV, Clark, TJ, Brown, DJ (1975) Airway function in healthy subjects and patients with left heart disease. Clin Sci Mol Med 49,217-228[ISI][Medline]
  2. Johnson, BD, Beck, KC, Olson, LJ, et al Ventilatory constraints during exercise in patients with chronic heart failure. Chest 2000;117,321-332[Abstract/Free Full Text]
  3. Guazzi, M, Marenzi, G, Alimento, M, et al Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997;95,1930-1936[Abstract/Free Full Text]
  4. Gehlbach, BK, Geppert, E The pulmonary manifestations of left heart failure. Chest 2004;125,669-682[Abstract/Free Full Text]
  5. Al-Rawas, OA, Carter, R, Stevenson, RD, et al The alveolar-capillary membrane diffusing capacity and the pulmonary capillary blood volume in heart transplant candidates. Heart 2000;83,156-160[Abstract/Free Full Text]
  6. Ng, TM, Munger, MA, Lombardi, WL, et al Chronically inhaled salmeterol improves pulmonary function in heart failure. J Cardiovasc Pharmacol 2002;40,140-145[CrossRef][ISI][Medline]
  7. Carstairs, JR, Nimmo, AJ, Barnes, PJ Autoradiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis 1985;132,541-547[ISI][Medline]
  8. Hamid, QA, Mak, JC, Sheppard, MN, et al Localization of ß2-adrenoceptor messenger RNA in human and rat lung using in situ hybridization: correlation with receptor autoradiography. Eur J Pharmacol 1991;206,133-138[CrossRef][ISI][Medline]
  9. Giembycz, MA, Raeburn, D Putative substrates for cyclic nucleotide-dependent protein kinases and the control of airway smooth muscle tone. J Auton Pharmacol 1991;11,365-398[ISI][Medline]
  10. Matalon, S, Lazrak, A, Jain, L, et al Invited review: biophysical properties of sodium channels in lung alveolar epithelial cells. J Appl Physiol 2002;93,1852-1859[Abstract/Free Full Text]
  11. Eaton, DC, Chen, J, Ramosevac, S, et al Regulation of Na+ channels in lung alveolar type II epithelial cells. Proc Am Thorac Soc 2004;1,10-16[Abstract/Free Full Text]
  12. Mahe, L, Chapelain, B, Gargouil, YM, et al Characterization of ß-adrenoceptor subtypes and indications for two cell populations in isolated bovine mesenteric lymphatic vessels. Eur J Pharmacol 1991;199,19-25[CrossRef][ISI][Medline]
  13. Lauweryns, JM, Baert, JH Alveolar clearance and the role of the pulmonary lymphatics. Am Rev Respir Dis 1977;115,625-683[ISI][Medline]
  14. Liggett, SB, Wagoner, LE, Craft, LL, et al The Ile 164 ß2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998;102,1534-1539[ISI][Medline]
  15. Dishy, V, Landau, R, Sofowora, GG, et al ß2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo. Pharmacogenetics 2004;14,517-522[CrossRef][ISI][Medline]
  16. Snyder, EM, Beck, KC, Dietz, NM, et al Influence of ß2-adrenergic receptor genotype on airway function during exercise in healthy adults. Chest 2006;129,762-770[Abstract/Free Full Text]
  17. Snyder, EM, Beck, KC, Dietz, NM, et al Arg16Gly polymorphism of the ß2-adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise in humans. J Physiol 2006;571,121-130[Abstract/Free Full Text]
  18. Cockcroft, JR, Gazis, AG, Cross, DJ, et al ß2-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000;36,371-375[Abstract/Free Full Text]
  19. Dishy, V, Sofowora, GG, Xie, HG, et al The effect of common polymorphisms of the ß2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 2001;345,1030-1035[Abstract/Free Full Text]
  20. Eisenach, JH, McGuire, AM, Schwingler, RM, et al The Arg16/Gly ß2-adrenergic receptor polymorphism is associated with altered cardiovascular responses to isometric exercise. Physiol Genomics 2004;16,323-328[Abstract/Free Full Text]
  21. Garovic, VD, Joyner, MJ, Dietz, NM, et al ß2-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans. J Physiol 2003;546,583-589[Abstract/Free Full Text]
  22. Kaye, DM, Lefkovits, J, Jennings, GL, et al Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995;26,1257-1263[Abstract]
  23. Cohn, JN, Levine, TB, Olivari, MT, et al Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311,819-823[Abstract]
  24. Bray, MS, Krushkal, J, Li, L, et al Positional genomic analysis identifies the ß2-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation 2000;101,2877-2882[Abstract/Free Full Text]
  25. Schiller, NB, Shah, PM, Crawford, M, et al Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2,358-367[Medline]
  26. Oh, JK, Appleton, CP, Hatle, LK, et al The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10,246-270[CrossRef][ISI][Medline]
  27. American Thoracic Society.. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995;152,1107-1136[ISI][Medline]
  28. McGraw, DW, Forbes, SL, Mak, JC, et al Transgenic overexpression of ß2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction. Am J Physiol Lung Cell Mol Physiol 2000;279,L379-L389[Abstract/Free Full Text]
  29. Planes, C, Blot-Chabaud, M, Matthay, MA, et al Hypoxia and ß2-agonists regulate cell surface expression of the epithelial sodium channel in native alveolar epithelial cells. J Biol Chem 2002;277,47318-47324[Abstract/Free Full Text]
  30. Drysdale, CM, McGraw, DW, Stack, CB, et al Complex promoter and coding region ß2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 2000;97,10483-10488[Abstract/Free Full Text]
  31. Tang, W, Devereux, RB, Kitzman, DW, et al The Arg16Gly polymorphism of the ß2-adrenergic receptor and left ventricular systolic function. Am J Hypertens 2003;16,945-951[CrossRef][ISI][Medline]
  32. Pavia, D, Bateman, JR, Lennard-Jones, AM, et al Effect of selective and non-selective ß blockade on pulmonary function and tracheobronchial mucociliary clearance in healthy subjects. Thorax 1986;41,301-305[Abstract]
  33. Bussieres, LM, Pflugfelder, PW, Ahmad, D, et al Evolution of resting lung function in the first year after cardiac transplantation. Eur Respir J 1995;8,959-962[Abstract]
  34. Agostoni, P, Cattadori, G, Bianchi, M, et al Exercise-induced pulmonary edema in heart failure. Circulation 2003;108,2666-2671[Abstract/Free Full Text]
  35. Chua, TP, Coats, AJ The lungs in chronic heart failure. Eur Heart J 1995;16,882-887[Free Full Text]
  36. Ohar, J, Osterloh, J, Ahmed, N, et al Diffusing capacity decreases after heart transplantation. Chest 1993;103,857-861[Abstract/Free Full Text]
  37. Ravenscraft, SA, Gross, CR, Kubo, SH, et al Pulmonary function after successful heart transplantation: one year follow-up. Chest 1993;103,54-58
  38. Wolk, R, Somers, VK, Turner, ST, et al Arg16/Arg16 polymorphism of the ß2-adrenergic receptor gene affects cardiovascular function in heart failure. Physiologist 2002;45,1
  39. Deegan, R, He, HB, Krivoruk, Y, et al Regulation of norepinephrine release by ß2-adrenergic receptors during halothane anesthesia. Anesthesiology 1995;82,1417-1425[CrossRef][ISI][Medline]
  40. Murugaiah, KD, O’Donnell, JM Facilitation of norepinephrine release from cerebral cortex is mediated by ß2-adrenergic receptors. Life Sci 1995;57,PL327-PL332[CrossRef][ISI][Medline]
  41. Schneider, DA, Kamimori, GH, Wu, SY, et al Plasma catecholamine and ventilatory responses to cycling after propranolol treatment. Med Sci Sports Exerc 1995;27,1616-1620
  42. Rahn, KH, Gierlichs, HW, Planz, G, et al Studies on the effects of propanolol on plasma catecholamine levels in patients with essential hypertension. Eur J Clin Invest 1978;8,143-148[ISI][Medline]
  43. Galbo, H, Holst, JJ, Christensen, NJ, et al Glucagon and plasma catecholamines during ß-receptor blockade in exercising man. J Appl Physiol 1976;40,855-863[Abstract/Free Full Text]
  44. Axelrod, J, Weinshilboum, R Catecholamines. N Engl J Med 1972;287,237-242[ISI][Medline]
  45. Halter, JB, Pflug, AE, Tolas, AG Arterial-venous differences of plasma catecholamines in man. Metabolism 1980;29,9-12[CrossRef][ISI][Medline]
  46. Knudson, RJ, Lebowitz, MD, Holberg, CJ, et al Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127,725-734[ISI][Medline]
  47. Miller, A, Thornton, JC Reference equations for the single-breath diffusing capacity. Am Rev Respir Dis 1986;133,1210-1211[ISI][Medline]




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