(Chest. 1999;116:1582-1586.)
© 1999
American College of Chest Physicians
Bronchial Hyperreactivity in Patients With Mitral Stenosis Before and After Successful Percutaneous Mitral Balloon Valvulotomy*
Sadi Gülec, MD;
Fatih Ertas, MD;
Eralp Tutar, MD;
Yavuz Demirel, MD;
Remzi Karaoguz, MD;
Kenan Omurlu, MD and
Dervis Oral, MD
*
From the Departments of Cardiology (Drs. Gülec, Ertas, Tutar, Karaoguz, Omurlu, and Oral) and Pulmonology (Dr. Demirel), Medical School of Ankara University, Ankara, Turkey.
Correspondence to: Fatih Sinan Ertas, MD, Yazikiri-B sitesi, A-3 Blok, No: 23, 06530, Ümitköy/Ankara, Turkey; e-mail: ertas{at}dialup.ankara.edu.tr
 |
Abstract
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Objectives: We aimed to identify the bronchial response
to inhaled methacholine in patients with mitral stenosis (MS) and to
clarify whether or not the bronchial hyperreactivity (BHR) is
reversible after percutaneous mitral balloon valvulotomy (PBMV).
Patients and setting: Thirty patients with MS and 28
age-matched healthy control subjects were prospectively evaluated with
pulmonary function tests and methacholine challenge. The productive
concentration of methacholine causing 20% decrease in FEV1
(PC20) was calculated and used as a parameter of bronchial
responsiveness. BHR was defined as a PC20 < 8 mg/mL. Mean
pulmonary artery pressure (PAP) and mean pulmonary capillary wedge
pressure (PCWP) were recorded in all patients through a Swan-Ganz
balloon-tipped catheter. Sixteen patients underwent PMBV, and a
methacholine test was repeated after each procedure.
Results: Bronchial response to methacholine was
significantly increased in patients with MS, so that 53% of them had
BHR, whereas all control subjects were nonresponders. The
PC20 was closely correlated with the PAP (r = - 0.777;
p < 0.001), PCWP (r = - 0.723; p < 0.001), and mitral valve
area (MVA; r = 0.676; p < 0.001). Balloon valvulotomy was
successfully performed in all of the 16 patients, and the cardiac
parameters (MVA, PAP, and PCWP) significantly improved after the
procedure. In contrast, no significant changes were shown in pulmonary
function test variables (total lung capacity, vital capacity [VC],
FEV1, and FEV1/VC). Although significant
improvement was observed in the mean PC20 values (from
4.97 ± 5.24 to 7.47 ± 6.96 mg/mL; p = 0.0006), BHR was
completely eliminated in only one patient.
Conclusions: Our data shows that BHR is fairly common among
patients with MS, and severity of bronchial responsiveness is
significantly correlated with the severity of MS. Moreover, PMBV leads
to significant reduction in pulmonary congestion and a consequent
improvement in BHR.
Key Words: bronchial hyperactivity • mitral stenosis • percutaneous transluminal mitral valvulotomy
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Introduction
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Bronchial
asthma is defined as hyperreactivity of the bronchi to a wide variety
of stimuli.1
Characteristic symptoms of this pulmonary
disorder are cough, wheezing, and acute episodic dyspnea. On the other
hand, these symptoms are frequently observed in patients with chronic
lung congestion due to heart disease.2
Recently,
investigators reported bronchial hyperreactivity (BHR) to inhaled
methacholine in patients with chronic left ventricular failure
(LVF),3
4
5
and mitral valve disease (MVD).6
Interstitial lung edema,6
airway edema,4
dilatation of the bronchial vessel,3
and decreased airway
caliber5
were suggested as possible mechanisms of BHR in
cardiac patients. However, whether or not this BHR is reversible by
reducing pulmonary congestion is still not clear.5
7
In
the present study, we measured bronchial responsiveness to inhaled
methacholine in 30 patients with mitral stenosis (MS) and 28 healthy
control subjects. Furthermore, a subgroup of 16 patients underwent
percutaneous mitral balloon valvulotomy (PMBV), and a methacholine test
was repeated after each procedure. Thus, we had the opportunity to test
the hypothesis that reduction of pulmonary congestion might improve
BHR.
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Materials and Methods
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Study Population
We prospectively studied 30 consecutive patients with MS who
were admitted to the Department of Cardiology at Ankara University
Medical School between July 1, 1996, and July 1, 1997. Twenty-eight
age-matched (within 3 years) healthy physicians were studied as control
subjects. Clinical and laboratory criteria for exclusion of the
patients and control subjects were as follows: (1) cigarette smoking
within the preceding 10 years; (2) history or present status of
bronchial asthma and/or other pulmonary disorders; (3) recent (within 8
weeks) airway infection; (4) FEV1 < 80% of
vital capacity (VC); (5) moderate to severe mitral regurgitation; and
(6) left ventricular systolic dysfunction (ejection fraction < 55%).
All patients were clinically stable, and most of them were receiving
medical treatment with digitalis (13 patients), diuretics (19
patients), or calcium antagonists (7 patients; diltiazem or verapamil)
at the time of enrollment. Informed consent was obtained from each
subject in the study.
Echocardiographic and Hemodynamic Evaluation
Comprehensive two-dimensional and Doppler echocardiographic
examinations were performed in all patients using an ultrasound imager
(model SSH-160A; Toshiba; Tokyo, Japan) with a 3.5-MHz
transducer. The mitral valve area (MVA) was measured by way of a
planimetric method, whereas mitral regurgitation was semiquantitatively
assessed using color-flow Doppler echocardiography as described
previously.8
Left ventricular ejection fraction (LVEF) was
measured according to the recommendations of the American Society of
Echocardiography.9
Mean pulmonary artery pressure (PAP)
and mean pulmonary capillary wedge pressure (PCWP) were recorded
through a Swan-Ganz balloon-tipped catheter within a week before the
methacholine inhalation test.
PMBV
Nineteen patients with New York Heart Association class II to IV
symptoms and/or moderate to severe MS (MVA < 1.5
cm2) were considered as possible candidates for
PMBV. Three patients were further excluded because of unfavorable valve
morphology for balloon valvulotomy. Thus, 16 patients underwent PMBV by
way of a transseptal approach, as described by Inoue et
al.10
Successful valvulotomy was defined as an MVA > 1.5
cm2 in the absence of complications including
severe mitral regurgitation (greater than second degree) and/or a large
atrial septal defect (> 1.5:1 left-to-right shunt).
Pulmonary Function Tests and Methacholine Challenge
Total lung capacity (TLC), VC, and FEV1
were obtained in all patients using computer-assisted spirometry
(model 2400; SensorMedics; Yorba Linda, CA). All medication was
stopped 48 h before the beginning of the methacholine challenge.
Methacholine was dissolved in physiologic saline solution to make
solutions of 0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, and 32.0 mg/mL. The
saline and methacholine solutions were inhaled from a nebulizer
(model 646; DeVilbiss Health Care; Somerset, PA) operated by
compressed air at 5 L/min. Saline solution was inhaled first for 2 min,
and the FEV1 was measured. If the change in
FEV1 from the baseline after inhalation of saline
solution was 
10%, inhalation of methacholine was started.
Methacholine solution was inhaled for 2 min under tidal breathing with
a nose clip, and this was followed immediately by spirometry. Twofold
incremental concentrations were given until a fall of 
20% in
FEV1 was noted. The productive concentration of
methacholine causing 20% decrease in FEV1
(PC20) was calculated and used as a parameter of
bronchial responsiveness. BHR was defined as a
PC20 < 8 mg/mL.11
In 16 patients,
pulmonary function tests and methacholine challenge were repeated 2 to
4 days after PMBV (4 to 7 days apart from the first test). Methacholine
challenges in one patient were performed at the same time of day to
avoid circadian differences in reactivity.
Statistical Analysis
Data are presented as mean ± SD. Intergroup comparisons of
discrete variables were performed using the Student’s t
test. Pearson’s correlation coefficient and simple linear regression,
using the least-squares method, were performed to test the correlation
between PC20 and cardiac and pulmonary function
parameters. Results with a p value < 0.05 were considered
significant.
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Results
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Study Population
Thirty patients with MS (24 were female, and 6 were male) and 28
control subjects (20 were female, and 8 were male) were included in
this study. The mean ± SD age of the patients and control subjects
were 38.3 ± 10.2 years and 36.9 ± 9.1 years, respectively. There
were no significant differences in age or sex between patients and
control subjects.
Cardiopulmonary Function
The results of baseline cardiopulmonary function tests and
methacholine challenge are summarized in Table 1
. Echocardiographic evaluation revealed that 10 patients had mild MS
(MVA 1.5 cm2), 14 patients had moderate MS
(MVA < 1.5 cm2 and > 1
cm2), and 6 patients had severe MS (MVA 1
cm2). All patients had good left
ventricular systolic function as a measure of LVEF (64.6 ± 11.8%).
Hemodynamic data demonstrated elevated values for PAP and PCWP in the
MS group: 29.6 ± 8.6 mm Hg and 20.8 ± 6.4 mm Hg, respectively.
The mean values for TLC, VC, and FEV1 were
significantly lower in MS patients compared with normal control
subjects, whereas the FEV1/VC did not
significantly differ among the two groups. Results of the methacholine
inhalation test showed that the mean value for
PC20 in the 30 patients with MS (9.22 ± 8.19
mg/mL) was significantly lower than that in the 22 control subjects
(46.14 ± 12.87 mg/mL; p < 0.0001). In six of the control subjects
(21%), however, the PC20 could not be calculated
with the doses of methacholine used. Sixteen of the 30 patients with MS
(53%) were found to have BHR (PC20 < 8 mg/mL),
whereas all of the control subjects had a normal response to
methacholine. A subgroup analysis showed that all patients with BHR had
either moderate or severe MS (MVA < 1.5 cm2).
Although the patients with mild MS had significantly lower
PC20 values than the control subjects
(15.62 ± 6.81 mg/mL vs 46.14 ± 12.87 mg/mL; p < 0.0001), none
of them had PC20 values < 8 mg/mL.
Correlation analyses between PC20 and cardiac and
pulmonary function parameters are shown in Table 2
. There were strong inverse correlations between
PC20 and PAP (r = - 0.777; p < 0.001), and
PC20 and PCWP (r = - 0.723; p < 0.001). In
addition, significant positive correlations were exhibited between
PC20 and MVA (r = 0.676; p < 0.001),
PC20 and FEV1 (r = 0.381;
p = 0.038), and PC20 and
FEV1/VC (r = 0.373; p = 0.04). None of the
other cardiopulmonary parameters including LVEF, VC, and TLC were
significantly correlated with PC20.
Effect of PMBV on Cardiac and Pulmonary Function Parameters
Balloon valvulotomy was successfully performed in all of the 16
patients. After PMBV, cardiac parameters (MVA, PAP, and PCWP)
significantly improved (Table 3
). In contrast, no significant changes were shown in pulmonary function
test variables (TLC, VC, FEV1, and
FEV1/VC; Table 4
). Although significant improvement was observed in the mean
PC20 values after the PMBV (from 4.97 ± 5.24
to 7.47 ± 6.96 mg/mL; p = 0.0006), BHR was not completely
eliminated in any, except one patient (Table 5
and Fig 1
).
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Figure 1. Individual bronchial response to methacholine in
16 patients with MS before and after successful PMBV. The
PC20 improved in all patients except for patient 7.
LOG = logarithm.
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Discussion
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Summary of Study Results
In the current study, we demonstrated that bronchial response to
methacholine is significantly increased in patients with MS, so that
53% of them had BHR. In addition, we found that
PC20 was closely correlated with MVA, PAP, and
PCWP, suggesting that the severity of BHR is significantly associated
with the severity of MS. Moreover, we observed significant improvement
in PC20 after successful PMBV. This finding
confirms the hypothesis that a reduction of pulmonary congestion might
improve bronchial response to methacholine in patients with MS.
Comparison With Results From Other Studies
It is well known that the reaction of normal populations to
methacholine is somewhat variable. This is due to the fact that uniform
standardization of methodology has not been achieved.12
Hargreave et al11
defined the subjects with a
PC20 < 8 mg/mL as responders and the subjects
with a PC20 > 8 mg/mL as nonresponders. On the
other hand, Wanger12
and Malo et al13
reported that normal individuals do not have PC20
values < 16 mg/mL of methacholine. In the present study, we defined
BHR by way of Hargreave et al.11
However, we noted that
none of our normal subjects had PC20 values
< 16 mg/mL.
There have been many reports of BHR in patients with
LVF4
5
14
and MVD,6
7
but how a patient’s
bronchial responsiveness was increased remains controversial. Rolla et
al6
and Nishimura et al7
reported a
significant inverse correlation between bronchial responsiveness to
methacholine and PCWP in patients with MVD. Accordingly, they suggested
that pulmonary congestion and/or edema might contribute to BHR in
cardiac patients. However, Eichacker and coworkers15
failed to observe BHR in seven of nine patients with severe LVF,
despite a remarkable increase in PCWP (27 mm Hg). In the current study,
chronic lung congestion is the most conceivable explanation for the
increased bronchial responsiveness, since we excluded the other factors
(COPD, atopy, recent airway infection, smoke, and drugs) that may
influence bronchial response to methacholine. Furthermore, the close
correlation between PCWP and PC20
(r = - 0.723; p < 0.001) strengthens the possibility of a link
between interstitial lung edema and bronchial responsiveness in our
patients. In experimental studies, it has been demonstrated that
pulmonary edema stimulates unmyelinated C-fiber nerve endings, in lung
parenchyma (J or juxtacapillary endings)16
17
and in
bronchi.18
Then, these forms of afferent stimulation
causes reflex narrowing of large and small airways. Moreover, Kikuchi
et al19
showed that in dogs pulmonary congestion made the
BHR through vagal reflexes by narrowing of peripheral airways.
Another subject of interest is whether or not BHR secondary to heart
disease is reversible by reducing pulmonary congestion. Pison et
al5
could not observe a significant improvement in
bronchial responsiveness after 5 to 15 days of intensive diuretic
therapy in 12 patients with acute decompensation of LVF. They
speculated that incomplete treatment might be responsible for the lack
of improvement in bronchial responsiveness, since radiologic signs of
cardiac failure were still present after diuretic therapy. On the other
hand, Nishimura et al7
noted a significant improvement in
bronchial responsiveness of patients with MVD after mitral valve
replacement. They reported that most of their patients, however,
remained hyperreactive to methacholine despite the disappearance of
interstitial lung edema. The remaining BHR in their patients
might be partly attributed to cigarette smoking, since more than one
third of them were heavy smokers. However, in a nonsmoking community,
we also found that BHR was not completely eliminated after PMBV in any,
except one patient. Thus, the increase in bronchial responsiveness that
we observed in MS patients could not be explained by interstitial edema
alone. Previous investigations suggested that chronic edema of the
bronchial wall may lead to a substantial increase in BHR as a result of
geometric narrowing in the airway.14
20
21
Furthermore,
Cabanes et al 3
and Moreno et al22
reported
that thickening of bronchial walls might also cause hyperresponsiveness
as well as bronchial narrowing.
In summary, our study demonstrated that BHR is fairly common in
patients with MS, as a result of pulmonary congestion due to the
obstruction at the pulmonary outflow. Balloon dilatation of the mitral
valve leads to significant reduction in pulmonary congestion and a
consequent improvement in bronchial responsiveness. However, BHR was
not completely eliminated in most of the patients. Taken together with
the previous investigations, the remaining BHR might be attributed to
factors such as airway edema,6
dilatation of the bronchial
vessel,3
and decreased airway caliber,7
resulting from long-standing pulmonary congestion.
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Footnotes
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Abbreviations:
BHR = bronchial hyperreactivity; LVEF = left ventricular ejection
fraction; LVF = left ventricular failure; MS = mitral stenosis;
MVA = mitral valve area; MVD = mitral valve disease;
PAP = pulmonary artery pressure; PC20 = productive
concentration of methacholine causing 20% decrease in
FEV1; PCWP = pulmonary capillary wedge pressure;
PMBV = percutaneous mitral balloon valvulotomy; TLC = total lung
capacity; VC = vital capacity
Received for publication October 20, 1998.
Accepted for publication July 19, 1999.
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Abstract
Introduction
