Bronchial Hyperresponsiveness in Patients with Chronic Congestive Heart Failure

Bronchial Hyperresponsiveness in Patients with Chronic Congestive Heart Failure* Fumihiko Sasaki, M.D.; Takeshi Ishizaki, M.D., F.C.C.P.; ]unichiro Mifune, M.D.; Masaki Fujimura, M.D.; Shinji Nishioka, M.D.; and Susumu Miyabo, M.D.

To investigate the relationship between pulmonary congestion and bronchial responsiveness, we measured bronchial responsiveness to acetylcholine in 51 patients with left heart disorders. The measurement of bronchial responsiveness was performed by inhaling doses of acetylcholine chloride (0.08 to 20 mglml) and calculating the PC20-FEV,. The median value for PC20-FEV, was above 20 mglml in the subjects without history of congestive heart failure (n 18), was 5.29 mglml in the subjects with clinical evidence of congestive heart failure in the past days (n 18; p
the grade of bronchial responsiveness. These results suggest that the bronchial responsiveness was increased in most of the patients with chronic congestive heart failure. We concluded that continuous pulmonary congestion may contribute to the pathogenesis of bronchial hyperresponsiveness. Chat 1990; 97:534-38)

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hyperresponsiveness to nonspecific stimBronchial uli is an almost universal finding in patients with bronchial asthma. On the other hand, paroxysmal dyspnea similar to an asthma attack frequently occurs in patients with congestive heart failure; however, no data are available in the literature on bronchial hyperresponsiveness in these patients. Therefore, to investigate the relationship between pulmonary congestion due to congestive heart failure and bronchial responsiveness, we measured bronchial responsiveness to acetylcholine in 51 patients with left heart disorders. MATERIALS AND METHODS

PCf.O.FEV, =provocative ccmcentration producing a ZO percent

faD in FEV,; CO=cardiac output; mPAP=mean pulmoaary arterial pressure; mPCWP =mean pulmooary capillary wedge

pressure; LVEDP=Ieft ventricular end-diastoUc pressure; CTR = cardiothoracic ratio; Zrs = respira~ system impedance; ~V\=mean of absolute values of changes in FEV, which resUlted in PCZO-FEV,

symptoms, eg, dyspnea on elrort, orthopnea, and paroxysmal nocturnal dyspnea; however, all of the patients did not have the symptoms of typical cardiac asthma attack. We divided the subjects into two groups on the basis of their history of congestive heart failure. Group 1 included 18 patients without a history of congestive heart failure. In addition, we divided the patients with a history of congestive heart failure (group 2) into two subgroups on the basis of clinical symptoms at the time of study. Group 2a consisted of 18 patients with clinical evidence of congestive heart failure in the past that had cleared by the time of study. Group 2b consisted of 15 patients who had mild clinical symptoms of congestive heart failure at the time of study. None of the subjects had ever used ~adrenergic blockers, P-adrenergic agonists, methylxanthines, or corticosteroids; however, they were given either diuretics, calcium antagonists, or nitrates (or some combination).

Subjects

Bronchial Prooocation Tests

Fifty-one patients (27 women and 24 men; age range, 37 to 77 years) participated in the study. We excluded atopic patients, current smokers, and patients whose FEV, was less than 70 percent of their FVC in order to exclude patients with chronic obstructive pulmonary disease or bronchial asthma. We could not detect other reasons fur these patients to have reactive airways, eg, a history of exposure to toluene diisocyanates or sensitivity to sodium metabisuffite. All of the patients had been proven by several cardiologists to have left heart disorders (idiopathic cardiomyopathy, valvular disease, old myocardial infarction, or hypertensive heart disease). The onset of congestive heart failure was identified according to the New York Heart Association's criteria on the basis of the patients' clinical

The tests were performed while the patient's symptoms were mild and stable. All medication was stopped at 9 PM on the previous day to allow a washout time of 18 hours before the measurement of bronchial responsiveness at 3:30 PM on the test day. Bronchial responsiveness was evaluated with acetylcholine. Acetylcholine chloride was dissolved in physiologic saline solution to malce solutions of0.08, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20 mw'ml. Saline and acetylcholine solutions were inhaled from a nebulizer (DeVilbiss 646) operated by compressed air at 5 Umin. Saline solution was inhaled first fur two minutes, and the FEV, was measured (Autospiror HI-498). Respiratory system impedance at 3 Hz was also measured (Nihon Kohden MZR-4000) at the same time. If the change in FEV, from the baseline after inhalation of saline solution was 10 percent or less, inhalation of acetylcholine was started. Acetylcholine solution was inhaled fur two minutes under tidal breathing with a nose clip, and this was followed immediately by spirometry. Increasing concentrations were given until a fall of 20 percent or more in FEV, was noted. The PC20-FEV, was calculated and used as a parameter of bronchial responsiveness.

*From the Third Department oflnternal Medicine, Fukui Medical School, and the Division of Pulmonary Disease, Fukui Cardiovascular Center, Fukui, Japan. Manuscript received May 9; revision accepted August 22. Reprint requests: Dr. Sasaki, 3rd Department of Internal Medkine, Fukui Medicul School, Matsuokocho, Fukui 910-11, Japan

534

Table !-General Characteristics and &seline Pulmonary Function Thst Heaulu* Data

Group 1

No. of patients Sex Age, yr FVC,L FEV,,L Zrs, em H,O/Usec ~FEV,, L

18 7M; llF 61±8 2.52±0.62 1.97±0.45 4.4± 1.0

Group2a

Group2b

15 18 10M; SF 7M; llF 60±15 62±7 2.41±0.72 2.62±0.77 1.86±0.57 1.92±0.56 4.4±1.3 4.2±1.3 0.47±0.23 0.50±0.25

0.1~±0.18t

Table 2-Hemodynamic Variables by Cardiac Catheterization and Chest Roentgenogram*

*Values are means± SD. tp
Cardiac Catheterizaticm and Chest Roentgenograms

Catheterization of the left side of the heart was performed on 32 of the 51 subjects. Swan-Ganz catheterization was also performed on each of them. Six of the other 17 subjects received Swan-Ganz catheterization alone. The interval between the bronchial provocation test and cardiac catheterization was less than 30 days. The CO, mPAP, mPCWP, LVEF, and LVEDP were measured, and the CI was calculated as follows: CI =CO/body surface area. Within a week after the bronchial provocation test, all subjects underwent standard postero-anterior chest roentgenograms, and the CfRs of these roentgenograms were collected. Statistics The variables of baseline pulmonary function tests and cardiac catheterization were analyzed using a one-way ANOVA and a modified Student's t-test. Since in our protocol, values of PC20FEV, of more than 20 mwml cannot be measured, they were combined and treated as a group. We compared PC20-FEV, between the groups by using their median value, and these were analyzed by a nonparametric procedure (Mann-Whitney U-test). Correlation coefficients between (PC20-FEV,) and each hemody-

Group 1

Data HR, beats per min Mean arterial pressure, mm Hg mPAP, mm Hg mPCWP, mmHg Cl, Umin!m• LVEF LVEDP, mm Hg CfR, percent

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79±22 (15)

94± 15 (9) 15±3 (8) 10±2 (8) 2.7±0.4 (7) 65± 11 (8) 16±7 (8) 54±6 (18)

90± 10 (15) 19±7 (15) 12±6 (15) 3.0±0.7 (15) 47±15 (12)* 14± 10 (12) 58±6 (18)t

98±21 (IS) 26± 13 (1S)t 18± 10 (1S)t 2.7±0.7 (15) 50± 14 (ll)* 23± 13 (10) 59±6 (lS)t

The baseline pulmonary function test results are shown in Table 1 and Figure 1. Each mean value for age, FVC, FEV 1 and Zrs at 3Hz did not statistically differ among the groups. The .1FEV 1 in group l (0.19±0.18 mg/ml) was lower than'that in group 2 (0.48±0.24 mglml; p<0.05 by Student t-test): The hemodynamic variables are shown in Table 2. The mean values for HR and CTR in group 2a were higher than those in group 1. The mean values for mPAP, mPCWP, and CTR in group 2b were also higher than those in group 1 (p<0.05). The mean values for

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RESULTS

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namic variable were calculated by using Spearman's rank (:orrelation coefficient. A p value of less that 0.05 was talten as significant.

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FIGURE 1. Values for FVC and FEV, in individual subjects. Mean values for FVC and FEV, did not diller among the groups. CHEST I 97 I 3 I MARCH, 1990

535

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statistically differ among the groups. DISCUSSION

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FIGURE 2. Values for PC20-FEV, in individual subjects. Arrows indicate median value of each group. Median values of PC20-FEV, in group 2a and group 2b were significantly lower than that for group 1.

LVEF in groups 2a and 2b were lower than that in group 1 {P<0.05). There were no statistical differences in LVEF between group 2a and group 2b. Figure 2 shows the PC20-FEV1 value of individual patients. The median value for PC20-FEV1 in group 1 {>20 mglml) was significantly higher than that in group 2a (5.29 mglml) and that in group 2b (5.74 mgl ml) (p<0.05 by the Mann-Whitney U-test), but there was no difference in PC2Q-FEV1 between group 2a and group 2b. Figure 3 shows PC2Q-FEV1 values for nonsmokers and ex-smokers. The median value for PC2Q-FEV1 in ex-smokers {>20 mglml) was not different statistically from that in nonsmokers {12.1 mglml). The relationship between hemodynamic variables and PC20-FEV1 are presented in Figure 4. None of these variables was significantly correlated with PC2QFEV1. Figure 5 shows the relationship between etiologies of congestive heart failure and PC2Q-FEV1 in group 2. All patients with hypertensive heart disease had increased bronchial responsiveness {PC2Q-FEV1 <10 mglml), but the median value for PC2Q-FEV1 did not 536

In the present study, we measured bronchial responsiveness to acetylcholine in patients with left heart disorders and noticed that the median value for PC20-FEV1 in patients with a history of congestive heart failure was lower than that in patients without such history. Makino et al 1have reported with the same protocols as our bronchial provocation test that the PC2Q-FEV1 value of asthmatic subjects was lower than 1 mglml and that of normal control subjects was higher than 10 mglml. In our study, because all patients without a clinical history of congestive heart failure {group 1) have a PC20-FEV1 above 1 mglml, their bronchial responsiveness was considered to be within normal limits. In contrast, the PC2Q-FEV1 in patients with a history of congestive heart failure {group 2) was lower than 1 mglml in 23 {70 percent) of 33. Their bronchial responsiveness seems to have increased considerably. There have been many reports of pulmonary mechanical abnormalities in patients with congestive heart failure; ie, pulmonary congestion has produced both restrictive and obstructive changes, 2-7 and rapid saline solution infusion into normal men has led to derangement of small airway function.ll- 10 Pathophysiologically, decreased lung compliance due to increased lung water and blood volume may explain the restric-

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FIGURE 3. Values for PC20-FEV, in nonsmokers and ex-smokers. Median value (arrow) for PC20-FEV, in ex-smokers (>20 mwml) was not difJerent statistically from that (arrow) in nonsmokers (12.1 mwml). Bronchial HyparntapOI'IIIMmes in Congestive Heart Failure (Sasaki et a/)

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tive changes in acute pulmonary congestion. Fibrosis and respiratory muscle fatigue may also contribute to later changes. Obstructive changes have been attributed to increased airway resistance due to airway edema resulting from the pulmonary edema. 11- 13

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Since we excluded the patients whose FEV /FVC less than 70 percent in the present study, all subjects were considered to have no obstructive change. In addition, because the mean values for FVC or FEV1 in all groups were above 80 percent, the was

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FIGURE 5. Values for PC20-FEV, in various etiologies of congestive heart failure in group 2. Arrows indicate median value of each group. Differences were not significant among groups.

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Idiopathic Dilated Cardiomyopathy

Old Myocardial Infarction

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CHEST I 97 I 3 I MARCH, 1990

537

restrictive changes, if any, seem to be modest. Moreover, the .1FEV 1 in group 2 was higher than that in group 1 (fable 1). Therefore, the increase in bronchial responsiveness that we observed could not be explained by narrowing of bronchial caliber alone. How a patient's bronchial responsiveness was increased remains a matter of speculation, but neural reOex is a possibility to be taken into consideration. Kikuchi et al 14 reported an increase of bronchial reponsiveness to histamine in dogs by inOating a balloon in the left atrium. These investigators 14 concluded that pulmonary vascular <:ongestion made the bronchial hyperreaction through vagal reOexes by narrowing of peripheral airways. Jones et al6 and Chung et al 15 also showed that pulmonary vascular congestion reduced small airway caliber by vagal reOexes. Rolla et al 16 documented that rapid saline solution infusion produced an increase of bronchial responsiveness to methacholine in normal men. These investigators 16 concluded that acute minimal interstitial pulmonary edema increased bronchial responsiveness. Other researchers have suggested that excess pericapillary interstitial Ouid may increase airway tone by stimulating the type-J receptors 17 •18 and the lung irritant receptors reOex. 19 Nevertheless, all of these studies were on acute pulmonary congestion. Therefore, the previously mentioned explanations could not be simply extrapolated into our chronic congestive cases. Our data show that the cardiac function and the grade of pulmonary congestion obtained by cardiac catheterization does not correlate with bronchial hyperresponsiveness. These results indicate that bronchial hyperresponsiveness is caused not only by reOex but also by some organic bronchial changes. Recently, airway edema has been considered to relate to bronchial hyperresponsiveness in bronchial asthma. 20 Therefore, airway edema is the most reasonable cause of bronchial hyperresponsiveness in patients with congestive heart failure. The clinical implication of bronchial hyperresponsiveness in patients with congestive heart failure remains unclear. Generally, the cause of wheezing in congestive heart failure has been recognized as a narrowing of bronchial caliber due to bronchial wall edema; however, functional bronchoconstriction similar to bronchial asthma may also contribute to wheezing. In conclusion, our observation of the increase of bronchial hyperresponsiveness to acetylcholine in patients with congestive heart failure suggests that bronchial hyperresponsiveness may be the product of sustained airway edema accompanying long-term pulmonary congestion. Whether or not this bronchial

538

hyperresponsiveness is reversible by reducing pulmonary congestion remains to be clarified. ACKNOWLEDGMENT: We thank the participating technical staff, Ms. Fusako Yamada, and Ms. Setsuko Matsugashita for performing the measurements ofbronchical responsiveness. REFERENCES 1 Makino S, Ikemori R, Fukuda T, Motojima S, Namai S, et al. Clinical evaluation of standard method of acetylcholine inhalation test in bronchial asthma. Jpn J Allergy 1984; 33:167-75 2 Andrew LR, Gabriel G, Paul JF, Jack LC. Pulmonary function tests in the detection of left heart failure: correlation with pulmonary artery wedge pressure. Respiration 1986; 49:241-50 3 Rice DL, Bedrossian C, Blair HT, Miller WC. Closing volumes with variations in pulmonary capillary wedge pressure. Am Rev Respir Dis 1981; 123:513-16 4 Depeursinge FB, Depeursinge CD, Boutaleb Ak, Feihl F, Perret CH. Respiratory system impedance in patients with acute ventricular failure: pathophysiology and clinical interest. Circulation 1986; 73:386-95 5 Hales CA, Kazemi H. Small-airways function in myocardial infarction. N Eng) J Med 1974; 290:761-65 6 Jones JG, Lemen R, Graf PD. Changes in airway calibre following pulmonary venous congestion. Br J Anaesth 1978; 50:743-52 7 Sawaki M. Studies on pulmonary function in cardiac disease: l. cardiac asthma. Jpn Circ J 1968; 32:321-27 8 Rolla G, Bucca C, Pollizzi S, Giachino 0, Maina A, Arrosa W. et al. Site of airway obstruction after rapid saline infusion in healthy subjects. Respiration 1983; 44:90-6 9 Muir AL, Flenley DC, Kirby BJ, Sudlow MF, Guyatt AR, Brash HM. Cardiorespiratory effects of rapid saline infusion in normal man. J Appl Physiol1975; 38:786-93 10 Goeree GW. Coates G, Powles CP, Basalygo M. Mechanisms of change in nitrogen washout and lung volumes after saline infusion in humans. Am Rev Respir Dis 1987; 136:824-28 11 Borgstrom KE, Ising U, Linder E, Lunderquist A. Experimental pulmonary edema. Acta Radiol1960; 54:97-119 12 Harken AH, Nicholas MC, O'Connor E. The influence of clinically undetectable pulmonary oedema on small airway closure in the dog. Ann Surg 1976; 184:183-88 13 Hogg JC, Agarawal JB, Gardiner AJS, Palmer WH, Macklem PT. Distribution of airway resistance with developing pulmonary edema in dogs. J Appl Physiol1972; 32:20-4 14 Kikuchi R, Sekizawa K, Sasaki H, Hirose Y, Matsumoto N, 'Thkishima T, et al. Effects of pulmonary congestion on airway reactivity to histamine aerosol in dogs. J Appl Physiol: Respir Environ Exercise Physiol1984; 57:1640-47 15 Chung KF, Keyes SJ, Morgan BM, Jones PW, Snashall PD. Mechanisms of airway narrowing in acute pulmonary oedema in dogs: influence of the vagus and lung volume. Clio Sci 1983; 65:289-96 16 Rolla G, Scappati<:ci E, Baldi C, Bucca C. Methacholine inhalation challenge after rapid saline infusion in healthy subjects. Respiration 1986; 50:18-22 17 Paintal AS, Damodaran VN, Guz A. Mechanism of excitation of type J receptors. Acta Neurobiol Exp 1973; 33:15-9 18 Paintal AS. Mechanism of stimulation of type J pulmonary receptors. J Physiol1969; 203:511-32 19 Lloyd TC. Reflex effects of left heart and pulmonary vascular distention on airways of dogs. J Appl Physiol: Respirat Environ Exen:ise Physiol1980; 49:620-26 20 HoggJC, Pare PD, Moreno R. The effect of submucosal edema on airways resistance. Am Rev Respir Dis 1987; 135:S54-6

Bronchial Hypenesponsiven in Congestive Heart Failure (Sasaki et at)