Angiotensin-converting enzyme inhibition restores the

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					                                                                                               Clinical Science (1999) 96, 17–22 (Printed in Great Britain)   17

     Angiotensin-converting enzyme inhibition
      restores the diffusing capacity for carbon
 monoxide in patients with chronic heart failure
   by improving the molecular diffusion across
               the alveolar capillary membrane
Marco GUAZZI and Piergiuseppe AGOSTONI
Istituto di Cardiologia dell’Universita' degli Studi, Centro di Studio per le Ricerche Cardiovascolari del Consiglio Nazionale delle
Ricerche, Fondazione ‘ Monzino ’, I.R.C.C.S., Via C. Parea 4, 20138 Milan, Italy

A      B      S     T     R      A      C      T

           Conductance of alveolar capillary membrane (DM) and capillary blood volume (VC) are the
           subcomponents of the pulmonary diffusing capacity for carbon monoxide (DLCO). In chronic
           heart failure, stress failure of the membrane provides a mechanism for reduced DM and
           subsequent impairment of DLCO. Angiotensin-converting enzyme inhibition improves DLCO in
           patients with chronic heart failure. This study was aimed at investigating which of the two
           subcomponents of DLCO is affected by angiotensin-converting enzyme inhibitors. Twenty-seven
           patients with NYHA class II to III chronic heart failure (group 1) and 13 age- and sex-matched
           normal subjects underwent pulmonary function testing with determination of DM and VC, while
           receiving placebo and 48 h and 1 and 2 months after starting enalapril treatment (10 mg twice
           daily). Nine similar patients (group 2) received isosorbide dinitrate (40 mg thrice daily) for a
           month then enalapril for another month, and underwent pulmonary function testing at 48 h and
           1 month after starting treatments. Effects of angiotensin-converting enzyme inhibition in normal
           controls were not significant in the short- or mid-term. In group 1 patients, the only change
           observed at 48 h was a reduction in VC (probably due to a decrease in capillary pulmonary
           pressure). There was a marked increase in DM to a similar extent at 1 and 2 months, resulting in
           a significant improvement in DLCO despite a decrease in VC. In group 2 patients, nitrates failed
           to improve DLCO and DM, whereas enalapril was as effective as in group 1. These observations
           suggest a modulatory effect of angiotensin-converting enzyme inhibition on the membrane
           function which emerges gradually and persists over time and is probably dissociated from
           changes in pulmonary capillary pressure and VC. Chronic heart failure disturbs the alveolar
           capillary interface and increases gas diffusion resistance ; angiotensin-converting enzyme
           inhibition restores the diffusive properties of the membrane and gas transfer, and protects the
           lung when the heart is failing.

INTRODUCTION                                                              blood vessels [3,4] and skeletal muscles [5,6]. Studies that
                                                                          focus primarily on pulmonary pathophysiology in this
Exercise intolerance in chronic heart failure has long been               syndrome are limited. Only recently have pulmonary
ascribed to cardiac and peripheral factors [1,2], including               factors been suggested as important determinants of the

Key words : enalapril, pulmonary capillary blood, pulmonary function.
Abbreviations : ACE, angiotensin-converting enzyme ; DLCO, pulmonary diffusing capacity for carbon monoxide ; FEV , forced
expiratory volume in 1.0 s ; VA, alveolar volume.
Correspondence : Dr M. Guazzi.

                                                                          # 1999 The Biochemical Society and the Medical Research Society
18   M. Guazzi and P. Agostoni

     debilitating symptoms [7,8]. A reduction in resting               were continued through the trial. Seven healthy indi-
     pulmonary diffusing capacity of carbon monoxide                   viduals and six subjects with mild untreated primary
     (DLCO) in chronic heart failure has been documented               hypertension, with no history of cardiorespiratory dis-
     [9–12] and proposed as being an independent predictor of          ease, with normal physical examination and chest X-ray,
     peak exercise oxygen uptake [7,11] in these patients.             who were of a similar age and sex to the patients, did not
        DLCO may be divided into two subcomponents                     smoke and were not taking cyclo-oxygenase inhibitors
     [13,14] : DM, the molecular diffusion of carbon monoxide          (patients and controls were carefully questioned con-
     across the alveolar-capillary membrane ; and VC, the              cerning medications that might contain aspirin, and
     chemical reaction (θ) of carbon monoxide with pul-                platelet aggregation was tested and found to be normal in
     monary capillary blood. Because a proportion of the total         all), volunteered to serve as controls. None of the patients
     diffusive resistance in heart failure is caused by reduced        and control subjects had participated in previous studies
     DM [11,15], the hypothesis has been advanced that                 in our laboratory.
     proliferation of alveolar cells, thickening of the alveolar          Left ventricular ejection fraction was assessed at rest, in
     capillary interstitium and some fibrotic changes in                the supine position by two-dimensional echocardi-
     response to a sustained pressure-induced trauma in the            ography according to Simpson’s rule.
     pulmonary microvasculature, may augment the thickness                Standard colour Doppler velocimetry was used to
     of alveolar capillary membrane and reduce DM [11].                measure the degree of mitral regurgitation, which was
        The observation that enalapril causes a significant             graded subjectively on a scale from none (0) to severe (5).
     increase of DLCO in patients with chronic heart failure
     [16] prompted us to investigate which of the two DLCO
                                                                       Pulmonary function testing
     subcomponents is affected by enalapril, because an
                                                                       Measurements of FEV . , vital capacity, mean voluntary
     improvement in the DM component would reflect an                                            "!
                                                                       ventilation and total lung capacity were made with Sensor
     ability of angiotensin-converting enzyme (ACE) in-
                                                                       Medics 2200 Pulmonary Function Test System. DLCO
     hibitors to specifically reverse or attenuate alterations in
                                                                       was measured in triplicate with washout intervals of at
     the alveolar capillary membrane that are associated with
                                                                       least 4 min (the average was taken as the final result), in
     a failing heart.
                                                                       the sitting position, with a standard single-breath tech-
                                                                       nique [14], using as a test gas 0.28 % carbon monoxide
                                                                       (CO). Measured diffusing capacity was corrected for the
                                                                       subject’s haemoglobin concentration by the equation of
     PATIENTS AND METHODS                                              Cotes et al. [17]. The single-breath alveolar volume (VA)
                                                                       was derived by methane dilution. Alveolar capillary
     Patients and controls
                                                                       membrane diffusing capacity (DM) and the capillary
     The study population was composed of patients referred
                                                                       volume of blood available for gas exchange (VC) were
     to the Institute of Cardiology, University of Milan,
                                                                       determined, with the same equipment, according to the
     between December 1995 and May 1998 for evaluation of
                                                                       classic method of Roughton and Forster [13,14].
     chronic heart failure. The cause of the disease was either
     idiopathic cardiomyopathy (cardiac enlargement and
     absence of a specific cause for cardiac failure) or ischaemic      Study design
     heart disease (documented previous myocardial infarc-             Patients were separated into group 1 (the first 30
     tion). Inclusion criteria were (1) willingness to participate     consecutive patients enrolled) and group 2 (the last 10
     in the study, (2) chronic stable NYHA functional class II         consecutive patients enrolled). Three patients in group 1
     to III due to cardiac dysfunction, (3) left ventricular           and one in group 2 and controls did not complete the
     ejection fraction      40 %. Exclusion criteria were (1)          study (due to non-compliance with appointments and
     current or past history of smoking (more than 10                  drugs, or for administrative reasons) and were excluded
     cigarettes per day during one of the past 5 years), (2)           from the final result analysis. Patients in group 1 and
     history of respiratory disease, (3) ACE inhibitor therapy,        controls received, in a single-blind fashion, placebo for 1
     acetylsalicylic acid or other cyclo-oxygenase inhibitors          week and then enalapril (10 mg twice daily) for 2 months.
     within the last 6 months, (4) evidence of airway ob-              Pulmonary function tests were performed at the begin-
     struction (FEV . to VC ratio 70 %, where FEV n is the             ning and at the end of the run-in, the former being
                     "!                                   "!
     forced expiratory volume in 1n0 s).                               utilized for screening patients with FEV \VC 70 % and
        The protocol was approved by the Ethics Committee              the latter as baseline values. Tests were repeated 48 h and
     of the Institute of Cardiology, University of Milan, and          1 and 2 months after starting enalapril, 3 h after a light
     informed consent was obtained from each patient.                  meal at the same time of the day. The present protocol
        Forty patients were enrolled into the study. All were          was chosen in an attempt to monitor the beginning and
     receiving optimal doses of frusemide and digoxin that             persistence of effects of enalapril. Patients in group 2
     had remained unaltered in the previous 2 months and               received, in a single-blind fashion, placebo for 1 week,

     # 1999 The Biochemical Society and the Medical Research Society
                                                                                                       Angiotensin-converting enzyme inhibition in heart failure   19

then isosorbide dinitrate (40 mg thrice daily) for a month                  run-in. The three populations were homogeneous with
and then, after a 3-day washout, enalapril (10 mg twice                     respect to age, sex and anthropometric characteristics ;
daily) for a month. Pulmonary function tests were                           mitral regurgitation was detected in 12 patients in group
performed during the run-in, as described, and repeated                     1 and in three patients in group 2 and did not exceed
48 h and a month after starting nitrates and after starting                 grade 3 ; blood pressure was higher in controls (six had
enalapril.                                                                  mild hypertension) ; FEV . , vital capacity, total lung
                                                                            capacity, DLCO and DM were lower and VC was greater in
Data analysis                                                               the two patient groups compared with control subjects.
Data from patients and controls were compared by                            In heart failure, the proportion of diffusive resistance
unpaired t-test and one-way ANOVA. The significance                          pertaining to the alveolar capillary membrane
of differences between serial measurements was assessed                     (DLCO\DM) was similar in groups 1 and 2 and was
by repeated-measures ANOVA and Newman–Keuls                                 greater than that in normal subjects. The reduction in DM
multiple comparison procedure. Differences at P 0.05                        was still evident when lung volume was taken into
were considered statistically significant. Results are                       account by plotting DM\VA.
expressed as meanspS.D.                                                        Figures 1 and 2 and Table 2 report the results of
                                                                            spirometry with enalapril in group 1 patients and
                                                                            controls. ACE inhibition had no effects in control
RESULTS                                                                     subjects, with respect to DLCO, its two subcomponents
                                                                            and lung volumes. In patients with heart failure, however,
The anthropometric, circulatory, respiratory and thera-                     changes were recorded at 1 and 2 months, which consisted
peutic data of group 1 and 2 patients and controls are                      of a significant increase in DLCO, in diffusion across the
summarized in Table 1. Pulmonary function and cir-                          alveolar capillary membrane (DM) and in the alveolar
culatory values reported were those recorded at the end                     capillary membrane diffusing capacity per unit effective
of run-in and were similar to those at the beginning of                     alveolar volume (DM\VA), and of a decrease in the

               Table 1 Anthropometric, circulatory, respiratory and therapeutic data in group 1 and 2
               patients and in control subjects
               Values are meanspS.D. Pulmonary function data are expressed in absolute values and as a percentage of predicted normal
               values on the basis of standard nomograms incorporating age, sex, height and weight. *P 0.01 compared with the
               corresponding control value.

                                                                 Controls                   Group 1                       Group 2
               No.                                               13                         27                            9
               Age (years)                                         59p8                       60p7                          62p4
               Sex (M/F)                                         7/5                        22/5                          7/2
               Body surface area (m2)                            1.90p0.20                  1.95p0.20                     1.88p0.18
               Blood pressure (mmHg)
                   Systolic                                      135p11                     115p8                         118p8
                   Diastolic                                       87p4                       76p5                          77p6
               Ejection fraction ( %)                              60p7                       35p13*                        37p11*
               Mitral regurgitation                              –                           1.7p0.1                       1.3p0.2
               FEV1.0 (litres)                                    3.4p0.2                   2.86p0.7*                     2.79p0.5*
                    % predicted                                  109p17                       85p10*                        83p12*
               Vital capacity (litres)                            4.6p0.8                    3.4p0.7*                      3.1p0.5*
                    % predicted                                    86p18                      77p13*                        79p8*
               Total lung capacity (litres)                       4.6p1                        4p1*                        3.9p0.9*
                    % predicted                                    72p16                      66p14*                        65p12*
               DLco (ml:min−1:mmHg−1)                              26p9                       23p7*                         22p5*
                    % predicted                                    96p20                      81p21*                        79p18*
               DM (ml:min−1:kg−1)                                  40p12                    30.5p8*                       29.5p7.7*
               V C (ml)                                          100p65                     135p59*                       127p32*
               DLco/DM ( %)                                      69                         76*                           76*
               DM/VA (ml:min−1:mmHg−1/l)                         8                          5*                            4.9*
               Frusemide (mg/day)                                –                            70p35                         80p30
               Digitalis (mg/day)                                –                          0n25p4                        0n25p3

                                                                            # 1999 The Biochemical Society and the Medical Research Society
20   M. Guazzi and P. Agostoni

     Figure 1 Pulmonary diffusing capacity for carbon monoxide
     (DLCO) and alveolar capillary membrane diffusing capacity
     (DM) in group 1 heart failure patients (
) and control
     subjects ( ) while on placebo and 48 h, 1 and 2 months after
                                                                              Figure 2 Pulmonary capillary blood volume (VC), proportion
     starting treatment with enalapril
                                                                              of total pulmonary diffusive resistance due to the alveolar
     Values are means (pS.D.). >P    0.01 versus controls, FP   0.01 versus
                                                                              capillary membrane (DLco/DM) and the alveolar capillary
     placebo, *P 0.01 versus 48 h.
                                                                              membrane diffusing capacity per unit effective alveolar
                                                                              volume (DM/VA) in group 1 patients with heart failure (
     volume of blood available for gas exchange (VC) and in the               and control subjects ( ) while on placebo and 48 h, 1 and 2
     proportion of the total diffusive resistance related to the              months after starting treatment with enalapril
     alveolar capillary membrane (DLCO\DM). As for the lung                   Values are means (pS.D.). >P    0.01 versus controls, FP   0.01 versus
     volumes, FEV . and mean voluntary ventilation were
                     "!                                                       placebo, *P 0.01 versus 48 h.
     augmented, vital and total lung capacities were unchanged
     compared with placebo. Interestingly (i) none of the
     changes described were detected at 48 h of active ACE                    functional status in chronic heart failure [7,11,12,16,17].
     inhibition, except a significant reduction of VC, and (ii)                Our previous observations have also shown that in this
     changes recorded at 1 month persisted at 2 months.                       syndrome a modulation of pulmonary gas transfer is
        Table 3 reports the respiratory data in group 2 patients              feasible with ACE inhibitors [16]. The present results
     and shows that, compared with placebo, values were                       provide the following additional information : ACE
     similar, while on isosorbide dinitrate, both at 48 h and                 inhibition is effective on DM, the molecular diffusion of
     after 1 month of therapy ; on the contrary, DLCO and DM                  carbon monoxide across the alveolar capillary membrane,
     were significantly raised and VC significantly reduced                     resulting in an improvement in DLCO even with a
     after 1 month of enalapril, compared with both placebo                   decreased VC ; this action is detectable in patients with
     and the corresponding nitrate values.                                    heart failure and not in normal individuals, suggesting
                                                                              that alterations related to the syndrome are the substrate
                                                                              for the enalapril activity ; the effect is not immediate (in
     DISCUSSION                                                               fact, it was not detectable at 48 h), but emerges gradually
                                                                              over time [18], is persistent (results at 2 months were
     That heart failure may be associated with an increased                   similar to those at 1 month) and is not duplicated by
     lung diffusive resistance has long been known to patho-                  nitrates.
     physiologists and clinicians [15]. More recent reports                      Diffusing capacity depends on (1) the exchange area
     have proven that the depressed alveolar capillary mem-                   (lung volume and capillary blood volume available for
     brane diffusing capacity is the major determinant of the                 gas exchange), (2) the distance between capillaries and
     excessive diffusive resistance [11], and impaired pul-                   alveoli [9] (which is mainly related to the hydrostatic and
     monary gas transfer correlates with exercise capacity and                osmotic forces governing transition of fluid from the

     # 1999 The Biochemical Society and the Medical Research Society
                                                                                                                        Angiotensin-converting enzyme inhibition in heart failure   21

Table 2     Respiratory function in control subjects and group 1 patients while on placebo and enalapril
Values are meanspS.D. *P          0.01 compared with the corresponding control value ; FP            0.05 compared with the placebo value.

                                                                                                        Mean voluntary                          Total lung capacity
                             FEV1.0 (litres)                          Vital capacity (litres)           ventilation (l/min)                     (litres)

                             Absolute              % predicted        Absolute         % predicted      Absolute              % predicted       Absolute         % predicted
   Placebo                       3.4p0.2           109p17             4.6p0.8          86p18            120p20                102p27            4.6p1            72p16
   Enalapril (48 h)              3.5p0.3           110p18             4.7p0.9          88p19            122p21                104p28            5.2p2            82p16
   Enalapril (1 month)           3.3p0.2           108p17             4.6p0.7          86p16            121p19                103p26            4.9p2            76p17
   Enalapril (2 months)          3.4p0.4           109p19             4.8p0.8          90p20            123p22                105p28              5p3            78p18
   Placebo                   2.86p0.7*                  85p10*        3.4p0.7*         77p13*            96p46*                89p18*             4p1*           66p14*
   Enalapril (48 h)          2.81p0.6*                  85p10*F       3.4p0.8*         77p13*            95p40*                88p18*             4p1*           66p12*
   Enalapril (1 month)       3.05p0.7                   89p9*F        3.5p0.6*         78p11*           100p36*F               93p16*F          4.2p0.8*         70p11*
   Enalapril (2 months)       3.1p0.8*F                 89p11*F       3.5p0.7*         79p14*           102p42*F               95p16*F          4.1p1*           68p10*

Table 3     Respiratory function in group 2 patients while on placebo, isosorbide dinitrate and enalapril
Values are meanspS.D. *P          0.01 compared with the corresponding value while on isosorbide dinitrate ; FP               0.01 compared with the placebo value.

                                                           Vital       voluntary         Total lung
                                                           capacity    ventilation       capacity        DLCO                        DM
                                      FEV1.0 (litres)      (litres)    (l/min)           (litres)        (ml:min−1:mmHg−1)           (ml:min−1:mmHg−1)          V C (ml)
Placebo                               2.79p0.5             3.1p0.5     86p19             3.9p1.1         21.7p5                      28.5p7.7                   127p32
Isosorbide dinitrate (48 h)           2.98p0.43            2.9p0.6     91p22F              4p0.8         21.3p4                      28.7p6.5                   103p17F
Isosorbide dinitrate (1 month)        2.99p0.41F           3.2p0.7     92p18F            3.7p1           19.8p3.9                    27.3p8.9                   107p23F
Enalapril (48 h)                      2.93p0.3F              3p0.5     92p18F            4.1p0.9         20.9p3.2                    28.6p9.7                   105p16F
Enalapril (1 month)                   3.15p0.5F            3.1p0.9     98p25F            3.9p1.2         24.5p2.9*F                  32.7p8.4*F                  99p12*F

intravascular to the extravascular phase), (3) the structural                            occur at 48 h even though the hydrostatic forces that
and functional properties of the alveolar capillary mem-                                 underlie the extravascular fluid accumulation diminish
brane. The diminished lung volume, which is a common                                     within a few hours after 10 mg of oral enalapril [20].
feature of chronic heart failure [8], would decrease the                                    Results in this study point in the direction of a
exchange area. However, improvement in DM, which                                         derangement of the alveolar capillary membrane. El-
persisted even when effective alveolar volume was                                        evation of pulmonary capillary pressure, as occurs in
accounted for (DM\VA), and steadiness of vital and total                                 heart failure, may produce vascular and alveolar epithelial
lung capacities during treatment with enalapril, do not                                  damage [8], stress failure and dysfunction [21] of the
explain the diminished alveolar capillary membrane                                       alveolar capillary membrane. A persistent restraint of the
diffusive resistance on the basis of variations in the gas                               inciting stimulus, i.e. the elevated hydrostatic pressure as
exchange area. The raised diastolic pressure in a dys-                                   an explanation for the benefits of ACE inhibitors, would
functioning left ventricle is the initiating hydrostatic                                 imply that all agents which lower the pulmonary capillary
force for an increased fluid filtration in the lung in-                                    pressure are also able to modulate the reduced diffusive
terstitial space [19] and has been interpreted as a reason                               conductance across the alveolar capillary membrane.
for the impairment of DLCO in heart failure [12]. Invasive                               However, short-term hydralazine and isosorbide di-
procedures in our patients were not included in the                                      nitrate do not produce such an effect [16] ; DLCO is
protocol approved by the ethics committee. There are,                                    reported to decline after heart transplantation and to be
however, some considerations that do not suggest a                                       stable after medical treatment of heart failure [22] and,
reabsorption of extravascular fluid volume as the main                                    even more convincing, enalapril was able to improve DM
determinant of the increase in DM with ACE inhibition :                                  and DLCO in the same patients (group 2) in whom
patients were receiving optimal doses of frusemide and                                   isosorbide dinitrate had failed, even though the reducing
did not present with physical signs of fluid retention and                                effect on VC was similar, suggesting a comparable
lung congestion ; significant changes in DLCO did not                                     lowering influence on the pulmonary capillary pressure.

                                                                                         # 1999 The Biochemical Society and the Medical Research Society
22   M. Guazzi and P. Agostoni

        At cardiac level, when an altered load and stretch of                 heart failure. Effects of physical training. Circulation 93,
     myocytes stimulates mitosis of cardiac fibroblasts, the               6   Mancini, D., Donchez, L. and Levine, S. (1997) Acute
     renin–angiotensin–aldosterone system participates in the                 unloading of the work of breathing extends exercise
     collagen synthesis and excessive collagen accumulation.                  duration in patients with heart failure. J. Am. Coll.
                                                                              Cardiol. 29, 590–596
     In these circumstances, ACE inhibitors can protect the               7   Kraemer, M. D., Kubo, S. H., Rector, S. T., Brusvold, N.
     heart by inhibiting the angiotensin-mediated synthesis of                and Bank, A. J. (1993) Pulmonary and peripheral vascular
                                                                              factors are important determinants of peak exercise oxygen
     collagen and by impeding its turnover through activation                 uptake in patients with heart failure. J. Am. Coll. Cardiol.
     of the prostaglandin system [23]. That this protection                   21, 641–648
     may also be at work at the lung level is an attractive               8   Chua, T. P., Piepoli, M. and Coats, A. J. S. (1997)
                                                                              Alveolar-capillary membrane diffusing capacity and its role
     hypothesis. The gradual emergence over time of the                       in the functional capacity of chronic heart failure patients.
     restored diffusive properties is in keeping with this                    Cardiologia 42, 265–268
                                                                          9   Siegel, J. L., Miller, A., Brown, L. K., De Luca, A. and
     interpretation. Lung biopsies before and after treatment                 Tierstein, A. J. (1990) Pulmonary diffusing capacity in left
     in a few patients were discouraged by the Institution                    ventricular failure. Chest 98, 550–553
     Ethics Committee, even though they were desirable to                10   Naum, C., Sciurba, F. C. and Rogers, R. M. (1992)
                                                                              Pulmonary function abnormalities in chronic severe
     strengthen this hypothesis.                                              cardiomyopathy preceding cardiac transplantation. Am.
        In conclusion, this study documents that heart failure                Rev. Respir. Dis. 145, 1334–1338
                                                                         11   Puri, S., Baker, B. L., Dutka, D. P., Oakley, C. M.,
     is associated with an impeded alveolar capillary interface               Hughes, J. M. B. and Cleland, J. G. F. (1995) Reduced
     resulting in excessive diffusive resistance ; ACE inhibition             alveolar-capillary diffusing capacity in chronic heart
                                                                              failure. Its pathophysiological relevance and relationship to
     restores the alveolar capillary membrane properties and                  exercise performance. Circulation 91, 2769–2774
     the pulmonary gas transfer, thus proving capable of                 12   Messner-Pellenc, P., Brasileiro, C., Ahmaidi, S. et al. (1995)
     protecting the lung from derangements due to the failing                 Exercise intolerance in patients with chronic heart failure :
                                                                              role of pulmonary diffusing limitation. Eur. Heart J. 16,
     heart.                                                                   201–209
                                                                         13   Roughton, F. J. W. and Forster, F. E. (1957) Relative
                                                                              importance of diffusion and chemical reaction rates in
                                                                              determining rate of exchange of gases in human lung, with
                                                                              special reference to true diffusing capacity of blood in the
                                                                              lung capillaries. J. Appl. Physiol. 11, 290–302
                                                                         14   Cotes, J. E. (1979) Lung Function (4th edn), pp. 239–249,
     ACKNOWLEDGMENT                                                           Blackwell Scientific Publications, Oxford, U.K.
                                                                         15   Burgess, J. H. (1974) Pulmonary diffusing capacity in
     This study was supported in part by a grant from the                     disorders of the pulmonary circulation. Circulation 49,
     National Research Council, Rome, and the Monzino                         541–550
                                                                         16   Guazzi, M., Marenzi, G., Alimento, M., Contini, M. and
     Foundation, Milan, Italy.                                                Agostoni, P. (1997) Improvement of alveolar-capillary
                                                                              membrane diffusing capacity with enalapril in chronic
                                                                              heart failure and counteracting effect of aspirin.
                                                                              Circulation 95, 1930–1936
                                                                         17   Cotes, J. E., Dabbs, J. M., Elwood, P. C., Hall, A. M.,
                                                                              McDonald, A. and Saunders, M. J. (1972) Iron deficiency
                                                                              anaemia : its effect on transfer factor for the lung (diffusing
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                                                                                     Received 3 July 1998/accepted 17 August 1998

     # 1999 The Biochemical Society and the Medical Research Society