Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin
Background KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar–capillary membrane diffusion.
Methods and Results In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (V̇o2), and exercise tolerance and reduced the ratio of dead space to tidal volume (Vd/Vt) and the ventilatory equivalent for carbon dioxide production V̇e/V̇co2). On enalapril, V̇o2 (r=.80, P<.0001) and Vd/Vt (r=−.69, P=.003) changes from placebo correlated with those in DLCO. These effects were inhibited by aspirin and were absent in control subjects. In 8 additional patients, hydralazine–isosorbide dinitrate, as an alternative treatment for reducing pulmonary capillary wedge pressure (PCWP) and increasing exercise capacity, were more effective than enalapril for the PCWP but did not affect DLCO and V̇e/V̇co2; amelioration in V̇o2 and Vd/Vt was unrelated to DLCO and was not modified by aspirin.
Conclusions ACE inhibition improved pulmonary diffusion in CHF. Hydralazine–isosorbide dinitrate failed to provide this result. Counteraction by aspirin, a prostaglandin inhibitor, bespeaks prostaglandin participation while on enalapril that might readjust capillary permeability or alveolar–capillary membrane diffusion.
Amelioration of functional capacity with ACE inhibitors in patients suffering from congestive cardiac failure has been interpreted as related to structural or functional improvement involving heart,1 2 3 4 5 peripheral circulation,6 7 or skeletal muscle.8 9 10 The relevance of a possible influence on the lungs has been largely underestimated in the past. This is amazing if one considers that the pulmonary circulation is the site of major conversion of angiotensin I to angiotensin II11 and ACE is highly concentrated on the luminal surface of the lung blood vessels.12 Is it purely by chance that this happens, or is it because ACE participates importantly in the regulation of pulmonary vascular tone and permeability?
Activation of endothelial B2 kinin receptors leads to the formation of NO and prostaglandins through the combination of the action of phospholipase A2 and cyclooxygenase.13 Circulating bradykinin is inactivated mainly during its passage through the lung by the same enzyme (KII ACE) that converts angiotensin I to angiotensin II. The pulmonary production rate of PGI2 is higher than the threshold dose required to inhibit platelet aggregation14 ; the relationship of tissue-specific, capacity-related indexes to pulmonary production rate of PGI2 in human cardiovascular disease awaits clarification.15
For the aforementioned reasons, the pharmacological effects of ACE inhibitors include not only the angiotensin system but also the kinin system.13 Blockade of KII ACE may increase local kinin concentration, leading to enhanced and sustained formation of NO and PGI2.16 Thus, ACE inhibitors in congestive heart failure seem to peculiarly reduce the exposure of the pulmonary vessels to angiotensin II and to increase the influences of NO and PGI2.
For a normal lung function, fine adjustments of the local vessel tone and of the microvascular permeability are critical. An attractive hypothesis is that in congestive heart failure, these fine regulations are disrupted and ACE inhibition contributes to their readjustment.
The present study was designed to determine whether ACE inhibition has some influence on the pulmonary function of patients with congestive heart failure and whether ACE inhibitors act, in this regard, as KII or as ACE blockers. For these purposes, pulmonary function tests and maximal exercise testing with expired gas analysis in patients with chronic heart failure were compared with those derived from normal volunteers or mild hypertensives; aspirin was used for inhibiting17 cyclooxygenase and prostaglandin synthesis.
Patients referred to the Institute of Cardiology, University of Milan, between January 1994 and December 1995 for evaluation of chronic heart failure were included in this analysis. The primary inclusion criteria were (1) chronic stable NYHA functional class II to III heart failure due to left ventricular dysfunction and (2) the ability to complete a maximal cardiopulmonary bicycle ergometer exercise test. The cause of heart failure was either ischemic heart disease or idiopathic cardiomyopathy. The diagnosis of ischemic heart disease was based on previous myocardial infarction, coronary artery bypass surgery, or coronary angiography documenting a >70% stenosis of at least one epicardial artery. Idiopathic cardiomyopathy was diagnosed in the presence of cardiac enlargement and in the absence of a specific cause for left ventricular dysfunction. Exclusion criteria were (1) current or past history (>10 years) of smoking; (2) ACE inhibitor therapy, acetylsalicylic acid, or other cyclooxygenase inhibitors within the previous 3 months; (3) joint disease or peripheral vascular disease sufficient to limit exercise; (4) FEV1 <60% of normal predicted; (5) exercise that was limited by symptoms other than dyspnea or fatigue or both; and (6) chest pain or ECG changes suggestive of ischemia during exercise (>1 mm horizontal or downsloping ST-segment depression measured 0.08 second after the J-point). All these tests were obtained within a 1- to 3-day period without knowledge of the other test results. Informed consent was obtained for each test. Even if it implied interruption of the ACE inhibitor while on placebo, the protocol was approved by the local Ethics Committee because no patients were on ACE inhibitors when admitted.
Twenty-six patients were enrolled, of which the first 18 were treated with enalapril (group 1) and the last 8 with the combination hydralazine–isosorbide dinitrate (group 2). The control population consisted of normal volunteers (n=8) or individuals with mild untreated primary hypertension (n=10) who were similar in age and sex to patients in group 1. They were nonsmokersand were not taking cyclooxygenase inhibitors. It is noteworthy that all individuals, patients and control subjects, recruited for the study were carefully questioned concerning medications that might have aspirin added, and platelet aggregation was tested in 82% of subjects and found to be normal. All heart failure patients were maintained on stable optimal doses of furosemide and digoxin.
Pulmonary Function Tests
Standard measurements of the FEV1, vital capacity, MVV, total lung capacity, and DLCO were made with Sensor Medics, 2200 Pulmonary Function Test System. Measured diffusing capacity was corrected for anemia by the equation of Cotes et al.18 These data were expressed in absolute values and as a percentage of predicted normal values on the basis of standard nomograms incorporating age, sex, height, and weight.19
Exercise Testing With Respiratory Gases
Maximal exercise tests with measurements of respiratory gases were performed in a sitting position on an isokinetic bicycle ergometer. For the exercise evaluation, we used an individualized ramp test with the ramp rate set to elicit a test duration of ≈10 minutes. To determine the ramp rates, each subject's maximal oxygen uptake was considered during a baseline test. Patients were encouraged to exercise until they felt unable to continue. Heart rate was monitored continuously, and arterial blood pressure was measured by cuff sphygmomanometry. Measurements of expiratory carbon dioxide, expired oxygen, and expired volume were determined at rest and throughout exercise with a single breath analysis (model 2900, Sensor Medics). Exercise was discontinued when the patient was unable to maintain the imposed workload because of dyspnea or fatigue (symptom-limited maximal exercise). Peak V̇o2 was determined by the highest V̇o2 achieved during exercise. Anaerobic threshold was defined by V-slope analysis. Ventilation was assessed by correlation of V̇e with V̇co2. V̇o2p and V̇o2 at the anaerobic threshold are expressed as the oxygen consumption (mL·min−1·kg−1) during the 30 seconds in which the examined event occurred. Reported values of V̇ep, V̇tp, volume of dead-space gas, and Vd/Vtp are also the averages over 30 seconds. For V̇ep and Vd/Vtp, the prediction equation of Jones20 was used.
A commercially available phased-array echocardiographic Doppler system (model Sonos 1000, Hewlett Packard) was used, which has 2.5- or 3.5-MHz transducers for M-mode and two-dimensional echocardiography and 2.0- or 2.5-MHz transducers for Doppler echocardiography. Standard Doppler color velocimetry was used to measure the degree of mitral regurgitation, which was graded subjectively on a scale from none (0) to severe (5) without knowledge of exercise test results. All subjects had LVEF assessed at rest, in the supine position, by two-dimensional echocardiography according to Simpson's rule.
Group 1 patients and control subjects received, in randomized order, placebo, enalapril, enalapril plus aspirin, and aspirin for a 15-day period each. Patients in group 2 were given, in randomized order, placebo, enalapril, enalapril plus aspirin, hydralazine–isosorbide dinitrate, this combination plus aspirin, and aspirin for a 15-day period each. Pulmonary function tests, exercise testing with respiratory gas analysis, and Doppler echocardiography were performed in the run-in and repeated at the end of each period 3 hours after a light meal at the same time of day. Patients and investigators were blinded to the treatment protocol. Enalapril was given at a dosage of 10 mg twice a day and aspirin at a daily dose of 325 mg.21 Hydralazine was titrated according to values of supine blood pressure, 100/70 mm Hg being the cutoff point; oral doses used varied from 50 to 100 mg twice daily. Isosorbide dinitrate was administered at a dose of 30 mg given orally three times daily.
After completion of the exercise and respiratory protocols, all patients in group 2 were hospitalized for hemodynamic measurements. All treatment had been interrupted at least 3 days before admission except furosemide and digoxin, which were continued on stable doses. A semifloating thermodilution balloon-tipped catheter was positioned in the pulmonary artery for 48 hours and advanced, when necessary, to the wedge position for the determination of PCWP. Cardiac output was determined with the thermodilution technique (average of three measurements each time). Records were taken in the supine position every 6 hours over two consecutive 24-hour periods after placebo, then active drug (enalapril or hydralazine–isosorbide dinitrate in random order), and then active drug plus aspirin were given, as represented in Fig 6⇓. Dosages were the same as were used in each single patient for the exercise-respiratory study.
Data from study and control subjects were compared by unpaired t test and one-way ANOVA. The relations between variables were examined by linear regression analysis. The significance of differences between serial measurements was assessed by repeated-measures ANOVA and Newman-Keuls multiple comparison procedure. Differences at the P<.05 level were considered statistically significant. Results are expressed as mean±SD.
Group 1 and Control Subjects
Two of the 18 patients enrolled in this group were not carried throughout the study because they moved far from the city. The matched control subjects for these patients were also excluded.
Pulmonary function. Table 1⇓ illustrates the mean results of spirometry and hemodynamic, therapeutic, and anthropometric details; individual results with respect to DLCO are plotted in Fig 1⇓. DLCO and lung volumes (FEV1, vital capacity, MVV, and total lung capacity) were reduced in patients compared with control subjects. Table 2⇓ and Fig 1⇓ illustrate the results of spirometry with different drug regimens. Results were not influenced by the sequence of drug administration. Compared with placebo, enalapril caused an increase of FEV1, MVV, and DLCO in chronic congestive heart failure. Changes in DLCO were counteracted by the addition of acetylsalicylic acid. Aspirin alone was not effective. Enalapril and aspirin, alone or in combination, did not exert any influence on the pulmonary function in control subjects.
Exercise testing. Fig 2⇓ shows the V̇o2p, V̇ep, Vtp, Vd/Vtp, V̇o2 at the anaerobic threshold, and the exercise tolerance time attained in all subjects with different drug interventions. Compared with placebo, enalapril increased exercise tolerance time, V̇o2p, V̇ep, and V̇tp and reduced Vd/Vtp. All these effects were counteracted by the combination with aspirin. Acetylsalicylic acid alone was not effective. Enalapril and aspirin, given either alone or in combination, did not affect these variables in control subjects.
V̇o2p changes from placebo correlated significantly with those in DLCO (Fig 3⇓, r=.80, P=.0001) but not with those in LVEF in heart failure patients. No such correlation was present when enalapril and aspirin were combined (r=.23, P=.37) or when aspirin was given alone (r=.32, P=.22). We also failed to find such a relationship in our control individuals (r=.27, P=.31). In patients with heart failure, variations from placebo of Vd/Vtp were related to those in DLCO (Fig 4⇓,r=−.69, P=.003) while the patients were on enalapril. No such relationship was present in the control subjects (r=.33, P=.2).
In heart failure patients, the ventilatory equivalent for carbon dioxide production per minute at 1 L22 was significantly diminished toward normal when enalapril was given alone and not in combination with aspirin (Fig 5⇓).
Sex (M=6, F=2), age (63±3 years), and blood pressure as well as pulmonary function and functional capacity on placebo (Table 3⇓) were comparable to those in group 1.
Exercise testing. As shown in Table 3⇑, enalapril and the hydralazine–isosorbide dinitrate combination both were associated with a significant increase from placebo in V̇o2p and decrease in Vd/Vtp. The ACE inhibitor but not the vasodilators improved the ventilatory equivalent for carbon dioxide production at 1 L and DLCO. No relationship was found between DLCO and vasodilator-induced changes in V̇o2p and Vd/Vtp (r=−.1, P=.9 and r=.23, P=.65, respectively). Aspirin alone was not effective on any of the variables examined; it interfered with changes in V̇o2p and Vd/Vtp produced by enalapril and not with those produced by hydralazine–isosorbide dinitrate.
Hemodynamic testing. Fig 6⇓ reports mean values (±SD) of the PCWP and cardiac index, as recorded every 6 hours over two 24-hour periods, after placebo, enalapril, hydralazine–isosorbide dinitrate, and the addition of aspirin to the active compounds. Results were not influenced by the sequence of drug administration. It is seen that both treatments increased cardiac index and decreased the PCWP, but differences from placebo were not significant with the ACE inhibitor; 6 hours after dosing, the cardiac index was significantly higher and PCWP lower with the vasodilators than with enalapril; combination with aspirin did not modify the response to hydralazine–isosorbide dinitrate and slightly but not significantly attenuated the response to the ACE inhibitor (PCWP was lowered by 1.8 mm Hg less, and cardiac index was raised by 97 mL·min−1·m−2 less).
Improvement by ACE inhibition of the pulmonary function and exercise capacity of patients with chronic heart failure but not of normal individuals suggests that alterations related to the syndrome are the substrate for the beneficial effects of enalapril.
Reduction in the pulmonary diffusing capacity for carbon monoxide is firmly established in chronic heart failure.25 DLCO can be partitioned into its two components: molecular diffusion of carbon monoxide across the alveolar capillary membrane and the mechanical reaction of carbon monoxide with pulmonary capillary blood. An increase in the pulmonary capillary volume causes an increased diffusing capacity and vice versa for a reduced alveolar–capillary membrane diffusing capacity. In congestive heart failure, interstitial edema may increase the distance between alveolar gas and red blood cells, and peribronchial edema may reduce ventilation to lung units, resulting in ventilation-perfusion mismatch. These factors would outweigh the greater capillary volume and result in a decreased capacity.25 However, a reduced alveolar–capillary membrane diffusing capacity has been documented in this syndrome and interpreted to be a possible consequence of stress failure of the membrane and the major component of the impaired pulmonary gas transfer as well as of the limited functional status.26
It is proven, in both hypertensive and normotensive humans, that ACE inhibitors produce pulmonary vasodilatation and an increase in capillary volume that are blocked by cyclooxygenase inhibitors.16 27 In group 2, enalapril reduced the PCWP to an extent comparable to that reported by others in similar acute studies28 ; failure to reach statistical significance was possibly due to the small number of cases. Thus, in our chronic heart failure patients, ACE inhibition could have improved the pulmonary hemodynamics, removed interstitial fluid and pulmonary vasoconstriction, and improved DLCO. Because of this, an inhibitory effect of aspirin might have been unmasked simply because of a changed background (less interstitial fluid/vasomotor tone). This explanation, however, is not convincing for the following reasons: one would expect an increase in DLCO in control subjects as well, if pulmonary vasodilatation were a mechanism; the inhibitory effect of aspirin was seemingly dissociated from significant changes in the PCWP response to enalapril; and with an alternative and more effective method of decreasing the PCWP (eg, hydralazine–isosorbide dinitrate), there was no improvement in the lung diffusing capacity and no interaction with aspirin.
The correlation existing between changes in DLCO with enalapril and V̇o2p is in keeping with the concept that pulmonary diffusion limitation is an important mediator of exercise impairment in heart failure. As shown in earlier works, the same does not seem to be true of systolic left ventricular function, because variations of V̇o2p were unrelated to changes in LVEF.29 30 Both enalapril and the vasodilators were associated with amelioration in oxygen uptake and Vd/Vt. Even though a diminished physiological dead space via an augmented cardiac output or a decreased interstitial fluid29 that improves diffusion capacity and lung compliance may be mechanisms shared by the two treatments, the correlation of DLCO versus oxygen uptake andVd/Vt, though not implying cause and effect, demonstrates a close association of these factors with enalapril and not with vasodilators. Notably, enalapril also reduced the ventilatory equivalent for carbon dioxide production, ie, it brought toward normal a major respiratory feature of heart failure that is interpreted as related to a decrease in diffusing capacity.30 31
It is hard to say whether and how inhibition of angiotensin II formation in the lung may have a role in these effects of enalapril. The peptide is known to cause an active, non–flow-dependent constriction of the pulmonary circulation.32 An interesting, novel finding is that angiotensin II powerfully influences vascular endothelial permeability through an increase of gene expression of vascular permeability factor.33 Nothing is known of these actions with regard to the lung vessels and heart failure.
An important consideration is that aspirin counteracted these effects of enalapril, bespeaking a substantial participation of prostaglandins. Do these eicosanoids act just as local vasodilators in the presence of an elevated vascular tone?34 This mechanism would provide only a partial explanation to our functional capacity findings and contrast the results obtained with other vasodilators35 or by improvement of pump performance with inotropic drugs22 or with successful cardiac transplantation.36 37 Do prostaglandins play a fundamental part in readjusting alveolar–capillary membrane diffusing capacity or capillary permeability and fluid content and distribution in the interstitial space of the lung? All results in our study point in this direction, although they are unable to discern which proportion of the total pulmonary diffusive resistance relates to each. Davies et al38 documented a reduced pulmonary microvascular permeability in 14 patients with chronic left ventricular failure; interestingly enough, all of them were taking ACE inhibitors at the time of the study.
This study is weakened by a lack of measurements of lung production of vasoactive substances, extravascular lung water, pulmonary compliance, and partition of pulmonary diffusing capacity into its component resistances. These limitations, however, do not substantially detract from the message of the study, ie, that in chronic heart failure, ACE inhibition exerts a modulatory influence on the pulmonary function, which is at least in part mediated through prostaglandins, whose primary feature is an improvement in alveolar–capillary membrane diffusing capacity and functional capacity.
Selected Abbreviations and Acronyms
|DLCO||=||pulmonary CO diffusing capacity|
|LVEF||=||left ventricular ejection fraction|
|MVV||=||maximum voluntary ventilation|
|PCWP||=||pulmonary capillary wedge pressure|
|TT||=||exercise tolerance time|
|V̇ co 2||=||minute CO2 production|
|Vd/Vtp||=||ratio of volume of dead space to tidal volume at peak exercise|
|V̇ e||=||minute ventilation|
|V̇ep||=||minute ventilation at peak exercise|
|Vtp||=||tidal volume at peak exercise|
This study was supported in part by a grant from the Ministry of Health, Rome; the National Research Council, Rome; the Italian Society of Internal Medicine; and the Monzino Foundation, Milan, Italy.
- Received July 10, 1996.
- Revision received November 13, 1996.
- Accepted November 21, 1996.
- Copyright © 1997 by American Heart Association
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