Sunteți pe pagina 1din 7

European Journal of Cardio-thoracic Surgery 17 (2000) 355361 www.elsevier.

com/locate/ejcts

Mechanisms of pulmonary transfer factor decline following heart transplantation


O.A. Al-Rawas a,*, R. Carter a, R.D. Stevenson a, S.K. Naik b, D.J. Wheatley b
b

Department of Respiratory Medicine, Glasgow Royal Inrmary, Glasgow G31 2ES, UK University Department of Cardiac Surgery, Glasgow Royal Inrmary, Glasgow G31 2ES, UK

Received 15 February 1999; received in revised form 28 December 1999; accepted 25 January 2000

Abstract Objective: Although the decline in the pulmonary transfer factor (TLCO) following heart transplantation is well documented, the causes and mechanisms of this decline remain unknown. The aim of this study was to determine the relative contribution of each of TLCO components (the diffusing capacity of the alveolar-capillary membrane (DM), the pulmonary capillary blood volume (VC) and haemoglobin concentration) to TLCO reduction in heart transplant recipients. Methods: TLCO and its components were measured in 75 heart transplant recipients (mean age 48 years, range 1961) between 6 weeks and 36 months after transplantation using the Roughton and Forster method and the single-breath technique. Results were compared with data from 38 heart transplant candidates (mean age 51 years, range 3461) and 26 normal subjects (mean age 47 years, range 2762). Results: The mean percentage predicted TLCO was reduced in recipients compared to candidates (56.9 and 69.9%, respectively, P , 0:001) and both were lower than normal controls (97.7%, P , 0:001). The mean percent predicted VC was also reduced in recipients compared to candidates (52.8% vs. 80.2 (4.2)%, P , 0:001) which was also lower than normal subjects (102%, P , 0:001). DM was equally reduced in recipients and candidates (77.7 and 81.4%, respectively, P 0:48) compared to normal subjects (100.0%, P , 0:001). Correction for haemoglobin concentration increased TLCO in recipients to 63.5% (P , 0:001), but it remained lower than haemoglobin-corrected TLCO in candidates (71.1%, P , 0:001). In recipients, the intra-capillary resistance (1/u VC) formed 60% of the total resistance to CO transfer (1/TLCO) compared to 50% in candidates and normal subjects. Conclusions: TLCO decline following heart transplantation is due to an increase in the intra-capillary resistance, and this appears to be due to a combination of anaemia and reduced pulmonary capillary blood volume, with the diffusing capacity of the alveolar-capillary membrane remaining unchanged. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: Heart transplantation; Pulmonary function; Pulmonary transfer factor; Alveolar-capillary membrane diffusing capacity; Pulmonary capillary blood volume

1. Introduction Chronic heart failure, the primary indication for heart transplantation is associated with a variety of pulmonary function abnormalities including reduced lung volumes, airway obstruction and reduced pulmonary transfer factor for carbon monoxide (TLCO) [1,2]. Heart transplantation has been shown to restore lung volumes and airway function towards normal [3,4]. In contrast, TLCO and TLCO per unit alveolar volume (KCO) have been persistently shown either to deteriorate or remain sub-normal following heart trans-

* Corresponding author. Present address: Department of Medicine, College of Medicine, Sultan Qaboos University, P.O. Box 35, Postal Code 123, Muscat, Sultanate of Oman. Tel.: 1968-513-355 (ext. 3404); fax: 1968-513-009. E-mail address: orawas@squ.edu.om (O.A. Al-Rawas)

plantation [513]. Although TLCO reduction in heart transplant recipients is well documented, the causes and mechanisms of this reduction remain unknown. It has been suggested that it might be due to a decline in the diffusing capacity of the alveolar-capillary membrane (DM) secondary to new insults to the membrane during or after heart transplantation [6,11]. In a longitudinal study [13] we have recently shown that TLCO decline occurs within 6 weeks after transplantation and persists for up to 3 years of follow-up, and suggested that this decline was probably due to a reduction in the pulmonary capillary blood volume secondary to the well-documented reduction in pulmonary vascular pressures following transplantation. However, TLCO components have not been determined in heart transplant recipients. The aim of this study was to determine the relative contribution of each of the TLCO components (DM, VC and haemo-

1010-7940/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 1010-794 0(00)00359-6

356

O.A. Al-Rawas et al. / European Journal of Cardio-thoracic Surgery 17 (2000) 355361

globin concentration) to TLCO reduction in heart transplant recipients. 2. Methods 2.1. Study population TLCO and its components were determined in 75 heart transplant recipients at 6 weeks to 36 months after transplantation. The ndings in heart transplant recipients were compared with data from 38 patients with severe chronic heart failure (mean left ventricular ejection fraction 12.8) awaiting heart transplantation (candidates) and 26 normal subjects recruited as volunteers from the general population in whom there was no evidence of cardiopulmonary disease. All patients were stable at the time of assessment. Antifailure treatment in heart transplant candidates consisted of diuretics (all patients), angiotensin-converting enzyme inhibitors (30 patients), digoxin (19 patients) and other vasodilators (13 patients). Heart transplant recipients were on a standard triple immunosuppressive therapy regimen consisting of prednisolone, cyclosporin and azathioprine. They were all free of rejection and systemic infection at the time of assessment. The exclusion criteria of the study were: (1) current smoking or smoking cessation for less than 1 year prior to assessment, (2) treatment with amiodarone or beta blockers and (3) history of primary lung disease. 2.2. Measurement of TLCO and its components Roughton and Forster showed that the measurement of TLCO at different alveolar oxygen tensions allows the estimation of the diffusing capacity of the alveolar-capillary membrane (DM) and the instantaneous pulmonary capillary blood volume available for gas transfer (VC) [14]. According to Roughton and Forster, the relationship between TLCO and its components is described by the following equation: 1=TLCO 1=DM 1 1=uVC 1 where 1/TLCO is the reciprocal of the transfer factor for the entire lung and represents the total resistance of the lung to carbon monoxide (CO) transfer. By analogy 1/DM represents the resistance of the alveolar-capillary membrane and 1/u VC represents the resistance of the total mass of erythrocytes in the capillary blood (intra-capillary resistance). Theta (u ) is the standard rate at which 1 ml of whole blood takes up CO and this is dependent on the prevailing alveolar oxygen tension and haemoglobin concentration. In the conventional calculation of TLCO, haemoglobin concentration is assumed to be normal (14.6 g dl 21) [15]. The effect of haemoglobin variability on TLCO values can be determined using a modied version of the classic Roughton and Forster equation as described by Cotes and recommended by both the European Respiratory Society and the American Thoracic Society [15,16]:

1=TLCO 1=DM 1 1=Hb uVC

where [Hb] is the haemoglobin concentration as a fraction of normal (i.e. actual haemoglobin divided by 14.6). Thus, the application of Roughton and Forster model, permits the determination of the relative contribution of DM, VC, and blood haemoglobin to TLCO changes. The steps and details of estimating TLCO and its components (DM and VC) were identical to a protocol we have previously validated [17]. In brief, TLCO was measured using the single-breath method (Transow; P.K. Morgan Ltd., Kent, UK) according to the recommendations of the ERS [15]. The standard oxygen gas consisted of CO (0.28%), helium (He) (14%), O2 (18%) with the remainder nitrogen whereas high oxygen gas mixture consisted of CO (0.28%), He (14%) with the remainder O2 (85.72%). The sequence of measurements was in the following order: TLCO at standard oxygen concentration was measured rst and the mean of two technically acceptable TLCO values were reported as the subject's TLCO. The subject was then allowed 5 min of room air breathing followed by another 5 min of pure oxygen breathing while wearing a nose clip. The single-breath TLCO at high oxygen concentration was then measured using the same steps of standard TLCO measurement, except for the use of the high oxygen mixture in the inspired gas mixture, and the mean of two technically acceptable values were reported as the subject's TLCO at high oxygen concentration. The values of u were derived from the original data of Roughton and Forster obtained from in vitro CO uptake in a suspension of human erythrocytes at 378C [14]. The values of TLCO at standard and high oxygen concentrations with their corresponding u values were used to determine DM and VC by solving the Roughton and Forster equation graphically (Fig. 1); the intersect of the plotted line (AB) with 1/TLCO equals 1/DM and its slope (BC/AB) equals 1/VC. The effect of haemoglobin variability on TLCO values was determined using the modied Rough-

Fig. 1. The graphical derivation of TLCO components (DM and VC) using the Roughton and Forster method. A plot of 1/TLCO against 1/u yields a straight line which intersects the ordinate 1/TLCO at point A. At this point, the value of 1/u equals zero and therefore the value of 1/TLCO at point A equals 1/DM. The triangular area above the intersection represents a plot of 1/u VC against 1/u . VC can therefore be obtained by dividing 1/u VC by 1/u (i.e. 1/VC BC/ AB), which is the slope of the line AC.

O.A. Al-Rawas et al. / European Journal of Cardio-thoracic Surgery 17 (2000) 355361 Table 1 Clinical characteristics of heart transplant recipients compared to heart transplant candidates and normal controls Recipients Number of subjects Age (mean in years (range)) Male Female Smoking status Non-smokers Ex-smokers Diagnosis Ischaemic heart disease Dilated cardiomyopathy Valvular heart disease Haemoglobin (g dl 21, mean (SD)) Left ventricular ejection fraction (mean (SD)) 75 47.7 (1961) 61 (81%) 14 (19%) 17 (23%) 58 (77%) 44 (59%) 27 (36%) 3 (5%) 12.1 (1.4) 47.2 (10.4) Candidates 38 50.6 (3461) 30 (79%) 8 (21%) 10 (26%) 28 (74%) 25 (66%) 10 (26%) 3 (8%) 14.0 (1.7) 12.8 (6.3) Normal 26 47.3 (2762) 20 (77%) 6 (23%) 21 (81%) 5 (19%)

357

Assumed 14.6

ton and Forster equation as described by Cotes (Eq. (2)) [18]. Haemoglobin concentration in patients was determined on the same day of TLCO measurement using venous blood samples. Normal subjects were assumed to have normal haemoglobin concentration (i.e. 14.6 g dl 21) [18]. 2.3. Data presentation and analysis TLCO and its components were expressed as percentages of predicted using the European Community for Steel and Coal equations for TLCO [15] and the reference values of Cotes for DM and VC [19]. The total resistance to CO transfer (1/TLCO) and its components (1/DM and 1/u VC) were expressed in absolute values (Pa min 21 mmol 21). Unless stated otherwise, values were presented as mean with standard error of the mean (SEM). Comparisons between groups were performed using one-way analysis of variance (ANOVA), whereas comparisons within groups (e.g. TLCO results before and after correction for haemoglobin) were performed using the paired samples Student's t-test.

3.2. TLCO and its components in recipients compared to candidates and normal controls Fig. 2 shows TLCO and its components in heart transplant recipients compared to candidates and normal controls. Mean TLCO was signicantly reduced in heart transplant recipients compared to heart transplant candidates (56.9 (1.4)% and 69.9 (2.0)% of predicted, respectively, P , 0:001) and in both it was signicantly lower than that of normal controls (97.7 (1.6)% of predicted, P , 0:001). Similarly, VC was reduced in recipients (52.8 (2.0)%) compared to candidates (80.2 (4.2)%, P , 0:001) and normal subjects (102 (1.1)% of predicted, P , 0:001). In contrast, DM was similar in heart transplant recipients and candidates (77.7 (2.5)% and 81.4 (5.4)% of predicted respectively, P 0:48) and in both it was signicantly lower than that of normal subjects (100.0 (1.3)% of predicted, P , 0:001). Fig. 3 shows that the change in TLCO and its components following heart transplantation is independent of the time between transplantation and assessment. Fig. 4 displays the diffusion parameters in terms of their reciprocals (i.e. resistance to diffusion) in the three study

3. Results 3.1. Subjects' characteristics Table 1 shows the clinical characteristics of the study groups. The three study groups have similar age and sex distribution. The smoking status was similar in heart transplant candidates and recipients, but there was signicantly more non-smokers in the normal controls (81%) compared to candidates (26%) and recipients (23%). Because of the selection criteria, the duration between smoking cessation and assessment was at least 1 year in all ex-smokers. All heart transplant candidates had severe chronic heart failure with mean left ventricular ejection fraction of 12.8 which was signicantly lower than that of recipients (47.2, P , 0:05).

Fig. 2. Mean values of percent predicted TLCO and its components in recipients compared to candidates and normal control.

358

O.A. Al-Rawas et al. / European Journal of Cardio-thoracic Surgery 17 (2000) 355361

3.3. The inuence of haemoglobin concentration Mean haemoglobin concentration in recipients was reduced compared to candidates (12.1 vs. 14.0 g dl 21, P , 0:001). Fig. 5 displays scatter plots of percent predicted TLCO against haemoglobin concentration in heart transplant recipients and candidates. There was a weak but signicant correlation between percent predicted TLCO and haemoglobin concentration in recipients (r 0:27, P , 0:05), but there was no signicant correlation between the two variables in candidates (r 0:16, P 0:33). Correction for haemoglobin in heart transplant candidates produced no signicant change (69.9 (3.0)% vs. 71.1 (3.1)% of predicted, P 0:09). In contrast, TLCO in heart transplant recipients increased from 56.9 (1.4)% to 63.5 (1.5)% of predicted (P , 0:001), but this was still lower than that of candidates (P , 0:05). 4. Discussion 4.1. TLCO and its components in heart transplant recipients In addition to conrming previous reports of TLCO impairment in heart transplant recipients [513], the present study identied the increase in the intra-capillary resistance (1/u VC) as the main component leading to this decline. The increase in 1/u VC was shown to be due to a combination of post-transplant decline in blood haemoglobin concentration and the pulmonary capillary blood volume (VC). Contrary to what has been suggested by other investigators [7], DM in heart transplant recipients was similar to that of candidates. The nding of anaemia in heart transplant recipients was not unexpected [20]. The possible causes include bone marrow suppression caused by immunosuppressive therapy, blood loss during surgery and repeated venous blood sampling. Although the effect of haemoglobin concentration on TLCO measurement is well documented and correction for its effect when outside the normal range is recommended [15], this study is the rst report on the relative contribution of anaemia to TLCO impairment in heart transplant recipients. Mean percent predicted TLCO was lower in heart transplant recipients than heart transplant candidates by 13, and this difference was reduced to eight after correction for haemoglobin in both groups. Thus, the difference in haemoglobin levels between recipients and candidates accounted for approximately 40% of the total difference in TLCO. Since DM was similar in both recipients and candidates and VC was signicantly reduced in recipients compared to candidates, the remaining difference (60% of the total difference) in TLCO was therefore due to the reduction in VC in heart transplant recipients. 4.2. The possible mechanism of VC decline after heart transplantation The volume of the pulmonary capillary blood at any

Fig. 3. Scatter plots of the mean values of percent predicted TLCO and its components at different intervals after heart transplantation.

groups. The total resistance to CO transfer (1/TLCO) was higher in heart transplant recipients compared to candidates (212.9 (7.8) vs. 176.1 (8.6) Pa min 21 mmol 21, P , 0:001) and in both it was higher than that of normal controls (113.9 (3.8) Pa min 21 mmol 21, P , 0:001). The increase in 1/ TLCO in heart transplant candidates was due to a proportionate increase in both the alveolar-capillary membrane resistance (1/DM) and the intra-capillary resistance (1/u VC), being 88.4 (6.3) and 87.7 (5.0) Pa min 21 mmol 21, respectively compared to 59.0 (1.0) and 54.9 (3.8) Pa min 21 mmol 21, in normal subjects. The increase in 1/ TLCO in heart transplant recipients above that of candidates was entirely due to the marked increase in intra-capillary resistance (127.4 (5.3) vs. 87.7 (5.0) Pa min 21 mmol 21, P , 0:001) with the alveolar-capillary membrane resistance being similar in both groups (85.5 (4.0) and 88.4 (6.3) Pa min 21 mmol 21, respectively, P 0:69). 1/DM and 1/u VC contributed equally to 1/TLCO (approximately 50% each) in both normal subjects and heart transplant candidates. In contrast, 1/u VC provided the main resistance to CO transfer in heart transplant recipients (60% of 1/TLCO).

Fig. 4. The total resistance to carbon monoxide transfer (1/TLCO) and its components (1/DM and 1/u VC) in recipients compared to candidates and normal controls.

O.A. Al-Rawas et al. / European Journal of Cardio-thoracic Surgery 17 (2000) 355361

359

Fig. 5. Scatter plots of percent predicted TLCO (before correction for haemoglobin) against haemoglobin concentration in heart transplant recipients and candidates.

instant (VC) depends on the number and dimensions of functioning pulmonary capillaries [21]. The mechanisms by which the size of the pulmonary capillary bed is increased are not fully understood, but experimental and clinical studies suggest that this is caused by increases in pulmonary blood ow or pulmonary capillary transmural pressure [22]. These haemodynamic factors are believed to increase the size and uniformity of the pulmonary capillary bed by vascular recruitment and distension thereby increasing VC, DM and TLCO [22]. This occurs during exercise, in congenital heart disease with left to right shunts and in the early stages of mitral stenosis and congestive heart failure [21]. Under these circumstances, a normal or reduced VC indicates derangement of the pulmonary vascular bed [21]. The aim of our study was to determine the relative contribution of each of TLCO components (DM, VC and haemoglobin concentration) to TLCO reduction in heart transplant recipients. We did not investigate the potential causes of this decline which may include; pre-transplant factors such as the duration and severity of heart failure, and intra-operative and post-operative factors such as cardiopulmonary bypass, the changes in pulmonary haemodynamics, pulmonary complications including pulmonary embolism and infections, cyclosporine pulmonary toxicity and cardiac allograft rejection [25,11,13]. Because of the non-invasive nature of our study we did not investigate the direct relationship between TLCO components and the pulmonary haemodynamics in heart transplant patients. However, previous reports on the relationship between TLCO components and pulmonary haemodynamics in patients with heart diseases suggest an important role for the changes in pulmonary haemodynamics in the decline of VC and TLCO after heart transplantation [2330]. Congenital heart diseases which result in pulmonary vascular congestion and increased pulmonary blood ow are associated with increased values of TLCO and its components with VC increasing relatively more than DM [23,24]. However, if pulmonary arterial hypertension or pulmonary vascular resistance is severe, these parameters are usually normal or reduced indicating established pulmonary vascular damage [23]. Furthermore,

surgical correction of the congenital defects results in restoration of the pulmonary haemodynamics towards normal and this has been shown to be associated with reduction in TLCO and its components [24]. The changes in TLCO and its components in mitral valve disease have also been shown to be related to the changes in pulmonary haemodynamics [25,26]. In moderately severe mitral stenosis, the increase in pulmonary venous pressure would be expected to increase VC by expanding and increasing the uniformity of the pulmonary vascular bed. However, VC is usually normal or even reduced in these cases [26]. This was explained by an opposite force which counterbalances the augmenting effect of pulmonary congestion; namely, the obliteration of the pulmonary vascular bed by progressive brosis and repeated pulmonary emboli which are common in severe mitral stenosis [25,27]. In addition, mitral valve surgery has been shown to result in further decline in TLCO and VC with DM remaining unchanged [2830] and these changes were explained by the relief of pulmonary congestion after surgery without concomitant restoration of the structural abnormalities in the pulmonary vascular bed [30]. The changes in TLCO and its components in our patients before and after heart transplantation were very similar to those reported in patients with mitral valve disease before and after mitral valve surgery, respectively. Heart transplant patients and patients with mitral valve disease have also very similar haemodynamic proles both before and after surgery [3,31]. These ndings suggest that TLCO changes have a common mechanism in both conditions. Like patients with mitral valve disease, VC in patients with severe chronic heart failure awaiting heart transplantation is determined by two factors acting in opposite directions; the increased pulmonary venous pressure tending to increase it and the pulmonary brosis and destruction of the pulmonary vascular bed tending to decrease it. The nding of equally reduced DM and VC before transplantation in our patients indicates that they have signicant structural pulmonary vascular abnormalities. The lack of any improvement in DM after transplantation, despite relief of

360

O.A. Al-Rawas et al. / European Journal of Cardio-thoracic Surgery 17 (2000) 355361 ing lung capacity and cyclosporine in patients with heart transplant. J Heart Transplant 1987;6:5456. Groen HJ, Bogaard JM, Balk AH, Kho SG, Hop WC, Hilvering C. Diffusion capacity in heart transplant recipients. Chest 1992;102:456 460. Niset G, Ninane V, Antoine M, Yernault JC. Respiratory dysfunction in congestive heart failure: correction after heart transplantation. Eur Respir J 1993;6:11971201. Ravenscraft SA, Gross CR, Kubo SH, Olivari MT, Shumway SJ, Bolman RM, Hertz MI. Pulmonary function after successful heart transplantation. One year follow-up. Chest 1993;103:5458. Ohar J, Osterloh J, Ahmed N, Miller L. Diffusing capacity decreases after heart transplantation. Chest 1993;103:857861. Degre SG. Are cardiac transplant recipients still suffering cardiac failure? Acta Cardiol 1993;48:19. Egan JJ, Kalra S, Yonan N, Hasleton PS, Brooks N, Woodcock AA. Pulmonary diffusion abnormalities in heart transplant recipients. Relationship to cytomegalovirus infection. Chest 1993;104:1085 1089. Bussieres LM, Pugfelder PW, Ahmad D, Taylor AW, Kostuk WJ. Evolution of resting lung function in the rst year after cardiac transplantation. Eur Respir J 1995;8:959962. Al-Rawas OA, Carter R, Stevenson RD, Naik SK, Wheatley DJ. The time course of pulmonary transfer factor changes following heart transplantation. Eur J Cardio-thorac Surg 1997;12:471479. Roughton FJW, Forster RE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physiol 1957;11:290302. Cotes JE, Chinn DJ, Quanjer PH, Roca J, Yernault JC. Standardization of the measurement of transfer factor (diffusing capacity). Report Working Party Standardization of lung function tests, european community for steel and coal. Ofcial statement of the European Respiratory Society. Eur Respir J Suppl 1993;16:4152. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:12021218. Carter R, Al-Rawas OA, Stevenson RD, Naik SK, Wheatley DJ. The measurement of the single-breath transfer factor for carbon monoxide using the Morgan Transow system. Respir Med 1998;92:628632. Cotes JE. Measurement of transfer factor diffusing capacity and its subdivisions. In: Cotes JE, editor. Lung function: assessment and applications in medicine, Oxford: Blackwell Scientic, 1993. pp. 299324. Cotes JE. Lung function throughout life: determinants and reference values. In: Cotes JE, editor. Lung function: assessment and applications in medicine, Oxford: Blackwell Scientic, 1993. pp. 445513. Hunt BJ, Amin S, Halil O, Yacoub M. The prevalence, course, and characteristics of chronic anaemia after heart and lung transplantation. Transplantation 1992;53:12511256. Forster RE. Interpretation of measurements of pulmonary diffusing capacity. In: Fenn WO, Rahn H, editors. Handbook of physiology section 3: respiration, Washington, DC: American Physiological Society, 1965. pp. 14531468. Forster RE. Diffusion of gases across the alveolar membrane. In: Farhi LE, Tenny SM, editors. Handbook of physiology, Bethesda, MD: American Thoracic Society, 1987. pp. 7188. Rankin J, Callies QC. Diffusing characteristics of the human lung in congenital and acquired heart disease. Circulation 1958;18:768. Bucci G, Cook CD, Hamann JF. Studies of respiratory physiology in children. VI. Lung diffusing capacity, diffusing capacity of the pulmonary membrane and pulmonary capillary blood volume in congenital heart disease. J Clin Invest 1961;40:14311441. Aber CP, Campbell JA. Signicance of changes in the pulmonary diffusing capacity in mitral stenosis. Thorax 1965;20:135145. Gazioglu K, Yu PN. Pulmonary blood volume and pulmonary capil-

pulmonary oedema and improvement of lung volumes [13] suggests that these structural abnormalities persist after transplantation. Thus, the decline in VC in heart transplant recipients is probably due to the reduction in pulmonary vascular pressures without concomitant resolution of the pre-transplant structural abnormalities of the pulmonary vascular bed. Cyclosporin pulmonary toxicity, cardiac allograft rejection and cytomegalovirus (CMV) infection have been proposed as possible causes of TLCO decline following heart transplantation [5,6,11]. The fact that TLCO and VC also decline after mitral valve surgery where immunosuppression, rejection and CMV infection are not a problem is against the implication of these factors. Finally, cigarette smoking can reduce TLCO and its components both by causing true lung damage and/ or increasing the levels of carboxyhaemoglobin [32]. However, our heart transplant recipients and candidates have similar smoking status and because of the exclusion criteria, all ex-smokers stop smoking at least 1 year before TLCO measurement. Furthermore, it has been shown that the effects of smoking on TLCO in asymptomatic subjects reverse within 1 year of smoking cessation [32]. In conclusion, the ndings of this study suggest that TLCO decline in heart transplant recipients is due to an increase in the intra-capillary resistance to CO transfer which was found to be due to a combination of anaemia and reduction in the pulmonary capillary blood volume (VC). The normalisation of pulmonary vascular pressures in the face of persisting pulmonary vascular abnormalities of the pretransplant severe chronic heart failure may be responsible for the observed reduction in VC and consequently the decline in haemoglobin-corrected TLCO after heart transplantation. Conrmation of this hypothesis requires assessment of the direct relationship between the changes in TLCO and its components and the changes in pulmonary haemodynamics before and after heart transplantation.

[6] [7] [8] [9] [10] [11]

[12] [13] [14]

[15]

[16] [17] [18]

[19]

References
[1] Wright RS, Levine MS, Bellamy PE, Simmons MS, Batra P, Stevenson LW, Batra P, Stevenson LW, Walden JA, Laks H, Tashkin DP. Ventilatory and diffusion abnormalities in potential heart transplant recipients. Chest 1990;98:816820. [2] Naum CC, Sciurba FC, Rogers RM. Pulmonary function abnormalities in chronic severe cardiomyopathy preceding cardiac transplantation. Am Rev Respir Dis 1992;145:13341338. [3] Bhatia SJS, Kirshenbaum JM, Shemin RJ, Cohn LH, Collins JJ, Di Sesa VJ, Young PJ, Mudge GH, St. John Sutton MG. Time course of resolution of pulmonary hypertension and right ventricular remodelling after orthotopic cardiac transplantation. Circulation 1987;76:819826. [4] Hosenpud JD, Stibolt TA, Atwal K, Shelley D. Abnormal pulmonary function specically related to congestive heart failure: comparison of patients before and after cardiac transplantation. Am J Med 1990;88:493496. [5] Casan P, Sanchis J, Cladellas M, Amengual MD, Caralps JM. Diffus-

[20] [21]

[22] [23] [24]

[25] [26]

O.A. Al-Rawas et al. / European Journal of Cardio-thoracic Surgery 17 (2000) 355361 lary blood volume in valvular heart disease. Circulation 1967;35:701 709. [27] Forster RE, Ogilvie CM. The single-breath carbon monoxide transfer test 25 years on: a reappraisal. Thorax 1983;38:19. [28] Yoshioka T, Nakanishi N, Okubo S, Kunieda T, Ishikura F, Nagata S. Improvement in pulmonary function in mitral stenosis after percutaneous transvenous mitral commissurotomy. Chest 1990;98:290294. [29] Kim YT, Kim WS, Lim CM, Chin JY, Koh Y, Kim JJ, Park SW, Park SJ, Lee JK, Kim WD. Effects of percutaneous balloon mitral valvuloplasty on static lung function and exercise performance. Tuberc Respir Dis 1994;41:110.

361

[30] Ray S, Dodds P, Wilson G, Morrison L, Walshaw M, Perry R. Effects of balloon mitral commissurotomy on the diffusing capacity of the alveolar capillary membrane and pulmonary capillary volume in patients with mitral stenosis. Am J Cardiol 1994;74:10681070. [31] Dalen JE, Matloff JM, Evans GLE. Early reduction of pulmonary vascular resistance after mitral valve replacement. N Engl J Med 1967;277:387394. [32] Knudson RJ, Kaltenborn WT, Burrows B. The effects of cigarette smoking and smoking cessation on carbon monoxide diffusing capacity of the lung in asymptomatic subjects. Am Rev Respir Dis 1989;140:645651.