(Circulation. 1999;100:1406-1410.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Impaired Pulmonary Diffusion During Exercise in Patients With Chronic Heart Failure
From the Clinical Research Initiative in Heart Failure, Institute of Biomedical and Life Sciences, University of Glasgow (A.A.S., M.E.P., M.D.), and Department of Respiratory Medicine, Western Infirmary (K.R.P.), Glasgow, UK; Department of Cardiology, University of Hull, Kingston-on-Hull, UK (P.J.C., J.G.F.C.); and Cardiothoracic Centre, Liverpool, UK (S.P.).
Correspondence to Professor John G.F. Cleland, Castle Hill Hospital, University of Hull, Kingston-on-Hull, HU 16 5JQ, UK.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Pulmonary diffusion is impaired at rest in patients with chronic heart failure (CHF) and has been implicated in the generation of symptoms and exercise intolerance. The aim of this study was to determine whether pulmonary diffusion is impaired during exercise in CHF, to examine its relationship to pulmonary blood flow, and to consider its functional significance in relation to metabolic gas exchange.
Methods and Results—Carbon monoxide transfer factor (TLCO) and pulmonary blood flow (QC) were measured by a rebreathe technique at rest and during steady-state cycling at 30 W in 24 CHF patients and 10 control subjects. Both patients and control subjects were able to raise TLCO and QC during exercise. However, the patient group had a lower diffusion for a given blood flow (TLCO/QC) both at rest (3.6±0.16 and 4.8±0.23 mL · L-1 · mm Hg-1; P<0.001) and during exercise (2.8±0.16 and 3.4±0.13 mL · L-1 · mm Hg-1 for CHF patients and control subjects, respectively; P<0.05). TLCO/QC was related to the ventilatory equivalent for carbon dioxide (VEVCO2) production at 30 W (TLCO/Qc versus VEVCO2, r=-0.58, P<0.01) and to peak exercise oxygen consumption measured during a progressive test (TLCO/Qc versus VO2peak, r=0.57, P<0.01) in these patients.
Conclusions—Patients with CHF are able to recruit reserves of TLCO and QC during exercise. However, the TLCO/QC ratio is consistently impaired in these patients and relates to both exercise hyperpnea and peak exercise oxygen consumption. Whether this impairment in alveolar gas exchange is reversible in CHF and therefore is a potential target for therapy has yet to be determined.
Key Words: heart failure • exercise • lung • ventilation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In healthy subjects, pulmonary diffusion increases during exercise1 because of absolute increases in ventilation and perfusion and improved ventilation-perfusion matching, with increased pulmonary capillary blood flow and capillary distension in ventilated areas of lung.2 These factors increase the effective surface area of lung available for gas exchange. Pulmonary capillary distension may also thin the alveolar-capillary membrane, improving diffusion even further.
With increasing exercise intensity, both diffusion and perfusion continue to rise with no evidence of an upper limit,2 although the increment in diffusion for a given rise in pulmonary blood flow decreases. Even after pneumonectomy, the relationship between pulmonary diffusion and pulmonary capillary blood flow is maintained; blood flow to the remaining lung increases, thereby maintaining diffusion.3 However, in patients with interstitial pulmonary fibrosis, there is impaired gas transfer across the alveolar-capillary membrane, which results in a marked reduction in diffusion for a given blood flow.4
In patients with chronic heart failure (CHF), pulmonary diffusion is impaired at rest5 6 7 and has been implicated in the generation of symptoms and exercise intolerance.8 9 Impaired diffusion in CHF is the result of a reduction in global perfusion of the lungs8 and a reduction in the conductance of the alveolar-capillary membrane.9 To date, however, pulmonary diffusion has not been measured during exercise in patients with CHF. The aim of the present study was to determine whether pulmonary diffusion impairment is present during exercise in CHF, to examine its relationship to pulmonary blood flow, and to consider its functional significance in relation to metabolic gas exchange.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
This study was approved by the local ethics committee, and all subjects gave written informed consent. Twenty-four male patients with stable, moderate to severe CHF secondary to left ventricular systolic dysfunction (clinical details are given in Table 1
) and 10
healthy, age-matched, male control subjects took part in the study.
Demographic details of both groups are given in Table 2. Patients with evidence of respiratory
disease or recent smokers (within 12 months) were excluded. Control
subjects were all nonsmokers, were on no medication, had normal
physical examinations and ECGs, and were not engaged in any regular
physical exercise.
|
|
Lung Function
Before entering the study, all subjects performed routine
spirometry (SensorMedics Pulmonet) for determination of static and
dynamic lung volumes. Data were compared with normal
standards.10
Pulmonary Diffusion and Blood Flow During Exercise
Pulmonary diffusion and effective pulmonary
blood flow were measured in duplicate, at rest, and during 8 minutes of
upright cycle ergometry (Bosch ERG551) at a steady workload of 30 W. A
rebreathe technique allowed the simultaneous measurement of
carbon monoxide transfer factor (TLCO) and effective pulmonary
blood flow (QC) during exercise.2
Subjects rebreathed a special gas mixture (35% oxygen, 3% sulfur
hexafluoride, 0.3% acetylene, and 0.3% carbon monoxide, with
the balance being nitrogen) for a period of 20 to 30 seconds at their
current breathing frequency and a depth 10% to 15% higher than the
preceding minute (a slightly higher ventilation is required to account
for the gradual reduction in alveolar oxygen content in the closed
breathing circuit). Decay rates of carbon monoxide and acetylene were
measured by mass spectrometry (AMIS2000, Innovision) for calculation of
TLCO and QC, respectively. This procedure was
performed in the fifth minute of exercise and repeated in the final
minute if the patient was able to complete the test.
The TLCO and QC values reported are the mean of 2 duplicate measures, except in 7 patients who could manage only a single measure in the fifth minute of exercise. In the 17 patients with duplicate measurements, the coefficient of variation for repeated measures was <5%. Analysis of the results with only the first measure of TLCO did not alter the findings of this study.
Incremental Exercise Test
After 30 minutes of recovery from steady-state exercise, all
subjects performed a progressive incremental exercise test on the
bicycle ergometer. Patients started with zero load warm-up, followed by
10-W/min increases until exhaustion; control subjects were provided
with individually tailored work-rate increases to achieve exhaustion in
8 to 15 minutes.11 Throughout exercise,
metabolic gas exchange was monitored by a mass spectrometer
metabolic cart (AMIS2000), heart rate was assessed by a
12-lead ECG (Siemens Megacart), and arterial oxygen
saturation was estimated by earlobe pulse oximetry (Ohmeda Biox
3700e).
Statistical Analysis
All data are expressed as mean±SEM. Group comparisons were made
by 1-way ANOVA, and correlations were represented by
univariate linear regression analysis. Statistical
significance was taken at the 95% level.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Resting Pulmonary Function
Table 2
illustrates the demographic and pulmonary
function details of the patient and control groups. Compared with
control subjects, patients had mildly reduced lung volumes but no
evidence of airflow obstruction, as demonstrated by the ratio of forced
expiratory volume in 1 second to forced vital capacity
(FEV1/FVC). In the patient group, there were
marked reductions in TLCO (P<0.001) and
QC (P<0.02) at rest compared with
control subjects. A reduction in stroke volume accounted for the
impaired QC in the patient group (50.6±2.7 and
62.6±3.3 mL for CHF patients compared with control subjects,
respectively; P<0.05), with both groups showing similar
resting heart rates (82.5±3.4 versus 78.3±4.3 bpm;
P=NS).
Steady-State Exercise
Results at 30 W of exercise are shown in Table 3. TLCO and Qc
increased during exercise both in healthy volunteers and in CHF
patients. The magnitude of increase in TLCO with respect to
Qc was normal in the patient group, although
diffusion was reduced at any given blood flow (Figure 1). The reduced QC
during exercise was again the result of a reduction in stroke volume
(65.6±4.4 versus 96.8±4.2 mL; P<0.001) and occurred
despite a greater elevation of heart rate in the patient group
(110.2±3.8 and 91.3±3.2 bpm; P<0.01). Oxygen consumption
was similar in patients and control subjects, but the patient group had
higher ventilation (VE; P<0.001) and a higher ventilatory
equivalent for carbon dioxide production
(VEVCO2; P<0.001). In patients with
CHF, both of these measures correlated significantly with the TLCO
achieved at the 30-W load (VE versus TLCO, r=-0.42,
P<0.05; VEVCO2 versus TLCO,
r=-0.65, P<0.001).
|
|
Pulmonary Diffusion and Effective Pulmonary
Blood Flow
The ratio of pulmonary diffusion to effective
pulmonary blood flow (TLCO/QC) provides
an index of the efficiency of gas exchange across the
alveolar-capillary membrane. TLCO/QC was impaired
in patients with CHF (Figure 2) compared
with control subjects both at rest (3.6±0.16 versus 4.8±0.23 mL
· L-1 ·
mm Hg-1 for CHF versus control subjects;
P<0.001) and during exercise (2.8±0.16 versus 3.4±0.13
mL · L-1 ·
mm Hg-1; P<0.05). In CHF patients,
the TLCO/QC ratio at rest was predictive of both
ventilatory efficiency during steady-state exercise
(VEVCO2 versus TLCO/QC,
r=-0.58, P<0.01) and peak exercise
O2 (Figure 3;
VO2peak versus
TLCO/QC, r=0.57,
P<0.01).
|
|
Maximal Exercise Test
Table 4 shows the results of the
maximal exercise test. All subjects were limited by breathlessness or
fatigue, with no patient describing angina during exercise. At peak
exercise, patients with CHF had markedly reduced work capacity
(P<0.001), oxygen consumption (P<0.001), minute
ventilation (P<0.001), heart rate (P<0.001),
and oxygen pulse (P<0.001) compared with control subjects.
No significant oxygen desaturation was demonstrated by pulse oximetry.
In the patient group, a significant relationship was observed between
VEVCO2 and peak
O2 (r=-0.52,
P<0.01). The only other measured variable that
correlated significantly with
VO2peak was the
TLCO/QC ratio (Figure 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Resting TLCO, measured by a single breath maneuver that can be performed practically only at rest,12 13 has previously been reported before and 5 minutes after a maximal exercise test in patients with CHF.8 In that study, TLCO declined significantly after exercise, leading the authors to conclude that pulmonary diffusion had not risen during exercise. The present study demonstrates for the first time that patients with CHF are able to recruit reserves of pulmonary diffusion and pulmonary blood flow with exercise.
In health, pulmonary diffusion increases during exercise because of a rise in the effective alveolar volume, with recruitment of pulmonary capillary beds that were underperfused at rest and an improvement in alveolar-capillary membrane conductance, brought about by thinning caused by pulmonary capillary distension.2 The relationship between pulmonary diffusion and pulmonary blood flow (TLCO/QC) has been used in other patient groups as an index of the efficiency of alveolar gas exchange. In patients who have undergone pneumonectomy, the ratio of diffusion to perfusion is maintained, with a proportionate increase in both parameters in the remaining lung.3 However, in patients with impaired alveolar-capillary membrane conductance, because of interstitial pulmonary fibrosis, there is a marked reduction in diffusion for a given pulmonary blood flow and an inability to raise diffusion significantly during exercise.4 This diffusion limitation contributes to systemic hypoxemia during exercise in that patient group.14
Patients with CHF have impaired alveolar-capillary membrane
conductance, which relates to exercise capacity9 and NYHA
functional class.7 Consistent with this is the
finding in the present study that CHF patients exhibit a reduction
in TLCO/QC ratio compared with normal controls
(Figure 2). However, in contrast to patients with
pulmonary fibrosis, CHF patients are able to recruit reserves
of both diffusion and perfusion during exercise to effectively maintain
arterial oxygenation.
In CHF patients who undergo heart transplantation, diffusion abnormalities and exercise intolerance persist despite an improvement in hemodynamic status.15 In this group, exercise may induce a systemic hypoxemia, especially in patients with abnormal pulmonary diffusion before transplantation or who have persisting pulmonary hypertension after transplantation.16 This would suggest that underlying impairment of alveolar-capillary membrane conductance can cause a functional hypoxemia when the pulmonary capillary transit time has been restored to normal.
Although CHF patients are able to maintain a normal arterial PO2 during exercise, it occurs at the expense of an elevation in ventilatory effort.17 18 19 20 This syndrome of exercise hyperpnea, measured as an increased ventilatory equivalent for VEVCO2, is predictive of the peak level of oxygen consumption that a given patient can achieve during exercise.21 It also carries independent prognostic value.19 Many factors may contribute to exercise hyperpnea, including augmentation of peripheral chemosensitivity22 and a chemoreceptor reflex driven from within the working muscle.23
In this study, we have shown a significant relationship between
VEVCO2 and TLCO and between
TLCO/QC and both VEVCO2 and
peak O2 (Figure 3),
suggesting that pulmonary diffusion limitation, particularly
impaired alveolar gas exchange, may be involved in the regulation of
exercise ventilation and ultimately of exercise tolerance. Although
patients with CHF do not become hypoxemic during
exercise,24 this may reflect the ability of increased
ventilation, driven by a dynamic peripheral
chemoreception,25 to maintain a normal end capillary
PO2 by increasing the
alveolar-arterial oxygen gradient. Further support for this
view comes from the finding that hyperoxic breathing, with resulting
improvement in pulmonary gas exchange and downregulation of the
peripheral chemoreceptors, improves exercise tolerance and
reduces exercise ventilation, with a tendency for reduced
VEVCO2, in CHF patients.26
Conclusions
Patients with CHF are able to recruit reserves of
pulmonary diffusion and pulmonary blood flow during
exercise. However, the level of diffusion for a given blood flow is
consistently reduced and relates to both exercise hyperpnea and
peak exercise oxygen consumption. Whether this impairment in alveolar
gas exchange is reversible in CHF and is therefore a potential target
for therapy has yet to be determined.
|
Acknowledgments |
|---|
This study was supported by a grant from the British Heart Foundation.
Received April 27, 1999; revision received June 10, 1999; accepted June 17, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Sackner MA, Greeneltch D, Heiman MS, Epstein S, Atkins N. Diffusing capacity, membrane diffusing capacity, capillary blood volume, pulmonary tissue volume, and cardiac output measured by a rebreathing technique. Am Rev Respir Dis. 1975;111:157–165.[Medline] [Order article via Infotrieve]
2. Hsia CCW, McBrayer DG, Ramanathan M. Reference values of pulmonary diffusing capacity during exercise by a rebreathing technique. Am J Respir Crit Care Med. 1995;152:658–665.[Abstract]
3. Hsia CCW, Ramanathan M, Estrera AS. Recruitment of diffusing capacity with exercise in patients after pneumonectomy. Am Rev Respir Dis. 1992;145:811–816.[Medline] [Order article via Infotrieve]
4. Hughes JMB, Lockwood DNA, Jones HA, Clark RJ. DLCO/Q and diffusion limitation at rest and on exercise in patients with interstitial fibrosis. Respir Physiol. 1991;83:155–166.[Medline] [Order article via Infotrieve]
5.
Seigel JL, Miller A, Brown LK, DeLuca A, Tierstein AJ.
Pulmonary diffusing capacity in left ventricular
failure. Chest. 1990;98:550–553.
6.
Wright RS, Levine MS, Bellamy PE, Simmons MS, Batra P,
Stevenson LW, Walden JA, Laks H, Tashkin DP. Ventilatory and diffusion
abnormalities in potential heart transplant recipients.
Chest. 1990;98:816–820.
7. Puri S, Baker BL, Oakley CM, Hughes JMB, Cleland JGF. Increased alveolar/capillary membrane resistance to gas transfer in patients with chronic heart failure. Br Heart J. 1994;72:141–144.
8.
Messner-Pellenc P, Brasileiro C, Ahmaidi S, Mercier J,
Ximenes C, Grolleau R, Prefaut C. Exercise intolerance in patients with
chronic heart failure: role of pulmonary diffusion limitation.
Eur Heart J. 1995;16:201–209.
9.
Puri S, Baker BL, Dutka DP, Oakley CM, Hughes JMB,
Cleland JGF. Reduced alveolar-capillary membrane diffusing capacity in
chronic heart failure: its pathophysiological
relevance and relationship to exercise performance.
Circulation. 1995;91:2769–2774.
10. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC, for the Working Party, Standardisation of Lung Function Tests, European Community for Steel and Coal. Lung volumes and forced ventilatory flows: official statement of the European Respiratory Society. Eur Respir J. 1993;6(suppl 16):5–40.
11.
ESC Working Group on Exercise Physiology,
Physiopathology, and Electrocardiography.
Guidelines for cardiac exercise testing. Eur Heart J. 1993;14:969–988.
12. Cotes JE, Chinn DJ, Quanjer PH, Roca J, Yernault JC, for the Working Party, Standardisation of Lung Function Tests, European Community for Steel and Coal.. Standardisation of the measurement of transfer factor (diffusing capacity): official statement of the European Respiratory Society. Eur Respir J. 1993;6(suppl 16):41–52.
13. Leech JA, Martz L, Liber A, Becklake MR. Diffusing capacity for carbon monoxide: the effect of different derivations of breathholding time and alveolar volume and of carbon monoxide back pressure on calculated results. Am Rev Respir Dis. 1985;132:1127–1129.[Medline] [Order article via Infotrieve]
14. Hempleman SC, Hughes JMB. Estimating exercise DLO2 and diffusion limitation in patients with interstitial fibrosis. Respir Physiol. 1991;83:167–178.[Medline] [Order article via Infotrieve]
15. Niset G, Hermans L, Depelchin P. Exercise and heart transplantation: a review. Sports Med. 1991;12:359–379.[Medline] [Order article via Infotrieve]
16. Braith RW, Limacher MC, Mills RM Jr, Leggett SH, Pollock ML, Staples ED. Exercise induced hypoxemia in heart transplant recipients. J Am Coll Cardiol. 1993;22:768–776.[Abstract]
17.
Sullivan MJ, Higgenbotham MB, Cobb FR. Increased
exercise ventilation in patients with chronic heart failure: intact
ventilatory control despite hemodynamic and
pulmonary abnormalities. Circulation. 1988;77:552–559.
18. Sovijarvi AR, Naveri H, Leinonin H. Ineffective ventilation during exercise in patients with chronic congestive heart failure. Clin Physiol. 1992;12:399–408.[Medline] [Order article via Infotrieve]
19. Chua TP, Ponikowski P, Harrington D, Anker SD, Webb-Peploe K, Clark AL, Poole-Wilson PA, Coats AJS. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29:1585–1590.[Abstract]
20. Metra M, Dei-Cas L. Role of exercise ventilation in the limitation of functional capacity in patients with congestive heart failure. Basic Res Cardiol. 1996;91(suppl 1):31–36.
21.
Davies SW, Emery TM, Watling MI, Wannamethee G, Lipkin
DP. A critical threshold of exercise capacity in the ventilatory
response to exercise in heart failure. Br Heart J. 1991;65:179–183.
22.
Chua TP, Ponikowski P, Webb-Peploe K, Harrington D,
Anker SD, Piepoli M, Coats AJ. Clinical characteristics of chronic
heart failure patients with an augmented peripheral
chemoreflex. Eur Heart J. 1997;18:480–486.
23.
Piepoli M, Clark AL, Volterrani M, Adamopoulos S,
Sleight P, Coats AJ. Contribution of muscle afferents to the
hemodynamic, autonomic and ventilatory responses to
exercise in patients with chronic heart failure: effects of physical
training. Circulation. 1996;93:940–952.
24. Clark AL, Volteranni M, Swan JW, Coats AJ. Ventilation-perfusion matching in chronic heart failure. Int J Cardiol. 1995;48:259–270.[Medline] [Order article via Infotrieve]
25. Datta AK, Nickol A. Dynamic chemoreceptiveness studied in man during moderate exercise breath by breath. Adv Exp Med Biol. 1995;393:245–248.[Medline] [Order article via Infotrieve]
26. Moore DP, Weston AR, Hughes JM, Oakley CM, Cleland JG. Effects of increased inspired oxygen concentrations on exercise performance in chronic heart failure. Lancet. 1992;339:850–853.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Guazzi Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 272 - 280. [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Snyder, B. D. Johnson, and K. C. Beck An open-circuit method for determining lung diffusing capacity during exercise: comparison to rebreathe J Appl Physiol, November 1, 2005; 99(5): 1985 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ravipati, W. S. Aronow, J. Sidana, G. P. Maguire, J. A. McClung, R. N. Belkin, and S. G. Lehrman Association of Reduced Carbon Monoxide Diffusing Capacity With Moderate or Severe Left Ventricular Diastolic Dysfunction in Obese Persons Chest, September 1, 2005; 128(3): 1620 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Trueblood, P. R. Inscore, D. Brenner, D. Lugassy, C. S. Apstein, D. B. Sawyer, and W. S. Colucci Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H244 - H249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guazzi, G. Reina, G. Tumminello, and M. D. Guazzi Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure J Appl Physiol, November 1, 2004; 97(5): 1866 - 1873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bussotti, D. Andreini, and P. Agostoni Exercise-induced changes in exhaled nitric oxide in heart failure Eur J Heart Fail, August 1, 2004; 6(5): 551 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Phansalkar, C. M. Hanson, A. R. Shakir, R. L. Johnson Jr., and C. C. W. Hsia Nitric Oxide Diffusing Capacity and Alveolar Microvascular Recruitment in Sarcoidosis Am. J. Respir. Crit. Care Med., May 1, 2004; 169(9): 1034 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guazzi Alveolar-Capillary Membrane Dysfunction in Heart Failure: Evidence of a Pathophysiologic Role Chest, September 1, 2003; 124(3): 1090 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P G Agostoni, M Bussotti, P Palermo, and M Guazzi Does lung diffusion impairment affect exercise capacity in patients with heart failure? Heart, December 1, 2002; 88(5): 453 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. W. Hsia Recruitment of Lung Diffusing Capacity: Update of Concept and Application Chest, November 1, 2002; 122(5): 1774 - 1783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Johnson, K. C. Beck, L. J. Olson, K. A. O'Malley, T. G. Allison, R. W. Squires, and G. T. Gau Pulmonary Function in Patients With Reduced Left Ventricular Function : Influence of Smoking and Cardiac Surgery Chest, December 1, 2001; 120(6): 1869 - 1876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P Faggiano, A D'Aloia, A Gualeni, and A Giordano Relative contribution of resting haemodynamic profile and lung function to exercise tolerance in male patients with chronic heart failure Heart, February 1, 2001; 85(2): 179 - 184. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||