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Alveolar Gas Diffusion Abnormalities in Heart Failure
Journal of Cardiac Failure Vol. 14 No. 8 2008
Review Article
Alveolar Gas Diffusion Abnormalities in Heart Failure MARCO GUAZZI, MD, PHD, FACC Milano, Italy
ABSTRACT In heart failure (HF), development of pressure or volume overload of the lung microcirculation elicits a series of structural adaptations, whose functional correlate is an increased resistance to gas transfer across the alveolar-capillary membrane. Acutely, hydrostatic mechanical injury causes endothelial and alveolar cell breaks, impairment of the cellular pathways involved in fluid filtration and reabsorption, and resistance to gas transfer. This process, which is reminiscent of the so-called alveolar-capillary stress failure, is generally reversible. When the alveolar membrane is chronically challenged, tissue alterations are sustained and a typical remodeling process may take place that is characterized by fixed extracellular matrix collagen proliferation and reexpression of fetal genes. Remodeling leads to a persistent reduction in alveolar-capillary membrane conductance and lung diffusion capacity. Changes in gas transfer not only reflect the underlying lung tissue damage but also bring independent prognostic information and may play a role in the pathogenesis of exercise limitation and ventilatory abnormalities. They are not responsive to fluid withdrawal by ultrafiltration and tend to be refractory even to heart transplantation. Some drugs can be effective that modulate lung remodeling (eg, angiotensin-converting enzyme inhibitors, whose impact on the natural course of cardiac remodeling is well known) or that increase nitric oxide availability and nitric oxide-mediated pulmonary vasodilation (eg, type 5 phosphodiesterase inhibitors). This review focuses on the current knowledge of these topics. (J Cardiac Fail 2008;14:695e702) KeyWords: Alveolar gas diffusion, exercise capacity, heart failure, lung function.
alveolar spaces (ie, the bloodegas barrier), whose clinical correlates can be explored by the study of gas diffusion.
During the last decade, recognition of the pathophysiologic and clinical impact of lung diffusion abnormalities and gas exchange inefficiency in patients with heart failure (HF) has progressively grown.1 This is also related to the increasing appreciation of frequency and costs of the pulmonary complications secondary to both acute and chronic left ventricular (LV) dysfunction.2 In regard to the abnormalities in lung mechanics and function, pressure elevation in the pulmonary circulation is generally the initial source of injury to the anatomic integrity and physiologic properties of lung capillaries and
Pathogenetic Mechanisms of Lung Diffusion Abnormalities in Acute and Chronic Heart Failure Alveolar-Capillary Membrane
To guarantee an optimal gas exchange, the alveolarcapillary unit needs to be thin, resistant, and ‘‘fluid-free.’’ Several important mechanisms preserve these physiologic properties. Figure 1 depicts the 3-layer configuration (epithelium, interstitial space, and endothelium) of the alveolar-capillary unit with cellular pathways involved in water and Naþ transport. Acute LV failure promotes an increase in capillary pressure or volume that disrupts the anatomic configuration of the membrane and challenges its physiologic features. Changes occur that are reminiscent of the so-called alveolar-capillary stress failure. Experimental models have provided important insights on this subject. West3 showed that if elevated enough, the pressure causes breaks and discontinuities in the endothelial and epithelial layers of the bloodegas barrier. In a similar rat model of progressive
From the Cardiopulmonary Unit, University of Milano, San Paolo Hospital, Milano, Italy. Manuscript received January 26, 2008; revised manuscript received May 2, 2008; revised manuscript accepted June 2, 2008. Reprint requests: Marco Guazzi, MD, PhD, FACC, University of Milano, Cardiology Division, San Paolo Hospital, Via A. di Rudinı`, 8, 20142 Milano, Italy. This report was supported by the Monzino Foundation, Milano, Italy. No conflict of interest exists. 1071-9164/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2008.06.004
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Fig. 1. Alveolar-capillary-membrane configuration showing the molecular and cellular pathways involved in fluid transport and clearance. Naþ enters the apical membrane of alveolar type II cells through the amiloride-sensitive epithelial Naþ channels (major pathway). Naþ is then transported across the basolateral membrane in to the interstitium through the ouabain-inhibitable Naþ/Kþ ATPase pump. This Naþ transport generates an osmotic gradient that induces removal of excessive intraalveolar fluid. In several clinical conditions, such as HF, a defect of these mechanism predisposes patients to pulmonary edema regardless of hydrostatic and oncotic pressures (Starling forces) and compensatory lymphatic drainage. ATPase, adenosine triphosphatase.
increase of left atrial pressure (LAP), a transient 50% decrease of alveolar fluid reabsorption was observed in lungs in which LAP was increased to 15 cm H2O or more,4 meaning that clearance of alveolar fluid and cellular mechanisms involved in the process come to failure. Under stress failure, the threshold pressure for developing capillary breaks varies across different animal populations.5 After seminal reports by West,3 studies investigating the biology of alveolar stress failure have brought new insights into the cellular factors involved in the response to mechanical stress, which suggest that mechanisms additional to membrane diffusing distance may determine the capillary stress. When volume or hydrostatic overloads are imposed on the capillaries, as occurs during controlled saline infusion in the rabbit lung at 0.5 mL $ min $ kg for 180 minutes, the morphometric analysis obtained in the early postinfusion phase documents that 44% of the fluid leaks into the extravascular interstitial space, a process that is accompanied by significant ultrastructural changes and impairment in gas conductance.6 Hydraulic edema has been shown to be associated with matrix proteoglycan fragmentation secondary to
metalloprotease activation,7 as well as with a marked alteration in plasma membrane composition and increase in endothelial membrane fluidity, a process that decreases the tensile strength in the membrane, contributing to endothelial stress failure.8 In patients with acute cardiogenic pulmonary edema, the damage to the alveolar-capillary barrier is documented by increased levels in plasma surfactant protein A and B and tumor necrosis factor (TNF)-a.9 Persistence of elevated TNF-a levels until 3 days after edema resolution is suggestive of pulmonary parenchymal inflammation and may explain the recurrence of fluid accumulation in the lung despite resolution of the hydrostatic burden. A recent study by our group10 in patients with acute myocardial infarction (MI) has provided pertinent results. In 118 such patients with LVejection fraction $ 50%, wedge pulmonary pressure ! 16 mm Hg, and normal plasma protein concentration, alveolar-capillary membrane gas conductance at admission was 27% lower that in normal controls, and the infusion of a small amount of saline (150 mL) in the lung circulation (to test sodium exchange across the pulmonary capillary wall)11 further depressed the membrane conductance by
Alveolar Gas Diffusion Abnormalities in Heart Failure
7.1% in patients and not in controls. In 83 patients (group 1) whose systolic and diastolic LV function remained steady, the alveolar capillary membrane conductance recovered within 1 week and saline became ineffective, whereas the barrier gas conductance further deteriorated and saline retained efficacy in 28 patients (group 2) who had LAP increase as the result of diastolic LV dysfunction. At 1 year, 3% of cases in group 1 and 37% of cases in group 2 had alveolar edema. Considerations on these findings are the following: The acute post-MI phase is associated with some alteration in pulmonary Naþ transport/water conductance system, which impairs gas transfer and is generally reversible. However, in cases of LV dysfunction supervenience, this may persist and worsen the outcome. A diminished plasma oncotic pressure or hydrostatic imbalance caused by LV dysfunction does not seem to be a requirement for such supervenience. The inflammatory burden carried by the lung (which in our cases was reflected by elevated C-reactive protein levels) and the remarkable neural, hormonal, and hemodynamic alterations caused by an abrupt interruption of myocardial perfusion play primary roles. When lung parenchyma is injured, there is a loss of protection against fluid accumulation by the usual safety factors and the amount of fluid and protein flow into the interstitium increases. Although increases in fluid and protein filtration across the barriers are removed by lymphatics and drained away from the alveolar walls as in increased pressure edema, more fluid and protein are filtered at any given sum of driving pressures because the barriers to their flow are less restrictive than normal. The respiratory pattern in acute MI is reminiscent of the acute lung injury (ALI), a disorder that may precede acute respiratory distress syndrome (ARDS).12 ALI has an acute onset, the pulmonary capillary wedge pressure is # 18 mm Hg, there is no clinical evidence of increased LAP, and the alveolar capillary endothelial cells and type I pneumocytes are injured, leading to a loss of the normal barrier to fluid and macromolecules. Fluid that is rich in protein accumulates in the interstitial and alveolar spaces, and impedes gas exchange. Significant concentrations of cytokines (eg, interleukin 1, interleukin 8, and TNF-a) are present in the lung. New causes of acute lung injury are continually being reported in humans and experimental animals. Future studies might reinforce the concept that acute MI can be included in these conditions. In regard to alveolar edema in MI, the worse outcome observed in patients in group 2 compared with group 1 in our study10 emphasizes a primary pathogenetic role of the elevated LAP and a possible contributory role of a persistent leaky bloodegas barrier. Edema formation in injured lungs is sensitive to driving pressures.13 Acute MI in some patients may be a clinical model of transition from a predominant permeability pulmonary edema in the acute phase to a predominant pressure pulmonary edema in the long term. Alveolar Fluid Clearance
Naþ transport across the alveolar epithelium helps to reabsorb fetal fluid,14 ensure a proper thinness of the adult alveolar
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fluid, the so-called film,15 and keep alveolar space free of fluid, especially in pathologic states when alveolar permeability to plasma proteins has been increased.16,17 The alveolar type II cell transport of Naþ (Fig 1) provides the major driving force for water removal from the alveolar space.18 After uptake, Naþ is pumped actively into the lung interstitium by Naþ-Kþ adenosine triphosphatase (ATPase). For an optimal gas exchange, the fine mechanisms that control the alveolar Naþ and water metabolism are basically involved. Although disorders in lung diffusion in patients with HF generally have been referred to as alterations of the endothelial and alveolar epithelial cells,19,20 experimental observations are also consistent with an involvement of alveolar water metabolism. Overexpressing the Naþ-Kþ ATPase b1-subunit in rats by adenovirus gene transfer potentiates fluid reabsorption from the alveoli.21 In the same model, Naþ transport and alveolar fluid clearance in the presence of elevated LAP was not different from that in animals studied at normal LAP.22 Hypoxia, another common association with chronic HF, is also capable of inhibiting the alveolar Naþ -Kþ ATPase function and transalveolar fluid transport.23 These observations advance the intriguing hypothesis that an impaired Naþ-Kþ ATPase gene expression occurs during acute lung injury and supports a pressure or volume overload in lung circulation as a potential trigger of sodium and water handling alterations with deregulation of local mechanisms for gas exchange. Alveolar-Capillary Remodeling
Although there is evidence of complete reversibility during acute conditions in experimental and clinical settings,24 alveolar changes are progressive and there is no definite proof of reversibility in the long term. In a pace-induced HF model, changes in alveolar-membrane ultrastructure were mainly represented by membrane thickening caused by excessive collagen type IV deposition, the major component of the alveolar lamina densa interposed between the epithelial and the endothelial layer.25 These changes are consistent with a remodeling process that, similar to what has been observed in patients with secondary pulmonary hypertension, may be protective against edema development on the one hand and may lengthen the diffusion path and impede gas exchange on the other hand.26 The factors leading to the transition from alveolar stress failure to chronic tissue damage or remodeling are not clearly identified. However, reexpression of fetal genes might play a considerable role.1 Clinical Relevance of Gas Diffusion Abnormalities in Chronic Heart Failure Measurement of lung diffusion capacity for carbon monoxide (DLCO) or nitric oxide (DLNO) is generally used in clinical practice to evaluate the effectiveness of diffusive O2 transport.27 As originally suggested by Roughton and Forster,28 for a given alveolar volume (VA) and hemoglobin concentration, gas diffusion depends on 2 resistances arranged in series according to the following equation:
698 Journal of Cardiac Failure Vol. 14 No. 8 October 2008 1/DLCO 5 1/DM þ 1/qCO Vc, where DM is the alveolar-capillary membrane conductance, qCO is the rate of CO uptake by the whole blood in combination with hemoglobin measured in vitro, and Vc is the lung capillary blood volume. Measurement of DM tracks structural alterations of the alveolar-capillary barrier and is a sensitive method to probe microvascular integrity in health and disease. Vc may increase according to pulmonary capillary wedge pressure. Vc tends to increase in patients with stable HF, but decreases in the advanced stages.29 In a seminal study, Puri et al30 first documented that patients with HF present with a low DLCO according to the disease severity, and this correlates with increased pulmonary vascular resistance. A reduction in the DM component accounted for observed gas diffusing abnormalities. Several subsequent reports11,31e44 have confirmed and expanded these findings. In studies in which VA has been measured, abnormalities in DM remained after DM expression as membrane transfer coefficient (DM/VA). The diffusing capacity is further reduced by comorbidities in which the thickness of the membrane is increased or by chronic obstructive pulmonary disease, caused by the loss of alveolar walls and capillaries, unevenness of ventilation, and diffusion properties. It is remarkable that patients with HF and diabetes comorbidity exhibit a more severe DM impairment than patients with similar hemodynamic dysfunction without diabetes.42 By analyzing these studies, a continuum may be observed of the ultrastructural changes occurring at the alveolar membrane level and the corresponding changes in DLCO, DM, and Vc (Fig 2). DM Determinants in Chronic Heart Failure
Investigators have been interested in whether a reduction in DM in chronic HF is fixed, reflecting sustained microvascular damage, or variable and whether an altered sodium exchange across the pulmonary capillary wall may have a role.7,45 Puri et al41 found that intravenously infused saline 10 mL/kg in patients with chronic HF was associated with a 13% reduction of DM, suggesting that abnormal pulmonary diffusion in chronic HF has a variable component that could be amenable to therapeutic intervention. A subsequent study by our group11 showed that even an amount of saline as small as the lung capillary blood volume (150 mL) infused in the pulmonary artery significantly interferes with DM in patients with chronic HF (and not in normal controls), without affecting the plasma oncotic pressure and right ventricular and LV filling pressures. In the same study, the infusion of an equal amount of 5% glucose solution did not affect DM. Pathophysiologic Correlates
Multiple mechanisms may be involved in shortness of breath and exercise intolerance in chronic HF, and different patients may have varying degrees of limitation in more than 1 mechanism. A debated issue is whether impairment in gas transport at the alveolar epithelial vascular endothelial
junction is significantly involved in causing exercise intolerance.30,41,46,47 The correlation existing between baseline DLCO and peak exercise oxygen uptake (pVO2),30 between DM and the ventilatory equivalent of carbon dioxide production (VE/VCO2),48 and between the improvement in DLCO and pVO2 after enalapril39 are in keeping with the concept that pulmonary diffusion limitation is one of the mediators of exercise impairment in HF. Although arterial blood gases can remain normal during exercise in these patients, an augmented ventilatory drive may be required that maintains or elevates alveolar oxygen tension49 at the expense of an anticipated exhaustion of the ventilatory reserve and an earlier exercise termination. The lack of a significant arterial oxygen desaturation on exercise in patients with HF, however, continues to cast some doubt on a cause and effect relationship between gas diffusion impairment and exercise limitation. Two further considerations, however, argue against a simple association. 1) In patients with HF, despite the fact that pulmonary perfusion (Q) is generally significantly reduced, the ability to appropriately recruit DM for that given Q preserves the DM/Q and prevents significant O2 saturation decreases.50 2) Significant hypoxia on exercise occurs in patients having further DM and DM/Vc reduction during the recovery phase of exercise,51 reflecting development of exercise subclinical pulmonary edema. This condition is reproducible experimentally by acutely infusing an amount of saline solution in the pulmonary circulation of patients with chronic HF, which lengthens the diffusion path for gas exchange and increases the resistance to gas transfer without causing hemodynamic disturbances. In such a study52 it was found that after saline administration (compared with the control condition), DLCO, DM, and pVO2 were reduced, Vc and VE/ VCO2 were increased, changes in DM were positively related with those in pVO2 and inversely related with those in VE/ VCO2, and, even more significant, arterial oxygen saturation was significantly decreased below baseline at peak exercise. No influence of saline on each of these variables was detected in normal subjects. Overall, evidence is in favor of an involvement of lung diffusion capacity and the conductance of the bloodegas barrier in symptoms and exercise limitation of patients with chronic cardiac failure. Interventions Improving Gas Diffusion in Chronic Heart Failure In patients with HF who undergo heart transplantation, diffusion abnormalities may persist despite an improvement in hemodynamic status.53 A relationship has also been established between the time course of the disease and extent of gas transfer alterations.54 Thus, impaired DLCO in chronic disease may not fully depend on a reduction of the global perfusion of the lung but may be related to the persistence of structural changes of the membrane. The clinical significance of this may even be greater, because, in a prospective examination of the lung function prognostic power in HF, DM emerged to be the only independent pulmonary predictor of worse prognosis.55 This section
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↓DLCO ↓↓ DM ↑↑ Vc
↔ DLCO ↓ DM ↑ Vc
↓↓ DLCO ↓↓ DM ↓ Vc
Stress failure
Injury
REVERSIBLE
Remodeling
IRREVERSIBLE
Fig. 2. Time course of changes in alveolar-capillary membrane conductance (DM) and capillary blood volume (Vc) in LV cardiac dysfunction. As detailed in the text, acute hydrostatic injury causes a reduction in DLCO because of a DM impairment and reduction in Vc. When alveolar membrane remodeling ensues, DM further deteriorates and Vc decreases, indicating hemodynamic worsening and lung hypoperfusion. At this stage, there is no evidence of lung tissue damage reversibility. DLCO, lung diffusion capacity for carbon monoxide.
examines whether the alveolar-capillary membrane may be affected and therefore become a potential target for therapy. Pharmacologic Interventions
Davies et al32 documented reduced pulmonary microvascular permeability in patients with severe chronic HF who were taking angiotensin-converting enzyme (ACE) inhibitors. Subsequently, it was reported that DLCO increased from a mean value of 79% to 89% of normal predicted after 15 days of treatment with enalapril in patients with chronic HF.39 Hydralazine-isosorbide dinitrate did not affect DLCO in these patients despite a pulmonary pressure lowering effect similar to that of the ACE inhibitor. In another study56 in which DLCO was partitioned into two subcomponents resistances, DM was proven to be the mediator of the increased diffusion capacity with ACE inhibition, an effect that was evident at 1 and 2 months of treatment. Two additional observations were that cyclooxygenase blockade with the combination of aspirin (daily dose of 325 mg) fully counteracted the benefits of enalapril39,57e59 and that AT1-receptor blockade with losartan58,59 was ineffective on DLCO and DM. Apart from the therapeutic and prognostic implications (the lung function improvement by ACE inhibitors might take part in the overall benefits on survival by this class of drugs), these 2 findings support the concept that the kinin system rather than the angiotensin system is primarily involved in the described effects and enalapril in this particular instance acts as an inhibitor of KII, the enzyme that inactivates circulating bradykinin, thus increasing local kinin concentration. Activation of endothelial B2
kinin receptors leads, via the combined action of phospholipase A2 and cyclooxygenase,60 to enhanced and sustained formation of nitric oxide (NO) and prostacyclin (PGI2),61 2 basic modulators of the pulmonary vascular tone and permeability.62 Thus, ACE inhibitors in chronic HF seem to increase the influences of NO and PGI2 and to reduce the exposure of the pulmonary vessels to angiotensin II. Whether the latter effect will translate into modulation in extracellular matrix synthesis and collagen turnover in the long term is reasonable but still unproven. Lisinopril inhibits angiotensin II-mediated apoptosis and loss of the alveolar epithelial cells,63 and ACE genotype polymorphism modulates pulmonary function and exercise capacity.43 Among the drugs currently being used in HF, spironolactone has been shown to produce some improvement in lung diffusion,64 whereas carvedilol did not affect DLCO and DM in a 6-month study.65 The b1-adrenergic receptor blocker, bisoprolol, has been reported to be beneficial for lung diffusion, possibly because it is devoid of any inhibitory activity on b2-adrenergic receptors located in the alveolar wall.66 In a different manner, b2-adrenergic receptor polymorphisms may control alveolar fluid clearance67 and pulmonary function in patients with HF.68 Drugs stimulating NO overexpression, such as type 5 phosphodiesterase (PDE5) inhibitors, are a promising class of drugs for the treatment of pulmonary hypertension.69 NO activates guanylate cyclase in pulmonary smooth muscle cells, which increases cyclic guanosine monophosphate and decreases intracellular calcium concentration, leading to smooth muscle relaxation. There are good reasons to hypothesize that PDE5 inhibition can positively affect the
700 Journal of Cardiac Failure Vol. 14 No. 8 October 2008 alveolar-capillary membrane conductance in HF. A defective NO release is typical of the syndrome70 and facilitates an increase in pulmonary arterial and venous tone and capillary filtering pressure. NO, similar to vasodilating prostaglandins,62,71 modulates the pulmonary vascular permeability and reduces the tissue component of resistance to O2 transfer from the alveolus to its uptake by hemoglobin. In an acute study of a small cohort of patients with HF, PDE5 inhibition with sildenafil provided a favorable reduction of the alveolar-capillary membrane impedance to gas exchange associated with a decrease in pulmonary pressure and resistance, an improvement in peak VO2, aerobic and ventilatory efficiencies, and oxygen debt.72 In a 6-month study of a larger cohort of similar patients, the efficacy of sildenafil on exercise performance was sustained.73 Diabetes mellitus may be associated with mild and silent impairment in gas exchange function74 because of alveolar and capillary laminae alteration. Patients with diabetes have a 4- to 5-fold increased risk of HF, and diabetes definitely enhances the deterioration of pulmonary gas exchange in HF in case of comorbidity.62 In patients with diabetes, and to a greater extent in those with comorbidity, acute infusion of insulin was associated with a considerable increase of DM and DM/VA, and a reduction of DLCO/ DM. This suggests62 that diabetes exerts a synergistic activity with HF regarding lung injury and that activation of the defective release of substances (eg, NO75 and vasodilating prostaglandins) that modulate the interface resistance to O2 transfer may underlie the pulmonary function improvement by insulin in diabetes alone or combined with HF. Nonpharmacologic Interventions
In addition to structural alterations of the alveolar membrane, an excess of lung interstitial fluid volume may be involved in reducing DM in chronic stable HF. The role of subclinical interstitial fluid accumulation has been probed by monitoring gas exchange variables before and after extracorporeal ultrafiltration, a therapeutic intervention known to reduce lung water content and pulmonary vascular pressure and to improve the clinical condition, exercise capacity, and pulmonary mechanical properties in patients with HF.76 In cases of stable HF and documented low DM, the procedure was effective on mechanical lung properties (ie, improved vital capacity, forced expiratory volume, and maximal voluntary ventilation) by reducing lung fluid content, but it did not affect DLCO and DM. These results suggest that although some lung subclinical interstitial fluid is removed, structural alterations of the alveolar unit retain a critical pathophysiologic key role.77 Interventions aimed at improving systemic endothelial function, such as aerobic exercise training, may also favorably affect gas exchange and pulmonary capillary properties.78 In patients with compensated HF, exercise training (for 8 weeks by stationary cycling, 4 times/week) significantly increased DLCO by 25%, DM by 15%, and peak
VO2 by 13%; reduced VE/VCO2 by 14%; and improved brachial artery flow-mediated dilatation by 71%. There was a significant correlation between the increase of brachial artery flow-mediated dilatation and that of DM. With detraining (8 weeks), all these variables reverted to levels similar to baseline.79 Repeated episodes of increased blood flow with exercise or metabolic effects of training may be the basis for a chronic stimulus to release endothelial paracrine agents that control pulmonary vascular tone and permeability,80 yielding to a facilitated O2 transfer across the alveolar-capillary membrane. This seems to be an additional mechanism whereby exercise training benefits patients with cardiac disease. Conclusions The resistance to gas diffusion across the alveolarcapillary membrane is increased in HF. Disruption of the alveolar anatomic configuration and impairment of cellular pathways involved in the fluideflux regulation and gas exchange efficiency (ie, ‘‘stress failure’’ of the alveolarcapillary membrane) are well characterized in different experimental models of lung capillary injury. Similar changes may distinguish acute HF in humans and may be reversible. In the chronic phase of HF, a reduced alveolar gas conductance is mainly related to structural changes of the membrane that are sustained and seemingly play a significant role in exercise limitation and ventilatory abnormalities. In chronic HF, alterations in gas transfer bring independent prognostic information and may be sensitive to pharmacologic or nonpharmacologic means that potentiate endothelial modulators of vascular tone and permeability, such as NO and PGI2.
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failure. Its pathophysiological relevance and relationship to exercise performance. Circulation 1995;91:2769e74. Wright RS, Levine MS, Bellamy PE, Simmons MS, Batra P, Stevenson LW, et al. Ventilatory and diffusion capacity in potential heart transplant recipients. Chest 1990;98:816e20. Davies SW, Bailey J, Keegan J, Balcon R, Rudd RM, Lipkin DP. Reduced pulmonary microvascular permeability in severe chronic left heart failure. Am Heart J 1992;124:137e42. Siegel JL, Miller A, Brown LK, De Luca A, Teirstein AS. Pulmonary diffusion capacity in left ventricular dysfunction. Chest 1990;8: 550e3. Naum C, Sciurba FC, Rogers MB. Pulmonary function abnormalities in chronic severe cardiomyopathy preceding cardiac transplantation. Am Rev Respir Dis 1992;145:1334e8. Ravenscraft SA, Gross CR, Kubo SH. Pulmonary function after successful heart transplantation. Chest 1993;103:54e5. Ohar J, Osterloh J, Ahmed N, Miller L. Diffusing capacity decreases after heart transplantation. Chest 1993;103:857e61. Kraemer MD, Kubo SH, Rector TS, Brunsvold N, Bank AJ. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol 1993;21:641e8. Messner-Pellenc P, Brasiliero C, Ahmadi S, Mercier J, Ximenes C, Grolleau R, et al. Exercise intolerance in patients with chronic heart failure: role of pulmonary diffusing limitation. Eur Heart J 1995;16:201e9. Guazzi M, Marenzi G, Alimento M, Contini M, Guazzi MD. Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997;95:1930e6. Assayag P, Benamer H, Aubry P, de Picciotto C, Brochet E, Besse S. Alteration of the alveolar-capillary membrane diffusing capacity in chronic left heart disease. Am J Cardiol 1998;82:459e64. Puri S, Dutka DP, Baker BL, Hughes JM, Cleland JG. Acute saline infusion reduces alveolar-capillary membrane conductance and increases airflow obstruction in patients with left ventricular dysfunction. Circulation 1999;99:1190e6. Guazzi M, Brambilla R, Pontone G, Agostoni P, Guazzi MD. Effect of non-insulin-dependent diabetes mellitus on pulmonary function and exercise tolerance in chronic congestive heart failure. Am J Cardiol 2002;89:191e7. Abraham MR, Olsen LJ, Joyner MJ, Turner ST, Beck KC, Johnson BD. Angiotensin-converting enzyme genotype modulates pulmonary function and exercise capacity in treated patients with congestive stable heart failure. Circulation 2002;106:1794e9. Agostoni P, Bussotti M, Cattadori G, Margutti E, Contini M, Muratori M, et al. Gas diffusion and alveolar-capillary unit in chronic heart failure. Eur Heart J 2006;27:2538e43. Matthay MA, Folkesson HG, Verkman AS. Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol 1996;270:L487e503. Kraemer MD, Kubo SH, Rector TS, Brunsvold M, Bank AJ. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol 1993;21:641e8. Smith AA, Cowbum PJ, Parker ME. Impaired pulmonary diffusion during exercise in patients with chronic heart failure. Circulation 1999;100:1406e10. Guazzi M, Reina G, Tumminello G, Guazzi MD. Alveolar-capillary membrane conductance is the best pulmonary correlate of exercise ventilatory efficiency in heart failure patients. Eur J Heart Fail 2005; 7:1017e22. Johnson BD, Beck KC, Olson LY, O’Malley KA, Allison TG, Squires RW, et al. Ventilation constraints during exercise in patients with chronic heart failure. Chest 2000;117:321e32. Hsia CCW. Recruitment of lung diffusing capacity: update of concept and application. Chest 2002;122:1774e83. Agostoni PG, Cattadori G, Bianchi M, Wasserman K. Exercise induced pulmonary edema in heart failure. Circulation 2003;108:2666e71.
702 Journal of Cardiac Failure Vol. 14 No. 8 October 2008 52. Guazzi M, Agostoni PG, Guazzi MD. Alveolar-capillary gas exchange and exercise performance in heart failure. Am J Cardiol 2001;88: 452e7. 53. Ewert R, Wensel R, Bettmann M, Spiegelsberger S, Grauhan O, Hummel M, et al. Ventilatory and diffusion abnormalities in longterm survivors after orthotopic heart transplantation. Chest 1999; 115:1305e11. 54. Mettauer B, Lampert E, Charloux A, Zhao OM, Epailly E, Oswald M, et al. Lung membrane diffusing capacity, heart failure, and heart transplantation. Am J Cardiol 1999;83:62e7. 55. Guazzi M, Pontone G, Brambilla R, Agostoni P, Reina G. Alveolarcapillary membrane gas conductance: a novel prognostic indicator in chronic heart failure. Eur Heart J 2002;23:467e76. 56. Guazzi M, Agostoni P. 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. Clin Sci 1999;96:17e22. 57. Guazzi M, Pontone G, Agostoni P. Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors. Am Heart J 1999;138:254e60. 58. Guazzi M, Melzi G, Agostoni P. Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997;80:1572e6. 59. Guazzi M, Agostoni P, Guazzi MD. Modulation of alveolar-capillary sodium handling as a mechanism of protection of gas transfer by enalapril and not by losartan, in chronic heart failure. J Am Coll Cardiol 2001;37:398e406. 60. Bhoola KD, Figueras CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992;44:1e80. 61. Linz W, Wiemer G, Gohlke P, Unger T, Scho¨lkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995;47:25e49. 62. Guazzi M, Brambilla R, De Vita S, Guazzi MD. Diabetes worsens pulmonary diffusion in heart failure, and insulin counteracts this effect. Am J Respir Crit Care Med 2002;166:978e82. 63. Dincer HE, Gangopadhyay N, Wang R, Bruce DU. Norepinephrine induces alveolar epithelial apoptosis mediated by alpha-, betha-, and angiotensin receptor activation. Am J Physiol 2001;281:L624e30. 64. Agostoni P, Magini A, Andreini D, Contini M, Apostolo A, Bussotti M, et al. Spironolactone improves lung diffusion in chronic heart failure. Eur Heart J 2005;26:159e64. 65. Guazzi M, Agostoni PG, Matturri M, Pontone G, Guazzi MD. Pulmonary function, cardiac function and exercise capacity in a follow-up of congestive heart failure patients treated with carvedilol. Am Heart J 1999;138:460e7. 66. Agostoni P, Contini M, Cattadori G, Apostolo A, Sciomer S, Bussotti M, et al. Lung function with carvedilol and bisoprolol in chronic heart failure: is beta selectivity relevant? Eur J Heart Fail 2007;9:827e33.
67. Snyder EM, Beck KC, Turner ST, Hoffman EA, Joyner MJ, Johnson BD. Genetic variation of the beta2-adrenergic receptor is associated with differences in lung fluid accumulation in humans. J Appl Physiol 2007;102:2172e8. 68. Snyder EM, Beck KC, Dietz NM, Joyner MJ, Turner ST, Johnson BD. Influence of beta2-adrenergic receptor genotype on airway function during exercise in healthy adults. Chest 2006;129:762e70. 69. Galie` N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LY, Badesch D, et al. Sildenafil use in pulmonary arterial hypertension (SUPER) study group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148e57. 70. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000;102:1718e23. 71. Stamler JS, Loh E, Roddy MA, Currie KE, Creager MA. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994;89:2035e40. 72. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol 2004;44:2339e48. 73. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50:2136e44. 74. Cooper BG, Taylor R, Alberti KGMM, Gibson GJ. Lung function in patients with diabetes mellitus. Respir Med 1990;84:235e9. 75. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1996;97:2601e10. 76. Agostoni P, Marenzi G, Lauri G, Perego G, Schianni M, Sganzerla P, et al. Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency. Failure of furosemide to provide the same result. Am J Med 1994;96: 191e6. 77. Agostoni P, Guazzi M, Bussotti M, Grazi M, Palermo P, Marenzi G. Lack of improvement of lung diffusing capacity following fluid withdrawal by ultrafiltration in chronic heart failure. J Am Coll Cardiol 2000;36:1600e4. 78. Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure. A randomised trial. JAMA 2000;283:3095e101. 79. Guazzi M, Reina G, Tumminello G, Guazzi MD. Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure. J Appl Physiol 2004;97:1866e73. 80. Maiorana A, O’Driscoll G, Dembo L, Cheetham C, Goodman C, Taylor R, et al. Effect of aerobic and resistance exercise training on vascular function in heart failure. Am J Physiol Heart Circ Physiol 2000;279:H1999e2005.
Review Article
Alveolar Gas Diffusion Abnormalities in Heart Failure MARCO GUAZZI, MD, PHD, FACC Milano, Italy
ABSTRACT In heart failure (HF), development of pressure or volume overload of the lung microcirculation elicits a series of structural adaptations, whose functional correlate is an increased resistance to gas transfer across the alveolar-capillary membrane. Acutely, hydrostatic mechanical injury causes endothelial and alveolar cell breaks, impairment of the cellular pathways involved in fluid filtration and reabsorption, and resistance to gas transfer. This process, which is reminiscent of the so-called alveolar-capillary stress failure, is generally reversible. When the alveolar membrane is chronically challenged, tissue alterations are sustained and a typical remodeling process may take place that is characterized by fixed extracellular matrix collagen proliferation and reexpression of fetal genes. Remodeling leads to a persistent reduction in alveolar-capillary membrane conductance and lung diffusion capacity. Changes in gas transfer not only reflect the underlying lung tissue damage but also bring independent prognostic information and may play a role in the pathogenesis of exercise limitation and ventilatory abnormalities. They are not responsive to fluid withdrawal by ultrafiltration and tend to be refractory even to heart transplantation. Some drugs can be effective that modulate lung remodeling (eg, angiotensin-converting enzyme inhibitors, whose impact on the natural course of cardiac remodeling is well known) or that increase nitric oxide availability and nitric oxide-mediated pulmonary vasodilation (eg, type 5 phosphodiesterase inhibitors). This review focuses on the current knowledge of these topics. (J Cardiac Fail 2008;14:695e702) KeyWords: Alveolar gas diffusion, exercise capacity, heart failure, lung function.
alveolar spaces (ie, the bloodegas barrier), whose clinical correlates can be explored by the study of gas diffusion.
During the last decade, recognition of the pathophysiologic and clinical impact of lung diffusion abnormalities and gas exchange inefficiency in patients with heart failure (HF) has progressively grown.1 This is also related to the increasing appreciation of frequency and costs of the pulmonary complications secondary to both acute and chronic left ventricular (LV) dysfunction.2 In regard to the abnormalities in lung mechanics and function, pressure elevation in the pulmonary circulation is generally the initial source of injury to the anatomic integrity and physiologic properties of lung capillaries and
Pathogenetic Mechanisms of Lung Diffusion Abnormalities in Acute and Chronic Heart Failure Alveolar-Capillary Membrane
To guarantee an optimal gas exchange, the alveolarcapillary unit needs to be thin, resistant, and ‘‘fluid-free.’’ Several important mechanisms preserve these physiologic properties. Figure 1 depicts the 3-layer configuration (epithelium, interstitial space, and endothelium) of the alveolar-capillary unit with cellular pathways involved in water and Naþ transport. Acute LV failure promotes an increase in capillary pressure or volume that disrupts the anatomic configuration of the membrane and challenges its physiologic features. Changes occur that are reminiscent of the so-called alveolar-capillary stress failure. Experimental models have provided important insights on this subject. West3 showed that if elevated enough, the pressure causes breaks and discontinuities in the endothelial and epithelial layers of the bloodegas barrier. In a similar rat model of progressive
From the Cardiopulmonary Unit, University of Milano, San Paolo Hospital, Milano, Italy. Manuscript received January 26, 2008; revised manuscript received May 2, 2008; revised manuscript accepted June 2, 2008. Reprint requests: Marco Guazzi, MD, PhD, FACC, University of Milano, Cardiology Division, San Paolo Hospital, Via A. di Rudinı`, 8, 20142 Milano, Italy. This report was supported by the Monzino Foundation, Milano, Italy. No conflict of interest exists. 1071-9164/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2008.06.004
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Fig. 1. Alveolar-capillary-membrane configuration showing the molecular and cellular pathways involved in fluid transport and clearance. Naþ enters the apical membrane of alveolar type II cells through the amiloride-sensitive epithelial Naþ channels (major pathway). Naþ is then transported across the basolateral membrane in to the interstitium through the ouabain-inhibitable Naþ/Kþ ATPase pump. This Naþ transport generates an osmotic gradient that induces removal of excessive intraalveolar fluid. In several clinical conditions, such as HF, a defect of these mechanism predisposes patients to pulmonary edema regardless of hydrostatic and oncotic pressures (Starling forces) and compensatory lymphatic drainage. ATPase, adenosine triphosphatase.
increase of left atrial pressure (LAP), a transient 50% decrease of alveolar fluid reabsorption was observed in lungs in which LAP was increased to 15 cm H2O or more,4 meaning that clearance of alveolar fluid and cellular mechanisms involved in the process come to failure. Under stress failure, the threshold pressure for developing capillary breaks varies across different animal populations.5 After seminal reports by West,3 studies investigating the biology of alveolar stress failure have brought new insights into the cellular factors involved in the response to mechanical stress, which suggest that mechanisms additional to membrane diffusing distance may determine the capillary stress. When volume or hydrostatic overloads are imposed on the capillaries, as occurs during controlled saline infusion in the rabbit lung at 0.5 mL $ min $ kg for 180 minutes, the morphometric analysis obtained in the early postinfusion phase documents that 44% of the fluid leaks into the extravascular interstitial space, a process that is accompanied by significant ultrastructural changes and impairment in gas conductance.6 Hydraulic edema has been shown to be associated with matrix proteoglycan fragmentation secondary to
metalloprotease activation,7 as well as with a marked alteration in plasma membrane composition and increase in endothelial membrane fluidity, a process that decreases the tensile strength in the membrane, contributing to endothelial stress failure.8 In patients with acute cardiogenic pulmonary edema, the damage to the alveolar-capillary barrier is documented by increased levels in plasma surfactant protein A and B and tumor necrosis factor (TNF)-a.9 Persistence of elevated TNF-a levels until 3 days after edema resolution is suggestive of pulmonary parenchymal inflammation and may explain the recurrence of fluid accumulation in the lung despite resolution of the hydrostatic burden. A recent study by our group10 in patients with acute myocardial infarction (MI) has provided pertinent results. In 118 such patients with LVejection fraction $ 50%, wedge pulmonary pressure ! 16 mm Hg, and normal plasma protein concentration, alveolar-capillary membrane gas conductance at admission was 27% lower that in normal controls, and the infusion of a small amount of saline (150 mL) in the lung circulation (to test sodium exchange across the pulmonary capillary wall)11 further depressed the membrane conductance by
Alveolar Gas Diffusion Abnormalities in Heart Failure
7.1% in patients and not in controls. In 83 patients (group 1) whose systolic and diastolic LV function remained steady, the alveolar capillary membrane conductance recovered within 1 week and saline became ineffective, whereas the barrier gas conductance further deteriorated and saline retained efficacy in 28 patients (group 2) who had LAP increase as the result of diastolic LV dysfunction. At 1 year, 3% of cases in group 1 and 37% of cases in group 2 had alveolar edema. Considerations on these findings are the following: The acute post-MI phase is associated with some alteration in pulmonary Naþ transport/water conductance system, which impairs gas transfer and is generally reversible. However, in cases of LV dysfunction supervenience, this may persist and worsen the outcome. A diminished plasma oncotic pressure or hydrostatic imbalance caused by LV dysfunction does not seem to be a requirement for such supervenience. The inflammatory burden carried by the lung (which in our cases was reflected by elevated C-reactive protein levels) and the remarkable neural, hormonal, and hemodynamic alterations caused by an abrupt interruption of myocardial perfusion play primary roles. When lung parenchyma is injured, there is a loss of protection against fluid accumulation by the usual safety factors and the amount of fluid and protein flow into the interstitium increases. Although increases in fluid and protein filtration across the barriers are removed by lymphatics and drained away from the alveolar walls as in increased pressure edema, more fluid and protein are filtered at any given sum of driving pressures because the barriers to their flow are less restrictive than normal. The respiratory pattern in acute MI is reminiscent of the acute lung injury (ALI), a disorder that may precede acute respiratory distress syndrome (ARDS).12 ALI has an acute onset, the pulmonary capillary wedge pressure is # 18 mm Hg, there is no clinical evidence of increased LAP, and the alveolar capillary endothelial cells and type I pneumocytes are injured, leading to a loss of the normal barrier to fluid and macromolecules. Fluid that is rich in protein accumulates in the interstitial and alveolar spaces, and impedes gas exchange. Significant concentrations of cytokines (eg, interleukin 1, interleukin 8, and TNF-a) are present in the lung. New causes of acute lung injury are continually being reported in humans and experimental animals. Future studies might reinforce the concept that acute MI can be included in these conditions. In regard to alveolar edema in MI, the worse outcome observed in patients in group 2 compared with group 1 in our study10 emphasizes a primary pathogenetic role of the elevated LAP and a possible contributory role of a persistent leaky bloodegas barrier. Edema formation in injured lungs is sensitive to driving pressures.13 Acute MI in some patients may be a clinical model of transition from a predominant permeability pulmonary edema in the acute phase to a predominant pressure pulmonary edema in the long term. Alveolar Fluid Clearance
Naþ transport across the alveolar epithelium helps to reabsorb fetal fluid,14 ensure a proper thinness of the adult alveolar
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fluid, the so-called film,15 and keep alveolar space free of fluid, especially in pathologic states when alveolar permeability to plasma proteins has been increased.16,17 The alveolar type II cell transport of Naþ (Fig 1) provides the major driving force for water removal from the alveolar space.18 After uptake, Naþ is pumped actively into the lung interstitium by Naþ-Kþ adenosine triphosphatase (ATPase). For an optimal gas exchange, the fine mechanisms that control the alveolar Naþ and water metabolism are basically involved. Although disorders in lung diffusion in patients with HF generally have been referred to as alterations of the endothelial and alveolar epithelial cells,19,20 experimental observations are also consistent with an involvement of alveolar water metabolism. Overexpressing the Naþ-Kþ ATPase b1-subunit in rats by adenovirus gene transfer potentiates fluid reabsorption from the alveoli.21 In the same model, Naþ transport and alveolar fluid clearance in the presence of elevated LAP was not different from that in animals studied at normal LAP.22 Hypoxia, another common association with chronic HF, is also capable of inhibiting the alveolar Naþ -Kþ ATPase function and transalveolar fluid transport.23 These observations advance the intriguing hypothesis that an impaired Naþ-Kþ ATPase gene expression occurs during acute lung injury and supports a pressure or volume overload in lung circulation as a potential trigger of sodium and water handling alterations with deregulation of local mechanisms for gas exchange. Alveolar-Capillary Remodeling
Although there is evidence of complete reversibility during acute conditions in experimental and clinical settings,24 alveolar changes are progressive and there is no definite proof of reversibility in the long term. In a pace-induced HF model, changes in alveolar-membrane ultrastructure were mainly represented by membrane thickening caused by excessive collagen type IV deposition, the major component of the alveolar lamina densa interposed between the epithelial and the endothelial layer.25 These changes are consistent with a remodeling process that, similar to what has been observed in patients with secondary pulmonary hypertension, may be protective against edema development on the one hand and may lengthen the diffusion path and impede gas exchange on the other hand.26 The factors leading to the transition from alveolar stress failure to chronic tissue damage or remodeling are not clearly identified. However, reexpression of fetal genes might play a considerable role.1 Clinical Relevance of Gas Diffusion Abnormalities in Chronic Heart Failure Measurement of lung diffusion capacity for carbon monoxide (DLCO) or nitric oxide (DLNO) is generally used in clinical practice to evaluate the effectiveness of diffusive O2 transport.27 As originally suggested by Roughton and Forster,28 for a given alveolar volume (VA) and hemoglobin concentration, gas diffusion depends on 2 resistances arranged in series according to the following equation:
698 Journal of Cardiac Failure Vol. 14 No. 8 October 2008 1/DLCO 5 1/DM þ 1/qCO Vc, where DM is the alveolar-capillary membrane conductance, qCO is the rate of CO uptake by the whole blood in combination with hemoglobin measured in vitro, and Vc is the lung capillary blood volume. Measurement of DM tracks structural alterations of the alveolar-capillary barrier and is a sensitive method to probe microvascular integrity in health and disease. Vc may increase according to pulmonary capillary wedge pressure. Vc tends to increase in patients with stable HF, but decreases in the advanced stages.29 In a seminal study, Puri et al30 first documented that patients with HF present with a low DLCO according to the disease severity, and this correlates with increased pulmonary vascular resistance. A reduction in the DM component accounted for observed gas diffusing abnormalities. Several subsequent reports11,31e44 have confirmed and expanded these findings. In studies in which VA has been measured, abnormalities in DM remained after DM expression as membrane transfer coefficient (DM/VA). The diffusing capacity is further reduced by comorbidities in which the thickness of the membrane is increased or by chronic obstructive pulmonary disease, caused by the loss of alveolar walls and capillaries, unevenness of ventilation, and diffusion properties. It is remarkable that patients with HF and diabetes comorbidity exhibit a more severe DM impairment than patients with similar hemodynamic dysfunction without diabetes.42 By analyzing these studies, a continuum may be observed of the ultrastructural changes occurring at the alveolar membrane level and the corresponding changes in DLCO, DM, and Vc (Fig 2). DM Determinants in Chronic Heart Failure
Investigators have been interested in whether a reduction in DM in chronic HF is fixed, reflecting sustained microvascular damage, or variable and whether an altered sodium exchange across the pulmonary capillary wall may have a role.7,45 Puri et al41 found that intravenously infused saline 10 mL/kg in patients with chronic HF was associated with a 13% reduction of DM, suggesting that abnormal pulmonary diffusion in chronic HF has a variable component that could be amenable to therapeutic intervention. A subsequent study by our group11 showed that even an amount of saline as small as the lung capillary blood volume (150 mL) infused in the pulmonary artery significantly interferes with DM in patients with chronic HF (and not in normal controls), without affecting the plasma oncotic pressure and right ventricular and LV filling pressures. In the same study, the infusion of an equal amount of 5% glucose solution did not affect DM. Pathophysiologic Correlates
Multiple mechanisms may be involved in shortness of breath and exercise intolerance in chronic HF, and different patients may have varying degrees of limitation in more than 1 mechanism. A debated issue is whether impairment in gas transport at the alveolar epithelial vascular endothelial
junction is significantly involved in causing exercise intolerance.30,41,46,47 The correlation existing between baseline DLCO and peak exercise oxygen uptake (pVO2),30 between DM and the ventilatory equivalent of carbon dioxide production (VE/VCO2),48 and between the improvement in DLCO and pVO2 after enalapril39 are in keeping with the concept that pulmonary diffusion limitation is one of the mediators of exercise impairment in HF. Although arterial blood gases can remain normal during exercise in these patients, an augmented ventilatory drive may be required that maintains or elevates alveolar oxygen tension49 at the expense of an anticipated exhaustion of the ventilatory reserve and an earlier exercise termination. The lack of a significant arterial oxygen desaturation on exercise in patients with HF, however, continues to cast some doubt on a cause and effect relationship between gas diffusion impairment and exercise limitation. Two further considerations, however, argue against a simple association. 1) In patients with HF, despite the fact that pulmonary perfusion (Q) is generally significantly reduced, the ability to appropriately recruit DM for that given Q preserves the DM/Q and prevents significant O2 saturation decreases.50 2) Significant hypoxia on exercise occurs in patients having further DM and DM/Vc reduction during the recovery phase of exercise,51 reflecting development of exercise subclinical pulmonary edema. This condition is reproducible experimentally by acutely infusing an amount of saline solution in the pulmonary circulation of patients with chronic HF, which lengthens the diffusion path for gas exchange and increases the resistance to gas transfer without causing hemodynamic disturbances. In such a study52 it was found that after saline administration (compared with the control condition), DLCO, DM, and pVO2 were reduced, Vc and VE/ VCO2 were increased, changes in DM were positively related with those in pVO2 and inversely related with those in VE/ VCO2, and, even more significant, arterial oxygen saturation was significantly decreased below baseline at peak exercise. No influence of saline on each of these variables was detected in normal subjects. Overall, evidence is in favor of an involvement of lung diffusion capacity and the conductance of the bloodegas barrier in symptoms and exercise limitation of patients with chronic cardiac failure. Interventions Improving Gas Diffusion in Chronic Heart Failure In patients with HF who undergo heart transplantation, diffusion abnormalities may persist despite an improvement in hemodynamic status.53 A relationship has also been established between the time course of the disease and extent of gas transfer alterations.54 Thus, impaired DLCO in chronic disease may not fully depend on a reduction of the global perfusion of the lung but may be related to the persistence of structural changes of the membrane. The clinical significance of this may even be greater, because, in a prospective examination of the lung function prognostic power in HF, DM emerged to be the only independent pulmonary predictor of worse prognosis.55 This section
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↓DLCO ↓↓ DM ↑↑ Vc
↔ DLCO ↓ DM ↑ Vc
↓↓ DLCO ↓↓ DM ↓ Vc
Stress failure
Injury
REVERSIBLE
Remodeling
IRREVERSIBLE
Fig. 2. Time course of changes in alveolar-capillary membrane conductance (DM) and capillary blood volume (Vc) in LV cardiac dysfunction. As detailed in the text, acute hydrostatic injury causes a reduction in DLCO because of a DM impairment and reduction in Vc. When alveolar membrane remodeling ensues, DM further deteriorates and Vc decreases, indicating hemodynamic worsening and lung hypoperfusion. At this stage, there is no evidence of lung tissue damage reversibility. DLCO, lung diffusion capacity for carbon monoxide.
examines whether the alveolar-capillary membrane may be affected and therefore become a potential target for therapy. Pharmacologic Interventions
Davies et al32 documented reduced pulmonary microvascular permeability in patients with severe chronic HF who were taking angiotensin-converting enzyme (ACE) inhibitors. Subsequently, it was reported that DLCO increased from a mean value of 79% to 89% of normal predicted after 15 days of treatment with enalapril in patients with chronic HF.39 Hydralazine-isosorbide dinitrate did not affect DLCO in these patients despite a pulmonary pressure lowering effect similar to that of the ACE inhibitor. In another study56 in which DLCO was partitioned into two subcomponents resistances, DM was proven to be the mediator of the increased diffusion capacity with ACE inhibition, an effect that was evident at 1 and 2 months of treatment. Two additional observations were that cyclooxygenase blockade with the combination of aspirin (daily dose of 325 mg) fully counteracted the benefits of enalapril39,57e59 and that AT1-receptor blockade with losartan58,59 was ineffective on DLCO and DM. Apart from the therapeutic and prognostic implications (the lung function improvement by ACE inhibitors might take part in the overall benefits on survival by this class of drugs), these 2 findings support the concept that the kinin system rather than the angiotensin system is primarily involved in the described effects and enalapril in this particular instance acts as an inhibitor of KII, the enzyme that inactivates circulating bradykinin, thus increasing local kinin concentration. Activation of endothelial B2
kinin receptors leads, via the combined action of phospholipase A2 and cyclooxygenase,60 to enhanced and sustained formation of nitric oxide (NO) and prostacyclin (PGI2),61 2 basic modulators of the pulmonary vascular tone and permeability.62 Thus, ACE inhibitors in chronic HF seem to increase the influences of NO and PGI2 and to reduce the exposure of the pulmonary vessels to angiotensin II. Whether the latter effect will translate into modulation in extracellular matrix synthesis and collagen turnover in the long term is reasonable but still unproven. Lisinopril inhibits angiotensin II-mediated apoptosis and loss of the alveolar epithelial cells,63 and ACE genotype polymorphism modulates pulmonary function and exercise capacity.43 Among the drugs currently being used in HF, spironolactone has been shown to produce some improvement in lung diffusion,64 whereas carvedilol did not affect DLCO and DM in a 6-month study.65 The b1-adrenergic receptor blocker, bisoprolol, has been reported to be beneficial for lung diffusion, possibly because it is devoid of any inhibitory activity on b2-adrenergic receptors located in the alveolar wall.66 In a different manner, b2-adrenergic receptor polymorphisms may control alveolar fluid clearance67 and pulmonary function in patients with HF.68 Drugs stimulating NO overexpression, such as type 5 phosphodiesterase (PDE5) inhibitors, are a promising class of drugs for the treatment of pulmonary hypertension.69 NO activates guanylate cyclase in pulmonary smooth muscle cells, which increases cyclic guanosine monophosphate and decreases intracellular calcium concentration, leading to smooth muscle relaxation. There are good reasons to hypothesize that PDE5 inhibition can positively affect the
700 Journal of Cardiac Failure Vol. 14 No. 8 October 2008 alveolar-capillary membrane conductance in HF. A defective NO release is typical of the syndrome70 and facilitates an increase in pulmonary arterial and venous tone and capillary filtering pressure. NO, similar to vasodilating prostaglandins,62,71 modulates the pulmonary vascular permeability and reduces the tissue component of resistance to O2 transfer from the alveolus to its uptake by hemoglobin. In an acute study of a small cohort of patients with HF, PDE5 inhibition with sildenafil provided a favorable reduction of the alveolar-capillary membrane impedance to gas exchange associated with a decrease in pulmonary pressure and resistance, an improvement in peak VO2, aerobic and ventilatory efficiencies, and oxygen debt.72 In a 6-month study of a larger cohort of similar patients, the efficacy of sildenafil on exercise performance was sustained.73 Diabetes mellitus may be associated with mild and silent impairment in gas exchange function74 because of alveolar and capillary laminae alteration. Patients with diabetes have a 4- to 5-fold increased risk of HF, and diabetes definitely enhances the deterioration of pulmonary gas exchange in HF in case of comorbidity.62 In patients with diabetes, and to a greater extent in those with comorbidity, acute infusion of insulin was associated with a considerable increase of DM and DM/VA, and a reduction of DLCO/ DM. This suggests62 that diabetes exerts a synergistic activity with HF regarding lung injury and that activation of the defective release of substances (eg, NO75 and vasodilating prostaglandins) that modulate the interface resistance to O2 transfer may underlie the pulmonary function improvement by insulin in diabetes alone or combined with HF. Nonpharmacologic Interventions
In addition to structural alterations of the alveolar membrane, an excess of lung interstitial fluid volume may be involved in reducing DM in chronic stable HF. The role of subclinical interstitial fluid accumulation has been probed by monitoring gas exchange variables before and after extracorporeal ultrafiltration, a therapeutic intervention known to reduce lung water content and pulmonary vascular pressure and to improve the clinical condition, exercise capacity, and pulmonary mechanical properties in patients with HF.76 In cases of stable HF and documented low DM, the procedure was effective on mechanical lung properties (ie, improved vital capacity, forced expiratory volume, and maximal voluntary ventilation) by reducing lung fluid content, but it did not affect DLCO and DM. These results suggest that although some lung subclinical interstitial fluid is removed, structural alterations of the alveolar unit retain a critical pathophysiologic key role.77 Interventions aimed at improving systemic endothelial function, such as aerobic exercise training, may also favorably affect gas exchange and pulmonary capillary properties.78 In patients with compensated HF, exercise training (for 8 weeks by stationary cycling, 4 times/week) significantly increased DLCO by 25%, DM by 15%, and peak
VO2 by 13%; reduced VE/VCO2 by 14%; and improved brachial artery flow-mediated dilatation by 71%. There was a significant correlation between the increase of brachial artery flow-mediated dilatation and that of DM. With detraining (8 weeks), all these variables reverted to levels similar to baseline.79 Repeated episodes of increased blood flow with exercise or metabolic effects of training may be the basis for a chronic stimulus to release endothelial paracrine agents that control pulmonary vascular tone and permeability,80 yielding to a facilitated O2 transfer across the alveolar-capillary membrane. This seems to be an additional mechanism whereby exercise training benefits patients with cardiac disease. Conclusions The resistance to gas diffusion across the alveolarcapillary membrane is increased in HF. Disruption of the alveolar anatomic configuration and impairment of cellular pathways involved in the fluideflux regulation and gas exchange efficiency (ie, ‘‘stress failure’’ of the alveolarcapillary membrane) are well characterized in different experimental models of lung capillary injury. Similar changes may distinguish acute HF in humans and may be reversible. In the chronic phase of HF, a reduced alveolar gas conductance is mainly related to structural changes of the membrane that are sustained and seemingly play a significant role in exercise limitation and ventilatory abnormalities. In chronic HF, alterations in gas transfer bring independent prognostic information and may be sensitive to pharmacologic or nonpharmacologic means that potentiate endothelial modulators of vascular tone and permeability, such as NO and PGI2.
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