Alveolar-Capillary Membrane Dysfunction in Heart Failure

Alveolar-Capillary Membrane Dysfunction in Heart Failure* Evidence of a Pathophysiologic Role Marco Guazzi, MD, PhD

Chronic heart failure (CHF) increases the resistance to gas transfer across the alveolar-capillary interface. Recent reports highlight the pathophysiologic relevance of changes in the lung leading to impaired fluid and gas exchange in the distal airway spaces. Under experimental conditions, an acute pressure or volume overload can injure the alveolar blood-gas barrier. This may disrupt its anatomic configuration, cause the loss of regulation of fluid-flux, and thereby affect alveolar gas conductance properties. These ultrastructural changes have been identified under the term of stress failure of the alveolar-capillary membrane. In the short term, these alterations are reversible due to the reparative properties of the alveolar surface. However, when the alveolarcapillary membrane is chronically challenged, for instance in patients with CHF, by noxious stimuli, such as humoral, cytotoxic, and genetic factors other than by mechanical trauma, remodeling of pathophysiologic and clinical importance may take place. These changes in some respects resemble the remodeling process in the heart. Emerging findings support the view that, in patients with CHF, alveolar-capillary membrane dysfunction may contribute to symptom exacerbation and exercise intolerance, and may be an independent prognosticator of clinical course. Angiotensin-converting enzyme inhibitors ameliorate the alveolar membrane gas conductance abnormality, reflecting improvement in the remodeling process. This article reviews the putative mechanisms involved in the impairment in gas diffusion in CHF patients and provides a link between physiologic changes and clinical findings. (CHEST 2003; 124:1090 –1102) Key words: alveolar gas diffusion; exercise; heart failure Abbreviations: ACE ⫽ angiotensin-converting enzyme; AQP ⫽ aquaporin; CHF ⫽ chronic heart failure; CO ⫽ carbon monoxide; Dlco ⫽ lung diffusing capacity for carbon monoxide; DM ⫽ alveolar-capillary membrane ˙ ⫽ perfusion; ␪CO ⫽ rate of conductance; Dmco ⫽ pulmonary membrane diffusing capacity for carbon monoxide; Q carbon monoxide uptake by whole blood; Sao2 ⫽ arterial oxygen saturation; Vc ⫽ pulmonary capillary blood volume available for gas exchange; V˙co2 ⫽ carbon dioxide output; V˙e ⫽ minute ventilation; V˙o2 ⫽ oxygen uptake

has become increasingly apparent that, in paI ttients with chronic heart failure (CHF), the involvement of the respiratory system and the occurrence of gas exchange inefficiency have important clinical and prognostic implications.1– 6 When left ventricular dysfunction develops, the lung circulation and distal airway spaces become susceptible to the untoward hemodynamic backward effects caused *From the Department of Medicine and Surgery, University of Milano, Cardiopulmonary Laboratory, Cardiology Division, San Paolo Hospital, Milano, Italy. Manuscript received April 26, 2002; revision accepted February 4, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Marco Guazzi, MD, PhD, Department of Medicine and Surgery, University of Milano, Cardiopulmonary Laboratory, Cardiology Division, San Paolo Hospital, Via A. di Rudini, 8, 20142 Milano, Italy; e-mail: [email protected] 1090

by elevated left ventricular end-diastolic pressure and pulmonary capillary stasis. With chronic increases in pulmonary venous pressure, pulmonary arteries and veins develop medial hypertrophy and intimal thickening.7,8 Interestingly, the pulmonary vascular bed appears to be a very early target of the regional circulatory alterations occurring in heart failure, as suggested by the experimental evidence that, during the compensated phase of left ventricular dysfunction, as induced by a small myocardial infarction, there is decreased vascular endothelial nitric oxide synthase messenger RNA expression and increased content of collagen and elastin in the pulmonary arterial wall, but not in the aortic wall.9 It is remarkable that, despite the extensive literature on vascular remodeling occurring in pulmonary arteries and veins,7,8 the remodeling of lung capillaries and alveolar spaces (ie, the blood-gas barrier) has been Reviews

largely overlooked. Experimental findings10 have drawn attention to the pathogenetic mechanisms that promote lung tissue damage and cause gas exchange abnormalities. Any nonphysiologic increase in the capillary pressure exposes the alveolar-capillary membrane to so-called stress failure that results in the disruption of the anatomic membrane configuration, alteration of the capillary permeability to water and ions, and altered local regulatory factors important in normal gas exchange. Subsequently, capillary and alveolar remodeling occurs, a process that seems in some respects suggestive of that occurring in the heart. There is abundant evidence that cardiac chamber remodeling is progressive, mainly because of a sequential activation of systemic and local neurohumoral and cytotoxic factors that promote organ tissue damage and loss of contractile performance.11 Remodeling is characterized by intrinsic abnormalities in the function of myocytes, and by an impaired extracellular matrix synthesis and turnover.12 The reexpression of genes that are typical of the fetal life is characteristic.13 That myocardial remodeling may have an anatomic functional equivalent at the level of the capillaries and lung tissues, and that these processes share common pathways of development, is an attractive hypothesis. So far, little is known about the local activation of neurohumoral and cytotoxic factors that can affect lung capillaries, the alveolar wall, and/or the interstitium, and any role played by fetal gene expression.14 This review will focus on these factors in addressing the pathophysiologic mechanisms responsible for an impaired gas exchange in CHF patients.

Physiology of the Alveolar-Capillary Membrane The major physiologic roles of the alveolarcapillary interface are as follows: (1) to allow gas exchange between blood and alveolar air; (2) to regulate the solute and fluid flux between the alveolar surface, interstitium, and blood; and (3) to promote active fluid clearance from the alveolar lumen to the interstitial space. These biological functions are mutually interrelated by the peculiar anatomic configuration of the blood-gas barrier, which is composed of the following three layers: the alveolar epithelium; the capillary endothelium; and the lamina densa, which is interposed between the first two layers. The ultrastructural appearance of the blood-gas barrier clearly shows that one side of the membrane is thinner than the other, and this difference is mainly related to the composition of the interstitium. The thinner side is www.chestjournal.org

involved primarily in the dynamic process of gas diffusion. The thicker portion shows a real basement membrane between the endothelial and epithelial layers. Its principal functions are the control of fluid flux and the regulation of alveolar-capillary membrane permeability. In addition, the thicker part of the interstitium provides a higher resistance against mechanical hydrostatic pressure and fluid swelling. The alveolar epithelium is less permeable than the capillary endothelium and consists of two types of cells. Type I cells provide mechanical support and represent 90% of the total alveolar surface. Type II cells are primarily devoted to surfactant production and can differentiate into type I cells in case of damage. They also have an important role in ion transport across the alveolar functional unit. Under conditions in which hydrostatic forces cause fluid to leak from capillaries, the alveolar epithelium is actively involved in fluid removal from the alveolar space by means of the following two types of channels: the differentiated ENaC channel; and the nonselective cation channel, which is located on the apical surface of type II cells. The ENaC channel is inhibited by substances like amiloride and is stimulated by ␤-adrenergic activation. Water reabsorption is thought to passively follow the osmotic gradient established by the active transport of Na⫹ across the alveolar epithelium, although the pathway followed is not known with certainty. Some of the water flux occurs through aquaporins (AQPs) such as AQP5, which is present on the apical surface of the alveolar type I cells. However, it is likely that at least some of the water flux occurs via a paracellular pathway since water reabsorption can occur even in transgenic mice lacking AQP5.15,16 A Na⫹/glucose cotransport system has been identified, and its activity seems to be species-dependent. It is unimportant for the mouse and more relevant to humans.17 Na⫹ extrusion from the basolateral side of the epithelium is facilitated by the Na⫹/K⫹ adenosine triphosphatase pump, the inhibition of which impairs the alveolar clearance of fluid under various experimental conditions. Efficient alveolar fluid clearance and the restriction of capillary filtration require anatomic and functional integrity of the alveolar epithelium and a normal sodium endothelium permeability. Capillary endothelial cell-cell tight junctions are important for normal functioning of the alveolar-capillary barrier. The junctions are regulated, in part, by the cytoskeletal proteins and Ca2⫹ concentration.18 However, the major permeability barrier for salt and water transport is the epithelium, which is at least an order of magnitude less permeable than the endothelium. According to the Fick law of diffusion, gas transfer across a barrier is directly proportional to its solubility, the total surface area participating in gas exCHEST / 124 / 3 / SEPTEMBER, 2003

1091

change, and the difference in its partial pressure across the membrane, and is inversely proportional to the thickness of the membrane and its molecular weight. The partial pressure of a gas species depends on its partial pressure in the alveolus and the capillary. The latter is determined by the dynamic exchange between the pressure of gas that is free in the plasma and its dissociation from chemical combination (combining power) with substances in the blood, such as hemoglobin. Thus, O2 diffusion depends on the following: (1) the alveolar ventilation/capillary perfusion ratio, which establishes the partial pressure gradient of O2 between alveolus and plasma; (2) the physical characteristics of the alveolar-capillary interface; (3) the capillary blood volume available for gas exchange; (4) the hemoglobin concentration; and (5) the reaction rate between O2 and hemoglobin. The diffusion characteristics of the lung are commonly assessed by using tests of carbon monoxide (CO) transfer.19 CO diffuses across the alveoli and binds to hemoglobin with a 240-fold greater affinity than O2. As a consequence, the pressure gradient remains maximal and the amount of CO taken up in the circulation depends primarily on the diffusion characteristics of the membrane. In addition, because of its strong affinity for hemoglobin, there is no significant plasma CO back-pressure. As described by the classic work of Roughton and Forster,20 the diffusing capacity of the lung for CO (Dlco) depends on two resistances arranged in series according to the following equation: 1 1 1 ⫽ ⫹ Dlco Dmco ␪CO ⫻ Vc where pulmonary membrane diffusing capacity for CO (Dmco) is the CO conductance across the alveolar-capillary tissue membrane and plasma barrier, ␪CO is the rate of CO uptake by whole blood and in combination with hemoglobin measured in vitro, and Vc is the pulmonary capillary blood volume. In healthy subjects, resistances of the membrane and erythrocyte components contribute almost equally to the overall diffusive resistance across the lung. Since O2 and CO compete for the same heme binding site, ␪CO is inversely related to alveolar O2 tension and is directly related to hemoglobin concentration. Dmco and Vc can be estimated from Dlco measured at two or more expired O2 tensions. Pathophysiology of the AlveolarCapillary Membrane Injury From Left Ventricular Failure When the heart is failing, the integrity of the lung capillaries is challenged by at least two factors: 1092

increased pressure and increased volume (ie, distension and recruitment). The consequences of a nonphysiologic abrupt rise in capillary pressure and the failure of the membrane to withstand physical stress have been characterized by West.21 In isolated preparations, acute stepwise increases of the pulmonary intracapillary pressure produce an increasing number of breaks at the level of the capillary endothelium and of the alveolar epithelium, starting from a pressure of approximately 24 mm Hg.22 This leads to a progressive transition from a low-permeability form of alveolar edema toward a high-permeability form. In a recent study, Conforti et al23 reproduced the morphometric alveolar changes occurring immediately after a controlled volume overload in a rabbit model preparation (ie, 180 min of saline solution infusion at 0.5 mL/min/ kg). The morphometric analysis obtained in the very early postinfusion phase showed that 44% of the fluid was partitioned in the extravascular spaces and that 85% of this was localized in the thicker portion of the membrane. This short-term effect causes transient ultrastructural changes and significant impairment in gas diffusion. There is, however, documentation24 that most of the ultrastructural changes observed during acute mechanical injury are reversible. Studies conducted in animals with paceinduced CHF, and thereby with chronic membrane stress failure, showed that alveolar-capillary membrane thickness was significantly increased compared to controls. This thickness was due mainly to the excessive deposition of collagen type IV (the major component of the alveolar-capillary membrane lamina densa)25 (Fig 1). This is similar to findings reported in patients with mitral stenosis26 and pulmonary venous hypertension,27 in whom the increased thickness of the extracellular matrix accounts for the more important structural changes. An increased collagen content has been interpreted as being protective against the increased amount of fluid leaking across the alveolar-capillary membrane permeability.21,25 In this regard, an attractive hypothesis has been proposed recently based on isolated experimental evidence, which suggests that during chronic capillary hydrostatic elevation, an increase in lung interstitial connective tissue would cause a parallel increase in extravascular fluid accumulation, given the high capability of the extracellular matrix components (mainly glycosaminoglycans) to absorb and hold fluid in the interstitial space. At least in conditions of subcritical, chronic, left atrial pressure elevation, this mechanism could be protective in restraining the fluid in the extravascular interstitial spaces with no or little interference with gas diffusion between alveolar-capillary blood and alveolar gas.28 Reviews

Figure 1. Electron micrograph images of the alveolar-capillary membrane obtained from a control dog (left, A) and after 4 weeks (middle, B) or 7 to 8 weeks (right, C) of long-term pacing therapy. The images show the qualitative difference in the basement membrane thickness. In particular, the arrow (middle, B) shows the better delineation of the basement membrane after 4 weeks. Adapted from Tomsley et al.25

Overall, the anatomic changes that take place in the alveolar-capillary unit lead to an increased resistance across the membrane and impair gas transfer. An additional factor that has been shown to specifically affect the extracellular matrix composition is the alveolar hypoxic stimulus. This promotes vascular remodeling in lung parenchyma by increasing the gene expression of extracellular matrix proteins.29 A crucial question is whether structural changes are the only reason for the excessive gas exchange impedance observed in patients with CHF, or whether local, hormonal, cytotoxic, or, possibly, genetic factors lead to further functional alterations that could impair alveolar fluid clearance and capillary sodium transport, and could increase alveolar-capillary membrane permeability. Angiotensin II promotes inappropriate apoptotic alveolar epithelial cell death.30 Likewise, norepinephrine induces alveolar epithelial apoptosis through a combined stimulation of ␣adrenoreceptors and ␤-adrenoreceptors followed by the autocrine generation of angiotensin II.31 Cellular growth factors and proinflammatory cytokines, particularly tumor necrosis factor-␣, also have been observed to alter the permeability of the membrane and to up-regulate Na⫹ and water transport.32,33 In cultured epithelial cells,34 hypoxia down-regulates the expression and activity of Na⫹ channels and Na⫹/K⫹ adenosine triphosphatase. In rats, hypoxia has been shown to impair transalveolar fluid transport.35,36 The pathophysiologic sequelae of the above factors are only partially known in the setting of CHF. However, they may reflect a multistep process that is similar to that observed when the heart muscle fails. A proposed schema of changes that take place in CHF leading to blood-gas barrier remodeling is www.chestjournal.org

shown in Figure 2. Experimental findings suggest that, in CHF patients, a dysregulation of sodium handling correlates with the structural alterations occurring in the alveolar-capillary interface.17 The investigation, on a clinical basis, of the interplay and the relative contribution of these factors in disturbing fluid metabolism is a very difficult task. If an elongation of the diffusion path causes a decrease in Dlco and alveolar-capillary membrane conductance (DM), then an infusion of specified volumes of saline solution could be used as a challenge to quantify endothelial Na⫹ permeability and/or the relative clearance of Na⫹ and water from the alveoli. In studies in patients with mild CHF37 or moderate CHF,38 changes in DM following the infusion of 0.9% saline solution were taken as indexes of the filtered fluid from the pulmonary capillaries. The infusion of an amount of saline solution (ie, 150 mL) that is equivalent to the lung capillary blood volume in a supine man produced small but significant decreases of Dlco and DM compared to those in control subjects.38 The effect was somewhat greater after the infusion of a fivefold larger amount of saline solution (ie, 750 mL). Notably, hemodilution or hydrostatic effects were not significant following the infusion of 150 mL (Table 1). The absence of changes in DM following the infusion of equal amounts of a sodium-free solution (5% glucose) further supports the view that CHF is associated with an increased permeability of the vascular endothelium to Na⫹, which can impair gas exchange by increasing the alveolar interstitium thickness. Presumably, an excessive hydrostatic load would initiate the alveolar-capillary membrane disruption that leads to alveolar-capillary remodeling, and to a disCHEST / 124 / 3 / SEPTEMBER, 2003

1093

Figure 2. Proposed scheme for the sequential changes that in CHF patients lead to the development of the blood-gas barrier remodeling process. Hemodynamic backward untoward effects of left ventricular dysfunction expose the alveolar membrane to a stress-failure process. In the acute cases, stress failure is reversible. In the long term, a combination of additional factors, other than the mechanical ones, such as neurohumoral cytotoxic and genetic factors, further injure lung capillaries and alveolar spaces, leading to a remodeling process, which is characterized by increased collagen synthesis with thickening of the alveolar-capillary membrane, loss of endothelial permeability, and impairment in the cellular mechanisms involved in fluid reabsorption. This, in turn, leads to an increased path for gas exchange. The changes described reflect local tissue damage, a clear reversibility of which has been documented under acute stress and not after the alveolar-capillary membrane has been exposed to chronic injury. TNF␣ ⫽ tumor necrosis factor-␣.

ordered salt and water metabolism. An alternative intriguing interpretation of these findings is that CHF induces the expression of genes encoding for fetal messenger RNA. During fetal life, Na⫹ channels work in a reverse direction, allowing for fluid movement from the capillary to the alveolar space.39 1094

Information regarding the Na⫹ and water pump transport system in the lungs in CHF is lacking, but the occurrence of a specific local regulatory disruption of these mechanisms as a part of the cellular abnormalities that characterize the syndrome could be reasonably suspected. Reviews

Table 1—Effects of Different Amounts of 0.9% Saline Solution Infusion on Variables in Healthy Control Subjects and CHF Patients* Control Subjects Variables Hemoglobin Hematocrit Plasma protein concentration Dlco DM Vc Wedge pressure

CHF Patients

150 mL 750 mL 150 mL 750 mL ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

2 2 2 ⫽ ⫽ ⫽ ⫽

⫽ ⫽ ⫽ 2 2 1 ⫽

2 2 2 2 2 1 ⫽

*The arrow indicates changes that are statistically significant compared to baseline condition, and equal sign indicates equivalence. Adapted from Guazzi et al.38

Clinical Correlates of the Alveolar Gas Diffusion Abnormalities Pulmonary abnormalities can explain part of the symptoms and functional disability encountered in patients with CHF syndrome. Puri et al3 first documented that CHF patients present with a reduction in Dlco that is proportional to the severity of the disease. The reduction depended specifically on a worsening of the DM component rather than on changes in capillary blood volume (Fig 3). Subsequent reports2,4 – 6 have confirmed and expanded these findings. In a recent study by our group,40 the possibility was explored that some subsets of CHF patients are more likely to be exposed to the risk of developing alveolar-capillary damage than are others. We focused on patients with type 2 diabetes mellitus and CHF, with the hypothesis that this comorbidity may potentiate lung dysfunction and gas exchange abnormalities. In fact, diabetes increases the likelihood of the development of CHF and, even when patients with prior coronary or rheumatic heart disease are excluded, diabetic subjects have a fourfold to fivefold increased risk of CHF,41 suggesting that these patients are more likely to develop respiratory dysfunction. In patients with diabetes, a major putative role seems to be played by microangiopathy or nonenzymatic glycosylation of tissue proteins that thicken the alveolar epithelial and basal laminae.42 This might alter lung mechanics and gas exchange independently of myocardial dysfunction.43 In 20 New York Heart Association class II to III CHF patients with type 2 diabetes, Dlco and its subcomponents, DM and Vc, were investigated and compared to those in 20 nondiabetic CHF patients with similar hemodynamic dysfunction and those in 20 healthy control subjects. As shown in Figure 4, Dlco was decreased in the CHF patients without diabetes, and were www.chestjournal.org

further decreased in the CHF patients with diabetes compared to control subjects. There was no overlapping of Dlco and DM between patients with comorbidity and control subjects.40 In other studies, we found that insulin improves Dlco and DM in diabetic patients,44 and to a significantly greater extent in those with comorbidity.45 In contrast, insulin had no or little effect on patients with CHF of similar severity, but without diabetes. These findings place emphasis on a new aspect of insulin therapeutic properties. The hormone, in fact, seems to be protective by attenuating the diabetes-mediated component of lung microangiopathy that in the presence of left ventricular dysfunction is emphasized and exerts more than an additive effect. Interestingly, the beneficial influence of insulin on Dlco has been found to translate into an improved peak exercise O2 uptake (V˙o2) and in a reduced excessive ventilatory response to exercise, expressed as minute ventilation (V˙e) per unit of carbon dioxide output (V˙co2) slope.46 In these reports and in that by Puri et al,3 abnormalities in DM persisted even after correction for alveolar volume,47 suggesting that the concomitant reduction in lung volumes, often observed in these patients, is unlikely to be a major factor. Several studies3,6,48,49 support the concept that abnormalities in lung diffusion contribute to the symptoms and exercise limitations in CHF patients, as follows: (1) gas diffusion is impaired as a result of the reduction in global lung perfusion and in the alveolar-capillary conductance3– 6,48; (2) DM at rest3,40 and relative changes when exercising48 strongly correlate with peak V˙o2; (3) Dlco is lower in patients than in control subjects after maximal exercise50; (4) an abnormal DM correlates with an increased V˙e/V˙co2 slope.40,48 In addition, in heart transplant recipients the persistence of abnormalities in gas diffusion has been identified as a possible contributory factor for the reduced exercise capacity in these patients.51,52 Despite this evidence, a significant diffusion limitation is not universally accepted as being important in CHF patients, based on the fact that CO2 diffuses much more easily than O2 and that arterial O2 tension generally remains normal during exercise.53,54 In order to define the contribution of lung diffusion impairment to exercise intolerance in CHF patients, there is a need to measure peak V˙o2 and V˙e/V˙co2 slope after specific interventions that affect Dlco, DM, and Vc.6,49 As described above, a short-term saline solution infusion was used as a method to increase the resistance to gas transfer. Acute variations in gas exchange produced by this experimental condition were correlated with the concomitant changes occurring in V˙e/V˙co2 slope and peak V˙o2. Infusion of 150 mL saline solution CHEST / 124 / 3 / SEPTEMBER, 2003

1095

Figure 3. Individual results and mean values for Dlco, DM, and Vc in CHF patients in New York Heart Association (NYHA) classes I, II, and III. * ⫽ p ⬍ 0.05; *** ⫽ p ⬍ 0.0001 vs normal subjects; † ⫽ p ⬍ 0.05; †† ⫽ p ⬍ 0.01; ††† ⫽ p ⬍ 0.001. Adapted from Puri et al.3 1096

Reviews

Figure 4. Individual results and mean values of Dlco, DM and Vc, expressed in absolute values (left) and per unit alveolar gas volume (right) in control subjects and in Group 1 (CHF) and 2 (CHF⫹diabetes) patients. Numbers in parentheses are percentages of predicted normal values. * ⫽ p ⬍ 0.01; NIDDM ⫽ noninsulin-dependent diabetes mellitus; Va ⫽ alveolar volume. Adapted from Guazzi et al.40

significantly decreased Dlco (decrease, 8.8%) and DM (decrease, 9.8%), and significantly enhanced the total diffusive resistance due to the membrane component (Dlco/DM increase, 7.5%) in CHF patients but not in healthy control subjects. The infusion of 750 mL saline solution was somewhat more effective (Dlco decrease, 9.4%; DM decrease, 17.5%; Dlco/DM increase, 15.2%). These changes were associated with a reduced peak V˙o2 (150-mL infuwww.chestjournal.org

sion, 9.4%; 750-mL infusion, 11.5%), a steeper V˙e/ V˙co2 slope (150-mL infusion, 9.8%; 750-mL infusion, 14.6%), and some degree of arterial O2 desaturation during exercise (150-mL infusion, 3.7%; 750-mL infusion, 5.3%). DM variations from baseline values with saline solution infusion were significantly related with those in peak V˙o2 and V˙e/V˙co2 slope.55 Thus, a depression in DM, even if slight, decreases exercise performance and ventilaCHEST / 124 / 3 / SEPTEMBER, 2003

1097

tory efficiency in CHF patients, supporting the implication of lung diffusion abnormalities in the pathophysiology of exercise intolerance in these patients. An interpretation of these data may be that diffusion increases during exercise through the recruitment of the pulmonary vascular bed, which is underperfused at rest, in healthy persons. This decreases the resistance of the alveolar capillary interface, which is thinned by pulmonary capillary distension.56 The ability to appropriately recruit DM and ˙ ) ratio is critical for match the DM/perfusion (Q maintaining a normal arterial O2 saturation (Sao2). ˙ may be severely impaired. In CHF patients, Q ˙ , DM recruitAlthough DM is reduced at a given Q ˙ ratio remains ment is normal. The exercise DM/Q above the critical threshold for maintaining a normal Sao2. In addition, an augmented ventilatory drive is required that maintains or elevates alveolar O2 tension at the expense of an anticipated exhaustion of the ventilatory reserve57,58 and of an earlier exercise interruption. The development of a degree of subclinical pulmonary edema during exertion is expected to impede gas exchange, to increase V˙e/V˙co2 slope, and to affect peak V˙o2. The further lowering of DM with saline solution infusion limits its recruitment during exercise and implies that O2 diffusion decreases, so as to interfere with exercise Sao2.

Alveolar-Capillary Membrane as a Therapeutic Target in CHF Despite the increasing evidence of a pathophysiologic role, little attention has been paid to the alveolar-capillary membrane as a specific target of anti-CHF therapies. The issue was first raised when clinicians became aware of the different efficacy of anti-CHF treatments on abnormalities in lung volumes compared to those in gas exchange. The major airway dysfunctions commonly seen in CHF patients may be improved by tailored drug therapies59 or fluid withdrawal with ultrafiltration,60 and may be fully reversed by heart transplantation.61 However, the Dlco remains low after heart transplantation50,51,61– 64 despite a substantial improvement in pulmonary hemodynamics and lung volumes. This suggests that a reduction of Dlco in CHF patients may reflect the presence of irreversible damage to the alveolar capillary interface. In some cases, a paradoxical decline in Dlco has been reported following heart transplantation because of an increase in intracapillary resistance. This might be due to a combination of anemia and reduced pulmonary capillary blood volume, with the diffusing capacity of the membrane remaining unchanged.64 In a large number of CHF patients, Ewert et al61 1098

have demonstrated that pulmonary gas transfer remains abnormal for up to several years after transplantation. This further supports the hypothesis that a reduction in DM may reflect the presence of a fixed structural damage of the blood-gas barrier. In another report,6 DM changes were found to be related directly to disease severity. Thus, it has been suggested that their reversibility might depend on the disease time course.6 In a prospective survival study, in which the prognostic power of lung volumes, DM, and Vc were investigated, DM was the only independent pulmonary predictor of worse prognosis in CHF patients.2 Patients who are at high risk for adverse outcome were identified by a DM of ⬍ 24.7 mL/min/mm Hg (Fig 5). These observations suggest that changes in the alveolar-capillary unit, more than those in airway motility, reflect a marker of tissue-specific organ damage that yields pathophysiologic and prognostic significance when multiorgan failure develops in CHF patients. Despite the absence of clear evidence of a complete Dlco and DM reversibility with treatment, a favorable modulatory activity on the DM properties by angiotensin-converting enzyme (ACE) inhibition in CHF patients has been reported.4,65– 67 An effect that becomes evident a few days after starting enalapril therapy (20 mg/d)4 persists over time,65 is unrelated to simply lowering pulmonary capillary pressure,4,66 and seems to be involved in the improvement of survival produced by this class of drugs.2 Mechanisms that underlie the improvement with ACE inhibitors may be a modulation in extracellular matrix synthesis and collagen turnover,68 as well as an improvement in endothelial capillary permeability4 and an increased alveolar epithelial reabsorption of Na⫹ and fluid.67 Exposure of alveolar epithelial cells to the ACE inhibitor lisinopril has been found to inhibit angiotensin II-mediated apoptosis and cell loss.31 However, in CHF patients, there is evidence that the bradykinin pathway and an increased level of prostaglandin release are involved in improving gas exchange. Consistently, ACE inhibition effects on Dlco are attenuated by blocking the vasodilator prostaglandins with a cyclooxygenase inhibitor, and the angiotensin type 1 receptor blocker losartan does not provide the same benefits as enalapril on Dlco and DM.67,69 It is noteworthy that the changes observed in Dlco with ACE inhibition correlate with those in peak V˙o2 and suggest a role in improving the exercise capacity of these patients. This is also substantiated by the observation that there are links among ACE genotype, Dlco, and exercise capacity in CHF patients. Findings from Abraham et al,70 in fact, show that, despite ACE inhibition, patients with a DD ACE genotype, compared to those with an ID Reviews

Figure 5. Kaplan-Meier curves of DM. The data were analyzed according to the 66th and 33rd percentile cutoffs. The three following curves were identified: dotted line ⫽ patients with a DM of ⬎35 mL/min/mm Hg; broken line ⫽ patients with a DM of ⱖ 24.7 to ⱕ 35.3 mL/min/mm Hg; continuous line ⫽ patients with a DM of ⱕ 24.7 mL/min/mm Hg. The difference between patients with a DM of ⬎ 35 mL/min/mm Hg and patients with a DM of ⱕ 24.7 mL/min/mm Hg was statistically significant (p ⫽ 0.007). The difference between patients with a DM of ⱖ 24.7 to ⱕ 35.3 mL/min/mm Hg and patients with a DM of ⱕ 24.7 mL/min/mm Hg was not statistically significant, but a clear trend was observed. df ⫽ degrees of freedom. Adapted from Guazzi et al.2

and II genotype, present with higher plasma ACE levels, and lower Dlco and peak V˙o2. This has a fundamental relevance in terms of therapeutic opportunities. An immediate implication is that CHF patients with the ACE DD genotype are more likely to benefit from higher doses of ACE inhibitors than those ordinarily prescribed. As to anti-CHF therapies, it is tempting to establish a parallelism between the benefits to the lungs, such as membrane remodeling, and those to the heart, such as cardiac remodeling. This parallel effect on these two organs might be true for therapy with ACE inhibitors, but does not seem to be the same for therapy with ␤-blockers. In this case, despite an ability to reverse myocardial remodeling, no improvement in Dlco and DM were observed in a 6-month follow-up of CHF patients who had been treated with carvedilol,71 suggesting that a beneficial effect to the heart will not necessarily improve the microangiopathy of the lungs. The antiarrhythmic drug amiodarone, and its metabolite desethylamiodarone, are known to induce pulmonary toxicity, which has been shown to be related in part to the induction of both alveolar www.chestjournal.org

epithelial cells necrosis and apoptosis.72 Nonetheless, the only clinical investigation73 available on the effects of amiodarone on Dlco in CHF patients has ruled out a potential for a drug-induced abnormality to Dlco. This somewhat surprising finding is consistent with the in vitro demonstration that the combined administration of amiodarone with the ACE inhibitor captopril significantly inhibited apoptosis and net cell loss.72

Summary Any excessive increase in the lung capillary pressure and/or volume exposes the alveolar-capillary membrane to a mechanical injury. This can lead to disruption of the alveolar-capillary membrane, disturbances in capillary permeability to water and ions, and impairment in the gas exchange process. Complete reversibility can occur following an acute event, thanks to the high alveolar reparative properties. Conversely, when the blood-gas barrier is challenged in the long term, as is the case in CHF patients, remodeling takes place in the lungs that acquires CHEST / 124 / 3 / SEPTEMBER, 2003

1099

pathophysiologic and clinical relevance. These changes, in some respects, resemble the remodeling process in the heart. In these patients, an abnormal lung diffusing capacity is commonly found. Specifically, the finding of an impaired DM has been recently identified as a powerful independent prognosticator of survival. Alveolar diffusion abnormalities are directly related to the severity and duration of the disease. Heart transplantation and normalization of pulmonary hemodynamics does not promote any improvement in DM properties and gas exchange, possibly reflecting fixed structural changes that involve primarily the extracellular matrix. The therapeutic benefits of ACE inhibitors on these abnormalities seem to result from bradykinin pathway overexpression. The effects of other antiCHF treatments on gas exchange have been underinvestigated. A better understanding of the mechanisms involved in alveolar-capillary membrane remodeling and the consequent development of new therapeutic strategies will clarify its pathophysiologic role in CHF syndrome. ACKNOWLEDGMENT: The invaluable contribution of Professor Karlman Wasserman, MD, PhD, in reviewing the manuscript is deeply appreciated.

References 1 Johnson RL Jr. Gas exchange efficiency in congestive heart failure. Circulation 2000; 101:2774 –2776 2 Guazzi M, Pontone G, Brambilla R, et al. Alveolar-capillary membrane conductance: a novel prognostic indicator in heart failure. Eur Heart J 2002; 23:467– 476 3 Puri S, Baker BL, Dutka DP, et al. Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure: its pathophysiological relevance and relationship to exercise performance. Circulation 1995; 91:2769 –2774 4 Guazzi M, Marenzi G, Alimento M, et al. Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997; 95:1930 –1936 5 Assayag P, Benamer H, Aubry P, et al. Alteration of the alveolar-capillary membrane diffusing capacity in chronic left heart failure. Am J Cardiol 1998; 82:459 – 464 6 Mettauer B, Lampert E, Charloux A, et al. Lung membrane diffusing capacity, heart failure and heart transplantation. Am J Cardiol 1999; 83:62– 67 7 Reid L. The pulmonary circulation: remodeling in growth and disease. Am Rev Respir Dis 1979; 119:531–546 8 Harris P, Heath D. Structural changes in the lung associated with pulmonary venous hypertension. In: Harris P, Heat D, eds. Human pulmonary circulation. New York, NY: Churchill Livingstone, 1986; 329 –342 9 Driss AB, Devaux C, Henrion D, et al. Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation 2000; 101:2764 –2770 10 West JB, Mathieu-Costello O. Vulnerability of pulmonary capillaries in heart disease. Circulation 1995; 92:622– 631 11 Cohn JN. Structural basis for heart failure: ventricular remodeling and its pharmacological inhibition. Circulation 1995; 91:2504 –2507 1100

12 Weber KT. Targeting pathological remodeling: concepts of cardioprotection and reparation. Circulation 2000; 102:1342– 1345 13 Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 1999; 341:1276 –1283 14 Lin MC, Rockman HA, Chien KR. Heart and lung disease in engineered mouse: technological miniaturization combined with the power of molecular genetics make the mouse a model animal for understanding human cardiovascular and pulmonary disease. Nat Med 1995; 1:749 –751 15 Ma T, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest 2000; 105:93–100 16 Verkman AS, Matthay MA, Song Y. Aquaporin water channels and lung physiology. Am J Physiol 2000; 278:L867–L879 17 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:L487–L503 18 Dudek SM, Garcia JGN. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol 2001; 91:1487– 1500 19 American Thoracic Society. Single-breath carbon monoxide diffusing capacity: recommendation for a standard technique; 1995 update. Am J Respir Crit Care Med 1995; 152:2185– 2198 20 Roughton FJW, Forster FE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in human lung, with special reference to true diffusing capacity of blood in the lung capillary. J Appl Physiol 1957; 11:290 –302 21 West J. Pulmonary capillary stress failure. J Appl Physiol 2000; 89:2483–2489 22 Tsukimoto K, Mathieu-Costello O, Prediletto R, et al. Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J Appl Physiol 1991; 71:573–582 23 Conforti E, Fenoglio C, Bernocchi G, et al. Morphofunctional analysis of lung tissue in mild interstitial edema. Am J Physiol 2002; 282:L766 –L774 24 Elliott AR, Fu Z, Tsukimoto K, et al. Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure. J Appl Physiol 1992; 23:1150 –1158 25 Tomsley MI, Fu Z, Mathieu-Costello O, et al. Pulmonary microvascular permeability; responses to high vascular pressure after induction of pacing induced heart failure in dogs. Circ Res 1995; 77:317–325 26 Kay JM, Edwards FR. Ultrastructure of the alveolar capillary wall in mitral stenosis. J Pathol 1973; 111:239 –245 27 Lee JS. Electron microscopic studies on the alveolar-capillary barrier in patients with chronic pulmonary edema. Jpn Circ J 1979; 43:945–954 28 Drake RE, Doursout MF. Pulmonary edema and elevated left atrial pressure: four hours and beyond. News Physiol Sci 2002; 17:223–226 29 Berg JT, Breen EC, Fu Z, et al. Alveolar hypoxia increases gene expression of extracellular matrix proteins and plateletderived growth factor-B in lung parenchyma. Am J Respir Crit Care Med 1998; 158:1920 –1928 30 Filippatos G, Tilak M, Pinillos H, et al. Regulation of apoptosis by angiotensin II in the heart and lungs. Int J Mol Med 2001; 7:273–280 31 Dincer HE, Gangopadhyay N, Wang R, et al. Norepinephrine induces alveolar epithelial apoptosis mediated by alpha-, beta-, and angiotensin receptor activation. Am J Physiol 2001; 281:L624 –L630 32 Hocking DC, Phillips PG, Ferro TJ, et al. Mechanism of pulmonary edema induced by tumor necrosis factor-␣. Circ Res 1990; 67:68 –77 Reviews

33 Fukuda N, Jayr C, Lazrak A, et al. Mechanisms of TNF-␣ stimulation of amiloride-sensitive sodium transport across alveolar epithelium. Am J Physiol 2001; 280:L1258 –L1265 34 Clerici C, Matthay MA. Hypoxia regulates gene expression of alveolar epithelial transport proteins. J Appl Physiol 2000; 88:1890 –1896 35 Suzuki S, Noda M, Sugita M, et al. Impairment of transalveolar fluid transport and lung Na(⫹)-K(⫹)-ATPase function by hypoxia in rats. J Appl Physiol 1999; 87:962–968 36 Hardiman KM, Matalon S. Modification of sodium transport and alveolar fluid clearance by hypoxia: mechanisms and physiological implications. Am J Respir Cell Mol Biol 2001; 25:538 –541 37 Puri S, Dutka DP, Baker BL, et al. Acute saline infusion reduces alveolar-capillary membrane conductance and increases airflow obstruction in patients with left ventricular dysfunction. Circulation 1999; 99:1190 –1196 38 Guazzi M, Agostoni P, Bussotti M, et al. Impeded alveolarcapillary gas transfer with saline infusion in heart failure. Hypertension 1999; 34:1202–1207 39 Matalon S, O’Brodovich H. Sodium channels in alveolar epithelial cells: molecular characterization, biophysical properties, and physiological significance. Annu Rev Physiol 1999; 61:627– 661 40 Guazzi M, Brambilla R, Pontone G, et al. Effect of noninsulin-dependent diabetes mellitus on pulmonary function and exercise tolerance in chronic congestive heart failure. Am J Cardiol 2002; 89:191–197 41 Savage MP, Krolewski AS, Kenien GG, et al. Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor. Am J Cardiol 1988; 62:665– 669 42 Wracko R. A comparison of the microvascular lesions in diabetes mellitus with those of normal ageing. J Am Geriatr Soc 1982; 30:201–205 43 Mori H, Okubo M, Okamura M, et al. Abnormalities in pulmonary function in patients with non-insulin-dependent diabetes mellitus. Intern Med 1992; 31:189 –193 44 Guazzi M, Oreglia I, Guazzi MD. Insulin improves the alveolar-capillary membrane gas conductance in type 2 diabetes mellitus. Diabetes Care 2002; 25:1802–1806 45 Guazzi M, Brambilla R, De Vita S, et al. Diabetes worsens alveolar-capillary gas diffusion and insulin contrasts this effect. Am J Respir Crit Care Med 2002; 166:978 –982 46 Guazzi M, Tumminello G, Guazzi MD. Insulin improves exercise ventilatory efficiency and exercise oxygen uptake in patients with heart failure and type 2 diabetes [abstract]. Circulation 2002; 106:II-646 47 Johnson DC. Importance of adjusting carbon monoxide diffusing capacity (Dlco) and carbon monoxide transfer coefficient (KCO) for alveolar volume. Respir Med 2000; 94:28 –37 48 Smith AA, Cowbum PJ, Parker ME. Impaired pulmonary diffusion during exercise in patients with chronic heart failure. Circulation 1999; 100:1406 –1410 49 Kraemer MD, Kubo SH, Rector TS, et al. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol 1993; 21:641– 648 50 Messner-Pellenc P, Brasileiro C, Ahmaidi S, et al. Exercise intolerance in patients with chronic heart failure: role of pulmonary diffusing limitation. Eur Heart J 1995; 16:201–209 51 Braith RW, Limacher MC, Millis RM Jr, et al. Exerciseinduced hypoxemia in heart transplant recipient. J Am Coll Cardiol 1993; 22:768 –776 www.chestjournal.org

52 Al Rawas OA, Carter R, Stevenson RD, et al. Exercise intolerance following heart transplantation: the role of pulmonary diffusing capacity impairment. Chest 2000; 118: 1661–1670 53 Rubin SA, Brown HV, Swan HJ. Arterial oxygenation and arterial oxygen transport in chronic myocardial failure at rest, during exercise and after hydralazine treatment. Circulation 1982; 66:143–148 54 Clark AL, Coats AJS. Usefulness of arterial blood gas estimations during exercise in patients with chronic heart failure. Br Heart J 1994; 71:528 –530 55 Guazzi M, Agostoni PG, Guazzi MD. Alveolar-capillary gas exchange and exercise performance in heart failure. Am J Cardiol 2001; 88:452– 457 56 Hsia CCW. Recruitment of lung diffusing capacity: update of concept and application. Chest 2002; 122:1774 –1783 57 Sullivan M, Higginbotham M, Coob F. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988; 77:552–559 58 Wasserman K, Zhang YY, Gitt A, et al. Lung function and exercise gas exchange in chronic heart failure. Circulation 1997; 96:2221–2227 59 Light R, George R. Serial pulmonary function in patients with acute heart failure. Arch Intern Med 1983; 143:429 – 433 60 Agostoni PG, Guazzi M, Bussotti M, et al. Lack of improvement of diffusing lung capacity following fluid withdrawal by ultrafiltration in chronic heart failure. J Am Coll Cardiol 2000; 36:1600 –1604 61 Ewert R, Wensel R, Bettmann M, et al. Ventilation and diffusion abnormalities in long-term survivors after orthotopic heart transplantation. Chest 1999; 115:1305–1314 62 Hosenpud JD, Stibolt TA, Atval K, et al. Abnormal pulmonary function specifically related to congestive heart failure: comparison of patients before and after cardiac transplantation. Am J Med 1990; 88:493– 496 63 Ohar J, Osterloh J, Ahmed N, et al. Diffusing capacity decreases after heart transplantation. Chest 1993; 103:857– 861 64 Al-Rawas OA, Carter R, Stevenson RD, et al. Mechanisms of pulmonary transfer factor decline following heart transplantation. Eur J Cardiothorac Surg 2000; 17:355–361 65 Guazzi M, Melzi G, Marenzi GC, et al. Angiotensin-converting enzyme inhibition facilitates alveolar-capillary gas transfer, and improves ventilation/perfusion coupling in patients with left ventricular dysfunction. Clin Pharmacol Ther 1999; 65:319 –327 66 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; 96:17–22 67 Guazzi M, Agostoni PG, Guazzi MD. Modulation of alveolarcapillary 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; 37:398 – 406 68 Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol 1997; 17: 467– 491 69 Guazzi M, Melzi G, Agostoni PG. 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; 80:1572–1576 CHEST / 124 / 3 / SEPTEMBER, 2003

1101

70 Abraham MR, Olsen LJ, Joyner MJ, et al. Angiotensinconverting enzyme genotype modulates pulmonary function and exercise capacity in treated patients with congestive stable heart failure. Circulation 2002; 106:1794 –1799 71 Guazzi M, Agostoni PG, Pontone G, et al. Pulmonary function, cardiac function and exercise capacity in a follow-up of congestive heart failure patients treated with carvedilol. Am Heart J 1999; 138:460 – 467

1102

72 Bargout R, Jankov A, Dincer E, et al. Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro. Am J Physiol 2000; 278:L1039 –L1044 73 Singh SN, Fisher SG, Deedwania PC, et al. Pulmonary effect of amiodarone in patients with heart failure: the congestive heart failure-survival trial of antiarrhytmic therapy (CHF-STAT) investigators. J Am Coll Cardiol 1997; 30: 514 –517

Reviews