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
conductance; Dmco ⫽ pulmonary membrane diffusing capacity for carbon monoxide; Q̇ ⫽ perfusion; ␪CO ⫽ rate of
carbon monoxide uptake by whole blood; Sao2 ⫽ arterial oxygen saturation; Vc ⫽ pulmonary capillary blood volume
available for gas exchange; V̇co2 ⫽ carbon dioxide output; V̇e ⫽ minute ventilation; V̇o2 ⫽ oxygen uptake
t has become increasingly apparent that, in paI tients
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]
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
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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
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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:
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
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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
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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
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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
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.
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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.
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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
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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 V̇o2 (150-mL infuwww.chestjournal.org
sion, 9.4%; 750-mL infusion, 11.5%), a steeper V̇e/
V̇co2 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 V̇o2 and
V̇e/V̇co2 slope.55 Thus, a depression in DM, even if
slight, decreases exercise performance and ventilaCHEST / 124 / 3 / SEPTEMBER, 2003
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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
match the DM/perfusion (Q̇) ratio is critical for
maintaining a normal arterial O2 saturation (Sao2).
In CHF patients, Q̇ may be severely impaired.
Although DM is reduced at a given Q̇, DM recruitment is normal. The exercise DM/Q̇ ratio remains
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 V̇e/V̇co2
slope, and to affect peak V̇o2. 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
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 V̇o2 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
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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 V̇o2. 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
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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.
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