State of the Art

Pathophysiology of Cor Pulmonale in Chronic Obstrurtive

Pulmonary Disease
Part One
W. MACNEE
Unit of Respiratory Medicine, Department of Medicine, Royal Infirmary, Edinburgh, Scotland

CONTENTS
Cor Pulmonale, Right Heart Failure, and Edema in COPO:
Problems of Definition
Structure and Function of the Normal Pulmonary Circulation
Structure
Function
The Pulmonary Circulation in COPD
Pathology
Factors Contributing to the Development of Pulmonary Arterial
Hypertension in COPO
Disruption of the Pulmonary Vascular Bed
Effects of Blood Gases
Effects of Abnormal Pulmonary Mechanics
Effects of Increased Cardiac Output
Effects of Blood Volume
Effects of Blood Viscosity
The Role of the Pulmonary Endothelium
Pulmonary Hemodynamics in COPD
The Consequences of Pulmonary Hypertension in COPD
The Natural History of Untreated Pulmonary Hypertension
in COPO
Prevalence and Incidence of Right Ventricular Hypertrophy and
Edema in COPO
Oxygen Transport in COPO
Methods of Assessing Cardiac Function in Patients with COPD
Clinical Assessment
Radiography
Electrocardiography
Echocardiography
Radionuclide Assessment of Right Ventricular Ejection Fraction
201Thallium Myocardial Scintigraphy
Right Ventricular Dimensions Measured by Magnetic
Resonance Imaging
Right Ventricular Physiology in Normal Subjects and Patients
with COPD
Normal Right Ventricular Physiology
Right Ventricular Function in Stable COPO
Right Ventricular Mechanics in COPO
Preload
Afterload
Contractility
Right Ventricular Function in Acute Exacerbations of COPD
(Received in original form May 25, 1993 and in revised form May 6, 1994)

(Part 1 of 2 parts)
Correspondence and requests for reprints should be addressed to Dr. W.
MacNee, Unit of Respiratory Medicine, Department of Medicine, Royal
Infirmary, Lauriston Place, Edinburgh EH3 9YW, Scotland, UK.
Am

J Respir Crit Care Med Vol 150. pp 833-852,1994

The pulmonary circulation in patients with chronic obstructive pulmonary disease (COPD) is often considered a no-man's land, faIling between the domains of the respirologist and the cardiologist
and understood only by the physiologist! Pulmonary arterial hypertension is the major cardiovascular complication of COPD, and
its development is a landmark in the natural history of the disease. Pulmonary hypertension is important, not only because it
is associated with right ventricular hypertrophy-so-called cor pulmonale (1)- but also because it adversely affects prognosis (2).
Progress in our understanding of pulmonary vascular disease in
COPD has been hindered by difficulties in studying the structure
and function of the pulmonary circulation and right ventricle, except by invasive techniques, and because of the paucity of treatments for patients with COPO complicated by pulmonary vascular disease.
This review covers the factors that lead to the development of
pulmonary hypertension in patients with COPD and the effects
of pulmonary hypertension on right ventricular function. The controversial issue of the etiology of the syndrome of edema in COPD
and whether it is truly associated with right ventricular failure is
discussed. The methods used to assess ventricular function are
assessed, and the noncardiac events that may mediate this syndrome are also reviewed.
Unraveling the mechanisms of pulmonary hypertension and
edema in cor pulmonale should lead to treatments for this condition
that are more logical than the limited therapy presently available.

COR PULMONALE, RIGHT HEART FAILURE, AND EDEMA

IN COPD: PROBLEMS OF DEFINITION
Pulmonary arterial hypertension in patients with COPD often attracts attention only when they develop edema. The term cor pulmonale was probably introduced by PaulO. White in 1931 and
is irrevocably entrenched in the literature. An expert committee
of the World Health Organization defined cor pulmonale as "hypertrophy of the right ventricle resulting from diseases affecting the
function and/or structure of the lungs, except when these pulmonary alterations are the result of diseases that primarily affect the
left side of the heart, as in congenital heart disease" (3). This is
a pathological rather than a functional definition and is thus of
limited clinical value, as methods of diagnosing right ventricular
hypertrophy in living subjects are imprecise and accurate diagnosis requires an autopsy (4). The definition was revised by Behnke
and colleagues (5), who replaced the term hypertrophy with alteration in the structure and function of the right ventricle. This definition is also imprecise, because it covers a spectrum of dysfunction from mild abnormality to frank right heart failure~

834

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 150

Cor pulmonale is often misused to indicate "right heart failure"

secondary to pulmonary disease or simply the presence of pulmonary arterial hypertension or edema in a patient with capo
(6-8). The problem of defining cor pulmonale produces considerable difficulty when comparing patients from different studies
in the literature.
A further problem stems from the lack of an accepted definition of heart failure (9). The European Society of Cardiology (10)
defined heart failure as "a state of any heart disease in which,
despite adequate ventricular filling, the heart's output is decreased
or in which the heart is unable to pump blood at a rate adequate
for satisfying the requirements of the tissues, with functional
parameters remaining within normallimits~ This definition is probably more applicable to the left side of the circulation. More appropriately, right ventricular failure could be defined as "an inability of one or more chambers of the heart to accept and expel the
venous return throughout the range of physiological activity, without alteration of normal circulatory hemodynamics" (11, 12). For
most clinicians, heart failure describes a clinical syndrome,
whereas experts in the field may include an assessment of the
peripheral circulation and tissue metabolism in the definition (13).
The textbook signs of right ventricular failure, consisting of raised
jugular venous pressure, liver enlargement, and peripheral edema,
may be present in patients with hypoxic capo and in patients
with congestive cardiac failure due, for example, to ischemic heart
disease. However, the cardiac output is usually normal, and there
is no vasoconstriction of the peripheral circulation in patientswith
capo (14).
The classic view of the development of "heart failure" in patients with capo states that hypoxia leads to pulmonary hypertension, which increases right ventricular work, producing right
ventricular hypertrophy and dilation, resulting eventually in right
ventricular failure and peripheral edema (4, 13, 15, 16). However,
the notion that the edema that occurs in cor pulmonale is purely
"cardiac" in origin has been questioned (17-20). Recently it has
been proposed that the term cor pulmonale should be abandoned
in favor of a more precise description that is based on objective
evidence of right ventricular hypertrophy, enlargement, functional
abnormality, or failure (21).

STRUCTURE AND FUNCTION OF THE NORMAL

PULMONARY CIRCULATION
Structure
The pulmonary circulation perfuses rather than nourishes the
lungs. Because it is in series with the systemic circulation the pulmonary vasculature is unique, as it receives all of the cardiac output. Cumming, Horsfield, and coworkers (22-24), using postmortem casts, measured the dimensions of the human pulmonary
arterial tree. They described 17 branching orders in the human
pulmonary arterial system, from the alveoli to the main pulmonary artery, but confusingly numbered the different generations
from the peripheral to the large vessels in the direction opposite
to flow. The ratio of the number of vessels from one order to the
next, the branching ratio, is 3.0 and is relatively constant, as are
the diameter ratio at 1.6 and the average length ratio at 1.5. These
dimensions have important implications for the resistance of the
pulmonary vasculature.
The walls of the large pulmonary arteries, which are thinner
than those of the systemic arteries, consist of smooth muscle inserting into short elastic fibers and thus appear to be designed
to enable the vessel to distend rather than actively constrict or
dilate (25). The potential for the large pulmonary arteries to constrict was first demonstrated in the early animal work on Von Euler

1994

and coworkers (26, 27). The small muscular pulmonary arteri~s

seem to be the predominant site of changes in pulmonary vascular tone. The terminal branches of the pulmonary arteries also
have a larger internal diameter and a thinner wall than the corresponding systemic arteries. Medial thickening in the small arteries, which develops in patients with pulmonary hypertension, will
potentiate the increase in resistance produced by active vasoconstriction and lessen the ability of the vessels to distend passively.
This will increase the contribution that the small arteries make
to the resistance to blood flow (28).
Systemic arterioles have a coat of circular smooth muscle and
are therefore able to constrict and thus make a large contribution
to the systemic vascular resistance. By contrast, precapillary muscularized arterioles are not normally present in the pulmonary circulation, so the arterioles make a lesser contribution to the total
pulmonary vascular resistance. Moreover, the arterioles can respond to changes in blood volume by passively changing their
caliber and can thus act as a reservoir for blood.
The pulmonary capillaries are difficult to distinguish as separate structures within the alveolar walls on standard 5-J.1m histological sections of the human lung. However, scanning electron
microscopy confirms that the pulmonary capillary bed consists
of a large number of capillary segments of varying diameters and
lengths (Figure 1). The number of capillary segments in postmortem lungs has been estimated by Weibel to be 1011, with an average diameter of 5 J.1m and average length of 11 J.1m (29). The average diameter of the pulmonary capillaries is smaller than that of
the systemic capillaries. These dimensions have been confirmed
recently in resected human lungs (30).
Neutrophils and erythrocytes have a larger average diameter
(7 J.1m) than the pulmonary capillaries (5 J.1m) (31). The erythrocyte is a fairly deformable cell because of its biconcave shape
and lack of a nucleus (32). Thus, the neutrophil is 700 times less
deformable than the erythrocyte because of its nucleus and viscous cytoplasm (32). This leads to trapping or sequestration of
neutrophils during their transit through the pulmonary capillary
segments in normal lungs (33). The pulmonary capillaries have
neither contractile cells nor smooth muscle in their walls. Thus,
capillaries do not contract actively but can change their dimensions passively. A reduction in capillary diameter can be produced
by swelling of the endothelial cells, by perivascular transudates

Figure 1. Scanning electron micrograph of the human lung. The pulmonary vasculature has been perfused to show the intermeshing capillary
segments in the alveolar walls. Kindly produced and supplied by Dr. Peter Jeffery, Department of Pathology, National Heart and Lung Institute,
London.

State of the Art: Pathophysiology of Cor Pulmonale in COPO

(34), or by an increase in alveolar (35) or pleural pressure (36).

The capillaries can also distend in response to an increase in local blood volume. The pulmonary alveolar-capillary surface area
in man is on the order of 50 to 70 m2 at rest, increasing to 90 m2
at 75% of total lung capacity (37), and can increase further in normal subjects during exercise without producing an inequality between alveolar ventilation and pulmonary capillary perfusion (38).
Function

A mean pressure of only 10 mm Hg is necessary to distribute the

cardiac output within the pulmonary vasculature at rest. This low
pressure prevents fluid from passing into the interstitial space and
enables the right ventricle to function un~er conditions of low
energy expenditure. The normal pulmonary circulation offers less
than a tenth of the resistance to flow than does the systemic circulation. Basal pUlmonary vasomotor tone is also low, because
vasodilators that reduce systemic vascular pressures have little
effect on the normal resting pulmonary arterial pressure (Ppa)
(39-41). The cardiac output needs to increase by 2.5 times the
normal value to produce any increase in Ppa in normal subjects
(42). This is due to recruitment of underperfused pulmonary capillaries as cardiac output increases, particularly in zone I of West
(43). Thus, during exercise in normal subjects the mean Ppa may
rise by 3 or 4 mm Hg, with the increase in systolic pressure generally exceeding that of the diastolic pressure, which may not change
(44). After exercise, the mean Ppa often falls below the resting
values (45, 46). Pulmonary vascular resistance either remains unchanged (47) or falls during exercise (48), as a result of passive
dilation of underperfused vessels.
The factors influencing the pulmonary vascular resistance are
complex (49). Most studies of pulmonary hemodynamics have simplified the definition of the resistance as the pressure drop across
a segment of the pulmonary vasculature divided by the flow
through it. Calculation of the pulmonary vascular resistance is
often oversimplified by dividing the mean Ppa by the cardiac output to produce the total pulmonary vascular resistance. However,
this calculation does not take into account the left atrial or the
pulmonary arterial wedge pressure. This is not a problem when
the pulmonary arterial wedge pressure is low, as in normal subjects, but this may not be the case in ill subjects. Moreover, in pa~
tients with capo the wedge pressure may not be an accurate
reflection of the left atrial pressure (50). Thus, this oversimplification presents a very limited view of pulmonary hemodynamics and
may lead to errors of interpretation, particularly as changes in resistance can result from changes in the cross-sectional area of
the pulmonary vascular bed. In addition, both flow and pressure
in the pulmonary circulation are pulsatile, and the time-averaged
values for each of these variables should be used when calculating their ratio.
The transmural pressure in the pulmonary vasculature is influenced by the alveolar pressure. This is particularly true of the
pulmonary capillaries, which pass through the alveolar walls.
Changes in the surface area of the pulmonary capillaries can arise
from a change in the diameter of the vessels or from a change
in the number of parallel paths that are being perfused as a result of the recruitment of previously underperfused vessels. A practical demonstration of this effect comes from direct measurements
of the relation between pressure and flow in the pulmonary vasculature, which were made in the early 1950s. In these studies,
balloon occlusion of a pulmonary artery, usually on the right, was
performed during cardiac catheterization (51). Under these conditions, when blood flow was almost doubled through the left lung
the relation between pressure and flow was linear in normal su-

835
pine man, and the pulmonary vascular resistance remained unchanged (52, 53). However, this is not the case in the upright position, where the more dependent pulmonary blood vessels are
in a partially collapsed state and can expand in response to an
increase in flow, resulting in a fall in the pUlmonary vascular resistance (54).
Thus, changes in pulmonary vascular resistance are not necessarily an accurate r~flection of active changes in pulmonary vascular caliber, unless all of the passive mechanisms affecting caliber have been taken into account. This has led to the use of
pulmonary arterial pressure/flow curves and pulmonary vascular resistance/flow curves to detect active changes in pulmonary
vascular caliber so that both of the effects of the changes in flow
and pressure on resistance can'.be assessed (55).
THE PULMONARY CIRCULATION IN COPO
Pathology

The development of hypoxemia in patients with capo is associated with pathological changes that occur characteristically
in the peripheral arteries (56-58). The small pulmonary arteries
develop accumulations of vascular smooth muscle cells in their
intima that are laid down longitudinally along the length of the
vessels (57). More recent studies have suggested that intimal thickening is an early event that occurs in association with progressive airflow limitation (58-60). Medial hypertrophy in the muscular pulmonary arteries, and less commonly fibrinoid necrosis in
these vessels, has also been reported in patients with capo who
develop sustained pulmonary arterial hypertension (61). Thus,
structural change, rather than simply hypoxic vasoconstriction,
is the major factor in the development of sustained pulmonary
hypertension in patients with capo (62).
Pulmonary thrombosis may also occur in patients with capo,
which may be secondary to peripheral airway inflammation (63).
Indeed, pathological changes in the small airways of patients with
capo appear to correlate with the vascular changes, including
thickening of all three layers of the vascular wall, which can be
shown in postmortem studies of patients with hypertensive pulmonary vascular disease (63, 64). However, this relation was not
confirmed in a study of patients undergoing lung resection (54).
This latter study (54) also demonstrated a stepwise increase in
arterial wall thickness in a comparison of nonsmokers and smokers
with mild to moderate emphysema, which was associated with
an increase in the thickness of all three vessel layers. However
the degree of intimal thickening was out of proportion to the
changes in the media or the adventitia. This confirms an earlier
study by Hale and colleagues (64) in postmortem lungs that
demonstrated intimal thickening in muscular pulmonary arteries
in a population of smokers.
In postmortem studies it is difficult to dissociate right ventricular hypertrophy (ie, increased right ventricular free wall mass) from
right ventricular dilatation (ie, increased free wall area) (65). Thus,
hypertrophy and dilatation are often considered together and referred to as right ventricular enlargement. Chronic hypoxemia
produces right ventricular hypertrophy in animal studies (66, 67),
and this relation is well established in normal subjects at altitude
(68). A correlation has also been demonstrated between the usual
partial pressure of oxygen in a group of patients receiving longterm oxygen therapy and the degree of right ventricular hypertrophy (69), confirming previous work (70). However, there is no
significant correlation between the weight of the right ventricle
or the pulmonary vascular resistance and the extent of emphysema measured in postmortem lungs (69, 70).

836

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

Factors Contributing to the Development of Pulmonary

Arterial Hypertension in CO PO
The increase in Ppa in patients with COPO (48, 71-73) probably
results from a combination of several factors that passively or actively affect pulmonary hemodynamics. However, the precise
mechanisms remain to be elucidated.
Disruption of the pulmonary vascular bed. In the early 1940s,
pulmonary hypertension was thought to arise from alveolar wall
and hence small vessel destruction in what was then called chronic
emphysema, which was thus considered to be irreversible (13).
Although vessel occlusion contributes to the pulmonary hypertension in thromboembolic disease (74), the destruction of alveolar vessels that occurs in emphysema is typically associated with
normal resting Ppa until late in the course of the disease (75).
The lack of a significant correlation between right ventricular hypertrophy and total alveolar surface area (76) (which reflects the size
of the capillary bed) suggests that loss of capillary bed per se
is not an important determinant of the development of sustained
pulmonary hypertension at rest in patients with COPO. However,
loss of the capillary bed may contribute to the pulmonary arterial
hypertension that develops during exercise in such patients.
Although previous studies have suggested that Ppa is raised
in the "bronchitic" and normal in the "emphysematous" clinical
types of patient with COPO (77, 78), these studies are open to
criticism because quantification of emphysema in living subjects
is difficult (79, 80). Recent studies using computed tomography
(CT) scanning to measure lung density (80), which correlates with
morphometric measurements of microscopic emphysema (81),
have shown a similar extent of emphysema in patients with the
so-called "pink and puffing" or "emphysematous" type of COPO
as in the "blue and bloated" or "bronchitic" type (82). Furthermore,
as in studies of resected or autopsy lungs (58, 60, 69), there was
no significant correlation between Ppa or resistance and the extent of emphysema, in this case as measured by CT lung density
in patients with COPO (82).
Effects ofblood gases. In 1946, Von Euler and Liljestrand (26),
in experiments in cats, were the first to show convincingly that
acute hypoxia induces pulmonary vasoconstriction. Although a
local disease in Po2produces systemic vasodilation, alveolar hypoxia is a potent arteriolar constrictor in the pulmonary circulation,
which reduces perfusion with respect to ventilation in an attempt
to restore Pa02 (67). Thus hypoxic vasoconstriction acts as a control mechanism that limits the effects of hypoxia on ventilation:perfusion ratios in the lungs.
Acute hypoxia induces pulmonary vasoconstriction in normal
subjects (83-86) without changing pulmonary artery wedge pressure (84). The negative correlation between Ppa and Sa02 in patients with COPO was first reported by Harvey and coworkers (85)
and has been confirmed by many other authors (86-94). Shortterm supplemental oxygen, even in high concentrations, produces
a variable and often trivial fall in Ppa in patients with COPO (89,
95-97). Oespite normalization of the Pao2, normal values of Ppa
are rarely achieved in these patients. Pulmonary hypertension is
also relieved only partially when mountain dwellers exposed to
chronic hypoxia are given oxygen acutely. Normal levels of Ppa
may only be achieved after residence at low altitude for 6 wk (98).
Moreover, breathing high concentrations of oxygen increased
Paco2 in some studies of COPO patients (89, 95, 97), which together with the associated acidemia may potentiate pulmonary
vasoconstriction.
In patients with COPO there is a positive correlation between
the arterial Paco2and the Ppa (89, 99). Raising the Paco2in patients with COPO produces a rise in Ppa that is probably not due

VOL 150

1994

to the direct vasoconstrictor effect of carbon dioxide, since cardiac

output also increases (100, 101). The mechanism of this effect may
relate to a change in lung mechanics as a result of the hyperventilation induced by hypercapnia (102) or the potentiation of the hypoxic pulmonary vasoconstrictor response (103) as a result of increasing Paco2.
Although an increase in arterial hydrogen ion concentration
causes a rise in Ppa in normal subjects (99), acute changes in
hydrogen ion concentration in patients with COPO produce inconsistent changes in Ppa (104-106). Furthermore, intravenous
infusion of sodium bicarbonate in normal subjects, which increased
the arterial pH to 7.5, had no effect on the Ppa or the cardiac output (107). Induction of an alkalemia in patients with COPO also
did not change the Ppa, but the cardiac output increased substantially, suggesting that pulmonary vasodilation had occurred
(104). However, the curvilinear relationship between pressure and
flow in the pulmonary circulation in patients with COPO means
that such a change may not result from pulmonary vasodilatation. Inconsistent changes in pulmonary hemodynamics have also
been reported when the arterial hydrogen ion concentration was
increased acutely by an intravenous infusion of hydrochloric acid
in patients with COPO (105, 106) or chronically over 5 to 7 d by
giving ammonium chloride orally (108). However, hypoxia and
acidemia act synergistically to produce pulmonary vasoconstriction in patients with COPO. Thus, for a given Sao2, the mean Ppa
is higher with increasing arterial hydrogen ion concentrations (104).
Effects of abnormal pulmonary mechanics. Changes in airway
resistance may augment pulmonary vascular resistance in patients with COPO by affecting the alveolar pressure. Harris and
coworkers (102) demonstrated that the linear relationship between
pressure and flow in the pulmonary circulation when alveolar pressure is normal changes when the alveolar pressure is increased
by increasing the gas pressure at the mouth. Under these conditions the slope of the pressurelflow relation in the pulmonary circulation is steeper initially and becomes curvilinear as the pressure increases so that pressure no longer increases in proportion
to blood flow, due to compression of the resistance vessels in the
lungs as a result of increased alveolar pressure (Figure 2A). Thus,
when alveolar pressure is increased in normal subjects, the relation between pressure and flow in the pulmonary circulation resembles the relation in patients with COPO during normal tidal breathing (73, 102) (Figure 28). The effect of airway resistance on Ppa
may be particularly important when ventilation increases (such
as in acute exacerbations of COPO). In normal subjects or in patients with mild COPO (102, 109), hyperventilation does not affect
the pulmonary circulation significantly, whereas in patients with
more severe COPO, hyperventilation increases both pulmonary
arterial and pulmonary artery wedge pressures without changing cardiac output (102). Thus the consequent increase in pulmonary vascular resistance results from a' reduction in the caliber
of the vessels. At least one study has demonstrated a correlation
between Ppa and FEV. in patients with! COPO (102). Moreover,
the amplitude of the respiratory swings\of the Ppa during exercise (which is related to changes in intrathoracic pressure) in patients with moderately severe COPO correlates with the Ppa (110).
Effects of increased cardiac output. In contrast to the situation
in normal subjects (42), in patients with COPO (in whom the vascular bed may be reduced) even the small increase in flow that
occurs during mild exercise may increase Ppa significantly (111).
Effects of blood volume. The effect on Ppa of expanding the
blood volume has been studied by Abraham and colleagues (112)
in patients with COPO. Hypoxia produced an increase in Ppa associated with a small increase in cardiac index, and thus pulmo-

837

State of the Art: Pathophysiology of Cor Pulmonale in COPD

30

15

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en

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E

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/

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:z:

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E

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10

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o

LEFT LUNG FLOW (,. min1)

o 0r
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4

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6

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LEFT LUNG FLOW (I'min l )

Figure 2. The relation between flow and pressure in the pulmonary circulation can be studied by increasing flow through the left lung by balloon
occlusion of the right pulmonary artery. In normal subjects (A) the influence of alveolar pressure on this relation is shown by increasing mouth pressure.
The relation between pressure and flow in normal subjects is similar to the relation in five patients with COPD (B). After Harris and Heath (49).

nary vascular resistance increased in these patients; however, the

infusion of albumin increased Ppa but produced a greater increase
in cardiac index, and thus pulmonary vascular resistance fell.
These data do not support the hypothesis that an increase in blood
volume is a major factor in the development of pulmonary hypertension in COPO (113). Indeed, the pulmonary blood volume is
either normal or low in patients with COPO. Moreover, there is
no significant correlation between Ppa and the plasma or total
blood volume in such patients (114).
Effects of blood viscosity. Polycythemia can develop secondary to chronic hypoxemia in patients with COPO, resulting in an
increase in blood viscosity. Since viscosity is a factor in tl:le
Poiseuille equation, in theory any increase may contribute to the
development of pulmonary arterial hypertension. Reducing
packed cell or blood volume and hence plasma viscosity in patients with COPO produces a small reduction in Ppa without changing cardiac output, and thus pulmonary vascular resistance falls
slightly (52) without any change in arterial blood gas values
(52, 115).
The role of the pulmonary endothelium. The mechanisms that
induce hypoxic vasoconstriction leading to sustained pulmonary
hypertension are not fully elucidated (116, 117). Previous studies
have focused on the leukotriene metabolites of the 5-lipoxygenase
pathway of arachidonic acid as mediators of hypoxic vasoconstriction. Their role is supported by studies showing enhancement of
hypoxic vasoconstriction by cyclooxygenase inhibition and leukotriene receptor blockers (118, 119). Thus, one hypothesis is that
pulmonary vascular tone in hypoxia is determined by the balance
between constricting leukotrienes (84 , C4 , and 0 4 ) and dilating
prostaglandins (largely prostacylin). However, this hypothesis has
been refuted by its original proponents (120). More recent work
suggests that potassium channels may also be involved in the
mechanism by which hypoxia is sensed by vascular smooth muscle cells and the signal transduced in the cell to produce vasoconstriction (121).

The nitrovasodilators appear to act by releasing an endothelium-derived relaxing factor. This is thought to be nitric oxide (NO)
or a nitroso-compound that releases NO (122). Increased blood
flow producing an increase in shear stress seems to be the stimulus for the release of NO from the luminal surface of endothelial
cells (123). This stimulates guanylate cyclase with a resultant increase in the second messenger cyclic guanosine monophosphate
in vascular smooth muscle, producing vasodilatation (124). Several lines of circumstantial evidence suggest that NO may play
a major role in modulating pulmonary vascular tone. NO is an endogenous vasodilator that is released from endothelial cells and
produces relaxation of isolated human pulmonary artery rings
(125-127). Removal of the endothelium from isolated vascular rings
(128, 129) or preventing formation of NO by pretreatment with an
L-arginine analogue (130, 131) increases the response of isolated
vascular rings to vasoconstrictors. These studies suggest a mechanism whereby NO acts as a "braking system" to prevent an excessive rise in pulmonary vascular tone. However, whether NO
release in vivo has a role in maintaining the normally low pulmonary vascular tone remains speculative.
Inhibition of NO synthesis enhances the vasoconstrictor effect
of acute hypoxia (132), suggesting that NO also acts in this case
as a chemical brake to counteract excessive hypoxic pulmonary
vasoconstriction. Endothelial cell proliferation and thickening occur in the intima of the small pulmonary arterioles in response
to chronic hypoxia, both in animals (133) and in patients with COPO
(56-59). Moreover, endothelium-dependent dilatation is impaired
in animals that are chronically exposed to hypoxia (134) and in
isolated pulmonary rings from patients undergoing heartllung
transplantation for end-stage COPO (129). Impaired endotheliumdependent vasodilatation may result from either a reduction in
NO synthesis or release as a result of hypoxia (135). These data
lend further support to the hypothesis that the endothelium has
a central role in regulating the pulmonary vasculature (136, 137).
Thus, the normal braking mechanism that ameliorates the effect

838

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

of vasoconstrictors on pulmonary vascular tone may be lacking

in COPO, which may relate to the structural changes in the intima
and media that occur in the small pulmonary arteries (129). A further extension of this hypothesis is that NO may inhibit cell proliferation in the pulmonary vasculature and may thus not only affect
pulmonary vasomotor tone but may also influence the vascular
remodeling that occurs in hypoxic COPO (135).
In summary, it is likely that a complex interaction occurs between the factors described above that contribute to the development of pulmonary arterial hypertension. An increase in pulmonary vascular resistance occurs, particularly during exercise, in
such patients because the ability to recruit underperfused vessels is compromised. Thus, patients with a severely restricted vascular bed with extensive loss of the pulmonary vasculature may
respond to exercise as though they started at the bend of the normal pressure/flow relation, so that any increase in cardiac output
augments pressure dramatically. Hypoxic vasoconstriction and
structural changes in the vessels will further reduce the pulmonary vascular reserve. At this stage, Ppa is elevated at rest and
the pressure/flow relation shifts upward and to the left, so that
small changes in flow produce large changes in pressure over
the entire range of the cardiac output. Changes. in plasma viscosity and alterations in pulmonary mechanics may also contribute to pulmonary arterial hypertension in patients with more severe COPO. The relative contribution of each of these factors to
the development of pulmonary hypertension in patients with COPO
is difficult to quantify and in any case varies between individuals.
The mechanism producing hypoxic vasoconstriction and the structural changes that ensue from chronic hypoxia have not been fully
elucidated. However; it seems likely that the pulmonary endothelial
cell has a central role in modulating vasomotor tone through a
mechanism that involves NO.

VOL 150

1994

TABLE 1
HEMODYNAMICS AND BLOOD GAS VALUES IN 74 PATIENTS
WITH PREVIOUS EPISODES OF ACUTE RESPIRATORY FAILURE
(BUT STUDIED WHEN STABLE) AND 32 NORMAL SUBJECTS
COPD

Normals

Variables

Mean

Range

Mean

Range

Pao2 , mm Hg
Paco2 , mm Hg
Q, Umin/m 2
Pra, mm Hg
Ppa, mm Hg
Ppw, mm Hg
PVRI, dyne/slcm 5/m 2
RVSWI, g/m

43
51
3.8
3
35
6
660
16

23-67
33-68
2.3-5.8
0-21
15-78
0-19
213-1,377
5-29

91
38
3.6
5
13
9
58
6

75-105
32-43
2.6-4.5
2-9
8-20
5-14
40-200
3-18

Definition of abbreviations: a = arterial; Q = cardiac output; Pra = right atrial pressure;

Ppa = mean pUlmonary arterial pressure; Ppw = pulmonary artery wedge pressure; PVAI =
pUlmonary vascular resistance index; AVSWI = right ventricular stroke work index.
From Naeije (148).

normalities worsen, and with the development of chronic hypoxemia and hypercapnia, pulmonary hypertension may be present
at rest and worsen with exercise. However, even in patients with
severe COPO, the increase in Ppa is usually rather small. Naeije
(148) studied 74 patients with severe but clinically stable COPO
who had all presented in the past with episodes of acute-on-chronic
respiratory failure and almost half with peripheral edema. They
all had severe airflow limitation (FE~ 25.7 1% of predicted,
mean SO) and hypoxemia (Pao2: mean, 43 mm Hg; range,
23-67 mm Hg), and the majority were also hypercapnic (Paco2:
mean, 51 mm Hg; range, 33-68 mm Hg). However, Ppa was only
modestly raised with a mean of 35 mm Hg in this group (Table 1).

PULMONARY HEMODYNAMICS IN COPD

THE CONSEQUENCES OF PULMONARY HYPERTENSION

IN COPD

Although Ppa may be normal or only slightly elevated when measured at rest in patients with COPO rn, 138-140), it may increase
to abnormal levels during exercise (48,71, 72)-the increase being greater in subjects over the age of 50 years (71, 72). Using
the technique of balloon occlusion of the right pulmonary artery
in supine patients with COPO, as previously described in normal
subjects (51-54, 141), the initial part of the relation is steeper than
normal indicating increased resistance (54). Moreover, at higher
flow rates the relation between pressure and flow is curvilinear,
so that resistance decreases due to distension of partially collapsed vessels at high flow rates (Figure 2).
Before the development of significant hypoxemia and hypercapnia, patients with mild COPO have a normal or low cardiac
output (1, 142-147). Right atrial and right ventricular end-diastolic
pressures are normal, and Ppa may be normal or slightly elevated
but inappropriately high for the level of cardiac output. The pulmonary vascular resistance is therefore normal, or only slightly
elevated when measured at rest, but may rise markedly during
exercise (48, 71). Patients with COPO stop exercising at a lower
level of cardiac output and maximal O2consumption than normal
subjects. However, the slope of the relation between oxygen consumption and cardiac output is normal (146, 147). Thus, the limitation to exercise in patients with COPO is not cardiovascular but
results from changes in pulmonary mechanics that affect ventilation.
In patients with mild COPO, right ventricular end-diastolic pressure and right ventricular stroke work, which are normal at rest,
increase during exercise due to an increase in work against a
higher P~a (146). As airflow limitation and arterial blood gas ab-

Chronic bronchitis and emphysema usually coexist pathologically.

Those patients with either predominant chronic bronchitis or
mainly emphysema form a minority at either end of the disease
spectrum of patients with COPO (149-152). The notion of two clinical patterns in patients with chronic bronchitis and emphysema
has been attributed to Dornhurst (153). The "blue and bloated"
type (154), also known as "type B" (155) or "nonfighter" (156), was
thought to characterize the "bronchial type" of disease (149). These
patients had hypoxemia, hypercapnia, and secondary polycythemia and developed pulmonary hypertension relatively early in the
course of the disease. Right ventricular hypertrophy or cor pulmonale ensued, and repeated episodes of "right heart failure" occurred, often during acute episodes of respiratory failure. In contrast, the "pink and puffing" variety, also known as "type ~' or
"fighter:' were thought to represent the emphysematous patients,
characterized by severe breathlessness but with preservation of
blood gas values and thus no pulmonary hypertension, right ventricular hypertrophy, or "heart failure," at least until the later stages
of the disease. The hypothesis that the "pink puffer" had predominantly emphysema and the "blue bloater" had predominantly
chronic bronchitis was perpetuated in several studies in the 1960s
(157-161). However; Thurlbeck (162) showed that the degree of mucous gland hypertrophy, indicative of chronic bronchitis, was similar whatever the clinical pattern of the disease and that more than
50% of patients with the "blue and bloated" clinical pattern had
severe emphysema. These pathological observations have been
confirmed in a study of autopsies from the National Institute of
Health Nocturnal Oxygen Therapy Trial (NOfT) that showed a complete overlap in the amount of mucous gland hypertrophy and em-

839

State of the Art: Pathophysiology of Cor Pulmonale in COPO

physema in the two clinical types (163). CT scanning has also confirmed that similar degrees of emphysema occur in patients with
both patterns of the disease (82). Furthermore, there is no significant correlation between Ppa and the extent of emphysema as
measured by CT scanning. However, autopsies of patients in the
NOTT trial (163) showed that the "blue bloaters" had heavier right
ventricles than the "pink puffers," and there was a significant correlation between the degree of the right ventricular hypertrophy and
the extent of chronic inflammatory changes in the airways.

The Natural History of Untreated Pulmonary Hypertension in COPO

The Ppa has been shown in numerous studies to be only moderately elevated in patients with COPO who have mild or moderate
hypoxemia and rarely if ever reaches the levels seen in patients
with primary pulmonary hypertension (164). The progression of
pulmonary arterial hypertension in patients with COPO is slow
(143, 165-169). Weitzenblum and colleagues (178) studied the
changes in Ppa in a group of patients with COPO over an average follow-up period of 5 yr and found a mean rise in the Ppa
of only 3 mm Hg per yr. In only 33% of these patients did the Ppa
increase by more than 5 mm Hg during this period. Those in whom
pulmonary hypertension progressed (defined as an increase in
Ppa of ~ 5 mm Hg) had baseline spirometry, arterial blood gas,
and pulmonary hemodynamic values similar to the group as a
whole. However, they were distinguished by progressive hypoxemia and hypercapnia, whereas those whose Ppa remained stable showed no change in arterial blood gas values over time. These
data demonstrate the importance of worsening hypoxemia in the
progression of pulmonary hypertension in COPO. Data on the
progression in Ppa in patients in the British Medical Research
Council (MRC) long-term oxygen trial support this view (170). Thus,
the Ppa rose in the untreated group by a mean of 3 mm Hg per
yr, whereas there was no significant change in the treated group.
However, not all studies support a relation between worsening hypoxemia and progression of pulmonary arterial hypertension.
Boushy and North (143) reported a mean increase in Ppa of 7
mm Hg associated with a 6% increase in cardiac output in 136
patients with COPO who were not receiving long-term oxygen therapy, studied before and after an average interval of 25 mo. By
contrast, Schrijen and colleagues (166) found no significant deterioration in pUlmonary hemodynamics in a group of patients with
COPO not receiving oxygen therapy, studied over 3 yr, even when
the Ppa was elevated when first measured. However, in the latter
study (166), 30% of the patients demonstrated a fall in systemic
arterial pressure over time, which was attributed to the peripheral vasodilation produced by hypercapnia.
Although the prevalence of chronic bronchitis and emphysema
has declined (171,172), COPO and allied disorders (International
Classification of Diseases, World Health Organization, Geneva,
Switzerland, 9th revised edition, category 490-496) accounted
for 4.5% of total deaths (almost 3,000 deaths) and was the fifth
leading cause of death in Scotland in 1989 (173), and resulted
in almost 28,000 deaths (5% of the total) in 1988 in England and
Wales. A large number of factors influence survival in patients with
COPO. In a recent review of the literature by Hodgkin (174), increasing age and a low postbronchodilator FEy' were the best
predictors of mortality in COPO. However, several studies have
shown that the presence of pulmonary arterial hypertension or
peripheral edema in patients with hypoxic COPO correlates with
survival (2, 175-185). Patients with COPO who develop peripheral edema have a 5-yr survival rate of only 27% to 33% (174).
Although pulmonary arterial hypertension progresses slowly
in patients with COPO, its presence infers a poor prognosis. Weitzenblum and coworkers (175) showed a 72% 4-yr survival rate in

patients whose Ppa was normal (Ppa < 20 mm Hg) compared

with a 49% survival in those with an elevated Ppa. Other investigators have also confirmed the prognostic value of Ppa (186). Burrows and colleagues (155) studied 50 patients with chronic airways obstruction over 7 yr and showed that the hemodynamic
parameter that correlated best with survival was pulmonary vascular resistance. In this study, none of the patients whose pulmonary vascular resistance exceeded 550 dyneslslcm s survived for
more than 3 yr. However, in one study of patients with COPO with
minimally raised Ppa (20 to 29 mm Hg at rest), although mortality
was 25% within 3 yr a similar percentage were alive after 10 yr
(187). These conflicting data may relate to the duration of pulmonary hypertension in an individual patient. Long-term oxygen therapy cannot account for any differences between the studies that
were carried out before the advent of this treatment. Thus, it is
clear that some patients with COPO tolerate an elevated Ppa remarkably well.
Weitzenblum and coworkers (175) also showed that although
the level of the Ppa affected survival, so did the FEy'. France and
colleagues (176), in a study of 115 patients with COPO, found that
a number of variables correlated significantly with survival, including Pao2, Paco2, FEy', and the presence of peripheral edema.
Thus, although numerous studies have shown an association between the presence of pulmonary arterial hypertension and the
prognosis in COPO, pulmonary hypertension may simply be a
reflection of the severity of the disease and may not have a direct
effect on mortality.

Prevalence and Incidence of Right Ventricular Hypertrophy

and Edema in COPO
Recent estimates of the incidence and prevalence of right ventricular hypertrophy in COPO are lacking because of the difficulty
in defining the condition clinically. In the United States, it has been
estimated that 10% to 30% of all admissions with congestive
cardiac failure are due to right ventricular hypertrophy and failure
(1, 188-193). Considering all heart diseases, cor pulmonale is
thought to account for 7% to 10% of all cases (189). An autopsy
study in the United Kingdom found evidence of right ventricular
hypertrophy in 40% of the patients with chronic bronchitis and
emphysema (190); in a larger study of 7,947 patients with chronic
lung diseases, right ventricular hypertrophy was present in 8.9%
at autopsy (20). Cor pulmonale increases in prevalence as airflow limitation worsens in patients with COPO. It is present in 40%
of patients with an FEy' < 1.0 L and in 70% when the FEy' falls
to 0.6 L (2, 152). The prevalence of cor pulmonale is also higher
in patients with hypercapnia, hypoxemia, and polycythemia (2, 152).
The development of edema in patients with hypoxic COPO occurs late in the course of the disease (194), often during acute
exacerbations of airflow limitation. However, a proportion of patients who develop pulmonary hypertension, or indeed right ventricular hypertrophy, never develop peripheral edema (195, 196).
In two studies of 100 and 59 patients with chronic bronchitis and
emphysema, respectively, who were free of edema at the time
of presentation, edema developed for the first time at a rate of
6% per annum over a 3- to 4-yr follow-up period (97, 197). In a
further study of 65 patients with COPO, of whom 58% had moderate to severe airflow limitation and most had hypoxaemia, at least
one episode of edema occurred over a follow-up period of 5.4 yr

(167).
Oxygen Transport in COPO
Survival in patients with COPO also appears to relate to oxygen
transport and mixed venous oxygenation. In a group of 50 patients with stable COPO, Kawakami and colleagues (198) assessed

840

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

survival over 4 yr, during which time 27 of the 50 patients died.

Initial values of pulmonary hemodynamics did not distinguish between survivors and nonsurvivors, nor did the oxygen transport
or the coefficient of oxygen delivery (the ratio of oxygen transport
to oxygen consumption). However, arterial and mixed venous Po2
were significantly lower in those who died. The authors concluded
that tissue oxygenation had a greater influence on survival than
defects in oxygen transport and delivery. However, these data in
a small group of patients should be interpreted with caution (199).
Furthermore, longitudinal hemodynamic or oxygen transport data
were not available.
In theory, oxygen is supplied to the tissues by two processes.
One process is convectional transport to the tissues in the vascular system, which depends on both oxygen delivery and oxygen
consumption. The ratio of these two variables is the coefficient
of oxygen delivery (200). The other process is mixed venous oxygen tension (PV02), which is an approximation of the "mean tissue oxygen tension:' This is a determinant of the diffusion of oxygen into the tissues. Thus, PV02 can be decreased by a reduction
in Pao2 due to lung disease or due to a reduction in oxygen delivery as a result of a reduction in cardiac output caused by heart
disease. In the study by Kawakami and coworkers (198), although
there was an association between Pvo2 and mortality, the coefficient of oxygen delivery was not different between survivors and
nonsurvivors. By inference, Tenney and Mithoefer (201) suggested
that oxygen supply to the tissues is the critical factor that determines survival in such patients, and thus the diffusional (mixed
venous) component of tissue oxygen supply is more important
than the convectional transport of oxygen in the vascular system,
as measured by the coefficient of oxygen delivery.
It has been proposed that maintenance of a normal or indeed
a high cardiac output may be an adaptive mechanism in patients
with COPO to maintain a normal tissue oxygen supply. Thus, failure to maintain cardiac output may worsen survival (198). It follows that vasodilators that increase oxygen delivery by increasing cardiac output may therefore be beneficial in COPO (202).
Naeije (148) has suggested that the increase in cardiac output
induced by hypoxemia is inadequate in most patients with COPO
and hypoxemia. He studied 61 patients with COPO who were
divided into two groups on the basis of a Pvo2 greater than, less
than, or equal to 20 mm Hg. The choice of a Pvo2 above or below
20 mm Hg was based on a study by Kasnitz and colleagues (203)
that showed that a Pvo2 of ~ 20 mm Hg was associated with a
uniformly fatal outcome in patients with COPO. Oespite the presence of more severe pulmonary hypertension and a lower Pao2
in those with a low Pvo2, cardiac output was not different between
the groups. However, stroke-volume index was lower in those
whose Pvo2 was ~ 20 mm Hg (148) and may have been insufficient for the degree of hypoxemia.
Paradoxically, breathing oxygen does not always increase oxygen delivery when given to patients with COPO. In 35 patients
presenting acutely with decompensated COPO (204), 28% oxygen given for 1 h did not change cardiac output in 15 of the patients with severe hypoxemia. However, oxygen delivery increased
because of an increase in Pao2. In the remaining 20 patients with
lesser degrees of hypoxemia, oxygen delivery did not change because the increase in arterial oxygen content was offset by a fall
in cardiac output, producing no overall significant change in oxygen delivery to the tissues (204). The observation that only a
proportion of patients "respond" to oxygen therapy by increasing
oxygen delivery has been confirmed in other studies in patients
with both stable and decompensated COPO (205, 206). Thus, in
patients with COPO who develop hypoxemia, one hypothesis

VOL 150

1994

would be that an increase in cardiac output is a necessary adaptation to maintain mixed venous oxygenation in the face of a low
oxygen saturation (207). In patients with COPO, cardiac output
generally remains normal or even slightly elevated until very late
in the course of the disease (208). It follows that an inability to
increase cardiac output in the face of worsening venous hypoxemia may be a maladaption in COPO that adversely affects survival. Although unproven, this hypothesis has important implications for therapy directed at maintaining cardiac output and oxygen
delivery (209).
In summary, although the development of pulmonary arterial
hypertension and edema in patients with COPO is associated with
a poor prognosis, these features are likely to simply reflect the
severity of the underlying disease as reflected by the degree of
airflow limitation and abnormalities in gas exchange.
METHODS OF ASSESSING CARDIAC FUNCTION
IN PATIENTS WITH COPD
One of the major difficulties in assessing pulmonary hemodynamics
and right ventricular function is the need to measure pressure
and flow, which involves the use of invasive techniques such as
cardiac catheterization. Moreover, measurement of right ventricular function and chamber volumes is difficult due to the variable
and irregular shape of the right ventricle, even in normal subjects
(210). Contrast angiography was until recently the only method
to assess right ventricular volumes (211). However, this technique
is invasive and thus has not been widely used to assess patients
with COPO. More recently, noninvasive techniques have been employed to study patients with COPO. These include chest radiography, M-mode and two-dimensional echocardiography, radionuclide ventriculography, and magnetic resonance imaging.

Clinical Assessment
Clinical examinations is relatively insensitive as a means of detecting pulmonary hypertensin or right ventricular dysfunction in
patients with COPO, as clinical signs are often obscured by
hyperinflation of the chest (1, 6, 12). The jugular venous pressure
is also often difficult to assess in patients with COPO because
of large swings in intrathoracic pressure. Peripheral edema can
be due to other causes (such as hypoalbuminemia) and does not
always occur in patients with pulmonary hypertension. A systolic
left parasternal heave indicates right ventricular hypertrophy; extra heart sounds, or the murmur of tricuspid regurgitation, suggest right ventricular dysfunction, but again these are not always
present and may be modified by hyperinflation. Accentuation of
the pulmonary component of the second heart sound indicates
pulmonary hypertension but is not a sensitive indicator of pulmonary hypertension in patients with COPO.

Radiography
The presence of pulmonary arterial hypertension in patients with
COPO has been shown to relate to the width of the right descending pulmonary artery (212, 213). In a study of 61 patients with
COPO, Matthay and coworkers (213) found that the right descending pulmonary artery was> 16 mm in its widest dimension in 43
of 46 patients with pulmonary hypertension, whereas Chetty and
colleagues (214) suggested that a right descending pulmonary
artery of ~ 20 mm Hg was the best discriminant between those
patients with and without pulmonary arterial hypertension. In addition, a high value for the hilar cardiothoracic ratio was 95% sensitive and 100% specific for the presence of pulmonary hypertension in patients with COPO (214). Although measurements on

841

State of the Art: Pathophysiology of Cor Pulmonale in COPD

plain chest radiography may be useful as an initial screening test

for the presence of pulmonary arterial hypertension, they cannot
be used to predict the level of Ppa in individual patients.
Although dilation of the right ventricle gives the heart a lobular appearance, right ventricular hypertrophy or dilation is not easily discernible on a plain chest radiograph. Encroachment of the
retrosternal airspace on a lateral film can be a helpful sign to confirm that the enlarged silhouette is a result of right ventricular dilation (215).
Electrocardiography

The detection of right ventricular hypertrophy by electrocardiography appears to be highly specific but has a low sensitivity. Right
ventricular hypertrophy, identified using a number of electrocardiographic criteria, was confirmed in 75% of cases at autopsy (216).
However isolated right ventricular hypertrophy was present in only
53%, and only 25% of these patients had COPD (216).
Vector cardiography is no more sensitive than conventional
electrocardiography at predicting patients with COPD with mild
to moderate right ventricular hypertrophy (217). Similarly, there
are no advantages of other techniques such as kinetocardiography (218) or orthostatic changes in CO transfer factor, which are
also of poor predictive value for right ventricular hypertrophy in
patients with COPD (219).
Echocardiography

Hyperinflation increases the retrosternal air space, which therefore transmits sound waves poorly, making echocardiography difficult in patients with COPD. However, an adequate examination
has been reported in up to 65% to 80% of patients with COPD
(219, 220). The use of transesophageal echocardiography should
improve these results (221).
Abnormal motion of the pulmonary valve as assessed by
M-mode echocardiography has been used to detect the presence
of pulmonary hypertension. Delayed opening of the valve, midsystolic closure, and an increase in the ratio of right ventricular
pre-ejection time to total ejection time have been reported in patients with pulmonary hypertension (222, 223). Measurement of
the velocity of blood flow in the main pulmonary artery can be
used to estimate the Ppa (224). The interval between the onset
of right ventricular ejection and peak velocity, known as the time
to peak velocity, correlates fairly well with the mean Ppa in patients with COPD (r = 0.73) (225). However, a record of the flowlvelocity from the pulmonary valve may not be possible in 50% of
patients using M-mode echocardiography (226).
The addition of Doppler echocardiography has improved the
assessment of right ventricular systolic ejection flow as an estimate of Ppa (227, 228). However, relatively few studies have been
performed in patients with COPD. Two measurements are required
to estimate peak systolic Ppa: the mean right atrial pressure and
the peak systolic gradient between the right atrium and right ventricle. The addition of these two pressures yields the systolic Ppa.
It is also possible to estimate the end-diastolic Ppa noninvasively
by summing the mean right atrial pressure and the end-diastolic
gradient between the pulmonary artery and the right ventricular
outflow tract. The right atrial pressure can be estimated from the
height of the jugular venous pulse. However, there is a poor correlation between this clinical assessment and pressures measured
at catheterization, particularly in patients with COPD due to the
large swings in intrathoracic pressure (227). A fixed estimate of
right atrial pressure of between 5 and 12 mm Hg has been proposed (228); however, this can lead to considerable error. A more
accurate estimate of right arterial pressure can be obtained by

studying the degree of collapse of the proximal inferior vena cava

by echocardiography during voluntary deep inspiration (229). However, this technique becomes inaccurate in patients with COPD
because the inferior vena cava collapses spontaneously during
respiration in these patients.
Measurement of the right ventricular-atrial gradient can be assessed by Doppler echocardiography from the tricuspid valve
regurgitant jet (230). Tricuspid regurgitation occurs in normal subjects (231) and in patients with COPD (232). The high prevalence
of tricuspid regurgitation was noted as long ago as 1908 by Sir
James McKenzie during his studies of external pulses using
kymography (233). He found that tricuspid insufficiency was so
common that he was "inclined to look upon the valves as being
rarely able to close the orifice properly:' More recently, Morrison
and colleagues (232), in a study of 100 patients with COPD, found
that significant tricuspid regurgitation was present in the majority.
Similarly, in a study by Himelman and coworkers (234), tricuspid
regurgitation was detected in 20 of 36 patients with COPD. The
quality of the signal to detect tricuspid insufficiency using
continuous-wave Doppler echocardiography can be improved by
augmenting the signal with an intravenous infusion of saline (234,
235). However, this may be a problem in patients with COPD, in
whom fluid overload may already be present. From the peak velocity of the tricuspid regurgitant jet (V), the modified Bernoulli
equation (P = 4V2) enables calculation of the peak pressure difference between the right ventricle and atrium (P). As indicated
above, the addition of this pressure gradient to the mean right
atrial pressure allows calculation of the systolic Ppa.
Continuous-wave Doppler echocardiography, even with intravenous saline contrast, fails to produce an adequate assessment
in 35% of patients (236). However, pulsed-wave Doppler echocardiography appears to be an even more sensitive technique to detect tricuspid insufficiency. Using this technique, Migueres and
coworkers (225) were able to measure Ppa in 91% of patients with
COPD. Moreover, pulsed-wave Doppler echocardiography is also
capable of assessing changes in Ppa during exercise (225). Several studies have shown correlations between echocardiographic
measurements of Ppa and pressures measured at cardiac catheterization (224-228), and some of these studies are in patients
with COPD (r 0.98) (224). However, these studies are in a highly
selected group in which those patients in whom the measurement
cannot be made are "selected out."
Two-dimensional echocardiography can be used to assess right
ventricular dimensions and wall thickening and hence to detect
right ventricular volume overload in patients with COPD (219, 237,
238). This technique is more accurate than conventional M-mode
echocardiography (226). However, calculation of right ventricular
volumes is fraught with problems, including the lack of a "gold
standard" by which echocardiographic measurements of volume
can be compared (238, 239). Measurement of right ventricular
volumes by contrast angiography involves a number of assumptions and mathematical calculations, due to the irregularity of the
right ventricular cavity (214, 240).
Detection of right ventricular hypertrophy by echocardiography is limited by the ability to differentiate the right ventricular
wall from its surrounding structures. Moreover, correlations between right ventricular wall thickness and right ventricular weight
are poor, even when measured at autopsy (241,242). Measurement of right ventricular diastolic diameter by echocardiography
may be useful in detecting right ventricular enlargement. This is
particularly true in patients who have had previous episodes of
decompensated right ventricular function (219).
Changes in right ventricular function are difficult to detect by

842

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

echocardiographyand Ooppler echocardiography in patients with

capo and pulmonary arterial hypertension. Prolongation of the

right ventricular pre-ejection time and shortening of the ejection
time may be present in such patients. However, right ventricular
systolic time intervals are also affected by increased right ventricular preload. The position and the curvature of the intraventricular septum also give an indication of right ventricular afterload.
In the normal heart, the interventricular septum moves to the left
during systolic ejection and to the right during diastolic filling. Right
ventricular volume overload tends to reverse this pattern during
cardiac ejection and filling. In addition, right ventricular pressure
overload displaces the septum further toward the left ventricle
(243).
In summary, Ooppler echocardiographic assessment of the tricuspid regurgitant jet appears to be the best method of estimating Ppa noninvasively. In patients with capo, this technique is
limited by the inability to obtain a satisfactory signal in a substantial proportion of patients and by inaccuracies in estimating the
right atrial pressure. Although impressive correlations have been
reported between Ooppler echocardiography and direct measurements of Ppa in highly selected groups of patients, this technique
cannot be used to accurately predict Ppa in individual patients
with capo.

Radionuclide Assessment of Right Ventricular Ejection Fraction

Contrast angiography has been used to measure right ventricular volumes, but the technique is difficult and tedious because
of the wide variability in right ventricular geometry (211, 214, 240,
244). Radionuclide ventriculography largely avoids this problem
and is usually performed using an intravenous injection of technetium-99m-labeled erythrocytes or human serum albumin (245).
A gamma camera is used to acquire a time/activity curve, either
during the first pass of the radiolabeled tracer through the central
circulation or by gating counts from several points throughout the
cardiac cycle once the radiotracer has equilibrated in the blood
pool (246). Because radioactive counts are proportional to volume, variations in the geometric configuration of the ventricle are
less important.
In the first-pass technique, a bolus of the radiotracer is injected
intravenously and followed during a few cardiac cycles as the bolus passes through the right side of the heart to obtain time/activity curves from a region of interest around the right ventricle. From
these time/activity curves the ejection fraction can be calculated,
based on indicator dilution theory (247). The addition of electrocardiographic gating during the first pass provides better definition of end-systole the end-diastole. The right ventricular ejection fraction (RVEF) can be calculated from the difference between
the end-diastolic and end-systolic counts, divided by the enddiastolic counts. The first-pass technique has the advantage that
the ventricles can be separated both in time and space, thus avoiding the problems of overlap between the two chambers. A major
disadvantage is the difficulty in performing sequential measurements, which requires repeated bolus injections of the radiotracer,
increasing the radiation burden to the patient. A further disadvantage is the short acquisition time during the first pass, which
produces low counts and thus statistical uncertainty in calculating the ejection fraction.
Gated-equilibrium ventriculography is usually performed using
a left anterior oblique view in order to separate the ventricles (247),
which can be achieved even in patients with capo (248). However, regions of interest must be drawn both at end-systole and
end-diastole to avoid overlap between the right atrium and right
ventricle, and a correction must be made for background counts

VOL 150

1994

(246, 248). The gated-equilibrium technique has the advantage

of providing better count statistics, since data from several hundred cardiac cycles are acquired. Moreover, repeated measurements can be made over 3 h following a single injection of a radiotracer.
The reproducibility of radionuclide measurements of RVEF appears to be good when measurements are repeated in patients
with capo studied in the same position (247) but not as good
when measurements are made on the same individual on different days (249). This may reflect the inherent variability of the RVEF
in patients with capo or variable ventricular and atrial overlap
resulting from positional changes. In 30 normal subjects, the mean
RVEF was 0.50 0.09 (range, 0.47 to 0.83) (247), giving a lower
limit of normal (two standard deviations below the mean) for RVEF
of 0.40 when measured at rest. RVEF increases in normal subject during exercise by at least 0.05 (258).
Radionuclide ventriculography therefore appears to be an ideal
technique to assess right ventricular function, because it overcomes the problems of the variations in ventricular geometry. It
has proved to be an accurate, reproducible, and noninvasive
method of assessing left ventricular global and regional function
(250). However, measurement of RVEF is more problematic. This
is due to several factors, including the overlap between the right
ventricle and right atrium and the presence, at least in a proportion of patients with capo, of significant tricuspid regurgitation
that leads to an overestimation of the RVEF (232, 251). Although
the mean RVEF in most studies of patients with capo is lower
on average than in normal subjects (245, 252-265), there is considerable overlap between values of RVEF in normal subjects and
patients with capo. Some studies suggest that only those patients who are edematous at the time of study have a low RVEF
(248,266). Indeed, values of RVEF in patients with capo are rarely
as low as in patients with right ventricular infarction (266). In most
studies, mean RVEF is greater than 0.40 when measured at rest
in patients with stable capo (254-257, 263, 265). However, the
normal increase in RVEF does not occur during exercise in such
patients (253, 254, 265, 267, 268), suggesting that latent right ventricular dysfunction is present in patients with capo.
01
'

Thallium Myocardial Scintigraphy

This technique has been used to diagnose right ventricular hypertrophy in patients with pulmonary arterial hypertension from various causes (269-272), including patients with capo (272, 273).
Oata from Weitzenblum and colleagues (273) in 46 patients with
capo showed that the sensitivity of 201thallium imaging in the
diagnosis of right ventricular pressure overloading was 73%. However, this technique is qualitative rather than quantitative and, because it has no advantage over echocardiography, has not found
favor clinically.

Right Ventricular Dimensions Measured by Magnetic

Resonance Imaging
Magnetic resonance imaging is probably now the gold standard
for measuring ventricular dimensions beoause it produces the best
images of the right ventricle (274). This technique is noninvasive
and does not impose a radiation burden on the patient. However,
it is expensive and is available only in specialized centers. Studies
in patients with capo (275) have demonstrated a correlation between the right ventricular free wall volume and both the Ppa
(r = 0.72, P < 0.01) and the pulmonary vascular resistance (r =
0.65, P < 0.01). Interestingly, the right ventricular free wall volume,
as an estimate of wall mass, correlates with the PaC02 but not
with the Pao2 (275). This noninvasive technique appears to be

843

State of the Art: Pathophysiology of Cor Pulmonale in COPD

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AORTIC PRESSURElmmHg
ARTERIAL PRESSURE
ImmHg)

0 10 20 30 40
ATRIAL PRESSURE (em H2O)

Figure 3. The effects of increasing afterload (A) and preload (B) on the right and left ventricles in the dog. Stroke
volume decreases rapidly when afterload is increased in the right ventricle, in contrast to the left ventricle, which
maintains stroke volume reasonably well against an augmented afterload (A). By contrast, stroke work of the
left ventricle increases dramatically when preload is increased, which is not the case with the right ventricle (B).
Modified from Braunwald (188).

the best method of measuring right ventricular dimensions. It can

be used to define right ventricular hypertrophy in patients with
COPO and to study the effect of therapeutic interventions.
RIGHT VENTRICULAR PHYSIOLOGY IN NORMAL
SUBJECTS AND PATIENTS WITH COPD
Normal Right Ventricular Physiology

The concave free wall and convex intraventricular septum of the

right ventricle produces a crescent-shaped chamber. The differences that exist between the two ventricles in adults appear to
be due to the different flow-resistance conditions in the two circulations (276, 277). Right ventricular contraction is achieved by three
maneuvers (22, 278, 279). First, the longitudinal axis of the chamber shortens and the trabeculae and papillary muscles force the
tricuspid valve plane downward toward the apex. This initial contraction contributes very little to the effective ejection. Thereafter,
there is contraction of the concave right ventricular free wall and
the convex septum, followed by left ventricular contraction, which
increases the curvature of the intraventricular septum. The purpose of right ventricular contraction seems to be the generation
of sufficient stroke volume to maintain an adequate cardiac output rather than the generation of pressure. Thus, the right ventricle operates as a "volume" rather than as a "pressure" pump (280).
In general, the thin-walled right ventricle, contracting against the
low-pressure pulmonary circulation, is more compliant than the
thicker-walled left ventricle. The geometric configuration of the
right ventricle is therefore more suited to ejecting large volumes
of blood with minimal myocardial shortening. This enables it to
adapt to considerable variations in systemic venous return without large changes in filling pressures (277, 280, 281) because of
the greater ratio of volume to surface area in the right compared
with the left ventricle. However, the right ventricle appears less

able to cope with an acute increase in afterload (277, 280, 281).

By contrast, the left ventricle acts as a pressure pump in the highresistance systemic circulation and has a small intracavity volume relative to its surface area (282).
Studies in the dog support the view that the right ventricle is
unable to cope with an acute increase in outflow pressure. Active
constriction of the pulmonary artery, producing only a small
change in Ppa, rapidly reduces stroke volume, whereas the stroke
volume is well maintained in the face of an increase in systemic
pressure (Figure 3). By contrast, a fourfold increase in ventricular preload, or filling pressure, induced by volume expansion has
the effect of increasing left ventricular work to five times greater
than that of the right ventricle (188). An interdependence between
the ventricles has been suggested (283), particularly in the presence of right ventricular overload that may shift the intraventricular septum leftward and impair the contractility of the left ventricle (237). However, the clinical significance of this is unknown.
Pulmonary arterial pressures in most patients with COPO and
respiratory failure are not markedly elevated (94, 148) (Table 1).
Furthermore, the rate of progression of pulmonary hypertension
is slow (167, 168). Thus, the effect on right ventricular configuration, mass, and function of moderate pulmonary hypertension,
which slowly progresses in patients with COPO, is likely to be different from the effects of acute pulmonary hypertension such as occurs in massive pulmonary embolism (284) or indeed the effects
of the sustained systemic levels of Ppa present in patients with
primary pulmonary hypertension (285). Therefore, the right ventricle has time to adapt to the modest increase in pressure load
in COPO.
Right Ventricular Function in Stable COPD

As described earlier, patients with mild COPO, without severe hypoxemia or hypercapnia, have a normal or low cardiac output and

844

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

normal right atrial and right ventricular end-diastolic pressures

(1,286,287). The Ppa may be only slightly elevated at rest, but
it is inappropriately high for the level of the cardiac output. Ouring exercise, the Ppa rises to abnormal levels (145, 288). However, as in normal subjects, the increase in cardiac output during
exercise is proportional to the increase in oxygen consumption
(145, 288, 289). Right ventricular end-diastolic pressure also rises
to abnormal levels during exercise, and the right ventricular stroke
work, which is normal at rest in these patients, increases on exercise (146) due to an increase in pressure work against a higher
Ppa. As the disease progresses, with worsening airflow limitation and the development of chronic hypoxemia, commonly associated with chronic hypercapnia, pulmonary hypertension is
present at rest and worsens on exercise (145, 146, 288, 289). Episodes of desaturation during rapid eye movement sleep may also
increase Ppa in patients with COPO (290, 291).
Once pulmonary hypertension is established, the right ventricular stroke work index increases due to an increase in pressure work. However, in patients with stable COPO, the relation
between the right ventricular stroke work index and right ventricular end-diastolic pressure suggests that despite a higher right
ventricular stroke work index, these patients operate on an extension of the normal right ventricular function curve (146). In addition, right ventricular diastolic pressure may be normal, even
in those patients who have reported episodes of peripheral edema
and who have clinical evidence of right ventricular enlargement
(145). Thus, the presence of a normal right ventricular end-diastolic
pressure at rest in patients with COPO does not necessarily indicate that right ventricular end-diastolic volume is also normal. Exercise, however, increases right ventricular end-diastolic pressure
abnormally in the majority of patients.

Right Ventricular Mechanics in COPD

The most important factors affecting right ventricular performance
are preload, afterload, contractility, and heart rate (292, 293).
Preload. Ventricular preload is the force per cross-sectional area
acting on the ventricular muscle fiber bundles immediately before they contract (293). Changes in preload affect end-diastolic
volume, an important determinant of ventricular function, which
can be assessed by the end-diastolic pressurelstoke volume curve
(294). However end-diastolic pressure is not always an accurate
substitute for end-diastolic volume, particularly in patients with
COPO (146, 147).
After/oad. Ventricular afterload is the instantaneous tension on
the ventricular wall during active contraction (243). It is directly
related to both the intracavity pressure in the ventricle and the
internal ventricular dimension and inversely related to the ventricular wall thickness. Afterload can be measured in the left ventricle as the mean midwall circumferential wall stress and has been
shown to correlate with left ventricle ejection fraction (295). This
measurement is not possible in the right ventricle due to geometric constraints (211).
The "right ventricular hypothesis" of the development of cor
pulmonale (296, 297) suggests that RVEF is highly afterload dependent. However, correlations between Ppa and RVEF vary
widely in the literature (47, 72, 252, 258, 263, 298-306). Although
this may be partly accounted for by differences in the technique
used to measure RVEF, it should be remembered that RVEF depends not only on right ventricular afterload but also on ventricular contractility and preload. Moreover, Ppa is not an accurate
reflection of the right ventricular afterload, which is more accurately
defined as the stress or tension acting on the fibers of the right

INCREASED
CONTRACTILITY
:I:

I.LJ

0:::

//

120

0:::

/// "'HEART
FAILURE

:::>

STROKE VOLUME

<{
.-oJ

0:::

,,/

I.LJ

LJ

/
/
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180

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0:::

~NORMAL
,,-

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1994

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VOL 150

60

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50
100
150
VENTRICULAR VOLUME ( ml )

Figure 4. A diagramatic representation of the relation between left ventricular volume and pressure. The end-systolic pressure volume relation
is linear, but it is displaced downward and to the right in heart failure and
upwards and to the left when contractility is increased. An idealized pressurelvolume loop is included (arrow), and the curvilinear line represents
the end-diastolic pressurelvolume relation.

ventricular wall immediately after the onset of shortening (307),

ie, the force per unit cross-sectional area acting on the right ventricular wall (292). The Ppa is often used as an estimate of the
right ventricular afterload; however, it represents only a fraction
of the true afterload. Pulmonary vascular resistance may be a
slightly more accurate reflection of the true right ventricular afterload, but it is still an approximation. Thus, the RVEF should not
be regarded as a noninvasive estimation of the Ppa in patients
with COPO.
Contractility. Ventricular contractility .is a measure of the ability
of cardiac muscle to perform stroke work independent of changes
in initial fiber length (293). It is useful to assess changes in ventricular contractility that are independent of those caused byalterations in preload, afterload, or both (294). It is also important
to distinguish between "myocardial contractility" and ventricular
"pump function:' Thus, adverse loading conditions can induce the
ventricle to fail as a pump without depressing myocardial contractility. Moreover, ventricular pump function may be maintained
by favorable loading conditions in the presence of poor myocardial contractility. According to Strobeck and Sonnenblick (294),
ventricular failure should be subdivided ,into "myocardial failure,"
resulting in a decrease in the speed and force of muscle contraction that (if severe) leads to "pump failur,' and a low cardiac output, and "congestive failure," which consists of the systemic responses to an inadequate pump, such as augmentation of
sympathetic nervous system activity, renal vasoconstriction, and
activation of the renin-angiotensin system. Thus, although myocardial failure always results in congestive failure, the reverse is
not always true (308). Categorizing heart failure in this way helps
to explain the incongruity between the hemodynamic findings and
the clinical picture in patients with COPO (279).
As discussed earlier, cardiac output is normal in the majority

State of the Art: Pathophyslology of Cor Pulmonale in COPO

90
80
c:TI

70

E
E

60

u
<5
iii

50

>.

II)

~
u.

40
30
20

30

50

70

90 110 130 150 170 190

ESVI mllm 2

Figure 5. Right ventricular end-systolic pressure relationship at rest (closed

circles) and during exercise (open circles) in 24 patients with COPO. The
mean values at rest (closed triangles) and during exercise (open triangles) are shown. In most patients there is a substantial increase in right

ventricular systolic pressure without large changes in end-systolic volume

index. PRV (systolic) = right ventricular systolic pressure; ESVI = right
ventricular end-systolic volume index. From Biernacki and colleagues (306).

of patients with COPO (287), even in those with clinical signs of

"congestive failure" (114, 265, 288). The RVEF is not a good measurement of intrinsic right ventricular contractility since it also depends on preload and afterload (251). Thus, to assess the contractility or inotropic state of the right ventricle rather than its global
performance, as measured by the RVEF, it is necessary to assess a function of the ventricle that is independent of changes
in preload and afterload.
Indexes of contractility, reviewed by Sagawa (309), were initially developed to assess left ventricular function. These depend
on the relationship between the pressure and volume of the ventricle at end-systole. The end-systolic pressure-volume relation was
first developed in isolated heart preparations (309-311) but has
also been shown to be applicable, in vivo, in man (312, 313).
Changes in the relation between ventricular pressure and volume
in isolated heart preparations can be plotted as a continuous
pressure-volume loop. The end-systolic pressure-volume relation
has been shown to be independent of the initial ventricular volume (314) so that for a given contractile state, an increase in atterload produces less complete emptying of the ventricle and an
increase in end-systolic volume (315). However, the end-systolic
pressure-volume ratio remains constant, indicating that this relation is also independent of changes in afterload. In conditions of
decreased contractility, such as heart failure, the relation between
end-systolic pressure and volume in the left ventricle shifts downward and to the right, whereas increased contractility shifts the
relation upward and to the left, increasing its slope (265, 311) (Figure 4). Thus, this relation defines the inotropic state of the ventricle independent of loading conditions (310). A similar relation has
also been demonstrated in the right ventricle (316).
The slope of the end-systolic pressure-volume relation describes the interaction between afterload and systolic performance
and is termed the ventricular systolic elastance (243). The peak

845

elastance is a particularly good index of the contractile state of

the ventricle (317). The slope of the end-systolic pressure-volume
relation in the right ventricle is less than that of the left ventricle,
resulting in a greater volume change for a given change in pressure (316, 317). Measurement of the end-systolic pressure-volume
relation in the right ventricle is fraught with difficulties. The relationship may not always be linear (318) and may not be entirely
independent of the loading conditions (319), because it may also
be sensitive to changes in ventricular compliance (320). Moreover,
if measurements of right ventricular volumes are made using radionuclide ventriculography, right ventricular end-ejection and true
end-systole may not always coincide (321). Furthermore, to assess the slope of the end-systolic pressure-volume relation, measurements must be made under two or more different loading conditions (322). Allowing for these constraints, simultaneous
measurements of stroke volume by right heart catheterization
using the thermodilution technique and RVEF by radionuclide ventriculography allow quantification of right ventricular volume (323).
This, together with simultaneous measurement of right ventricular pressure, enables measurement of the end-systolic pressurevolume relation in patients with COPO as an assessment of right
ventricular contractility.
In a study of 20 patients with severe but stable COPO (318) who
were hypoxemic with variable degrees of hypercapnia and pulmonary hypertension (25 9 mm Hg), the mean end-systolic
pressurelvolume index was '.IT 16 ( SO) ml/m3 . Measurements
of the right ventricular pressure-volume relation measured as a
single point or the slope of this relation which suggest relatively
well-preserved right ventricular contractility in patieAts with COPO,
even in the face of pulmonary hypertension (323). Thus, in most
patients with COPO the end-systolic pressure-volume ratio is displaced to the left, compared with the normal values, suggesting
normal if not hypernormal right ventricular contractility. These data
have been confirmed by other researchers (263). Indeed, in one
study of patients with pulmonary hypertension secondary to left
ventricular dysfunction in which the mean Ppa was 47 12 mm
Hg (ie, much higher than in patients with stable COPO), the slope
of the pressure-volume relation was more than unity in many of
the patients, again indicating a well-preserved right ventricular
contractility in the face of a substantial increase in Ppa (324). Further data in support of the presence of relatively normal right ventricular contractility in patients with hypoxic COPO come from
studies of the effect of exercise on the right ventricular pressurevolume relation. In 24 patients with COPO, most of whom had pulmonary arterial hypertension during exercise, there was relatively
little change in the end-systolic volume, even in the face of a large
increase in right ventricular systolic pressure, which suggests good
ventricular contractility (306) (Figure 5). However, Brent and coworkers (47), in a combined radionuclidelcardiac catheterization
study, found evidence of depressed right ventricular contractility
in COPO. This discrepancy in the literature is likely to be due to
differences in the technique used to measure RVEF.
Relatively normal right ventricular function in patients with
COPO and pulmonary hypertension has also been suggested in
studies in which other indexes have been used to assess right
ventricular function. Stein and coworkers (284) measured the right
ventricular maximal isovolumic rate of development of ventricular pressure, which they found to be normal, even in those patients with pulmonary hypertension and previous evidence of "right
ventricular failure," consequent on left ventricular dysfunction. In
patients with pulmonary hypertension secondary to mitral stenosis, Wroblewski and colleagues (324) assessed right ventricular

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

846

r----------,
I
I

:,

~ Effective Renal Plasma Flow

t Filtration Fraction
t Peritibular Oncotic Pressure

r--------

: Dopami
I
I
L

H~P02

t pC0 2

RBFt

I,- Dopamine Jl-_J __

AN_

Plasma Renin
Activity

VOl150

1994

1
t Tubular Na+-H+
Exchange

1
r---

iL AN_

Angiotensin II I

1
It Plasma
Aldosterone

r---

iAN
L _

tArginine
Vasopressin
level

Na+ Retention:
Edema

1+

---I
I
I

ne

__ J

H 0 Retention;
2
Hyponatremia

Figure 6. Mechanisms of salt and water disturbance in patients with COPO. The continuous lines and boxes
indicate the abnormalities in renal functions, salt water, and hormonal balance. The dotted lines indicate proposed protective mechanisms against this disturbance. RBF = renal blood flow; ANP = atrial natriuretic peptide;
ANG II = angiotensin II; Na+ = sodium; H+ = hydrogen ion; AVP = arginine vasopressin.

performance by plotting stroke work against end-diastolic pressure and stroke volume; this was similar to the analysis done by
Khaja and Parker (146) in patients with COPO. These authors concluded that patients with stable COPO had normal right ventricular function despite the presence of pulmonary arterial hypertension.
Recently, Chappuis and colleagues (325) developed a technique to measure right ventricular function by intravenous digital
angiography. Simultaneous measurements of right ventricular volume were generated by computer from the timeJvolume curve during the cardiac cycle and measurements of right ventricular pressure using a catheter-tip manometer. This sophisticated technique
holds some promise for measuring right ventricular function, as
does magnetic resonance imaging (326).
Right Ventricular Function in Acute Exacerbations of COPO

Although the mean Ppa is between 25 and 35 mm Hg in most

studies of patients with stable hypoxic COPO (306), during exacerbations the Ppa rises to 45 to 70 mg Hg (327-329) due to
several mechanisms that include worsening hypoxia, acidosis,
and changes in pulmonary mechanics. However, not every patient who develops pulmonary hypertension during an acute exacerbation has signs of "right ventricular failure." The pathophysiology of edema formation in COPO remains unresolved but is
unlikely to be due entirely to right ventricular dysfunction as a result of the presence of chronic but mild pulmonary hypertension
(see below).
Relatively few studies have been done in patients with COPO
who present acutely with edema (50, 114, 146,330-332). An important early study was done by Abraham and coworkers (114)
in eight patients with COPO presenting with acute respiratory failure, of whom six had peripheral edema. Hemodynamics were
measured by cardiac catheterization on the day of admission, daily
thereafter for 5 d, and again upon recovery. This study showed
convincing evidence of a rise in Ppa during exacerbations of
COPO. However, right ventricular mechanics were not measured.

In a more recent study, the end-systolic and end-diastolic volumes

in patients with COPO presenting acutely with edema were higher,
and therefore the pressure-volume ratio was lower than in stable
patients, suggesting decreased contractility in the group with
edema (331). Although cardiac output was preserved in both
groups, the right ventricle, at least by its inability to "accept and
expel the venous return" (11,12), can be said to have failed. The
increase in ventricular volume in those with edema did not appear to result from an augmented right ventricular afterload alone,
since ventricular volumes were normal in a group of patients with
a similar level of Ppa and pulmonary vascular resistance but without peripheral edema (331). Thus, the cause of the decreased right
ventricular contractility in these patients with edema remains unclear.
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