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Cor pulmonale
E Weitzenblum1 and A Chaouat2
1University
The term cor pulmonale is still popular but there is presently no consensual definition and it
seems more appropriate to define the condition by the presence of pulmonary hypertension
(PH) resulting from diseases affecting the structure and/or the function of the lungs: PH results
in right ventricular enlargement and may lead with time to right heart failure (RHF). Chronic
obstructive pulmonary disease (COPD) is the first cause of cor pulmonale, far before idiopathic
pulmonary fibrosis and obesityhypoventilation syndrome. In chronic respiratory disease
(CRD) PH is pre-capillary, due to an increase of pulmonary vascular resistance (PVR).
The first cause of increased PVR is chronic long-standing alveolar hypoxia which induces pulmonary vascular remodeling. The main characteristic of PH in CRD and particularly in COPD
is its mild to moderate degree, resting pulmonary artery mean pressure (PAP) in a stable state of
the disease usually ranging between 20 and 35 mmHg. However, PH may worsen during exercise, sleep, and exacerbations of the disease. These acute increases in afterload can favor the
development of RHF. A minority (<5%) of COPD patients exhibit severe or disproportionate PH (PAP >40 mmHg), the mechanism of which is not well understood. At present longterm oxygen therapy (LTOT) is the logical treatment of PH since alveolar hypoxia is considered
to be the major determinant of the elevation of PAP and PVR. LTOT stabilizes or at least
attenuates and sometimes reverses the progression of PH, but PAP seldom returns to normal.
Vasodilators (prostacyclin, endothelin receptor antagonists, sildenafil, nitric oxide) could be
considered in patients with severe PH but controlled studies in this field are presently lacking. Chronic Respiratory Disease 2009; 6: 177185
Key words: chronic respiratory failure; COPD; cor pulmonale; pulmonary hypertension
The term cor pulmonale is still popular in the medical literature, but there is presently no consensual
definition. In 1963, 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,1 but this pathological definition is in fact of
limited value in clinical practice. As pulmonary
hypertension (PH) is the sine qua non of cor pulmonale,2 we believe that the best definition of cor
pulmonale is the following: PH resulting from diseases affecting the structure and/or the function of
the lungs; PH results in right ventricular enlargement
and may lead with time to right heart failure (RHF).
This article reviews the current state of knowledge about PH resulting from disorders of the respiratory system and/or from chronic hypoxemia.
Particular emphasis will be placed on chronic
Correspondence to: E Weitzenblum (Professor), Service de Pneumologie, Nouvel Hpital Civil, 67091 Strasbourg Cedex, France.
Email: emmanuel.weitzenblum@chru-strasbourg.fr
The Author(s), 2009.
Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Definition
In the new diagnostic classification of PH,3 cor
pulmonale corresponds to the third group of the
classification (PH associated with disorders of the
respiratory system and/or hypoxemia) and must be
distinguished from idiopathic pulmonary arterial
hypertension (IPAH) and neighboring conditions
(group 1), from pulmonary venous hypertension
(group 2) and from thromboembolic PH (group 4).
PH complicating chronic respiratory disease, particularly COPD, was generally defined by the presence of a pulmonary artery mean pressure (PAP)
> 20 mmHg, which is slightly different from the
definition of IPAH (PAP > 25 mmHg).4 In young,
healthy subjects, PAP is most often between 10 and
15 mmHg.5 With aging, there is a slight increase in
PAP, not exceeding 1 mmHg/10 years as a mean.5
10.1177/1479972309104664
Cor pulmonale
E Weitzenblum and A Chaouat
178
bRelatively
Pathophysiology: mechanisms of PH
in chronic respiratory disease
As stated above, PH is the sine qua non of cor
pulmonale. Accordingly, the mechanisms of cor
Cor pulmonale
E Weitzenblum and A Chaouat
179
pulmonale are first those of PH. In chronic respiratory diseases, PH results from increased pulmonary
vascular resistance (PVR), whereas cardiac output
and pulmonary capillary wedge pressure
(PCWP) are generally normal; PH is said to be
precapillary.
The factors leading to an increased PVR in chronic
respiratory diseases are listed in Table 2. These factors are numerous,13,14 but alveolar hypoxia is by
far the predominant one,2,13,15 at least in COPD,
kyphoscoliosis, and the obesity-hypoventilation
syndrome.16 In interstitial lung diseases, the elevated
PVR is due to a variable combination of anatomical
(tissue destruction and loss of pulmonary vascular
bed consecutive to lung fibrosis17) and physiological
factors (alveolar hypoxia17,18).
Two distinct mechanisms of action of alveolar
hypoxia must be considered: acute hypoxia causes
pulmonary vasoconstriction and chronic hypoxia
induces with time structural changes in the pulmonary vascular bed, the so-called remodeling of the
pulmonary vasculature.
Acute alveolar hypoxia induces in humans and
in almost all species of mammals a rise of PVR
and PAP, which is accounted for by hypoxic pulmonary vasoconstriction. Hypoxic vasoconstriction is
observed in normal subjects as well as in patients
with chronic respiratory disease.19 This vasoconstriction is localized in small precapillary arteries,
and its mechanism is now better understood.20 In
fact, the reactivity of the pulmonary circulation to
acute hypoxia varies from one individual to another
and this interindividual variability is also found in
COPD patients.21
Chronic alveolar hypoxia induces in healthy people living at altitudes > 3500 m precapillary PH,
nearly identical to that observed in COPD,22 and
Table 2 Factors increasing pulmonary vascular resistance in
chronic respiratory diseases
Anatomic factors: reduction (destruction, obstruction) of the
pulmonary vascular bed
Thromboembolic lesions
Fibrosis
Emphysema
Functional factors
Alvolar hypoxiaa
Acute hypoxia (pulmonary vasoconstriction)
Chronic hypoxia (remodeling of the pulmonary vascular bed)
Acidosis, hypercapnia
Hyperviscosity (polycythemia)
Hypervolemia (polycythemia)
Mechanical factors (compression of alveolar vessels)
aMost
important factor.
Cor pulmonale
E Weitzenblum and A Chaouat
180
Cor pulmonale
E Weitzenblum and A Chaouat
181
Table 3 Comparison of pulmonary hypertension in chronic hypoxic lung disease (COPD, IPF, OHS) to idiopathic PAH and
CTEPH
References
Number of patients
Age
FEV1 (mL)
FEV1 (% of predicted)
PaO2 (mmHg)
PaCO2 (mmHg)
PAP (mmHg)
PCWP (mmHg)
Q (L/min/m)
COPD
IPF
OHS
Idiopathic PAH
CTEPH
Weitzenblum, et al.32
62
55 8
1170 390
60 9
45 6
26 6
82
3.8 1.1
Weitzenblum, et al.18
31
58 16
1655 650
68 12
35 5
24 11
74
3.4 0.8
Kessler, et al.11
36
62 12
1610 600
59 8
50 4
26 10
2.9 0.9
Humbert, et al.34
259
50
>70
56
8
2.3
Jamieson, et al.35
500
46
2.2
Severe or disproportionate PH
in chronic respiratory disease
The concept of disproportionate PH is recent and
relates to COPD patients33,45 but can be extended to
other causes of chronic respiratory disease. We have
seen that in COPD, PH is usually mild to moderate.
A minority of patients exhibit severe PH, which can
be defined by a resting PAP > 3540 mmHg. This
level of PH is considered as disproportionate
and recent studies aimed to evaluate its frequency
and understand its mechanisms.
From PH to RHF
The progression of PH is slow, at least in
COPD.43,46,47 To our knowledge, similar studies
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Cor pulmonale
E Weitzenblum and A Chaouat
182
Table 4 Comparison of three groups of patients with chronic obstructive pulmonary disease classified according to the presence
and severity of pulmonary hypertension
Age (years)
FEV1 (% predicted)
FEV1/VC (%)
DLCO (mL/min/mmHg)
PaO2 (mmHg)
PaCO2 (mmHg)
A-aO2 (mmHg)
PAP (mmHg)
PCWP (mmHg)
Q (L/min/m)
TPR (IU/m)
Group 1
Group 2
Group 3
67
50
49
4.6
46
32
56
48
6
2.3
21.3
66
27
34
10.3
56
47
30
25
7
2.8
9.0
62
35
39
13
72
40
28
16
7.5
3.3
4.0
(6268)
(4456)
(3953)
(4.26.7)
(4153)
(2837)
(5068)
(4650)
(47)
(1.82.5)
(17.636.6)
(6373)
(2334)
(2638)
(8.912.8)
(5464)
(4449)
(2737)
(2237)
(6.57.5)
(2.43.1)
(7.49.9)
(5375)
(2950)
(3152)
(11.017.0)
(6876)
(3742)
(2534)
(1318)
(77.5)
(2.94.0)
(3.75.5)
observed in some COPD patients. There is a relationship between the severity of PH and the development of RHF.
Peripheral edema is frequently observed in
advanced COPD patients and is considered to
reflect RHF, but the possible occurrence of RHF
in these patients has been questioned,26,27 in particular because the degree of PH is most often mild in
COPD. Peripheral edema is not synonymous with
RHF13,27 and may simply indicate the presence
of secondary hyperaldosteronism induced by functional renal insufficiency.48
The role of pressure overload in the development
of RHF in these patients has also been debated.
MacNee, et al.49 comparing COPD patients with
and without clinical (edema) and hemodynamic
signs of RHF concluded that RHF was probably
due to other causes than PH. A study from our
group44 has led to different conclusions: in 9/16
patients with marked peripheral edema, hemodynamic signs of RHF were present and were
probably accounted for by a significant worsening
of PH during the episode of edema which in turn
was explained by a worsening of hypoxemia.
Right ventricular contractility, assessed by the
end-systolic pressurevolume relation, is near normal in COPD patients with PH investigated in a
stable state but has been found decreased during
Cor pulmonale
E Weitzenblum and A Chaouat
183
References
Treatment of cor pulmonale
The treatment of RHF involves diuretics (most
often frusemide) and oxygen therapy. The treatment
of PH includes LTOT and vasodilators. Is it really
necessary to treat PH in chronic hypoxic lung disease? We have seen that PH, when present, is mild to
moderate in most COPD patients and the necessity
for treatment can be questioned. The best argument
in favor of treatment is that PH, even when modest
during a stable state of the disease, may worsen particularly during acute exacerbations, and these acute
increases in PAP can contribute to the development
of RHF.44
LTOT, which is prescribed to markedly hypoxemic (PaO2 < 55 mmHg) respiratory patients has
favorable pulmonary hemodynamic effects as
demonstrated by the pivotal NOTT and MRC
studies.51,52 Further studies more specifically
devoted to the pulmonary hemodynamic evolution
under LTOT54,55 have shown either a tendency to
the reversal of the progression of PH54 or a stabili-
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