Cardiovascular Involvement in General Medical Conditions

Pulmonary Diseases and the Heart

MeiLan K. Han, MD, MS; Vallerie V. McLaughlin, MD; Gerard J. Criner, MD;
Fernando J. Martinez, MD, MS

Abstract—The complex nature of interactions between the pulmonary and cardiovascular systems is becoming increasingly
appreciated. Pulmonary vascular abnormalities are frequently present in patients with respiratory disorders, including
chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, sarcoidosis, neuromuscular or chest wall
disorders, and disorders of ventilatory control including sleep apnea syndromes and obesity hypoventilation syndrome.
Pulmonary hypertension, classified as group III in the World Health Organization classification scheme for pulmonary
hypertension, may result in severe right ventricular dysfunction caused by lung disease, also known as cor pulmonale.
The development of cor pulmonale is generally associated with poorer prognosis and increased death. Systemic
manifestations of lung disease, particularly obstructive disorders, are also particularly relevant because they are
associated with increased cardiac death and impaired health status. This article will discuss the most common pulmonary
diseases and disorders of ventilatory control that cause pulmonary vascular abnormalities and cor pulmonale, with
particular concentration on how treatment of these diseases may affect the heart. In addition, the complex nature of
cardiac and lung disease will also be explored, particularly with respect to the relationship between chronic obstructive
pulmonary disease, systemic inflammation, atherosclerosis, and cardiovascular death, which is currently a very active
focus of research. (Circulation. 2007;116:2992-3005.)
Key Words pulmonary heart disease 䡲 pulmonary disease, chronic obstructive 䡲 hypertension, pulmonary 䡲
inflammation

S ystemic manifestations have become increasingly recog-

nized in lung diseases, particularly obstructive disorders.1
hypertrophy, dilation, or both secondary to PH caused by
pulmonary disorders.4 Between 10% and 30% of heart failure
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Cardiovascular involvement is particularly relevant because it
is associated with impaired health status and worsened
mortality. In the present targeted review we will discuss
evolving data regarding pulmonary vascular abnormalities in
the most common respiratory disorders, including chronic
obstructive pulmonary disease (COPD), idiopathic pulmo-
nary fibrosis, sarcoidosis, neuromuscular or chest wall disor-
ders, and disorders of ventilatory control. We will also
explore the relationship between COPD and systemic inflam-
mation, atherosclerosis, and cardiovascular death.
Pulmonary Vascular Disease in
Respiratory Illness
The classification of pulmonary hypertension (PH) has re-
cently been revised, and PH associated with hypoxemic
pulmonary disorders falls into World Health Organization
group III.2 Cor pulmonale was defined by the World Health
Organization in 1963 as “hypertrophy of the right ventricle
(RV) resulting from diseases affecting the function and/or
structure of the lungs, except when these pulmonary alter-
ations are the result of diseases that primarily affect the left
side of the heart, as in congenital heart disease.”3 Since then
the definition has come to encompass both right ventricular
admissions in the US are the result of cor pulmonale with the
most common cause in the United States being COPD, in 1
study accounting for 84% of cases.5,6 Other lung diseases
known to cause cor pulmonale include interstitial lung dis-
eases, restrictive ventilatory defects caused by thoracic cage
deformities or neuromuscular diseases that cause respiratory
muscle weakness, and disorders of ventilatory control includ-
ing sleep-disordered breathing and obesity hypoventilation
syndrome (OHS).
PH in hypoxemic lung diseases is likely the result of
multiple factors including pulmonary vasoconstriction caused
by alveolar hypoxia,7 acidemia,7 hypercarbia,8 the distortion
of pulmonary vessels by parenchymal changes, and increased
cardiac output and blood viscosity from polycythemia sec-
ondary to hypoxia. This has been best conceptualized in
COPD (Figure 1). The hypoxic pulmonary vasoconstrictor
response is an important adaptive mechanism in human
physiology, shunting blood away from hypoxic regions to-
ward better-ventilated areas of the lung, thus improving
ventilation-perfusion matching within the lung. Pulmonary
vascular remodeling in response to hypoxia is also mediated
by a number of other factors including nitric oxide,9 endo-
thelin,10 serotonin, and hypoxia inducible factor-1. The role

From the University of Michigan Health System (M.K.H., V.M., F.J.M.), Ann Arbor, Mich, and Temple University School of Medicine (G.C.),
Philadelphia, Pa.
Correspondence to Fernando J. Martinez, MD, MS, 1500 E Medical Center Dr, 3916 Taubman Center, Ann Arbor, MI. E-mail fmartine@umich.edu
© 2007 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.106.685206

2992
 Han et al
Figure 1. Biological mechanisms for the development of pulmo-
nary hypertension in COPD. Diagram shows various cigarette
smoke–related processes that drive vasoconstriction, vasodila-
tion, and cell proliferation in the walls of the small pulmonary
arteries. Most of the effects shown are potentially directly medi-
ated by oxidants in the smoke acting on the vessel wall. The
vessel is shown in the centre with muscular layer and adventitial
layers highlighted. Oxidants in the smoke cause production of
the vasoconstrictor endothelin and the vasoproliferative agents
endothelin and vascular endothelial growth factor (VEGF).
Smoke interferes with nitric oxide mediated vasodilation by
decreasing nitric oxide bioactivity. Air trapping as part of
chronic airflow obstruction appears to play an early role by
inducing vascular compression, and hypoxia causes vasocon-
striction, but only when the oxygen tension is extremely low.
Reprinted from Wright et al,11 with permission from the BMJ
Publishing Group, Ltd. Copyright 2005.
of inflammatory mediators has become increasingly accept-
ed.11,12 Acidosis increases pulmonary vascular resistance
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(PVR) and acts synergistically with hypoxia.7 With the
development of structural changes such as intimal prolifera-
tion and smooth muscle cell hypertrophy, sustained PH
ensues.
The RV is a thin-walled, compliant, low-pressure chamber
that pumps the same stroke volume as the left ventricle (LV)
with ⬇25% of the stroke work because of the normally low
resistance of the pulmonary vasculature.13 The right coronary
artery provides the blood supply to the RV free wall in both
systole and diastole. When chronically pressure-overloaded,
the RV hypertrophies and dilates, which results in both
systolic and diastolic dysfunction.14 RV ischemia may also
result because the right coronary artery is unable to provide
adequate flow to the hypertrophied RV, caused in part by the
reduced right coronary artery to right ventricular cavity
pressure gradient in both systole and diastole. RV dysfunction
is one of the most important prognostic factors in idiopathic
PH.15 In addition, hyperinflation seen in patients with ob-
structive lung disease may also decrease venous return,
further reducing right ventricular filling. In restrictive lung
disease, the inability of the thoracic cage to distend has also
been postulated to impair cardiac filling.16
The degree of LV dysfunction secondary to RV dysfunc-
tion has been an issue of debate. The RV and LV share the
interventricular septum and the pericardial sack, both of
which may allow 1 ventricle to influence the other. The
limited ability of the pericardium to stretch means that a large
change in the volume of the RV may limit the volume of the
LV because of a leftward shift of the interventricular septum.
The markedly negative swings in pleural pressure that occur
Pulmonary Diseases and the Heart 2993
in patients with lung disease may also contribute to increases
in pulmonary artery pressures (PAP) and increases in venous
return to the right heart.17 Subsequent RV dilation may cause
the LV to become stiffer, thus theoretically increasing LV
end-diastolic pressure, decreasing pulmonary venous return,
and reducing LV stroke volume. LV afterload may also
increase with the fall in pleural pressure during inspiration,
which may increase LV end-diastolic volume and thus
decrease LV ejection fraction. In a retrospective review of
434 patients with end-stage pulmonary disease including
COPD, interstitial lung disease, and PH (primary and Eisen-
menger’s syndrome), the prevalence of RV dysfunction (RV
ejection fraction ⬍45%) was 66%, with prevalence being
greater in those with PH as opposed to airway or parenchymal
lung disease.18 However, LV dysfunction (LV ejection frac-
tion ⬍45%) was present in only 6.4% of patients, being more
common in patients with PH (19.6%) as opposed to those
with parenchymal or airway disease (3.6%). Thus clinically,
ventricular interdependence likely plays a greater role when
PH is severe.
Clinical Presentation
PH in hypoxemic lung diseases is relatively common but
generally mild to moderate in severity. Dyspnea is the most
common symptom, but may not be helpful because dyspnea is
so prevalent in this patient population. A change in dyspnea
or the development of additional symptoms such as chest
pain, light-headedness, syncope, and lower extremity edema
may prompt further evaluation. Physical examination find-
ings common in idiopathic PH such as a RV heave, loud
pulmonic component to the second heart sound, tricuspid
regurgitant murmur, and right-sided S4 may also be masked
by the presence of parenchymal lung disease. Severe PH may
also lead to ascites and peripheral edema. Some patients with
severe COPD may develop peripheral edema in the absence
of RV failure, the cause of which is not well understood but
appears to occur more frequently in patient with hypercapnia,
suggesting that an elevated partial pressure of carbon dioxide
may be responsible for sodium retention.19 Hypoxemia itself
may also lead to renal vasoconstriction, thus reducing urinary
sodium excretion and also leading to edema.20
Several ECG findings reflective of cor pulmonale have
been reported, including rightward P-wave axis deviation, an
S1S2S3 pattern, an S1Q3 pattern, evidence of RV hypertrophy,
and right bundle-branch block.21 Low-voltage QRS has also
been reported, more frequently seen in cor pulmonale asso-
ciated with COPD than other pulmonary diseases. Unfortu-
nately, ECG findings are insensitive for detection of PH. In a
small series of COPD patients, only 33% of patients with
elevated PVR had ECG signs of cor pulmonale.22 In a
separate study of COPD patients, the presence of ECG
abnormalities associated with cor pulmonale in addition to an
elevated alveolar-arterial oxygen gradient (⬎48 mm Hg)
during oxygen therapy was associated with a 1.8 greater risk
of death.21 Thus ECG abnormalities suggestive of RV hyper-
trophy can be helpful if present, but if the clinical picture is
still suggestive of cor pulmonale, further testing should be
pursued.
 2994 Circulation December 18/25, 2007

the diagnosis of PH is outlined in Table 1. Overall sensitivity

Figure 2. Correlation between pulmonary arterial pressures
made by echocardiography versus catheterization. (r⫽0.69,
P⬍0.0001). DE indicates Doppler echocardiography; sPAP, sys-
tolic pulmonary artery pressure; and RHC, right heart catheter-
ization. Reprinted from Arcasoy et al,24 with permission from the
American Thoracic Society. Copyright 2003.
The chest x-ray may demonstrate enlargement of the
proximal pulmonary arteries and reduction in retrosternal air
space. Although echocardiography is an invaluable tool in the
evaluation of most forms of PH,23 its utility is more limited in
patients with parenchymal lung disease because suboptimal
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was 85% and specificity was 55%. Given that sensitivity is
better than specificity, a normal echocardiogram can help
exclude significant cor pulmonale, but an elevated estimated
RV systolic pressure must be interpreted with caution.
Right heart catheterization is required to make a definitive
diagnosis of PH.23 The hemodynamic definition includes a
mean PAP ⱖ25 mm Hg with a wedge pressure (or LV
end-diastolic pressure) ⱕ15 mm Hg and a calculated PVR
ⱖ3 Wood Units. Pressures should be carefully measured at
end expiration. The role of pulmonary venous hypertension,
that is, elevated left-heart filling pressures caused most
commonly by LV systolic or diastolic dysfunction, cannot be
overlooked, requiring an accurate measurement of left-heart
filling pressures via pulmonary artery occlusion pressure
measurement. Frequently, patients with chronic lung disease
have diastolic LV dysfunction and may have PH in the setting
of an elevated pulmonary artery occlusion pressure. In these
patients, more aggressive blood pressure control and diuresis
should be initiated. The role of vasodilator testing has not
been extensively studied in this population. In sarcoid-
associated PH, a small series has suggested frequent vasore-
activity,25 whereas another group has not confirmed this26;
the clinical significance of this finding remains unclear.
Patients with significant PH should also be evaluated for
chronic thromboembolic disease because this is a potentially
treatable form of PH. A higher prevalence of pulmonary
emboli in COPD patients with an acute exacerbation27 and in
idiopathic pulmonary fibrosis (IPF) patients has been

images are more frequently encountered. In a recent study of suggested.28

374 lung transplant candidates, Doppler echocardiography
and right heart catheterization were performed within a
72-hour period.24 The correlation between pulmonary arterial
pressures made by echocardiography versus catheterization
can be seen in Figure 2. In almost half of cases patients were
misclassified as having PH by echocardiography. The sensi-
tivity, specificity, and positive and negative predictive values
of RV systolic pressure estimation by echocardiography for
Surrogate markers for the presence of PH in advanced lung
disease have been evaluated. Natriuretic peptides are pro-
duced and released by cardiac myocytes29; B-type natriuretic
peptide (BNP) is produced and released by both the atria and
ventricles. The propeptide circulates and is cleaved into a
biologically active fragment and the N-terminal pro-B-type
natriuretic peptide (NT-proBNP).29 The NT-proBNP has a
longer plasma half-life and considerably higher concentra-

Table 1. Sensitivity, Specificity, and Positive and Negative Predictive Values of Doppler Echocardiography Findings for Diagnosis of
Pulmonary Hypertension
Patient
Group/Finding Sensitivity, % (95% CI) Specificity, % (95% CI) PPV, % (95% CI) NPV, % (95% CI)
All patients*
sPAP 85 (73 to 93) 55 (45 to 64) 52 (41 to 62) 87 (76 to 94)
RV findings† 82 (73 to 89) 57 (51 to 62) 39 (32 to 46) 90 (85 to 94)
OLD
sPAP 76 (50 to 93) 65 (54 to 75) 32 (18 to 48) 93 (83 to 98)
RV findings 84 (67 to 95) 56 (49 to 62) 22 (15 to 30) 96 (91 to 99)
ILD
sPAP 85 (68 to 95) 17 (5 to 39) 60 (44 to 74) 44 (14 to 79)
RV findings 76 (61 to 87) 53 (40 to 67) 57 (43 to 69) 74 (58 to 86)
PPV indicates positive predictive value; NPV, negative predictive value; sPAP, systolic pulmonary artery pressure; RV, right ventricular; OLD, obstructive lung disease;
and ILD, interstitial lung disease.
*Defined as the total group of patients for whom the Doppler echocardiography finding could be ascertained (n⫽166 patients for whom sPAP could be estimated
and n⫽372 patients for whom RV could be visualized).
†RV findings are defined as the presence of RV dilation, hypertrophy, or systolic dysfunction.
Reprinted from Arcasoy et al,24 with permission from the American Thoracic Society. Copyright 2003.
 Han et al
tions.29 Importantly, intraindividual coefficients of variation
vary greatly. Levels tend to rise with advancing age, female
gender, and renal dysfunction, and they decrease with in-
creasing body mass index.29 BNP (level ⬎33.3 pg/mL) has
been suggested to be significantly elevated in patients with
pulmonary fibrosis and PH.30 Sensitivity for moderate to
severe PH was 100% and specificity was 89%. BNP has also
been investigated in patients with COPD. A study that
examined 38 patients with COPD, 20 with cor pulmonale,
demonstrated a significant correlation between BNP and
PAPs.31 Patients with cor pulmonale had significantly higher
BNP levels than those without (73.9 pg/mL versus 21
pg/mL). In a separate study of 176 patients with chronic lung
disease, elevated BNP level identified PH with a sensitivity of
85% and specificity of 88%; an increased BNP also was an
independent risk factor for death.32 A recent study examined
the value of BNP and NT-proBNP in outpatients diagnosed
with COPD by their primary care physicians (spirometrically
confirmed in 59%).33 BNP and NT-proBNP exhibited a high
negative predictive value for systolic heart failure, slightly
lower for diastolic heart failure; no patient had PH given the
mild nature of the underlying pulmonary dysfunction. Given
the high sensitivity of BNP for moderate to severe PH, we
recommend including a BNP measurement in the evaluation
of suspected PH. The combined utility of BNP in conjunction
with echocardiography in patients with lung disease for the
diagnosis of PH is an area where more prospective investi-
gation is required.
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Determination of the cause of increased dyspnea in patients
with chronic lung disease is another arena where BNP
measurement may be useful. Baseline BNP measurements
may be elevated in COPD patients as compared with those
without, but are not as high as those with heart failure.34
Substudy analysis of patients with asthma or COPD included
in the Breathing Not Properly study revealed that a BNP
cutoff of 100 pg/mL exhibited a 93.1% sensitivity, 77.3%
specificity, 51.9% positive predictive value, and 97.7% neg-
ative predictive value for the diagnosis of heart failure, which
was identified in 20.9% of patients.34 If added to clinical
judgment, 95.4% of the congestive heart failure (CHF)
subjects would have been diagnosed correctly. In the Brain
Natriuretic Peptide for Acute Shortness of Breath Evaluation
(BASEL) trial, patients with acute dyspnea were considered
unlikely to have CHF with a BNP ⬍100 pg/mL and very
likely to have CHF with a BNP ⬎500 pg/mL.35 Patients with
BNP levels between 100 and 500 pg/mL were treated based
on best clinical judgment. In a substudy that examined
patients with chronic pulmonary disease (62% with COPD,
12% with asthma), the primary discharge diagnosis was CHF
in 39% of patients and acute exacerbation of COPD in 33%.
This approach resulted in significant reductions in length of
stay and treatment costs. These data suggest that in patients
with COPD, a low BNP (⬍100 pg/mL) can be very helpful in
ruling out significant heart failure, and a very high BNP
(⬎500 pg/mL) can be helpful in ruling in heart failure. Values
between 100 and 500 pg/mL must be interpreted with caution
and in context of the entire clinical picture.
Pulmonary Diseases and the Heart 2995
Chronic Obstructive Pulmonary Disease
COPD has been defined as a “disease with some significant
extrapulmonary effects that may contribute to the severity in
individual patients. Its pulmonary component is characterized
by airflow limitation that is not fully reversible and frequently
progressive due to an abnormal inflammatory response of the
lung to noxious particles or gases.”36 The percentage of
COPD patients who develop cor pulmonale has not been
clearly defined. Available studies vary widely with respect to
the populations studied and the methodology used to define
PH. Some of this variability is likely a result of diagnostic
modality (echocardiography versus right heart catheteriza-
tion) and diagnostic criteria. Table 2 lists a wide range of
available studies, highlighting this variability in prevalence
rates. In general the magnitude of PH is modest, with severe
resting PH being uncommon. Studies that used exercise
challenge document a higher overall prevalence of PH.
Several groups have described “disproportionate” PH in
small numbers of COPD patients. In general, these patients
seem to be characterized by less severe airflow obstruction
but more severe hypoxemia and decreased diffusing
capacity.40,46,47
Longitudinal data addressing PH in COPD are infrequent.
One group examined 131 COPD patients who underwent 2
right heart catheterizations a mean of 6.8 years apart.44 At
initial evaluation no patient had resting PH, although 76
patients exhibited exercise-induced PH. At the second eval-
uation 25% of patients exhibited resting PH (the majority in
those patients with exercise-induced changes at initial eval-
uation); the magnitude of PH was mild. When PH is present
in COPD, numerous groups have documented that its pres-
ence significantly increases the risk for hospitalization48 and
is associated with worsened survival.49,50
Theoretically, any therapy for COPD that slows the loss of
lung function should positively impact cor pulmonale. Of all
COPD therapies, smoking cessation has the most significant
clinical impact in slowing progression of disease, although
there are no longitudinal data linking hemodynamic changes
with smoking cessation.51
Oxygen Therapy
Oxygen is the only therapy for COPD that has been convinc-
ingly shown to improve PH and cor pulmonale and is 1 of the
few noninvasive therapies for COPD that improves mortality.
Two sentinel prospective, controlled studies of long-term O2
in COPD, the British Medical Research Council Long-Term
Domiciliary Oxygen Treatment Trial and the Nocturnal
Oxygen Therapy Trial (NOTT), reported hemodynamic stud-
ies in small subsets of patients. In the British Medical
Research Council trial, PVR increased to a greater extent in
those not treated with O2 as opposed to those treated ⱖ15
hours/d with 2 L/d of O2.52 The NOTT investigators reported
that both resting and exercise PVR were more sharply
reduced in those using continuous O2.53,54 The reported
changes in pulmonary hemodynamics, however, were small.
Although the decreased PVR and increased stroke volume
index were associated with reduced death, NOTT failed to
demonstrate that supplemental O2 was responsible for either
the hemodynamic changes or the survival difference. In
 2996 Circulation December 18/25, 2007

Table 2. Prevalence, Incidence, and Characteristics of Pulmonary Hypertension in Selected COPD Cohorts
Reference Cohort Characteristics Diagnostic Modality N FEV1 PaO2 Proportion With PH
Himelman et al37 Nonhypoxemia cohort Echocardiography 33 1.0 L 70.9 mm Hg 75% with cor pulmonale
Oswald-Mammosser Emphysema cohort Right heart catheterization 84 0.85 L 52 65 of 84 (77%) patients
et al38 with mPAP ⬎20
31 of 84 (37%) patients
with mPAP ⬎30
Bach et al39 LVRS evaluation Echocardiography 206/207* 27.3% pred 67.0 mm Hg 40.1%†
Right heart catheterization 92 NA NA Resting mPAP
⬎35 mm Hg in 5.4%
Chaouat et al40 Chronic respiratory failure Right heart catheterization 998 50% pred 46 mm Hg Resting mPAP
⬎40 mm Hg in 2.7%;
11 patients had COPD
as primary cause
(1.1%)
Christensen et al41 General cohort Right heart catheterization with 17 35% pred 10.4 kPa mPAP with exercise
exercise ⬎30 mm Hg in 65%
Scharf et al42 Emphysema cohort evaluated Right heart catheterization 120 27.0% pred 65.9 mm Hg Resting mPAP
for LVRS ⬎20 mm Hg in 90.8%;
resting mPAP
⬎35 mm Hg in 5.0%
Doi et al43 Emphysema cohort Right heart catheterization 53 39.8% pred 70.9 mm Hg mPAP ⱖ2.7 mPa in 43%
Kessler et al44 Mild to moderate hypoxemia Right heart catheterization 131 44.6% pred 67.0 mm Hg Resting mPAP
cohort ⬎20 mm Hg in none;
exercise mPAP ⬎30 in
58%; mean of 6.8
years later, resting
mPAP ⬎20 mm Hg in
25%
Thabut et al45 LVRS or LT evaluation Right heart catheterization 215 18.5% pred LT; 55.4 mm Hg Resting mPAP
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27.0 % pred in LT; ⬎25 mm Hg in 50.2%;

LVRS 66.2 mm Hg resting mPAP 35 to
in LVRS 45 mm Hg in 9.8%;
resting mPAP
⬎45 mm Hg in 3.7%
PaO2 indicates partial pressure of oxygen in arterial blood: Oswald reference, 52 mm Hg and mPAP ⬎20 mm Hg and mPAP ⬎30 mm Hg; pred, predicted; mPAP,
mean pulmonary artery pressure; LVRS, lung volume reduction surgery; and LT, lung transplantation.
*Adequate image for chamber assessment.
†Abnormal right heart.

addition, the NOTT hemodynamic data were limited to
longitudinal measurement performed only once after treat-
ment, a time point that may have been too soon to document
substantial O2-induced changes in hemodynamic variables.
Finally, the NOTT was also unable to predict the long-term
hemodynamic effects of O2 on the basis of patients’ acute
responses to O2. Three subsequent, small studies examined
the long-term effects of supplemental oxygen on the pulmo-
nary circulation in COPD.55–57 Long-term O2 administration
does appear to be associated with modest decreases in PAPs.
However, the interruption of daily oxygen is followed by an
increase in PVR. These studies, however, were small and
lacked fully characterized subjects and documentation of
compliance with O2. They leave unclear the effect of inter-
mittent versus continuous use of supplemental O2 on hemo-
dynamics in chronic mild-moderate hypoxemic COPD.
Vasodilators
There are limited data regarding the role of vasodilators to
ameliorate PH in COPD patients. One group examined the
effects of sildenafil (50 mg intravenously once followed by
50 mg twice daily orally for 3 months) in 6 patients with
severe COPD (forced expiratory volume in 1 second (FEV1)
16% to 48% predicted).58 The intravenous dose decreased
mean PAP, whereas 3 months of dosing led to decreases in
mean PAP in 5 patients who completed the study
(30.2 mm Hg to 24.6 mm Hg). In contrast, in a separate study
48 weeks of losartan led to little beneficial result in 40 COPD
patients with PH.59 Similarly, a single administration of
nifedipine resulted in modest improvement in mean PAP
without much change in PVR in 33 COPD patients.60 Impor-
tantly, in a series of 6 patients with PH secondary to COPD,
nifedipine reduced PVR but decreased arterial PaO2 as a
result of alteration in V/Q matching.61
Interstitial Lung Disease
Diffuse parenchymal lung diseases (DPLDs) have also been
associated with cor pulmonale. DPLDs are a heterogeneous
group of disorders with similar clinical, radiographic, and
physiological manifestations. These disorders result in
 Han et al Pulmonary Diseases and the Heart 2997

Table 3. Prevalence, Incidence, and Clinical Characteristics of Pulmonary Hypertension in Selected ILD Cohorts
Reference Cohort Characteristics Diagnostic Modality N FVC, % pred DLCO, % pred Proportion With PH
IPF
Nadrous et al62 Random sample Echocardiography 88 63.5 to 72.3* 38.8 to 53.9* Resting estimated sPAP
⬎35 mm Hg in 84%;
resting estimated sPAP
⬎50 mm Hg in 30.7%
Lettieri et al63 Evaluated for LT Right heart catheterization 79 49.3† 31.1† Resting mPAP ⬎25 mm Hg
in 31.6%
Hamada et al64 Prospective random cohort Right heart catheterization 70 76 45 Resting mPAP ⬎25 mm Hg
in 8.1%
Nathan et al65 Mostly evaluated for LT Right heart catheterization 118 54.6† 33.2† Resting mPAP ⬎25 mm Hg
in 40.7%
Sarcoidosis
Sulica et al66 Random sample Echocardiography 106 54† 39† Resting estimated sPAP
ⱖ40 mm Hg in 50.9%
Shorr et al67 Listed for LT Right heart catheterization 363 46.4† NA Resting mPAP ⬎25 mm Hg
in 73.8%; resting mPAP
ⱖ40 mm Hg in 36.1%
Handa et al68 Prospective study of random sample Echocardiography 212 90† 81† Resting estimated sPAP
ⱖ40 mm Hg in 5.7%
pred indicates predicted; FVC, forced vital capacity.
*Lower values in those with lower estimated sPAP.
†In those with PH.

changes in the alveolar walls, perialveolar tissue, and sup-
porting structures. Occupational and environmental expo-
sures can cause DPLD, although frequently the cause is
unknown.
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DLCO and resting hypoxemia should raise clinical suspicion
for PH.
Table 3 also confirms a similar wide range of prevalence
rates in sarcoidosis that likely reflects differences in the

The prevalence of PH in patients with DPLDs varies
greatly.62,66,67 Table 3 presents recent studies of IPF. The
prevalence has varied from as low as 8% to as high as 84%.
As in COPD, diagnostic modality and criteria contribute to
the variability between studies, with prevalence tending to be
higher where echocardiography was used. The recent work of
Hamada and colleagues sheds the most valuable insight. This
group performed a right heart catheterization on 61 IPF
patients at initial evaluation.64 At the time of initial evaluation
only 8.1% of patients exhibited PH; importantly the presence
of elevated PAPs was associated with impaired survival.
Studies of patients undergoing evaluation for lung transplan-
tation have consistently demonstrated a higher prevalence
(Table 3).63,65 An autopsy evaluation study of the RV in
patients with IPF and emphysema suggests that the preva-
lence of RV enlargement between the 2 groups is similar.69
These data, however, may be biased by the fact that all
individuals were deceased and clearly ill, thus the prevalence
of PH and frequency of disease in IPF as compared with
emphysema in less severely ill patients may differ. In another
study of IPF patients alone, the presence of resting hypox-
emia (pulse oximetryⱕ88% or a PaO2ⱕ55 mm Hg) combined
with a carbon monoxide diffusing capacity (DLCO) ⱕ40%
predicted identified the presence of PH with a positive
predictive value of 87% and negative predictive value of
82%.63 A separate retrospective study of 118 IPF patients
(40.7% with PH) noted a modest correlation between DLCO
and PH; DLCO ⬍ 30% predicted was associated with a 2-fold
higher prevalence of PH.65 Thus in patients with IPF, a low
patient populations, diagnostic modality, and diagnostic cri-
teria among studies. As such, patients listed for lung trans-
plantation seem to have greater PH than a more general group
of sarcoid patients. In general a lower total lung capacity is
associated with PH in this setting,68 although a second group
noted only weak association between DLCO and pulmonary
pressures.26
The distinction between primary PH and secondary PH in
DPLD becomes a little less clear. Hypoxic vasoconstriction
contributes to the development of PH in DPLD.70 Destruction
and obliteration of the vasculature secondary to loss of lung
parenchyma and fibrosis likely also plays a role.70,71 Studies
in IPF have reported loss of blood vessels in areas of
honeycomb lung and reductions in the mean capillary surface
area.72,73 Vessel compression may lead to in situ thrombosis,
fibrous organization of vessels, and luminal obliteration.74
Abnormal anastomoses between the pulmonary and systemic
circulation have also been noted in patients with IPF.75 The
degree to which PH in IPF results directly from pulmonary
vascular remodeling is unknown, but has been proposed as a
possible explanation for the apparent disconnect in some
patients between the degree of ventilatory restriction, PH, and
survival.70 Primary vascular involvement may be present in
sarcoidosis; obstruction of vessel walls by granulomas or
perivascular fibrosis has been described.76
Antiinflammatory Therapy
Antiinflammatory agents have been commonly used in treat-
ing DPLDs. Very little data that address the effect of
 2998 Circulation December 18/25, 2007
antiinflammatory therapy on pulmonary vascular disease in
DPLDs are available. Theoretically, agents that slow progres-
sion of fibrotic lung disease should also slow progression of
pulmonary vascular abnormalities. Several groups have ex-
amined the effect of corticosteroid treatment on PH in
patients with sarcoidosis. In a retrospective case series of 10
patients with sarcoidosis and PH who were treated with either
0.5 to 1 mg/kg per d oral prednisone in addition to metho-
trexate or cyclophosphamide, 31.8% of the patients had PH in
the absence of pulmonary fibrosis.26 Three of the 5 cases with
PH and no pulmonary fibrosis experienced substantial and
sustained improvement, which suggests that primary vascu-
lopathy may play a significant role in PH in sarcoidosis that
may be responsive to antiinflammatory therapies, but more
research is needed prior to recommending routine antiinflam-
matory therapy to patients with sarcoidosis and PH in the
absence of pulmonary fibrosis.
Oxygen Therapy
Several studies have shown that oxygen desaturation is
associated with poorer prognosis in IPF.77–79 Scant data exist
addressing the role of oxygen therapy in DPLD patients. A
Cochrane review identified only 1 randomized controlled trial
that failed to show a mortality difference between the
oxygen-treated and control group.80
Advanced Therapies
Very limited data exist regarding novel vasodilators in DPLD
patients. Such therapies can theoretically worsen ventilation-
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perfusion mismatch and thereby increase hypoxemia. One
group documented that both sildenafil and intravenous
epoprostenol decreased PVR in 16 patients with PH and
pulmonary fibrosis; sildenafil improved oxygenation whereas
epoprostenol decreased arterial oxygenation.81 An open-label
study of sildenafil in 14 IPF patients suggested an increased
6-min walk distance (49 meters), although 3 of the subjects
could not finish the 3-month study.82 A retrospective study of
8 patients with sarcoidosis-associated PH noted hemodynam-
ic improvement during an acute vasodilator trial in 6/7
patients; 5 of the 6 responding patients continued chronic
therapy with an average clinical improvement of 1 to 2 New
York Heart Association/World Health Organization classes.83
Such therapies should be considered investigational in DPLD
patients.
Neuromuscular and Chest Wall Diseases
Restrictive lung disease may result from neuromuscular
diseases such as muscular dystrophy, poliomyelitis, myasthe-
nia gravis, or other factors affecting chest wall expansion
such as severe obesity and kyphoscoliosis. This is a diverse
category of diseases, and the exact prevalence of cor pulmo-
nale in each is not known with certainty. Respiratory muscle
weakness and abnormalities in lung and chest wall compli-
ance lead to reductions in vital capacity and in extreme cases
may result in hypoxemia, hypercapnia, and acidosis. For
patients with advanced disease, mechanical ventilation may
ultimately be initiated. Before the development of true
respiratory failure, however, it is believed that the risk for cor
pulmonale is increased by a high prevalence of sleep-
disordered breathing, specifically nocturnal hypoventilation,
in this patient population.84 Nocturnal hypoventilation may
develop before daytime respiratory failure is apparent. Thus
the clinician must be vigilant for patient complaints of
daytime sleepiness, fatigue and lethargy, morning headaches
or impaired concentration that may signal sleep disruption
and nocturnal hypoventilation. Respiratory muscle weakness
contributes to REM-associated nocturnal hypoventilation and
oxygen desaturation, and the severity of diaphragmatic dys-
function has been shown to correlate with the extent of
REM-associated nocturnal oxygen desaturation.85 Nocturnal
oxygen desaturation is less frequent without concomitant
daytime hypercapnia. In patients with neuromuscular disease
and restrictive lung disease, PAP increases with alveolar
hypoventilation during sleep, and a correlation between the
severity of sleep-disordered breathing and cor pulmonale has
been made in several studies.86 – 88
Therapy
Relief of hypoxemia has been demonstrated to improve
hemodynamics. In a study of 8 patients with severe Duchenne
muscular dystrophy, right heart catheterization documented
severe PH in 5 patients. Correction of hypoxemia relieved the
PH.89 Oxygen therapy alone, however, does not correct the
hypoventilation that causes hypoxemia and may actually
worsen preexisting hypercapnia. Frequently, therapy with
nocturnal ventilation, either via tracheotomy and intermittent
positive pressure ventilation or via noninvasive ventilation,
may alleviate the symptoms of respiratory failure and correct
hypercapnia, hypoxemia, and acidosis. Patients should be
considered for nocturnal ventilation if daytime PaCO2 exceeds
or equals 45 mm Hg or if nocturnal hypoventilation with
sustained oxygen desaturation and symptoms of sleep distur-
bance are present.90 Noninvasive positive pressure ventilation
has been documented in patients with neuromuscular and
chest wall diseases to improve nocturnal alveolar hypoventi-
lation, dyspnea, and symptoms associated with sleep-
disordered breathing. In chest wall diseases, noninvasive
positive pressure ventilation but not oxygen improves dys-
pnea and symptoms associated with sleep disturbance.91
Patients treated with noninvasive positive pressure ventilation
demonstrate improved nocturnal and daytime oxygen satura-
tions as compared with the group treated with oxygen alone.
Several case reports have suggested that cor pulmonale can
be at least partially reversed, and PH improved with the
initiation of noninvasive positive pressure ventilation in
patients with restrictive lung disease, although no prospective
studies have specifically addressed this issue. Invasive ven-
tilation with tracheostomy has also been demonstrated to RV
failure in patients with restrictive lung disease.92
Disorders of Ventilatory Control
This category of disorders includes sleep-disordered breath-
ing and obesity hypoventilation syndrome. Sleep-disordered
breathing encompasses several disorders characterized by
abnormalities of respiratory pattern or ventilation during
sleep. Obstructive sleep apnea (OSA) is the most common of
these disorders with an estimated prevalence of 9.1% of men
and 4% of women.93 Diagnosis should be suspected in
 Han et al
patients that have excessive daytime somnolence, obesity,
hypertension, neck circumference ⬎16 inches in a woman or
⬎17 inches in a man,94 history of habitual snoring, or
observed reports of nocturnal choking or gasping. Polysom-
nography remains the gold-standard diagnostic test for OSA.
OHS is characterized by hypersomnolence, dyspnea, and
resting hypoxemia, leading to PH in severe cases. Arterial
blood gas testing is required to confirm daytime hypercapnia
and typically demonstrates hypoxemia and a compensated
respiratory acidosis. Laboratory testing may also reveal
polycythemia caused by chronic hypoxemia. Whereas most
patients with OSA do not have OHS, most patients with OHS
have OSA. These patients frequently demonstrate both OSA
and daytime hypoventilation, likely secondary to a combina-
tion of increased work of breathing and a decreased respira-
tory drive.
Although OSA is frequently cited as a cause of secondary
PH and chronic daytime hypoxemia clearly leads to PH and
cor pulmonale,95 the data that link intermittent nocturnal
hypoxemia and PH are less clear.96 OSA alone may cause
mild PH, but coexisting daytime hypoxia is typically required
for sustained severe PH and cor pulmonale. In 1 observational
study of 50 patients with OSA, patients with cor pulmonale
had more severe nocturnal and daytime hypoxemia; nocturnal
hypoxemia in the absence of daytime hypoxemia was not
associated with cor pulmonale, suggesting that prolonged
hypoxemia was necessary to cause cor pulmonale.97 An
observational study of 27 patients with OSA reported that
41% had mild PH but none had severe PH or cor pulmonale.98
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A study of 90 patients with frequent respiratory disturbances
during sleep noted that patients with more frequent respira-
tory disturbances had a small but statistically significant
increase in RV wall thickness but no differences in right atrial
size, ventricular size, or ventricular function.99 Therefore it is
difficult to ascribe severe PH and cor pulmonale to OSA
alone.
In addition to PH, OSA has also been associated with the
development of hypertension, most clearly demonstrated in
the Wisconsin Sleep Cohort study, which linked the presence
of moderate OSA with a 3-fold increased risk of incident
hypertension.100 Three randomized controlled trials have also
shown that continuous positive airway pressure (CPAP)
therapy for OSA resulted in small but significant reductions
in systemic hypertension (1.3 to 5.3 mm Hg).101–103 OSA has
been associated with increased risk for arrhythmias (includ-
ing sinus bradycardia, atrioventricular block, atrial fibrilla-
tion, and ventricular ectopy) and stroke.104 It has been
hypothesized that the hypoxemia, hypercapnia, sympathetic
activation, and blood pressure alterations that accompany
OSA may also result in myocardial ischemia. The Sleep Heart
Health Study did report OSA as an independent risk factor for
the development of coronary artery disease.105 ST segment
depressions are also more frequent in those with severe
OSA,106 and CPAP therapy has been shown to reduce the
duration of ST segment depressions in individuals with
OSA.107 As with COPD, C-reactive protein (CRP) levels have
also been demonstrated to be elevated in patients with OSA
suggesting systemic inflammation may also be involved in
the pathogenesis of atherosclerosis.104
Pulmonary Diseases and the Heart 2999
Therapy
For patients with OSA and OHS, loss of 10 kg has been
shown to significantly reduce daytime PaCO2 and facilitate
treatment, although weight loss frequently is not curative.108
The mainstay of therapy for OSA is CPAP. Very few studies,
however, have actually examined the effect of CPAP on PAP
or cor pulmonale.109,110 The largest treatment effects have
been noted in patients with elevated PAP prior to therapy.
Theoretically, positive pressure ventilation may also have
direct positive effects on cardiac function by decreasing
preload, decreasing afterload, and improving LV perfor-
mance. In a study of CPAP versus supplemental O2 in patients
with chronic heart failure and central sleep apnea, patients
who received CPAP for 12 weeks had significant improve-
ments in LV ejection fraction.111
Surgical therapy for OSA includes uvulopalatopharyngo-
plasty, which may help select patients, and tracheostomy may
be indicated in severe disease. A series of 19 patients
undergoing uvulopalatopharyngoplasty for OSA demon-
strated a statistically significant increase in RV ejection
fraction (45% to 50%, P⫽0.007).112 Tracheostomy can be
considered both in treatment refractory OSA and OHS.
Atherosclerosis and COPD
Beyond cor pulmonale and PH, other cardiac abnormalities
may be present in patients with COPD. Impaired heart rate
recovery after exercise has been reported in patients with
abnormal spirometry, the cause of which is not clear but may
be related to altered autonomic tone associated with pulmo-
nary dysfunction.113 The prevalence of atrial fibrillation,
atherosclerosis, and CHF is also high among patients with
COPD.114,115 Although some of the association between
COPD and atherosclerosis may be the result of common risk
factors such as tobacco use, epidemiological evidence sug-
gests that impaired lung function is a risk factor for increased
cardiovascular death independent of tobacco use. Analysis of
participants in the National Health and Nutrition Examination
Survey revealed that patients in the lowest FEV1 quintile had the
highest risk of cardiovascular death, with a relative risk of 3.36
after adjusting for Framingham risk factors such as smoking
status, blood pressure, body mass index, and diabetes.116 Fur-
thermore, in a meta-analysis of studies linking reduced FEV1 to
increased cardiovascular death adjusted for smoking status, the
relative risk was 1.77 (95% CI, 1.46 to 1.97).116
COPD, like atherosclerosis,117 is a disease of systemic
inflammation and as such may hasten the progression of
atherosclerotic disease and contribute to the higher rate of
cardiovascular-related morbidity and death in COPD. Recent
evidence suggests that inflammation is noted in all stages of
COPD; numerous systemic inflammatory markers, some of
which are found in cardiovascular disease (IL-6, IL1-␤,
TNF-␣, MMP-9, MCP-1, and high-sensitivity CRP), are
elevated in COPD. Patients with more frequent or severe
exacerbations exhibit particularly robust endogenous proin-
flammatory responses. A meta-analysis of 14 studies recently
confirmed the association between reduced lung function in
COPD and systemic inflammation (eg, CRP, fibrinogen,
IL-6).118 A summary of studies examining CRP levels in
COPD is presented in Table 4. It is notable that elevated CRP
 3000 Circulation December 18/25, 2007
Table 4. Summary of Studies for CRP and COPD That Examined Relationship to Lung Function or Outcomes
Reference Cohort Description
Dentener et al119 Stable COPD, median
FEV1 34% predicted
Eid et al120 Clinically stable patients
with COPD, mean
FEV1 31.2%
predicted
Mannino et al121 Patients with COPD
evaluated as part of
NHANES III
Sin and Man122 Third NHANES cohort
with ageⱖ50 years
and acceptable
spirometry
Yasuda et al123 Stable COPD
Perera et al124 During stability, during
exacerbation, and
Downloaded from http://ahajournals.org by on January 25, 2024
after exacerbation
Dahl et al125 Copenhagen City Heart
Study
Hurst et al126 Mean FEV1 % predicted,
43.9; measurements
of CRP before and
during exacerbation
Man et al127 Lung Health Study
Pinto-Plata et al128 Cross-sectional cohort 88 with COPD; 33 smokers;
study comparing
patients with COPD,
smokers, and
nonsmokers
de Torres et al129 Prospective cohort
study
N FEV1 Study Results
55 FEV1 ⬍80% predicted; CRP elevated in COPD subjects
␤2-agonist reversibility compared to controls
⬍15% or 200 mL;
FEV1/FVC ratio ⬍70%
68 ␤2-agonist bronchodilator CRP elevated in COPD subjects
reversibility ⬍10% compared to healthy subjects
2366 FEV1/FVC ⬍70% CRP elevated in COPD compared
to patients with no lung disease;
higher CRP levels noted in
patients with lower levels of
lung function
6629 FEV1/FVC ⬍70% Severe airflow obstruction
associated with increased CRP
level; moderate to severe airflow
obstruction associated with
increased ischemic change on
ECG; both increased CRP and
moderate to severe airflow
obstruction markedly increased
Cardiac Infarction Injury Score
39 Mild and moderate/severe CRP elevated in COPD compared
COPD to controls; CRP levels similar in
patients with severe disease
compared to mild/moderate
disease
73 FEV1/FVC ⬍70% and CRP elevated in exacerbations;
␤2-agonist high serum CRP concentration
bronchodilator 14 days after exacerbation
reversibility ⬍15% or predicted recurrent exacerbation
200 mL within 50 days
1302 FEV1/FVC ⬍70% After adjusting for ischemic heart
disease and tobacco
consumption, increased risk of
death for CRP ⬎3 mg/L;
baseline CRP higher in those
who subsequently were
hospitalized for or died of COPD
90 FEV1/FVC ⬍70%; FEV1 CRP significantly elevated during
⬍80%; minimal to no exacerbations
reversibility to inhaled
␤2-agonist
4803 Mild to moderate airflow CRP associated with increased risk
obstruction defined as for all-cause, cardiovascular,
FEV1 ⬍90% predicted and cancer-specific causes of
but ⱖ55% predicted in death; elevated CRP associated
the presence of with accelerated decline in FEV1
FEV1/FVC ⬍0.70
FEV1 ⬍55% predicted CRP elevated in patients with
38 nonsmokers COPD compared to smokers and
nonsmokers; CRP lower in
patients treated with inhaled
corticosteroids
130 Postbronchodilator CRP levels higher in COPD patients
FEV1/FVC ⬍0.7 after compared to controls;
inhaled albuterol correlation was found between
CRP and lung function, 6-minute
walk distance, and arterial
oxygen tension
 Han et al Pulmonary Diseases and the Heart 3001

levels correlate with the presence of COPD, the presence of

exacerbations, severity of lung function, and risk for hospi-
talization and death. Importantly, these correlations have
therapeutic implications. Sin et al noted that withdrawal of
inhaled steroids in 27 of 41 COPD patients with moderate-
to-severe disease led to a mean 71% increase in serum CRP
levels.130 Subsequent therapy with inhaled or oral steroids
resulted in 50% and 63% reductions in CRP (P⫽0.039),
respectively, whereas those receiving placebo had 8% reduc-
tions (NS). These data suggest that an inflammatory process
within the COPD lung has systemic correlates and that
antiinflammatory therapy can modulate this systemic inflam-
mation. Another group suggested that COPD patients with
PH exhibited higher serum CRP and TNF-␣ levels. Thus
systemic inflammation may also play a role in the develop-
ment of PH in COPD.12
Multiple clinical trials confirm that ischemic heart disease
is a leading but underrecognized cause of death in COPD.131–
133 In fact, COPD patients are at 2 to 3 times greater risk for

cardiovascular death, accounting for almost 50% of all COPD

deaths.132,134,135 An inverse relationship exists between FEV1
and the presence of atherosclerosis, or cardiovascular death.
FEV1 is an independent predictor of cardiovascular death.136 –
138 Patients with an FEV1⬍2.0 L have a 5-fold increase in

cardiovascular death risk compared with patients with an
FEV1⬎2.0 L (relative risk; 5.03, 95% CI, 3.07 to 8.22).139
The magnitude of death attributed to reduced FEV1 in COPD
is comparable to the magnitude of cardiovascular death
attributable to hypercholesterolemia.140 Furthermore, FEV1
Downloaded from http://ahajournals.org by on January 25, 2024
Figure 3. Retrospective meta-analysis of Canadian database
suggests that statin therapy in COPD patients with a low known
risk for cardiovascular disease can have a profound effect on
reducing the likelihood of COPD hospitalization and cardiovas-
cular morbidity and death. Reprinted from Pinto-Plata et al,143
with permission from Elsevier Limited. Copyright 2006.

decline is associated with increased cardiovascular death.141

Additional support for a causal relationship between
COPD and an increased risk for cardiovascular disease and
death is provided by the Lung Health Study.142 More than
5887 patients with mild to moderate airways obstruction were
followed, with 25% dying from a cardiovascular cause.
Among patients hospitalized at least once over the 5-year
period, cardiovascular causes accounted for 42% of the first
hospitalizations and 48% of the second hospitalizations. The
Tucson Epidemiologic Study of Airways Obstructive Disease
reported cardiovascular as the primary cause of death in
⬇50% of obstructive lung disease cases.132
Because 3-hydroxy-3-methylglutaryl coenzyme A reduc-
tase inhibitors (statins) reduce cardiovascular risk beyond
their lipid-lowering effects and these non–lipid-reducing
actions of statins appear to be antiinflammatory in nature, it
has been hypothesized that statin therapy could have signif-
icant clinical impact in patients with COPD. A recent retro-
spective analysis of a large Canadian database suggests that
statin therapy in COPD patients with a low known risk for
cardiovascular disease can have a profound effect on reduc-
ing the likelihood of COPD hospitalization and cardiovascu-
lar morbidity and death (Figure 3).143 A second, retrospective
cohort study similarly suggested improved survival in COPD
patients treated with statins (hazard ratio, 0.57; 95% CI, 0.38
to 0.87).144
cardiac disease in patients with chronic lung disease portends
a poor prognosis. PH and cor pulmonale are perhaps the best
described cardiac consequences of lung disease, and treat-
ment should be directed at the underlying disorder. Patients
who present with severe PH should be evaluated for another
disease process that is responsible for high PAP before it is
attributed to the underlying lung disease. Although the link
between sleep-disturbed breathing and cor pulmonale is less
clear, the degree of hypoxemia likely correlates with the
development of PH. Sleep-disturbed breathing should cer-
tainly be sought out and treated in patients with PH and cor
pulmonale and in those who have clear risk factors, including
patients with neuromuscular disease, chest wall disease, and
obesity. Although multiple therapies are currently available
for the treatment of World Health Organization group I PH,
none of these have been studied systematically for either
efficacy or safety in the population with lung disease.
Cardiovascular death in patients with COPD is high, and
mounting evidence suggests that systemic inflammation,
particularly in COPD, may also contribute to cardiovascular
disease. Whether therapies such as statins should be initiated
in COPD patients without known cardiovascular disease will
need to be the area of future investigation. Clearly, this is an
area of profound potential impact that requires active
investigation.

Conclusion Disclosures
The present review highlights the complex relationship be- Dr McLaughlin has received research grants from Actelion, En-
tween pulmonary and cardiac disease. The presence of cysive, LungRx, Pfizer, and United Therapeutics. She is a member of
 3002 Circulation December 18/25, 2007
the speaker’s bureau of, received honoraria from, and is a member of
an advisory board for Actelion, Gilead, and Pfizer. Dr Criner has
received research grants from Actelion, Aeris, Boehringer In-
gelheim, Emphasys, GlaxoSmithKline, Novartis, Pfizer, and Scher-
ing Plough. He has received honoraria from Boehringer Ingelheim
and Sepracor. He is also a member of an advisory board for Actelion,
Schering Plough, Sepracor, and Otsuka. Dr Martinez has received
research grants from GlaxoSmithKline. He is a member of the
speaker’s bureau, received honoraria from, and is a member of an
advisory board for Boehringer Ingelheim, GlaxoSmithKline, and
Pfizer. He has also received honoraria payments and is a member of
an advisory board for Altana Pharma and Novartis. Dr Han reports
no conflicts.
References
1. Agusti A. COPD, a multicomponent disease: implications for man-
agement. Respir Med. 2005;99:670 – 682.
2. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domen-
ighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A
Clinical classification of pulmonary hypertension. J Am Coll Cardiol.
2004;43(suppl S):5S–12S.
3. World Health Organization. Chronic cor pulmonale: a report of the
expert committee. Circulation. 1963;27:594 –598.
4. Niederman MS, Matthay RA. Cardiovascular function in secondary
pulmonary hypertension. Heart Lung. 1986;15:341–351.
5. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive
pulmonary disease: part one. Am J Respir Crit Care Med. 1994;150:
833– 852.
6. Ben Jrad I, Slimane ML, Boujnah MR, Ben Hamda K, Ameur Y.
Prognosis and treatment of chronic cor pulmonale [in French]. Tunis
Med. 1993;71:505–508.
7. Enson Y, Giuntini C, Lewis ML, Morris TQ, Ferrer MI, Harvey RM.
The influence of hydrogen ion concentration and hypoxia on the pul-
monary circulation. J Clin Invest. 1964;43:1146 –1162.
8. Durand J, Le Roy Ladurie M, Ranson-Bitker B. Effects of hypoxia and
Downloaded from http://ahajournals.org by on January 25, 2024
hypercapnia on the repartition of pulmonary blood flow in supine
subjects. Respir Res. 1970;5:156 –165.
9. Clini E, Cremona G, Campana M, Scotti C, Pagani M, Bianchi L,
Giordano A, Ambrosino N. Production of endogenous nitric oxide in
chronic obstructive pulmonary disease and patients with cor pulmonale:
correlates with echo-Doppler assessment. Am J Respir Crit Care Med.
2000;162:446 – 450.
10. Cargill RI, Kiely DG, Clark RA, Lipworth BJ. Hypoxaemia and release
of endothelin-1. Thorax. 1995;50:1308 –1310.
11. Wright J, Levy R, Churg A. Pulmonary hypertension in chronic
obstructive pulmonary disease: current theories of pathogenesis and
their implications for treatment. Thorax. 2005;60:605– 609.
12. Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in
patients with COPD and pulmonary hypertension. Chest. 2006;130:
326 –333.
13. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD,
Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ,
Gladwin M, Denholm EM, Gail DB. Right ventricular function and
failure: report of a National Heart, Lung, and Blood Institute working
group on cellular and molecular mechanisms of right heart failure.
Circulation. 2006;114:1883–1891.
14. Weitzenblum E. Chronic cor pulmonale. Heart. 2003;89:225–230.
15. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC,
Fortin T, Ahearn G Prognosis of pulmonary arterial hypertension: ACCP
evidence-based clinical practice guidelines. Chest. 2004;126(suppl):
78S–92S.
16. Hsia CC. Cardiopulmonary limitations to exercise in restrictive lung
disease. Med Sci Sports Exerc. 1999;31(suppl):S28 –S32.
17. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive
pulmonary disease: part two. Am J Respir Crit Care Med. 1994;150:
1158 –1168.
18. Vizza CD, Lynch JP, Ochoa LL, Richardson G, Trulock EP. Right and
left ventricular dysfunction in patients with severe pulmonary disease.
Chest. 1998;113:576 –583.
19. Farber MO, Roberts LR, Weinberger MH, Robertson GL, Fineberg NS,
Manfredi F. Abnormalities of sodium and H2O handling in chronic
obstructive lung disease. Arch Intern Med. 1982;142:1326 –1330.
20. Schafer JA. Robert F. Pitts Memorial Lecture: mechanisms coupling the
absorption of solutes and water in the proximal nephron. Kidney Int.
1984;25:708 –716.
21. Incalzi RA, Fuso L, De Rosa M, Di Napoli A, Basso S, Pagliari G,
Pistelli R. Electrocardiographic signs of chronic cor pulmonale: a
negative prognostic finding in chronic obstructive pulmonary disease.
Circulation. 1999;99:1600 –1605.
22. Burrows B, Kettel LJ, Niden AH, Rabinowitz M, Diener CF. Patterns of
cardiovascular dysfunction in chronic obstructive lung disease. N Engl
J Med. 1972;286:912–918.
23. McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA,
Loyd JE Screening, early detection, and diagnosis of pulmonary arterial
hypertension: ACCP evidence-based clinical practice guidelines. Chest.
2004;126(suppl):14S–34S.
24. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blu-
menthal NP, Pochettino A, Kotloff RM. Echocardiographic assessment
of pulmonary hypertension in patients with advanced lung disease. Am J
Respir Crit Care Med. 2003;167:735–740.
25. Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS.
Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension.
Chest. 2001;120:866 – 872.
26. Nunes H, Humbert M, Capron F, Brauner M, Sitbon O, Battesti JP,
Simonneau G, Valeyre D. Pulmonary hypertension associated with sar-
coidosis: mechanisms, haemodynamics and prognosis. Thorax. 2006;61:
68 –74.
27. Tillie-Leblond I, Marquette C, Perez T, Scherpereel A, Zanetti C,
Tonnel A, Remy-Jardin M. Pulmonary embolism in patients with unex-
plained exacerbation of chronic obstructive pulmonary disease: prev-
alence and risk factors. Ann Int Med. 2006;144:390 –396.
28. Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration
in patients with idiopathic pulmonary fibrosis: causes and assessment.
Am J Med. 1990;88:396 – 404.
29. Burke MA, Cotts WG. Interpretation of B-type natriuretic peptide in
cardiac disease and other comorbid conditions. Heart Fail Rev. 2007;
12:23–36.
30. Leuchte HH, Neurohr C, Baumgartner R, Holzapfel M, Giehrl W,
Vogeser M, Behr J. Brain natriuretic peptide and exercise capacity in
lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med.
2004;170:360 –365.
31. Bozkanat E, Tozkoparan E, Baysan O, Deniz O, Ciftci F, Yokusoglu M.
The significance of elevated brain natriuretic peptide levels in chronic
obstructive pulmonary disease. J Int Med Res. 2005;33:537–544.
32. Leuchte H, Baumgartner R, Nournou M, Vogeser M, Neurohr C,
Trautnitz M, Behr J. Brain natriuretic peptide is a prognostic parameter
in chronic lung disease. Am J Respir Crit Care Med. 2006;173:744 –750.
33. Rutten FH, Cramer MJ, Zuithoff NP, Lammers JW, Verweij W,
Grobbee DE, Hoes AW. Comparison of B-type natriuretic peptide
assays for identifying heart failure in stable elderly patients with a
clinical diagnosis of chronic obstructive pulmonary disease. Eur J Heart
Fail. 2007;9:651– 659.
34. McCullough PA, Hollander JE, Nowak RM, Storrow AB, Duc P,
Omland T, McCord J, Herrmann HC, Steg PG, Westheim A, Knudsen
CW, Abraham WT, Lamba S, Wu AH, Perez A, Clopton P, Krish-
naswamy P, Kazanegra R, Maisel AS. Uncovering heart failure in
patients with a history of pulmonary disease: rationale for the early use
of B-type natriuretic peptide in the emergency department. Acad Emerg
Med. 2003;10:198 –204.
35. Mueller C, Laule-Kilian K, Frana B, Rodriguez D, Scholer A, Schindler
C, Perruchoud AP. Use of B-type natriuretic peptide in the management
of acute dyspnea in patients with pulmonary disease. Am Heart J.
2006;151:471– 477.
36. The Global Initiative for Chronic Obstructive Lung Disease. Global
strategy for the diagnosis, management and prevention of COPD.
Available at: http://www.goldcopd.org. Accessed December 4, 2007.
37. Himelman RB, Struve SN, Brown JK, Namnum P, Schiller NB.
Improved recognition of cor pulmonale in patients with severe chronic
obstructive pulmonary disease. Am J Med. 1988;84:891– 898.
38. Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A,
Charpentier C, Kessler R. Prognostic factors in COPD patients receiving
long-term oxygen therapy: importance of pulmonary artery pressure.
Chest. 1995;107:1193–1198.
39. Bach D, Curtis J, Christensen P, Iannettoni M, Whyte R, Kazerooni E,
Armstrong W, Martinez F. Preoperative echocardiographic evaluation of
patients referred for lung volume reduction surgery. Chest. 1998;114:
972–980.
 Han et al
40. Chaouat A, Bugnet AS, Kadaoui N, Schott R, Enache I, Ducolone A,
Ehrhart M, Kessler R, Weitzenblum E. Severe pulmonary hypertension
and chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
2005;172:189 –194.
41. Christensen CC, Ryg MS, Edvardsen A, Skjonsberg OH. Relationship
between exercise desaturation and pulmonary haemodynamics in COPD
patients. Eur Respir J. 2004;24:580 –586.
42. Scharf S, Iqbal M, Keller C, Criner G, Lee S, Fessler H, National
Emphysema Treatment Trial (NETT) Research Group. Hemodynamic
characterization of patients with severe emphysema. Am J Respir Crit
Care. 2002;166:314 –322.
43. Doi M, Nakano K, Hiramoto T, Kohno N. Significance of pulmonary
artery pressure in emphysema patients with mild-to-moderate
hypoxemia. Respir Med. 2003;97:915–920.
44. Kessler R, Faller M, Weitzenblum E, Chaouat A, Aykut A, Ducolone A,
Ehrhart M, Oswald-Mammosser M. “Natural history” of pulmonary
hypertension in a series of 131 patients with chronic obstructive lung
disease. Am J Respir Crit Care Med. 2001;164:219 –224.
45. Thabut G, Dauriat G, Stern J, Logeart D, Levy A, Marrash-Chahla R,
Mal H. Pulmonary hemodynamics in advanced COPD candidates for
lung volume reduction surgery or lung transplantation. Chest. 2005;127:
1531–1536.
46. Weitzenblum E, Chaouat A. Severe pulmonary hypertension in COPD:
is it a distinct disease? Chest. 2005;127:1480 –1482.
47. Thabut G, Dauriat G, Stern JB, Logeart D, Levy A, Marrash-Chahla R,
Mal H. Pulmonary hemodynamics in advanced COPD candidates for
lung volume reduction surgery or lung transplantation. Chest. 2005;127:
1531–1536.
48. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Pre-
dictive factors of hospitalization for acute exacerbation in a series of 64
patients with chronic obstructive pulmonary disease. Am J Respir Crit
Care Med. 1999;159:158 –164.
49. Weitzenblum E, Hirth C, Ducolone A, Mirhom R, Rasaholinjanahary J,
Ehrhart M. Prognostic value of pulmonary artery pressure in chronic
obstructive pulmonary disease. Thorax. 1981;36:752–758.
50. Finlay M, Middleton HC, Peake MD, Howard P. Cardiac output, pul-
Downloaded from http://ahajournals.org by on January 25, 2024
monary hypertension, hypoxaemia and survival in patients with chronic
obstructive airways disease. Eur J Respir Dis. 1983;64:252–263.
51. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of
Lung Health Study participants after 11 years. Am J Respir Crit Care
Med. 2002;166:675– 679.
52. Long-term domiciliary oxygen therapy in chronic hypoxic cor pul-
monale complicating chronic bronchitis and emphysema. Report of the
Medical Research Council Working Party. Lancet. 1981;1:681– 686.
53. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal
oxygen therapy in hypoxemic chronic obstructive lung disease. Ann
Intern Med. 1980;93:391–398.
54. Timms RM, Khaja FU, Williams GW. Hemodynamic response to
oxygen therapy in chronic obstructive pulmonary disease. Ann Intern
Med. 1985;102:29 –36.
55. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A.
Long-term oxygen therapy can reverse the progression of pulmonary
hypertension in patients with chronic obstructive pulmonary disease. Am
Rev Respir Dis. 1985;131:493– 498.
56. Sliwinski P, Hawrylkiewicz I, Gorecka D, Zielinski J. Acute effect of
oxygen on pulmonary arterial pressure does not predict survival on
long-term oxygen therapy in patients with chronic obstructive pulmo-
nary disease. Am Rev Respir Dis. 1992;146:665– 669.
57. Selinger SR, Kennedy TP, Buescher P, Terry P, Parham W, Gofreed D,
Medinger A, Spagnolo SV, Michael JR. Effects of removing oxygen
from patients with chronic obstructive pulmonary disease. Am Rev
Respir Dis. 1987;136:85–91.
58. Alp S, Skrygan M, Schmidt WE, Bastian A. Sildenafil improves hemo-
dynamic parameters in COPD: an investigation of six patients. Pulm
Pharmacol Ther. 2006;19:386 –390.
59. Morrell NW, Higham MA, Phillips PG, Shakur BH, Robinson PJ,
Beddoes RJ. Pilot study of losartan for pulmonary hypertension in
chronic obstructive pulmonary disease. Respir Res. 2005;6:88.
60. Kanazawa H, Tateishi Y, Yoshikawa J. Acute effects of nifedipine
administration in pulmonary hemodynamics and oxygen delivery during
exercise in patients with chronic obstructive pulmonary disease: impli-
cation of the angiotensin-converting enzyme gene polymorphisms. Clin
Physiol Funct Imaging. 2004;24:224 –228.
Pulmonary Diseases and the Heart 3003
61. Melot C, Hallemans R, Naeije R, Mols P, Lejeune P. Deleterious effect
of nifedipine on pulmonary gas exchange in chronic obstructive pulmo-
nary disease. Am Rev Respir Dis. 1984;130:612– 616.
62. Nadrous HF, Pellikka PA, Krowka MJ, Swanson KL, Chaowalit N,
Decker PA, Ryu JH. Pulmonary hypertension in patients with idiopathic
pulmonary fibrosis. Chest. 2005;128:2393–2399.
63. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and
outcomes of pulmonary arterial hypertension in advanced idiopathic
pulmonary fibrosis. Chest. 2006;129:746 –752.
64. Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T,
Mishima M, Kitaichi M, Izumi T. Clinical courses of patients with
idiopathic pulmonary fibrosis complicated with pulmonary arterial
hypertension. Chest. 2007;131:650 – 656.
65. Nathan S, Shlobin O, Ahmad S, Urbanek S, Barnett S. Pulmonary
hypertension and pulmonary function testing in idiopathic pulmonary
fibrosis. Chest. 2007;131:657– 663.
66. Sulica R, Teirstein AS, Kakarla S, Nemani N, Behnegar A, Padilla ML.
Distinctive clinical, radiographic, and functional characteristics of
patients with sarcoidosis-related pulmonary hypertension. Chest. 2005;
128:1483–1489.
67. Shorr AF, Helman DL, Davies DB, Nathan SD. Pulmonary hypertension
in advanced sarcoidosis: epidemiology and clinical characteristics. Eur
Respir J. 2005;25:783–788.
68. Handa T, Nagai S, Miki S, Fushimi Y, Ohta K, Mishima M, Izumi T.
Incidence of pulmonary hypertension and its clinical relevance in
patients with sarcoidosis. Chest. 2006;129:1246 –1252.
69. Packe GE, Cayton RM, Edwards CW. Comparison of right ventricular
weight at necropsy in interstitial pulmonary fibrosis and in chronic
bronchitis and emphysema. J Clin Pathol. 1986;39:594 –595.
70. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and
pulmonary hypertension: connecting the dots. Am J Respir Crit Care
Med. 2007;175:875– 880.
71. Weitzenblum E, Ehrhart M, Rasaholinjanahary J, Hirth C. Pulmonary
hemodynamics in idiopathic pulmonary fibrosis and other interstitial
pulmonary diseases. Respiration. 1983;44:118 –127.
72. Heath D, Gillund TD, Kay JM, Hawkins CF. Pulmonary vascular
disease in honeycomb lung. J Pathol Bacteriol. 1968;95:423– 430.
73. Cassan SM, Divertie MB, Brown AL Jr. Fine structural morphometry on
biopsy specimens of human lung: 2: diffuse idiopathic pulmonary
fibrosis. Chest. 1974;65:275–278.
74. Crystal RG, Gadek JE, Ferrans VJ, Fulmer JD, Line BR, Hunninghake
GW. Interstitial lung disease: current concepts of pathogenesis, staging
and therapy. Am J Med. 1981;70:542–568.
75. Renzoni EA, Walsh DA, Salmon M, Wells AU, Sestini P, Nicholson
AG, Veeraraghavan S, Bishop AE, Romanska HM, Pantelidis P, Black
CM, Du Bois RM. Interstitial vascularity in fibrosing alveolitis. Am J
Respir Crit Care Med. 2003;167:438 – 443.
76. Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular
involvement in sarcoidosis: a report of 40 autopsy cases. Hum Pathol.
1992;23:1216 –1223.
77. Lettieri CJ, Nathan SD, Browning RF, Barnett SD, Ahmad S, Shorr AF.
The distance-saturation product predicts mortality in idiopathic pulmo-
nary fibrosis. Respir Med. 2006;100:1734 –1741.
78. Flaherty KR, Andrei AC, Murray S, Fraley C, Colby TV, Travis WD,
Lama V, Kazerooni EA, Gross BH, Toews GB, Martinez FJ. Idiopathic
pulmonary fibrosis: prognostic value of changes in physiology and
six-minute-walk test. Am J Respir Crit Care Med. 2006;174:803– 809.
79. Lama VN, Flaherty KR, Toews GB, Colby TV, Travis WD, Long Q,
Murray S, Kazerooni EA, Gross BH, Lynch JP, 3rd, Martinez FJ.
Prognostic value of desaturation during a 6-minute walk test in idio-
pathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168:
1084 –1090.
80. Crockett AJ, Cranston JM, Antic N. Domiciliary oxygen for interstitial
lung disease. Cochrane Database Syst Rev. 2001(3):CD002883.
81. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H,
Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F.
Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a
randomised controlled trial. Lancet. 2002;360:895–900.
82. Collard H, Anstrom K, Schwartz M, Zisman D. Sildanefil improves
walk distance in idiopathic pulmonary fibrosis. Chest. 2007;131:
897– 899.
83. Fisher KA, Serlin DM, Wilson KC, Walter RE, Berman JS, Farber HW.
Sarcoidosis-associated pulmonary hypertension: outcome with
long-term epoprostenol treatment. Chest. 2006;130:1481–1488.
 3004 Circulation December 18/25, 2007
84. Krachman SL, Criner GJ, Chatila W. Cor pulmonale and sleep-
disordered breathing in patients with restrictive lung disease and neu-
romuscular disorders. Semin Respir Crit Care Med. 2003;24:297–306.
85. Bye PT, Ellis ER, Issa FG, Donnelly PM, Sullivan CE. Respiratory
failure and sleep in neuromuscular disease. Thorax. 1990;45:241–247.
86. Mezon BL, West P, Israels J, Kryger M. Sleep breathing abnormalities
in kyphoscoliosis. Am Rev Respir Dis. 1980;122:617– 621.
87. Hill R, Robbins AW, Messing R, Arora NS. Sleep apnea syndrome after
poliomyelitis. Am Rev Respir Dis. 1983;127:129 –131.
88. Melacini P, Vianello A, Villanova C, Fanin M, Miorin M, Angelini C,
Dalla Volta S. Cardiac and respiratory involvement in advanced stage
Duchenne muscular dystrophy. Neuromuscul Disord. 1996;6:367–376.
89. Yotsukura M, Miyagawa M, Tsuya T, Ishihara T, Ishikawa K. Pulmo-
nary hypertension in progressive muscular dystrophy of the Duchenne
type. Jpn Circ J. 1988;52:321–326.
90. Meyer TJ, Hill NS. Noninvasive positive pressure ventilation to treat
respiratory failure. Ann Intern Med. 1994;120:760 –770.
91. Masa JF, Celli BR, Riesco JA, Sanchez de Cos J, Disdier C, Sojo A.
Noninvasive positive pressure ventilation and not oxygen may prevent
overt ventilatory failure in patients with chest wall diseases. Chest.
1997;112:207–213.
92. Hoeppner VH, Cockcroft DW, Dosman JA, Cotton DJ. Nighttime ven-
tilation improves respiratory failure in secondary kyphoscoliosis. Am
Rev Respir Dis. 1984;129:240 –243.
93. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The
occurrence of sleep-disordered breathing among middle-aged adults.
N Engl J Med. 1993;328:1230 –1235.
94. Davies RJ, Stradling JR. The relationship between neck circumference,
radiographic pharyngeal anatomy, and the obstructive sleep apnoea
syndrome. Eur Respir J. 1990;3:509 –514.
95. Judd BG, Liu S, Sateia MJ. Cardiovascular abnormalities in sleep-
disordered breathing. Semin Respir Crit Care Med. 2003;24:315–322.
96. Atwood CW Jr, McCrory D, Garcia JG, Abman SH, Ahearn GS Pul-
monary artery hypertension and sleep-disordered breathing: ACCP
evidence-based clinical practice guidelines. Chest. 2004;126(suppl):
72S–77S.
Downloaded from http://ahajournals.org by on January 25, 2024
97. Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky
H, Phillipson EA. Role of daytime hypoxemia in the pathogenesis of
right heart failure in the obstructive sleep apnea syndrome. Am Rev
Respir Dis. 1985;131:835– 839.
98. Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, McEvoy RD. Pul-
monary hypertension and hypoxemia in obstructive sleep apnea
syndrome. Am J Respir Crit Care Med. 1994;149:416 – 422.
99. Guidry UC, Mendes LA, Evans JC, Levy D, O’Connor GT, Larson MG,
Gottlieb DJ, Benjamin EJ. Echocardiographic features of the right heart
in sleep-disordered breathing: the Framingham Heart Study. Am J Respir
Crit Care Med. 2001;164:933–938.
100. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the
association between sleep-disordered breathing and hypertension.
N Engl J Med. 2000;342:1378 –1384.
101. Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter
JH. Effect of nasal continuous positive airway pressure treatment on
blood pressure in patients with obstructive sleep apnea. Circulation.
2003;107:68 –73.
102. Dimsdale JE, Loredo JS, Profant J. Effect of continuous positive airway
pressure on blood pressure: a placebo trial. Hypertension. 2000;35(1 Pt
1):144 –147.
103. Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized
placebo-controlled trial of continuous positive airway pressure on blood
pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care
Med. 2001;163:344 –348.
104. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea:
implications for cardiac and vascular disease. JAMA. 2003;290:
1906 –1914.
105. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto
F, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered
breathing and cardiovascular disease: cross-sectional results of the Sleep
Heart Health Study. Am J Respir Crit Care Med. 2001;163:19 –25.
106. Franklin KA, Nilsson JB, Sahlin C, Naslund U. Sleep apnea and noc-
turnal angina. Lancet. 1995;345:1085–1087.
107. Peled N, Abinader EG, Pillar G, Sharif D, Lavie P. Nocturnal ischemic
events in patients with obstructive sleep apnea syndrome and ischemic
heart disease: effects of continuous positive air pressure treatment. J Am
Coll Cardiol. 1999;34:1744 –1749.
108. Barvaux V, Aubert G, Rodenstein D. Clinical review article: weight loss
as a treatment for obstructive sleep apnea. Sleep Med Rev. 2000;4:
435– 452.
109. Sajkov D, Wang T, Saunders NA, Bune AJ, McEvoy RD. Continuous
positive airway pressure treatment improves pulmonary hemodynamics
in patients with obstructive sleep apnea. Am J Respir Crit Care Med.
2002;165:152–158.
110. Arias MA, Garcia-Rio F, Alonso-Fernandez A, Martinez I, Villamor J.
Pulmonary hypertension in obstructive sleep apnea: effects of con-
tinuous positive airway pressure: a randomized, controlled cross-over
study. Eur Heart J. 2006;27:1106 –1113.
111. Arzt M, Schulz M, Wensel R, Montalvan S, Blumberg FC, Riegger GA,
Pfeifer M. Nocturnal continuous positive airway pressure improves
ventilatory efficiency during exercise in patients with chronic heart
failure. Chest. 2005;127:794 – 802.
112. Zohar Y, Talmi YP, Frenkel H, Finkelstein Y, Rudnicki C, Fried M,
Zahavi Y. Cardiac function in obstructive sleep apnea patients following
uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg. 1992;107:
390 –394.
113. Seshadri N, Gildea TR, McCarthy K, Pothier C, Kavuru MS, Lauer MS.
Association of an abnormal exercise heart rate recovery with pulmonary
function abnormalities. Chest. 2004;125:1286 –1291.
114. Mapel DW, Dedrick D, Davis K. Trends and cardiovascular
co-morbidities of COPD patients in the Veterans Administration
Medical System, 1991–1999. Copd. 2005;2:35– 41.
115. LeJemtel TH, Serrano C. Vasopressin dysregulation: hyponatremia,
fluid retention and congestive heart failure. Int J Cardiol. 2007;120:1–9.
116. Sin DD, Wu L, Man SF. The relationship between reduced lung function
and cardiovascular mortality: a population-based study and a systematic
review of the literature. Chest. 2005;127:1952–1959.
117. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;
340:115–126.
118. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between
chronic obstructive pulmonary disease and systemic inflammation: a
systematic review and a meta-analysis. Thorax. 2004;59:574 –580.
119. Dentener MA, Creutzberg EC, Schols AM, Mantovani A, van’t Veer C,
Buurman WA, Wouters EF. Systemic anti-inflammatory mediators in
COPD: increase in soluble interleukin 1 receptor II during treatment of
exacerbations. Thorax. 2001;56:721–726.
120. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB,
Griffiths TL, Shale DJ. Inflammatory response and body composition in
chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
2001;164:1414 –1418.
121. Mannino DM, Ford ES, Redd SC. Obstructive and restrictive lung
disease and markers of inflammation: data from the Third National
Health and Nutrition Examination. Am J Med. 2003;114:758 –762.
122. Sin DD, Man SF. Why are patients with chronic obstructive pulmonary
disease at increased risk of cardiovascular diseases? The potential role of
systemic inflammation in chronic obstructive pulmonary disease. Cir-
culation. 2003;107:1514 –1519.
123. Yasuda N, Gotoh K, Minatoguchi S, Asano K, Nishigaki K, Nomura M,
Ohno A, Watanabe M, Sano H, Kumada H, Sawa T, Fujiwara H. An
increase of soluble Fas, an inhibitor of apoptosis, associated with pro-
gression of COPD. Respir Med. 1998;92:993–999.
124. Perera WR, Hurst JR, Wilkinson TM, Sapsford RJ, Mullerova H,
Donaldson GC, Wedzicha JA. Inflammatory changes, recovery and
recurrence at COPD exacerbation. Eur Respir J. 2007;29:527–534.
125. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nor-
destgaard BG. C-reactive protein as a predictor of prognosis in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:
250 –255.
126. Hurst JR, Donaldson GC, Perera WR, Wilkinson TM, Bilello JA, Hagan
GW, Vessey RS, Wedzicha JA. Use of plasma biomarkers at exacer-
bation of chronic obstructive pulmonary disease. Am J Respir Crit Care
Med. 2006;174:867– 874.
127. Man SF, Connett JE, Anthonisen NR, Wise RA, Tashkin DP, Sin DD.
C-reactive protein and mortality in mild to moderate chronic obstructive
pulmonary disease. Thorax. 2006;61:849 – 853.
128. Pinto-Plata VM, Mullerova H, Toso JF, Feudjo-Tepie M, Soriano JB,
Vessey RS, Celli BR. C-reactive protein in patients with COPD, control
smokers and non-smokers. Thorax. 2006;61:23–28.
129. de Torres JP, Cordoba-Lanus E, Lopez-Aguilar C, Muros de Fuentes M,
Montejo de Garcini A, Aguirre-Jaime A, Celli BR, Casanova C.
C-reactive protein levels and clinically important predictive outcomes in
stable COPD patients. Eur Respir J. 2006;27:902–907.
 Han et al
130. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic
markers of inflammation in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med. 2004;170:760 –765.
131. Hansell AL, Walk JA, Soriano JB. What do chronic obstructive pulmo-
nary disease patients die from? A multiple cause coding analysis. Eur
Respir J. 2003;22:809 – 814.
132. Camilli AE, Robbins DR, Lebowitz MD. Death certificate reporting of
confirmed airways obstructive disease. Am J Epidemiol. 1991;133:
795– 800.
133. Janssens JP, Herrmann F, MacGee W, Michel JP. Cause of death in
older patients with anatomo-pathological evidence of chronic bronchitis
or emphysema: a case-control study based on autopsy findings. J Am
Geriatr Soc. 2001;49:571–576.
134. Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Symptoms of chronic
bronchitis and the risk of coronary disease. Lancet. 1996;348:567–572.
135. Engstrom G, Wollmer P, Hedblad B, Juul-Moller S, Valind S, Janzon L.
Occurrence and prognostic significance of ventricular arrhythmia is
related to pulmonary function: a study from “men born in 1914,”
Malmo, Sweden. Circulation. 2001;103:3086 –3091.
136. Speizer FE, Fay ME, Dockery DW, Ferris BG Jr. Chronic obstructive
pulmonary disease mortality in six US cities. Am Rev Respir Dis.
1989;140:S49 –S55.
137. Schunemann HJ, Dorn J, Grant BJ, Winkelstein W, Jr., Trevisan M.
Pulmonary function is a long-term predictor of mortality in the general
Downloaded from http://ahajournals.org by on January 25, 2024
Pulmonary Diseases and the Heart 3005
population: 29-year follow-up of the Buffalo Health Study. Chest. 2000;
118:656 – 664.
138. Hospers JJ, Postma DS, Rijcken B, Weiss ST, Schouten JP. Histamine
airway hyper-responsiveness and mortality from chronic obstructive
pulmonary disease: a cohort study. Lancet. 2000;356:1313–1317.
139. Higgins MW, Keller JB. Predictors of mortality in the adult population
of Tecumseh. Arch Environ Health. 1970;21:418 – 424.
140. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor
for cardiovascular morbidity and mortality. Proc Am Thorac Soc. 2005;
2:8 –11.
141. Tockman MS, Pearson JD, Fleg JL, Metter EJ, Kao SY, Rampal KG,
Cruise LJ, Fozard JL. Rapid decline in FEV1. A new risk factor for
coronary heart disease mortality. Am J Respir Crit Care Med. 1995;151:
390 –398.
142. Anthonisen NR, Connett JE, Enright PL, Manfreda J. Hospitalizations
and mortality in the Lung Health Study. Am J Respir Crit Care Med.
2002;166:333–339.
143. Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM,
Brophy JM. Reduction of morbidity and mortality by statins, angioten-
sin-converting enzyme inhibitors, and angiotensin receptor blockers in
patients with chronic obstructive pulmonary disease. J Am Coll Cardiol.
2006;47:2554 –2560.
144. Soyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with
reduced mortality in COPD. Eur Respir J. 2007;29:279 –283.