Introduction to Cor Pulmonale

Cor pulmonale is defined as an alteration in the structure and function of the

right ventricle (RV) of the heart caused by a primary disorder of the respiratory
system. Pulmonary hypertension is often the common link between lung
dysfunction and the heart in cor pulmonale. Right-sided ventricular disease
caused by a primary abnormality of the left side of the heart or congenital heart
disease is not considered cor pulmonale, but cor pulmonale can develop
secondary to a wide variety of cardiopulmonary disease processes. Although cor
pulmonale commonly has a chronic and slowly progressive course, acute onset
or worsening cor pulmonale with life-threatening complications can occur. [1]
Etiology and Pathophysiology of Cor Pulmonale
The pathophysiology of cor pulmonale is a result of increased right-sided filling
pressures from pulmonary hypertension that is associated with diseases of the
lung. The increased afterload leads to structural alterations in the right ventricle
(RV) including RV hypertrophy (RVH) which can be seen in chronic cor
pulmonale.
Acute cor pulmonale: pulmonary embolism (more common) and acute
respiratory distress syndrome (ARDS). The underlying pathophysiology in a
massive pulmonary embolism causing cor pulmonale is the sudden increase in
pulmonary resistance. In ARDS, RV overload can occur due to mechanical
ventilation and the pathologic features of the syndrome itself. [2] Mechanical
ventilation, especially higher tidal volumes, requires a higher transpulmonary
pressure.
In the case of ARDS, cor pulmonale is associated with an increased possibility
of right-to-left shunting through a patent foramen ovale, which carries a poorer
prognosis. [3]
Several different pathophysiologic mechanisms can lead to pulmonary
hypertension and, subsequently, to cor pulmonale. The World Health
Organization (WHO) has five classifications for pulmonary hypertension, and
all except one of these groups can result in cor pulmonale (WHO Classification
group 2 is pulmonary artery hypertension due to left ventricular [LV]
dysfunction). [4] Note the following WHO classifications:
 Group 1: Pulmonary artery hypertension, including heritable causes;
connective-tissue disorders, including scleroderma; and other
idiopathic causes
 Group 3: Pulmonary hypertension due to lung disease and/or
hypoxia; these disorders include chronic obstructive pulmonary
disease (COPD), which is the most common cause of for pulmonale.
There have been studies correlating the degree of hypoxia with the
severity of cor pulmonale. Other disorders that can result in cor
pulmonale in this group include interstitial lung disease (ILD) and
obstructive sleep apnea (OSA)
  Group 4: Chronic thromboembolic pulmonary hypertension; blood
clots that form in the lungs can lead to increased resistance,
pulmonary hypertension and, subsequently, cor pulmonale
 Group 5: Pulmonary hypertension caused by other diseases or
conditions, including sarcoidosis, polycythemia vera (which can lead
to increased blood viscosity and, subsequently, pulmonary
hypertension), vasculitis, and other disorders.
The end result of the above mechanisms is increased pulmonary arterial
pressure and resistance.
RV and LV output
The RV is a thin-walled chamber that is a better volume pump than a pressure
pump. It is better suited to adapt to changing preload than afterload. With an
increase in afterload, the RV systolic pressure is increased to maintain the
circulatory gradient. At a critical point, a further increase in pulmonary arterial
pressure and resistance produces significant RV dilatation, an increase in RV
end-diastolic pressure, and RV circulatory failure.
A decrease in RV output leads to a decrease in LV filling, which results in
decreased cardiac output. Because the right coronary artery originates from the
aorta, decreased LV output causes decreased right coronary blood flow and
ischemia to the RV wall. What ensues is a vicious cycle between decreases in
LV and RV output.
RV and LV morphogenesis
Genetic investigations have confirmed that morphogenesis of the right and left
ventricle originated from different sets of progenitor cells. Their differing
embryologic origins could explain the differing rates of hypertrophy of the right
and left ventricles. [5]
RV overload
RV pressure and volume overload is associated with septal displacement toward
the left ventricle. Septal displacement, which can be visualized on
echocardiography, is an additional factor that decreases LV filling and output in
the setting of cor pulmonale and RV enlargement.
Epidemiology of Cor Pulmonale
Although the prevalence of COPD in the United States is reported to be about
15 million, the exact prevalence of cor pulmonale is difficult to determine, as
physical examination and routine tests are relatively insensitive for the detection
of pulmonary hypertension and RV dysfunction.
Cor pulmonale is estimated to account for 6-7% of all types of adult heart
disease in the United States, with chronic obstructive pulmonary disease
(COPD) due to chronic bronchitis or emphysema the causative factor in more
than 50% of cases. Mortality in patients with concurrent COPD and cor
pulmonale is higher than that in patients with COPD alone. In addition, cor
pulmonale accounts for 10-30% of decompensated heart failure–related
admissions in the United States. [6]
In contrast, acute cor pulmonale is usually secondary to massive pulmonary
embolism. Acute massive pulmonary thromboembolism is the most common
cause of acute life-threatening cor pulmonale in adults; 50,000 deaths in the
United States are estimated to occur per year from pulmonary emboli and about
half occur within the first hour due to acute right heart failure.
Globally, the incidence of cor pulmonale varies widely among countries,
depending on the prevalence of cigarette smoking, air pollution, and other risk
factors for various lung diseases. [7]
Cor Pulmonale Presentation
The clinical manifestations of cor pulmonale may be nonspecific. The
symptoms may be subtle, especially in early stages of the disease, and they may
be mistakenly attributed to the underlying pulmonary pathology.
Symptoms
Patients may report a combination of fatigue, tachypnea, exertional dyspnea,
and cough. Anginal chest pain can also occur and may be due to right
ventricular ischemia or pulmonary artery stretching, which typically do not
respond to nitrates. A variety of neurologic symptoms may be seen due to
decreased cardiac output and hypoxemia.
Hemoptysis may occur due to rupture of a dilated or atherosclerotic pulmonary
arteriole. Other conditions, such as tumors, bronchiectasis, and pulmonary
infarction, should be excluded before attributing hemoptysis to pulmonary
hypertension. Rarely, the patient may complain of hoarseness due to
compression of the left recurrent laryngeal nerve by a dilated pulmonary artery.
In advanced stages, passive hepatic congestion secondary to severe right
ventricular failure may lead to anorexia, right upper quadrant abdominal
discomfort, and jaundice. In addition, syncope with exertion, which may also be
seen in severe disease, reflects a relative inability to increase cardiac output
during exercise with a subsequent drop in the systemic arterial pressure.
Elevated pulmonary artery pressure can lead to elevated right atrial, peripheral
venous, and capillary pressure. By increasing the hydrostatic gradient, it leads to
transudation of fluid and accumulation of peripheral edema. Although this is the
simplest explanation for peripheral edema in cor pulmonale, other factors may
contribute, especially in a subset of patients with chronic obstructive pulmonary
disease (COPD) who do not have an increase in right atrial pressure. A decrease
in glomerular filtration rate (GFR) and filtration of sodium as well as
stimulation of arginine vasopressin (which decreases free water excretion) by
hypoxemia may play important pathophysiologic roles in this setting and may
even have a role for peripheral edema in patients with cor pulmonale. [8]
Signs
Physical findings may reflect the underlying lung disease or pulmonary
hypertension, right ventricular hypertrophy (RVH), and RV failure. An increase
in chest diameter, labored respiratory efforts with retractions of the chest wall,
distended neck veins with prominent a or v waves, and cyanosis may be seen.
On auscultation of the lungs, wheezes and crackles may be heard as signs of
underlying lung disease. Turbulent flow through recanalized vessels in chronic
thromboembolic pulmonary hypertension [9] may be heard as systolic bruits in
the lungs. On percussion, hyperresonance of the lungs may be a sign of
underlying COPD.
Splitting of the second heart sound with accentuation of the pulmonic
component can be heard in the early stages. A systolic ejection murmur with a
sharp ejection click over the region of the pulmonary artery may be heard in
advanced disease, along with a diastolic pulmonary regurgitation murmur.
Other findings upon auscultation of the cardiovascular system may be RV third
and fourth sounds or the systolic murmur of tricuspid regurgitation.
RVH is characterized by a left parasternal or subxiphoid heave. Hepatojugular
reflux and pulsatile liver are signs of RV failure with systemic venous
congestion. In severe disease, ascites can also be present.
Examination of the lower extremities reveals evidence of pitting edema. Edema
in cor pulmonale is strongly associated with hypercapnia. [10]
Diagnostic Considerations
A general approach to diagnose cor pulmonale and to investigate its etiology
starts with routine laboratory tests, chest radiography, and electrocardiography
(see the separate sections below). Echocardiography gives valuable information
about the disease and right ventricular (RV) function, as well as assisting in
determining the etiology of pulmonary hypertension and cor pulmonale. Right
heart catheterization is the most accurate but invasive test to confirm the
diagnosis of cor pulmonale and gives important information regarding
underlying causes. [11, 12]
Once a diagnosis of cor pulmonale is made, it should be followed by further
investigation to determine the underlying lung pathology. Sometimes a common
lung disease such as chronic obstructive pulmonary disease (COPD) is not the
only lung pathology causing cor pulmonale; other lung diseases may coexist.
Thus, pulmonary function tests may be required to confirm the presence of
other lung pathologies. Ventilation/perfusion (V/Q) scanning or chest computed
tomography (CT) scanning may be performed if the patient’s history and
physical examination suggest pulmonary thromboembolism as the cause or if
other diagnostic tests do not provide a specific etiology.
Imaging studies may show evidence of underlying cardiopulmonary diseases,
pulmonary hypertension, or RV enlargement. Cardiac magnetic resonance
(CMR) imaging is another form of noninvasive imaging that does not use
ionizing radiation. CMR can be used to evaluate cor pulmonale, and it is useful
in determining RV structure, remodeling, and function; this modality is
especially useful in assessing pulmonary artery dimensions when compared to
traditional echocardiography.
Differentials
When diagnosing cor pulmonale, it is important to consider the possibility of
thromboembolic disease and primary pulmonary hypertension as possible
etiologies. In addition, also assess for the following conditions:
 Atrial myxoma
 Blood disorders that are associated with increased blood viscosity
 Congestive (biventricular) heart failure
 Constrictive pericarditis
 High-output heart failure
 Infiltrative cardiomyopathies
 Primary pulmonic stenosis
 Right heart failure due to right ventricular infarction
 Right heart failure due to congenital heart diseases
 Ventricular septal defect
Diagnostic Tests
Laboratory investigations are directed toward defining the potential underlying
etiologies as well as evaluating the complications of cor pulmonale. In specific
instances, appropriate laboratory studies may include the following:
 Hematocrit for polycythemia, which can be a consequence of
underlying lung disease but can also increase pulmonary arterial
pressure by increasing viscosity
 Serum alpha1-antitrypsin, if deficiency is suspected
 Antinuclear antibody (ANA) level for collagen vascular disease, and
anti-SCL-70 antibodies in scleroderma
 Coagulations studies to evaluate hypercoagulability states (eg, serum
levels of proteins S and C, antithrombin III, factor V Leyden,
anticardiolipin antibodies, homocysteine)
Arterial Blood Gas Analysis
Arterial blood gas measurements may provide important information about the
level of oxygenation and type of acid-base disorder.
Brain Natriuretic Peptide
Brain natriuretic peptide (BNP) is a peptide hormone that is released in response
to volume expansion and the increased wall stress of cardiac myocytes. BNP
helps to promote diuresis, natriuresis, vasodilation of the systemic and
pulmonary vasculature, and reduction of circulating levels of endothelin and
aldosterone. As a result, both congestive heart failure due to left ventricular
(LV) failure and cor pulmonale due to noncardiac pulmonary hypertension can
lead to elevations in plasma BNP. Although not specific, severe acute
decompensated LV heart failure can result in higher levels of BNP.
Chest Radiography
In patients with chronic cor pulmonale, the chest radiograph may show
enlargement of the central pulmonary arteries with oligemic peripheral lung
fields. Pulmonary hypertension should be suspected when the right descending
pulmonary artery is larger than 16 mm in diameter and the left pulmonary artery
is larger than 18 mm in diameter. Right ventricular enlargement leads to an
increase of the transverse diameter of the heart shadow to the right on the
posteroanterior view and filling of the retrosternal air space on the lateral view.
These findings have reduced sensitivity in the presence of kyphoscoliosis or
hyperinflated lungs.
Electrocardiography
Electrocardiographic (ECG) abnormalities in cor pulmonale reflect the presence
of right ventricular hypertrophy (RVH), RV strain, or underlying pulmonary
disease (see the image below). Such ECG changes may include the following:
 Right axis deviation
 R/S amplitude ratio in V1 greater than 1 (an increase in anteriorly
directed forces may be a sign of posterior infarction)
 R/S amplitude ratio in V6 less than 1
 P-pulmonale pattern (an increase in P wave amplitude in leads 2, 3,
and aVF)
 S1 Q3 T3 pattern and incomplete (or complete) right bundle branch
block, especially if pulmonary embolism is the underlying etiology
 Low-voltage QRS because of underlying COPD with hyperinflation
Severe RVH may reflect as Q waves in the precordial leads that may be
mistakenly interpreted as an anterior myocardial infarction (however, as
electrical activity of the RV is significantly less than the left ventricle [LV],
small changes in RV forces may be lost in the ECG). See the image below.

This ECG shows some

typical abnormalities that may be seen in cor pulmonale and other chronic
pulmonary diseases: (1) R/S ratio >1 in V1 and <1 in V6 suggestive of right
ventricular hypertrophy/enlargement, (2) right superior axis deviation, (3) left
atrial type of p wave with increased width of the p wave and biphasic p wave in
V1, and (4) right bundle branch block pattern with wide QRS and RsR1 pattern
in V1 and slurred s wave in V6.This ECG also presents a sinus bradycardia
rhythm with first-degree AV block and left anterior fascicular block.
Additionally, many rhythm disturbances may be present in chronic cor
pulmonale; these range from isolated premature atrial depolarizations to various
supraventricular tachycardias, including paroxysmal atrial tachycardia,
multifocal atrial tachycardia, atrial fibrillation, atrial flutter, and junctional
tachycardia. These dysrhythmias may be triggered by processes secondary to
the underlying disease, (eg, anxiety, hypoxemia, acid-base imbalance,
electrolyte disturbances, excessive use of bronchodilators, heightened
sympathetic activity). Life-threatening ventricular tachyarrhythmias are less
common.
In selected cases, pulmonary function testing may be indicated to determine
underlying obstructive or interstitial lung disease.
2-D and Doppler Echocardiography
Two-dimensional (2-D) echocardiography usually demonstrates signs of
chronic right ventricular (RV) pressure overload. As this overload progresses,
increased thickness of the RV wall with paradoxical motion of the
interventricular septum during systole occurs. At an advanced stage, RV
dilatation occurs, and the septum shows abnormal diastolic flattening. In
extreme cases, the septum may actually bulge into the left ventricular (LV)
cavity during diastole, resulting in decreased LV diastolic volume and reduction
of LV output.
Doppler echocardiography is used to estimate pulmonary arterial pressure,
taking advantage of the functional tricuspid insufficiency that is usually present
in pulmonary hypertension. This imaging modality is considered the most
reliable noninvasive technique to estimate pulmonary artery pressure. However,
the efficacy of Doppler echocardiography may be limited by the ability to
identify an adequate tricuspid regurgitant jet, which may be further enhanced by
using saline contrast. [13]
Several methods exist to assess RV function. One method includes tricuspid
annular plane systolic excursion (TAPSE), which is measured by viewing the
heart in the apical four-chamber view and using the M-mode function along the
lateral tricuspid annulus. By measuring the distance traveled of this reference
point during systole, the longitudinal shortening of the RV can be used as a
surrogate for global RV function. Limitations include inadequate M-mode
placement and the assumption that one segment of RV motion is representative
of the entire RV.
Strain, which is distinct from measuring wall-motion abnormalities in
traditional echocardiography, involves measuring myocardial deformation to
quantitatively assess myocardial function. Two methods currently exist for
measuring strain, including tissue Doppler imaging (TDI) and 2-D speckle
tracking. TDI uses postprocessing to convert velocity to strain and strain rates,
but it is significantly limited by the Doppler angle of incidence. 2-D speckle
tracking uses greyscale to detect speckle patterns by tracking natural acoustic
markers to calculate velocity vectors with 2-D ultrasonography. However, 2-D
speckle tracking relies on high image quality. [14, 15]
Additionally, myocardial performance index (MPI) can also be used to measure
RV function by calculating the isovolumetric relaxation time and contraction
time divided by the ejection time. Higher MPI indicates greater RV dysfunction,
and it is independent of RV chamber size and geometry. 
Pulmonary Thromboembolism Imaging Studies
Pulmonary thromboembolism has a wide range of clinical presentations—from
massive embolism with acute and severe hemodynamic instability to multiple
chronic peripheral embolisms—that may present with cor pulmonale. [16]
Pulmonary angiography was historically the gold standard for diagnosing acute
pulmonary embolism. The injection of a radiocontrast dye under fluoroscopy
allows for direct imaging of the pulmonary vasculature. This has been largely
replaced by computed tomography pulmonary angiography (CTPA), which
involves the injection of an iodinated contrast while obtaining CT scanning of
the chest. CTPA is both sensitive and specific and only requires intravenous
(IV) access; as a result, it is the first-line diagnostic imaging modality to
diagnose a suspected pulmonary embolism.
Ventilation/perfusion (V/Q) scanning is often performed in cases in which the
iodinated contrast agent used in CTPA is contraindicated (eg, pregnancy, renal
insufficiency, contrast allergy). By comparing both ventilation and perfusion
using a radionucleotide, perfusion deficits within areas of normal ventilation are
highly suspicious of a pulmonary embolism. V/Q scanning is the test of choice
in diagnosing chronic thromboembolic pulmonary hypertension (CTEPH), as it
is more sensitive than CTPA. [17]
Ultrafast, ECG-gated CT scanning
Ultrafast, electrocardiographically (ECG)-gated computed tomography (CT)
scanning has been evaluated to study right ventricular (RV) function. In
addition to estimating RV ejection fraction (RVEF), this imaging modality can
estimate RV wall mass. Although the use of ultrafast, ECG-gated CT scanning
is still experimental, with further improvement, it may be used to evaluate the
progression of cor pulmonale in the near future.
Magnetic Resonance Imaging
Cardiac magnetic resonance (CMR) imaging has been used as a method of
providing high-quality images and diagnostic capabilities that are currently
being explored. Electrocardiographic (ECG)-gated techniques and respiratory
motion suppression have enabled protocols that can provide valuable
information about right ventricular (RV) mass, septal flattening, and ventricular
function. By incorporating gadolinium, myocardial scar and fibrosis can also be
evaluated via CMR. Such a technique can be useful in determining the size and
location of an infarction. Spin echo, which causes blood to appear black, can be
used for anatomic imaging and identifying abnormal myocardium, and cine
imaging, in which blood appears bright and the myocardium appears dark, can
help in the assessment of wall motion abnormalities, valve function, and
patterns of blood flow. As a result, CMR is being explored to better characterize
and quantify pulmonary hypertension. [18, 19]
Nuclear Imaging
Radionuclide ventriculography can noninvasively determine right ventricular
ejection fraction. Myocardial perfusion may also show a permanent increase in
brightness of the right ventricle. [20]
Ventilation/perfusion (V/Q) scanning can be particularly useful in evaluating
patients with cor pulmonale, especially if pulmonary hypertension is due to
chronic thromboembolic pulmonary hypertension (CTEPH). V/Q scans are
performed by having the patient inhale a radionucleotide (typically xenon or
technetium) to assess ventilation, whereas perfusion is evaluated by the
intravenous injection of another radionucleotide. The two images are then
analyzed to determine if there are any mismatched perfusion defects, which is
suggestive of a pulmonary embolism.
V/Q scans are typically interpreted as being normal, or having a high,
intermediate, or low probability for pulmonary embolism. In CTEPH, the V/Q
scan typically demonstrates having a high probability for pulmonary embolism
as well as having multiple mismatched perfusion defects which can be
visualized.
 
Cardiac Catheterization
Although high-resolution echocardiography and magnetic resonance imaging
are accurate methods to measure pulmonary pressure, [21] right heart
catheterization is considered the most precise method for diagnosis and
quantification of pulmonary hypertension. This procedure is indicated when
echocardiography cannot assess the severity of a tricuspid regurgitant jet, thus
excluding an assessment of pulmonary hypertension.
In patients with cor pulmonale, right heart catheterization reveals evidence of
right ventricular (RV) dysfunction without left ventricular (LV) dysfunction.
Hemodynamically, this typically presents as a mean pulmonary artery pressure
(PAP) above 25 mmHg, which leads to elevated RV systolic pressures and
central venous pressures (CVP). However, these findings are also seen in LV
dysfunction. One method of differentiating left-sided from right-sided disease
includes measuring the pulmonary capillary wedge pressure (PCWP), which is
an estimation of left atrial pressure. Thus, RV dysfunction is also defined as
having a PCWP below 15 mmHg, because failure of the LV would result in
elevated LV end diastolic pressures and, subsequently, left atrial pressures. [6]
Right heart catheterization is occasionally important for differentiating cor
pulmonale from occult left ventricular dysfunction, especially when the
presentation is confusing. Another indication is for evaluation of the potential
reversibility of pulmonary arterial hypertension with vasodilator therapy or
when a left-sided heart catheterization is indicated.
Lung Biopsy
Lung biopsy may occasionally be indicated to determine the etiology of
underlying lung disease. This is especially true if interstitial lung disease (ILD)
is the suspected etiology for pulmonary hypertension resulting in cor
pulmonale.
ILD encompasses a broad range of diagnoses, including but not limited to
exposure-related causes (eg, asbestosis, silicosis), complications of connective
tissue disorders (eg, rheumatoid arthritis, systemic lupus erythematosus,
scleroderma), and idiopathic pneumonia (eg, usual interstitial pneumonia, acute
interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic
organizing pneumonia).
Typically, laboratory tests, pulmonary function tests, and imaging studies,
including high-resolution computed tomography (HRCT) scanning, are
performed before proceeding to invasive lung biopsy. Lung biopsy can
sometimes be important in determining prognosis and management, depending
on the diagnosis obtained via pathology. Biopsies can be obtained with the use
of transbronchial biopsy, thoracotomy, or video-assisted thoracoscopic surgery
(VATS). 
Overview of Cor Pulmonale Management
Medical therapy for chronic cor pulmonale is generally focused on treatment of
the underlying pulmonary disease and improving oxygenation and right
ventricular (RV) function by increasing RV contractility and decreasing
pulmonary vasoconstriction. [22] However, the approach might be different to
some degree in an acute setting, with priority given to stabilizing the patient.
Cardiopulmonary support for patients experiencing acute cor pulmonale with
resultant acute RV failure includes fluid loading and vasoconstrictor (eg,
epinephrine) administration to maintain adequate blood pressure. Of course, the
primary problem should be corrected, if possible. For example, for massive
pulmonary embolism, consider administration of anticoagulation, thrombolytic
agents or surgical embolectomy, especially if circulatory collapse is impending;
consider bronchodilation and infection treatment in patients with chronic
obstructive pulmonary disease (COPD); and consider steroid and
immunosuppressive agents in infiltrative and fibrotic lung diseases.
Oxygen therapy, diuretics, vasodilators, digitalis, theophylline, and
anticoagulation therapy are all different modalities used in the long-term
management of chronic cor pulmonale.
Patient education
Patient education regarding the importance of adherence to medical therapy is
vital because appropriate treatment of both hypoxia and underlying medical
illness can improve mortality and morbidity.
Complications
Complications of cor pulmonale include syncope, hypoxia, pedal edema,
passive hepatic congestion, and death.
Oxygen Therapy
Oxygen therapy is of great importance in patients with underlying chronic
obstructive pulmonary disease (COPD), [23] particularly when administered on a
continuous basis. With cor pulmonale, the partial pressure of oxygen (PaO2) is
likely to be below 55 mm Hg and decreases further with exercise and during
sleep.
Oxygen therapy relieves hypoxemic pulmonary vasoconstriction, which then
improves cardiac output, lessens sympathetic vasoconstriction, alleviates tissue
hypoxemia, and improves renal perfusion. The multicenter, randomized
Nocturnal Oxygen Therapy Trial (NOTT) showed that continuous low-flow
oxygen therapy for patients with severe COPD resulted in significant reduction
in the mortality rate. [24]
In general, in patients with COPD, long-term oxygen therapy is recommended
when the PaO2 is less than 55 mm Hg or the O 2 saturation is less than 88%.
However, in the presence of cor pulmonale or impaired mental or cognitive
function, long-term oxygen therapy can be considered even if the PaO 2 is
greater than 55 mm Hg or the O2 saturation is greater than 88%.
Although the impact of oxygen therapy on survival in patients with cor
pulmonale due to pulmonary disorders other than COPD is unclear, it may
provide some degree of symptomatic relief and improvement in functional
status. Therefore, oxygen therapy plays an important role in both the immediate
setting and long-term management, especially in patients who are hypoxic and
have COPD.
Pharmacotherapy
Diuretics are used to decrease the elevated right ventricular (RV) filling volume
in patients with chronic cor pulmonale. Calcium channel blockers are
pulmonary artery vasodilators that have some efficacy in the long-term
management of chronic cor pulmonale secondary to primary pulmonary arterial
hypertension (PAH). [25]
US Food and Drug Administration (FDA)–approved prostacyclin analogues and
endothelin-receptor antagonists are available for treatment of pulmonary arterial
hypertension (PAH). The beneficial role of cardiac glycosides, namely digitalis,
on the failing right ventricle are controversial; these agents may improve RV
function but must be used with caution and should be avoided during acute
episodes of hypoxia.
The main indication for oral anticoagulants in the management of cor
pulmonale is in the setting of an underlying thromboembolic event or PAH.
Methylxanthines, like theophylline, can be used as an adjunctive treatment for
chronic cor pulmonale secondary to chronic obstructive pulmonary disease
(COPD). Besides the moderate bronchodilatory effect of methylxanthine, this
agent improves myocardial contractility, causes a mild pulmonary vasodilatory
effect, and enhances diaphragmatic contractility.
Diuretic agents
Diuretics are used in the management of chronic cor pulmonale, particularly
when the RV filling volume is markedly elevated and in the management of
associated peripheral edema. These agents may result in improvement of the
function of both the right and left ventricles; however, diuretics may produce
hemodynamic adverse effects if they are not used cautiously. Excessive volume
depletion can lead to a decline in cardiac output.
Another potential complication of diuresis is the production of a hypokalemic
metabolic alkalosis, which diminishes the effectiveness of carbon dioxide
stimulation on the respiratory centers and lessens ventilatory drive. The adverse
electrolyte and acid-base effect of diuretic use can also lead to cardiac
arrhythmia, which can diminish cardiac output. Therefore, diuresis, while
recommended in the management of chronic cor pulmonale, needs to be used
with great caution.
Vasodilator drugs
Vasodilators have been advocated in the long-term management of chronic cor
pulmonale with modest results. Calcium channel blockers, particularly oral
sustained-release nifedipine [26] and diltiazem, can lower pulmonary pressures,
although these agents appear more effective in primary rather than secondary
pulmonary hypertension. [27]
Other classes of vasodilators, such as beta agonists, nitrates, and angiotensin-
converting enzyme (ACE) inhibitors have been tried but, in general,
vasodilators have failed to show sustained benefit in patients with COPD, and
they are not routinely used. A trial of vasodilator therapy may be considered
only in patients with COPD with disproportionately high pulmonary
hypertension.
Beta-selective agonist drugs
Beta-selective agonists have an additional advantage of bronchodilator and
mucociliary clearance effect. Right heart catheterization has been recommended
during initial administration of vasodilators to objectively assess the efficacy
and detect the possible adverse hemodynamic consequences of vasodilators.
Prostacyclin analogues and receptor agonists
Epoprostenol, treprostinil, and bosentan are prostacyclin (PGI2) analogues and
have potent vasodilatory properties. [28] Epoprostenol is administered
intravenously (IV). Treprostinil can be administered IV and subcutaneously
(SC); the FDA has approved oral and inhaled formulations. Iloprost is
commonly inhaled but requires frequent dosing.
Of these prostacyclin analogues, epoprostenol has been the most studied; it has
been shown to improve survival in idiopathic pulmonary arterial hypertension
as well as some benefit in other types of World Health Organization (WHO)
classification group 1 pulmonary hypertension, particularly in patients with
more severe functional status. [29]
Selexipag is a prostacyclin receptor agonist, which acts to vasodilate the
pulmonary vasculature. It is administered orally and has been shown to reduce
disease progression in PAH. [30]
Endothelin receptor antagonists
Bosentan and macitentan are mixed endothelin-A and endothelin-B receptor
antagonists, whereas ambrisentan is a selective endothelin-A receptor
antagonist. Endothelins are peptides that act via vasoconstriction; thus,
endothelin receptor antagonists indicated result in subsequent vasodilation. In
clinical trials, bosentan improved exercise capacity, decreased rate of clinical
deterioration, and improved hemodynamics. [28]
The endothelin receptor antagonists are indicated in idiopathic pulmonary artery
hypertension as well as pulmonary hypertension secondary to connective tissue
disorders (group I pulmonary hypertension). Common side effects include
elevated liver function test findings.
Phosphodiesterase type 5 (PDE5) inhibitors
The PDE5 inhibitors function by preventing the degradation of cyclic GMP and
subsequently prolonging the vasodilatory effect of nitric oxide. Of
these, sildenafil has been intensively studied [31, 32, 33] and was approved by the
FDA for treatment of pulmonary hypertension. Sildenafil promotes selective
smooth muscle relaxation in lung vasculature. [34]  Tadalafil and vardenafil are
other PDE5 inhibitors also approved by the FDA for the treatment of PAH to
improve exercise ability. [35]
There are not enough data available yet regarding the efficacy of these drugs in
patients with secondary pulmonary hypertension, such as in patients with
COPD.
Guanylate cyclase stimulants
Riociguat is a soluble guanylate cyclase stimulant that mimics the function of
nitric oxide as well as acts synergistically with it to promote vasodilation.
Unlike other advanced therapies, riociguat has been FDA approved for the
treatment of group I pulmonary hypertension as well as group 4 pulmonary
hypertension (chronic thromboembolic pulmonary hypertension). It was shown
to improve exercise tolerance as well as reduce symptoms. [36]
Cardiac glycoside agents
The use of cardiac glycosides, such as digitalis, in patients with cor pulmonale
has been controversial, and the beneficial effect of these drugs is not as obvious
as in the setting of left heart failure. Nevertheless, studies have confirmed a
modest effect of digitalis on the failing right ventricle in patients with chronic
cor pulmonale. [37] This drug must be used cautiously, however, and should not
be used during the acute phases of respiratory insufficiency when large
fluctuations in levels of hypoxia and acidosis may occur. Patients with
hypoxemia or acidosis are at increased risk of developing arrhythmias due to
digitalis through different mechanisms, including sympathoadrenal stimulation.
Theophylline
In addition to bronchodilatory effects, theophylline has been reported to reduce
pulmonary vascular resistance and pulmonary arterial pressures acutely in
patients with chronic cor pulmonale secondary to COPD. [38] Theophylline has a
weak inotropic effect and thus may improve right and left ventricular ejection.
Low doses of theophylline have also been suggested to have anti-inflammatory
effects that help to control underlying lung diseases such as COPD. [39] As a
result, considering the use of theophylline as adjunctive therapy in the
management of chronic or decompensated cor pulmonale is reasonable in
patients with underlying COPD. Theophylline has a narrow therapeutic index,
and adverse effects include seizures, tachycardia, and other cardiac arrhythmias.
Warfarin
Anticoagulation with warfarin is recommended in patients at high risk for
thromboembolism. The beneficial role of anticoagulation in improving the
symptoms and mortality in patients with primary PAH has been demonstrated in
several studies. [40, 41, 42] The evidence of benefit, however, has not been
established in patients with secondary PAH. Therefore, anticoagulation therapy
may be used in patients with cor pulmonale secondary to thromboembolic
phenomena and with underlying primary PAH.
Thrombolytic therapy
Thrombolytic therapy is indicated in patients with acute cor pulmonale due to a
pulmonary embolism resulting in hemodynamic instability. In some cases,
thrombolytic therapy may be indicated in patients with severe RV dysfunction
without resultant hypotension to prevent further
 [43] 
decompensation. Thrombolytic agents, including tissue plasminogen activator
(tPA), result in accelerated lysis of clots and can be administered systemically
or via a catheter. As always, the risk of bleeding must be a strong consideration
when using thrombolytic therapy.
Surgical Management of Cor Pulmonale
Phlebotomy is indicated in patients with chronic cor pulmonale and chronic
hypoxia causing severe polycythemia, defined as hematocrit of 65% or more.
Phlebotomy results in a decrease in mean pulmonary artery pressure, a decrease
in mean pulmonary vascular resistance, [44] and an improvement in exercise
performance in such patients. However, no evidence suggests improvement in
survival.
Generally, phlebotomy should be reserved as an adjunctive therapy for patients
with acute decompensation of cor pulmonale and patients who remain
significantly polycythemic despite appropriate long-term oxygen therapy.
Replacement of the acute volume loss with a saline infusion may be necessary
to avoid important decreases in systemic blood pressure.
Uvulopalatopharyngoplasty (UPPP) in selected patients with sleep apnea and
hypoventilation may relieve cor pulmonale. [45]
Pulmonary embolectomy is indicated in patients with acute pulmonary
embolism and hemodynamic instability when thrombolytic therapy is
contraindicated. Catheter-directed embolectomy can be accomplished with a
variety of modalities, including suction embolectomy, rotational embolectomy,
and rheolytic embolectomy, which involves the injection of pressured saline and
concurrent aspiration of the macerated thrombus. 
Surgical embolectomy may be also be indicated in similar patients or in patients
whose previous thrombolytic therapy failed, particularly if the location of the
thrombus is in a more proximal location. 
Single-lung, double-lung, and heart-lung transplantation are all used to salvage
the terminal phases of several diseases (eg, PPH, emphysema, idiopathic
pulmonary fibrosis, cystic fibrosis) complicated by cor pulmonale. Lung
transplantation may lead to a reversal of right ventricular dysfunction from the
chronic stress of pulmonary hypertension. However, strict selection criteria for
lung transplant recipients must be met because of the limited availability of
organ donors.
Outpatient Monitoring
Patients with cor pulmonale generally require close attention in the outpatient
setting. It is appropriate to regularly assess the patient’s oxygen needs and
pulmonary function. Consider a formal program of pulmonary rehabilitation, as
many patients benefit from this therapy.
Prognosis of Cor Pulmonale
The prognosis of cor pulmonale is variable depending upon the underlying
pathology. Development of cor pulmonale as a result of a primary pulmonary
disease usually heralds a poorer prognosis. For example, patients with chronic
obstructive pulmonary disease (COPD) who develop cor pulmonale have a 30%
chance of surviving 5 years. However, whether cor pulmonale carries an
independent prognostic value or is simply reflecting the severity of underlying
COPD or other pulmonary disease is not clear.
Prognosis in the acute setting due to massive pulmonary embolism or acute
respiratory distress syndrome (ARDS) has not previously been shown to be
dependent on the presence or absence of cor pulmonale. However, a
prospective, multicenter cohort study by Volschan et al indicated that in cases
of pulmonary embolism, cor pulmonale may be a predictor of inhospital
mortality. [46] The authors collected demographic, comorbidity, and clinical
manifestation data on 582 patients admitted to emergency or intensive care units
and diagnosed with pulmonary embolism. Assessing the information using
logistic regression analysis, the investigators built a prediction model. Their
results indicated that in hemodynamically stable patients with pulmonary
embolism, the following factors may be independent predictors of inhospital
mortality [46] :
 Age older than 65 years
 Bed rest for longer than 72 hours
 Chronic cor pulmonale
 Sinus tachycardia
 Tachypnea
A Chinese study indicated that chronic cor pulmonale is one of the major risk
factors for early hospital readmission in patients following hospitalization for
acute exacerbation of COPD. The study, by Lin et al, of 692 patients, included
63 patients who were readmitted to the hospital within 31 days after discharge.
Through multivariate analysis, the investigators found that risk factors for early
readmission included, in order of significance, chronic cor pulmonale (odds
ratio [OR], 2.14), hypoproteinemia (OR, 2.02), and an elevated partial pressure
of CO2 (Pa CO2 [OR,