Cor Pulmonale Overview of Cor Pulmonale

Management
http://emedicine.medscape.com/article/154062-overview

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]

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 failurerelated admissions in the United
States.[5]

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 between countries, depending on the
prevalence of cigarette smoking, air pollution, and other risk factors for various lung diseases.
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. 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.[2]

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).[3] 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 sisease (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.[4]

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.

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.[6]

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[7] 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

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
pulomale. Right heart catheterization is the most accurate but invasive test to confirm the
diagnosis of cor pulmonale and gives important information regarding underlying causes.[9, 10]
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 patients 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)

S 1 Q 3 T 3 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.[11]

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 travelled 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 for 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.[12, 13]

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 presentationsfrom massive
embolism with acute and severe hemodynamic instability to multiple chronic peripheral
embolismsthat may present with cor pulmonale.[14]

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 (CT)
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.[15]

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

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.[18]

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,[19] 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, a wedge pressure below
15 mmHg, and a calculated pulmonary vascular resistance (PVR) above 3 Wood units.[5] Other
signs of RV dysfunction include elevated central venous pressure (CVP) and elevated RV end-
diastolic pressure.

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.[20] 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),[21] 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.[22]

In general, in patients with COPD, long-term oxygen therapy is recommended when the PaO2 is
less than 55 mm Hg or the O2 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 PaO2 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).[23]

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[24] and
diltiazem, can lower pulmonary pressures, although these agents appear more effective in
primary rather than secondary pulmonary hypertension.[25]

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 recepter agonists

Epoprostenol, treprostinil, and bosentan are prostacyclin (PGI2) analogues and have potent
vasodilatory properties.[26] 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.[27]

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.[28]

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, endotelin receptor antagonists indicated result in subsequent vasodilation.
In clinical trials, bosentan improved exercise capacity, decreased rate of clinical deterioration,
and improved hemodynamics.[26]

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[29, 30, 31] and was approved by the FDA for treatment of pulmonary hypertension. Sildenafil
promotes selective smooth muscle relaxation in lung vasculature.[32] Tadalafil and vardenafil are
other PDE5 inhibitors also approved by the FDA for the treatment of PAH to improve exercise
ability.[33]

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 hyprtension as well as group 4
pulmonary hypertension (chronic thromboembolic pulmonary hypertension). It was shown to
improve exercise tolerance as well as reduce symptoms.[34]

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.[35] 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.[36] 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.[37]
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.[38, 39, 40] 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
decompensation.[41] 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,[42] 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.[43]

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 patients 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.[44]
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[44] :

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, 1.03]).[45]