documents cor pulmonale,thetheory
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Overview
Pulmonary arterial hypertension causes an increased pressure load on the right ventricle (RV) that subsequently results inthe normal adaptive response of hypertrophy and dilation. Right ventricular failure occurs when the ventricle is unable torespond further to the hemodynamic burden ?. Cor pulmonale is defined as right ventricular hypertrophy dilation anddysfunction as a result of pulmonary hypertension secondary to a variety of chronic lung diseases (?). Pulmonaryhypertension may also develop in the absence of cardiac or pulmonary parenchymal disease.
!"O was held in #vian $rance ?. %ubstantial progress had been made since the
Incidence and Risk Factors
Right ventricular failure is an important predictor of increased mortality in patients with chronic lung disease. &t
commonly occurs in individuals with 'OP which causes an estimated **** deaths each year in the +nited
%tates ?. , study of patients with 'OP found that -* had evidence of cor pulmonale at autopsy ?. $urthermore in
the /ational &nstitutes of "ealth (/&") Primary Pulmonary "ypertension /ational Registry mortality was found to
correlate best with indices of right ventricular hemodynamic function ?. 'or pulmonale is also associated with
increased morbidity in patients with chronic lung disease leading to reduced exercise tolerance, increased sensation
of dyspnea, and reduced functional status?. Other causes of cor pulmonale are less common. 0he incidence of PP"
is estimated to be one to two cases per million in the general population ?. Pulmonary vascular disease that is
clinically and pathologically indistinguishable from PP" can occur in association with human immunodeficiency virus
infection portal hypertension cocaine inhalation monocrotaline (a compound from the plant Crotalariathat is found
in bush tea) and drugs including appetite suppressants and chemotherapeutic agents ?. &n the 123*s the
anore4igenic agent aminore4 was found to be associated with an increased ris5 of pulmonary hypertension ?. +se of
the appetite suppressants fenfluramine and de4fenfluramine has been found to be associated with an increased ris5
of pulmonary hypertension (odds ratio 3.6) ?. 0his ris5 increased to an odds ratio of greater than 7* when the drugs
were ta5en for more than 6 months independent of body mass inde4. Other entities such as progressive systemic
sclerosis and 'R#%0 (calcification Raynaud8s esophageal dysmotility sclerodactyly and telangiectasis) may
present with progressive severe pulmonary hypertension often without associated parenchymal lung disease.
Genetics of Primary Pulmonary Hypertension
0he genetics of PP" are becoming unraveled. ,ppro4imately 3 of patients with PP" have the familial variety. 0his
disease is transmitted in the autosomal dominant manner with a ris5 of clinical e4pression of appro4imately 1* to
7* and demonstrates genetic anticipation. %tudies of genetic lin5age revealed that the locus for familial PP" is on
chromosome 7q61967. 0he 5nown genes in this region have been surveyed for biologically plausible candidates.
0he results of a detailed genetic study of a large 5indred of familial PP" patients has now provided additional
information ?. 0he gene that is associated with a unique member of the transforming growth factor: ? (0;$:?)
receptor family 5nown as bone morphogenetic protein receptor II (-
of BMPR2. 0his mutation was located in e4on 6 of the gene and was present in all of the affected family members.
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=ore recently it was discovered that the sporadic form of PP" is also associated with germline mutations of BMPR2
?.
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not correlate with the degree of pulmonary hypertension ?. &n addition in the absence of significant underlying lung
disease pulmonary artery pressure and pulmonary vascular resistance (PVR) remain normal after
pneumonectomy ? although right ventricular eection fraction (RV#$) at rest can be significantly decreased up to 6
wee5s postoperatively. Right ventricular dysfunction during e4ercise also occurs with increases in right ventricular
end diastolic volume pulmonary artery pressure and PVR ?. %ignificant elevation in mean pulmonary arterial
pressure develops only after one:half to two:thirds of the pulmonary vascular bed is occluded e4perimentally ?.
0herefore vascular bed obliteration does not appear to be a maor mechanism in the development of pulmonary
hypertension and cor pulmonale.
Hypoxic Pulmonary Vasoconstriction
,lveolar hypo4ia is a maor contributor to the development of pulmonary hypertension. &n 12- =otley and
associates ? found in five human subects that breathing 1* o4ygen for 1* minutes caused increases in pulmonary
artery pressure with a concomitant decrease in cardiac output as determined by the $ic5 method. 0his was
subsequently confirmed in 12>7 by $ishman and colleagues ? in the steady state despite the finding that the
application of the $ic5 principle by =otley and associates was found to be erroneous. "ypo4ic pulmonary
vasoconstriction involving small arteries and arterioles is thought to be a defense mechanism that determines local
ventilation:perfusion (?A?)relationships as first suggested by von #uler and Bilestrand ? in 12-3. &t is unclear
however if the vasoconstriction is due specifically to the hypo4ia or whether it is caused by vasoactive mediators
including prostaglandins endothelin brady5inin acetylcholine angiotensin catecholamines histamine or serotonin
which lead to calcium influ4 ?.
&n recent years advances have been made in understanding the regulation of pulmonary vascular tone with the
discovery of nitric o4ide (/O). #ndothelium:derived rela4ation factor discovered in 12C* ? is produced by
endothelial cells in a constitutive manner from arginine and is now identified as /O ? or a nitroso compound that
ultimately releases /O ?. /O synthase produces /O and citrulline from B:arginine and the endothelial form of this
enDyme depends on calcium and calmodulin to regulate /O production in a constitutive manner ?. #ndothelium:
dependent rela4ation has been found in isolated pulmonary arteries from most mammalian species including
humans ?. %tudies have demonstrated that inhibition of /O production by B:arginine analogs mar5edly enhances the
pulmonary pressor response to acute hypo4ic challenges which demonstrates the role that /O has in regulating
pulmonary vascular tone at rest and during acute hypo4ia ?. &n addition impaired /O production or release by
endothelial cells or both is seen in chronic hypo4ic vasoconstriction ?. , number of mediators cause calcium
influ4es into vascular smooth muscle cells activating the endothelial constitutive /O synthase ?. &mpairment of /O
production allows for e4cessive vasoconstriction and reduces the ability of the pulmonary vasculature to rela4.
'hronic vasoconstriction eventually leads to structural changes in the walls of the pulmonary vasculature. 'hanges
in the vasculature begin to appear even 1 hour after the onset of hypo4ia in e4perimental models ?. ,lthough the
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mechanisms that lead to these changes are not fully understood lac5 of /O production may allow mitogenesis and
proliferation of cells within the vessel walls ?. 0he changes in the pulmonary vasculature include increases in the
percentage of vessels with a muscular layer due to proliferation of vascular smooth muscle cells medial hypertrophy
and eccentric intimal fibrosis ?. 0hese changes may also allow for increased platelet aggregation and development
of thrombi causing further increases in PVR ?. ,s a result the cross:sectional area of the pulmonary vasculature
decreases and pulmonary arterial hypertension is irreversible ?.
Myocardial Blood Flow
&nadequate blood supply to the RV may also contribute to the development of right ventricular failure. 0he RV
responds to chronic increases in PVR with dilation and hypertrophy. !ith increases in muscle mass o4ygen
demands increase ?. O4ygen also demands an increase in the BV with the development of systolic hypertension.
/onetheless left ventricular coronary perfusion pressures are maintained or even increased because of increased
diastolic pressures ?. +nli5e the case with the BV the perfusion (diastolic) pressure of the right coronary artery is
unchanged or reduced when o4ygen demands increase because right ventricular cardiac output remains unchanged
or is diminished ?. &n addition the systolic component of right ventricular coronary blood flow is reduced due to the
increase in chamber pressure that occurs with dilation of the RV ?.
0he relationship between right coronary blood flow and right ventricular performance was studied in e4perimental
animal models by
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'OP and interstitial lung disease (&B) are common causes of pulmonary parenchymal disease. &n the +nited
%tates 'OP is the most common pulmonary disease that results in right ventricular dysfunction and it is a factor
that adversely affects survival ?. &n 1233 a Veterans ,dministration cooperative trial found that patients with cor
pulmonale had a -:year mortality of 6 ?. 0hese findings were reproduced by Bindsay and Read in 127 ? as well
as by 0raver and colleagues in 122 ?.
,ssessment of right ventricular systolic function is commonly done in patients with pulmonary disease by measuring
the RV#$. espite the variability of RV#$ in patients with 'OP it has been shown that those with clinically evident
cor pulmonale consistently have a reduced RV#$ ?. &n addition patients without clinical cor pulmonale but with a
depressed RV#$ have severe obstructive ventilatory defects. &n 'OP patients with a history of cor pulmonale and
elevated pulmonary artery pressure the latter measure is inversely related to arterial o4ygen tension and increased
PVR has been found to correlate with mortality ?. 0herefore it appears that increased right ventricular afterload
leads to a depressed RV#$. /onetheless when right ventricular contractility was measured with load:independent
methods it did notappear to correlate with RV#$ ?. 0hus RV#$ may be a poor indicator of intrinsic contractility
although it is usually depressed in the setting of pulmonary artery hypertension.
0he &Bs are disorders that cause thic5ening and fibrosis of the alveolar walls resulting in disruption of the alveolar:
capillary unit. 0he maority of these is of un5nown etiology. 0he fibrosis can entrap segments of the pulmonary
vasculature compressing the vessels and subsequently leading to thrombosis and fibrous organiDation of the
vessels with complete obliteration of some areas of the vasculature ?. 0his leads to hypo4emia from diffusion
impairment and ?A?mismatching. Patients with &B die from respiratory failure or right ventricular failure. &nitially
hyperventilation at rest allows for normal o4ygenation and desaturation occurs during e4ercise. ,s the disease
progresses o4ygen consumption increases as the wor5 of breathing increases leading to hypo4emia at rest ?.
#ventually pulmonary artery hypertension develops that correlates with the degree of hypo4emia. 0he pulmonary
artery pressure is moderately elevated in such patients until late in the disease. ,gain as in their counterparts with
'OP pulmonary artery pressures are important predictors of survival ?. %arcoidosis may result in significant
parenchymal disease with hypo4emia and pulmonary hypertension. ,lternatively the predominant abnormality may
appear to be intrinsic to the vasculature or due to compressionAtethering of the vessels. Pulmonary hypertension may
also result from left ventricular dysfunction in sarcoidosis.
Pulmonary Arterial Hypertension
&n 122C on the 7>:year anniversary of the original !"O meeting the !orld %ymposium on PP" cosponsored by
the !"O was held in #vian $rance ?. %ubstantial progress had been made since the prior meeting. One of the
significant outcomes of this symposium was to propose a new more clinically useful classification system for
pulmonary hypertension. 0raditionally pulmonary hypertension has been classified as being either EprimaryF or
Esecondary.F ,lthough PP" is relatively rare secondary pulmonary hypertension is distinctly more common and
includes a heterogeneous group of diseases. , consensus was reached at the 122C symposium to develop a more
inclusive and clinically useful classification system (?). ,n important result was to emphasiDe the significance of the
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entity of pulmonary arterial hypertension. 0he latter indicates that the disease is a pulmonary vascular process
caused by direct involvement of the pulmonary arteries.
PP" is a clinical condition characteriDed by an une4plained persistent elevation of pulmonary artery pressures. 0he
criteria for the diagnosis established by the /&" PP" Registry include a mean pulmonary artery pressure of greater
than 7> mm "g at rest or 6* mm "g or greater with e4ercise and the e4clusion of any 5nown cause of pulmonary
hypertension including left:sided cardiac valvular disease myocardial disease congenital heart disease and
clinically important pulmonary connective tissue or thromboembolic disease. ,ccording to this registry the median
survival of 1C patients was estimated at 7.C years and was independent of age se4 age at onset of symptoms
symptom duration or family history of PP" ?. 0he hemodynamic profiles of these patients demonstrated an average
mean pulmonary artery pressure of 3* mm "g and those with worse functional class had higher pulmonary artery
pressures. 0he abnormalities in pulmonary hemodynamics persist over time leading to decline in cardiac output and
increase in PVR. Very high correlations with mortality were obtained for the independent variables of pulmonary
artery pressure right atrial pressure and cardiac inde4 as determined by catheteriDation (?). ,dditional studies have
shown a correlation between mi4ed venous o4ygen saturation functional class e4ercise tolerance and response to
vasodilators ?. Patients with PP" die primarily of right ventricular failure or less commonly of sudden death. &t is
unusual for patients who are clinically stable and who have early /ew Gor5 "eart ,ssociation class &&& or milder
symptoms to die une4pectedly.
0he pathology of PP" is not unique to this disease entity. &t includes medial hypertrophy of the pulmonary arteries
intimal hyperplasia musculariDed pulmonary arterioles thrombotic microangiopathy and ple4iform lesions (?).
&ncreased PVR is thought to occur as a result of a combination of vasoconstriction vascular wall remodeling and in
situ thrombosis ?. %ustained vasoconstriction may be due to several mechanisms that can lead to altered
vasoreactivity (?). 0he proposed mechanisms include an imbalance in the production of specific vasodilators such
as prostacyclin endothelium:derived rela4ation factor or /O and vasoconstrictors such as thrombo4ane
endothelin or serotonin ?. ,nother mechanism that has been considered includes impaired smooth muscle
rela4ation as a primary event or secondary to endothelial cell inury ?. /onetheless the lac5 of supportive data
ma5es this hypothesis less li5ely. $inally alterations that are present in potassium ion channels may lead to calcium
influ4 causing smooth muscle contraction?
, thrombophilic state that contributes to the formation of microthrombi may contribute to the development of PP".
,bnormalities in the coagulation system such as abnormal fibrinolysis or von !illebrand8s factor production have
been found in some PP" patients ?. =icrothrombi are frequently noted in advanced vascular lesions of patients with
PP" ma5ing this finding difficult to categoriDe as a cause or a secondary event in the disease process ?.
%mooth muscle migration and proliferation can be a consequence of the increased production increased availability
or upregulation of receptors or increased production of growth factors ?. ;rowth factors such as 0;$: ? basic
fibroblastic growth factor platelet:derived growth factor and insulin:li5e growth factor:1 have been implicated ?.
0hese growth factors in turn can lead to increased levels of e4tracellular matri4 proteins such as thrombospondin
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tropoelastin and fibronectin which have been found in patients with PP" ?. 0he increased levels of e4tracellular
matri4 proteins can also be due to increased proteolytic activity ?.
&n a distinct minority of patients with pulmonary hypertension the vascular lesions involve predominantly the
pulmonary veins with occlusive intimal lesions. 0his disorder has been termed pulmonary venoocclusive diseaseand
mimics classic PP" in many respects ?. 0he pathologic diagnosis is based on the presence of obstructive eccentric
fibrous intimal lesions and sinusoidal channels that fill long segments of the pulmonary vein and venule lumina.
,rterialiDation of pulmonary veins may occur with the development of a distinct medial muscle coat bounded by
internal and e4ternal laminae. of the vascular bed had increases in pulmonary artery pressures.
/onetheless the mean pulmonary artery pressure did not e4ceed -* mm "g even in patients with greater than >*
occlusion of the vascular bed. 0herefore a mean pulmonary artery pressure of greater than -* mm "g is rarely
generated acutely by the previously normal thin:walled RV. 0he RV dilates and increases its filling pressure and
there is a linear correlation between right atrial pressure (and pulmonary artery pressure) and the degree of
obstruction by angiography ?. Patients with acute pulmonary embolism and mean pulmonary artery pressure greater
than -* mm "g nearly always have prior cardiopulmonary disease ?. &n such patients less obstruction is required to
increase the pulmonary artery pressure. &n patients with right ventricular hypertrophy however no correlation is seen
between the e4tent of obstruction and the elevation in pulmonary artery pressure ?. On the other hand right atrial
and pulmonary artery pressures correlate closely indicating that the RV still ma5es use of its preload reserve in the
setting of increased afterload ?.
Pulmonary Hypertension and Normal *ung Parenchyma
, number of entities can result in pulmonary hypertension in the absence of structural cardiac disease and with
normal lung parenchyma. 0hese include sleep apnea chronic alveolar hypoventilation high:altitude sic5ness and
neuromuscular disease. 'hest wall and neuromuscular disease as well as sleep apnea are briefly discussed
offering some potential e4planations for the resulting pulmonary hypertension.
Toracic !a"e Deformities and #euromuscular Disease
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/euromuscular diseases including muscular dystrophy amyotrophic lateral sclerosis postpolio syndrome and
numerous others can result in respiratory failure hypo4emia and occasionally pulmonary hypertension ? as may
thoracic cage deformities including severe 5yphoscoliosis. 0he management of hypoventilation in neuromuscular and
chest wall disorders is based on the premise that preventing further reductions in alveolar ventilation during sleep will
result in an improvement in nocturnal and subsequently daytime arterial blood gases a reduction in pulmonary
hypertension and cor pulmonale and the prevention of premature death. Patients who have been previously
disabled by profound dyspnea sleep fragmentation cor pulmonale and unstable respiratory failure have in many
instances returned to full:time activities.
Hypo$entilation and %leep Apnea
%leep apnea may lead to the development of pulmonary hypertension and right ventricular failure ?. &n obstructive
sleep apnea airflow ceases as a result of complete occlusion of the upper airway despite continued activity of the
inspiratory muscles. &n central sleep apnea airflow ceases because there is transient loss of central drive to the
respiratory muscles. =ost individuals with sleep apnea have a mi4ed obstructive and central picture. Obstructive
apneas are often accompanied by intermittent elevations in pulmonary artery pressure above the baseline level that
occur during wa5efulness. 0he ma4imum increase in pulmonary artery pressure occurs at or shortly after the onset
of arousal and ventilation which usually coincides with the ma4imum e4tent of arterial o4yhemoglobin desaturation.
%upplemental o4ygen mar5edly attenuates but does not abolish these increases in pulmonary artery pressure.
"ypo4ia:induced pulmonary vasoconstriction certainly plays a role in the pathogenesis of these elevations in
pulmonary artery pressure but it is probably not the only contributing factor. "ypercapnia and acidosis can also
induce pulmonary vasoconstriction leading to elevations in pulmonary artery pressure ?. 0hus it is not surprising
that elevations in pulmonary artery pressure are not completely abolished by supplemental o4ygen. ,lthough a
number of factors contribute to the development of chronic hypercapnia and cor pulmonale in patients with
obstructive sleep apnea reversal of the obstruction alone is sufficient in most cases to alleviate symptoms and
reverse right ventricular failure.
(linical Profile -valuation of the Patient "ith Pulmonary Hypertension
History and Physical -.amination
symptomatic years before diagnosis was documented ?. 0his is also true of other chronic
lung diseases including 'OP.
yspnea is commonly reported early in the pulmonary patient. !ith the development of hypo4emia and right
ventricular failure this symptom increases in severity and is uniformly present in nearly all patients. 'hest pain is
also common and can be difficult to distinguish from angina. Orthopnea is relatively common in patients with severe
'OP although it is not necessarily accompanied by worsening cardiac function. Orthopnea in these patients is
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believed to be related to hyperinflation of the lungs and the subsequent effects on ventricular function or reduction or
both in venous return. #vidence of right ventricular dysfunction with increased venous and hepatic congestion can
present with the development of early satiety increasing lower e4tremity edema and fluid overload. $inally in
patients with PP" Raynaud8s phenomenon is common but also suggests the possibility of collagen:vascular
disease. ? Presyncope and syncope are usually e4ertional in patients with severe pulmonary hypertension due to
the inability to increase cardiac output in response to the increased demand.
'ertain physical findings may suggest pulmonary hypertension or cor pulmonale independent of their cause. 0he
presence of a loud and occasionally palpable pulmonic valve closure sound is a common finding in patients with
pulmonary hypertension. , parasternal or epigastric lift may be present due to the hypertrophied RV. !ith
progression to cor pulmonale tricuspid valvular regurgitation develops as a result of dilation of the RV which causes
a prominent ugular V wave. Progressive signs of chronic right ventricular dilation and failure include pulmonic valve
insufficiency a right ventricular third heart sound ugular venous distention hepatougular reflu4 hepatomegaly
lower e4tremity edema ascites and eventually anasarca.
Patients with cor pulmonale and pulmonary hypertension due to 'OP invariably have findings that are associated
with their obstructive lung disease including decreased breath sounds and hyperinflation. &ndividuals with cor
pulmonale secondary to &B often have dry crac5les at the lung bases. ,uscultation of the lungs in PP" and chronic
thromboembolic pulmonary hypertension are generally unremar5able although bruits may be evident over the
peripheral lung in the latter group. 'lubbing is a common finding in chronic pulmonary disorders particularly
pulmonary fibrosis cystic fibrosis and other bronchiectatic disorders. ? ? &t is also very common in individuals with
pulmonary hypertension due to congenital heart disease. 'yanosis either peripheral or central may be present in
individuals with hypo4emia due to advanced cardiopulmonary disease. Other pertinent physical findings include
those associated with collagen:vascular disease such as telangiectasias sclerodactyly or calcinosis and findings
that might suggest alveolar hypoventilation such as muscle wea5ness 5yphoscoliosis and e4treme obesity.
,lgorithms for determining the presence and the cause of pulmonary hypertension are presented (? and ?).
-lectrocardiography
0he electrocardiogram in the patient with pulmonary hypertension and cor pulmonale reveals evidence of right heart
strain including P:pulmonale right:a4is deviation right ventricular hypertrophy and a right ventricular strain
pattern. ? ? ? &n addition atrial fibrillation atrial flutter and paro4ysmal atrial tachycardia often occur in the setting of
chronic pulmonary disorders. ,lthough the electrocardiogram may not be sensitive in the presence of mild or early
pulmonary hypertension it is more often abnormal in those with advanced disease. &n PP" patients evidence of
right heart strain appears to be present in appro4imately C* of patients ?. ? ? "owever particularly with the ready
availability of echocardiography electrocardiography does not offer much useful information regarding the cause or
severity of pulmonary hypertension in the vast maority of settings.
(hest Radiography
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0he chest radiograph is an important tool in the evaluation of patients with suspected pulmonary hypertension or cor
pulmonale (? ?). &t may be helpful in identifying parenchymal lung abnormalities such as pulmonary fibrosis or
hyperinflation associated with emphysema. %5eletal abnormalities that may lead to right ventricular failure such as
5yphoscoliosis can also be identified. &n addition the chest radiogram allows for assessment of cardiac siDe
especially of the RV. ,bnormalities in distribution of pulmonary blood flow may offer clues to the presence of
vascular obstruction due to thromboembolic disease. Prominence of the pro4imal pulmonary arteries is usually
present in patients with pulmonary hypertension and may be accompanied by pruning of the distal vessels ?. +nli5e
classic PP" even rarer entities such as pulmonary venoocclusive disease may be associated with interstitial
infiltrates and Herley < lines due to alveolar septal lymphatic edema.
Pulmonary Function &esting
Pulmonary function tests sometimes suggest the presence of pulmonary vascular disease and may aid in identifying
the etiology of pulmonary hypertension and right ventricular failure. %pirometry may reveal evidence of as well as
determining the e4tent of obstructive abnormalities. =easurement of lung volumes may identify restrictive lung
disease as well as its severity. ,n isolated reduction in the carbon mono4ide diffusing capacity is often noted in PP"
although mild reductions in lung volumes or spirometric values may be present also ?.
Pulmonary gas e4change abnormalities are commonly found in patients with pulmonary hypertension and cor
pulmonale. "ypo4emia is frequently observed in patients with significant pulmonary hypertension and cor pulmonale
although the severity depends on the underlying disease. /evertheless arterial o4ygen tensions are normal or mildly
abnormal early in the disease process. Patients with PP" may have normal o4ygen tension values until very late in
the disease. &n patients with sleep:related disorders o4ygen desaturation occurs during apneic or hypopneic
episodes. 0herefore abnormalities may not be present during wa5eful periods. &n the maority of such patients gas
e4change abnormalities with hypercarbia are present early in the course of the disease. =ild sleep apnea in the
setting of more severe pulmonary hypertension could represent either coincident disease or an unusually low
threshold for the development of pulmonary hypertension. 'linically significant hypo4ic vasoconstriction occurs at an
arterial o4ygen tension of less than 3* mm "g which may further e4acerbate pulmonary hypertension regardless of
the cause.
-chocardiography Anatomic (orrelations and (linical !se
'or pulmonale is defined to some e4tent by structural changes of the RV including right ventricular hypertrophy and
dilation. ? ? On gross inspection right ventricular hypertrophy is usually defined as a posterior wall thic5ness of
greater than or equal to > mm at the level of the inferior border of the posterior leaflet of the tricuspid valve e4cluding
the papillary muscles ?. "owever the sensitivity of this measurement as an indicator of pulmonary hypertension has
been shown on multiple occasions to be poor ?. 0he most accurate method to determine the presence of cor
pulmonale pathologically includes measurement of the weight of the free wall of the RV and the ratio of the combined
weight of the septum and the free left ventricular wall to the right ventricular weight ?. 0hese measurements in
normal adult hearts are right ventricular weight less than 3> g combined ventricular weights less than 7>* g and the
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ratio (as defined above) of 7.6 to 6.6. #vidence of right ventricular failure defined by the presence pathologically of
chronic hepatic congestion was seen in 7 of cases with a right ventricular weight of > to 22 g in 3- of those
with weights of 1** to 1>* g and in 26 of cases with weights greater than 1>* g ?. ;ross e4amination of the RV
also reveals a change in its shape with the development of cor pulmonale. 0he volume of the RV appears to
decrease relative to its mass@ in addition it becomes less ':shaped and more concentric the so:called left
ventriculariDation of the RV ?.
&n the past the echocardiographic evaluation of the RV was more difficult because of its crescentic shape and
substernal location which limited adequate visualiDation of its chambers and subected it to near:field acoustic
artifacts. !ith the advent of two:dimensional echocardiographyIoppler and color oppler imagingIcame a
growing interest in right heart function and evaluation. 0he echocardiographic views that best depict right:sided
anatomy include the apical four:chamber the right ventricular inflow long:a4is the oblique short:a4is the subcostal
the long:a4is pulmonary the short:a4is view of the great vessels the angulated short:a4is view of the pulmonary
artery and the short:a4is ventricular view ?.
0he ideal method to evaluate the RV in cor pulmonale adequately includes measurement of chamber siDes
volumes flow and pressures. 0he echocardiogram is helpful in establishing secondary causes for pulmonary
hypertension such as left ventricular dysfunction mitral valve abnormalities or congenital heart disease. ,lthough
echocardiography is not foolproof in detecting mild to moderate pulmonary hypertension it is quite sensitive in
detecting severe elevations in pulmonary artery pressure. Patients with pulmonary hypertension e4hibit an early
pea5 velocity on pulsed:wave oppler patterns in the pro4imal pulmonary artery because of poor compliance of the
pulmonary vascular bed ?. 0he maority of such patients has tricuspid regurgitation thereby allowing a reasonably
accurate estimate of pulmonary artery systolic pressure. &n the absence of right ventricular outflow tract obstruction
the relationship of the squared pea5 velocity of the tricuspid et multiplied by four (
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(1* or less) who have undergone lung transplantation appear to have considerable improvement of right ventricular
function by echocardiography ?. ,nother study in patients who underwent pulmonary thromboendarterectomy for
chronic thromboembolic pulmonary hypertension compared catheteriDation data with echocardiography. %trong
correlations were seen between the ma4imal velocity of the regurgitant tricuspid et by oppler and the
measurements of pulmonary artery pressures by cardiac catheteriDation postoperatively ?. ,lthough
transesophageal echocardiography can be used to evaluate the RV there do not appear to be any maor
advantages with the latter technique for this particular indication. 0hree:dimensional echocardiography is being
increasingly investigated and although the technique has not yet been systematically investigated in patients with
right ventricular dysfunction this approach appears promising ?.
Nuclear Imaging 'odalities
Ventriculo"rapy
0he gold standard for the measurement of cardiac volumes and eection fractions is usually considered to be
contrast ventriculography. 0hese measurements are normally calculated from geometric models that closely
resemble the shape of the structure being studied ?. /onetheless unli5e the left ventricle the comple4 shape of the
normal RV renders the methods that ma5e use of such mathematical models prone to error. ,dditionally in cor
pulmonale the changes in the shape of the RV can further invalidate measurements derived from models of the
normal ventricle. /uclear imaging techniques may overcome some of these difficulties because they are count based
and relatively independent of the geometric constraints of the RV. &mages in the septal left anterior oblique view are
used in determining RV#$ ?.
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determine whether the process is related primarily to pulmonary vascular involvement or to underlying fibrosis. 0he
'0 scan may reveal a mosaic perfusion pattern that suggests the presence of chronic thromboembolic pulmonary
hypertension. &n spite of the ability to visualiDe the pulmonary arteries with contrast:enhanced '0 scanning
pulmonary arteriography should be performed if there is any question about proceeding with a potentially curable
pulmonary thromboendarterectomy.
Pulmonary Arteriography
0he role of the pulmonary arteriogram in the evaluation of the patient with pulmonary hypertension and cor
pulmonale is to diagnose thromboembolic disease and it is especially useful if the ?A? scan is nondiagnostic. &n
chronic thromboembolic disease the arteriogram can reveal conve4:bordered occlusions stenoses intravascular
webs and large central thrombi with filling defects and vessel cutoffs ?. 0he arteriogram in the PP" patient reveals
dilation of the pro4imal vessels with pruning of the distal vessels. Performing pulmonary arteriography in patients
with severe pulmonary hypertension carries a small ris5 although it is generally safe in the absence of overt severe
right ventricular failure. &n the /&" PP" Registry >* patients underwent the procedure without significant adverse
events ?. One patient e4perienced transient hypotension. 0he ris5 is li5ely inversely proportional to the e4perience of
the center performing the procedures ?. Pulmonary angioscopy may be necessary to determine the precise e4tent of
thromboembolism ?.
Right Heart (atheteri/ation
0he gold standard for the diagnosis of pulmonary hypertension remains the right heart catheteriDation. 0his
technique uses a thermodilution balloon catheter to measure right atrial right ventricular pulmonary artery and
pulmonary capillary wedge pressures ?. Patients with pulmonary arterial hypertension should have normal wedge
pressures. 0he presence of an abnormal capillary wedge pressure usually requires left heart catheteriDation for
further evaluation. &n addition right heart catheteriDation allows for comparisons between the o4ygen saturations in
the central veins right atrium RV and pulmonary artery. 0his helps determine if a left:to:right shunt is present. 0he
right heart catheteriDation may supplement the echocardiographic data in the diagnosis and evaluation of congenital
heart disease.
'agnetic Resonance Imaging
0he use of magnetic resonance imaging (=R&) has been introduced to evaluate ventricular volume and eection
fraction ? (??e$ig. 7.-.1, ??e$ig. 7.-.1
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data with regard to the RV have not been validated. =R& is also being used in the evaluation of patients with
thromboembolic disease especially those with emboli in the pro4imal pulmonary arteries ?.
?
Raynaud8s disease. +lcers and gangrene on the fingertips are shown (arrows) caused by vasospasm and abnormalities of
digital vessels. ,ssociated cardiac findings are coronary vasospasm and primary pulmonary hypertension.
?
'lubbing. 0here is bullous enlargement of the distal portion of the digit as a result of increased soft tissue. 0his may be
associated with cyanotic heart disease.
?
'lubbing. 0here is enlargement of the distal digits as a result of long:standing endocarditis.
?
Figure 01%2 'hest radiograph in a patient with primary pulmonary hypertension. 0he pro4imal pulmonary arteries are
dramatically enlarged. 0his is evident on the posteroanterior 3A4and the lateral 354views (arrow). 0he lateral film also
reveals severe right ventricular enlargement (arrowhead).
?Figure 01%2 'hest radiograph in a patient with primary pulmonary hypertension. 0he pro4imal pulmonary arteries are
dramatically enlarged. 0his is evident on the posteroanterior 3A4and the lateral 354views (arrow). 0he lateral film also
reveals severe right ventricular enlargement (arrowhead).
Principles of 'anagement
).ygen
,s was previously stated a low arterial o4ygen tension value is a predictor of reduced survival in patients with cor
pulmonale. %upplemental o4ygen not only relieves tissue hypo4ia but can also reduce hypo4ic pulmonary
vasoconstriction thereby reducing PVR pulmonary artery pressures and afterload. 0he reduction in such
hemodynamic parameters might then allow right ventricular dysfunction to reverse. 0wo large trials have
demonstrated the benefit of supplemental o4ygen therapy in patients with hypo4emia and cor pulmonaleJ the
/octurnal O4ygen 0herapy 0rial ;roup (/O00) ? and the =edical Research 'ouncil !or5ing Party (=R') ?. 0he
/O00 study enrolled 7*6 patients with hypo4emia and 'OP at si4 treatment centers in the +nited %tates. 0he
patients were randomiDed to continuous versus nocturnal o4ygen therapy. =ortality was significantly reduced in
patients who received continuous o4ygen when compared with the other treatment group (?). /onetheless
statistically significant differences in mortality between each group were not evident when considering the specific
subset of patients with altered pulmonary hemodynamics despite an improvement in PVR with continuous o4ygen
therapy.
0he =R' trial performed in the +nited Hingdom enrolled C patients with 'OP and severe arterial hypo4emia and
hypercarbia ?. 0he patients were randomiDed to o4ygen therapy for at least 1> hours per day versus no o4ygen.
,gain mortality was significantly reduced in the treatment group versus the control group (?) after >** days of
therapy. !hen e4amining the hemodynamic data mean pulmonary artery pressure in the treatment group remained
stable whereas it increased significantly in the control group. 0herefore in both trials the decrease in mortality did
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not appear to correlate with improvement in pulmonary hemodynamics. "owever !eitDenblum and colleagues ?
subsequently evaluated a small group of patients with pulmonary hypertension and underlying 'OP. 0welve of the
13 patients had improvement in their pulmonary hypertension after the institution of o4ygen therapy of 1> to 1C hours
per day. uring long:term o4ygen therapy there was a yearly decrease in pulmonary artery pressures of 7.1> K -.-
mm "g. 0hus long:term o4ygen therapy is recommended when the arterial o4ygen tension is >> mm "g or less or
when the o4ygen tension is 3* mm "g or less in patients with cor pulmonale polycythemia or other evidence of
cardiac disease.
&reatment of Airflo" )struction and Parenchymal *ung +isease
0he therapy of patients with cor pulmonale due to 'OP involves ma4imiDing lung function. %everal classes of drugs
are used in patients with obstructive lung diseases for their bronchodilatory properties. 0heophylline has been shown
in animal models to have a bronchodilator effect and inotropic effects and to improve diaphragmatic contractility ?.
0he effects on ventricular function are attenuated by beta:receptor or calcium channel bloc5ade ?. "owever the use
of this agent to improve diaphragmatic as well as cardiac function appears to be controversial in humans.
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!alcium !annel Bloc'ers
'alcium channel bloc5ers have been the most widely tested and used group of drugs in patients with PP". &n such
individuals sustained improvement occurs in 7> to 6* ?. /ifedipine and diltiaDem are the most commonly used
because verapamil has been shown to have negative inotropic effects. 0ypically the patients who e4perience the
most sustained improvement in hemodynamics during an acute vasodilator challenge are those who show
improvement in symptoms and prolonged survival ?. "owever these agents may also result in significant adverse
effects such as hypotension which can be life threatening in patients with severely compromised right ventricular
function. 0herefore indiscriminate use of these agents should be avoided.
ata from the /&" PP" Registry suggested that patients with greatly depressed right ventricular function are at
greatest ris5 of adverse outcomes with acute administration of vasodilators ?. &f oral calcium channel bloc5er doses
are changed in PP" patients who have already undergone right heart catheteriDation the change should ta5e place
with careful monitoring of the blood pressure. &n patients with other causes for pulmonary hypertension and cor
pulmonale the use of these agents is controversial. , study of 11 patients with 'OP and cor pulmonale who were
treated with nifedipine revealed no improvement in survival over age: and disease:matched control subects despite
improvements in PVR ?. Other studies have shown improvement in the hemodynamics of 'OP patients but these
were accompanied by worsening of arterial o4ygenation due to ?A?mismatching. 0herefore treatment of 'OP
patients should be carefully considered on an individual basis. Other oral vasodilators have been evaluated. espite
a possible role of angiotensin:converting enDyme in the pathophysiology of pulmonary hypertension ? the evaluation
of inhibitors of this enDyme has not revealed significant benefit and these drugs have not been studied in large
prospective randomiDed trials ?.
Prostacyclin
0he use of prostacyclin (epoprostenol P;&7) as long:term therapy developed from observations of hemodynamic
parameters during its acute administration ?. &t has a very short half:life and it is rapidly inactivated by the low
gastric p". 0herefore it must be given as a continuous intravenous infusion via a permanent indwelling catheter with
a portable infusion pump. %ubstantial preliminary data ? led to a large prospective randomiDed multicenter trial that
compared prostacyclin plus conventional therapy with conventional therapy alone in patients with class &&& and &V
PP" ?. 0he patients who were treated with prostacyclin had significant improvements in e4ercise capacity
hemodynamics and survival (??$ig. 7.3). =ore recently patients with severe pulmonary hypertension due to the
scleroderma spectrum of diseases were randomiDed in a similar prospective trial ?. &mprovement in e4ercise
capacity and hemodynamics at 6 months was demonstrated in the prostacyclin cohort. Bong:term benefits have also
been reported even in patients who have not demonstrated hemodynamic improvement during the acute infusion.
0he dose of the drug is increased generally once or twice per wee5 and tolerance develops if it is not increased.
0he long:term effects have been suggested to be due not only to the vasodilator properties but also to antiplatelet or
anti9smooth muscle proliferation properties. ,dverse events are related to catheter:related infections and thrombosis
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and pump malfunction. ose:related side effects include diarrhea aw pain flushing and arthralgias. 0his drug
should be administered by a team of individuals who are e4perienced with its use and aware of the time commitment
that is required for proper teaching and maintenance. ,lternatives to this form of prostacyclin are under investigation
and include inhaled prostacyclin ? nebuliDed iloprost (a prostacyclin analog) ? and oral prostacyclin in the pill
form ?. %ubcutaneous prostacyclin delivered by a small pump (+0:1>ARemodulin) is pending approval by the +.%.
$ood and rug ,dministration.
(ndotelin Anta"onists
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models of hypo4ic pulmonary hypertension due to its inhibitory effects on smooth muscle proliferation ? the drug of
choice is warfarin@ an international normaliDed ratio of 1.> to 7.> is considered therapeutic ?. 0he ris5:benefit ratio
has to be considered on an individual basis when using anticoagulant therapy.
Atrial 6eptostomy
Patients with PP" often begin to shunt blood from right to left as the pulmonary artery pressure rises. 0his is due to
the opening of a patent foramen ovale. &t is li5ely that in some patients this serves as a means by which to EunloadF
the RV to some degree. 'reation of a shunt atrial septostomy has been performed as palliation in a few cases with
severe PP" ?. &n such patients the RV is massively dilated thereby encroaching on left ventricular filling. , right:to:
left shunt is created in an attempt to improve forward output and allow for better filling of the left ventricle. 0he
unfortunate tradeoff is the potential for causing profound systemic arterial hypo4emia or pulmonary edema by
overloading the left ventricle. 0herefore this procedure is still considered investigational but may be used in e4treme
cases.
6urgical &reatment
Pulmonary Tromboendarterectomy
0hromboendarterectomy has been the treatment of choice for pulmonary hypertension that is associated with
chronic thromboembolic disease. ,nticoagulation should be instituted and inferior vena cava filters are
recommended in patients with this entity but the only means by which to alleviate symptoms and to have an impact
on survival is surgery. Pulmonary thromboendarterectomy is performed via median sternotomy on cardiopulmonary
bypass. 0he overall mortality continues to improve and is now less than >. 0he response to therapy is often
impressive with dramatic reversal of right ventricular dysfunction ?. Bung transplantation can be performed in
patients in whom thrombi are too distal to e4tract.
*un" Transplantation
Bung transplantation and heart:lung transplantation are being used as surgical therapy for patients with a variety of
pulmonary parenchymal and vascular disorders ?. Patients should be referred for evaluation for transplantation if
class &&& or class &V symptoms are present. 0he length of the waiting list at a given center (generally 3 to 1C months)
helps to determine the appropriate time for listing and transplantation. Patients with PP" or pulmonary arterial
hypertension due to the scleroderma spectrum of diseases should undergo a trial of prostacyclin therapy by
continuous infusion before proceeding to lung transplantation because this drug has proved so efficacious in these
settings. %ingle and bilateral lung transplantation rather than heart:lung transplantation are the procedures of
choice due to the limited availability of organs. 0he RV has a tremendous capacity to recover in spite of severe
dysfunction once the afterload posed by the abnormal pulmonary vasculature is removed. %ingle:lung transplants
are done in all patients with pulmonary parenchymal disorders e4cept those with suppurative diseases such as
cystic fibrosis in which case bilateral lung transplantation is performed. =ost centers prefer bilateral lung
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transplantation for PP" as well. One advantage of the bilateral approach may be that the new lung is less li5ely to
suffer from reperfusion pulmonary edema immediately after operation. 'hronic reection may also be more easily
tolerated with a bilateral transplant than when the e4tremely abnormal native PP" lung remains ?. "owever the
waiting time on the list is shorter for a single:lung transplant and a set of donor lungs can be offered to two patients
when single:lung transplantation is used for PP". =any transplant teams prefer the single:lung procedure. "eart:
lung transplantation is reserved for patients with associated left heart disease or congenital heart disease with
pulmonary hypertension when the atrial or ventricular septal defect cannot be repaired. =ar5edly depressed right
ventricular function is not a contraindication to single or bilateral lung transplantation because right ventricular
function improves considerably after transplantation ?. Right ventricular shape also appears to normaliDe after single
and bilateral lung transplantation. One:year survival rates for lung transplantation are appro4imately C*.
Obliterative bronchiolitis (chronic reection) is the maor long:term complication of transplantation. Patients with PP"
appear to have higher mortality as well as a higher frequency of obliterative bronchiolitis. Recurrence of the primary
pulmonary disorder in the transplanted lung can occur in certain conditions but has not been reported in PP".??
Figure 01%0,n approach to the diagnosis of primary pulmonary hypertension (P"). '& cardiac inde4@ P,P pulmonary
artery pressure@ R,P right atrial pressure@ RV right ventricle@ RV%P right ventricular systolic pressure. L0he absence of
perceived tricuspid insufficiency by echocardiography may not absolutely e4clude P". ?Other tests may already have
revealed potential etiology(ies) of P". 0hese tests may also strongly suggest the etiology. ($rom 8,lonDo ;# antD5er
R. iagnosing primary pulmonary hypertension. &nJ Rubin BM Rich % eds. Primary pulmonary hypertension/ew Gor5J
=arcel e55er &nc 122J7797>7 with permission.)
?
Figure 01%7,n approach to determining the cause of primary pulmonary hypertension. NRadionuclide ventriculography
may be needed to confirm. 88%piral computed tomography may also suggest pulmonary embolism. &n addition to emboli a
mosaic perfusion pattern may indicate chronic thromboembolic pulmonary hypertension. LPulmonary angiography may be
needed to confirm. ($rom 8,lonDo ;# antD5er R. iagnosing primary pulmonary hypertension. &nJ Rubin BM Rich %
eds. Primary pulmonary hypertension/ew Gor5J =arcel e55er &nc 122J7797>7 with permission.)
Table 27.1 Pulmonary hypertension: nomenclature and classification
Pulmonary arterial hypertension
Primary pulmonary hypertension
Sporadic
Familial
Related to
Collagen-vascular disease
Congenital systemic to pulmonary shunts
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Portal hypertension
Human immunodeficiency virus infection
Drugs/toxins
norexigens
!ther
Persistent pulmonary hypertension of the ne"#orn
!ther
Pulmonary venous hypertension
$eft-sided atrial or ventricular heart disease
$eft-sided valvular heart disease
%xtrinsic compression of central pulmonary veins
Fi#rosing mediastinitis
denopathy/tumors
Pulmonary venoocclusive disease
!ther
Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia
Chronic o#structive pulmonary disease
&nterstitial lung disease
Sleep disordered #reathing
lveolar hypoventilation disorders
Chronic exposure to high altitude
'eonatal lung disease
lveolar-capillary dysplasia
!ther
Pulmonary hypertension due to chronic thromboembolic disease
(hrom#oem#olic o#struction of proximal pulmonary arteries
!#struction of distal pulmonary arteries
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Pulmonary em#olism )throm#us* tumor* ova/parasites* foreign material+
In situthrom#osis
Sic,le cell disease
Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature
&nflammatory
Schistosomiasis
Sarcoidosis
!ther
Pulmonary capillary hemangiomatosis
Right Ventricular #nlargement
0he right ventricle is enlarged in persons with diseases that increase the wor5 of this chamber. 0hese include a number of
pulmonary diseases as well as primary pulmonary vascular disease that results in pulmonary hypertension. %tenosis of
the pulmonary valve or infundibulum and other congenital cardiac lesions such as truncus arteriosus and septal defects
may also result in enlargement of this ventricle. =itral valvular disease was formerly a common cause of pulmonary
hypertension but is not often seen at present in developed countries.
!hen enlargement occurs the outflow tract is the site of the earliest dilatation. #nlargement of the outflow tract e4tends
from the ape4 of the right ventricle to the pulmonary valve and includes the anterior wall along with the upper half of the
interventricular septum. 0he inflow tract that e4tends from the tricuspid valve to the ape4 includes the lower half of the
interventricular septum inferiorly and the lower part of its outer wall anteriorly. #nlargement of the outflow tract of the right
ventricle results in lengthening of the anterior ventricular wall which is manifested radiographically by prominence of the
distal right ventricle or pulmonary conus. 0he result is an anterior bulge in the upper:anterior cardiac contour ust below
the pulmonary artery. 0here often is associated enlargement of the pulmonary artery which adds to the anterior
prominence of the upper border of the heart in this proection. !hen this occurs there is more prominence and conve4ity
of the pulmonary artery segment in the frontal proection than is normal. 0his results in straightening or conve4ity of the
left:upper cardiac contour below the aortic 5nob. !hen the enlargement of the right ventricle becomes greater the heart
tends to be rotated to the left (countercloc5wise as viewed from the front) so that the conus of the right ventricle may
become border:forming. &n the lateral proection the anterolateral bulge in the region of the outflow tract of the right
ventricle reduces the siDe of the retrosternal space between the upper cardiac border and the sternum. 0he pulmonary
artery also contributes to this narrowing.
!hen the inflow tract of the right ventricle enlarges the diaphragmatic portion of this ventricle is increased in length
resulting in an anterior rounding or bulge in the right ventricular area. 0his enlargement may displace the left ventricle
posteriorly and elevate the cardiac ape4 as seen in the frontal proection. 0his finding is most common in infants and
children with congenital cardiac disease resulting in right ventricular enlargement. !hen right ventricular dilatation is
associated with enlargement of the left ventricle differentiation and evaluation of the relative siDe of each chamber is often
very difficult.