Documents Cor Pulmonale,Thetheory

8/12/2019 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
http://127.0.0.1:83/images/vdot.gifhttp://127.0.0.1:83/images/vdot.gifhttp://127.0.0.1:83/images/qdot.gifhttp://127.0.0.1:83/images/vdot.gifhttp://127.0.0.1:83/images/qdot.gif


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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.