pah

Stuart Rich and Marlene RabinovitchCategory 1) Pulmonary Hypertension−Diagnosis and Treatment of Secondary (Non

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Diagnosis and Treatment of Secondary (Non–Category 1)Pulmonary Hypertension

Stuart Rich, MD; Marlene Rabinovitch, MD

Pulmonary hypertension occurs commonly in cardiopul-monary disease. In 1998, a new clinical classification was

proposed that divided pulmonary hypertension into 5 catego-ries on the basis of the presumed underlying etiology of thepulmonary vascular disease1 (Table 1). Although it was neverintended that this classification be used as a guideline todetermine appropriate therapy, somewhat surprisingly, theregulatory authorities decided that all medications that wereclinically tested and approved for patients with idiopathicpulmonary arterial hypertension (PAH) and patients withpulmonary hypertension associated with connective tissuediseases be applied to all category 1 patients.2 The wisdom ofthis can be debated at a later date. However, it has leftclinicians somewhat confused about the utilization oftherapies to treat patients who fall outside of category 1pulmonary hypertension, often referred to as secondarypulmonary hypertension.

There are 3 classes of approved therapies for PAH, all ofwhich are considered to be pulmonary vasodilators: endo-thelin receptor blockers, phosphodiesterase-5 inhibitors,and prostacyclins.3 Their clinical efficacy has been basedon a short-term improvement in exercise tolerance, asmeasured by a 6-minute walk test. In all of the clinicaltrials, an improvement in walk was apparent within thefirst 4 weeks of use, allowing a judgment about efficacy tobe made quickly.4 Hemodynamically, their effects aremodest, but they tend to raise cardiac output with littleeffect on pulmonary artery pressure. This has importantimplications when they are considered for unapproved use.We review the distinctive features of these causes ofpulmonary hypertension and the data on the evidence thatsupports or refutes the use of these therapies in non–category 1 pulmonary hypertension.

Category 2: Pulmonary Venous HypertensionPatients with pulmonary venous hypertension have elevatedpulmonary venous pressure (as reflected in the pulmonarycapillary wedge pressure), most frequently as a consequenceof either mitral valve disease5 or left ventricular (LV)diastolic dysfunction.6 Although mitral stenosis was the mostcommon cause of this entity decades ago, LV diastolicdysfunction is the most common cause of pulmonary venous

hypertension seen in our referral practice.7 It is presumed thatthe mechanism of both is similar. Specifically, a chronicelevation in the diastolic filling pressure of the left heartcauses a backward transmission of the pressure to thepulmonary venous system, which triggers vasoconstriction inthe pulmonary arterial bed.8

Histologically, abnormal thickening of the veins andformation of a neointima are seen.9 The latter can be quiteextensive (Figure 1). As secondary features, medial hyper-trophy and, with time, thickening of the neointima on thearterial side of the pulmonary circulation occur as well.There is great potential for reversibility of these changeswith improvement in the cause of the venous hypertension(see below). The variability in the response of the pulmo-nary arterial circulation to the elevated venous pressureindicates that genetic factors also dictate the potentialreversibility of the disease. We have shown experimentallythat insulin resistance, frequently observed in associationwith impaired LV diastolic function, is independentlylinked to the development of PAH.10 We also know thatwhen pulmonary venous hypertension is not the result ofLV diastolic dysfunction or obstruction at the level of themitral valve, (ie, pulmonary veno-occlusive disease), thegenetic etiology may be similar to that of idiopathicpulmonary hypertension.11

The clinical profile of LV diastolic dysfunction has beenstudied extensively and is characteristically observed in anolder patient with hypertension, diabetes, coronary arterydisease, and/or obesity.12 The clinical signs and symptomscharacteristic of pulmonary venous hypertension includedyspnea with effort and eventually right ventricular (RV)failure with edema, similar to category 1 PAH. However,important and distinctive symptoms are orthopnea andparoxysmal nocturnal dyspnea, which are not featuresof PAH.13

Clinical tests will often reveal findings that suggest that thepatient likely has pulmonary venous hypertension and notPAH (Table 2). The ECG may show LV hypertrophy ratherthan RV hypertrophy. The chest x-ray will often showpulmonary vascular congestion, pleural effusions, and, onoccasion, pulmonary edema. High-resolution chest computedtomography can be helpful because it will often reveal

From the University of Chicago Pritzker School of Medicine, Chicago, Ill (S.R.); Stanford University School of Medicine, Stanford, Calif (M.R.); andPulmonary Vascular Research Institute, Chicago, Ill (S.R., M.R.).

Correspondence to Stuart Rich, MD, University of Chicago, Section of Cardiology, 5841 S Maryland Ave, MC 2016, Chicago, IL 60637. [email protected]

(Circulation. 2008;118:2190-2199.)© 2008 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.723007

2190

Pulmonary Vascular Diseases



ground-glass opacities and a mosaic perfusion pattern con-sistent with chronic pulmonary edema.

Essential in the evaluation of these patients is an echocar-diogram, which readily allows the assessment of LV systolicfunction. It has been emphasized that the differentiationbetween systolic and diastolic dysfunction cannot be made onthe basis of the history, physical examination, or chestx-ray.14 Pulmonary hypertension occurring in the setting of areduced LV ejection fraction has been well described andappears to be one of the most powerful predictors of prog-nosis for patients with LV failure.15 The echocardiogram willalso detect any significant underlying mitral or aortic valvedisease.16,17 Doppler echocardiography is widely used toassess diastolic dysfunction in patients with both normal andreduced LV systolic function.18 However, because pulmonaryhypertension itself produces diastolic filling abnormalities inthe LV, Doppler echocardiography cannot be relied on todistinguish between category 1 and category 2 pulmonaryhypertension.19

Demonstration of an elevated pulmonary capillary wedgepressure at cardiac catheterization should secure the diagnosisof pulmonary venous hypertension. However, this determi-nation is often imprecisely made20 because it is frequentlydifficult to get an accurate wedge pressure. Obtaining a bloodsample for determination of oxygen saturation can be helpfulin confirming that the catheter is in the wedged position.21 Wehave found that measurement of LV end-diastolic pressure(LVEDP) at the time of initial diagnosis is very helpful in

confirming the wedge pressure measurement. In patients withsevere RV failure, the effect of pericardial constraint andtransmission of elevated RV filling pressure across theintraventricular septum may also be a factor. Some patientscan have a markedly augmented “a” wave that can raise theLVEDP above the pulmonary capillary wedge pressure. Anaccurate assessment of LVEDP or pulmonary capillarywedge pressure can only be made at end expiration; usinga digitally derived mean pulmonary capillary wedge pres-sure will generally yield erroneous information and often amisclassification of the patient as having normal fillingpressures22 (Figure 2).

Two hemodynamic profiles have been described that arecommon in these patients. Some patients will have anelevation in pulmonary arterial pressure with only a minimalincrease in the transpulmonary gradient (mean pulmonaryarterial pressure�pulmonary capillary wedge pressure), as areflection of the passive increase in pulmonary arterialpressure necessary to overcome the increased downstreamresistance (Figure 3A). Indeed, a preserved right ventriclemust generate high systolic pressures to ensure adequateforward blood flow in these patients, and thus moderatedegrees of pulmonary hypertension are not only characteristicbut also favorable. However, a subset of these patients willhave reactive pulmonary vasoconstriction, resulting inmarked elevations in pulmonary arterial pressure beyond thatwhich is necessary to maintain cardiac output. These patientsare frequently distinguished by a marked elevation in pulmo-nary arterial diastolic pressure (Figure 3B). This has beenstudied extensively in patients with mitral stenosis and is lesswell characterized in patients with LV diastolic dysfunction.It is believed that these patients have a permissive genotypethat, when exposed to high pulmonary venous resistance,develops reactive pulmonary hypertension with more severearterial changes, including neointima formation, than theother subgroup.23

A normal LVEDP at rest may, however, still be present inpatients with LV diastolic dysfunction.24 When this occurs inthe setting of reactive pulmonary hypertension, it is verydifficult to know whether these patients have PAH or pulmo-nary venous hypertension. Using exercise,25 a vasodilatorchallenge,26 or an inotropic challenge27 at the time of diag-nostic cardiac catheterization to increase the cardiac outputmay be helpful. If a significant increase in cardiac output isunaccompanied by an increase in pulmonary capillary wedgepressure, the patient more likely has PAH. On the other hand,if the increase in cardiac output is accompanied by anincrease in pulmonary capillary wedge pressure, the patientlikely has pulmonary venous hypertension. Interestingly,experimental studies indicate that an elevation in meanpulmonary arterial pressure may actually precede an eleva-tion in pulmonary venous pressure.28 Thus, there may be nodefinitive way to identify pulmonary venous hypertensionhemodynamically in some patients.

Treatment of these patients remains uncertain. Lessonslearned from treating patients with mitral stenosis can beinstructive. Patients with mitral stenosis who present withpulmonary edema will respond to the use of diuretics as atemporizing measure before the definitive therapy of mitral

Table 1. Current Clinical Classification of PulmonaryHypertension1

Category 1: PAH

Idiopathic

Familial

Pulmonary hypertension associated with:

Collagen vascular disease

Congenital systemic-to-pulmonary shunts

Portal hypertension

Drugs/toxins

HIV infection

Other (Gaucher’s, hereditary hemorrhagic telangiectasia,hemoglobinopathies, splenectomy)

Associated with significant venous or capillary involvement

Pulmonary veno-occlusive disease

Pulmonary capillary hemangiomatosis

Persistent pulmonary hypertension of the newborn

Category 2: Pulmonary venous hypertension

Category 3: Pulmonary hypertension associated with disorders of therespiratory system and/or hypoxemia

Category 4: Pulmonary hypertension due to chronic thrombotic and/orembolic disease

Category 5: Pulmonary hypertension due to miscellaneous disorders directlyaffecting the pulmonary vasculature, eg, sarcoidosis, histocytosis X,lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor,fibrosing mediastinitis)

Rich and Rabinovitch Secondary Pulmonary Hypertension 2191



valve repair or replacement. Several clinical studies haveshown that removing the mitral valve gradient, either surgi-cally or percutaneously, will result in an immediate fall in thepulmonary artery pressure.29–32 The magnitude of the fall,however, can be quite variable, with some patients achievingnormal hemodynamics within 24 hours, and others takingmany months to improve. The magnitude and rate of im-provement may be related to the severity of the vasculardisease dictated by both the duration of the pulmonaryhypertension and genetic factors that either induce moresevere vascular disease or impede regeneration and remodel-ing after removal of the mitral valve obstruction. It is likelythat these same issues are relevant to pulmonary hypertensionin patients with LV diastolic dysfunction.

A review of the management of LV systolic failure inpatients with coexisting pulmonary hypertension is beyondthe scope of this article. However, a few important points areworth mentioning. Regarding the approved treatments forcategory 1 pulmonary hypertension, bosentan has been dem-onstrated to be ineffective in patients with systolic heartfailure,33 and epoprostenol was associated with increasedmortality in patients with systolic heart failure.34 In contrast,patients with systolic heart failure and elevated pulmonarycapillary wedge pressures tolerate the acute administration ofsildenafil with a trend toward beneficial hemodynamicchanges.35 Sildenafil has also been shown to be associatedwith improvement in measures of exercise performance whenadded to existing therapy in patients with systolic heartfailure and pulmonary hypertension.36

Chronic pulmonary vasodilator therapy has not been suc-cessful in patients with mitral stenosis and is unlikely to be

beneficial in patients whose pulmonary hypertension is aresult of LV diastolic dysfunction. Because the major hemo-dynamic effect of these therapies is to raise cardiac output, itwill predictably cause a worsening of pulmonary edema if thepulmonary venous obstruction is not being relieved. There aremultiple reports of rapid deterioration and death when pul-monary vasodilators are used in the presence of pulmonaryvenous hypertension.37–39

There are no randomized clinical trials of pulmonaryvasodilator therapy for patients with pulmonary venous hy-pertension associated with normal LV systolic function, andno treatment has yet been shown to favorably affect patientswith pulmonary hypertension associated with LV diastolicheart failure. Our approach to treating these patients has beento use medical measures to lower LV filling pressures (suchas nitrates, diuretics, and aggressive treatment of systemichypertension). When successful, we have found that thepulmonary arterial pressure will also fall, and the cardiacoutput will increase. Given the expense of the approvedtreatment with pulmonary vasodilators and the potential forclinical deterioration, we believe that these treatments shouldonly be considered in the setting of a supervised clinical trial.

Category 3: Patients With PulmonaryHypertension Associated With Lung Disease

Pulmonary hypertension occurs in patients with lung disease.However, because it would be inappropriate to characterizeall cardiac disease associated with pulmonary hypertension assimilar, it would be equally inappropriate to characterize alllung diseases associated with pulmonary hypertension as

Figure 1. Pulmonary occlusive venopa-thy. A, Septal veins with nearly occludedlumens by fibrous intimal thickening(asterisk), marked lymphatic dilation(arrow), and congested alveolar capillar-ies. Verhoeff–van Gieson stain; magnifi-cation �50. B, Obstructive fibrous inti-mal thickening and recanalizationchannels in a septal vein; pulmonarymicrovasculopathy. Magnification �200.C, Focal thickening of alveolar septa byproliferated capillaries. Hematoxylin-eosin stain; magnification �20. D, Nodu-lar capillary proliferation, hemosiderin-laden alveolar macrophages, and type IIpneumocytes (arrows); pulmonaryvenous disease. Hematoxylin-eosinstain; magnification �300. Reprintedfrom Pietra et al,79 with permission fromElsevier. Copyright 2004, American Col-lege of Cardiology Foundation.

2192 Circulation November 18, 2008



similar. The most commonly encountered lung disease,chronic obstructive pulmonary disease (COPD), has quitedifferent clinical manifestations than interstitial lung disease(ILD). In both COPD and ILD, there are changes in the distalpulmonary arterial vessels related to hypoxia similar to thoseobserved in experimental animals40 and in high-altitudedwellers, as well as changes due to the loss of lung paren-chyma.41 Hypoxia induces muscularization of distal vesselsand medial hypertrophy of more proximal arteries as well asa loss of vessels, which is compounded by a loss of lungparenchyma in the setting of lung disease. Neither neointimaformation nor the development of plexiform lesions is ob-served.42 However, in patients with mild COPD in association

with smoking, severe fibroproliferative neointimal formationcan be observed (Figure 4).

Clinically, patients with COPD will present with dyspneaand signs of right heart failure, usually in the setting ofmarked hypoxemia. Pulmonary function tests and chestcomputed tomographic imaging are helpful in making adiagnosis in these patients. At cardiac catheterization, thelevel of the pulmonary hypertension typically is relativelymild. Indeed, the mean pulmonary arterial pressure seen inthese patients is usually lower than the mean pulmonaryarterial pressure obtained in patients with PAH who respondfavorably to pulmonary vasodilator therapy.43 The fact thatthese patients are clinically failing may indicate that it is notthe severity of the pulmonary hypertension but the degree ofhypoxemia that is determining their clinical symptomatolo-gy.44 When RV failure occurs at this level of pulmonaryhypertension, it is probable that the RV in these patients isadversely affected by the hypoxemia and behaves more likean ischemic RV than a pressure-loaded RV.45 Pulmonaryhypertension in COPD patients can also be affected byadditional factors, including acidemia, hypercarbia, compres-sion of pulmonary vessels by high lung volume, loss of smallvessels in the vascular bed of regions of emphysema and lungdestruction, and increased cardiac output and blood viscosityfrom polycythemia secondary to hypoxia.46

Although relatively mild, the level of the PAH is predictiveof prognosis in patients with COPD.44,47,48 Nonetheless, therehas never been a clinical trial showing a sustained beneficialeffect of any pulmonary vasodilator in these patients. Wors-ening ventilation-perfusion mismatch from vasodilators hasbeen demonstrated with short-term use and is justification forwhy these medications are not used.49 The only effectivetreatment for patients with COPD and pulmonary hyperten-sion has been supplemental oxygen, with several studiesshowing an improvement in morbidity and mortality.50,51

Clinicians also need to monitor the level of hemoglobin inthese patients. Patients with hypoxemia should have reactivepolycythemia as a basic biological mechanism to compensatefor their cardiopulmonary disease. A hemoglobin level in thelow-normal range, although well tolerated in patients withnormal oxygenation, may not be tolerated in patients withhypoxemia and pulmonary hypertension.

There is a subset of patients with COPD (�5%) whodevelop severe PAH (mean pulmonary arterial pressure�45 mm Hg).52 Their clinical characteristics have beendescribed. These patients have a distinctive pattern of cardio-pulmonary abnormalities with mild to moderate airway ob-struction, severe hypoxemia, hypocapnia, and a very lowdiffusing capacity for carbon monoxide. These observationssuggest that a different biological mechanism results inchanges in the pulmonary vascular bed in susceptible patientsand that severe pulmonary hypertension occurs in the pres-ence of lung disease rather than as a result of the lung disease.For example, a genetic predisposition to pulmonary hyper-tension in COPD patients as a result of a 5-HTT poly-morphism has been described, which may predispose to moresevere pulmonary hypertension in hypoxemic patients.53

These patients have a hemodynamic profile more typical ofPAH with a dramatic increase in pulmonary arterial pressure,

Table 2. Diagnosis of Category 2 Pulmonary Hypertension

Clinical AssessmentFeatures of Pulmonary Venous

Hypertension

Symptoms Orthopnea

Paroxysmal nocturnal dyspnea

Signs Elevated jugular venouspressure

Edema

ECG RV hypertrophy may be absent

LV hypertrophy may be present

Chest x-ray Pulmonary vascular congestion

Pulmonary edema

Pleural effusions

Chest CT scan Mosaic perfusion pattern

Ground-glass opacities

Echocardiogram RV enlargement

Elevated pulmonary arterialpressure by Doppler

Aortic or mitral valve disease

Reduced or normal LV ejectionfraction

Cardiac catheterization With reduced LV systolicfunction

Normal or elevated PCWP

Normal or reduced cardiacoutput

Features of aortic or mitralvalve disease

With normal LV systolicfunction

Elevated PCWP

Normal PCWP and normalcardiac output (considerchallenge with exercise orshort-acting pulmonaryvasodilator)

Normal PCWP and reducedcardiac output (considerchallenge with exercise orinotropic agents)

CT indicates computed tomographic; PCWP, pulmonary capillary wedgepressure.




normal pulmonary capillary wedge pressures, and markedlyelevated pulmonary vascular resistance. There are no dataregarding whether pulmonary vasodilators have any clinicalbenefit in this subset of patients.

ILD can also be associated with pulmonary hypertension.54

The majority of these patients will have an underlyingconnective tissue disease. Patients without diagnostic find-ings of a connective tissue disease are considered to haveidiopathic pulmonary fibrosis. Patients with connective tissuedisease (eg, scleroderma) represent an additional diagnosticchallenge.55 Approximately 20% of those who have pulmo-nary fibrosis will have pulmonary hypertension, and �20%of those without pulmonary fibrosis will also have pulmonaryhypertension.56 This makes it often uncertain if the pulmo-nary hypertension is due to the lung disease, pulmonaryvascular disease, or both.57 Most series show that a markedreduction in diffusing capacity for carbon monoxide is aconsistent feature of the patients with connective tissuediseases who have pulmonary hypertension,58,59 but it doesnot correlate with the degree of pulmonary fibrosis.

The hemodynamic profile of patients with ILD (withoutscleroderma) and pulmonary hypertension is quite distinctfrom that of patients with idiopathic PAH.60–62 It is rare forthe mean pulmonary arterial pressure ever to be �40 mm Hgin these patients, whereas it is rare for the mean pulmonaryarterial pressure ever to be �40 mm Hg in patients withidiopathic PAH. Consequently, the combination of an abnor-mality consistent with ILD on the chest computed tomo-graphic scan and mild pulmonary hypertension should pointto the diagnosis of pulmonary hypertension associated withILD and not idiopathic PAH.

Most therapies for ILD have been directed toward haltingprogression or inducing regression of the interstitial diseaseprocess with immunosuppressive and anti-inflammatoryagents.63 Overall, the results of these trials have been disap-pointing, which makes the treatment of any associated pul-monary hypertension an attractive therapeutic target. How-ever, although pulmonary vasodilator therapy has beenavailable for decades, there are no randomized clinical trialsshowing benefit of these agents in ILD. One rationale fortheir use has been to reduce the effects of chronic hypoxicvasoconstriction. In hypoxic rabbits, it has been demonstratedthat sildenafil can prevent the development of RV hypertro-phy, and iloprost was able to prevent the development ofPAH.64 One clinical study compared the acute effects ofinhaled nitric oxide, intravenous epoprostenol, and oral sil-denafil in 16 patients with pulmonary fibrosis in whichimproved gas exchange was noted with the oral sildenafil butnot the intravenous prostacyclin.65 Recent results of a ran-domized clinical trial with bosentan showed no effect on theprimary end point, the 6-minute walk test.66 Given theirpotential to cause worsening gas exchange, we stronglycaution against their anecdotal use in any patient until moredefinitive data support their chronic use. To date, lungtransplantation is the only intervention proven to improvesurvival.67

Category 4: Chronic ThromboembolicPulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH)is a very distinctive disorder that has been well character-ized.68 Although the physiological trigger (procoagulant state,inadequate thrombolytic system, antecedent deep vein throm-

Figure 2. Pulmonary capillary wedge tracing in a patient with respiratory variation. The correct pressure is measured at end expiration.In this case, the digitally derived mean pressure, 7 mm Hg, is 50% of the actual end-expiratory wedge pressure of 15 mm Hg.




bosis) can be quite variable, these patients characteristicallypresent similar to those with idiopathic PAH. They have aslowly progressive onset of dyspnea with effort and ulti-mately develop signs and symptoms of right heart failure.Hypoxemia is very common. A perfusion lung scan is always

abnormal, although the perfusion scan will often underesti-mate the severity of the underlying thromboembolic disease.Spiral computed tomographic scanning is the favored imag-ing modality to determine the presence, severity, and proxi-mal extent of thromboembolic disease and is essential in

Figure 3. Simultaneous pulmonary arterial and LV pressures. A, Patient with LV diastolic dysfunction. In this patient, the LVEDP is ele-vated, and the pulmonary arterial diastolic pressure equals the LVEDP. The increase in pulmonary arterial pressure (PAP) is directlyrelated to the elevated LV filling pressure. B, In contrast, the simultaneous pulmonary arterial and LV pressures are shown in anotherpatient with LV diastolic dysfunction. In this patient, there is a substantial gradient between the pulmonary arterial diastolic pressure,which is 35 mm Hg, and the LVEDP, which is 20 mm Hg. In this situation, it is believed that changes in the pulmonary arteriolar bedoccur from reactive pulmonary vasoconstriction, which contributes further to the severity of the pulmonary hypertension.




determining whether the patients would be surgical candi-dates for pulmonary thromboendarterectomy.

The pathology of CTEPH has features that usually candistinguish it from idiopathic PAH69 (Figure 5). The lesionsare frequently more variable, ie, there are arterial pathwaysthat appear relatively unaffected by vascular disease andothers that typically show recanalized vascular thromboses.However, the involvement of distal microvessels, particularlywhen the thromboses have occurred in subsegmental arteries,often indicates a worse prognosis. In these cases, the pathol-ogy may more closely resemble that of IPAH with associatedplexiform lesions.70,71

Hemodynamically, these patients are indistinguishablefrom patients with category 1 PAH. However, because thereis no way for the clinician to know whether the vessel that isutilized to obtain the wedge pressure tracing has distalthrombus, we recommend direct measurement of LVEDP atthe time of diagnosis if there is any doubt. Interestingly, somepatients will have a reactive component to their pulmonaryhypertension believed to be a response to the increasepulmonary resistance created by the thromboembolic disease.It has been suggested that pulmonary vasoconstriction isoccurring in the vasculature that is uninvolved with pulmo-nary thromboemboli. One clinical dilemma involves thepatient with a documented solitary pulmonary embolism whodevelops pulmonary hypertension. Whether this representscoincidence, a cause-and-effect phenomenon, or a subset ofgenetically susceptible individuals may be impossible toresolve.

The definitive therapy of these patients is pulmonarythromboendarterectomy.72 In specialized centers, these pa-tients can have a dramatic improvement in their symptoms,hemodynamics, and survival, and this is the treatment ofchoice. However, some patients will have extensive diseasethat is either inoperable or only partially amenable to surgicalremoval. The use of pulmonary vasodilators has been testedin open-label acute and short-term studies with some suc-cess.73,74 One study tested sildenafil over 6 months in 12patients who were deemed inoperable and found a modestreduction in pulmonary arterial pressure that was associatedwith a 54-m increase in the 6-minute walk.75 Another trialused bosentan in 16 patients who were inoperable andshowed a 92-m improvement in the 6-minute walk butwithout hemodynamic monitoring.76 Because there havenever been any prospective randomized trials of vasodilatorsin CTEPH, it remains unknown whether these changes willtranslate into a clinically meaningful and sustained improve-ment in the patients. Nonetheless, in patients with inoperableCTEPH, a clinical trial of pulmonary vasodilator therapy maybe warranted, with the goal of improving the patient’ssymptomatology and quality of life.

Category 5: Miscellaneous CausesThis category includes uncommon causes of pulmonaryhypertension such as sarcoidosis, schistosomiasis, histocyto-sis X, and lymphangiomatosis. The pathology between theseentities is quite diverse, and their clinical presentations arehighly variable. There have never been controlled trials ofpulmonary vasodilator therapy, and thus there is no way toknow their potential efficacy. Open-label trials have demon-strated favorable effects of intravenous epoprostenol in pa-tients with sarcoidosis and severe pulmonary hyperten-sion.77,78 However, given the lack of established benefit ofthese drugs for other secondary forms of pulmonary hyper-tension, we urge caution before attempting to use them inthese patients.

Because the diagnosis of pulmonary hypertension isbeing made more frequently in patients with coexistingcardiac and lung diseases, the following guidelines may behelpful:

Figure 4. Histological stains of serial sections of a pulmonarymuscular artery from a patient with COPD. a, Orcein stain; b,Masson’s trichrome stain; c, Alcian blue stain. Observe theabundant amount of elastin (a) and collagen (b) within the inti-mal layer, with a scarce proportion of proteoglycans (c). Internalscale bar�100 �m. Observe the abundant amount of elastin (a)and collagen (b) within the intimal layer, with a scarce propor-tion of proteoglycans (c). Internal scale bar�100 �m. Reprintedfrom Santos et al.80




● In distinction from category 1 pulmonary hypertension, inwhich the treatment is focused on lowering the pulmonaryarterial pressure, in non–category 1 pulmonary hyperten-sion, the treatment should focus on treating the underlyingdisease.

● The use of conventional therapies (diuretics, oxygen)should be tried initially to correct related clinical problems.Exercise testing may be helpful to uncover exercise-induced hypoxemia, which may benefit from treatment.

● The acute testing of short-acting pulmonary vasodilatorswith hemodynamic guidance is recommended to evaluatethe potential for beneficial or adverse effects before pul-monary vasodilators are considered as chronic therapy:

— inhaled nitric oxide (20 to 40 ppm).— intravenous adenosine (50 to 200 �g/kg per minute).— intravenous epoprostenol (2 to 6 ng/kg per minute).

● Patients who respond favorably to pulmonary vasodilatorsshould manifest unequivocal improvements within 4 to 6weeks:

— symptoms related to the pulmonary hypertensionshould improve by 1 functional class.

— echocardiography should show a reduction in RVenlargement.

— exercise testing should demonstrate substantial in-creases (�20%) that correlate with the patient’ssymptoms.

— catheterization should document an important reductionin pulmonary arterial pressure and pulmonary vascularresistance (�20%).

— Patients who fail to improve or who demonstrateworsening clinical findings (tachycardia, hypoxemia,hypotension, or worsening edema) should have thepulmonary vasodilator therapy promptly discontinued.

In conclusion, pulmonary hypertension is a common clin-ical feature of cardiac and pulmonary diseases. Making asecure diagnosis can be clinically challenging, and at times it

can be impossible to distinguish patients with coexistingPAH. In all series, the development of pulmonary hyperten-sion portends a worse prognosis. However, the use ofpulmonary vasodilators as a chronic therapy remains largelyunproven.

DisclosuresNone.

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KEY WORDS: � heart failure � hypertension � pulmonary � pulmonaryheart disease




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