Pulmonary arterial hypertension: Classification, diagnosis, and prognosis

November 1, 2006

Abstract: Our understanding of the pathobiology of pulmonary arterial hypertension (PAH) has evolved considerably over the past 2 decades, with increasing recognition of the important role that aberrant vasoproliferative responses play in conjunction with disordered vasoconstriction. Classification of the many forms of PAH into categories sharing a similar pathophysiology and clinical presentations help the practicing clinician approach a complex differential diagnosis. Noninvasive tests can be used to narrow this differential but must be applied with an appreciation for their limitations. Transthoracic echocardiography is the screening tool of choice; the workup should also include chest radiography and electrocardiography. However, right heart catheterization is ultimately required to establish the diagnosis. While PAH remains a progressive and generally fatal disease, existing therapies have a significant impact on survival and new therapeutic targets offer great hope for improving the prognosis. (J Respir Dis. 2006;27(11):487-493)

Since Romberg's1 original description of "sclerosis of the pulmonary arteries" in 1891, our understanding of pulmonary arterial hypertension (PAH) has evolved. Particularly during the past 2 decades, a rapidly growing body of knowledge of the science of endothelial function (and dysfunction) has revolutionized our approach to this disorder2,3 and offers great hope for new therapies for this generally fatal disease.

In this article, we present a historical overview of PAH. We then review the pitfalls encountered in diagnosis, and discuss the prognosis before and after our current era of therapeutics.

HISTORICAL PERSPECTIVE

The phenomenon of abnormal sclerosis of the pulmonary arteries was first discussed in 1891 when Romberg1 described his histopathologic observations of persons dying of what is now called idiopathic PAH. An appreciation of this description was propagated by Ayerza, who lectured in 1901 on a syndrome of dyspnea, pulmonary artery sclerosis, and polycythemia that became known as "Ayerza's disease."4 Ayerza's student Arrillaga proposed that syphilis caused this disease, a belief widely held until the 1940s,4 when Brenner's5 careful review of 100 case reports from autopsy files at Massachusetts General Hospital discounted this association.

In 1951, Dresdale and coworkers6 described a daughter and mother with PAH and added considerably to our understanding by demonstrating that vasoconstriction is involved in addition to sclerosis.7 Their work was corroborated by Wood,8 who showed that intravenous acetylcholine vasodilates pulmonary arteries in PAH. The "epidemic" of aminorex-induced pulmonary hypertension (PH) between 1967 and 1972 led to increased interest in PAH.9 This prompted the World Health Organization (WHO) to convene experts in Geneva in 1975 to begin a systematic approach to gathering the scattered data on primary PH.10 A subsequent directive of the NIH resulted in a national registry in the United States to better understand the natural history and prognosis of this disease. This led to more standardized clinical and pathologic criteria for diagnosis and a more systematic evaluation of pulmonary vasodilator candidates as research entered the "vasodilator years."

As the application of basic science tools improved, it became increasingly recognized that vasoproliferation and dysregulated endothelial function are equally important.2,3 The recognition that a similar histopathologic lesion of pulmonary arteries could be seen in a variety of settings led to efforts to create clinical classifications for all pulmonary hypertensive diseases at WHO meetings in Evian, France,11 and Venice, Italy.12 Although these conferences have produced useful clinical criteria, the current efforts aimed at the molecular basis of vascular biology are making great strides and hold promise for further discoveries about the cellular and molecular basis for control of the pulmonary circulation.4

PAH: A ROSE BY ANY OTHER NAME?

As our understanding of PAH unfolds, it is becoming clear that the entity we call PAH is in fact more than 1 disease, with a shared histopathologic end point. Histologic examination of the pulmonary arteries of patients with PAH reveals a variety of abnormalities, including neointimal formation and abnormal proliferation of both endothelial and smooth muscle cells,13 with encroachment on the vascular lumen. In their most dramatic expression, these changes result in the classic plexiform lesion of PAH.13

Tuder and colleagues14 have likened this abnormal proliferation to malignant transformation. Although the prototype for these lesions is described in idiopathic PAH, the same essential histology is evident in PAH associated with scleroderma, congenital heart disease, HIV infection, portopulmonary disease, and anorexigen use.13 Increased endothelin-1 and thromboxane expression and decreased nitric oxide and prostacylin production appear to be common features in most forms of this disease.2,3,15-18 The prevailing view is that the resulting abnormal vascular response common to all forms of PAH occurs in the setting of genetic predisposition combined with an inciting trigger, which may be hypoxia, an anorexigen, a virus, or a sheer stress injury.2,3,19

CLASSIFICATION

Although an earlier paradigm proposed the concept of primary PAH as distinguished from secondary PAH, which is associated with concomitant disorders, this has been abandoned in favor of classification into categories sharing similar pathophysiologic mechanisms, clinical presentations, and therapeutic options.11,12 As such, 5 broad categories were proposed by a panel of international PAH experts (Table):

• PAH.

• PH associated with left-sided heart disease.

• PH associated with lung disease or hypoxemia or both.

• PH associated with chronic thromboembolic or embolic disease or both.

• Miscellaneous PH.

It is particularly important to note that the therapeutic options afforded patients in different categories may inherently differ (especially for PH associated with left-sided heart disease), since current therapies for precapillary PAH may actually worsen patients with pulmonary venous hypertension by inducing pulmonary edema.20,21 It is essential to use right heart catheterization, and often concomitant left heart catheterization, to distinguish between the true arteriopathy of PAH and that of venous PH.22 Although this classification is helpful schematically for the practicing clinician, it does not preclude classification based on histologic findings; functional classification based on severity of symptoms; or potential genetic classification, as our knowledge of the genetic defects and their modifiers in this disorder expands.

DIAGNOSIS

Although Doppler echocardiography remains a useful screening tool, it provides only an estimate of right ventricular systolic pressure and should not be relied on to diagnose PAH. To do so would increase the risk of a false diagnosis of PAH, with the attendant emotional trauma for the patient and potential misuse of expensive medications that could result in serious adverse effects.

In contrast to the diagnosis of PH, the diagnosis of PAH requires a sustained mean pulmonary artery pressure (mPAP) of 25 mm Hg or greater at rest or of 30 mm Hg or greater with exercise, with simultaneous pulmonary capillary wedge pressures of 15 mm Hg or less.23-25 All patients, therefore, require right heart catheterization.24,25 Many clues from the history and physical examination, along with a variety of noninvasive tests, can help direct the clinician in deciding when more invasive testing is indicated.

The history

The symptoms of PAH are nonspecific and often are confounded by comorbid conditions that might explain them. Dyspnea is the most common complaint (60%), followed by fatigue (19%), syncope (8%), chest pain (7%), near-syncope (5%), palpitations (5%), and leg edema (3%).26 In the NIH registry trial, a median of 2.03 years transpired before the correct diagnosis of PAH was established.26 Therefore, it is incumbent on the clinician to have a high index of suspicion when dyspnea, chest pain, palpitations, presyncopal events, or syncopal events are reported and no other clear explanation exists.

Since idiopathic PAH is more common in young women than in other populations,27 it is important to resist the temptation to attribute these symptoms to anxiety, vasovagal episodes, or somatization when the findings from the physical examination and on an ECG and chest radiograph appear normal. In addition, conditions that are often associated with PAH, such as scleroderma,28 portal hypertension,29 and sickle cell disease,30,31 warrant increased concern on the part of the front-line practitioner. One must suspect PAH in order to diagnose it.

Physical examination

Because many conditions are associated with PAH, a variety of examination clues may present themselves to the savvy clinician. These include testicular atrophy, palmar erythema, spider telangiectasia, and ascites in patients with cirrhosis; calcinosis, mat telangiectasia, and Raynaud phenomenon in patients with scleroderma; oral mucosal telangiectasia in patients with hereditary hemorrhagic telangiectasia syndrome; and clubbing in patients with interstitial lung disease or congenital heart disease.32

Right ventricular failure may result in jugular venous distention to greater than 9 cm H2O with heightened A-wave and V-wave amplitude.33 Delayed closure of the pulmonic valve resulting in audible differentiation of A2 and P2 is common with advanced PAH.34 When this "splitting" of A2 and P2 is fixed throughout inspiration and expiration, an atrial septal defect should be suspected.34

A variety of murmurs may be encountered on heart auscultation, including the lower left sternal, high-pitched, holosystolic murmur of tricuspid regurgitation35; the crescendo-decrescendo systolic ejection murmur at the left upper sternal border associated with pulmonic stenosis36; and the early diastolic, high-pitched Graham Steell murmur of pulmonic regurgitation. The latter is best heard by having the patient sit upright and lean forward in fixed expiration.36 Interestingly, murmurs of ventricular septal defects are paradoxically louder the smaller the defect; the intensity of their high-pitched sound does not change with inspiration nor does it radiate from its fourth through sixth intercostal location.37,38 For more information about the cardiac findings associated with PAH, the reader is directed to an interactive CD-ROM available from the Pulmonary Hypertension Association.39

Electrocardiography and radiography

Although the ECG lacks sufficient sensitivity and specificity to serve as a screening tool in PAH, it can contribute important prognostic information and should be obtained. Right ventricular hypertrophy and right axis deviation can be detected 87% and 79% of the time, respectively.40 The clinician should also look for right atrial enlargement (P waves in leads II, III, and/or aVF greater than 2.5 mm). However, the absence of any of these findings does not exclude a diagnosis.40 Bossone and associates41 found the ECG to be helpful in determining prognosis, because the presence of right atrial enlargement was associated with a 2.8-fold greater risk of death over 6 years of observation.

The posteroanterior chest radiograph is not specific or sensitive as a screening tool but may offer helpful information. Suggestive clues include attenuated peripheral vascular markings, enlarged main and hilar pulmonary artery shadows, and obscuration of the retrosternal clear space by an enlarged right ventricle.25 The chest radiograph may also define concurrent parenchymal disease; the pulmonary venous congestion of pulmonary veno-occlusive disease; hyperinflation of chronic obstructive pulmonary disease (COPD); or findings suggestive of chronic thromboembolic disease, such as mosaic oligemia or an enlarged descending right pulmonary artery.42 However, the extent of such radiographic findings does not correlate well with the degree of PAH.42

Transthoracic echocardiography

The transthoracic echocardiogram is the screening tool of choice in PAH (Figure). Although many studies have reported an excellent correlation with right heart catheterization,25 technical aspects of interrogation make tricuspid regurgitant jet discernible in 39%43 to 86%44 of patients. Enhancement of the Doppler envelope with agitated saline can improve tricuspid regurgitant jet detection, especially in patients with COPD,45-47 but it is not routinely applied in all centers. In one study of 166 patients with advanced lung disease who were being evaluated for lung transplantation, systolic pulmonary artery pressure (PAP) could be estimated in only 44%.48Discordance of PAP estimates and right heart catheterization is not uncommon at extremes of pressure estimates.49

Advanced lung disease poses a special challenge. In a cohort of 374 patients, PAH was incorrectly diagnosed in 48%, and 52% of pressure estimates were inaccurate.48 McQuillan and colleagues50 demonstrated that 6% of healthy persons and 5% of obese (body mass index greater than 30) persons have incidental PH on echocardiography. Also, PAH was overestimated in 32% of one cohort of pregnant women.51

Exercise echocardiography to unmask PAH remains controversial.52 No clear standardization of exercise or Doppler interrogation protocols is evident in the literature. Bossone and associates53 have found that highly conditioned athletes often have "hypertensive" PAP elevations with normal pulmonary vascular resistance. Despite these caveats, proponents have suggested a role for stress echocardiography in patients with collagen vascular disease who have normal findings on resting echocardiography when symptoms cause a high level of suspicion.54-59 Stress echocardiography has also been suggested for family members of patients with idiopathic PAH to identify a subgroup of asymptomatic carriers of the PAH gene.60,61

When PAH is suspected, a bubble-contrast Doppler echocardiogram should always be obtained in order to assess for left-to-right shunting.41 The presence of left atrial enlargement, even in the absence of left ventricular dysfunction, should raise the possibility of elevated left-sided pressures that may contribute to observed pulmonary pressure elevations. When present, right heart catheterization and often left heart catheterization are crucial for measuring the transpulmonary gradient and for assessing for diastolic dysfunction.62

Since false-positive test results are more common when the prevalence of disease is low and PAP is more likely to be overestimated in populations with normal pressures, focused ordering of Doppler echocardiography is advisable.25,32 Risk factors that warrant screening echocardiography include being a first-degree relative of a patient with familial PAH, having a diagnosis of scleroderma, having a diagnosis of portal hypertension before orthotopic liver transplantation, and having congenital heart disease with systemic-to-pulmonary shunts.25,32

Exclusion of thromboembolic disease

Chronic thromboembolic pulmonary hypertension (CTEPH) may develop in up to 4% of patients who survive pulmonary embolism.63 Since CTEPH can mimic idiopathic PAH, all patients presenting with unexplained PAH must be screened for CTEPH. This diagnosis must be excluded to avoid missing a potentially surgically remediable cause. The ventilation-perfusion (V./Q. ) scan is the screening method of choice; it typically shows 1 or more segmental unmatched defects.64 A normal V./Q. scan effectively rules out CTEPH.65,66

CT pulmonary angiography and MRI have value in defining alternative diagnoses and may be complementary to V./Q. scanning. However, these techniques should not be used as stand-alone methods for excluding CTEPH because of the potential to miss the webs, bands, and other sequelae of CTEPH.25,52

Other adjunctive testing

Pulmonary function testing; nocturnal polysomnography; selected serologic testing for collagen-vascular disease, HIV infection, or thyroid function; and cardiopulmonary exercise testing may add useful information in the evaluation of suspected or confirmed PH and should be ordered when appropriate.52

Cardiac catheterization

As emphasized above, right heart catheterization remains the gold standard for diagnosing PAH. This technique is crucial for avoiding an inaccurate diagnosis24,25,51 and the subsequent use of medications that could worsen the condition of patients with postcapillary causes of elevated PAP. Right heart catheterization also allows for the collection of information proven to aid in prognosis, such as cardiac index, right atrial pressure, and mPAP. This information might affect the choice of intravenous prostanoid therapy over oral alternatives,27 and it is the only means of identifying the small but important subset of patients that may benefit from treatment with high-dose calcium channel blockers.67

PROGNOSIS

The NIH registry data revealed the sobering gravity of untreated PAH. The 1-, 3-, and 5-year overall survival rates were 68%, 48%, and 34%, respectively, when the standard supportive care available at that time--digoxin, diuretics, and oxygen therapy--was administered. Elevated right atrial pressure, cardiac index, and mPAP, along with New York Heart Association functional class III or IV status, portended worse outcomes.27 Subsequent work has revealed that patients with scleroderma fare even worse than patients with idiopathic PAH.68

Three limited (2 retrospective68,69 and 1 prospective70) series support the premise that anticoagulation with warfarin improves survival, at least in patients with idiopathic PAH.69-71 For this reason, most experts administer warfarin to all patients who have idiopathic PAH, with the goal of an international normalized ratio of 1.8 to 2.0. With the administration of epoprostenol, survival rates were improved for the first time in placebo-controlled studies.72-74 The most recent data with epoprostenol suggested 1-, 2-, and 3-year survival rates of 88%, 76%, and 62%, respectively.75

Survival also appears improved to a similar magnitude with bosentan therapy,76 although the addition of second therapies often proved necessary in the experience of Provencher and colleagues.77 The impact of treprostinil on survival has only recently been examined, with Lang and colleagues78 finding 1- and 3-year survival rates of 83.2% and 69%, respectively, in 99 patients with PAH and 23 patients with CTEPH. Sildenafil's impact on survival after 1 year also appears favorable.79 However, all data on bosentan and sildenafil are limited by either a retrospective study design; the absence of a placebo control group (made ethically impermissible by the original finding on epoprostenol's effect); or the potential for lead-time bias, since disease of lesser severity is detected and treated earlier.

Although encouraging, these findings clearly leave room for improvement. New therapies, including inhaled vasointestinal peptide,80 inhaled treprostinil, oral imatinib,81 and combinations of existing therapies,82,83 suggest the potential for a better prognosis for PAH in the future.

References:

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