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J Am Coll Cardiol, 2004; 43:40-47 © 2004 by the American College of Cardiology Foundation |
* Columbia University College of Physicians and Surgeons, New York, New York, USA
Mayo Clinic, Rochester, Minnesota, USA
Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
Hôpital Antoine Béclère, Clamart, France
|| Medical Clinic II, University Clinic, Giessen, Germany
¶ Mater Misericordiae Hospital, University College, Dublin, Ireland
Manuscript received November 26, 2003; accepted February 3, 2004.
*
Reprint requests and correspondence: Dr. Robyn J. Barst, Columbia University College of Physicians & Surgeons, 622 West 168 Street, PH 2 East, Suite 200, New York, New York 10032, USA.
rjb3{at}columbia.edu
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Abstract |
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Detection |
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TopAbstractDetectionCharacterization: essential...Characterization: contingent...Assessment of PAH severityReferences |
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Incidental discovery. The clinical significance and natural history of asymptomatic or mild PAH is unclear; thus, the implications for further assessment and/or treatment when discovered incidentally, as a result of screening or during evaluation of nonspecific symptoms, remain uncertain. Moreover, the criterion of clinically significant PH when detected under these circumstances by Doppler echocardiography, which in itself is an isolated estimate of right ventricular systolic pressure (RVSP), is not precisely defined. Commonly used definitions of PH are a pulmonary artery systolic pressure (PASP) >35 mm Hg or mean >25 mm Hg at rest or mean >30 mm Hg with exercise. However, PASP >40 mm Hg is present in 6% of otherwise normal individuals older than 50 years and 5% with a body mass index (BMI) >30 kg/m2 (2).
In general, any degree of PH should prompt an attempt to define or exclude possible causes, because it may be the first evidence of a modifiable substrate. However, the severity of PH and the reliability of the measurement should temper the aggressiveness of the evaluation. Confirmation by right heart catheterization (RHC) is warranted before embarking on extensive evaluation for an underlying cause or considerations of prognosis or treatment.
Detection assessment. Components of assessment to detect PAH include the physical examination (e.g., left parasternal lift, accentuated pulmonary component of S2, pansystolic murmur of tricuspid regurgitation, diastolic murmur of pulmonary insufficiency, right ventricular S3, jugular vein distension, hepatomegaly, peripheral edema, ascites, cool extremities), chest X-ray, electrocardiogram (ECG), and Doppler echocardiogram. Findings of central pulmonary arterial and/or right ventricular enlargement on chest X-ray suggest the presence of PAH. Additional clues to possible associated diseases should be considered, such as pulmonary venous hypertension—for example, septal lines and pleural effusions (pulmonary venous hypertension due to left heart filling abnormality, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis); hyperinflation (chronic obstructive pulmonary disease); or kyphosis (restrictive pulmonary disease). Marked asymmetry of the enlarged central pulmonary arteries may be a clue to chronic thromboembolic disease.
The ECG may provide suggestive or supportive evidence of PAH by demonstrating right ventricular hypertrophy and strain, and right atrial dilation. Right ventricular hypertrophy on ECG is present in 87% and right axis deviation in 79% of patients with IPAH (3). The ECG has inadequate sensitivity (55%) and specificity (70%) to be a screening tool for detecting significant PAH (4).
Transthoracic Doppler echocardiography (TTE) estimates PASP and can provide additional information about the cause and consequences of PH. The PASP is equivalent to RVSP in the absence of pulmonary outflow obstruction. The RVSP is approximated by measurement of the systolic regurgitant tricuspid flow velocity v and an estimate of right atrial pressure (RAP) applied in the formula: RVSP = 4v 2 + RAP. The RAP is either a standardized value, or an estimated value from characteristics of the inferior vena cava (5) or from jugular venous distension. Tricuspid regurgitant jets can be assessed in 39% to 86% of patients. Careful Doppler examination by experienced sonographers yields quantifiable tricuspid regurgitant signals in 74% of cases (6). Most studies report a high correlation (0.57 to 0.93) between TTE and RHC measurements of PASP (7). Reported sensitivity of TTE-estimated PASP for detecting PAH ranges from 0.79 to 1.00 (7–9) and specificity from 0.60 to 0.98. However, these figures are strongly influenced by the value used to define PH.
The range of RVSP among healthy controls has been well characterized. Among a broad population of male and female subjects ranging from 1 to 89 years of age, RVSP was reported as 28 ± 5 mm Hg (range 15 to 57 mm Hg). The RVSP increases with age and BMI (2). Athletically conditioned men also have higher resting RVSP. Defining the normal distribution of RVSP does not ipso facto define the point at which an elevated RVSP is clinically important or predictive of future consequences.
Mild PH is defined as a PASP of approximately 36 to 50 mm Hg or a resting tricuspid reguritant velocity of 2.8 to 3.4 m/s. Possible explanations for mildly elevated PASP detected by echocardiography include 1) overestimation of the RVSP in a patient with true normal pulmonary pressure; 2) serendipitous observation of a rare transient pressure elevation in an otherwise healthy individual; 3) discovery of stable mild PH, possibly of long duration; or 4) discovery of early progressive PH in an individual with PAH. In addition, pulmonary artery pressure differences may be observed in different populations and conditions, including age, level of conditioning, exercise or stress. No clear guidelines are available that delineate normal from pathologic in all circumstances.
Pulmonary hemodynamics can also be estimated from the pulmonary regurgitant Doppler signal, right ventricular outflow patterns, and time intervals, including pre-ejection period, acceleration and deceleration times, and relaxation and contraction times.
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Characterization: essential tests |
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TopAbstractDetectionCharacterization: essential...Characterization: contingent...Assessment of PAH severityReferences |
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Pulmonary function testing will exclude or characterize the contribution of underlying airway or parenchymal disease. Although obstructive pulmonary disease with hypoxemia may be confirmed by testing, abnormalities occur in other types of PH. Approximately 20% of patients with chronic pulmonary embolism have restrictive parameters (i.e., lung volumes <80% predicted) but may have near normal diffusing capacity for carbon monoxide (DLCO). The DLCO of 20% of patients with limited systemic sclerosis is below normal; a DLCO of <55% of predicted may be associated with future development of PAH.
Screening overnight oximetry will exclude significant obstructive sleep apnea/hypopnea.
Ventilation-perfusion (
/
) lung scintigraphy is an indispensable component of assessment because chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially curable cause of PH. The / scans of patients with chronic pulmonary embolism generally show at least one segmental-sized or larger perfusion defect. Patients with PH who have normal / scans are unlikely to have chronic pulmonary embolism, and more likely to have IPAH. In three studies (10–12), / scanning showed sensitivity of 90% to 100%, with a specificity of 94% to 100% for distinguishing between IPAH and CTEPH. The / scans tend to correlate poorly with the severity of obstruction and to underestimate the degree of severity of large vessel obstruction. Scans consistent with thromboembolism may represent false positives, where the actual underlying pathology is pulmonary artery sarcoma, large vessel pulmonary vasculitis, extrinsic vascular compression, or pulmonary veno-occlusive disease.
Blood tests for evaluation of PAH include antinuclear antibody (ANA) titer to screen for connective tissue disease, HIV serology, complete blood count with platelet count, liver function tests, and antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies). Although 40% of patients with IPAH have positive but low ANA titers (
1:80 dilutions) (13), patients with a substantially elevated ANA and/or suspicious clinical features require further serologic assessment and rheumatology consultation.
Assessment of exercise capacity is a key part of the evaluation of PH. The goals of exercise testing vary under different clinical circumstances, and they determine the specific testing modality to employ. These objectives include: searching for alternative or contributory reasons for symptoms (e.g., myocardial ischemia); determining maximal exercise tolerance; characterizing comfortable activity level (functional capacity) of the patient; obtaining predictive data; establishing a baseline measure of exercise capacity and following the response to therapy; assessing the interaction of the circulatory and ventilatory systems; or attempting to discover abnormal pulmonary hemodynamic responses to exercise before clinically evident PH at rest.
The most commonly used exercise tests for PH are the 6-min walk test (6MWT) and cardiopulmonary exercise testing with gas exchange measurements. Other options include exercise testing in conjunction with noninvasive Doppler echocardiographic assessment of RVSP, and exercise testing in conjunction with RHC.
The 6MWT, developed for evaluation of congestive heart failure (14), is predictive of survival in IPAH and also correlates inversely with WHO functional status severity, moderately with baseline cardiac output and total pulmonary resistance (but not mean pulmonary arterial pressure), and strongly with peak exercise oxygen consumption (VO 2), peak oxygen pulse, and minute ventilation–carbon dioxide output slope (VE-VCO 2 slope) in IPAH. Arterial oxygen desaturation >10% during the 6MWT increases mortality risk 2.9 times over a median follow-up of 26 months (15).
Cardiopulmonary exercise testing is discussed in more detail elsewhere in this Supplement. Consistent observations in PAH are reduced peak VO 2, peak work rate, the ratio of VO 2 increase to work rate increase, anaerobic threshold, peak oxygen pulse, and increased VE-VCO 2 slope. These observations indicate that the mechanism(s) of exercise limitations in PAH include V/Q mismatching, lactic acidosis at a low work rate, arterial hypoxemia, and inability to adequately increase stroke volume and cardiac output (16).
Exercise Doppler echocardiography has been utilized to evaluate RVSP responses with exercise. In healthy men, tricuspid regurgitant velocity increases from an average of 1.72 m/s at baseline to a peak of 2.46 m/s at mid-level exercise and to 2.27 m/s at peak exercise (240 W); in trained athletes the baseline value is 2.25 m/s and increases to 3.41 m/s at peak exercise (17). As with invasive exercise studies, the criteria for an abnormal response are not well established.
Right heart catheterization is required to confirm the diagnosis of PAH. Cardiac output, determined by thermodilution or Fick (with measured oxygen consumption) during RHC is also required to calculate pulmonary vascular resistance. Pulmonary arterial hypertension is defined by a mean pulmonary artery pressure (mPAP) >25 mm Hg at rest or >30 mm Hg with exercise; in PAH, pulmonary capillary wedge pressure or left ventricular end diastolic pressure is 
15 mm Hg and pulmonary vascular resistance is >3 units. The RHC also characterizes intracardiac shunting, and it establishes pulmonary venous pressure. An elevated pulmonary capillary wedge pressure supports the presence of left heart disease or pulmonary vein obstruction, though a normal pulmonary capillary wedge pressure does not rule out pulmonary veno-occlusive disease.
Hemodynamic measurements have been used to estimate the natural history of IPAH in an individual patient. The probability of survival P(t) one, two, or three years after diagnosis can be estimated as P(t) = {H(t)}A(x,y,z), where H(t) = {0.88 – 0.14t + 0.01t2}, A(x,y,z) = e(0.007325x + 0.0526y – 0.3275z), t = years, x = mPAP (mm Hg), y = mRAP (mm Hg), and z = cardiac index (CI) (l/min/m2) (18). Other logistic regression equations have been reported to predict survival or death within one year.
Importantly, a vasodilator study should be performed whenever PAH is discovered or confirmed during RHC in patients in whom symptoms and/or disease severity warrant treatment. All patients in whom vasodilator treatment is to be initiated require hemodynamic monitoring for detection of either beneficial or detrimental effects of acute treatment. Uncontrolled studies have suggested that long-term administration of calcium-channel blockers (CCB) prolongs survival in the rare subset of responsive patients compared with unresponsive patients. Unfortunately, no clinical or hemodynamic parameters exist that can predict acute and/or chronic responses to CCB in PAH patients. It is generally accepted that patients who may benefit from long-term CCB can be identified by an acute vasodilator challenge performed during RHC; that is, a sustained benefit from CCB treatment is seen in patients in whom, during acute vasodilator testing, mPAP decreases 10 mm Hg to reach a mPAP 40 mm Hg with a normal or high cardiac output (19). Owing to the potential risk of severe life-threatening hemodynamic compromise occurring with acute vasodilator challenge with CCB, acute vasodilator testing should be done using a safe, potent, and short-acting vasodilator with limited side effects to identify with accuracy those patients who may benefit from long-term CCB therapy.
The acute pulmonary effect of short-acting vasodilators (e.g., intravenous epoprostenol, inhaled nitric oxide [NO], intravenous adenosine, or inhaled iloprost) predicts the hemodynamic response to long-term CCB. Thus, the efficacy of the short-acting drug has been used to determine whether chronic CCB treatment should be initiated. However, with novel oral and inhaled therapeutic agents combining vasodilatory and antiproliferative properties now available (e.g., endothelin receptor antagonists, prostacyclin analogues, and phosphodiesterase type 5 inhibitors), the usefulness of invasive testing for pulmonary vasoreactivity in selecting optimal treatment is now less clear. Although it is reasonable to believe that patients who respond to intravenous epoprostenol, inhaled NO, intravenous adenosine, or inhaled iloprost will respond to such oral or inhaled therapies, no study has evaluated the acute and chronic responses to these drugs in vasoreactive patients.
The abrupt development of pulmonary edema during acute vasodilator testing suggests the presence of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis and is a contraindication to chronic vasodilator treatment.
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Characterization: contingent tests |
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TopAbstractDetectionCharacterization: essential...Characterization: contingent...Assessment of PAH severityReferences |
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Additional imaging may be required if the / scan is suggestive of chronic pulmonary embolism. Chest computerized tomography (CT) provides supportive noninvasive evidence, but if negative it should not obviate the use of pulmonary angiography. A mosaic pattern of lung attenuation in a noncontrast CT scan raises the possibility of chronic thromboembolism. Contrast-enhanced spiral (or helical) CT or electron-beam CT (EBCT) can visualize central chronic pulmonary thromboemboli. The CT features of chronic thromboembolic disease are complete occlusion of pulmonary arteries, eccentric filling defects consistent with thrombi, recanalization, and stenoses or webs.
The sensitivity of spiral CT for detecting central pulmonary embolism is >85% to 90%. Though sensitivity for detecting distal emboli is lower, detection rates of up to 97% for distal emboli (compared with high probability / scans or angiography) have been reported (20). Specificity is also 90%, with occasional misclassification of IPAH as being CTEPH (20).
The EBCT signs of pulmonary vein obstruction (e.g., pulmonary veno-occlusive disease) are smooth thickening of interlobular septa, peribronchovascular cuffing, and alveolar ground-glass opacification.
High-resolution CT provides detailed views of the lung parenchyma during evaluation of PH or hypoxia and aids in the diagnosis of pulmonary fibrosis. Diffuse bilateral thickening of the interlobular septae and the presence of small, centrilobular, poorly circumscribed nodular opacities suggest pulmonary capillary hemangiomatosis; diffuse central ground-glass opacification and thickening of interolobular septa suggest pulmonary veno-occlusive disease.
Pulmonary angiography is required to confirm CTEPH and assess operability. Chronic thrombi appear different from acute thrombi and occur in highly variable locations, often incorporated into and retracting the vessel wall. Obstructions can take the form of bands or webs, sometimes with post-stenotic dilation. Irregular intimal surface, rounded or pouch-like termination of segmental branches, luminal narrowing of the central vessel, and odd-shaped pulmonary arteries all may indicate the presence of chronic pulmonary embolism.
For patients with known or suspected CTEPH, further evaluation of a potential clotting diathesis is warranted (bleeding time, coagulation Factors VIII, VII, II, and V, von Willebrand factors, Protein C and S). Factor V Leiden mutation (the most common cause of activated protein C resistance) has been implicated as high risk for idiopathic venous thromboembolism, though not specifically in pulmonary embolism or CTEPH. Serum viscosity, serum protein electrophoresis, and Hgb electrophoresis may be helpful under certain circumstances.
Additional blood tests may provide prognostic data. Arterial blood gas or oximetry measurements showing desaturation may signal abnormal gas exchange, right-to-left shunting, ventilation/perfusion mismatching, interstitial fibrosis, other parenchymal lung disease, or hypoventilation. Failure to normalize with high FiO2 oxygen inhalation supports a component of right-to-left shunting. Arterial blood gas measurement or oximetry during exercise may disclose desaturation requiring supplemental oxygen treatment to improve exercise capacity. Overnight oximetry may disclose disordered sleep with frequent desaturations and may be the first clue to sleep apnea sufficient to cause or contribute to PH. Nocturnal hypoxemia occurs in >75% of IPAH patients independent of the occurrence of apneas or hypopneas (22).
Hyperuricemia occurs with high frequency in patients with PH and correlates with hemodynamic abnormalities (e.g., right atrial pressure) and mortality in IPAH (23).
Brain natriuretic peptide (BNP) is elevated in right ventricular pressure overload and correlates with severity of right ventricular dysfunction and mortality in PAH (24).
If the history and/or screening overnight oximetry is suggestive, polysomnography should be considered to assess a possible contributory role in PH. Up to 20% to 27% of patients with sleep apnea syndromes have PH (25). The degree of waking PH in obstructive sleep apnea is generally mild and reversible by six months of continuous positive airway pressures, i.e., CPAP (26). Open or thoracoscopic lung biopsy entails substantial risk of morbidity and mortality. Because of the low likelihood of altering the diagnosis, routine biopsy is discouraged. Under certain circumstances, histopathologic findings may provide useful information by excluding or establishing a diagnosis of active vasculitis, granulomatous pulmonary disease, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, interstitial lung disease, or bronchiolitis (27).
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Assessment of PAH severity |
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TopAbstractDetectionCharacterization: essential...Characterization: contingent...Assessment of PAH severityReferences |
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Various demographic and hemodynamic characteristics, as well as exercise capacity, acute pulmonary vasoreactivity, assessment of right ventricular function, neurohormonal levels (e.g., BNP [24], norepinephrine [28]), as well as endothelin-1 (29), uric acid (23), and troponin (31), correlate with survival. Some of these modalities may provide prognostic information similar to that derived from invasive tests (e.g., cardiac catheterization) and may prove more useful and convenient in assessing treatment efficacy. These tools may also increase predictive accuracy when used in combination. Because many of these variables have been shown to correlate with one another, which parameter(s) will prove to be most useful for decision making and optimizing treatment (e.g., timing of transplantation) will require further study. It is important to remember that these tests evaluated IPAH patients and not patients with PAH related to connective tissue disorders, congenital systemic to pulmonary shunts, HIV infection, or portal hypertension. Thus, these parameters must be applied cautiously to PAH patients in whom comorbid factors might contribute to the overall outcome; for example, patients with PAH related to connective tissue disorders are known to have a worse prognosis than do IPAH patients, whereas patients with PAH related to congenital systemic to pulmonary shunts have a more slowly progressive course than do IPAH patients.
In addition to evaluating various parameters, such as functional class (32) or exercise capacity, at the time of diagnosis prior to initiation of medical therapy, repeating these parameters on treatment is useful in predicting outcome with a given therapy (e.g., epoprostenol). McLaughlin et al. (30) as well as Sitbon et al. (32) demonstrated that the baseline functional class in patients with IPAH treated with epoprostenol (i.e., before epoprostenol is started) is predictive of survival with epoprostenol (Fig. 2). In addition, patients' functional class on chronic intravenous epoprostenol is also predictive of outcome with continued epoprostenol (Fig. 3) (30,32). Additional survival parameters include: 1) right atrial size and pericardial effusion assessed by echocardiography; 2) exercise endurance assessed by the 6MWT, both at the time of diagnosis as well as on chronic medical therapy (e.g., epoprostenol); and 3) hemodynamics. It appears that although the baseline 6-min walk distance prior to epoprostenol treatment is useful as a parameter in predicting disease severity, once a patient is on epoprostenol, the actual 6-min walk distance on chronic epoprostenol is more predictive of survival than the change in 6-min walk distance with epoprostenol (Fig. 4) (32). By multivariate analysis in IPAH patients treated with epoprostenol, Sitbon et al. (32) reported that the only parameter independently predictive of outcome prior to starting epoprostenol is the presence of right heart failure; after three months of epoprostenol, persistence of functional class III or IV, mPAP <59 mm Hg and a drop in pulmonary vascular resistance <30% relative to baseline are associated with a poor prognosis.
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