Diagnosis and differential assessment of pulmonary arterial hypertension
Robyn J. Barst, MD*,*,
Michael McGoon, MD ,
Adam Torbicki, MD ,
Olivier Sitbon, MD ,
Michael J. Krowka, MD,
Horst Olschewski, MD|| and
Sean Gaine, MD¶
* 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
 |
Abstract
|
|---|
Pulmonary arterial hypertension (PAH) is diagnosed by various investigations that are essential for making the diagnosis, and by additional tests to clarify the category of pulmonary hypertension (PH). A diagnostic algorithm can guide the evaluation of PH, but like all guidelines the algorithm can be modified according to specific clinical circumstances. Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed during screening of asymptomatic populations at risk. Right heart catheterization (RHC) must be performed in patients with suspected PH to establish the diagnosis and document pulmonary hemodynamics. Before initiation of medical therapy, assessment of acute vasoreactivity (during catheterization) is necessary to determine the appropriate therapy for an individual patient. An acute response is generally defined as a decrease in mean pulmonary arterial pressure of at least 10 mm Hg with the mean pulmonary arterial pressure decreasing to 40 mm Hg or below, accompanied by a normal or high cardiac output. After PAH is diagnosed, disease severity should be assessed in order to accurately determine risk:benefit profiles for various therapeutic options. Useful tools to predict outcome include functional class, exercise capacity, pulmonary hemodynamics, acute vasoreactivity, right ventricular function, as well as brain natriuretic peptide, endothelin-1, uric acid, and troponin levels. Repeating these tests serially on treatment is useful for monitoring the response to a given therapy. Close follow-up at a center specializing in management of PH is recommended, with careful periodic reassessment and adjustment of therapy.
|
Abbreviations and Acronyms
| | BMI | = body mass index | | CI | = cardiac index | | CTEPH | = chronic thromboembolic pulmonary hypertension | | ECG | = electrocardiogram | | IPAH | = idiopathic pulmonary arterial hypertension | | PA | = pulmonary artery | | PAH | = pulmonary arterial hypertension | | PASP | = pulmonary artery systolic pressure | | PH | = pulmonary hypertension | | RAP | = right atrial pressure | | RHC | = right heart catheterization | | RVSP | = right ventricular systolic pressure | | TTE | = transthoracic Doppler echocardiography |  /
| = ventilation–perfusion |
|
The diagnosis of pulmonary hypertension (PH) involves two stages: detection (determining the cause of a patient's symptoms, or to detect the presence of pulmonary arterial hypertension [PAH] in a high-risk patient) and characterization (determining the specific clinical context of the PH, including causal factors, associated diseases or substrates, hemodynamic perturbations and their localization, and sequelae).
|
Detection
|
|---|
Symptom evaluation.
Symptoms that suggest PH are exertional dyspnea, fatigue or weakness, angina, syncope, peripheral edema, and abdominal distension (Fig. 1). Exertional intolerance is quantitated with the World Health Organization (WHO) classification (Table 1).
Screening.
Periodic assessment of patients with an underlying predisposition may be warranted to introduce therapy at an early stage, or to initiate more aggressive surveillance to detect progression. Screening for the presence of PAH using Doppler echocardiography is advisable when risk is sufficiently high to justify the expense (i.e., when diagnosis could lead to further evaluation and/or change in management). This currently includes individuals with: 1) a known genetic-mutation–associated PAH or a first-degree relative with idiopathic pulmonary arterial hypertension (IPAH); 2) scleroderma spectrum of disease; 3) patients with congenital heart disease and systemic-to-pulmonary shunts; or 4) portal hypertension undergoing evaluation for orthotopic liver transplantation (1). Other potential PAH substrates do not warrant routine screening (e.g., previous use of appetite suppressant, HIV infection, other connective tissue disorders, obstructive pulmonary disease, or high-altitude residence because of the infrequency and/or low likelihood of altering treatment at a presymptomatic stage).
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.
|
Characterization: essential tests
|
|---|
Certain tests are essential if PH is suspected in order to characterize potential substrates, to determine severity and prognosis accurately, and to select treatment (Fig. 1). The Doppler echocardiogram provides essential information in addition to screening, as noted above, including estimation of baseline and follow-up PASP, estimated pulmonary vascular resistance, right ventricular size and function, semiquantitative right atrial size, left ventricular systolic and diastolic function, presence of prognostically relevant pericardial effusion, morphology and function of all cardiac valves, as well as patent foramen ovale, and intracardiac or intrapulmonary shunts (using "bubble" contrast techniques).
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.
|
Characterization: contingent tests
|
|---|
Certain tests are contingent on the presentation and results of essential testing (Fig. 1). They may not be necessary in all patients. Transesophageal echocardiography (TEE) provides important data that may alter treatment in up to 25% of patients. Useful in the detection of intracardiac shunts, especially atrial septal defects, TEE can also detect central pulmonary emboli including chronic thromboemboli causing PAH, with a reported sensitivity of 80% (20), and up to 96%, with a specificity of 88%, in patients with documented severe central acute or chronic thromboembolism (21).
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).
|
Assessment of PAH severity
|
|---|
After PAH is diagnosed, in order to assess risk:benefit profiles for various therapeutic options accurately, precise assessment of prognosis as a function of disease severity is required. Measurable descriptors of disease severity have several potential applications: 1) accurate comparison of patient populations, 2) precise characterization of a patient population for the purpose of homogeneous enrollment into clinical protocols, 3) valid comparison of baseline severity with post-treatment severity as a measurement of therapeutic efficacy, 4) valid comparison of post-treatment severity of similar patients on alternative treatment strategies, 5) accurate longevity prediction (or surrogate for survival in clinical studies), and 6) useful early prediction for timing of transplantation. The characteristics of ideal descriptor(s) of disease severity include: 1) easily performed assessment procedure, 2) reproducible results temporally and between centers, 3) high correlation with outcome of interest (e.g., survival), 4) low risk, 5) low expense, 6) low discomfort level, and 7) wide availability.
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.
View larger version (18K):
[in this window]
[in a new window]
|
Figure 2 (A) Long-term (7-year) survival in patients with idiopathic pulmonary arterial hypertension (IPAH) based on functional class (III vs. IV) at the time of epoprostenol initiation. p = 0.0001 by log-rank test (30). (B) Survival in patients with IPAH treated with intravenous epoprostenol according to New York Heart Association (NYHA) functional class. Estimated percentages of survival for patients in NYHA functional class IV at baseline (dashed line) were 76%, 60%, and 47% at one, two, and three years, respectively, as compared with 90%, 76%, and 71% for patients in NYHA functional class III at baseline (solid line) (p < 0.001 by the Cox-Mantel log-rank test) (32).
|
|
View larger version (20K):
[in this window]
[in a new window]
|
Figure 3 (A) Subsequent survival in patients with idiopathic pulmonary arterial hypertension (IPAH) stratified by functional class after 1 year epoprostenal treatment 1: p < 0.001 for functional class III vs. functional class IV and for functional class III vs. functional class I and functional class II (30). (B) Survival in patients with IPAH treated with intravenous epoprostenol according to New York Heart Association (NYHA) functional class. After three months of treatment with epoprostenol, survival rates for patients reclassified in NYHA functional class I or II (solid line) were 100%, 93%, and 88% at one, two, and three years, respectively, as compared with 77%, 46%, and 33% for patients persisting in NYHA functional class III or IV (dashed line) (p < 0.001 by the Cox-Mantel log-rank test) (32).
|
|
View larger version (18K):
[in this window]
[in a new window]
|
Figure 4 (A) Kaplan-Meier survival estimates in 156 patients with idiopathic pulmonary arterial hypertension (IPAH), according to the results of the 6-min walk (6MW) test performed after three months of epoprostenol therapy. Survival rates for patients walking >380 m during the 6MW test (corresponding to the median value) (solid line) were 99%, 88%, and 81% at one, two, and three years, respectively, as compared with 86%, 64%, and 56% for patients walking <380 m (dashed line) (p = 0.0005 by the Cox-Mantel log-rank test). (B) Kaplan-Meier survival estimates in 156 patients with IPAH, according to the change in the 6MWT between baseline and three months of epoprostenol therapy. No difference in survival was demonstrated in patients who improved their 6-min walk distance to >112 m (corresponding to the median value) (solid line), as compared with those who did not (dashed line) (p = 0.86 by the Cox-Mantel log-rank test) (32).
|
|
In conclusion, evaluating disease severity as a function of: 1) end-organ consequences (e.g., right heart failure), 2) symptoms and functional limitation, and 3) markers of decreased survival is necessary for decision making to optimize the appropriate aggressiveness of PAH patients' care.
|
References
|
|---|
1. Rich S, McLaughlin VV. Clinics in Chest Medicine. Philadelphia, PA: W. B. Saunders; 2001.
2. McQuillan BM, Picard MH, Leavitt M, Weymann AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797–2802
3. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: A national prospective study. Ann Intern Med. 1987;107:216–223
4. Ahearn GS, Tapson VF, Rebeiz A, Greenfield JC. Electrocardiography to define clinical status in primary pulmonary hypertension and pulmonary arterial hypertension secondary to collagen vascular disease. Chest. 2002;122:524–527
5. Ommen SR, Nishimura RA, Hurrell DG, Klarich KW. Assessment of right atrial pressure with 2-dimensional and Doppler echocardiography: A simultaneous catheterization and echocardiographic study. Mayo Clin Proc. 2000;75:24–29
6. Borgeson DD, Seward JB, Miller FA Jr., Oh JK, Tajik AJ. Frequency of Doppler measurable pulmonary artery pressures. J Am Soc Echocardiogr. 1996;9:832–837
7. Denton C, Cailes J, Phillips G, Wells A, Black C, Du Bois R. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol. 1997;36:239–243
8. Bossone E, Avelar E, Bach DS, Gillespie B, Rubenfire M, Armstrong WF. Diagnostic value of resting tricuspid regurgitation velocity and right ventricular ejection flow parameters for the detection of exercise-induced pulmonary arterial hypertension. Int J Card Imaging. 2000;16:429–436
9. Penning S, Robinson K, Major C, Garite T. A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension. Am J Obstet Gynecol. 2001;184:1568–1570
10. D'Alonzo GE, Bower JS, Dantzker DR. Differentiation of patients with primary and thromboembolic pulmonary hypertension. Chest. 1984;85:457–461
11. Bergin CJ, Hauschildt J, Rios G, Belezzuoli EV, Huynh T, Channick RN. Accuracy of MR angiography compared with radionuclide scanning in identifying the cause of pulmonary arterial hypertension. Am J Roentgenol. 1997;168:1549–1555
12. Worsley DF, Palevsky HI, Alavi A. Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med. 1994;35:793–796
13. Rich S, Kieras K, Hart K, Groves BM, Stobo JD, Brundage BH. Antinuclear antibodies in primary pulmonary hypertension. J Am Coll Cardiol. 1986;8:1307–1311
14. Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: A new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132:919–923
15. Paciocco G, Martinez F, Bossone E, Pielsticker E, Gillespie B, Rubenfire M. Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J. 2001;17:647–652
16. Sun X-G, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation. 2001;104:429–435
17. Bossone E, Rubenfire M, Bach DS, Ricciardi M, Armstrong WF. Range of tricuspid regurgitation velocity at rest and during exercise in normal adult men: Implications for the diagnosis of pulmonary hypertension. J Am Coll Cardiol. 1999;33:1662–1666
18. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med. 1991;115:343–349
19. Sitbon O, Humbert M, Ioos V, et al. Who benefits from long-term calcium-channel blocker therapy in primary pulmonary hypertension? (abstr)Am J Respir Crit Care Med. 2003;167:A440
20. Pruszczyk P, Torbicki A, Pacho R, et al. Noninvasive diagnosis of suspected severe pulmonary embolism: Transesophageal echocardiography vs. spiral ct. Chest. 1997;112:722–728
21. Wittlich N, Erbel R, Eichler A, et al. Detection of central pulmonary artery thromboemboli by transesophageal echocardiography in patients with severe pulmonary embolism. J Am Soc Echocardiogr. 1992;5:515–524
22. Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001;120:894–899
23. Nagaya N, Uematsu M, Satoh T, et al. Serum uric acid levels correlate with the severity and mortality of primary pulmonary hypertension. Am J Respir Crit Care Med. 1999;160:487–492
24. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865–870
25. Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax. 2000;55:934–939
26. Alchanatis M, Tourkohorti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou J. Daytime pulmonary hypertension in patients with obstructive sleep apnea: The effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration. 2001;68:566–572
27. Moser K, Bloor C. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993;103:685–692
28. Nootens M, Kaufmann E, Rector T, et al. Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: Relation to hemodynamic variables and endothelin levels. J Am Coll Cardiol. 1995;26:1581–1585
29. Rubens C, Ewert R, Halank M, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest. 2001;120:1562–1569
30. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension. The impact of epoprostenol therapy. Circulation. 2002;106:1477–1482
31. Torbicki A, Kurzyna M, Kuca P, et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation. 2003;108:844–848
32. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–788
33. Rich S. Primary pulmonary hypertension: executive summary from the World Symposium on Primary Pulmonary Hypertension. Evian, France: World Health Organization, 1998.
This article has been cited by other articles:
|
|
|
|
 
H. C. Champion, E. D. Michelakis, and P. M. Hassoun
Comprehensive Invasive and Noninvasive Approach to the Right Ventricle-Pulmonary Circulation Unit: State of the Art and Clinical and Research Implications
Circulation,
September 15, 2009;
120(11):
992 - 1007.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hoetzenecker, H. J. Ankersmit, and I. M. Lang
Reply to the Editor
J. Thorac. Cardiovasc. Surg.,
September 1, 2009;
138(3):
786 - 786.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J-L. Vachiery and G. Coghlan
Screening for pulmonary arterial hypertension in systemic sclerosis
Eur. Respir. Rev.,
September 1, 2009;
18(113):
162 - 169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Kahler
Chronic thromboembolic pulmonary hypertension as a cause of dyspnoea in an older patient with a complex history
Eur. Respir. Rev.,
September 1, 2009;
18(113):
170 - 173.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rubenfire, G. Lippo, B. D. Bodini, F. Blasi, L. Allegra, and E. Bossone
Evaluating Health-Related Quality of Life, Work Ability, and Disability in Pulmonary Arterial Hypertension: An Unmet Need
Chest,
August 1, 2009;
136(2):
597 - 603.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. M. Robbins, J. H. Newman, R. F. Johnson, A. R. Hemnes, R. D. Fremont, R. N. Piana, D. X. Zhao, and D. W. Byrne
Association of the Metabolic Syndrome With Pulmonary Venous Hypertension
Chest,
July 1, 2009;
136(1):
31 - 36.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. D. Halpern and D. B. Taichman
Misclassification of Pulmonary Hypertension Due to Reliance on Pulmonary Capillary Wedge Pressure Rather Than Left Ventricular End-Diastolic Pressure
Chest,
July 1, 2009;
136(1):
37 - 43.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B. Taichman, M. D. McGoon, M. O. Harhay, C. Archer-Chicko, J. S. Sager, M. Murugappan, M. M. Chakinali, H. I. Palevsky, and R. Gallop
Wide Variation in Clinicians' Assessment of New York Heart Association/World Health Organization Functional Class in Patients With Pulmonary Arterial Hypertension
Mayo Clin. Proc.,
July 1, 2009;
84(7):
586 - 592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. E. Roberts, M. B. Fallon, M. J. Krowka, R. L. Benza, J. A. Knowles, D. B. Badesch, R. S. Brown Jr, D. B. Taichman, J. Trotter, S. Zacks, et al.
Serotonin Transporter Polymorphisms in Patients With Portopulmonary Hypertension
Chest,
June 1, 2009;
135(6):
1470 - 1475.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Fisher, P. R. Forfia, E. Chamera, T. Housten-Harris, H. C. Champion, R. E. Girgis, M. C. Corretti, and P. M. Hassoun
Accuracy of Doppler Echocardiography in the Hemodynamic Assessment of Pulmonary Hypertension
Am. J. Respir. Crit. Care Med.,
April 1, 2009;
179(7):
615 - 621.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. W. Thackeray and F. S. McDonald
25-Year-Old Woman With Increasing Abdominal Girth and Shortness of Breath
Mayo Clin. Proc.,
April 1, 2009;
84(4):
369 - 372.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Lapa, B. Dias, C. Jardim, C. J.C. Fernandes, P. M.M. Dourado, M. Figueiredo, A. Farias, J. Tsutsui, M. Terra-Filho, M. Humbert, et al.
Cardiopulmonary Manifestations of Hepatosplenic Schistosomiasis
Circulation,
March 24, 2009;
119(11):
1518 - 1523.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hoetzenecker, H. J. Ankersmit, D. Bonderman, W. Hoetzenecker, R. Seitelberger, W. Klepetko, and I. M. Lang
Atrial septal defect repair after a 10-month treatment with bosentan in a patient with severe pulmonary arterial hypertension: a case report.
J. Thorac. Cardiovasc. Surg.,
March 1, 2009;
137(3):
760 - 761.
[Full Text]
[PDF]
|
|
|
|
|
|
|
X-Q Xu and Z-C. Jing
High-altitude pulmonary hypertension
Eur. Respir. Rev.,
March 1, 2009;
18(111):
13 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanz, M. Kariisa, S. Dellegrottaglie, S. Prat-Gonzalez, M. J. Garcia, V. Fuster, and S. Rajagopalan
Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance.
J. Am. Coll. Cardiol. Img.,
March 1, 2009;
2(3):
286 - 295.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Tan, N. N. Wynn, M. Umerov, A. Henderson, A. Gillham, S. Junejo, and S. K. Bansal
Arm Span to Height Ratio Is Related to Severity of Dyspnea, Reduced Spirometry Volumes, and Right Heart Strain
Chest,
February 1, 2009;
135(2):
448 - 454.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D. McGoon and G. C. Kane
Pulmonary Hypertension: Diagnosis and Management
Mayo Clin. Proc.,
February 1, 2009;
84(2):
191 - 207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Skoro-Sajer, N. Hack, R. Sadushi-Kolici, D. Bonderman, J. Jakowitsch, W. Klepetko, M. A. R. Hoda, M. P. Kneussl, P. Fedullo, and I. M. Lang
Pulmonary Vascular Reactivity and Prognosis in Patients With Chronic Thromboembolic Pulmonary Hypertension: A Pilot Study
Circulation,
January 20, 2009;
119(2):
298 - 305.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S Holverda, H Rietema, N Westerhof, J T Marcus, C T-J Gan, P E Postmus, and A Vonk-Noordegraaf
Stroke volume increase to exercise in chronic obstructive pulmonary disease is limited by increased pulmonary artery pressure
Heart,
January 15, 2009;
95(2):
137 - 141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. R. Henkens, C. T.-J. Gan, S. A. van Wolferen, M. Hew, A. Boonstra, J. W. R. Twisk, O. Kamp, E. E. van der Wall, M. J. Schalij, A. Vonk Noordegraaf, et al.
ECG Monitoring of Treatment Response in Pulmonary Arterial Hypertension Patients
Chest,
December 1, 2008;
134(6):
1250 - 1257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L Hrometz and K. M Shields
Role of Ambrisentan in the Management of Pulmonary Hypertension
Ann. Pharmacother.,
November 1, 2008;
42(11):
1653 - 1659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanchez-Roman, C. F. Opitz, O. Kowal-Bielecka, F. J. Garcia-Hernandez, M. J. Castillo-Palma, D. Pittrow, and for the EPOSS-OMERACT Group
Screening for PAH in patients with systemic sclerosis: focus on Doppler echocardiography
Rheumatology,
October 1, 2008;
47(suppl_5):
v33 - v35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C P Denton, J E Pope, H-H Peter, A Gabrielli, A Boonstra, F H J van den Hoogen, G Riemekasten, S De Vita, A Morganti, M Dolberg, et al.
Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases
Ann Rheum Dis,
September 1, 2008;
67(9):
1222 - 1228.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Warwick, P. S. Thomas, and D. H. Yates
Biomarkers in pulmonary hypertension
Eur. Respir. J.,
August 1, 2008;
32(2):
503 - 512.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Bourbonnais and L. Samavati
Clinical predictors of pulmonary hypertension in sarcoidosis
Eur. Respir. J.,
August 1, 2008;
32(2):
296 - 302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Provencher, P. Herve, O. Sitbon, M. Humbert, G. Simonneau, and D. Chemla
Changes in exercise haemodynamics during treatment in pulmonary arterial hypertension
Eur. Respir. J.,
August 1, 2008;
32(2):
393 - 398.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Stolz, M. Christ-Crain, N. G. Morgenthaler, D. Miedinger, J. Leuppi, C. Muller, R. Bingisser, J. Struck, B. Muller, and M. Tamm
Plasma Pro-Adrenomedullin But Not Plasma Pro-Endothelin Predicts Survival in Exacerbations of COPD
Chest,
August 1, 2008;
134(2):
263 - 272.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Overbeek, J-W. Lankhaar, N. Westerhof, A. E. Voskuyl, A. Boonstra, J. G. F. Bronzwaer, K. M. J. Marques, E. F. Smit, B. A. C. Dijkmans, and A. Vonk-Noordegraaf
Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension
Eur. Respir. J.,
June 1, 2008;
31(6):
1160 - 1166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Terrier, M. C. Tamby, L. Camoin, P. Guilpain, C. Broussard, G. Bussone, A. Yaici, F. Hotellier, G. Simonneau, L. Guillevin, et al.
Identification of Target Antigens of Antifibroblast Antibodies in Pulmonary Arterial Hypertension
Am. J. Respir. Crit. Care Med.,
May 15, 2008;
177(10):
1128 - 1134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. R. Henkens, K. T. B. Mouchaers, A. Vonk-Noordegraaf, A. Boonstra, C. A. Swenne, A. C. Maan, S.-C. Man, J. W. R. Twisk, E. E. van der Wall, M. J. Schalij, et al.
Improved ECG detection of presence and severity of right ventricular pressure load validated with cardiac magnetic resonance imaging
Am J Physiol Heart Circ Physiol,
May 1, 2008;
294(5):
H2150 - H2157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Rietema, S. Holverda, H. J. Bogaard, J. T. Marcus, H. J. Smit, N. Westerhof, P. E. Postmus, A. Boonstra, and A. Vonk-Noordegraaf
Sildenafil treatment in COPD does not affect stroke volume or exercise capacity
Eur. Respir. J.,
April 1, 2008;
31(4):
759 - 764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
National Pulmonary Hypertension Centres of the UK
Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland
Heart,
March 1, 2008;
94(Suppl_1):
i1 - i41.
[Full Text]
[PDF]
|
|
|
|
|
|
|
National Pulmonary Hypertension Centres of the UK
Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland
Thorax,
March 1, 2008;
63(Suppl_2):
ii1 - ii41.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Golbin, V. K. Somers, and S. M. Caples
Obstructive Sleep Apnea, Cardiovascular Disease, and Pulmonary Hypertension
Proceedings of the ATS,
February 15, 2008;
5(2):
200 - 206.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. D. Ivy, A. K. Doran, K. J. Smith, G. B. Mallory Jr, M. Beghetti, R. J. Barst, D. Brady, Y. Law, D. Parker, L. Claussen, et al.
Short- and Long-Term Effects of Inhaled Iloprost Therapy in Children With Pulmonary Arterial Hypertension
J. Am. Coll. Cardiol.,
January 15, 2008;
51(2):
161 - 169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. D. Williams, B. M. Philip, L. F. Chu, M. G. Boltz, K. Kamra, H. Terwey, G. B. Hammer, S. B. Perry, J. A. Feinstein, and C. Ramamoorthy
Ketamine Does Not Increase Pulmonary Vascular Resistance in Children with Pulmonary Hypertension Undergoing Sevoflurane Anesthesia and Spontaneous Ventilation
Anesth. Analg.,
December 1, 2007;
105(6):
1578 - 1584.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Huez, F. Roufosse, J-L. Vachiery, A. Pavelescu, G. Derumeaux, J-C. Wautrecht, E. Cogan, and R. Naeije
Isolated right ventricular dysfunction in systemic sclerosis: latent pulmonary hypertension?
Eur. Respir. J.,
November 1, 2007;
30(5):
928 - 936.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Reichenberger, R. Voswinckel, B. Enke, M. Rutsch, E. El Fechtali, T. Schmehl, H. Olschewski, R. Schermuly, N. Weissmann, H. A. Ghofrani, et al.
Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension
Eur. Respir. J.,
November 1, 2007;
30(5):
922 - 927.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.C. Vonk, M.H. Sander, F.H.J. van den Hoogen, P.L.C.M. van Riel, F.W.A. Verheugt, and A.P.J. van Dijk
Right ventricle Tei-index: A tool to increase the accuracy of non-invasive detection of pulmonary arterial hypertension in connective tissue diseases
Eur J Echocardiogr,
October 1, 2007;
8(5):
317 - 321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Hoeper and F. Laenger
Challenging cases in PH
Eur. Respir. Rev.,
August 1, 2007;
16(102):
19 - 23.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. R. Henkens, K. T. B. Mouchaers, H. W. Vliegen, W. J. van der Laarse, C. A. Swenne, A. C. Maan, H. H. M. Draisma, I. Schalij, E. E. van der Wall, M. J. Schalij, et al.
Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography
Am J Physiol Heart Circ Physiol,
August 1, 2007;
293(2):
H1300 - H1307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. T.-J. Gan, S. Holverda, J. T. Marcus, W. J. Paulus, K. M. Marques, J. G.F. Bronzwaer, J. W. Twisk, A. Boonstra, P. E. Postmus, and A. Vonk-Noordegraaf
Right Ventricular Diastolic Dysfunction and the Acute Effects of Sildenafil in Pulmonary Hypertension Patients
Chest,
July 1, 2007;
132(1):
11 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Edelman
Clinical Presentation, Differential Diagnosis, and Vasodilator Testing of Pulmonary Hypertension
Seminars in Cardiothoracic and Vascular Anesthesia,
June 1, 2007;
11(2):
110 - 118.
[Abstract]
[PDF]
|
|
|
|
|
|
|
E. Voskaridou, G. Tsetsos, A. Tsoutsias, E. Spyropoulou, D. Christoulas, and E. Terpos
Pulmonary hypertension in patients with sickle cell/{beta} thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations
Haematologica,
June 1, 2007;
92(6):
738 - 743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M Engelfriet, M. G J Duffels, T. Moller, E. Boersma, J. G P Tijssen, E. Thaulow, M. A Gatzoulis, and B. J M Mulder
Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease
Heart,
June 1, 2007;
93(6):
682 - 687.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Perros, P. Dorfmuller, R. Souza, I. Durand-Gasselin, V. Godot, F. Capel, S. Adnot, S. Eddahibi, M. Mazmanian, E. Fadel, et al.
Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension
Eur. Respir. J.,
May 1, 2007;
29(5):
937 - 943.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-X. Wang, F.-R. Zhang, Y.-P. Shang, J.-H. Zhu, X.-D. Xie, Q.-M. Tao, J.-H. Zhu, and J.-Z. Chen
Transplantation of Autologous Endothelial Progenitor Cells May Be Beneficial in Patients With Idiopathic Pulmonary Arterial Hypertension: A Pilot Randomized Controlled Trial
J. Am. Coll. Cardiol.,
April 10, 2007;
49(14):
1566 - 1571.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. McMurtry, R. Moudgil, K. Hashimoto, S. Bonnet, E. D. Michelakis, and S. L. Archer
Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension
Am J Physiol Lung Cell Mol Physiol,
April 1, 2007;
292(4):
L872 - L878.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanz, P. Kuschnir, T. Rius, R. Salguero, R. Sulica, A. J. Einstein, S. Dellegrottaglie, V. Fuster, S. Rajagopalan, and M. Poon
Pulmonary Arterial Hypertension: Noninvasive Detection with Phase-Contrast MR Imaging
Radiology,
April 1, 2007;
243(1):
70 - 79.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Jardim, C. E. Rochitte, M. Humbert, G. Rubenfeld, D. Jasinowodolinski, C. R. R. Carvalho, and R. Souza
Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study
Eur. Respir. J.,
March 1, 2007;
29(3):
476 - 481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Ryu, M. J. Krowka, K. L. Swanson, P. A. Pellikka, and M. D. McGoon
Pulmonary Hypertension in Patients With Interstitial Lung Diseases
Mayo Clin. Proc.,
March 1, 2007;
82(3):
342 - 350.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-P. Diller and M. A. Gatzoulis
Pulmonary Vascular Disease in Adults With Congenital Heart Disease
Circulation,
February 27, 2007;
115(8):
1039 - 1050.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Reesink, M. N. van der Plas, N. E. Verhey, R. P. van Steenwijk, J. J. Kloek, and P. Bresser
Six-minute walk distance as parameter of functional outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension
J. Thorac. Cardiovasc. Surg.,
February 1, 2007;
133(2):
510 - 516.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Hoeper, S. H. Lee, R. Voswinckel, M. Palazzini, X. Jais, A. Marinelli, R. J. Barst, H. A. Ghofrani, Z.-C. Jing, C. Opitz, et al.
Complications of Right Heart Catheterization Procedures in Patients With Pulmonary Hypertension in Experienced Centers
J. Am. Coll. Cardiol.,
December 19, 2006;
48(12):
2546 - 2552.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Armigliato, R. Paolini, S. Aggio, S. Zamboni, M. P. Galasso, P. Zonzin, and G. Cella
Hyperthyroidism as a Cause of Pulmonary Arterial Hypertension: A Prospective Study
Angiology,
October 1, 2006;
57(5):
600 - 606.
[Abstract]
[PDF]
|
|
|
|
|
|
|
E. Cenedese, R. Speich, L. Dorschner, S. Ulrich, M. Maggiorini, R. Jenni, and M. Fischler
Measurement of quality of life in pulmonary hypertension and its significance
Eur. Respir. J.,
October 1, 2006;
28(4):
808 - 815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Tamby, M. Humbert, P. Guilpain, A. Servettaz, N. Dupin, J. J. Christner, G. Simonneau, J. Fermanian, B. Weill, L. Guillevin, et al.
Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension
Eur. Respir. J.,
October 1, 2006;
28(4):
799 - 807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. V. McLaughlin and M. D. McGoon
Pulmonary Arterial Hypertension
Circulation,
September 26, 2006;
114(13):
1417 - 1431.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ulrich, M. Fischler, R. Speich, V. Popov, and M. Maggiorini
Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties.
Chest,
September 1, 2006;
130(3):
841 - 846.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Joppa, D. Petrasova, B. Stancak, and R. Tkacova
Systemic Inflammation in Patients With COPD and Pulmonary Hypertension.
Chest,
August 1, 2006;
130(2):
326 - 333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Souza, C. Jardim, and C. Carvalho
The Need for National Registries in Rare Diseases
Am. J. Respir. Crit. Care Med.,
July 15, 2006;
174(2):
228 - 228.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. S. Zabka, F. E. Campbell, and D. W. Wilson
Pulmonary arteriopathy and idiopathic pulmonary arterial hypertension in six dogs.
Vet. Pathol.,
July 1, 2006;
43(4):
510 - 522.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Fijalkowska, M. Kurzyna, A. Torbicki, G. Szewczyk, M. Florczyk, P. Pruszczyk, and M. Szturmowicz
Serum N-Terminal Brain Natriuretic Peptide as a Prognostic Parameter in Patients With Pulmonary Hypertension
Chest,
May 1, 2006;
129(5):
1313 - 1321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Humbert, O. Sitbon, A. Chaouat, M. Bertocchi, G. Habib, V. Gressin, A. Yaici, E. Weitzenblum, J.-F. Cordier, F. Chabot, et al.
Pulmonary Arterial Hypertension in France: Results from a National Registry
Am. J. Respir. Crit. Care Med.,
May 1, 2006;
173(9):
1023 - 1030.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Tji-Joong Gan, J.-W. Lankhaar, J. T. Marcus, N. Westerhof, K. M. Marques, J. G. F. Bronzwaer, A. Boonstra, P. E. Postmus, and A. Vonk-Noordegraaf
Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension
Am J Physiol Heart Circ Physiol,
April 1, 2006;
290(4):
H1528 - H1533.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Scheindlin
When She Says Yes, But He Needs NO: Some Reflections on Nitric Oxide.
Mol. Interv.,
February 1, 2006;
6(1):
8 - 13.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Provencher, D. Chemla, P. Herve, O. Sitbon, M. Humbert, and G. Simonneau
Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension
Eur. Respir. J.,
January 1, 2006;
27(1):
114 - 120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Galie, H. A. Ghofrani, A. Torbicki, R. J. Barst, L. J. Rubin, D. Badesch, T. Fleming, T. Parpia, G. Burgess, A. Branzi, et al.
Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension
N. Engl. J. Med.,
November 17, 2005;
353(20):
2148 - 2157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Sitbon, M. Humbert, X. Jais, V. Ioos, A. M. Hamid, S. Provencher, G. Garcia, F. Parent, P. Herve, and G. Simonneau
Long-Term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension
Circulation,
June 14, 2005;
111(23):
3105 - 3111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B. Santana, J. G. Barra, J. C. Grignola, F. F. Gines, and R. L. Armentano
Pulmonary artery smooth muscle activation attenuates arterial dysfunction during acute pulmonary hypertension
J Appl Physiol,
February 1, 2005;
98(2):
605 - 613.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Detection