• Information
  1. Introduction
  2. Etiology of Primary P-HTN
  3. Etiology of Secondary P-HTN
  4. Pathogenesis
  5. Symptoms
  6. Diagnosis
  7. Functional Classification
  8. Treatment
  9. Prognosis
• Resources

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A. Introduction

1. Abnormally high pressures in the pulmonary vasculature [4]
   1. Sustained elevated pulmonary artery (PA) pressure >25mm Hg at rest OR
   2. PA pressure >30mm Hg with exercise
   3. AND mean pulmonary capitally wedge pressure and left ventricular end diastolic pressure <15mm Hg
2. May be due to abnormal arterioles, capillaries, or due to pulmonary venous congestion
3. Abnormalities may be instrinsic (primary), or secondary to other disease processes
4. World Health Organization (WHO) Classification of P-HTN
   1. Category 1: Pulmonary Arterial HTN
   2. Category 2: Pulmonary Venous HTN
   3. Category 3: Associated with disorders of respiratory system and/or hypoxemia (secondary P-HTN)
   4. Category 4: Chronic thromboembolic disease [3]
   5. Cateogry 5: Directly due to disorders directly affecting the pulmonary vasculature
5. Pulmonary Arterial HTN (Categories 1 and 3)
   1. Formerly included both primary and secondary P-HTN
   2. Sporadic / Idiopathic (primary)
   3. Familial (see below; primary)
   4. Autoimmune disease (primary), usually in 20-40 year old women
   5. Shunting: Eisenmenger's (Right to Left) shunt, other systemic shunts, pulmonary shunts
   6. Portal HTN
   7. Drugs / Toxins
   8. Other chronic hypoxic conditions
   9. Persistent P-HTN of the neonate
6. Primary P-HTN (PPH; Category 1)
   1. Leads to severe right heart failure and poor pulmonary perfusion, often fatal
   2. Affects mainly young people, female to male ratio is 1.7:1
   3. Incidence is 1-2 per million population (about 400 patients in USA)
   4. Mean age at diagnosis is 36 years
7. Pulmonary Venous HTN (Category 2) [7]
   1. Mainly secondary P-HTN
   2. Left-sided atrial or ventricular dysfunction
   3. Left-sided valvular heart disease
   4. Extrinsic compression of pulmonary veins: fibrosing mediastinitis, tumor
   5. Pulmonary veno-occlusive disease - idiopathic or iatrogenic
8. Secondary P-HTN (Category 3)
   1. Most commonly due to chronic obstructive pulmonary disease (COPD) in older men
   2. Minority associated with autoimmune diseases, usually in 20-40 year old women

B. Etiology of Primary P-HTN (PPH) [1,4,5]

1. Idiopathic (sporadic)
2. Familial Primary PPH [5,8]
   1. About 6% of cases of PPH are familial
   2. Most familial cases are due to mutations in genes of TGFß family of receptors
   3. Autosomal dominant with reduced penetrance in most cases
   4. Mutations in bone morphogenic protein receptor II (BMPR2) on chromosome 2q31-32 implicated in >50% of familial P-HTN
   5. >20% of person with BMPR2 mutations develop symptomatic P-HTN
   6. BBMPR2 forms complexes with BMPs and BMPR1 activating BMPR1 kinase domain
   7. Activated BMPR1 phosphorylates Smad-1, -5, -8 which activated Smad-4
   8. Smad-4 migrates to nucleus and inhibits cell growth, particularly after injury
   9. BMPR2 is the receptor for BMP-2, -4, -6, -7 and GDF-5, possibly others
   10. BMPR2 mutations (reduced activity) causes increased pulmonary vascular growth after injury
   11. Imbalanced activation of other TGFß receptors coupled with reduced activity of mutated BMPR2 increase likelihood of developing P-HTN
   12. Angiopoietin 1 signalling through TIE2 shuts down BMPR2 by blocking BMPR1A expression [15]
   13. Pulmonary HTN occurs in some patients with hereditary hemorrhagic telangiectasia with mutations in ALK-1 (a protein involved in TGFß signalling) [16]
3. Drug and Toxin Associated [13]
   1. Anorexic (appetitie suppressant) drugs [17]
   2. Cocaine
   3. Intravenous Drug Abuse
   4. Other stimulants (amphetamines)
   5. L-tryptophan
   6. Toxic rapeseed oil
   7. Some chemotherapuetic agents
4. Also associated with human herpesvirus 8 (HHV-8) [34]
5. Neonatal P-HTN - reduced levels of nitric oxide and its precursors and metabolites [35]
6. Prevalence of disease (about 8 per million) is ~5X fold higher than incidence

C. Etiology of Secondary P-HTN

1. Congenital Anomalies
   1. Pulmonic stenosis and others
   2. Repair of congenital heart disease (VSD, ASD, others) [33]
2. Pulmonary Embolism
   1. Thrombus, tumor, ova or parasites, foreign material
   2. Acute massive pulmonary embolism causes cor pulmonale
   3. Chronic pulmonary emboli leading to chronic P-HTN, ~4% at 2 years [39]
   4. Sickle cell disease - incidence up to 30% of adults [6]; risk factor for early death [21]
   5. Prothrombotic disorders
3. Chronic Pulmonary Parenchymal Disease Process
   1. Chronic Obstructive Pulmonary Disease
   2. Chronic thromboembolic disease
4. Collagen Vascular Diseases
   1. Mixed Connective Tissue Disease (MCTD)
   2. Progressive Systemic Sclerosis (PSS) and CREST Syndrome [27]
   3. Inflammatory Myositis
   4. SLE
5. Directly due to disorders directly affecting the pulmonary vasculature
   1. Schistosomiasis
   2. Sarcoidosis
   3. Other disorders
6. Sleep Apnea Syndrome
   1. Hypoxia induces pulmonary vasoconstriction
   2. This leads to chronic pulmonary hypertension
7. Obesity - small increased risk in absence of sleep apnea

D. Pathogenesis [1,2,4]

1. Overview
   1. Endothelial Dysfunction
   2. Extracellular Matrix
   3. Serotonin excess - vasoconstrictor and induces proliferation, procoagulant effects
   4. Voltage gated potassium channels
   5. Angiotensin converting enzyme
   6. Plasminogen activator inhibitor type 1 - impaired fibrinolysis
   7. Carbamoyl phosphate synthase
   8. Possible genetic predisposition beyond BMPR2 mutations
   9. Increased risk of PAH in sickle cell disease and HIV infection
2. Increased vsoconstrictor responses potentiated by known triggers
3. Pulmonary Vasculature Dysfunction
   1. Poor production of vasodilators, particularly nitric oxide from endothelium
   2. Intimal proliferation
   3. Abnormal signalling through angiopoietin 1, TIE2, BMP receptors 1A and 2 [15]
   4. Abnormally high signalling of angiopoietin 1 through its TIE2 receptor implicated [15]
4. Vasoconstrictor / Vasodilator Imbalance
   1. Thromboxanes (TxA2) increased relative to prostacyclin in these arteries
   2. Serotonin plasma levels are highly elevated in primary P-HTN [9]
   3. Primary P-HTN patients had reduced levels of platelet serotonin levels
   4. Abnormal serotonin handling may be central to this disease
   5. Role for serotonin strengthened by increased risk of P-HTN with fenfluramine use [17] and with various amphetamines and ergot alkaloids [4]
   6. Serotonin receptor 5-HT2B implicated in vasoconstriction, cell proliferation, and plexiform lesion formation in PAH [4]
   7. Reduced prostacyclin (PGI2) levels
   8. Thrombomodulin levels abnormally low in patients with precapillary P-HTN [14]
   9. Vasoactive intestinal polypeptide (VIP) levels reduced [4]
5. Endothelin-1
   1. Potent vasoconstricting compounds, made by endothelium, lung, brain, kidney
   2. Increased in P-THN
   3. Three closely related endothelins encoded on different chromosomes
   4. Angiotensin II, shear stress, TFGß, and Interleukin 1 stimulate endothelin production
   5. Levels increased with reduced cardiac output as in heart failure (CHF)
   6. Two receptors - ETa and ETb found in vascular smooth muscle
   7. Blockade of endothelin receptors reduces P-HTN and improves symptoms [38]
6. Nitric Oxide (NO)
   1. Potent vasodilator, previously called "endothelial derived relaxing factor" (EDRF)
   2. Levels of endothelial nitric oxide synthase (NOS) are reduced in lungs in P-HTN
   3. Levels of constitutive NOS correlate with severity of disease
   4. Reduced levels of NO and metabolites may be genetically determined in neonates [35]
   5. NO synthetase levels are elevated in plexiform lesions and may be enhance lesions [4]
7. Impaired vasodilatory voltage-gated potassium channel (KV1.5)
8. Net results is hypoxemia and cardiac dysfunction
   1. Hypoxemia leads to pulmonary vasoconstriction
   2. This leads to increased Right (R) sided heart pressures
   3. R ventricle undergoes minimal hypertrophy, then dilation and failure
   4. Result is highly increased R sided preload, peripheral edema, distented neck veins
9. Pathology - Heath and Edwards Grading System
   1. Medial Hypertrophy - increased medial thickness
   2. Fibroelastosis in laminae - intimal fibrosis
   3. Angiomatoid Lesions - plexiform lesions
   4. Fibrinoid Necrosis - pulmonary arterial occlusions

[Figure] "Heart Cycle in Pulmonary Hypertension"

E. Symptoms

1. Dyspnea on exertion (DOE) is most common presentation
2. Fatigue
3. Shortness of breath and chronic hypoxia as disease progresses
4. Angina [26]
   1. May be present in >50% of patients
   2. Due to or exacerbated by hypoxemia
   3. Left main coronary artery compression present in up to 20% overall [26]
5. Symptoms of right sided heart failure
   1. Peripheral edema and hepatic congestion (abdominal pain)
   2. Distended neck veins and fluid retention
   3. Ineffective filling of Left ventricle, with resultant hypotension
6. Increased risk of developing atrial fibrillation
   1. Especially with elevated right atrial pressures
   2. Risk for tachycardia and decompensation is high
7. Increased risk for thromboembolic events (higher with atrial fibrillation)
8. About 10% of primary and >50% of secondary P-HTN patients have Raynaud's phenomenon
9. In NIH registry, time of onset from first symptoms to diagnosis was ~2 years

F. Diagnosis

1. Clinical Definition
   1. Presence of pulmonary HTN: mean PA pressure >25mm Hg at rest (or 30mm in exercise)
   2. Normal pulmonary capillary wedge pressure (PCWP) or left atrial pressure <15mm Hg
   3. Abscence of secondary etiology (for primary P-HTN)
   4. Echocardiography with doppler pressure assessments is primary diagnostic modality
2. Rule out secondary etiology [1]
   1. Echocardiography
   2. Ventilation-Perfusion (V/Q) Scanning
   3. Autoantibody Serogies
   4. Pumonary Function Testing
   5. Pulmonary Angiography
   6. Note that many patients with primary P-HTN have low titer autoantibodies
3. Confirmation of Diagnosis - right heart catheterization
4. Von Willebrand Factor [25]
   1. Elevated levels of circulating von Willebrand factor predict a poor 1 year survival
   2. Therefore, consider treating patients with P-HTN and elevated vWF levels more aggressively, including "early" heart/lung or lung transplantation
5. Consider open lung or thoracoscopic biopsy if diagnosis is in question

G. Functional Classification [2,28]

1. Class I
   1. PAH without resulting limitation of physical activity
   2. Ordinary physical activity doesn't cause undue dyspnea, fatigue, chest pain or near syncope
2. Class II
   1. PAH resulting in slight limitation of physical activity
   2. Ordinary physical activity causes undue dyspnea, fatigue, chest pain or near syncope
3. Class III
   1. PAH resulting in marked limitation of physical activity
   2. Comfortable at rest
   3. Less than ordinary activity causes undue dyspnea, fatigue, chest pain or near syncope
4. Class IV
   1. PAH resulting in inability to carry out ANY physical activity without symptoms
   2. Patient has signs of right heart failure
   3. Dyspnea, fatigue or both may be present even at rest
   4. Discomfort increased with NY physical activity

H. Treatment [2,23]

1. Therapeutic Overview
   1. Little data are available in Class I or II patients; most data for Class III/IV
   2. Reduction in pulmonary vascular pressures (resistance, PVR) is major goal
   3. This must be achieved with minimal reduction in systemic vascular resistance (SVR)
   4. Many vasodilators show only mild selectivity for pulmonary vasculature
   5. Anticoagulation with warfarin is recommended in most cases of PPH
   6. Most patients benefit from loop diuretic for symptomatic right sided CHF
   7. Oxygen provides some symptomatic (and vasodilatory) benefit
2. Overview of Therapy for Class III and IV
   1. Several classes of drugs specifically for PAH are now approved
   2. These include endothelin receptor antagonists (ETRA), prostacyclins, phosphodiesterase (PDE) 5 inhibitors
   3. Oral anticoagulation ± diuretics ± oxygen are to most Class III and IV patients
   4. Oral anticoagulation with warfarin INR 1.5-2.5 due to modest mortality benefits in PPH
   5. Oxygen (usually nasal canula) to maintain O2 saturation at >90%
   6. Diuretics are used as needed for symptoms of edema, ascites, other fluid overload
   7. Caution with diuretics as preload (volume) reduction can precipitate syncope
   8. Most patients are relatively hypotensive due to poor right heart function
   9. Atrial septotstomy or lung transplantation to Class IV patients with severe symptoms
3. Vasodilator Responses
   1. Given for class II-IV PAH
   2. Response to acute vasodilator predicts chronic response to calcium channel blockers (CCB)
   3. Acute responses to nitric oxide, epoprostenol, or adenosine is evaluated
   4. Acute response defined as ~10mmHg reduction in mean PA pressures with vasodilator
   5. Acute response in ~10% of patients; these patients may be given long acting CCB
   6. Other patients should receive specific PAH drugs: ETRA, PDE5 inhibitors, prostacyclins [10]
   7. Combination therapies are increasingly used
   8. Invasive monitoring should be in place during acute infusions in patients
4. Adenosine (intravenous)
   1. May be used in the short-term evaluation for vasodilator responses
   2. Bradycardia may occur and must be monitored
   3. Adenosine response used to predict response to prostacyclines, CCB
5. Nitric Oxide
   1. Nitric oxide vasodilation may predict response to CCB and iloprost [24]
   2. Nitric oxide testing and vasodilator use should be done in intensive care unit setting
   3. Pulsed chronic nitric oxide is being investigated for chronic outpatient use [32]
6. ETRA
   1. Bosentan (Tracleer®)
   2. Ambrisentan (Letairis®)
   3. Sitaxentan (Thelin®; experimental)
7. Bosentan (Tracleer®) [38,40,42]
   1. Bosentan is an orally active, mixed ETRa/ETRb receptor antagonist
   2. Bosentan 62.5-125mg po bid reduced pulmonary pressures and improved functional class in patients with severe, symptomatic Class III/IV P-HTN
   3. Patients on bosentan had primary P-HTN or scleroderma associated P-HTN
   4. In class II primary P-HTN, treatment for 6 months improved 6 minute walk distance as well as pulmonary vascular resistance [46]
   5. Initial dose is 62.5mg po bid x 4 weeks, then increase to 125mg bid (preferred)
   6. 250mg bid is associated with abnormal transaminases in 14% of cases
   7. FDA approved for P-HTN with Class III or IV symptoms
   8. Dose dependent transaminase increases and teratogenic
   9. Monthly hepatic monitoring is required
   10. Preferred initial agent due to good efficacy and oral dosing
   11. Strongly consider combination trial with sildenafil (see below)
   12. Additional endothelin blockers are in development
8. Ambrisentan (Letairis®) [45]
   1. FDA approved for PPH; selective for ETRa receptor
   2. Dose is 5mg qd initially, then up to 10mg po qd
   3. Increased 6 minute walk distance 44 meters (10mg) or 23 meters (5mg) at 12 weeks
   4. Much reduced incidence of drug-induced hepatitis compared with bosentan
   5. Patients with drug-induced hepatitis on bosentan may be able to tolerate ambrisentan
9. PDE5 Inhibitors
   1. Sildenafil (Revatio®)
   2. Tadalafil (Cialis®; not approved for PPH, available for erectile dysfunction)
10. Sildenafil (Revatio®, Viagra®) [22,23,37,41]
    1. Phosphodiesterase 5 (PDE5) inhibitor, selectively induces pulmonary vascular relaxation
    2. Improves symptoms and objective findings in patients with lung fibrosis and P-HTN [37]
    3. Improves oxygenation and maintained V/Q matching (contrast with epoprostenol)
    4. Well tolerated oral agent dosed at 20-80mg po tid as monotherapy [22,23]
    5. Similar eduction of symptoms and PA pressures at 20-80mg po tid
    6. Dose 80mg po tid had greatest reduction in pulmonary vascular resistance
    7. Improved 6-minute walk distance 40-45 meters (no dose effect 20-80mg tid)
    8. Labeled dose is 20mg po tid 4-6 hours apart, with or without food
    9. May be combined with inhaled iloprost with efficacy in severe PAH [41]
    10. Do not use with nitrates; caution with resting hypotension (BP 90/50mmHg)
    11. Side effects: erection (priapsim), headache, flushing, pyrexia, insomnia, epistaxis
11. Prostacyclin (PGI2) Analogs
    1. Epoprostenol
    2. Treprostinil
    3. Iloprost
12. Epoprostenol (Flolan®) [11,12,20]
    1. Prostacyclin analog
    2. Approved for continuous IV infusion at 10-20ng/kg/min
    3. Primary P-HTN survival improved to ~63% at 3 years [20]
    4. Scleroderma related P-HTN exercise capacity and NYHA heart failure class improved markedly with continous epoprostenol [29]
    5. Twelve weeks of PGI2 improved exercise capacity, RV pressures, quality of life [10]
    6. Survival improved by 10-15% above annual rates with epoprostenol [19]
    7. Long-term benefits of PGI2 include improved cardiac output, symptoms, and mortality
    8. Diarrhea, flushing, lower extremity edema, hypotension most common adverse events
    9. Annual cost for at 10ng/kg/min is ~ $58,000 per year; 20ng/kg/min is ~ $72,000 [36]
13. Treprostinil (Remodulin®) [36]
    1. Prostacyclin analog
    2. Approved for chronic subcutaneous treatment at initially 0.625 up to 20ng/kg/min
    3. Generally well tolerated but all patients experience infusion site reactions
    4. Improves hemodynamics, symptoms in patients with severe P-HTN
    5. Jaw pain, diarrhea, flushing, lower extremity edema, gastrointestinal hemorrhage
14. Iloprost (Ventavis®) [24]
    1. Iloprost is a long acting stable analog of PGI2 taken IV or inhaled
    2. IV iloprost is given through central venous catheter and is well tolerated
    3. Aerosolized PGI2 or iloprost is very effective at reducing pulmonary pressures [12,30]
    4. Aerosolized iloprost is active for 60-120 minutes and causes little reduction in BP [12]
    5. Aerosolized iloprost improved primary or secondary P-HTN in resistant patients [30]
    6. Inhalation of 2.5-5.0µg 6-9 times per day during waking hours over 1 year improved exercise, NYHA Class, and pulmonary hemodynamics [31,43]
    7. Increase in exhaled nitric oxide following iloprost is marker for efficacy of therapy [24]
    8. Inhaled iloprost combined with sildenafil is more effective than either agent alone [41]
15. Beraprost
    1. Oral prostacyclin analog, elimination half-life 35-40 minutes
    2. Some benefit in Class II/III patients in 3 month studies, not sustained in 12 month study
    3. Approved in Japan only
16. CCB
    1. Long acting CCB should only be tried after a good response to a short acting vasodilator
    2. Amlodopine (Norvasc®) 2.5mg initially has been recommended first line [22]
    3. Nifedipine drops SVR considerably; hypotension; reflex tachycardia can worsen SOB
    4. Overall, nifedipine does improve symptoms and reduce PAP; survival effect not clear [18]
    5. Long acting diltiazem may be considered in patients intolerant of nifedipine
    6. Diltiazem (± oxygen) may be effective in some patients, 120-900mg per day
17. Anticoagulation
    1. Reduces clot formation in dysfunctional right ventricle
    2. In addition, high risk of atrial fibrillation suggests that anti-coagulation should be used
    3. Use of anti-coagulation appears to prolong life in P-HTN
    4. Warfarin is agent of choice, target INR is about 2.0
18. Chronic Thromboembolic P-HTN [39]
    1. Pulmonary thromboendarterectomy for symptomatic disase
    2. Contraindication to surgery is severe underlying chronic lung disease
    3. If surgery deferred, close monitoring for progression is required
19. Indications for Lung Transplantation [44]
    1. NHYA functional Class III or IV
    2. Mean pulmonary-artery pressure >55 mm Hg
    3. Mean right atrial pressure >15 mm Hg
    4. Cardiac index <2 liters/min/m2
    5. Failure of medical therapy (especially IV epoprostenol)
20. Novel Treatments
    1. Thromboxane receptor blockers
    2. Serotonin (5HT) 2B receptor antagonists
    3. Additional prostacyclin analogs
    4. Gene transfer to pulmonary vascular bed

H. Prognosis [1,2]

1. Correlated with R Atrial Pressure, PA Pressure, and Cardiac Index
   1. One year: ~77%
   2. Two year: ~51%
   3. Three year: ~40%
   4. Five year survival in non-transplanted patients is ~30%
   5. Therefore, patients with PPH should be referred to specialized centers for evaluation
2. Indicators Predicting Poor Outcome
   1. Mean PA pressure >85mm Hg - survival is <12 months
   2. Response to vasodilatr therapy
   3. Functional Class (see above)
   4. Right Atrial Pressure - higher levels predict worse outcome
   5. Cardiac index and mixed venous oxygen level

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Resources

Pulmonary Vascular Resistance

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