Pulmonary Hypertension

Epidemiology

  • Prevalence
    • Group 1: approximately 5-15 cases per one million adults
      • Compared to other groups of pulmonary hypertension, idiopathic pulmonary arterial hypertension affects younger adults with a female predominance
      • In older patient populations, group 1 pulmonary hypertension is uncommon
  • Data from the Nationwide Emergency Department Sample (2015) [MEDLINE]
    • From 2007-2011: presumably due to better pulmonary hypertension care, hospitalization rate decreased from 79 -> 38 per 100,000 hospitalizations
    • From 2007-2011: presumably due to better pulmonary hypertension care, population-based death rate decreased from 4.6 -> 1.7 per million

Etiology (5th World Symposium Classification; Nice, France 2013)

Group 1: Pulmonary Arterial Hypertension

1.1: Idiopathic Pulmonary Arterial Hypertension (IPAH) (see Idiopathic Pulmonary Arterial Hypertension, [[Idiopathic Pulmonary Arterial Hypertension]])

  • General Comments: idiopathic pulmonary arterial hypertension is clinically indistinguishable from heritable pulmonary hypertension

1.2: Heritable Pulmonary Arterial Hypertension

  • General Comments: a heritable cause of pulmonary hypertension is present in only 6-10% of group 1 pulmonary hypertension patients
  • Familial Pulmonary Hypertension Due to BMPR2 Gene Mutation [MEDLINE] (see Familial Pulmonary Hypertension, [[Familial Pulmonary Hypertension]])
    • Epidemiology: heterozygous BMPR2 mutations occur in 75% of familial pulmonary hypertension cases (and in 25% of apparently sporadic pulmonary hypertension cases)
    • Physiology: BMPR2 encodes a type 2 receptor for bone morphogenetic proteins involved in the control of vascular cell proliferation
  • Familial Pulmonary Hypertension Due to Activin-Like Receptor Kinase-1 (ALK1) Gene Mutation [MEDLINE] (see Familial Pulmonary Hypertension, [[Familial Pulmonary Hypertension]])
  • Familial Pulmonary Hypertension Due to Endoglin (ENG) Gene Mutation (see Familial Pulmonary Hypertension, [[Familial Pulmonary Hypertension]])
  • Familial Pulmonary Hypertension Due to Mothers Against Decapentaplegic 9 (Smad 9) Gene Mutation [MEDLINE] (see Familial Pulmonary Hypertension, [[Familial Pulmonary Hypertension]])
  • Familial Pulmonary Hypertension Due to Caveolin-1 (CAV1) Gene Mutation [MEDLINE] (see Familial Pulmonary Hypertension, [[Familial Pulmonary Hypertension]])
  • Familial Pulmonary Hypertension Due to Potassium Channel Subfamily K Member 3 (KCNK3) Gene Mutation [MEDLINE] (see Familial Pulmonary Hypertension, [[Familial Pulmonary Hypertension]])
  • Unknown Heritable Defect

1.3: Drug and Toxin-Induced: Definite Association

  • General Comments: epidemic or large multicenter epidemiologic studies demonstrating an association between drug and pulmonary hypertension
  • Anorexigens
    • Aminorex (see Aminorex, [[Aminorex]])
    • Benfluorex (Mediator, Modulator) (see Benfluorex, [[Benfluorex]])
    • Dexfenfluramine (see Dexfenfluramine, [[Dexfenfluramine]])
    • Diethylpropion
    • Fenfluramine (see Fenfluramine, [[Fenfluramine]])
  • Contaminated Rapeseed Oil (see Contaminated Rapeseed Oil, [[Contaminated Rapeseed Oil]])
  • Selective Serotonin Reuptake Inhibitors (SSRI) (see Selective Serotonin Reuptake Inhibitors, [[Selective Serotonin Reuptake Inhibitors]]): no clear association between SSRI’s and the development adult pulmonary hypertension
    • Maternal Use of SSRI: maternal use may result in persistent pulmonary hypertension of the neonate
    • Use of SSRI by Patients with Established Pulmonary Hypertension: associated with worse prognosis
  • Zinostatin (see Zinostatin, [[Zinostatin]])

1.3: Drug and Toxin-Induced: Likely Association

  • General Comments: single case-control study demonstrating an association between drug and pulmonary hypertension)
  • Amphetamine (see Amphetamine, [[Amphetamine]])
  • L-Tryptophan (see Eosinophilia-Myalgia Syndrome, [[Eosinophilia-Myalgia Syndrome]])
  • Methamphetamine (see Methamphetamine, [[Methamphetamine]]): smoked, oral, or IV
  • Dasatinib (Sprycel) (see Dasatinib, [[Dasatinib]]): tyrosine-kinase inhibitor
  • Leflunomide (Arava) (see Leflunomide, [[Leflunomide]])

1.3: Drug and Toxin-Induced: Possible Association

  • General Comments: drugs with similar mechanisms of action as those in the definite or likely categories, but which have not yet been studied
  • Amphetamine-Like Agents
    • 4-Methyl-Aminorex (Ice, Euphoria, U-4-E-uh) (see 4-Methyl-Aminorex, [[4-Methyl-Aminorex]]): designer amphetamine analog which is recreationally used
    • Mazindol (see Mazindol, [[Mazindol]])
    • Methylphenidate (Ritalin) (see Methylphenidate, [[Methylphenidate]])
    • Phentermine/Topiramate (Qsiva) (see Phentermine, [[Phentermine]])
    • Ropinirole (Requip) (see Ropinirole, [[Ropinirole]])
  • Cocaine (see Cocaine, [[Cocaine]])
  • Interferons (see Interferons, [[Interferons]]): unclear mechanism
    • Interferon Alpha (see xxxx, [[xxxx]]): when used to treat hepatitis
    • Interferon Beta (see xxxx, [[xxxx]]): when used to treat multiple sclerosis
  • Pergolide (see Pergolide, [[Pergolide]])
  • Phenylpropanolamine (Acutrim) (see Phenylpropanolamine, [[Phenylpropanolamine]])
  • St. John’s Wort (see St Johns Wort, [[St Johns Wort]])

1.3: Drug and Toxin-Induced: Unlikely Association

  • General Comments: drug has been studied in epidemiologic studies and an association with pulmonary hypertension has not been demonstrated
  • Tobacco (see Tobacco, [[Tobacco]])
  • Estrogen (see Estrogen, [[Estrogen]])
  • Oral Contraceptives (OCP) (see Oral Contraceptives, [[Oral Contraceptives]])

1.4: Associated Pulmonary Arterial Hypertension (APAH)

  • Connective Tissue Disease
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
    • Epidemiology: pulmonary hypertension occurs in 0.5% of HIV-infected patients
  • Portopulmonary Hypertension (see Portopulmonary Hypertension, [[Portopulmonary Hypertension]])
    • Epidemiology: pulmonary hypertension occurs in 0.7-6% of patients with liver disease (rates may be as high as 16% in patients with end-stage liver disease)
  • Congenital Heart Disease in Adults
    • Eisenmenger Syndrome (see Eisenmenger Syndrome, [[Eisenmenger Syndrome]]): includes all large intracardiac/extracardiac defects which begin as systemic-to-pulmonary shunts, progress to severe elevation of pulmonary vascular resistance, and progress to reverse shunting (pulmonary-to-systemic) or bidirectional shunting
      • Cyanosis, secondary erythrocytosis, and multiple organ involvement are usually present
    • Left-to-Right Intracardiac Shunt (see Intracardiac and Extracardiac Shunt, [[Intracardiac and Extracardiac Shunt]]): includes moderate-large defects
      • Pulmonary vascular resistance is mildly to moderately increased
      • Systemic-to-pulmonary shunting is still prevalent
      • Cyanosis is not a feature
    • Pulmonary Hypertension with Small/Coincidental Congenital Heart Disease: includes conditions with marked elevation in pulmonary vascular resistance in the presence of small cardiac defects, which themselves do not account for the development of elevated pulmonary vascular resistance
      • Clinical picture is very similar to idiopathic pulmonary arterial hypertension
      • Closing the defect is contraindicated
    • Pulmonary Hypertension Occurring Post-Operatively Following Repair of Congenital Heart Disease: includes conditions where the congenital heart disease is repaired but pulmonary arterial hypertension either persists immediately after surgery or recurs months or years later after surgery (in the absence of significant post-operative hemodynamic lesions)
      • Clinical phenotype is often aggressive
  • Schistosomiasis (see Schistosomiasis, [[Schistosomiasis]]): probably the most common worldwide etiology of pulmonary hypertension
    • Epidemiology: schistosomiasis is the most common cause of pulmonary hypertension worldwide
    • Physiology: schistosome ova embolize to the lung and induce a granulomatous reaction in the pulmonary arterioles

1′: Other

  • Pulmonary Veno-Occlusive Disease (VOD) (see Pulmonary Veno-Occlusive Disease, [[Pulmonary Veno-Occlusive Disease]])
    • Physiology: extensive diffuse occlusion of pulmonary veins, resulting in tortuous dilation of the pulmonary capillaries
  • Pulmonary Capillary Hemangiomatosis (see Pulmonary Capillary Hemangiomatosis, [[Pulmonary Capillary Hemangiomatosis]])

1”: Other

  • Persistent Pulmonary Hypertension of the Newborn (PPHN)

Group 2: Pulmonary Arterial Hypertension Due to Left Heart Disease

  • General Comments
    • Pulmonary hypertension due to left heart disease is the most frequent cause of pulmonary hypertension
    • Diagnostic Features: left atrial-mean pressure >14 mm Hg with associated pulmonary venous hypertension
      • Importantly, the degree of pulmonary hypertension that results from a given level of left atrial hypertension is highly variable due to individual differences in the vasoconstrictive and vascular remodeling responses in the pulmonary arterial circulation
  • 2.1: Left Ventricular Systolic Dysfunction (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Mechanisms of Development of Pulmonary Hypertension in the Setting of Systolic Dysfunction
      • Chronic Pulmonary Venous Congestion
      • Recurrent Transient Hypoxemia
      • Sleep-Disordered Breathing
    • Presence of Pulmonary Hypertension in the Setting of Systolic Dysfunction Portends a Higher Risk of Hospitalization and Death [MEDLINE]
  • 2.2: Left Ventricular Diastolic Dysfunction (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Constrictive Pericarditis (see Constrictive Pericarditis, [[Constrictive Pericarditis]])
    • Left Atrial Myxoma (see Atrial Myxoma, [[Atrial Myxoma]])
    • Restrictive Cardiomyopathy
      • Obesity-Associated Restrictive Cardiomyopathy: characterized by fatty infiltration of cardiac myocytes, restrictive physiology, and elevation in left and right heart filling pressure -> severe pulmonary hypertension secondary to occlusive vasculopathy of the small pulmonary arteries and arterioles may also occur
  • 2.3: Left Heart Valvular Disease (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • 2.4: Congenital/Acquired Left Heart Inflow/Outflow Tract Obstruction and Congenital Cardiomyopathies

Group 3: Pulmonary Arterial Hypertension Due to Lung Disease and/or Hypoxemia

3.1: Chronic Obstructive Pulmonary Disease (COPD) and Obstructive Lung Diseases

  • Chronic Obstructive Pulmonary Disease (COPD) see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])
    • Epidemiology: 90% of COPD patients have mild-moderate pulmonary hypertension (while only 3-5% have severe pulmonary hypertension)
    • Severe pulmonary hypertension portends a worse prognosis: PA-mean pressure >45 mm Hg has a significantly worse 5–year survival (<10% versus >90%) [MEDLINE]
    • Patients with PA-Mean ≥35 mmHg or ≥25 mm Hg + Cardiac Index <2 L/min/m2: this subset of COPD/ILD/CPFE patients (at higher risk for mortality) is defined under the NICE classification as having severe pulmonary hypertension, meriting consideration of care at a specialized center or being enrolled in investigational therapy
  • Bronchiectasis (see Bronchiectasis, [[Bronchiectasis]]): with severe, diffuse disease
  • Cystic Fibrosis (CF) (see Cystic Fibrosis, [[Cystic Fibrosis]])

3.2: Interstitial Lung Disease (ILD)

  • General Comments
    • Epidemiology: pulmonary hypertension occurs in 8-32% of ILD cases
    • Patients with PA-Mean ≥35 mmHg or ≥25 mm Hg + Cardiac Index <2 L/min/m2: this subset of COPD/ILD/CPFE patients (at higher risk for mortality) is defined under the NICE classification as having severe pulmonary hypertension, meriting consideration of care at a specialized center or being enrolled in investigational therapy
  • Idiopathic Pulmonary Fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis, [[Idiopathic Pulmonary Fibrosis]]): pulmonary hypertension is more common when hypoxemia and severe pulmonary dysfunction are present
  • Other Severe Interstitial Lung Disease of Any Etiology (see Interstitial Lung Disease, [[Interstitial Lung Disease]]): pulmonary hypertension is more common when hypoxemia and severe pulmonary dysfunction are present

3.3: Other Pulmonary Disease with Mixed Restriction-Obstruction

  • Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])
  • Combined Pulmonary Fibrosis and Emphysema (see Combined Pulmonary Fibrosis and Emphysema, [[Combined Pulmonary Fibrosis and Emphysema]]): pulmonary hypertension is a common complication (and pulmonary hypertension is more frequent and severe, as compared to COPD and ILD alone)
    • Patients with PA-Mean ≥35 mmHg or ≥25 mm Hg + Cardiac Index <2 L/min/m2: this subset of COPD/ILD/CPFE patients (at higher risk for mortality) is defined under the NICE classification as having severe pulmonary hypertension, meriting consideration of care at a specialized center or being enrolled in investigational therapy

3.4: Sleep-Disordered Breathing

3.5: Chronic Hypoventilation (see Chronic Hypoventilation, [[Chronic Hypoventilation]])

  • Various Disorders

3.6: Chronic High Altitude

3.7: Developmental Lung Diseases

  • Alveolar Capillary Dysplasia (ACD)
  • Bronchopulmonary Dysplasia (BPD) (see Bronchopulmonary Dysplasia, [[Bronchopulmonary Dysplasia]])
  • Congenital Diaphragmatic Hernia
  • Lung Hypoplasia: primary or secondary
  • Pulmonary Alveolar Proteinosis (PAP) (see Pulmonary Alveolar Proteinosis, [[Pulmonary Alveolar Proteinosis]])
  • Pulmonary Interstitial Glycogenosis
  • Pulmonary Lymphangiectasia
  • Surfactant Protein Abnormalities
    • ATP-Binding Cassette A3 Mutation
    • Surfactant Protein B Deficiency
    • Surfactant Protein C Deficiency
    • Thyroid Transcription Factor 1/Nkx2.1 Homeobox Mutation

Group 4: Pulmonary Arterial Hypertension Due to Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Other Pulmonary Artery Obstruction

  • Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
  • Other Pulmonary Artery Obstruction
    • Congenital Pulmonary Artery Stenosis
    • Pulmonary Artery Angiosarcoma (see Pulmonary Artery Angiosarcoma, [[Pulmonary Artery Angiosarcoma]])
    • Other Pulmonary Artery Intravascular Tumors
    • Pulmonary Arteritis
    • Parasites (Hydatidosis)

Group 5: Pulmonary Arterial Hypertension Due to Unclear Multifactorial Mechanisms

5.1: Hematologic Disorders

5.2: Systemic Disorders

5.3: Metabolic Disorders

5.4: Other

Other Disorders Not Included in Classification


Physiology

Normal Pulmonary Artery Pressure

  • Normal Pulmonary Arterial-Systolic Pressure: 15-30 mm Hg
  • Normal Pulmonary Artery-Diastolic Pressure: 4-12 mm Hg
  • Normal Pulmonary Artery-Mean Pressure: ≤20 mmHg

Hypoxic Pulmonary Vasoconstriction

Background

  • Hypoxic Pulmonary Vasoconstriction is a Normal Physiologic Mechanism Designed to Decrease Blood Flow to Hypoxic Alveoli and Optimize Ventilation/Perfusion Matching

Acute Hypoxic Pulmonary Vasoconstriction

  • Reversibility: completely reversible with oxygen therapy
  • Mechanisms of Acute Hypoxic Pulmonary Vasoconstriction
    • Immediate Pre-Capillary Arteriolar Vasoconstriction Mediated by Mitochrondrial Signaling and Smooth Muscle Ion Channels

Chronic Hypoxic Vasoconstriction

  • Reversibility: initially reversible with oxygen therapy, but eventually becomes only partially reversible (due to superimposed vascular remodeling)
    • The degree of vascular remodeling is individually variable, explaining the variable progression to pulmonary hypertension in diseases such as COPD
  • Mechanisms of Chronic Hypoxic Vasoconstriction (and Narrowing)
    • Decreased Endothelial Nitric Oxide Synthase (eNOS) with Resulting Decreased NO Synthesis and Increased Hemoglobin-Mediated Inactivation
    • Decreased Voltage-Gated Potassium Channel Alpha Subunits or Voltage-Gated Potassium Channel Activity with Resulting Change in Resting Membrane Potential: results in increased free calcium and pulmonary arterial smooth muscle contraction (vasoconstriction)
    • Increased Cytosolic Phospholipase A2 (cPLA2) Activity with Increased Arachidonic Acid Release from Membranes: arachidonic acid is metabolized by cyclooxygenases/lipoxygenases to eicosoanoids (prostaglandins, thomboxanes, and leukotrienes)
    • Increased Endothelin Expression
    • Neomuscularization, Intimal Thickening, and Medial Hypertrophy of Pulmonary Arterioles: later in course, collagen matrix is deposited in the adventitia

Pathophysiology of Pulmonary Hypertension by Group

  • Group 1: proliferative vasculopathy of small muscular pulmonary arterioles
    • Intimal Hyperplasia
    • Medial Hypertrophy
    • Plexiform Lesions
  • Group 2-5: pathophysiology is less well understood
    • Increased Pulmonary Vascular Resistance
    • Vascular Remodeling

Diagnosis

Chest X-Ray (see Chest X-Ray, [[Chest X-Ray]])

  • Findings: CXR is abnormal in 90% of cases at the time of diagnosis [MEDLINE]
    • Central Pulmonary Arterial Dilatation
    • “Pruning” (Loss) of the Peripheral Blood Vessels
    • Right Atrial Enlargement: seen late in course
    • Right Ventricular Enlargement: seen late in course

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

  • Findings: EKG is more likely to be abnormal in severe pulmonary hypertension
    • P Pulmonale
    • QRS Prolongation: suggests more severe pulmonary hypertension
    • QTc Prolongation: suggests more severe pulmonary hypertension
    • Right Axis Deviation
    • Right Bundle Branch Block
    • Right Ventricular Hypertrophy (RVH): sensitivity (55%)/specificity (70%)
    • RV Strain: more sensitive than RVH

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
    • Nocturnal Hypoxemia: common
  • Hypocapnia (see Hypocapnia, [[Hypocapnia]]): due to hyperventilation

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • Clinical Utility: PFT’s are useful to assess for underlying lung disease, but may demonstrate findings which are specific for the pulmonary hypertension itself
  • Findings
    • Mild-Moderate Restriction: may be seen (and is related to disease severity)
    • Decreased DLCO: variable
      • Normal DLCO does not rule out pulmonary hypertension
      • DLCO <45% pred is asscociated with a worse outcome

Echocardiogram (see Echocardiogram, [[Echocardiogram]])

  • Clinical Utility: echocardiogram is a screening test for the presence of pulmonary hypertension
    • However, due to its limitations (in terms of sensitivity/specificity), Swan-Ganz catheter measurement of pulmonary artery pressure is considered the gold standard
  • Findings
    • Tricuspid Regurgitation
      • Estimated PA-Sys= TR Jet Peak Velocity (in m/sec) squared x 4 + CVP
    • Right Ventricle/Left Ventricle Basal Diameter Ratio >1.0
    • Flattening of Intraventricular Septum: left ventricular eccentricity index >1.1 in systole and/or diastole
    • Right Ventricular Outflow Doppler Acceleration Time <105 msec and/or Midsystolic Notching
    • Early Diastolic Pulmonary Regurgitation Velocity >2.2 m/sec
    • IVC Diameter >21 mm with Decreased Inspiratory Collapse (<50% with a Sniff or <20% with Quiet Inspiration)
    • Right Atrial Area (End-Systole) >18 cm2

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

  • Clinical Utility: V/Q scan should be performed to rule out chronic thromboembolic pulmonary hypertension (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
    • V/Q scan has traditionally been considered the screening method of choice for chronic thromboembolic pulmonary hypertension because of its higher sensitivity than CT pulmonary angiogram (especially in inexperienced centers)
    • Normal CT Pulmonary Angiogram: 90-100% sensitivity/94-100% specificity for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)
    • However, many V/Q scans are not diagnostic
  • Idiopathic Pulmonary Arterial Hypertension (IPAH): normal or “mottled” appearance (small peripheral unmatched or non-segmental perfusion defects)
    • However, unmatched perfusion defects may also be seen in pulmonary veno-occlusive disease (PVOD) (see Pulmonary Veno-Occlusive Disease, [[Pulmonary Veno-Occlusive Disease]])
  • Chronic Thromboembolic Pulmonary Hypertension (CTEPH): 1 or more segmental or lobar defects

Computed Tomography (CT) Pulmonary Angiogram (see Computed Tomography Pulmonary Angiogram, [[Computed Tomography Pulmonary Angiogram]])

  • xxx

Pulmonary Artery Magnetic Resonance Imaging (MRI) (see Magnetic Resonance Imaging, [[Magnetic Resonance Imaging]])

  • Clinical Utility: 3-dimensional magnetic resonance perfusion mapping has been demonstrated to be as sensitive as V/Q scanning in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)

Swan-Ganz (Pulmonary Artery) Catheterization (see Swan-Ganz Catheter, [[Swan-Ganz Catheter]])

General Comments

  • Definition of Pulmonary Hypertension: defined as resting pulmonary arterial-mean pressure ≥25 mmHg at rest (confirmed by Swan-Ganz catheterization)
    • PA-Mean 21-24 mm Hg: borderline elevated -> unclear clinical significance
  • Definition of Exercise-Associated Pulmonary Hypertension: due to the lack of reliable data which defines this entity, standard diagnostic parameters (for pulmonary pressures and PVR) have not been defined
  • Swan-Ganz catheter Measurement of Pulmonary Artery Pressure is Considered the Gold Standard

Pulmonary Hypertension with Elevated Pulmonary Capillary Wedge Pressure (PCWP)

  • Cardiac Etiology
  • Pulmonary Venous Disease
    • Pulmonary Venous Obstruction
    • Pulmonary Venous Fibrosis
    • Pulmonary Veno-Occlusive Disease (VOD) (see Pulmonary Veno-Occlusive Disease, [[Pulmonary Veno-Occlusive Disease]])
      • Normal (most cases): in cases where venules are the involved site
      • Elevated (some cases): in cases where large veins are the involved site

Pulmonary Hypertension with Normal Pulmonary Capillary Wedge Pressure (PCWP)

  • Pulmonary Vascular Disease
    • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])
    • Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
    • Pulmonary Vasculitis
    • Pulmonary Veno-Occlusive Disease (VOD) (see Pulmonary Veno-Occlusive Disease, [[Pulmonary Veno-Occlusive Disease]])
      • Normal (most cases): in cases where venules are the involved site
      • Elevated (some cases): in cases where large veins are the involved site
  • Pulmonary Parenchymal Disease
  • Chest Bellows Disease
    • Neuromuscular Disease
    • Post-Thoracotomy
    • Extensive Pleural Disease
    • Chest Wall Disease
  • Chronic Upper Airway Obstruction
    • Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]]): in adults
    • Tonsillar Hypertrophy: in children
    • Tracheal Stenosis
  • Central Nervous System Disease

Vasodilator (Vasoreactivity) Testing

  • Technique
    • Swan-Ganz Catheter Monitoring of Pulmonary Artery Pressure with Short-Acting Pulmonary Vasodilator Administration
      • Adenosine (see Adenosine, [[Adenosine]])
      • Epoprostenol (Prostacyclin, Flolan) (see Epoprostenol, [[Epoprostenol]])
      • Inhaled Nitric Oxide (iNO) (see Nitric Oxide, [[Nitric Oxide]])
  • Contraindications
    • Hypotension (see Hypotension, [[Hypotension]]): since vasoreactivity testing may precipitate hypotension
    • Low Cardiac Output
    • Presence of WHO Functional Class IV Symptoms
  • Interpretation
    • Vasoreactivity: defined as a >10 mm Hg decrease in PA-mean and to a value <40 mm Hg with an increased or unchanged cardiac output (and a minimally decreased or unchanged systemic blood pressure_
  • Recommendations (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • In the Absence of Contraindications, All Patients with Pulmonary Hypertension Should Undergo Acute Vasoreactivity Testing with a Short-Acting Pulmonary Vasodilator at a Center Experienced in Performing Such Testing (Grade CB Recommendation)

Pulmonary Artery Angiogram (see Pulmonary Artery Angiogram, [[Pulmonary Artery Angiogram]])

  • IPAH: angio rules out clots and demonstrate “pruned” vessels
  • CTEPH: evidence of proximal clots

Lower Extremity Venous Doppler Ultrasound (see Lower Extremity Venous Doppler Ultrasound, [[Lower Extremity Venous Doppler Ultrasound]])

  • xxx

6-Minute Walk Test (see 6-Minute Walk Test, [[6-Minute Walk Test]])

  • xxx

Clinical Manifestations

General Comments

  • Presentation is Typically Non-Specific: consequently, the correct diagnosis may be delayed by years

PULM HTN PROG

World Health Organization (WHO) Functional Classification of Pulmonary Hypertension

  • Functional Class I
    • No Limitation of Physical Activity
    • Ordinary Physical Activity Does Not Cause Undue Dyspnea, Fatigue, Chest Pain, or Near Syncope
  • Functional Class II
    • Slight Limitation of Physical Activity
    • Comfortable at Rest
    • Ordinary Physical Activity Causes Undue Dyspnea, Fatigue, Chest Pain, or Near Syncope
  • Functional Class III
    • Marked Limitation of Physical Activity
    • Comfortable at Rest
    • Less than Ordinary Physical Activity Causes Undue Dyspnea, Fatigue, Chest Pain, or Near Syncope
  • Functional Class IV
    • Inability to Carry Out Any Physical Activity without Symptoms
    • Signs of Right-Sided Heart Failure
    • Dyspnea or Fatigue May Be Even Present at Rest
    • Discomfort is Increased by Any Physical Activity

Cardiovascular Manifestations

  • Angina (see Chest Pain, [[Chest Pain]]): due to compression of left main coronary artery by dilated pulmonary artery
  • Atypical Chest Pain (see Chest Pain, [[Chest Pain]])
  • Elevated Jugular Venous Pressure (JVP)
  • Increased Intensity of the Pulmonic Component of Second Heart Sound
  • Left Parasternal Lift/Heave
  • Palpitations (see Palpitations, [[Palpitations]])
  • RV Third Heart Sound
  • Signs of Right Ventricular Failure/Cor Pulmonale
  • Supraventricular Arrhythmias: occur with more advanced pulmonary hypertension (cumulative incidence: 25% over 5 years)
    • General Comments: atrial arrhythmias compromise cardiac output and may lead to clinical deterioration
    • Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])
    • Atrial Flutter (see Atrial Flutter, [[Atrial Flutter]])
  • Syncope (see Syncope, [[Syncope]]): particularly with bending over
  • Tricuspid Regurgitation Murmur (see Tricuspid Regurgitation, [[Tricuspid Regurgitation]])

Gastrointestinal Manifestations

  • Ascites/Abdominal Distention (see Ascites, [[Ascites]]): due to RV failure
  • Cardiac Cirrhosis (see xxxx, [[xxxx]]): due to RV failure
  • Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy, [[Congestive Hepatopathy]]): due to RV failure
  • Exercise-Induced Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]]): occasional
  • Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]]): due to RV failure

Neurologic Manifestations

  • Fatigue (see Fatigue, [[Fatigue]])

Otolaryngologic Manifestations

  • Hoarseness (see Hoarseness, [[Hoarseness]]): due to compression of the left recurrent laryngeal nerve by dilated pulmonary artery

Pulmonary Manifestations

  • Hemoptysis (see Hemoptysis, [[Hemoptysis]]): may occur in some cases due to rupture of hypertrophied bronchial arteries
  • Hypoxemia with Hypocapnia (see Hypoxemia, [[Hypoxemia]]): due to hyperventilation
  • Nocturnal Hypoxemia (see Hypoxemia, [[Hypoxemia]]): common in pulmonary hypertension (occurs in 70-80% of cases) [MEDLINE]
  • Central Sleep Apnea (CSA) (see Central Sleep Apnea, [[Central Sleep Apnea]]): common in pulmonary hypertension (occurs in 70-80% of cases) [MEDLINE]
  • Exertional Dyspnea (see Dyspnea, [[Dyspnea]]): due to inability to increase cardiac output during exercise
  • Wheezing: may occur in some cases due to large airway compression by dilated pulmonary artery

Rheumatologic Manifestations

  • Anasarca/Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]]): due to RV failure
  • Cool Extremities

Reproductive Manifestations

Increased Risk of Death with Pregnancy (see Pregnancy, [[Pregnancy]])

  • General Comments
    • Diagnosis of Pulmonary Hypertension May Be Delayed/Missed During Pregnancy: due to the dyspnea that occurs in normal pregnancy (that is believed to be related to high levels of circulating progesterone)
    • Pregnancy Increases the Mortality Rate in Pulmonary Hypertension: due to the increased physiologic demands of pregnancy and childbirth
      • Parturition and the First Postpartum Week are the Most Vulnerable Period for Pregnant Patients with Pulmonary Hypertension
  • Physiology
    • During Pregnancy, Cardiac Output Increases by Up to 30-50% Above Pregestational Levels (Begin During First Trimester and Peak During 20-24 wks of Gestation): stroke volume increases with decrease in systemic vascular resistance and blood pressure
    • During Pregnancy, Plasma Volume Increases by Up to 30-50% Above Pregestational Levels (Begin During First Trimester and Peak During 20-24 wks of Gestation)
    • During Pregnancy, Heart Rate Increases 10-20 Beats/min (Begin During First Trimester and Peak During 20-24 wks of Gestation)
    • During Delivery, Valsalva Manuever and Pain Increase the Heart Rate and Vascular Resistances
    • In Hours-Days Post-Parturition, Autotransfusion of Blood from Contracting Uterus and Shifting of Peripheral Edema from the Extravascular Compartment Back into the Systemic Vascular Space Occur
  • Clinical Data
    • Systematic Review of Mortality of Pulmonary Hypertension in Pregnancy (Eur Heart J, 2009) [MEDLINE]
      • Mortality Rate of Pulmonary Hypertension in Pregnancy Has Decreased from 30-56% (Mean: 38%) in the Articles Published in the Period 1978-1996 to 17-33% (Mean: 25%) in the Articles Published in the Period 1997-2006
      • 78% of Deaths Occurred Within the First Month After Delivery
      • Primigravidae and Parturients who Received General Anesthesia were at the Highest Risk of Death
    • Case Series of 18 Pregnant Patients with Pulmonary Hypertension (Chest, 2013) [MEDLINE]
      • 33% (6/18) Patients Had the Pregnancy Terminated in the First Trimester
        • None of These Patients Experienced Maternal Complications
      • 66% (12/18) Patients Received Care Consisting of Daily Fluid Restriction, Anticoagulation, Diuretics, and Supplemental Oxygen
        • Maternal Mortality Rate in This Group: 16.7% (this mortality rate is lower than previously reported and may be related to care early termination in a significant number of pregnant patients and for those who did not, care in a experienced pulmonary hypertension center)
        • 75% of Patients Received Pulmonary Hypertension-Specific Therapy Several Weeks Prior to Delivery

Increased Risk of Small-for-Gestational Age Infants

  • Epidemiology: demonstrated in women with idiopathic pulmonary arterial hypertension

Increased Risk of Congenital Anomalies

  • Epidemiology: has been reported

Increased Risk of Death with Mechanical Ventilation, General Anesthesia, and Surgical Procedures

  • Rate of Major Complications in Patients with Pulmonary Hypertension Undergoing Surgery: 6% (Anaesth Intensive Care, 2009) [MEDLINE]
  • Rate of Perioperative Mortality in Patients with Pulmonary Hypertension Undergoing Surgery: 3.5% (Anaesth Intensive Care, 2009) [MEDLINE]
  • Risk Factors Predicting Major Complications
    • 6-Minute Walk Test (6MWT) Distance ≤399 meters (see 6-Minute Walk Test, [[6-Minute Walk Test]]): odd ratio 2.2
    • Right Atrial Pressure >7 mm Hg: odds ratio 1.1
    • Emergency Surgery: odds ratio 2.4
    • Perioperative Use of Vasopressors: odds ratio 1.5

Treatment

General Measures

  • Avoidance of High Altitude (see High Altitude, [[High Altitude]])
    • Supplemental Oxygen Should Be Used at Altitude to Maintain SaO2 >91% (Grade CB Recommendation) (see Oxygen, [[Oxygen]]) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
  • Avoidance of Non-Essential Surgery (Grade CB Recommendation) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • If Surgery is Necessary, Should Be Performed at a Center Specializing in Pulmonary Hypertension Care and with Cardiovascular Anesthesia Services (Grade CB Recommendation)
  • Avoidance of Pregnancy (with Adequate Contraception) (see Pregnancy, [[Pregnancy]]) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • Estrogen-Containing Contraceptives Increase the Risk of Venous Thromboembolism and are Not Recommended for Women of Childbearing Age with Pulmonary Hypertension
    • Bosentan May Decrease the Efficacy of Hormonal Contraception
    • Termination of Pregnancy May Be Recommended in Specific High-Risk Cases
  • Tobacco Smoking Cessation (see Tobacco, [[Tobacco]]): crucial
  • Supplemental Oxygen (see Oxygen, [[Oxygen]]): as required
  • Pulmonary Rehabilitation (see Pulmonary Rehabilitation, [[Pulmonary Rehabilitation]]): as required
  • Vaccinations
    • Influenza Vaccination (Grade CB Recommendation) (see Influenza Virus, [[Influenza Virus]]) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • Pneumocccal Vaccination (Grade CB Recommendation) (see Streptococcus Pneumoniae, [[Streptococcus Pneumoniae]]) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
  • Recommendations-General Recommendations (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • Pulmonary Hypertension Should Be Evaluated Using a Combination of World Health Organization (WHO) Functional Class, Exercise Capacity, Echocardiogram, and Laboratory/Hemodynamic Variables (Grade CB Recommendation)
    • When Possible, All Pulmonary Hypertension Patients Should Be Evaluated at a Center with Expertise in the Diagnosis of Pulmonary Hypertension (Grade CB Recommendation)
    • Care of Pulmonary Hypertension Patients Should Be Coordinated Between Local Physicians and Those with Expertise in Pulmonary Hypertension Care (Grade CB Recommendation): may involve cardiologists, pulmonologists, rheumatologists, primary care, etc
  • Recommendations-Treatment Naive Patients without Symptoms (WHO Functional Class I) and Patients at Increased Risk for the Development of Pulmonary Hypertension (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • For Treatment Naive Patients without Symptoms (WHO Functional Class I), Continued Monitoring is Recommended to Detect Symptoms that Would Merit the Initiation of Pharmacotherapy (Grade CB Recommendation)
    • For Patients at Risk of the Development of Pulmonary Hypertension (Scleroderma, Known Mutation Associated with Pulmonary Hypertension), Patient Should Be Monitored to Detect Symptoms Consistent with Pulmonary Hypertension (Grade CB Recommendation)
    • Contributing Causes of Pulmonary Hypertension (Obstructive Sleep Apnea, Systemic Hypertension) Should Be Treated Aggressively in Patients with Pulmonary Hypertension (Grade CB Recommendation)

Recommended Therapies by WHO Functional Class (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]

WHO Functional Class II

  • For WHO Functional Class II Patients Who are Not Candidates for (or Who Have Failed) Calcium Channel Blocker Therapy, Monotherapy with Endothelin Receptor Antagonist, Phosphodiesterase Type 5 Inhibitor, or Soluble Guanylate Cyclase Stimulator is Recommended
    • Ambrisentan is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
    • Bosentan is Recommended to Delay the Time to Clinical Worsening (Grade CB Recommendation)
    • Macitentan is Recommended to Delay the Time to Clinical Worsening (Grade CB Recommendation)
    • Sildenafil is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
    • Tadalafil is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
    • Riociguat is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), Delay the Time to Clinical Worsening (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
  • Inhaled/Parenteral Prostanoids Should Not Be Chosen as the Initial Therapy for Treatment Naive WHO Functional Class II Patients or as Second-Line Agents for WHO Functional Class II Patients Who Have Not Met Their Treatment Goals (Grade CB Recommendation)

WHO Functional Class III

  • For Treatment Naive WHO Functional Class III Patients, Who are Not Candidates for (or Who Have Failed) Calcium Channel Blocker Therapy, Monotherapy with Endothelin Receptor Antagonist, Phosphodiesterase Type 5 Inhibitor, or Soluble Guanylate Cyclase Stimulator is Recommended
    • Ambrisentan is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
    • Bosentan is Recommended to Increase 6MWT Distance (Grade 1B Recommendation)
    • Bosentan is Recommended to Decrease Hospitalizations Related to Pulmonary Hypertension in the Short-Term (Grade 2C Recommendation) and to Improve Cardiopulmonary Hemodynamics
    • Macitentan is Recommended to Improve WHO Functional Class (Grade CB Recommendation) and Delay the Time to Clinical Worsening (Grade CB Recommendation)
    • Sildenafil is Recommended to Increase 6MWT Distance (Grade 1C Recommendation), to Improve WHO Functional Class (Grade CB Recommendation), and to Improve Cardiopulmonary Hemodynamics
    • Tadalafil is Recommended to Increase 6MWT Distance (Grade CB Recommendation), to Improve WHO Functional Class (Grade CB Recommendation), to Delay the Time to Clinical Worsening (Grade CB Recommendation), and to Improve Cardiopulmonary Hemodynamics
    • Riociguat is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), Delay the Time to Clinical Worsening (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
  • For Treatment Naive WHO Functional Class III Patients Who Have Evidence of Rapid Progression or Other Markers of Poor Clinical Prognosis, Parenteral Prostanoid Should Be Initially Considered
    • Eposprostenol (Continuous IV) is Recommended to Improve WHO Functional Class (Grade CB Recommendation), Increase 6MWT Distance (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
    • Treprostinil (Continuous IV) is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
    • Treprostinil (Continuous SQ) is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve Cardiopulmonary Hemodynamics
  • For WHO Functional Class III Patients Who Have Evidence of Disease Progression and/or Other Markers of Poor Clinical Prognosis Despite Treatment with One of Two Classes of Oral Agents, Inhaled or Parenteral Prostanoid Should Be Considered
    • Eposprostenol (Continuous IV) is Recommended to Improve WHO Functional Class (Grade CB Recommendation), Increase 6MWT Distance (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
    • Treprostinil (Continuous IV) is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve Cardiopulmonary Hemodynamics
    • In Patients Who Remain Symptomatic on Stable and Appropriate Doses of an Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, the Addition of Inhaled Treprostinil is Recommended to Increase 6MWT Distance (Grade 2C Recommendation
      • Usual Initial Dose of Inhaled Treprostinil is 3 Inhalations (18 mg) q6hrs: however, optimal effect of inhaled treprostinil may require titrating dose up to 9 inhalations (54 mg) q6hrs
    • In Patients Who Remain Symptomatic on Stable and Appropriate Doses of an Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, the Addition of Inhaled Iloprost is Recommended to Improve WHO Functional Class (Grade CB Recommendation) and Delay the Time to Clinical Worsening (Grade CB Recommendation)
  • In Patients Initiating Eposprostenol (Continuous IV) Therapy, Routine Simultaneous Initiation of Bosentan is Not Recommended (Grade CB Recommendation)

WHO Functional Class IV

  • For Treatment Naive WHO Functional Class IV Patients, Monotherapy with a Parenteral Prostanoid is Recommended
    • Eposprostenol (Continuous IV) is Recommended to Improve WHO Functional Class (Grade CB Recommendation), Increase 6MWT Distance (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
    • Treprostinil (Continuous IV) is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
    • Treprostinil (Continuous SQ) is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve Cardiopulmonary Hemodynamics
  • For Treatment Naive WHO Functional Class IV Patients Who are Unable or Do Not Desire to Manage Parenteral Prostanoid Therapy, Inhaled Prostanoid in Combination with an Endothelin Receptor Antagonist is Recommended
    • Bosentan is Recommended to Increase 6MWT Distance (Grade 2B Recommendation) and Improve Cardiopulmonary Hemodynamics
    • Inhaled Iloprost is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve WHO Functional Class (Grade CB Recommendation)
    • Inhaled Treprostinil (in Combination Only) is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
  • In Patients Initiating Eposprostenol (Continuous IV) Therapy, Routine Simultaneous Initiation of Bosentan is Not Recommended (Grade CB Recommendation)

WHO Functional Class III or IV with Unacceptable Clinical Status Despite Established Pulmonary Hypertension-Specific Monotherapy

  • In Patients with WHO Functional Class III or IV with Unacceptable Clinical Status Despite Established Pulmonary Hypertension-Specific Monotherapy, Addition of a Second Class of Pulmonary Hypertension Therapy is Recommended to Improve Exercise Capacity: these patients are best evaluated at specialized pulmonary hypertension centers
    • In Patients Who Remain Symptomatic on Stable Doses of Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, Addition of Inhaled Iloprost is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
    • In Patients Who Remain Symptomatic on Stable Doses of Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, Addition of Inhaled Treprostinil is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
      • Usual Initial Dose of Inhaled Treprostinil is 3 Inhalations (18 mg) q6hrs: however, optimal effect of inhaled treprostinil may require titrating dose up to 9 inhalations (54 mg) q6hrs
    • In Patients Who Remain Symptomatic on Stable Doses of Eposprostenol (Continuous IV), Addition of Sildenafil or Uptitration is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
    • In Patients Who Remain Symptomatic on Stable Doses of Bosentan/Ambrisentan/Inhaled Prostanoid, Addition of Soluble Guanylate Cyclase Stimulator is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics and Delay the Time to Clinical Worsening (Grade CB Recommendation)
    • In Patients Who Remain Symptomatic on Stable Doses of Phosphodiesterase Type 5 Inhibitor or Inhaled Prostanoid, Macitentan is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), and Delay the Time to Clinical Worsening (Grade CB Recommendation)
  • In Patients with WHO Functional Class III or IV with Unacceptable or Deteriorating Clinical Status Despite Established Pulmonary Hypertension-Specific Therapy with Two Classes of Pharmacotherapy, Addition of a Third Class of Pulmonary Hypertension Therapy is Recommended (Grade CB Recommendation): these patients are best evaluated at specialized pulmonary hypertension centers

Calcium Channel Blockers (see Calcium Channel Blockers, [[Calcium Channel Blockers]])

  • Agents
    • Nifedipine (Procardia, Adalat) (see Nifedipine, [[Nifedipine]])
  • Use in Pregnancy: may be used
  • Recommendations (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
    • In the Absence of Contraindications, All Patients with Pulmonary Hypertension Should Undergo Acute Vasoreactivity Testing with a Short-Acting Pulmonary Vasodilator at a Center Experienced in Performing Such Testing (Grade CB Recommendation)
    • Patients with Vasoreactive Pulmonary Hypertension without Contraindications to Calcium Channel Blocker Should Be Considered for a Trial of Oral Calcium Channel Blocker Therapy (Grade CB Recommendation)
    • Calcium Channel Blockers Should Not Be Used Empirically to Treat Pulmonary Hypertension without Evidence of Pulmonary Vasoreactivity (Grade CB Recommendation)

Prostacyclin Analogues (Prostanoids)

General Comments

  • Clinical Efficacy: when used as monotherapy, prostanoids generally have more significant impact on pulmonary hypertension mortality than do other classes of agents
    • Meta-Analysis of Pulmonary Hypertension Therapies (Eur Heart J, 2009) [MEDLINE]
      • Treatment with Prostanoid, Endothelin Receptor Antagonist, or Phosphodiesterase Type 5 Inhibitor Improved mortality, as Compared to Control

Epoprostenol (PGI2, Prostacyclin, Flolan, Veletri) (see Epoprostenol, [[Epoprostenol]])

  • Clinical Efficacy
    • When Used as Monotherapy, Prostacyclin Analogues Generally Have More Significant Impact on Pulmonary Hypertension Mortality Than Do Other Classes of Agents
      • Epoprostenol has been shown to decrease pulmonary hypertension mortality rates (J Am Coll Cardiol, 2002) [MEDLINE]
  • Administration
    • IV: xxx
  • Use in Pregnancy: may be used
  • Adverse Effects
    • Hypotension (see Hypotension, [[Hypotension]])
    • Jaw Pain

Inhaled Iloprost (Ilomedin, Ventavis) (see Iloprost, [[Iloprost]])

  • Pharmacology: longer half life and has fewer systemic side effects than epoprostenol, because of local delivery to the lungs
  • Clinical Efficacy
    • When Used as Monotherapy, Prostacyclin Analogues Generally Have More Significant Impact on Pulmonary Hypertension Mortality Than Do Other Classes of Agents
    • Improves 6-Minute Walk Distance and Pulmonary Hemodynamics
  • Administration
    • INH: xxx
  • Adverse Effects
    • xxx

Treprostinil (Remodulin, Tyvaso) (see Treprostinil, [[Treprostinil]])

  • Clinical Efficacy
    • When Used as Monotherapy, Prostacyclin Analogues Generally Have More Significant Impact on Pulmonary Hypertension Mortality Than Do Other Classes of Agents
    • Improves 6-Minute Walk Distance and Pulmonary Hemodynamics
  • Administration
    • INH: initial dose of 3 inhalations (18 mg) q6hrs -> however, optimal effect of inhaled treprostinil may require titrating dose up to 9 inhalations (54 mg) q6hrs
    • IV: xxx
    • SQ: xxx
  • Adverse Effects
    • xxx

Endothelin Receptor Antagonists (see Endothelin Receptor Antagonists, [[Endothelin Receptor Antagonists]])

General Comments

  • Clinical Efficacy
    • Meta-Analysis of Pulmonary Hypertension Therapies (Eur Heart J, 2009) [MEDLINE]
      • Treatment with Prostanoid, Endothelin Receptor Antagonist, or Phosphodiesterase Type 5 Inhibitor Improved mortality, as Compared to Control
    • Meta-Analysis of Oral Therapies for Pulmonary Hypertension (Am Heart J, 2015) [MEDLINE]
      • Oral Agents Decreased “Combined Clinical Worsening” Events, But Had Less Favorable Effects on Mortality Rate

Ambrisentan (Letairis) (see Ambrisentan, [[Ambrisentan]])

  • Contraindications
    • Pregnancy (Category X Agent) (see Pregnancy, [[Pregnancy]])
  • Clinical Efficacy
    • AMBITION Trial (NEJM, 2015) [MEDLINE]
      • Initial Ambrisentan and Tadalafil Resulted in Significantly Decreased Risk of Clinical Failure Events than with Each Agent Alone

Bosentan (Tracleer) (see Bosentan, [[Bosentan]])

  • Contraindications
    • Pregnancy (Category X Agent) (see Pregnancy, [[Pregnancy]])
  • Adverse Effects

Macitentan (Opsumit) (see Macitentan, [[Macitentan]])

  • Contraindications
    • Pregnancy (Category X Agent) (see Pregnancy, [[Pregnancy]])
  • Clinical Efficacy
    • Randomized Controlled Trial of Macitentan in Symptomatic Pulmonary Hypertension (NEJM, 2013) [MEDLINE]
      • Macitentan Improved Morbidity and Mortality in Pulmonary Hypertension: this is unique, as other non-prostacyclin analogue agents have not been demonstrated to have a mortality benefit in the treatment of pulmonary hypertension

Phosphodiesterase Type 5 Inhibitors (see Phosphodiesterase Type 5 Inhibitors, [[Phosphodiesterase Type 5 Inhibitors]])

General Comments

  • Clinical Efficacy
    • Meta-Analysis of Pulmonary Hypertension Therapies (Eur Heart J, 2009) [MEDLINE]
      • Treatment with Prostanoid, Endothelin Receptor Antagonist, or Phosphodiesterase Type 5 Inhibitor Improved mortality, as Compared to Control
    • Meta-Analysis of Oral Therapies for Pulmonary Hypertension (Am Heart J, 2015) [MEDLINE]
      • Oral Agents Decreased “Combined Clinical Worsening” Events, But Had Less Favorable Effects on Mortality Rate

Sildenafil (Viagra, Revatio) (see Sildenafil, [[Sildenafil]])

  • Use in Pregnancy: may be used
  • Clinical Efficacy
    • Improve 6-Minute Walk Distance and Pulmonary Hemodynamics

Tadalafil (Adcirca, Cialis) (see Tadalafil, [[Tadalafil]])

  • Use in Pregnancy: may be used
  • Clinical Efficacy
    • Improves 6-Minute Walk Distance and Pulmonary Hemodynamics
    • AMBITION Trial (NEJM, 2015) [MEDLINE]: initial ambrisentan and tadalafil resulted in significantly decreased risk of clinical failure events than with J each agent alone

Riociguat (Adempas) (see Riociguat, [[Riociguat]])

  • Contraindications
    • Pregnancy (Category X Agent) (see Pregnancy, [[Pregnancy]])
  • Pharmacology
    • Soluble Guanylate Cyclase Stimulator
  • Clinical Efficacy
    • PATENT-1 Study of Riociguat in Symptomatic Pulmonary Hypertension (NEJM, 2013) [MEDLINE]
      • Riociguat Improved Exercise Capacity (6-Minute Walk Test)
      • Riociguat Improved Pulmonary Vascular Resistance (PVR)
      • Riociguat Decreased NT Pro-BNP Levels
      • Riociguat Improved WHO Functional Class
      • Riociguat Improved Time to Clinical Worsening
      • Riociguat Improved Borg Dyspnea Score
    • Meta-Analysis of Oral Therapies for Pulmonary Hypertension (Am Heart J, 2015) [MEDLINE]
      • Oral Agents Decreased “Combined Clinical Worsening” Events, But Had Less Favorable Effects on Mortality Rate

Diuretics

  • Agents
    • Loop Diuretics
      • Bumetanide (Bumex) (see Bumetanide, [[Bumetanide]])
      • Furosemide (Lasix) (see Furosemide, [[Furosemide]])
  • Clinical Efficacy: no impact on pulmonary hypertension mortality

Inhaled Nitric Oxide (iNO) (see Nitric Oxide, [[Nitric Oxide]])

  • Use in Pregnancy: may be used
  • Indications
    • Decompensated Pulmonary Hypertension (CTEPH): particularly in the ICU setting

Lung Transplantation (see Lung Transplant, [[Lung Transplant]])

  • Indications
    • xxx

Specific Management of Pulmonary Hypertension During Pregnancy

  • Anticoagulation
    • Low Molecular Weight Heparin
      • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
    • Unfractionated Heparin (see Heparin, [[Heparin]])
  • Cesarean Section (C-Section) Delivery (see Cesarean Section, [[Cesarean Section]])
    • Although Vaginal Delivery is, in General, Associated with Fewer Bleeding Complications and Infections, C-Section in Pregnant Pulmonary Hypertension Patients Avoids Prolonged Labor, Allows Preparation of Anesthesia, Allows More Precise Optimization of Hemodynamics, and Allows Development of Contingency Plans (Should Problems Arise)
    • C-Section Does Not Appear to Negatively Impact Outcome in Pregnant Pulmonary Hypertension Patients
    • Regional Anesthesia is Preferred Over General Anesthesia: due to a lesser effect on systemic vascular tone and cardiac function
  • Diuretic Administration During the 3rd Trimester
    • Agents
      • Loop Diuretics
        • Bumetanide (Bumex) (see Bumetanide, [[Bumetanide]])
        • Furosemide (Lasix) (see Furosemide, [[Furosemide]])
  • Early Initiation of Pulmonary Vasodilator Therapy
    • Epoprostenol (Prostacyclin, Flolan) (see Epoprostenol, [[Epoprostenol]])
    • Phosphodiesterase Type 5 Inhibitors are FDA Pregnancy Category B Agents (see Phosphodiesterase Type 5 Inhibitors, [[Phosphodiesterase Type 5 Inhibitors]]): acceptable for use
      • Sildenafil (Viagra, Revatio) (see Sildenafil, [[Sildenafil]])
      • Tadalafil (Adcirca, Cialis) (see Tadalafil, [[Tadalafil]])
    • Endothelin Receptor Antagonists are Contraindicated in Pregnancy (see Endothelin Receptor Antagonists, [[Endothelin Receptor Antagonists]]): due to teratogenicity
    • Riociguat (Adempas) is Contraindicated in Pregnancy (see Riociguat, [[Riociguat]]): due to teratogenicity
  • Fluid Restriction to 1.5-2.0L Per Day: especially during the 3rd trimester
  • Sodium Restriction
  • Management of Pregnancy in a Center Specializing in Pulmonary Hypertension Care and with High-Risk Obstetrical and Cardiovascular Anesthesia Services (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]

Specific Management of Hypotension Associated with Right Ventricular Failure

Strategies to Decrease Pulmonary Artery Pressures and/or Decrease RV Afterload

  • Ventilatory Strategies
    • Avoid Acidosis (see Metabolic Acidosis-General, [[Metabolic Acidosis-General]])
      • Acidosis Enhances Hypoxic Pulmonary Vasoconstriction
    • Avoidance of Hypoxemia/Hypoxia (see Hypoxemia, [[Hypoxemia]])
      • Hypoxemia Induces Pulmonary Vasoconstriction
      • Hypoxic Pulmonary Vasoconstriction is Enhanced by Acidosis
    • Avoidance of Hypercapnia (see Hypercapnia, [[Hypercapnia]])
      • Hypercapnia Induces Pulmonary Vasoconstriction: this effect may be attenuated by nitric oxide
      • Hypercapnic Pulmonary Vasoconstriction with High PEEP in ARDS May Lead to RV Dilatation and Decreased Cardiac Output (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])
    • Avoidance of Compression of Pulmonary Vasculature at the Very Low Tidal Volumes (or in Areas of Atelectasis) (see Hemodynamics, [[Hemodynamics]]): at low lung volumes/with atelectasis, capillaries are compressed -> this increases PVR
    • Avoidance of Compromise of Pulmonary Vasculature at Very High Tidal Volumes or with High Plateau Pressure (see Hemodynamics, [[Hemodynamics]]): at high tidal volume/high plateau pressure, capillaries are stretched, decreasing their caliber -> this increases PVR
  • Pharmacologic Strategies
  • Mechanical Strategies
    • Atrial Septostomy (see Atrial Septostomy, [[Atrial Septostomy]])
      • Has Been Used as a Bridge to Transplantation in Severe Pulmonary Hypertension (Although Not in Patients with Very Severe RV Failure)
      • Creates a Right-to-Left Intracardiac Shunt: improves LA filling and LV function, decreases RV end-diastolic pressure, and improves RV contractility
    • Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) (see Extracorporeal Membrane Oxygenation, [[Extracorporeal Membrane Oxygenation]])
      • Has Been Used in the Setting of Severe Pulmonary Hypertension, as a Bridge to Transplant, After Pulmonary Endarterectomy, with Massive Acute PE
    • Intra-Aortic Balloon Pump (IABP) (see Intra-Aortic Balloon Pump, [[Intra-Aortic Balloon Pump]])
      • Has Been Used for RV Dysfunction After Cardiopulmonary Bypass (CPB) and Transplantation
      • Augments Left Coronary Artery Blood Flow: does not have direct effects on the RV
    • Right Ventricular Assist Device (RVAD) (see Ventricular Assist Device, [[Ventricular Assist Device]])

Clinical Efficacy

  • Systematic Review of Treatments of RV Dysfunction in the Critical Care Setting (Crit Care, 2010) [MEDLINE]
    • Monitoring of the RV is Advised as Volume Loading May Worsen RV Performance (Weak Recommendation, Very Low-Quality Evidence)
    • Low-Dose Norepinephrine is an Effective Pressor for Patients with RV Dysfunction (Weak Recommendation, Low-Quality Evidence)
    • Low-Dose Vasopressin May Be Useful to Manage Patients with Resistant Vasodilatory Shock
    • Low-Dose Dobutamine (<10 μg/kg/min) Improves RV Function in Pulmonary Vascular Dysfunction (Weak Recommendation, Low to Moderate-Quality Evidence)
    • Phosphodiesterase Type III Inhibitors (Enoximone, Milrinone, Amrinone) Decrease PVR and Improve RV Function (Although Hypotension is Frequent) (Strong Recommendation, Moderate-Quality Evidence)
    • Levosimendan May Be Useful for Short-term Improvement in RV Function (Weak Recommendation, Low-Quality Evidence)
    • Pulmonary Vasodilators Decrease PVR and Improve RV Function (Especially with Pulmonary Vascular Dysfunction Post-Cardiac Surgery (Strong Recommendation, Moderate-Quality Evidence)
      • Side Effects are Decreased by Using Inhaled Agents (Inhaled Nitric Oxide, Inhaled Iloprost, Inhaled Prostacyclin-Epoprostenol, Nebulized Milrinone), as Compared to Systemic Agents
    • Mechanical Therapies (Right Ventricular Assist Device, Venoarterial Extracorporeal Membrane Oxygenation, Intra-Aortic Balloon Pump) May Be Useful as Rescue Therapy in Some Settings of Pulmonary Vascular Dysfunction Awaiting Definitive Therapy (Weak Recommendation, Very Low-Quality Evidence)

Prognosis

Overall Mortality Rates

  • From 1980-2002: pulmonary hypertension mortality rate has increased from 5.2 -> 5.4 per 100,000 [MEDLINE]
    • Greatest rate of increase has been observed in African-Americans and women

Group 1

  • Group 1 Patients Have Overall Worse Survival Than Groups 2-5: of note, group 4 (chronic thromboembolic pulmonary hypertension) survival is dependent on candidacy for pulmonary thromboendarterectomy (which may be curative)
    • There are variable survival rates across the group 1 etiologies: for example, mortality rates for scleroderma-associated pulmonary hypertension is worse than that for idiopathic pulmonary arterial hypertension (particularly when associated with co-existent interstitial lung disease)
  • Median Survival in Idiopathic Pulmonary Arterial Hypertension (Untreated): approximately 3 years
  • Predictors of Poor Survival
    • Age >45 y/o
    • BMPR2 Mutations
    • Comorbid Conditions: COPD, diabetes mellitus
    • Decreased Pulmonary Arterial Capacitance: stroke volume divided by the pulmonary arterial pulse pressure
    • Echocardiographic findings of Pericardial Effusion/Large Right Atrial Size, Elevated Right Atrial Pressure, or Septal Shift During Diastole
    • Failure to Improve to a Lower WHO Functional Class During Treatment
    • Hypocapnia
    • Increased NT-Pro-BNP
    • Low Right Ventricular Ejection Fraction (<25%) as determined by planar radionuclide angiography
    • Low Von Willebrand Factor Levels
    • Male Sex
    • Poor Right Ventricular Contractile Reserve: determined by an increase in pulmonary artery systolic of <30 mm Hg with exercise on stress echocardiogram
    • Prolonged QRS Duration
    • Selective Serotonin Reuptake Inhibitors (SSRI)
    • Supraventricular Arrhythmias: persistent atrial fibrillation/atrial flutter
    • WHO Functional Class III-IV

Groups 2-5

  • Prognosis Varies with That of the Underlying Disease

References

General

  • Pulmonary Arterial Hypertension: Screening, Management, and Treatment [Internet] [MEDLINE]
  • Role of hypoxia in the pulmonary hypertension of chronic bronchitis and emphysema. Scand J Respir Dis Suppl. 1971;77:61 [MEDLINE]
  • Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–223 [MEDLINE]
  • Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 1992 Jun 1;116(11):888-95 [MEDLINE]
  • Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-744 [MEDLINE]
  • Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest 2001;120:894-899 [MEDLINE]
  • Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 2003;41:1028-1035
  • Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(Suppl 1):S5–S12 [MEDLINE]
  • Pulmonary hypertension surveillance–United States, 1980-2002. MMWR Surveill Summ. 2005;54(5):1 [MEDLINE]
  • Pulmonary arterial hypertension in ANCA-associated vasculitis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:223–8 [MEDLINE]
  • Pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:1527-1538 [MEDLINE]
  • Pulmonary hypertension: an increasingly recognized complication of hereditary hemolytic anemias and HIV infection. JAMA. 2008;299:324-331 [MEDLINE]
  • Updated Clinical Classification of Pulmonary Hypertension. J Am Coll Cardiol 2009; 54: S43-S45 [MEDLINE]
  • Role of obesity in cardiomyopathy and pulmonary hypertension. Clin Chest Med. 2009 Sep;30(3):509-23 [MEDLINE]
  • Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-2497 [MEDLINE]
  • Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(Suppl):S32-S42 [MEDLINE]
  • Anaesthesia and right ventricular failure. Anaesth Intensive Care. 2009 May;37(3):370-85 [MEDLINE]
  • Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J. 2009;30(3): 256-265 [MEDLINE]
  • Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010;181:851-861 [MEDLINE]
  • Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 2011; 32:1385-1389 [MEDLINE]
  • Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms. J Obes. 2012;2012:505274. Epub 2012 Sep 3 [MEDLINE]
  • Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 2012;5:336-343 [MEDLINE]
  • Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-41 [MEDLINE]
  • High occurrence of hypoxemic sleep respiratory disorders in precapillary pulmonary hypertension and mechanisms. Chest 2013;143:47-55 [MEDLINE]
  • Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur Respir J 2013;42:1575–1585
  • A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013;369:351-361 [MEDLINE]
  • Scope of problem of pulmonary arterial hypertension. Am J Med. 2015;128(8):844 [MEDLINE]
  • 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29 [MEDLINE]

Treatment

  • Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980 Sep;93(3):391-8 [MEDLINE]
  • Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780 [MEDLINE]
  • Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896 [MEDLINE]
  • Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev 2006;3:CD00-4434 [MEDLINE]
  • A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394 [MEDLINE]
  • Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493-2537 [MEDLINE]
  • Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169 [MEDLINE]
  • Riociguat for chronic thomboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010;36:792-799 [MEDLINE]
  • Safety, tolerability, pharmacokinetics and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple dose study in healthy subjects. J Clin Pharmacol 2013;53(11):1131-1138 [MEDLINE]
  • Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917 [MEDLINE]
  • CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657 [MEDLINE]
  • PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655 [MEDLINE]
  • Management of pulmonary arterial hypertension during pregnancy. A retrospective, multicenter experience. Chest. 2013 May; 143(5): 1330–1336 [MEDLINE]
  • Idiopathic pulmonary arterial hypertension. Semin Respir Crit Care Med. 2013 Oct;34(5):560-7. doi: 10.1055/s-0033-1355439. Epub 2013 Sep 13 [MEDLINE]
  • Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults. CHEST Guideline and Expert Panel Report. Chest. 2014 Aug; 146(2): 449–475 [MEDLINE]
  • Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Am J Health Syst Pharm. 2014 Nov 1;71(21):1839-44. doi: 10.2146/ajhp130777 [MEDLINE]
  • What’s new: the management of acute right ventricular decompensation of chronic pulmonary hypertension. Intensive Care Med. 2014;40:1930–1933 [MEDLINE]
  • Current treatment approaches to pulmonary arterial hypertension. Can J Cardiol. 2015;31:460–477 [MEDLINE]
  • Perspectives on oral pulmonary hypertension therapies recently approved by the U.S. Food and Drug Administration. Ann Am Thorac Soc. 2015;12:269–273 [MEDLINE]
  • Effects of oral treatments on clinical outcomes in pulmonary arterial hypertension: A systematic review and meta-analysis. Am Heart J. 2015 Jul;170(1):96-103, 103.e1-14. doi: 10.1016/j.ahj.2015.04.003. Epub 2015 Apr 9 [MEDLINE]
  • AMBITION Trial. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug;373(9):834-844 [MEDLINE]