Primary pulmonary hypertension

I. What every physician needs to know.

PPH is the former collective name of a group of pulmonary arterial hypertension (PAH) disorders including idiopathic PAH (IPAH), heritable PAH (HPAH) and anorexigen-induced PAH.

This is part of the Group I in the revised WHO Pulmonary Hypertension (PH) classification based on the most recent concensus.

The basic pathophysiology is thought to be endothelial dysfunction, with disregulation and imbalance of vasocontrictors, vasodilators, various mediators and cytokines, proliferation and apoptosis – at the capillary, precapillary and smooth muscle cell levels. This contributes to abnormal smooth muscle growth into arterioles, with luminal narrowing, increased pulmonary vascular resistance and pressure, decreased pulmonary autoregulation and ultimately, resultant increase in larger arterial and RV pressures, finally leading to RV failure.

II. Diagnostic Confirmation: Are you sure your patient has Primary Pulmonary Hypertension?

PAH is defined by a resting mean pulmonary artery pressure (mPAP) of greater than 25mmHg, pulmonary vascular resistance (PVR) greater than 3 Wood units and pulmonary capillary wedge pressure (PCWP) of less than 15mmHg – in the absence of other causes of PH.

In idiopathic PAH (IPAH) – there is lack of typical risk factors or family history.

In heritable type (HPAH) – there is a family history of disease. In most cases (up to 70%), there is a mutation of BMPR2 (bone morphogenetic protein type-2) receptor. Mutations in activin-receptor like kinase 1 (ALK-1) and endoglin receptor have also been associated with heritable PAH. Single-nucleotide polymorphisms (SNPs) are also recognized.

In the remainder of familial cases, there are no identified mutations.

In anorexigen induced PAH, exposure to drugs such as fenfluramine, desfenfluramine (developed in 1980s), aminorex fumarate (noted in Europe in 1960s) for at least 3 months has contributed to PAH. Other drugs/toxins contributing to PAH include L-tryptophan, cocaine, rapeseed oil and methamphetamines.

Patients with pulmonary hypertension, regardless of the cause, can be identified based on comprehensive history, physical exam findings and diagnostic studies.

Many patients, unfortunately, are diagnosed in the later stages of disease.

A. History Part I: Pattern Recognition:

Patients with classic pulmonary hypertension will complain of:

  • Dyspnea – most common symptom, especially dyspnea with exertion

  • Fatigue

In advanced cases, additional symptoms of RV failure will be present:

  • Peripheral edema

  • Chest pain

  • Syncope

Other coexistent symptoms such as chronic cough, snoring, sleep abnormalities, excessive daytime sleepiness, esophageal/swallowing disorders, wheezing, liver dysfunction, etc, will point to other diseases that may be contributing to secondary pulmonary hypertension.

B. History Part 2: Prevalence:

Heritable PAH (HPAH) has a strong genetic basis. Approximately 70% of involved families have an autosomal dominant BMPR2 mutation (gene located in chromosome 2, in region of q31-33).

Mutations in other regions including ALK1 and ENG, also associated with hereditary hemorrhagic telangiectasia (HHT), have also been identified.

Mutations of BMPR2 also contribute to approximately 10% of IPAH cases, either through inheritance with low penetrance or through de novo mutations and up to 15% of fenfluramine-related PAH.

Prevalence of IPAH is approximately 6 per million.

Disease onset can occur at any age, even in HPAH cases, due to variation in penetrance and disease expressivity. There is a strong female predominance (>2 :1 female:male ratio). Due to genetic anticipation in some families, generations that express the PAH phenotype may tend to express it earlier and exhibit more advanced disease.

A good social and occupational history should be obtained from all patients to exclude other causes of PAH due to medications (e.g., fenfluramine), drugs (e.g., cocaine), risk factors for HIV, tobacco use (with signs of COPD), occupational exposures, etc.

C. History Part 3: Competing diagnoses that can mimic Primary Pulmonary Hypertension.

IPAH and HPAH are similar to each other from a clinical and pathological perspective. It has been suggested that patients with some BMPR2 mutations have more severe disease.

Differential diagnoses of IPAH/HPAH:

1) PH caused by other etiology (see secondary causes) – complete history, physical exam and investigation will help identify or exclude potential underlying contributing diseases.

2) Congestive heart failure due to LV dysfunction – patients will have predominantly left sided heart failure signs and symptoms, including bibasilar crackles on lung exam. Echocardiography can help confirm systolic or diastolic dysfunction.

3) Coronary artery disease (CAD) – patients may also present with dyspnea on exertion and have fatigue/chest pain, but will not have pedal edema – typical history, EKG changes, cardiac markers and stress testing will help identify patients with CAD.

4) Aortic stenosis (AS) – patients will have similar symptoms on exam. Typical AS murmur is a crescendo-decrescendo systolic murmur best heard in right second intercostal space, with radiation to carotids and delayed carotid upstroke. Echocardiography can confirm AS.

D. Physical Examination Findings.

Neck – elevated JVP, possible hepatojugular reflux.

Cardiopulmonary exam findings – resting tachycardia (in more advanced cases), increased pulmonic heart sound P2, S3/S4, TR murmur (ejection systolic murmur at left lower sternal border).

Abdomen – hepatomegaly, ascites in more severe cases.

Extremities – pedal edema.

E. What diagnostic tests should be performed?


1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There is no diagnostic lab test confirming PAH.

However, some biomarkers thought to be predictors of prognosis in group 1 PAH include uric acid, brain natriuretic peptide (BNP), N-terminus fragment (NT)-proBNP, anticentromere antibodies and serum creatinine. Other biomarkers associated with PAH include thyroid tests, anticardiolipin antibodies and ANA.

An arterial blood gas (ABG) usually demonstrates normal paO2 at rest and hypoxemia with exercise. Daytime hypocapnea at rest and exertion is a mortality predictor. The presence of hypercapnia or more severe hypoxemia may also help indicate the presence of other underlying cardiopulmonary disorders.

Other basic lab tests should also be performed such as complete blood count, comprehensive metabolic panel, thyroid function testing, screening for autoimmune disorders, HIV/hepatitis testing, urine/serum tox screens will help exclude anemia, renal/hepatic dysfunction, collagen diseases, infectious diseases, etc, that may yield an alternative diagnosis for non-specific symptoms such as dyspnea, fatigue, etc, or diagnosis of underlying diseases that may be associated with secondary PH.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Tests considered essential for initial evaluation of PAH include EKG, CXR, echocardiogram, VQ Scan (or CT angiogram), pulmonary function tests (PFTs), overnight oximetry, functional tests (including 6 minute walk test or cardiopulmonary exercise testing) and ultimately, right heart catheterization.

These tests with findings seen in PAH patients are listed below:

1.Electrocardiogram (EKG)- right axis deviation, right atrial enlargement, right ventricular hypertrophy, signs of RV strain due to S1, Q3,T3 (S wave in lead 1, q wave in lead 3 and t inversion in lead 3).

Unable to use as a screening test, but may help support findings of RV strain/failure.

2.Chest x-ray(CXR) – enlargement of main pulmonary arteries and hilum, “peripheral pruning” of distal pulmonary arteries due to obliteration, and pulmonary artery calcification.

Unable to use as a screening test, but may also help evaluate for/exclude the presence of other cardiopulmonary disorders.

3.Pulmonary function testing- Up to 50% of patients show restrictive defects, with reduction in diffusing capacity for carbon monoxide (DLCO).

4.Functional tests:

a) 6 minute walk test (6MWT) – helps classify patients based on WHO functional classification (SeeTable I) and helps determine prognosis and supplemental O2 needs.

b) Cardiopulmonary exercise testing (CPET) – PAH patients have decreased exercise capacity and peak O2 uptake, decreased lactic acidosis threshold and decreased mixed venous O2 saturation at maximum exercise. The 6MWT is preferred to CPET due to ease, similar end point and reproducibility.

5.Echocardiography- Noninvasive screening test and essential in initial diagnosis of PAH. Estimates pulmonary artery pressure (PAP) and degree of pulmonary hypertension. Also helps in evaluation of RV ejection fraction, right atrial/ventricular enlargement and dysfunction and tricuspid regurgitation. Pericardial effusion, if present, predicts severity and mortality.

6.VQ Scanning- Screens for presence of thromboembolic disease, which is absent in PAH patients (if present, pt belongs in Group 4 of PH classification). If abnormal, further evaluation with CT Scan/pulmonary angiography can be performed.

7.Computed tomography scanning- May show prominent/enlarged pulmonary arteries, calcification, mosaic attenuation, RV hypertrophy and occasional diffuse micronodules in IPAH. Will also determine if there are thromboemboli or other pulmonary parenchymal or mediastinal abnormalities.

In presence of renal dysfunction, noncontrast CT can be performed for further evaluation of non-thromboembolic processes.

8.Magnetic resonance imaging (MRI) – evaluates RV size and function, pulmonary artery stiffness and pulmonary perfusion. This is not part of standard testing yet, but continues to be in evolution.

9.Right heart catheterization (RHC) -gold standard test for final diagnosis/confirmation of PAH. Degree of severity of PAH can be categorized, with confirmation of RV function. Helps establish accurate hemodynamic assessments and can be used for vasodilator testing for initial treatment/prognostication purposes.

This is performed at rest and the potential of exercise RHC is being researched.

Table I.
Class I No limitation in physical activity
Class II Slight limitation in physical activity. No symptoms at rest. Ordinary physical activity causes dysnpea/fatigue/chest pain or near syncope
Class III Marked limitation in physical activity. No symptoms at rest. Less than ordinary physical activity causes dyspnea/fatigue/chest pain or near syncope
Class IV Severe limitation in physical activity. Symptoms may be present at rest and any activity causes symptoms. Signs of right heart failure present.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Lung biopsy – does not show any characteristic findings that would change management. Due to inherent procedural risks, this is not recommended for diagnostic purposes for PAH.

III. Default Management.

Management steps are geared towards:

  • Symptom improvement

  • Improving hemodynamic parameters

  • Decrease progression of the disease

  • Decrease mortality and improve survival

A. Immediate management.

1. Supplement O2 to maintain saturation above 90% as hypoxia contributes to pulmonary vasoconstriction.

2. Patients with severe PAH with signs of RV failure with dyspnea and pedal edema may benefit from diuretics as well as close monitoring for arrhythmias.

3. Anticoagulation is currently recommended for all idiopathic PAH patients, and in the absence of contraindications, for other PAH patients with severe disease as well (e.g., on continuous IV therapy), with therapeutic INR target of 1.5-2.5.

4. If a patient is on IV epoprostenol, then DO NOT suddenly discontinue infusion as that may precipitate acute RV failure.

5. Digoxin can be used if there are atrial arrhythmias and in some patients with right heart failure – long term data are not available.

Pulmonary consultation is warranted for all PAH patients.

B. Physical Examination Tips to Guide Management.

Monitor signs of right heart failure, and adjust dose of diuretics as indicated.

Monitor pulse/heart rate while patient is on calcium channel blockers.

Monitor side effects of prostanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients on warfarin should have their CBC and PT/INR monitored regularly.

Endothelin receptor antagonists – LFTs to be monitored monthly.

D. Long-term management.


Calcium channel blockers (CCB) (long acting nifedipine, diltiazem or amlodipine) are first line therapy for vasodilator responders (based on vasodilator testing with right heart catheterization). Verapamil is typically not used due to negative inotropy.

CCBs should not be tried in non-responders.

Common side-effects: hypotension, pedal edema, constipation.

In non-responders, the following are used:

1. Prostanoids: favored drugs. Due to inactivation by gastric fluid, these are administered parenterally. They have potent vasodilatory effects. Commonly used drugs are:

1) IV epoprostenol – delivered by continuous IV infusion pump, usually started at 2ng/kg/min dose and further titrated as tolerated. Improves symptoms, hemodynamic parameters, quality of life and survival.

2) SC or IV treprostinil – IV is used in patients unable to tolerate SC infusions. Has similar benefits to IV treprostinil. Indicated for functional classes 2, 3 and 4.

3) Iloprost – delivered by aerosol technique. Multiple inhalations per day required (approx. 6-9 daily) due to short half-life. Used for functional class 3 and 4.

Common side-effects: jaw pain, flushing, nausea, diarrhea, headache.

2. Endothelin Receptor Antagonists (ERA): Counteract endothelin-1, a potent vasoconstrictor, levels of which are higher in PAH.

1) Bosentan – nonselective ERA, used in class 3 or 4 patients. Improves 6MWT and exercise capacity.

2) Ambrisentan – selective ERA, used in class 2 or 3.

Common side-effects: hepatotoxicity, flushing, syncope, pedal edema, anemia, nasal congestion, teratogenicity.

3. Phosphodiesterase inhibitors (PDE5 inhibitors): contributes to vasodilation by increasing cGMP levels.

1) Sildenafil (Viagra, Revatio) – can be used as first line therapy in class 2-3 patients; improves 6MWT, oxygenation and functional capacity.

2) Tadalafil (Cialis, Adcirca) – Also improves 6MWT and functional capacity.

Common side-effects: headache, flushing.

Combination therapy: typically used when monotherapy alone fails to adequately control symptoms.

SUMMARYof medical therapy based on functional class in non-responders:

Functional class 2 – Monotherapy with ERA or PDE5I, dose adjustments to optimize response

Functional class 3 – ERA, PDE51, inhaled iloprost or IV epoprostenol. Can also use SQ or IV treprostinil, IV iloprost or beraprost

Functional class 4 – Prostanoids are first choice – IV epoprostenol, SQ treprostinil, inhaled iloprostanil and combination with ERA/PDE5I is also used.


1.Atrial septostomy – Considered in patients with progressive right heart failure despite optimization of medical therapy.

An atrial right-to-left shunt is created,

improving left heart output, which balances the decrease in oxygenation of systemic blood. Frequently used as a bridge to transplantation, this procedure carries a mortality of approximately 15%.

2.Lung transplantation – Single-lung, double-lung (to decrease reperfusion injuries compared to single-lung transplant) or combined heart-lung transplantations (in patients with severe right heart failure) are undertaken based on appropriate patient/functional class/disease characteristics. Patients should be referred when they are not responsive to medical therapies. This is often the eventual outcome for patients with progressive IPAH, and the only therapeutic option for certain patients.


Serial testing during followup visits – echocardiograms, 6 minute walk tests, BNPs, possible repeat right heart catheterizations (based on clinical condition and stage of disease).

Physical activity as tolerated and pulmonary rehab can also assist in improving quality of life.

E. Common Pitfalls and Side-Effects of Management.

Care must be taken to avoid over-diuresis of patients with advanced PAH as RV function in these cases is preload dependant, and may contribute to exertional pre-syncope, orthostasis or syncope.

Catheter-related infections are common in patients on IV prostanoid infusions and with a permanent central venous catheter. Sterile techniques and appropriate care while handling these devices are essential.

Phosphodiesterase inhibitors should not be used in combination with nitrates used for treatment of other conditions.

IV. Management with Co-Morbidities.


A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

ERAs to be used with caution or avoided in patients with liver dysfunction.

Patients treated with ERAs need monthly LFTs for monitoring due to effects on cytochrome P450 system. Aminotransferase elevation is dose dependant and dose adjustment or discontinuation is necessary with significant elevation.

Patients with known liver dysfunction/portal hypertension (portopulmonary hypertension) likely have secondary cause of pulmonary hypertension.

C. Systolic and Diastolic Heart Failure.

Avoid overdiuresis as mentioned previously.

Systolic/diastolic CHF may be contributing to secondary pulmonary hypertension.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

HIV infection can contribute to pulmonary hypertension.

H. Primary Lung Disease (COPD, Asthma, ILD).

Primary lung diseases contribute to secondary pulmonary hypertension (group 3 of WHO classification).

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

Patients requiring anticoagulation will need evaluation of any underlying bleeding risks beforehand.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Monitor on telemetry – consider digoxin or CCBs for atrial arrhythmias.

Bridging therapy is not required if warfarin needs to be discontinued for a short period for tests or procedures.

B. Anticipated Length of Stay.

4-7 days

C. When is the Patient Ready for Discharge.

Patients will be ready for discharge when symptoms have improved and doses of medications have been regulated to allow safe transition to outpatient or rehab setting.

If INR is not therapeutic at time of discharge, instructions are to be provided to patient regarding time for next INR check

D. Arranging for Clinic Follow-up.

Patients should followup with pulmonologists with experience in treating pulmonary hypertension, and monitored closely.

1. When should clinic follow up be arranged and with whom.

Pulmonary hypertension clinic within 2-3 weeks and coumadin clinic within a few days when next INR check is desired.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Echocardiogram for baseline assessment.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Renal function and electrolytes for patients on diuretics.

INR and hemoglobin for patients on anticoagulation.

E. Placement Considerations.

Patients requiring IV prostanoids will need central venous catheter placement prior to discharge, and education on catheter care, infusion pumps and sterile techniques

F. Prognosis and Patient Counseling.

Prognosis of IPAH: Prognosis used to be much poorer prior to advancement of therapeutic options, with previous mean life expectancy of 2-3 years after initial diagnosis. With newer therapies, life expectancy and quality of life has improved in these patients. Responders to vasodilator challenge have up to 95% 5-year survival with CCB therapy. Patients with advanced right heart failure and cardiogenic shock may have inpatient mortality rate of up to 40%.


Dietary/salt and fluid restriction counseling, especially for patients on diuretics.

Dietary counseling to limit/avoid Vitamin K rich foods, for patients on warfarin.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

No JCAHO Core indicators.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

PUD prophylaxis is useful in patients on anticoagulation.

DVT prophylaxis not required if INR is in the therapeutic range.

In specialized centers, regular monitoring, including nurse telephone calls can help to ensure adequate support for the discharged patient and timely assistance with any worsening of symptoms that may prevent readmissions.

VII. What's the evidence?

McLaughlin, VV, Archer, SL, Badesch, DB. “ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association”. Circulation. vol. 119. 2009. pp. 2250-94.

Nef, HM, Mollmann, H, Hamm, C. “Pulmonary hypertension: updated classification and management of pulmonary hypertension”. Heart. vol. 96. 2010. pp. 552-9.

Gladwin, MT, Ghofrani, HA. “Update on pulmonary hypertension 2009”. Am J Respir Crit Care Med. vol. 181. 2010. pp. 1020-6.

Humbert, M. “Update in pulmonary hypertension 2008”. J Respir Crit Care Med. vol. 179. 2009. pp. 650-6.

Agarwal, R, Gomberg-Maitland, M. “Current therapeutics and practical management strategies for pulmonary arterial hypertension”. Am Heart J. vol. 162. 2011. pp. 201-13.

Saggar, R, Saggar, R, Aboulhosn, J. “Diagnosis and hemodynamic assessment of pulmonary arterial hypertension”. Semin Respir Crit Care Med. vol. 30. 2009. pp. 399-410.

Austin, ED, Loyd, JE, Phillips, JA. “3rd. Genetics of pulmonary arterial hypertension”. Semin Respir Crit Care Med. vol. 30. 2009. pp. 386-98.

Heresi, GA, Dweik, RA. “Pulmonary hypertension: evaluation and management”. Compr Ther. vol. 33. 2007. pp. 150-61.

Shifren, A. Washington Manual Pulmonary Medicine Subspecialty Consult.. 2006. pp. 148-157.

Kasper, DL, Braunwald, E, Fauci, AS. Harrison's Principles of Internal Medicine. 2005. pp. 1405

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