I. Definitions/Classification

  1. Primary pulmonary hypertension (PPH)

    1. Defined by the NIH as mean pulmonary artery pressure (PAP) > 25mm Hg at rest of 30mm Hg w/exertion in the absence of heart or lung disease (e.g. normal pulmonary artery wedge pressure), chronic thromboembolic disease, or other secondary causes (Ann. Int. Med. 107:216, 1987)

    2. Causes/risk factors (note—in the literature, pulmonary hypertension due to the following causes is variably designated as PPH or not)

      1. Genetic (probably a minority of cases)

      2. Drugs (fenfluramine, amphetamines, cocaine, certain chemotherapeutic agents)

      3. HIV infection

      4. Portal hypertension

      5. Collagen vascular diseases

    3. OTHER causes of pulmonary hypertension:

      1. COPD

      2. Interstitial lung disease

      3. Sleep-disorder breathing including obstructive sleep apnea

      4. Alveolar hypoventilation disorders

      5. Chronic high altitude exposure

      6. Thromboembolic obstruction of pulmonary aa. (pulmonary embolism, parasitic disease, sickle cell anemia, etc.)

II. Pathophysiology and natural history of PPH

  1. Obstructive angiopathy of the small pulmonary arteries with medial hypertrophy, intimal fibrosis, and thromboses

  2. Also, an imbalance between vasodilators and vasoconstrictors favoring vasoconstriction.

  3. Natural history w/o tx is right heart failure, with median survival from dx of 2.8y.

III. Clinical presentation

  1. Symptoms

    1. Dyspnea (the initial symptom in about 60% of cases)

    2. Fatigue

    3. Chest pain

    4. Syncope and presyncope

    5. Palpitations

    6. Peripheral edema

  2. Physical findings

    1. Loud P2

    2. Right-sided S3 or S4

    3. Systolic murmur from tricuspid regurgitation

    4. Hepatomegaly, ascites, and peripheral edema

  3. ECG findings

    1. RAD

    2. Prominent p’s in the inferior leads

    3. R > S in V1

    4. RV “strain” pattern

IV. Diagnosis:

  1. Doppler echocardiography is the most common non-invasive diagnostic modality but may not be highly accurate (Am. j. Resp. Crit. Care Med. 179:615, 2009-JW; Chest 139:988, 2011-JW )

  2. Right heart catheterization with selective pulmonary vasodilator testing can confirm

V. Treatment:

  1. Anticoagulation

    1. Commonly used because of the frequent findings of thrombotic lesions in pulmonary arterioles in pts with PPH

    2. Data from nonrandomized trials only as of 2003.

  2. Calcium-channel blockers

    1. Ass’d with hemodynamic improvement and increased survival in those pts with PPH and good response to an initial challenge with such meds (i.e. 20% decrease in mean PAP and pulmonary vascular resistance).

  3. Prostacyclin analogues

    1. Prostacyclin is a strong vasodilator also with antiplatelet action

    2. All these meds can cause headaches, flushing, diarrhea, and nausea

    3. Epoprostanol

      1. Associated in RCTs with significant improvement in exercise tolerance, hemodynamic measures, and survival (5y mortality reduced from 73% to 46% with epoprostenol in one trial).

      2. Data from nonrandomized trial suggests benefit in pulmonary hypertension from scleroderma, systemic lupus erythematosus, congenital heart disease, HIV infection, connective-tissue disorders, sarcoid, and portopulmonary hypertension.

      3. Very short t-1/2 so given by continuous IV infusion through a long-term indwelling catheter, with all the associated risks of that (e.g. sepsis, thromboemboli, etc.).

    4. Beraprost

      1. An oral prostacyclin analogue

      2. Ass’d with improved hemodynamic measures, exercise tolerance, and survival in one 3y nonrandomized trial (JACC 34:1188-92, 1999) and improved exercise tolerance and sx in one 12-week randomized trial (JACC 39:1496-502, 2002); about 50% of the pts in the latter trial had non-primary PH.

    5. Iloprost (Ventavis)

      1. An inhaled prostacyclin analogue

      2. Requires 6-8 doses daily

      3. Can cause flushing, headache, and cough

      4. Associated with improvements in exercise capacity, dyspnea, and hemodynamic parameters in one12-week  randomized placebo-controlled trial (NEJM 347:322-29, 2002)

    6. Treprostinil

      1. A prostacyclin analogue for continuous SQ infusion

      2. Associated with improvements in exercise capacity, dyspnea, and hemodynamic parameters in one 12-week randomized placebo-controlled trial (Am. J. Resp. Crit. Care Med. 165:800-4, 2002)

      3. In the same trial, ass’d with infusion-site pain in 85% and pump malfunctions in 24% of subjects

  4. Endothelin 1 antagonists

    1. Endothelin 1 is a potent vasoconstrictor

    2. Bosentan (Tracleer)

      1. An orally active antagonist of endothelin 1

      2. Associated with improvements in exercise capacity and sx in two RCTs (Lancet 358:1119-23, 2001; NEJM 346:896-903, 2002)

      3. 2% had significant hepatotoxicity; may be teratogenic

      4. Causes headache, facial flushing, and pedal edema

    3. Sitaxsentan

      1. Only preliminary studies as of 2003

  5. Phosphodiesterase inhibitors

    1. Prevent the breakdown of cGMP, a potent vasodilator

    2. Sildenafil

      1. Sildenafil 25-100mg TID (based on body weight) vs. placebo x 6wks was ass'd with sig. greater increases in maximal treadmill walking time in 22 pts with primary pulmomnary hypertension (J. Am. Coll. Cardiol. 43:1149, 2004--abst)

      2. In a study in 278 pts with pulmonary hypertension randomized to sildenafil 20-80mg TID vs. placebo, at 12wks, the sildenafil groups all had sig. increase in 6min walking distance c/w placebo (NEJM 353:2148, 2005--JW)

  6. L-arginine

    1. Involved in synthesis of nitric oxide, a potent vasodilator

    2. Lowers PAP in pts with pulmonary HTN but no long-term or randomized studies as of 2003

  7. Nitric oxide—An inhaled vasodilator; no studies on long-term use in outpatients as of 2003.

  8. Atrial septostomy (creation of a small perforation in the atrial septum) ass’d with improvement of syncope and improved exercise tolerance, but is also associated with a risk of life-threatening arterial hypoxemia.

  9. Lung transplantation

    1. Constitutes curative therapy

    2. Single-lung transplants may have identical benefits to double-lung transplants

(Sources include those cited above and Lancet 2003;361:1533-44)