An evidence-based approach to the management of pulmonary arterial hypertension.
OBJECTIVE
Evidence-based therapies and guidelines for pulmonary arterial hypertension are critiqued.


RESULTS
Morbidity and mortality in pulmonary arterial hypertension reflects failure of right ventricular compensation for increased afterload caused by obstructive pulmonary arterial remodeling. This predominantly reflects excessive proliferation/impaired apoptosis of smooth muscle and endothelial cells, rather than vasoconstriction. To exclude confounding effects of cardiac output and left ventricular end-diastolic pressure, the diagnosis of pulmonary arterial hypertension should require a pulmonary vascular resistance >3 Wood-units, not simply a mean pulmonary arterial pressure >25 mmHg. A 'positive' response (20% fall in pulmonary arterial pressure/pulmonary vascular resistance PAP/PVR) to acute, selective, pulmonary vasodilators (e.g. inhaled nitric oxide), occurs in 20% of patients, portends a favorable prognosis and justifies a trial of calcium channel blockers. Randomized controlled trials support treatment of NYHA class III pulmonary arterial hypertension with oral endothelin antagonists or phosphodiesterase-5 inhibitors. Prostacyclin analogues (inhaled/subcutaneous) are useful adjunctive therapies. Intravenous epoprostenol remains the therapeutic mainstay for class IV PAH. Emerging antiproliferative-proapoptotic therapies that merit investigator-initiated clinical trials include: statins, Imatinib, NONO-ates, anti-survivin, potassium channel modulation, and dichloroacetate.


CONCLUSIONS
The diagnostic criteria for pulmonary arterial hypertension should be revised to include PVR. Sildenafil's efficacy and price recommend it as a first-line oral therapy. New pulmonary arterial hypertension-regression therapies and therapeutic combinations offer the potential for cure of pulmonary arterial hypertension.
Archer
Stephen L
SL
Vascular Biology Group, Division of Cardiology, Canada. sarcher@cha.ab.ca
Michelakis
Evangelos D
ED
D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides; D000077300:Bosentan; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D015897:Comorbidity; D003999:Dichloroacetic Acid / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000627:therapeutic use; D019317:Evidence-Based Medicine; D005473:Fluoxetine / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000188:drug therapy* / Q000503:physiopathology; D016285:Iloprost / Q000627:therapeutic use; D000068877:Imatinib Mesylate; D007555:Isoxazoles / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011465:Prostaglandins, Synthetic / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011687:Purines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000068677:Sildenafil Citrate; D019821:Simvastatin / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D001549:Benzamides; D002121:Calcium Channel Blockers; D007555:Isoxazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011465:Prostaglandins, Synthetic; D011687:Purines; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; D013876:Thiophenes; D014665:Vasodilator Agents; D005473:Fluoxetine; D000068877:Imatinib Mesylate; D003999:Dichloroacetic Acid; D019821:Simvastatin; D000068677:Sildenafil Citrate; D011464:Epoprostenol; C106276:sitaxsentan; D016285:Iloprost; D000077300:Bosentan; C427248:treprostinil