Affiliations: Boniface General Hospital, Winnipeg, MB, Canada
Dr. Sharma is Assistant Professor, Sections of Pulmonary Medicine and Critical Care, University of Manitoba.
Correspondence to: Sat Sharma, MD, FCCP, Site Coordinator, Department of Respiratory Medicine, St. Boniface General Hospital, BG034-409 Tache Ave, Winnipeg, MB, Canada R2H 2A6; e-mail: email@example.com
No great improvements in the lot of mankind are possible, until a great change takes place in the fundamental constitution of their modes of thought.
John Stuart Mill, 1873
Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the pulmonary vascular bed. If untreated, PAH progresses to death from right-heart failure. Median survival is < 2 years following diagnosis. PAH is characterized by vasospasm, intimal fibrosis, thrombosis in situ, proliferation of smooth muscles, and medial hypertrophy; plexogenic arteriopathy is the pathologic hallmark of this disorder.1–
Similar vascular lesions, clinical picture, and natural history are encountered in many other conditions, including collagen vascular diseases, portal hypertension, HIV infection, and exposure to anorectic drugs. The new classification scheme incorporates pulmonary hypertension (PH) associated with these illnesses and primary PH (PPH) as types of PAH.2
Advances in understanding of pathogenesis of PAH, along with cellular and molecular research, have led to the development of newer approaches to treatment for a disease previously considered untreatable.
The pulmonary circulation is a high-flow, low-pressure, highly compliant system that may accommodate up to a sixfold rise in cardiac output. The low-pressure state is maintained by a variety of active mediators produced by the pulmonary arterial endothelium. Normally, there is a balance between the endothelium-derived relaxing factors (nitric oxide and prostacyclin) and endothelium-derived constricting factors (endothelin [ET]-1, thromboxane, serotonin). An imbalance of these endothelium-derived factors elevate vasomotor tone, promote endothelial smooth-muscle–cell proliferation, induce vascular remodeling, and incite thrombosis.3
Our current understanding of pathogenesis of PAH has been revolutionized; PAH is presently regarded as a vasoproliferative rather than vasoconstrictive disorder. Likewise, emphasis on treatment has evolved from vasodilators to antiproliferative agents that target vascular remodeling.
ET-1, a vasoconstrictor peptide, is produced by the endothelial cells and plays a pivotal role in pathogenesis of PAH. ET-1 is not only a powerful vasoconstrictor, but it has other effects, such as mitogenesis, promotion of inflammation, and smooth-muscle–cell proliferation.4–
Endothelium emanates pro-ET, which is proteolytically cleaved to big ET-1; endothelin-converting enzyme converts big ET-1 to functional ET-1. The vasoconstrictor and proliferative effects of ET-1 are mediated through two known receptors, ET-A and ET-B, present on vascular smooth muscles. ET-1 causes vasoconstriction via ET-A receptors on smooth muscles and vasodilation via ET-B receptors located on endothelial cells. Additionally, ET-B indirectly modulates ET-1 synthesis and is responsible for clearance of circulating ET-1.5–
The ET system is complex, and the receptors mediate a wide variety of vascular effects; however, blockade of both ET-A and ET-B is required to inhibit the effects of ET-1 on pulmonary circulation. Recent discoveries have identified a role for transforming growth factors (transforming growth factor β) and vascular endothelial cell growth factor (VEGF) in the pathogenesis of PH. VEGF blockade produces PH and pulmonary vascular remodeling, explaining beneficial effects of prostaglandins, which provoke VEGF production.6–
Mutations in the bone morphogenetic protein receptor type II have been reported in patients with familial and sporadic PPH.7
Dysfunction of this receptor may contribute to proliferation of smooth-muscle cells and partake in pathogenesis of PAH.
Therapy for PAH previously consisted of calcium-channel blockers that resulted in beneficial response in approximately 20% of patients, and detrimental effects in nonresponders. The responders are identified when vasoreactivity (hemodynamic improvement) is demonstrated during acute vasodilator trial.8–
Continuous IV epoprostenol therapy improved functional capacity and survival irrespective of vasoreactivity, and became the first-line therapy for patients with PAH who were symptomatic equivalent to New York Heart Association (NYHA) functional class III and class IV.9–
Prostaglandins are vasodilators with antiplatelet effects and achieve anti-inflammatory, antifibrotic, and antiproliferative effects. Difficulties with drug administration, high costs, and undesirable side effects of epoprostenol necessitated the development of prostacyclin analogues administered by continuous subcutaneous infusion, orally or by intermittent inhalation.10–11
Treprostinil administered by continuous subcutaneous infusion is presently available in the United States. Oral beraprost and inhaled iloprost, in placebo- controlled clinical trials,12–13
appear promising for patients in NYHA class II and class III. Inhaled iloprost has the disadvantage of short duration of action and requires 6 to 12 inhalations per day.
Phosphodiesterase inhibitors increase the intracellular concentration of cyclic guanosine monophosphate and cyclic adenosine monophosphate, and have shown to possess vasodilatory properties on pulmonary circulation. Beneficial effects of sildenafil have been reported in published case reports.14–
Inhalation of nitric oxide, a vasodilator of pulmonary circulation, has been shown to improve exercise capacity in patients with PAH. Oral L-arginine, a nitric oxide donor, decreased pulmonary vascular resistance, and improved circulation and exercise capacity in patients with PAH.15
However, the experience with sildenafil and L-arginine is limited; further clinical trials are required to document efficacy and safety of these drugs.
Inhibiting effects of ET by ET-receptor blockade is a novel and effective therapy for patients with PAH. Bosentan, an orally active nonpeptide, is a highly specific competitive antagonist of both ET receptors—ET-A and ET-B. Several experimental animal studies16–18
established efficacy of bosentan in preventing development of PH. These studies16–18
also demonstrated that bosentan effectively reversed established PH and arrested pulmonary vascular remodeling commonly associated with PAH.
A 12-week, randomized, placebo-controlled, double-blind study17
demonstrated significant improvement in exercise capacity (distance walked in 6 min), pulmonary vascular resistance, cardiac index, and pulmonary arterial and right arterial pressures in patients with PPH or PAH associated with collagen vascular disease who were treated with bosentan compared to placebo. At the conclusion of the study,17–
43% of bosentan-treated patients improved to class II as opposed to only 9% of placebo-treated patients. In the bosentan randomized trial of ET antagonist therapy for PAH,18
144 patients belonging to NYHA functional class III and IV were randomized to receive bosentan (125 mg or 250 mg) or placebo for 28 weeks. At week 16, patients treated with bosentan had significant improvement in 6-min minute walking distance by 44 m, Borg dyspnea index, NYHA functional class, and considerably postponed the time to clinical worsening. Bosentan therapy was associated with elevations in hepatic transaminases with high dose (14% of patients with 250 mg bid) than low dose (5% of patients with 125 mg bid), which was transient in all but three patients. Bosentan did not affect warfarin dose and did not cause systemic hypotension.18
Whether the beneficial effects of bosentan are maintained long term or development of tolerance occurs over time has not been studied. In this issue of CHEST (see page 367), Sitbon et al report the long-term safety and efficacy data in patients with PAH in an open-label extension to the previous placebo-controlled study. All 29 patients of NYHA functional class III or class IV were enrolled in the open-label study and received bosentan for an additional year. Continuing bosentan treatment maintained the improvement in walk distance observed at the end of previous study (60 ± 11 m) [mean ± SD]. An increase in walk distance by 45 ± 13 m occurred in patients previously treated with placebo. Significant improvements in cardiac index and pulmonary vascular resistance were noted in 11 patients who underwent cardiac catheterization after 15 ± 4 months of bosentan treatment. Furthermore, after 1 year of therapy, 11 of 29 patients improved to functional class II, 1 patient improved to class I, and 1 patient deteriorated. Although asymptomatic rise in liver enzymes and decrease in hemoglobin concentration was observed in a minority of patients, this did not result in discontinuation of bosentan. This study established that long-term administration of bosentan is safe and efficacious in the treatment of PAH.
In the absence of long-term data comparing different treatments, the choice of therapy will depend on clinical experience, patient preferences, and costs. All patients should be treated with oral anticoagulation unless otherwise contraindicated. In patients with mild-to-moderate PAH who belong to NYHA class I and class II, and who demonstrate vasoreactivity on acute vasodilator trial, calcium-channel blockers remain the treatment of choice. Nonresponders of NYHA class II who are in stable condition may be closely observed; if therapy is required, oral beraprost or bosentan are the most appropriate choices. The first-line treatment for patients in NYHA class III could be either oral/inhaled/subcutaneous prostaglandin or ET antagonist. IV prostacyclin should be administered if deterioration ensues. For most patients with severe PAH (NYHA class IV), the treatment of choice is IV prostacyclin. Therapy with ET antagonist, however, can be initiated in patients with stable clinical status under careful supervision. Inhaled prostacyclin has been reported to be effective in the treatment of severe PAH and is a reasonable alternative, if available, and in those who acquire severe hypotension receiving IV therapy.19
In the future, clinical trials will help define a place for various agents in the treatment of PAH. Long-term studies will also address the issues of survival, quality of life, side effects, and costs with a range of therapeutic agents. Another promising approach is combining two agents with diverse pharmacologic actions; such clinical studies are currently underway. Finally, reversal of PH and regression of histologic changes in pulmonary circulation may potentially become a therapeutic reality.20
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