Pulmonary Arterial Hypertension: Current Therapeutic Strategies

Summary and Introduction

Summary

The treatment of pulmonary arterial hypertension-once a lethal condition-has evolved considerably over the past few years as the number of therapeutic options available to treat this disease has increased. In this Review we attempt to summarize the current knowledge of the pathogenesis of pulmonary hypertension, in relation to the therapies presently available and those that could become available in the near future. The use of prostacyclin and its analogs, calcium-channel blockers, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors is reviewed. Newer concepts, such as the use of combination therapy, and the potential for long-term disease amelioration and improvement of outcomes, are also discussed. The role of supportive care and medications not specific to pulmonary hypertension is also examined. In addition, we review the novel emerging therapies, such as imatinib, fasudil, simvastatin, ghrelin and vasoactive intestinal peptide, which hold therapeutic potential for disease modification as well as treatment of symptoms.

Introduction

Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure (PAP) of greater than 25 mmHg at rest or at least 30 mmHg during exercise. These rises in PAP have to be associated with elevated pulmonary vascular resistance (PVR), and a mean pulmonary wedge pressure and left ventricular end diastolic pressure of less than 15 mmHg for diagnosis of PAH. Ultimately, continuous elevation of PAP and PVR causes failure of the right ventricle, leading to an inability to support the circulation and subsequent death.^[1]

In 1998, the WHO (Evian) classification system was proposed, which sought to categorize different forms of pulmonary hypertension (PH) according to similarities in pathophysiological mechanisms, clinical presentation and therapeutic options.^[2] In 2003 in Venice, modifications were made to this system, with the aim of making it more comprehensive, easier to follow and more practical for clinicians (Figure 1).^[3] In this system the risk factors and associated conditions were updated and modifications were proposed, including replacing the term 'primary pulmonary hypertension' with 'idiopathic pulmonary arterial hypertension (IPAH)'. Guidelines were also proposed to improve the classification of congenital systemic-to-pulmonary shunts.

Figure 1. (click image to zoom) Revised clinical classification of pulmonary hypertension (Venice 2003).

IPAH-that is, PAH of unknown cause-is a rare disease that has in the past been associated with poor survival if patients do not receive treatment.^[4] PAH prevalence is increased when associated with other conditions, such as collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, and chronic hypoxemic lung disease.^[5] Some patients with IPAH have a familial variety, which in the NIH registry accounted for 6% of patients,^[3] and presents identically to the sporadic form of the disease.^[6] The bone morphogenetic protein receptor type II gene (BMPR2), a member of the transforming growth factor beta (TGF-β) cell signaling family, has been implicated in PAH.^[7,8] Heterozygous mutations within BMPR2 have been identified in familial PAH and in sporadic cases of IPAH, and could be associated with TGF-β signaling abnormalities^[9,10]-a potential area for therapeutic intervention.A recent study has shown that patients with familial PAH or IPAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity, indicating that genetic testing could have a future role in guiding therapy.^[11] Other causes of PH include left-sided heart disease, chronic thromboembolic disease and inflammatory conditions that affect the lungs. This Review attempts to examine what is currently known about the pathogenesis of PAH, in relation to presently available and novel emerging therapies that hold promise for treatment as well as disease modification.