Publications

Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases characterized by pulmonary vasoconstriction and remodeling of the lung circulation. Although PAH is a disease of the lungs, patients with PAH frequently die of right heart failure. Indeed, survival of patients with PAH depends on the adaptive response of the right ventricle (RV) to the changes in the lung circulation. PAH-specific drugs affect the function of the RV through afterload reduction and perhaps also through direct effects on the myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors, and guanylyl cyclase stimulators may directly enhance myocardial contractility through increased cyclic adenosine and guanosine monophosphate availability. Although this may initially improve cardiac performance, the long-term effects on myocardial oxygen consumption and function are unclear. Cardiac effects of endothelin receptor antagonists may be opposite, as endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly considered as a disease with quasimalignant growth of cells in the pulmonary vascular wall, therapies are being developed that inhibit hypertrophy and angiogenesis, and promote apoptosis. The inherent danger of these therapies is a further compromise to the already ischemic, fibrotic, and dysfunctional RV. More recently, the right heart has been identified as a direct treatment target in PAH. The effects of well established therapies for left heart failure, such as β-adrenergic receptor blockers, inhibitors of the renin-angiotensin system, exercise training, and assist devices, are currently being investigated in PAH. Future treatment of patients with PAH will likely consist of a multifaceted approaches aiming to reduce the pressure in the lung circulation and improving right heart adaptation simultaneously.

Inflammation is associated with multiple forms of pulmonary arterial hypertension (PAH), including autoimmune (scleroderma) and infectious (HIV, schistosomiasis) etiologies. More than 200 million people worldwide are infected with Schistosoma, predominantly in Brazil, Africa, the Middle East, and South Asia. Schistosomiasis causes PAH in about 6.1% of those chronically infected and is particularly associated with the species Schistosoma mansoni. Treatment for schistosomiasis-associated PAH includes antihelminthic treatment, if active infection is present (although associated with little immediate benefit to the pulmonary hypertension), and then pharmacologic treatment with targeted pulmonary vascular therapies, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists. The pathophysiological mechanism by which this parasitic infection causes pulmonary hypertension is unknown but is unlikely to be simple mechanical obstruction of the pulmonary vasculature by parasite eggs. Preexisting hepatosplenic disease due to Schistosoma infection is likely important because of portopulmonary hypertension and/or because it allows egg embolization to the lung by portocaval shunts. Potential immune signaling originating in the periegg granulomas causing the pulmonary vascular disease includes the cytokines interleukin (IL)-4, IL-6, IL-13, and transforming growth factor β. Modulating these pathways may be possible targets for future therapy of schistosomiasis-associated PAH specifically, and study of this disease may provide novel insights into other inflammatory causes of PAH.