Pulmonary hypertension: have we learned enough yet?

Abstract

[''when you are a child you want to be like your father, as you grow to be a teenager you want to be anything except your father, and then as a man you realize that you are your father''] (Adapted from Charles Farmer quote, Farmer the Astronaut) Pulmonary arterial hypertension (PAH) is a lifethreatening, vascular proliferative disease of the lung, which is characterized by vasoconstriction and remodeling of small pulmonary arteries. Consequently, PAH is characterized by an increase in mean pulmonary arterial pressure (mPAP [ 25 mmHg) with limited treatment options and poor prognosis [1,2]. Specifically, the disorder causes right ventricular hypertrophy and can quickly lead to death, especially with the severe forms of pulmonary hypertension.In the United States (USA), PAH affects an estimated two to three times as many women as men. PAH usually develops between 20 and 60 years of age; however, it can occur at any age. According to Centers for Disease Control and Prevention (CDC) statistics, between 2000 and 2002, 807,000 patients were hospitalized with PH; 61 % were female, and 66 % were 65 years or older. Statistics from the CDC also report that PAH led to 15,688 deaths and 260,000 hospitalizations in 2002. Prior to 1995, individuals with PAH live, on average, less than 3 years after diagnosis; however, with emerging therapies, survival rates and quality of life for those living with this condition have improved [3]. Despite large advances in the last 10 years, there is still about a 15 % annual mortality for diagnosed patients in the US.Recent strategies have shown promise in animal models to prevent the onset of pulmonary hypertension when it is induced. As such, over the past decades, a large number of experimental animal models of PAH have been developed, and mainly rely on hypoxic or monocrotaline injected rodents; the creation of left to right shunts in lambs or piglets, and the ligation of the ductus arteriosus in newborn lambs [4]. While none of the models have yet reproduced PAH, each allows investigation of a specific hypothesis.More recently, an increasing number of genetically manipulated rodents and tissue cultures are becoming available for the investigation of specific signaling pathways, resulting in recent molecular and cellular approaches [5]. Consequently, animal models of PAH that share basic biological abnormalities, which, together with the study of lung tissue from patients with severe diseases have led to a better understanding of the pathology and therapeutic innovation. As a result, current therapies include endothelin receptor antagonists, prostacyclin agonists, and cGMP-specific 3 0 , 5 0 -cyclic phosphodiesterase (PDE5) inhibitors [6].In a recent study, Grimminger and Schermuly [7] have investigated the development of a causal treatment aiming at normalization of the vessel wall structure. The authors have investigated new non-vasoactive drugs in relevant preclinical animal models of PAH. Some substances such as tyrosine kinase inhibitors, elastase inhibitors, and phosphodiesterase-...