Future Perspectives for the Treatment of Pulmonary Arterial Hypertension

Genetic Variation of Pulmonary Arterial Hypertension

Approaching the genetics of pulmonary arterial hypertension (PAH), the working group reviewed the current status of understanding of multiple pathways already implicated in PAH, including the bone morphogenetic protein receptor 2 gene and the downstream regulators, the Smad proteins. The group reviewed the latest updates regarding types and occurrence of mutations in PAH and hypothesized potential mechanisms of disease related to these mutations, including their central role in cellular proliferation and vascular remodeling. Polymorphisms in the genes that encode endothelin receptors, serotonin pathway members, prostacyclin synthase and receptors, and endothelial nitric oxide synthase were also discussed. In all, this section highlighted the current status and the complexity of genetic mutations in the pathogenesis of PAH.

Mutations and polymorphisms in other systems such as G-protein-coupled receptors, potassium channels, naturetic peptides, and the NADPH oxidase system, which have been implicated not only in PAH but also in hypertension and heart failure, were discussed as well. While direct links to PAH therapeutics have not yet been identified, these mechanisms represented new genetic targets to consider in the pathogenesis of disease and potential new targets for treatment.

One of the most important discussions regarding genetics in PAH centered on the evolving field of pharmacogenomics and the potential for personalized PAH therapies. Clearly, pharmacogenomics in PAH is in its infancy, but this discussion highlighted the importance of including genetic analyses in future clinical studies.

Angiogenesis

The committee was very saddened by the unexpected death of Dr Judah Folkman just prior to the Dana Pont meeting. He was invited to review this important topic for the working group, as his research has led to many of the seminal findings in angiogenesis, and his absence was deeply felt. The group reviewed the potential role of antiangiogenesis strategies in PAH, including current inhibitors of vascular endothelial growth factor, the tyrosine kinase inhibitors, and other intracellular targets including PI3K/AKT, among others. The following discussion focused on the unresolved questions of the role of angiogenesis in PAH—most importantly, is angiogenesis a friend or foe? While no clear conclusion was drawn regarding the role of angiogenesis, the potential use of these agents in PAH was considered.

Growth Factor Inhibitors

With the understanding that clinical trials of growth factor inhibitors are underway, the working group reviewed the available clinical and preclinical information on PAH. While much of the discussion focused on PDGF, other growth factors were also discussed as viable targets for PAH therapies. Overall, there is broad enthusiasm for growth factors as important therapeutic targets in the near future.

Endothelial Stem/Progenitor Cells

The therapeutic potential of stem/progenitor cells in the treatment of PAH brought the working group up to date with the status of current clinical trials. Importantly, the discussion also considered the potential pathogenic contribution of stem/progenitor cells on the pulmonary circulation in actually precipitating PAH. One significant limitation in this area has been the lack of clear understanding of the localization of administered stem/progenitor cells in the PAH lung. Molecular imaging techniques may be very useful in long-term “visualization” of therapeutic transgenes.

RV Remodeling

Regardless of the etiology of PAH, the performance of the right ventricle (RV) will ultimately determine patient outcome. Limited therapies specifically target the RV, and the importance of focusing on the right heart (separate from the left ventricle [LV]) was emphasized in both diagnostic evaluation and therapies.

Understanding the fundamental components of the RV workload (including understanding ventricular-vascular coupling) and the hypertrophy/failure response of the cardiac myocyte was reviewed. Much discussion of the pathogenic vs physiologic adaptation of the RV again demonstrated the need to increase understanding of the RV as distinct from the LV as application of LV-derived therapies in heart failure cannot be extrapolated to the RV.

Summary

Overall, the Future Perspectives working group tackled a broad array of topics focusing on identifying seminal areas for ongoing therapeutic development. Like so many of the working groups, the understood goal is ultimately a cure for PAH. Until then, creative, thoughtful approaches to new therapies in PAH are urgently needed. The group certainly felt hopeful that, prior to the next World Symposium, some of the targets discussed will have been tested in the clinical arena.