Figure 1. “Multiple Hit” Hypothesis for the Development of Pulmonary Hypertension.

In this model, individuals may possess a genetic background that could predispose to the development of pulmonary hypertension. Since there is incomplete penetrance, even for heritable cases of PAH, other modifier events are highly likely to be causal, and can include environmental triggers such as exposures or infections, or the co-existence of modifier genes, either germline, somatic or epigenetic modifications. The interplay between genes and environment will undoubtedly prove extremely important in the definition of the etiology of the disease.