Targeting Neurohumoral Signaling to Treat Pulmonary Hypertension

Adverse remodeling of the right ventricle (RV) that affects RV systolic or diastolic function directly or indirectly by modulating changes to cavitary geometry is a principal determinant of poor outcome across the global spectrum of cardiopulmonary diseases.1,2 Indeed, even subclinical increases in RV mass are associated with substantially elevated risk for future heart failure and decreased lifespan.3 Unique embryological and anatomic features of the RV provide a pathophysiological basis by which to account for this observation. For example, precursor cells of the RV and left ventricle (LV) derive from the primary and anterior heart fields,4 respectively, indicating a different cellular lineage for each ventricle despite their close proximity and placement in series. In contrast to the LV, the RV is a triangular structure that is thin walled and noncompacted, and, thus, tolerates pressure-loading conditions poorly.5 Moreover, poor coronary blood flow reserve with increased RV strain due to elevations in wall tension is associated with decreased RV microvascular perfusion.6Article see p 2859Although these properties establish the RV-specific pressure–volume relationship profile, factors that precipitate impaired RV performance are less well characterized. Take, for example, the wide swath of classical reports that describe LV hemodynamic (patho)physiological responses to acute and chronic myocardial ischemia, systemic hypertension, valvular dysfunction, and pericardial disease.7 By contrast, a paucity of data exists to characterize the mechanistic and clinical contributions of similar processes (including LV dysfunction) to the natural history of adverse RV remodeling in non–congenital heart disease patients, despite the attendant clinical relevance of RV failure. Furthermore, the basic mechanism(s) that underpin RV dysfunction when contemporaneous with pulmonary hypertension, the most common end-pathophenotype associated with changes to RV loading,8 are largely unknown. In fact, only recently has consideration been given to …