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Molecular and Hemodynamic Determinants of Right Ventricular Response to Pulmonary Hypertension

Hunter Champion


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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.22.2008

Presentation Type: Slide Shows

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The vast majority of patients with pulmonary hypertension (PH), regardless of the etiology, ultimately succumb to the disease because of sudden death or intractable right heart failure. While there has been great focus on the pulmonary vascular abnormalities associated with pulmonary hypertension, there has been a relative paucity of mechanistic studies addressing the role of the right ventricle (RV) in this disease and, specifically, the role of the interaction of the RV with the pulmonary vasculature. Even with the developmentof new drugs to treat PAH such as epoprostenol and bosentan, mortality remains high and is strongly correlated with the decline in RV failure. Despite its profound clinical consequences, little is known about right ventricular (RV) adaptation and failure within the context of PH. An underrecognized factor that may play an important role in patients with PAH is ventricular-vascular uncoupling secondary to pulmonaryvascular stiffening. Moreover, there is a paucity of information as to the interaction between the pulmonary vasculature and the RV (RV-PA coupling). Recent data suggest that exercise limitation in PH may primarily be related to poor RV-PA coupling.

The initial response of the heart to hemodynamic and neurohormonal stress is hypertrophy. Numerous studies on the left ventricle have concluded that hypertrophy caused by hemodynamic and neurohormonal stressors is unstable and often progresses to cardiac dysfunction and maladaptive remodeling culminating in heart failure. A critical aspect to the future understanding of the nature of RV function/failure is to better delineate the differences and similarities between RV and LV hypertrophy and failure. An understanding of RV hypertrophy and failure signaling will allow for future therapies that will promote the growth of the adult heart (hypertrophy) to produce a stable molecular and cellular response to adverse hemodynamic and/or neurohormonal stress. Accordingly, disrupted intracellular signaling along this signaling axis leads to decompensation, maladaptive remodeling and right ventricular failure.

In this talk, we will discuss the results of screens for molecular mechanisms that differ between RV and LV hypertrophy and failure. Moreover, we will discuss the potential for targeting pathways dedicated to preserving NOS coupling and deducing ROS signaling in the RV.