Table 6.

Key Knowledge Gaps and Solution Approaches for Deciphering the Underlying Molecular and Pathogenic Mechanisms of Right Ventricular Function and Failure

Key knowledge gaps

• Is angiogenesis and/or capillary maintenance necessary to preserve RV function during remodeling, and does capillary rarefaction cause maladaptive RV remodeling?

• Does myocardial fibrosis promote RVF, and can it be reversed?

• Are metabolic alterations necessary for transition from adaptive to maladaptive RV remodeling? If so, which changes are the most important ones in this process? Which alterations in myocardial metabolic pathways should be targeted therapeutically, and how?

• Are apoptosis and other forms of cellular death necessary for transition from adaptive to maladaptive RV remodeling?

• Are myocardial inflammation and oxidative stress causes or consequences of RVF?

• What is the role of circulating and resident progenitor cells in modulating RV hypertrophy, angiogenesis, fibrosis, metabolism, cell death, inflammation, oxidative stress, and contractile signaling?

• How do established and novel PAH therapies modulate RV hypertrophy, angiogenesis, fibrosis, metabolism, cell death, inflammation, oxidative stress, and contractile signaling?

• Are potential short-term detrimental effects on RV contractile function with neurohormonal modulators (e.g., β-adrenergic receptor antagonists) offset by long-term beneficial effects on other signaling pathways?

Solution approaches/pathways forward

• More human studies focused on identifying mechanisms of RVF and facilitated through RV biopsy samples, tissue repositories, and development of advanced imaging techniques. In order to enhance scientific impact, human subjects need to be well phenotyped

• Identification and validation of biomarkers of RV remodeling and dysfunction to facilitate human studies in PH-induced RV dysfunction

• Use of stereological methods in all morphometric analyses, including both human tissue and animal models

• More studies investigating the roles of sex and age as modifiers of RV function

• More studies investigating the roles of circulating and resident progenitor cells as modifiers of RV function

• Next-generation sequencing techniques in humans and animals to identify genetic contributors to RV adaptation and maladaptation

• Correlation of findings from cellular and animal studies with human phenotypes

• Identification/clarification of important mechanistic differences between preclinical models of RV adaptation and RVF

• Expanded use of RV working heart models and in vitro analyses of diverse myocardial cell types to evaluate specific regulatory pathways

Definition of abbreviations: PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RV = right ventricular; RVF = right ventricular failure.