Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

Abstract

Pulmonary arterial hypertension (PAH) is a rare, life-threatening condition characterized by dysregulated metabolism, pulmonary vascular remodeling, and loss of pulmonary vascular cross-sectional area due to a variety of etiologies. Right ventricular (RV) dysfunction in PAH is a critical mediator of both long-term morbidity and mortality. While combinatory oral pharmacotherapy and/or intravenous prostacyclin aimed at decreasing pulmonary vascular resistance (PVR) have improved clinical outcomes, there are currently no treatments that directly address RV failure in PAH. This is, in part, due to the incomplete understanding of the pathogenesis of RV dysfunction in PAH. The purpose of this review is to discuss the current understanding of key molecular mechanisms that cause, contribute and/or sustain RV dysfunction, with a special focus on pathways that either have led to or have the potential to lead to clinical therapeutic intervention. Specifically, this review discusses the mechanisms by which vessel loss and dysfunctional angiogenesis, sex hormones, and metabolic derangements in PAH directly contribute to RV dysfunction. Finally, this review discusses limitations and future areas of investigation that may lead to novel understanding and therapeutic interventions for RV dysfunction in PAH.

Off‐label use of PAH‐targeted medications approved for adults and their financial coverage by health insurances are vital for children with pulmonary hypertension

“…There is an urgent need for advanced pharmacotherapy in children with progressive, life-limiting PH (11,12,16). For this reason, the following measures are proposed as next steps:…”

“…11 The development and availability of new, so-called "targeted" or "advanced" therapies, which are approved for adults with PAH, have significantly improved quality of life and life expectancy of paediatric PAH patients as well. 12,13 The pathogenesis of pulmonary hypertensive vascular disease, however, in most cases, is still chronically progressive: In end-stage PH, defined as advanced pulmonary vascular disease (PVD) and severe right ventricular (RV) dysfunction, [14][15][16][17][18] bilateral lung transplantation remains the only treatment option. [19][20][21]…”

RNA expression profiles and regulatory networks in human right ventricular hypertrophy due to high pressure load

“…RV adaptation and remodeling in high pressure afterload involves a number of interdependent complex processes, such as altered bioenergetics (hypoxia/ischemia and mitochondrial remodeling/dysfunction) and neurohormonal and immunological activation. In concert with underlying genetic and epigenetic alterations (e.g., microRNAs), these pathobiological events ultimately lead to RV dilation and failure (“decompensated RVH”) ( Agrawal et al., 2020 ; van der Bruggen et al., 2017 ). Right ventricular hypertrophy may occur in the setting of RV outflow tract obstruction (PS; normal pulmonary vascular resistance) or in hypertensive pulmonary vascular disease with anatomically normal RV outflow ( Hansmann, 2017 ; Hansmann et al., 2019 ; Santens et al., 2020 ).…”

“…Right ventricular hypertrophy may occur in the setting of RV outflow tract obstruction (PS; normal pulmonary vascular resistance) or in hypertensive pulmonary vascular disease with anatomically normal RV outflow ( Hansmann, 2017 ; Hansmann et al., 2019 ; Santens et al., 2020 ). Both etiologies have been studied in various animal models ( Andersen et al., 2020 ); however, none of them fully simulate human RVH in vivo ( Agrawal et al., 2020 ; Andersen et al., 2020 ; Bernardo et al., 2020 ; Santens et al., 2020 ).…”

“…The hallmarks of maladaptive decompensated cardiac hypertrophy are cell death, fibrosis, dysregulation of Ca 2+ -handling proteins, mitochondrial dysfunction, metabolic reprogramming, reactivation of fetal gene expression, altered sarcomere structure, and insufficient angiogenesis ( Agrawal et al., 2020 ; Nakamura and Sadoshima, 2018 ). More specifically, a number of microRNAs (miRNAs) have been suggested to be involved in the pathobiology of RV hypertrophy and dysfunction in conditions of high pressure afterload (pulmonary hypertension or PS/pulmonary artery banding).…”