Current Understanding of the Right Ventricle Structure and Function in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a disease resulting in increased right ventricular (RV) afterload and RV remodeling. PAH results in altered RV structure and function at different scales from organ-level hemodynamics to tissue-level biomechanical properties, fiber-level architecture, and cardiomyocyte-level contractility. Biomechanical analysis of RV pathophysiology has drawn significant attention over the past years and recent work has found a close link between RV biomechanics and physiological function. Building upon previously developed techniques, biomechanical studies have employed multi-scale analysis frameworks to investigate the underlying mechanisms of RV remodeling in PAH and effects of potential therapeutic interventions on these mechanisms. In this review, we discuss the current understanding of RV structure and function in PAH, highlighting the findings from recent studies on the biomechanics of RV remodeling at organ, tissue, fiber, and cellular levels. Recent progress in understanding the underlying mechanisms of RV remodeling in PAH, and effects of potential therapeutics, will be highlighted from a biomechanical perspective. The clinical relevance of RV biomechanics in PAH will be discussed, followed by addressing the current knowledge gaps and providing suggested directions for future research.

Dynamic Changes in miR-21 Regulate Right Ventricular Dysfunction in Congenital Heart Disease-Related Pulmonary Arterial Hypertension

“…PAH is a complex, progressive vascular disease clinically defined as a maladaptive increase in pulmonary arterial pressure in the absence of elevated left heart pressure [3,4,15]. In response to PAH, the RV undergoes structural and functional remodeling, including RV hypertrophy, which is a key determinant of long-term PAH outcomes and is associated with an increased risk of heart failure as well as sudden death [12,15]. However, most previous studies have concentrated predominantly on the impact of biomechanical forces such as shear stress on the pulmonary vasculature.…”

“…Additionally, Nour et al suggested that intrapulmonary shear stressmediated endothelial function enhancement could provide an effective target for PAH treatment [17]. Notably, the key determinant of mortality and morbidity of patients with PAH is the consequence of RV dysfunction [15], but the molecular mechanisms driving RV decompensation in the process of PAH remain largely unknown. Hereby, starting from a clinical observation, we found that despite an increasing expression of circulating miR-21 in patients with PAH, there was a significant drop in circulating miR-21 expression along with RV dysfunction among patients who were hospitalized for decompensated HF.…”

“…Among them, miR-21 is reported to be highly expressed in pulmonary arterial tissues of several types of human PAH and rodent models [9,12]. Through literature searches, we identified miR-21-targeted genes, including Sprouty 2 (SPRY2) and phosphatase and tensin homology deleted on chromosome 10 (PTEN), which are involved in cardiomyocyte apoptosis [11,15,16]. Green et al demonstrated that PPARγ ligands regulate proliferative responses by suppressing miR-21 and activating PTEN in pulmonary artery smooth muscle cells post hypoxia [18].…”

“…Our findings indicated that the upregulation of miR-21 in the early phase and downregulation in the late phase may contribute to the initial RV hypertrophy and subsequent dysfunction facing PAH. Since the major contributors to the outcomes of patients with PAH are not only pulmonary arterial pressures but also RV dysfunction [15], the compensatory expression of miR-21 could possibly rescue the failing RV. Given that previous studies have shown that miR-21 mimic-based therapy could be safely delivered to rodents as a novel opportunity to manage obesity and cutaneous wounds [25,26], further in vivo studies focusing on the potentially therapeutic role of miR-21 is crucial.…”

Using Synchrotron Radiation Imaging Techniques to Elucidate the Actions of Hexarelin in the Heart of Small Animal Models

“…Various known factors that compromise pulmonary endothelial function also lead to progressive remodeling of the pulmonary arteries and/or veins, and together, leads to elevated pulmonary arterial pressure (>25 mmHg at rest), as well as increased afterload in the right ventricle (RV) (Thenappan et al, 2018). Initially, the increased work imposed on the RV to maintain right heart output stimulates RV hypertrophy (adaptive phase) but becomes maladaptive with RV dilatation, increasing myocardial energetic demand, thereby, resulting in greatly elevated risk of death (Vonk Noordegraaf et al, 2017;Sharifi Kia et al, 2021). Activation of the sympathetic nervous system, endothelin-1, and adrenal production of catecholamines is considered to be important both for the early compensatory increase in RV contractility and in subsequent RV dysfunction and remodeling in the long term (De Man et al, 2013;Vaillancourt et al, 2017;Cassady and Ramani, 2020;Prisco et al, 2020).…”