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.

Keywords: Pulmonary arterial hypertension (PAH); coronary vasculature; metabolism; right ventricular failure (RV failure); sex hormones.

Figure 1

The vicious cycle of RV failure in PAH. In the setting of underlying genetic predispositions, initiating or modifying factors such as drugs, inflammation, infection, and/or sex hormones begin the vicious cycle of RV failure either through direct action upon the RV (via altered metabolism or transcriptional regulation), or secondarily through increased PVR and RV ischemia. RV, right ventricular; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; RVSP, right ventricular systolic pressure.

Figure 2

Schematic diagram of mechanisms underlying dysfunctional angiogenesis in the progression from adaptive RV hypertrophy to maladaptive RV failure in PAH. RV, right ventricular; PAH, pulmonary arterial hypertension.

Figure 3

Sex hormone synthesis pathways with known effects of intermediates upon pulmonary vascular and RV cardiomyocyte remodeling. RV, right ventricular.

Figure 4

Summary of metabolic derangements identified in RV cardiomyocytes in PAH. Solid arrows denote pathways increased in PAH, and dashed arrows represent pathways decreased in PAH. RV, right ventricular; PAH, pulmonary arterial hypertension.

Figure 5

Main mechanisms of action of metformin, dichloroacetate (DCA), and PPARγ agonist pioglitazone in cardiomyocytes in the prevention and/or treatment of RV failure in PAH. RV, right ventricular; PAH, pulmonary arterial hypertension. SLC22A1, organic cation transporter; mGPD, mitochondrial glycerophosphate dehydrogenase; AMPK, 5' AMP-activated protein kinase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; HK 1/2, hexokinase 1/2; PFK, phosphofructokinase; Glut1/4, glucose transporter 1/4; FFA, free fatty acid; TCA, tricarboxylic acid; PPAR, peroxisome proliferator-activated receptor.