Mechanism and Treatment of Right Ventricular Failure Due to Pulmonary Hypertension in Children

Abstract

Pulmonary hypertension (PH) is a progressive disorder characterized by obstructive changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance (PVR), right ventricular (RV) strain, and eventual RV failure (RVF). Despite advancements in medical therapy, PH remains associated with significant morbidity and mortality, particularly in children. RVF is a clinical syndrome resulting from complex structural and functional remodeling of the right heart, leading to inadequate pulmonary circulation, reduced cardiac output, and elevated venous pressure. Management paradigms for pediatric PH diverge significantly from those in adults, particularly due to the predominance of congenital heart disease (CHD) and the dynamic nature of pediatric cardiovascular and pulmonary development. CHD remains a principal driver of PH in children, and its associated pathophysiology demands a nuanced approach. In patients with unrepaired left-to-right shunts, elevated pulmonary blood flow can lead to progressive pulmonary vascular remodeling and increased PVR. The postoperative persistence or progression of PH may occur if irreversible vascular changes have already developed. Current PH treatments primarily focus on reducing PVR, yet distinguishing between therapeutic approaches that target the pulmonary vasculature and those aimed at improving RV function remain challenging. In pediatric patients with progressive PH despite optimal therapy, additional targeted interventions may be necessary to mitigate RV dysfunction and disease progression. This review provides a comprehensive analysis of the mechanisms underlying RVF in PH, incorporating insights from clinical studies in adults and experimental models, while highlighting the unique considerations in children. Furthermore, it explores current pharmacological and interventional treatment strategies, emphasizing the need for novel therapeutic approaches aimed at directly reversing RV remodeling. Given the complexities of RV adaptation in pediatric PH, further research into disease-modifying treatments and innovative interventions is crucial to improving long-term outcomes in affected children.

Keywords: pulmonary hypertension; right heart failure; right ventricular failure.

Figure 1

Types of pulmonary hypertension based on hemodynamics (original diagram) [IpcPH, isolated postcapillary pulmonary hypertension; CpcPH, combined postcapillary and precapillary PH; PVOD/PCH, pulmonary vaso-occlusive disease/pulmonary capillary hemangiomatosis].

Figure 2

Pressure—volume loop of the RV (original diagram) [ESP, end-systolic pressure; EDP, end-diastolic pressure; ESV, end-systolic volume; EDV, end-diastolic volume; ESPVR, end-systolic pressure—volume relationship; EDPVR, end-diastolic pressure—volume relationship; Ea, arterial elastance; Ees, ventricular elastance].

Figure 3

Hemodynamic progression in pulmonary hypertension (original diagram) [PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; CO, cardiac output; NYHA, New York Hearth Association; RV-PA, right ventricle—pulmonary artery].

Figure 4

Experimental therapies for right ventricular failure (RVF) targeting novel pathways and therapeutic strategies (original diagram created for illustrative purposes). [Green arrows indicate pathway activation or stimulation. Red lines denote pathway inhibition. Note: Some pathways have been simplified for clarity and visual representation. HIF, hypoxia inducible factor; sGC, soluble guanylate stimulator; PDE5, phosphodiesterase 5; ECM, extracellular matrix; TLR9, toll-like receptor 9 (TLR9); NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; ARNI, angiotensin neprilysin inhibitors; SGLT2i, sodium–glucose cotransporter 2 inhibitors; PDE3, phosphodiesterase 3; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; FDGF, fibroblast growth factor; AMPK, 5′-adenosine monophosphate-activated protein kinase; MAPK, mitogen-activated protein kinase; p53, tumor protein 53; PGC-1α, peroxisome gamma coactivator-one alpha (PGC-1α); PARP, poly (ADP–ribose) polymerase; PPAR, peroxisome proliferator activated receptor; ATP, adenosine triphosphate].

Figure 5

Mechanisms of action of established therapies for pulmonary hypertension (PH) targeting key signaling pathways (original diagram created for illustrative purposes). [Blue lines indicate pathway activation or stimulation. Red lines denote pathway inhibition. Note: Some pathways have been simplified for clarity and visual representation. ETA: endothelin receptor A; ETB: endothelin receptor B; ERA, endothelin receptor antagonist; cAMP: cyclic adenosine monophosphate; PGI₂: prostaglandin I₂; IP, prostacyclin receptor; NO: nitric oxide; sGC: soluble guanylate cyclase; PDE5: phosphodiesterase type 5; GTP: guanosine diphosphate; cGMP: cyclic guanosine monophosphate; GMP: guanosine monophosphate].

Figure 6

Proposed sequencing of add-on therapy for pediatric patients with PH [RHC: right heart catheterization; PDE-5: phosphodiesterase-5; ERA: endothelial receptor antagonists; IP: prostacyclin receptor; sGC: soluble guanylate cyclase].

Figure 7

Mechanisms of selected novel therapies for the treatment of PH which also target RV remodeling (original diagram). [The green line indicates pathway stimulation; the red line indicates inhibition. Some pathways have been simplified for the purposes of depiction within the diagram. KIT, CD117 or c-lit; ASK1, apoptosis signal-regulating kinase 1; JAK, Janus kinase; BMP 9, bone morphogenetic protein 9; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; PARP, poly (ADP–ribose) polymerase; PDH, pyruvate dehydrogenase; PDGFR, platelet-derived growth factor receptor; PDK, pyruvate dehydrogenase kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma; ROCK, Rho-associated protein kinase; ACTRII, activin receptor type II; DHEA, dehydroepiandrosterone; ALK, activin receptor-like kinase; CSF1R, colony-stimulating factor 1 receptor; SMAD, SMA- and MAD-related proteins; STAT3, signal transducer and activator of transcription; TP, thromboxane-prostanoid receptor].