A Review of Contemporary and Future Pharmacotherapy for Chronic Heart Failure in Children

Abstract

This review delves into the most recent therapeutic approaches for pediatric chronic heart failure (HF) as proposed by the International Society for Heart and Lung Transplantation (ISHLT), which are not yet publicly available. The guideline proposes an exhaustive overview of the evolving pharmacological strategies that are transforming the management of HF in the pediatric population. The ISHLT guidelines recognize the scarcity of randomized clinical trials in children, leading to a predominance of consensus-based recommendations, designated as Level C evidence. This review article aims to shed light on the significant paradigm shifts in the proposed 2024 ISHLT guidelines for pediatric HF and their clinical ramifications for pediatric cardiology practitioners. Noteworthy advancements in the updated proposed guidelines include the endorsement of angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), and soluble guanylate cyclase (sGC) stimulators for treating chronic HF with reduced ejection fraction (HFrEF) in children. These cutting-edge treatments show potential for enhancing outcomes in pediatric HFrEF. Nonetheless, the challenge persists in validating the efficacy of therapies proven in adult HFrEF for the pediatric cohort. Furthermore, the proposed ISHLT guidelines address the pharmacological management of chronic HF with preserved ejection fraction (HFpEF) in children, marking a significant step forward in pediatric HF care. This review also discusses the future HF drugs in the pipeline, their mechanism of actions, potential uses, and side effects.

Keywords: HF with preserved ejection fraction (HFpEF); HF with reduced ejection fraction (HFrEF); chronic heart failure; heart failure in children; pharmacotherapy for HFrEF and HFpEF in children.

Figure 1

Pathophysiology of chronic HFrEF. ↓ Decrease, ↑ Increase. Reproduced from: Das, B.B. Children. 2018, 5(7), 88; [5] Creative Commons user license: https://creativecommons.org/licenses/by/4.0//.

Figure 2

Mechanism of action of SGLT2i and ARNI to improve Chronic HFrEF.

Figure 3

Mechanism of action of sGC stimulator (vericiguat) in HFrEF. [eNOS = endothelial nitric oxide synthetase, sGC = soluble guanylate cyclase].

Figure 4

Mechanism of action of new investigational drugs for HF in the pipeline. sGC, soluble guanylate cyclase; cGMP, cyclic guanylate monophosphate; SGLT-2, sodium glucose co-transporter-2; ROS, reactive oxygen species; LGR, leucine-rich repeat-containing G-protein coupled receptor; NO, nitric oxide; NFκB, nuclear factor kappa B transcription factor; cGMP, cyclic guanylate monophosphate; SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase; ATP, adenosine triphosphate; VEGF, vascular endothelial growth factor; ET, endothelin receptors; TGF, transforming growth factor; PKG, protein kinase G.

Figure 5

Newer drugs for HFpEF in the pipeline with their mechanism of action. TNF-α = tumor necrosis factor-α; IL-6 = interleukin-6; IL-1β = interleukin-1β; sST2 = soluble ST2 (receptor for IL-1 and 33); cGMP = cyclic guanosine monophosphate; PKG = protein kinase G; SNS = sympathetic nervous system.