Pediatric heart failure: Current approach and treatment

Abstract

Pediatric heart failure (HF) is a heterogenous disease process. While the incidence is low compared to adults, resource utilization and in hospital mortality is higher. We aim to review the current approaches and treatment strategies for pediatric HF and discuss ongoing efforts to improve outcomes for this patient population. Pediatric HF is a diverse disease entity with variable pathophysiologic processes and symptoms. This review will focus on myocardial failure related to intrinsic cardiomyocyte, or cardiac muscle cell, dysfunction. While myocardial failure is a shared pathway in adult and pediatric HF, unique disease mechanisms are observed in pediatric patients, providing potential explanations for why existing HF treatment regimens are more effective in adults than children. Diagnosis and serial assessment of pediatric HF is achieved by employing multimodality imaging techniques, laboratory evaluation, and cardiac catheterization, as well as sleep and exercise studies. Pharmacologic therapies are largely based on adult guideline directed medical therapy, although supportive evidence is lacking in pediatric HF. Novel therapies are being developed that have potential for efficacy based on the current understanding of pediatric specific HF pathophysiology. Medical therapy for HF is often complemented by non-pharmacologic therapies, and in cases of end stage HF, patients may require ventricular assist devices or heart transplantation. The current approaches and treatments of pediatric HF face unique challenges; however, there is reason for an optimistic future. Improved outcomes can be achieved by utilizing emerging therapies and technologies, increasing collaboration, and through a dedication to delivering equitable care.

Background

Pediatric heart failure (HF) is a complex, heterogeneous disease entity with wide ranging pathophysiology and symptomatic manifestations. As such, defining HF as an all-encompassing syndrome is difficult. For the purposes of this review, Hsu et al provide a compelling definition stating that pediatric HF is “[…] a progressive clinical and pathophysiological syndrome caused by cardiovascular and non-cardiovascular abnormalities that results in characteristic signs and symptoms including edema, respiratory distress, growth failure, and exercise intolerance, and accompanied by circulatory, neurohormonal, and molecular derangements.¹” More broadly speaking, the American Heart Association/American College of Cardiology/HF Society of America define HF as “[…] a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood.²” Historically speaking, the medical community’s understanding of heart function and failure has undergone a fascinating evolution, advancing from Galen’s theory that the heart served the purpose of generating heat to Harvey’s recognition that the heart is a circulatory pump.³ Despite advancements in diagnostic approaches, therapies, and interventions, there is still substantial work to be done to improve the care of pediatric patients with HF. With an incidence of 0.87-7.6 per 100,000 children, the prevalence of the condition is low compared to adult HF rates.⁴ However, these figures significantly underestimate the true disease burden, as pediatric cases involve a greater number of at-risk productive life years, higher resource and emergency care utilization, and increased hospital mortality compared to adult HF.⁵ Direct comparisons of pediatric and adult HF patients with cardiomyopathy suggests that mortality is higher for children (7.7% vs 5.6%), charges are greater, and length of stay is longer.⁶ Furthermore, 40% of pediatric cardiomyopathy patients die or require transplant within 2 years of diagnosis, whereas the mortality rate for an ambulatory adult with HF is 13.5%.⁷ The purpose of this review is to explore the current approaches and treatment strategies for pediatric HF and outline future developments aimed at improving outcomes for this patient population. There are some important limitations of this review to consider. Management of acute decompensated HF is not discussed, and there is only brief mention of treatment of HF for the failing Fontan as well as the use of mechanical circulatory support and heart transplantation.

Pathophysiology of pediatric HF

The understanding of the pathophysiologic mechanisms of pediatric HF has advanced substantially over the last century, and with this development has come the recognition that pediatric HF is a diverse clinical syndrome. Broadly speaking, the underlying etiologies can be grouped into two categories: patients with structurally normal hearts and those with structurally abnormal hearts. Contained within these two categories is a wide array of distinct disease entities, including but not limited to cardiomyopathies, arrhythmias, myocarditis, and congenital heart disease (CHD). Among patients with CHD, patients can be distinguished depending on whether their pathology is related to pressure overload, volume overload, or a combination of the two. Alternatively, in the management of adult HF, patients are categorized based on their left ventricular ejection fraction (EF) given the prognostic implications.⁸ Future study will be required to determine if this same approach to functional categorization carries similar clinical significance in pediatric HF. This review will specifically focus on HF related to intrinsic cardiomyocyte, or cardiac muscle, pathology with the unifying feature of myocardial failure.1, 9

Unique attributes of pediatric HF and therapeutic implications

While there are some similarities between the underlying pathophysiology of myocardial failure in adults and children, there are also distinct differences. Recognition of these differences are critically important in understanding differential therapeutic response and in driving identification of age- and disease-specific treatments of HF. At the molecular level, there are distinctly different miRNA and transcriptome profiles in the myocardium of adult and pediatric patients with idiopathic dilated cardiomyopathy (DCM).10, 11 Specifically, these differences point towards maintenance of an incompletely differentiated state in pediatric DCM and a gene expression pattern that predicts cardiac dysfunction in the absence of cardiomyocyte hypertrophy and fibrosis, both of which are hallmark findings in adult HF and a direct target of therapy.11, 12

It is compelling to consider that molecular and histologic differences in the pediatric myocardium could provide some rationale for age-related responses to HF therapies. For example, while a clinical trial of chronic milrinone therapy in adults demonstrated an increased risk of all-cause and cardiovascular mortality,¹³ the pediatric literature suggests that milrinone, a phosphodiesterase-3 inhibitor (PDE3i), can be safely administered as a bridge to transplant or recovery.14, 15, 16 A potential explanation of this differential treatment response is the finding that in pediatric myocardium chronic administration of PDE3i results in partial restoration of cAMP levels and rescue of phospholamban (PLB) phosphorylation, while the myocardium of adults treated with PDE3i remains depleted of cAMP and with low levels of phosphorylated PLB.¹⁷ Additionally, adaptations of the beta adrenergic system are different between pediatric and adult patients, with downregulation of both β₁ and β₂ adrenergic receptor expression in the myocardium of children with DCM, whereas adult patients only exhibit downregulation of β₁ receptors.¹⁸ While there were many limitations to the randomized controlled clinical trial (RCT) of carvedilol in children, it is worth considering that age-related differences in β receptor subtype remodeling could have contributed to the neutral results of this trial.¹⁹

Adaptations of the failing single ventricle

Pediatric patients born with single ventricle CHD, such as hypoplastic left heart syndrome, are at risk for HF and exhibit unique pathophysiology that must be taken into account when considering therapeutics. As was described above in the explanted hearts of children with end-stage DCM, a study of failing single ventricle myocardium also demonstrated absence of pro-fibrotic gene expression and histologic fibrosis.²⁰ In terms of beta-adrenergic receptor expression, the myocardium of failing single ventricles demonstrate downregulated β₁ and preserved β₂ expression, similar to adults with HF.²¹ However, as opposed to adults with HF, downstream signaling molecules that increase contractility, such as calcium/calmodulin-dependent protein kinase II and cAMP are increased and preserved compared to non-failing myocardium, respectively, potentially explaining why there was a trend towards a detrimental effect of carvedilol in children with systemic right ventricular failure in the pediatric trial.19, 21 Lastly, myocardium from failing single right ventricles exhibit impaired bioenergetics, as demonstrated by decreased mitochondrial carnitine palmitoyl transferase I and II activity, reduced mitochondrial oxidative phosphorylation, and impaired myocyte ATP production.²² Together these data suggest that both age and the etiology of myocardial failure are important considerations in identifying efficacious therapies in children.

Patients with single ventricle heart disease undergo surgical palliation in infancy and childhood, culminating in the Fontan operation. With the growing population of patients with single ventricle heart disease surviving into adolescence and adulthood, the burden of Fontan-associated complications, including HF, has become a prominent focus among congenital cardiology healthcare teams. There is very little evidence to guide the treatment of HF in this patient population, but efforts are ongoing to develop consensus approaches for the classification and treatment of HF that represent a more complete discussion than can be included in this review, so are referenced here.23, 24., 25, 26, 27

Diagnosis and assessment

Diagnosis and assessment of pediatric HF begins with the foundation of a thorough history and physical examination, chest X-ray, electrocardiogram, echocardiogram, and laboratory evaluation. Additional diagnostic modalities and their application are outlined in Table 1. Typical symptoms include respiratory distress, poor growth, feeding difficulties, fatigue, and exercise intolerance. Importantly, clinicians must recognize that symptoms, and exam findings will vary depending on the age of the child and underlying pathophysiology. Borrowing from adult guidelines, clinicians utilize ACC/AHA staging as well as functional New York Heart Association classification for older children and the Ross classification for infants with Stage C and D HF.8, 28

Table 1.

Diagnostic Modalities and Their Applications in Pediatric Heart Failure

Modality	Recommendation
Genetic Testing	Comprehensive or targeted panel: for pediatric patients with any type of cardiomyopathy.
	Variant-specific genetic testing: for 1st degree family members after identifying a pathogenic/likely pathogenic variant.
	Exome or genome sequencing: for severe or complex cardiomyopathy after inconclusive panel.
	Mitochondrial gene sequencing: for patients with multisystemic disease or excessively elevated lactate levels.
	Whole exome testing: initial step in testing for cardiomyopathy subtypes such as infantile, syndromic, metabolic.
Laboratory Testing	BNP/NT-proBNP: part of initial diagnostic testing; serial monitoring can help with prognosis and response to treatment.
	Metabolic tests: lactate, pyruvate, ammonia, etc., for patients with multisystem disease cardiomyopathy.
Echocardiography	2-D imaging: evaluation for CHD (including coronary artery anatomy), serial assessment of ventricular dimensions, function, mass, and remodeling.
	Diastolic function: mitral inflow, tissue doppler imaging (TDI), pulmonary venous doppler as part of serial monitoring.
	3-D imaging, strain, TDI: for serial evaluation of pediatric cardiomyopathy or HF, though evidence is limited.
	Right heart pressure estimation: for tracking treatment response and monitoring for evidence of progression of left ventricle restrictive physiology.
Cardiac MRI	Phenotyping: for identifying cardiomyopathy phenotype in those not well characterized by echo including arrhythmogenic ventricular cardiomyopathy and left ventricular non-compaction.
	General Diagnostics: for assessing ventricular size, function, detecting fibrosis/edema/inflammation.
Exercise and Physical Activity	Cardiopulmonary exercise testing (CPET) with peak VO2 measurement: for prognosis and assessment.
	6-minute walk test (6MWT): risk stratification and assessment if CPET can’t be performed.
Cardiac Catheterization	Hemodynamic assessment: management guidance and risk stratification.
	Coronary angiography: for patients with unexplained HF, concern for ischemic myocardial injury, and inconclusive non-invasive imaging (especially in infants with new onset DCM).
	Endomyocardial biopsy: considered when the benefit of actionable results (e.g., inform management or determine prognosis such as in giant cell myocarditis) outweigh the risks (e.g., perforation, tricuspid valve injury, complications of anesthesia).
Sleep Evaluation	Sleep study: assessment for sleep disordered breathing in patients with history suggestive of apnea.

Abbreviations: CHD, congenital heart disease; HF, heart failure.

Pharmacologic treatment for HF with reduced EF

Despite advancements in the understanding of the mechanistic underpinnings of pediatric HF, due to the heterogeneity and rarity of the disease, development of pediatric specific HF therapies has been limited. Consequently, treatment of pediatric HF remains grounded in principles from adult guideline directed medical therapy (GDMT), in which therapies target maladaptive circulatory, neurohormonal, and molecular changes discovered in adult HF patients.3, 9 GDMT, validated through large RCTs, has resulted in dramatic improvements in adult HF survival, morbidities, HF hospitalizations, and quality of life.²⁹ However, there remains limited evidence demonstrating the efficacy of GDMT in pediatric HF, with most recommendations based on level of evidence C (expert consensus) as outlined in the 2014 International Society for Heart and Lung Transplantation Guidelines for the management of pediatric HF.⁹

Diuretics

Diuretics are administered to treat children with HF when the individual is determined to be fluid overloaded. Loop diuretics, such as furosemide, inhibit the Na⁺/ K⁺/2 Cl^- transporter located in the thick ascending limb of the loop of Henle, and is typically first line diuretic therapy.30, 31 Thiazide diuretics work synergistically with loop diuretics by inhibiting sodium reabsorption in the distal convoluted tubule and are therefore employed to increase diuretic effect or overcome tolerance.³⁰ Adult patients with HF have demonstrated improved clinical outcomes when initiated on diuretics prior to discharge.³² Similar evidence does not exist in the pediatric literature; however, diuretic therapy is a mainstay for symptomatic management in the volume overloaded patient.

Digoxin

Digoxin, or digitalis, is a cardiac glycoside that has been administered for medicinal purposes dating back to the late 18th century.³³ Through its inhibition of the Na-K-ATPase, calcium influx is increased and contractility augmented.³⁴ Adult HF patients treated with digoxin demonstrated improved functional status and reduced hospitalizations; however, efficacy was limited by digoxin’s narrow therapeutic window. Despite this narrow therapeutic window, digoxin may be considered for the treatment of symptomatic pediatric HF.³⁴ Specific to the single ventricle population, in a retrospective analysis of data collected through the National Pediatric Cardiology Quality Improvement Collaborative, use of digoxin was associated with decreased mortality for single ventricle patients between stage I and II palliation. In this study, reduced EF was not the indication for digoxin treatment, and the findings were independent of the patient’s ventricular function.³⁵ In general, there is wide practice variation, but with the development of more contemporary therapies, the use of digoxin for the treatment of pediatric and adult HF is fairly uncommon. However, based on the National Pediatric Cardiology Quality Improvement Collaborative study, digoxin is frequently used for infants with single ventricle CHD during the interstage period.

Renin-angiotensin-aldosterone system inhibitors

Activation of the renin-angiotensin-aldosterone system is considered a hallmark of HF, and several medications are employed to block this pathway, including, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, aldosterone antagonists, and angiotensin receptor neprilysin inhibitors (ARNI). Early application of ACE inhibition in uncontrolled studies of pediatric cardiomyopathy associated with HF with reduced ejection fraction (HFrEF) demonstrated favorable hemodynamic effects, as well as a trend towards improved 1 year survival.36, 37 In one of the few pediatric HF RCTs, PANORAMA-HF sought to assess the efficacy of angiotensin receptor neprilysin inhibition (e.g., Entresto) as compared to ACE inhibition in children with HFrEF.³⁸ Early results of this study demonstrated a reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) in children treated with ARNI, resulting in FDA approval of the combined drug, sacubitril/valsartan.³⁹ At the conclusion of the study, there was no difference in the primary outcome (a global rank end point) between children treated with ARNI compared to the ACE inhibitor, enalapril. However, both treatment groups demonstrated improvement in patient reported disease severity, functional status, and NT-proBNP, suggesting renin-angiotensin-aldosterone system inhibition is beneficial for children with HF.⁴⁰ Based on the results of the PANORAMA-HF study, combined with extrapolation of adult data, the use of ACE inhibitors or ARNIs are recommended for the treatment of pediatric HFrEF. Despite lack of data specific to children, angiotensin receptor blockers (e.g., losartan) are used for children intolerant of ACEi, and aldosterone antagonists (e.g., spironolactone) are considered reasonable for the treatment of children with symptomatic HFrEF.

Beta-blockade

β-receptor antagonism, or beta-blockers, are central to adult GDMT. Selective beta antagonism, such as with the use of metoprolol (a β₁-specific blocker), has been shown to improve functional class/ventricular function in small retrospective analyses of pediatric patients with HFrEF related to a variety of etiologies.⁴¹ There are no controlled studies of metoprolol for the treatment of HF in children. A retrospective analysis of carvedilol, a non-selective beta-blocker, demonstrated improved left ventricular systolic function and symptom severity in children with DCM.42, 43 Based on these promising results, as well as the dramatic efficacy in adults with HF, an RCT of carvedilol was performed in children with symptomatic HFrEF. There was no difference between carvedilol and placebo in this study, although the study was limited by a highly heterogenous participant population and a higher-than-expected spontaneous improvement rate in study participants. Additionally, subgroup analysis demonstrated a trend towards improvement in children with a systemic left ventricle and a trend towards worsening in children with a systemic right ventricle.¹⁹ As discussed previously, differential β receptor adaptation in children compared to adults is thought provoking when considering the results of this trial.18, 21 Additionally, the results of the carvedilol trial underscored the importance of considering ventricular morphology, and future RCTs (including the PANORAMA-HF study) excluded children with single ventricle heart disease or a systemic right ventricle. Regardless, the use of beta-blockers, either carvedilol or β₁-selective blockers such as metoprolol, for the treatment of children with HFrEF due to systemic left ventricular systolic dysfunction in a biventricular circulation is reasonable.

Ivabradine

Elevated resting heart rates are associated with an increased risk of death in adults with HFrEF44, 45 and in children with cardiomyopathy.⁴⁶ While beta-blockers are the mainstay in controlling heart rate in patients with HF, ivabradine emerged as an alternative for those recalcitrant to the chronotropic effects of beta-blockers. By inhibiting the I_f, or funny channels, ivabradine slows phase 4 of the cardiac action potential and consequently reduces heart rate without any negative inotropic effect.⁴⁷ In the SHIFT study, ivabradine resulted in reduced rates of cardiovascular death or hospitalization in adults with an elevated resting heart rate despite being treated with GDMT.⁴⁸ Subsequently, an RCT of ivabradine vs placebo was performed in pediatric patients greater than 6 months of age with DCM and symptomatic HFrEF (e.g., Functional Class > II and left ventricular EF < 45%). The primary endpoint of heart rate reduction by >20% in the ivabradine treatment group was met, resulting in FDA approval for the use of ivabradine for the treatment of symptomatic HFrEF in children over the age of 6 months.⁴⁹

Sodium-glucose cotransporter 2 inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally prescribed for the treatment of diabetes given their glucose lowering properties. However, patients with Type 2 diabetes and HFrEF demonstrated improved cardiovascular outcomes when treated with SGLT2i.⁵⁰ Further RCTs in adults have demonstrated that the beneficial HF treatment effects are seen regardless of the presence of diabetes.⁵¹ The mechanism by which SGLT2i exerts its effect remains unclear, especially since SGLT2 receptors are not expressed on cardiomyocytes.⁵² Proposed mechanisms include improvement in mitochondrial function and metabolic reprogramming with increased utilization of more efficient energy sources for the heart, including free fatty acids and ketones.⁵³ To date, pediatric HF studies evaluating the efficacy of SGLT2i are limited; however, there have been small uncontrolled studies demonstrating safety and improved ventricular systolic function.24., 54 Based on extrapolation of adult clinical trial data and the small pediatric studies to date, it is reasonable to consider SGLT2i (e.g., dapagliflozin, empagliflozin) for the treatment of pediatric HFrEF, but larger, controlled studies are needed.

Emerging therapies

In addition to these established therapies, there are emerging HF agents with novel mechanisms of action. Alpha-myosin activators such as omecamtiv mecarbil and danicamtiv have been developed to directly stimulate myocardial contractility. In the clinical trial GALACTIC-HF, omecamtiv reduced the risk of the combined primary outcome, HF events, or cardiovascular death;⁵⁵ however, the FDA determined that there was not enough evidence that the benefits outweighed the risks. Therefore, additional clinical trials are underway to further assess the efficacy and safety of alpha-myosin activators in adults with HFrEF.56., 57 Decreased alpha-myosin gene expression in decompensated HF patients with a single right ventricle suggests that this therapy may be efficacious in this cohort of patients.²¹

Histone deacetylase (HDAC) inhibitors have been studied after recognition that certain HDAC subtypes are upregulated in adult HF.⁵⁸ Some HDAC subtypes are also upregulated in the myocardium of failing single ventricles, supporting consideration of the study of HDAC inhibitors in the single ventricle population as well.⁵⁹

Vericiguat is a soluble cyclic guanosine monophosphate stimulator and sensitizes cyclic guanosine monophosphat to nitric oxide. In early adult studies this therapy was demonstrated to be safe and reduced the risk of death or HF hospitalization.⁶⁰ A phase II/III RCT of vericiguat vs placebo (VALOR) is presently underway in children.

Lastly, elamipretide, a novel agent directed at cardiolipin, a phospholipid located on the inner mitochondrial membrane, was developed as a mitochondria-targeted therapeutic to improve coupling of the electron transport chain.⁶¹ Elamipretide is currently under FDA review for the specific management of Barth syndrome, which is associated with altered cardiolipin remodeling.⁶² In addition, ex vivo treatment with elamipretide improves mitochondrial function in explanted failing hearts regardless of age and HF etiology, suggesting elamipretide warrants further investigation in the treatment of HF.⁶³

As demonstrated, it has been challenging to generate an evidence-basis in children for the therapies developed for adult HF. This may be partly explained by the heterogenous etiologies of HF in children, the fact that pediatric HF studies are limited by small patient numbers, and the low frequency of traditional clinical endpoints. Importantly, these deficiencies are being increasingly recognized and addressed through an emphasis on pediatric specific research and improved study design.⁶⁴ Furthermore, dosing of HF medications is also variable in children.⁶⁵ The Advanced Cardiac Therapies Improving Outcomes Network (ACTION), an international learning health system formed in 2017 to improve pediatric HF outcomes, draws on the strength of collaboration and is leading the effort to disseminate and standardize dosing of HF therapies in children. Similar to the consensus-directed medical therapy document published by ACTION, Table 2 (adapted from Nandi et al⁶⁵) lists the HF therapies discussed above for children with HFrEF and their recommended starting and goal doses.

Table 2.

Oral Heart Failure Therapies Used in Pediatric Patients Less Than 50 kg With Recommended Starting Dose Followed by Minimum Goal Dose

Medication	Indication	Starting dose	Minimum goal dose
Digoxin *	Symptomatic HFrEF	Age Based	Not to exceed digoxin level of 0.5-0.9 ng/ml
Captopril**	Reduced ejection fraction	0.33 mg/kg TID (max 6.25 mg)	1 mg/kg TID
Enalapril**	Reduced ejection fraction	0.05-0.1 mg/kg BID	0.2 mg/kg BID
Lisinopril**	Reduced ejection fraction	0.1 mg/kg daily	0.4 mg/kg daily
Entresto (No Prior ACE/ARB)**	Symptomatic HFrEF	0.8 mg/kg BID (suspension)	3.1 mg/kg BID
Entresto (Prior ACE/ARB)**	Symptomatic HFrEF	1.6 mg/kg BID (suspension)	3.1 mg/kg BID
Spironolactone**	Symptomatic HFrEF	0.5-1 mg/kg daily	0.5 mg/kg daily
Carvedilol**	Reduced ejection fraction	0.05 mg/kg BID	0.5 mg/kg BID
Metoprolol Immediate Release**		0.25 mg/kg BID	0.5 mg/kg BID
Ivabradine***	To achieve HR reduction in a patient with stable HF	0.02 mg/kg BID (6-12 months), 0.05 mg/kg BID (>12 months)	Titrated to achieve target heart rate
Dapagliflozin****	Symptomatic HFrEF	0.1-0.2 mg/kg daily	0.1-0.2 mg/kg daily

Asterisks denote the source for dosing determination *,³⁴ **,⁶⁵ ***,⁴⁹ ****.⁵⁴

Pharmacologic treatment for HF with preserved EF

The majority of the discussion thus far has been dedicated to HFrEF; however, clinical HF can develop in patients with predominantly diastolic dysfunction and preserved ventricular function; so called HF with preserved EF (HFpEF). In HFpEF there is impaired ventricular relaxation and increased ventricular stiffness. Understanding of this disease phenotype, and thus treatment, has been made difficult by the heterogenous etiologies of HFpEF in children, which include cardiomyopathies (e.g., hypertrophic cardiomyopathy and restrictive cardiomyopathy) and CHD.⁶⁶ To date there have been no RCTs to guide the treatment of HFpEF in children. Treatment of adults with HFpEF, from which pediatric recommendations are based, has been challenged by several neutral RCTs of existing GDMT agents.67, 68, 69, 70 Symptom management with the use of diuretics is recommended, with the goal of achieving euvolemia while avoiding excessive diuresis in patients that are preload dependent.30, 31 Additional recommended pharmacotherapy now includes the use of SLGT2i in adults with HFpEF given findings from the EMPEROR-Preserved trial demonstrating improvement in HF hospitalization or cardiovascular death,⁷¹ in addition to improvements in reported health status and quality of life.⁷² Despite the lack of controlled studies of the pharmacokinetics, safety, and efficacy of SGLT2i in pediatric HF, these medications are being frequently prescribed in children with HFpEF based on the small pediatric series previously described and extrapolation of adult studies.

Non-pharmacologic interventions and advanced cardiac therapies

Non-pharmacologic interventions for HF are wide ranging, complementing pharmacotherapies to achieve improved outcomes for pediatric HF. Lifestyle, nutritional, and psychosocial support ensures that attention is extended beyond the heart pathology and that co-morbidities are being addressed (Figure 1). Such support relies on interprofessional teams to provide well-rounded patient care. Regular physical activity and cardiac rehabilitation, in particular, deserve further investigation and should be guided by appropriate risk stratification and shared-decision making approaches.⁷³

Figure 1.

Non-pharmacologic therapies to be used in conjunction with pharmacotherapy in pediatric patients with heart failure.73, 74, 75, 76, 77, 78, 79, 80, 81 Created in BioRender. https://BioRender.com/f97m245.

In the case of end stage HF, patients can be managed with heart transplantation. Approximately 600 pediatric heart transplants are performed worldwide each year, and CHD is the most common underlying condition in infants, whereas cardiomyopathy is most common in children.82, 83 Outcomes post-transplantation continues to improve, with reported 10-year survival of 68% and 70% for patients with CHD and cardiomyopathy, respectively.⁸⁴ Ventricular assist devices (VADs) are also being used more frequently to support pediatric patients with HF as a bridge to decision, recovery, or transplant. Roughly 1/3 of all transplanted patients are being bridged with a VAD, and approximately 50% of children with DCM requiring transplant were bridged with a VAD in place.82, 85 Additionally, pediatric patients with CHD are comprising an increasing proportion of pediatric patients supported with a VAD as demonstrated by the most recent Pedimacs report in which 26% of the patients had underlying CHD.⁸⁵ Also, there is evidence that patients with complex CHD are more likely to be in advanced HF at the time of implantation, suggesting that earlier referral may improve outcomes for this patient population.⁸⁶ Recognizing that VAD technology was developed for use in adult HF, there has been a push to develop pediatric specific devices, to supplement the Berlin Heart, that are better designed to support smaller patients.⁸⁷ Additional technologies, including pacemakers to achieve resynchronization, are utilized in children with electrical dyssynchrony and systolic HF.⁸⁸ Internal cardioverter defibrillators are implanted as secondary prevention of sudden cardiac arrest, as well as primary prevention in certain high-risk cardiomyopathy patients.⁸⁹

Emerging technologies include devices such as CardioMEMS which can be implanted in the pulmonary arteries and used for remote HF monitoring and data collection, allowing for more data driven titration of medications.90, 91 Less invasively, wearables such as fitness watches that monitor step counts are being utilized in the management of adult HF given the evidence that average step count correlates with hemodynamic exercise testing performance, patient-reported outcomes and health status, and all-cause mortality and cardiovascular events.92, 93, 94 Similar efforts to establish the utility of wearables in the monitoring of children with HF are underway through a prospective observational study being performed by ACTION. In the not-too-distant future researchers may even develop the ability to bioengineer cardiac tissue using induced pluripotent stem cells for use as an alternative to human donor-derived heart transplantation.95, 96

Future directions and innovations in pediatric HF treatment

While treatment of pediatric HF faces unique challenges with clear room for improvement, there is reason to be optimistic as we observe advances in biomarker testing, improved collaboration, as well as greater emphasis on improving healthcare equity. Multi-omic profiling has greatly advanced our understanding of the underlying disease mechanisms driving pediatric HF, including transcriptomics, proteomics, and metabolomics.22, 97 Furthermore, multi-omic testing can be used to provide prognostic information and more specifically predict which patients will respond to pharmacotherapy.98, 99, 100, 101

As described earlier, pediatric HF research has been hampered by limited sample size. Acknowledging this, collaboration among centers is essential. In addition to multicenter clinical trials, collaboration has been enhanced through ACTION. By uniting patients, families, clinicians, researchers, payors, and industry partners, ACTION employs a quality improvement and research-based approach to share data, discover innovations, and implement better solutions in pediatric HF care.¹⁰²

Lastly, none of these scientific advancements will bear fruit if the medical community does not emphasize the delivery of equitable healthcare to all pediatric patients affected by HF and address barriers to care, including health literacy, distance from a pediatric HF center, and socioeconomic status. Focus should be directed towards ensuring that patients and their families understand their disease, improving access to high quality and specialized HF experts, and facilitating a transition from pediatric to adult care. It is imperative that delivery of equitable healthcare is at the center of all treatment models for pediatric HF.

Conclusion

The understanding and treatment of pediatric HF has demonstrated substantial and accelerating progress; however, rates of morbidity and mortality remain unacceptably high with outcomes that are inferior to those of adult HF. There is increasing recognition that pediatric HF can benefit from adult-based therapies, but there are important differences that could be leveraged to better identify responders vs non-responders to GDMT and explore unique therapies targeted specifically to the mechanisms driving HF in children. The shared goals of the pediatric HF community to advance the field through mechanistic studies, collaborative learning, consideration of novel clinical trial designs, equitable delivery of care, and enhanced device development leaves reason for optimism.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Shelley D. Miyamoto reports a relationship with Bayer Corporation that includes: board membership. Shelley D. Miyamoto reports a relationship with Secretome Therapeutics that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.