Narrative review of pediatric heart failure in the age of precision medicine

Introduction

The landscape of therapies available in heart failure management has been rapidly expanding within the past decade. The American Heart Association (AHA) heart failure guidelines in 2013 only recommended medical therapy with angiotensin converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARB), beta blockers, mineralocorticoid receptor antagonists (MRA), and in select populations, hydralazine and isosorbide dinitrate (ISDN) combination (1). Development of new therapies has been accelerating with multiple new classes of medications [ARB-neprilysin inhibitors (ARNi), soluble guanylate cyclase (sGC) stimulators, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and I_f current inhibitors] becoming available and recommended for heart failure management most recently (2). Unfortunately, many of these recommendations for newer medications are based on data from studies in adult populations with cardiomyopathy. Pediatric studies are lacking and often adult data is extrapolated to the pediatric population due to insufficient data (3). Heart failure in pediatrics can generally be considered as a progressive syndrome with varying causes, including congenital heart malformations and genetic abnormalities, leading to cardiac dysfunction resulting in classical signs and symptoms (3).

The advent of rapid whole genome sequencing and identification of genetic etiologies of multiple pathologies has turned a focus on the possibilities of precision medicine. Pediatric patients with cardiomyopathy comprise a heterogeneous population with many different genetic loci that may present similar phenotypes through distinct mechanisms. As costs for whole genome sequencing have decreased (4), the potential for more widespread identification of genetic anomalies has increased as has the possibility of tailoring therapy to impact specific subpopulations. The National Research Council described the goal of precision medicine as “the selection of a subset of patients, with a common biological basis of disease, who are most likely to benefit from a drug or other treatment (5)”. This review focuses on some of these advances in this developing field of medicine. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-22-431/rc).

Methods

A literature search of PubMed utilizing the terms ‘pediatric’, ‘cardiomyopathy’, ‘heart failure’, revealed 1073 results. When the search was narrowed to the last 22 years (January 2000–August 2022) published in the English language, 993 records were obtained. Of these results, studies pertaining to the genetic basis and treatment modalities of pediatric heart failure were examined. Adding “genetics” and “precision medicine” to our search strategy further narrowed the search to 8 results. Additional notable studies were obtained from ClinicalTrials.gov. Our search strategy is summarized in Table 1.

Pathophysiology of chronic heart failure (CHF) in the general population

Systolic heart failure stems from inadequate cardiac output. The body compensates to maintain cardiac output by either increasing stroke volume or increasing heart rate (6). These mechanisms are achieved primarily through activation of the sympathetic nervous system (SNS) and activation of the renin-angiotensin-aldosterone system (RAAS). The SNS releases catecholamines that increase systemic vascular resistance and heart rate, resulting in increased mean arterial pressure and increased organ perfusion. Activation of RAAS leads to increased angiotensin II and aldosterone release resulting in increased vasoconstriction and increased water retention.

These compensatory mechanisms exacerbate heart failure as well through adverse cardiac remodeling. Increased catecholamine levels lead to hyperactivity of the SNS, enhancing apoptotic pathways and resulting in cardiomyocyte death. Chronic catecholamine exposure can cause interstitial fibrosis and induce pump dysfunction through left ventricular (LV) dilation (7). Angiotensin II leads to fibroblast activation within cardiomyocytes, myocardial scarring, among other changes that involve complex cascades of signaling molecules (8). Atrial natriuretic peptide and B-type natriuretic peptide (BNP) which have a role in regulation of extracellular volume, natriuresis and diuresis, also inhibit renin secretion of aldosterone production. Their levels are increased in patients with CHF. These molecules also inhibit cardiac remodeling, apoptosis, and fibrosis (9,10). However, these mechanisms do not prevent or stop the development of heart failure as they are easily cleared by neprilysin, levels of which are increased in CHF (11,12). These have been the primary targets of traditional heart failure therapy that are the first line therapies for patient with progressive heart failure regardless of the molecular cause of heart failure (2).

Genetic basis of disease

The identified genetic causes of cardiomyopathy are known to have varying penetrance and variable expressivity within a population. Many pathogenic mutations have been identified to have different phenotypic expressions of disease (13). As more genes have been identified, genetic testing yielding positive results for pathogenic mutations have been increasing. These diagnostic yields can potentially be further increased by also incorporating genetic testing for genes known to cause heritable arrhythmias with cardiomyopathy testing (14). Table 2 summarizes certain genetic syndromes with associated cardiomyopathies, and gene-targeted therapies.

Hypertrophic cardiomyopathy (HCM)

HCM is largely caused by mutations in sarcomeric proteins with autosomal dominant inheritance. While these genes have been well defined, yield of genetic testing in adult populations has been decreasing as less phenotypically severe disease is being diagnosed in the recent era. Identification of a causative mutation had been nearly 60% in the early era, that yield has fallen to under 40% more recently with the detection of more benign disease (15). A recent study in pediatric HCM reported sarcomeric variants in 63% of the HCM population when patients with non-sarcomeric variants are excluded, suggesting the yield of genetic testing in pediatrics remains quite robust (16). Non-sarcomeric causes of HCM [e.g., RASopathies, lysosome-associated membrane protein-2 (LAMP2), and α-galactosidase] comprise a proportion of the pediatric HCM and can be detected by genetic testing as well (17).

Dilated cardiomyopathy (DCM)

DCM is more genetically heterogenous with primarily autosomal dominant inheritance and over 100 genes that may have variants presenting with a DCM phenotype (18). Where the genes associated with development of HCM are most commonly sarcomeric, genes associated with DCM encode proteins for various functions including sarcomeric, cytoskeletal, mitochondrial, and desmosomal proteins (18). A pathogenic gene variation can be found in nearly 50% of patients with familial DCM (19). Studies of DCM may not include patients with neuromuscular syndromes [e.g., Duchenne muscular dystrophy (DMD)] known to develop a DCM phenotype, though they comprise 26% of the pediatric DCM population as the clinical pathology and progression appear to be distinct (20).

Restrictive cardiomyopathy (RCM)

RCM can be inherited or acquired. As it is a less common form of cardiomyopathy, there have been fewer studies into the genetic etiology of RCM. Two studies with small sample sizes have described an association with variants in sarcomeric proteins that can present with an HCM phenotype (21,22). A pathogenic mutation was detected in as many as 60% of patients with RCM in one cohort (22). Other inherited causes of RCM include many of the storage diseases [e.g., glycogen storage disease, Fabry disease (FD), Gaucher disease, Hurler syndrome, Hunter syndrome, and Niemann Pick disease].

Single ventricle disease

While the phenotypes that comprise single ventricle heart disease are diverse, outcomes are universally poorer in patients with a hypoplastic or inadequate left ventricle (23). Our understanding of the molecular basis for development of single ventricular disease continues to develop, one pathway is due to primary ventricular hypoplasia (24). This has been demonstrated in a murine model of hypoplastic left heart syndrome (HLHS) where mutations of genes related to cardiomyocyte proliferation (Sap130) and epithelial to mesenchymal transition (Pcdha9) produced a functional phenotype with the features of HLHS (25).

Precision medicine prescriptions

Sarcomeric HCM

HCM often results in significant left-ventricular outflow tract (LVOT) obstruction leading to inadequate cardiac output and exertional intolerance. In 2006, a study reported 70% of patient with HCM having some level of obstruction (26), though this prevalence may be reduced with the recognition of more benign disease in the current era. As the disease progresses, patients can develop diastolic heart failure due to myocardial ischemia, myocyte disarray and progressive interstitial fibrosis. The traditional therapy for symptomatic HCM with LVOT obstruction when medical management fails has been septal reduction therapy to relieve the obstruction and allow for cardiac remodeling to improve systolic and diastolic function.

Data from mice showing losartan therapy prevented development of hypertrophy (27), prompting a study of valsartan in pediatric patients with sarcomeric gene mutations without clinically apparent disease in the VANISH Trial (28). A composite score including cardiac dimensions, cardiac biomarkers and surrogates for diastolic function was prospectively measured. There was a significantly better composite score in patients receiving valsartan when compared to placebo. This result was primarily driven by favorable N-terminal prohormone of brain natriuretic peptide (NT-proBNP) trends, tissue Doppler diastolic velocities, and LV end diastolic volume (28).

Mavacamten, a selective allosteric inhibitor of cardiac myocyte ATPase, improves myocardial energetics by reducing actin-myosin cross-bridge formation. In the phase 3 trial, patients on Mavacamten demonstrated greater improvement in New York Heart Association (NYHA) functional class and greater reductions in post-exercise LVOT gradient than those on placebo. Many patients also improved by NYHA class as well (29). Cardiac MRI in patients with HCM on Mavacamten demonstrated reduced LV mass index and reduced LV wall thickness (30). A recent study strikingly showed that after 16 weeks of therapy in patients that met criteria for septal reduction therapy, 77% of patients on placebo met criteria for septal reduction therapy or underwent the procedure compared to 18% of patients on Mavacamten P<0.001) (31). The United States Food and Drug Administration approved Mavacamten for treatment of obstructive HCM in symptomatic adults and unfortunately pediatric data are lacking at this time.

MEK inhibition and Noonan syndrome (NS)

NS is an autosomal dominant condition caused by hyperactivation of RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway in about 85% of patients. Though there are other causes of the phenotypic presentation of NS that may not involve the RAS/MAPK pathway, the collective group are generally termed “RASopathies” (32). Many patients with NS have cardiovascular involvement including semilunar valve abnormalities and HCM. Infants with NS and HCM have elevated morbidity and mortality at one year of age compared to children with sarcomeric mutations, especially if heart failure occurs prior to 6 months of age (33,34).

Drugs to inhibit the RAS/MAPK signaling pathway, such as trametinib, cobimetinib, and binimetinib have been developed and approved for use in certain cancers. These drugs can potentially benefit patients with NS caused by mutations that result in gain-of-function changes in the RAS/MAPK pathway. This has been studied in murine models with mutation of RAF1 that can be seen in a small portion of patient with NS. Postnatal therapy with MEK inhibition reversed hypertrophy, normalized cardiomyocyte size, and reduced fractional shortening more towards the normal range (35). Since that time there have been several case reports describing anecdotal improvements with MEK inhibition in patients with NS. Three groups have now described cases of four patients with observed improvement in patients with NS and HCM after use of trametinib (36-38). Additionally, studies have described resolution of arrhythmia and lymphatic abnormalities after initiation of MEK inhibition therapy (38-40). More investigation is needed in this domain, though there are some encouraging early reports of this medical therapy for a patient population commonly thought to only have cardiac transplantation as a therapeutic option (33).

Barth syndrome (BS)

BS is a rare genetic disorder, inherited in an X-linked recessive pattern, resulting in various phenotypic expressions of cardiomyopathy, skeletal myopathy, growth delay, and neutropenia. Cardiac findings in patients with BS can include DCM, HCM, endocardial fibroelastosis, LV non-compaction, ventricular arrhythmia, sudden cardiac death, and prolonged QTc interval (41). BS is caused by a loss-of-function mutation in the TAZ gene, which encodes for tafazzin, a phospholipid located in the mitochondrial membrane that plays a role in cardiolipin remodeling (42). Heart failure is a significant cause of mortality in these patients with 70% developing cardiomyopathy in their first year and 14% requiring heart transplantation (41).

Elamipretide is a mitochondria-targeting tetrapeptide that binds to cardiolipin and is thought to reduce the bioenergetic dysfunction (43). In addition to improved muscle strength and 6-minute walk test after long term therapy with elamipretide, improvement was seen in cardiac function with increased indexed stroke volume (43). Another promising therapy is bezafibrate, a peroxisome proliferator-activated receptor agonist, has been shown to significantly improve cardiac function in TAZ knockdown mice (44,45).

Duchenne muscular dystrophy

DMD is caused by mutations in the dystrophin gene, which plays a role in skeletal and cardiac muscle function, generally resulting in a truncated protein. The dystrophin gene is the largest known gene and as a result the mutations resulting in the DMD phenotype are diverse. It is characterized by progressive muscular atrophy with an associated cardiomyopathy that may progress to heart failure in some patients. Cardiac causes are the leading cause of mortality in the DMD population (46).

The goal of therapy in DMD has been to delay the onset of decline in skeletal and cardiac muscle function. As a result, patients are prophylactically treated with corticosteroids and ACE-i or ARB to promote favorable ventricular remodeling and slow the decline of function (47,48). MRA have also shown to attenuate the decline in cardiac function when added to ACE-i therapy (49,50). Beta blockade has shown conflicting results in the DMD population, though it is generally added after ACE-i and MRA (51).

Therapies directly targeting the underlying dystrophin deficiency are in various stages of development. These therapies target the most common dystrophin mutations—premature stop codons, and deletions. Eteplirsen is an exon-skipping drug that may improve myopathy by restoring production of dystrophin in patients with DMD who have a mutation amenable to exon 51 skipping (47). Clinical trials are ongoing, though one small study did show preserved cardiac function in a small cohort with no control arm over the 240-week study period (52). Ataluren works through stop codon readthrough and can benefit patients with DMD due to a nonsense mutation (53). It has conditional approval for use in the European Union and is under investigation with a multitude of clinical studies. Further research is needed to demonstrate the cardiac benefits of this drug. Viral gene therapy is also under investigation using adeno-associated virus to deliver micro-dystrophins.

Fabry cardiomyopathy

FD is caused by deficiency in activity of α-galactosidase A resulting in accumulation of glycolipid in many organs and tissues. Though many patients present in adulthood with symptoms, asymptomatic children that have yet to develop significant glycolipid deposits are prime targets for therapies that can prevent development of clinical disease. Italy and Taiwan have developed universal screening programs that have detected disease causing variants in 1 in 1,250 to 1 in 4,600 people screened, which is much higher than any previously cited population studies (54). Heart failure is the most common first cardiac event and cardiac complications are the main source of FD-related morbidity and mortality (54).

Available since 2001, enzyme replacement therapy (ERT) has been the standard treatment for most patients. Unfortunately, this only delays the progression of FD and most patients develop antibodies of uncertain clinical significance to the biweekly infusions (55). Chaperone therapy is a more recent option for patients with FD due to certain mutations (56). Migalastat can be administered orally and acts as a pharmacologic chaperone in binding, stabilizing, and allowing proper lysosomal trafficking of α-galactosidase A enzyme for it to breakdown glycolipid (56). Patients treated for 18 months with Migalastat showed similar trajectories as those treated with ERT and there was a durable effect to 30 months (57). Second generation ERT and substrate reduction therapy are in varying stages of clinical study and may provide further benefit in attenuating and possibly reversing disease in the FD population (55).

Laminopathies

Striated muscle laminopathies are caused by various LMNA gene mutations resulting in DCM with or without varying degrees of muscular dystrophy (58). These mutations are inherited in an autosomal dominant manner and account for 5–8% of DCM (18). In a murine model as well as human hearts with LMNA DCM, p38a MAPK signaling has been shown to be hyperactive (59). This study also demonstrated that pharmacologic inhibition of p38a MAPK signaling significantly reduced LV dimensions and increased fractional shortening when compared to placebo therapy (59). Using this basis, a phase II study of ARRY-371797, a p38a inhibitor, in patients with symptomatic LMNA-related DCM (NCT02351856) has been completed and enrollment has begun in the phase III study (NCT03439514) with expected completion in 2024.

Single ventricle failure

Patients with single ventricle physiology are most at risk of developing heart failure within the congenital heart disease population and a focus has turned towards improving outcomes in these patients throughout the course of their disease. Survival after Fontan palliation continues to improve into the modern era with a more recent study reporting over 80% survival 20 years after surgery (60). An earlier study reported prevalence of heart failure, as defined by peak oxygen uptake (VO₂) <50% of predicted for age and sex, to be near 50% in the third decade of life (61). Studies evaluating medical therapy in the single ventricle population are lacking and recommendations are mostly in line with medical interventions shown to benefit patients with two ventricle circulation and systemic left ventricles (62).

A recent phase III trial showed that treatment over 26 weeks with udenafil, a phosphodiesterase-5 (PDE5) inhibitor, improved several measures of exercise capacity in teenagers with Fontan circulation and pre-existing peak VO₂ >50% (63). More study is needed to know if this will be a durable effect and if this will have any impact on patients with more significant exercise limitation. The development of vericiguat, a sGC stimulator, also has the potential to enhance the effect of PDE5 inhibitor therapy due to complimentary mechanisms of action, though this has not been studied.

More pre-clinical studies are being conducted to investigate the benefit of stem cell therapy in the earlier stages of single ventricle palliation. Cardiomyocyte proliferation rates in humans are reported to be 1% in the third decade and fall to 0.45% at age 75 (64). These rates are potentially higher in the neonatal heart with murine models showing potential for replenishing functional myocardium in the first week after birth (65). A phase II study using autologous cardiosphere-derived cells injected in coronary arteries 4 weeks after either stage II or stage III palliation showed improved ventricular function and reduced scar size when compared to controls three months after the experimental intervention (66). More rigorous studies with longer observation periods and larger sample sizes will be needed to confirm these benefits and a phase III trial (NCT02781922) is currently underway with completion expected in 2023.

Hydralazine/ISDN: precision medicine in the African ancestry population and pediatric experience

As our understanding of genetic diversity within the human population has grown, studying the benefit of specific therapies in different races has been of greater focus. Many clinical trials in heart failure therapy have represented patients that disproportionately skew towards the Caucasian race (67). An early study of ACE-i therapy that showed significant benefit in the Caucasian population did not show any benefit in patients of African descent (68). A study comparing hydralazine/ISDN combination with enalapril therapy showed similar reductions in mortality between the two groups (69). Hydralazine/ISDN has also shown significant benefit in treating African Americans with NYHA III or IV heart failure (70), though subsequent reports showed significant underutilization in patients with African ancestry despite guideline recommendations (71). There are limited data in pediatrics though the ability to reduce blood pressure while preserving renal perfusion is appealing and a small retrospective analysis did show benefits with use of hydralazine/ISDN in a diverse pediatric patient population, most of which had heart failure (72).

Conclusions

The rapidly expanding understanding of the human genome and pharmacogenomics is leading to a flurry of diverse therapeutics for diseases with similar phenotypes and different genotypes. Table 3 summarizes many of these completed and ongoing studies. Within pediatric heart failure specifically, the focus continues to shift from treating the maladaptive response to heart failure and the RAAS to gene-specific therapies with the potential to prevent and potentially reverse disease. Outside of the phenotype, a variety of factors must now be considered when selecting therapeutic option, from ethnicity/race, to the specific genetic cause of heart failure, to concurrent comorbid conditions, as well as the unique failure of the univentricular heart. Tailored therapies to the specific genotypes exist and for many conditions have recently proven benefit. Pediatric providers are in a unique position to begin therapies before significant pathology has developed and it will be of crucial importance for the pediatric clinician to keep abreast of this rapidly evolving reality of precision medicine that will dictate care for their patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-22-431/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-22-431/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-431/coif). JG serves as an unpaid editorial board member of Translational Pediatrics from January 2023 to December 2024. He also serves as a consultant to Daiichi Sankyo. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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