Skip main navigation

Treatment Strategies for Cardiomyopathy in Children: A Scientific Statement From the American Heart Association

Originally published 2023;148:174–195


This scientific statement from the American Heart Association focuses on treatment strategies and modalities for cardiomyopathy (heart muscle disease) in children and serves as a companion scientific statement for the recent statement on the classification and diagnosis of cardiomyopathy in children. We propose that the foundation of treatment of pediatric cardiomyopathies is based on these principles applied as personalized therapy for children with cardiomyopathy: (1) identification of the specific cardiac pathophysiology; (2) determination of the root cause of the cardiomyopathy so that, if applicable, cause-specific treatment can occur (precision medicine); and (3) application of therapies based on the associated clinical milieu of the patient. These clinical milieus include patients at risk for developing cardiomyopathy (cardiomyopathy phenotype negative), asymptomatic patients with cardiomyopathy (phenotype positive), patients with symptomatic cardiomyopathy, and patients with end-stage cardiomyopathy. This scientific statement focuses primarily on the most frequent phenotypes, dilated and hypertrophic, that occur in children. Other less frequent cardiomyopathies, including left ventricular noncompaction, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy, are discussed in less detail. Suggestions are based on previous clinical and investigational experience, extrapolating therapies for cardiomyopathies in adults to children and noting the problems and challenges that have arisen in this experience. These likely underscore the increasingly apparent differences in pathogenesis and even pathophysiology in childhood cardiomyopathies compared with adult disease. These differences will likely affect the utility of some adult therapy strategies. Therefore, special emphasis has been placed on cause-specific therapies in children for prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments. Current investigational strategies and treatments not in wide clinical practice, including future direction for investigational management strategies, trial designs, and collaborative networks, are also discussed because they have the potential to further refine and improve the health and outcomes of children with cardiomyopathy in the future.

Pediatric cardiomyopathy is an uncommon but life-threatening disease affecting 1 in 100 000 children. There are many pathogeneses, but in aggregate, cardiomyopathy remains a leading cause of heart transplantation in childhood. Lipshultz et al1 previously published an American Heart Association (AHA) scientific statement focused on the classification and diagnosis of cardiomyopathy in children. This follow-up scientific statement discusses treatment strategies for pediatric cardiomyopathies with an emphasis on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) and 2 areas of focus: the unique variation of causes of pediatric cardiomyopathy that guide management and pediatric cardiomyopathy as a problem for which therapeutic considerations exist for patients who are at risk for developing cardiomyopathy, patients with asymptomatic cardiomyopathy, patients with symptomatic cardiomyopathy, and those with end-stage disease. Treatment strategies specifically for left ventricular (LV) noncompaction, restrictive cardiomyopathy (RCM), and arrhythmogenic cardiomyopathy are discussed but in less detail. Figure 1 shows the central illustration of this article.

Figure 1.

Figure 1. Central illustration of the article. CM indicates cardiomyopathy; cMRI, cardiac magnetic resonance imaging; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; and SCD, sudden cardiac death.

Stages of Cardiomyopathy in Children

Dilated Cardiomyopathy

Strategies for Treating Pediatric DCM

Recent AHA guidelines have proposed a 4-stage system for therapeutic interventions in adult heart failure (HF).2 In stage A (at-risk patients), the patient is at risk for HF but has no structural heart disease or symptoms of HF. Stage B (asymptomatic patients) is characterized by structural heart disease but without signs or symptoms of HF. Stage C (symptomatic patients) is marked by cardiomyopathic heart disease with current or past symptoms of HF. Patients with stage D disease (refractory patients) have refractory HF requiring specialized interventions. This staging system can be harmonized with the various clinical milieus one can observe in pediatric DCM as a framework with which to consider specific therapeutic interventions.

Over the past 3 decades, a series of large, randomized, placebo-controlled clinical trials in adults with HF associated with reduced LV ejection fraction found that certain drugs reduced the incidence of hospitalization and mortality. These drugs are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, β-blockers, mineralocorticoid receptor antagonists, angiotensin receptor/neprilysin inhibitors, ivabradine, and most recently sodium-glucose cotransporter 2 inhibitors. Although there are evidence-based, goal-directed medical therapy treatment algorithms that are often updated by the AHA,3 the American College of Cardiology,4 and the European Society of Cardiology5 (Figure 2),4 a similar evidence basis does not yet exist for children.

Figure 2.

Figure 2. The most recent revision of American College of Cardiology/AHA treatment algorithms for treating adults with HF and reduced left ventricular ejection fraction. Green ovals show Class I therapy; and yellow oval, Class II therapy. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor/neprilysin inhibitor; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; NYHA, New York Heart Association; and SGLT2, sodium-glucose contransporter-2. *The 4 Class 1 therapies that are simultaneously initiated in adults with HFrEF. Reprinted from Maddox et al3 with permission. Copyright © 2021 American College of Cardiology Foundation.

A review of the literature identifies only limited data on managing children with HF. The most recent treatment guidelines, by the International Society for Heart and Lung Transplantation in 2014, include 35 recommendations for pharmacological therapy but only 8 Class I (strong) recommendations supported at best with Level of Evidence B (moderate).6 Current pediatric guidelines are therefore based primarily on expert consensus and generally mirror the recommended goal-directed medical therapies for adults but with less certainty and overall lower quality of evidence from primarily single-center trials and few large, multicenter trials in children.6,7

Another issue in applying goal-directed medical therapy HF guidelines developed for adults to children is that the use of ACE inhibitors and β-blockers for HF with DCM in children has not been shown to improve transplantation-free survival.8,9 Furthermore, symptoms and outcomes did not improve in a randomized trial of 161 children with HF who received carvedilol in addition to ACE inhibitors.10 Relative to adult HF populations, there are additional barriers to executing clinical trials in children with heart conditions, including inadequate statistical power associated with small sample sizes, phenotypic heterogeneity, limited observational periods, and age-specific variation in pharmacokinetics and pharmacodynamics. In addition, there is accumulating evidence that HF in children differs in important ways from that in adults, and children lack many of the comorbid conditions present in adults, contributing to the accumulating evidence that HF in children differs in important ways from that in adults.11,12

Therefore, although extrapolating the results of studies in adults may be reasonable in certain diseases or age groups, it is not uniformly appropriate across all diseases, underscoring the importance of developing standards for the care of and for conducting studies in children with cardiomyopathy and HF. Current studies of pediatric cardiomyopathies and HF differ widely in the medications used, dosing, frequency of follow-up, and expertise of medical teams. All of these differences, given the lack of multi-institutional data in children, hamper assessment of the responses to therapy.

Unique Characteristics of HF in Children

The pathophysiology of HF in children is similar to that in adults, although increasing evidence indicates some inherent differences in myocardial adaptations secondary to DCM. The natural history of pediatric DCM also differs from that of adult DCM in that death or transplantation usually occurs within 2 years after presentation with DCM, suggesting that many children and adolescents have advanced disease at presentation.13,14 These differences may contribute to the differential responses reported in clinical trials in children with HF treated with therapies developed for adults, as discussed previously. For example, total myocardial β-adrenergic receptor expression is decreased in both children and adults with idiopathic DCM, but children downregulate both the β-1 and the β-2 adrenergic receptors, whereas adults downregulate only the β-1 adrenergic receptors.15 This differential receptor expression could influence the response of children to nonselective β-blocker drugs such as carvedilol because the effects of medical blockade of the already downregulated β-2 adrenergic receptors are unknown.

With respect to the phosphodiesterase system, both children and adults with idiopathic DCM have decreased myocardial cAMP concentrations, but these concentrations improve only in children treated with phosphodiesterase-3 inhibitors (eg, milrinone) and remain low in adults.16 Although long-term treatment of adults with HF with phosphodiesterase-3 inhibitors is associated with increased morbidity and mortality, several clinical series have reported that long-term use of milrinone in children is safe and efficacious as a bridge to oral HF therapies or transplantation.17–19 However, there are no large controlled studies on the long-term use of phosphodiesterase-3 inhibitors in children with HF.

Echocardiograms of children with DCM show LV dilation and decreased systolic function, but the extent of adverse cardiac alterations, defined by cardiac fibrosis, cardiomyocyte hypertrophy, inflammation, and capillary loss, is less than in adults with HF.20–22 Compared with age-matched nonfailing control subjects, coronary microvascular density as assessed by CD34 staining is higher in children with DCM compared with adults. 20 It is important to note that these findings seem unrelated to the time since diagnosis of DCM or the presence of cardiovascular comorbidities (eg, hypertension, chronic kidney disease, diabetes).

Other studies have shown differences in stem cells and their signaling in children with failing hearts compared with those with nonfailing hearts. In a global transcriptome study of (n=37) explanted pediatric DCM hearts, genes associated with pluripotent stem cell signaling (eg, enrichment of WNT, fibroblast growth factor, Notch), cell growth, and differentiation were dysregulated compared with those in age-matched nonfailing donor controls.21 These results complement the finding that children with end-stage HF have more cardiac stem cells than age-matched children with congenital heart disease but normal cardiac function.23 In another study of explanted DCM hearts, genes associated with sarcomeric remodeling, inflammation, and fatty acid metabolism were upregulated in adults, whereas genes associated with cell adhesion and ion and transmembrane transport were upregulated in children.20

An important point is that differences in DCM between adults and children are not limited to heart tissue. Among 1310 plasma proteins, a DNA aptamer array found 20 peptides and proteins that were significantly increased in pediatric patients with DCM compared with age-matched healthy control subjects and that circulating protein biomarkers differed greatly between children and adults with DCM.24 Many studies have evaluated microRNAs as biomarkers of HF in adults, and although studies of children are fewer, the circulating microRNA profiles in children are unique compared with the profile seen in adults with DCM. An unbiased array revealed that 4 microRNAs (microRNA-155, -636, -646, and -639) were differentially regulated between children with DCM who required a heart transplantation and those who recovered ventricular function.25,26 None of these 4 microRNAs are biomarkers of DCM in adults. Although the studies are limited by their cross-sectional nature, they provide a framework for understanding the novel molecular and biomarker signatures associated with pediatric DCM, emphasizing the importance of better understanding the mechanisms of this disease and identifying age-appropriate therapies.

Therapy in Pediatric Patients at Risk for Developing DCM (Phenotype Negative)

The American College of Cardiology and AHA Task Force on Practice Guidelines devised a classification of HF that emphasized the expected progression of heart disease.2 This classification underscores the important possibility that, for patients in stage A, progression of further HF could be delayed or prevented.

In pediatrics, one of the most recognizable conditions for which this type of categorization is relevant is the dystrophinopathies. The dystrophinopathies, including Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy, are a group of neuromuscular disorders caused by abnormal dystrophin. Treating this condition in Stage A is now being practiced. Although the primary manifestation of dystrophinopathies is skeletal muscle weakness, the incidence of DCM increases with age. Among male individuals with DMD, >50% will have cardiac involvement by 10 years of age, and 90% will have cardiac dysfunction after 18 years of age.27

Current treatment guidelines for dystrophinopathies recommend beginning ACE inhibition therapy before adolescence when patients are in stage A (at risk).28,29 Initial studies30,31 suggested that ACE inhibition delayed the development of DCM and ultimately improved survival. A Cochrane review32 suggested that early use of ACE inhibitors or angiotensin receptor blocker inhibitors may be beneficial, although the quality of the evidence was low. However, a recent retrospective analysis of the French multicenter DMD registry33 found that ACE inhibition in patients in stage A markedly improved survival and reduced hospitalizations for HF. Early mineralocorticoid receptor inhibition may also stabilize and slow progressive LV systolic dysfunction.34 These small studies are promising, but larger controlled trials are needed to establish the efficacy of this treatment.

It is estimated that ≈70% of patients with deletions associated with DMD can be treated by single exon skipping.35 Four US Food and Drug Administration–approved antisense oligonucleotides (AONs) administered as weekly intravenous infusions circumvent this problem by skipping over the mutated exons. AONs consist of 20 to 30 nucleotides that act on the pre-mRNA to splice out the mutated exons, thereby converting an out-of-frame mutation to a less severe in-frame mutation. However, this therapy is limited to certain mutations and by issues of tissue penetration and efficiency because it provides <5% of normal dystrophin content.36 The cardiac efficacy of AON treatments is unknown.

Adeno-associated virus gene therapy to produce microdystrophin is currently being investigated. Case findings in mild Becker muscular dystrophy have helped identify the essential regions of the gene.37 Theoretically, adeno-associated virus gene therapy can be used to treat all forms of DMD, regardless of mutation, and requires only a single administration. Furthermore, the amount of dystrophin produced is greater than that of AON therapies, and cardiac expression is expected, given the use of specific cardiac and skeletal muscle promotors.38 If successful, microdystrophins would be the first gene therapy for a form of childhood-onset cardiomyopathy.

Last, precision gene-editing techniques hold great potential for the development of gene therapies. In particular, delivery of CRISPR/Cas9 nucleases capable of genome editing with delivery through adeno-associated virus vectors has been shown to be feasible in preclinical studies. These studies aim to restore the gene reading frame to produce a truncated but partially active protein, an approach similar to AON treatment. As in gene therapy, gene editing may require only a single administration. Again, given the affinity of certain adeno-associated virus serotypes for the heart, cardiac correction is expected.

Treatment in Pediatric Cardio-Oncology

Advances in cancer therapy and standardization of care over the past decades have substantially improved the number of childhood cancer survivors. Currently, 5-year survival among children with cancer is ≈85%, with an estimated 500 000 survivors as of 2020.39

All children who have received cardiotoxic cancer therapies are at risk for HF (stage A disease). Cardiovascular complications such as cardiomyopathy (with progression from a dilated to restrictive physiology)40 and valvular and vascular dysfunction that can lead to HF are more prevalent in cancer survivors than in the general population. These complications can compromise otherwise successful cancer treatment in childhood and early adulthood41 unless these complications are addressed.42

Risk factors for cardiotoxicity in cancer survivors include higher anthracycline doses, radiation therapy that includes the heart in the treatment field, younger age at diagnosis, female sex, and underlying cardiovascular disease, in addition to the common risk factors for cardiovascular disease.40 Furthermore, new cancer therapies may be cardiotoxic. Chimeric antigen receptor T-cell therapy manufactures genetically engineered T cells that target cancer cells. During this process, patients are at risk for cytokine-release syndrome, which can cause major cardiac events, including HF. Treatment begun during stage A could prevent cardiovascular events related to this syndrome. For example, anti–interleukin-6 receptor antagonist such as tocilizumab can reduce morbidity and mortality during this stage.43–46 Small-molecule inhibitors such as tyrosine kinase inhibitors have become first-line treatments for some pediatric cancers and may be useful in treating relapses. Monitoring acute and early-onset cardiac toxicities, including HF, pericardial effusions, and hypertension, is necessary to identify the range of cardiovascular side effects of both new and conventional chemotherapy agents.44–51

Immune checkpoint inhibitors, which are increasingly used to treat cancer in adults, are now being studied in children. The cardiotoxic effects of these inhibitors include immune-mediated myocarditis (which can be fulminant) and are reported in ≈1% of adult patients with cancer. These cardiotoxic effects allow risk stratification that can guide the development of preventive measures to reduce further injury to the myocardium.40,41

The importance of beginning treatment in stage A for children exposed to cardiotoxic cancer therapies is now beginning to be recognized among practitioners. Furthermore, several genetic variants that may increase the risk of anthracycline-mediated cardiotoxicity can now identify patients most likely to benefit from preventive therapies such as concurrently giving the iron chelator dexrazoxane at the time of anthracycline administration.52

Current evidence does not support using standard oral HF therapies to prevent treatment-related cardiotoxicity in asymptomatic children. Instead, consensus statements have emphasized primary prevention strategies such as managing modifiable cardiovascular risk factors (hypertension, hyperlipidemia, obesity, diabetes) and the use of cardioprotective medications.53,54 Dexrazoxane can prevent or reduce anthracycline-related cardiotoxicity in adults and children without reducing the effectiveness of cancer therapies or increasing the incidence of secondary malignancies.55–57 Dexrazoxane is the only drug approved by the US Food and Drug Administration for the primary prevention of cardiac toxicity in adults and has been granted pediatric orphan drug status.58 Furthermore, in 2017, the European Medicines Agency issued a decision that treatment with dexrazoxane is no longer contraindicated in children expected to receive a cumulative dose of >300 mg/m2 doxorubicin or the equivalent cumulative dose of another anthracycline.59–61 The European Medicines Agency found no data indicating that dexrazoxane was associated with an increase in second primary malignancies, interfered with chemotherapy, or increased the risk for early death in children. This recent decision allows virtually all children to receive dexrazoxane starting with the first dose of anthracycline at the discretion of the treating health care professional.

Treating phenotype-negative pediatric patients at risk for developing DCM as described earlier for young children with dystrophinopathies and childhood cancer survivors has the potential to increase survival and to improve the quality of life for these high-risk patients. Identifying genetic, mechanistic-based, or lifestyle modification approaches to treating children with stage A disease and other cardiomyopathies could improve disease prevention and outcomes. Centers with dedicated HF teams have begun to form multidisciplinary teams that have begun to see patients with muscular dystrophy or cancer and survivors. Multidisciplinary programs are a platform to screen, treat, follow, and conduct quality improvement (QI) and research in a systemic approach that will ideally improve outcomes.

Therapy in Pediatric Patients With DCM (Phenotype Positive) Who Are Asymptomatic

Identifying patients in this stage depends primarily on screening those with a family history of cardiomyopathy for an associated genetic variant or those such as dystrophinopathy or childhood cancer survivors who were at risk for developing DCM and undergo periodic surveillance for development of DCM. When cardiomyopathy is identified in a child without a known preexisting risk, panel genetic testing or whole-exome sequencing is recommended. A pathogenic or likely pathogenic variant in the proband should prompt cascade genetic testing of first-degree relatives who are at risk for cardiomyopathy. Cardiac surveillance is no longer necessary for family members with informative negative genetic test results. In 83 consecutive unrelated patients referred for genetic evaluation of cardiomyopathy between 2006 and 2009, 63 had a familial, syndromic, or metabolic basis for their disease.62 Findings were similar in the study by Ware et al.63 Therefore, both clinical surveillance and cascade genetic testing for first-degree relatives of probands with cardiomyopathy are important. Indeed, screening guidelines recommend a 3-generation pedigree, cardiac screening, and cascade genetic testing for at-risk family members.1 The Heart Failure Society of America recommends screening for children with a first-degree relative with DCM: annually for children 0 to 5 years of age, every 1 to 2 years for children 6 to 12 years of age, every 1 to 3 years for children 13 to 19 years of age, every 2 to 3 years for adults 20 to 50 years of age, and every 5 years for adults >50 years of age.64 Treatment strategies at this stage focus on treating risk factors, intervening in structural heart disease when applicable, and initiating medical therapy with ACE inhibitors. ACE inhibitors are proposed as first-line therapy and β-blockers are also considered for patients with ejection fraction <40% in the recently proposed adult HF guidelines.4

Therapy in Symptomatic Pediatric Patients With DCM

The current guidelines for adults with stage C HF (Figure 2) recommend combination therapy with angiotensin receptor/neprilysin inhibitors, β-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors and the addition of ivabradine if the heart rate cannot be reduced enough with β-blockade. A combination of hydralazine and isosorbide dinitrate is recommended for persistently symptomatic Black patients.4,65

No large randomized controlled trials have identified effective therapies for stage C HF in children, although most clinical studies in pediatric cardiomyopathy have focused on these patients. A randomized, placebo-controlled trial of carvedilol for treating children with symptomatic HF found no difference between groups in the primary composite outcome.10 However, several factors made interpretation of this trial challenging. First, symptom improvement in the placebo-treated study subjects was greater than expected and may have been related to the requirement for all subjects to be on ACE inhibitor therapy at the time of enrollment, with many being on additional HF treatments such as digoxin, diuretics, and spironolactone. Second, the trial enrolled subjects with HF from a wide range of diagnoses, including single ventricle and other forms of congenital heart disease. Although the study was not powered to evaluate the primary outcome in DCM specifically, subjects with a systemic LV treated with carvedilol did have an improvement in fractional shortening. In addition, a post hoc analysis10,66 found that children with a systemic LV treated with carvedilol had echocardiographic evidence of reduced LV size and natriuretic peptide concentrations.

In a recent phase 2/3 randomized trial comparing ivabradine with placebo,67 most of the 116 children were on ACE inhibitors or angiotensin-receptor blockers (98%), mineralocorticoid receptor antagonists (79%), and β-blockade (76%) after 1 year. Children in the ivabradine group had significantly improved LV ejection fraction and reduced natriuretic peptide concentrations with a trend toward improved functional status. In children of all ages, 70% of those receiving ivabradine achieved the targeted 20% reduction in resting heart rate, whereas only 12% of control subjects did. This study made ivabradine the first US Food and Drug Administration–approved medication for treating children >6 months of age with symptomatic HF. Furthermore, the study population expanded to other cardiomyopathies and LV dysfunction beyond DCM.

Most recently the PANORAMA-HF trial (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF)68 compared the effects of sacubitril/valsartan (Entresto) with enalapril in pediatric HF. On the basis of a preliminary data analysis showing improvement in natriuretic peptide levels in subjects 1 to 18 years of age who received sacubitril/valsartan compared with those receiving enalapril, the US Food and Drug Administration approved the use of the drug in children >1 year of age. However, when the primary results of the study were analyzed, no differences in HF outcome measures were seen between the groups 12 months after randomization, including natriuretic peptide levels.69 The impact of this study on the future use of this combination drug remains to be determined.

The most recent PCMR (Pediatric Cardiomyopathy Registry) report of outcomes of children with DCM9 found that mortality (but not the rate of heart transplantation) was significantly lower between 2000 and 2010 than between 1990 and 2000. The authors concluded that nontransplantation therapies improved survival, with survival curves diverging both in the first months after diagnosis and during follow-up (Figure 3). Figure 3 shows estimated time to death for children with idiopathic DCM. Children in the early cohort were more likely to die without heart transplantation (P<0.001). The reasons for this improvement were likely multifactorial and potentially the result of overall improvements in therapies for children with acute and chronic HF. Although only an associative finding, it is consistent with findings from other studies done during the same periods.70,71 It is also consistent with the observation that pediatric cardiologists increasingly treated these children with ACE inhibitors and β-blockade, as well as with mineralocorticoid receptor antagonists, between 2010 and 2020.72 Newer therapies are being investigated in patients with stage C disease. In particular, this targeted approach may benefit children, who are more likely to have monogenetic forms of cardiomyopathy.

Figure 3.

Figure 3. Era effect on survival after a diagnosis of pediatric cardiomyopathy between 1990 and 1999 vs 2000 and 2009.9 Red dashed lines are for 2000 to 2010; blue solid lines are for 1990 to 1999. In each group, the estimate is the middle line, and the outer lines are 95% CIs for the estimate.

Newer therapies targeting the mechanisms producing cardiomyopathy in patients with stage C (symptomatic) disease are promising according to adult studies. The myosin activator omecamtiv mecarbil acts directly on the sarcomere to improve contractility in adults with HF with reduced ejection fraction.73 Sodium-glucose cotransporter 2 inhibitors may also improve sarcomere function by improving passive stiffness of cardiomyocytes.74

Mendelian diseases provide specific genetic targets for research into the mechanism of disease. For example, a high incidence of sudden cardiac death (SCD) and major ventricular arrhythmias stimulated studies of diagnostic and prognostic biomarkers and new therapeutic genetic targets in LMNA cardiomyopathy.75 The REALM-DCM study (A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation) is an ongoing phase 3 trial evaluating the efficacy of ARRY-371797, an oral p38 mitogen-activated protein kinase inhibitor, in adults with symptomatic DCM caused by Lamin A/C mutations.76 Despite the initial focus on adults, this research can enhance our understanding of the associated genetic variants in children, improve personalized risk stratification, and provide the basis for developing targeted therapies.77

Therapy in End-Stage Pediatric DCM

AHA stage D HF identifies patients with refractory HF who remain symptomatic despite maximal medical therapy. These patients may benefit from specialized interventional strategies such as mechanical circulatory support, continuous intravenous inotropic infusions, cardiac transplantation, and palliative or hospice care.65 Acute decompensated HF in DCM is generally apparent; however, the gradual deterioration of chronic HF from stage C to D may be less noticeable. Identifying stage D HF is vital given the limited treatment options and substantial morbidity and mortality. The current treatment guidelines for children with advanced HF from DCM recommend evaluation for cardiac transplantation in carefully selected patients with stage D disease who remain symptomatic despite maximal medical therapy.78 According to current adult HF guidelines, for carefully selected patients with stage D disease with acute hemodynamic compromise, nondurable mechanical circulatory support options, including a percutaneous ventricular assist device (VAD) are reasonable as a bridge to recovery or a bridge to a decision.65 In a multicenter study on implantations in children and adolescents, cardiogenic shock (28 of 39, 73%) was the most common indication for implantation. Explantation was due to ventricular recovery in 16 patients, transition to another device in 12, death in 5, and cardiac transplantation in 1.79 Mechanical support such as extracorporeal membrane oxygenation has been a standard of care in pediatric end-stage HF as a bridge to heart transplantation; however, it is associated with high wait-list mortality and poor survival to hospital discharge.80 The use of paracorporeal and continuous-flow VADs in children has experienced exponential growth in use in the past decade, mainly because of improved technology, reduced adverse effects, enhanced survival statistics, and changes to listing status policy that prioritize patients with cardiomyopathy on mechanical support. According to the International Society for Heart and Lung Transplantation guidelines for the management of pediatric HF, durable mechanical circulatory support is beneficial in carefully selected patients with advanced HF as a bridge to cardiac transplantation, candidacy, or destination therapy.6 In pediatric DCM, the wait-list mortality in advanced HF has dramatically improved with mechanical assist device use.78,81 According to the current Pediatric Interagency Registry for Mechanical Circulatory Support report, the indications for pediatric VADs implantation were a bridge to cardiac transplantation (listed) in 48%, bridge to candidacy in 38%, bridge to recovery in 9%, and destination therapy in 1%.81 Continuous home inotrope infusions may be used as palliative therapy to improve end-of-life quality in select patients with DCM with advanced HF who are refractory to medical management and are not eligible for heart transplantation or mechanical circulatory support.65,82 According to an adult study, long-term intravenous inotrope use was associated with high mortality with a median survival of 3.4 months but reduced hospital readmissions and improved quality of life.83 In addition, adult trials have shown that destination mechanical circulatory support is superior to long-term inotropic treatment in select patients with advanced stage D HF.65 Palliative care should be considered early in the course of stage D HF to help ensure that the parent’s and child’s goals of care are clearly identified. Refractory HF care across the disease spectrum may gradually transition from aggressive intervention to palliation, comfort, and quality of life. A multidisciplinary team approach involving advanced HF specialists, cardiothoracic surgeons, and palliative care is essential in making these decisions.82

Myocardial Recovery

Despite our best efforts to determine the most appropriate timing and treatment of children with HF, complete recovery is uncommon. Among children with DCM in the PCMR, only 22% recovered normal heart function within 2 years of diagnosis. Full recovery was more likely in children <10 years of age with less severe ventricular dilation.14 Of children recovering normal ventricular size and function, 9% eventually underwent heart transplantation or died within 2 years, indicating a risk of HF relapse.14 The effectiveness of medications in both recovery and relapse was not clear in the PCMR population. The recovery rate in adults is 15% to 20%, which is similar to that in children.84 However, the withdrawal of pharmacological treatment for HF in patients with recovered DCM (TRED-HF study [Therapy Withdrawal in Recovered Dilated Cardiomyopathy–Heart Failure]) indicated that one-third to one-half of adults who “recovered” from DCM relapsed from HF within 6 months of discontinuing their HF medications.85

Mechanical unloading with a VAD combined with pharmacological therapy can reverse the progression of HF. However, despite beneficial changes in myocardial shape and function secondary to mechanical unloading, recovery leading to VAD explantation is uncommon.81,86–88 The fifth Pediatric Interagency Registry for Mechanical Circulatory Support report81 notes that ≈10% of children with VADs recover enough to allow explantation. Recovery rates are higher in children with myocarditis or congenital heart disease than in children with DCM. In addition, recovery rates were higher for children managed with paracorporeal continuous-flow devices, although it is not possible to determine whether device choice was influenced by the perceived potential for recovery.81,86

Assessment and Management of Pediatric HCM

The diagnosis of HCM is defined in the AHA 2020 guidelines as the presence of LV hypertrophy (LVH) without evidence of a cardiac, systemic, or metabolic disorder that can explain the magnitude of hypertrophy.89 In contrast, the 2014 European Society of Cardiology guidelines on HCM90 and the AHA scientific statement on cardiomyopathy in children1 define HCM on the basis of cardiac morphology rather than pathogenesis as the presence of increased LV wall thickness that is not explained solely by abnormal loading conditions, regardless of the presence of extracardiac disease, thereby including both sarcomeric and nonsarcomeric causes. The threshold level of wall thickness considered diagnostic for HCM in adults is 15 mm, with 13 to 14 mm constituting probable HCM. In contrast to the recommended diagnostic criteria in adults, the wall thickness value considered diagnostic of HCM in children must account for body size. This is typically calculated as the wall thickness z score relative to body surface area (the number of SDs from the normal mean value relative to body surface area). In an adult of 1.8 m2, 15 mm is equivalent to a z score of 5, and 13 to 14 mm is equivalent to a z score of 3 to 4.

As detailed in the 2019 AHA scientific statement,1 the causes of HCM in children are heterogeneous, and causes other than maternal diabetes are almost exclusively genetic. Clinical findings, outcomes, and response to therapy differ substantially among the various causes, indicating that the first step in management is determination of origin. For example, sarcomeric HCM (SHCM) is associated with a higher risk of SCD compared with HCM associated with systemic disorders such as the RASopathies (genetic conditions caused by mutations in genes of the RAS/mitogen-activated protein kinase pathway) and mitochondrial and storage diseases.91 In contrast, morbidity and mortality due to HCM secondary to RASopathy presenting before 1 year of age is high during the first 2 years of life (24%) secondary to congestive HF, whereas sudden death in this group of disorders is uncommon (9%), highlighting the utility in defining the origin.75,91

Furthermore, SHaRe (Sarcomeric Human Cardiomyopathy Registry) has determined that specific sarcomeric mutations can be an important risk predictor. For example, in SHCM due to MHY7, the onset is earlier and the incidence of adverse events (eg, death, HF, malignant arrhythmias, and atrial fibrillation) is higher than with other mutations. In general, pathogenic or likely pathogenic sarcomeric mutations confer the highest risk of death, transplantation, LV assist device implantation, and stroke.90 In addition, even variants of unknown importance in sarcomeric genes may be clinically relevant.90

Although cause-specific therapies are few, the importance of cause-specific diagnosis has become greater with the increasing availability of disease-specific therapies. For example, α-glucosidase (enzyme) replacement therapy or α-glucosidase in vivo gene transfer using adeno-associated virus vectors is now in phase 1 trials92 for Pompe disease. In mice with Noonan syndrome secondary to mutations in the PTPN11 gene, low-dose dasatinib improved cardiomyocyte contractility and function.93 Trametinib, a highly selective reversible allosteric inhibitor of MEK1/2, approved for treating RAS/mitogen-activated protein–mitogen-activated protein kinase–mutated cancers, reversed cardiac failure and valvar obstruction in 2 newborns with RIT1 mutations, Noonan syndrome, HCM, and severe hypertrophy.94 In 2 other patients, trametinib was associated with a reduction in LVH and valvar obstruction over 17 months and returned NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentrations to normal.95 Last, mavacamten is a promising, new, non–mutation-specific, negative modulator of cardiac myosin that directly diminishes sarcomeric force generation, markedly reduces NT-proBNP and cardiac troponin I concentrations, and is associated with improved health status in adults with obstructive HCM.96,97

Strategies for Treating Pediatric HCM

Pediatric patients may present for treatment of HCM when they are phenotypically negative but at risk for developing HCM, have the phenotype of HCM but are currently asymptomatic, have symptomatic HCM, or have end-stage disease. Although the primary symptom in pediatric DCM is HF that is generally progressive and fits in with a concept of progressive stages of HF, this progressive pattern is not replicated in HCM because symptoms are frequently not related to HF or may require therapeutic considerations in multiple clinical milieus. This issue is most relevant in therapeutic considerations for sudden death in pediatric HCM that are relevant to pediatric patients with HCM who are asymptomatic, symptomatic, or have end-stage disease.

Management of Therapy in Pediatric Patients at Risk for Developing HCM (Phenotype Negative)

Current guidelines recommend that genotype-positive, phenotype-negative patients and all children who are first-degree relatives of affected individuals be screened with echocardiography every 1 to 2 years through adolescence and every 3 to 5 years as adults.89 At present, it is not known whether the presence of preclinical findings such as reduced diastolic tissue velocities and nonspecific electrocardiographic changes (as reported in the VANISH study [Valsartan for Attenuating Disease Evolution in Early SHCM]98,99) justifies longitudinal monitoring in individuals without identifiable pathogenic variants. Currently, genotype-positive, phenotype-negative individuals have no exercise or activity restrictions, although there is considerable interest in identifying and starting disease-attenuating interventions for these at-risk genotype-positive individuals in this group.

One study of patients with early phenotypic manifestations of disease but no LVH has shown that the calcium channel blocker diltiazem may improve early LV remodeling in patients.100

The VANISH study found that high-dose valsartan titrated to a target dose based on age and weight with a maintenance dose for 2 years improved cardiac structure and function more than placebo in patients with LVH.98,99,101

Management of Risk of Sudden Death in HCM

For asymptomatic children who meet diagnostic criteria for HCM, routine diagnostic testing for the risk of sudden death is recommended regardless of symptom status. The goal of longitudinal testing is to identify potential opportunities to reduce the risk of sudden death, to provide early intervention for new-onset symptoms, and to detect the unusual development of pulmonary hypertension in children with HCM. Periodic electrocardiography, echocardiography, exercise testing, and ambulatory monitoring for rhythm disturbances are the primary modalities for longitudinal monitoring in children with HCM and are recommended every 1 to 2 years in preadolescents and annually during adolescence. The options for longer-term rhythm monitoring have increased over the past 5 years, including the availability of monitors with longer recording times and implantable options. The utility of exercise stress tests for evaluating arrhythmias and stress echocardiography to detect exercise-induced or exacerbated outflow tract obstruction is well documented.102 Periodic cardiac magnetic resonance imaging evaluation of late gadolinium enhancement as evidence of myocardial fibrosis is recommended, although the frequency of testing and the threshold level of fibrosis that represents a risk factor for sudden death remain uncertain in pediatrics given the limited outcome data. Monitoring for the development of restrictive physiology is based on assessment of left atrial size and Doppler assessment of pulmonary and tricuspid regurgitant velocities, with right-sided heart catheterization for patients with findings suggestive of pulmonary or right ventricular hypertension. Similarly, various blood and imaging biomarkers are being studied in the hope of categorizing the degree of myocyte disarray and fibrosis for risk stratification in children.103

Predictive models of outcomes in pediatric HCM have generally relied at least in part on data extrapolated from adults because data on pediatric-specific risk factors are limited. Only recently have SHCM risk prediction models specific to children become available. Norrish et al104 performed a retrospective evaluation of the European Society of Cardiology guidelines, evaluating 411 children for the contribution of several potential risk factors, including severe LVH, unexplained syncope, nonsustained ventricular tachycardia, and a family history of SCD. The primary end point was a composite of SCD or an equivalent event, which included aborted cardiac arrest, appropriate implantable cardioverter defibrillator (ICD) discharge, or sustained ventricular tachycardia. The area under the receiver operating characteristic curve (C statistic) was 0.62 at 5 years.

Norrish et al105 also reported a multicenter study that included 1024 children followed up for a median of 5.3 years with a sudden death or equivalent event rate of 8.7%. The risk model, which they labeled HCM Risk-Kids, included functional class, unexplained syncope, nonsustained ventricular tachycardia, maximal wall thickness z score, left atrial diameter z score, and maximal LV outflow gradient. It achieved a 5-year risk of sudden death prediction model with a C statistic of 0.69. Miron et al106 performed a similar analysis based on 572 children with HCM, assessing the predictive value of age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal and LV posterior wall thickness z scores, left atrial diameter z score, peak LV outflow tract (LVOT) gradient, and the presence of a pathogenic gene variant. The 5-year composite outcome was SCD, resuscitated sudden cardiac arrest, or an appropriate shock from an ICD used in primary prevention. The C statistic for this study was 0.75 in the base model and 0.76 when gene variants were included.

Ostman-Smith et al107 reported an analysis of 151 children <19 years of age with either SHCM (n=110) or RASopathy HCM (n=41) and calculated a risk score for SCD or cardiac arrest using a previously published risk algorithm derived from electrocardiographic findings alone.108 They reported a 5-year C statistic of 0.87 (95% CI 0.80-0.94).

Norrish et al109 have reported the HCM Risk-Kids risk prediction model, which is based on unexplained syncope, degree of hypertrophy, left atrial diameter, and nonsustained supraventricular tachycardia in a cohort of 421 patients 1 to 16 years of age. If all 4 risk factors were present, the 5-year risk of experiencing the composite end point was ≈10%. The composite outcome was SCD, aborted cardiac arrest, appropriate cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise. The strongest association with the study outcome was nonsustained supraventricular tachycardia.

A primary limitation of 3 of the above models104,106 is the inclusion of appropriate ICD discharge as an outcome, which is known to overestimate the incidence of sudden death. The predictive capacity of other models that include additional potential risk factors such as blood and imaging biomarkers (eg, magnetic resonance imaging T1 mapping) is being studied.103 Given that the risk of major cardiac events associated with SHCM relates primarily to arrhythmias, placing an ICD as a primary preventive measure remains an important consideration in managing children with HCM, but at present, this decision relies in large part on data gathered in adults.

Management of the risk of exercise-associated sudden death in children with HCM has been a controversial topic, in large part because of its rarity, the limited relevant data, and the challenge encountered in determining the risk-benefit ratio in this population, resulting in reliance on consensus rather than data-driven recommendations. Mild- to moderate-intensity exercise is associated with improved cardiorespiratory fitness, physical functioning, and quality of life, and no restriction on these activities is recommended. Although exclusion from participation in high-intensity sports as a means of preventing exercise-associated SCD has been advised by prior AHA recommendations,110 a causal relationship with exercise has not been definitively established, as demonstrated in a recent population study of SCD in individuals 10 to 45 years of age in Ontario in which 44 cases of definite HCM-related sudden death were identified with an annual incidence of 0.31 per 1000 HCM person-years. Of these, 64.8% of deaths occurred during rest and 18.5% during light activity.111 The benefit of exclusion from high-intensity sports participation is difficult to assess, but this exclusion clearly impinges on the usual freedom of self-determination, and the net risk-to-benefit ratio for sports participation remains elusive. It should be noted that the current outcomes and long-term follow-up studies related to exercise risk and outcomes have been affected by the long-standing recommendation to avoid competitive exercise. It is unclear whether liberalizing exercise decisions will change the risk of SCD moving forward. The most recent AHA guidelines89 have taken a more nuanced approach to this conflict by recommending a comprehensive evaluation to inform a shared discussion about the potential for increased risk of sudden death and ICD discharges. Regardless, eligibility for participation may still be subject to oversight by third-party representatives from schools or teams.

Consideration of ICD Implantation

Current published guidelines by others for ICD implantation for primary prevention in adults with SHCM include documented cardiac arrest, sustained ventricular tachycardia, or a composite score of 2 or more of the following risk factors: SCD in a first-degree relative, massive LVH (≥30 mm), ≥2 recent episodes of syncope suspected by clinical history to be arrhythmic, LV apical aneurysm, and reduced ejection fraction.89 These recommendations are the same as those for adolescents 16 to 18 years of age, with the additional recommendation that adolescents engage in shared decision-making. Evaluating late gadolinium enhancement with cardiac magnetic resonance imaging is a 2B recommendation and is generally not done in preteens given the potential need for general anesthesia. Recommendations to implant an ICD have to be age stratified when applied to children given the risk of unintentional shocks and the other risks associated with placement of an ICD in small children. Current AHA guidelines for ICD implantation in children are the same as those for adults with the caveat that “ICD placement is reasonable after considering the relatively high complication rates of long-term ICD placement in younger patients.”89

Therapy in Symptomatic Pediatric Patients With HCM

As discussed, management of the risk of sudden death in HCM encompasses multiple clinical milieus from asymptomatic patients to those with end-stage disease. The approach to management of symptoms in patients with HCM is highly variable and is based on clinical experience and observational studies with limited data to support specific mechanisms. Some experts reserve medications for patients with symptoms, whereas others initiate therapy, usually with β-blockers, in any patient who has moderate or greater LVOT obstruction regardless of symptoms. Patients who have LVOT obstruction are known to be at greater risk for the development of symptoms and progression to death from HF,112 although progression to HF is rare in pediatrics. Medical or surgical therapy aimed at reducing LVOT obstruction is the primary strategy for reducing symptoms of chest pain, dyspnea, and fatigue. β-Blockers and calcium channel blockers are typically chosen as first-line therapies. Disopyramide has been used alone or in combination with one of the above-mentioned medications, although the pediatric experience with this medication is substantially less than in adults.113

  1. β-Blockers are the most commonly used medication in HCM for relief of chest pain and dyspnea. They are also used for rate control in patients with arrhythmias. Their proposed primary mechanism of action for chest pain and dyspnea is speculated to be secondary to prolonging diastole and increasing ventricular filling by heart rate reduction and a possible decrease in outflow tract obstruction by reducing inotropy, but they have not been shown to improve exercise tolerance. Nonvasodilating β-blockers are favored in patients with HCM with obstruction to avoid exacerbating the outflow gradient.114 Side effects, including depression, disordered sleep, and impaired school performance, can be an issue. Use of cardioselective agents such as atenolol or metoprolol may help to ameliorate some of these unwanted effects.

  2. Nondihydropyridine calcium channel blockers such as verapamil are thought to improve dyspnea and exercise tolerance by increasing diastolic relaxation, leading to reduced diastolic LV pressure and mean atrial pressure.115 They also improve microvascular function and increase myocardial perfusion,116 thought to be the mechanism by which they reduce chest pain. Early in the experience with verapamil, there were isolated case reports of cardiovascular collapse with intravenous administration of verapamil in patients with supraventricular tachycardia and hypotension. However, oral verapamil is well tolerated in children, even in neonates.117 Side effects are rarely encountered in young patients with HCM despite the association of calcium channel blockers with HF in older adults.

  3. Disopyramide is an antiarrhythmic agent with negative inotropic properties and is used as second-line therapy in combination with either β-blockers or calcium channel blockers. Disopyramide inhibits multiple ion channels, leading to lower calcium transients and force generation, ultimately resulting in decreased LVOT obstruction.118,119 Although it has not been studied extensively in pediatric patients with HCM, it has demonstrated a reasonable side-effect profile in pediatric patients with neurocardiogenic syncope,120 and associated vagolytic side effects are generally managed with cholinesterase inhibitors.119,121,122 However, disopyramide can prolong QTc and accelerate atrioventricular nodal conduction and is therefore not generally used as first-line therapy.119

  4. Septal infarction after transcatheter infusion of absolute alcohol or coil septal coronary perforators can reduce septal thickness and reduce LVOT obstruction, with improved symptoms and increased exercise tolerance in adults. Procedural complications are higher than for surgical myectomy, related primarily to a significant incidence of permanent complete heart block.89 Success is highest when obstruction is related to basilar septal hypertrophy, whereas patients with intrinsic mitral valve abnormalities or obstruction that is more apical are poor candidates. There is almost no reported experience with these techniques in children, related in part to the smaller coronary vessels in younger children and concerns about the lifetime consequences of a large septal infarction. Accordingly, the American College of Cardiology Foundation/AHA guidelines currently advise against routine use of alcohol septal ablation in childhood and young adulthood.123

  5. Surgical myotomy-myectomy in symptomatic subaortic stenosis results in symptomatic improvement in nearly all patients, and most contemporary studies have documented a high success rate, near-zero mortality, and few complications with the procedure in adults when performed by high-volume, experienced HCM surgeons.124 Results in children have been similar to those reported in adults, with survival rates as high as 98.6% at 5 years.125,126 Mitral regurgitation often improves in response to myectomy as a result of improved intraventricular flow patterns, and surgery permits concomitant mitral valve repair in patients with underlying mitral valve abnormalities. Although recurrence of obstruction is rare in older patients (2%),127 it is more common in neonates and infants, likely because of continued myocardial growth and associated disease states, when present, in these age groups.

Both supraventricular and ventricular arrhythmias are encountered in HCM. Atrial fibrillation is the most common supraventricular dysrhythmia, although it is infrequent in patients <30 years of age. Patients with left atrial enlargement, mitral regurgitation, severe LVH, extensive myocardial fibrosis, and symptoms of HF are at highest risk for developing atrial fibrillation. The risk of thromboembolism is high, and prophylactic anticoagulation is necessary. In general, therapy is aimed at rate reduction (β-blockers/calcium channel blockers, alone or in combination) and may include cardioversion in those who are markedly symptomatic or hemodynamically unstable. Ventricular arrhythmias are common and range from isolated ventricular premature beats to nonsustained (>3 beats) to sustained (>30 seconds) ventricular tachycardia and ventricular fibrillation. As assessed by ambulatory electrocardiographic monitoring, ventricular premature beats are highly prevalent, seen in 88%, with nonsustained ventricular tachycardia present in 31% in a study of 178 adult patients.128 For patients who experience repeat ICD shocks secondary to frequent ventricular arrhythmias, agents such as a class III antiarrhythmic drug (eg, sotalol) may be effective. Amiodarone may also be considered in such cases, although long-term oral amiodarone is associated with photosensitivity, thyroid dysfunction, and pulmonary and hepatic toxicity, and this side-effect profile limits its use in pediatric patients.

Therapy in End-Stage Pediatric HCM

Patients with end-stage HCM have unmanageable HF, arrhythmias, or pulmonary hypertension requiring specialized interventions. The patterns of disease in this so-called end-stage disease typically manifest with either restrictive physiology (noncompliant ventricles with relatively preserved systolic function) or transition to systolic dysfunction, usually accompanied by ventricular dilation. Heart transplantation has traditionally been reserved for patients with HCM who have progressed to end stage, defined as LV systolic failure with ejection fraction <50%.89 Even in the absence of LVOT obstruction, diastolic dysfunction can cause symptoms of HF, necessitating invasive testing with or without exercise testing to identify the cause of functional limitation and to aid in the selection of patients for heart transplantation. Heart transplantation evaluation should also be considered in patients with HCM with intractable ventricular arrhythmias refractory to maximal antiarrhythmic therapy and ablation.89 A subset of patients transition to severe restrictive physiology with a risk of developing pulmonary hypertension. These patients require frequent careful monitoring of pulmonary vascular resistance to ensure that they remain candidates for heart transplantation. In summary, cardiac transplantation is the only option for the small percentage of pediatric patients with HCM who manifest uncontrollable congestive HF secondary to systolic or diastolic dysfunction, and these patients require careful longitudinal monitoring for the potential development of pulmonary hypertension.

Rare Cardiomyopathies

Noncompaction Cardiomyopathy

Ventricular noncompaction is a spectrum of clinical profiles including an apparently normal variant in otherwise healthy individuals, including athletes and pregnant women. It is associated with underlying chronic health conditions (chronic polycystic kidney disease, sickle cell disease), congenital heart disease (eg, Ebstein anomaly), and cardiomyopathy of various phenotypes, including DCM, HCM, and RCM.129–131 Although this spectrum has been observed in children and adults, children with ventricular noncompaction more commonly have associated congenital heart disease,132 abnormal genetic findings, or both, including single pathogenic variants in sarcomere genes and multiple genetic abnormalities in single individuals.133

Treatment of LV noncompaction associated with cardiomyopathies generally follows treatment of the associated phenotype (dilated, hypertrophic, or restrictive).131 The potential for thrombotic complications associated with LV complications had led to recommendations for antithrombotic therapy when LV noncompaction is associated with a cardiomyopathy phenotype but not LV noncompaction with normal cardiac structure and function.134,135 Established echocardiographic or imaging features to stratify risk for thromboembolism for this patient population are limited,135 making the timing to start antithrombotic therapy and the specific therapy unclear.

Information from genetic investigations may also identify opportunities for tailored management or potential therapies. For example, Barth syndrome has a form of ventricular noncompaction associated with DCM and severe HF. The syndrome is a common initial presentation of noncompaction,136–138 with an undulating phenotype in some patients, so quickly proceeding to heart transplantation should be carefully considered.137–139 Recognition of associated Barth syndrome and its effect on mitochondrial cardiolipin metabolism may lead to targeted therapy.140

Restrictive Cardiomyopathy

RCM is a rare form of heart muscle disease characterized by impaired ventricular filling leading to progressive elevation of pulmonary vascular resistance and nondilated biventricular failure with relatively preserved systolic function. Pediatric RCM is associated with poor prognosis, with more than half of children dying or requiring transplantation within 2 years of diagnosis.141,142 Both sarcomeric and nonsarcomeric mutations are associated with pediatric RCM. In a PCMR study by Webber et al,141 RCM accounted for 4.5% of cases of pediatric cardiomyopathies; a pure RCM phenotype was seen in approximately two-thirds of patients, whereas the rest had a mixed restrictive/hypertrophic phenotype. Webber et al141 reported that survival did not differ between patients with pure RCM and those with mixed restrictive/hypertrophic phenotype; however, transplantation-free survival was superior in the mixed phenotype. Although idiopathic RCM is most common, secondary causes of RCM include infiltrative, iatrogenic, and oncological origins; fibrotic processes; and storage disorders. Although treatment for RCM should target the cause, in most cases, no apparent reason for RCM can be identified, leading to an individualized treatment approach. Cardiac transplantation is the preferred treatment that offers long-term survival, but the optimal timing for listing these patients is unknown.143 The development of dysrhythmias, thromboembolic disease, diastolic and eventually systolic HF, and progressive pulmonary hypertension is associated with poor outcomes and can inform the timing of listing for transplantation. All children with RCM should undergo serial monitoring of their pulmonary vascular resistance, and any significant finding should prompt consideration of a transplantation evaluation.144 Cynicism about offering LV assist device therapy to these patients is based on concerns about impaired LV assist device therapy function resulting from compromised diastolic filling due to restrictive pathophysiology and inflow cannula obstruction in a small LV cavity.145 A national database study reported low VAD use in patients without DCM, with ≈4.5% of children with RCM listed for cardiac transplantation having a VAD compared with ≈24% of children with DCM.146 Novel modifications to the LV cannulation techniques reported for patients without DCM include (1) transseptal left atrium–to-aorta VAD cannulation, (2) atrial cannulation, or (3) biventricular support with atrial cannulation of the right atrium and LV cannulation with excision of the mitral valve and papillary muscles.145,147,148 The incidence of thrombosis in pediatric RCM is high; therefore, antithrombotic and anticoagulation therapy is recommended at diagnosis.147 Management of volume status in patients with RCM can be challenging; they rely on high filling pressures to maintain cardiac output, and excessive diuresis may result in decreased perfusion to the body. β-Blockers or calcium channel blockers to increase filling time or to treat arrhythmias should be used with caution because these agents may not be well tolerated. Data supporting the beneficial effects of ACE inhibitors and angiotensin II receptor blockers in RCM are lacking, and these agents may not be well tolerated. The evolution of genomics may help characterize cellular and molecular mechanisms leading to myocardial restriction and identify targets for potential interventional strategies.

Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy has been defined as an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease.149 According to this definition, arrhythmogenic cardiomyopathy incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory cardiomyopathies. One of the best characterized of these cardiomyopathies is arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), which shows pathologic fibrous and fibrofatty replacement of the right ventricular myocardium. The ventricular tachycardia with this entity shows a left bundle-branch pattern. Most ARVC is caused by variants in one of several genes encoding desmosomal proteins or proteins involved with the desmosome, or a desmosomopathy.

It is recognized that most patients with ARVC develop LV involvement, which can be observed with cardiac magnetic resonance imaging. LV involvement may result not only in LV arrhythmias but also in LV dysfunction leading a DCM phenotype and HF, which can lead to transplantation. These patients may present with a clinical and pathological diagnosis of acute myocarditis.150,151 Although ARVC presents primarily in adulthood, recent studies150–152 suggest that genetic disease affecting the desmosome that presents with HF and a DCM phenotype may occur in children and adolescents more frequently than has previously been appreciated.

Therapeutic strategies for ventricular arrhythmias seen with desmosomopathies generally follow those used for similar complications in HCM. HF and LV dysfunction strategies in a similar fashion follow those used for DCMs. A unique therapeutic intervention for ARVC and other presentations of desmosomopathies is exercise limitation. Current consensus149 states that exercise increases arrhythmic risk and structural dysfunction in patients with ARVC. Guidelines for the management of ARVC state that individuals with ARVC should not participate in competitive or frequent high-intensity endurance exercise.149 Furthermore, it is recommended that clinicians counsel adolescent and adult individuals who have a positive test for ARVC but are phenotype negative that competitive or high-frequency endurance exercise is associated with an increased likelihood of developing ARVC and ventricular arrhythmias. Thus, exercise guidance for ARVC and perhaps all presentations of desmosomopathies is different from that for HCM. The potential to mitigate the development of the overt cardiomyopathy in these patients would also lead to an added importance of genetic testing of family members to initiate these exercise interventions for genotype-positive family members.

Future Directions

Investigational Management Strategies

Pulmonary Artery Banding

The use of a pulmonary artery banding has emerged as a potential therapeutic alternative in infants with advanced HF due to DCM with preserved right ventricular function. Schranz et al153 from Germany originally described the application of pulmonary artery banding as an additional strategy to delay or even avoid heart transplantation in infants and young children with end-stage HF due to DCM. This study was expanded to a multicenter retrospective analysis with participants from 11 different nations (World Network Reports) and found that pulmonary artery banding was associated with significant improvement in patients with DCM.154 A recent multicenter retrospective analysis by Spigel and colleagues155 from the United States and the World Network Reports by Schranz et al154 found pulmonary artery banding to be associated with myocardial functional recovery in approximately one-third to one-half of the children with DCM.

Although both the US and Germany series exhibited a high prevalence of achieving cardiac recovery or a transplantation, the recovery rate in the US series was lower (one-third) than in Germany (more than two-thirds).153,155 A lower recovery rate in the United States could indicate a sicker patient population with advanced HF, suggesting selection bias, a limitation inherent to any retrospective case series.

Cell-Based Therapies

Some stem cell studies have reported improved function and LV dimension in adults. Preliminary data in animal models of DCM have shown improved cardiac function and reduced myocardial fibrosis.156,157 However, the results of stem cell therapy for children with DCM are mixed. Although some pediatric case reports have not described strong benefits,158,159 other studies have reported that stem cell therapy improved ejection fraction and decreased LV end-diastolic volume.160,161

Collaborative Networks and Registries

One of the challenges in studying rare diseases is establishing QI models that apply rigorous scientific methods to improve quality of care, building robust data infrastructures, and gaining insights into the high- impact research topics critical in eliminating health care gaps and disparities for children with cardiomyopathy.162 The Quality in Pediatric Subspecialty Care workgroup, established by the American Board of Pediatrics, launched pediatric collaborative improvement networks in 2002.162 These multisite, collaborative clinical networks provide a foundation for QI research into rare childhood diseases to translate evidence into best clinical practice.162,163 The Children’s Oncology Group and the Cystic Fibrosis Foundation are 2 successful collaborations that have produced spectacular results in collecting and using data to transform patient outcomes.162

This network approach has also been successful in pediatric cardiology, which now has collaborative networks that include the North American PCMR, the Pediatric Heart Transplant Society, and the Pediatric Heart Network. Specific to pediatric HF, ACTION (Advanced Cardiac Therapies Improving Outcomes Network) was developed in 2017.164,165 ACTION involves the key stakeholders, including patients, families, clinicians, and researchers. This network provides invaluable support and education to families and patients.165 One of the initial QI projects launched by ACTION was the “ABCs of stroke prevention.” This project focused on preventing stroke in children with end-stage HF and VADs. Within 2 years, this project likely contributed significantly to stroke rates at participating sites dropping by 60%.165,166 In particular, stroke rates among patients receiving pediatric durable VAD were significantly reduced from 30% to 11% in ACTION locations.167 The Table displays the ongoing ACTION network HF-specific QI initiatives.

Table. The Ongoing ACTION Network HF-Specific QI Initiatives165

1.Implantable pulmonary artery pressure monitoring in advanced pediatric heart failureThe implantable pulmonary artery pressure monitor protocol discusses patient selection, preimplantation, postimplantation follow-up, and outpatient monitoring after discharge. The implantable pulmonary artery pressure monitor protocol is in the data collection phase.
2.DMD therapy harmonizationThe DMD harmonization protocol helps harmonize dystrophin-related cardiomyopathy medications, especially early in the disease when significant practice variability exists across pediatric institutions.
3.Inpatient rounding checklist to improve pediatric HF symptom assessmentThe inpatient communication checklist helps improve pediatric heart failure symptom assessment and management.
4.Inpatient and outpatient medication checklist to optimize goal-directed medical therapiesThe inpatient and outpatient medication checklist discusses initiating and optimizing goal-directed medical therapy in inpatient and outpatient settings to reduce hospital readmission rates and outpatient medication titration harmonization.
5.Discharge-standardizing processes to reduce hospital readmission rates in pediatric HF

ACTION indicates Advanced Cardiac Therapies Improving Outcomes Network; DMD, Duchenne muscular dystrophy; HF, heart failure; and QI, quality improvement.

Linking large clinical registries is a popular strategy to broaden analytic options. Outcomes research using linked registries can set benchmarks in pediatric HF and support research into complex questions that individual databases cannot answer alone.164,168 Large databases can be linked to indirect patient identifiers (probabilistic matching) or unique, direct identifiers (deterministic matching).168–170 Furthermore, establishing a standardized global unique patient identifier to facilitate linkage across collaborating registries would allow integration of new data into existing registries.164 Given the challenges of conducting randomized trials in children with HF, a collaborative platform is particularly suited to this field of research. Integrated multimodality registries, including joint biorepositories with genomic and clinical data sets, could be leveraged to speed the translation of research findings into clinical practice guidelines.

In summary, pediatric collaborative networks are a successful model for sharing knowledge, providing a platform for research, and facilitating community engagement. However, adequate, long-term, reliable funding is essential to sustain these networks.

New Trial Designs and End Points

Legislative changes in the United States and European Union since the late 1990s have fostered an increase in the number of pediatric clinical trials though a combination of mandates and incentives.171 Alternative trial formats or recruiting strategies may also help increase the number of higher-quality trials. Registry-based randomized trials can be conducted at lower costs with greater generalizability. Such trials could test approved medications for new pediatric indications when there is no financial incentive for industry to support such trials or when funding is available but not to the scale needed for clinical trials.172,173 Registry-based trials may also decrease selection bias, particularly in studies of underserved populations.

Adaptive trial designs may help address inadequate sample sizes, dose selection, and comparators based on the questionable assumptions that plague pediatric clinical trials. Adaptive trials allow results from interim data analyses to modify the ongoing trial without undermining validity or integrity. Ongoing adaptive trials can refocus enrollment toward participants most likely to benefit from a treatment, alter trial arm allocation ratios, abandon less promising treatments or doses sooner, add new treatment arms, or stop a trial early for success or futility.174 These designs save time and money, require fewer patients, protect patients from ineffective treatments, decrease the probability of inadequate statistical power, and lead to earlier and more precise conclusions.175,176

Death and transplantation are appropriate end points for clinical trials of adults with HF, but studies of children with HF rarely enroll enough patients to provide adequate statistical power for these end points. As a result, identifying surrogate end points for clinical trials is critical to test evidence-based therapies. Recently, the use of composite, global rank primary end points has gained favor in pediatric HF trials. The utility of circulating and imaging biomarkers and measures of exercise and functional capacity also needs to be assessed. In PANORAMA-HF, patients are ranked by their outcome from worst to best: death, need for mechanical life support, listing for heart transplantation, worsening HF, New York Heart Association/Ross scores, and patient-reported outcomes.68

Transition of Care

Regardless of the type of cardiomyopathy, it is vital to have a cohesive and stepwise transition from child to adult care to achieve optimal long-term outcomes.177 Health care professionals must ensure that their adolescent and young adult patients with cardiomyopathy have the independence that enables them to navigate a new medical system, understand the need for and effects of their medications, and receive adequate medical education about their diagnosis. One systematic review of studies on children with congenital heart disease found that transition failed when patients were not explicitly told that specialized cardiac care was required, had not undergone cardiac surgeries, had less complex disease, had no specific adult health care professional, and had insufficient documentation of the need for a cardiac specialist who treated adults. In contrast, factors associated with successful transitions included the belief that specialized cardiac care was necessary, a history of cardiac surgery, multiple discussions in advance about the need for and the importance of transitioning to adult care, attendance of appointments without parents, older age, referral to an adult cardiac specialist, and a thorough understanding of their cardiac disease.178–181 The literature on the transition of adolescents and young adults with cardiomyopathy is scarce. Given the additional complexity of transitioning asymptomatic but at-risk children, strategies are needed to determine best practices for transitioning this unique population.


This scientific statement emphasizes the important differences between the types of and treatments for cardiomyopathies and HF in children and adults. Nevertheless, treatments for children can be informed by the results from studies of adults, as well as by new mechanistic-based therapeutic targets identified through preclinical work and tested in humans through phased clinical studies. Efforts to promote learning networks and registries focused on pediatric cardiomyopathies and HF can optimize data collection and provide a platform for research and the infrastructure needed to implement quality initiatives. New clinical trial designs, validated clinically relevant surrogate and composite outcomes suitable for smaller and shorter studies in children, and advancements in precision medicine with the development of cause-specific therapies should advance our ability to diagnose and treat cardiomyopathies in children.

Article Information

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on March 6, 2023, and the American Heart Association Executive Committee on April 4, 2023. A copy of the document is available at by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email

The American Heart Association requests that this document be cited as follows: Bogle C, Colan SD, Miyamoto SD, Choudhry S, Baez-Hernandez N, Brickler MM, Feingold B, Lal AK, Lee TM, Canter CE, Lipshultz SE; on behalf of the American Heart Association Young Hearts Pediatric Heart Failure and Transplantation Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young (Young Hearts). Treatment strategies for cardiomyopathy in children: a scientific statement from the American Heart Association. Circulation. 2023;148:174–195. doi: 10.1161/CIR.0000000000001151

The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit Select the “Guidelines & Statements” drop-down menu, then click “Publication Development.”

Permissions: Multiple copies, modification, alteration, enhancement, and distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at A link to the “Copyright Permissions Request Form” appears in the second paragraph (


The writing team would like to acknowledge Miriam A. Mestre, MA, for playing a central role in managing the development of this statement.


Circulation is available at


  • 1. Lipshultz SE, Law YM, Asante-Korang A, Austin ED, Dipchand AI, Everitt MD, Hsu DT, Lin KY, Price JF, Wilkinson JD, et al; on behalf of the American Heart Association Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Council on Genomic and Precision Medicine. Cardiomyopathy in children: classification and diagnosis: a scientific statement from the American Heart Association.Circulation. 2019; 140:e9–e68. doi: 10.1161/CIR.0000000000000682LinkGoogle Scholar
  • 2. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure).Circulation. 2001; 104:2996–3007. doi: 10.1161/hc4901.102568LinkGoogle Scholar
  • 3. Maddox TM, Januzzi JL, Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, Masoudi FA, et al. 2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.J Am Coll Cardiol. 2021; 77:772–810. doi: 10.1016/j.jacc.2020.11.022CrossrefMedlineGoogle Scholar
  • 4. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2022; 145:e895–e1032. doi: 10.1161/CIR.0000000000001063LinkGoogle Scholar
  • 5. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, et al; ESC Scientific Document Group. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur Heart J. 2021; 42:3599–3726. doi: 10.1093/eurheartj/ehab368CrossrefMedlineGoogle Scholar
  • 6. Kirk R, Dipchand AI, Rosenthal DN, Addonizio L, Burch M, Chrisant M, Dubin A, Everitt M, Gajarski R, Mertens L, et al. The International Society for Heart and Lung Transplantation guidelines for the management of pediatric heart failure: executive summary [corrected].J Heart Lung Transplant. 2014; 33:888–909. doi: 10.1016/j.healun.2014.06.002CrossrefMedlineGoogle Scholar
  • 7. Kantor PF, Lougheed J, Dancea A, McGillion M, Barbosa N, Chan C, Dillenburg R, Atallah J, Buchholz H, Chant-Gambacort C, et al; Children’s Heart Failure Study Group. Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines.Can J Cardiol. 2013; 29:1535–1552. doi: 10.1016/j.cjca.2013.08.008CrossrefMedlineGoogle Scholar
  • 8. Kantor PF, Abraham JR, Dipchand AI, Benson LN, Redington AN. The impact of changing medical therapy on transplantation-free survival in pediatric dilated cardiomyopathy.J Am Coll Cardiol. 2010; 55:1377–1384. doi: 10.1016/j.jacc.2009.11.059CrossrefMedlineGoogle Scholar
  • 9. Singh RK, Canter CE, Shi L, Colan SD, Dodd DA, Everitt MD, Hsu DT, Jefferies JL, Kantor PF, Pahl E, et al; Pediatric Cardiomyopathy Registry Investigators. Survival without cardiac transplantation among children with dilated cardiomyopathy.J Am Coll Cardiol. 2017; 70:2663–2673. doi: 10.1016/j.jacc.2017.09.1089CrossrefMedlineGoogle Scholar
  • 10. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, et al; Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart failure: a randomized controlled trial.JAMA. 2007; 298:1171–1179. doi: 10.1001/jama.298.10.1171CrossrefMedlineGoogle Scholar
  • 11. Rossano JW, Shaddy RE. Update on pharmacological heart failure therapies in children: do adult medications work in children and if not, why not?Circulation. 2014; 129:607–612. doi: 10.1161/CIRCULATIONAHA.113.003615LinkGoogle Scholar
  • 12. Harris KC, Mackie AS, Dallaire F, Khoury M, Singer J, Mahle WT, Klassen TP, McCrindle BW. Unique challenges of randomised controlled trials in pediatric cardiology.Can J Cardiol. 2021; 37:1394–1403. doi: 10.1016/j.cjca.2021.06.013CrossrefMedlineGoogle Scholar
  • 13. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie PR, Hsu D, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children.JAMA. 2006; 296:1867–1876. doi: 10.1001/jama.296.15.1867CrossrefMedlineGoogle Scholar
  • 14. Everitt MD, Sleeper LA, Lu M, Canter CE, Pahl E, Wilkinson JD, Addonizio LJ, Towbin JA, Rossano J, Singh RK, et al; Pediatric Cardiomyopathy Registry Investigators. Recovery of echocardiographic function in children with idiopathic dilated cardiomyopathy: results from the Pediatric Cardiomyopathy Registry.J Am Coll Cardiol. 2014; 63:1405–1413. doi: 10.1016/j.jacc.2013.11.059CrossrefMedlineGoogle Scholar
  • 15. Miyamoto SD, Stauffer BL, Nakano S, Sobus R, Nunley K, Nelson P, Sucharov CC. Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy.Eur Heart J. 2012; 35:33–41. doi: 10.1093/eurheartj/ehs229CrossrefMedlineGoogle Scholar
  • 16. Nakano SJ, Miyamoto SD, Movsesian M, Nelson P, Stauffer BL, Sucharov CC. Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy.Circ Heart Fail. 2015; 8:57–63. doi: 10.1161/CIRCHEARTFAILURE.114.001218LinkGoogle Scholar
  • 17. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al. Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE Study Research Group.N Engl J Med. 1991; 325:1468–1475. doi: 10.1056/NEJM199111213252103CrossrefMedlineGoogle Scholar
  • 18. Price JF, Towbin JA, Dreyer WJ, Moffett BS, Kertesz NJ, Clunie SK, Denfield SW. Outpatient continuous parenteral inotropic therapy as bridge to transplantation in children with advanced heart failure.J Card Fail. 2006; 12:139–143. doi: 10.1016/j.cardfail.2005.11.001CrossrefMedlineGoogle Scholar
  • 19. Berg AM, Snell L, Mahle WT. Home inotropic therapy in children.J Heart Lung Transplant. 2007; 26:453–457. doi: 10.1016/j.healun.2007.02.004CrossrefMedlineGoogle Scholar
  • 20. Patel MD, Mohan J, Schneider C, Bajpai G, Purevjav E, Canter CE, Towbin J, Bredemeyer A, Lavine KJ. Pediatric and adult dilated cardiomyopathy represent distinct pathological entities.JCI Insight. 2017; 2:e94382. doi: 10.1172/jci.insight.94382CrossrefMedlineGoogle Scholar
  • 21. Tatman PD, Woulfe KC, Karimpour-Fard A, Jeffrey DA, Jaggers J, Cleveland JC, Nunley K, Taylor MR, Miyamoto SD, Stauffer BL, et al. Pediatric dilated cardiomyopathy hearts display a unique gene expression profile.JCI Insight. 2017; 2:e94249. doi: 10.1172/jci.insight.94249CrossrefMedlineGoogle Scholar
  • 22. Woulfe KC, Siomos AK, Nguyen H, SooHoo M, Galambos C, Stauffer BL, Sucharov C, Miyamoto S. Fibrosis and fibrotic gene expression in pediatric and adult patients with idiopathic dilated cardiomyopathy.J Card Fail. 2017; 23:314–324. doi: 10.1016/j.cardfail.2016.11.006CrossrefMedlineGoogle Scholar
  • 23. Wehman B, Sharma S, Mishra R, Guo Y, Colletti EJ, Kon ZN, Datla SR, Siddiqui OT, Balachandran K, Kaushal S. Pediatric end-stage failing hearts demonstrate increased cardiac stem cells.Ann Thorac Surg. 2015; 100:615–622. doi: 10.1016/j.athoracsur.2015.04.088CrossrefMedlineGoogle Scholar
  • 24. Gropler MRF, Lipshultz SE, Wilkinson JD, Towbin JA, Colan SD, Canter CE, Lavine KJ, Simpson KE. Pediatric and adult dilated cardiomyopathy are distinguished by distinct biomarker profiles.Pediatr Res. 2021; doi: 10.1038/s41390-021-01698-xCrossrefMedlineGoogle Scholar
  • 25. Miyamoto SD, Karimpour-Fard A, Peterson V, Auerbach SR, Stenmark KR, Stauffer BL, Sucharov CC. Circulating microRNA as a biomarker for recovery in pediatric dilated cardiomyopathy.J Heart Lung Transplant. 2015; 34:724–733. doi: 10.1016/j.healun.2015.01.979CrossrefMedlineGoogle Scholar
  • 26. Kennel PJ, Schulze PC. A review on the evolving roles of MiRNA-based technologies in diagnosing and treating heart failure.Cells. 2021; 10:3191. doi: 10.3390/cells10113191CrossrefMedlineGoogle Scholar
  • 27. Nigro G, Comi LI, Politano L, Bain RJI. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy.Int J Cardiol. 1990; 26:271–277. doi: 10.1016/0167-5273(90)90082-gCrossrefMedlineGoogle Scholar
  • 28. Feingold B, Mahle WT, Auerbach S, Clemens P, Domenighetti AA, Jefferies JL, Judge DP, Lal AK, Markham LW, Parks WJ, et al; on behalf of the American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council. Management of cardiac involvement associated with neuromuscular diseases: a scientific statement from the American Heart Association.Circulation. 2017; 136:e200–e231. doi: 10.1161/CIR.0000000000000526LinkGoogle Scholar
  • 29. Buddhe S, Cripe L, Friedland-Little J, Kertesz N, Eghtesady P, Finder J, Hor K, Judge DP, Kinnett K, McNally EM, et al. Cardiac management of the patient with duchenne muscular dystrophy.Pediatrics. 2018; 142:S72–S81. doi: 10.1542/peds.2018-0333ICrossrefMedlineGoogle Scholar
  • 30. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy.J Am Coll Cardiol. 2005; 45:855–857. doi: 10.1016/j.jacc.2004.09.078CrossrefMedlineGoogle Scholar
  • 31. Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A, Berard C, Vaksmann G, Weber S, Becane HM. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ follow-up.Am Heart J. 2007; 154:596–602. doi: 10.1016/j.ahj.2007.05.014CrossrefMedlineGoogle Scholar
  • 32. Bourke JP, Bueser T, Quinlivan R. Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy.Cochrane Database Syst Rev. 2018; 10:CD009068. doi: 10.1002/14651858.CD009068.pub3CrossrefMedlineGoogle Scholar
  • 33. Porcher R, Desguerre I, Amthor H, Chabrol B, Audic F, Rivier F, Isapof A, Tiffreau V, Campana-Salort E, Leturcq F, et al. Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy: analysis of registry data.Eur Heart J. 2021; 42:1976–1984. doi: 10.1093/eurheartj/ehab054CrossrefMedlineGoogle Scholar
  • 34. Raman SV, Hor KN, Mazur W, Cardona A, He X, Halnon N, Markham L, Soslow JH, Puchalski MD, Auerbach SR, et al. Stabilization of early Duchenne cardiomyopathy with aldosterone inhibition: results of the multicenter AIDMD trial.J Am Heart Assoc. 2019; 8:e013501. doi: 10.1161/JAHA.119.013501LinkGoogle Scholar
  • 35. Yokota T, Duddy W, Partridge T. Optimizing exon skipping therapies for DMD.Acta Myol. 2007; 26:179–184.MedlineGoogle Scholar
  • 36. Johnston JR, McNally EM. Genetic correction strategies for Duchenne muscular dystrophy and their impact on the heart.Prog Pediatr Cardiol. 2021; 63:101460. doi: 10.1016/j.ppedcard.2021.101460CrossrefMedlineGoogle Scholar
  • 37. England SB, Nicholson LV, Johnson MA, Forrest SM, Love DR, Zubrzycka-Gaarn EE, Bulman DE, Harris JB, Davies KE. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin.Nature. 1990; 343:180–182. doi: 10.1038/343180a0CrossrefMedlineGoogle Scholar
  • 38. Duan D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy.Mol Ther. 2018; 26:2337–2356. doi: 10.1016/j.ymthe.2018.07.011CrossrefMedlineGoogle Scholar
  • 39. Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities.Nat Rev Cancer. 2014; 14:61–70. doi: 10.1038/nrc3634CrossrefMedlineGoogle Scholar
  • 40. Lipshultz SE, Adams MJ, Colan SD, Constine LS, Herman EH, Hsu DT, Hudson MM, Kremer LC, Landy DC, Miller TL, et al; on behalf of the American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Basic Cardiovascular Sciences, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Radiology and Intervention, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Council on Nutrition, Physical Activity and Metabolism. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association [published correction appears in Circulation. 2013;128:e394].Circulation. 2013; 128:1927–1995. doi: 10.1161/CIR.0b013e3182a88099LinkGoogle Scholar
  • 41. Armstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y, Leisenring W, Stovall M, Chow EJ, Sklar CA, Mulrooney DA, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer.J Clin Oncol. 2013; 31:3673–3680. doi: 10.1200/JCO.2013.49.3205CrossrefMedlineGoogle Scholar
  • 42. Feijen E, Font-Gonzalez A, Van der Pal HJH, Kok WEM, Geskus RB, Ronckers CM, Bresters D, van Dalen EC, van Dulmen-den Broeder E, van den Berg MH, et al; DCOG-LATER Study Group. Risk and temporal changes of heart failure among 5-year childhood cancer survivors: a DCOG-LATER study.J Am Heart Assoc. 2019; 8:e009122. doi: 10.1161/JAHA.118.009122LinkGoogle Scholar
  • 43. Alvi RM, Frigault MJ, Fradley MG, Jain MD, Mahmood SS, Awadalla M, Lee DH, Zlotoff DA, Zhang L, Drobni ZD, et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T).J Am Coll Cardiol. 2019; 74:3099–3108. doi: 10.1016/j.jacc.2019.10.038CrossrefMedlineGoogle Scholar
  • 44. Lefebvre B, Kang Y, Smith AM, Frey NV, Carver JR, Scherrer-Crosbie M. Cardiovascular effects of CAR T cell therapy: a retrospective study.JACC CardioOncol. 2020; 2:193–203. doi: 10.1016/j.jaccao.2020.04.012CrossrefMedlineGoogle Scholar
  • 45. Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE, McCabe C, Welch SB, Whitney A, O’Gara P, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.Lancet. 2004; 363:203–209. doi: 10.1016/s0140-6736(03)15326-3CrossrefMedlineGoogle Scholar
  • 46. Shalabi H, Sachdev V, Kulshreshtha A, Cohen JW, Yates B, Rosing DR, Sidenko S, Delbrook C, Mackall C, Wiley B, et al. Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies.J Immunother Cancer. 2020; 8:e001159. doi: 10.1136/jitc-2020-001159CrossrefMedlineGoogle Scholar
  • 47. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy.N Engl J Med. 2005; 353:172–187. doi: 10.1056/NEJMra044389CrossrefMedlineGoogle Scholar
  • 48. Chaar M, Kamta J, Ait-Oudhia S. Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities.Onco Targets Ther. 2018; 11:6227–6237. doi: 10.2147/OTT.S170138CrossrefMedlineGoogle Scholar
  • 49. Jain D, Russell RR, Schwartz RG, Panjrath GS, Aronow W. Cardiac complications of cancer therapy: pathophysiology, identification, prevention, treatment, and future directions.Curr Cardiol Rep. 2017; 19:36. doi: 10.1007/s11886-017-0846-xCrossrefMedlineGoogle Scholar
  • 50. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.Lancet. 2007; 370:2011–2019. doi: 10.1016/S0140-6736(07)61865-0CrossrefMedlineGoogle Scholar
  • 51. Ewer MS, Suter TM, Lenihan DJ, Niculescu L, Breazna A, Demetri GD, Motzer RJ. Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events.Eur J Cancer. 2014; 50:2162–2170. doi: 10.1016/j.ejca.2014.05.013CrossrefMedlineGoogle Scholar
  • 52. Petrykey K, Andelfinger GU, Laverdiere C, Sinnett D, Krajinovic M. Genetic factors in anthracycline-induced cardiotoxicity in patients treated for pediatric cancer.Expert Opin Drug Metab Toxicol. 2020; 16:865–883. doi: 10.1080/17425255.2020.1807937CrossrefMedlineGoogle Scholar
  • 53. Alexandre J, Cautela J, Ederhy S, Damaj GL, Salem JE, Barlesi F, Farnault L, Charbonnier A, Mirabel M, Champiat S, et al. Cardiovascular toxicity related to cancer treatment: a pragmatic approach to the American and European cardio-oncology guidelines.J Am Heart Assoc. 2020; 9:e018403. doi: 10.1161/JAHA.120.018403LinkGoogle Scholar
  • 54. Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M, Nathan PC, Tissing WJ, Shankar S, Sieswerda E, et al; International Late Effects of Childhood Cancer Guideline Harmonization Group. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.Lancet Oncol. 2015; 16:e123–e136. doi: 10.1016/S1470-2045(14)70409-7CrossrefMedlineGoogle Scholar
  • 55. Chow EJ, Aplenc R, Vrooman LM, Doody DR, Huang YV, Aggarwal S, Armenian SH, Baker KS, Bhatia S, Constine LS, et al. Late health outcomes after dexrazoxane treatment: a report from the Children’s Oncology Group.Cancer. 2022; 128:788–796. doi: 10.1002/cncr.33974CrossrefMedlineGoogle Scholar
  • 56. Chow EJ, Asselin BL, Schwartz CL, Doody DR, Leisenring WM, Aggarwal S, Baker KS, Bhatia S, Constine LS, Freyer DR, et al. Late mortality after dexrazoxane treatment: a report from the Children’s Oncology Group.J Clin Oncol. 2015; 33:2639–2645. doi: 10.1200/JCO.2014.59.4473CrossrefMedlineGoogle Scholar
  • 57. Bansal N, Adams MJ, Ganatra S, Colan SD, Aggarwal S, Steiner R, Amdani S, Lipshultz ER, Lipshultz SE. Strategies to prevent anthracycline-induced cardiotoxicity in cancer survivors.Cardiooncology. 2019; 5:18. doi: 10.1186/s40959-019-0054-5CrossrefMedlineGoogle Scholar
  • 58. US Food and Drug Administration. Orphan drug designations and approvals.2014. Accessed December 8, 2021. Scholar
  • 59. European Medicines Authority. Outcome of a procedure under Article 13 of Regulation (EC) No 1234/2008.Accessed February 12, 2018. Scholar
  • 60. European Commission. Cardioxane Art 13.Accessed February 12, 2018. Scholar
  • 61. Lipshultz SE. Letter by Lipshultz regarding article, “anthracycline cardiotoxicity: worrisome enough to have you quaking?”Circ Res. 2018; 122:e62–e63. doi: 10.1161/CIRCRESAHA.118.312918LinkGoogle Scholar
  • 62. Kindel SJ, Miller EM, Gupta R, Cripe LH, Hinton RB, Spicer RL, Towbin JA, Ware SM. Pediatric cardiomyopathy: importance of genetic and metabolic evaluation.J Card Fail. 2012; 18:396–403. doi: 10.1016/j.cardfail.2012.01.017CrossrefMedlineGoogle Scholar
  • 63. Ware SM, Bhatnagar S, Dexheimer PJ, Wilkinson JD, Sridhar A, Fan X, Shen Y, Tariq M, Schubert JA, Colan SD, et al; Pediatric Cardiomyopathy Registry Study Group. The genetic architecture of pediatric cardiomyopathy.Am J Hum Genet. 2022; 109:282–298. doi: 10.1016/j.ajhg.2021.12.006CrossrefMedlineGoogle Scholar
  • 64. Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.J Card Fail. 2018; 24:281–302. doi: 10.1016/j.cardfail.2018.03.004CrossrefMedlineGoogle Scholar
  • 65. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.Circulation. 2013; 128:e240–e327. doi: 10.1161/CIR.0b013e31829e8776LinkGoogle Scholar
  • 66. Petko C, Minich LL, Everitt MD, Holubkov R, Shaddy RE, Tani LY. Echocardiographic evaluation of children with systemic ventricular dysfunction treated with carvedilol.Pediatr Cardiol. 2010; 31:780–784. doi: 10.1007/s00246-010-9700-2CrossrefMedlineGoogle Scholar
  • 67. Bonnet D, Berger F, Jokinen E, Kantor PF, Daubeney PEF. Ivabradine in children with dilated cardiomyopathy and symptomatic chronic heart failure.J Am Coll Cardiol. 2017; 70:1262–1272. doi: 10.1016/j.jacc.2017.07.725CrossrefMedlineGoogle Scholar
  • 68. Shaddy R, Canter C, Halnon N, Kochilas L, Rossano J, Bonnet D, Bush C, Zhao Z, Kantor P, Burch M, et al. Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study).Am Heart J. 2017; 193:23–34. doi: 10.1016/j.ahj.2017.07.006CrossrefMedlineGoogle Scholar
  • 69. Shaddy R, Burch M, Kantor P, Solar-Yohay S, Garito T, Zhang S, Kocun M, Mao C, Cilliers A, Wang X, et al. Angiotensin receptor neprilysin inhibition in paediatirc patients with heart failure due to systemic left ventricular systolic dysfunction: primary results of the PANORAMA-HF trial. Paper presented at: European Society of Cardiology; August 27, 2022; Barcelona, Spain.Google Scholar
  • 70. Harmon WG, Sleeper LA, Cuniberti L, Messere J, Colan SD, Orav EJ, Towbin JA, Wilkinson JD, Lipshultz SE. Treating children with idiopathic dilated cardiomyopathy (from the Pediatric Cardiomyopathy Registry).Am J Cardiol. 2009; 104:281–286. doi: 10.1016/j.amjcard.2009.03.033CrossrefMedlineGoogle Scholar
  • 71. Moffett BS, Price JF. National prescribing trends for heart failure medications in children.Congenit Heart Dis. 2015; 10:78–85. doi: 10.1111/chd.12183CrossrefMedlineGoogle Scholar
  • 72. Stidham J, Feingold B, Almond CS, Burstein DS, Krack P, Price JF, Schumacher KR, Spinner JA, Rosenthal DN, Lorts A, et al. Establishing baseline metrics of heart failure medication use in children: a collaborative effort from the ACTION Network.Pediatr Cardiol. 2021; 42:315–323. doi: 10.1007/s00246-020-02485-xCrossrefMedlineGoogle Scholar
  • 73. Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Adams KF, Anand I, Arias-Mendoza A, Biering-Sorensen T, et al; GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.N Engl J Med. 2021; 384:105–116. doi: 10.1056/NEJMoa2025797CrossrefMedlineGoogle Scholar
  • 74. Pabel S, Wagner S, Bollenberg H, Bengel P, Kovacs A, Schach C, Tirilomis P, Mustroph J, Renner A, Gummert J, et al. Empagliflozin directly improves diastolic function in human heart failure.Eur J Heart Fail. 2018; 20:1690–1700. doi: 10.1002/ejhf.1328CrossrefMedlineGoogle Scholar
  • 75. Chen H, Li X, Liu X, Wang J, Zhang Z, Wu J, Huang M, Guo Y, Li F, Wang X, et al. Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort.Orphanet J Rare Dis. 2019; 14:29. doi: 10.1186/s13023-019-1010-zCrossrefMedlineGoogle Scholar
  • 76. Accessed January 5, 2022. https://clinicaltrials.govGoogle Scholar
  • 77. Sinagra G, Dal Ferro M, Merlo M. Lamin A/C cardiomyopathy: cutting edge to personalized medicine.Circ Cardiovasc Genet. 2017; 10: e002004. doi: 10.1161/CIRCGENETICS.117.002004LinkGoogle Scholar
  • 78. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC, Francis GS, Lenihan D, Lewis EF, McNamara DM, et al; on behalf of the American Heart Association Committee on Heart Failure and Transplantation of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research. Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association [published correction appears in Circulation. 2016;134:e652].Circulation. 2016; 134:e579–e646. doi: 10.1161/CIR.0000000000000455LinkGoogle Scholar
  • 79. Dimas VV, Morray BH, Kim DW, Almond CS, Shahanavaz S, Tume SC, Peng LF, McElhinney DB, Justino H. A multicenter study of the Impella device for mechanical support of the systemic circulation in pediatric and adolescent patients.Catheter Cardiovasc Interv. 2017; 90:124–129. doi: 10.1002/ccd.26973CrossrefMedlineGoogle Scholar
  • 80. Almond CS, Singh TP, Gauvreau K, Piercey GE, Fynn-Thompson F, Rycus PT, Bartlett RH, Thiagarajan RR. Extracorporeal membrane oxygenation for bridge to heart transplantation among children in the United States: analysis of data from the Organ Procurement and Transplant Network and Extracorporeal Life Support Organization Registry.Circulation. 2011; 123:2975–2984. doi: 10.1161/CIRCULATIONAHA.110.991505LinkGoogle Scholar
  • 81. Rossano JW, VanderPluym CJ, Peng DM, Hollander SA, Maeda K, Adachi I, Davies RR, Simpson KE, Fynn-Thompson F, Conway J, et al. Fifth annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report.Ann Thorac Surg. 2021; 112:1763–1774. doi: 10.1016/j.athoracsur.2021.10.001CrossrefMedlineGoogle Scholar
  • 82. Fang JC, Ewald GA, Allen LA, Butler J, Westlake Canary CA, Colvin-Adams M, Dickinson MG, Levy P, Stough WG, Sweitzer NK, et al; Heart Failure Society of America Guidelines Committee. Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee.J Card Fail. 2015; 21:519–534. doi: 10.1016/j.cardfail.2015.04.013CrossrefMedlineGoogle Scholar
  • 83. Hershberger RE, Nauman D, Walker TL, Dutton D, Burgess D. Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure.J Card Fail. 2003; 9:180–187. doi: 10.1054/jcaf.2003.24CrossrefMedlineGoogle Scholar
  • 84. Mann DL, Barger PM, Burkhoff D. Myocardial recovery and the failing heart: myth, magic, or molecular target?J Am Coll Cardiol. 2012; 60:2465–2472. doi: 10.1016/j.jacc.2012.06.062CrossrefMedlineGoogle Scholar
  • 85. Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Rahneva T, Wage R, Smith G, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.Lancet. 2019; 393:61–73. doi: 10.1016/S0140-6736(18)32484-XCrossrefMedlineGoogle Scholar
  • 86. Morales DLS, Adachi I, Peng DM, Sinha P, Lorts A, Fields K, Conway J, St Louis JD, Cantor R, Koehl D, et al. Fourth annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report.Ann Thorac Surg. 2020; 110:1819–1831. doi: 10.1016/j.athoracsur.2020.09.003CrossrefMedlineGoogle Scholar
  • 87. Adachi I, Zea-Vera R, Tunuguntla H, Denfield SW, Elias B, John R, Teruya J, Fraser CD. Centrifugal-flow ventricular assist device support in children: a single-center experience.J Thorac Cardiovasc Surg. 2019; 157:1609–1617.e2. doi: 10.1016/j.jtcvs.2018.12.045CrossrefMedlineGoogle Scholar
  • 88. Miera O, Germann M, Cho MY, Photiadis J, Delmo Walter EM, Hetzer R, Berger F, Schmitt KRL. Bridge to recovery in children on ventricular assist devices: protocol, predictors of recovery, and long-term follow-up.J Heart Lung Transplant. 2018; 37:1459–1466. doi: 10.1016/j.healun.2018.08.005CrossrefMedlineGoogle Scholar
  • 89. Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, Evanovich LL, Hung J, Joglar JA, Kantor P, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2020;142:e633].Circulation. 2020; 142:e558–e631. doi: 10.1161/CIR.0000000000000937LinkGoogle Scholar
  • 90. Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, Cirino AL, Fox JC, Lakdawala NK, Ware JS, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).Circulation. 2018; 138:1387–1398. doi: 10.1161/CIRCULATIONAHA.117.033200LinkGoogle Scholar
  • 91. Wilkinson JD, Lowe AM, Salbert BA, Sleeper LA, Colan SD, Cox GF, Towbin JA, Connuck DM, Messere JE, Lipshultz SE. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry.Am Heart J. 2012; 164:442–448. doi: 10.1016/j.ahj.2012.04.018CrossrefMedlineGoogle Scholar
  • 92. Colella P, Mingozzi F. Gene therapy for Pompe disease: the time is now.Hum Gene Ther. 2019; 30:1245–1262. doi: 10.1089/hum.2019.109CrossrefMedlineGoogle Scholar
  • 93. Yi JS, Huang Y, Kwaczala AT, Kuo IY, Ehrlich BE, Campbell SG, Giordano FJ, Bennett AM. Low-dose dasatinib rescues cardiac function in Noonan syndrome.JCI Insight. 2016; 1:e90220. doi: 10.1172/jci.insight.90220CrossrefMedlineGoogle Scholar
  • 94. Mussa A, Carli D, Giorgio E, Villar AM, Cardaropoli S, Carbonara C, Campagnoli MF, Galletto P, Palumbo M, Olivieri S, et al. MEK inhibition in a newborn with RAF1-associated Noonan syndrome ameliorates hypertrophic cardiomyopathy but is insufficient to revert pulmonary vascular disease.Genes (Basel). 2021; 13:6. doi: 10.3390/genes13010006CrossrefMedlineGoogle Scholar
  • 95. Andelfinger G, Marquis C, Raboisson MJ, Theoret Y, Waldmuller S, Wiegand G, Gelb BD, Zenker M, Delrue MA, Hofbeck M. Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition.J Am Coll Cardiol. 2019; 73:2237–2239. doi: 10.1016/j.jacc.2019.01.066CrossrefMedlineGoogle Scholar
  • 96. Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, Choudhury L, Edelberg JM, Hegde SM, Jacoby D, Lakdawala NK, Lester SJ, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2020; 75:2649–2660. doi: 10.1016/j.jacc.2020.03.064CrossrefMedlineGoogle Scholar
  • 97. Spertus JA, Fine JT, Elliott P, Ho CY, Olivotto I, Saberi S, Li W, Dolan C, Reaney M, Sehnert AJ, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2021; 397:2467–2475. doi: 10.1016/S0140-6736(21)00763-7CrossrefMedlineGoogle Scholar
  • 98. Ho CY, McMurray JJV, Cirino AL, Colan SD, Day SM, Desai AS, Lipshultz SE, MacRae CA, Shi L, Solomon SD, et al; VANISH Trial Investigators and Executive Committee. The design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial.Am Heart J. 2017; 187:145–155. doi: 10.1016/j.ahj.2017.02.008CrossrefMedlineGoogle Scholar
  • 99. Ho CY, Day SM, Axelsson A, Russell MW, Zahka K, Lever HM, Pereira AC, Colan SD, Margossian R, Murphy AM, et al. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.Nat Med. 2021; 27:1818–1824. doi: 10.1038/s41591-021-01505-4CrossrefMedlineGoogle Scholar
  • 100. Ho CY, Lakdawala NK, Cirino AL, Lipshultz SE, Sparks E, Abbasi SA, Kwong RY, Antman EM, Semsarian C, Gonzalez A, et al. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression.JACC Heart Fail. 2015; 3:180–188. doi: 10.1016/j.jchf.2014.08.003CrossrefMedlineGoogle Scholar
  • 101. Ho CY, Cirino AL, Lakdawala NK, Groarke J, Valente AM, Semsarian C, Colan SD, Orav EJ. Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers.Heart. 2016; 102:1805–1812. doi: 10.1136/heartjnl-2016-310015CrossrefMedlineGoogle Scholar
  • 102. El Assaad I, Gauvreau K, Rizwan R, Margossian R, Colan S, Chen MH. Value of exercise stress echocardiography in children with hypertrophic cardiomyopathy.J Am Soc Echocardiogr. 2020; 33:888–894.e2. doi: 10.1016/j.echo.2020.01.020CrossrefMedlineGoogle Scholar
  • 103. Nakano SJ, Menon SC. Risk stratification in pediatric hypertrophic cardiomyopathy: insights for bridging the evidence gap?Prog Pediatr Cardiol. 2018; 49:31–37. doi: 10.1016/j.ppedcard.2018.03.001CrossrefMedlineGoogle Scholar
  • 104. Norrish G, Ding T, Field E, McLeod K, Ilina M, Stuart G, Bhole V, Uzun O, Brown E, Daubeney PEF, et al. A validation study of the European Society of Cardiology guidelines for risk stratification of sudden cardiac death in childhood hypertrophic cardiomyopathy.Europace. 2019; 21:1559–1565. doi: 10.1093/europace/euz118CrossrefMedlineGoogle Scholar
  • 105. Norrish G, Ding T, Field E, Ziolkowska L, Olivotto I, Limongelli G, Anastasakis A, Weintraub R, Biagini E, Ragni L, et al. Development of a novel risk prediction model for sudden cardiac death in childhood hypertrophic cardiomyopathy (HCM Risk-Kids).JAMA Cardiol. 2019; 4:918–927. doi: 10.1001/jamacardio.2019.2861CrossrefMedlineGoogle Scholar
  • 106. Miron A, Lafreniere-Roula M, Steve Fan CP, Armstrong KR, Dragulescu A, Papaz T, Manlhiot C, Kaufman B, Butts RJ, Gardin L, et al. A validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy.Circulation. 2020; 142:217–229. doi: 10.1161/CIRCULATIONAHA.120.047235LinkGoogle Scholar
  • 107. Ostman-Smith I, Sjoberg G, Alenius Dahlqvist J, Larsson P, Fernlund E. Sudden cardiac death in childhood hypertrophic cardiomyopathy is best predicted by a combination of electrocardiogram risk-score and HCMRisk-Kids score.Acta Paediatr. 2021; 110:3105–3115. doi: 10.1111/apa.16045CrossrefMedlineGoogle Scholar
  • 108. Ostman-Smith I, Wisten A, Nylander E, Bratt EL, Granelli A, Oulhaj A, Ljungstrom E. Electrocardiographic amplitudes: a new risk factor for sudden death in hypertrophic cardiomyopathy.Eur Heart J. 2010; 31:439–449. doi: 10.1093/eurheartj/ehp443CrossrefMedlineGoogle Scholar
  • 109. Norrish G, Qu C, Field E, Cervi E, Khraiche D, Klaassen S, Ojala TH, Sinagra G, Yamazawa H, Marrone C, et al. External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy.Eur J Prev Cardiol. 2022; 29:678–686. doi: 10.1093/eurjpc/zwab181CrossrefMedlineGoogle Scholar
  • 110. Maron BJ, Udelson JE, Bonow RO, Nishimura RA, Ackerman MJ, Estes NAM, Cooper LT, Link MS, Maron MS; on behalf of the American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and the American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 3: hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and other cardiomyopathies, and myocarditis: a scientific statement from the American Heart Association and American College of Cardiology.Circulation. 2015; 132:e273–e280. doi: 10.1161/CIR.0000000000000239LinkGoogle Scholar
  • 111. Weissler-Snir A, Allan K, Cunningham K, Connelly KA, Lee DS, Spears DA, Rakowski H, Dorian P. Hypertrophic cardiomyopathy-related sudden cardiac death in young people in Ontario.Circulation. 2019; 140:1706–1716. doi: 10.1161/CIRCULATIONAHA.119.040271LinkGoogle Scholar
  • 112. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy.N Engl J Med. 2003; 348:295–303. doi: 10.1056/NEJMoa021332CrossrefMedlineGoogle Scholar
  • 113. Jacobs JP. Cardiology in the young: where we have been, where we are, where we are going.Cardiol Young. 2014; 24:981–1007. doi: 10.1017/S1047951114002297CrossrefMedlineGoogle Scholar
  • 114. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, et al; Task Force Members. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35:2733–2779. doi: 10.1093/eurheartj/ehu284CrossrefMedlineGoogle Scholar
  • 115. Posma JL, Blanksma PK, Van der Wall E, Lie KI. Acute intravenous versus chronic oral drug effects of verapamil on left ventricular diastolic function in patients with hypertrophic cardiomyopathy.J Cardiovasc Pharmacol. 1994; 24:969–973. doi: 10.1097/00005344-199424060-00015CrossrefMedlineGoogle Scholar
  • 116. Gistri R, Cecchi F, Choudhury L, Montereggi A, Sorace O, Salvadori PA, Camici PG. Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy.Am J Cardiol. 1994; 74:363–368. doi: 10.1016/0002-9149(94)90404-9CrossrefMedlineGoogle Scholar
  • 117. Moran AM, Colan SD. Verapamil therapy in infants with hypertrophic cardiomyopathy.Cardiol Young. 1998; 8:310–319. doi: 10.1017/s1047951100006818CrossrefMedlineGoogle Scholar
  • 118. Coppini R, Ferrantini C, Pioner JM, Santini L, Wang ZJ, Palandri C, Scardigli M, Vitale G, Sacconi L, Stefano P, et al. Electrophysiological and contractile effects of disopyramide in patients with obstructive hypertrophic cardiomyopathy: a translational study.JACC Basic Transl Sci. 2019; 4:795–813. doi: 10.1016/j.jacbts.2019.06.004CrossrefMedlineGoogle Scholar
  • 119. O’Connor MJ, Miller K, Shaddy RE, Lin KY, Hanna BD, Ravishankar C, Rossano JW. Disopyramide use in infants and children with hypertrophic cardiomyopathy.Cardiol Young. 2018; 28:530–535. doi: 10.1017/S1047951117002384CrossrefMedlineGoogle Scholar
  • 120. Sokoloski MC. Evaluation and treatment of pediatric patients with neurocardiogenic syncope.Prog Pediatr Cardiol. 2001; 13:127–131. doi: 10.1016/s1058-9813(01)00095-9CrossrefMedlineGoogle Scholar
  • 121. Ostman-Smith I. Beta-blockers in pediatric hypertrophic cardiomyopathies.Rev Recent Clin Trials. 2014; 9:82–85. doi: 10.2174/1574887109666140908125158CrossrefMedlineGoogle Scholar
  • 122. Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2005; 45:1251–1258. doi: 10.1016/j.jacc.2005.01.012CrossrefMedlineGoogle Scholar
  • 123. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.Circulation. 2011; 124:e783–e831. doi: 10.1161/CIR.0b013e318223e2bdLinkGoogle Scholar
  • 124. Nguyen A, Schaff HV, Nishimura RA, Geske JB, Ackerman MJ, Bos JM, Dearani JA, Ommen SR. Survival after myectomy for obstructive hypertrophic cardiomyopathy: what causes late mortality?Ann Thorac Surg. 2019; 108:723–729. doi: 10.1016/j.athoracsur.2019.03.026CrossrefMedlineGoogle Scholar
  • 125. Altarabsheh SE, Dearani JA, Burkhart HM, Schaff HV, Deo SV, Eidem BW, Ommen SR, Li Z, Ackerman MJ. Outcome of septal myectomy for obstructive hypertrophic cardiomyopathy in children and young adults.Ann Thorac Surg. 2013; 95:663–669. doi: 10.1016/j.athoracsur.2012.08.011CrossrefMedlineGoogle Scholar
  • 126. Bansal N, Barach P, Amdani SM, Lipshultz SE. When is early septal myectomy in children with hypertrophic cardiomyopathy justified?Transl Pediatr. 2018; 7:362–366. doi: 10.21037/tp.2018.09.08CrossrefMedlineGoogle Scholar
  • 127. Minakata K, Dearani JA, Schaff HV, O’Leary PW, Ommen SR, Danielson GK. Mechanisms for recurrent left ventricular outflow tract obstruction after septal myectomy for obstructive hypertrophic cardiomyopathy.Ann Thorac Surg. 2005; 80:851–856. doi: 10.1016/j.athoracsur.2005.03.108CrossrefMedlineGoogle Scholar
  • 128. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy.J Am Coll Cardiol. 2005; 45:697–704. doi: 10.1016/j.jacc.2004.11.043CrossrefMedlineGoogle Scholar
  • 129. Arbustini E, Favalli V, Narula N, Serio A, Grasso M. Left ventricular noncompaction: a distinct genetic cardiomyopathy?J Am Coll Cardiol. 2016; 68:949–966. doi: 10.1016/j.jacc.2016.05.096CrossrefMedlineGoogle Scholar
  • 130. Towbin JA, Lorts A, Jefferies JL. Left ventricular non-compaction cardiomyopathy.Lancet. 2015; 386:813–825. doi: 10.1016/S0140-6736(14)61282-4CrossrefMedlineGoogle Scholar
  • 131. Jefferies JL, Wilkinson JD, Sleeper LA, Colan SD, Lu M, Pahl E, Kantor PF, Everitt MD, Webber SA, Kaufman BD, et al; Pediatric Cardiomyopathy Registry Investigators. Cardiomyopathy phenotypes and outcomes for children with left ventricular myocardial noncompaction: results from the Pediatric Cardiomyopathy Registry.J Card Fail. 2015; 21:877–84. doi: 10.1016/j.cardfail.2015.06.381CrossrefMedlineGoogle Scholar
  • 132. Tsai SF, Ebenroth ES, Hurwitz RA, Cordes TM, Schamberger MS, Batra AS. Is left ventricular noncompaction in children truly an isolated lesion?Pediatr Cardiol. 2009; 30:597–602. doi: 10.1007/s00246-008-9382-1CrossrefMedlineGoogle Scholar
  • 133. van Waning JI, Caliskan K, Hoedemaekers YM, van Spaendonck-Zwarts KY, Baas AF, Boekholdt SM, van Melle JP, Teske AJ, Asselbergs FW, Backx A, et al. Genetics, clinical features, and long-term outcome of noncompaction cardiomyopathy.J Am Coll Cardiol. 2018; 71:711–722. doi: 10.1016/j.jacc.2017.12.019CrossrefMedlineGoogle Scholar
  • 134. Vergani V, Lazzeroni D, Peretto G. Bridging the gap between hypertrabeculation phenotype, noncompaction phenotype and left ventricular noncompaction cardiomyopathy.J Cardiovasc Med (Hagerstown). 2020; 21:192–199. doi: 10.2459/JCM.0000000000000924CrossrefMedlineGoogle Scholar
  • 135. Di Fusco SA, Luca F, Madeo A, Massimiliano Rao C, Iorio A, Rizzo M, Dalila Luisella Delcre S, Colivicchi F, Gabrielli D, Paolo Pino G, et al. Left ventricular noncompaction: diagnostic approach, prognostic evaluation, and management strategies.Cardiol Rev. 2020; 28:125–134. doi: 10.1097/CRD.0000000000000251CrossrefMedlineGoogle Scholar
  • 136. Roberts AE, Nixon C, Steward CG, Gauvreau K, Maisenbacher M, Fletcher M, Geva J, Byrne BJ, Spencer CT. The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study.Am J Med Genet A. 2012; 158:2726–2732. doi: 10.1002/ajmg.a.35609CrossrefGoogle Scholar
  • 137. Rigaud C, Lebre AS, Touraine R, Beaupain B, Ottolenghi C, Chabli A, Ansquer H, Ozsahin H, Di Filippo S, De Lonlay P, et al. Natural history of Barth syndrome: a national cohort study of 22 patients.Orphanet J Rare Dis. 2013; 8:70. doi: 10.1186/1750-1172-8-70CrossrefMedlineGoogle Scholar
  • 138. Kang SL, Forsey J, Dudley D, Steward CG, Tsai-Goodman B. Clinical characteristics and outcomes of cardiomyopathy in Barth syndrome: the UK experience.Pediatr Cardiol. 2016; 37:167–176. doi: 10.1007/s00246-015-1260-zCrossrefMedlineGoogle Scholar
  • 139. Yester J, Feingold B. Extended recovery of cardiac function after severe infantile cardiomyopathy presentation of Barth syndrome.JIMD Rep. 2022; 63:114–122. doi: 10.1002/jmd2.12264CrossrefMedlineGoogle Scholar
  • 140. Thompson RW, Hornby B, Manuel R, Bradley E, Laux J, Carr J, Vernon HJ. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism.Genet Med. 2021; 23:471–478. doi: 10.1038/s41436-020-01006-8CrossrefMedlineGoogle Scholar
  • 141. Webber SA, Lipshultz SE, Sleeper LA, Lu M, Wilkinson JD, Addonizio LJ, Canter CE, Colan SD, Everitt MD, Jefferies JL, et al. Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: a report from the Pediatric Cardiomyopathy Registry.Circulation. 2012; 126:1237–1244. doi: 10.1161/CIRCULATIONAHA.112.104638LinkGoogle Scholar
  • 142. Fenton MJ, Chubb H, McMahon AM, Rees P, Elliott MJ, Burch M. Heart and heart-lung transplantation for idiopathic restrictive cardiomyopathy in children.Heart. 2006; 92:85–89. doi: 10.1136/hrt.2004.049502CrossrefMedlineGoogle Scholar
  • 143. Lipshultz SE, Cochran TR, Briston DA, Brown SR, Sambatakos PJ, Miller TL, Carrillo AA, Corcia L, Sanchez JE, Diamond MB, et al. Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies.Future Cardiol. 2013; 9:817–848. doi: 10.2217/fca.13.66CrossrefMedlineGoogle Scholar
  • 144. Weller RJ, Weintraub R, Addonizio LJ, Chrisant MR, Gersony WM, Hsu DT. Outcome of idiopathic restrictive cardiomyopathy in children.Am J Cardiol. 2002; 90:501–506. doi: 10.1016/s0002-9149(02)02522-5CrossrefMedlineGoogle Scholar
  • 145. Lorts A, Conway J, Schweiger M, Adachi I, Amdani S, Auerbach SR, Barr C, Bleiweis MS, Blume ED, Burstein DS, et al. ISHLT consensus statement for the selection and management of pediatric and congenital heart disease patients on ventricular assist devices.J Heart Lung Transplant. 2021; 40:709–732. doi: 10.1016/j.healun.2021.04.015CrossrefMedlineGoogle Scholar
  • 146. Amdani S, Boyle G, Saarel EV, Godown J, Liu W, Worley S, Karamlou T. Waitlist and post-heart transplant outcomes for children with nondilated cardiomyopathy.Ann Thorac Surg. 2021; 112:188–196. doi: 10.1016/j.athoracsur.2020.05.170CrossrefMedlineGoogle Scholar
  • 147. Denfield SW. Overview of pediatric restrictive cardiomyopathy: 2021.Prog Pediatr Cardiol. 2021; 62:101415. doi: 10.1016/j.ppedcard.2021.101415CrossrefGoogle Scholar
  • 148. Maeda K, Nasirov T, Yarlagadda V, Hollander SA, Navarathnum M, Rosenthal DN, Chen S, Almond CS, Kaufman BD, Reinhartz O, et al. Novel trans-septal left atrial VAD cannulation technique for hypertrophic/restrictive cardiomyopathy.J Heart Lung Transplant. 2019; 38:S479. doi: 10.1016/j.healun.2019.01.1218CrossrefGoogle Scholar
  • 149. Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy.Heart Rhythm. 2019; 16:e301–e372. doi: 10.1016/j.hrthm.2019.05.007CrossrefMedlineGoogle Scholar
  • 150. Ammirati E, Raimondi F, Piriou N, Sardo Infirri L, Mohiddin SA, Mazzanti A, Shenoy C, Cavallari UA, Imazio M, Aquaro GD, et al. Acute myocarditis associated with desmosomal gene variants.JACC Heart Fail. 2022; 10:714–727. doi: 10.1016/j.jchf.2022.06.013CrossrefMedlineGoogle Scholar
  • 151. Lota AS, Hazebroek MR, Theotokis P, Wassall R, Salmi S, Halliday BP, Tayal U, Verdonschot J, Meena D, Owen R, et al. Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy.Circulation. 2022; 146:1123–1134. doi: 10.1161/CIRCULATIONAHA.121.058457LinkGoogle Scholar
  • 152. Tadros H, Choudhry S, Kearney D, Hope K, Yesso A, Miyake C, Price J, Spinner J, Tunuguntla H, Puri K, et al. Arrhythmogenic cardiomyopathy is under-recognized is end-stage pediatric heart failure: a 36-year single center experience.Pediatr Transplant. 2023; 27:e14442. doi: 10.1111/petr.14442CrossrefMedlineGoogle Scholar
  • 153. Schranz D, Rupp S, Muller M, Schmidt D, Bauer A, Valeske K, Michel-Behnke I, Jux C, Apitz C, Thul J, et al. Pulmonary artery banding in infants and young children with left ventricular dilated cardiomyopathy: a novel therapeutic strategy before heart transplantation.J Heart Lung Transplant. 2013; 32:475–481. doi: 10.1016/j.healun.2013.01.988CrossrefMedlineGoogle Scholar
  • 154. Schranz D, Akintuerk H, Bailey L. Pulmonary artery banding for functional regeneration of end-stage dilated cardiomyopathy in young children: World Network report.Circulation. 2018; 137:1410–1412. doi: 10.1161/CIRCULATIONAHA.117.029360LinkGoogle Scholar
  • 155. Spigel ZA, Razzouk A, Nigro JJ, Karamlou TB, Kavarana MN, Roeser ME, Adachi I. Pulmonary artery banding for children with dilated cardiomyopathy: US experience.Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2020; 23:69–76. doi: 10.1053/j.pcsu.2020.03.002CrossrefMedlineGoogle Scholar
  • 156. Hirai K, Baba K, Ohtsuki S, Oh H. Cardiosphere-derived exosomal microRNAs for cardiac repair in pediatric dilated cardiomyopathy: preclinical and safety lead-in phase 1 clinical studies.Eur Heart J. 2020; 41(suppl 2):ehaa946.3608. doi: 10.1093/ehjci/ehaa946.3608CrossrefGoogle Scholar
  • 157. Kaushal S, Jacobs JP, Gossett JG, Steele A, Steele P, Davis CR, Pahl E, Vijayan K, Asante-Korang A, Boucek RJ, et al. Innovation in basic science: stem cells and their role in the treatment of paediatric cardiac failure: opportunities and challenges.Cardiol Young. 2009; 19(suppl 2):74–84. doi: 10.1017/S104795110999165XCrossrefMedlineGoogle Scholar
  • 158. Selem SM, Kaushal S, Hare JM. Stem cell therapy for pediatric dilated cardiomyopathy.Curr Cardiol Rep. 2013; 15:369. doi: 10.1007/s11886-013-0369-zCrossrefMedlineGoogle Scholar
  • 159. Vrtovec B, Poglajen G, Lezaic L, Sever M, Socan A, Domanovic D, Cernelc P, Torre-Amione G, Haddad F, Wu JC. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy.Circulation. 2013; 128:S42–S49. doi: 10.1161/CIRCULATIONAHA.112.000230LinkGoogle Scholar
  • 160. Pioner JM, Fornaro A, Coppini R, Ceschia N, Sacconi L, Donati MA, Favilli S, Poggesi C, Olivotto I, Ferrantini C. Advances in stem cell modeling of dystrophin-associated disease: implications for the wider world of dilated cardiomyopathy.Front Physiol. 2020; 11:368. doi: 10.3389/fphys.2020.00368CrossrefMedlineGoogle Scholar
  • 161. Bergmane I, Lacis A, Lubaua I, Jakobsons E, Erglis A. Follow-up of the patients after stem cell transplantation for pediatric dilated cardiomyopathy.Pediatr Transplant. 2013; 17:266–270. doi: 10.1111/petr.12055CrossrefMedlineGoogle Scholar
  • 162. Lannon CM, Peterson LE. Pediatric collaborative networks for quality improvement and research.Acad Pediatr. 2013; 13:S69–S74. doi: 10.1016/j.acap.2013.07.004CrossrefMedlineGoogle Scholar
  • 163. Lannon CM, Miles PV, Stockman JA. The path forward: collaborative networks and the future for children’s health care.Pediatrics. 2013; 131(suppl 4):S226–S227. doi: 10.1542/peds.2012-3786LCrossrefMedlineGoogle Scholar
  • 164. Godown J, Gaies M, Wilkinson JD. Leveraging big data to advance knowledge in pediatric heart failure and heart transplantation.Transl Pediatr. 2019; 8:342–348. doi: 10.21037/tp.2019.07.09CrossrefMedlineGoogle Scholar
  • 165. Advanced Cardiac Therapies Improving Outcomes Network (ACTION).Accessed December 1, 2022. Scholar
  • 166. Villa CR, VanderPluym CJ; ACTION Investigators. ABCs of stroke prevention: improving stroke outcomes in children supported with a ventricular assist device in a quality improvement network.Circ Cardiovasc Qual Outcomes. 2020; 13:e006663. doi: 10.1161/CIRCOUTCOMES.120.006663LinkGoogle Scholar
  • 167. Jaquiss RD, Humpl T, Canter CE, Morales DL, Rosenthal DN, Fraser CD. Postapproval outcomes: the Berlin Heart EXCOR pediatric in North America.ASAIO J. 2017; 63:193–197. doi: 10.1097/MAT.0000000000000454CrossrefMedlineGoogle Scholar
  • 168. O’Gara P, Harrington RA. The future of clinical research and the ACC: empowerment through registries, data, and our members.J Am Coll Cardiol. 2014; 64:1751–1752. doi: 10.1016/j.jacc.2014.09.005CrossrefMedlineGoogle Scholar
  • 169. Choudhry S, Dharnidharka VR, Castleberry CD, Goss CW, Simpson KE, Schechtman KB, Canter CE. End-stage renal disease after pediatric heart transplantation: a 25-year national cohort study.J Heart Lung Transplant. 2017; 37:217–224. doi: 10.1016/j.healun.2017.09.027CrossrefGoogle Scholar
  • 170. Pasquali SK, Jacobs JP, Shook GJ, O’Brien SM, Hall M, Jacobs ML, Welke KF, Gaynor JW, Peterson ED, Shah SS, et al. Linking clinical registry data with administrative data using indirect identifiers: implementation and validation in the congenital heart surgery population.Am Heart J. 2010; 160:1099–1104. doi: 10.1016/j.ahj.2010.08.010CrossrefMedlineGoogle Scholar
  • 171. Kern SE. Challenges in conducting clinical trials in children: approaches for improving performance.Expert Rev Clin Pharmacol. 2009; 2:609–617. doi: 10.1586/ecp.09.40CrossrefMedlineGoogle Scholar
  • 172. James S, Rao SV, Granger CB. Registry-based randomized clinical trials: a new clinical trial paradigm.Nat Rev Cardiol. 2015; 12:312–316. doi: 10.1038/nrcardio.2015.33CrossrefMedlineGoogle Scholar
  • 173. Li G, Sajobi TT, Menon BK, Korngut L, Lowerison M, James M, Wilton SB, Williamson T, Gill S, Drogos LL, et al; 2016 Symposium on Registry-Based Randomized Controlled Trials in Calgary. Registry-based randomized controlled trials: what are the advantages, challenges, and areas for future research?J Clin Epidemiol. 2016; 80:16–24. doi: 10.1016/j.jclinepi.2016.08.003CrossrefMedlineGoogle Scholar
  • 174. Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, Holmes J, Mander AP, Odondi L, Sydes MR, et al. Adaptive designs in clinical trials: why use them, and how to run and report them.BMC Med. 2018; 16:29. doi: 10.1186/s12916-018-1017-7CrossrefMedlineGoogle Scholar
  • 175. Mulangu S, Dodd LE, Davey RT, Tshiani Mbaya O, Proschan M, Mukadi D, Lusakibanza Manzo M, Nzolo D, Tshomba Oloma A, Ibanda A, et al. A randomized, controlled trial of Ebola virus disease therapeutics.N Engl J Med. 2019; 381:2293–2303. doi: 10.1056/NEJMoa1910993CrossrefMedlineGoogle Scholar
  • 176. Ader F; Discovery French Trial Management Team. Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults.BMJ Open. 2020; 10:e041437. doi: 10.1136/bmjopen-2020-041437CrossrefMedlineGoogle Scholar
  • 177. White PH, Cooley WC; Transitions Clinical Report Authoring Group; American Academy of Pediatrics; American Academy of Family Physicians; American College of Physicians. Supporting the health care transition from adolescence to adulthood in the medical home.Pediatrics. 2018; 142:e20182587. doi: 10.1542/peds.2018-2587CrossrefMedlineGoogle Scholar
  • 178. Heery E, Sheehan AM, While AE, Coyne I. Experiences and outcomes of transition from pediatric to adult health care services for young people with congenital heart disease: a systematic review.Congenit Heart Dis. 2015; 10:413–427. doi: 10.1111/chd.12251CrossrefMedlineGoogle Scholar
  • 179. Hilderson D, Saidi AS, Van Deyk K, Verstappen A, Kovacs AH, Fernandes SM, Canobbio MM, Fleck D, Meadows A, Linstead R, et al. Attitude toward and current practice of transfer and transition of adolescents with congenital heart disease in the United States of America and Europe.Pediatr Cardiol. 2009; 30:786–793. doi: 10.1007/s00246-009-9442-1CrossrefMedlineGoogle Scholar
  • 180. Reid GJ, Irvine MJ, McCrindle BW, Sananes R, Ritvo PG, Siu SC, Webb GD. Prevalence and correlates of successful transfer from pediatric to adult health care among a cohort of young adults with complex congenital heart defects.Pediatrics. 2004; 113:e197–e205. doi: 10.1542/peds.113.3.e197CrossrefMedlineGoogle Scholar
  • 181. Stewart KT, Chahal N, Kovacs AH, Manlhiot C, Jelen A, Collins T, McCrindle BW. Readiness for transition to adult health care for young adolescents with congenital heart disease.Pediatr Cardiol. 2017; 38:778–786. doi: 10.1007/s00246-017-1580-2CrossrefMedlineGoogle Scholar


eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.