Abstract
Background
Dilated cardiomyopathy (DCM) is the most common cause of pediatric heart failure (HF), but most studies focus on early survival. We examined prognostic factors and outcomes of routine care in childhood-onset DCM followed into adulthood.
Methods
From January 2001 to August 2023, we studied a cohort of patients with childhood-onset DCM using electronic medical records from a tertiary pediatric hospital and linked province–wide health care administrative data. DCM cases with or without echocardiographic recovery and matched controls were compared on demographic and disease characteristics and various health outcomes. We used Cox proportional hazards regression and cause–specific hazard models to identify prognostic factors for all-cause mortality and heart transplantation, respectively.
Results
Over a median follow-up of 13.8 years, DCM cases (n = 156) had higher rates of all-cause death, heart transplantation, and HF admission than controls (n = 780), as did nonrecovered (n = 103) compared with recovered cases (all p < 0.001). Cases had higher incidence rates of chronic kidney disease (p < 0.001) and diabetes (p = 0.002) than controls. As some recovered cases later died or underwent transplantation, this may constitute DCM relapse. On multivariable analysis, idiopathic and familial DCM (vs myocarditis), lower left ventricular ejection fraction, rural residence, and not receiving HF medications were associated with heart transplantation. Diagnosis in 2010-2017 (vs 2001-2009), recovery, beta blockers, and the lack of troponin I or T mutations were protective against mortality.
Conclusions
Childhood DCM is associated with adverse health and increased health care utilization even into adulthood. While echocardiographic normalization and routine treatments are associated with improved prognosis, some patients may relapse after recovery.
KEYWORDS: pediatric cardiology, dilated cardiomyopathy, heart failure, heart transplantation, pediatric heart failure
Background
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children1, 2, 3, 4, 5, 6 and the most common cause of pediatric heart failure (HF) and heart transplantation.1, 2, 4, 7, 8 It is characterized by systolic dysfunction and ventricular dilatation, with most cases presenting with acute decompensated HF.2, 5, 6, 9, 10, 11, 12 Previous studies estimate its annual incidence to range from 0.34 to 1.13 cases per 100,000 children.4, 9 While most cases are idiopathic, other causes include “burnt-out” myocarditis, metabolic disorders, and inherited sarcomeric-related mutations.3, 6, 9 Its prognosis is poor, with an estimated 40% undergoing heart transplantation or dying within 2 years of diagnosis.6, 9
Most studies on pediatric DCM examine early survival.1 While the first few years after diagnosis are associated with the highest incidence of adverse health,1, 6, 12 it is expected that patients continue to have increased morbidity and health care utilization into adulthood, attributable to the disease itself and to complications associated with its treatment, particularly heart transplantation.1, 13, 14 Adult treatment guidelines for HF are often assumed to translate to the pediatric population without sufficient evidence.3, 9, 15 Only 2 previous major cohorts include children with DCM: the Pediatric Cardiomyopathy Registry (PCMR) and the National Australian Childhood Cardiomyopathy Study (NACCS).2, 9, 12 The PCMR combined retrospective and prospective cohorts of over 1,400 patients diagnosed with childhood-onset DCM across the United States and Canada.2 The NACCS followed 184 children diagnosed with DCM between the ages of 0 and 10 years across Australia for over 15 years.1, 5, 12 We aimed to describe a long-term cohort of patients with childhood-onset DCM in Canada, assessing risk factors for death and heart transplantation and outcomes of routine care. Due to Canada’s single–payer health care system, we were able to link an internal cohort of children with DCM with several public health care administrative databases to facilitate comprehensive and long-term follow-up.
Methods
The present study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.16 Ethics approval was obtained at The Hospital for Sick Children (SickKids), Toronto, Canada, with waiver of consent. This project complies with the ISHLT (International Society for Heart and Lung Transplantation) Ethics statement.
Study design
From January 2001 to August 2023, we studied a cohort of patients with childhood-onset DCM. We compared various demographic and clinical characteristics and outcomes between DCM cases (with or without echocardiographic recovery during follow-up) and matched controls. We also identified prognostic factors for each primary outcome: death, heart transplantation, and the composite of transplant-free survival.
Participant selection, setting, and data sources
Electronic medical records from a tertiary pediatric hospital (SickKids) were used to retrospectively follow children diagnosed with DCM before 18 years of age from January 2001 to July 2017. Supervised by 2 pediatric cardiologists, data were abstracted by cardiology fellows, pediatric residents, and experienced study staff, with regular audits (15%-50%) based on extractor experience. Included DCM cases were patients with a left ventricular end-diastolic diameter (LVEDD) z-score >2, left ventricular ejection fraction (LVEF) <50%, or at least mildly reduced qualitative systolic function on echocardiography.9, 11, 17 Idiopathic, myocarditis-related, and familial DCM (identified by family history or sarcomeric mutations) were included. We excluded cases due to metabolic disorders, ischemic heart disease, tachycardia- or anthracycline-induced cardiomyopathy, and other congenital causes (e.g., neuromuscular disorders) (for details see Table S1), as these are clinically distinct and underrepresented. Pediatric cardiologists reviewed records to assess patients for inclusion, with consensus between 2 adjudicators required for any uncertain diagnoses. Missing data were minimal (∼2%) for most variables.
Using linkages to databases at ICES (formerly the Institute for Clinical Evaluative Sciences)18 via each patient’s unique encrypted health card number, we followed cases into adulthood for all outcomes recorded until outcomes of death or heart transplant occurred. Patients were censored if no events occurred as of August 2023. Deaths were identified using the Registered Persons Database for vital status. Heart transplants, procedures, and hospitalizations were identified using the Canadian Institute for Health Information Discharge Abstract Database, which uses the Canadian Classification of Health Interventions for procedures and the International Classification of Diseases (ICD) 8th to 10th Canadian Modification for disease diagnoses (Table S2). Cases were matched 1:5 with controls identified using ICES data on age (±14 days), sex, and urban vs rural residence, with index dates set as the date of presentation of the case to SickKids. To be included in ICES datasets, children must have received health care in Ontario, either as an inpatient or outpatient; children were not eligible to be controls if they had any cardiology-related admission, outpatient visit, or emergency visit from birth to their proposed index date, as defined by ICD or Canadian Classification of Health Interventions codes (Table S3). The National Ambulatory Care Reporting System was used to identify ambulatory care, and the Ontario Health Insurance Plan database was used for physician claims. All datasets were linked using unique encoded identifiers and analyzed at ICES. Previous studies have detailed the quality of ICES data in cardiovascular research.19
Variables
Primary outcomes included death, heart transplantation, and their composite (transplant-free survival). Secondary health and health service outcomes included chronic kidney disease (CKD), diabetes, extracorporeal membrane oxygenation (ECMO), cardiac health care utilization, hospitalization for HF, emergency department visit for HF, implantable cardioverter-defibrillator insertion, myocardial infarction, stroke, and ventricular assist device (VAD) use (Table S4). Covariates examined included baseline demographic and disease characteristics, comorbidities, treatment characteristics, and results of investigations, including genetic testing, echocardiography, electrocardiography, and exercise stress testing (Tables S5 and S6).
Statistical methods
We compared DCM cases with or without echocardiographic recovery (LVEDD z-score < 2 and LVEF ≥ 55%) and controls using Student’s t-tests, analysis of variance (ANOVAs), Wilcoxon rank sum tests, chi-square tests, or Fisher exact tests, as appropriate. For the present analysis, participants were classified as recovered if they met echocardiographic criteria at any point during follow-up; this did not preclude them from redeveloping HF afterward.
Among cases, to identify covariates associated with each primary outcome, we used Cox proportional hazards regression for death and the composite outcome, and a cause–specific hazard model for heart transplant, accounting for death as a competing risk. Candidate variables were selected based on univariate analysis and clinical judgment. Final models were developed using backward selection with a retention threshold of p < 0.05. For death and the composite primary outcome, we plotted the inverse of the Kaplan-Meier plot to visualize incidence over time for cases (recovered and nonrecovered) and controls; for all other primary and secondary outcomes, we developed cumulative incidence functions. Group comparisons for mortality and transplant-free survival used the log-rank test; all other outcomes used the Fine-Gray test, accounting for death as a competing event. Due to ∼2% missing data, participants with missing values were excluded or, for categorical variables, included as a separate category.
Results
Of 216 patients identified with DCM, 156 were included in the present study (Figure 1). Of these, 53 (34.0%) had normalization in their LVEF and LVEDD (“recovery”) over the duration of follow-up. Baseline demographic, disease, and treatment characteristics for cases with and without recovery and controls are reported in Table 1. Participants were studied for a median of 13.8 years (interquartile range [IQR] 9.9-17.4) (cases 11.3 years, IQR 7.3-14.9; controls 14.1 years, IQR 10.8-17.5). Maximum follow-up was 22.5 years (22.3 years for cases, 22.5 years for controls). At the end of follow-up, median age was 16.2 years (IQR 11.9-24.0) (cases 13.9 years, IQR 9.4-22.0; controls 17.0 years, IQR 12.3-24.4), and 43.7% of participants (34.6% of cases, 45.5% of controls) were adults aged 18 or older. Most DCM cases were idiopathic (91/156, 58.3%), with about one-fifth being familial (29, 18.6%) or caused by myocarditis (36, 23.1%), respectively.
Figure 1.
Participant inclusion and exclusion criteria for matched cohort study on patients with childhood–onset dilated cardiomyopathy. DCM, dilated cardiomyopathy; HF, heart failure; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction.
Table 1.
Demographic and Disease Characteristics, Results of Investigations, and Treatments Received for Childhood–Onset Dilated Cardiomyopathy (DCM) Cases and Controls
| Characteristic | Cases (n = 156) | Controls (n = 780) | p-value | Nonrecovered cases (n = 103) | Recovered cases (n = 53) | p-value |
|---|---|---|---|---|---|---|
| Demographics | ||||||
| Age at baseline, years | ||||||
| Mean (SD) | 4.33 (5.70) | 4.33 (5.69) | 1.0 | 4.78 (5.95) | 3.47 (5.12) | 0.18 |
| Median (Q1-Q3) | 0.00 (0.00-9.50) | 0.00 (0.00-9.50) | 0.99 | 1.00 (0.00-10.00) | 0.00 (0.00-7.00) | 0.25 |
| Female sex, n (%) | 78 (50.0) | 390 (50.0) | 1.0 | 60 (58.3) | 18 (34.0) | 0.004 |
| Rural residence (vs urban), n (%) | 7 (4.5) | 35 (4.5) | 1.0 | 6 (5.8) | 1-5 | 0.26 |
| Income quintile, n (%) | 0.28 | 0.10 | ||||
| 1—lowest | 38 (24.4) | 191 (24.5) | 30 (29.1) | 8-12 | ||
| 2 | 34 (21.8) | 144 (18.5) | 22 (21.4) | 12 (22.6) | ||
| 3 | 22 (14.1) | 148 (19.0) | 17 (16.5) | 1-5 | ||
| 4 | 26 (16.7) | 157 (20.1) | 15 (14.6) | 11 (20.8) | ||
| 5—highest | 36 (23.1) | 140 (17.9) | 19 (18.4) | 17 (32.1) | ||
| Disease characteristics | ||||||
| Era of diagnosis, n (%) | 0.8 | |||||
| 2001-2010 | 95 (60.9) | - | 62 (60.2) | 33 (62.3) | ||
| 2010-2018 | 61 (39.1) | - | 41 (39.8) | 20 (37.7) | ||
| Type of DCM, n (%) | 0.051 | |||||
| Idiopathic | 91 (58.3) | - | 67 (65.0) | 24 (45.3) | ||
| Myocarditis | 29 (18.6) | - | 15 (14.6) | 14 (26.4) | ||
| Sarcomeric mutation/family history | 36 (23.1) | - | 21 (20.4) | 15 (28.3) | ||
| Disposition at diagnosis, n (%) | 0.36 | |||||
| Intensive care unit (ICU) admission | 71 (45.5) | - | 49 (47.6) | 22 (41.5) | ||
| Inpatient cardiac/other ward | 43 (27.6) | - | 30 (29.1) | 13 (24.5) | ||
| Outpatient | 42 (26.9) | - | 24 (23.3) | 18 (34.0) | ||
| Symptoms of HF at diagnosis, n (%) | 112 (71.8) | - | 80 (77.7) | 32 (60.4) | 0.023 | |
| Congenital heart disease, n (%) | 11 (7.1) | 0 (0.0) | <0.001 | 7 (6.8) | 1-5 | 0.86 |
| Chromosomal abnormality not related to cardiomyopathy (e.g., Trisomy 21), n (%) | 1-5 | 0 (0.0) | 0.002 | 1-5 | 0 (0.0) | 0.31 |
| Echocardiographic parameters | ||||||
| LVEDD z-score | ||||||
| Median (Q1-Q3) | 4.40 (3.40-5.20) | - | 4.60 (3.69-5.50) | 3.90 (3.00-4.90) | 0.019 | |
| Range | 1.20-8.20 | - | 1.51-8.20 | 1.20-7.30 | ||
| LVEDD z-score (categorical), n (%) | 0.090 | |||||
| 1.2-3.9 | 56 (35.9) | - | 31 (30.1) | 25 (47.2) | ||
| 4.0-8.2 | 89 (57.1) | - | 65 (63.1) | 23-27 | ||
| LVEF | ||||||
| Median (Q1-Q3) | 24.0 (17.0-36.0) | - | 21.0 (16.5-33.0) | 31.5 (20.0-42.5) | 0.043 | |
| Min-max | 7.0-67.0 | - | 7.00-67.00 | 8.00-59.00 | ||
| LVEF (2 groups), n (%) | 0.24 | |||||
| 7-35 | 105 (67.3) | - | 74 (71.8) | 31 (58.5) | ||
| ≥36 | 40 (25.6) | - | 23 (22.3) | 17-21 | ||
| LVEF (3 groups), n (%) | 0.39 | |||||
| 7-35 | 105 (67.3) | - | 74 (71.8) | 31 (58.5) | ||
| 36-54 | 32 (20.5) | - | 18 (17.5) | 14 (26.4) | ||
| ≥55 | 8 (5.1) | - | 1-5 | 1-5 | ||
| ≥Moderate mitral regurgitation, n (%) | 55 (35.3) | - | 40 (38.8) | 15 (28.3) | 0.19 | |
| Electrocardiography | ||||||
| Left ventricular hypertrophy, n (%) | 56 (35.9) | - | 31 (30.1) | 25 (47.2) | 0.035 | |
| Ectopy or arrhythmia, n (%) | 1-5 | - | 1-5 | 1-5 | 0.98 | |
| Ischemic changes, n (%) | 20 (12.8) | - | 10 (9.7) | 10 (18.9) | 0.11 | |
| Exercise stress testing | ||||||
| Peak VO2, ml/kg/min | ||||||
| Mean (SD) | 33.7 (13.8) | - | 33.70 (13.78) | - | ||
| Median (Q1-Q3) | 30.5 (24.7-47.4) | - | 30.5 (24.7-47.4) | - | ||
| Min-max | 12.9-51.3 | - | 12.9-51.3 | - | ||
| Workload, W | ||||||
| Mean (SD) | 121.6 (83.2) | - | 121.6 (83.2) | - | ||
| Median (Q1-Q3) | 93.0 (60.0-187.0) | - | 93.0 (60.0-187.0) | - | ||
| Min-max | 39.0-279.0 | - | 39.0-279.0 | - | ||
| Identified pathologic mutations, n (%) | ||||||
| MYBC3 | 1-5 | 0 (0.0) | <0.001 | 0 (0.0) | 1-5 | 0.005 |
| MYH7 | 8 (5.1) | 0 (0.0) | <0.001 | 6 (5.8) | 1-5 | 0.58 |
| Troponin I or T | 1-5 | 0 (0.0) | <0.001 | 1-5 | 0 (0.0) | 0.21 |
| ACTC | 1-5 | 0 (0.0) | <0.001 | 0 (0.0) | 1-5 | 0.16 |
| Vinculin | 1-5 | 0 (0.0) | <0.001 | 1-5 | 1-5 | 0.23 |
| α-actinin-2 | 1-5 | 0 (0.0) | <0.001 | 0 (0.0) | 1-5 | 0.16 |
| Any sarcomeric mutation | 20 (12.8) | 0 (0.0) | <0.001 | 10 (9.7) | 10 (18.9) | 0.11 |
| Treatment characteristics | ||||||
| Inpatient or outpatient ACEi use after study entry, n (%) | ||||||
| Ever | 112 (71.8) | 0 (0.0) | <0.001 | 69 (67.0) | 43 (81.1) | 0.063 |
| Within 3 months | 90 (57.7) | 0 (0.0) | <0.001 | 57 (55.3) | 33 (62.3) | 0.41 |
| Within 6 months | 100 (64.1) | 0 (0.0) | <0.001 | 63 (61.2) | 37 (69.8) | 0.29 |
| Inpatient or outpatient beta blocker use after study entry, n (%) | ||||||
| Ever | 95 (60.9) | 0 (0.0) | <0.001 | 54 (52.4) | 41 (77.4) | 0.003 |
| Within 3 months | 71 (45.5) | 0 (0.0) | <0.001 | 41 (39.8) | 30 (56.6) | 0.046 |
| Within 6 months | 81 (51.9) | 0 (0.0) | <0.001 | 47 (45.6) | 34 (64.2) | 0.028 |
| Received one HF medication, n (%) | 109 (69.9) | 0 (0.0) | <0.001 | 65 (63.1) | 44 (83.0) | 0.010 |
| Received 2 HF medications, n (%) | 87 (55.8) | 0 (0.0) | <0.001 | 49 (47.6) | 38 (71.7) | 0.004 |
Abbreviations: ACEi, angiotensin–converting enzyme inhibitor; DCM, dilated cardiomyopathy; HF, heart failure; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; SD, standard deviation.
p-values were calculated using Student’s t-tests, ANOVAs, Wilcoxon rank sum tests, chi-square tests, or Fisher’s exact tests, as appropriate. Recovery from DCM was based on echocardiographic findings of LVEDD z-score <2 and LVEF ≥55%.
Baseline characteristics of recovered and nonrecovered DCM cases
A larger proportion of recovered (n = 53) than nonrecovered (n = 103) cases were male (66.0% vs 41.7%; p = 0.004). Compared with recovered cases, nonrecovered cases were more often idiopathic (65.0% vs 45.3%) and less commonly myocarditis-related (14.6% vs 26.4%) or familial (20.4% vs 28.3%; p = 0.051). Recovered cases had lower baseline disease burden, with a higher median LVEF (31.5% vs 21.0%; p = 0.043) and fewer having left ventricular hypertrophy or HF symptoms at diagnosis. Recovered cases more frequently received inpatient or outpatient HF medications, including angiotensin–converting enzyme inhibitors (ACEi) (81.1% vs 67.0%; p = 0.063) and beta blockers (77.4% vs 52.4%; p = 0.003) (Table 1).
Incidence of outcomes for DCM cases and controls
Among 156 cases, 31 (19.9%) died, 53 (34.0%) underwent heart transplant, and 77 (49.4%) were living transplant-free at the end of follow-up (Table 2). Most primary outcome events occurred within 5 years of follow-up, with rates higher among cases than controls and among nonrecovered than recovered cases (all p < 0.001). Notably, 1 to 5 recovered cases still experienced adverse outcomes, with some dying or undergoing transplant even beyond 5 years after diagnosis (Table 3, Figure 2).
Table 2.
Prevalence of the Primary Outcomes of Death, Heart Transplant, and Their Composite at 1, 2, 5, 10, and 15 Years
| Outcome | Cases (n = 156) | Controls (n = 780) | |
|---|---|---|---|
| Death, % by (95% confidence interval [CI]) (years) | |||
| 1 | 11.5 (7.4-17.7) | 0 | |
| 2 | 14.7 (10.1-21.3) | 0 | |
| 5 | 16.0 (11.1-22.8) | 0 | |
| 10 | 19.6 (14.1-26.9) | 0 | |
| 15 | 21.4 (15.3-29.6) | 0.23 (0.03-1.60) | |
| Heart transplantation, % by (95% CI) (years) | |||
| 1 | 24.3 (17.9-31.3) | 0 | |
| 2 | 27.6 (20.8-34.8) | 0 | |
| 5 | 31.4 (24.3-38.8) | 0 | |
| 10 | 32.2 (25.0-39.7) | 0 | |
| 15 | 36.0 (27.9-44.2) | 0 | |
| Death or heart transplantation, % by (95% CI) (years) | |||
| 1 | 35.9 (28.9-44.0) | 0 | |
| 2 | 41.0 (33.8-49.2) | 0 | |
| 5 | 45.5 (38.1-53.7) | 0 | |
| 10 | 49.3 (41.7-57.5) | 0 | |
| 15 | 53.1 (44.9-61.8) | 0.23 (0.03-1.60) | |
Table 3.
Incidence of Primary and Secondary Outcomes Comparing Childhood–Onset DCM Cases and Controls
| Outcome | All cases (n = 156) |
Controls (n = 780) |
Recovered cases (n = 53) |
Nonrecovered cases (n = 103) |
Recovered cases (n = 53) |
Controls (n = 265) |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Incidence rate (/1,000 person-years, 95% CI) | n | Incidence rate (/1,000 person-years, 95% CI) | p-value | n | Incidence rate (/1,000 person-years, 95% CI) | n | Incidence rate (/1,000 person-years, 95% CI) | p-value | n | Incidence rate (/1,000 person-years, 95% CI) | n | Incidence rate (/1,000 person-years, 95% CI) | p-value | |
| Primary outcomes | |||||||||||||||
| Death | 31 | 18.2 (12.8-25.9) | 1-5 | - | <0.001 | 1-5 | - | 29 | 27.1 (18.8-39.0) | <0.001 | 1-5 | - | 0 | 0 | |
| Heart transplantation | 53 | 48.1 (36.8-63.0) | 0 | 0 | <0.001 | 1-5 | - | 52 | 110.1 (83.9-144.5) | <0.001 | 1-5 | - | 0 | 0 | |
| Death or heart transplantation | 79 | 71.7 (57.5-89.4) | 1-5 | - | <0.001 | 1-5 | - | 76 | 160.9 (128.5-201.5) | <0.001 | 1-5 | - | 0 | 0 | |
| Secondary outcomes | |||||||||||||||
| Chronic kidney disease | 8 | 4.8 (2.4-9.7) | 0 | 0 | <0.001 | 1-5 | - | 6 | 5.8 (2.6-13.0) | 0.45 | 1-5 | - | 0 | 0 | |
| Diabetes mellitus | 6 | 3.6 (1.6-8.0) | 6 | 0.5 (0.2-1.2) | 0.002 | 0 | 0 | 6 | 5.8 (2.6-12.9) | 0.02 | 0 | 0 | 0 | 0 | |
| ECMO | 61 | 55.1 (42.8-70.8) | 1-5 | - | <0.001 | 1-5 | - | 58 | 118.1 (91.3-152.7) | <0.001 | 1-5 | - | 1-5 | - | 0.006 |
| Cardiac health care utilization | 80 | 83.6 (67.1-104.0) | 1-5 | - | <0.001 | 7 | 11.9 (5.7-25.1) | 73 | 196.5 (156.2-247.2) | <0.001 | 7 | 11.9 (5.7-25.1) | 1-5 | - | <0.001 |
| Cardiac surgery/cath lab | 75 | 76.8 (61.3-96.3) | 1-5 | <0.001 | 7 | 12.1 (5.8-25.3) | 68 | 171.3 (135.1-217.2) | <0.001 | 7 | 12.1 (5.8-25.3) | 1-5 | - | <0.001 | |
| HF inpatient admission | 26 | 18.0 (12.3-26.4) | 0 | 0 | <0.001 | 1-5 | - | 23 | 27.5 (18.3-41.4) | <0.001 | 1-5 | - | 0 | 0 | |
| HF ED visit | 14 | 8.8 (5.2-14.8) | 0 | 0 | <0.001 | 1-5 | - | 13 | 13.4 (7.8-23.1) | 0.006 | 1-5 | - | 0 | 0 | |
| HF leading to or occurring during admission | 33 | 23.5 (16.7-33.1) | 0 | 0 | <0.001 | 1-5 | - | 29 | 36.5 (25.4-52.6) | <0.001 | 1-5 | - | 0 | 0 | |
| Implantable cardioverter-defibrillator implantation | 25 | 48.1 (36.8-63.0) | 0 | 0 | <0.001 | 1-5 | - | 24 | 28.9 (19.3-43.1) | <0.001 | 1-5 | - | 0 | 0 | |
| Myocardial infarction | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||
| Stroke | 1-5 | - | 0 | 0 | 0 | 0 | 1-5 | - | 0 | 0 | 0 | 0 | |||
| VAD | 32 | 22.7 (16.1-32.1) | 0 | 0 | <0.001 | 1-5 | - | 31 | 39.8 (28.0-56.6) | <0.001 | 1-5 | - | 0 | 0 | |
Abbreviations: DCM, dilated cardiomyopathy; ECMO, extracorporeal membrane oxygenation; ED, emergency department; HF, heart failure; VAD, ventricular assist device.
p-values were calculated with chi-square tests using a Poisson regression model. Incidence rates were suppressed in the event of small event numbers (n = 1-5). Cardiac health care utilization included all adult or pediatric cardiology or cardiac surgery.
Figure 2.
(A) 1-Kaplan-Meier curve for death, and cumulative incidence functions for (B) heart transplantation and (C) death and heart transplantation, comparing patients with childhood–onset dilated cardiomyopathy and matched controls on age, sex, and urban vs rural residence. Blue = all cases, red = nonrecovered cases, green = recovered cases, brown = controls. Shaded areas represent 95% confidence intervals.
Compared to controls, DCM cases had higher rates of secondary outcomes, including diabetes, HF–related emergency visits and admissions, and CKD. Nonrecovered cases also had higher rates than recovered cases for the same outcomes other than CKD. Health care utilization was greater in nonrecovered cases, with more receiving cardiac procedures, including cardiac surgery, cardiac catheterization, ECMO, implantable cardioverter-defibrillator insertion, VAD use, and cardiac diagnostic procedures (e.g., echocardiography, endocardial biopsy). Although recovered cases received fewer procedures during follow-up, 7 of 53 (13.2%) still required such care within 10 years (Figure 3).
Figure 3.
Cumulative incidence functions for (A) cardiac health care utilization (all procedures of pediatric or adult cardiology or cardiac surgery), (B) any procedure of cardiac surgery, (C) heart failure emergency department visit, and (D) heart failure inpatient admission, comparing patients with childhood–onset dilated cardiomyopathy and matched controls on age, sex, and urban vs rural residence. Blue = all cases, red = nonrecovered cases, green = recovered cases, brown = controls. Shaded areas represent 95% confidence intervals.
Models identifying determinants of all-cause death and heart transplantation in DCM cases
Table 4 shows baseline characteristics of DCM cases by our primary outcomes. Final Cox regression models are available in Table 5 (see Tables S7-S9 for candidate variables).
Table 4.
Univariable Analyses Comparing Demographic and Disease Characteristics, Results of Investigations, and Treatments Received for Dilated Cardiomyopathy (DCM) Cases With and Without Primary Outcomes of (1) Death, (2) Heart Transplantation, and (3) Their Composite
| Characteristic | No death (n = 125) | Death (n = 31) | p-value | No heart transplant (n = 103) | Heart transplant (n = 53) | p-value | No death or heart transplant (n = 77) | Death or heart transplant (n = 79) | p-value |
|---|---|---|---|---|---|---|---|---|---|
| Demographics | |||||||||
| Age at baseline, years | |||||||||
| Mean (SD) | 4.24 (5.70) | 4.71 (5.77) | 0.68 | 4.20 (5.73) | 4.58 (5.69) | 0.69 | 4.17 (5.76) | 4.49 (5.67) | 0.72 |
| Median (Q1-Q3) | 0.00 (0.00-9.00) | 2.00 (0.00-10.00) | 0.43 | 0.00 (0.00-8.00) | 0.00 (0.00-10.00) | 0.86 | 0.00 (0.00-8.00) | 1.00 (0.00-10.00) | 0.72 |
| Female sex, n (%) | 61 (78.2) | 17 (21.8) | 0.55 | 45 (57.7) | 33 (42.3) | 0.03 | 29 (37.2) | 49 (62.8) | 0.002 |
| Rural residence (vs urban), n (%) | 6 (85.7) | 1-5 | 0.70 | 1-5 | 1-5 | 0.03 | 1-5 | 1-5 | 0.26 |
| Income quintile, n (%) | |||||||||
| 1—lowest | 30 (78.9) | 8 (21.1) | 0.71 | 25 (65.8) | 13 (34.2) | 0.41 | 17 (44.7) | 21 (55.3) | 0.25 |
| 2 | 25 (73.5) | 9 (26.5) | 23 (67.6) | 11 (32.4) | 15 (44.1) | 19 (55.9) | |||
| 3 | 18 (81.8) | 2-6 | 11 (50.0) | 11 (50.0) | 8 (36.4) | 14 (63.6) | |||
| 4 | 23 (88.5) | 1-5 | 20 (76.9) | 6 (23.1) | 17 (65.4) | 9 (34.6) | |||
| 5—highest | 29 (80.6) | 7 (19.4) | 24 (66.7) | 12 (33.3) | 20 (55.6) | 16 (44.4) | |||
| Disease characteristics | |||||||||
| Era of diagnosis, n (%) | 0.09 | 0.66 | 0.77 | ||||||
| 2001-2010 | 72 (75.8) | 23 (24.2) | 64 (67.4) | 31 (32.6) | 46 (48.4) | 49 (51.6) | |||
| 2010-2018 | 53 (86.9) | 8 (13.1) | 39 (63.9) | 22 (36.1) | 31 (50.8) | 30 (49.2) | |||
| Type of DCM, n (%) | 0.28 | 0.04 | 0.005 | ||||||
| Idiopathic | 69 (75.8) | 22 (24.2) | 53 (58.2) | 38 (41.8) | 35 (38.5) | 56 (61.5) | |||
| Myocarditis | 25 (86.2) | 1-5 | 24 (82.8) | 1-5 | 20 (69.0) | 9 (31.0) | |||
| Sarcomeric mutation/family history | 31 (86.1) | 4-8 | 26 (72.2) | 10-14 | 22 (61.1) | 14 (38.9) | |||
| Disposition at diagnosis, n (%) | 0.13 | 0.24 | 0.02 | ||||||
| ICU admission | 19 (26.8) | 0.402 | 43 (60.6) | 28 (39.4) | 28 (39.4) | 43 (60.6) | |||
| Inpatient cardiac/other ward | 7-11 | 0.143 | 28 (65.1) | 15 (34.9) | 21 (48.8) | 22 (51.2) | |||
| Outpatient | 1-5 | 0.325 | 32 (76.2) | 10 (23.8) | 28 (66.7) | 14 (33.3) | |||
| Symptoms of HF at diagnosis, n (%) | 85 (75.9) | 26-30 | 0.03 | 69 (61.6) | 43 (38.4) | 0.06 | 46 (41.1) | 66 (58.9) | 0.001 |
| Congenital heart disease, n (%) | 8 (72.7) | 1-5 | 0.52 | 10 (90.9) | 1-5 | 0.07 | 7 (63.6) | 1-5 | 0.33 |
| Chromosomal abnormality not related to CM (e.g., Trisomy 21), n (%) | 1-5 | 1-5 | 0.28 | 1-5 | 0 (0.0) | 0.31 | 1-5 | 1-5 | 0.99 |
| Recovery from DCM, n (%) | 51 (96.2) | 1-5 | <0.001 | 52 (98.1) | 1-5 | <0.001 | 50 (94.3) | 1-5 | <0.001 |
| Echocardiographic parameters | |||||||||
| LVEDD z-score | |||||||||
| Median (Q1-Q3) | 4.50 (3.40-5.28) | 4.03 (2.90-4.90) | 0.13 | 4.20 (3.00-5.01) | 4.70 (3.90-5.92) | 0.02 | 4.40 (3.10-5.20) | 4.57 (3.55-5.23) | 0.43 |
| Range | 1.20 - 8.20 | 1.60 - 7.20 | 1.60 - 8.20 | 1.20 - 7.70 | 2.00 - 8.20 | 1.20 - 7.70 | |||
| LVEDD z-score (categorical), n (%) | 0.48 | 0.10 | 0.42 | ||||||
| 1.2-3.9 | 42 (75.0) | 11-15 | 43 (76.8) | 13-17 | 30-34 | 25 (44.6) | |||
| 4.0-8.2 | 74 (83.1) | 15 (16.9) | 54 (60.7) | 35 (39.3) | 42 (47.2) | 47 (52.8) | |||
| LVEF | 0.22 | ||||||||
| Median (Q1-Q3) | 24.5 (17.0-38.0) | 22.3 (16.0-33.0) | 28.5 (19.5-42.5) | 18.0 (15.0-30.0) | <0.001 | 32.0 (20.0-44.0) | 20.0 (16.0-30.0) | <0.001 | |
| Min-max | 8.00 - 67.00 | 7.00 - 52.00 | 7.00 - 67.00 | 8.00 - 58.00 | 8.00 - 67.00 | 7.00 - 58.00 | |||
| LVEF (2 groups), n (%) | 0.64 | 0.01 | 0.002 | ||||||
| 7-35 | 82 (78.1) | 23 (21.9) | 62 (59.0) | 43 (41.0) | 42 (40.0) | 63 (60.0) | |||
| ≥36 | 34 (85.0) | 3-7 | 34 (85.0) | 5-9 | 29 (72.5) | 11-15 | |||
| LVEF (3 groups), n (%) | 0.51 | 0.004 | |||||||
| 7-35 | 82 (78.1) | 23 (21.9) | 62 (59.0) | 43 (41.0) | 0.03 | 42 (40.0) | 63 (60.0) | ||
| 36-54 | 26 (81.3) | 3-7 | 27 (84.4) | 5-9 | 22 (68.8) | 10 (31.3) | |||
| ≥55 | 8 (100.0) | 0 (0.0) | 7 (87.5) | 1-5 | 7 (87.5) | 1-5 | |||
| At least moderate mitral regurgitation, n (%) | 43 (78.2) | 12 (21.8) | 0.65 | 34 (61.8) | 21 (38.2) | 0.41 | 23 (41.8) | 32 (58.2) | 0.16 |
| Left ventricular hypertrophy, n (%) | 48 (85.7) | 8 (14.3) | 0.19 | 39 (69.6) | 17 (30.4) | 0.48 | 31 (55.4) | 25 (44.6) | 0.26 |
| Ectopy or arrhythmia, n (%) | 1-5 | 1-5 | 0.56 | 1-5 | 1-5 | 0.98 | 1-5 | 1-5 | 0.58 |
| Ischemic changes, n (%) | 18 (90.0) | 1-5 | 0.24 | 11 (55.0) | 9 (45.0) | 0.26 | 9 (45.0) | 11 (55.0) | 0.68 |
| Sarcomeric mutations, n (%) | |||||||||
| MYBC3 | 1-5 | 0 (0.0) | 0.31 | 1-5 | 1-5 | 0.70 | 1-5 | 1-5 | 0.30 |
| MYH7 | 7 (87.5) | 1-5 | 0.59 | 6 (75.0) | 1-5 | 0.58 | 1-5 | 1-5 | 0.45 |
| Troponin I or T | 1-5 | 1-5 | 0.04 | 1-5 | 1-5 | 0.98 | 0 (0.0) | 1-5 | 0.08 |
| ACTC | 1-5 | 0 (0.0) | 0.62 | 1-5 | 0 (0.0) | 0.47 | 1-5 | 0 (0.0) | 0.31 |
| Vinculin | 1-5 | 0 (0.0) | 0.38 | 1-5 | 0 (0.0) | 0.21 | 1-5 | 0 (0.0) | 0.08 |
| α-actinin-2 | 1-5 | 0 (0.0) | 0.62 | 1-5 | 0 (0.0) | 0.47 | 1-5 | 0 (0.0) | 0.31 |
| Any sarcomeric mutation | 17 (85.0) | 1-5 | 0.56 | 16 (80.0) | 1-5 | 0.16 | 13 (65.0) | 7 (35.0) | 0.13 |
| Treatment characteristics | |||||||||
| Inpatient or outpatient ACEi use after study entry, n (%) | |||||||||
| Ever | 94 (83.9) | 18 (16.1) | 0.06 | 78 (69.6) | 34 (30.4) | 0.13 | 62 (55.4) | 50 (44.6) | 0.02 |
| Within 3 months | 76 (84.4) | 14 (15.6) | 0.11 | 59 (65.6) | 31 (34.4) | 0.88 | 46 (51.1) | 44 (48.9) | 0.61 |
| Within 6 months | 83 (83.0) | 17 (17.0) | 0.23 | 67 (67.0) | 33 (33.0) | 0.73 | 52 (52.0) | 48 (48.0) | 0.38 |
| Inpatient or outpatient beta blocker use after study entry, n (%) | |||||||||
| Ever | 84 (88.4) | 11 (11.6) | 0.001 | 64 (67.4) | 31 (32.6) | 0.66 | 54 (56.8) | 41 (43.2) | 0.02 |
| Within 3 months | 62 (87.3) | 9 (12.7) | 0.04 | 46 (64.8) | 25 (35.2) | 0.77 | 38 (53.5) | 33 (46.5) | 0.34 |
| Within 6 months | 71 (87.7) | 10 (12.3) | 0.01 | 53 (65.4) | 28 (34.6) | 0.87 | 44 (54.3) | 37 (45.7) | 0.20 |
| Received 1 HF medication, n (%) | 93 (85.3) | 16 (14.7) | 0.01 | 77 (70.6) | 32 (29.4) | 0.06 | 63 (57.8) | 46 (42.2) | 0.001 |
| Received 2 HF medications, n (%) | 77 (88.5) | 10 (11.5) | 0.003 | 61 (70.1) | 26 (29.9) | 0.23 | 52 (59.8) | 35 (40.2) | 0.004 |
Abbreviations: ACEi, angiotensin–converting enzyme inhibitor; HF, heart failure; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; SD, standard deviation.
p-values were calculated using Student’s t-tests, ANOVAs, Wilcoxon rank sum tests, chi-square tests, or Fisher’s exact tests, as appropriate.
Table 5.
Cox Proportional Hazards Regression Analyses Identifying Prognostic Factors for Death, Heart Transplant, and Their Composite Among Patients With Childhood–Onset Dilated Cardiomyopathy (DCM)
| Death or heart transplant | Heart transplant | Death | |
|---|---|---|---|
| HR (95% CI) | |||
| DCM etiology—idiopathic (vs myocarditis) | 3.9 (1.9-8.2) | 4.2 (1.4-12.2) | - |
| DCM etiology—sarcomeric (vs myocarditis) | 3.4 (1.3-9.1) | 9.9 (2.3-42.3) | - |
| Ever received 1 HF medication | 0.23 (0.14-0.39) | 0.21 (0.10-0.41) | - |
| Troponin I or T mutation | 6.1 (1.6-24.0) | - | 11.3 (2.2-58.6) |
| HF symptoms at diagnosis | 2.3 (1.2-4.6) | - | - |
| LVEF—≥ 36% (vs 7-35%) | 0.39 (0.19-0.79) | - | - |
| LVEF, per % | - | 0.94 (0.91-0.97) | - |
| Sarcomeric-related mutation | - | 0.21 (0.05-0.94) | - |
| Rural residence (vs urban) | - | 6.0 (1.7-20.7) | - |
| Recovered from DCM | - | - | 0.16 (0.04-0.70) |
| DCM diagnosis in 2010-2018 (vs 2001-2010) | - | - | 0.38 (0.16-0.95) |
| Inpatient or outpatient beta blocker use | - | - | 0.34 (0.16-0.73) |
Abbreviations: HR, hazards ratio; LVEF, left ventricular ejection fraction.
Analyses for death and the composite of death and heart transplantation incorporated 156 DCM cases, and for heart transplantation incorporated 140 cases. Heart failure (HF) medications analyzed included angiotensin–converting enzyme inhibitors and beta blockers.
Recovery from DCM, diagnosis of DCM in 2010-2017 (vs 2001-2009), and beta blocker use were all associated with reduced all–cause mortality. A confirmed pathogenic troponin I or T mutation was associated with increased all–cause mortality risk. For heart transplantation, rural residence (vs urban) and idiopathic or familial DCM, compared with myocarditis, was associated with increased risk. Higher LVEF, any sarcomeric mutation (vs none), and use of either an ACEi or beta blocker were associated with lower heart transplantation risk. For the composite outcome of death or transplant, confirmed pathogenic troponin I or T mutation and idiopathic or familial DCM (vs myocarditis) were associated with increased risk, while HF medication use and LVEF ≥36% (vs 7%-35%) were protective. HF symptoms at diagnosis were associated with poorer transplant-free survival.
Discussion
This study aimed to evaluate risk factors for long-term morbidity, mortality, and outcomes of care in childhood-onset DCM. Our cohort of 156 cases was recruited from a major Canadian tertiary pediatric center. By linking to provincial health care administrative data, we captured data on a broad range of outcomes into adulthood, including all health care encounters across Ontario, comprising the most comprehensive long–term follow-up among pediatric DCM cohorts. We also included comparisons to a provincial cohort of children without cardiac disease, an approach not previously seen in the literature.
Key findings
After a median follow-up of 13.8 years, a third of DCM cases required heart transplantation. Recovery, as defined by normalization in LVEF and LVEDD, was also seen in one-third of patients. Five-year transplant–free survival was 49.4%. Of note, 19.9% of children with DCM died, much fewer than in the NACCS (59%).1 This difference may be attributable to advances in HF management, as the NACCS cohort represented a much earlier era (1987-1996). A similar observation was seen in the presentation of symptomatic HF between our study cohort and the NACCS (71.8% vs 93%), potentially representing earlier detection and family screening protocols.
As expected, DCM cases had higher incidence rates for all primary and multiple secondary outcomes compared with controls, as did nonrecovered compared to recovered cases. Nonrecovered cases more often accessed cardiovascular care, received transplants and mechanical circulatory support, and had higher mortality. The rates of diabetes and CKD were higher in cases than in controls. Diabetes also had greater incidence in nonrecovered compared with recovered cases.20 The higher transplant rate among DCM cases—particularly nonrecovered—likely explains increased diabetes and CKD incidence, reflecting calcineurin inhibitor use post-transplant.21
Although recovered cases had lower rates of most outcomes than nonrecovered cases, a small number still died and received transplants—unlike their matched controls—more than 5 years postdiagnosis. These results suggest that recovery from HF, while associated with significantly improved prognosis, may be more appropriately conceptualized as “remission” with potential for relapse, particularly since most health outcomes in DCM occur early after diagnosis, as shown in our study and previous cohorts.22 The PCMR similarly found that, among 96 children with echocardiographic normalization during follow-up, 7 subsequently underwent transplantation and 2 died.22 In our study, cardiac health care utilization in recovered DCM cases may have also represented disease recurrence, or alternatively the increased surveillance or care before echocardiographic normalization, as these outcomes did not constitute censoring events.
Use of a beta blocker or ACEi after study entry was associated with improved transplant-free survival. While this may have been due to treatment effect, DCM cases with less severe disease may also have been more likely to tolerate medical management compared to those in end-stage HF.23, 24 Additionally, those presenting with end-stage HF may have died or undergone transplant before starting medical therapy.25, 26 Patients with stage D HF may also have been less likely to be started on or tolerate HF medications after study entry due to their disease previously being refractory to pharmacotherapy.25 However, diagnosis with DCM in 2010-2017 (vs 2001-2009) and living in an urban area over a rural area were both associated with improved prognosis, these variables acting as surrogates for access to modern specialist treatment. With other cohorts showing similar results,1, 11, 27 this suggests that current HF management and access to care may improve outcomes in childhood-onset DCM, although results should be interpreted with caution due to potential confounding by indication.
Current guidelines recommend afterload-reducing agents and beta blockers in children with HF with reduced ejection fraction regardless of symptoms.7, 23, 28 Despite this, only 71.8% and 60.9% of our cases received ACEi and beta blocker therapy, respectively. The use of ACEi was similar to that in other cohorts (64%).9, 15, 29 Beta blocker use was markedly more frequent in our study,9, 15 with other cohorts only reporting use in 4% and 18% of DCM cases.2 These differences may be explained by our cohort being more contemporary.7, 23, 28 Studies also show that, even among children taking HF medications, few are achieving target dosing, with none in a study by Nandi et al receiving target beta blocker or ACEi doses at discharge.29, 30 Our study did not consider whether target doses were achieved. These findings suggest that greater adherence to medical therapy may be associated with further improvements in outcomes.
Our study novelly identified rural residence as a potential risk factor associated with increased need for heart transplantation. One-quarter (26.4%) of all children in Canada with heart disease (excluding Quebec) live >300 km from their nearest pediatric cardiac surgical center.31 Despite Canada’s universal health care system, time and financial costs of traveling to publicly funded, centralized subspecialist care may still drive poorer health care access.31, 32 These disparities may lead to delays in pre and postnatal diagnosis and treatment.31, 32
A previous study of children with heart disease in Alberta found that greater remoteness of residence was associated with fewer annual cardiology visits and, along with lower socioeconomic status (SES), increased annual emergency room visits, with no impacts identified on age at diagnosis, time to intervention, annual primary care visits, and transplant–free all-cause survival.32 A national study of children with congenital heart disease found that greater remoteness of residence was associated with increased mortality, albeit only for patients with moderate and not those with severe congenital heart disease due to greater delays in diagnosis and referral.31 Combined with our results, these findings suggest that strategies to bridge the gap between urban and rural care are important targets to address geographic health disparities in Canadian children with HF and other heart diseases.32
A strength of the present study was the use of linked health care administrative data from ICES. These data include all care province-wide received outside of the recruiting tertiary care center, facilitating comprehensive follow-up into adulthood. Using these data, patients from rural communities were able to be followed, allowing the present cohort to novelly identify rural residence as a risk factor for worse DCM prognosis. ICES data also allowed for the identification of healthy controls to which our DCM cases were compared, an approach not previously seen in the PCMR and NACCS. To our knowledge, when compared with the PCMR and NACCS, our cohort most extensively documents outcomes of care other than just death and heart transplantation, such as comorbidities and metrics of health care utilization. It is also the first to compare such outcomes between DCM cases who did and did not have echocardiographic normalization over the course of follow-up, depicting a more comprehensive picture of long-term health for patients with childhood-onset DCM.
Study limitations
The present study was subject to referral bias, as DCM cases were recruited from a tertiary care center, potentially overestimating disease severity and limiting generalizability. Use of routine care data, including electronic medical records and provincial health care administrative databases, while improving follow-up, may also increase the risk of misclassification bias related to exposure and outcomes. Notably, administrative data make it difficult to ascertain whether comorbidities, such as CKD and diabetes, occurred before or after heart transplantation. Furthermore, etiologic work-up may have varied by era of diagnosis, particularly due to increased availability and innovations in genetic testing.33 Cases previously classified as idiopathic may have genetic mutations that have since become identifiable. Lastly, as Ontario's health care system is publicly funded, results may not be generalizable to different health system structures.
Future directions
Future studies should continue long–term follow-up of childhood-onset DCM to better characterize adult outcomes, especially disparities by demographics (e.g., sex, race, geography) and disease factors. Interventions such as remote monitoring and virtual care should be evaluated to address rural-urban inequities. Assessment of these interventions should consider how they may differentially perform in children with varying disease severity and SES. Although our study did not identify any relationship between income quintile and DCM prognosis, it may not have been powered to identify such discrepancies, particularly at the intersection of low SES and rurality.
Of particular interest is the transition to adult care and differences in access to follow-up, given the prevalence of long–term adverse health identified in the present study. Future research should identify demographic, disease, and treatment factors associated with disease recurrence to guide targeted postrecovery surveillance and management. At-risk populations for relapse, based on, for instance, baseline disease severity, could be targeted for more frequent or longer follow-up. Future studies should examine whether medication withdrawal may be a contributor to disease recurrence. As survival after pediatric DCM is improving in the modern era,11, 25 researchers should move toward generating evidence-based guidelines for long–term follow-up.
Investigators should focus on assessing treatment efficacy via trials in children, since current evidence is mostly observational or derived from adult samples.1, 3, 12, 15 Improved therapies may reduce reliance on transplantation and its risks and costs.
Conclusion
The present study represents one of the few cohorts of patients with childhood-onset DCM with long–term follow-up. This condition is associated with long–term adverse health and health care utilization. While routine treatment and DCM recovery are associated with improved prognosis, our results suggest that, even after recovery, the disease may relapse. Further studies focusing on disparities in outcomes, risk factors for relapse, pediatric–specific treatment recommendations, and post-treatment surveillance may help further improve care for all patients with childhood-onset DCM.
Funding Sources
This work was supported by the Canadian Institutes of Health Research, Circulatory and Respiratory Health (FRN: 437188) and the Labatt Family Heart Centre Innovation Fund (SickKids, Toronto). Jose M. Navarro was funded by the Ted Rogers Centre for Heart Research and the Queen’s University Summer Studentship Program. Funding organizations did not have a role in data collection, analysis, interpretation, or manuscript preparation.
CRediT authorship contribution statement
Jose M. Navarro: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Aamir Jeewa: Conceptualization, Methodology, Investigation, Writing – review & editing, Supervision, Project administration, Funding acquisition. Jiming Fang: Methodology, Software, Validation, Formal analysis, Data curation, Writing – review & editing, Visualization. Douglas S. Lee: Conceptualization, Methodology, Investigation, Writing – review & editing, Supervision, Project administration, Funding acquisition. Emilie Jean-St-Michel: Conceptualization, Methodology, Investigation, Writing – review & editing, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Emilie Jean-St-Michel reports financial support was provided by Canadian Institutes of Health Research. Emilie Jean-St-Michel reports financial support was provided by Institute of Circulatory and Respiratory Health. Jose M. Navarro reports financial support was provided by the University Health Network. Jose M. Navarro reports financial support was provided by Queen’s University. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada. Parts of this material are based on data and/or information compiled and provided by CIHI and the Ontario Ministry of Health. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.
Footnotes
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jhlto.2026.100521.
Appendix A. Supplementary data
Supplementary material
.
Data availability
Research data will not be shared to maintain the privacy and security of patient information held at ICES.
References
- 1.Alexander P.M.A., Daubeney P.E.F., Nugent A.W., et al. Long-term outcomes of dilated cardiomyopathy diagnosed during childhood. Circulation. 2013;128:2039–2046. doi: 10.1161/CIRCULATIONAHA.113.002767. [DOI] [PubMed] [Google Scholar]
- 2.Wilkinson J.D., Landy D.C., Colan S.D., et al. The pediatric cardiomyopathy registry and heart failure: key results from the first 15 years. Heart Fail Clin. 2010;6:401–413. doi: 10.1016/j.hfc.2010.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lee T.M., Hsu D.T., Kantor P., et al. Pediatric cardiomyopathies. Circ Res. 2017;121:855–873. doi: 10.1161/CIRCRESAHA.116.309386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Alvarez J.A., Wilkinson J.D., Lipshultz S.E. Outcome predictors for pediatric dilated cardiomyopathy: a systematic review. Prog Pediatr Cardiol. 2007;23:25–32. doi: 10.1016/j.ppedcard.2007.05.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nugent A.W., Daubeney P.E.F., Chondros P., et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med. 2003;348:1639–1646. doi: 10.1056/NEJMoa021737. [DOI] [PubMed] [Google Scholar]
- 6.Towbin J.A., Lowe A.M., Colan S.D., et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA. 2006;296:1867–1876. doi: 10.1001/jama.296.15.1867. [DOI] [PubMed] [Google Scholar]
- 7.Kantor P.F., Lougheed J., Dancea A., et al. 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.2013.08.008. [DOI] [PubMed] [Google Scholar]
- 8.Lipshultz S.E., Sleeper L.A., Towbin J.A., et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med. 2003;348:1647–1655. doi: 10.1056/NEJMoa021715. [DOI] [PubMed] [Google Scholar]
- 9.Malinow I., Fong D.C., Miyamoto M., et al. Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis. Front Pediatr. 2024;12 doi: 10.3389/fped.2024.1404942. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lipshultz S.E., Cochran T.R., Briston D.A., et al. Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies. Future Cardiol. 2013;9:817–848. doi: 10.2217/fca.13.66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Singh R.K., Canter C.E., Shi L., et al. Survival without cardiac transplantation among children with dilated cardiomyopathy. J Am Coll Cardiol. 2017;70:2663–2673. doi: 10.1016/j.jacc.2017.09.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Daubeney P.E.F., Nugent A.W., Chondros P., et al. Clinical features and outcomes of childhood dilated cardiomyopathy. Circulation. 2006;114:2671–2678. doi: 10.1161/CIRCULATIONAHA.106.635128. [DOI] [PubMed] [Google Scholar]
- 13.Sparks J.D., Cantor R.S., Pruitt E., et al. New-onset diabetes after pediatric heart transplantation: a review of the Pediatric Heart Transplant Study. Pediatr Transplant. 2019;23 doi: 10.1111/petr.13476. [DOI] [PubMed] [Google Scholar]
- 14.Hathout E.H., Chinnock R.E., Johnston J.K., et al. Pediatric post-transplant diabetes: data from a large cohort of pediatric heart-transplant recipients. Am J Transplant. 2003;3:994. doi: 10.1034/j.1600-6143.2003.00186.x. [DOI] [PubMed] [Google Scholar]
- 15.Harmon W.G., Sleeper L.A., Cuniberti L., et al. Treating children with idiopathic dilated cardiomyopathy (from the Pediatric Cardiomyopathy Registry) Am J Cardiol. 2009;104:281–286. doi: 10.1016/j.amjcard.2009.03.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Vandenbroucke J.P., von Elm E., Altman D.G., et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med. 2007;147:W-163. doi: 10.7326/0003-4819-147-8-200710160-00010-w1. [DOI] [PubMed] [Google Scholar]
- 17.Molina K.M., Shrader P., Colan S.D., et al. Predictors of disease progression in pediatric dilated cardiomyopathy. Circ Heart Fail. 2013;6:1214–1222. doi: 10.1161/CIRCHEARTFAILURE.113.000125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Schull M., Azimaee M., Marra M., et al. ICES: data, discovery, better health. Int J Popul Data Sci. 2020;4:1135. doi: 10.23889/ijpds.v4i2.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Tu J.V., Chu A., Donovan L.R., et al. The cardiovascular health in ambulatory care research team (CANHEART) Circ Cardiovasc Qual Outcomes. 2015;8:204–212. doi: 10.1161/CIRCOUTCOMES.114.001416. [DOI] [PubMed] [Google Scholar]
- 20.Ndumele C.E., Neeland I.J., Tuttle K.R., et al. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation. 2023;148:1636–1664. doi: 10.1161/CIR.0000000000001186. [DOI] [PubMed] [Google Scholar]
- 21.Feingold B., Zheng J., Law Y.M., et al. Risk factors for late renal dysfunction after pediatric heart transplantation: a multi-institutional study. Pediatr Transplant. 2011;15:699–705. doi: 10.1111/j.1399-3046.2011.01564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Everitt M.D., Sleeper L.A., Lu M., et al. Recovery of echocardiographic function in children with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2014;63:1405–1413. doi: 10.1016/j.jacc.2013.11.059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kirk R., Dipchand A.I., Rosenthal D.N., et al. The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary. J Heart Lung Transplant. 2014;33:888–909. doi: 10.1016/j.healun.2014.06.002. [DOI] [PubMed] [Google Scholar]
- 24.Canter C.E., Shaddy R.E., Bernstein D., et al. Indications for heart transplantation in pediatric heart disease. Circulation. 2007;115:658–676. doi: 10.1161/CIRCULATIONAHA.106.180449. [DOI] [PubMed] [Google Scholar]
- 25.Bogle C., Colan S.D., Miyamoto S.D., et al. Treatment strategies for cardiomyopathy in children: a scientific statement from the American Heart Association. Circulation. 2023;148:174–195. doi: 10.1161/CIR.0000000000001151. [DOI] [PubMed] [Google Scholar]
- 26.Amdani S., Conway J., George K., et al. Evaluation and management of chronic heart failure in children and adolescents with congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2024;150:e33–e50. doi: 10.1161/CIR.0000000000001245. [DOI] [PubMed] [Google Scholar]
- 27.Kirk R., Naftel D., Hoffman T.M., et al. Outcome of pediatric patients with dilated cardiomyopathy listed for transplant: a multi-institutional study. J Heart Lung Transplant. 2009;28:1322–1328. doi: 10.1016/j.healun.2009.05.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Masarone D., Valente F., Rubino M., et al. Pediatric heart failure: a practical guide to diagnosis and management. Pediatr Neonatol. 2017;58:303–312. doi: 10.1016/j.pedneo.2017.01.001. [DOI] [PubMed] [Google Scholar]
- 29.Price J.F., Taylor B.N., Jeewa A., et al. Inpatient initiation and target dosing of ACE inhibitors and beta-blockers in children with heart failure. J Card Fail. 2012;18:S92. doi: 10.1016/j.cardfail.2012.06.353. [DOI] [Google Scholar]
- 30.Nandi D., Wright L.K., Sublett-Smith J., et al. Suboptimal titration of heart failure medications in pediatric patients: baseline data from ACTION. J Card Fail. 2025;31:741–745. doi: 10.1016/j.cardfail.2024.10.445. [DOI] [PubMed] [Google Scholar]
- 31.Olugbuyi O., Smith C., Kaul P., et al. Impact of socioeconomic status and residence distance on infant heart disease outcomes in Canada. J Am Heart Assoc. 2022;11 doi: 10.1161/JAHA.122.026627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Conway J., Mackie A.S., Smith C., et al. Impact of remoteness of residence and socioeconomic status on outcomes among children with heart disease in Alberta. JACC Adv. 2024;3 doi: 10.1016/j.jacadv.2024.101351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Mestroni L., Brun F., Spezzacatene A., et al. Genetic causes of dilated cardiomyopathy. Prog Pediatr Cardiol. 2014;37:13–18. doi: 10.1016/j.ppedcard.2014.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material
Data Availability Statement
Research data will not be shared to maintain the privacy and security of patient information held at ICES.