Article ID: CJ-20-1239
Background: There has been no nationwide survey on the prognosis of pediatric dilated cardiomyopathy (DCM) in Japan. Therefore, we designed this retrospective multicenter study to investigate the long-term survival rate in pediatric patients with DCM in Japan.
Methods and Results: In this multicenter retrospective observational study, data were reviewed for 106 patients aged <18 years who had been diagnosed with DCM at any 1 of 18 Japanese institutions between 1990 and 2014. The median age at diagnosis was 2.0 years and the median duration of observation was 3.3 years. Most DCM patients were diagnosed because of symptoms of heart failure. On echocardiography, the median left ventricular end-diastolic dimension z score was 5.4 and fractional shortening was 0.10. Freedom from death or transplantation rates at 1, 3, 5, 10, and 20 years after diagnosis were 76%, 66%, 64%, 58%, and 43%, respectively. Freedom from death rates at 1, 5, 10, and 20 years after diagnosis were 81%, 75%, 72%, and 53%, respectively. The incidence of heart transplantation at 1, 5, 10, and 20 years after diagnosis was 6%, 15%, 20%, and 20%, respectively, suggesting that only 15% of patients in Japan underwent heart transplantation within 5 years of diagnosis.
Conclusions: In Japan, the prognosis of pediatric DCM is poor and the rate of heart transplantation is low.
Idiopathic dilated cardiomyopathy (DCM) is characterized by a dilated left ventricle and reduced systolic function without identifiable hemodynamic causes.1 It commonly results in congestive heart failure in both children and adults, and DCM patients may not survive without heart transplantation,1,2 with worse prognosis reported in children than adults.3 In population-based studies from Australia, freedom from death or heart transplantation in pediatric patients with DCM at 1 and 5 years after diagnosis was 72% and 63%, respectively,4,5 with similar survival rates reported from the US.6,7 The availability of organ donors for heart transplantation varies depending on the country, and is very limited in Japan. The long-term prognosis of pediatric DCM may vary depending on the healthcare system in different countries. There has been no nationwide survey regarding the prognosis of pediatric DCM in Japan. Therefore, we designed this retrospective multicenter study to investigate the long-term survival rate and risk factors for poor prognosis in Japanese pediatric patients with DCM.
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We performed a multicenter retrospective observational study to assess the outcomes of pediatric cardiomyopathy in Japan. Cardiomyopathy was defined according to the World Health Organization classification.8 Patients with DCM aged <18 years were included, with data reviewed for the period 1990–2014. Eighteen institutions across Japan participated in the study.
M-Mode echocardiographic measurements were normalized according to body surface area (BSA). DCM was defined as left ventricular (LV) dilatation with diminished LV systolic function. LV dimensions were expressed as z scores, which were calculated as follows:
(LV dimension measured − mean LV dimension for the patient’s BSA) / LV dimension SD for the patient’s BSA
where the mean and SD values according to BSA were obtained from Kervanciouglu et al.9 LV dilation was defined as an LV end-diastolic dimension z score >2 and LV systolic dysfunction was defined as fractional shortening (FS) <0.20 in the absence of regional wall-motion abnormalities or typical pathologic features at autopsy.1 Children with cardiac dysfunction secondary to neuromuscular disorders, inborn errors of metabolism with multiple organ involvement, and significant structural heart disease were excluded. Patients with biopsy-confirmed or clinically diagnosed lymphocytic myocarditis were also excluded. Patients with LV systolic dysfunction clinically indistinguishable from myocarditis were included. Family history was considered positive if a first- or second-degree relative had DCM. Information regarding the etiology of DCM, such as gene mutations, was not included in the present study.
Information was collected from medical records regarding age at diagnosis, medications, initial symptoms, family history, laboratory data, cardiothoracic ratio on chest roentgenogram at onset, and device therapy, including cardiac resynchronization therapy (CRT), implantable cardioverter defibrillator (ICD), and CRT defibrillator (CRT-D). The primary end-point was death or heart transplantation from the time of diagnosis. The study was approved by local institutional review boards at all participating hospitals.
Statistical AnalysisContinuous variables are presented as the median with interquartile range (IQR), whereas categorical data are presented as numbers and percentages. Chi-squared tests was used for the analysis of particular probability distribution between categorical data. Kaplan-Meyer survival time was calculated using the time from diagnosis to death or heart transplantation. Cox regression multivariate analysis was used to assess survival rate. Cumulative incidence was assessed to draw event rate curves and to calculate subdistribution hazard ratios. Two-tailed P<0.05 was considered statistically significant. All statistical analyses were performed using STATA/SE version 15 (StataCorp, College Station, TX, USA).
In all, 106 patients were diagnosed with DCM (Table 1). There was no difference in prevalence by sex. The most frequent age at diagnosis was <1 year (42%; Figure 1). The median age at diagnosis was 2.0 years and the median duration of observation was 3.3 years at the time of this study. A family history of cardiomyopathy was observed in 9% of patients.
| No. patients | 106 |
| Male sex | 48 (45) |
| Age at diagnosis (years) | 2.0 [0.4, 10.9] |
| No. patients diagnosed at <1 year of age | 42 (40) |
| Observation duration (years) | 3.3 [0.9, 9.8] |
| Family history of cardiomyopathy | 9 (8.5) |
| Asymptomatic patients | 13 (12) |
| Abnormal ECG* | 5 (38) |
| Heart murmur* | 4 (31) |
| Screening* | 4 (31) |
| Symptomatic patients | 93 (88) |
| Symptoms related to heart failure† | 85 (91) |
| Clinical arrhythmia† | 2 (2) |
| Resuscitated death† | 2 (2) |
| Others† | 4 (4) |
| Laboratory data | |
| Initial BNP (pg/dL) | 1,457 [589, 2,475] |
| Initial CTR (%) | 64 [61, 68] |
| Echocardiographic findings | |
| LVIDd (z score) | 5.4 [4.2, 6.7] |
| PWTd (z score) | 0.6 [−0.7, 2.0] |
| IVSd (z score) | −0.2 [−1.2, 0.8] |
| FS | 0.10 [0.07, 0.14] |
Unless indicated otherwise, data are given as the median [interquartile range] or n (%). *Percentage of asymptomatic patients. †Percentage of symptomatic patients. BNP, B-type natriuretic peptide; CTR, cardiothoracic ratio; ECG, electrocardiography; FS, fractional shortening; IVSd, interventricular septum thickness at diastole; LVIDd, left ventricular internal dimension at diastole; PWTd, posterior wall thickness at diastole.
Age at diagnosis. Diagnoses were highest in children aged <1 year.
Major reasons for the diagnosis of DCM were symptoms of heart failure, seen in 85 patients (80%). Only 13 patients (12%) were asymptomatic. The median B-type natriuretic peptide concentration was 1,457 pg/dL, and the median cardiothoracic ratio was 64%. On echocardiography, the median value of the LV end-diastolic dimension z score was 5.4 and FS was 0.10 (Table 1).
Management and OutcomesNinety-eight percent of patients were on some medication (Table 2). Beta-blockers and angiotensin-converting enzyme inhibitors (ACEI) were administered to 63 (59%) and 72 (68%) patients, respectively. Beta-blockers and ACEI were introduced a median of 0.10 years (IQR 0.08–0.38 years) and 0.09 years (IQR 0.01–0.18 years) after diagnosis, respectively. Five patients (5%) had received CRT or CRT-D. Sixteen patients (15%) underwent heart transplantation and 31 patients (29%) died without heart transplantation.
| No medication | 2 (2) |
| Medication | 104 (98) |
| β-blocker | 63 (59) |
| Diuretics | 91 (86) |
| ACEI | 72 (68) |
| Aspirin | 22 (21) |
| Warfarin | 10 (9) |
| Devices | |
| CRT | 4 (4) |
| CRT-D | 1 (0.9) |
| ICD | 0 (0) |
| ECMO | 7 (7) |
| VAD | 10 (9) |
Data are given as n (%). ACEI, angiotensin-converting enzyme inhibitor; CRT, cardiac resynchronization therapy; CRT-D, CRT defibrillator; ECMO, extracorporeal membrane oxygenator; ICD, implantable cardiac defibrillator; VAD, ventricular assist device.
Freedom from death or transplantation at 1, 3, 5, 10, and 20 years after diagnosis was 76%, 66%, 64%, 58%, and 43%, respectively (Figure 2A). Survival rates at 1, 5, 10, and 20 years after diagnosis were 81%, 75%, 72%, and 53%, respectively (Figure 2B). The incidence of heart transplantation at 1, 5, 10, and 20 years after diagnosis was 6%, 15%, 20%, and 20%, respectively (Figure 2C). These results show a high risk of death or transplantation within 1 year after diagnosis, which decreased over time.
(A) Freedom from death or heart transplantation. The rate of freedom from death or transplantation at 1, 3, 5, 10, and 20 years was 76%, 66%, 64%, 58%, and 43%, respectively. (B) Freedom from death. The rate of freedom from death at 1, 5, 10, and 20 years was 81%, 75%, 72%, and 53%, respectively. (C) Incidence of heart transplantation. The incidence of heart transplantation at 1, 5, 10, and 20 years was 6%, 15%, 20%, and 20%, respectively.
Multivariate analysis showed that FS <0.1% was a significant risk factor for death or transplantation (Table 3). The rate of freedom from death or transplantation in patients diagnosed before 1 year of age was not significantly different from that in patients diagnosed at or after 1 year of age (Figure 3A). Among the 42 patients diagnosed before 1 year of age, 21 (50%) and 28 patients (67%) were administered β-blockers and ACEI, respectively, at 0.09 years after diagnosis in the case of both drugs. These numbers were not significantly different from those in patients diagnosed at or after 1 year of age (data not shown). Freedom from death or transplantation in patients with LV FS <0.1% was significantly lower than in those with LV FS >0.1% (Figure 3B). Of the 55 patients with LV FS <0.1%, 42 (76%) and 44 (80%) patients were administered β-blockers and ACEI, respectively, at 0.09 years after diagnosis in the case of both drugs. Among the 51 patients with LV FS >0.1%, 31 (61%) and 41 (80%) patients were administered β-blockers and ACEI, respectively, at 0.18 and 0.09 years after diagnosis, respectively. These numbers in patients with LV FS <0.1% were not significantly different from those in patients with LV FS >0.1%. There was no significant difference in Freedom from death or transplantation between patients treated with and those without β-blocker treatment (Figure 3C). However, the risk of death or transplantation was significantly lower in patients being treated with ACEI than in those without ACEI (Figure 3D).
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Age at diagnosis | ||||||
| <1 year | Reference | |||||
| 1–5 years | 0.598 | 0.232–1.544 | 0.288 | |||
| 6–12 years | 1.733 | 0.776–3.871 | 0.180 | |||
| >12 years | 1.767 | 0.783–3.992 | 0.171 | |||
| Family history of DCM | ||||||
| No | Reference | |||||
| Yes | 0.741 | 0.228–2.409 | 0.619 | |||
| Sex | ||||||
| Female | Reference | |||||
| Male | 1.39 | 0.751–2.573 | 0.295 | |||
| Echocardiographic parameters | ||||||
| LVIDd (z score) | 1.059 | 0.927–1.21 | 0.399 | |||
| IVSd (z score) | 0.861 | 0.700–1.060 | 0.158 | |||
| PWTd (z score) | 0.982 | 0.857–1.125 | 0.791 | |||
| FS <0.10 | 3.256 | 1.644–6.451 | 0.001 | 3.042 | 1.514–6.111 | 0.002 |
| Laboratory data and chest X-ray | ||||||
| Initial log[BNP] > median | 1.300 | 0.940–1.790 | 0.117 | |||
| Initial CTR > median | 1.021 | 0.969–1.076 | 0.430 | |||
| Presence of symptoms | ||||||
| Resuscitated death | 2.498 | 0.340–18.37 | 0.368 | |||
| Heart failure | 2.316 | 0.822–6.524 | 0.112 | |||
| Clinical arrhythmia | 2.151 | 0.515–8.988 | 0.294 | |||
| Management | ||||||
| No medication | Reference | |||||
| β-blockers | 0.72 | 0.389–1.332 | 0.296 | 0.629 | 0.336–1.180 | 0.149 |
| ACEI | 0.523 | 0.28–0.977 | 0.042 | 0.613 | 0.320–1.176 | 0.141 |
| Diuretics | 1.663 | 0.59–4.688 | 0.336 | |||
CI, confidence interval; DCM, dilated cardiomyopathy; HR, hazard ratio. Other abbreviarions as in Tables 1,2.
Comparison of the time from diagnosis to death or heart transplantation in patients with dilated cardiomyopathy according to (A) age at diagnosis, (B) fractional shortening (FC), and (C,D) the use of β-blockers (C) or angiotensin-converting enzyme inhibitors (ACEI; D). (A) There was no significant difference in the freedom from death or transplantation in patients diagnosed <1 and >1 year of age. (B) Freedom from death or transplantation was significantly lower in patients with left ventricular FS <0.1 than in those with FS >0.1. (C) There was no significant difference in the freedom from death or transplantation in patients being treated with vs. without a β-blocker. (D) Freedom from death or transplantation was significantly higher in patients being treated with than without ACEI.
This study is the first report of a nation-wide multicenter study regarding the survival rate of pediatric DCM in Japanese children. Freedom from death or transplantation at 1, 5, 10, and 20 years after diagnosis was 76%, 64%, 58%, and 43%, respectively (Figure 2A).
Clinical CharacteristicsAge at diagnosis in the present study (median 2.0 years) was similar to that reported in the US (median 1.5 years).6 In the present study, 72% of patients were diagnosed because of symptoms of heart failure. Other clinical phenotypes, such as the symptoms and echocardiographic measurements, in this study (Table 1) were similar to previous studies from the US and Australia.4–6
OutcomeThe present study showed that the prognosis of pediatric DCM was poor in Japan, but was similar to the Australian national cohort study in pediatric patients up to 10 years of age.4,5 In the Australian national cohort study, survival rates free from death or transplantation at 1, 5, 10, and 20 years after diagnosis were 74%, 65%, 62% and 56%, respectively.4,5 The underlying cause of DCM (e.g., idiopathic DCM, myocarditis, or neuromuscular disease) is one of the determinants of prognosis.6 Patients with clear evidence of myocarditis were included in the studies from Australia, but were excluded from the present study. It has been shown that the prognosis of myocarditis is better than that of idiopathic DCM, and that LV function often recovers after myocarditis.5 Therefore, it is possible that freedom from death or transplantation in patients with idiopathic DCM, excluding myocarditis, in Australia is lower than in Japan.
In a population-based study from the US, Towbin et al reported that survival rates free from death or transplantation in patients with idiopathic DCM, excluding myocarditis, at 1, 5, and 10 years after diagnosis were 61%, 47%, and 44%, respectively.6 The freedom from death or transplantation rates in the US were lower than the rates in Japan. The US registry study reported transplantation rates at 1, 5, and 10 years after diagnosis of 27%, 38%, and 42%, respectively,6 suggesting that approximately 40% of patients underwent transplantation within 5 years of diagnosis. In contrast, the incidence of heart transplantation in the present study was 6%, 15%, and 20% at 1, 5, and 10 years after diagnosis, respectively (Figure 2C), and only 15% of patients underwent transplantation within 5 years of diagnosis. Thus, the higher freedom from death or transplantation rates observed in the US study are most likely due to the lower transplantation rate in Japan.
In the present study, freedom from death at 1, 5, and 10 years was 81%, 75%, and 72%, respectively, which is similar to the data from the US study (84%, 76%, and 74%, respectively).6
Risk FactorsIn previous reports from Australia and the US, lower baseline LV FS was associated with increased risk of death or transplantation.4–6 In accordance with these studies, lower LV FS was a risk factor for death or transplantation in the present study. In previous reports, age ≥6 years and familial cardiomyopathy were associated with an increased risk of death or transplantation.4–6 In the present study, older age and familial cardiomyopathy were not significant risk factors. The reasons for this difference remain unclear, but they may be multifactorial, and could include factors such as racial differences or differences in healthcare systems. There are some differences in genetic variants between Japanese and Caucasian DCM patients, including children and adults,10 but phenotype-genotype correlations need to be studied further in pediatric DCM cases. There is a school screening system for children aged ≥6 years in Japan,11 but the contribution of this system to the reduction in rates of cardiac death in patients aged ≥6 years remains unclear.
ManagementFor adults with DCM, many clinical trials have shown the efficacy of diuretics, ACEI, and β-blockers,12,13 and practice guidelines have been established.14 However, for pediatric DCM, medical management has not been established, mainly because of the small number of patients. In the present study, 98% of patients had received medication, with 68% having received ACEI and 59% having received β-blockers. In the US, 82% of patients had received an anticongestive agent, with 38% receiving ACEI and only 4–18% receiving β-blockers.6 Although carvedilol has been shown to reduce mortality in adult DCM,15 conflicting results have been reported in children. Some studies reported that the β-blocker was effective in the treatment of pediatric DCM.16 However, in a randomized placebo-controlled study, carvedilol had no significant effect in pediatric patients with DCM.17 In the present study, the survival rate in patients receiving β-blockers was not significantly different from that in patients not receiving β-blockers. Therefore, the efficacy of β-blockers cannot be concluded from the present study. As shown in Figure 3D, the survival rate in patients receiving ACEI was significantly higher than that in patients not receiving ACEI. Although the efficacy of ACEI in children has not been established, the use of ACEI is recommended for use as per the guideline.18 Further studies with larger numbers of patients are warranted to determine the efficacy of ACEI in pediatric DCM.
In the present study, 5% of patients received CRT. However, the efficacy of CRT remains unclear because of the small number of patients.
Tsirka et al19 reported that following heart transplantation, actuarial survival at 1 and 5 years after diagnosis improved in the US to 90% and 83%, respectively. The number of pediatric cardiac transplantations in Japan remains much less than in other countries such as the US.20 In Japan, the organ transplant law was revised in 2010 so that children aged <15 years can be organ donors. Despite the revision of the law, there were only 1–3 annual pediatric organ donations between 2010 and 2014. The number of pediatric donors has been gradually increasing and reached 15 in 2019.21 Furthermore, the Berlin Heart Excor, a ventricular assist device that can be used in small children, was approved for clinical use in Japan in 2015. Although these changes may increase the number of heart transplantations, because there are few effective treatments for DCM, strategies to further increase the number of pediatric organ donors should be considered to improve the prognosis of pediatric DCM in Japan.
Study LimitationsThe present study has several limitations. First, the study has a small sample size. Second, due to its retrospective nature, this study did not include serial echocardiographic data regarding LV function during follow-up. Patients with mildly reduced LV function, by definition, were not included in the study. Therefore, disease severity may have been overestimated. The true natural course and prognosis of pediatric DCM may be obtained by including genotype-positive patients with a milder phenotype. A prospective registration system for Japanese pediatric cardiomyopathy patients should be established to clarify the prevalence, mortality, risk factors, and, in particular, the efficacy of drug and device therapy.
This study shows that the prognosis of pediatric DCM is poor and the transplantation rate is low in Japan.
This work was supported by a Health and Labour Sciences Research Grant from the Ministry of Health and Labour (Grant no. H25-102).
The authors declare no conflicts of interest.
This study was approved by the Medical Ethics Committee of the Tokyo Women’s Medical University (Clinical Study #2714).
List of investigators and institutions participating in this study.
Hiroki Mori, Mikito Shimizu-Ishido, Toshio Nakanishi (Tokyo Women’s Medical University); Tadahiro Yoshikawa, Hitomi Kimura (Sakakibara Heart Institute); Hiroshi Ono, Hitoshi Kato (National Center for Child Health and Development); Yasuo Ono, Masaki Nii (Shizuoka Children’s Hospital); Takahiro Shindo, Ryo Inuzuka (Tokyo University); Hitoshi Horigome (Tsukuba University); Fukiko Ichida, Keiichi Hirono (Toyama University); Tomio Kobayashi (Gunma Children’s Medical Center); Shigetoyo Kogaki (Osaka University); Susumu Miura (Tokyo Metropolitan Children’s Medical Center); Junko Shiono (Ibaraki Children’s Hospital); Motoki Takamuro (Hokkaido Medical Center for Child Health and Rehabilitation); Mamoru Ayusawa (Nihon University); Minako Hoshiai (Yamanashi University); Shunichi Ogawa (Nihon Medical School); Kiyoshi Ogawa (Saitama Children’s Medical Center); Toshiki Kobayashi (Saitama Medical University International Medical Center); Hiromichi Hamada (Tokyo Women’s Medical University Yachiyo Medical Center); Hiroyuki Matsuura (Toho University Omori Medical Center); Isao Shiraishi (National Cerebral and Cardiovascular Center).
