Author + information
- Received May 30, 2017
- Revision received November 9, 2017
- Accepted November 11, 2017
- Published online February 26, 2018.
- Chesney D. Castleberry, MDa,∗ (, )
- John L. Jefferies, MD, MPHb,
- Ling Shi, PhDc,
- James D. Wilkinson, MD, MPHd,
- Jeffrey A. Towbin, MDe,
- Ryan W. Harrison, MSc,
- Joseph W. Rossano, MD, MSf,
- Elfriede Pahl, MDg,
- Teresa M. Lee, MDh,
- Linda J. Addonizio, MDh,
- Melanie D. Everitt, MDi,
- Justin Godown, MDj,
- Joseph Mahgerefteh, MDk,
- Paolo Rusconi, MDl,
- Charles E. Canter, MDa,
- Steven D. Colan, MDm,
- Paul F. Kantor, MBBChn,
- Hiedy Razoky, BS, MBAd,
- Steven E. Lipshultz, MDd and
- Tracie L. Miller, MDl
- aDepartment of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
- bDepartment of Pediatrics, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- cNew England Research Institutes, Watertown, Massachusetts
- dDepartment of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, Michigan
- eDepartment of Pediatrics, The Heart Institute, Le Bonheur Children’s Hospital, Memphis, Tennessee
- fDepartment of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
- gDepartment of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
- hDepartment of Pediatrics, Columbia University Medical Center, New York, New York
- iDepartment of Pediatrics, Children’s Hospital Colorado, University of Colorado, Aurora, Colorado
- jDepartment of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee
- kDepartment of Pediatrics, Children’s Hospital at Montefiore, Bronx, New York
- lDepartment of Pediatrics, University of Miami, Miller School of Medicine, Miami, Florida
- mDepartment of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- nDepartment of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada
- ↵∗Address for correspondence:
Dr. Chesney D. Castleberry, Washington University in St. Louis, One Children’s Place, Campus Box 8116-NWT, St. Louis, Missouri 63110.
Objectives This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM).
Background In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival.
Methods The National Heart, Lung, and Blood Institute–funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI] <5% for age ≥2 years or weight-for-length <5% for <2 years), obesity (BMI >95% for age ≥2 years or weight-for-length >95% for <2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (n = 214) were MN, 13.3% (n=120) were obese, and 63.1% (n=570) were NB.
Results Obese patients were older (9.0 vs. 5.7 years for NB; p < 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p = 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p < 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p = 0.012), cardiac dimension z-scores >2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p < 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p = 0.03), but no difference in transplant rate (p = 0.159).
Conclusions Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric Cardiomyopathy Registry; NCT00005391)
Children with heart failure are at increased risk for developing malnutrition because of their higher than normal energy requirements (1). Poor growth is frequent even in patients receiving supplemental enteral feedings (2). In children undergoing heart transplantation, malnutrition has been implicated as a risk factor for mortality before and after transplant (3,4).
Obesity is another important consideration in the pediatric population. Adults with obesity are at increased risk for developing heart failure (5,6). Although obesity is a risk factor for mortality after heart transplant in adults, an “obesity paradox” exists in which obese adults with systolic dysfunction or clinical symptoms of heart failure survive longer than adults who are malnourished or are of normal weight (7–10). The mechanism of this difference in outcomes is not well understood and has not been investigated in children (11). Because the rate of childhood obesity and metabolic syndrome is now sufficiently high, encountering children with cardiomyopathy and obesity is no longer uncommon (12).
The primary aim of this study was to describe the impact of malnourishment and obesity on clinical outcomes (death or heart transplantation) in children with dilated cardiomyopathy (DCM). We hypothesized that there would be an increased frequency of death or transplantation in malnourished patients, whereas obesity would not adversely affect death or transplantation compared with patients with normal anthropometric measurements.
The National Heart, Lung, and Blood Institute—funded Pediatric Cardiomyopathy Registry (PCMR) was used to identify patients with DCM. This registry consists of demographic, echocardiographic, and clinical data on more than 3,000 children (age <18 years at diagnosis) with cardiomyopathy diagnosed at any of 98 pediatric cardiac centers in the United States and Canada since the registry was established in 1990. Data, including anthropometric and echocardiographic data, are collected within 30 days of diagnosis and enrollment in the study as well as annually until a patient reaches the age of 18 years. Each participating center obtains institutional review board or ethics committee approval for the study. Detailed information regarding registry design and conduct are detailed elsewhere (13,14). Data used for this study were frozen on January 14, 2013.
The PCMR defines DCM based on echocardiographic measurements of ventricular size and function, pathological findings on biopsy or autopsy, or clinical diagnosis (15). Patients with a neuromuscular disorder, malformation syndrome, or inborn error of metabolism were excluded from the current analysis because the underlying disease in these patients was believed to influence outcomes independently of DCM. Patients were also excluded if weight or height measurements were not available in the registry.
Participants were categorized into 1 of 3 mutually exclusive nutrition groups based on anthropometric measurement at time of diagnosis. The categories were: malnourished (MN), normal bodyweight (NB), and obese. Participants 2 years of age and older were considered MN if their BMI was lower than the fifth percentile for age and gender; participants younger than 2 years were considered MN if their weight-for-length was less than the fifth percentile. Participants 2 years of age or older were considered obese if their BMI for age and gender was above the 95th percentile, and participants younger than 2 years were obese if their weight-for-length was greater than the 95th percentile.
Echocardiographic variables, including left ventricular (LV) end-diastolic dimension (EDD), posterior wall thickness, septal thickness, and mass, were expressed as z-scores conditional on body surface area and calculated using best possible fit with body surface area as the determinant and were calculated using the lambda mu sigma method as described by Foster et al. (16,17). LV fractional shortening and posterior wall thickness to EDD ratio were expressed as the z-score conditional on age (16).
The New England Research Institutes (Watertown, Massachusetts) was the PCMR Statistical and Data Coordinating Center and performed all data analyses. To describe the patients’ characteristics and baseline echocardiographic parameters, mean ± SD were used for normally distributed variables and frequencies and percentages were used for categorical variables. Analysis of variance and chi-square tests were used to assess overall differences across the 3 nutritional groups. Kaplan-Meier plots of time from diagnosis to death and/or transplantation were generated, and log-rank p values were calculated. Patients were censored at 7 years given duration of study follow-up.
Analysis of variance and chi-square tests were used for overall comparison across the nutritional groups. Pair-wise comparisons were conducted when the overall p value is <0.05. Post hoc Bonferroni-corrected p values <0.017 (0.05/3 comparison groups) were considered statistically significant. Cox proportional hazard regression models were used to determine the effect of nutritional status on survival and freedom from transplant as the outcome of interest while adjusting for potential confounders. First, univariate Cox regression models were fit for a selection of predictors that were chosen based on prior knowledge that they were potentially associated with survival outcomes; multivariable Cox regression models were then fit step by step by adding covariates that were significant in the univariate analyses at the <0.10 level, including age, congestive heart failure, anti-congestive therapy, fractional shortening z-score, height for age z-score, and ratio of LV end-diastolic posterior wall thickness/EDD z-score. Finally, backwards model selection was used to determine the final model. To test the proportionality assumption, Kaplan-Meier plots were used to check the proportional hazards for categorical covariates, whereas scatterplot smooths were used to examine the relationship between scaled Schoenfeld residuals and follow-up time for continuous covariates. We also assessed proportional hazards assumption by testing the interaction between the covariate and the follow-up time. Estimates of cumulative incidence for each of the 3 competing outcomes (death, transplantation, or survival and freedom from transplant) were calculated in the competing risk analysis. Statistical significance was established at a p value <0.05. Analysis was performed using SAS, version 9.3 (Cary, North Carolina), and R version 3.1.1.
There were 1,755 patients with DCM who did not have neuromuscular disorder, malformation syndrome, or an inborn error of metabolism. Of the 1,755 participants who met inclusion criteria, 851 were excluded because of missing height and weight measurements. Demographics of excluded patients revealed younger age and a different race distribution among excluded patients (Online Table 1). The study population therefore included 904 participants with documented height and weight information. Of these participants, 23.7% (n = 214) were MN, 63.1% (n = 570) were NB, and 13.3% (n = 120) were obese. The median follow-up time was 1.4 years (2.8 ± 3.4) for all participants, 1.3 (3.0 ± 3.8), 1.6 (2.9 ± 3.4), and 0.9 (1.9 ± 2.7) years for MN, NB, and obese participants, respectively. MN patients were more likely to be younger, have a lower weight-for-age z-score, have heart failure at time of diagnosis, and receive anti—heart failure therapy compared with patients with NB (p < 0.05 for all). Compared with NB, obese patients were more likely to be older, have lower height-for-age z-score, higher weight-for-age z-score, and a family history of cardiomyopathy (p < 0.05 for all). These patterns were similar for MN compared with obese with MN being younger, more frequently female, greater height-for-age z-score, lower weight for age z-score, lower BMI, more heart failure at diagnosis, and on anti—heart failure therapy. Otherwise, there were no significant differences between the groups by race, etiology, family history of sudden death, or anti—heart failure therapy (Table 1).
Echocardiographic features differed among the anthropometric classifications (Table 2). MN patients had larger LVEDD and end-systolic dimension z-scores than those with NB (p < 0.001). LV fractional shortening z-scores were lower in MN patients (p < 0.001); however, there was no difference in LV posterior wall thickness to EDD ratio and ejection fraction z-scores. There was also no difference in percentage of patients with mitral regurgitation or left atrial dilatation between the study groups (Table 2).
Logarithmic tests from Kaplan-Meier analysis demonstrated that there was decreased survival in both MN and obese patients compared with NB (84.7% transplant-free survival in MN patients; 86.2% in obese patients), compared with 91.8% in NB patients at 2 years after diagnosis (p = 0.01 and p = 0.02, respectively) (Table 3, Figure 1A) with a corresponding increase in event rate (56.3 and 64.5 events/1,000 person-years, respectively, compared with 32.2 in NB participants). There was an increased risk of death or transplant as a composite endpoint in obese versus NB patients (55.9% 2-year transplant-free survival and 248 events/1,000 person-years) in obese patients compared with 67.4% and 132.8 events/1,000 person-years in NB; p = 0.016 (Table 3, Figure 1B), although no difference was seen in MN versus NB (p = 0.191). Conversely, in competing risk analysis, there was increased mortality in MN patients compared with NB (p = 0.030), but not between obese and NB (p = 0.223). The cumulative incidence rate of death in this analysis was 19.1% in MN patients, significantly higher than the 13.0% in NB patients; however, there was no difference between the groups in rate of transplantation between any of the nutritional groups (p = 0.159) (Figure 2).
In a multivariable model derived from univariate analysis, there was an increased risk for death in MN patients compared with NB patients (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.17 to 3.65; p = 0.042). When risk for death or transplant was analyzed, MN was not associated with greater risk for death or transplant compared with NB patients. Likewise, there was no increased risk of listing for transplant in the MN patients. There was also no increased risk of death, death or transplant, or transplant alone in obese patients compared with those who were NB (p > 0.05 for all) (Table 3).
Sub-analysis was performed to determine the impact of MN and obesity on survival, stratified by age (<1 year, 1 to 10 years, and >10 years). There was no difference in transplant-free survival between patients of different nutritional status based on age (p > 0.05 for all) (Figure 3).
In this study from 1 of the largest registries in pediatric cardiomyopathy with data collection from more than 98 pediatric cardiac centers in the United States and Canada that includes patients from the time of diagnosis of DCM, we found that MN was a significant risk factor for death after diagnosis of DCM. Additionally, there was decreased overall survival in obese pediatric patients, although obesity was not associated with increased mortality in multivariable analysis.
Our findings of higher mortality in pediatric DCM with MN have been noted in other pediatric heart failure cohorts. Malnutrition has been associated with increased mortality in pediatric patients listed for transplant (11–21). The higher mortality seen in this population is believed to be secondary to an increase in neurohormonal and inflammatory activation that leads to further increases in metabolic demands, whereas tolerance of feeds diminishes because of gut perfusion (2). Additionally, heart failure leads to maladaptive gastrointestinal responses that produce decreased appetite, poor absorption of nutrients, and increased protein catabolism (21). These patients have higher rates of emergency room visits and hospitalizations, hospital morbidities, and all-cause mortality (22–24).
Although malnutrition leads to adverse outcomes in pediatric patients both before and after transplant, it has not been an established risk factor in pediatric patients before listing for transplant (18,19). We saw that, as with patients with end-stage heart disease, malnutrition remained a significant risk factor for mortality in all comers with DCM. This suggests that early recognition of malnutrition in this patient population could potentiate outcomes and should be a focus of future study.
Obesity is associated with heart failure in both the adult and pediatric general populations (5,6). This is believed to be secondary to an obesity-related increased heart rate and stroke volume that leads to LV concentric remodeling (normal LV mass with elevated mass-to-volume ratio), and subsequently to increased LV mass and diastolic dysfunction (25–27). This can progress to LV systolic dysfunction and dilation (27). Length of time with obesity is associated with lower LV systolic function and greater diastolic dysfunction (28,29). These effects are independent of hypertension or other cardiovascular risk factors (30).
The effect of obesity on outcomes in patients with heart failure is not well understood. Several large studies have demonstrated that obese patients do better than those with normal weight including decreased mortality and hospitalizations, leading to the theory of an existence of an “obesity paradox” (31,32). This has been confirmed in the meta-analysis by Sharma et al. (31), in which MN was associated with increased mortality; however, obesity was associated with lower risk of hospitalization and cardiovascular mortality. Mechanisms believed to be associated with this difference in outcome include greater metabolic reserve, protective cytokines, attenuated response to renin-angiotensin-aldosterone system, or different cause of heart failure, among others (1). Recent data, however, have challenged the link between obesity and decreased mortality, suggesting that it is explained by a confounding bias within the population (11). Additionally, these patients may be more closely monitored for cardiac complications and have incidental ventricular dilation from obesity-related adaptive changes; thus, clinical symptoms related to obesity are often unrelated to cardiac causes (33–35). Gustafsson et al. (36) found that heart failure patients with a preserved LV ejection fraction demonstrated better survival, and that outcome was worse in patients with obesity and depressed LV systolic function compared with patients with normal anthropometric measurements. Although we found that there was decreased event-free survival in obese patients, obesity itself was not a risk factor for death in this pediatric cardiomyopathy population as a whole, including symptomatic and asymptomatic individuals.
Malnutrition and obesity are both significant considerations in transplant suitability given the increased risk of post-transplant morbidity and mortality (37). Because of the impact of obesity in particular on morbidity post-transplant, current International Society for Heart and Lung Transplantation recommendations for adult candidates are to delay listing for transplantation until patients reach a BMI <35 kg/m2 (38). Neither obesity nor malnutrition was found to affect frequency of transplantation in our pediatric cohort.
The effect of malnutrition or obesity may not be the same across all age ranges; for instance, infants with malnutrition may have worse outcomes given their limited reserve (21). Likewise, obesity may have a greater impact in older patients, especially adolescents, given that the chronicity of obesity has been shown to affect outcomes (39). Although there were no differences seen in the age subgroups, there was a trend toward worse survival over time for both malnutrition and obesity across all age groups.
Although the patient cohort studied was large, 1 significant limitation was the amount of missing height and weight data in the population. These patients were also sicker (Online Table 2), possibly reflecting the difficulty of obtaining accurate height and weight measurements in patients who present in extremis. Also, body composition, including lean or fat mass, as estimates of nutritional status was not collected in the registry and body surface normalization through the use of standardized z-scores for echocardiographic measurements may be misleading at the extremes of the weight spectrums. Information regarding body composition, especially for patients meeting criteria for malnutrition, is largely unknown and not part of the registry. Weight information was collected prospectively at the time of enrollment; however, detailed information regarding presence or absence of edema is also unknown. Information on clinical symptoms, including New York Heart Association and Ross classification of heart failure, was available for too few patients to allow inclusion of symptomatic status in the analysis.
Malnutrition is associated with an increased risk of death after the diagnosis of DCM. Additionally, obesity was not protective in this population as it is in adults; there was, in fact, decreased overall survival in the obese population compared with the NB. Obesity itself was not an explanatory factor, however. Neither malnutrition nor obesity was associated with a significant difference in rate of transplantation compared to the normal body weight. Prospective studies of nutritional interventions are needed to understand the influence of nutritional status on clinical outcomes in children with DCM.
COMPETENCY IN MEDICAL KNOWLEDGE: Our study has significant implications for both the pediatric and population. Ongoing emphasis on improving nutrition in patients with dilated cardiomyopathy is important as it has significant prognostic implications, thus providing an avenue to improve clinical outcomes. Likewise, obesity should be taken seriously in this patient population, as there was no association with decreased morbidity. Lifestyle modification in these young patients is most likely an avenue for improving outcomes, as this factor is also potentially modifiable.
TRANSLATIONAL OUTLOOK: Future studies are needed to understand the impact of standard nutritional interventions addressing malnutrition in pediatric DCM. Additionally, understanding the impact of lifestyle modification on pediatric patients with DCM who are obese may be helpful in managing these patients as well possibly contributing to a better understanding of the obesity paradox in adult heart failure.
The authors thank the participating centers for subject recruitment and follow-up data collection. They also thank the Children’s Cardiomyopathy Foundation for their ongoing support of the Pediatric Cardiomyopathy Registry’s research efforts.
Supported by grants from the National Heart, Lung, and Blood Institute (NHLBI; HL 53392) and the Children’s Cardiomyopathy Foundation (CCF). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI or CCF. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body mass index
- confidence interval
- dilated cardiomyopathy
- end-diastolic dimension
- hazard ratio
- left ventricular
- normal bodyweight
- Received May 30, 2017.
- Revision received November 9, 2017.
- Accepted November 11, 2017.
- 2018 American College of Cardiology Foundation
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