First name
Elfriede
Last name
Pahl

Title

Survival Without Cardiac Transplantation Among Children With Dilated Cardiomyopathy.

Year of Publication

2017

Number of Pages

2663-2673

Date Published

2017 Nov 28

ISSN Number

1558-3597

Abstract

BACKGROUND: Studies of children with dilated cardiomyopathy (DCM) have suggested that improved survival has been primarily due to utilization of heart transplantation.

OBJECTIVES: This study sought to determine transplant-free survival for these children over 20 years and identify the clinical characteristics at diagnosis that predicted death.

METHODS: Children <18 years of age with some type of DCM enrolled in the Pediatric Cardiomyopathy Registry were divided by year of diagnosis into an early cohort (1990 to 1999) and a late cohort (2000 to 2009). Competing risks and multivariable modeling were used to estimate the cumulative incidence of death, transplant, and echocardiographic normalization by cohort and to identify the factors associated with death.

RESULTS: Of 1,953 children, 1,199 were in the early cohort and 754 were in the late cohort. Most children in both cohorts had idiopathic DCM (64% vs. 63%, respectively). Median age (1.6 vs. 1.7 years), left ventricular end-diastolic z-scores (+4.2 vs. +4.2), and left ventricular fractional shortening (16% vs. 17%) at diagnosis were similar between cohorts. Although the rates of echocardiographic normalization (30% and 27%) and heart transplantation (24% and 24%) were similar, the death rate was higher in the early cohort than in the late cohort (18% vs. 9%; p = 0.04). Being in the early cohort (hazard ratio: 1.4; 95% confidence interval: 1.04 to 1.9; p = 0.03) independently predicted death.

CONCLUSIONS: Children with DCM have improved survival in the more recent era. This appears to be associated with factors other than heart transplantation, which was equally prevalent in both eras. (Pediatric Cardiomyopathy Registry [PCMR]; NCT00005391).

DOI

10.1016/j.jacc.2017.09.1089

Alternate Title

J. Am. Coll. Cardiol.

PMID

29169474

Title

The genetic architecture of pediatric cardiomyopathy.

Year of Publication

2022

Date Published

2022 Jan 10

ISSN Number

1537-6605

Abstract

<p>To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants &lt; 1 year were less likely to have a molecular diagnosis (p &lt; 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p &lt; 0.001) and SPARK parental controls (p &lt; 1&nbsp;× 10). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.</p>

DOI

10.1016/j.ajhg.2021.12.006

Alternate Title

Am J Hum Genet

PMID

35026164

Title

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

Year of Publication

2021

Number of Pages

e017731

Date Published

2021 Apr 28

ISSN Number

2047-9980

Abstract

<p>Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (=0.005 and =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.</p>

DOI

10.1161/JAHA.120.017731

Alternate Title

J Am Heart Assoc

PMID

33906374

Title

Baseline Characteristics of the VANISH Cohort.

Year of Publication

2019

Number of Pages

e006231

Date Published

2019 Dec

ISSN Number

1941-3297

Abstract

<p><strong>BACKGROUND: </strong>The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers.</p>

<p><strong>METHODS: </strong>Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy.</p>

<p><strong>RESULTS: </strong>In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required.</p>

<p><strong>CONCLUSIONS: </strong>The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and variants, suggesting both phenotype and genotype contribute to disease manifestations.</p>

<p><strong>CLINICAL TRIAL REGISTRATION: </strong>URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.</p>

DOI

10.1161/CIRCHEARTFAILURE.119.006231

Alternate Title

Circ Heart Fail

PMID

31813281

Title

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

Year of Publication

2019

Number of Pages

1-10

Date Published

2019 Jun

ISSN Number

1058-9813

Abstract

<p><strong>Background: </strong>Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy.</p>

<p><strong>Study Design: </strong>The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure.</p>

<p><strong>Results: </strong>There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years.</p>

<p><strong>Conclusion: </strong>The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children.</p>

<p><strong>Clinical Trial Registration NCT01873976: </strong>https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&amp;…;

DOI

10.1016/j.ppedcard.2019.02.004

Alternate Title

Prog. Pediatr. Cardiol.

PMID

31745384

Title

No Obesity Paradox in Pediatric Patients With Dilated Cardiomyopathy.

Year of Publication

2018

Number of Pages

222-230

Date Published

2018 Mar

ISSN Number

2213-1787

Abstract

<p><strong>OBJECTIVES: </strong>This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM).</p>

<p><strong>BACKGROUND: </strong>In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival.</p>

<p><strong>METHODS: </strong>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]&nbsp;&lt;5% for&nbsp;≥2 years or weight-for-length&nbsp;&lt;5% for&nbsp;&lt;2 years), obesity (BMI &gt;95% for age&nbsp;≥2 years or weight-for-length &gt;95% for&nbsp;&lt;2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (214) were MN, 13.3% (120) were obese, and 63.1% (570) were NB.</p>

<p><strong>RESULTS: </strong>Obese patients were older (9.0 vs. 5.7 years for NB; p&nbsp;&lt; 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p&nbsp;= 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p&nbsp;&lt; 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p&nbsp;= 0.012), cardiac dimension z-scores &gt;2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard&nbsp;ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p&nbsp;&lt; 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&nbsp;=&nbsp;0.03), but no difference in transplant rate (p&nbsp;= 0.159).</p>

<p><strong>CONCLUSIONS: </strong>Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical&nbsp;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&nbsp;Cardiomyopathy Registry; NCT00005391).</p>

DOI

10.1016/j.jchf.2017.11.015

Alternate Title

JACC Heart Fail

PMID

29428438

Title

Clinical practice patterns are relatively uniform between pediatric heart transplant centers: A survey-based assessment.

Year of Publication

2017

Date Published

2017 Jul 03

ISSN Number

1399-3046

Abstract

<p>Clinical practice variations are a barrier to the study of pediatric heart transplants and coordination of multicenter RCTs in this patient population. We surveyed centers to describe practice patterns, understand areas of variation, and willingness to modify protocol. Pediatric heart transplant centers were identified, and one survey was completed per center. Simple descriptive statistics were used. The response rate was 77% (40 responses from 52 contacted centers, 37 with complete responses). Median center volume of respondents was eight transplants/year (IQR 3-19). Most centers reported tacrolimus (36/38, 95%) and mycophenolate mofetil (36/38, 95%) as maintenance immunosuppression. Other immunosuppression agents reported were cyclosporine (7/38, 18%), everolimus or sirolimus (3/38, 8%), and azathioprine (2/38, 5%). Overall, respondents answered similarly for questions regarding clinical practices including induction therapy, maintenance immunosuppression, and rejection treatment threshold (&gt;85% agreement for all). Additionally, willingness to change clinical practices was over 70% for all practices surveyed (35 total respondents), and 97% of centers (36/37) were willing to participate in a RCT of maintenance immunosuppression. In conclusion, we found many similar clinical practice protocols. Most centers are willing to collaborate on a common protocol in order to participate in a RCT and support a trial investigating maintenance immunosuppression.</p>

DOI

10.1111/petr.13013

Alternate Title

Pediatr Transplant

PMID

28670871

Title

Development and validation of a major adverse transplant event (MATE) score to predict late graft loss in pediatric heart transplantation.

Year of Publication

2018

Number of Pages

441-450

Date Published

2018 Apr

ISSN Number

1557-3117

Abstract

<p><strong>BACKGROUND: </strong>There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT.</p>

<p><strong>METHODS: </strong>Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score.</p>

<p><strong>RESULTS: </strong>Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was &gt;85% using the MATE score.</p>

<p><strong>CONCLUSION: </strong>The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.</p>

DOI

10.1016/j.healun.2017.03.013

PMID

28465118

Title

Use of sirolimus in pediatric heart transplant patients: A multi-institutional study from the Pediatric Heart Transplant Study Group.

Year of Publication

2016

Date Published

2016 Oct 04

ISSN Number

1557-3117

Abstract

<p><strong>BACKGROUND: </strong>Proliferation signal inhibitors, such as sirolimus, are increasingly used in solid-organ transplantation. However, limited data exist on sirolimus-treated pediatric patients. We aimed to describe sirolimus use in pediatric heart transplant patients and test the hypothesis that sirolimus use is associated with improved outcomes.</p>

<p><strong>METHODS: </strong>A retrospective review and propensity-matched analysis of the Pediatric Heart Transplant Study database was performed on patients undergoing primary heart transplantation from 2004 to 2013 with at least 1 year of follow-up comparing patients treated vs not treated with sirolimus at 1 year after transplant. The primary outcome of interest was patient survival, with secondary outcomes including cardiac allograft vasculopathy, rejection, malignancy, and renal insufficiency.</p>

<p><strong>RESULTS: </strong>Between 2004 and 2013, 2,531 patients underwent transplantation. At least 1 year of follow-up was available for 2,080 patients, of whom 144 (7%) were on sirolimus at 1 year post-transplant. Sirolimus-treated and non-treated patients had similar survival in the overall cohorts and in the propensity-matched analysis. The secondary outcomes measures were also similar, including a composite end point of all outcome measures. There was a trend toward increased time to cardiac allograft vasculopathy (p = 0.09) and decreased time to infection (p = 0.05) among sirolimus-treated patients in the overall cohort (p = 0.19) but not in the propensity-matched cohort (p = 0.17).</p>

<p><strong>CONCLUSIONS: </strong>Sirolimus was used in less than 10% of patients at 1 year post-transplant. Overall outcomes of sirolimus treated and non-treated patients were similar with respect to survival and major transplant adverse events. Further study of sirolimus in pediatric heart transplant patients is needed.</p>

DOI

10.1016/j.healun.2016.09.009

Alternate Title

J. Heart Lung Transplant.

PMID

28029575

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