First paediatric cohort for the evaluation of inflammation in endomyocardial biopsies derived from congenital heart surgery

Degener, F.; Salameh, Aida; Manuylova, Tatiana; Pickardt, Thomas; Kostelka, Martin; Dähnert, Ingo; Berger, Felix; Messroghli, Daniel; Schubert, Stephan; Klingel, Karin

doi:10.1016/j.ijcard.2019.10.006

Cited by 11 publications

(8 citation statements)

References 31 publications

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“…Endomyocardial biopsies (EMB) were taken according to the clinical routine from the left, right, or both ventricles as a diagnostic approach or transmural specimen during VAD implantation from all patients ( n = 12). All biopsies were analyzed histopathologically and immunohistologically as previously described and by quantitative polymerase chain reaction (qPCR) for myocardial detection of viral RNA/DNA by one specialized center for Cardiopathology (Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany) [ 14 , 29 , 30 ]. Histological analysis followed the Dallas criteria as the gold standard for the evaluation of myocarditis and was completed by different immunohistochemical staining [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Seidel

Laser

Klingel³

et al. 2022

JCDD

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Myocarditis is an inflammatory disease of the heart. Pediatric myocarditis with the dilated cardiomyopathy (DCM) phenotype may be caused by likely pathogenic or pathogenic genetic variants [(L)P] in cardiomyopathy (CMP) genes. Systematic analysis of immune disorder gene defects has not been performed so far. We analyzed 12 patients with biopsy-proven myocarditis and the DCM phenotype together with their parents using whole-exome sequencing (WES). The WES data were filtered for rare pathogenic variants in CMP (n = 89) and immune disorder genes (n = 631). Twelve children with a median age of 2.9 (1.0–6.8) years had a mean left ventricular ejection fraction of 28% (22–32%) and myocarditis was confirmed by endomyocardial biopsy. Patients with primary immunodeficiency were excluded from the study. Four patients underwent implantation of a ventricular assist device and subsequent heart transplantation. Genetic analysis of the 12 families revealed an (L)P variant in the CMP gene in 8/12 index patients explaining DCM. Screening of recessive immune disorder genes identified a heterozygous (L)P variant in 3/12 index patients. This study supports the genetic impact of CMP genes for pediatric myocarditis with the DCM phenotype. Piloting the idea that additional immune-related genetic defects promote myocarditis suggests that the presence of heterozygous variants in these genes needs further investigation. Altered cilium function might play an additional role in inducing inflammation in the context of CMP.

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Section: Methodsmentioning

confidence: 99%

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Seidel

Laser

Klingel³

et al. 2022

JCDD

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“…All EMB specimens were analyzed histopathologically and immunohistologically and by polymerase chain reaction [(RT-)PCR] for myocardial detection of viral RNA/DNA by one specialized center for Cardiopathology (Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany) as previously described ( 15 ).…”

Section: Methodsmentioning

confidence: 99%

Compensatory Upregulation of Anti-Beta-Adrenergic Receptor Antibody Levels Might Prevent Heart Failure Presentation in Pediatric Myocarditis

et al. 2022

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BackgroundMyocarditis can be associated with severe heart failure and is caused by different inflammatory and autoimmune responses. The aim of this study was to describe the immunological response in children with myocarditis by analyzing anti-beta-adrenergic receptor antibodies (anti-β-AR Abs).MethodsSera of children who were hospitalized with biopsy-proven myocarditis were prospectively collected between April 2017 and March 2019. Anti-β1-AR Ab, anti-β2-AR Ab, and anti-β3-AR Ab were quantified by a CE-certified ELISA kit. According to normal values for immunoglobulin G (IgG), three age groups, <1, 1–5, and >5–17 years, were defined. Children without inflammatory cardiac pathology and no heart failure signs were served as a control group.ResultsWe compared 22 patients with biopsy-proven myocarditis and 28 controls. The median age (interquartile range) of the myocarditis group (MYC) was 12.1 (2.7–16.4) years, 13 men, left ventricular ejection fraction (LVEF) 51% and for control group, the median age was 5.0 (3.0–6.8) years, nine men, LVEF 64%. Myocarditis patients in the age group >5–17 years showed significantly higher anti-β3-AR Ab levels as compared to controls (p = 0.014). Lower anti-β2-AR Ab and anti-β3-AR Ab levels were significantly correlated with higher left ventricular diameters in myocarditis patients. The event-free survival using a combined endpoint (mechanical circulatory support [MCS], transplantation, and/or death) was significantly lower in myocarditis patients with antibody levels below the median as compared to myocarditis patients with antibody levels ≥ the median.ConclusionAnti-β-AR Ab levels are increased in children with myocarditis and >5 years of age. These antibodies might be upregulated compensatory to prevent further cardiac deterioration. A worse event-free survival in patients with lower anti-β-AR Ab levels might be a therapeutic target for immunoglobulin substitution.

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“…Hierbei ist von Vorteil, dass sowohl die histologischen Färbungen (Hämatoxylin-Eosin [HE], Masson Trichrom, Giemsa) als auch die immunhistologischen Färbungen z. B. zur Differenzierung von Entzündungszellinfiltraten (CD3 + T-Lymphozyten, CD68 + Makrophagen mit MHCII Expression), aber auch in situ Hybridisierungen zum Nachweis viraler Nukleinsäuren oder diverser zellulärer mRNAs an 4 % gepuffertem Formalin-fixiertem Herzmuskelgewebe durchgeführt werden können [3,41,42]. Für molekularpathologische, molekulargenetische und infektionspathologische Untersuchungen durch q(RT-) PCR ist es zudem sinnvoll, dass 1-2 EMB in RNAlater fixiert werden.…”

Section: Endomyokardbiopsie (Ebm)unclassified

“…Der immunhistologische Nachweis eines zellulären Infiltrates von ≥ 14 Lymphozyten und Makrophagen/mm 2 bei mindestens 7 Lymphozyten/mm 2 Myokardgewebe bei Erwachsenen sichert somit die Diagnose einer chronischen Myokarditis/inflammatorischen Kardiomyopathie auch bei fehlendem Nachweis von Myozytolysen [35]. Bei kleinen Kindern wurden niedrigere Normalwerte der Immunzellen als bei Erwachsenen gemessen und betragen im Median 2,5/mm 2 (1,0-4,0) CD3 + T-Zellen, 0,5/mm 2 (0,0-0,6) CD20 + B-Zellen und 4,0/mm 2 (2, 5-6, 0) CD68 + Makrophagen [42] (▶ abb. 1).…”

Section: Histologie/immunhistologie An Embunclassified

“…Eine Therapie mit Interferon-β bei inflammatorischer Kardiomyopathie und positivem Virusnachweis ist bislang nur in einer Pilotstudie mit einer Verringerung der Viruslast bei Enterovirus- und Adenovirus-positiven Patienten und Verbesserung der NYHA-Klasse veröffentlicht worden. Bei Kindern sind die Nachweisraten von Viren im Myokard höher als bei Erwachsenen, wobei die Therapie mit Interferon-β bei positivem Virusnachweis für Entero- oder Adenoviren in der Endomyokardbiopsie und fortbestehender Herzinsuffizinz mit klinischer Beeinträchtigung nach kritischer Prüfung der Nebenwirkungen in Erwägung gezogen werden kann 42 .…”

Section: Therapieunclassified

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Leitlinie Myokarditis der Deutschen Gesellschaft für Pädiatrische Kardiologie

et al. 2023

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First paediatric cohort for the evaluation of inflammation in endomyocardial biopsies derived from congenital heart surgery

Cited by 11 publications

References 31 publications

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Compensatory Upregulation of Anti-Beta-Adrenergic Receptor Antibody Levels Might Prevent Heart Failure Presentation in Pediatric Myocarditis

Leitlinie Myokarditis der Deutschen Gesellschaft für Pädiatrische Kardiologie

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