Thorac Cardiovasc Surg 2022; 70(S 02): S67-S103
DOI: 10.1055/s-0042-1742990
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AKT/mTOR and MAPK Inhibition Improves Childhood RASopathic Cardiomyopathy

Authors

  • C. M. Wolf

    1   Lazarettstr. 36, München, Deutschland

  • M. Zenker

    2   Institute of Human Genetics and Applied Genomics, Magdeburg, Deutschland

  • G. Norrish

    1   Lazarettstr. 36, München, Deutschland

  • M. Russell

    3   University of Michigan, Michigan, United States

  • J. K. Meisner

    3   University of Michigan, Michigan, United States

  • D. M. Peng

    3   University of Michigan, Michigan, United States

  • T. Prendiville

    4   Children's Health Ireland at Crumlin, Dublin, Ireland

  • J. Kleinmahon

    5   Ochsner Hospital for Children, New Orleans, United States

  • P. F. Kantor

    6   Children's Hospital Los Angeles, Los Angeles, United States

  • D. Gottlieb Sen

    7   Johns Hopkins School of Medicine, Baltimore, United States

  • D. G. Human

    8   British Columbia's Children's Hospital, Vancouver, Canada

  • P. Ewert

    1   Lazarettstr. 36, München, Deutschland

  • M. Krueger

    9   Department of Neonatology, Municipal Hospital Munich Schwabing, Munich, Deutschland

  • D. Reber

    9   Department of Neonatology, Municipal Hospital Munich Schwabing, Munich, Deutschland

  • B. C. Donner

    10   Pediatric Cardiology, University Children's Hospital of Basel (UKBB), University of Basel, Basel, Switzerland

  • C. Hart

    11   Paediatric Heart Center, Children's Hospital, University of Bonn, Bonn, Deutschland

  • I. Odri-Komazec

    12   Medizinische Universität Innsbruck, Innsbruck, Austria

  • S. Rupp

    13   Launsbacher Straße 29a, Gießen, Deutschland

  • A. Hahn

    14   Kinderklinik Gießen, Gießen, Deutschland

  • A. Hanser

    15   Hoppe-Seyler-Str. 1, Tübingen, Deutschland

  • M. Hofbeck

    15   Hoppe-Seyler-Str. 1, Tübingen, Deutschland

  • J. M. Draaisma

    16   Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, The Netherlands

  • F.E.A. Udink Ten Cate

    16   Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, The Netherlands

  • A. Mussa

    17   Department of Public Health and Pediatric Sciences, University of Torino, Torino, Italy

  • G. B. Ferrero

    18   Department of Clinical and Biological Sciences, School of Medicine, University of Torino, Torino, Italy

  • C. Marquis

    19   Department of Pediatrics, CHU Sainte Justine, Université de Montréal, Montreal, Canada

  • Y. Théoret

    19   Department of Pediatrics, CHU Sainte Justine, Université de Montréal, Montreal, Canada

  • J. P. Kaski

    20   FRCP, Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, London, United Kingdom

  • B. D. Gelb

    21   Icahn School of Medicine at Mount Sinai, New York, United States

  • G. Andelfinger

    22   Cardiovascular Genetics, CHU Sainte Justine, Université de Montreal, Montreal, Canada
Further Information
 
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Background: RASopathies are a spectrum of pleomorphic syndromic disorders and caused by germline mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway. They cause progressive RASopathy-associated cardiomyopathy (RAS-CM) for which no preventive or curative therapies exist. Young infants presenting with heart failure suffer from high mortality. RAS-CM presenting later in life is morbid with increased risk for sudden cardiac death or cardiac transplantation. Animal studies and limited case reports have suggested that small molecule inhibitors of target of rapamycin (mTOR) or mitogen-activated protein kinase kinase (MEK), pathways activated in certain RASopathies, are beneficial. The aim of this study is to report on 25 patients from Europe and North America with progressive and/or life-threatening RAS-CM in whom we initiated off-label or compassionate inhibition of mTOR or MEK after exhaustion of standard therapies.

Method: This study was done by retrospective data collection.

Results: Over a follow-up period of 296 patient-months (median, 5.5 months; range, 1.5–50), we observed increased transplant-free survival in critically ill patients <6 months of age treated with mTORi and/or MEKi as compared with that from natural history studies (75 vs. 39%, p = 0.031). Freedom from surgical intervention was 52% (11 of 21 patients in whom surgical outflow tract resection was indicated), and clinically meaningful improvement (greater than 20% from baseline) in 50% or more of preselected cardiac outcome variables occurred in 18 of 25 patients (72%) undergoing mTORi and/or MEKi treatment. No life-threatening adverse events related to mTORi or MEKi occurred.

Conclusion: These data suggest that selected RASopathy patients may benefit from mechanism-informed therapeutics guided by the biological understanding of cardiac pathology in this disease spectrum.


No conflict of interest has been declared by the author(s).

Publication History

Article published online:
12 February 2022

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