Thorac Cardiovasc Surg 2023; 71(S 02): S73-S106
DOI: 10.1055/s-0043-1761854
Sunday, 12 February
Joint Session DGPK/DGTHG: Basic Research auf den Punkt gebracht

MAPK and mTOR Inhibition Improves Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

C. M. Wolf
1   German Heart Center Munich, Technical University Munich, Munich, Deutschland
,
M. Zenker
2   Institute of Human Genetics and University Children's Hospital, Magdeburg, Deutschland
,
O. Boleti
3   Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, London, United Kingdom
,
G. Norrish
3   Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, London, United Kingdom
,
M. Russell
4   University of Michigan, Michigan, United States
,
J. K. Meisner
4   University of Michigan, Michigan, United States
,
D. M. Peng
4   University of Michigan, Michigan, United States
,
T. Prendiville
5   Children's Health Ireland at Crumlin, Crumlin, Ireland
,
J. Kleinmahon
6   Ochsner Hospital for Children, New Orleans, United States
,
P. Kantor
7   Children's Hospital Los Angeles, Los Angeles, United States
,
S. D. Gottlieb
8   Johns Hopkins School of Medicine, Baltimore, United States
,
D. Human
9   British Columbia's Children's Hospital, Vancouver, Canada
,
P. Ewert
1   German Heart Center Munich, Technical University Munich, Munich, Deutschland
,
M. Krueger
10   Municipal Hospital Munich Schwabing, Munich, Deutschland
,
D. Reber
10   Municipal Hospital Munich Schwabing, Munich, Deutschland
,
B. Donner
11   University Children's Hospital of Basel, Basel, Switzerland
,
C. Hart
12   University of Bonn, Bonn, Deutschland
,
I. O. Komazec
13   Medical University of Innsbruck, Innsbruck, Austria
,
S. Rupp
14   University of Giessen and Marburg, Giessen, Deutschland
,
A. Hahn
15   University of Giessen, Giessen, Deutschland
,
A. Hanser
16   University Hospital Tübingen, Eberhard-Karls University Tübingen, Tübingen, Deutschland
,
J. M. Draaisma
17   Radboud University Medical Center, Nijmegen, Netherlands
,
C. F.E. Ten
17   Radboud University Medical Center, Nijmegen, Netherlands
,
A. Mussa
18   University of Torino, Torino, Italy
,
G. B. Ferrero
18   University of Torino, Torino, Italy
,
L. Vaujois
19   Université de Laval, Quebec, Canada
,
M. J. Raboisson
20   Université de Montréal, Montreal, Canada
,
C. Marquis
20   Université de Montréal, Montreal, Canada
,
Y. Théoret
20   Université de Montréal, Montreal, Canada
,
S. Bogarapu
21   University of Illinois College of Medicine, Peoria, United States
,
A. Dancea
22   McGill University Health Center, Montreal, Canada
,
H. M. Moller
23   Aarhus University Hospital, Copenhagen, Denmark
,
M. Kemna
24   Seattle Children´s Hospital, Seattle, United States
,
J. P. Kaski
3   Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, London, United Kingdom
,
B. D. Gelb
25   Icahn School of Medicine at Mount Sinai, New York, United States
,
G. Andelfinger
20   Université de Montréal, Montreal, Canada
› Author Affiliations

Background: To evaluate the benefit of mutation-specific small molecule inhibitors of target of rapamycin (mTORi) or MAPK kinase (MEKi) in RAS-CM patients with severe pediatric-onset cardiomyopathy associated with distinct germline mutations in RAS/mitogen-activated protein kinase (MAPK) pathway (RAS-CM).

Method: Retrospective case–control analysis on 33 children with progressive RAS-CM receiving off-label or compassionate use mTORi and/or MEKi in addition to standard therapies (“treatment group”) and 40 age-, gender-, genotype- and disease-matched natural history patients (“control group”) in 21 European, North American, and British centers.

Results: Over a follow-up period of 3,200 patient-months, 67% of critically ill patients presenting in severe heart failure survived in the treatment versus none in the control group (p = 0.013). Transplant-free survival without undergoing surgical outflow tract resection was 79% in the treatment compared to 20% in the controls (p < 0.001). From baseline to last follow-up time point, there was a greater decrease in heart failure classification and myocardial wall thickness Z-score measured on echocardiography in treatment compared to control cases (median [IQR] change in Ross classification −2 [−2; −1] vs. −1 [−1.5; −0.5], p = 0.024; and in myocardial wall thickness −1.2 [−2.5; −0.1] vs. −0.7 [−0.9; 0.5], p = 0.027). Skin and mucous membranes were the most common organs affected by side effects, requiring cessation or reduction of therapy in 27% of patients. No life-threatening adverse events related to mTORi or MEKi were observed.

Conclusion: Selected RASopathy patients may benefit from novel mechanism-informed therapeutics targeting the RAS/MAPK pathway. Clinical trials are needed to substantiate the findings reported in this retrospective case-control analysis.



Publication History

Article published online:
28 January 2023

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