{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T18:41:53Z","timestamp":1788028913723,"version":"build-2784847793"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":454,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T00:00:00Z","timestamp":1732147200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["81X2600253"],"award-info":[{"award-number":["81X2600253"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["81Z0600207"],"award-info":[{"award-number":["81Z0600207"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Deutsche Herzstiftung e.V."},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["81X2600253"],"award-info":[{"award-number":["81X2600253"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["81Z0600207"],"award-info":[{"award-number":["81Z0600207"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>No curative treatment is available for RASopathy-associated childhood-onset hypertrophic cardiomyopathy (RAS-CM). Preclinical data and individual reports suggest a beneficial effect of small molecules targeting the RAS\u2013mitogen-activated protein (MAP) kinase (MAPK) pathway in severely affected RAS-CM patients. The aim of this study was to evaluate the biophysical effects of trametinib, rapamycin and dasatinib on cultivated myocardial tissue slices of a paediatric RAS-CM patient using biomimetic cultivation chambers (BMCCs) and to correlate the findings with clinical data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Contracting right ventricular (RV) tissue slices were prepared from resected myocardium, cultivated in BMCCs and treated with distinct molecules directly and indirectly targeting the RAS\u2013MAPK pathway (trametinib, rapamycin and dasatinib) or dimethyl sulfoxide (DMSO). Tissue biophysical properties were assessed using electrical stimulation protocols. Contractile function, force\u2013frequency relationship and post-pause potentiation were compared before and after treatment. These parameters correlated to L-type Ca2+ channel function and sarcoplasmic Ca2+ loading.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In vivo, off-label treatment with MAPK kinase (MEK) inhibitor trametinib of a child with severe RAS-CM resulted in a modest reduction of RV outflow tract (RVOT) obstruction (RVOT 151 to 122 mmHg after 11 weeks) and improved diastolic function (E\/A 0.68 to 1.09 after 11 weeks) and myocardial strain [RV global radial strain (RV-GRS) 25.94 to 42.76; RV global circumferential strain (RV-GCS) \u221215.26 to \u221218.61; and RV global longitudinal strain (RV-GLS) \u221210.31 to \u221216.78 at 11 weeks], as determined by echocardiography and cardiac magnetic resonance tomography. In cultivated RV myocardial tissue slices, contraction force decreased after addition of trametinib and rapamycin but not after addition of DMSO and dasatinib. Improvement of Ca2+ handling, as depicted by a more positive force\u2013frequency relationship and enhanced post-pause potentiation (31.2%), was noted in the trametinib-treated slice. The increase in post-pause potentiation was less pronounced in rapamycin-treated (26%) and absent in dasatinib-treated (&amp;lt;1%) slices.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Ex vivo analysis of cultivated and electrically stimulated RV myocardial tissue slices of a patient with RAS-CM showed decreased contractility and improved sarcoplasmic reticulum function after addition of trametinib and in part after addition of rapamycin, but not after addition of dasatinib.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.15173","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T01:41:14Z","timestamp":1732239674000},"page":"2321-2334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Trametinib Alters Contractility of Paediatric Noonan Syndrome-Associated Hypertrophic Myocardial Tissue Slices"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9715-2005","authenticated-orcid":false,"given":"Jules","family":"Hamers","sequence":"first","affiliation":[{"name":"Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital of Munich, LMU Munich , Munich ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA) , Munich ,","place":["Germany"]},{"name":"Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU), LMU Munich , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-7760","authenticated-orcid":false,"given":"Payel","family":"Sen","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital of Munich, LMU Munich , Munich ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA) , Munich ,","place":["Germany"]},{"name":"Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU), LMU Munich , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarala Raj","family":"Murthi","sequence":"additional","affiliation":[{"name":"Department of Congenital Heart Defects and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich School of Medicine and Health , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Papanakli","sequence":"additional","affiliation":[{"name":"Department of Congenital Heart Defects and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich School of Medicine and Health , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"von Stumm","sequence":"additional","affiliation":[{"name":"Department of Congenital and Pediatric Heart Surgery, German Heart Centre Munich, Technical University of Munich, School of Medicine and Health , Munich ,","place":["Germany"]},{"name":"Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, LMU Munich , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Baessato","sequence":"additional","affiliation":[{"name":"Department of Congenital Heart Defects and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich School of Medicine and Health , Munich ,","place":["Germany"]},{"name":"Department of Cardiology, San Maurizio Regional Hospital , Bolzano ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Cleuziou","sequence":"additional","affiliation":[{"name":"Department of Congenital and Pediatric Heart Surgery, German Heart Centre Munich, Technical University of Munich, School of Medicine and Health , Munich ,","place":["Germany"]},{"name":"Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, LMU Munich , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Meierhofer","sequence":"additional","affiliation":[{"name":"Department of Congenital Heart Defects and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich School of Medicine and Health , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ewert","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research (DZHK), Partner 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