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Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a \u2018foetal gene programme\u2019 contributing to pathological cardiac remodelling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>In this study, Hand2F\/F and MCM- Hand2F\/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived haemodynamic parameters as well as molecular remodelling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control-banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV pressure-overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass, and impaired cardiac function. RNA-sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressu re overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.<\/jats:p><\/jats:sec>","DOI":"10.1093\/cvr\/cvab299","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T19:15:42Z","timestamp":1631733342000},"page":"2688-2702","source":"Crossref","is-referenced-by-count":9,"title":["The adult heart requires baseline expression of the transcription factor Hand2 to withstand right ventricular pressure overload"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7017-2487","authenticated-orcid":false,"given":"Raquel F","family":"Videira","sequence":"first","affiliation":[{"name":"Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The 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Netherlands"},{"name":"Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1067-2404","authenticated-orcid":false,"given":"Ella M","family":"Poels","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-4771","authenticated-orcid":false,"given":"Jordy M M","family":"Kocken","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"},{"name":"Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1052-7490","authenticated-orcid":false,"given":"Cristobal","family":"Dos Remedios","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, University of Sidney, Sidney, NSW 2006 and Molecular Cardiology Group at Victor Chang Cardiac Research institute , Darlinghurst, NSW 2010 , Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-6785","authenticated-orcid":false,"given":"Pedro","family":"Mendes-Ferreira","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto , Alameda professor Hern\u00e2ni Monteiro, 4200-319 Porto , Portugal"}]},{"given":"Kees W","family":"Van De Kolk","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, The Central Animal Facility , Hanzeplein 1, 9713 GZ Groningen , The Netherlands"},{"name":"University Medical Center Groningen, Gronsai (Groningen Small Animal Imaging Facility) , Hanzeplein 1, 9713 GZ Groningen , The Netherlands"}]},{"given":"Gideon J","family":"Du Marchie Sarvaas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, Center for Congenital Heart Diseases , Hanzeplein 1, 9713 GZ Groningen , The Netherlands"}]},{"given":"Andr\u00e9","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto , Alameda professor Hern\u00e2ni Monteiro, 4200-319 Porto , Portugal"}]},{"given":"Aida","family":"Lluci\u00e0-Valldeperas","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, PHEniX laboratory, Amsterdam Cardiovascular Sciences , De Boelelaan 1108, 1081HZ Amsterdam , The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-4245","authenticated-orcid":false,"given":"Dian aS","family":"Nascimento","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto , Rua Alfredo Allen 208, 4200-135 Porto , Portugal"},{"name":"INEB\u2014Instituto de Engenharia Biom\u00e9dica, Universidade do Porto , Rua Alfredo Allen 208, 4200-135 Porto , Portugal"},{"name":"ICBAS\u2014Instituto de Cie\u0302ncias Biom\u00e9dicas de Abel Salazar, Universidade do Porto , R. Jorge de Viterbo Ferreira 228, 4050-313 Porto , Portugal"}]},{"given":"Leon J","family":"De Windt","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"},{"name":"Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"}]},{"given":"Frances S","family":"De Man","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, PHEniX laboratory, Amsterdam Cardiovascular Sciences , De Boelelaan 1108, 1081HZ Amsterdam , The Netherlands"}]},{"given":"In\u00eas","family":"Falc\u00e3o-Pires","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto , Alameda professor Hern\u00e2ni Monteiro, 4200-319 Porto , Portugal"}]},{"given":"Rolf M F","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, Center for Congenital Heart Diseases , Hanzeplein 1, 9713 GZ Groningen , The Netherlands"}]},{"given":"Paula A","family":"da Costa Martins","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"},{"name":"Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University , Universiteitssingel 50, 6200 MD Maastricht , The Netherlands"},{"name":"Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto , Alameda professor Hern\u00e2ni Monteiro, 4200-319 Porto , Portugal"}]}],"member":"286","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"2022092120253929400_cvab299-B1","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.jacc.2013.11.053","article-title":"The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries","volume":"63","author":"Ambrosy","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2022092120253929400_cvab299-B2","first-page":"124","article-title":"Real-world, long-term survival of incident patients with pulmonary arterial hypertension","volume":"23","author":"Marques-Alves","year":"2017","journal-title":"J Pulmonol"},{"key":"2022092120253929400_cvab299-B3","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.jacc.2010.08.647","article-title":"The forgotten left ventricle in right ventricular pressure overload","volume":"57","author":"Dell\u2019Italia","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"2022092120253929400_cvab299-B4","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nrcardio.2013.12","article-title":"Assessment and treatment of right ventricular failure","volume":"10","author":"Simon","year":"2013","journal-title":"Nat Rev Cardiol"},{"key":"2022092120253929400_cvab299-B5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.cellbio.23.090506.123331","article-title":"Heart field: from mesoderm to heart tube","volume":"23","author":"Abu-Issa","year":"2007","journal-title":"Annu Rev Cell Dev Biol"},{"key":"2022092120253929400_cvab299-B6","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nrg1710","article-title":"Building the mammalian heart from two sources of myocardial cells","volume":"6","author":"Buckingham","year":"2005","journal-title":"Nat Rev Genet"},{"key":"2022092120253929400_cvab299-B7","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.cell.2006.11.031","article-title":"A common progenitor at the heart of development","volume":"127","author":"Garry","year":"2006","journal-title":"Cell"},{"key":"2022092120253929400_cvab299-B8","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S1534-5807(04)00133-9","article-title":"The clonal origin of myocardial cells in different regions of the embryonic mouse heart","volume":"6","author":"Meilhac","year":"2004","journal-title":"Dev Cell"},{"key":"2022092120253929400_cvab299-B9","first-page":"195","article-title":"TBX5: A Key Regulator of Heart Development. 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