{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:16:38Z","timestamp":1779164198486,"version":"3.51.4"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,2,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">PDE2 (phosphodiesterase 2) is upregulated in human heart failure. Cardiac PDE2\u2010transgenic mice are protected against contractile dysfunction and arrhythmias in heart failure but whether an acute elevation of PDE2 could be of therapeutic value remains elusive. This hypothesis was tested using cardiac PDE2 gene transfer in preclinical models of heart failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">C57BL\/6 male mice were injected with serotype 9 adeno\u2010associated viruses encoding for PDE2A. This led to a \u224810\u2010fold rise of PDE2A protein levels that affected neither cardiac structure nor function in healthy mice. Two weeks after inoculation with serotype 9 adeno\u2010associated viruses, mice were implanted with minipumps delivering either NaCl, isoproterenol (60\u2009mg\/kg per day), or isoproterenol and phenylephrine (30\u2009mg\/kg per day each) for 2\u2009weeks. In mice injected with serotype 9 adeno\u2010associated viruses encoding for LUC (luciferase), isoproterenol or isoproterenol+phenylephrine infusion induced left ventricular hypertrophy, decreased ejection fraction unveiled by echocardiography, and promoted fibrosis and apoptosis assessed by Masson's trichrome and Tunel, respectively. Furthermore, inotropic responses to isoproterenol of ventricular cardiomyocytes isolated from isoproterenol+phenylephrine\u2010LUC mice loaded with 1\u2009\u03bcmol\/L Fura\u20102AM and stimulated at 1\u2009Hz to record calcium transients and sarcomere shortening were dampened. Spontaneous calcium waves at the cellular level were promoted as well as ventricular arrhythmias evoked in\u00a0vivo by catheter\u2010mediated ventricular pacing after isoproterenol (1.5\u2009mg\/kg) and atropine (1\u2009mg\/kg) injection. However, increased PDE2A blunted these adverse outcomes evoked by sympathomimetic amines.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Cardiac gene therapy with PDE2A limits left ventricle remodeling, dysfunction, and arrhythmias evoked by catecholamines, providing evidence that increasing PDE2A activity acutely could prevent progression toward heart failure.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.037343","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T10:15:06Z","timestamp":1738577706000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart\u00a0Failure"],"prefix":"10.1161","volume":"14","author":[{"given":"Rima","family":"Kamel","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-9512","authenticated-orcid":false,"given":"Aur\u00e9lia","family":"Bourcier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean Piero","family":"Margaria","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"},{"name":"Molecular Biotechnology Center \u201cGuido Tarone\u201d, Department of Molecular Biotechnology and Health Sciences University of Torino Italy"},{"name":"Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology Universit\u00e0 Vita\u2010Salute San Raffaele Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentin","family":"Jin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1709-2333","authenticated-orcid":false,"given":"Audrey","family":"Varin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5626-6836","authenticated-orcid":false,"given":"Agn\u00e8s","family":"Hivonnait","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CNRS, INSERM, l\u2019institut du thorax Nantes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-7232","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Mercier\u2010Nom\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm US31, CNRS UMS3679, IPSIT Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2895-7173","authenticated-orcid":false,"given":"Delphine","family":"Mika","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-5296","authenticated-orcid":false,"given":"Alessandra","family":"Ghigo","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology Center \u201cGuido Tarone\u201d, Department of Molecular Biotechnology and Health Sciences University of Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5057-0998","authenticated-orcid":false,"given":"Flavien","family":"Charpentier","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CNRS, INSERM, l\u2019institut du thorax Nantes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5971-1235","authenticated-orcid":false,"given":"Vincent","family":"Algalarrondo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-6024","authenticated-orcid":false,"given":"Emilio","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology Center \u201cGuido Tarone\u201d, Department of Molecular Biotechnology and Health Sciences University of Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-9865","authenticated-orcid":false,"given":"Rodolphe","family":"Fischmeister","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4046-4171","authenticated-orcid":false,"given":"Gr\u00e9goire","family":"Vandecasteele","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5168-0606","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Leroy","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR\u2010S 1180 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-060121-041653"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1947-z"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198409273111303"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw128"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199605233342101"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2016.25"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)04440-2"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020265"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.03.563"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00756-z"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119460"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174077"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt193"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000200178.34179.93"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.042573"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2019.05.025"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.197947"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.05.057"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310069"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192374899"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.06.020"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.305892"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.322031"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.21374"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1800996115"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.76"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000160853.19867.61"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.274.3.H747"},{"key":"e_1_3_2_30_2","doi-asserted-by":"crossref","unstructured":"Wobbrock JO Findlater L Gergle D Higgins JJ. The aligned rank transform for nonparametric factorial analyses using only anova procedures. CHI '11: Proceedings of the SIGCHI Conference on Human Factors in Computing Systems. 2011:143\u2013146.","DOI":"10.1145\/1978942.1978963"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2008.123"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.300308"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.307157"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-022-00920-z"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094816"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000165128.39715.87"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(85)90460-0"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199111213252103"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44747"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvae094"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.65.3.657"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/415206a"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7965"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.599241"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.09.005"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.060210"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)68134-2"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.792798"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409077"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40001-022-00880-z"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add5799"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.07.006"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00778a018"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.037343","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T11:02:34Z","timestamp":1738666954000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.037343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,4]]},"references-count":53,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,2,4]]}},"alternative-id":["10.1161\/JAHA.124.037343"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.037343","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,4]]},"assertion":[{"value":"2024-08-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e037343"}}