{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:51:40Z","timestamp":1792547500948,"version":"4.5.0"},"reference-count":113,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in\u00a0vitro and in\u00a0vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR\u2010377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in\u00a0vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial\u2010dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin\u2010independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.<\/jats:p>","DOI":"10.1111\/apha.14199","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T07:37:33Z","timestamp":1720597053000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations"],"prefix":"10.1111","volume":"240","author":[{"given":"Tanawat","family":"Attachaipanich","sequence":"first","affiliation":[{"name":"Cardiac Electrophysiology Research and Training Center, Faculty of Medicine Chiang Mai University  Chiang Mai Thailand"},{"name":"Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University  Chiang Mai Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-7052","authenticated-orcid":false,"given":"Siriporn C.","family":"Chattipakorn","sequence":"additional","affiliation":[{"name":"Cardiac Electrophysiology Research and Training Center, Faculty of Medicine Chiang Mai University  Chiang Mai Thailand"},{"name":"Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University  Chiang Mai Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3026-718X","authenticated-orcid":false,"given":"Nipon","family":"Chattipakorn","sequence":"additional","affiliation":[{"name":"Cardiac Electrophysiology Research and Training Center, Faculty of Medicine Chiang Mai University  Chiang Mai Thailand"},{"name":"Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University  Chiang Mai Thailand"},{"name":"Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine Chiang Mai University  Chiang Mai Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.019655"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.34067\/KID.0002472021"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00262.2020"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000150332.42276.69"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(78)91970-0"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199410273311702"},{"issue":"1","key":"e_1_2_13_8_1","first-page":"52","article-title":"Cyclosporin a induces cardiomyocyte injury through calcium\u2010sensing receptor\u2010mediated calcium overload","volume":"66","author":"Tang J","year":"2011","journal-title":"Pharmazie"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-012-1336-5"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2015.11.012"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10216"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/15216540600957438"},{"issue":"2","key":"e_1_2_13_13_1","first-page":"141","article-title":"Cardiovascular effects of cyclosporin treatment in an experimental model","volume":"21","author":"Tavares P","year":"2002","journal-title":"Rev Port Cardiol"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2008.00651.x"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3109\/0886022X.2012.656563"},{"issue":"12","key":"e_1_2_13_16_1","first-page":"968","article-title":"Involvement of the calcium\u2010sensing receptor in cyclosporin A\u2010induced cardiomyocyte apoptosis in rats","volume":"66","author":"Zhao Y","year":"2011","journal-title":"Pharmazie"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.4203"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2007.06.096"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2006.00368.x"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2005.04.020"},{"issue":"3","key":"e_1_2_13_21_1","first-page":"761","article-title":"Alterations induced by cyclosporine a in myocardial fibers and extracellular matrix in rat","volume":"17","author":"Rezzani R","year":"2002","journal-title":"Histol Histopathol"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-023-08506-1"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/jfbc.13435"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3109\/15376516.2014.963773"},{"issue":"4","key":"e_1_2_13_25_1","first-page":"439","article-title":"Pomegranate seed oil protects against tacrolimus\u2010induced toxicity in the heart and kidney by modulation of oxidative stress in rats","volume":"12","author":"Hosseini A","year":"2022","journal-title":"Avicenna J Phytomed"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370215616709"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2009.06.007"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)00898-6"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2001.1413"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.3317\/jraas.2007.009"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.20.15239"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81573-1"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.10.937"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00052-3"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(01)01387-5"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2018.02.017"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.87.4.1368"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.054317"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5273(91)90262-N"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199806000-00005"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12050"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/phy2.174"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.84.6.735"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.20.2431"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.24.2863"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.18.2134"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/2578"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.84.6.722"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.84.6.729"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008071200"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.1.360"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.18.2269"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.16.1996"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2893"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.6.H2115"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01051.2003"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.281.5383.1690"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1113"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13893"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11093"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000109415.17511.18"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.509bm.x"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.275.6.H2041"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.3.H886"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00258.2006"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.79.6.1110"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1997.sp022025"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00661-2"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00014.2006"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.199828"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(99)00396-3"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025339819051"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq028"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.11.008"},{"key":"e_1_2_13_75_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0163com"},{"key":"e_1_2_13_76_1","doi-asserted-by":"publisher","DOI":"10.1177\/0748233712456065"},{"key":"e_1_2_13_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep27915"},{"key":"e_1_2_13_78_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.23.6.957"},{"key":"e_1_2_13_79_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.90.6.3018"},{"key":"e_1_2_13_80_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1998.00014.x"},{"key":"e_1_2_13_81_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.32.5.849"},{"key":"e_1_2_13_82_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.26.6.932"},{"issue":"6","key":"e_1_2_13_83_1","first-page":"1469","article-title":"Calcium blockers inhibit cyclosporine A\u2010induced hyperreactivity of vascular smooth muscle cells","volume":"5","author":"Grzesk G","year":"2012","journal-title":"Mol Med Rep"},{"key":"e_1_2_13_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2015.08.012"},{"key":"e_1_2_13_85_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1999.00366.x"},{"key":"e_1_2_13_86_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.33.1.130"},{"key":"e_1_2_13_87_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr304"},{"key":"e_1_2_13_88_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.602532"},{"key":"e_1_2_13_89_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1608859113"},{"key":"e_1_2_13_90_1","doi-asserted-by":"publisher","DOI":"10.5301\/jn.5000174"},{"key":"e_1_2_13_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(88)80331-0"},{"key":"e_1_2_13_92_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.23.8222"},{"key":"e_1_2_13_93_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2497"},{"key":"e_1_2_13_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)90011-X"},{"key":"e_1_2_13_95_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-200209270-00015"},{"issue":"2","key":"e_1_2_13_96_1","first-page":"116","article-title":"Tacrolimus related hypertrophic cardiomyopathy in liver transplant recipients","volume":"13","author":"Dehghani SM","year":"2010","journal-title":"Arch Iran Med"},{"key":"e_1_2_13_97_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-200005150-00039"},{"key":"e_1_2_13_98_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-3046.2001.00052.x"},{"issue":"3","key":"e_1_2_13_99_1","first-page":"180","article-title":"Effects of cyclosporine on the transplanted human heart","volume":"6","author":"Stovin PG","year":"1987","journal-title":"J Heart Transplant"},{"key":"e_1_2_13_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2021.01.007"},{"key":"e_1_2_13_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2005.02.011"},{"key":"e_1_2_13_102_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bmt.1703304"},{"key":"e_1_2_13_103_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10396-019-00990-y"},{"key":"e_1_2_13_104_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.10299"},{"key":"e_1_2_13_105_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2019.01.041"},{"key":"e_1_2_13_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5223(19)36181-1"},{"issue":"2","key":"e_1_2_13_107_1","first-page":"567","article-title":"Invasive haemodynamics in de novo everolimus vs. calcineurin inhibitor heart transplant recipients. ESC","volume":"7","author":"Bergh N","year":"2020","journal-title":"Heart Fail"},{"key":"e_1_2_13_108_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12809"},{"key":"e_1_2_13_109_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5223(19)36981-8"},{"key":"e_1_2_13_110_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1053-2498(01)00471-5"},{"issue":"5","key":"e_1_2_13_111_1","first-page":"100","article-title":"Prevalence of accelerated coronary artery disease in heart transplant survivors. Comparison of cyclosporine and azathioprine regimens","volume":"80","author":"Gao SZ","year":"1989","journal-title":"Circulation"},{"key":"e_1_2_13_112_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfh739"},{"key":"e_1_2_13_113_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(99)00631-1"},{"key":"e_1_2_13_114_1","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2012.8"}],"container-title":["Acta Physiologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.14199","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T05:22:56Z","timestamp":1723785776000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apha.14199"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,10]]},"references-count":113,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1111\/apha.14199"],"URL":"https:\/\/doi.org\/10.1111\/apha.14199","archive":["Portico"],"relation":{},"ISSN":["1748-1708","1748-1716"],"issn-type":[{"value":"1748-1708","type":"print"},{"value":"1748-1716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,10]]},"assertion":[{"value":"2024-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14199"}}