{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:49:52Z","timestamp":1787161792896,"version":"build-2736575974"},"reference-count":69,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K\u201008\u2010HL074290"],"award-info":[{"award-number":["K\u201008\u2010HL074290"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010HL66034"],"award-info":[{"award-number":["R01\u2010HL66034"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"\n Abstract<\/jats:title>\n \n Chronic coronary artery stenosis can lead to regional myocardial dysfunction in the absence of myocardial infarction by repetitive stunning, hibernation or both. The molecular mechanisms underlying repetitive stunning\u2010associated myocardial dysfunction are not clear. We used non\u2010targeted metabolomics to elucidate responses to chronically stunned myocardium in a canine model with and without \u03b2\u2010adrenergic blockade treatment. After development of left ventricular systolic dysfunction induced by ameroid constrictors on the coronary arteries, animals were randomized to 3\u00a0months of placebo, metoprolol or carvedilol. We compared these two \u03b2\u2010blockers with their different \u03b2\u2010adrenergic selectivities on myocardial function, perfusion and metabolic pathways involved in tissue undergoing chronic stunning. Control animals underwent sham surgery. Dysfunction in stunned myocardium was associated with reduced fatty acid oxidation and enhanced ketogenic amino acid metabolism, together with alterations in mitochondrial membrane phospholipid composition. These changes were consistent with impaired mitochondrial function and were linked to reduced nitric oxide and peroxisome proliferator\u2010activated receptor signalling, resulting in a decline in adenosine monophosphate\u2010activated protein kinase. Mitochondrial changes were ameliorated by carvedilol more than metoprolol, and improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. In summary, repetitive myocardial stunning commonly seen in chronic multivessel coronary artery disease is associated with adverse metabolic remodelling linked to mitochondrial dysfunction and specific signalling pathways. These changes are reversed by \u03b2\u2010blockers, with the non\u2010selective inhibitor having a more favourable impact. This is the first investigation to demonstrate that \u03b2\u2010blockade\u2010associated improvement of ventricular function in chronic myocardial stunning is associated with restoration of mitochondrial function.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n The mechanisms responsible for the metabolic changes associated with repetitive myocardial stunning seen in chronic multivessel coronary artery disease have not been fully investigated.<\/jats:p>\n <\/jats:list-item>\n \n \n In a canine model of repetitive myocardial stunning, we showed that carvedilol, a non\u2010selective \u03b2\u2010receptor blocker, ameliorated adverse metabolic remodelling compared to metoprolol, a selective \u03b2\n 1<\/jats:sub>\n \u2010receptor blocker, by improving nitric oxide synthase and adenosine monophosphate protein kinase function, enhancing calcium\/calmodulin\u2010dependent protein kinase, probably increasing hydrogen sulphide, and suppressing cyclic\u2010adenosine monophosphate signalling.\n <\/jats:p>\n <\/jats:list-item>\n \n Mitochondrial fatty acid oxidation alterations were ameliorated by carvedilol to a larger extent than metoprolol; this improvement was linked to nitric oxide and possibly hydrogen sulphide signalling.<\/jats:p>\n <\/jats:list-item>\n \n Both \u03b2\u2010blockers improved the cardiac energy imbalance by reducing metabolites in ketogenic amino acid and nucleotide metabolism.<\/jats:p>\n <\/jats:list-item>\n \n These results elucidated why metabolic remodelling with carvedilol is preferable to metoprolol when treating chronic ischaemic left ventricular systolic dysfunction caused by repetitive myocardial stunning.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp285720","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T12:40:31Z","timestamp":1718628031000},"page":"3423-3448","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Metabolomics of repetitive myocardial stunning in chronic multivessel coronary artery stenosis: Effect of non\u2010selective and selective \u03b21\u2010receptor blockers"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3921-0692","authenticated-orcid":false,"given":"D. Elizabeth","family":"Le","sequence":"first","affiliation":[{"name":"Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA"},{"name":"Veterans Affairs Portland Health Care System Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3489-4730","authenticated-orcid":false,"given":"Nabil J.","family":"Alkayed","sequence":"additional","affiliation":[{"name":"Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA"},{"name":"Department of Anesthesiology and Perioperative Medicine Oregon Health and Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Cao","sequence":"additional","affiliation":[{"name":"Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA"},{"name":"Department of Anesthesiology and Perioperative Medicine Oregon Health and Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4786-9363","authenticated-orcid":false,"given":"Natasha N.","family":"Chattergoon","sequence":"additional","affiliation":[{"name":"Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2987-2913","authenticated-orcid":false,"given":"Manuel","family":"Garcia\u2010Jaramillo","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Toxicology Oregon State University Corvallis OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5561-4785","authenticated-orcid":false,"given":"Kent","family":"Thornburg","sequence":"additional","affiliation":[{"name":"Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjiv","family":"Kaul","sequence":"additional","affiliation":[{"name":"Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666171006151408"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-5299.2002.00718.x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00011.2013"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/HCG.0000000000000032"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01270569"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12030354"},{"issue":"9","key":"e_1_2_6_8_1","first-page":"1","article-title":"Organization of GC\/MS and LC\/MS metabolomics data into chemical libraries","volume":"2","author":"DeHaven C. D.","year":"2010","journal-title":"Journal of Cheminform"},{"key":"e_1_2_6_9_1","volume-title":"Metabolomics","author":"DeHaven C. D.","year":"2012"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/ac901536h"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12475"},{"key":"e_1_2_6_12_1","first-page":"H446","article-title":"A canine model of chronic ischemic cardiomyopathy: Characterization of regional flow\u2010function relations","volume":"276","author":"Firoozan S.","year":"1999","journal-title":"American Journal of Physiology"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-014-1237-z"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115634109"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199219001-00027"},{"key":"e_1_2_6_16_1","first-page":"221","article-title":"Apoptosis and the heart","volume":"6","author":"Feuerstein G. Z.","year":"1996","journal-title":"Journal of Basic and Applied Mycology"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2018.01.017"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1159\/000138836"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5701172"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.05.009"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.05.007"},{"issue":"1","key":"e_1_2_6_23_1","first-page":"52","article-title":"Blood flow measurements with radionuclide\u2010labeled","volume":"20","author":"Heyman M. A.","year":"1977","journal-title":"Progress in Cardiovascular Diseases"},{"key":"e_1_2_6_24_1","first-page":"52","article-title":"Blood flow measurements with radionuclide\u2010labeled","volume":"20","author":"Heyman M. A.","year":"1997","journal-title":"Progress in Cardiovascular Diseases"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20060307"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.4161\/chan.23006"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503824200"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1474"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.81"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.692893"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-3084(97)00095-9"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2020.10.004"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.29.17513"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(96)00013-6"},{"key":"e_1_2_6_35_1","first-page":"823","article-title":"Targeted metabolomic profiling of plasma and survival in heart failure patients","volume":"5","author":"Lanfear D. E.","year":"2017","journal-title":"Journal of the American College of Cardiology CHF"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-013-0384-7"},{"key":"e_1_2_6_37_1","first-page":"1","article-title":"AMPK\u2010dependent metabolic regulation by PPAR agonists","volume":"2010","author":"Lee W. H.","year":"2010","journal-title":"Peroxisome Proliferator Activated Receptor Research"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.10.035"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318241"},{"key":"e_1_2_6_40_1","first-page":"129","article-title":"Carvedilol a new beta adrenoreceptor blocker and free radical scavenger, attenuates myocardial\u2010perfusion injury in hypercholesterolemic rabbits","volume":"277","author":"Ma X. L.","year":"1996","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(01)01471-1"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311002"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81574-3"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623309336152"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1071-9164(98)90252-4"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab382"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1067\/mje.2001.113232"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13800-7"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.277.2.H643"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddmec.2010.07.005"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.021310"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2558"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0894-7317(14)80100-4"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1530509100"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12369"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/RES.0000000000000097"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-08-1071"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.12010"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.2174\/157016112798829760"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1177\/2042018810381066"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.87.5.1513"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801498R"},{"issue":"12","key":"e_1_2_6_63_1","article-title":"Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling","volume":"11","author":"Voros G.","year":"2019","journal-title":"Circulation: Heart Failure"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.20.2441"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.06.005"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1159\/000481758"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(99)00253-2"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01186"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120849"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15180"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP285720","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T04:04:43Z","timestamp":1721189083000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP285720"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,17]]},"references-count":69,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1113\/JP285720"],"URL":"https:\/\/doi.org\/10.1113\/jp285720","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,17]]},"assertion":[{"value":"2023-09-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}