{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:17:04Z","timestamp":1784297824748,"version":"3.55.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Heart failure with preserved ejection fraction is proposed to be caused by endothelial dysfunction in cardiac microvessels. Our goal was to identify molecular and cellular mechanisms underlying the development of cardiac microvessel disease and diastolic dysfunction in the setting of type 2 diabetes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We used\n              <jats:italic toggle=\"yes\">Lepr<\/jats:italic>\n              <jats:sup>db\/db<\/jats:sup>\n              (leptin receptor\u2013deficient) female mice as a model of type 2 diabetes and heart failure with preserved ejection fraction and identified Hhipl1 (hedgehog interacting protein-like 1), which encodes for a decoy receptor for HH (hedgehog) ligands as a gene upregulated in the cardiac vascular fraction of diseased mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We then used\n              <jats:italic toggle=\"yes\">Dhh<\/jats:italic>\n              (desert HH)-deficient mice to investigate the functional consequences of impaired HH signaling in the adult heart. We found that\n              <jats:italic toggle=\"yes\">Dhh<\/jats:italic>\n              -deficient mice displayed increased end-diastolic pressure while left ventricular ejection fraction was comparable to that of control mice. This phenotype was associated with a reduced exercise tolerance in the treadmill test, suggesting that\n              <jats:italic toggle=\"yes\">Dhh<\/jats:italic>\n              -deficient mice do present heart failure. At molecular and cellular levels, impaired cardiac relaxation in\n              <jats:italic toggle=\"yes\">Dhh<\/jats:italic>\n              <jats:sup>ECKO<\/jats:sup>\n              mice was associated with a significantly decreased PLN (phospholamban) phosphorylation on Thr17 (threonine 17) and an alteration of sarcomeric shortening ex vivo. Besides, as expected,\n              <jats:italic toggle=\"yes\">Dhh<\/jats:italic>\n              -deficient mice exhibited phenotypic changes in their cardiac microvessels including a prominent prothrombotic phenotype. Importantly, aspirin therapy prevented the occurrence of both diastolic dysfunction and exercise intolerance in these mice. To confirm the critical role of thrombosis in the pathophysiology of diastolic dysfunction, we verified\n              <jats:italic toggle=\"yes\">Lepr<\/jats:italic>\n              <jats:sup>db\/db<\/jats:sup>\n              also displays increased cardiac microvessel thrombosis. Moreover, consistently, with\n              <jats:italic toggle=\"yes\">Dhh<\/jats:italic>\n              -deficient mice, we found that aspirin treatment decreased end-diastolic pressure and improved exercise tolerance in\n              <jats:italic toggle=\"yes\">Lepr<\/jats:italic>\n              <jats:sup>db\/db<\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Altogether, these results demonstrate that microvessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.123.320040","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T05:00:24Z","timestamp":1701320424000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Thrombosis in the Coronary Microvasculature Impairs Cardiac Relaxation and Induces Diastolic Dysfunction"],"prefix":"10.1161","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1221-8280","authenticated-orcid":true,"given":"Paul","family":"Rouault","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1034, Biology of Cardiovascular Diseases, University of Bordeaux, Pessac, France (P.R., S.G., L.C., C.B., N.F., P.A., C.C., A.-P.G., T.C., M.-A.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-7679","authenticated-orcid":true,"given":"Sarah","family":"Guimbal","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1034, Biology of Cardiovascular Diseases, University of Bordeaux, Pessac, France (P.R., S.G., L.C., C.B., N.F., P.A., C.C., A.-P.G., T.C., M.-A.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3515-7190","authenticated-orcid":true,"given":"Lauriane","family":"Cornuault","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1034, Biology of Cardiovascular Diseases, University of Bordeaux, Pessac, France (P.R., S.G., L.C., C.B., N.F., P.A., C.C., A.-P.G., T.C., M.-A.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7547-5719","authenticated-orcid":true,"given":"C\u00e9lia","family":"Bourguignon","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1034, Biology of Cardiovascular Diseases, University of Bordeaux, Pessac, France (P.R., S.G., L.C., C.B., N.F., P.A., C.C., A.-P.G., T.C., 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