{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:19:33Z","timestamp":1791976773533,"version":"4.4.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,10,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71\u00b16 years; ejection fraction, 63\u00b15%) and 36 controls without a diagnosis of HFpEF (mean age, 74\u00b17 years; ejection fraction, 61.5\u00b18%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Compared with controls, there was an enrichment of\n                      <jats:italic>TET2<\/jats:italic>\n                      -mediated CH in the HFpEF patient cohort (12% versus 0%, respectively;\n                      <jats:italic>P<\/jats:italic>\n                      =0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E\/e\u2032 (14.9 versus 11.7, respectively;\n                      <jats:italic>P<\/jats:italic>\n                      =0.0096) and E\/A (1.69 versus 0.89, respectively;\n                      <jats:italic>P<\/jats:italic>\n                      =0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age \u226570 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06;\n                      <jats:italic>P<\/jats:italic>\n                      =0.042) compared with patients with HFpEF and an age \u226570 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with\n                      <jats:italic>Tet2<\/jats:italic>\n                      \u2013wild-type or\n                      <jats:italic>Tet2<\/jats:italic>\n                      -deficient bone marrow and were subsequently subjected to a high-fat diet\/L-NAME (N\n                      <jats:sub>\u03c9<\/jats:sub>\n                      -nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of\n                      <jats:italic>Tet2<\/jats:italic>\n                      -CH exacerbated cardiac hypertrophy by heart weight\/tibia length and cardiomyocyte size, diastolic dysfunction by E\/e\u2032 and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the\n                      <jats:italic>Tet2<\/jats:italic>\n                      \u2013wild-type condition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of\n                      <jats:italic>Tet2<\/jats:italic>\n                      -mediated CH displays greater features of HFpEF.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.123.064170","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T05:01:10Z","timestamp":1694149270000},"page":"1165-1178","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":73,"title":["Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction"],"prefix":"10.1161","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9705-5785","authenticated-orcid":true,"given":"Jesse D.","family":"Cochran","sequence":"first","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."},{"name":"Medical Scientist Training Program (J.D.C.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimitsu","family":"Yura","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1512-6242","authenticated-orcid":true,"given":"Mark C.","family":"Thel","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0720-3164","authenticated-orcid":true,"given":"Heather","family":"Doviak","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5413-7238","authenticated-orcid":true,"given":"Ariel H.","family":"Polizio","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Arai","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Arai","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Horitani","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5609-4622","authenticated-orcid":true,"given":"Eunbee","family":"Park","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9058-0245","authenticated-orcid":true,"given":"Nicholas W.","family":"Chavkin","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupreet","family":"Kour","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3361-0839","authenticated-orcid":true,"given":"Soichi","family":"Sano","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Mosaicism, National Cerebral and Cardiovascular Center, Osaka, Japan (S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0907-6410","authenticated-orcid":true,"given":"Nitin","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Wugen Inc., St. Louis, MO (N.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7338-3060","authenticated-orcid":true,"given":"Megan","family":"Evans","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0554-4851","authenticated-orcid":true,"given":"Mahalia","family":"Huba","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia Martinez","family":"Naya","sequence":"additional","affiliation":[{"name":"Mission Bio, South San Francisco, CA (N.M.N., T.E.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8171-1098","authenticated-orcid":true,"given":"Hanna","family":"Sun","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1936-204X","authenticated-orcid":true,"given":"Young Ho","family":"Ban","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7116-0130","authenticated-orcid":true,"given":"Karen K.","family":"Hirschi","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."},{"name":"Department of Cell Biology (K.K.H.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1588-4019","authenticated-orcid":true,"given":"Stefano","family":"Toldo","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1930-785X","authenticated-orcid":true,"given":"Antonio","family":"Abbate","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, Division of Cardiovascular Medicine (J.D.C., Y.Y. [now with the Department of Cardiovascular Medicine, Nagoya University School of Medicine, Japan], M.C.T., H.D., A.H.P., Yuka Arai, Yohei Arai, K.H. [now with the Department of Internal Medicine II, Kansai Medical University, Osaka, Japan], E.P., N.W.C., A.K., M.E., M.H., K.K.H., H.S., Y.H.B., S.T., A.A., K.W.), University of Virginia School of Medicine, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3245-7561","authenticated-orcid":true,"given":"Todd E.","family":"Druley","sequence":"additional","affiliation":[{"name":"Mission Bio, South San Francisco, CA (N.M.N., T.E.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6424-4413","authenticated-orcid":true,"given":"Frederick L.","family":"Ruberg","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine, Department of Medicine and Amyloidosis Center, Boston University Chobanian &amp; Avedisian School of Medicine\/Boston Medical Center, MA (F.L.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5400-5008","authenticated-orcid":true,"given":"Mathew S.","family":"Maurer","sequence":"additional","affiliation":[{"name":"Seymour, Paul, and Gloria Milstein Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY (M.S.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2724-4086","authenticated-orcid":true,"given":"Justin A.","family":"Ezekowitz","sequence":"additional","affiliation":[{"name":"Alberta Heart Failure Etiology and Analysis Research Team (HEART) project (J.A.E., J.R.B.D.), Canada."},{"name":"Department of Medicine, Division of Cardiology (J.A.E.), University of Alberta, Edmonton, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-2884","authenticated-orcid":true,"given":"Jason R.B.","family":"Dyck","sequence":"additional","affiliation":[{"name":"Alberta Heart Failure Etiology and Analysis Research Team (HEART) project (J.A.E., J.R.B.D.), Canada."},{"name":"Cardiovascular Research Centre, Department of Pediatrics (J.R.B.D.), University of Alberta, Edmonton, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-2276","authenticated-orcid":true,"given":"Kenneth","family":"Walsh","sequence":"additional","affiliation":[{"name":"Robert M. 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