{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:38:57Z","timestamp":1760236737595,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan","award":["18590815","21590898"],"award-info":[{"award-number":["18590815","21590898"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The purpose of this study was to evaluate whether heart failure with mildly reduced ejection fraction (HFmrEF) is associated with vascular dysfunction and whether vascular function predicts future deterioration of LVEF in patients with HFmrEF. We evaluated endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID) in 69 patients with HFmrEF and 426 patients without HF and evaluated the future deterioration of LVEF, defined as a decrease in LVEF to &lt;40%, in 39 patients with HFmrEF for up to 3 years. Both FMD and NID were significantly lower in patients with HFmrEF than in patients without HF. We categorized patients into two groups based on low tertiles of NID: a low group (NID of &lt;7.0%) and an intermediate and high group (NID of \u22657.0%). There were significant differences between the Kaplan\u2013Meier curves for the deterioration of LVEF in the two groups (p &lt; 0.01). Multivariate Cox proportional hazard analysis revealed that NID of &lt;7.0% was an independent predictor of future deterioration of LVEF in patients with HFmrEF. Both endothelial function and vascular smooth muscle function are impaired in patients with HFmrEF compared with those in patients without HF. In addition, low NID of &lt;7.0% predicts future deterioration of LVEF.<\/jats:p>","DOI":"10.3390\/jcm10245980","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"5980","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vascular Dysfunction Predicts Future Deterioration of Left Ventricular Ejection Fraction in Patients with Heart Failure with Mildly Reduced Ejection Fraction"],"prefix":"10.3390","volume":"10","author":[{"given":"Shinji","family":"Kishimoto","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Maruhashi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Kajikawa","sequence":"additional","affiliation":[{"name":"Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Yamaji","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiming","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya","family":"Mizobuchi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Nakano","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuaki","family":"Chayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikara","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Faculty of General Rehabilitation, Hiroshima International University, Hiroshima 739-2695, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farina Mohamad","family":"Yusoff","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-1494","authenticated-orcid":false,"given":"Ayumu","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5813-3672","authenticated-orcid":false,"given":"Yukihito","family":"Higashi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, Japan"},{"name":"Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.ahj.2014.07.008","article-title":"Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population","volume":"168","author":"Cheng","year":"2014","journal-title":"Am. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1016\/j.jacc.2017.08.074","article-title":"Heart Failure with Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes","volume":"70","author":"Shah","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1161\/01.CIR.0000153349.77489.CF","article-title":"Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure","volume":"111","author":"Katz","year":"2005","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1161\/01.CIR.84.4.1589","article-title":"Endothelium-dependent vasodilation is attenuated in patients with heart failure","volume":"84","author":"Kubo","year":"1991","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1136\/hrt.2006.087999","article-title":"Carvedilol improves endothelium-dependent vasodilation in patients with dilated cardiomyopathy","volume":"93","author":"Nishioka","year":"2007","journal-title":"Heart"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ijcard.2017.01.024","article-title":"Endothelial dysfunction and abnormal vascular structure are simultaneously present in patients with heart failure with preserved ejection fraction","volume":"231","author":"Kishimoto","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mayocpiqo.2018.12.006","article-title":"Rethinking Endothelial Dysfunction as a Crucial Target in Fighting Heart Failure","volume":"3","author":"Premer","year":"2019","journal-title":"Mayo Clin. Proceedings. Innov. Qual. Outcomes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.jacc.2018.05.042","article-title":"Dynamic Trajectories of Left Ventricular Ejection Fraction in Heart Failure","volume":"72","author":"Ferrer","year":"2018","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jchf.2018.11.019","article-title":"Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure","volume":"7","author":"Savarese","year":"2019","journal-title":"JACC Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1002\/ejhf.807","article-title":"Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study","volume":"19","author":"Tsuji","year":"2017","journal-title":"Eur. J. Heart Fail."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.jjcc.2020.10.018","article-title":"The predictive value of global longitudinal strain in patients with heart failure mid-range ejection fraction","volume":"77","author":"Chang","year":"2020","journal-title":"J. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ijcard.2020.01.039","article-title":"Prognostic value of sST2 in patients with heart failure with reduced, mid-range and preserved ejection fraction","volume":"304","author":"Song","year":"2020","journal-title":"Int. J. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1253\/circj.CJ-08-1102","article-title":"Endothelial function and oxidative stress in cardiovascular diseases","volume":"73","author":"Higashi","year":"2009","journal-title":"Circ. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJM199901143400207","article-title":"Atherosclerosis\u2014An inflammatory disease","volume":"340","author":"Ross","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/0140-6736(92)93147-F","article-title":"Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis","volume":"340","author":"Celermajer","year":"1992","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1161\/ATVBAHA.111.227892","article-title":"Rho-associated kinase activity, endothelial function, and cardiovascular risk factors","volume":"31","author":"Soga","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1161\/01.CIR.0000012543.55874.47","article-title":"Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: A prospective study","volume":"105","author":"Gokce","year":"2002","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1161\/ATVBAHA.112.300934","article-title":"Nitroglycerine-induced vasodilation for assessment of vascular function: A comparison with flow-mediated vasodilation","volume":"33","author":"Maruhashi","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1161\/01.CIR.0000153339.27064.14","article-title":"Endothelial function: Cardiac events","volume":"111","author":"Lerman","year":"2005","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1161\/HYPERTENSIONAHA.116.08327","article-title":"Arterial Stiffness and Risk of Overall Heart Failure, Heart Failure With Preserved Ejection Fraction, and Heart Failure With Reduced Ejection Fraction: The Health ABC Study (Health, Aging, and Body Composition)","volume":"69","author":"Pandey","year":"2017","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ejhf.592","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"18","author":"Ponikowski","year":"2016","journal-title":"Eur. J. Heart Fail."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"(2017). 2. Classification and Diagnosis of Diabetes. Diabetes Care, 40, S11\u2013S24.","DOI":"10.2337\/dc17-S005"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"(2001). Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama, 285, 2486\u20132497.","DOI":"10.1001\/jama.285.19.2486"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1161\/ATVBAHA.112.249680","article-title":"Intima-media thickness of brachial artery, vascular function, and cardiovascular risk factors","volume":"32","author":"Iwamoto","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"448","DOI":"10.2337\/diabetes.52.2.448","article-title":"Preferential stiffening of central over peripheral arteries in type 2 diabetes","volume":"52","author":"Kimoto","year":"2003","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/j.jacc.2011.11.082","article-title":"Endothelial dysfunction, arterial stiffness, and heart failure","volume":"60","author":"Marti","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1161\/01.RES.69.4.1088","article-title":"Diminished endothelium-derived relaxing factor activity in an experimental model of chronic heart failure","volume":"69","author":"Ontkean","year":"1991","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1016\/j.jacc.2012.07.036","article-title":"Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction","volume":"60","author":"Akiyama","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1161\/01.CIR.0000094403.78467.C3","article-title":"Physiology and pathophysiology of vascular signaling controlled by guanosine 3\u2019,5\u2019-cyclic monophosphate-dependent protein kinase","volume":"108","author":"Feil","year":"2003","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1161\/ATVBAHA.109.193490","article-title":"Carotid intima-media thickness, systemic inflammation, and incidence of heart failure hospitalizations","volume":"29","author":"Melander","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.amjcard.2007.01.036","article-title":"Association of multiple inflammatory markers with carotid intimal medial thickness and stenosis (from the Framingham Heart Study)","volume":"99","author":"Thakore","year":"2007","journal-title":"Am. J. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1161\/hc0202.102119","article-title":"Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction","volume":"105","author":"Neglia","year":"2002","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0002-8703(03)00364-8","article-title":"Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction","volume":"146","author":"Prasad","year":"2003","journal-title":"Am. Heart J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1161\/HYPERTENSIONAHA.115.06839","article-title":"Combination of Flow-Mediated Vasodilation and Nitroglycerine-Induced Vasodilation Is More Effective for Prediction of Cardiovascular Events","volume":"67","author":"Kajikawa","year":"2016","journal-title":"Hypertension"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/24\/5980\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:49:57Z","timestamp":1760168997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/24\/5980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,20]]},"references-count":34,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["jcm10245980"],"URL":"https:\/\/doi.org\/10.3390\/jcm10245980","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2021,12,20]]}}}