{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:39:03Z","timestamp":1791905943751,"version":"4.3.4"},"reference-count":35,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Cardiovascular-kidney-metabolic syndrome (CKM) represents a multisystem condition involving obesity, diabetes, chronic kidney disease, and cardiovascular diseases. Frailty, as measured by the Frailty Index (FI), is linked to adverse outcomes, but its association with CKM severity and mortality remains unclear. This study aimed to evaluate the relationship between frailty status, CKM staging, and mortality risk. Methods: We analysed data from 19,407 adults aged \u2265 45 years from NHANES 1999\u20132018. Frailty status was assessed using a 49-item Frailty Index (FI) and categorised as robust (FI \u2264 0.08), pre-frail (0.08 &lt; FI &lt; 0.25), or frail (FI \u2265 0.25). CKM was staged from 1 to 4 based on established clinical criteria. Multinomial logistic regression assessed the association between frailty status and CKM staging. Cox proportional hazards models evaluated the associations between frailty status and all-cause, cardiovascular, and non-cardiovascular mortality among CKM patients. Results: A total of 19,407 participants (median [IQR] age: 63.00 [54.00\u201372.00] years, 50.77% male), with 19,089 CKM patients. Frail individuals exhibited significantly higher odds of being assigned to advanced CKM stages. Over a median follow-up of 8.4 years, 4794 participants died. Kaplan\u2013Meier curves and restricted cubic spline analyses demonstrated a clear gradient in mortality risk across frailty categories. Compared with the robust group, pre-frail and frail individuals had significantly higher risks of all-cause (HR = 1.47 and 2.83, respectively), cardiovascular (HR = 1.71 and 3.78), and non-cardiovascular mortality (HR = 1.40 and 2.57). Conclusions: Frailty status demonstrated a significant association with CKM staging and mortality outcomes. Early identification of frailty may help guide risk stratification and inform tailored interventions for individuals with CKM.<\/jats:p>","DOI":"10.3390\/jcm14176008","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:26:31Z","timestamp":1756189591000},"page":"6008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Association of Frailty Status with Staging and Mortality Risk of Cardiovascular-Kidney-Metabolic Syndrome in Middle-Aged and Older Populations: Insights from the 1999\u20132018 National Health and Nutrition Examination Survey"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6028-9364","authenticated-orcid":false,"given":"Zhenkun","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Wu","sequence":"additional","affiliation":[{"name":"National Center for Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China"},{"name":"Department of Emergency Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjie","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Research Institute of Anesthesiology, Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK"},{"name":"Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5073-1798","authenticated-orcid":false,"given":"Manlin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK"},{"name":"Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Engineering Research Center of Medical Devices for Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Tianjin Medical University General Hospital, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 407219, Taiwan"},{"name":"Cardiovascular Center, Taichung Veterans General Hospital, Taichung 407219, Taiwan"},{"name":"Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Cardiovascular Research Center, College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-6286","authenticated-orcid":false,"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK"},{"name":"Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 7ZX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-1626","authenticated-orcid":false,"given":"Gregory Y. H.","family":"Lip","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK"},{"name":"Danish Centre for Health Services Research, Department of Clinical Medicine, Aalborg University, DK-9220 Aalborg, Denmark"},{"name":"Department of Cardiology, Lipidology and Internal Medicine, Medical University of Bialystok, ul. \u017burawia 14, 15-540 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1161\/CIR.0000000000001184","article-title":"Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory from the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"ref_2","first-page":"e895","article-title":"2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"145","author":"Heidenreich","year":"2022","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.diabres.2011.10.029","article-title":"IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030","volume":"94","author":"Whiting","year":"2011","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"KDIGO (2024). 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int., 105, S117\u2013S314.","DOI":"10.1016\/j.kint.2023.10.018"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1161\/CIR.0000000000001186","article-title":"A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement from the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102344","DOI":"10.1016\/j.cpcardiol.2023.102344","article-title":"Cardiovascular-Kidney-Metabolic (CKM) syndrome: A state-of-the-art review","volume":"49","author":"Sebastian","year":"2024","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1097\/CM9.0000000000003230","article-title":"Oxidative stress in diabetes mellitus and its complications: From pathophysiology to therapeutic strategies","volume":"138","author":"Chen","year":"2025","journal-title":"Chin. Med. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"00089-2020","DOI":"10.1183\/23120541.00089-2020","article-title":"The impact of muscle strength on exercise capacity and symptoms","volume":"6","author":"Farooqi","year":"2020","journal-title":"ERJ Open Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/S0140-6736(19)31785-4","article-title":"Management of frailty: Opportunities, challenges, and future directions","volume":"394","author":"Dent","year":"2019","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5041","DOI":"10.1039\/D4FO00870G","article-title":"The association between oxidative balance score and frailty in adults across a wide age spectrum: NHANES 2007\u20132018","volume":"15","author":"Liu","year":"2024","journal-title":"Food Funct."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s11357-017-9993-7","article-title":"A frailty index from common clinical and laboratory tests predicts increased risk of death across the life course","volume":"39","author":"Blodgett","year":"2017","journal-title":"GeroScience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1093\/ageing\/afw054","article-title":"A frailty index based on laboratory deficits in community-dwelling men predicted their risk of adverse health outcomes","volume":"45","author":"Blodgett","year":"2016","journal-title":"Age Ageing"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/ageing\/afx162","article-title":"Frailty index as a predictor of mortality: A systematic review and meta-analysis","volume":"47","author":"Kojima","year":"2018","journal-title":"Age Ageing"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1111\/dom.15676","article-title":"Long-term changes in frailty and incident type 2 diabetes: A prospective cohort study based on the UK Biobank","volume":"26","author":"Sun","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100651","DOI":"10.1016\/j.lanhl.2024.100651","article-title":"Frailism: A scoping review exploring discrimination against people living with frailty","volume":"6","author":"Braude","year":"2025","journal-title":"Lancet Healthy Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103588","DOI":"10.1016\/j.redox.2025.103588","article-title":"Role of oxidative balance score in staging and mortality risk of cardiovascular-kidney-metabolic syndrome: Insights from traditional and machine learning approaches","volume":"81","author":"Chen","year":"2025","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e039751","DOI":"10.1161\/JAHA.124.039751","article-title":"Impact of DNA-Methylation Age Acceleration on Long-Term Mortality Among Us Adults with Cardiovascular-Kidney-Metabolic Syndrome","volume":"14","author":"Wu","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1161\/CIR.0000000000001191","article-title":"Novel Prediction Equations for Absolute Risk Assessment of Total Cardiovascular Disease Incorporating Cardiovascular-Kidney-Metabolic Health: A Scientific Statement from the American Heart Association","volume":"148","author":"Khan","year":"2023","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ki.2010.483","article-title":"The definition, classification, and prognosis of chronic kidney disease: A KDIGO Controversies Conference report","volume":"80","author":"Levey","year":"2011","journal-title":"Kidney Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1053\/j.ajkd.2025.01.012","article-title":"Cardiovascular Disease Risk Estimates in the US CKD Population Using the PREVENT Equation","volume":"86","author":"Walther","year":"2025","journal-title":"Am. J. Kidney Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101789","DOI":"10.1016\/j.arr.2022.101789","article-title":"Progression of frailty as measured by a cumulative deficit index: A systematic review","volume":"84","author":"Kaskirbayeva","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1093\/eurheartj\/ehad885","article-title":"Changes in frailty and incident cardiovascular disease in three prospective cohorts","volume":"45","author":"He","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s12933-023-01937-x","article-title":"The cardio-renal-metabolic connection: A review of the evidence","volume":"22","author":"Marassi","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1111\/dom.14829","article-title":"Interconnection between cardiovascular, renal and metabolic disorders: A narrative review with a focus on Japan","volume":"24","author":"Kadowaki","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1249\/MSS.0000000000001448","article-title":"Associations of Muscle Mass and Strength with All-Cause Mortality Among US Older Adults","volume":"50","author":"Li","year":"2018","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/ajcn\/84.3.475","article-title":"The underappreciated role of muscle in health and disease","volume":"84","author":"Wolfe","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_27","first-page":"34","article-title":"Unintentional Weight Loss in Older Adults","volume":"104","author":"Gaddey","year":"2021","journal-title":"Am. Fam. Physician"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eadi3902","DOI":"10.1126\/sciadv.adi3902","article-title":"Association between frailty and depression: A bidirectional Mendelian randomization study","volume":"9","author":"Deng","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e25750","DOI":"10.1016\/j.heliyon.2024.e25750","article-title":"Association between oxidative balance score and frailty in chronic obstructive pulmonary disease","volume":"10","author":"He","year":"2024","journal-title":"Heliyon"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.numecd.2023.10.018","article-title":"The bidirectional association between frailty index and cardiovascular disease: A Mendelian randomization study","volume":"34","author":"Xu","year":"2024","journal-title":"Nutr. Metab. Cardiovasc. Dis. NMCD"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e650","DOI":"10.1016\/S2468-2667(20)30113-4","article-title":"Frailty index and all-cause and cause-specific mortality in Chinese adults: A prospective cohort study","volume":"5","author":"Fan","year":"2020","journal-title":"Lancet Public Health"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1093\/eurheartj\/ehab850","article-title":"Frailty and cardiovascular mortality in more than 3 million US Veterans","volume":"43","author":"Shrauner","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1093\/europace\/euac123","article-title":"EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA)","volume":"25","author":"Savelieva","year":"2023","journal-title":"Europace"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.1016\/S2666-7568(23)00054-5","article-title":"Cardiometabolic multimorbidity, lifestyle behaviours, and cognitive function: A multicohort study","volume":"4","author":"Jin","year":"2023","journal-title":"Lancet Healthy Longev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejim.2024.12.034","article-title":"Hypertensive heart disease in older patients: Considerations for clinical practice","volume":"134","author":"Camafort","year":"2025","journal-title":"Eur. J. Intern. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/17\/6008\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:39Z","timestamp":1760034759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/17\/6008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":35,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["jcm14176008"],"URL":"https:\/\/doi.org\/10.3390\/jcm14176008","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,25]]}}}