Klotho Plasma Levels Are an Independent Predictor of Mortality in Women with Acute Coronary Syndrome

INTRODUCTION Alterations in plasma levels of the components of the mineral metabolism (MM) system (calcidiol, fibroblast growth factor-23 [FGF23], phosphate, parathormone [PTH] and klotho) are related to cardiovascular diseases. However, gender differences of the whole MM system in patients with acute coronary syndrome (ACS) have not been reported so far. METHODS We studied 1,230 patients with ACS. At baseline clinical data were collected and plasma levels of MM components were assessed. The primary outcome was a composite of acute ischaemic events, heart failure and all-cause mortality. Secondary outcomes included each component separately. RESULTS 282 patients (22.9%) were female. At baseline, FGF23, PTH, phosphate, and klotho plasma levels were higher in women than in men. After 5.44 (3.03-7.46) years of follow-up, the primary outcome occurred in 28.0% women and 23.5% men, and death in 10.6% and 9.4% respectively. At multivariate Cox regression analysis, FGF23 levels were associated with incidence of the primary outcome in both, women (Hazard ratio [HR] 1.02 [95%CI:1.01-1.04];p=0.001) and men (HR 1.04 [1.00-1.03];p=0.016), in whom calcidiol levels were also an independent predictor of this outcome. Klotho (HR 0.80 [95%CI:0.67-0.96];p=0.019) and phosphate (HR=2.24 [95%CI: 1.11-4.50];p=0.025) were independent predictors of death in women, while calcidiol (HR=0.84 [95%CI0.72-0.98];p=0.024) and FGF23 levels (HR=1.02 [1.00-1.03];p=0.048) were predictors in men. CONCLUSIONS Klotho levels are inversely and independently related to all-cause mortality after an ACS in women, but not in men. Furthermore, the MM profile in ACS patients differs in both genders. Future research should explore the underlying mechanisms of these associations. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Our prospective study did not involve any specific intervention or treatment. However, the research protocol suited the ethical guidelines of the1975 Declaration of Helsinki as reflected in a priori approval by the human research committees of the institutions participating in this study: Fundación Jiménez Díaz University Hospital, Fundación Alcorcón Hospital, Fuenlabrada Hospital, Puerta de Hierro Majadahonda University Hospital, and Móstoles University Hospital. The date of approval by the Ethics Committee was 24 April 2007 (act number 05-07). ### Funding Statement This work was supported by grants from Carlos III Health Institute (ISCIII) (PI17/01495; PI20/00923; PI23/00119; PI24/00978), Spain's Ministry of Science and Innovation (RTC2019-006826-1), Spanish Society of Cardiology and Carlos III Health Institute FEDER (FJD biobank: RD09/0076/00101). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approval by the human research committees of the institutions participating in this study: Fundación Jiménez Díaz University Hospital, Fundación Alcorcón Hospital, Fuenlabrada Hospital, Puerta de Hierro Majadahonda University Hospital, and Móstoles University Hospital. The date of approval by the Ethics Committee was 24 April 2007 (act number 05-07). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data referred to in the manuscript are available upon reasonable request to the corresponding author (Dr. Marcelino Cortés, e-mail: mcortesg@quironsalud.es).