Klotho plasma levels are an independent predictorof mortality in women with acute coronary syndrome

Klotho plasma levels are an independent predictorof mortality in women with acute coronary syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Klotho plasma levels are an independent predictorof mortality in women with acute coronary syndrome Marcelino Cortés, Andrea Kallmeyer, Nieves Tarín, Carmen Cristóbal, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5676287/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 May, 2025 Read the published version in Scientific Reports → Version 1 posted 8 You are reading this latest preprint version Abstract Alterations in plasma levels of the components of the mineral metabolism (MM) system are related to cardiovascular diseases. However, gender differences of the whole MM system in patients with acute coronary syndrome (ACS) have not been reported. Our objective was to analyse the potential differences on the prognostic role of MM in women suffering an ACS as compared to men. We included 1,230 patients with ACS and collected clinical data and plasma levels of MM components. Primary outcome was a composite of acute ischaemic events, heart failure and all-cause mortality. Secondary outcomes included each component separately. 282 patients (22.9%) were female. After 5.44 years of follow-up, primary outcome occurred in 28.0% women and 23.5% men, and death in 10.6% and 9.4% respectively. FGF23 was associated with primary outcome in both sexes, and calcidiol only in men (HR 1.04, CI95%1.00-1.03). Klotho levels are inversely related to all-cause mortality only in women (HR 0.80, CI95% 0.67–0.96), while calcidiol (HR 0.84, CI95%0.72–0.98) and FGF23 levels (HR 1.02 CI95%1.00-1.03) were predictors in men, highlighting a possible gender-specific prognostic biomarker. These results underline the importance of considering MM biomarkers in risk stratification and management of patients with acute coronary syndromes, with attention to gender differences. Health sciences/Biomarkers/Prognostic markers Health sciences/Cardiology klotho protein gender acute coronary syndrome mineral metabolism cardiovascular risk Figures Figure 1 INTRODUCTION The main role of the mineral metabolism (MM) system (calcidiol, fibroblast growth factor-23 [FGF23], phosphate, parathormone [PTH] and klotho) is to maintain mineral homeostasis. Specifically, FGF23helps the failing kidneys to eliminate phosphorus and calcium 1 .Italso promotes a reduction of the concentration of 1-25-dihydroxyvitamin D, that leads to a decrease in intestinal calcium absorption, stimulating PTH secretion. However, these compensatory changes of the different components of MM may promote the development of cardiovascular disorders (CVD), and their plasma levels may also have a prognostic role in certain CVD 2 – 5 . In the case of klotho, it works as a co-receptor of FGFR1 for the canonical actions of FGF23 6 . The non-canonical actions of FGF23, such as cytokine production and the development of cardiac hypertrophy and fibrosis, are mediated mainly by FGFR2-4 receptors without the participation of klotho. Then, a decrease of klotho levels favours an increase of the deleterious, non-canonical effects of FGF23 7 , and it has been said that this molecule possesses protective effects 8 – 10 . In addition, these MM abnormalities are not limited to patients with chronic kidney disease (CKD), because they have been observed in patients with preserved renal function 11 . Furthermore, a prognostic role of abnormal plasma levels of MM has been demonstrated in subjects with average renal function 4 , 12 – 14 . Moreover, CVD is the most frequent cause of mortality worldwide. In this setting, there are important gender differences in acute coronary syndromes (ACS): different comorbidities, cardiovascular risk factors, differences in clinical presentation and in the quality of diagnostic and therapeutic medical management 15 . Even more, the risk of death is known to be higher in women, especially in the context of younger populations 16 – 18 . To our knowledge, there are no previous publications in the literature assessing the prognostic role of the whole MM after an ACS focusing on gender differences. In this work we have analysed the potential differences on the prognostic role of MM in women suffering an ACS as compared to men. METHODS Patients and study design We analysed the BACS & BAMI (Biomarkers in Acute Coronary Syndrome & Biomarkers in Acute Myocardial Infarction) study population, which included patients admitted to five hospitals in Madrid with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation acute coronary syndrome (NSTEACS, including non-STEMI and unstable angina). Inclusion and exclusion criteria have been detailed previously 19,20 . Between July 2006 and June 2014, a total of 2,740 patients were discharged from the study hospitals with a diagnosis of NSTEACS or STEMI. Of these, 1,483 patients were excluded based on the following predefined criteria: presence of survival-limiting toxic conditions or habits (29.8%), age >85 years (16.4%),inability to complete follow-up (16.3%), clinical instability beyond day six after the index event (10.9%),inability of the investigators to include them (9.8%), inability to undergo cardiac revascularisation (9.6%), presence of other significant cardiac conditions (5.7%), and refusal to participate in the study (1.5%). Of the 1,257 patients included, 1,230 completed the follow-up (figure 1). On admission, baseline clinical variables were documented, and 12-hour fasting venous blood samples were collected in EDTA tubes. These samples were centrifuged at 2500 g for 10 minutes, and the plasma was stored at -80°C. After discharge from hospital, all patients underwent annual assessments at their respective medical centres. At the conclusion of the follow-up period, medical records were reviewed, and patient status was confirmed through telephone contact. The last follow-up visits were conducted in June 2016. The research protocol suited the ethical guidelines of the1975 Declaration of Helsinki. This protocol was approved by the Ethics Committee of Fundación Jiménez Díaz University Hospital. The date of approval by this Ethics Committee was 24 April 2007 (act number 05-07). In addition, this protocol was also approved by the Ethics Committees of the other institutions participating in the study: Fundación Alcorcón Hospital, Fuenlabrada Hospital, Puerta de Hierro Majadahonda University Hospital, and Móstoles University Hospital. All participants were provided informed consent during the study. Outcomes The primary outcome was a composite of acute ischemic events (including non-STEMI, STEMI, unstable angina, ischaemic stroke, and transient ischemic attack), heart failure, and all-cause mortality. Secondary outcomes included each component of the primary outcome: acute ischemic events, heart failure, and death. NSTEACS was defined as rest angina lasting more than 20 minutes within the preceding 24 hours, or new-onset class III-IV angina, accompanied by transient ST depression or T wave inversion on the electrocardiogram, as interpreted by the attending cardiologist, and/or elevated troponin levels. STEMI was defined by angina-like symptoms persisting for more than 20 minutes, ST elevation in at least two contiguous leads on the electrocardiogram, lack of response to nitroglycerin, and elevated troponin levels. A previous acute myocardial infarction was diagnosed in the presence of new pathological Q waves on the electrocardiogram, along with corresponding new myocardial scarring identified via echocardiography or nuclear magnetic resonance imaging. Heart failure was defined as the presence of typical symptoms, with or without signs, associated with left ventricular systolic dysfunction (<50%) or, in case of preserved systolic function, associated with objective evidence of cardiac structural and/or functional abnormalities, including elevated natriuretic peptide levels. Ischaemic stroke was defined as the rapid onset of a neurological deficit attributable to a specific vascular territory, lasting more than 24 hours, or confirmed by new ischemic lesions on imaging studies. A transient ischemic attack was characterized by transient neurological signs and symptoms of cerebral ischemia that resolved within 24 hours, without acute ischemic lesions on imaging studies. Although all events were recorded for each patient, only the first event was included in the Cox regression analysis. Therefore, while the total number of events is reported, patients who experienced multiple events were counted only once in these analyses. Biochemical analysis Plasma analyses were conducted at the Mineral Metabolism laboratory of La Paz Hospital and at the Vascular Pathology and Biochemistry laboratories of Fundación Jiménez Díaz University Hospital. The investigators responsible for these laboratory studies were blinded to the clinical data. Soluble-α-klotho levels (here in after referred to as "klotho") were assessed by ELISA (Human Soluble Alpha Klotho Assay Kit, Immuno-Biological Laboratories Co., Hokkaido, Japan). FGF23 was measured through an enzyme-linked immunosorbent assay (ELISA) that targets epitopes within the carboxyl-terminal region of FGF23 (Human FGF23, C-Term, Immutopics Inc, San Clemente, CA). Calcidiol plasma levels were quantified using a chemiluminescent immunoassay on the LIAISON XL analyzer (LIAISON 25OH-Vitamin D Total Assay, DiaSorin, Saluggia, Italy). Intact parathyroid hormone (PTH) was analyzed using a second-generation automated chemiluminescent method (Elecsys 2010 platform, Roche Diagnostics, Mannheim, Germany), and phosphate levels were determined by an enzymatic method (Integra 400 analyzer, Roche Diagnostics, Mannheim, Germany). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured via immunoassay (VITROS, Ortho Clinical Diagnostics, Raritan, NJ, USA), troponin I through an immunometric immunoassay using a biotinylated monoclonal mouse antibody and a luminescent reaction (Ortho Clinical Diagnostics Vitros XT 7600, Raritan, NJ, USA), and high-sensitivity C-reactive protein (hs-CRP) by latex-enhanced immunoturbidimetry (ADVIA 2400 Chemistry System, Siemens, Munich, Germany). Lipid, glucose, and creatinine levels were determined using standard methods (ADVIA 2400 Chemistry System, Siemens, Munich, Germany). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Statistical analysis Quantitative data following a normal distribution are presented as mean ± standard deviation, and those with a not normal distribution are displayed as median (interquartile range). Categorical variables are expressed using frequency measurements (absolute frequencies and percentages) A baseline comparative analysis of variables was conducted based on gender. Categorical data were evaluated using the χ² test or Fisher’s exact test. For continuous variables, a Student’s t-test was applied to those with a normal distribution, while the Mann–Whitney U test was employed for those not normally distributed. A p-value of less than 0.05 was considered indicative of statistical significance. A univariate Cox regression analysis was conducted to determine which variables were associated with the development of various outcomes, separately for men and women. Subsequently, a multivariate regression analysis was performed to identify significant predictors of clinical outcomes in both genders. The selection criteria for variables included in the multivariate analysis were based on clinical and biological plausibility, as well as statistical significance observed in the univariate analyses. The magnitude of the effects of the variables was expressed in the form of hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were conducted using the Statistical Package for the Social Sciences (SPSS v.26.0, IBM, Armonk, NY, USA), the R statistical language version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria) and the statistical package for the biomedical sciences (MedCalc v.23.0.2, Ostend, Belgium; https://www.medcalc.org). RESULTS Baseline characteristics 1,230 patients were included in our study. Of these, 282 (22.9%) were women. Women were older than men (65.7 vs 60.5 years, p<0.001), with a higher percentage of hypertension (70.6% vs 53.2%), and of CKD prior to admission (28.7% vs 15.9%) (Table 1). On the other hand, men had a significantly higher rate of smokers (46.6% vs 28.0%), with more coronary heart disease and peripheral arterial disease prior to inclusion in the study. In both genders, the percentage of STEMI included in our population was around 50%. On average, men had a greater number of affected vessels (1.51 vs. 1.22, p<0.001), and a higher percentage of them received revascularization treatment. This translated into a lower proportion of women with P2Y12 inhibitors at discharge (85.5% vs 91.6%, p 0.004), with no other difference in treatment at discharge between men and women. Regarding the biomarkers analyzed, women generally presented significantly higher levels of PTH, FGF23, klotho, phosphorus, and NT-proBNP. Median time for blood extraction from admission was 4 (2-5) days. Primary outcome Median follow-up was 5.44 (3.03-7.46) years. During follow-up, 79 women (28.0%) and 223 men (23.5%) developed a primary event (a composite of acute ischemic events, heart failure, and all-cause mortality). We performed a multivariate Cox regression analysis of our study population to identify independent predictors of primary outcomes separately for men and women, as described previously. This analysis revealed that FGF23 levels were directly and significantly related to the occurrence of a primary outcome in both sexes (Table 2). PTH also showed a relationship with primary outcome in the male group, but not in the female group. Other variables (clinical or treatment) also showed a significant relationship with outcomes in both groups, although no other biomarker showed a significant relationship. Secondary outcomes At the end of follow-up, 55 women (19.5%) and 133 men (14%) presented an acute ischemic event. For each of these groups, we performed a multivariate Cox regression analysis to identify significant predictors of this outcome (Table 3). Variables such as eGFR, heart failure (prior to inclusion), hypertension, etc. were shown to be a predictor of acute ischemic events. However, none of the analyzed biomarkers showed a statistically significant relationship in either group. Twenty women (7.1%) and 48 men (5.1%) developed heart failure during follow-up. After multivariate Cox regression analysis, again FGF23 was an independent risk factor for the development of heart failure in both men and women (Table 4). PTH also showed a statistically significant relationship with this event but as observed for the primary outcome, only in the male population. Finally, we analyzed the variables related to all-cause mortality in both genders. By the end of follow-up, 30 women (10.6%) and 89 men (9.4%) had died. We observed that klotho was an independent protective factor in the female population for all-cause mortality (HR 0.80, CI95% 0.67-0.96; p=0.019) (Table 5). Phosphate levels were also independently but positively associated with this outcome in this population (HR 2.24 (1.11-4.50; p=0.025). In contrast, in men the MM components associated with this outcome included only FGF23 (HR 1.02 (1.00-1.03); p=0.048) and calcidiol (HR 0.84 (0.72-0.98); p=0.024) but not klotho and phosphate plasma levels. DISCUSSION Many differences have been described between men and women regarding coronary artery disease. Women have less coronary atherosclerosis 21 , and a lower risk of suffering ACS than men 22 . In addition, the age of onset is higher in women than in men, with a higher prevalence of comorbidities 23 . The impact of the different risk factors according to gender also presents differences; with the greater importance in women of diabetes, hypertension and smoking 24 – 26 . Thus, the risk of death is known to be higher in women. This higher mortality in women is described mainly in the earlier phases after ACS, with a worse prognosis and higher mortality having been observed immediately after percutaneous intervention 23 , 27 . The possible causes of this worse prognosis are diverse, and they may include a delay in the diagnosis of ACS favored by the higher likelihood of atypical symptoms 28 and differences in high-sensitivity troponin levels as compared to men 29 . Furthermore, women with ACS are less likely to receive optimal therapy than men 30 – 34 . Changes in plasma levels of the different components of MM have been related to different cardiovascular abnormalities. Low calcidiol and high PTH levels have been associated with left ventricular hypertrophy, hypertension, coronary heart disease and increased cardiovascular risk 2 , 20 , 35 . Increased FGF23 has been related with left ventricular hypertrophy 3 , 36 , 37 , heart failure 38 , 39 , atrial fibrillation 40 and coronary heart disease 4 and is associated with worse prognoses both in the general population and in patients with CVD 5 , 41 – 44 . Furthermore, MM abnormalities are not restricted to patients with CKD, but they are also present in patients with normal renal function 11 , where they may also have prognostic value 4 , 12 – 14 . In spite of this, there is no information regarding the behaviour of MM components in women with ACS. In this paper we demonstrate that women with ACS present a worse MM profile than men, with higher FGF23, PTH, and phosphate levels. Regarding prognosis, FGF23 levels were independent predictors of the primary outcome in both genders, while PTH added independent predictive value only in men. Similar results were obtained in the prediction of heart failure, where PTH showed significant predictive value in the multivariate study only in males (in agreement with the observations of other authors where PTH level was related to clinical and subclinical markers of congestion 45 ), but not in females. However, for the prediction of all-cause mortality there were marked differences between both groups, with low klotho levels being predictive in women, along with phosphate levels, while in men high FGF23 and low calcidiol levels were the independent predictors for this outcome. Klotho is the co-receptor of FGFR1 for FGF23, which exerts its beneficial actions through this canonical pathway, such as helping the failing kidneys to eliminate phosphate. However, in the absence of klotho, FGF23 binds to other receptors promoting cardiac hypertrophy and fibrosis and stimulating the production of pro-inflammatory cytokines 7 . Then, it has been said to have protective effects. Klotho suppression in animal models is associated with early ageing, shorter life expectancy, multi-organ dysfunction and marked alterations in mineral homeostasis (hyperphosphataemia, hypercalcaemia, amongothers.) 46 , 47 . More recently, an independent association between low klotho levels with left ventricular hypertrophy 48 , heart failure 49 – 52 , atrial fibrillation 53 and myocardial infarction 50 has been described in humans. Klotho has also demonstrated a prognostic role in heart failure 49 , 54 , with low levels also being a marker of total and cardiovascular mortality in CKD patients 55 and in the general population 56 , 57 . Basic research studies report results that may explain in part a potential benefit of klotho in ACS. The administration of klotho in animal models protects the myocardium from ischaemic and reperfusion damage through the activation of different pathways that reduce oxidative stress and restore autophagy levels 58 , 59 . Klotho has been described to modulate platelet activity 60 . Klotho therapy improves cardiac remodelling in a murine model of myocardial infarction 61 and it also ameliorates diastolic function 62 , although there are not clinical studies confirming these findings. In several other studies, authors have also observed a beneficial effect of klotho on the vascular endothelium, reducing oxidative stress at this level or attenuating cell apoptosis, among other mechanisms 63 – 66 . However, there are no published data on the prognostic role of klotho after an ACS. To our knowledge, our work is the first to describe an independent protective role of klotho after ACS. According to the present findings, we have recently shown that cardiac rehabilitation after ACS is associated with increases of klotho levels 67 , suggesting an increase in klotho could explain, at least in part, the benefits of cardiac rehabilitation. Of interest, the protective role of klotho is limited to women. It is possible that the higher cardiovascular risk profile of men, with more extensive coronary disease and a greater number of affected vessels, may interfere with the prognostic role of klotho, attenuating its protective effect after ACS. It is also striking that our results show that other MM biomarkers have a prognostic value in men but not in women. Nevertheless, we have demonstrated previously that it is common that several MM biomarkers have independent prognostic value 14 , 41 , even after adjusting for established biomarkers such as NT-proBNP. This underlines the need to make a complete assessment of MM to investigate the prognostic value of its components. Limitations First, the percentage of women in our study population is relatively low. This is in line with many other published studies. There are several factors that may influence the lower recruitment of women, among them, a higher prevalence of ACS in men could partly account for this difference. Second, the design of the study required the collection of plasma for analysis at discharge no later than 6 days after admission, to achieve homogeneous results. This led to the exclusion of ACS patients who did not meet this condition and that fact may explain the low number of cases with LVEF < 40% that were included. Therefore, these results should not be extrapolated to populations with a high percentage of patients with moderate or severe LV systolic dysfunction. Third, the inclusion period ended in 2014. Since then, new pharmacological and non-pharmacological treatments (stents, catheters, etc.) have emerged that could influence the results of similar studies in current populations. Fourth, almost all the women included in our study population were in the postmenopausal period. However, the variables collected in our study did not include the presence of osteoporosis or the use of specific gynaecological therapies. It is possible that hormonal or osteoporosis treatments may influence some of the parameters and/or biomarkers obtained. Conclusions In conclusion, our results show that klotho levels are inversely related to all-cause mortality in women after an ACS, highlighting a possible gender-specific prognostic biomarker. These results underline the importance of considering MM biomarkers in the risk stratification and management of ACS patients, with attention to gender differences. Future research should explore the underlying mechanisms of these associations. Declarations Funding support/Acknowledgements 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 Contribution Conceptualization, M.C. and J.T.; Methodology, N.T., C.C., C.G.L., A.H., J.A., L.L.B., M.L.G.C., J.E. and J.T.; Formal Analysis, I.M.F.; Investigation, M.C., A.K.M., A.M., A.A. and O.L.; Resources, N.T., C.C., C.G.L., A.H., J.A., L.L.B., M.L.G.C., J.E. and J.T.; Writing-Original Draft, M.C.; Writing-Review & Editing, J.T.; Supervision, J.T.; Funding Acquisition, J.T. and J.E. Acknowledgement 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). Data Availability Data is provided within the manuscript. Further information and requests for resources and data base should be directed to and will be fulfilled by the lead contact, Dr.Marcelino Cortés ( [email protected] ). References Wolf, M. Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease. Journal of the American Society of Nephrology 21 , 1427–1435 (2010). Michos, E. D., Cainzos-Achirica, M., Heravi, A. S. & Appel, L. J. Vitamin D, Calcium Supplements, and Implications for Cardiovascular Health. Journal of the American College of Cardiology 77 , 437–449 (2021). Falkner, B., Keith, S. W., Gidding, S. S. & Langman, C. B. 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Associations Between Serum Soluble α-Klotho and the Prevalence of Specific Cardiovascular Disease. Front. Cardiovasc. Med. 9 , 899307 (2022). Cai, J. et al. Association between serum Klotho concentration and heart failure in adults, a cross-sectional study from NHANES 2007–2016. International Journal of Cardiology 370 , 236–243 (2023). Luo, W., Wei, N., Sun, Z. & Gong, Y. Association between serum α-klotho level and the prevalence of heart failure in the general population. Cardiovasc J Afr 34 , 1–6 (2023). Nowak, A. et al. Prognostic value and link to atrial fibrillation of soluble Klotho and FGF23 in hemodialysis patients. PLoS One 9 , e100688 (2014). Bergmark, B. A. et al. Klotho, fibroblast growth factor-23, and the renin-angiotensin system - an analysis from the PEACE trial. Eur J Heart Fail 21 , 462–470 (2019). Memmos, E. et al. Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol 20 , 217 (2019). Kresovich, J. K. & Bulka, C. M. Low Serum Klotho Associated With All-cause Mortality Among a Nationally Representative Sample of American Adults. The Journals of Gerontology: Series A 77 , 452–456 (2022). Yang, Z. et al. The prognostic value of serum α-klotho in age-related diseases among the US population: A prospective population-based cohort study. Prev Med Rep 42 , 102730 (2024). Olejnik, A., Radajewska, A., Krzywonos-Zawadzka, A. & Bil-Lula, I. Klotho inhibits IGF1R/PI3K/AKT signalling pathway and protects the heart from oxidative stress during ischemia/reperfusion injury. Sci Rep 13 , 20312 (2023). Qiu, Z. et al. Activation of Klotho/SIRT1 signaling pathway attenuates myocardial ischemia reperfusion injury in diabetic rats. Shock (2024) doi:10.1097/SHK.0000000000002418. Yang, K. et al. Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice. Blood 129 , 2667–2679 (2017). Yue, C. et al. Ultrasound‑targeted microbubble destruction technology delivering β‑klotho to the heart enhances FGF21 sensitivity and attenuates heart remodeling post‑myocardial infarction. Int J Mol Med 53 , 54 (2024). Daneshgar, N. et al. Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways. GeroScience 46 , 4729–4741 (2024). Ikushima, M. et al. Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 339 , 827–832 (2006). Cui, W., Leng, B., Liu, W. & Wang, G. Suppression of Apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) by Klotho Protein is Associated with Reduced Endoplasmic Reticulum Oxidative Stress and Activation of the PI3K/AKT Pathway. Med Sci Monit 24 , 8489–8499 (2018). Maltese, G. et al. The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. J Cell Mol Med 21 , 621–627 (2017). Kawarazaki, W. et al. 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Tables Table 1: Baseline characteristis of study population Variable Female(n=282) Male (n=948) p Age (years) 65.7 ± 13.0 60.5 ± 11.6 70 years 127 (45.0%) 241 (25.4%) <0.001 Caucasian race 275 (97.5%) 917 (96.7%) NS Diabetes 70 (24.8%) 210 (22.2%) NS Hypertension 199 (70.6%) 504 (53.2%) <0.001 Body mass index (kg/m 2 ) 28.5 ± 5.16 28.3 ± 4.02 NS Dyslipidaemia 165 (58.5%) 575 (60.7%) NS Smoking 79 (28.0%) 442 (46.6%) <0.001 eGFR < 60 mL/min/1.73 m 2 81 (28.7) 151 (15.9) < 0.001 Heart failure (prior to inclusion) 4 (1.4%) 10 (1.1%) NS Coronary artery disease (prior) 42 (14.9%) 202 (21.3%) 0.022 Peripheral artery disease (prior) 7 (2.5%) 64 (6.8%) 0.011 Cerebrovascular accident (prior) 13 (4.6%) 27 (2.8%) NS Atrial fibrillation (prior) 8 (2.8%) 20 (2.1%) NS Laboratory results Hemoglobin (g/dl) 13.5 ± 1.50 15.1 ± 1.88 <0.001 Glycaemia (mg/dL) 116 ± 38.4 117 ± 39.1 NS eGFR (mL/min/1.73 m 2 ) 74.9 ± 22.3 79.8 ± 19.2 0.001 Troponin (ng/mL) 8.13 (0.80, 30.1) 11.4 (0.82, 59.4) 0.022 LDL (mg/dL) 119 ± 39.4 116 ± 36.1 NS Triglycerides (mg/dL) 122 (82.5, 177) 134 (98.0, 185) 0.006 HDL (mg/dL) 47.2 ± 14.2 38.1 ± 10.2 <0.001 Calcidiol (ng/mL) 16.4 (12.4, 24.6) 18.6 (13.5, 24.7) 0.095 PTH (pg/mL) 54.0 (40.3, 70.0) 45.0 (36.0, 60.0) <0.001 FGF23 (RU/mL) 126 (95.0, 173) 105 (82.0, 138) <0.001 Klotho (pg/mL) 657 ± 219 621 ± 205 0.013 Phosphorus (mg/dL) 3.44 (3.12, 3.82) 3.21 (2.85, 3.58) <0.001 NT-proBNP (pg/mL) 551 (226, 1500) 348 (121, 912) <0.001 hs-CRP (ng/dL) 1.36 (0.59, 2.85) 1.74 (0.78, 3.62) 0.012 Type of ACS and coronary findings NSTEMI 114 (40.4%) 326 (34.4%) NS STEMI 129 (45.7%) 482 (50.8%) NS Unstable Angina 39 (13.8%) 140 (14.8%) NS LVEF < 40% 41 (14.6%) 131 (13.8%) NS Number of affected vessels 1.22 ± 0.80 1.51 ± 0.79 <0.001 Left main disease 9 (3.3%) 33 (3.5%) NS Complete revascularization 211 (74.8%) 660 (69.6%) NS Type of revascularization <0.001 No revascularization 70 (24.8%) 115 (12.1%) Drug eluting stent 142 (50.4%) 492 (51.9%) Bare metal stent 52 (18.4%) 261 (27.5%) Balloon angioplasty 11 (3.9%) 27 (2.8%) Coronary artery bypass grafting 7 (2.5%) 53 (5.6%) Treatments at discharge ASA 264 (93.6%) 911 (96.2%) NS P2Y12 inhibitors 241 (85.5%) 867 (91.6%) 0.004 Anticoagulant 22 (7.8%) 60 (6.3%) NS Statins 264 (93.6%) 916 (96.7%) NS Ezetimibe 4 (1.4%) 18 (1.9%) NS Insulin 25 (8.9%) 57 (6.0%) NS Oral antidiabetic drugs 39 (13.8%) 149 (15.7%) NS ACEI/ARB 227 (80.5%) 770 (81.3%) NS MRAs 26 (9.2%) 71 (7.5%) NS Beta-blockers 227 (80.5%) 789 (83.4%) NS Nitrates 53 (18.8%) 133 (14.0%) NS Diuretics 48 (17.0%) 139 (14.7%) NS ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; ASA: acetylsalicylic acid; eGFR: estimated glomerular filtration rate; FGF23: fibroblast growth factor 23; HDL: high density lipoprotein; hs-CRP: high sensitivity C-reactive protein; LDL: low density lipoprotein; LVEF: left ventricular ejection fraction; NS: statistically not significant; NSTEMI: non-ST elevation myocardial infarction; MRAs: mineralocorticoid receptor antagonists; NT-ProBNP: N-terminal-probrainnatriuretic peptide; PTH: parathormone; STEMI: ST-elevation myocardial infarction. Table 2: Multivariable Cox regression analysis for the primary outcome of acute ischemic event, heart failure or death Gender Variable HR (CI 95%) p Female eGFR 0.85 (0.77-0.95) 0.006 Nitrates 2.34 (1.40-3.90) 0.001 CVA 4.17 (1.98-8.78) <0.001 FGF23 1.02 (1.01-1.04) 0.001 Diltiazem 2.41 (1.07-5.40) 0.034 Diabetes 1.65 (1.02-2.66) 0.040 Statins 0.497 (0.25-0.99) 0.049 Male Age 1.0 (1.02-1.04) <0.001 Diuretics 1.77 (1.29-2.43) <0.001 CAD 1.40 (1.05-1.88) 0.023 Diabetes 1.50 (1.13-2.01) 0.006 ASA 0.52 (0.31-0.86) 0.012 PTH 1.06 (1.01-1.11) 0.016 FGF23 1.04 (1.00-1.03) 0.027 ASA: acetylsalicylic acid; CVA: cerebrovascular accident (prior to inclusion); CAD: coronary artery disease (prior to inclusion); eGFR: estimated glomerular filtration rate; FGF23: fibroblast growth factor 23; HR: Hazar Ratio; PTH: parathormone. Table 3: Multivariable Cox regression analysis for the secondary outcome of acute ischemic events Gender Variable HR (CI 95%) p Female Heart failure 6.43 (2.09-19.79) 0.002 Nitrates 3.19 (1.79-5.66) <0.001 Glycaemia 1.09 (1.03-1.15) 0.004 eGFR 0.87 (0.76-0.98) 0.028 Male CCB 2.43 (1.59-3.40) <0.001 Heart failure 3.75 (1.37-10.29) 0.011 Hypertension 1.75 (1.20-2.57) 0.004 Triglycerides 1.01 (1.00-1.02) 0.018 ACEI/ARB 0.65 (0.44-0.97) 0.033 ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; eGFR: estimated glomerular filtration rate; HR: Hazar Ratio. Table 4: Multivariable Cox regression analysis for the secondary outcome of heart failure Gender Variable HR (CI 95%) p Female MRAs 9.22 (3.21-26.55) <0.001 FGF23 1.03 (1.01-1.06) 0.009 Insulin 5.56 (1.71-18.31) 0.008 ASA 0.23 (0.06-0.94) 0.042 Male FGF 23 1.04 (1.03-1.06) <0.001 PTH 1.14 (1.06-1.23) 0.002 Age 1.06 (1.02-1.09) 0.001 Oral antidiabetic drugs 3.02 (1.60-5.71) 0.001 LVEF < 40% 3.73 (1.99-6.95) <0.001 Diltiazem 4.97 (1.68-14.69) 0.005 Hypertension 2.23 (1.03-4.84) 0.043 ASA: acetylsalicylic acid; eGFR: estimated glomerular filtration rate; FGF23: fibroblast growth factor 23; LVEF: left ventricular ejection fraction; MRAs: mineralocorticoid receptor antagonists; HR: Hazar Ratio; PTH: parathormone Table 5: Multivariable Cox regression analysis for the secondary outcome of all-cause mortality Gender Variable HR (CI 95%) p Female eGFR 0.97 (0.95-0.98) 0.001 Anticoagulant 6.77 (2.69-17.05) <0.001 Diuretics 3.67 (1.58-8.51) 0.004 P2Y12 inhibitors 0.33 (0.14-0.77) 0.013 Phosporus 2.24 (1.11-4.50) 0.025 Klotho 0.80 (0.67-0.96) 0.019 LVEF < 40% 2.45 (1.05-5.76) 0.040 Male Age 1.10 (1.07-1.13) <0.001 Insulin 2.59 (1.44-4.66) 0.002 NT-proBNP 1.02 (1.01-1.03) 0.002 Heart failure (prior) 4.28 (1.78-10.27) 0.001 ASA 0.41 (0.20-0.84) 0.015 Smoking 1.71 (1.00-2.92) 0.049 Calcidiol 0.84 (0.72-0.98) 0.024 FGF23 1.02 (1.00-1.03) 0.048 ASA: acetylsalicylic acid; eGFR: estimated glomerular filtration rate; FGF23: fibroblast growth factor 23; LVEF: left ventricular ejection fraction; HR: Hazar Ratio; NT-ProBNP: N-terminal-probrain natriuretic peptide. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5676287","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":445276479,"identity":"53a2f83f-9f3d-4a9a-8293-05e1a63b695f","order_by":0,"name":"Marcelino 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Díaz","correspondingAuthor":false,"prefix":"","firstName":"Jesús","middleName":"","lastName":"Egido","suffix":""},{"id":445276495,"identity":"57706683-1904-48fd-96f3-0dcb85b1e6a0","order_by":14,"name":"José Tuñón","email":"","orcid":"","institution":"Fundación Jiménez Díaz","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"","lastName":"Tuñón","suffix":""}],"badges":[],"createdAt":"2024-12-19 11:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5676287/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5676287/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-01334-2","type":"published","date":"2025-05-14T15:58:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81031009,"identity":"ae63247b-6972-49f0-8d63-dd4dc968243f","added_by":"auto","created_at":"2025-04-21 11:21:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":88543,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5676287/v1/46ee2222599f7f7a740092c9.jpg"},{"id":83067887,"identity":"d4802920-b60d-4fe4-89d1-d2a2c116d914","added_by":"auto","created_at":"2025-05-19 16:07:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1205257,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5676287/v1/7de54bbe-e89c-4fbe-b761-72330bbf76fc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Klotho plasma levels are an independent predictorof mortality in women with acute coronary syndrome","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe main role of the mineral metabolism (MM) system (calcidiol, fibroblast growth factor-23 [FGF23], phosphate, parathormone [PTH] and klotho) is to maintain mineral homeostasis. Specifically, FGF23helps the failing kidneys to eliminate phosphorus and calcium\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.Italso promotes a reduction of the concentration of 1-25-dihydroxyvitamin D, that leads to a decrease in intestinal calcium absorption, stimulating PTH secretion. However, these compensatory changes of the different components of MM may promote the development of cardiovascular disorders (CVD), and their plasma levels may also have a prognostic role in certain CVD\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In the case of klotho, it works as a co-receptor of FGFR1 for the canonical actions of FGF23\u003csup\u003e6\u003c/sup\u003e. The non-canonical actions of FGF23, such as cytokine production and the development of cardiac hypertrophy and fibrosis, are mediated mainly by FGFR2-4 receptors without the participation of klotho. Then, a decrease of klotho levels favours an increase of the deleterious, non-canonical effects of FGF23 \u003csup\u003e7\u003c/sup\u003e, and it has been said that this molecule possesses protective effects\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn addition, these MM abnormalities are not limited to patients with chronic kidney disease (CKD), because they have been observed in patients with preserved renal function \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Furthermore, a prognostic role of abnormal plasma levels of MM has been demonstrated in subjects with average renal function \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMoreover, CVD is the most frequent cause of mortality worldwide. In this setting, there are important gender differences in acute coronary syndromes (ACS): different comorbidities, cardiovascular risk factors, differences in clinical presentation and in the quality of diagnostic and therapeutic medical management\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Even more, the risk of death is known to be higher in women, especially in the context of younger populations\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo our knowledge, there are no previous publications in the literature assessing the prognostic role of the whole MM after an ACS focusing on gender differences. In this work we have analysed the potential differences on the prognostic role of MM in women suffering an ACS as compared to men.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003ePatients and study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analysed the BACS \u0026amp; BAMI (Biomarkers in Acute Coronary Syndrome \u0026amp; Biomarkers in Acute Myocardial Infarction) study population, which included patients admitted to five hospitals in Madrid with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation acute coronary syndrome (NSTEACS, including non-STEMI and unstable angina). Inclusion and exclusion criteria have been detailed previously\u0026nbsp;\u003csup\u003e19,20\u003c/sup\u003e. Between July 2006 and June 2014, a total of 2,740 patients were discharged from the study hospitals with a diagnosis of NSTEACS or STEMI. Of these, 1,483 patients were excluded based on the following predefined criteria: presence of survival-limiting toxic conditions or habits (29.8%), age \u0026gt;85 years (16.4%),inability to complete follow-up (16.3%), clinical instability beyond day six after the index event (10.9%),inability of the investigators to include them (9.8%), inability to undergo cardiac revascularisation (9.6%), presence of other significant cardiac conditions (5.7%), and refusal to participate in the study (1.5%). Of the 1,257 patients included, 1,230 completed the follow-up (figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn admission, baseline clinical variables were documented, and 12-hour fasting venous blood samples were collected in EDTA tubes. These samples were centrifuged at 2500 g for 10 minutes, and the plasma was stored at -80\u0026deg;C.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter discharge from hospital, all patients underwent annual assessments at their respective medical centres. At the conclusion of the follow-up period, medical records were reviewed, and patient status was confirmed through telephone contact. The last follow-up visits were conducted in June 2016.\u003c/p\u003e\n\u003cp\u003eThe research protocol suited the ethical guidelines of the1975 Declaration of Helsinki. \u0026nbsp;This protocol was approved by the Ethics Committee of Fundaci\u0026oacute;n Jim\u0026eacute;nez D\u0026iacute;az University Hospital. The date of approval by this Ethics Committee was 24 April 2007 (act number 05-07). \u0026nbsp; In addition, this protocol was also approved by the Ethics Committees of the other institutions participating in the study: Fundaci\u0026oacute;n Alcorc\u0026oacute;n Hospital, Fuenlabrada Hospital, Puerta de Hierro Majadahonda University Hospital, and M\u0026oacute;stoles University Hospital. All participants were provided informed consent during the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome was a composite of acute ischemic events (including non-STEMI, STEMI, unstable angina, ischaemic stroke, and transient ischemic attack), heart failure, and all-cause mortality. Secondary outcomes included each component of the primary outcome: acute ischemic events, heart failure, and death. NSTEACS was defined as rest angina lasting more than 20 minutes within the preceding 24 hours, or new-onset class III-IV angina, accompanied by transient ST depression or T wave inversion on the electrocardiogram, as interpreted by the attending cardiologist, and/or elevated troponin levels. STEMI was defined by angina-like symptoms persisting for more than 20 minutes, ST elevation in at least two contiguous leads on the electrocardiogram, lack of response to nitroglycerin, and elevated troponin levels. A previous acute myocardial infarction was diagnosed in the presence of new pathological Q waves on the electrocardiogram, along with corresponding new myocardial scarring identified via echocardiography or nuclear magnetic resonance imaging. Heart failure was defined as the presence of typical symptoms, with or without signs, associated with left ventricular systolic dysfunction (\u0026lt;50%) or, in case of preserved systolic function, associated with objective evidence of cardiac structural and/or functional abnormalities, including elevated natriuretic peptide levels. Ischaemic stroke was defined as the rapid onset of a neurological deficit attributable to a specific vascular territory, lasting more than 24 hours, or confirmed by new ischemic lesions on imaging studies. A transient ischemic attack was characterized by transient neurological signs and symptoms of cerebral ischemia that resolved within 24 hours, without acute ischemic lesions on imaging studies.\u003c/p\u003e\n\u003cp\u003eAlthough all events were recorded for each patient, only the first event was included in the Cox regression analysis. Therefore, while the total number of events is reported, patients who experienced multiple events were counted only once in these analyses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiochemical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlasma analyses were conducted at the Mineral Metabolism laboratory of La Paz Hospital and at the Vascular Pathology and Biochemistry laboratories of Fundaci\u0026oacute;n Jim\u0026eacute;nez D\u0026iacute;az University Hospital. The investigators responsible for these laboratory studies were blinded to the clinical data. Soluble-\u0026alpha;-klotho levels (here in after referred to as \u0026quot;klotho\u0026quot;) were assessed by ELISA (Human Soluble Alpha Klotho Assay Kit, Immuno-Biological Laboratories Co., Hokkaido, Japan). FGF23 was measured through an enzyme-linked immunosorbent assay (ELISA) that targets epitopes within the carboxyl-terminal region of FGF23 (Human FGF23, C-Term, Immutopics Inc, San Clemente, CA). Calcidiol plasma levels were quantified using a chemiluminescent immunoassay on the LIAISON XL analyzer (LIAISON 25OH-Vitamin D Total Assay, DiaSorin, Saluggia, Italy). Intact parathyroid hormone (PTH) was analyzed using a second-generation automated chemiluminescent method (Elecsys 2010 platform, Roche Diagnostics, Mannheim, Germany), and phosphate levels were determined by an enzymatic method (Integra 400 analyzer, Roche Diagnostics, Mannheim, Germany). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured via immunoassay (VITROS, Ortho Clinical Diagnostics, Raritan, NJ, USA), troponin I through an immunometric immunoassay using a biotinylated monoclonal mouse antibody and a luminescent reaction (Ortho Clinical Diagnostics Vitros XT 7600, Raritan, NJ, USA), and high-sensitivity C-reactive protein (hs-CRP) by latex-enhanced immunoturbidimetry (ADVIA 2400 Chemistry System, Siemens, Munich, Germany). Lipid, glucose, and creatinine levels were determined using standard methods (ADVIA 2400 Chemistry System, Siemens, Munich, Germany). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQuantitative data following a normal distribution are presented as mean \u0026plusmn; standard deviation, and those with a not normal distribution are displayed as median (interquartile range). Categorical variables are expressed using frequency measurements (absolute frequencies and percentages)\u003c/p\u003e\n\u003cp\u003eA baseline comparative analysis of variables was conducted based on gender. Categorical data were evaluated using the \u0026chi;\u0026sup2; test or Fisher\u0026rsquo;s exact test. For continuous variables, a Student\u0026rsquo;s t-test was applied to those with a normal distribution, while the Mann\u0026ndash;Whitney U test was employed for those not normally distributed. A p-value of less than 0.05 was considered indicative of statistical significance.\u003c/p\u003e\n\u003cp\u003eA univariate Cox regression analysis was conducted to determine which variables were associated with the development of various outcomes, separately for men and women. Subsequently, a multivariate regression analysis was performed to identify significant predictors of clinical outcomes in both genders. The selection criteria for variables included in the multivariate analysis were based on clinical and biological plausibility, as well as statistical significance observed in the univariate analyses. The magnitude of the effects of the variables was expressed in the form of hazard ratios (HRs) and 95% confidence intervals (CIs).\u003c/p\u003e\n\u003cp\u003eAll analyses were conducted using the Statistical Package for the Social Sciences (SPSS v.26.0, IBM, Armonk, NY, USA), the R statistical language version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria) and the statistical package for the biomedical sciences (MedCalc v.23.0.2, Ostend, Belgium; https://www.medcalc.org).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1,230 patients were included in our study. Of these, 282 (22.9%) were women. Women were older than men (65.7 vs 60.5 years, p\u0026lt;0.001), with a higher percentage of hypertension (70.6% vs 53.2%), and of CKD prior to admission (28.7% vs 15.9%) (Table 1). On the other hand, men had a significantly higher rate of smokers (46.6% vs 28.0%), with more coronary heart disease and peripheral arterial disease prior to inclusion in the study. In both genders, the percentage of STEMI included in our population was around 50%. On average, men had a greater number of affected vessels (1.51 vs. 1.22, p\u0026lt;0.001), and a higher percentage of them received revascularization treatment. This translated into a lower proportion of women with P2Y12 inhibitors at discharge (85.5% vs 91.6%, p 0.004), with no other difference in treatment at discharge between men and women. Regarding the biomarkers analyzed, women generally presented significantly higher levels of PTH, FGF23, klotho, phosphorus, and NT-proBNP. Median time for blood extraction from admission was 4 (2-5) days. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedian follow-up was 5.44 (3.03-7.46) years. During follow-up, 79 women (28.0%) and 223 men (23.5%) developed a primary event (a composite of acute ischemic events, heart failure, and all-cause mortality).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe performed a multivariate Cox regression analysis of our study population to identify independent predictors of primary outcomes separately for men and women, as described previously. This analysis revealed that FGF23 levels were directly and significantly related to the occurrence of a primary outcome in both sexes (Table 2). PTH also showed a relationship with primary outcome in the male group, but not in the female group. Other variables (clinical or treatment) also showed a significant relationship with outcomes in both groups, although no other biomarker showed a significant relationship.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the end of follow-up, 55 women (19.5%) and 133 men (14%) presented an acute ischemic event. For each of these groups, we performed a multivariate Cox regression analysis to identify significant predictors of this outcome (Table 3). Variables such as eGFR, heart failure (prior to inclusion), hypertension, etc. were shown to be a predictor of acute ischemic events. However, none of the analyzed biomarkers showed a statistically significant relationship in either group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwenty women (7.1%) and 48 men (5.1%) developed heart failure during follow-up. After multivariate Cox regression analysis, again FGF23 was an independent risk factor for the development of heart failure in both men and women (Table 4). PTH also showed a statistically significant relationship with this event but as observed for the primary outcome, only in the male population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, we analyzed the variables related to all-cause mortality in both genders. By the end of follow-up, 30 women (10.6%) and 89 men (9.4%) had died. We observed that klotho was an independent protective factor in the female population for all-cause mortality (HR 0.80, CI95% 0.67-0.96; p=0.019) (Table 5). Phosphate levels were also independently but positively associated with this outcome in this population (HR 2.24 (1.11-4.50; p=0.025). In contrast, in men the MM components associated with this outcome included only FGF23 (HR 1.02 (1.00-1.03); p=0.048) and calcidiol (HR 0.84 (0.72-0.98); p=0.024) but not klotho and phosphate plasma levels.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eMany differences have been described between men and women regarding coronary artery disease. Women have less coronary atherosclerosis\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, and a lower risk of suffering ACS than men\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In addition, the age of onset is higher in women than in men, with a higher prevalence of comorbidities \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The impact of the different risk factors according to gender also presents differences; with the greater importance in women of diabetes, hypertension and smoking \u003csup\u003e\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Thus, the risk of death is known to be higher in women. This higher mortality in women is described mainly in the earlier phases after ACS, with a worse prognosis and higher mortality having been observed immediately after percutaneous intervention\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The possible causes of this worse prognosis are diverse, and they may include a delay in the diagnosis of ACS favored by the higher likelihood of atypical symptoms\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003eand differences in high-sensitivity troponin levels as compared to men\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Furthermore, women with ACS are less likely to receive optimal therapy than men\u003csup\u003e\u003cspan additionalcitationids=\"CR31 CR32 CR33\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eChanges in plasma levels of the different components of MM have been related to different cardiovascular abnormalities. Low calcidiol and high PTH levels have been associated with left ventricular hypertrophy, hypertension, coronary heart disease and increased cardiovascular risk\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Increased FGF23 has been related with left ventricular hypertrophy\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, heart failure\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, atrial fibrillation\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003eand coronary heart disease\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003eand is associated with worse prognoses both in the general population and in patients with CVD\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Furthermore, MM abnormalities are not restricted to patients with CKD, but they are also present in patients with normal renal function\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, where they may also have prognostic value\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In spite of this, there is no information regarding the behaviour of MM components in women with ACS.\u003c/p\u003e \u003cp\u003eIn this paper we demonstrate that women with ACS present a worse MM profile than men, with higher FGF23, PTH, and phosphate levels. Regarding prognosis, FGF23 levels were independent predictors of the primary outcome in both genders, while PTH added independent predictive value only in men. Similar results were obtained in the prediction of heart failure, where PTH showed significant predictive value in the multivariate study only in males (in agreement with the observations of other authors where PTH level was related to clinical and subclinical markers of congestion\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e), but not in females. However, for the prediction of all-cause mortality there were marked differences between both groups, with low klotho levels being predictive in women, along with phosphate levels, while in men high FGF23 and low calcidiol levels were the independent predictors for this outcome.\u003c/p\u003e \u003cp\u003eKlotho is the co-receptor of FGFR1 for FGF23, which exerts its beneficial actions through this canonical pathway, such as helping the failing kidneys to eliminate phosphate. However, in the absence of klotho, FGF23 binds to other receptors promoting cardiac hypertrophy and fibrosis and stimulating the production of pro-inflammatory cytokines\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Then, it has been said to have protective effects. Klotho suppression in animal models is associated with early ageing, shorter life expectancy, multi-organ dysfunction and marked alterations in mineral homeostasis (hyperphosphataemia, hypercalcaemia, amongothers.)\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. More recently, an independent association between low klotho levels with left ventricular hypertrophy\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, heart failure\u003csup\u003e\u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, atrial fibrillation\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003eand myocardial infarction\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e has been described in humans. Klotho has also demonstrated a prognostic role in heart failure\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e, with low levels also being a marker of total and cardiovascular mortality in CKD patients\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003eand in the general population\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBasic research studies report results that may explain in part a potential benefit of klotho in ACS. The administration of klotho in animal models protects the myocardium from ischaemic and reperfusion damage through the activation of different pathways that reduce oxidative stress and restore autophagy levels\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. Klotho has been described to modulate platelet activity\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e. Klotho therapy improves cardiac remodelling in a murine model of myocardial infarction\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e and it also ameliorates diastolic function\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e, although there are not clinical studies confirming these findings. In several other studies, authors have also observed a beneficial effect of klotho on the vascular endothelium, reducing oxidative stress at this level or attenuating cell apoptosis, among other mechanisms\u003csup\u003e\u003cspan additionalcitationids=\"CR64 CR65\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, there are no published data on the prognostic role of klotho after an ACS. To our knowledge, our work is the first to describe an independent protective role of klotho after ACS. According to the present findings, we have recently shown that cardiac rehabilitation after ACS is associated with increases of klotho levels\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e, suggesting an increase in klotho could explain, at least in part, the benefits of cardiac rehabilitation. Of interest, the protective role of klotho is limited to women. It is possible that the higher cardiovascular risk profile of men, with more extensive coronary disease and a greater number of affected vessels, may interfere with the prognostic role of klotho, attenuating its protective effect after ACS. It is also striking that our results show that other MM biomarkers have a prognostic value in men but not in women. Nevertheless, we have demonstrated previously that it is common that several MM biomarkers have independent prognostic value\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, even after adjusting for established biomarkers such as NT-proBNP. This underlines the need to make a complete assessment of MM to investigate the prognostic value of its components.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eFirst, the percentage of women in our study population is relatively low. This is in line with many other published studies. There are several factors that may influence the lower recruitment of women, among them, a higher prevalence of ACS in men could partly account for this difference. Second, the design of the study required the collection of plasma for analysis at discharge no later than 6 days after admission, to achieve homogeneous results. This led to the exclusion of ACS patients who did not meet this condition and that fact may explain the low number of cases with LVEF\u0026thinsp;\u003cem\u003e\u0026lt;\u003c/em\u003e\u0026thinsp;40% that were included. Therefore, these results should not be extrapolated to populations with a high percentage of patients with moderate or severe LV systolic dysfunction. Third, the inclusion period ended in 2014. Since then, new pharmacological and non-pharmacological treatments (stents, catheters, etc.) have emerged that could influence the results of similar studies in current populations. Fourth, almost all the women included in our study population were in the postmenopausal period. However, the variables collected in our study did not include the presence of osteoporosis or the use of specific gynaecological therapies. It is possible that hormonal or osteoporosis treatments may influence some of the parameters and/or biomarkers obtained.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our results show that klotho levels are inversely related to all-cause mortality in women after an ACS, highlighting a possible gender-specific prognostic biomarker. These results underline the importance of considering MM biomarkers in the risk stratification and management of ACS patients, with attention to gender differences. Future research should explore the underlying mechanisms of these associations.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eFunding support/Acknowledgements\u003c/h2\u003e\n\u003cp\u003eThis work was supported by grants from Carlos III Health Institute (ISCIII) (PI17/01495; PI20/00923; PI23/00119; PI24/00978), Spain\u0026rsquo;s Ministry of Science and Innovation (RTC2019-006826-1), Spanish Society of Cardiology and Carlos III Health Institute FEDER (FJD biobank: RD09/0076/00101).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eConceptualization, M.C. and J.T.; Methodology, N.T., C.C., C.G.L., A.H., J.A., L.L.B., M.L.G.C., J.E. and J.T.; Formal Analysis, I.M.F.; Investigation, M.C., A.K.M., A.M., A.A. and O.L.; Resources, N.T., C.C., C.G.L., A.H., J.A., L.L.B., M.L.G.C., J.E. and J.T.; Writing-Original Draft, M.C.; Writing-Review \u0026amp; Editing, J.T.; Supervision, J.T.; Funding Acquisition, J.T. and J.E.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThis work was supported by grants from Carlos III Health Institute (ISCIII) (PI17/01495; PI20/00923; PI23/00119; PI24/00978), Spain\u0026rsquo;s Ministry of Science and Innovation (RTC2019-006826-1), Spanish Society of Cardiology and Carlos III Health Institute FEDER (FJD biobank: RD09/0076/00101).\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eData is provided within the manuscript. Further information and requests for resources and data base should be directed to and will be fulfilled by the lead contact, Dr.Marcelino Cort\u0026eacute;s ([email protected]).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWolf, M. Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease. \u003cem\u003eJournal of the American Society of Nephrology\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 1427\u0026ndash;1435 (2010).\u003c/li\u003e\n\u003cli\u003eMichos, E. D., Cainzos-Achirica, M., Heravi, A. S. \u0026amp; Appel, L. J. Vitamin D, Calcium Supplements, and Implications for Cardiovascular Health. \u003cem\u003eJournal of the American College of Cardiology\u003c/em\u003e \u003cstrong\u003e77\u003c/strong\u003e, 437\u0026ndash;449 (2021).\u003c/li\u003e\n\u003cli\u003eFalkner, B., Keith, S. W., Gidding, S. S. \u0026amp; Langman, C. B. 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Low Serum Klotho Associated With All-cause Mortality Among a Nationally Representative Sample of American Adults. \u003cem\u003eThe Journals of Gerontology: Series A\u003c/em\u003e \u003cstrong\u003e77\u003c/strong\u003e, 452\u0026ndash;456 (2022).\u003c/li\u003e\n\u003cli\u003eYang, Z. \u003cem\u003eet al.\u003c/em\u003e The prognostic value of serum \u0026alpha;-klotho in age-related diseases among the US population: A prospective population-based cohort study. \u003cem\u003ePrev Med Rep\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 102730 (2024).\u003c/li\u003e\n\u003cli\u003eOlejnik, A., Radajewska, A., Krzywonos-Zawadzka, A. \u0026amp; Bil-Lula, I. Klotho inhibits IGF1R/PI3K/AKT signalling pathway and protects the heart from oxidative stress during ischemia/reperfusion injury. \u003cem\u003eSci Rep\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 20312 (2023).\u003c/li\u003e\n\u003cli\u003eQiu, Z. \u003cem\u003eet al.\u003c/em\u003e Activation of Klotho/SIRT1 signaling pathway attenuates myocardial ischemia reperfusion injury in diabetic rats. \u003cem\u003eShock\u003c/em\u003e (2024) doi:10.1097/SHK.0000000000002418.\u003c/li\u003e\n\u003cli\u003eYang, K. \u003cem\u003eet al.\u003c/em\u003e Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e129\u003c/strong\u003e, 2667\u0026ndash;2679 (2017).\u003c/li\u003e\n\u003cli\u003eYue, C. \u003cem\u003eet al.\u003c/em\u003e Ultrasound‑targeted microbubble destruction technology delivering \u0026beta;‑klotho to the heart enhances FGF21 sensitivity and attenuates heart remodeling post‑myocardial infarction. \u003cem\u003eInt J Mol Med\u003c/em\u003e \u003cstrong\u003e53\u003c/strong\u003e, 54 (2024).\u003c/li\u003e\n\u003cli\u003eDaneshgar, N. \u003cem\u003eet al.\u003c/em\u003e Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways. \u003cem\u003eGeroScience\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 4729\u0026ndash;4741 (2024).\u003c/li\u003e\n\u003cli\u003eIkushima, M. \u003cem\u003eet al.\u003c/em\u003e Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. \u003cem\u003eBiochem Biophys Res Commun\u003c/em\u003e \u003cstrong\u003e339\u003c/strong\u003e, 827\u0026ndash;832 (2006).\u003c/li\u003e\n\u003cli\u003eCui, W., Leng, B., Liu, W. \u0026amp; Wang, G. Suppression of Apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) by Klotho Protein is Associated with Reduced Endoplasmic Reticulum Oxidative Stress and Activation of the PI3K/AKT Pathway. \u003cem\u003eMed Sci Monit\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, 8489\u0026ndash;8499 (2018).\u003c/li\u003e\n\u003cli\u003eMaltese, G. \u003cem\u003eet al.\u003c/em\u003e The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. \u003cem\u003eJ Cell Mol Med\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 621\u0026ndash;627 (2017).\u003c/li\u003e\n\u003cli\u003eKawarazaki, W. \u003cem\u003eet al.\u003c/em\u003e Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency. \u003cem\u003eJ Clin Invest\u003c/em\u003e \u003cstrong\u003e130\u003c/strong\u003e, 4152\u0026ndash;4166 (2020).\u003c/li\u003e\n\u003cli\u003ePello L\u0026aacute;zaro, A. M. \u003cem\u003eet al.\u003c/em\u003e Cardiac Rehabilitation Increases Plasma Klotho Levels. \u003cem\u003eJ Clin Med\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 1664 (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Baseline characteristis of study population\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale(n=282)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale (n=948)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e65.7 \u0026plusmn; 13.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e60.5 \u0026plusmn; 11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u0026gt;\u0026nbsp;70\u0026nbsp;years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e127 (45.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e241 (25.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eCaucasian race\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e275 (97.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e917 (96.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eDiabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e70 (24.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e210 (22.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e199 (70.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e504 (53.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e28.5 \u0026plusmn; 5.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e28.3 \u0026plusmn; 4.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eDyslipidaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e165 (58.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e575 (60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e79 (28.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e442 (46.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eeGFR\u0026nbsp;\u0026lt;\u0026nbsp;60\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e81 (28.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e151 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eHeart failure (prior to inclusion)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e4 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e10 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eCoronary artery disease (prior)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e42 (14.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e202 (21.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003ePeripheral artery disease (prior)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e7 (2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e64 (6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eCerebrovascular accident (prior)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e13 (4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e27 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eAtrial fibrillation (prior)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e8 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e20 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaboratory results\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eHemoglobin (g/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e13.5 \u0026plusmn; 1.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e15.1 \u0026plusmn; 1.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eGlycaemia (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e116 \u0026plusmn; 38.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e117 \u0026plusmn; 39.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eeGFR (mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e74.9 \u0026plusmn; 22.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e79.8 \u0026plusmn; 19.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eTroponin (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e8.13 (0.80, 30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e11.4 (0.82, 59.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eLDL (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e119 \u0026plusmn; 39.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e116 \u0026plusmn; 36.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e122 (82.5, 177)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e134 (98.0, 185)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eHDL (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e47.2 \u0026plusmn; 14.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e38.1 \u0026plusmn; 10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eCalcidiol (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e16.4 (12.4, 24.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e18.6 (13.5, 24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003ePTH (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e54.0 (40.3, 70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e45.0 (36.0, 60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eFGF23 (RU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e126 (95.0, 173)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e105 (82.0, 138)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eKlotho (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e657 \u0026plusmn; 219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e621 \u0026plusmn; 205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e3.44 (3.12, 3.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e3.21 (2.85, 3.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eNT-proBNP (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e551 (226, 1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e348 (121, 912)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003ehs-CRP (ng/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e1.36 (0.59, 2.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e1.74 (0.78, 3.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of ACS and coronary findings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eNSTEMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e114 (40.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e326 (34.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eSTEMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e129 (45.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e482 (50.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eUnstable Angina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e39 (13.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e140 (14.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eLVEF\u0026nbsp;\u0026lt;\u0026nbsp;40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e41 (14.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e131 (13.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eNumber of affected vessels\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e1.22 \u0026plusmn; 0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e1.51 \u0026plusmn; 0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eLeft main disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e9 (3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e33 (3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eComplete revascularization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e211 (74.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e660 (69.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of revascularization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eNo revascularization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e70 (24.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e115 (12.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eDrug eluting stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e142 (50.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e492 (51.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eBare metal stent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e52 (18.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e261 (27.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eBalloon angioplasty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e11 (3.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e27 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eCoronary artery bypass grafting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e7 (2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e53 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatments at discharge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e264 (93.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e911 (96.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eP2Y12 inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e241 (85.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e867 (91.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eAnticoagulant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e22 (7.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e60 (6.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eStatins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e264 (93.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e916 (96.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eEzetimibe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e4 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e18 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eInsulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e25 (8.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e57 (6.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eOral antidiabetic drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e39 (13.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e149 (15.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eACEI/ARB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e227 (80.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e770 (81.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eMRAs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e26 (9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e71 (7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eBeta-blockers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e227 (80.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e789 (83.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eNitrates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e53 (18.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e133 (14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eDiuretics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e48 (17.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e139 (14.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; ASA: acetylsalicylic acid; eGFR: estimated glomerular filtration rate; FGF23: fibroblast growth factor 23; HDL: high density lipoprotein; hs-CRP: high sensitivity C-reactive protein; LDL: low density lipoprotein; LVEF: left ventricular ejection fraction; NS: statistically not significant; NSTEMI: \u0026nbsp;non-ST elevation myocardial infarction; MRAs: mineralocorticoid receptor antagonists; \u0026nbsp;NT-ProBNP: N-terminal-probrainnatriuretic peptide; PTH: parathormone; STEMI: ST-elevation myocardial infarction.\u003c/p\u003e\n\u003cp\u003eTable 2: Multivariable Cox regression analysis for the primary outcome of acute ischemic event, heart failure or death\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (CI 95%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eeGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e0.85 (0.77-0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eNitrates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e2.34 (1.40-3.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eCVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e4.17 (1.98-8.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eFGF23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.02 (1.01-1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eDiltiazem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e2.41 (1.07-5.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eDiabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.65 (1.02-2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eStatins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e0.497 (0.25-0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.0 (1.02-1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eDiuretics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.77 (1.29-2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eCAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.40 (1.05-1.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eDiabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.50 (1.13-2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e0.52 (0.31-0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003ePTH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.06 (1.01-1.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eFGF23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1.04 (1.00-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eASA: acetylsalicylic acid; CVA: cerebrovascular accident (prior to inclusion); \u0026nbsp;CAD: coronary artery disease (prior to inclusion); \u0026nbsp;eGFR: estimated glomerular filtration rate; FGF23: fibroblast growth factor 23; HR: Hazar Ratio; PTH: parathormone.\u003c/p\u003e\n\u003cp\u003eTable 3: Multivariable Cox regression analysis for the secondary outcome of acute ischemic events\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (CI 95%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eHeart failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e6.43 (2.09-19.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eNitrates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e3.19 (1.79-5.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eGlycaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e1.09 (1.03-1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eeGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e0.87 (0.76-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eCCB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003e2.43 (1.59-3.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eHeart failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003e3.75 (1.37-10.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003e1.75 (1.20-2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eTriglycerides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003e1.01 (1.00-1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eACEI/ARB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003e0.65 (0.44-0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; eGFR: estimated glomerular filtration rate; HR: Hazar Ratio.\u003c/p\u003e\n\u003cp\u003eTable 4: Multivariable Cox regression analysis for the secondary outcome of heart failure\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (CI 95%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eMRAs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9.22 (3.21-26.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eFGF23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.03 (1.01-1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eInsulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5.56 (1.71-18.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.23 (0.06-0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eFGF 23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.04 (1.03-1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003ePTH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.14 (1.06-1.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.06 (1.02-1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eOral antidiabetic drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3.02 (1.60-5.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eLVEF\u0026nbsp;\u0026lt;\u0026nbsp;40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3.73 (1.99-6.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eDiltiazem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.97 (1.68-14.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.23 (1.03-4.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eASA: acetylsalicylic acid; eGFR: estimated glomerular filtration rate; \u0026nbsp;FGF23: fibroblast growth factor 23; LVEF: left ventricular ejection fraction; \u0026nbsp;MRAs: mineralocorticoid receptor antagonists; HR: Hazar Ratio; PTH: parathormone\u003c/p\u003e\n\u003cp\u003eTable 5: Multivariable Cox regression analysis for the secondary outcome of all-cause mortality\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (CI 95%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eeGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.97 (0.95-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eAnticoagulant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6.77 (2.69-17.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eDiuretics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3.67 (1.58-8.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eP2Y12 inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.33 (0.14-0.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003ePhosporus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.24 (1.11-4.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eKlotho\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.80 (0.67-0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eLVEF\u0026nbsp;\u0026lt;\u0026nbsp;40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.45 (1.05-5.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.10 (1.07-1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eInsulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.59 (1.44-4.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eNT-proBNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.02 (1.01-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eHeart failure (prior)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.28 (1.78-10.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.41 (0.20-0.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eSmoking\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.71 (1.00-2.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eCalcidiol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.84 (0.72-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003eFGF23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.02 (1.00-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eASA: acetylsalicylic acid; eGFR: estimated glomerular filtration rate; \u0026nbsp;FGF23: fibroblast growth factor 23; LVEF: left ventricular ejection fraction; \u0026nbsp;HR: Hazar Ratio; NT-ProBNP: N-terminal-probrain natriuretic peptide.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"klotho protein, gender, acute coronary syndrome, mineral metabolism, cardiovascular risk","lastPublishedDoi":"10.21203/rs.3.rs-5676287/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5676287/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAlterations in plasma levels of the components of the mineral metabolism (MM) system are related to cardiovascular diseases. However, gender differences of the whole MM system in patients with acute coronary syndrome (ACS) have not been reported. Our objective was to analyse the potential differences on the prognostic role of MM in women suffering an ACS as compared to men. We included 1,230 patients with ACS and collected clinical data and plasma levels of MM components. Primary outcome was a composite of acute ischaemic events, heart failure and all-cause mortality. Secondary outcomes included each component separately. 282 patients (22.9%) were female. After 5.44 years of follow-up, primary outcome occurred in 28.0% women and 23.5% men, and death in 10.6% and 9.4% respectively. FGF23 was associated with primary outcome in both sexes, and calcidiol only in men (HR 1.04, CI95%1.00-1.03). Klotho levels are inversely related to all-cause mortality only in women (HR 0.80, CI95% 0.67\u0026ndash;0.96), while calcidiol (HR 0.84, CI95%0.72\u0026ndash;0.98) and FGF23 levels (HR 1.02 CI95%1.00-1.03) were predictors in men, highlighting a possible gender-specific prognostic biomarker. These results underline the importance of considering MM biomarkers in risk stratification and management of patients with acute coronary syndromes, with attention to gender differences.\u003c/p\u003e","manuscriptTitle":"Klotho plasma levels are an independent predictorof mortality in women with acute coronary syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 11:21:03","doi":"10.21203/rs.3.rs-5676287/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-05-05T17:35:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-05T10:43:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-30T06:24:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227565907620865576151705552582506399663","date":"2025-04-22T21:27:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63287393533853896509348371144086356103","date":"2025-04-20T05:53:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-18T05:11:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-15T10:33:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-04-12T15:42:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7924baae-4427-4def-a9fa-35aab9e7805c","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47405570,"name":"Health sciences/Biomarkers/Prognostic markers"},{"id":47405571,"name":"Health sciences/Cardiology"}],"tags":[],"updatedAt":"2025-05-19T16:03:13+00:00","versionOfRecord":{"articleIdentity":"rs-5676287","link":"https://doi.org/10.1038/s41598-025-01334-2","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-05-14 15:58:13","publishedOnDateReadable":"May 14th, 2025"},"versionCreatedAt":"2025-04-21 11:21:03","video":"","vorDoi":"10.1038/s41598-025-01334-2","vorDoiUrl":"https://doi.org/10.1038/s41598-025-01334-2","workflowStages":[]},"version":"v1","identity":"rs-5676287","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5676287","identity":"rs-5676287","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}