Elevated FGF23 levels predict cardiovascular and cerebrovascular events in acute ischaemic stroke patients

Elevated FGF23 levels predict cardiovascular and cerebrovascular events in acute ischaemic stroke patients | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (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];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Elevated FGF23 levels predict cardiovascular and cerebrovascular events in acute ischaemic stroke patients View ORCID Profile Lingyun Gu , Liping Shen , Weizhang Li , Jinfeng Zhou , Qi Jin , Jiangsheng Yang , Junyou Cui , Zufu Zhu , Zhuowen Xu , Yulong Weng doi: https://doi.org/10.1101/2024.12.12.24318962 Lingyun Gu The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lingyun Gu Liping Shen The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: shenlpapplele{at}163.com zhuowenxu{at}126.com wyljyry{at}163.com Weizhang Li The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jinfeng Zhou The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Qi Jin The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jiangsheng Yang The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Junyou Cui The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zufu Zhu The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zhuowen Xu The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: shenlpapplele{at}163.com zhuowenxu{at}126.com wyljyry{at}163.com Yulong Weng The Affiliated Jiangyin Clinical College of Xuzhou Medical University , Jiangyin, Jiangsu, China MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: shenlpapplele{at}163.com zhuowenxu{at}126.com wyljyry{at}163.com Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract BACKGROUND There have been recent studies on fibroblast growth factor 23 (FGF23) and acute ischaemic stroke (AIS), but some of the results were conflicting. Therefore, the objective of this study was to assess whether baseline FGF23 was associated with the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in AIS patients. METHODS This study enrolled 394 patients with AIS and followed for a median period of 43 months. 130 people who underwent health check-ups in our hospital were selected as the control group. The study endpoint was the first occurrence of MACCE outside the hospital. Serum FGF23 levels were quantified using an enzyme-linked immunosorbent assay. RESULTS Serum FGF23 levels were found to be significantly higher in the AIS group than in the control group (525.14±167.40 vs 338.62±161.71, P <0.05). Furthermore, serum FGF23 levels were observed to be elevated in the MACCE group in comparison to the no MACCE group (646.09±164.05 vs 491.87±152.54, P <0.05). According to the receiver operating characteristic curve analysis, the predictive value of the combination of the three [FGF23, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS)] for the occurrence of MACCE in AIS was higher than that of any of them ( P <0.05), while the difference between the three was not statistically significant. The cumulative MACCE-free survival was found to be significantly higher in the group with low FGF23 levels than in the group with high FGF23 levels, as demonstrated by Kaplan-Meier analysis ( P <0.05). The multifactorial Cox analysis revealed that the elevated baseline serum FGF23 level (HR: 3.731, 95% CI: 2.157-6.452) was a significant predictor of MACCE in AIS patients. CONCLUSIONS Elevated baseline serum FGF23 levels were considered to be a valid predictor of MACCE in patients with AIS. Acute ischaemic stroke (AIS), as one of the common clinical neurological disorders, is the second leading cause of disability and death worldwide. 1 AIS patients have a high risk of major adverse cardiovascular and cerebrovascular events (MACCE), resulting in a significant socioeconomic burden. 2 – 4 The study found that the cumulative risk of recurrence of thrombotic arterial events, including the recurrent AIS, cardiovascular events and death, was greater than 11 percent within five years of the first occurrence of AIS. 5 The risk of AIS recurrence is about 15 percent 10 years after AIS onset, and the risk of hospitalisation for cardiovascular events and AIS recurrence is about 20 percent 15 years later. 6 – 8 Therefore, early identification and aggressive treatment of AIS patients at high risk of developing MACCE is clinically important. Although multiple methods can predict the prognosis of patients with AIS, the predictive efficacy is limited. However, biomarkers may provide additional information to existing predictive methods to guide clinical practice. 9 It has been found that several biomarkers, such as osteoprotegerin, C-reactive protein, galectin-3, and brain-derived neurotrophic factor, have been associated with the prognosis of AIS and have good predictive value. 10 – 13 In recent years, studies related to fibroblast growth factor 23 (FGF23) in cerebrovascular disease have received increasing attention. FGF23 is a phosphotropic hormone secreted mainly by osteoblasts and osteoclasts and acts in various organs via endocrine forms. 14 FGF23 in the blood could be transported into the brain through the blood-brain barrier or the blood-cerebrospinal fluid barrier. 15 Previous studies have found that FGF23 levels were associated with the severity and prognosis of a variety of diseases, including diabetes mellitus, chronic coronary heart disease, heart failure and chronic kidney disease. 16 – 19 Recent studies found that serum FGF23 levels were significantly elevated in patients with AIS and correlated with short-term prognosis. 20 The North Manhattan study found that elevated FGF23 levels were a risk factor for stroke and cerebral haemorrhage events in the population and were associated with small vessel disease and cerebral infarction, but not with chronic kidney disease. 21 , 22 A meta-analysis of seven high-quality prospective studies found a significant positive association between baseline FGF23 levels and stroke incidence, and that elevated FGF23 levels were an independent predictor of stroke. 23 However, there are still inconsistencies in the findings of studies correlating FGF23 levels with AIS. The Multi-Ethnic Atherosclerosis Study (MESA) that included 6,547 members of the general population initially free of cardiovascular disease found that FGF23 levels were not associated with stroke. 24 The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study including 615 stroke patients found that elevated levels of FGF23 were associated with cardioembolic stroke, but not with other stroke subtypes, in community-living adults. 25 Moreover, there are fewer studies correlating FGF23 levels with the occurrence of MACCE in AIS. Therefore, the purpose of this study was to assess whether baseline FGF23 levels were associated with AIS and had the ability to predict the occurrence of MACCE. METHODS Study population This was a prospective study. This study enrolled 394 patients who met the definition of AIS in the Chinese AIS Diagnostic and Treatment Guidelines for AIS. 26 All these patients received standardised treatment according to the guidelines between January 2020 and September 2020 at the affiliated jiangyin clinical college of xuzhou medical university. 130 cases of the general population who had physical examination during the same period served as the control group. The following were the exclusion criteria: recurrent ischemic stroke or cerebral haemorrhage with neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease or vascular dementia, transient ischemic attack, haematological diseases, autoimmune diseases, co-infections, inability to follow up. This study was obtained approval from the Ethics Committee of Jiangyin People’s Hospital (Approval No. 2020008). Informed consent was obtained from the patients or their families (patients who were unable to communicate) prior to enrolment of all patients. Clinical and Laboratory Assessments After the patients were enrolled, a detailed neurological physical examination was performed and recorded after detailed questioning of their current and past medical history by experts with extensive clinical experience. The height and weight of the patients were recorded to calculate the body mass index (BMI). The National Institutes of Health Stroke Scale (NIHSS) score was used to assess the severity of AIS immediately after patient enrolment. 27 The Oxfordshire Community Stroke Project criteria and the TOAST (Trialof Org 10172 in Acute Stroke Treatment) classification criteria were used to identify stroke syndromes and stroke etiology in the enrolled patients, respectively. 28 Elbow venous blood was drawn from fasting enrolled patients on the morning of the second day of hospitalisation. A portion of the blood sample was delivered to the central laboratory where total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and creatinine levels were measured using the Roche e602 and c701 modules, respectively. The other part of the blood sample was left at room temperature for 1 hour and then centrifuged at 3000 r/min for 15 minutes to obtain the upper serum layer, which was stored at -80°C in a refrigerator. After following the instructions of the human enzyme-linked immunosorbent assay kit (Elabscience), serum FGF23 concentration was measured at 450 nm using an enzyme marker. Follow-up Patients or their families were followed up monthly through clinic visits or by telephone. The median follow-up time in this study as of December 2023 was 43 months (interquartile range, 39-44 months). The endpoint event in this study was the first out-of-hospital MACCE, including AIS, lacunar cerebral infarction, cerebral haemorrhage, non-fatal myocardial infarction, heart failure, and all-cause mortality. At the end of the follow-up, a modified Rankin Scale (mRS) was used to assess the neurological recovery of the enrolled patients. Statistical analysis Statistical analysis was performed using the SPSS 25.0 statistical package. Quantitative variables were expressed as means ± standard deviations and compared using Student’s t-test. Categorical variables were expressed as absolute numbers (percentages) and compared using the chi-squared test and the Mann-Whitney-Wilcoxon test. The receiver operating characteristic (ROC) curve was used to determine the best cut-off value for each variable to predict the occurrence of MACCE in patients with AIS. Comparisons between different ROC curves were Z-tested by MedCalc software. Kaplan-Meier survival curves were used for survival analysis and compared using the log-rank test. Univariate and multivariate cox proportional hazards models were used to analyse the relationships between serum FGF23 levels and the occurrence of MACCE, calculating hazard ratios (HRs) and 95% confidence intervals (CIs). All variables that reached statistical significance in the univariate cox analysis were included in the multivariate cox analysis. A p-value < 0.05 was considered statistically significant (two-tailed). RESULTS Baseline Characteristics of Study Participants The comparisons of demographic and baseline clinical characteristics between the AIS and control groups were shown in Table 1 . Serum FGF23 levels were significantly higher in the AIS group than in the control group, and the difference was statistically significant (525.14±167.40 vs 338.62±161.71, P <0.05). The prevalence of hypertension, diabetes mellitus and atrial fibrillation was significantly higher in the AIS group than in the control group ( P <0.05). There was also a statistical difference between the two groups in terms of BMI and blood LDL-C levels, whereas there was no statistical difference in terms of gender, age, blood total cholesterol, triglycerides, HDL-C and creatinine levels. View this table: View inline View popup Download powerpoint Table 1. The Demographic and Baseline Clinical Characteristics of the Patients Comparison of clinical data between the MACCE and no MACCE groups of AIS patients In this study, 394 patients with AIS were followed up for a median duration of 43 months (interquartile range, 39-44 months). By the end of follow-up, a total of 85 MACCEs were recorded, including 33 AIS recurrences, 17 lacunar cerebral infarctions, 4 cerebral haemorrhages, 11 non-fatal myocardial infarctions, 6 heart failures and 9 all-cause deaths. Patients with AIS were divided into a MACCE group and a no MACCE group, based on whether or not a MACCE occurred. The comparison of demographic and baseline clinical characteristics between the two groups was shown in Table 2 . View this table: View inline View popup Download powerpoint Table 2. The Comparison of clinical data between the MACCE and no MACCE group in AIS patients Serum FGF23 levels were significantly elevated in the MACCE group compared to the no MACCE group (646.09±164.05 vs 491.87±152.54, P <0.05). The MACCE group exhibited superior NIHSS and mRS scores in comparison to the NO MACCE group ( P <0.05). The prevalence of total anterior circulation syndrome and cardioembolic was markedly elevated in the MACCE group than in the NO MACCE group ( P <0.05). There was a statistical difference between the two groups in terms of age, history of hypertension, history of atrial fibrillation, blood LDL cholesterol and HDL cholesterol levels, whereas there was no statistically significant difference in terms of gender, BMI, history of diabetes mellitus, blood levels of total cholesterol, triglycerides and creatinine. ROC analyses to predict the occurrence of MACCE in AIS patients To assess the value of FGF23 in predicting the occurrence of MACCE in patients with AIS, a ROC analysis was performed, and the NIHSS and mRS were selected for comparison ( Figure 1 ). According to the ROC analysis, the area under the curve (AUC) of FGF23 was 0.754 (95% CI: 0.693-0.816), which was lower than that of NIHSS (AUC: 0.774, 95% CI: 0.714-0.833) and mRS (AUC: 0.809, 95% CI: 0.751-0.867). However, the difference between the three was not statistically significant. The AUC of the combination of the three was 0.851 (95% CI: 0.797-0.905), which was greater than that of mRS, NIHSS, and FGF23 (Z: 2.557, 3.051, and 3.679, respectively; all P <0.05). Download figure Open in new tab Figure 1. ROC analyses to predict the occurrence of MACCE in AIS patients. AUC, area under the curve; mRS, modified Rankin Scale; NIHSS, national institute of health stroke scale; FGF23, fibroblast growth factor 23. Kaplan-meier analysis of FGF23 and the occurrence of MACCE in AIS patients The optimal cut-off value of FGF23 (642.42pg/mL) based on the Jordon’s index was then used to perform survival analyses. A kaplan-meier analysis based on this cut-off value showed a significant difference between the two groups in terms of cumulative survival rates without MACCE ( Figure 2 ). The cumulative MACCE-free survival rate was significantly higher in the low FGF23 level group than in the high FGF23 level group ( P <0.05). Moreover, the difference between the two groups gradually increased over time, indicating that high FGF23 levels were associated with lower MACCE-free survival. Download figure Open in new tab Figure 2. Kaplan-meier analysis of FGF23 and the occurrence of MACCE in AIS patients. MACCE, major adverse cardiovascular and cerebrovascular events; FGF23, fibroblast growth factor 23. Univariate and Multivariate COX Analysis for MACCE in AIS Patients The univariate COX analysis showed that elevated baseline serum FGF23 levels along with advanced age, elevated BMI, previous history of hypertension and atrial fibrillation, elevated LDL-C levels, high NIHSS and mRS scores, and Stroke syndrome were predictive factors for the development of MACCE in AIS patients ( Table 3 ). Further multifactorial COX analyses of statistically significant metrics showed that elevated baseline serum FGF23 levels (HR: 3.731, 95%CI:2.157-6.452) remained a potent predictor of the development of MACCE in patients with AIS, as did advanced age, a history of previous AF, elevated LDL-C levels, high NIHSS and mRS scores, and Stroke syndrome. View this table: View inline View popup Download powerpoint Table 3. Univariate and Multivariate COX Analysis for MACCE in AIS Patients Variables Univariate analysis Multivariate analysis DISCUSSION In the present study, serum FGF23 levels were found to be elevated in AIS patients. After a median follow-up of 43 months, serum FGF23 levels were further elevated in AIS patients who incurred MACCE. FGF23 had similar high predictive value as NIHSS and mRS for the occurrence of MACCE in AIS patients. Moreover, elevated baseline serum FGF23 level was an effective predictor of the occurrence of MACCE in AIS patients. It has been found that multiple factors involved in the development of AIS such as inflammatory response, hypoxia, energy and metabolism promote FGF23 production. 29 , 30 FGF23, secreted by osteoblasts and osteoclasts, acts via endocrine forms in several organs throughout the body, including the kidneys, parathyroid glands, heart, bones and brain. 14 , 31 FGF23 was found to not only inhibit the expression of NPT2a and NPT2c sodium-phosphate cotransporters, but also reduce 1,25(OH) 2 D levels to inhibit renal proximal tubular and intestinal phosphate reabsorption and thereby reduce serum phosphate levels. 32 As a key molecule in cellular metabolic processes, phosphate plays an important role in the development of AIS by participating in energy metabolism, cellular signal transduction, inflammatory response, oxidative stress, and calcium overload. 33 – 35 Reduced serum phosphate levels were strongly associated with AIS. A follow-up of 3,437 patients undergoing haemodialysis for a median of 3.9 years found that the lower the serum phosphate level, the higher the risk of AIS. 36 As for AIS patients, reduced serum phosphate levels were associated not only with severity but also with the occurrence of MACCE. 37 – 39 Inhibition of FGF23 overactivity in certain diseases caused by hypophosphatemia is considered a new therapy for the treatment of these diseases, as human MAB (burosumab) for FGF23 has been approved in several countries including Europe, North America and Japan. 32 Elevated FGF23 were found to predispose to vascular calcification and were associated with vascular stiffness and endothelial dysfunction, all of which may contribute to AIS. 40 The FGF23 receptor Klotho, which is widely expressed in the brain, has anti-inflammatory and antioxidant effects, and its levels decline with age and cardiovascular disease. 41 Statins and renin-angiotensin system inhibitors, which are widely used in clinical practice, can increase Klotho levels and improve the prognosis of cardiovascular diseases. 31 It has been shown that elevated serum FGF23 levels associated with an increased risk of AIS in individuals without chronic kidney disease. 21 Furthermore, for these individuals, FGF23 was not only independently associated with insulin resistance, inflammation, and obesity status, but has also been shown to be a strong predictor of MACCE in patients with cardiovascular disease. 42 – 44 In addition, a large number of studies found that NIHSS and mRS were predictors of the occurrence of MACCE in AIS patients s. 28 , 45 This is similar to our findings that FGF23 had the same value as NIHSS and mRS for predicting the occurrence of MACCE in patients with AIS. However, the MESA and REGARDS studies found that serum FGF23 levels were not associated with AIS or were only associated with cardioembolic stroke. 24 , 25 The reason for the inconsistent findings may be related to the different study populations. For example, the MESA study enrolled people without known cardiovascular disease, whereas the REGARDS study enrolled black and white US adults ≥ 45 years of age, irrespective of cardiovascular disease. In contrast, the present study enrolled patients with AIS. There were some limitations to this study. Firstly, this study was a single-centre study with patient enrolment in only one hospital in one region, which inevitably resulted in selection bias. Second, this study only tested the baseline serum FGF23 levels of the patients and failed to re-test their levels at the time of MACCE, which did not allow for a before-and-after controlled study. Therefore, multicentre, large-scale, long-term clinical studies are still needed to explore the relationship between FGF23 and AIS. CONCLUSIONS The present study demonstrated that serum FGF23 levels were elevated in patients with AIS. Baseline serum FGF23 levels exhibited a high predictive value for MACCE in AIS patients. Furthermore, elevated baseline serum FGF23 levels were identified as a robust and effective predictor of MACCE in AIS patients. Data Availability The data supporting the findings of this study are availablefrom the corresponding author upon reasonable request. Sources of Funding This research was funded by the Medical Research Program of Jiangsu Provincial Health and Wellness Commission (grant no. Z2021042), the Development Fund of Affiliated Hospital of Xuzhou Medical University (grant no. XYFY202349), and the Jiangyin Young and Middle-aged Reserve Excellent Talents Program (grant no. JYROYT202309). Disclosures The authors have no conflicts to declare. REFERENCES 1. ↵ Saini V , Guada L , Yavagal DR . Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions . Neurology . 2021 ; 97 : S6 – S16 . doi: 10.1212/WNL.0000000000012781 OpenUrl CrossRef 2. ↵ Scheitz JF , Sposato LA , Schulz-Menger J , Nolte CH , Backs J , Endres M . Stroke-Heart Syndrome: Recent Advances and Challenges . J Am Heart Assoc . 2022 ; 11 : e026528 . doi: 10.1161/JAHA.122.026528 OpenUrl CrossRef PubMed 3. Chen Y , Wright N , Guo Y , Turnbull I , Kartsonaki C , Yang L , Bian Z , Pei P , Pan D , Zhang Y , et al. Mortality and recurrent vascular events after first incident stroke: a 9-year community-based study of 0.5 million Chinese adults . Lancet Glob Health . 2020 ; 8 : e580 – e590 . doi: 10.1016/S2214-109X(20)30069-3 OpenUrl CrossRef 4. ↵ Flach C , Muruet W , Wolfe CDA , Bhalla A , Douiri A . Risk and Secondary Prevention of Stroke Recurrence: A Population-Base Cohort Study . Stroke . 2020 ; 51 : 2435 – 2444 . doi: 10.1161/STROKEAHA.120.028992 OpenUrl CrossRef PubMed 5. ↵ Putaala J , Haapaniemi E , Metso AJ , Metso TM , Artto V , Kaste M , Tatlisumak T . Recurrent ischemic events in young adults after first-ever ischemic stroke . Ann Neurol . 2010 ; 68 : 661 – 671 . doi: 10.1002/ana.22091 OpenUrl CrossRef PubMed 6. ↵ Putaala J . Ischemic Stroke in Young Adults . Continuum (Minneap Minn ) . 2020 ; 26 : 386 – 414 . doi: 10.1212/CON.0000000000000833 OpenUrl CrossRef PubMed 7. Aarnio K , Siegerink B , Pirinen J , Sinisalo J , Lehto M , Haapaniemi E , Nave AH , Kaste M , Tatlisumak T , Putaala J . Cardiovascular events after ischemic stroke in young adults: A prospective follow-up study . Neurology . 2016 ; 86 : 1872 – 1879 . doi: 10.1212/WNL.0000000000002689 OpenUrl Abstract / FREE Full Text 8. ↵ Pezzini A , Grassi M , Lodigiani C , Patella R , Gandolfo C , Zini A , Delodovici ML , Paciaroni M , Del Sette M , Toriello A , et al. Predictors of long-term recurrent vascular events after ischemic stroke at young age: the Italian Project on Stroke in Young Adults . Circulation . 2014 ; 129 : 1668 – 1676 . doi: 10.1161/CIRCULATIONAHA.113.005663 OpenUrl Abstract / FREE Full Text 9. ↵ Montellano FA , Ungethum K , Ramiro L , Nacu A , Hellwig S , Fluri F , Whiteley WN , Bustamante A , Montaner J , Heuschmann PU . Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review . Stroke . 2021 ; 52 : 543 – 551 . doi: 10.1161/STROKEAHA.120.029232 OpenUrl CrossRef PubMed 10. ↵ Zhu Z , Guo D , Zhang K , Yang P , Jia Y , Shi M , Peng Y , Chen J , Wang A , Xu T , et al. Osteoprotegerin and Ischemic Stroke Prognosis: A Prospective Multicenter Study and Mendelian Randomization Analysis . Stroke . 2023 ; 54 : 509 – 517 . doi: 10.1161/STROKEAHA.122.040800 OpenUrl CrossRef PubMed 11. VanGilder RL , Davidov DM , Stinehart KR , Huber JD , Turner RC , Wilson KS , Haney E , Davis SM , Chantler PD , Theeke L , et al. C-reactive protein and long-term ischemic stroke prognosis . J Clin Neurosci . 2014 ; 21 : 547 – 553 . doi: 10.1016/j.jocn.2013.06.015 OpenUrl CrossRef PubMed 12. Sayed A , Munir M , Nabet MS , Alghamdi BS , Ashraf GM , Bahbah EI , Elfil M . Galectin-3: A Novel Marker for the Prediction of Stroke Incidence and Clinical Prognosis . Mediators Inflamm . 2022 ; 2022 : 2924773 . doi: 10.1155/2022/2924773 OpenUrl CrossRef PubMed 13. ↵ Zhu Y , Sun L , Huang T , Jia Y , Yang P , Zhang Q , Fang C , Shi M , Guo D , Peng Y , et al. High Serum Brain-Derived Neurotrophic Factor Is Associated With Decreased Risks of Poor Prognosis After Ischemic Stroke . Stroke . 2023 ; 54 : 1789 – 1797 . doi: 10.1161/STROKEAHA.122.042362 OpenUrl CrossRef PubMed 14. ↵ Ho BB , Bergwitz C . FGF23 signalling and physiology . J Mol Endocrinol . 2021 ; 66 : R23 – R32 . doi: 10.1530/JME-20-0178 OpenUrl CrossRef PubMed 15. ↵ Ursem SR , Diepenbroek C , Bacic V , Unmehopa UA , Eggels L , Maya-Monteiro CM , Heijboer AC , la Fleur SE . Localization of fibroblast growth factor 23 protein in the rat hypothalamus . Eur J Neurosci . 2021 ; 54 : 5261 – 5271 . doi: 10.1111/ejn.15375 OpenUrl CrossRef PubMed 16. ↵ van der Vaart A , Bakker SJL , Laverman GD , van Dijk PR , de Borst MH . NT-proBNP Mediates the Association Between FGF23 and All-Cause Mortality in Individuals With Type 2 Diabetes . J Am Heart Assoc . 2023 ; 12 : e031873 . doi: 10.1161/JAHA.123.031873 OpenUrl CrossRef PubMed 17. Wallentin L , Eriksson N , Olszowka M , Grammer TB , Hagstrom E , Held C , Kleber ME , Koenig W , Marz W , Stewart RAH , et al. Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study . PLoS Med . 2021 ; 18 : e1003513 . doi: 10.1371/journal.pmed.1003513 OpenUrl CrossRef 18. Koller L , Kleber ME , Brandenburg VM , Goliasch G , Richter B , Sulzgruber P , Scharnagl H , Silbernagel G , Grammer TB , Delgado G , et al. Fibroblast Growth Factor 23 Is an Independent and Specific Predictor of Mortality in Patients With Heart Failure and Reduced Ejection Fraction . Circ Heart Fail . 2015 ; 8 : 1059 – 1067 . doi: 10.1161/CIRCHEARTFAILURE.115.002341 OpenUrl Abstract / FREE Full Text 19. ↵ Poelzl G , Trenkler C , Kliebhan J , Wuertinger P , Seger C , Kaser S , Mayer G , Pirklbauer M , Ulmer H , Griesmacher A . FGF23 is associated with disease severity and prognosis in chronic heart failure . Eur J Clin Invest . 2014 ; 44 : 1150 – 1158 . doi: 10.1111/eci.12349 OpenUrl CrossRef PubMed 20. ↵ Wei Z , Zhong C , Wu C , Liu Y . The effects of fibroblast growth factor-23 on diagnosis of cerebral infarction and vertebral basilar artery stenosis(⋆) . Clinics (Sao Paulo ) . 2024 ; 79 : 100457 . doi: 10.1016/j.clinsp.2024.100457 OpenUrl CrossRef PubMed 21. ↵ Wright CB , Shah NH , Mendez AJ , DeRosa JT , Yoshita M , Elkind MS , Sacco RL , DeCarli C , Rundek T , Silverberg S , et al. Fibroblast Growth Factor 23 Is Associated With Subclinical Cerebrovascular Damage: The Northern Manhattan Study . Stroke . 2016 ; 47 : 923 – 928 . doi: 10.1161/STROKEAHA.115.012379 OpenUrl Abstract / FREE Full Text 22. ↵ Wright CB , Dong C , Stark M , Silverberg S , Rundek T , Elkind MS , Sacco RL , Mendez A , Wolf M . Plasma FGF23 and the risk of stroke: the Northern Manhattan Study (NOMAS) . Neurology . 2014 ; 82 : 1700 – 1706 . doi: 10.1212/WNL.0000000000000410 OpenUrl Abstract / FREE Full Text 23. ↵ Yao XY , Li S , Zhang LG , Liu ZH , Bao JN , Wu ZY . Higher Serum Fibroblast Growth Factor-23 Levels and the Risk of Stroke and Its Subtypes: Evidence From a Meta-Analysis of Prospective Studies . J Stroke Cerebrovasc Dis . 2018 ; 27 : 3076 – 3083 . doi: 10.1016/j.jstrokecerebrovasdis.2018.06.040 OpenUrl CrossRef PubMed 24. ↵ Kestenbaum B , Sachs MC , Hoofnagle AN , Siscovick DS , Ix JH , Robinson-Cohen C , Lima JA , Polak JF , Blondon M , Ruzinski J , et al. Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis . Circ Heart Fail . 2014 ; 7 : 409 – 417 . doi: 10.1161/CIRCHEARTFAILURE.113.000952 OpenUrl Abstract / FREE Full Text 25. ↵ Panwar B , Jenny NS , Howard VJ , Wadley VG , Muntner P , Kissela BM , Judd SE , Gutierrez OM . Fibroblast growth factor 23 and risk of incident stroke in community-living adults . Stroke . 2015 ; 46 : 322 – 328 . doi: 10.1161/STROKEAHA.114.007489 OpenUrl Abstract / FREE Full Text 26. ↵ Chinese Society of N , Chinese Stroke S . Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018 . Chinese Journal of Neurology . 2018 ; 51 : 666 – 682 . OpenUrl 27. ↵ Brott T , Adams HP , Jr. , Olinger CP , Marler JR , Barsan WG , Biller J , Spilker J , Holleran R , Eberle R , Hertzberg V , et al. Measurements of acute cerebral infarction: a clinical examination scale . Stroke . 1989 ; 20 : 864 – 870 . doi: 10.1161/01.str.20.7.864 OpenUrl Abstract / FREE Full Text 28. ↵ Tu WJ , Qiu HC , Liu YK , Liu Q , Zeng X , Zhao J . Elevated levels of adiponectin associated with major adverse cardiovascular and cerebrovascular events and mortality risk in ischemic stroke . Cardiovasc Diabetol . 2020 ; 19 : 125 . doi: 10.1186/s12933-020-01096-3 OpenUrl CrossRef PubMed 29. ↵ Qin C , Yang S , Chu YH , Zhang H , Pang XW , Chen L , Zhou LQ , Chen M , Tian DS , Wang W . Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions . Signal Transduct Target Ther . 2022 ; 7 : 215 . doi: 10.1038/s41392-022-01064-1 OpenUrl CrossRef PubMed 30. ↵ Simic P , Babitt JL . Regulation of FGF23: Beyond Bone . Curr Osteoporos Rep . 2021 ; 19 : 563 – 573 . doi: 10.1007/s11914-021-00703-w OpenUrl CrossRef PubMed 31. ↵ Prud’homme GJ , Kurt M , Wang Q . Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations . Front Aging . 2022 ; 3 : 931331 . doi: 10.3389/fragi.2022.931331 OpenUrl CrossRef PubMed 32. ↵ Fukumoto S . FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment . J Mol Endocrinol . 2021 ; 66 : R57 – R65 . doi: 10.1530/JME-20-0089 OpenUrl CrossRef PubMed 33. ↵ Shehjar F , Maktabi B , Rahman ZA , Bahader GA , James AW , Naqvi A , Mahajan R , Shah ZA. Stroke: Molecular mechanisms and therapies: Update on recent developments . Neurochem Int . 2023 ; 162 : 105458 . doi: 10.1016/j.neuint.2022.105458 OpenUrl CrossRef PubMed 34. DeLong JH , Ohashi SN , O’Connor KC , Sansing LH . Inflammatory Responses After Ischemic Stroke . Semin Immunopathol . 2022 ; 44 : 625 – 648 . doi: 10.1007/s00281-022-00943-7 OpenUrl CrossRef 35. ↵ Nanetti L , Raffaelli F , Vignini A , Perozzi C , Silvestrini M , Bartolini M , Provinciali L , Mazzanti L . Oxidative stress in ischaemic stroke . Eur J Clin Invest . 2011 ; 41 : 1318 – 1322 . doi: 10.1111/j.1365-2362.2011.02546.x OpenUrl CrossRef PubMed 36. ↵ Yamada S , Tsuruya K , Taniguchi M , Tokumoto M , Fujisaki K , Hirakata H , Fujimi S , Kitazono T . Association Between Serum Phosphate Levels and Stroke Risk in Patients Undergoing Hemodialysis: The Q-Cohort Study . Stroke . 2016 ; 47 : 2189 – 2196 . doi: 10.1161/STROKEAHA.116.013195 OpenUrl Abstract / FREE Full Text 37. ↵ Schwedhelm E , Schwieren L , Tiedt S , von Lucadou M , Gloyer NO , Boger R , Magnus T , Daum G , Thomalla G , Gerloff C , et al. Serum Sphingosine-1-Phosphate Levels Are Associated With Severity and Outcome in Patients With Cerebral Ischemia . Stroke . 2021 ; 52 : 3901 – 3907 . doi: 10.1161/STROKEAHA.120.033414 OpenUrl CrossRef PubMed 38. Jia J , Guo J , Liu X , Li G , Liu Y , Zhao X . Impact of serum phosphate on severity and functional outcomes after ischemic stroke in young adults . Nutr Metab Cardiovasc Dis . 2022 ; 32 : 2553 – 2560 . doi: 10.1016/j.numecd.2022.08.008 OpenUrl CrossRef PubMed 39. ↵ Zhang JF , Jing J , Meng X , Pan Y , Wang YL , Zhao XQ , Lin JX , Han XS , Song BB , Jia ZC , et al. Serum Phosphate and 1-Year Outcome in Patients With Acute Ischemic Stroke and Transient Ischemic Attack . Front Neurol . 2021 ; 12 : 652941 . doi: 10.3389/fneur.2021.652941 OpenUrl CrossRef PubMed 40. ↵ Marebwa BK , Adams RJ , Magwood GS , Kindy M , Wilmskoetter J , Wolf M , Bonilha L . Fibroblast growth factor23 is associated with axonal integrity and neural network architecture in the human frontal lobes . PLoS One . 2018 ; 13 : e0203460 . doi: 10.1371/journal.pone.0203460 OpenUrl CrossRef PubMed 41. ↵ Lanzani C , Citterio L , Vezzoli G . Klotho: a link between cardiovascular and non-cardiovascular mortality . Clin Kidney J . 2020 ; 13 : 926 – 932 . doi: 10.1093/ckj/sfaa100 OpenUrl CrossRef PubMed 42. ↵ Hanks LJ , Casazza K , Judd SE , Jenny NS , Gutierrez OM . Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults . PLoS One . 2015 ; 10 : e0122885 . doi: 10.1371/journal.pone.0122885 OpenUrl CrossRef PubMed 43. Girerd N , Cleland J , Anker SD , Byra W , Lam CSP , Lapolice D , Mehra MR , van Veldhuisen DJ , Bresso E , Lamiral Z , et al. Inflammation and remodeling pathways and risk of cardiovascular events in patients with ischemic heart failure and reduced ejection fraction . Sci Rep . 2022 ; 12 : 8574 . doi: 10.1038/s41598-022-12385-0 OpenUrl CrossRef PubMed 44. ↵ Wang F , Ma R , Wang C . Perioperative variation in serum FGF-23 level and its correlation with MACCE risk in unprotected left main coronary artery disease patients receiving coronary artery bypassing grafting . Front Surg . 2022 ; 9 : 937342 . doi: 10.3389/fsurg.2022.937342 OpenUrl CrossRef PubMed 45. ↵ Chen YB , Zhou ZY , Li GM , Xiao CX , Yu WB , Zhong SL , Cai YF , Jin J , Huang M . Influences of an NR1I2 polymorphism on heterogeneous antiplatelet reactivity responses to clopidogrel and clinical outcomes in acute ischemic stroke patients . Acta Pharmacol Sin . 2019 ; 40 : 762 – 768 . doi: 10.1038/s41401-018-0178-4 OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted December 14, 2024. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Elevated FGF23 levels predict cardiovascular and cerebrovascular events in acute ischaemic stroke patients Lingyun Gu , Liping Shen , Weizhang Li , Jinfeng Zhou , Qi Jin , Jiangsheng Yang , Junyou Cui , Zufu Zhu , Zhuowen Xu , Yulong Weng medRxiv 2024.12.12.24318962; doi: https://doi.org/10.1101/2024.12.12.24318962 Share This Article: Copy Citation Tools Elevated FGF23 levels predict cardiovascular and cerebrovascular events in acute ischaemic stroke patients Lingyun Gu , Liping Shen , Weizhang Li , Jinfeng Zhou , Qi Jin , Jiangsheng Yang , Junyou Cui , Zufu Zhu , Zhuowen Xu , Yulong Weng medRxiv 2024.12.12.24318962; doi: https://doi.org/10.1101/2024.12.12.24318962 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Neurology Subject Areas All Articles Addiction Medicine (574) Allergy and Immunology (865) Anesthesia (304) Cardiovascular Medicine (4462) Dentistry and Oral Medicine (445) Dermatology (383) Emergency Medicine (611) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1517) Epidemiology (15251) Forensic Medicine (31) Gastroenterology (1132) Genetic and Genomic Medicine (6621) Geriatric Medicine (669) Health Economics (1002) Health Informatics (4564) Health Policy (1372) Health Systems and Quality Improvement (1617) Hematology (544) HIV/AIDS (1272) Infectious Diseases (except HIV/AIDS) (15938) Intensive Care and Critical Care Medicine (1107) Medical Education (624) Medical Ethics (147) Nephrology (670) Neurology (6643) Nursing (346) Nutrition (1001) Obstetrics and Gynecology (1149) Occupational and Environmental Health (957) Oncology (3350) Ophthalmology (981) Orthopedics (369) Otolaryngology (421) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1698) Pharmacology and Therapeutics (694) Primary Care Research (714) Psychiatry and Clinical Psychology (5465) Public and Global Health (9259) Radiology and Imaging (2212) Rehabilitation Medicine and Physical Therapy (1372) Respiratory Medicine (1199) Rheumatology (598) Sexual and Reproductive Health (716) Sports Medicine (533) Surgery (715) Toxicology (100) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a03e1d94aa9e493d',t:'MTc4MDE0ODA1OA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();