Correlation between the upregulation of circulating FABP4 and prognosis of joint replacement in patients with osteoarthritis

doi:10.21203/rs.3.rs-4699232/v1

Objective

The aim of this study was to investigate the potential significance of FABP4 in predicting prognosis following total hip arthroplasty (THA) or total knee arthroplasty (TKA).

Method

This study selected patients undergoing THA/TKA aged >18 years who were hospitalized in Anqing First People’s Hospital of Anhui Medical University. A total of 400 patients and 100 healthy subjects were finally included. Based on the results of 90-day follow-up data were included in the complication group, otherwise, they were classified as the no complications group. The demographic and clinical data of the two groups were compared, and the clinical characteristics and risk factors of local complications within 90 days of TKA/THA were evaluated.

Results

FABP4 concentration (odds ratio (OR)=1.521 95% confidence interval (CI)=1.190–1.944, P =0.001), ASA class (OR=0.064 95% CI=0.005–0.811, P =0.034) and estimated intraoperative blood loss (OR=1.070, 95% CI=1.008–1.135, P=0.027) were found to be predictors of 90-Day Local Complications.

Conclusions

Higher FABP4 concentration is very common in patients with adverse events occurring locally within the 90 days of TKA/THA and the prevalence of adverse events occurring locally within the 90 days of TKA/THA was higher in patients combined with higher FABP4 concentration, higher ASA class or EIBL. FABP4 concentration, ASA class and EIBL are risk factors for the development of adverse events occurring locally within the 90 days of TKA/THA, but validation in larger sample studies is still needed.

90-day local complications

TKA

THA

FABP4 concentration

ASA class

Osteoarthritis

Osteoarthritis (OA) is a prevalent joint disorder that predominantly afflicts the elderly, impacting millions of individuals globally. By 2020, OA had ascended to become the fourth leading cause of disability in humans[1]. The pathological features of OA include the deterioration of joint cartilage and restructuring of subchondral bone, leading to symptoms like joint inflammation, pain, and decreased joint functionality[2]. The knee and hip joints are primarily affected by OA, with lesser occurrences in the elbow, wrist, shoulder (glenohumeral joint), and ankle joints. Treatment options for OA are currently limited, mainly centered on symptom management. Total hip or knee arthroplasty (THA/TKA) stands out as an effective intervention for managing advanced hip or knee OA[3, 4].Overall, THA and TKA show good long-term results, but the recovery process can take weeks to months. Complications may occur during and after arthroplasty, including anaesthesia-related risks, worsening of concomitant disease, adverse drug reactions and allergies, and complications specific to arthroplasty.

Fatty Acid Binding Protein (FABP aP2), also referred to as FABP4, is a key fat-related factor predominantly expressed in adipocytes and macrophages[5]. FABP4 functions as a lipid escort, facilitating the transportation of lipids to specific cellular regions. Previous research indicates that elevated concentrations of FABP4 in the body are linked to conditions such as obesity and metabolic disorders[6–10]. These include type 2 diabetes, atherosclerosis, and coronary heart disease. Furthermore, studies have demonstrated that administering FABP4 inhibitors to mice in animal trials can effectively reduce the risk of joint stiffness.

In summary, variations in the concentration levels of FABP4 in the body may play a significant role in OA disease. However, to date, there is a lack of literature investigating the relationship between FABP4 levels and the postoperative prognosis of OA patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA) surgeries. Therefore, the purpose of this study is to explore the potential association between FABP4 concentration levels and outcomes following TKA/THA procedures. Our research involves recruiting OA patients who have undergone TKA/THA surgeries as well as healthy individuals for comparison, measuring FABP4 levels in their plasma, and conducting a 90-day postoperative follow-up to assess any complications or adverse events.

Participants and collection of blood

We enrolled a cohort of 400 patients who underwent TKA or THA surgeries at our hospital between January 2020 and January 2024, along with 100 healthy participants matched during the same period. This study has been approved by our hospital's ethics committee, and all participants have provided signed informed consent.

Participants under the age of 18 will be excluded. Additionally, patients with underlying conditions such as liver or kidney diseases, cancer, or incomplete information will also be excluded from the study. To maintain uniformity in assessing patient outcomes, only patients treated by surgeons conducting over 30 procedures per year will be included in the study.

We collect patients' basic information and laboratory test results from their medical records during hospitalization, while data for the 90-day follow-up period are retrieved from the outpatient medical records system. We use EDTA anticoagulant tubes to collect fasting venous blood from patients, separate the plasma using a low-temperature centrifugation method, and store it in a -80°C freezer for future use.

Determination of FABP4

We will dilute the plasma 20 times and use an ELISA kit to detect the plasma concentration of FABP4.

Outcome Assessment

As in the previous study, the primary outcome (locally within the 90 days) was defined as any of the following: reoperation, readmission, venous thromboembolism, pulmonary embolism, blood transfusion, peripheral nerve injury, and surgical site infection.

Statistical analyses

We will conduct statistical analysis using IBM SPSS Statistics 26.0. For quantitative parameters, we will report the mean ± standard deviation and use the Student's t-test or the Mann-Whitney nonparametric test to compare differences between groups. Qualitative parameters will be reported in percentage form and compared using the chi-square test. Multiple regression analysis will be performed to determine the risk factors for locally within the 90 days after THA/TKA surgery. Receiver Operating Characteristic (ROC) curve analysis will be used to determine the sensitivity, specificity, area under the curve (AUC), and risk factors for locally within the 90 days after THA/TKA surgery. A p-value less than 0.05 will be considered statistically significant.

Plasma FABP4 was closely associated with OA

After an initial screening of 454 patients with OA and 100 healthy subjects, a total of 400 patients were included in the analysis following exclusions, as depicted in Fig. 1. Based on their plasma FABP4 concentrations, the patients were categorized into a low expression group, consisting of 265 patients, and a high expression group, consisting of 135 patients. Within the primary cohort, 24 patients (6.0%) experienced at least one locally within the 90 days. Elevated plasma FABP4 concentrations were observed in OA patients compared to healthy subjects (20.5 ± 9.8 ng/ml vs. 12.2 ± 3.1 ng/ml, p < 0.001), as demonstrated in Fig. 2

Clinical significance of FABP4 in OA patients

In order to further investigate the clinical relevance of FABP4 in OA, the correlation between FABP4 levels and clinicopathological characteristics was examined. Patients were categorized into two groups according to their plasma FABP4 levels. It was observed that low FABP4 expression was significantly associated with BMI (P = 0.001). No significant correlations were found between FABP4 and other clinicopathological variables, including gender, age, white blood cell count, neutrophil count, mononuclear leucocyte count, D-dimer levels, C-reactive protein levels, total cholesterol levels, triglyceride levels, and the presence of complications (Table 1).

Table 1

Correlation between the expression of FABP4 and clinicopathological characteristics
Variables	Number	FABP4,n(%)		P-value
		Low expression	High expression
Gender
Male	381	251(98.04)	130(74.81)	0.439
Female	19	14(1.96)	5(25.19)	0.439
Age
< 60	263	166(62.64)	97(71.85)	0.160
≥ 60	137	90(37.36)	38(28.15)	0.160
BMI
Thin	22	10(3.77)	12(8.89)	0.001
normal	183	138(52.07)	45(33.33)	0.001
overweight	195	117(44.16)	78(57.78)
white blood cell
Normal	191	135(50.94)	56(41.48)	0.073
High	209	130(49.06)	79(58.52)	0.073
Neutrophil
Normal	219	152(57.36)	67(49.63)	0.142
High	181	113(42.64)	68(50.37)	0.142
Mononuclear leucocyte
Normal	186	118(44.52)	88(65.18)	0.268
High	214	147(55.48)	47(34.82)	0.268
D-dimer
Normal	235	157(59.24)	78(57.78)	0.778
High	165	108(40.76)	57(42.22)	0.778
C-reactive protein
Normal	264	168(63.39)	96(71.11)	0.124
High	136	97(36.61)	39(28.89)	0.124
Total Cholesterol
Normal	196	129(48.68)	67(49.63)	0.857
High	204	136(51.32)	68(50.37)	0.857
Triglycerides
normal	209	134(50.57)	75(55.55)	0.345
High	191	131(49.43)	60(44.45)	0.345
Complication
hypertensio
Yes	123	88(33.21)	35(25.92)	0.136
No	277	177(66.79)	100(74.08)	0.136
diabetes
Yes	125	79(29.81)	46(34.07)	0.384
No	275	186(70.19)	89(65.93)	0.384
coronary heart disease
Yes	177	124(46.79)	53(39.26)	0.151
no	223	141(53.21)	82(60.74)	0.151
Abbreviations: BMI: Body mass index;

Characteristics of after 90-day follow-up data

90-day follow-up parameters of no complications patients and complications patients are summarized in Table 2. Compared to no complications patients, complications patients had significantly higher BMI (27.10 ± 2.19 vs. 22.95 ± 2.90; P = 0.033), FABP4 concentration (20.0 ± 5.74 vs. 12.6 ± 3.04; P < 0.001), ASA class(P < 0.001), operative time (P < 0.001) and estimated intraoperative blood loss (EIBL) (263.09 ± 58.02 vs. 174.15 ± 41.80; P = 0.001). No significant variances were observed in comorbidities, total cholesterol (P = 0.170), triglycerides (P = 0.290), and other variables between the two groups.

Table 2

Patient and Clinicopathologic Characteristics of the no complications and complications
Characteristic	No complications(n = 376)	Complications(n = 24)	P-value
Age, year	67.46 ± 9.41	70.88 ± 9.31	0.605
Sex
Male	359(95.48)	22(91.67)	0.395
Female	17(4.52)	2(8.33)	0.395
Primary diagnosis
OA	360(95.74)	21(87.5)	0.066
RA and others	16(4.26)	3(12.5)	0.066
BMI	22.95 ± 2.90	27.10 ± 2.19	0.033
BSA	1.67 ± 0.14	1.72 ± 0.16	0.393
white blood cell, 10^9/L	5.50 ± 1.11	6.10 ± 1.19	0.844
Hemoglobin, g/L	154.2 ± 10.26	153.2 ± 7.99	0.242
platelet count, 10^9/L	232.2 ± 35.20	239.1 ± 28.08	0.257
Serum albumin, g/dL	48.64 ± 2.19	49.04 ± 2.28	0.752
D-dimer
Normal	220(58.51)	15(62.5)	0.700
High	156(41.49)	9(37.5)	0.700
FABP4 concentration, ng/ml	12.6 ± 3.04	20.0 ± 5.74	< 0.001
Osteoporosis
Yes	7(1.86)	1(4.17)	0.434
no	369(98.14)	23(95.83)	0.434
ASA class
≥ 3	18(4.79)	20(83.33)	< 0.001
≤ 2	358(95.21)	4(16.67)	< 0.001
Anesthesia
general	24(6.38)	3(12.5)	0.247
intraspinal	352(93.62)	21(87.5)	0.247
Operative time, min
≤ 150	351(93.35)	13(54.17)	< 0.001
> 150	25(6.65)	11(45.83)	< 0.001
EIBL, mL	174.15 ± 41.80	263.09 ± 58.02	0.001
Lowest heart rate, bpm	62.06 ± 8.76	60.20 ± 9.37	0.902
Lowest MAP, mmHg	106.21 ± 13.54	110.86 ± 13.80	0.889
Smoking habit
Yes	178(47.34)	13(54.17)	0.516
no	198(52.66)	11(45.83)	0.516
Alcohol drinking habit
yes	209(55.59)	9(37.5)	0.085
no	167(44.41)	15(62.5)	0.085
comorbidity
Hypertension
Yes	114(30.32)	9(37.5)	0.460
No	262(69.68)	15(62.5)	0.460
Diabetes mellitus
Yes	117(31.12)	8(33.33)	0.820
No	259(68.89)	16(66.67)	0.820
dyslipidemia
Yes	134(35.63)	8(33.33)	0.819
No	242(64.36)	16(66.67)	0.819
coronary heart disease
Yes	166(44.15)	11(45.83)	0.872
no	210(55.85)	13(54.17)	0.872
AST(IU/L)	19.5 ± 6.68	17.4 ± 5.55	0.345
ALT(IU/L)	22.76 ± 5.88	20.1 ± 4.04	0.066
Blood urea nitrogen (mg/dL)	15 ± 3.93	15 ± 4.12	0.453
eGFR(ml/min/1.73m²)	79.2 ± 12.95	78.3 ± 17.30	0.149
Total cholesterol(mmol/L)	4.23 ± 0.64	4.19 ± 0.53	0.170
LDL cholesterol(mmol/L)	2.39 ± 0.54	2.34 ± 0.38	0.057
HDL cholesterol (mmol/L)	1.25 ± 0.31	1.07 ± 0.28	0.696
Triglycerides (mmol/dL)	1.20 ± 0.16	1.17 ± 0.15	0.290

Table 3

Results of Univariable Logistic Regression for Prediction of 90-Day Local Complications
Variable	Prediction model, OR(95% CI)	P value
BMI	1.885(0.917–3.872)	0.084
FABP4 concentration	1.521(1.190–1.944)	0.001
ASA class
≥ 3	0.064(0.005–0.811)	0.034
≤ 2	1.00(reference)	-
Operative time, min
≤ 150	1.00(reference)	-
> 150	4.001(0.027-597.837)	0.587
EIBL	1.070(1.008–1.135)	0.027

Variables are expressed as number (%), means ± SD or medians (interquartile ranges)

Multiple logistic regression analysis of factors associated with the occurrence of complications after 90-day follow-up

Based on the stepwise multiple logistic regression analysis involving BMI, FABP4 concentration, ASA class, operative time, and EIBL, the study identified the following factors associated with 90 days Localized complications:

FABP4 concentration (odds ratio [OR] = 1.521, 95% confidence interval [CI] = 1.190–1.944, P = 0.001)
ASA class (OR = 0.064, 95% CI = 0.005–0.811, P = 0.034)

EIBL (OR = 1.070, 95% CI = 1.008–1.135, P = 0.027)

The ROC curves for FABP4 concentration, ASA class, and EIBL in predicting 90 days Localized complications are depicted in Fig. 3.

TKA or THA can significantly improve patients' quality of life and restore joint function[11]. The long-term efficacy of joint prostheses can reach up to 90% over 15 years. Due to its cost-effectiveness, TKA and THA procedures have seen an increasing trend annually, becoming the gold standard treatment for end-stage severe osteoarthritis[12]. However, the first 90 days post-surgery are a high-risk period for complications such as postoperative infections and peripheral neuritis. These unexpected complications can prolong hospital stays, increase healthcare costs, and in severe cases, impact patients' postoperative recovery, leading to disability or death[13, 14]. Therefore, controlling the occurrence of postoperative complications is crucial for evaluating postoperative outcomes and the quality of care. This study aims to explore the potential impact of a novel adipokine, FABP4, on the prognosis after TKA or THA. The research findings indicate that the concentration levels of FABP4 in the body are associated with the incidence of postoperative complications.

FABP4 is a protein widely expressed in adipocytes and macrophages, first discovered in adipose tissue and mature fat cells in the 1980s. As a key regulator of lipid metabolism, FABP4 plays a crucial role in the body's metabolic processes. Its main functions include regulating lipid metabolism and inflammatory responses, which significantly influence the transport and utilization of fatty acids in the body. Studies have shown that elevated levels of FABP4 may be associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, and atherosclerosis. Experimental evidence indicates that the FABP4 molecule directly impacts various cell types, including hepatocytes, macrophages, cardiomyocytes, vascular endothelial cells, and vascular smooth muscle cells. Despite some advances in research, the specific mechanisms of action of FABP4 and its potential receptors remain areas for further exploration. Therefore, FABP4 may play a crucial regulatory role in disease development, either by indirectly exacerbating traditional risk factors or by directly interfering with the metabolic processes in patients, leading to potential increased risks. Further studies on the mechanisms of action of FABP4 and its specific roles in metabolic diseases will contribute to a deeper understanding of its potential pathophysiological functions.

In this study, the researchers discovered that the levels of FABP4 concentration within the body, ASA classification, and intraoperative EIBL were linked to the occurrence of early postoperative complications in patients undergoing TKA and THA. Despite the data originating solely from patients at a single medical facility, the varied sources of patients and the adequate sample size ensured the representation and applicability of the study outcomes. By utilizing multivariate logistic analysis, the researchers isolated FABP4 concentration, ASA classification, and EIBL as autonomous prognostic elements. When compared to the approach of single-variable analysis for selecting forecasting elements, the multivariate analysis not only outperforms but also integrates these elements to more precisely forecast the likelihood of postoperative complications. These results align with prior investigations and deepen our comprehension of how these prognostic factors contribute to postoperative complications[13, 14].

Based on our knowledge, we are the first to investigate the correlation between intra-body concentration levels of FABP4 and postoperative complications following TKA or THA surgeries. However, we must acknowledge that the study has certain limitations. Firstly, since we only included Chinese patients, the generalizability to other ethnic groups remains to be validated. Secondly, despite adhering to predefined inclusion and exclusion criteria, the retrospective nature of the study may introduce some degree of selection bias. Lastly, the TKA/THA surgeries in our study were performed by multiple different surgeons, potentially leading to variations in surgical techniques. To enhance the reliability of our findings, we are actively expanding our recruitment scope to cover diverse geographical regions and clinical settings, and considering incorporating additional variables for future analyses.

Higher FABP4 concentration is very common in patients with adverse events occurring locally within the 90 days of TKA/THA and the prevalence of adverse events occurring locally within the 90 days of TKA/THA was higher in patients combined with higher FABP4 concentration, higher ASA class or EIBL. FABP4 concentration, ASA class and EIBL are risk factors for the development of adverse events occurring locally within the 90 days of TKA/THA, but validation in larger sample studies is still needed.

AUC area under the curve

AST aspartate transaminase,

ALT alanine transaminase,

CI confidence interval

EIBL estimated intraoperative blood loss

eGFR estimated glomerular filtration rate,

FABP Fatty Acid Binding Protein

HDL high-density lipoprotein,

LDL low-density lipoprotein,

MAP mean arterial pressure,

OR odds ratio

OA Osteoarthritis

ROC receiver operating characteristic

THA total hip arthroplasty

TKA total knee arthroplasty

Acknowledgements

We are particularly grateful to all the people who have given us help on our

Article.

Author contributions

Conception and design of the research: Silong Lin, Xianqi Zhang; Acquisition of data: Xishang Xia; Analysis and interpretation of the data: Xishang Xia¹, Guishui Xu; Statistical analysis: Xianqi Zhang, Hong Pan; Obtaining financing: Hong Pan; Writing of the manuscript: Silong Lin; Critical revision of the manuscript for intellectual content: Xianqi Zhang, Xishang Xia, Guishui Xu, Hong Pan; All authors read and approved the final draft

Funding

This study was supported by university-level scientific research program of South Anhui Medical College (JXYY202278) and Anhui Medical University Research Fund (2022XKJ094).

Data availability

All data generated or analysed during this study are included in this article.

Further enquiries can be directed to the corresponding author

Disclosure

The authors declare that they have no conflicts of interest regarding this work.

Ethics approval and consent to participate

This study has been approved by Ethics Committee of Anqing First People’s Hospital of Anhui Medical University, and all participants have provided signed informed consent.

Author details

¹ Orthopedic surgery, Anqing First People’s Hospital of Anhui Medical University, Anqing 246003, Anhui province, China

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Correlation between the upregulation of circulating FABP4 and prognosis of joint replacement in patients with osteoarthritis

Status:

Version 1

Abstract

Figures

Introduction

Materials and methods

Participants and collection of blood

Determination of FABP4

Outcome Assessment

Statistical analyses

Results

Plasma FABP4 was closely associated with OA

Clinical significance of FABP4 in OA patients

Characteristics of after 90-day follow-up data

Multiple logistic regression analysis of factors associated with the occurrence of complications after 90-day follow-up

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1