A relationship among the blood serum levels of interleukin‐6, albumin, and 25‐hydroxyvitamin D and frailty in elderly patients with chronic coronary syndrome

Abstract Background With the aggravation of the aging of the world population, frailty has become one of the common complications in elderly people. Its diagnosis is not objective, the pathogenesis is not clear, and interventions are not sound, thus intensifying the problem. Furthermore, frailty is closely associated with the occurrence and poor prognosis of coronary atherosclerotic heart disease. Moreover, few studies report on the prevalence of frailty in elderly patients with the chronic coronary syndrome (CCS). Objective We aimed to investigate the prevalence of frailty in elderly patients with CCS. We analyzed the correlation between the blood serum levels of interleukin‐6 (IL‐6), albumin (Alb), and 25‐hydroxyvitamin D (25(OH)D) with frailty in elderly patients with CCS. We have also provided recommendations for helping the objective diagnosis as well as proposed new intervention methods in the future. Methods Two hundred eight‐eight inpatients (≥60 years) with the chronic coronary syndrome were recruited at the Department of Geriatrics, the First People's Hospital of Yunnan Province, China. General information and laboratory examination data were collected. The comprehensive geriatric assessment was conducted via an internet‐based platform of the Comprehensive Geriatric Assessment (inpatient version) developed by us, among which frailty was assessed by the Chinese version of Fried Frailty Phenotype, a component of the assessment scale. Results Among the total number of old patients with CCS, 87 (30.2%) had no frailty, 93 (32.3%) had early frailty, and 108 (37.5%) had frailty. According to the multivariate logistic regression analysis, after adjusting for confounding factors, IL‐6 (OR = 1.066, 95% CI 1.012–1.127), Alb (OR = 0.740, 95% CI 0.560–0.978), and 25(OH)D (OR = 0.798, 95% CI 0.670–0.949) were independently associated with frailty in the three groups of models. Conclusion IL‐6 proved to be a risk factor for frailty in elderly patients with CCS, while Alb and 25(OH)D were protective factors, which make the potential targets for predicting and intervening frailty in elderly patients with CCS.


| INTRODUC TI ON
With an in-depth understanding of the pathophysiology and dynamic changes in the course of coronary artery disease, the ESC (European Society of Cardiology) published the ESC guidelines for the diagnosis and management of chronic coronary syndromes (CCSs), and the concept of CCSs was formally proposed. It refers to the different stages of coronary heart disease other than the clinical presentation dominated by acute coronary thrombosis. 1 It further emphasized that the steady-state period of non-acute coronary syndromes was relative and could progress to acute coronary syndromes at any time.
Frailty is a special state in which the physical functions of elderly people gradually decline. It is characterized by weakened muscle strength and endurance, decreased physiological functions, increased vulnerability, decreased anti-stress ability with subsequent adverse consequences such as disability, cognitive impairment, malnutrition, mental abnormalities, and even death. 2,3 Some studies have shown that frailty patients with coronary artery disease (CAD) were more likely to have adverse events than non-frailty patients. 4 In addition, in elderly CAD patients, longer life expectancy leads to more focus on improving patients' functional ability and quality of life. 5 Therefore, frailty has attracted increasing attention as a way to identify adverse outcomes in patients with coronary artery disease. 6 With the aging of the world population, the problem of frailty in old age is becoming increasingly prominent. To screen old adults at high risk of frailty, Fried et al. proposed the use of clinical phenotypes to characterize frailty, which consisted of five body components, including decreased muscle strength, reduced walking speed, fatigue, reduced physical activity, and unconscious weight loss. 7 Nowadays, these criteria are widely used in clinics for the diagnosis of frailty.
Unfortunately, they do not provide an objective diagnostic basis, clear pathogenesis, and sound intervention methods. Studies have shown a high prevalence of senile frailty, and there was a close relationship among CGA and various serum indicators and frailty. [8][9][10] Similarly, our previous study found that disabled 25-hydroxyvitamin D (25(OH)D) and interleukin-6 (IL-6) were independent influencing factors of frailty in patients with stable chronic diseases. 11 However, the studies on the prevalence and related factors of frailty in elderly patients with CCS were scarce. Moreover, there is a lack of objective biological markers for the diagnosis of frailty. Here, we aim to investigate the prevalence of frailty in elderly patients with CCS. Our main focus is on the correlation between the blood levels of IL-6, albumin (Alb), and 25(OH)D with frailty in elderly patients with CCS. Establishing such a relation would be a good and solid theoretical basis for the objective diagnosis of frailty in elderly CCS patients as well as for proposing some interventions for improving the condition.

| Study design and participants
This is a cross-sectional study conducted in Yunnan province, China. A total number of 288 elderly inpatients at the age of 60 years and above, diagnosed with CCS, were recruited at the with asymptomatic or stable symptoms within 1 year after ACS or patients who recently underwent revascularization; (4.4) patients whose initial diagnosis or revascularization were done more than one year ago; (4.5) patients with angina pectoris, suspected vasospasm, or microcirculation diseases; (4.6) asymptomatic patients with coronary heart disease found during screening. The applied exclusion criteria were: (1) patients with Vitamin D supplementation, with albumin blood products, and antiinflammatory drugs in the past one month; (2) Table 1.

| Data quality control
Data quality control was done on two steps: (1)  as a statistically significant difference. To assess the relative contribution of these related factors to vulnerability, we conducted an analysis based on three different models.

| General comparison among the demographic data of elderly patients' in different frailty stages diagnosed with CCS
According to the Fried scale, the study population was divided into non-frailty, pre-frailty, and frailty groups, as shown in Table 2. with the increase of the severity of frailty, namely the older the patients were, the higher the estimated risk of frailty (p < 0.001).
Our results show that patients with impaired hearing and vision were more likely to have frailty (p < 0.05). Elderly patients with CCS were prone to a variety of chronic diseases, and a higher risk of frailty (p = 0.001) was estimated for the patients with more chronic diseases. In addition, patients with polypharmacy (taking ≥5 oral drugs) had a higher incidence of frailty than those without polypharmacy (p = 0.001).

| Comparison of blood serum biomarkers in elderly patients with CCS in different frailty states
A plethora of blood serum biomarkers have been studied in elderly patients with different frailty stages. They were thoroughly described in

| Regression analysis of influencing factors in elderly patients with CCS frailty
To further look at possible interrelation among IL-6, Alb, 25(OH)D, and frailty in elderly people with CCS, we conducted a multivariate logistic regression analysis and the results are shown in Table 5. independently associated with frailty in the three groups of models.

| Correlational analyses of frail elderly patients with CCS
Spearman rank correlation analysis showed that Alb (r s = −0.366,

| The incidence of frailty in elderly patients is associated with CCS
Previous studies in Brazil, China, and Europe have shown that the overall incidence of frailty in senior citizens was 24%, 9.9%, and 7.7%, respectively. [20][21][22] Our results showed that the prevalence of frailty among the studied elderly patients in China with CCS was 37.5%, thus suggesting that the prevalence of frailty was higher in elderly patients with CCS. Certain confirmation for our results comes from a cross-sectional study in Eastern China 23 where the prevalence of frailty in 208 elderly patients (≥60 years old) with CCS was 30.3%.
This estimation was slightly lower than our results; we consider that the difference in the frailty assessment tools and the regional differences between Eastern and Western China could be a possible explanation for this difference. In addition, Ozmen et al. 4 included 99 CCS patients aged ≥70 years in Turkey and found that the risk of adverse cardiac events in frailty patients was 3.48 times higher than that in non-frailty patients, and the risk of death was 6.05 times higher than that in non-frailty patients, suggesting that the prognosis of frailty in the elderly patients with CCS was worse. These data confirm our hypothesis that CCS and frailty are interrelated. We further suggest that the early screening and intervention of elderly people can greatly reduce the prevalence of frailty and then reduce the risk of adverse events in old patients with CCS.

| Blood serum levels of IL-6, Alb, and 25(OH) D could be prognostic factors for frailty in patients with CCS
A meta-analysis of 23,910 old adults (including 32 cross-sectional studies) showed that patients with frailty and pre-frailty had higher levels of inflammation, indicated in the high blood serum levels of CRP and IL-6, than those without frailty. 24 Elevated serum levels of IL-6 and CRP were closely related to muscle loss and reduced grip strength. 25 High IL-6 and CRP blood serum levels were also associated with a 40% higher risk of grip strength reduction that gradually increased two to three times 3 years after diagnosis. 26 This study further reconfirmed the relationship between the blood serum levels of inflammatory factors and frailty. And though the blood serum levels of CRP was not an independent risk factor for frailty in our study, it was still statistically significant when the univariate analysis was conducted (p < 0.001). The reason for this difference may be that IL-6 is located upstream of CRP in the inflammatory cascade, thus playing a broader role. 27 According to a 3.5-year follow-up observation of elderly women in the community reported by Ferrucci et al., the increased IL-6 blood serum levels were considered an important predictor of function loss, muscle strength, and motor ability decline in elderly women. 28 It was found that IL-6 directly stimulated muscle consumption by activating the ubiquitin-proteome pathway, thus destroying the cytoplasm and nucleoprotein in fibrocytes. 29,30 It indirectly lowered the levels of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) and reduced protein synthesis, leading to sarcopenia. 31   In a study of 1368 subjects living in Tanushimaru, Japan, Yamamoto et al. found that lower albumin levels showed a linear trend with an indicator of frailty, namely the grip strength. 34 The results of a cohort study showed that for every 1g/dL increase in the blood serum albumin concentrations, frailty scores decreased by 0.4 points, suggesting that patients with higher serum protein levels were at lower risk of frailty. 35 Our study also showed that blood serum albumin concentrations in elderly patients with the frailty of CCS were significantly lower than that in pre-frailty and non-frailty patients. The multivariate logistic regression showed that the blood serum albumin was a protective factor for elderly patients with the frailty of CCS. Therefore, we speculate that serum albumin may be a biomarker of frailty in elderly patients with CCS. According to another prospective cohort study, changes in the blood serum protein concentrations are associated with various inflammatory indicators, especially when CRP and IL-6 were analyzed. 36 To date, the specific mechanism underlying this finding is not completely clear. Previous has been proved to be associated with an increased prevalence of frailty and the risk of CVD, as well as with elevated serum IL-6 levels. 51

| CON CLUS IONS
The results of this study showed that the prevalence of frailty was 37.5% among elderly patients with CCS. We also confirm that CCS and frailty interact and promote each other and prompt that early screening and intervention can greatly reduce the prevalence of frailty and the risk of adverse events in elderly patients with CCS.
Meanwhile, we found that the blood serum levels of IL-6, Alb, and There are also some limitations to our study. First, we excluded patients who could not cooperate with the comprehensive geriatric assessment, like critically ill patients, resulting in lower than actual morbidity levels. At the same time, in the diagnostic criteria of CCS, patients with stable symptoms within 1 year after ACS or who have received revascularization recently (within 1 year) are the main ones.
Because this criterion is easy to identify and has a clear diagnosis, while other diagnostic criteria are relatively difficult. Therefore, relatively few subjects were included. Second, the sample size of this study was relatively small as it was a single-center study with certain regional differences, which may lack high representativeness.
Finally, it was a cross-sectional study and could not directly investigate the causal relationship between serum IL-6, Alb, 25(OH)D, and frailty in elderly patients with CCS. All these limitations exert the need for future investigations in the field.

ACK N OWLED G M ENTS
We are very grateful to the participants of this study and the medical staff who facilitated the data collection of this study.

CO N FLI C T O F I NTE R E S T
There is no conflict of interest in this article.

AUTH O R CO NTR I B UTI O N S
Jing-rong Dai was responsible for the conception and design of the paper, the analysis and interpretation of the results, as well as the writing of the paper. Yan Li carried out the implementation and feasibility analysis of the research and was responsible for the quality control and review of the paper. Data collection was done by Jie Li, Xu He, and Hong Huang. Xu He and Hong Huang sorted out and handled input data. Jie Li conducted the statistical processing and revised the paper. Yan Li was responsible for the supervision and management of the article.