Adiponectin and basic fibroblast growth factor predict coronary collateral development in chronic total occlusion

Abstract

BACKGROUND

Coronary collateral circulation is an adaptive mechanism to protect myocardial perfusion in patients with chronic total occlusion. However, the relative importance of metabolic and angiogenic biomarkers in collateral development remained unclear.

AIM

To examine the associations of serum adiponectin and basic fibroblast growth factor (bFGF) with coronary collateral development.

METHODS

A cross-sectional study was carried out on 54 patients with angiographically proven chronic total occlusion. Coronary collateralization was classified by Rentrop grading system as poor and good with grades of 0-1 and 2-3, respectively. Serum adiponectin and bFGF levels were measured using enzyme-linked immunosorbent assay. Spearman correlation, multivariate logistic regression, and receiver operating characteristic analyses were conducted to assess associations, identify independent predictors, and evaluate diagnostic performance.

RESULTS

Serum adiponectin levels were significantly higher in patients with good collateralization compared to those in the poor category (P < 0.001). Adiponectin was positively correlated with Rentrop grade and remained an independent predictor of good collateral development after multivariable adjustment. Serum bFGF levels were not significantly different between groups and were not independently associated with collateral maturation. Furthermore, adiponectin-bFGF model produced better prediction performance than either biomarker alone.

CONCLUSION

Serum adiponectin was an independent predictor of coronary collateral development. Meanwhile, circulating bFGF had limited utility as a systemic biomarker of collateral maturation.

Key Words: Adiponectin; Angiogenesis; Basic fibroblast growth factor; Chronic total occlusion; Coronary collateral circulation

Core Tip: Coronary collateral development is an important adaptive response in chronic total occlusion. This study shows that serum adiponectin is independently associated with well-developed coronary collateral circulation, while circulating basic fibroblast growth factor has limited predictive value. The results show that adiponectin serves as a useful clinical biomarker and risk stratification for collateral assessment and ischemia, respectively. It also shows the complementary roles of metabolic and angiogenic pathways in adaptive coronary vascular remodeling.

INTRODUCTION

Coronary artery disease is an important cause of morbidity and mortality worldwide despite major advances in cardiovascular prevention and revascularization strategies[1]. Chronic total occlusion is defined as a total occlusion of a coronary artery for > 3 months and the most challenging presentation of coronary artery disease[2]. This total occlusion is often associated with chronic myocardial ischemia, impaired ventricular function, and adverse cardiovascular outcomes. Coronary collateral circulation has important compensatory value in maintaining myocardial perfusion distal to the occluded vessel and limiting ischemic injury in the setting of chronic total occlusion[3].

Coronary collateral vessels are adaptive vascular channels formed by complex processes that include arteriogenesis, angiogenesis, endothelial activation, inflammatory signaling, and extracellular matrix remodeling[4]. Well-developed collateral circulation is associated with smaller infarct size, better left ventricular function, lower incidence of heart failure, and reduced cardiovascular mortality[5]. However, collateral development in chronic total occlusion patients is highly variable, suggesting that the adaptive vascular remodeling in chronic ischemia is regulated by many biological and molecular factors[6]. Among the molecular pathways included in collateral formation, metabolic and angiogenic mediators have received increasing attention[7]. Adiponectin is a cytokine secreted by adipocytes with anti-inflammatory, antioxidative, and endothelial-protective properties, and is believed to play a role in vascular homeostasis and ischemic adaptation[8]. Experimental studies showed that adiponectin increases endothelial nitric oxide synthase activity, nitric oxide bioavailability, and decreases oxidative stress, promoting endothelial survival and angiogenesis in ischemic conditions[9]. Low adiponectin levels have been associated with endothelial dysfunction, progression of atherosclerosis, and defective vascular repair mechanisms in patients with cardiovascular disease[10].

Basic fibroblast growth factor (bFGF), also called fibroblast growth factor-2, is another important mediator of angiogenesis and vascular remodeling[11]. This mediator stimulates proliferation, migration, and extracellular matrix remodeling of the endothelial cells and neovascularization of the ischaemic tissue[12]. Experimental evidence has shown that basic fibroblast growth factor promotes collateral vessel formation and myocardial repair after ischemic injury[13]. However, clinical data on the relationship between circulating bFGF levels and coronary collateral development are inconsistent. Systemic serum bFGF levels may not directly reflect local angiogenic activity within the ischemic myocardial microenvironment[14].

Previous studies investigating biomarkers of coronary collateral development have mainly focused on single inflammatory or angiogenic mediators. The combined contributions of metabolic-endothelial and angiogenic biomarkers in patients with chronic total occlusion remain poorly understood. However, the clinical significance of serum adiponectin and bFGF in predicting coronary collateral maturation has not been well evaluated. It remains uncertain whether these biomarkers provide complementary information on distinct mechanisms of endothelial protection, vascular homeostasis, and angiogenic remodeling. Filling these knowledge gaps may improve understanding of adaptive coronary vascular remodeling and enable biomarker-based ischemic risk stratification. This study aimed to investigate the association between serum adiponectin and bFGF and coronary collateral development in patients with chronic total occlusion, and the incremental predictive value of circulating biomarkers for adaptive coronary collateral formation.

MATERIALS AND METHODS

Study design

A cross-sectional observational study was carried out at the Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Syiah Kuala/RSUD Dr. Zainoel Abidin, Banda Aceh, Indonesia, from August 2022 to December 2025.

Population of the study

Patients were aged ≥ 18 years with angiographically proven chronic total occlusion. This condition was defined as occlusion of a coronary artery with thrombolysis in myocardial infarction grade 0 flow and an estimated occlusion duration of ≥ 3 months. The exclusion criteria were patients with acute coronary syndrome, active inflammatory disease, malignancy, severe renal or hepatic dysfunction, autoimmune disease, history of previous coronary artery bypass grafting, and incomplete clinical or laboratory data. A total of 54 eligible patients were enrolled and divided into poor and good collateralization, with Rentrop grades of 0-1 and 2-3, respectively.

Clinical and biomarker evaluation

Baseline demographic and clinical characteristics, including age, sex, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking status, and left ventricular ejection fraction, were obtained from medical records and patient interviews. Fasting peripheral venous blood was collected before coronary intervention. Serum adiponectin and bFGF concentrations were measured by commercially available enzyme-linked immunosorbent assay kits according to the manufacturer’s protocols. Routine laboratory tests included fasting blood glucose, lipid profile, hemoglobin, and serum creatinine levels[15].

Assessment of coronary collaterals

Coronary angiography was carried out using a standard femoral or radial access method. Coronary collateral circulation was graded according to Rentrop classification, with grades 0 to 3 representing no visible collateral circulation, filling of side branches without visualization of the epicardial segment, partial epicardial artery filling through collateral channels, and complete epicardial artery filling, respectively. Patients were classified as having poor (Rentrop grades 0-1) or good collateralization (Rentrop grades 2-3). Collateral grading was independently evaluated by two experienced interventional cardiologists, blinded to biomarker results, and discrepancies were resolved by consensus[16].

Statistics analysis

All statistical analyses were carried out using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, United States). Continuous variables were expressed as mean ± SD or median interquartile range (IQR) and categorical variables as n (%). Data normality was tested using the Shapiro-Wilk test. This was followed by group comparisons using independent t-tests, Mann-Whitney U tests, χ² tests, or Fisher’s exact tests. Spearman correlation analysis was used to analyze the relationship between serum biomarker levels and Rentrop collateral grade. Multivariate logistic regression analysis was used to identify independent predictors of good collateralization. Receiver operating characteristic (ROC) curve analysis evaluated the predictive performance of adiponectin, bFGF, and the combined biomarker model. Statistical significance was defined as a two-tailed P value < 0.05.

Ethical aspects

The study protocol was approved by the Health Research Ethics Committee of RSUD Dr. Zainoel Abidin, Banda Aceh, Indonesia (approval No. 034/ETIK-RSUDZA/2025). Before enrolment, all participants provided written informed consent. All procedures carried out in studies including human participants were in accordance with the ethical standards of the Declaration of Helsinki and the CIOMS guidelines 2016.

RESULTS

Table 1 shows baseline clinical and laboratory characteristics of chronic total occlusion patients according to the development of coronary collateral. The cohort was predominantly male with a mean age of approximately 56 years. More than 50% of patients had good collateralization (Rentrop 2-3). The common cardiovascular risk factors were hypertension, diabetes mellitus, dyslipidemia, and smoking. Patients with good collaterals had lower rates of diabetes and smoking, higher left ventricular ejection fraction, and higher high-density lipoprotein cholesterol. The most common chronic total occlusion target vessel was the left anterior descending artery, specifically in patients with good collateral circulation.

Table 1 Baseline clinical characteristics of patients with chronic total occlusion, n (%)/mean ± SD/median (interquartile range).

Variable	Total population (n = 54)1	Poor collateral (Rentrop 0-1) (n = 25)	Good collateral (Rentrop 2-3) (n = 29)	P value
Age (years)	56.1 ± 8.7	57.4 ± 8.9	55.0 ± 8.5	0.312
Male sex	45 (83.3)	20 (80.0)	25 (86.2)	0.548
Body mass index (kg/m2)	25.7 ± 3.2	26.1 ± 3.4	25.3 ± 3.0	0.401
Hypertension	23 (42.6)	12 (48.0)	11 (37.9)	0.462
Diabetes mellitus	20 (37.0)	12 (48.0)	8 (27.6)	0.118
Dyslipidemia	29 (53.7)	13 (52.0)	16 (55.2)	0.812
Current smoker	31 (57.4)	16 (64.0)	15 (51.7)	0.361
Left ventricular ejection fraction (%)	51.8 ± 8.1	49.6 ± 8.5	53.7 ± 7.4	0.071
Hemoglobin (g/dL)	13.7 ± 1.4	13.5 ± 1.3	13.9 ± 1.5	0.298
Fasting blood glucose (mg/dL)	118 (96-156)	132 (102-178)	109 (91-140)	0.084
Total cholesterol (mg/dL)	198.4 ± 41.7	203.8 ± 44.2	193.7 ± 39.5	0.386
LDL cholesterol (mg/dL)	126.3 ± 35.6	131.8 ± 37.2	121.6 ± 33.9	0.297
HDL cholesterol (mg/dL)	39.8 ± 8.4	37.6 ± 7.9	41.7 ± 8.5	0.073
Triglycerides (mg/dL)	156 (121-203)	168 (132-228)	149 (116-187)	0.214
Serum creatinine (mg/dL)	1.01 (0.82-1.19)	1.05 (0.86-1.24)	0.98 (0.80-1.16)	0.442
CTO target vessel				0.218
LAD	24 (44.4)	9 (36.0)	15 (51.7)
RCA	21 (38.9)	12 (48.0)	9 (31.0)
LCx	9 (16.7)	4 (16.0)	5 (17.3)

¹Combined cohort of integrated adiponectin and basic fibroblast growth factor datasets.

Statistical comparisons were performed using independent t-tests, Mann-Whitney U tests, χ² tests, or Fisher’s exact tests, as appropriate. LDL: Low-density lipoprotein; HDL: High-density lipoprotein; CTO: Chronic total occlusion; LAD: Left anterior descending artery; RCA: Right coronary artery; LCx: Left circumflex artery.

Figure 1 distribution of coronary collateral grades in chronic total occlusion patients according to Rentrop classification system. The most frequent was Rentrop grade 2 (35.2%), followed by grade 1 (31.5%), 3 (18.5%), and 0 (14.8%). In 53.7% of the cohort, collateralization was good (Rentrop 2-3), with the remaining percentage in the poor category (Rentrop 0-1). These results suggested adaptive coronary collateral remodeling as a common feature in patients with chronic total occlusion, being the basis for further biomarker analyses of adiponectin and bFGF.

Figure 1 Distribution of coronary collateral grades in patients with chronic total occlusion. A: Proportional distribution of Rentrop collateral grades; B: Number and percentage of patients in each Rentrop category; C: Classification of collateral circulation into poor collateralization (Rentrop 0-1) and good collateralization (Rentrop 2-3).

Figure 2A reports the serum adiponectin levels in chronic total occlusion patients according to coronary collateral development. Serum adiponectin concentrations were significantly higher in patients with good collateralization (Rentrop grades 2-3) compared with those with poor collateralization (Rentrop grades 0-1). Box and violin plots clearly segregated the two groups with little overlap, showing different adiponectin distributions by collateral status. Spearman correlation analysis also showed a significant positive correlation between serum adiponectin levels and Rentrop collateral grade. This result suggested that higher circulating adiponectin concentrations were associated with better coronary collateral maturation and adaptive vascular remodeling. Data were presented as individual values (dots), median and IQR in box plots, and data distribution in violin plots. The Mann-Whitney U test was used for group comparisons, with statistical significance set at P < 0.05.

Figure 2 Serum adiponectin levels and basic fibroblast growth factor levels according to coronary collateral development in patients with chronic total occlusion. A: Adiponectin levels; B: Basic fibroblast growth factor levels. IQR: Interquartile range; bFGF: Basic fibroblast growth factor.

Figure 2B shows the distribution of serum bFGF levels according to coronary collateral development in patients with chronic total occlusion. Serum bFGF levels were similar between patients with poor and good collateralization, showing comparable median levels and distribution patterns. Consistent with these results, there was no significant correlation between serum bFGF levels and Rentrop collateral grade (P = 0.312, Mann-Whitney U test). This result suggested that circulating bFGF did not adequately reflect local angiogenic and vascular remodeling activity in the ischemic myocardial microenvironment. Data were presented as individual data points (dots), box plots showing the median and IQR, and violin plots representing the distribution of the data. IQR, bFGF, and SD were acronyms for IQR, bFGF, and standard deviation. P < 0.05 was considered statistically significant for all analyses.

Table 2 presents the Spearman correlation analysis of serum biomarkers, selected clinical variables, and coronary collateral grade. Serum adiponectin was significantly correlated with Rentrop collateral grade (P = 0.462, P < 0.001). Furthermore, serum bFGF and other clinical variables, including age, diabetes mellitus, hypertension, and current smoking, were not significantly correlated with collateral development. This result suggested a stronger association of circulating adiponectin with coronary collateral maturation than with bFGF or traditional clinical risk factors.

Table 2 Correlation between biomarkers and coronary collateral grade.

Variable	Spearman ρ	95% confidence interval	P value
Coronary collateral grade (Rentrop score)
Serum adiponectin (μg/mL)	0.462	0.217-0.660	< 0.001
Serum bFGF (pg/mL)	0.086	-0.160 to 0.321	0.312
Other clinical variables
Age (years)	-0.128	-0.366 to 0.127	0.377
Diabetes mellitus (yes/no)	-0.214	-0.439 to 0.032	0.087
Hypertension (yes/no)	-0.097	-0.331 to 0.153	0.458
Current smoking (yes/no)	-0.191	-0.420 to 0.063	0.136

Data are presented as Spearman correlation coefficients (ρ). bFGF: Basic fibroblast growth factor.

Figure 3 shows ROC curve analysis to assess the predictive value of serum adiponectin, bFGF, and combined biomarker model for good coronary collateral development (Rentrop grades 2-3) in patients with chronic total occlusion. Serum adiponectin had good discriminative power [area under the curve (AUC) = 0.801, 95% confidence interval (CI): 0.679-0.923], and circulating bFGF showed limited predictive performance (AUC = 0.576, 95%CI: 0.426-0.727). The combined model of adiponectin and bFGF had the highest diagnostic accuracy (AUC = 0.873, 95%CI: 0.764-0.982). This result suggested that the combination of metabolic and angiogenic biomarkers was better in predicting favorable coronary collateralization than individual biomarkers. Furthermore, the results supported adiponectin as the major circulating marker of coronary collateral maturation. bFGF was also shown to provide additional biological information when added to a multimarker predictive model.

Figure 3 Receiver operating characteristic analysis of adiponectin and basic fibroblast growth factor for predicting good coronary collateral development. AUC: Area under the curve; CI: Confidence interval.

DISCUSSION

Coronary collateral circulation is an important adaptive vascular response that maintains myocardial perfusion and limits ischemic injury in patients with chronic total occlusion[17]. This study evaluated the association of serum adiponectin and bFGF with coronary collateral development, providing an in-depth assessment of metabolic and angiogenic biomarkers associated with adaptive coronary vascular remodeling. Baseline demographic, clinical, and laboratory characteristics were generally comparable between patients with poor and good collateralization, as shown in Table 1. Patients with poor collateral development had more often diabetes mellitus and current smoking. Similarly, patients with good collateralization tended to have higher left ventricular ejection fraction and high-density lipoprotein cholesterol levels. However, these differences did not reach statistical significance. The trends are biologically relevant, as diabetes and smoking are known to contribute to endothelial dysfunction, oxidative stress, and impaired angiogenic signaling, all of which negatively affect collateral vessel formation[18]. The high prevalence of left anterior descending artery occlusion among patients with good collateralization may also be a surrogate for a higher ischemic burden and prolonged stimulation of collateral recruitment, consistent with previously reported observations in chronic total occlusion populations[19].

The distribution of collateral grades further supports the adaptive nature of collateral formation in chronic ischemia. Figure 1 shows that most of the study population had good collateralization (Rentrop grades 2-3), with Rentrop grade 2 being the most frequent collateral grade. However, a total absence of collateral flow (Rentrop grade 0) was relatively rare. These data are consistent with previous results showing that prolonged coronary occlusion promotes arteriogenesis and collateral maturation, which maintains myocardial viability in the setting of chronic epicardial coronary obstruction[20]. The predominance of moderate to good collateral development observed in this cohort shows the remarkable potential for adaptive vascular remodeling in patients with chronic ischemic heart disease[21].

The most important result of this study is the strong association between serum adiponectin and collateral formation in coronary arteries. Serum adiponectin concentrations were significantly higher in patients with good collateralization than in the other category, as shown in Figure 2A. A significant positive correlation between adiponectin levels and Rentrop collateral grade was also observed in Spearman correlation analysis (Table 2). This result showed that higher circulating adiponectin levels are associated with more mature collateralization. In multivariate logistic regression analysis, only adiponectin was an independent predictor for good coronary collateral development after adjustment for standard cardiovascular risk factors (Table 3). The results suggest that adiponectin is associated with collateral formation and serves as an independent systemic marker of adaptive coronary vascular remodeling in patients with chronic total occlusion.

Table 3 Multivariate logistic regression for predictors of good coronary collateral development.

Variable	Adjusted OR	95%CI	P value
Serum adiponectin (per 1 μg/mL increase)	1.86	1.25-2.77	0.002a
Serum basic fibroblast growth factor (per 1 pg/mL increase)	0.91	0.48-1.73	0.776
Age (per 1-year increase)	0.98	0.91-1.05	0.531
Diabetes mellitus (yes vs no)	0.46	0.16-1.35	0.156
Hypertension (yes vs no)	0.82	0.28-2.42	0.720
Current smoking (yes vs no)	0.69	0.23-2.08	0.513
CTO target vessel (LAD vs RCA/LCx)	1.74	0.63-4.84	0.286

^aP < 0.05.

Table 3 summarizes the multivariate logistic regression analysis for predictors of good coronary collateral development. After adjustment for the conventional cardiovascular risk factors, serum adiponectin was the only independent predictor of good collateralization (adjusted odds ratio = 1.86, 95% confidence interval: 1.25-2.77; P = 0.002). However, serum basic fibroblast growth factor, age, diabetes mellitus, hypertension, smoking status, and chronic total occlusion target vessel were not independently associated with the development of coronary collateral. These results suggested that adiponectin was a better systemic marker of coronary collateral maturation than circulating basic fibroblast growth factor or conventional clinical risk factors. Outcome: Good coronary collateral development (Rentrop grades 2-3). OR: Odds ratio; CI: Confidence interval; CTO: Chronic total occlusion; LAD: Left anterior descending artery; RCA: Right coronary artery; LCx: Left circumflex artery.

Several biological explanations exist for these results. Adiponectin has robust anti-inflammatory, antioxidative, anti-atherogenic, and endothelial protective effects by activating adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase signaling pathways. This process increases the bioavailability of nitric oxide, improves endothelial function, and sustains vascular homeostasis[22]. Adiponectin also suppresses inflammatory cytokine production and oxidative stress, thereby promoting a microenvironment conducive to collateral vessel growth and stabilization in chronic myocardial ischemia. Similar vascular protective effects were evident in previous experimental and clinical studies supporting the biological plausibility of adiponectin as a mediator of collateral maturation[23].

Serum bFGF levels were not significantly different between patients with good and poor collateralization, as shown in Figure 2B. Circulating bFGF concentrations were not significantly correlated with Rentrop collateral grade (Table 2), while bFGF was not an independent predictor in multivariate analysis (Table 3). bFGF has been reported to be the main regulator of angiogenesis, endothelial proliferation, extracellular matrix remodeling, and vascular repair[24]. The results of this study showed that circulating levels of serum were not representative of the biological activity of fibroblast growth factor in ischemic myocardial tissue.

The lack of a significant association between circulating bFGF and collateral development should not be taken as evidence against its angiogenic function. bFGF appeared to act mainly through local paracrine signaling in the ischemic myocardial microenvironment rather than the systemic circulation. According to a previous study, local tissue expression may differ widely from serum concentrations[24]. Therefore, systemic measurements of bFGF may underestimate active angiogenic remodeling at the level of coronary tissue. This result is consistent with previous molecular studies showing that fibroblast growth factors are the primary regulators of local endothelial proliferation and extracellular matrix remodeling during arteriogenesis[25].

The clinical significance of these biomarkers was shown by ROC analysis (Figure 3). Serum adiponectin showed a high discriminative ability to identify patients with well-developed collateral circulation, while circulating bFGF had limited predictive ability. The combined adiponectin-bFGF model had the highest AUC, suggesting that integrating metabolic and angiogenic biomarkers improves the prediction of favorable collateral development compared with either biomarker alone. These results are consistent with the idea that coronary collateral formation is regulated by complex interactions between endothelial homeostasis, inflammation regulation, metabolic signaling, and localized angiogenic activation, rather than by a single biological pathway[26].

Figure 3 shows the integrated biomarker model, providing further evidence for the complementary biological roles of adiponectin and bFGF in coronary collateral formation. Adiponectin appears to be a systemic circulating biomarker primarily in endothelial protection, anti-inflammatory activity, vascular homeostasis, and collateral maturation. However, bFGF tends to participate in local myocardial angiogenic signaling, tissue remodeling, and neovascularization, a process not completely captured by serum measurements alone[27]. These complementary mechanisms explain the improved predictive performance achieved by combining the two biomarkers, although circulating bFGF has limited independent value. From a clinical perspective, this study suggests that serum adiponectin could be a useful non-invasive marker for assessing coronary collateral maturity and refining ischemic risk stratification in patients with chronic total occlusion. Moreover, the inclusion of metabolic and angiogenic biomarkers in a multimarker model might enable a more comprehensive evaluation of adaptive coronary vascular remodeling and support personalized therapeutic decision-making in chronic ischemic heart disease.

Several limitations should be considered when interpreting the results of this study. First, the cross-sectional design does not allow for causal inference in the association between circulating biomarkers and collateral development. Second, the external validity may be limited by the relatively small sample size and single-center recruitment. Third, measurements of circulating biomarkers, particularly serum bFGF, may not reflect localized myocardial angiogenic activity. Therefore, large, prospective, multicenter studies with tissue-level molecular analyses and longitudinal follow-up are required to confirm the results and better understand the mechanisms underlying adaptive coronary collateral formation.

CONCLUSION

In conclusion, serum adiponectin is independently associated with favorable coronary collateral development in patients with chronic total occlusion. Circulating bFGF has limited value as a systemic biomarker of collateral maturation. The combined adiponectin-bFGF model shows the strongest performance, suggesting that integrating metabolic and angiogenic biomarkers may improve the assessment of adaptive coronary vascular remodeling. These results suggest that adiponectin may be a promising non-invasive biomarker for evaluating coronary collaterals and stratifying ischemic risk in patients with chronic total occlusion. Additional multicenter prospective studies are needed to validate these results and to determine the molecular mechanisms behind coronary collateral formation.

ACKNOWLEDGEMENTS

The authors are grateful to the Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Syiah Kuala/RSUD Dr. Zainoel Abidin Banda Aceh for the support and help in conducting this study. The authors are also grateful to all patients who participated in this study and the clinical laboratory staff for the contribution to biomarker analysis and data collection.