Correlation between serum uric acid and coronary collateral circulation in patients with coronary chronic total occlusion : Cardiology Plus

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Correlation between serum uric acid and coronary collateral circulation in patients with coronary chronic total occlusion

Li, Jing1,2; Pei, Haifeng1,2; Ye, Xianglin1,2; Tian, Jing3; Yang, Haixia4; Liu, Qing5; Wang, Xiong2,*; Wang, Peng2,*

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Cardiology Plus 7(4):p 200-204, October-December 2022. | DOI: 10.1097/CP9.0000000000000033
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Abstract

INTRODUCTION

Atherosclerotic coronary heart disease is one of the primary cardiovascular diseases with high mortality and disability[1]. Coronary chronic total occlusion (CTO) is defined as an occluded vessel with thrombolysis in myocardial infarction (TIMI) grade 0 forward flow and an occlusion time of more than 3 months, and typically occurs at the terminal stage of the development of atherosclerosis[2]. Coronary CTO is detected in 18 to 52% of patients with coronary artery disease (CAD) receiving coronary angiography[3]. For patients with CTO, the mortality rate and prognosis are dismal, and the percutaneous coronary intervention (PCI) is rarely effective. For such patients, early establishment of coronary collateral circulation (CCC) is particularly important. Small traffic branches exist between the main coronary vessels, but are not functional under physiological conditions. When blood flow through the main coronary vessels becomes compromised, these small traffic branches become open under the stimulation of a variety of factors[4]. CCC attenuates myocardial ischemia and hypoxia, improves cardiac function, inhibits myocardial remodeling, and reduces mortality[5,6]. The formation of CCC is influenced by a variety of factors, including blood flow shear force, hypoxia, growth factors, and inflammation, but the molecular mechanism of CCC formation is not fully understood[7]. Uric acid is the final product of purine metabolism in human beings[8]. Since serum uric acid (SUA) contributes to endothelial dysfunction by inducing inflammatory reactions and increasing oxidative stress[9], it is has been hypothesized that SUA might be associated with the progression of CCC. We conducted a retrospective analysis to examine the potential correlation between SUA and the formation of CCC in patients with CTO.

MATERIALS AND METHODS

Study population

This retrospective analysis included 94 patients who underwent coronary angiography for CTO in at least one of the left anterior descending artery, circumflex artery, and right coronary artery (TIMI grade 0 of forward flow) for at least 3 months in the General Hospital of Western Theater Command during a period from January 2017 to January 2021. Patients with one of more of the following conditions were excluded from the analysis: (1) the use of any uric acid-lowering drugs (eg, diuretics and allopurinol); (2) missing key data (eg, coronary angiography or uric acid); (3) previous PCI; (4) acute myocardial infarction; (5) acute or chronic infection, tumor and immune diseases; (6) severe hepatic and kidney insufficiency [The child-Pugh grade for liver function was C and estimate glomerular filtration rate (eGFR)  < 60 mL/min]. This study was approved by the Ethics Committee of the General Hospital of Western Theater Command (2022EC2-KY021; date: April 24, 2022). The requirement for informed consent was waived by the Committee. This study was conducted in compliance with the Declaration of Helsinki Ethical Guidelines (as revised in 2013).

Data collection

Demographic information (age, sex, height, and body mass index), histories of hypertension, diabetes, hyperlipidemia, and smoking were collected through the electronic case system of Western Theater Command General Hospital. Smoking was defined as continuous or cumulative smoking for more than 6 months in a lifetime. Fast venous blood within 24 hours after admission was used to analyze the following using an automatic biochemical analyzer: total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), high-sensitivity C-reactive protein (hs-CRP), and glycosylated hemoglobin (HbA1c). Coronary angiography was routinely performed with the Judkin methodology. The study sample was divided into three groups of equal size based on SUA.

Coronary collateral circulation

CCC was categorized to four different grades using the Rentrop classification system: level 0 for no collateral circulation; level 1 for branch artery filling without filling of the main epicardial artery; level 2 for partial filling of the epicardial artery; and level 3 for complete filling of the epicardial artery. Rentrop level ≥ 2 was defined as favorable collateral circulation and a Rentrop level ≤ 1 was defined as inferior collateral circulation[10]. The angiographic data were evaluated by two experienced cardiologists blinded to SUA information. Each enrolled patient was evaluated for CCC based on Rentrop grading.

Statistical analysis

Continuous variables with normal distribution were analyzed by one-way analysis of variance (ANOVA), and expressed as mean ± standard deviation (SD). Continuous variables not following normal distribution were analyzed using a nonparametric rank sum test, and expressed as median (P25, P75). Categorical variables were analyzed using the χ2 test, and expressed as proportions. Forward bivariate logistic regression was used to analyze the factors that were associated with inferior collateral circulation and the correlation between SUA and CCC. P < 0.05 was considered as a statistically significant difference. All statistical analyses were performed with SPSS 26.0 (Armonk, NY: IBM Corp., USA).

RESULTS

Distribution of CTOs in coronary arteries and source of collateral circulation

In this study, there were 77 cases of single CTO lesions, including 21 cases of anterior descending branch CTO, 26 cases of circumflex branch CTO, 19 cases of right coronary artery CTO, and 11 cases of other vessels CTO. There were 15 cases of double-branched CTO disease, most of which were anterior descending branch combined with circumflex branch CTO (nine cases). Two cases of three CTO lesions. There were 42 CTO patients with good collateral circulation of coronary artery, and the collateral circulation of anterior descending branch occlusion was mostly from right coronary artery, followed by autogenous source. In the occluded circumflex branch, the collateral circulation was mainly from the right crown, followed by the anterior descending branch. In the patients with right crown occlusion, the lateral circulation was mainly from the anterior descending branch, followed by the circumflex branch.

Comparison of clinical data among the three groups of patients

The final analysis included 94 patients (66.03 ± 10.10 years of age; 54 men and 40 women). The average age of the patients with poor CCC (55.3% of the sample) was 65.16 ± 11.22 years. The average age of the patients with good CCC (54.7% of the sample) was 67.12 ± 8.53 years. The three groups with low, medium, versus high SUA did not differ significantly in age, sex, body mass index, smoking history, diabetes mellitus, hypertension, hyperlipidemia, glycosylated hemoglobin, Hs-CRP, LDL-C, HDL-C, and TC (all P > 0.05) (Table 1). The rate of poor CCC was 44.5%, 54.8%, and 77.4% in the low, medium, and high SUA groups, respectively (P < 0.05; Table 1).

Table 1 - Demographic and clinical characteristics in the three groups of patients based on serum uric acid (µmol/L)
Projects Low SUA (<337) Middle SUA (337–429) High SUA (>429) F2/H P
Age (years) 66.5 (61.25, 74.25) 69 (61, 73) 65 (59, 72) 0.722 0.697
Male, n (%) 21/11 22/9 26/5 2.826 0.243
Smoking, n (%) 19 (59.40) 18 (58.10) 22 (71) 1.343 0.511
BMI (kg/m2) 24.48 (23.06, 26.27) 25.58 (23.23, 26.95) 24.21 (23.23, 26.67) 0.697 0.706
Diabetes mellitus, n (%) 23 (71.90) 21 (67.70) 22 (71) 0.141 0.932
Hypertension, n (%) 16 (50) 10 (32.30) 13 (41.90) 2.046 0.360
Hypercholesterolemia, n (%) 9 (28.10) 10 (32.30) 11 (35.50) 0.395 0.821
HbA1c (%) 6.7 (6.13, 7.83) 6.1 (5.90, 7.10) 6.4 (6.00, 7.10) 2.124 0.346
FBG (mmol/L) 6.54 (5.37, 8.25) 5.49 (5.05, 6.28) 6.15 (5.48, 7.81) 6.761 0.034
Hs-CRP (mg/L) 3.08 (1.70, 5.10) 2.69 (1.16, 4.19) 2.23 (1.33, 3.64) 2.034 0.362
LDL-C (mmol/L) 2.45 (1.92, 3.34) 2.26 (1.84, 3.62) 2.34 (1.89, 3.68) 0.013 0.994
HDL-C (mmol/L) 1.10 (0.81, 1.03) 1.14 (0.83, 1.45) 1.06 (0.84, 1.28) 0.65 0.524
TC (mmol/L) 4.06 (3.26, 4.96) 3.78 (3.06, 5.57) 4.12 (3.44, 5.18) 0.491 0.782
Poor collateral circulation,
n (%)
11 (44.50) 17 (54.80) 24 (77.40) 11.808 0.003
The data without normal distribution are expressed as median (P25, P75), The measurement data were compared between groups with nonparametric rank sum test. The count data are expressed as percentages, and the count data between groups are expressed by the χ2 test; categorical variables are expressed as proportions. Low SUA group 303 (276.50, 317.25), middle SUA group 394 (367, 418), high SUA group 473 (451, 520).
ANOVA: Analysis of variance; BMI: Body mass index; FBG: Fasting blood glucose; HbA1c: Glycated hemoglobin; HDL-C: High-density lipoprotein cholesterol; Hs-CRP: High-sensitive C-reactive protein; LDL-C: Low-density lipoprotein cholesterol; SUA: Serum uric acid; TC: Total cholesterol.

Logistic regression analysis of poor CCC and SUA

In the univariate regression, elevated SUA was independently associated with the occurrence of poor CCC (P < 0.001). After adjusting for age, sex, BMI, HbA1c, Hs-CRP, blood glucose, blood lipids, smoking and history of hypertension, elevated SUA remained associated with the occurrence of poor CCC (P = 0.001; Table 2).

Table 2 - Logistic regression analysis of poor coronary collateral circulation
Variables β value SE Wald OR (95% CI) P value
Univariate
Serum uric acid (µmol/L) 0.011 0.003 13.843 1.011 (1.005–1.017) <0.001
Multivariate
Serum uric acid (µmol/L) 0.012 0.003 12.062 1.012 (1.005–1.018) 0.001
 Age (years) −0.016 0.028 0.331 0.984 (0.932–1.039) 0.565
 Male, n (%) 1.107 0.846 1.711 3.025 (0.576–15.887) 0.191
 BMI (kg/m2) −0.153 0.099 2.392 0.858 (0.707–1.042) 0.122
 Smoking, n (%) 0.255 0.746 0.117 1.291 (0.299–5.571) 0.732
 HbA1c (%) 0.085 0.262 0.106 1.089 (0.651–1.821) 0.745
 FBG (mmol/L) 0.068 0.129 0.274 1.070 (0.831–1.378) 0.600
 Hs-CRP (mg/L) −0.180 0.104 2.989 0.835 (0.681–1.024) 0.084
 LDL-C (mmol/L) −0.118 0.515 0.053 0.889 (0.324–2.436) 0.819
 HDL-C (mmol/L) −1.732 1.242 1.945 0.177 (0.016–2.018) 0.163
 TC (mmol/L) 0.245 0.452 0.293 1.277 (0.526–3.100) 0.589
 FBG (mmol/L) −0.560 0.123 0.208 0.945 (0.742–1.204) 0.648
 Hypertension −0.472 0.552 0.732 0.624 (0.211–1.840) 0.392
BMI: Body mass index; CI: Confidence interval; FBG: Fasting blood glucose; HbA1c: Glycated hemoglobin; HDL-C: High-density lipoprotein cholesterol; Hs-CRP: High-sensitive C-reactive protein; LDL-C: Low-density lipoprotein cholesterol; OR: Odds ratio; TC: Total cholesterol.

In comparison to the patients with low SUA, there was a statistically non-significant trend for increased risk of poor CCC (odds ratio [OR] 2.277, 95% confidence interval [CI]: 0.753–6.884) in the patient with mid-level SUA. The risk of poor CCC was significantly elevated in the patients with high SUA (OR 6.243, 95% CI: 1.872–20.828).

DISCUSSION

Hyperuricemia is extremely common in clinical practice and is an important factor in the pathogenesis of cardiovascular disease[10]. Considering the current large number of patients with coronary atherosclerotic heart disease with hyperuricemia, the prevention and treatment of hyperuricemia in patients with coronary atherosclerotic heart disease may represent a useful approach. Uric acid has both protective and negative effects. Uric acid is a natural antioxidant that can remove oxygen free radicals and other active free radicals[11]. Oyama et al also reported that uric acid reacts with superoxide to generate stable nitric oxide donors, and reduces superoxide-mediated tissue damage and produces vasodilatory effects[12]. In contrast, Strazzullo et al found that uric acid can promote the oxidation of low-density lipoprotein and lipid peroxidation, accelerate vascular injury and the progression of atherosclerotic plaque[13–15]. Oğuz et al demonstrated that uric acid can activate NF-κB, ERK, and p38/MAPK signaling pathways, thereby inducing proliferation and inflammation of vascular endothelial cells[16,17]. Under physiological conditions, uric acid plays a positive role in blood such as anti-oxidative stress, but when uric acid level is higher than physiological level, it activates oxidative stress, inflammatory reaction, and other negative effects. The potential relationship between high uric acid and CCC after myocardial ischemia has not been reported.

In the current study, there was no significant difference in age, sex, BMI, HbA1c, TC, TG, hdl-c, ldl-c, and hs-crp among the patients with varying SUA level. Consistent with studies[18,19], the average age of patients with poor CCC was 65.16 ± 11.22 years, while that of patients with good collateral circulation was 67.12 ± 8.53 years, indicating that the age of onset of poor collateral circulation was young in CTO patients. The current study also found higher rate of poor CCC in patients with hyperuricemia. In multivariate regression, high SUA level on admission was independently associated with poor CCC. The related mechanism for poor CCC in patients with elevated SUA level may be related to the direct or indirect damage to vascular endothelial cells: When the blood uric acid concentration is too high, urate crystals can be precipitated and deposited under the local cardiovascular intima, directly damaging endothelial cells, and at the same time, monocytes can release relevant inflammatory mediators, inducing monocyte macrophages to adhere, and inducing the inflammatory injury reaction of vascular intima[20]. A large number of reactive oxygen species and oxygen free radicals can also be produced during uric acid metabolism. The former can not only reduce the bioavailability of nitric oxide, prevent endothelial cell proliferation, induce endothelial cell dysfunction, but also promote the oxidation and lipid peroxidation of low-density lipoprotein, accelerate vascular injury and plaque formation. The increase of the latter can cause inflammation and further aggravate the injury of endothelial cells[21,22].

European League Against Rheumatism (EULAR) recommendations suggested starting urate-lowering therapy (ULT) in patients with a very high SUA level (>8.0 mg/dL; 480 mmol/L) and/or comorbidities (eg, hypertension, ischemic heart disease, and heart failure)[10]. However, whether uric acid-lowering therapy can really reduce the risk of cardiovascular events and delay the progression of coronary heart disease in clinical practice is still controversial. At present, there are no extensive prospective clinical studies to evaluate whether uric acid-lowering therapy is associated with the development of CCC. This study showed that the incidence of CCC establishment increased sequentially with increasing SUA levels, 44.5%, 54.8%, and 77.4%, respectively, and that elevated SUA was independently associated with the occurrence of arterial collateral circulation formation. These findings encourage early ULT in patients with CTO.

The current study has several limitations. First, this is single-center study with small sample size. The preliminary findings must be verified by multicenter, large-scale study in the future. More importantly, whether treatments that lower SUA conveys a clinical benefit is unknown. Second, we failed to observe an association between poor CCC with the traditional risk factors of atherosclerotic diseases, including blood pressure, blood lipids, HbA1c, and smoking. Lack of association between poor CCC with these traditional risks may be due to the small sample size, or alternatively, the bias caused by the use of antihypertensive, hypoglycemic, and lipid-lowering drugs.

In conclusion, elevated SUA level was associated with CCC in CTO patients. This finding encourages clinical studies of agents that lower SUA in such patients.

FUNDING

This work was supported by the National Natural Science Foundation of China (81970241 to Haifeng Pei), Key Projects of Hospital Management of the General Hospital of the Western Theater Command of PLA (2021-XZYG-A03 to Haifeng Pei).

AUTHOR CONTRIBUTIONS

LI, PHF, and WP participated in the writing of the paper. LI, PHF, WX, and WP participated in the research design and the performance of the research. LJ, WX participated in data analysis. LI, YXL, TJ revised the paper.

CONFLICTS OF INTEREST STATEMENT

The authors declare that they have no financial conflict of interest with regard to the content of this manuscript.

DATA SHARING STATEMENT

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

REFERENCES

[1]. Roth GA, Mensah GA, Johnson CO, et al.; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol 2020;76:2982–3021. doi:10.1016/j.jacc.2020.11.010.
[2]. Dash D. Coronary chronic total occlusion intervention: a pathophysiological perspective. Indian Heart J 2018;70:548–555. doi:10.1016/j.ihj.2018.01.021.
[3]. Brilakis ES, Banerjee S, Karmpaliotis D, et al. Procedural outcomes of chronic total occlusion percutaneous coronary intervention: a report from the NCDR (National Cardiovascular Data Registry). JACC Cardiovasc Interv 2015;8:245–253. doi:10.1016/j.jcin.2014.08.014.
[4]. Bhatnagar UB, Nelson G, Stys A. Collateral flow reversal: exploring protective role of collateral circulation in acute coronary syndrome. S D Med 2019;72:174–177.
[5]. Meier P, Lansky AJ, Fahy M, et al. The impact of the coronary collateral circulation on outcomes in patients with acute coronary syndromes: results from the ACUITY trial. Heart 2014;100:647–651. doi:10.1136/heartjnl-2013-304435.
[6]. Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol 2012;59:991–997. doi:10.1016/j.jacc.2011.12.007.
[7]. Zhao Y, Wang S, Yang J, et al. Association of fibrinogen/albumin ratio and coronary collateral circulation in stable coronary artery disease patients. Biomark Med 2020;14:1513–1520. doi:10.2217/bmm-2020-0333.
[8]. Woodward OM. ABCG2: the molecular mechanisms of urate secretion and gout. Am J Physiol Renal Physiol 2015;309:F485–F488. doi:10.1152/ajprenal.00242.2015.
[9]. Maruhashi T, Hisatome I, Kihara Y, et al. Hyperuricemia and endothelial function: From molecular background to clinical perspectives. Atherosclerosis 2018;278:226–231. doi:10.1016/j.atherosclerosis.2018.10.007.
[10]. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 2017;76:29–42. doi:10.1136/annrheumdis-2016-209707.
[11]. Spitsin S, Markowitz CE, Zimmerman V, et al. Modulation of serum uric acid levels by inosine in patients with multiple sclerosis does not affect blood pressure. J Hum Hypertens 2010;24:359–362. doi:10.1038/jhh.2009.83.
[12]. Oyama J, Tanaka A, Sato Y, et al.; PRIZE Study Investigators. Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat: the PRIZE study. Cardiovasc Diabetol 2016;15:87. doi:10.1186/s12933-016-0409-2.
[13]. Strazzullo P, Puig JG. Uric acid and oxidative stress: relative impact on cardiovascular risk. Nutr Metab Cardiovasc Dis 2007;17:409–414. doi:10.1016/j.numecd.2007.02.011.
[14]. Sánchez-Lozada LG, Soto V, Tapia E, et al. Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia. Am J Physiol Renal Physiol 2008;295:F1134–F1141. doi:10.1152/ajprenal.00104.2008.
[15]. Gür M, Sahin DY, Elbasan Z, et al. Uric acid and high sensitive C-reactive protein are associated with subclinical thoracic aortic atherosclerosis. J Cardiol 2013;61:144–148. doi:10.1016/j.jjcc.2012.08.023.
[16]. Oğuz N, Kirça M, Çetin A, et al. Effect of uric acid on inflammatory COX-2 and ROS pathways in vascular smooth muscle cells. J Recept Signal Transduct Res 2017;37:500–505. doi:10.1080/10799893.2017.1360350.
[17]. Yang X, Gu J, Lv H, et al. Uric acid induced inflammatory responses in endothelial cells via up-regulating(pro)renin receptor. Biomed Pharmacother 2019;109:1163–1170. doi:10.1016/j.biopha.2018.10.129.
[18]. Gorgulu S, Kalay N, Norgaz T, et al. Femoral or radial approach in treatment of coronary chronic total occlusion: a randomized clinical trial. JACC Cardiovasc Interv 2022;15:823–830. doi:10.1016/j.jcin.2022.02.012.
[19]. Liistro F, Weinberg I, Almonacid Popma A, et al. Paclitaxel-coated balloons versus percutaneous transluminal angioplasty for infrapopliteal chronic total occlusions: the IN.PACT BTK randomised trial. EuroIntervention 2022;17:e1445–e1454. doi:10.4244/EIJ-D-21-00444.
[20]. White J, Sofat R, Hemani G, et al. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol 2016;4:327–336. doi:10.1016/s2213-8587(15)00386-1.
[21]. Higgins P, Dawson J, Lees KR, et al. Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther 2012;30:217–226. doi:10.1111/j.1755-5922.2011.00277.x.
[22]. Biscaglia S, Ceconi C, Malagù M, et al. Uric acid and coronary artery disease: an elusive link deserving further attention. Int J Cardiol 2016;213:28–32. doi:10.1016/j.ijcard.2015.08.086.
Keywords:

Coronary occlusion; Coronary circulation; Uric acid; Serum

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