Effects of bilirubin on perioperative myocardial infarction and its long-term prognosis in patients undergoing percutaneous coronary intervention

lNTRODUCTlON

Perioperative myocardial infarction(PMI)is a frequent complication of percutaneous coronary intervention(PCI)[1,2].Despite technological advances over the past two decades,the frequency of PMI remains between 5% and 30% with higher rates in patients with complex lesions.PMI may occurseveral mechanisms,including side branch occlusion,distal embolization,inflammation and endothelial injury,all of which may contribute to myocardial damage[3].Many other causative factors affecting PMI risk remain controversial.

Traditionally,the end product of heme catabolism,bilirubin,has been considered a cytotoxic waste product.More recently,an appreciation of its anti-oxidant and anti-inflammatory effects,involving scavenging of ROS to improve vascular and microvascular dysfunction,has emerged[4-6].Indeed,it is more than 20 years since the antioxidant role of bilirubin inischemia-reperfusion was established[7]and,more recently,Bösch[8]also found an ameliorating effect on ischemia reperfusion damage in mice[8].A number of recent clinical studies have reported a protective role of bilirubin in coronary artery disease(CAD)[4-6],although there are also some contradictory reports[9,10].Indeed,elevated bilirubin has been associated with increased in-hospital mortality in acute coronary syndrome[11]and positively correlated with SYNTAX score[10].Thus,the relationship between bilirubin and CAD remains controversial.No previous study has investigated its effect on PMI and its utility for long-term prognosis.

The current study was designed to explore the relationship between bilirubin and PMI in patients undergoing PCI and its utility for predicting long-term outcomes.The following article is presented in accordance with the STROBE reporting checklist.

MATERlALS AND METHODS

Study population

A total of 1310 post-PMI patients were followed up long-term.The median follow-up period was 3.2 years(interquartile range:1.8-5.0).During follow-up,258(19.7%)cases of MACE were identified,including 53(4.0%)cardiac deaths,31(2.4%)non-fatal MIs,6(0.5%)non-fatal strokes and 182(13.9%)revascularizations.Kaplan-Meier curves were used to demonstrate that the cumulative incidence of MACEs decreased with the higher tertile of TB level(log-rank test;= 0.022;Figure 3).The data indicated that better outcomes were correlated with higher TB levels.

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The study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Sir Run Run Shaw Hospital.

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Procedures

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Definitions of outcome

PMI was defined as a post-procedural cTnI ＞ 5 × ULN(revised diagnosis criteria from the third or fourth version of the universal MI definition published in 2012 and 2018[13,14].End points were defined as major adverse cardiovascular events(MACEs),a composite of cardiac death,MI,stroke and revascularization.PMI is not a composition of MACEs.

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Statistical analysis

Statistical analyses were performed by the SPSS 22.0 statistical package(Chicago,Illinois,United States).Continuous variables were reported as mean ± SD or as median with interquartile range.Continuous variables were compared by the t-test(normal distribution)or Kruskal-Wallis test(non-normal distribution).Comparisons of continuous variables among three groups were performed by ANOVA.Categorical variables were expressed as frequencies and compared by chi-square test.

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Multivariate logistical analysis was performed to determine independent predictors of PMI after adjustment for significant variables by univariate analysis(＜ 0.05).Events rates were calculated using the Kaplan-Meier method.Analysis of factors relative to reported events was performed by multivariate Cox proportional hazards modeling.Hazard ratios(HRs)were presented with 95%CIs.A value of＜ 0.05 was considered to show statistical significance.

RESULTS

Patient characteristics

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Predictor of PMI

PMI was detected in 526(15.3%),431(12.7%)and 424(12.5%)of patients with pre-PCI TB levels of ＜10.2,10.2-14.4 and ＞ 14.4 μmol/L(= 0.001),respectively(Figure 2).Recorded rates of PMI were lower in patient groups with the two higher TB levels[TB 10.2-14.4 μmol/L:Odds ratio(OR):0.854;95%confidence interval(CI):0.739-0.987;= 0.032;TB ＞ 14.4 μmol/L:OR:0.846;95%CI:0.735-0.975;=0.021;Table 2]compared with the lowest level group after adjustment for age,gender,smoking,hypertension,renal function,left ventricular ejection fraction(LVEF),prior MI,the use of ACEI or ARB,American Heart Association/American College of Cardiology(AHA/ACC)classification,calcification,the use of fractional flow reserve(FFR)/intravascular ultrasound(IVUS)/optical coherence tomography(OCT)and number of implanted stents.

Clinical outcomes

The current retrospective study enrolled 10263 patients who had been diagnosed with CAD without pre-PCI elevation of cardiac troponin I(cTnI)between January 2014 and September 2018.All patients had elected to have single-vessel PCI.Patients were excluded for the following reasons:(1)Acute or chronic liver injury,biliary tract disease,hematological disease,vitamin B12 deficiency,heart failure or other factors leading to elevated bilirubin;(2)Acute myocardial infarction(MI)in the previous 4 wk;(3)Elective PCI for chronic total occlusion;and(4)Intraoperative factors leading to elevated cTnI,including side-branch occlusion during the procedure,severely calcified lesions with a rotablator or dissection,to enable evaluation of bilirubin effects with less confounding intraoperative factors.Acute liver injury was screened with an acute elevation of transaminases.Chronic liver injury was screened mainly by chronic elevation of transaminases with the case history,such as viral hepatitis,fatty liver disease,alcoholic hepatitis,autoimmune liver disease,biliopancreatic disease,drug-induced liver injury,liver cancer,liver cirrhosis and so on.Heart failure was defined according to the 2021 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure[12].

Cox proportional hazard analysis was performed after adjustment for age,diabetes,unstable angina,low-density lipoprotein cholesterol(LDL-C)and number of stents implanted.The results demonstrated that patients with TB ＞ 14.4 μmol/L had a reduced risk of long-term MACEs with an adjusted HR of 0.667(95%CI:0.485-0.918;= 0.013;Table 3)compared with patients with TB ＜ 10.2 μmol/L.Multivariate Cox models were constructed for further analysis of the relationships between TB levels and MACE component events.Patients with TB ＞ 14.4 μmol/L were at decreased risk of revascularization(HR:0.633;95%CI:0.458-0.875;= 0.006;Table 4)compared to those with TB ＜ 10.2 μmol/L.Adjusted HRs for different TB tertiles did not differ significantly with regard to cardiac death,non-fatal MI and non-fatal stroke(Table 4).

DlSCUSSlON

The current study presents data to demonstrate an independent association between higher preoperative TB levels and a lower incidence of PMI in patients receiving PCI.Furthermore,a high TB level is a protective factor producing a better long-term prognosis in post-PMI patients.

Persistent high rates of PMI,which are of particular concern among patients with complex lesions,are thought to be largely due to oxidative stress causing free radical and inflammatory damage to vascular endothelial cells[3,15,16].There is an adverse impact on long-term morbidity for patients with PMI[17,18]which has stimulated the search for potential targets or risk factors to avoid development of the condition.Patients,lesion and procedure-related factors are all implicated[3].Consistent with previous studies,current findings also indicate that age,gender,renal impairment,complexity of lesions and the number of stents implanted are all predictors of PMI development.Interestingly,the present study also suggests that use of FFR,OCT or IVUS may increase the likelihood of PMI.All these would not only increase additional procedures,but also prolong the operating time and increase the dose of contrast agent,which may aggravate myocardial damage.

Antioxidant properties have been attributed to bilirubin[19]and this breakdown product of heme may directly scavenge ROS[20]and inhibit NADPH oxidase[21].Furthermore,bilirubin has been shown to inhibit peroxidation of lipids and lipoproteins,especially low-density lipoprotein[22-24],indirectly improving microvascular dysfunction.Any resulting improvement in endothelial function will beinstrumental in inhibiting the development of atherosclerosis and reducing cardiovascular complications.

Several clinical studies have demonstrated a negative correlation between serum bilirubin concentrations and cardiovascular disease risk.Schwertner[4]were the first to report serum bilirubin as an inverse risk factor for CAD and several other studies supported this protective role[4-6,25].Interestingly,patients with Gilbert's syndrome,a hereditary disorder resulting in mild hyperbilirubinemia,have lower rates of ischemic heart disease than the general population(2%12%)[19].In contrast to previous studies,the present study focused on PMI,finding a negative association between the incidence of PMI and TB levels.After adjustment for age,gender,body mass index,hypertension,diabetes and LDL-C,plasma TB levels were inversely correlated with C-reactive protein(r = -0.023;=0.019)and white blood cell count(r = -0.062;＜ 0.001),suggesting an anti-inflammatory effect of elevated bilirubin.Peyton[26]demonstrated that bilirubin blocks the proliferation and migration of vascular smooth muscle cells,thus reducing post-PCI stenosis.The present study also found a lower risk of post-PMI revascularization in patients with elevated TB levels.

To explore the impact of bilirubin levels on PMI and long-term prognosis in post-PMI patients.

However,a number of studies found contradictory results.Kaya[10]demonstrated a positive association between high TB levels and the severity of CAD in non-ST-elevation MI.Similarly,Gul[27]and Celik[28]found an association between high TB level and increased in-hospital adverse outcomes in patients with ST-elevation MI.Contrary findings among these studies may be attributed to differences in study populations.Previous trials included AMI patients while the present study focused on patients with normal pre-PCI cTnI.Heme oxygenase 1(HO-1),a rate-limiting enzyme in bilirubin breakdown,can be activated by cellular stresses due to MI,resulting in elevated bilirubin levels[29,30].Xu[31]reported a positive correlation between TB levels and C-reactive protein in AMI patients,reflecting inflammatory activation.Thus,upregulated HO-1 activity and bilirubin would seem to be a defense mechanism to protect the myocardiumantioxidant activity.Previous experiments found that exogenous bilirubin decreased infarct size and ameliorated left ventricular function in the post-ischemic rat heart[32,33].

The findings of the present study assist our understanding of bilirubin actions and our search for therapeutic targets for the management of PMI and other oxidative diseases.A number of drugs are known to induce HO-1,including aspirin and statins[34].Inhibition of bilirubin UDP-glucuronosyl transferase(the key enzyme responsible for bilirubin conjugation)or prevention of bilirubin oxidation may be other routes to elevated bilirubin concentrations[35].Moreover,synthetic materials or naturally occurring tetrapyrrolic molecules structurally related to bilirubin may act as mimetics[36].

Limitations

We acknowledge several limitations in the present study.Firstly,due to its retrospective nature,data regarding ischemic symptoms and electrocardiographs were difficult to collect.PMI in our study was alternatively defined as an isolated rise in cTnI,which did not fulfill the requirement of the revised diagnosis criteria published in 2012 and 2018[13,14].In addition,patients with abnormal pre-PCI cTnI levels were excluded since AMI may affect pre-PCI bilirubin.Secondly,PMI is known to be associated with surgical factors,such as branch occlusion and distal embolism.Patients with intraoperative factors,including side-branch occlusion and severely calcified lesions with a rotablator or dissection,were excluded to reduce the influence of surgical complications.However,although adjustment for many known predictors of PMI was made,confounding factors may not have been completely eliminated.For example,plaque characteristics,such asIVUS/OCT,were only available for a proportion of patients.Thirdly,since HO-1 enzyme activity was not measured,the association between HO-1 level,bilirubin and the risk of PMI could not be assessed.Lastly,our findings show that indirect bilirubin,rather than direct bilirubin,has the predictive value for PMI.Although a previous study has shown that patients with mildly elevated indirect serum bilirubin have a much lower incidence of CAD[37],any difference in mechanism between the two forms remains unconfirmed.Due to potential bias,results regarding the different effects of the two forms on PMI and its long-term outcome are not shown.

CONCLUSlON

Bilirubin was an inverse predictor of PMI and has a protective effect.In patients who experienced PMI,elevated levels of bilirubin were independently associated with a reduced risk of MACEs during longterm follow-up.

ARTlCLE HlGHLlGHTS

Research background

As a frequent complication of percutaneous coronary intervention(PCI),the rate of perioperative myocardial infarction(PMI)remains high and patients suffering from PMI have poor outcomes.

Research motivation

Higher bilirubin was associated with a reduced rate of PMI and major adverse cardiovascular events.

Research objectives

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Research methods

Logistic regression and Cox regression analyses were used to explore the association between bilirubin,PMI and its long-term prognosis.

Research results

To identify whether bilirubin could be a potential target for PMI avoidance.

Research conclusions

Bilirubin was a protective factor in PMI prediction and produced a better long-term prognosis in post-PMI patients.

Stent implantation was performed by experienced cardiac surgeons using the radial artery approach,according to current clinical practice.Patients were treated with aspirin(100 mg/night)and PYinhibitor(clopidogrel:75 mg/d or ticlopidine:180 mg twice daily)for three days before PCI.In the absence of pre-treatment,patients received 300 mg aspirin plus 300 mg clopidogrel or 180 mg ticlopidine before the operation as a loading dose.CTnI levels were measured by immunoassay pre-PCI and at 8,16 and 24 h post-PCI.The peak value of cTnI over 24 h was used for analysis[upper limit of normal(ULN):0.011 ng/mL].Serum bilirubin level was measured before PCI.

Research perspectives

The study provides evidence of bilirubin as a therapeutic target in PMI prevention.

FOOTNOTES

Li Y and Li DB reviewed the literature and contributed to manuscript drafting;Lv QB,Wang Y,Zhao LD and Ren YF contributed to data collection,interpretation,and analysis;Zhang WB was responsible for revision of the manuscript for important intellectual content;all authors issued final approval for the version to be submitted.

The study was reviewed and approved by Sir Run Run Shaw Hospital.

The design of the present study is shown in Figure 1.Baseline clinical and procedural characteristics of the 10236 participants,grouped by pre-operative serum TB concentrations(＜ 10.2;10.2-14.4;＞ 14.4 μmol/L),are shown in Table 1.Patients with lower TB were more likely to be older,female and to have a prevalence of unstable angina,hypertension,diabetes,and renal failure(estimated glomerular filtration rate:＜ 60 mL/min/1.73 m).Patients in the lower TB group were also more likely to be taking angiotensin-converting enzyme inhibitors(ACEI)and angiotensin receptor blocker(ARB),calciumchannel blocker(CCB),receiving more stents and greater balloon pre-dilation.

All authors have nothing to disclose.

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China

Ya Li 0000-0002-3216-5403;Duan-Bin Li 0000-0003-1720-0538;Li-Ding Zhao 0000-0003-4862-7294;Qing-Bo Lv 0000-0002-6531-505X;Yao Wang 0000-0003-4115-9571;Ya-Fei Ren 0000-0002-0222-2120;Wen-Bin Zhang 0000-0003-4746-9570.

Fan JR

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Webster JR

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