Association of NT-proBNP and Subsequent Major Adverse Cardiovascular and Cerebral Events in Patients with Successful PCI for ACS and Normal LVEF

Background: Does N-Terminal pro-brain natriuretic peptide (NT-proBNP) predict subsequent major adverse cardiovascular and cerebral event (MACCE) in patients received successful percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and had normal left ventricular ejection fraction (LVEF)? Methods: 3986 ACS patients were divided into 4 groups based on the quartile (Q) values of peak NT-proBNP measured during hospitalization. All patients were followed for MACCE, a composite of all-cause death, non-fatal myocardial infarction (MI) or stroke, and heart failure requiring hospitalization (HFRH), during a median of 35 months. The incidence of MACCE was compared among Q1-Q4. Receiver operation characteristic curves (ROC) were generated to compare the area under the curve (AUC) for MACCE, cardiovascular (CV) death and HFRH by adding NT-proBNP to the TIMI (thrombolysis in myocardial infarction) risk score. Results: The incidences of MACCE (5.6%, 9.1%, 13.0%, 20.1%, P <0.001), all-cause death (1.0%, 2.5%, 4.1%, 8.4%, P <0.001), non-fatal MI (2.0%,3.4%,4.8%,6.2%, P <0.001) and HFRH (1.5%, 2.3%, 4.1%, 5.9%, P <0.001) were signicantly increased from Q1 to Q4, but, not stroke (1.4%, 1.4%, 1.3%, 2.1%, P =0.438). Each median level (337pg/ml) increase in NT-proBNP was signicantly and independently associated with increased risk of MACCE (HR 1.02, 95%CI, 1.01-1.03; P <0.001). Compared with TIMI (thrombolysis in myocardial infarction) risk score alone, TIMI+NT-proBNP examine whether NT-proBNP is associated with myocardial ischemic injury and inammation and (2)determine whether NT-proBNP at the time of ACS predicts subsequent major adverse cardiovascular and cerebral events (MACCE) in the patients with successful PCI and normal LVEF, therefore, to evaluate the prognostic value of adding NT-proBNP to the existing TIMI (thrombolysis in myocardial infarction) risk score 2 for subsequent MACCE in this population. NT-proBNP, N-Terminal pro-brain natriuretic peptide; BP, blood pressure; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; UAP, unstable angina pectoris; LDL-C, low-density lipoprotein cholesterol; cTNI, cardiac troponin I; CK-MB, creatine kinase-MB; hs-CRP, high-sensitivity C-reactive protein; LAD, atrium ventricular end-diastolic diameter; ACEI, angiotensin-converting enzyme inhibitors, left ventricular fraction; ARB, receptor blockers. lipoprotein cholesterol; cTNI, cardiac troponin I; CK-MB, creatine kinase-MB; hs-CRP, high-sensitivity C-reactive protein; ACEI, angiotensin-converting enzyme inhibitors, ARB, angiotensin receptor blockers.


Background
Despite the continued advancements in modern treatment strategies including percutaneous coronary intervention (PCI) and medical therapies for coronary artery disease, acute coronary syndrome (ACS) remains to be the leading cause of death worldwide. Major efforts have been made for risk strati cation with attempt to guide the early aggressive therapies in the high-risk patient population 1,2 .In addition, reduced left ventricular ejection fraction (LVEF) by echocardiography (echo) is well established independent predictor associated with poor clinical outcomes post ACS [3][4][5] .However, LVEF does not provide information on myocardial remodeling caused by the ischemic condition and reperfusion injury before reaching abnormal systolic function post ACS 6 .
N-Terminal pro-brain natriuretic peptide (NT-proBNP) has been considered as a useful biomarker for assessing myocardial remodeling condition 7,8 .Elevated NT-proBNP as response to ventricular pressure overload and ventricular wall stretch 9 is associated with development of heart failure and poor clinical Page 3/21 outcomes 10 .A number of studies have demonstrated that NT-proBNP value was a predictor of clinical outcomes in ACS patients 11,12 .However, the prognostic value of NT-proBNP in patients with successful PCI for ACS and normal LVEF has not been fully investigated. The present study was designed to: (1) examine whether NT-proBNP is associated with myocardial ischemic injury and in ammation and (2)determine whether NT-proBNP at the time of ACS predicts subsequent major adverse cardiovascular and cerebral events (MACCE) in the patients with successful PCI and normal LVEF, therefore, to evaluate the prognostic value of adding NT-proBNP to the existing TIMI (thrombolysis in myocardial infarction) risk score 2 for subsequent MACCE in this population.

Study population
A total of 6023 ACS patients, who were admitted to Beijing Friendship Hospital and underwent PCI between January 2013 and June 2018, were enrolled into the retrospective observational cohort study. ACS including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP) was diagnosed and con rmed based on symptoms, electrocardiogram (ECG) changes, cardiac biomarkers, and results of coronary angiography 13 . The decision of PCI treatment was made by two interventional cardiologists simultaneously consistent with the international standards and guideline 14 .
Patients were included consecutively if they met the 3 following criteria: (1) ACS patients≥18 years of age. (2) patients with de nite diagnosis of ACS and successful PCI procedure. Successful PCI was de ned as the attainment of a residual vessel diameter stenosis ≤20% and normal epicardial coronary ow (TIMI-3 ow), and without overt complication and ischemic symptom at discharge. (3) patients with LVEF≥50% assessed by echo during hospitalization. As shown in Figure 1, 1336 cases were excluded due to missing data, 510 were removed for LVEF<50%, and 191 were excluded for the medical history of prior heart failure (HF).
Finally, 3986 patients were included and classi ed into 4 groups based on peak NT-proBNP quartile values during hospitalization, as group Q1, Q2, Q3, Q4, in this analysis. The study protocol was approved by Institutional Ethics Committee of Beijing Friendship Hospital, and the study was also in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Data collection
Patient demographic information, medical history, cardiovascular risk factors, laboratory assessments, medical therapy for ACS and PCI procedures were collected and recorded in the Cardiovascular Center Beijing Friendship Hospital Database Bank (CBD Bank).In addition to the routine biochemistry testing, serum NT-proBNP, cardiac troponin I (cTnI), creatine kinase-MB (CK-MB) were measured at the initial admission and monitored during hospitalization for ACS. The peak value of each of these measurements was selected and used in the current study.
Echocardiography, both M-mode and two-dimensional echo, was performed (Philips IE33) after admission for routine assessments of heart structure and function post ACS. We included LVEF, left atrium diameter (LAD), and left ventricular end-diastolic diameter (LVEDD) in the current analysis.
Coronary angiography was performed at the time of PCI for ACS for identifying the culprit lesion and assessing results of PCI. It also provided an overall evaluation of coronary stenosis severity in the nonculprit levels. A number of epicardial main coronary arteries with stenosis ≥50% were determined for each patient.

Study endpoints and follow-up
Composite MACCE including all-cause death, non-fatal MI, stroke, and HF requiring hospitalization (HFRH) was de ned as the primary study endpoint. The secondary endpoints involved cardiovascular (CV) death and each component of the MACCE mentioned above. CV death was de ned as death from MI, HF, or documented cardiac sudden death. Stroke was referred to new ischemic stroke, con rmed by symptoms and results of computed tomography (CT) scan. Non-fatal MI and HF were determined by symptom, physical sign, results of ECG and echo, and the value of biomarkers. All adverse cardiac events were reviewed and con rmed by two separate cardiologists. After discharge, regular follow-up was completed by clinic visits or by phone interviews every 3-6 months up to June 2019 with a median followup duration of 35months (IQR: 23, 48).

Statistical analysis
Continuous variables were expressed as a mean ±SD (standard deviation) or median with IQR (interquartile range) and were compared with the Mann-Whitney U test. Categorical data were expressed as numbers and percentages and were compared by Chi-square or Fisher's exact statistics. Spearman's correlation coe cients were calculated to assess the relationship between log [NT-proBNP] (logtransformed NT-proBNP) and LVEF, LVEDD, peak cTnI, and hs-CRP. The primary and secondary endpoints were compared among the 4 groups respectively by Chi-square test.
Survival analysis was performed using Kaplan-Meier method with the log-rank test. Univariable and multivariable Cox proportional hazards analysis were used to estimate the hazard ratios (HR) and 95% con dence intervals (CI). Multivariable Cox regression models with stepwise forward approach to include confounding variables identi ed from the univariate analysis were used to identify the independent risk predictors of the primary endpoint.
Receiver operating characteristic (ROC) curves were generated for predictive accuracy of subsequent MACCE post successful PCI for ACS. The area under the curve (AUC) was calculated using TIMI risk score and NT-proBNP added to TIMI risk score. Then, AUCs were compared between TIMI risk score and NT-proBNP added to TIMI risk score for predictive accuracy of MACCE.
A two-sided P value 0.05 was considered to be statistically signi cant. All statistical analyses were performed using the SPSS software version 23.0(IBM, Armonk, NY, USA)
Fasting glucose levels at admission were signi cantly higher in the Q3-Q4 group (P < 0.001), but Hb1C levels were not different in the 4 groups (P = 0.567).

Incidence of MACCE and NT-proBNP
Overall, the incidence of MACCE was 11.9% (n=476) during the median follow-up period of 35  Figure 3A-3F).
*P2Y12 receptor antagonist within 12 months after PCI Improved prediction of MACCE ROCs were generated using the TIMI risk score and NT-proBNP added to TIMI risk score. As shown in Figure 5, Advancements in PCI and medical management in the past several decades have signi cantly improved the clinical outcomes in patients with ACS 15,16 . A successful PCI is achieved when residual diameter stenosis severity is reduced to < 30% in all treated lesions without an in-hospital major adverse cardia event including death, MI or repeat coronary revascularization of the target lesions 17 . It is also important for a better outcome if LVEF remains normal at discharge [3][4][5] . However, MACCE continue to occur in patients undergoing a successful PCI and with normal LVEF. The current study in 3986 ACS patients demonstrated that 12% developed MACCE during a median of 35 months post successful PCI. Importantly, the study found that higher NT-proBNP during the initial ACS hospitalization was independently and signi cantly associated with increased risk of subsequent MACCE including all-cause death, non-fatal MI, stroke, and HFRH. Furthermore, the predictions of MACCE, CV death and HFRH were signi cantly improved when adding NT-proBNP to the TIMI risk score.
NT-proBNP is well established biomarker for diagnosis and prognosis of HF [18][19][20] . In the acute HF setting, the PRIDE study demonstrated that the sensitivity and speci city of NT-proBNP were 90% and 85% for diagnosis using a cut-point of 900 pg/ml in emergency department 18 . Furthermore, NT-proBNP level < 300 pg/ml was optimal for ruling out acute HF with a negative predictive value of 99%. Study from Berin R et al. also displayed that serum NT-proBNP was the strongest predictor of long-term mortality in patients with chronic HF (HR 3.76, 95% Cl, 1.20-11.80; P = 0.008) 20 . In addition, higher NT-proBNP levels were strongly associated with increased risks of all-cause death, cardiac death, and MACCE (P < 0.01) in CAD patients with three-vessel disease 21 and has been considered as a useful biomarker for risk strati cation and therapeutic decision-making. The present study found that there was a wide range of NT-proBNP values in the ACS patients undergoing successful PCI and with LVEF ≥ 50%. The median levels were 56 pg/ml and 2706 pg/ml in the lowest and highest NT-proBNP quartile groups. More importantly, incidence of MACCE showed stepwise increase from low to high quartiles (Q1-Q4) (5.6%, 9.1%, 13.0%, 20.1%, P < 0.001). Similar signi cant trends were also detected in the incidences of all-cause mortality, cardiovascular death, nonfatal MI and HFRH (all with P < 0.001), but, stroke. Multivariate analysis revealed that the risk of MACCE increased independently by 1.02-fold (95%CI, 1.01-1.03; P < 0.001) for every 337 pg/ml increase in NT-proBNP. These ndings suggest that NT-proBNP, as a common and routine parameter assessed during ACS hospitalization, can effectively predict long-term (a median of 35 months) adverse outcomes after successful PCI for ACS and with LVEF ≥ 50%.
In the current study, multivariate Cox regression analysis also identi ed clinical factors such as age, heart rate, history of hypertension and diabetes mellitus, three-vessel disease and length of stay in the hospital, in addition to NT-proBNP (Fig. 5) Previous studies have demonstrated that increased levels of NT-proBNP were associated with myocardial ischemic injury, in ammation and remodeling during ACS [24][25][26] . Indeed, our study found signi cant positive correlations between Log (NT-proBNP) values and peak cTnI (r = 0.418, P < 0.001) and between Log (NT-proBNP) and hs-CRP (r = 0.397, P < 0.001). It is well known that reduced LVEF due to myocardial remodeling during and post ischemic injury predicts cardiovascular morbidity and mortality [3][4][5] . Previous studies also showed that NT-proBNP is marker of myocardial remodeling 7 Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
Not applicable.
Authors' contributions JLW and SMZ performed study, statistical analysis and wrote manuscript. HWL and HC provided support, designed study and reviewed manuscript. CYG participated in study data collection. XQZ designed study and revised manuscript. All authors read and approved the nal manuscript.    Factors independently associated with MACCE in multivariable Cox regression analysis. MACCE, major adverse cardiovascular and cerebral events.