Abstract
目的
探讨急性冠脉综合征（ACS）患者血浆N-乙酰-神经氨酸水平与心肌梗死溶栓治疗临床试验危险评分（TIMI危险评分）和临床预后之间的相关性。
方法
该研究为前瞻性单中心观察性研究，连续纳入2018年10月~2019年7月在我院拟行冠状动脉造影检查的患者708例。收集所有患者的一般临床资料、实验室检查结果、影像学资料和介入治疗资料。根据病史和检查结果分为：ACS组（597例）和对照组（111例）。根据TIMI危险评分对ACS组患者进一步分为高危组（104例）、中危组（425例）和低危组（68例）。采用液相色谱串联质谱法检测患者的血浆Neu5Ac水平；所有患者均行冠状动脉造影检查，计算血管病变支数和Gensini评分。设计调查表，出院后对ACS组患者通过电话或门诊随访平均15个月，统计Mace事件的发生，根据Mace事件将ACS组患者分为Mace组（80例）和非Mace组（517例）。
结果
ACS组患者血浆Neu5Ac水平明显高于对照组（P < 0.05），ROC曲线显示血浆Neu5Ac水平可以辅助ACS诊断[0.648（0.597~0.699）]，敏感性为39.2%，特异性为86.5%，其临界值为288.50 ng/mL。TIMI危险分层显示，高危组患者血浆Neu5Ac水平明显高于中危组和低危组患者（P < 0.05），ROC曲线显示血浆Neu5Ac水平可以协助高危组患者诊断[0.645（0.588~0.703）]，敏感性为42.3%，特异性为80.1%，其临界值为327.50 ng/mL。相关性分析显示：血浆Neu5Ac与年龄、血尿酸、肌酐、脂蛋白a、D-二聚体、C反应蛋白、肌酸激酶同工酶和Gensin评分成正相关性报告P值，与高密度脂蛋白水平成负相关性报告P值。对ACS组患者随访平均15个月后，发现Mace事件组的患者血浆Neu5Ac水平明显高于非Mace事件组的患者。二元Logistic回归显示，血浆Neu5Ac水平、既往脑卒中病史是Mace事件发生的独立危险因素。
结论
血浆Neu5Ac水平对ACS的诊断和危险分层具有参考价值，是ACS患者临床预后的独立危险因素。
Keywords: 急性冠脉综合征, 血浆N-乙酰-神经氨酸, TIMI危险评分, 临床预后
Abstract
Objective
To explore the correlation of plasma N-acetyl-neuraminic acid level with Thrombolysis In Myocardial Infarction (TIMI) risk score and clinical outcomes of patients with acute coronary syndrome (ACS).
Methods
We consecutively enrolled 708 consecutive patients (401 male and 307 female, mean age 63.6±10.6 years) undergoing coronary angiography in our hospital between October, 2018 and July, 2019, including 597 patients with ACS and 111 without ACS (control group). The patients with ACS group were divided into high (n=104), moderate (n=425) and low (n=68) risk groups according to their TIMI risk scores. All the participants were examined for plasma Neu5Ac level using liquid chromatography-tandem mass spectrometry and underwent coronary angiography with their Gensini scores calculated. The patients with ACS were followed up after discharge for a mean of 15 months for the occurrence of major adverse cardiac events (Mace). Binary logistic regression analysis was performed to identify the risk factors of Mace in these patients.
Results
Plasma Neu5Ac levels were significantly higher in ACS group than in the control group (P < 0.05). ROC curve analysis showed that plasma Neu5Ac level could assist in the diagnosis of ACS (0.648 [0.597-0.699]) with a sensitivity of 39.2% and a specificity of 86.5% at the cutoff value of 288.50 ng/mL. In the ACS patients, plasma Neu5Ac level was significantly higher in the high-risk group than in the moderate-risk and low-risk groups (P < 0.05) and could assist in the diagnosis of a high risk (0.645 [0.588-0.703]) with a sensitivity of 42.3% and a specificity of 80.1% at the cutoff value of 327.50 ng/ mL. Plasma Neu5Ac was positively correlated with age, serum uric acid, creatinine, lipoprotein a, Ddimer, C-reactive protein, MB isoform of creatine kinase and Gensini score and negatively correlated with high-density lipoprotein level. During the followup, 80 ACS patients experienced Mace, who had significantly higher plasma Neu5Ac level than those without Mace (n=517). Logistic regression analysis showed that plasma Neu5Ac level and a history of previous stroke were independent risk factors for the occurrence of Mace.
Conclusion
Plasma Neu5Ac level can provide assistance in the diagnosis and risk stratification of ACS and is an independent risk factor for prognosis of ACS patients.
Keywords: acute coronary syndrome, plasma N-acetyl-neuraminic acid, Thrombolysis In Myocardial Infarction risk score, prognosis
急性冠脉综合征（ACS）是一类复杂的代谢紊乱性疾病，是临床导致死亡的重要原因之一[1-2]，检测某些代谢产物可能有助于了解其病理生理学机制[3-4]。血浆N-乙酰-神经氨酸（Neu5Ac）是许多糖蛋白、糖肽和糖脂的基本组成部分，具有广泛的生物学功能。有动物实验研究显示[5]：抑制Neu5Ac调解酶-神经氨酸苷酶1活性有可能保护大鼠心肌细胞的缺血损伤，针对神经氨酸苷酶-1的靶向治疗可能成为冠心病治疗的新方法。但Neu5Ac与ACS之间既往临床研究入选病例少，且仅观察到急性心肌梗死患者血浆Neu5Ac变化，与ACS患者临床危险评分和临床预后之间的研究未见报道。心肌梗死溶栓治疗临床试验危险评分（TIMI）是临床上针对于ACS患者预后的具有代表性的评分系统，评分越高，发生重大心血管事件的可能性越大。因此观察血浆Neu5Ac和TIMI危险评分之间的相关性至关重要。本研究采用串联液谱质谱（LC-MS）方法对708例患者血浆Neu5Ac进行检测，旨在观察血浆Neu5Ac水平变化及其与TIMI危险评分、临床预后之间的相关性，从而为ACS的早期诊断、病情评估、新药研发和个体化治疗提供可能的依据。
1. 资料和方法
1.1. 研究对象
本研究为前瞻性单中心观察性研究，连续纳入2018年10月~2019年7月在我院拟行冠状动脉造影检查的患者708例。男性401例，女性307例，年龄（63.6± 10.6）岁。
诊断标准：ACS包括不稳定型心绞痛（UAP）、ST段抬高型心肌梗死（STEMI）和非ST段抬高型心肌梗死（STEMI）[6-7]。
对照组标准：选择同期在我科行冠状动脉造影检查，未见冠状动脉病变的患者。
排除标准：严重的肝肾功能不全，造血系统疾病，感染性疾病，肿瘤及其他消耗性疾病等。
本研究经蚌埠医学院第一附属医院伦理委员会审批（批准文号：BYYFY-2018KY23）。
1.2. 样品收集
708例患者入院即刻分别抽取肘静脉血5 mL于肝素钠抗凝和EDTA抗凝的试管中，前者送至检验中心进行心肌酶谱和肌钙蛋白分析；后者送至心肺实验室，30 min内分离血清，-80 ℃低温冰箱保存，待所有样品收集后，解冻复温度、离心取上清液，采用液相色谱串联质谱法[8-10]检查每位患者的血浆Neu5Ac水平。次日清晨空腹抽取肘静脉血5 mL于肝素钠抗凝的试管中，送至检验中心进行血尿酸、肌酐、血糖、血脂、C反应蛋白等生化指标分析[11-12]。
1.3. 冠状动脉造影
由心内科专业医师操作完成，采用Judkins[13]法行冠状动脉造影，结果判断采用2001年美国ACC/AHA[14]关于心血管疾病诊断和治疗的报道。造影提示有明确冠状动脉狭窄≥70%给予冠状动脉内支架置入术，病变部位植入药物涂层支架，并详细记录患者冠脉造影结果及支架植入过程。支架植入成功标准按照国际惯例，即残余狭窄≤20%，TIMI3级血流。采用Gensini评分[15]对每支血管病变狭窄程度进行定量计算，由2位熟练的心脏科医师独立评估，计算均值。
1.4. TIMI危险分层
采用心肌梗死溶栓治疗临床试验危险评分（TIMI危险评分）[16-17]对不稳定型心绞痛和急性心肌梗死组患者进行危险分层，UA/NSTEMI和STEMI患者按不同评分标准计算。
1.5. 随访
对患者住院期间严密观察。出院后通过电话或门诊每月随访，平均15月，记录Mace[18-19]事件的发生（再发胸痛、心力衰竭、脑卒中、再发心梗、出血、再次血运重建、支架内血栓、支架内再狭窄、死亡）。
1.6. 统计学处理
采用IBM SPSS Statistics 21.0统计软件包对数据进行分析处理。计量资料用均数±标准差表示，正态分布资料采用方差分析，非正态分布资料采用非参数检验，两组比较采用t检验。分类资料的描述采用构成比，比较采用χ2检验。相关性分析采用了双变量相关性分析和二元Logistic回归。P < 0.05为差异有统计学意义。
2. 结果
2.1. 研究对象基线资料比较
ACS组在男性患者、年龄、吸烟、合并高血压、糖尿病、血尿酸、血糖、血肌酐、C反应蛋白水平上明显高于对照组，高密度脂蛋白水平低于对照组（P < 0.01，表 1）。
1.
急性冠脉综合征组和对照组观察对象基线资料比较
Baseline characteristics ofACS patients and control patients
| Items | ACS (n=597) | Control (n=111) | t/χ2 | P |
| *P < 0.05 vs control. ACS: Acute coronary syndrome; DM: Diabetes mellitus; AF: Atrial fibrillation; FBG: Fasting blood glucose; TC: Total cholesterol; TG: Triglyceride; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; CRP: Creactive protein; cholesterol; TG: Triglyceride; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; CRP: C-reactive protein. | ||||
| Age (year) | 64.79±10.28* | 57.01±9.84 | 7.372 | 0.000 |
| Male (n, %) | 360 (0.60)* | 41 (0.37) | 20.805 | 0.000 |
| Smoker (n, %) | 107 (0.18)* | 11 (0.10) | 4.327 | 0.038 |
| Hypertension (n, %) | 385 (0.64)* | 59 (0.53) | 5.144 | 0.023 |
| DM (n, %) | 158 (0.26)* | 10 (0.09) | 15.760 | 0.000 |
| AF (n, %) | 25 (0.04) | 6 (0.05) | 0.332 | 0.565 |
| Previous stroke (n, %) | 53 (0.09) | 6 (0.05) | 1.477 | 0.224 |
| FBG (mmol/L) | 5.20 (4.56; 6.76)* | 4.95 (4.57; 5.69) | 5.001 | 0.025 |
| UA (μmol/L) | 305.00 (253.00; 369.00)* | 282.00 (242.00; 352.00) | 4.676 | 0.030 |
| SCr (μmol/L) | 67.00 (61.00; 74.00)* | 63.00 (55.00; 69.00) | 24.085 | 0.000 |
| TC (mmol/L) | 3.82 (3.06; 4.58) | 3.64 (2.98; 4.61) | 0.263 | 0.608 |
| TG (mmol/L) | 1.35 (0.96; 1.95) | 1.24 (0.84; 1.79) | 2.968 | 0.085 |
| LDL-C (mmol/L) | 2.04 (1.54; 2.56) | 1.99 (1.50; 2.65) | 0.131 | 0.717 |
| HDL-C (mmol/L) | 0.88 (0.73; 1.04)* | 0.95 (0.79; 1.12) | 7.977 | 0.005 |
| Lp(a) (mg/L) | 216.00 (95.00; 463.00) | 216.50 (88.00; 378.75) | 0.182 | 0.670 |
| CRP (mg/L) | 2.06 (0.80; 5.00)* | 1.30 (0.60; 4.00) | 6.729 | 0.009 |
| D-dimer (mg/L) | 0.29 (0.19; 0.49) | 0.28 (0.19; 0.43) | 1.876 | 0.171 |
2.2. 两组观察对象N-乙酰神经氨酸比较
ACS组患者血浆Neu5Ac水平明显高于N组[238.00（116.37；317.00）vs 206.00（106.15；268.00）ng/mL，P < 0.01]。ROC曲线显示N-乙酰神经氨酸水平可以辅助ACS诊断，敏感性为39.2%，特异性为86.5%，ROC曲线下面积为[0.648（0.597~0.699）]，其临界值为288.50 ng/mL（图 1）。
1.
ROC曲线分析血清N-乙酰神经氨酸对ACS诊断的预测价值
ROC curve analysis of the predictive value of serum N-acetylneuraminic acid in the diagnosis of ACS.
2.3. TIMI危险分层结果
2.3.1. 三组观察对象基线资料比较
高危组患者在年龄、合并高血压、糖尿病、血糖、血尿酸、C反应蛋白、D-二聚体和Gensin评分高于中危组，中危组高于低危组，而低危组患者男性比例高于高危组和中危组。在吸烟、合并房颤、脑卒中上无明显差别。高危组患者三支血管病变高于低危组，而单支血管病变低于低危组（表 2）。
2.
急性冠脉综合征高、中、低三组观察对象基线资料比较
Baseline characteristics ofACS patients with different TIMI risk levels
| Items | Low-risk (n=68) | Medium-risk (n=425) | High-risk (n=104) | F/χ2 | P |
| *P < 0.05 vs High-risk, **P < 0.05 vs Low-risk, #P < 0.05 vs Low-risk. | |||||
| Age (years) | 54.79±6.83* | 65.22±10.15* | 69.59±8.20 | 51.203 | 0.000 |
| Male (n, %) | 50 (0.73) | 254 (0.60)** | 56 (0.54)** | 6.832 | 0.033 |
| Smoker (n, %) | 12 (0.18) | 72 (0.17) | 20 (0.19) | 0.307 | 0.858 |
| Hypertension (n, %) | 33 (0.49)* | 269 (0.63)* | 83 (0.80) | 18.485 | 0.000 |
| DM (n, %) | 8 (0.12)* | 89 (0.21)* | 61 (0.59) | 69.548 | 0.000 |
| AF (n, %) | 2 (0.03) | 18 (0.04) | 5 (0.05) | 0.365 | 0.833 |
| Previous stroke (n, %) | 5 (0.07) | 38 (0.09) | 10 (0.10) | 0.268 | 0.875 |
| FBG (mmol/L) | 4.94 (4.25; 5.96)* | 5.09 (4.55; 6.41)* | 6.42 (4.96; 9.29) | 26.141 | 0.000 |
| UA (μmol/L) | 294.50 (232.35; 355.50)* | 303.00 (253.50; 369.50)* | 325.00 (277.00; 394.00) | 6.782 | 0.034 |
| SCr (μmol/L) | 68.50 (63.00; 75.25) | 67.50 (61.00; 74.00) | 67.00 (60.25; 75.75) | 0.444 | 0.801 |
| TC (mmol/L) | 3.81 (2.84; 4.92) | 3.59 (2.99; 4.47) | 3.78 (2.94; 4.91) | 1.167 | 0.558 |
| TG (mmol/L) | 1.33 (0.95; 1.93) | 1.34 (0.98; 1.92) | 1.47 (0.92; 1.98) | 1.068 | 0.586 |
| LDL-C (mmol/L) | 2.18 (1.39; 2.90) | 1.95 (1.52;2.53) | 2.06 (1.47; 2.75) | 1.609 | 0.447 |
| HDL-C (mmol/L) | 0.97 (0.81; 1.09) | 0.90 (0.75; 1.05) | 0.84 (0.72; 1.01) | 5.247 | 0.073 |
| Lp(a) (mg/L) | 163.50 (97.25; 296.75） | 222.50 (88.25; 386.00) | 218.50 (66.00; 445.25) | 1.660 | 0.436 |
| CRP (mg/L) | 1.34 (0.63; 5.00)* | 2.00 (0.80; 5.00)* | 4.15 (1.40; 5.98) | 17.200 | 0.000 |
| D-dimer (mg/L) | 0.21 (0.05; 0.32)* | 0.27 (0.19; 0.48)* | 0.36 (0.20; 0.54) | 15.171 | 0.001 |
| Gensini score | 12.00 (6.25; 32.00)* | 28.00 (12.00; 46.00)* | 40.00 (14.00; 70.00) | 20.951 | 0.000 |
| Single vessel | 25 (0.37） | 90 (0.21) | 14 (0.13)# | 13.323 | 0.001 |
| Two vessels | 24 (0.35） | 151 (0.36) | 36 (0.35) | 0.031 | 0.985 |
| Three vessels | 19 (0.28） | 184 (0.43) | 54 (0.52)# | 9.682 | 0.008 |
2.3.2. 三组观察对象N-乙酰神经氨酸比较
高危组患者血浆Neu5Ac水平明显高于中危组和低危组患者[254.50（123.58；343.00）vs 244.00（116.45；319.50）vs 209.00（110.96；272.75）ng/mL，P < 0.05]。ROC曲线显示N-乙酰神经氨酸水平可以辅助高危组患者诊断，敏感性为42.3%，特异性为80.1%，ROC曲线下面积为[0.645（0.588~0.703）]，其临界值为327.50 ng/mL（图 2）。
2.
ROC曲线分析血清N-乙酰神经氨酸对ACS患者TIMI危险评分高危组的预测价值
ROC curve analysis of the predictive value of serum N-acetylneuraminic acid on admission for high-risk TIMI score inACS patients.
2.4. N乙酰神经氨酸相关性分析
相关性分析显示：血浆Neu5Ac与年龄、血尿酸、肌酐、脂蛋白a、D-二聚体、C反应蛋白、肌酸激酶同工酶和Gensin评分成正相关，与高密度脂蛋白水平成负相关（表 3，P < 0.05）。
3.
血浆Neu5Ac相关性分析
Correlation of serum Neu5Ac with clinical characteristics
| Neu5Ac (ng/mL) | r | P |
| CK-MB: MB isoform of creatine kinase. | ||
| Age (years) | 0.224 | 0.000 |
| UA (μmol/L) | 0.195 | 0.000 |
| SCr (μmol/L) | 0.278 | 0.000 |
| Lp(a) (mg/L) | 0.138 | 0.000 |
| D-dimer (mg/L) | 0.130 | 0.000 |
| CRP (mg/L) | 0.122 | 0.001 |
| CK-MB (U/L) | 0.087 | 0.020 |
| Gensini score | 0.183 | 0.000 |
| HDL-C (mmol/L) | -0.142 | 0.001 |
| LDL-C (mmol/L) | 0.069 | 0.075 |
随访：对ACS组患者出院后通过电话或门诊随访平均15月，出现Mace事件患者80例，其血浆Neu5Ac水平明显高于非Mace事件组的患者[272.00（131.35；338.25）vs 226.50（115.23；314.50）ng/mL，P < 0.01]。二元Logistic回归显示，血浆Neu5Ac水平、既往脑卒中病史是Mace事件发生的独立危险因素（表 4）。
4.
二元回归分析
Results of binary regression analysis
| Variables | OR (95%CI) | P |
| Neu5Ac (ng/mL) | 1.003 (1.001-1.005） | 0.003 |
| Male (n, %) | 1.477 (0.862-2.532） | 0.156 |
| Age (years) | 1.002 (0.977-1.027） | 0.883 |
| Hypertension (n, %) | 1.128 (0.678-1.877） | 0.642 |
| Smoker (n, %) | 0.649 (0.224-1.884） | 0.427 |
| DM (n, %) | 0.917 (0.503-1.669） | 0.776 |
| AF (n, %) | 0.451 (0.100-2.031) | 0.300 |
| Previous stroke (n, %) | 4.638 (1.078-19.963) | 0.039 |
| FBG (mmol/L) | 1.046 (0.955-1.147) | 0.332 |
| UA (μmol/L) | 1.000 (0.997-1.003) | 0.884 |
| SCr (μmol/L) | 0.992 (0.977-1.008) | 0.344 |
| TC (mmol/L) | 0.765 (0.377-1.552) | 0.458 |
| TG (mmol/L) | 0.917 (0.653-1.287) | 0.615 |
| HDL-C (mmol/L) | 2.183 (0.989-4.820) | 0.053 |
| LDL-C (mmol/L) | 1.400 (0.560-3.500) | 0.471 |
| Lp(a) (mg/L) | 1.000 (1.000-1.001) | 0.408 |
| CRP (mg/L) | 1.004 (0.989-1.018) | 0.629 |
| D-dimer (mg/L) | 1.003 (0.887-1.134) | 0.967 |
3. 讨论
近年来，代谢组学在心血管疾病中的应用研究逐渐受到关注，研究生物体受内外环境干扰后其内源性代谢物质的变化及其规律，寻找与疾病相关的代谢标志物群，可能为疾病的早期诊断、早期干预提供新思路、新途径[20-22]。
Neu5Ac又被称为唾液酸，是一个具有9碳主链的单糖家族，具有高度的结构多样性。近年来国际上的许多研究发现Neu5Ac与生物学功能有关，作为病毒受体，可能与细胞恶变、癌转移、浸润、失去接触性抑制、细胞粘附性降低以及抗原性密切相关[23-24]。但其在冠心病中的作用机制研究较少。目前研究提示[25]，血浆Neu5Ac可能通过炎症反应、干扰铁代谢、促进血小板血栓形成等机制促进动脉粥样硬化形成，且血浆Neu5Ac水平有可能与CHD的严重程度有关。
本研究选取了708例行冠状动脉造影检查的患者，结果显示，ACS组患者血浆Neu5Ac水平明显高于N组，分析受试者工作曲线显示血浆Neu5Ac水平可以辅助ACS诊断，其敏感性为39.2%，特异性为86.5%，其临界值为288.50 ng/mL；Neu5Ac水平和患者基线资料、生化标志物和冠脉病变程度之间的相关性分析，提示血浆Neu5Ac与年龄、血尿酸、肌酐、脂蛋白a、D-二聚体、C反应蛋白、肌酸激酶同工酶和Gensin评分成正相关，与高密度脂蛋白水平成负相关；基线资料也显示，ACS组患者的年龄、血尿酸、血肌酐、C反应蛋白水平明显高于N组，高密度脂蛋白水平低于N组；提示血浆Neu5Ac水平可能反映心机坏死程度、机体代谢水平和冠脉病变程度，对ACS的诊断具有参考价值。
采用TIMI法[26-28]对ACS组患者进行危险分层，结果显示高危组患者的年龄、合并高血压、糖尿病、血糖、血尿酸、C反应蛋白、D二聚体和Gensin评分高于中危组，中危组高于低危组。高危组患者血浆Neu5Ac水平及三支血管病变明显高于低危组患者，ROC曲线显示血浆Neu5Ac水平可以协助高危组患者的鉴别诊断，其敏感性为42.3%，特异性为80.1%，其临界值为327.50 ng/mL。对ACS组患者出院后随访发现出现Mace事件的患者，其血浆Neu5Ac水平明显高于非Mace事件组，且二元相关性分析显示，血浆Neu5Ac水平和既往脑卒中病史是Mace发生的独立危险因素。说明血浆Neu5Ac水平对ACS患者的危险分层具有参考价值且与ACS患者临床预后有关。
Zhang等[5]通过非靶向代谢组学对血浆样本进行队列研究，发现Neu5Ac通过结合RhoA和Cdc42激活Rho-ROCK信号通路，从而在体外和体内引发心肌损伤。Rho/Rho激酶信号通路通过不同途径活化后，使肌球蛋白轻链磷酸化及整合素聚集，导致内皮细胞通透性增加，促进单核/巨噬细胞、氧化的低密度脂蛋白、炎性因子等刺激中膜平滑肌细胞增生，促进动脉粥样硬化的形成。临床研究显示，合并流感的心血管病患者，使用奥司他韦等抗流感药物治疗组的心血管病复发率明显低于未使用抗流感药物治疗组[29-30]，而奥司他韦的活性代谢产物是通过抑制神经氨酸酶-1来发挥作用的。对不合并流感的冠心病患者的相关研究尚未见报道。
本研究具有一定的局限性：研究来源于单中心的观察，样本量较小；排除了严重的肝肾功能不全和心肺功能不全的患者，Mace事件的发生率偏低；随访时间短，只是初步的经验总结，尚有待进一步的深入研究。
综上所述，血浆Neu5Ac水平对ACS的诊断和危险分层具有参考价值，可能是ACS患者临床预后的独立危险因素。血浆Neu5Ac水平可能成为ACS诊断的一个代谢标志物，抑制Neu5Ac调解酶活性、降低血浆Neu5Ac水平可能为保护心肌缺血损伤提供新的思路。
Biography
李妙男，博士，副主任医师，副教授，E-mail: 524760484@qq.com
Funding Statement
国家自然科学基金（81970313）；安徽省教育厅自然科学研究重点项目（KJ2018A0219）；心血管损伤与保护基础与临床应用创新团队（BYKC201906）
Supported by National Natural Science Foundation of China (81970313)
Contributor Information
李 妙男 (Miaonan LI), Email: 524760484@qq.com.
王 洪巨 (Hongju WANG), Email: hongjuwang1@sina.com.
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