Association of residual cholesterol with early-onset myocardial infarction and its clinical outcome
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摘要: 目的 观察残余胆固醇(RC)与早发心肌梗死(MI)及其临床结局的相关性。方法 连续纳入2019年1月—2022年8月于沧州市人民医院住院首次诊断为MI的患者637例，并依据发病年龄(男性≤50岁，女性≤60岁)分为早发MI组(129例)和非早发MI组(508例)，所有患者均接受经皮冠状动脉介入治疗和冠心病规律药物治疗，并将早发MI患者依据随访期间是否再住院分为再住院组(21例)和非再住院组(108例)。收集患者一般临床资料和总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)及低密度脂蛋白胆固醇(LDL-C)等指标，并根据公式计算出RC。比较组间患者的临床特征，采用多因素logistic回归分析早发MI的影响因素。绘制受试者工作特征曲线(ROC)，评估RC对早发MI患者再住院的预测价值。Kaplan-Meier生存曲线比较组间再住院事件率的差异。多因素Cox比例风险回归分析早发MI患者再住院的影响因素，确定RC与再住院的关系。结果 早发MI组TC、LDL-C、RC、尿酸水平均高于非早发MI组，均差异有统计学意义(P < 0.05)。再住院组TC、TG、RC水平均高于非再住院组，均差异有统计学意义(P < 0.05)。多因素logistic回归分析结果显示，尿酸(OR=1.002，95%CI 1.000~1.004，P=0.026)、LDL-C(OR=3.031，95%CI 1.253~7.333，P=0.014)和RC(OR=2.856，95%CI 1.253~6.507，P=0.013)均为早发MI的独立危险因素。RC预测早发MI患者再住院的ROC曲线下面积(AUC)为0.703(95%CI 0.644~0.762，P=0.000)。高RC组和低RC组再住院率比较，差异有统计学意义(Log-rank χ2=16.218，P=0.000)。多因素Cox回归分析结果显示，LDL-C(HR=23.905，95%CI 1.546~369.646，P=0.023)、RC(HR=29.837，95%CI 1.976~450.493，P=0.014)和TG(HR=2.045，95%CI 1.458~2.869，P=0.000)均为早发MI患者再住院的独立危险因素。结论 高RC是早发MI和预后不良的独立危险因素。Abstract: Objective To observe the association of residual cholesterol(RC) with early-onset myocardial infarction(MI) and its clinical outcomes.Methods A total of 637 patients who were hospitalized in Cangzhou People's Hospital for the first time from January 2019 to August 2022 were continuously included. According to the age of onset(male≤50 years old, female≤60 years old), it was divided into early-onset MI group(129 cases) and non-early-onset MI group(508 cases), and all patients received percutaneous coronary intervention and regular drug treatment for coronary heart disease, and the early-onset MI were divided into rehospitalized group(21 cases) and non-rehospitalized group(108 cases) according to whether they were rehospitalized during the follow-up period. The clinical characteristics of patients were compared between groups, and the influencing factors of early-onset MI were analyzed by multivariate logistic regression. Receiver operating characteristic curve(ROC) was plotted to evaluate the predictive value of RC for readmission in patients with early-onset MI. Kaplan-Meier survival curve was used to compare the rate of readmission events between the groups. Multivariate Cox proportional risk regression analysis was conducted to determine the relationship between RC and readmission in patients with early-onset MI.Results The levels of TC, LDL-C, RC and uric acid in the early-onset MI group were higher than those in the non-early-onset MI group, and the differences were statistically significant(P < 0.05). The levels of TC, TG and RC in the rehospitalization group were higher than those in the nonrehospitalization group(P < 0.05). The results of multivariate logistic regression analysis showed that uric acid(OR=1.002, 95%CI1.000-1.004, P=0.026), LDL-C(OR=3.031, 95%CI1.253-7.333, P=0.014) and RC(OR=2.856, 95%CI1.253-6.507, P=0.013) were independent risk factors for early-onset MI. AUC for RC predicting rehospitalization in patients with early-onset MI was 0.703(95%CI0.644-0.762, P=0.000). There were significant differences in the rehospitalization rates between the high RC group and the low RC group(Log-rank χ2=16.218, P=0.000). The results of multivariate Cox regression analysis showed that LDL-C(HR=23.905, 95%CI1.546-369.646, P=0.023), RC(HR=29.837, 95%CI1.976-450.493, P=0.014) and TG(HR=2.045, 95%CI1.458-2.869, P=0.000) were independent risk factors for rehospitalization of patients with early-onset MI.Conclusion High RC is an independent risk factor for early-onset MI risk and poor prognosis.
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心肌梗死(MI)为冠心病的严重临床表现类型，也是一项重大的公共卫生挑战，严重威胁人们的生命和健康。血脂异常在冠心病的发病机制中起核心作用，传统的脂质指标如总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)一直被认为是临床实践中冠心病预防和治疗的重要工具。大量证据表明，高TC、高LDL-C和低HDL-C均为心血管疾病的独立危险因素[1-2]。研究也发现，即使将LDL-C降低到适当水平并控制其他危险因素后，人群中心血管疾病风险和预后也可能存在显著差异[3]。近年来，残余胆固醇(RC)与心血管疾病风险和全因死亡率的关系已经得到了证实[4-7]。然而，随着MI发病年龄越来越年轻，国内有关RC与早发MI的相关研究却很少。本研究的目的是评估RC在早发MI风险及其预后中的价值，对识别和管理早发MI危险因素具有重要的临床和公共卫生意义，同时为寻找更可靠的预后指标来评估早发MI的长期预后提供理论依据。
1. 对象与方法
1.1 对象
本研究以2019年1月—2022年8月连续入住我院心血管内科首次诊断为MI的患者637例作为研究对象。排除标准：冠状动脉肌桥、冠状动脉痉挛等非阻塞性MI；陈旧性MI；院外服用他汀类、胆汁酸螯合剂和贝特类等调脂药物；家族性高胆固醇血症；扩张型心肌病、肥厚性心肌病、心脏瓣膜病、风湿性心脏病等器质性心脏病；Killip分级≥Ⅲ级，或心脏彩色超声提示左室射血分数(LVEF) < 40%；心房颤动、心房扑动；脑梗死；恶性肿瘤；免疫、血液系统疾病；严重肝肾功能异常；严重肺部疾病；周围血管性疾病或栓塞性疾病；临床资料或随访资料不全。本研究得到了沧州市人民医院伦理委员会的批准。
1.2 分组
目前对于早发MI并无统一年龄界值，参照既往文献标准[8-11]，本研究中使用的早发MI发病年龄为男性≤50岁和女性≤60岁。依据发病年龄将患者分为早发MI组(129例)和非早发MI组(508例)。
根据早发MI患者是否再住院将其分为再住院组(21例)和非再住院组(108例)。
1.3 临床资料
记录人口统计学指标：年龄、性别、吸烟史和饮酒史。吸烟史定义为每天至少吸1支烟且连续或累积达6个月，饮酒史定义为每周至少摄入30 g乙醇且达1年以上。记录合并症病史：高血压和糖尿病。记录入院时首次测定的相关指标：肌酐、尿酸、白蛋白、谷丙转氨酶、TC、HDL-C、LDL-C和TG。其中，白蛋白、谷丙转氨酶、TC、HDL-C、LDL-C和TG均在空腹状态下检测的。空腹RC的计算公式：RC=TC-HDL-C-LDL-C，并以mmol/L表示[12-13]。
1.4 随访观察
所有患者出院后的基础药物治疗均为冠心病规范化药物治疗。本研究终点事件为出院后再住院。通过电话随访的方式对患者进行随访，所有患者均随访至再住院、失访或随访至截止时间2023年2月，平均随访时间为(19.97±9.90)个月。随访人员均由心血管内科专科医师担任，在研究开展前对随访内容和注意事项进行统一培训学习。
随访的早发MI患者中有21例再住院，其中，3例因再发MI住院，15例因频发心绞痛住院，1例因心律失常住院，2例因心力衰竭住院。
1.5 统计学处理
使用SPSS 26.0软件进行分析。符合正态分布的计量资料采用X±S形式表示，组间比较采用t检验；非正态分布的计量资料采用M(P25，P75)形式表示，组间比较采用Mann-Whitney U检验；计数资料采用例(%)形式表示，组间比较采用χ2检验。采用logistic回归分析影响早发MI的相关因素。根据受试者工作特征曲线(ROC曲线)评价RC对再住院的预测价值。采用Kaplan-Meier生存曲线(Log-rank检验)法比较高RC组和低RC组间再住院事件率的差异；采用Cox比例风险回归模型分析早发MI患者再住院的危险因素。P < 0.05为差异具有统计学意义。
2. 结果
2.1 早发MI组和非早发MI组患者临床资料比较
637例MI中，男437例，女200例。129例早发MI中，男90例，女39例。与非早发MI组比较，早发MI组患者TC、LDL-C、RC、尿酸水平均偏高，均差异有统计学意义(P < 0.05)。2组患者TG、HDL-C、白蛋白、肌酐、谷丙转氨酶、男性比例、吸烟史比例、饮酒史比例、糖尿病史比例、高血压史比例比较，均差异无统计学意义(P>0.05)。见表 1。
表 1 早发MI组和非早发MI组临床资料Table 1 Clinical data of early-onset MI group and non-early-onset MI group例(%), X±S, M(P25, P75) 指标 早发MI组(129例) 非早发MI组(508例) χ2/t/Z P值 男性 90(69.77) 347(68.31) 0.102 0.750 吸烟史 34(26.36) 132(25.98) 0.007 0.931 饮酒史 30(23.26) 106(20.87) 0.350 0.554 高血压史 69(53.49) 308(60.63) 2.172 0.141 糖尿病史 26(20.16) 130(25.59) 1.644 0.200 白蛋白/(g/L) 42.01±4.01 42.04±3.96 0.455 0.932 肌酐/(μmol/L) 61.75±10.51 61.97±11.40 1.901 0.842 尿酸/(μmol/L) 307.42±103.80 287.19±101.03 0.697 0.044 谷丙转氨酶/(U/L) 21.67±13.42 20.25±12.26 2.884 0.247 TC/(mmol/L) 4.98±1.24 4.54±0.98 3.424 0.000 TG/(mmol/L) 1.96±1.22 1.80±1.34 0.006 0.216 HDL-C/(mmol/L) 1.09±0.27 1.12±0.29 1.542 0.454 LDL-C/(mmol/L) 2.98(2.43，3.86) 2.79(2.22，3.34) 5.432 0.001 RC/(mmol/L) 0.72±0.73 0.61±0.43 2.798 0.025 | Show Table
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2.2 早发MI影响因素的二元logisitic回归分析
以研究对象是否为早发MI(否=0，是=1)为因变量，将单因素分析中有显著统计学差异(P < 0.1)的指标(TC、LDL-C、RC、尿酸)纳入多因素二元logisitic回归模型，结果显示，尿酸(OR=1.002，95%CI 1.000~1.004，P=0.026)、LDL-C(OR=3.031，95%CI 1.253~7.333，P=0.014)和RC(OR=2.856，95%CI 1.253~6.507，P=0.013)均为早发MI的独立危险因素，见表 2。
表 2 早发MI的多因素logisitic回归分析Table 2 Multivariate logisitic regression analysis of early onset MI变量 B SE Wald OR 95%CI P 尿酸 0.002 0.001 4.982 1.002 1.000~1.004 0.026 LDL-C 1.109 0.451 6.055 3.031 1.253~7.333 0.014 RC 1.049 0.420 6.235 2.856 1.253~6.507 0.013 | Show TableDownLoad:
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2.3 再住院组和非再住院组患者临床资料比较
与非再住院组比较，再住院组患者TC、TG、RC水平均偏高，均差异有统计学意义(P < 0.05)。2组患者LDL-C、HDL-C、白蛋白、肌酐、尿酸、谷丙转氨酶、年龄、吸烟史比例、饮酒史比例、男性比例、糖尿病史比例、高血压史比例比较，均差异无统计学意义，见表 3。
表 3 再住院组和非再住院组临床资料Table 3 Clinical data of readmission group and non-readmission group例(%), X±S, M(P25, P75) 指标 再住院组(21例) 非再住院组(108例) χ2/t/Z P值 年龄/岁 43.76±8.34 46.44±7.15 1.409 0.129 男性 14(66.67) 76(70.37) 0.114 0.735 吸烟史 5(23.81) 29(26.85) 0.084 0.772 饮酒史 5(23.81) 25(23.15) 0.004 0.948 高血压史 10(47.62) 59(54.63) 0.347 0.556 糖尿病史 5(23.81) 21(19.44) 0.208 0.648 白蛋白/(g/L) 41.95±3.56 42.02±4.09 0.682 0.946 肌酐/(μmol/L) 62.71±10.00 61.58±10.63 0.319 0.669 尿酸/(μmol/L) 321.84±114.09 304.93±02.27 0.676 0.514 谷丙转氨酶/(U/L) 22.95±15.51 21.46±13.09 0.941 0.656 TC/(mmol/L) 5.95(4.70，6.38) 4.63(4.16，5.37) 6.356 0.007 TG/(mmol/L) 2.73(1.77，3.65) 1.51(1.11，2.03) 10.385 0.004 HDL-C/(mmol/L) 1.07±0.34 1.10±0.26 1.795 0.632 LDL-C/(mmol/L) 3.39(2.53，4.48) 2.93(2.42，3.74) 10.161 0.185 RC/(mmol/L) 1.10(0.68，1.42) 0.55(0.38，0.74) 30.343 0.017 | Show TableDownLoad:
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2.4 RC预测早发MI患者再住院的ROC分析
以RC作为检验变量，早发MI患者再住院作为预测变量，进行ROC分析并绘制ROC曲线，结果显示，RC的ROC曲线下面积(AUC)为0.703(95%CI 0.644~0.762，P=0.000)，这表明RC对早发MI患者再住院的预测效果较好，见图 1。
2.5 高RC组和低RC组患者再住院事件率的Kaplan-Meier生存曲线
根据ROC曲线分析结果得到RC最佳截断值将早发MI患者分为高RC组(54例)和低RC组(75例)。以结局(生存结局：是否再住院；时间结局：出院至再住院间隔时间，以月为单位)绘制2组再住院事件率的Kaplan-Meier曲线，结果显示，2组间再住院率比较，差异具有统计学意义(Log-rank χ2=16.218，P=0.000)，见图 2。
2.6 影响早发MI患者再住院的Cox比例风险回归
以早发MI患者是否再住院(否=0，是=1)为因变量，将单因素分析中有显著统计学差异(P < 0.1)的指标(TC、TG、LDL-C、RC、年龄)纳入多因素Cox回归分析，结果显示，LDL-C(HR=23.905，95%CI 1.546~369.646，P=0.023)、RC(HR=29.837，95%CI 1.976~450.493，P=0.014)和TG(HR=2.045，95%CI 1.458~2.869，P=0.000)均为早发MI患者再住院的独立危险因素，见表 4。
表 4 早发MI患者再住院的多因素Cox回归分析Table 4 Multivariate Cox regression analysis of re-hospitalization in early MI变量 B SE Wald HR 95%CI P LDL-C 3.174 1.397 5.161 23.905 1.546~369.646 0.023 RC 3.396 1.385 6.011 29.837 1.976~450.493 0.014 TG 0.716 0.173 17.172 2.045 1.458~2.869 0.000 | Show TableDownLoad:
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3. 讨论
RC定义为富含TG的乳糜微粒残体、中密度脂蛋白和极低密度脂蛋白[14]。由于RC成分通常较为复杂且代谢快速，准确测量RC是复杂的。研究表明，通过磁共振波谱法测量的高RC浓度与MI患病风险增加有关[15]。在禁食条件下，RC值可以通过使用易于检测的既定公式轻松计算，即RC=TC-HDL-LDL。一项观察性研究表明，无论是实验室测量还是公式计算，RC水平升高均与心血管疾病风险增加存在关联[16]。然而，Varbo等[17]却提出，与准确测量的RC相比，公式计算的RC可以更准确地识别MI风险较高的患者。另外，RC水平在禁食期和正常饮食期之间变化不大，即使在非禁食条件下，也可以通过上述公式计算RC水平。本研究患者血脂指标均在禁食条件下获得，并以公式计算的空腹RC进行了一系列研究。
本研究评估了RC与早发MI患病风险的关系，结果表明，早发MI患者RC浓度较非早发MI患者明显升高[(0.72±0.73) mmol/L vs (0.61±0.43) mmol/L，P=0.025]，RC(OR=2.856，P=0.013)是早发MI的独立危险因素。RC作为残余心血管风险指标与冠心病风险之间存在因果关系，高RC和高LDL在增加MI患病风险方面具有相似效应[18-24]。然而，RC可能具有更强的致动脉粥样硬化能力[25-26]。RC可以很容易地穿透血管壁，优先于LDL-C直接被巨噬细胞中的清除受体直接降解而不进行氧化修饰，形成泡沫细胞并促进动脉粥样硬化斑块的形成和进展[27-30]。RC具有更大的数量和体积，携带胆固醇的能力是LDL-C的40倍，更易导致动脉粥样硬化斑块形成[31]。此外，它还可以通过增加氧化应激、抑制一氧化氮的产生，从而引起内皮细胞功能障碍[32-33]。最后，高RC也可诱导肿瘤坏死因子-α、白细胞介素和促动脉粥样硬化黏附分子的产生，增加单核细胞的炎症反应并诱导慢性低度炎症[34]。所有这些机制都可导致斑块形成和破裂，从而导致MI的发生[35]。另外，目前研究表明，RC升高与独立于全身性炎症的他汀类药物治疗的冠心病患者的复发性心血管事件风险增加有关，较高RC可能是冠心病患者心血管结局不良的独立预测指标[36-38]。本研究也发现，患病初期RC浓度是早发MI患者再住院的独立预测因素(HR=29.837，P=0.014)。与既往研究相似[22]。
本研究有几个局限性：首先这是一项单中心研究，样本量相对较小；其次，通过公式计算出的空腹RC浓度，结果可能与准确测量有偏差；最后，仅考虑了空腹RC水平，忽略了非禁食RC水平与早发MI的相关性。
利益冲突 所有作者均声明不存在利益冲突
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表 1 早发MI组和非早发MI组临床资料
Table 1. Clinical data of early-onset MI group and non-early-onset MI group
例(%), X±S, M(P25, P75) 指标 早发MI组(129例) 非早发MI组(508例) χ2/t/Z P值 男性 90(69.77) 347(68.31) 0.102 0.750 吸烟史 34(26.36) 132(25.98) 0.007 0.931 饮酒史 30(23.26) 106(20.87) 0.350 0.554 高血压史 69(53.49) 308(60.63) 2.172 0.141 糖尿病史 26(20.16) 130(25.59) 1.644 0.200 白蛋白/(g/L) 42.01±4.01 42.04±3.96 0.455 0.932 肌酐/(μmol/L) 61.75±10.51 61.97±11.40 1.901 0.842 尿酸/(μmol/L) 307.42±103.80 287.19±101.03 0.697 0.044 谷丙转氨酶/(U/L) 21.67±13.42 20.25±12.26 2.884 0.247 TC/(mmol/L) 4.98±1.24 4.54±0.98 3.424 0.000 TG/(mmol/L) 1.96±1.22 1.80±1.34 0.006 0.216 HDL-C/(mmol/L) 1.09±0.27 1.12±0.29 1.542 0.454 LDL-C/(mmol/L) 2.98(2.43，3.86) 2.79(2.22，3.34) 5.432 0.001 RC/(mmol/L) 0.72±0.73 0.61±0.43 2.798 0.025
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表 2 早发MI的多因素logisitic回归分析
Table 2. Multivariate logisitic regression analysis of early onset MI
变量 B SE Wald OR 95%CI P 尿酸 0.002 0.001 4.982 1.002 1.000~1.004 0.026 LDL-C 1.109 0.451 6.055 3.031 1.253~7.333 0.014 RC 1.049 0.420 6.235 2.856 1.253~6.507 0.013
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表 3 再住院组和非再住院组临床资料
Table 3. Clinical data of readmission group and non-readmission group
例(%), X±S, M(P25, P75) 指标 再住院组(21例) 非再住院组(108例) χ2/t/Z P值 年龄/岁 43.76±8.34 46.44±7.15 1.409 0.129 男性 14(66.67) 76(70.37) 0.114 0.735 吸烟史 5(23.81) 29(26.85) 0.084 0.772 饮酒史 5(23.81) 25(23.15) 0.004 0.948 高血压史 10(47.62) 59(54.63) 0.347 0.556 糖尿病史 5(23.81) 21(19.44) 0.208 0.648 白蛋白/(g/L) 41.95±3.56 42.02±4.09 0.682 0.946 肌酐/(μmol/L) 62.71±10.00 61.58±10.63 0.319 0.669 尿酸/(μmol/L) 321.84±114.09 304.93±02.27 0.676 0.514 谷丙转氨酶/(U/L) 22.95±15.51 21.46±13.09 0.941 0.656 TC/(mmol/L) 5.95(4.70，6.38) 4.63(4.16，5.37) 6.356 0.007 TG/(mmol/L) 2.73(1.77，3.65) 1.51(1.11，2.03) 10.385 0.004 HDL-C/(mmol/L) 1.07±0.34 1.10±0.26 1.795 0.632 LDL-C/(mmol/L) 3.39(2.53，4.48) 2.93(2.42，3.74) 10.161 0.185 RC/(mmol/L) 1.10(0.68，1.42) 0.55(0.38，0.74) 30.343 0.017
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表 4 早发MI患者再住院的多因素Cox回归分析
Table 4. Multivariate Cox regression analysis of re-hospitalization in early MI
变量 B SE Wald HR 95%CI P LDL-C 3.174 1.397 5.161 23.905 1.546~369.646 0.023 RC 3.396 1.385 6.011 29.837 1.976~450.493 0.014 TG 0.716 0.173 17.172 2.045 1.458~2.869 0.000
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