Effect of early use of ivabradine on cardiac function in patients with acute myocardial infarction after percutaneouscoronary intervention
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摘要:
目的 探讨早期应用伊伐布雷定对急性心肌梗死（AMI）经皮冠状动脉介入治疗（PCI）术后患者心功能的影响。 方法 选取2020年2月至2021年5月在我院接受住院治疗的80例AMI患者为研究对象，按1∶1比例随机分为伊伐布雷定组和对照组。所有患者均成功接受急诊PCI术治疗，术后伊伐布雷定组给予伊伐布雷定联合美托洛尔治疗，对照组单纯给予美托洛尔治疗，两组患者均随访1年，比较两组患者的心脏超声参数、心率及心肌损伤标志物。 结果 伊伐布雷定组术后1周、3个月及1年的左心室射血分数均高于对照组（均P＜0.05）。伊伐布雷定组术后1周的心率低于对照组（P＜0.05），两组术后3个月、1年的心率差异无统计学意义（均P＞0.05）。与对照组比较，伊伐布雷定组术后第2天和第3天的脑钠肽水平降低（P＜0.05），术后第5天的肌钙蛋白Ⅰ水平降低（P＜0.05）。 结论 AMI患者PCI术后早期应用伊伐布雷定能够更好地控制心率，减轻心肌损伤，改善患者的心功能。 -
关键词:
- 急性心肌梗死 /
- 伊伐布雷定 /
- 经皮冠状动脉介入治疗 /
- 心脏功能
Abstract:Objective To investigate the effect of early use of ivabradine on cardiac function in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Methods Eighty patients with AMI who were hospitalized in our hospital from Feb. 2020 to May 2021 were enrolled, and were randomly assigned to ivabradine group or control group (1∶1). All patients were successfully treated with emergency PCI, and the ivabradine group was treated with ivabradine combined with metoprolol after PCI, while the control group was treated with metoprolol only. Both groups were followed up for 1 year. Echocardiography-derived parameters, heart rate and myocardial markers were analyzed. Results Theleft ventricular ejection fraction was significantly higher in the ivabradine group than in the control group at 1 week, 3 months, and 1 year after PCI (all P < 0.05). The heart rate of the ivabradine group was significantly lower than that of the control group at 1 week after PCI (P < 0.05), while there was no significant difference in heart rates between the 2 groups at 3 months or 1 year after PCI (both P > 0.05). The brain natriuretic peptide of the ivabradine group was significantly lower than that of the control group on day 2 and day 3 after PCI (both P < 0.05). The troponin I level of the ivabradine group was significantly lower than that of the control group on day 5 after PCI (P < 0.05). Conclusion Early use of ivabradine in patients with AMI after PCI can achieve effective heart rate control, reduce myocardial injury and improve cardiac function. -
急性心肌梗死（acute myocardial infarction，AMI）是严重威胁人类健康的心血管疾病之一，其特点是病情进展快、并发症严重、死亡率高[1]。及时有效的血运重建是挽救AMI患者生命的重要手段，但仍有部分患者术后左心收缩功能下降，进而发展为心力衰竭[2]。AMI患者经皮冠状动脉介入治疗（percutaneous coronary intervention，PCI）术后仍需持续优化药物治疗，从而进一步提高心脏功能，降低死亡率。心率控制是改善AMI患者远期预后的重要措施[3]。β受体阻滞剂作为目前最常用的一类控制心率的药物，能够减少心肌梗死面积、减轻心肌炎症反应、延缓心肌重塑过程[4]，但它的负性传导、负性肌力等不良反应也在一定程度上限制了其临床应用。伊伐布雷定（ivabradine）是首个窦房结If电流特异性抑制剂，具有单纯减慢心率的作用，对心肌收缩力和心脏传导无明显影响[5]。既往研究表明伊伐布雷定在心力衰竭、稳定型冠心病的治疗中展现出良好效果[6-7]，但其在AMI中的治疗效果尚不明确。本研究旨在探讨早期应用伊伐布雷定对AMI患者PCI术后心功能的影响，为心肌梗死的治疗提供新思路。
1 资料和方法
1.1 研究对象
选择2020年2月至2021年5月在我院接受住院治疗的106例AMI患者为研究对象。纳入标准：（1）所有患者均符合AMI诊断标准[1]，成功行急诊PCI手术；（2）窦性心律且心率≥75 min－1；（3）年龄18~85岁。排除标准：（1）有支气管哮喘病史；（2）有缓慢性心律失常病史；（3）收缩压≤90 mmHg（1 mmHg＝0.133 kPa）；（4）PCI术后6 h后仍因休克使用血管活性药物。根据纳入和排除标准，排除患者26例（心动过缓12例，低血压9例，PCI术后6 h后仍使用血管活性药物5例），最终共80例患者纳入研究。80例患者按1∶1比例随机分为伊伐布雷定组和对照组。整个研究过程中无退出、失访及死亡病例。本研究通过我院伦理委员会审批，所有研究对象均签署了知情同意书。
1.2 样本量估算
根据心室重塑（remodelage ventriculaire，REVE）研究[8]估算样本量，以AMI患者左心室射血分数（left ventricular ejection fraction，LVEF）为主要结局变量，伊伐布雷定组与对照组均值相差2.6%，标准差为6.4%。基于这一假设，为达到80%检验效能和双侧t检验α＝0.05检验水准，在两组间检测到最小显著性差异时，每组需入选至少39例患者。本研究选取40例患者，总样本量为80例。
1.3 干预措施
两组患者均接受急诊PCI术。所有患者PCI术前均口服负荷剂量的阿司匹林300 mg和替格瑞洛180 mg（或氯吡格雷300 mg），术中根据患者病情需要选择应用Ⅱb/Ⅲa受体拮抗剂、低分子肝素、临时起搏器植入、主动脉内球囊反搏等，术后均常规给予双联抗血小板、他汀类药物以及血管紧张素转化酶抑制剂（angiotensin converting enzyme inhibitor，ACEI）/血管紧张素Ⅱ受体拮抗剂（angiotensinⅡreceptor blocker，ARB）/血管紧张素受体脑啡肽酶抑制剂（angiotensin receptor neprilysin inhibitor，ARNI）等药物治疗。对照组术后12 h口服酒石酸美托洛尔12.5 mg，每天2次；伊伐布雷定组在口服酒石酸美托洛尔基础上，联合口服盐酸伊伐布雷定5 mg，每天2次。术后第3天将酒石酸美托洛尔调整为长效的琥珀酸美托洛尔，根据欧洲心脏病学会公布的2017版ST段抬高型急性心肌梗死管理指南[9]对β受体阻滞剂进行剂量滴定。同时两组患者根据心率个体化调整药物剂量，目标心率定位70 min－1。两组患者若治疗过程中出现心动过缓（心率持续＜50 min－1）则停止给药，终止试验。
1.4 观察指标
（1）心脏超声参数：采用单盲的方法，由超声科医师使用彩色多普勒超声诊断仪对两组患者进行超声心动图检查，记录两组患者基线及治疗后（术后1周、3个月、1年）的心脏超声参数，包括LVEF、左心室收缩末期内径（left ventricular end-systolic diameter，LVESD）、左心室舒张末期内径（left ventricular end-diastolic diameter，LVEDD）、左心房内径（left atrial diameter，LAD）、室间隔厚度（interventricular septal thickness，IVST）和E/e’比值。（2）心率和血压：记录两组患者基线及治疗后（术后1周、3个月、1年）的心率和血压水平。（3）心肌损伤标志物：PCI术前、术后2 h及术后1~6 d每日采集外周血，检测两组患者的脑钠肽（brain natriuretic peptide，BNP）、肌钙蛋白（troponin，Tn）Ⅰ和肌酸激酶-MB同工酶（creatine kinase-MB，CK-MB）水平。
1.5 统计学处理
应用SPSS 25.0软件进行统计学分析。符合正态分布的计量资料用x±s表示，组间比较采用t检验；非正态分布的计量资料用M（Q1，Q3）表示，组间比较采用Wilcoxon秩和检验。计数资料用例数和百分数表示，组间比较采用χ2检验。检验水准（α）为0.05。
2 结果
2.1 两组AMI患者的基线资料
两组AMI患者的年龄、性别、伴随疾病、生化指标、冠状动脉病变及用药情况差异均无统计学意义（均P＞0.05），提示基线资料具有可比性。见表 1。
表 1 两组AMI患者的基线资料比较Table 1 Comparison of baseline data between AMI patients of 2 groupsN＝40 Item Ivabradine group Control group Statistic P value Age/year, x±s 68.53±10.21 67.43±11.44 t＝0.454 0.651 Male, n (%) 30 (75.00) 33 (82.50) χ2＝0.672 0.412 Hypertension, n (%) 20 (50.00) 24 (60.00) χ2＝0.808 0.369 Diabetes mellitus, n (%) 14 (35.00) 10 (25.00) χ2＝0.952 0.329 Hyperlipemia, n (%) 15 (37.50) 11 (27.50) χ2＝0.912 0.340 STEMI, n (%) 23 (57.50) 28 (70.00) χ2＝1.352 0.245 Number of diseased vessels, n (%) χ2＝1.200 0.549 1 14 (35.00) 10 (25.00) 2 13 (32.50) 17 (42.50) 3 13 (32.50) 13 (32.50) Infarct-related artery, n (%) χ2＝2.317 0.314 LAD 24 (60.00) 27 (67.50) LCX 6 (15.00) 2 (5.00) RCA 10 (25.00) 11 (27.50) ALT/(U·L－1), M (Q1, Q3) 40.00 (25.50, 56.75) 40.00 (28.25, 87.25) Z＝0.356 0.722 AST/(U·L－1), M (Q1, Q3) 142.00 (54.75, 236.00) 163.00 (81.00, 377.00) Z＝0.986 0.324 Creatinine/(μmol·L－1), M (Q1, Q3) 70.50 (60.00, 84.75) 69.50 (59.50, 83.25) Z＝0.183 0.855 Urea nitrogen/(mmol·L－1), M (Q1, Q3) 5.65 (4.53, 7.63) 6.25 (4.60, 7.68) Z＝0.582 0.600 Uric acid/(μmol·L－1), M (Q1, Q3) 336.00 (286.75, 415.75) 390.00 (305.75, 460.50) Z＝1.742 0.082 Total cholesterol/(mmol·L－1), x±s 5.28±1.29 5.21±1.29 t＝0.275 0.784 Triglyceride/(mmol·L－1) 1.35 (1.05, 2.09) 1.26 (0.89, 1.93) Z＝0.986 0.324 LDL-C/(mmol·L－1), x±s 3.63±0.98 3.63±1.04 t＝0.014 0.989 HDL-C/(mmol·L－1), x±s 1.16±0.20 1.11±0.26 t＝0.911 0.365 Medication, n (%) ACEI/ARB/ARNI 32 (80.00) 31 (77.50) χ2＝0.075 0.785 β blocker 40 (100.00) 40 (100.00) χ2＝0.000 1.000 Aldosterone receptor antagonist 8 (20.00) 6 (15.00) χ2＝0.346 0.556 Loop diuretic 8 (20.00) 5 (12.50) χ2＝0.827 0.363 Dual antiplatelet therapy 40 (100.00) 40 (100.00) χ2＝0.000 1.000 AMI: Acute myocardial infarction; STEMI: ST-segment elevation myocardial infarction; LAD: Left atrial diameter; LCX: Left circumflex branch; RCA: Right coronary artery; ALT: Alanine aminotransferase; AST: Aspartate transferase; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; ACEI: Angiotensin converting enzyme inhibitor; ARB: AngiotensinⅡreceptor blocker; ARNI: Angiotensin receptor neprilysin inhibitor. 2.2 两组AMI患者手术前后心脏超声参数比较
两组AMI患者PCI术前的LVEF比较差异无统计学意义（P＞0.05）；伊伐布雷定组PCI术后1周、3个月及1年的LVEF均高于对照组，差异均有统计学意义（均P＜0.05）。伊伐布雷定组PCI术后1周的LAD低于对照组，差异有统计学意义（P＜0.05）；两组AMI患者PCI术前及术后3个月、1年的LAD比较差异均无统计学意义（均P＞0.05）。两组AMI患者PCI术前及术后1周、3个月、1年的LVESD、LVEDD、IVST、E/e’比值的差异均无统计学意义（均P＞0.05）。见表 2。
表 2 两组AMI患者PCI前后心脏超声参数比较Table 2 Comparison of echocardiography-derived parameters between 2 groups of AMI patients before and after PCIn＝40, x±s Parameter Ivabradine group Control group t value P value LVEF/% Before PCI 52.05±7.42 50.08±9.05 0.491 0.623 1 week after PCI 57.00±7.87 50.70±10.79 2.110 0.042 3 months after PCI 56.57±9.99 50.97±10.30 2.268 0.023 1 year after PCI 59.32±8.11 51.94±11.75 2.768 0.006 LVESD/mm Before PCI 33.88±5.60 34.15±5.86 0.685 0.493 1 week after PCI 32.20±5.49 34.85±5.91 1.641 0.101 3 months after PCI 32.93±6.39 35.42±6.56 1.813 0.070 1 year after PCI 33.74±6.63 36.38±7.81 1.442 0.149 LVEDD/mm Before PCI 47.35±5.10 48.43±5.67 0.892 0.375 1 week after PCI 48.20±5.60 50.60±5.37 1.383 0.175 3 months after PCI 48.82±7.18 49.76±5.04 0.921 0.357 1 year after PCI 49.39±5.91 50.76±6.42 0.897 0.373 LAD/mm Before PCI 37.90±3.78 38.00±3.40 0.334 0.739 1 week after PCI 37.30±3.13 39.50±2.78 2.349 0.024 3 months after PCI 36.96±4.69 38.06±5.04 0.874 0.385 1 year after PCI 37.55±3.02 37.97±3.93 0.357 0.721 IVST/mm Before PCI 10.72±1.19 10.77±1.21 0.112 0.911 1 week after PCI 10.40±1.39 10.95±1.28 1.653 0.098 3 months after PCI 9.82±1.36 10.42±1.42 1.753 0.080 1 year after PCI 10.00±1.34 10.18±2.11 0.357 0.721 E/e’ ratio Before PCI 11.80±4.26 11.17±3.00 0.212 0.832 1 week after PCI 10.86±3.03 12.42±3.18 1.392 0.124 3 months after PCI 11.01±5.13 10.26±3.39 0.536 0.592 1 year after PCI 10.32±2.32 10.06±2.72 0.770 0.441 AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; LVEF: Left ventricular ejection fraction; LVESD: Left ventricular end-systolic diameter; LVEDD: Left ventricular end-diastolic diameter; LAD: Left atrial diameter; IVST: Interventricular septal thickness. 2.3 两组AMI患者手术前后心率和血压比较
两组AMI患者PCI术前及术后3个月、1年的心率比较差异均无统计学意义（均P＞0.05）；伊伐布雷定组PCI术后1周的心率低于对照组，差异有统计学意义（P＜0.05）。两组AMI患者PCI术前及术后1周、3个月、1年的血压比较差异均无统计学意义（均P＞0.05）。见表 3。
表 3 两组AMI患者PCI前后心率和血压比较Table 3 Comparison of heart rate and blood pressure between 2 groups of AMI patients before and after PCIn＝40, x±s Parameter Ivabradine group Control group t value P value Heart rate/min－1 Before PCI 90.00±8.80 87.95±9.66 1.248 0.212 1 week after PCI 73.20±4.54 76.95±5.87 2.590 0.010 3 months after PCI 65.38±4.06 66.83±4.40 1.470 0.142 1 year after PCI 65.50±3.34 65.83±3.18 0.446 0.657 SBP/mmHg Before PCI 135.23±22.05 128.43±19.55 1.459 0.148 1 week after PCI 130.23±12.98 124.83±13.18 1.846 0.069 3 months after PCI 130.20±8.32 126.45±9.54 1.874 0.065 1 year after PCI 130.50±11.63 127.35±17.43 0.761 0.450 DBP/mmHg Before PCI 77.65±12.56 75.20±9.00 1.003 0.319 1 week after PCI 76.00±7.85 73.03±6.56 1.839 0.070 3 months after PCI 75.55±5.55 74.23±4.90 1.132 0.261 1 year after PCI 75.71±8.71 74.77±10.22 0.358 0.722 1 mmHg＝0.133 kPa. AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; SBP: Systolic blood pressure; DBP: Diastolic blood pressure. 2.4 两组AMI患者心肌损伤标志物比较
外周血检测结果（图 1）显示，伊伐布雷定组术后第2天和第3天的BNP水平均低于对照组（均P＜0.05）；伊伐布雷定组术后第5天的TnI水平低于对照组（P＜0.05），两组间术后2 h及术后1~4 d的TnI水平差异均无统计学意义（均P＞0.05）；两组AMI患者术后2 h及术后1~6 d的CK-MB水平差异均无统计学意义（均P＞0.05）。
图 1 两组AMI患者心肌损伤标志物比较Fig. 1 Comparison of myocardial injury markers between 2 groups of AMI patients*P < 0.05 vs control group at the same time point. n＝40, x±s. AMI: Acute myocardial infarction; BNP: Brain natriuretic peptide; TnI: Troponin I; CK-MB: Creatine kinase-MB; PCI: Percutaneous coronary intervention.
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2.5 两组AMI患者用药情况比较
两组AMI患者在基线和术后1年随访时的ACEI/ARB/ARNI、β受体阻滞剂、醛固酮受体拮抗剂、袢利尿剂及双联抗血小板的用药情况比较，差异均无统计学意义（均P＞0.05），见表 4。
表 4 两组AMI患者用药情况比较Table 4 Comparison of medication between 2 groups of AMI patientsN＝40, n (%) Parameter Ivabradine group Control group χ2 value P value Baseline ACEI/ARB/ARNI 32 (80.00) 31 (77.50) 0.075 0.785 Maximum tolerable/standard dose 26 (65.00) 28 (70.00) 0.228 0.633 β blocker 40 (100.00) 40 (100.00) 0.000 1.000 Maximum tolerable/standard dose 25 (62.50) 20 (50.00) 1.270 0.260 Aldosterone receptor antagonist 8 (20.00) 6 (15.00) 0.346 0.556 Loop diuretic 8 (20.00) 5 (12.50) 0.827 0.363 Dual antiplatelet therapy 40 (100.00) 40 (100.00) 0.000 1.000 1 year after PCI ACEI/ARB/ARNI 34 (85.00) 33 (82.50) 0.092 0.762 Maximum tolerable/standard dose 28 (70.00) 29 (72.50) 0.061 0.805 β blocker 40 (100.00) 40 (100.00) 0.000 1.000 Maximum tolerable/standard dose 29 (72.50) 34 (85.00) 1.867 0.172 Aldosterone receptor antagonist 3 (7.50) 2 (5.00) 0.000 1.000 Loop diuretic 1 (2.50) 4 (10.00) 0.853 0.356 Dual antiplatelet therapy 40 (100.00) 39 (97.50) 0.000 1.000 AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; ACEI: Angiotensin converting enzyme inhibitor; ARB: AngiotensinⅡreceptor blocker; ARNI: Angiotensin receptor neprilysin inhibitor. 3 讨论
AMI主要由冠状动脉粥样硬化斑块破裂及继发血栓形成所致，这些病理变化可导致血管急性闭塞，进而引发心肌缺血、缺氧和坏死。该病常并发恶性心律失常、心力衰竭、心源性休克甚至心源性猝死等严重并发症[10]。目前急诊PCI手术可快速开通闭塞血管，恢复心肌细胞血流灌注，但目前我国心肌梗死的死亡率仍未控制到理想水平[11]。心率加快与AMI死亡率显著相关，其潜在机制包括[12-14]：（1）心率加快会缩短心室舒张期，进而导致冠状动脉灌注不足，影响心肌供血；（2）心率加快会引起心肌耗氧量增加，造成氧供需失衡，从而进一步加重心肌缺血；（3）心率加快常伴随交感神经的过度激活和儿茶酚胺水平升高，这可能会直接导致血管内皮损伤、心肌重构等。因此，心肌梗死PCI术后应严格控制心率，以改善患者的心功能及长期预后。
美托洛尔是临床最常用的β受体阻滞剂，它具有减慢心率、降低心肌耗氧量、降低儿茶酚胺水平、抑制心肌重构等作用，但是长期大量的使用可能会产生负性肌力、负性传导、哮喘及低血压等不良反应[15]。伊伐布雷定是一种高选择性If离子通道抑制剂，可以降低窦房结节律，进而减慢心率，且该药在降低心率的同时不会影响房室传导时间和心肌收缩力[16]。
本研究通过心脏超声评估AMI患者的心功能，发现伊伐布雷定组患者PCI术后1周、3个月及1年的LVEF均高于对照组（均P＜0.05），且术后1年两组的LVEF差异更为明显，提示早期应用伊伐布雷定可以更有效地改善患者的左心室收缩功能，且随着时间的延长其改善心功能的作用能够持续。Gerbaud等[17]采用心脏MRI测量相关指标，同样发现成功接受PCI的ST段抬高型心肌梗死患者在标准药物治疗基础上加用伊伐布雷定可明显改善左心室重构。
Xu等[18]研究显示，伊伐布雷定组患者PCI术后3个月和6个月的LVEF均较对照组升高，但两组仅术后3个月时的差异有统计学意义（P＜0.05）。在本研究中，伊伐布雷定组患者PCI术后3个月、6个月、1年的LVEF均较对照组升高，且差异均有统计学意义（均P＜0.05），但本研究中6个月时的LVEF数据未展示。2项研究术后6个月的结果略有不同，这可能与患者用药依从性的差异有关。本研究结果显示，在PCI术后1周时，伊伐布雷定组患者的心率明显低于对照组（P＜0.05），提示早期应用伊伐布雷定可更快、更好地控制心率；但在术后3个月及1年的随访中两组心率进一步下降且趋于一致，表明虽然伊伐布雷定联合美托洛尔治疗在早期较单纯美托洛尔治疗能更显著降低心率，但这一优势在长期随访中并未持续存在。伊伐布雷定早期对患者心率的控制可能是患者心脏负荷减轻、心肌重构改善的根本原因，这与一些大型多中心临床研究结果一致。BEAUTIFUL研究表明，降低静息心率可以降低全因死亡率，尤其对于心肌梗死及射血分数下降的心力衰竭患者；在心率＞70 min－1的亚组分析中发现，伊伐布雷定可减少致死性与非致死性心肌梗死再住院率及冠状动脉血运重建率[19]。SHIFT研究亚组分析表明，伊伐布雷定降低心率的同时可以逆转射血分数下降的心力衰竭患者的左心室重构，从而改善心脏功能及远期预后[20]。
BNP是预测心肌梗死预后的可靠指标，与AMI患者的心力衰竭发作呈正相关[21-22]。本研究发现伊伐布雷定组患者PCI术后的外周血BNP水平低于对照组，且术后第2天和第3天的BNP水平在两组间差异均有统计学意义（均P＜0.05），表明伊伐布雷定能够降低早期心肌梗死后心力衰竭的发生风险，其原因可能是它能更早地减慢心率，从而改善心脏功能。本研究发现伊伐布雷定组患者PCI术后1~5 d的TnI水平均低于对照组，且术后第5天两组间差异有统计学意义（P＜0.05），提示随着用药时间延长，伊伐布雷定能够显著减轻患者的心肌损伤程度，其作用机制可能与伊伐布雷定能够降低心率、减少心肌耗氧量及缩小心肌梗死面积有关。心肌梗死后较高水平的Tn常提示预后不良，严格的心率控制可以减轻心肌缺血、减少Tn释放，改善患者的长期预后。Chughtai等[23]在调整了糖尿病、高血压、冠状动脉病变支数和既往心肌梗死病史等混杂因素后，发现AMI患者的心率与Tn升高、射血分数降低呈独立正相关。此外，有研究表明伊伐布雷定不仅有降心率的作用，还能直接增加冠状动脉血流储备来改善心肌供血，从而缩小心肌梗死面积[24]；抑制氧化应激反应、减轻心肌炎症，维持保护心肌细胞活力[25]；通过增加梗死区室壁厚度、抑制梗死扩展，保护远端存活心肌的收缩功能及协调性[26]。
本研究为前瞻性、单中心随机对照研究，纳入的样本量较少，导致结果可能存在偏倚，今后需开展多中心、大样本的研究进一步验证。同时，本研究未设立安慰剂组及未采用盲法，这可能也会对结果的客观性产生影响。
综上所述，本研究结果表明AMI患者PCI术后早期应用伊伐布雷定能够更好地控制心率、减轻心肌损伤，从而改善患者的心功能，值得临床上进一步推广应用。
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图 1 两组AMI患者心肌损伤标志物比较
Fig. 1 Comparison of myocardial injury markers between 2 groups of AMI patients
*P < 0.05 vs control group at the same time point. n＝40, x±s. AMI: Acute myocardial infarction; BNP: Brain natriuretic peptide; TnI: Troponin I; CK-MB: Creatine kinase-MB; PCI: Percutaneous coronary intervention.
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表 1 两组AMI患者的基线资料比较
Table 1 Comparison of baseline data between AMI patients of 2 groups
N＝40 Item Ivabradine group Control group Statistic P value Age/year, x±s 68.53±10.21 67.43±11.44 t＝0.454 0.651 Male, n (%) 30 (75.00) 33 (82.50) χ2＝0.672 0.412 Hypertension, n (%) 20 (50.00) 24 (60.00) χ2＝0.808 0.369 Diabetes mellitus, n (%) 14 (35.00) 10 (25.00) χ2＝0.952 0.329 Hyperlipemia, n (%) 15 (37.50) 11 (27.50) χ2＝0.912 0.340 STEMI, n (%) 23 (57.50) 28 (70.00) χ2＝1.352 0.245 Number of diseased vessels, n (%) χ2＝1.200 0.549 1 14 (35.00) 10 (25.00) 2 13 (32.50) 17 (42.50) 3 13 (32.50) 13 (32.50) Infarct-related artery, n (%) χ2＝2.317 0.314 LAD 24 (60.00) 27 (67.50) LCX 6 (15.00) 2 (5.00) RCA 10 (25.00) 11 (27.50) ALT/(U·L－1), M (Q1, Q3) 40.00 (25.50, 56.75) 40.00 (28.25, 87.25) Z＝0.356 0.722 AST/(U·L－1), M (Q1, Q3) 142.00 (54.75, 236.00) 163.00 (81.00, 377.00) Z＝0.986 0.324 Creatinine/(μmol·L－1), M (Q1, Q3) 70.50 (60.00, 84.75) 69.50 (59.50, 83.25) Z＝0.183 0.855 Urea nitrogen/(mmol·L－1), M (Q1, Q3) 5.65 (4.53, 7.63) 6.25 (4.60, 7.68) Z＝0.582 0.600 Uric acid/(μmol·L－1), M (Q1, Q3) 336.00 (286.75, 415.75) 390.00 (305.75, 460.50) Z＝1.742 0.082 Total cholesterol/(mmol·L－1), x±s 5.28±1.29 5.21±1.29 t＝0.275 0.784 Triglyceride/(mmol·L－1) 1.35 (1.05, 2.09) 1.26 (0.89, 1.93) Z＝0.986 0.324 LDL-C/(mmol·L－1), x±s 3.63±0.98 3.63±1.04 t＝0.014 0.989 HDL-C/(mmol·L－1), x±s 1.16±0.20 1.11±0.26 t＝0.911 0.365 Medication, n (%) ACEI/ARB/ARNI 32 (80.00) 31 (77.50) χ2＝0.075 0.785 β blocker 40 (100.00) 40 (100.00) χ2＝0.000 1.000 Aldosterone receptor antagonist 8 (20.00) 6 (15.00) χ2＝0.346 0.556 Loop diuretic 8 (20.00) 5 (12.50) χ2＝0.827 0.363 Dual antiplatelet therapy 40 (100.00) 40 (100.00) χ2＝0.000 1.000 AMI: Acute myocardial infarction; STEMI: ST-segment elevation myocardial infarction; LAD: Left atrial diameter; LCX: Left circumflex branch; RCA: Right coronary artery; ALT: Alanine aminotransferase; AST: Aspartate transferase; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; ACEI: Angiotensin converting enzyme inhibitor; ARB: AngiotensinⅡreceptor blocker; ARNI: Angiotensin receptor neprilysin inhibitor. 表 2 两组AMI患者PCI前后心脏超声参数比较
Table 2 Comparison of echocardiography-derived parameters between 2 groups of AMI patients before and after PCI
n＝40, x±s Parameter Ivabradine group Control group t value P value LVEF/% Before PCI 52.05±7.42 50.08±9.05 0.491 0.623 1 week after PCI 57.00±7.87 50.70±10.79 2.110 0.042 3 months after PCI 56.57±9.99 50.97±10.30 2.268 0.023 1 year after PCI 59.32±8.11 51.94±11.75 2.768 0.006 LVESD/mm Before PCI 33.88±5.60 34.15±5.86 0.685 0.493 1 week after PCI 32.20±5.49 34.85±5.91 1.641 0.101 3 months after PCI 32.93±6.39 35.42±6.56 1.813 0.070 1 year after PCI 33.74±6.63 36.38±7.81 1.442 0.149 LVEDD/mm Before PCI 47.35±5.10 48.43±5.67 0.892 0.375 1 week after PCI 48.20±5.60 50.60±5.37 1.383 0.175 3 months after PCI 48.82±7.18 49.76±5.04 0.921 0.357 1 year after PCI 49.39±5.91 50.76±6.42 0.897 0.373 LAD/mm Before PCI 37.90±3.78 38.00±3.40 0.334 0.739 1 week after PCI 37.30±3.13 39.50±2.78 2.349 0.024 3 months after PCI 36.96±4.69 38.06±5.04 0.874 0.385 1 year after PCI 37.55±3.02 37.97±3.93 0.357 0.721 IVST/mm Before PCI 10.72±1.19 10.77±1.21 0.112 0.911 1 week after PCI 10.40±1.39 10.95±1.28 1.653 0.098 3 months after PCI 9.82±1.36 10.42±1.42 1.753 0.080 1 year after PCI 10.00±1.34 10.18±2.11 0.357 0.721 E/e’ ratio Before PCI 11.80±4.26 11.17±3.00 0.212 0.832 1 week after PCI 10.86±3.03 12.42±3.18 1.392 0.124 3 months after PCI 11.01±5.13 10.26±3.39 0.536 0.592 1 year after PCI 10.32±2.32 10.06±2.72 0.770 0.441 AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; LVEF: Left ventricular ejection fraction; LVESD: Left ventricular end-systolic diameter; LVEDD: Left ventricular end-diastolic diameter; LAD: Left atrial diameter; IVST: Interventricular septal thickness. 表 3 两组AMI患者PCI前后心率和血压比较
Table 3 Comparison of heart rate and blood pressure between 2 groups of AMI patients before and after PCI
n＝40, x±s Parameter Ivabradine group Control group t value P value Heart rate/min－1 Before PCI 90.00±8.80 87.95±9.66 1.248 0.212 1 week after PCI 73.20±4.54 76.95±5.87 2.590 0.010 3 months after PCI 65.38±4.06 66.83±4.40 1.470 0.142 1 year after PCI 65.50±3.34 65.83±3.18 0.446 0.657 SBP/mmHg Before PCI 135.23±22.05 128.43±19.55 1.459 0.148 1 week after PCI 130.23±12.98 124.83±13.18 1.846 0.069 3 months after PCI 130.20±8.32 126.45±9.54 1.874 0.065 1 year after PCI 130.50±11.63 127.35±17.43 0.761 0.450 DBP/mmHg Before PCI 77.65±12.56 75.20±9.00 1.003 0.319 1 week after PCI 76.00±7.85 73.03±6.56 1.839 0.070 3 months after PCI 75.55±5.55 74.23±4.90 1.132 0.261 1 year after PCI 75.71±8.71 74.77±10.22 0.358 0.722 1 mmHg＝0.133 kPa. AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; SBP: Systolic blood pressure; DBP: Diastolic blood pressure. 表 4 两组AMI患者用药情况比较
Table 4 Comparison of medication between 2 groups of AMI patients
N＝40, n (%) Parameter Ivabradine group Control group χ2 value P value Baseline ACEI/ARB/ARNI 32 (80.00) 31 (77.50) 0.075 0.785 Maximum tolerable/standard dose 26 (65.00) 28 (70.00) 0.228 0.633 β blocker 40 (100.00) 40 (100.00) 0.000 1.000 Maximum tolerable/standard dose 25 (62.50) 20 (50.00) 1.270 0.260 Aldosterone receptor antagonist 8 (20.00) 6 (15.00) 0.346 0.556 Loop diuretic 8 (20.00) 5 (12.50) 0.827 0.363 Dual antiplatelet therapy 40 (100.00) 40 (100.00) 0.000 1.000 1 year after PCI ACEI/ARB/ARNI 34 (85.00) 33 (82.50) 0.092 0.762 Maximum tolerable/standard dose 28 (70.00) 29 (72.50) 0.061 0.805 β blocker 40 (100.00) 40 (100.00) 0.000 1.000 Maximum tolerable/standard dose 29 (72.50) 34 (85.00) 1.867 0.172 Aldosterone receptor antagonist 3 (7.50) 2 (5.00) 0.000 1.000 Loop diuretic 1 (2.50) 4 (10.00) 0.853 0.356 Dual antiplatelet therapy 40 (100.00) 39 (97.50) 0.000 1.000 AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; ACEI: Angiotensin converting enzyme inhibitor; ARB: AngiotensinⅡreceptor blocker; ARNI: Angiotensin receptor neprilysin inhibitor. -
[1] WHITE H D, CHEW D P. Acute myocardial infarction[J]. Lancet, 2008, 372(9638): 570-584. DOI: 10.1016/S0140-6736(08)61237-4. [2] BHATT A S, AMBROSY A P, VELAZQUEZ E J. Adverse remodeling and reverse remodeling after myocardial infarction[J]. Curr Cardiol Rep, 2017, 19(8): 71. DOI: 10.1007/s11886-017-0876-4. [3] DOBRE D, KJEKSHUS J, ROSSIGNOL P, et al. Heart rate, pulse pressure and mortality in patients with myocardial infarction complicated by heart failure[J]. Int J Cardiol, 2018, 271: 181-185. DOI: 10.1016/j.ijcard.2018.05.017. [4] IBANEZ B, MACAYA C, SÁNCHEZ-BRUNETE V, et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the effect of metoprolol in cardioprotection during an acute myocardial infarction (METOCARD-CNIC) trial[J]. Circulation, 2013, 128(14): 1495-1503. DOI: 10.1161/CIRCULATIONAHA.113.003653. [5] IMAMURA T, KINUGAWA K. Optimal heart rate modulation using ivabradine[J]. Int Heart J, 2021, 62(4): 717-721. DOI: 10.1536/ihj.21-355. [6] GAMMONE M A, RICCIONI G, D'ORAZIO N. Ivabradine: a new frontier in the treatment of stable coronary artery disease and chronic heart failure[J]. Clin Ter, 2020, 171(5): e449-e453. DOI: 10.7417/CT.2020.2256. [7] BRYAN RICHARD S, HUANG B, LIU G, et al. Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: meta-analysis of randomized controlled trials[J]. Clin Cardiol, 2021, 44(4): 463-471. DOI: 10.1002/clc.23581. [8] SAVOYE C, EQUINE O, TRICOT O, et al. Left ventricular remodeling after anterior wall acute myocardial infarction in modern clinical practice (from the REmodelage VEntriculaire[REVE] study group)[J]. Am J Cardiol, 2006, 98(9): 1144-1149. DOI: 10.1016/j.amjcard.2006.06.011. [9] IBANEZ B, JAMES S, AGEWALL S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[J]. Eur Heart J, 2018, 39(2): 119-177. DOI: 10.1093/eurheartj/ehx393. [10] MITCHELL G F, LAMAS G A, VAUGHAN D E, et al. Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape[J]. J Am Coll Cardiol, 1992, 19(6): 1136-1144. DOI: 10.1016/0735-1097(92)90314-d. [11] 《中国心血管健康与疾病报告》 编写组. 《中国心血管健康与疾病报告2020》 概述[J]. 中国心血管病研究, 2021, 19(7): 582-590. DOI: 10.3969/j.issn.1672-5301.2021.07.002. [12] KOSMIDOU I, MCANDREW T, REDFORS B, et al. Correlation of admission heart rate with angiographic and clinical outcomes in patients with right coronary artery ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: horizons-AMI (the harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial[J]. J Am Heart Assoc, 2017, 6(7): e006181. DOI: 10.1161/JAHA.117.006181. [13] INOUE T, ISEKI K, OHYA Y. Heart rate as a possible therapeutic guide for the prevention of cardiovascular disease[J]. Hypertens Res, 2013, 36(10): 838-844. DOI: 10.1038/hr.2013.98. [14] PARODI G, BELLANDI B, VALENTI R, et al. Heart rate as an independent prognostic risk factor in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention[J]. Atherosclerosis, 2010, 211(1): 255-259. DOI: 10.1016/j.atherosclerosis.2010.02.017. [15] ESCOBAR C, BARRIOS V. High resting heart rate: a cardiovascular risk factor or a marker of risk?[J]. Eur Heart J, 2008, 29(22): 2823-2824. DOI: 10.1093/eurheartj/ehn447. [16] KAMISAH Y, CHE HASSAN H H. Therapeutic use and molecular aspects of ivabradine in cardiac remodeling: a review[J]. Int J Mol Sci, 2023, 24(3): 2801. DOI: 10.3390/ijms24032801. [17] GERBAUD E, MONTAUDON M, CHASSERIAUD W, et al. Effect of ivabradine on left ventricular remodelling after reperfused myocardial infarction: a pilot study[J]. Arch Cardiovasc Dis, 2014, 107(1): 33-41. DOI: 10.1016/j.acvd.2013.12.001. [18] XU Y, ZHANG W, ZHONG X, et al. Effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: a pilot test[J]. Ann Noninvasive Electrocardiol, 2021, 26(2): e12816. DOI: 10.1111/anec.12816. [19] FOX K, FORD I, GABRIEL STEG P, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial[J]. Lancet, 2008, 372(9641): 817-821. DOI: 10.1016/S0140-6736(08)61171-X. [20] TARDIF J C, O'MEARA E, KOMAJDA M, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy[J]. Eur Heart J, 2011, 32(20): 2507-2515. DOI: 10.1093/eurheartj/ehr311. [21] YANG Y, LIU J, ZHAO F, et al. Analysis of correlation between heart failure in the early stage of acute myocardial infarction and serum pregnancy associated plasma protein-A, prealbumin, C-reactive protein, and brain natriuretic peptide levels[J]. Ann Palliat Med, 2022, 11(1): 26-34. DOI: 10.21037/apm-21-2993. [22] OLEYNIKOV V E, DUSHINA E V, GOLUBEVA A V, et al. Early predictors of heart failure progression in patients after myocardial infarction[J]. Kardiologiia, 2020, 60(11): 1309. DOI: 10.18087/cardio.2020.11.n1309. [23] CHUGHTAI H L, MENGNJO A, MODI J, et al. Effect of initial heart rate on cardiac troponin and ejection fraction in patients with non-ST segment elevation myocardial infarction[J]. Am J Med Sci, 2012, 344(3): 171-174. DOI: 10.1097/MAJ.0b013e31825b5f95. [24] HEUSCH G, SKYSCHALLY A, GRES P, et al. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction[J]. Eur Heart J, 2008, 29(18): 2265-2275. DOI: 10.1093/eurheartj/ehn337. [25] KLEINBONGARD P, GEDIK N, WITTING P, et al. Pleiotropic, heart rate-independent cardioprotection by ivabradine[J]. Br J Pharmacol, 2015, 172(17): 4380-4390. DOI: 10.1111/bph.13220. [26] O'CONNOR D M, SMITH R S, PIRAS B A, et al. Heart rate reduction with ivabradine protects against left ventricular remodeling by attenuating infarct expansion and preserving remote-zone contractile function and synchrony in a mouse model of reperfused myocardial infarction[J]. J Am Heart Assoc, 2016, 5(4): e002989. DOI: 10.1161/JAHA.115.002989.
