探索可預測急性心肌梗塞患者接受氣球擴張術後的冠狀動脈再狹窄和左心室重塑之血液標誌因子

Abstract

急性心肌梗塞患者儘管接受先進的再灌流治療，發病率和死亡率仍然顯著。引發梗塞的病灶動脈血管再狹窄仍是經皮冠狀動脈介入（percutaneous coronary intervention, PCI）的主要限制。臨床上無法由患者症狀的有無來正確診斷冠狀動脈再狹窄的發生，且研究顯示無症狀的血管再狹窄會增加不良事件的風險。此外急性心肌梗塞後左心室的重塑作用是造成心衰竭的主要原因。雖然梗塞後的發炎反應是癒合過程必不可少的，但過度的炎症反應會造成左心室的不良重塑作用而影響心臟功能。因此，臨床上如能找到新的生物標誌因子可預測或診斷病灶冠狀動脈血管再狹窄及左心室的重塑作用是重要的。 本研究內容分成三個部分，在第一部分中，我們欲探討血漿中的氧化態低密度脂蛋白（oxidized low-density lipoprotein, oxLDL）和氧化態低密度脂蛋白抗體（oxidized low-density lipoprotein autoantibodies, OLAB）濃度高低是否可用於預測急性心肌梗塞患者接受氣球擴張術後的冠狀動脈血管再狹窄。研究的第二部分，我們欲探討血漿中的鐵離子濃度高低是否可用於預測急性心肌梗塞患者，接受氣球擴張術後六個月的左心室收縮功能。以及探討血液中鐵離子濃度是否和Thrombolysis in Myocardial Infarction risk score (TIMI風險評量分數)相關。研究的第三部分，我們欲探討血漿中Cyclophilin A (CyPA) 濃度前後的改變，是否和急性心肌梗塞後左心室的重塑相關。 本研究的主要結果為如下，(一)、急性心肌梗塞患者接受氣球擴張術後，若血漿中OLAB濃度相對較低下的患者，其清除oxLDL的能力相對較差，故發生氣球擴張術後的冠狀動脈血管再狹窄的風險顯著增加。於急性心肌梗塞患者其血漿中OLAB和oxLDL濃度比值與TIMI風險評量分數成趨勢正相關。我們的研究結果支持較高的OLAB/oxLDL比值是有血管保護作用的假說。且此OLAB/oxLDL比值有機會成為評估急性心肌梗塞後併發症的生物指標。(二)、急性心肌梗塞患者、若接受氣球擴張術前其血漿中的鐵離子濃度較低下者，其六個月後左心室收縮功能的恢復顯著受到不良影響。且血中IL-6的濃度於急性心肌梗塞後會顯著上昇，此IL-6的濃度和血漿中的鐵離子濃度成負相關。此外血漿中的鐵離子濃度與TIMI 風險評量分數成負相關。因此急性心肌梗塞後之低血鐵，不只是發炎反應的指標，也有機會成為評估急性心肌梗塞後左心室功能恢復的生物指標。並成為治療參考的依據。(三)、急性心肌梗塞患者接受氣球擴張術後，若一個月後的血漿中CyPA濃度比發生急性心肌梗塞時之CyPA濃度下降者，其六個月後左心室收縮功能的保存顯著優於CyPA濃度未下降者。且其六個月後左心室收縮的同步性顯著優於CyPA濃度未下降者。若發生急性心肌梗塞時之CyPA濃度相對較高者，其於一個月後之血中第二型金屬基質蛋白酶（matrix metalloproteinases-2, MMP-2）濃度上昇顯著高於CyPA濃度相對較低者。且一個月後之血中MMP-2濃度與一個月後CyPA濃度成正相關。而一個月後之血中MMP-2濃度與左心室收縮的同步性顯著相關。所以血漿中CyPA濃度前後的改變，可成為評估急性心肌梗塞預後的生物指標。

Despite state-of-the-art reperfusion therapy, morbidity and mortality remain significant in patients with an acute myocardial infarction. Restenosis following percutaneous coronary intervention (PCI) stays the principal limitation to the long-term efficacy of this revascularization technique. Recent studies have found that patient’s symptom status is an unreliable index of development of restenosis after PCI and patients with asymptomatic restenosis are at increased risk for adverse event. In addition, adverse cardiac remodeling following myocardial infarction (MI) remains a significant cause of congestive heart failure. Although post-infarction inflammation is essential for the healing process, excessive inflammation could play an important role in the development of left ventricle (LV) remodeling. Therefore, exploring novel biomarkers that improve our ability to predict, diagnose, or treat LV remodeling and coronary artery restenosis are needed. This dissertation is composed of three parts of experiments. In the first part, we investigated the prognostic value of plasma oxidized low-density lipoproteins (oxLDL) and oxidized low-density lipoprotein autoantibodies (OLAB) in infarct related artery restenosis. In the second part, we investigated the prognostic value of serum iron concentration on LV ejection fraction at 6 months and its relationship to thrombolysis in myocardial infarction (TIMI) risk score in post MI patients. In the third part, we investigated the relationships between changes in plasma Cyclophilin A (CyPA) concentrations and LV remodeling in patients with ST-elevation myocardial infarction (STEMI). The major results of this study are: (1) we found that patients with lower OLAB levels within 7 days after STEMI were significantly more likely to have restenosis in the infarct-related artery after primary angioplasty. The ratio of OLAB to oxLDL positively correlated with the TIMI risk score in the subacute stages of STEMI. Our data support the hypothesis that higher circulating OLAB/oxLDL ratio is associated with an atheroprotective phenotype and that it is a potential prognostic biomarker for post-STEMI complications; (2) We found an association between lower serum iron concentration before PCI and impaired recovery of LV systolic function 6 months later. The circulating concentration of IL-6 was increased after STEMI and negatively correlated with serum iron concentration. Serum iron concentration was also negatively correlated with TIMI risk score. Hypoferremia is not only a marker of inflammation but also a potential prognostic factor for LV systolic function after revascularization therapy for AMI, and may be a novel biomarker for therapeutic intervention; and (3) Patients with a decrease in plasma CyPA concentration between baseline and 1 month after primary PCI for STEMI had better preservation of LV systolic function and better LV synchrony at 6 months. Patients with a higher baseline CyPA concentration had a significantly increased MMP-2 concentration at 1 month after STEMI. The 1-month MMP-2 concentration was positively correlated with quartiles of 1-month CyPA concentration, and was significantly correlated with LV dyssynchrony. Changes in CyPA, therefore, may be a prognosticator of patient outcome.