高血壓患者及冠心症患者心肌纖維化的研究

Abstract

越來越多的研究顯示心肌纖維化在高血壓心臟及冠狀動脈疾病的心臟病變中扮演了相當重要的角色。利用免疫組織化學呈相法顯示在高血壓心臟病的患者，其心臟間質及冠狀動脈週圍有大量的第一類及第三類纖維膠原沉積。大量的心臟纖維化會導致心室舒張功能異常、冠狀動脈血流異常、及心律不整。在各種人體有關心臟纖維化的病理研究中發現心肌細胞的超音波反射度與膠原堆積的量有相當程度的關聯性。因此對研究心肌纖維化而言，心臟超音波的整合背散射週期改變(Cyclic variation of integrated backscatter; CVIBS)便成為一種優良的非侵襲性工具。另一方面，膠原纖維形成的過程中會釋放纖維原胜肽(procollagen propeptides) 如第一型纖維原碳端胜肽(carboxy-terminal propeptide of procollagen type I; PICP)，第一型纖維原氨基端胜肽(amino-terminal propeptide of procollagen type I; PINP)，及第三型纖維原氨基端胜肽(amino-terminal propeptide of procollagen type III; PIIINP)等至血清中。據研究顯示，這些血清中的膠原纖維分解物與心肌纖維化有量化性的相關。因此我們在下列兩個研究中分別討論高血壓患者及冠狀動脈心臟病患者心肌纖維化之情形。 在第一個研究中，共有21個病人加入研究並根據其血壓狀況及血漿的第一型纖維原碳端胜肽的濃度分成三組: 第一組為血漿的第一型纖維原碳端胜肽≧127μg/l的高血壓患者(7人)，第二組為血漿的第一型纖維原碳端胜肽<127μg/l的高血壓患者(7人), 第三組為血漿的第一型纖維原碳端胜肽<127μg/l的血壓正常對照組(7人)。我們同時檢測血漿的第三型纖維原氨基端胜肽的濃度，壓力鉈-201心肌攝影 (stress thalium-201 scintigraphy) 及心臟超音波的整合背散射的數值。結果在第一組病人在左心室中後壁所得的整合背散射週期改變及相位代償後整合背散射週期改變(Phase-compensated CVIBS)的數值明顯較其他兩組為低(p<0.05)；在壓力鉈-201心肌攝影中有可逆或固定灌注缺損的病人有較高的第三型纖維原氨基端胜肽值(p<0.05)。在壓力鉈-201心肌攝影中有固定灌注缺損的病人在左心室中前膈有較低的的相位代償後整合背散射的值(p=0.002)。本研究的結果指出在高血壓病人中血漿第一型纖維原碳端胜肽濃度較高的病人具較明顯的心肌纖維化；若心臟超音波的整合背散射週期改變之數值降低時且伴隨血漿中第三型纖維原氨基端胜肽濃度上升則可能有伴隨著心肌缺氧的所引起之心肌纖維化存在。 雖然心肌梗塞後的膠原纖維沉積已為人所熟知，但是探討未心肌梗塞之冠狀動脈狹窄患者的心肌纖維化的研究卻很少。而且再灌流治療(reperfusion therapy)對於心肌纖維化是否有逆轉之功效尚未為人所知。因此，我們進一步設計第二個實驗來探討冠狀動脈狹窄患者的心肌纖維化及再灌流治療對於心肌纖維化的影響。 共有46個臨床上有胸痛且左心室功能正常的患者加入研究；心肌梗塞、嚴重的辦膜性心臟病及左心室功能不全的患者則被排除在外。所有患者均接受壓力鉈-201心肌攝影及血漿的第一型纖維原氨基端胜肽(amino-terminal propeptide of procollagen type I; PINP)及血漿中第三型纖維原氨基端胜肽的濃度檢測；若壓力鉈-201心肌攝影中有可逆灌注缺損則進一步進行冠狀動脈攝影。患者依壓力鉈-201心肌攝影及冠狀動脈攝影的結果分成三組: 第一組病患為壓力鉈-201心肌攝影中無可逆灌注缺損; 第二組病患為壓力鉈-201心肌攝影中有可逆灌注缺損但冠狀動脈攝影無明顯阻塞; 第三組病患為壓力鉈-201心肌攝影中有可逆灌注缺損且冠狀動脈攝影有明顯阻塞。若病患有接受經導管冠狀動脈介入治療則十二週後再次接受血漿第一及第三型纖維原氨基端胜肽的濃度檢測。結果在第一、二、三組的病人數為9、13、24。在第三組中，有12個病人有一條、6個病人有兩條、6個病人有三條冠狀動脈有明顯狹窄。在壓力鉈-201心肌攝影中有可逆灌注缺損的患者，血漿中第三型纖維原氨基端胜肽的濃度與有明顯狹窄冠狀動脈的數目有顯著相關(p=0.032)；但血漿中第一型纖維原氨基端胜肽的濃度無此關係。有22個患者(28條冠狀動脈)接受經導管冠狀動脈介入治療；其中有20個患者(25條冠狀動脈) 於十二週後再次接受血漿第一及第三型纖維原氨基端胜肽的濃度檢測。分析顯示經導管冠狀動脈介入治療前後的血漿血漿第一及第三型纖維原氨基端胜肽的濃度並無明顯差別。本研究的結果指出血漿第三型纖維原氨基端胜肽的濃度與冠心症的嚴重程度有顯著相關;接受經導管冠狀動脈介入治療後血漿第三型纖維原氨基端胜肽的濃度在十二週後並無明顯改變。 心臟疾病是台灣居民住院及死亡的重要原因，高血壓及冠狀動脈心臟病更是其中常見的原因。然而關於高血壓心臟及冠狀動脈疾病的心臟病變的病理機轉研究尚在起步階段，目前已知心肌纖維化扮演了相當重要的角色；幸然分子生物學的技術近來日益成熟，希望寄由這些研究開啟本土性心肌纖維化研究的新頁。

More and more studies reveal that myocardial fibrosis plays a very important role in hypertensive myocardium and ischemic myocardium. In immunohistochemical stain, large amount type I and type III collagen accumulate in the interstitial and perivascular space of extracelluar matrix in hypertensive myocardium. Myocardial fibrosis results in ventricular diastolic dysfunction, coronary flow disturbance, and arrhythmia. In various clinical and pathological studies relating myocardial fibrosis reveal that there is a significant association between echo reflection of myocardium and collagen amount. Cyclic variation of integrated backscatter (CVIBS) is an excellent, noninvasive tool to evaluate myocardial fibrosis. Procollagen propeptides, such as carboxy-terminal propeptide of procollagen type I, amino-terminal propeptide of procollagen type I, and amino-terminal propeptide of procollagen type III, are released to serum as by-products during collagen synthesis. In various studies, the procollagen propeptides are quantitatively related to myocardial fibrosis. So we design these two studies to evaluate myocardial fibrosis in hypertensive patients and patients with coronary artery disease (CAD). A total of 21 patients were enrolled into the first study and were divided in 3 groups according to presence of hypertension and serum carboxy-terminal propeptide of procollagen type I (PICP) concentration: 7 hypertensive patients with PICP≧127μg/l (group 1), 7 hypertensive patients with PICP<127μg/l (group 2), 7 normotensive subjects with PICP<127μg/l (group 3). In addition to PICP, serum amino-terminal propeptide of type III procollagen (PIIINP), stress thalium-201 scintigraphy and CVIBS were examined. Amplitudes of CVIBS and phase-compensated amplitudes of CVIBS at mid posterior segments were significantly lower in group 1 (p<0.05). Patients with reversible or fixed thallium-201 perfusion defects had higher PIIINP concentrations (p<0.05). Patients with fixed thallium-201 perfusion defects had lower phase-compensated amplitudes of CVIBS at mid antero-septal segment (p=0.002). In conclusions, decrease of myocardial phase-compensated amplitude accompanied with increase of serum PICP concentration may be indicative of the underlying fibrotic process of hypertensive myocardium. Decrease of this CVIBS parameter with increase of serum PIIINP implies concomitant myocardial ischemia. Although the collagen accumulation after myocardial infarction is well established, there is little known about the myocardial fibrosis in patients having CAD without myocardial infarction. The effect of reperfusion to myocardial fibrosis is not known. We design the second study to evaluate the myocardial fibrosis in patients with CAD and the effect of reperfusion therapy. A total of 46 patients (32 men and 14 woman; mean age 64 years) with chest pain and normal left ventricular contractility were enrolled into this study. Myocardial infarction was excluded by history and electrocardiograms. All patients received stress thallium-201 scintigraphy and analysis of the serum levels of the aminoterminal propeptide of type I procollagen (PINP) and PIIINP. Results: Nine patients had no perfusion defects in stress thallium-201 SPECT (group1). The other 37 patients with reversible perfusion defects received coronary angiography. There were 13 patients with patent coronary arteries (group2). In 24 patients with significant CAD (group 3), the patient numbers of 1-, 2-, and 3-vessel disease are 12, 6, and 6, respectively. In patients with thallium-201 perfusion defects, the number of diseased vessels was associated significantly with PIIINP (p=0.024) rather than PINP. Reperfusion therapy with percutaneous coronary intervention was performed in 28 vessels out of 22 patients. Serum PINP and PIIINP levels were followed after coronary intervention (mean 84 days) and revealed no significant change comparing with baseline level. In conclusions, serum PIIINP level is significantly associated with the severity of CAD in patients without myocardial infarction or hibernation. Short term follow-up fails to document the changes of serum PIIINP levels after reperfusion therapy. Cardiac diseases are the main causes of death and hospitalization in Taiwan. Hypertension and CAD are two of the most common causes. The studies associated with the mechanism of myocardial fibrosis in hypertensive and ischemic myocardium are primitive. We hope that we can open a new window for basic research of myocardial fibrosis.