| 摘要: | 動脈硬化疾病所造成的腦血管與心血管疾病，無論在全世界或是在台灣，都是造成人類死亡最重要的危險因子，因此徹底了解動脈硬化的各種複雜機轉與疾病發展病程，並依此去做早期預防與治療，對於臨床心臟科醫師來說，便是一個很重要的課題。從機轉來看，近??，動脈硬化疾病被視為是一種慢性血管發炎疾病，而其中低密?膽固醇(LDL)之代謝?常，被認為是致病的一個顯著危險因子。然而，由於血漿中之低密?膽固醇絕對值的高低，無法真正用?衡?血管疾病形成之風險，目前學界依舊致?於尋找真正造成動脈硬化的特定低密?膽固醇。過去許多研究顯示，氧化低密?膽固醇(Oxidized LDL)會誘發動脈硬化的各種機轉，包括單核球移行至血管內膜下並轉化為巨噬細胞與泡沫細胞、血管內皮之發炎反應、血管內皮細胞凋亡、與血管平滑肌細胞之增生…等。但氧化低密?膽固醇至今仍未直接從人?血漿分?出?，並由此?檢視其致病機轉。相反地，陰電性低密?膽固醇 (electronegative LDL)，分佈於人?血漿中低密?膽固醇，對體外培養之血管細胞，有促進動脈硬化之獨特性質。我們研究團隊?用陰?子交換色譜法(anion-exchange chromatograpgy)，從心血管疾病高風險族群的病患血漿中，分?出一種陰電性最強的極端型態陰電性低密?膽固醇，並將之名為L5。L5 ?但在健康人體內非常稀少，並且和人工製造之氧化低密?膽固醇同樣地，能促使血管細胞產生動脈硬化之變化。另一方面，由過去研究可得知，血管內皮細胞老化，也是造成動脈硬化的重要機轉之一；因此我們假設，L5能藉由促成血管內皮老化，造成血管內皮功能失調與後續之動脈硬化。因此在基礎研究中，我們藉由人類血管內皮細胞驗，研究L5是否會藉由DNA damage response之機轉造成細胞老化，並希望藉此找到動脈硬化治療的新方向。
有關動脈硬化致病機轉探討的另一方面，由於我們假設動脈硬化是一種血管發炎的反應，為了藉由臨床觀察更進一步的證實這種現象，我們與放射腫瘤科及核醫科共同合作，收錄頭頸癌接受放射治療的病人，藉由放射治療前後PET/CT的系列追蹤，來觀察放射治療是否會造成全身血管發炎之現象。之所以選擇這樣的病患做研究，是因為放射線治療本身已知會造成組織與血管的發炎反應，而過去臨床觀察研究也發現，頭頸癌接受放射治療的病人，其腦中風風險會顯著上升。因此，我們若能利用系列PET/CT攝影，證實接受放療後頸動脈血管發炎程度顯著升高，便是另一個有力證據證實，血管發炎是造成動脈硬化與血管病變的重要因素。在本文中，我們將會針對這樣的臨床觀察結果做更進一步的描述。
另外關於腦血管梗塞的危險因子方面，除了過去傳統的老化、血壓、血糖、與膽固醇…等部分，心房顫動也被發現是顯著增加中風的一項危險因子。心房顫動之所以被認為會增加中風風險，被認為是因為心房無法有效收縮，導致血液流速下降與凝血因子活化，造成血栓與增加遠端栓塞風險。但由於心房顫動是一種老化疾病，年紀越大盛行率越高，因而常伴隨著三高、冠狀動脈疾病、與高齡等共病因子，故常常無法釐清心房顫動本身對於中風的風險增加程度如何。為了釐清這個問題，我們將會利用健保資料庫，針對台灣本土年輕且無任何已知心血管共病的心房顫動患者，探討其中風風險是否會有顯著升高之現象，以研究在這種年輕無傳統共病、看似低風險的心房顫動患者身上，是否有可能有其他因素導致中風風險增加。
最後，動脈硬化另一個嚴重的血管病變，便是我們所熟悉的急性心肌梗塞，其原因大多是因為冠狀動脈斑塊破裂產生血栓、造成血管急性阻塞及心肌急性壞死，因此需要接受緊急心導管手術，快速將阻塞的血管打通，以拯救瀕臨壞死的心肌。心肌梗塞病患從進入急診開始，到真正接受緊急心導管打通血管為止，這段時間稱作Door-to-balloon (D2B) time。過去臨床觀察顯示，若D2B time拖延越久，病患整體預後越差、死亡率也越高。為了更進一步了解D2B time與心臟功能間之關係，我們利用中國附醫胸痛中心資料庫，研究D2B time與急性心肌梗塞病患心臟擴張功能間的關聯。此外，我們更研究利用各種品管改進，包括胸痛中心成立與24小時在院值班等措施，是否能有效縮短急性心肌梗塞病患的D2B time。我們希望藉由這樣的研究，可以為臨床醫師在急性心肌梗塞的處理上帶來更多實證醫學指引，以達到改善病患預後的目的。
總結而言，藉由上述結合基礎與臨床之研究，可讓我們對於動脈硬化與血管疾病的機轉與臨床表現更為了解。希望未來能以這樣的研究結果為基礎做更深入的探討，以期能找到更有效的治療，來減少腦血管與心血管疾病所帶來的死亡與後遺症。
Atherosclerosis and the subsequent cerbrovascular/cardiovascular diseases are the leading causes of human death in Taiwan or in the whole world. Therefore, for a cardiologist, it is important to understand the underlying mechanisms and the atherosclerotic disease natural courses to achieve the purpose of early prevention and treatment. About the underlying mechanisms, atherosclerosis was regarded as a chronic vascular inflammatory disease in recent years, and low-density lipoprotein (LDL) was thought to be an important causative factor. However, the plasma level of LDL was not proportional to the risk of vascular diseases development. Therefore, researchers are devoted to discover the specific modified LDL that may truly responsible for the atherosclerosis formation. Previous studies have shown that the oxidized LDL is involved in every key step of atherosclerosis development, including the transformation from monocytes to macrophages and foam cells, the endothelial inflammation, and the endothelial cell apoptosis…, etc. However, the oxidized LDL has never been has been retrieved from human plasma to undergo mechanistic scrutiny. In contrast, electronegative LDL is a subclass of human plasma LDL that has been found to exhibit atherogenic properties in cultured vascular cells. L5, the most negatively charged subfraction of LDL, is an extreme form of electronegative LDL that we isolated through anion-exchange chromatograpgy in the plasma of patients with increased cardiac risks. L5, which is scant in healthy normal subjects, is as potent as artificially prepared oxLDL in inducing a spectrum of atherogenic responses in vascular cells. In addition, previous studies also showed that vascular senescence is also one of the important mechanisms responsible for the atherosclerosis development. Thus, we hypothesized that L5 may induce the vascular endothelium senescence, which will lead to the subsequent endothelial dysfunction and atherosclerosis formation. By in-vitro studies, we studied whether L5 will cause endothelial senescence via DNA damage response pathway. In this way, we hope to find the novel therapeutic target of atherosclerotic diseases.
In addition, about the study of atherosclerosis mechanisms, we assume that atherosclerosis is a vascular inflammatory disease. For further confirmation of our hypothesis, we are in collaboration with nuclear medicine doctors and radiology oncologists in China Medical University Hospital (CMUH) to enroll pharyngeal cancer patients who received head and neck radiation therapy for our observational study. All of the enrolled patients received serial PET/CT follow-up before and after the radiation therapy. It was well known that radiation therapy will lead to tissue and vascular inflammation, and previous observations also demonstrated that the risk of ischemic stroke increased in cancer patients who received head and neck radiation. Therefore, by PET/CT scan, if we can confirm that the vascular inflammation severity increased significantly after radiation therapy, it will be the solid evidence that vascular inflammation is a key factor leading to atherosclerosis and vascular diseases. In the main text, we will focus on this clinical observation to study the underlying mechanisms of atherosclerosis.
Furthermore, in addition to the traditional risk factors of cerebrovascular diseases such as hypertension, diabetes, or hypercholesterolemia…, etc, atrial fibrillation (AF) was found to be associated with the increased risk of ischemic stroke. The reason may be due to the ineffective atrial contraction in AF patients, which lead to blood flow reduction and the pro-thrombotic factors activation, and will finally induce thrombus formation and increase the risk of distal embolization. However, since the prevalence of AF is higher in aged population, it is usually accompanied with the vascular disease risk factors such as hypertension, diabetes, hyperlipidemia, and vascular diseases…, etc. Therefore, it is difficult to clarify the independent role of AF on cerebrovascular disease attack. We utilized the National Health Insurance research database in Taiwan to assess the risk of first-ever ischemic stroke in younger patients with AF who have none of the traditional risk factors. In this way, we hope to study if better stroke risk stratification tools are needed to prioritize younger patients with AF for thromboprophylactic therapy.
Finally, another severe vascular disease as the subsequence of atherosclerosis is acute myocardial infarction (AMI). The most common etiology of AMI attack is the coronary plaque rupture, which will lead to acute thrombotic occlusion of coronary arteries and the subsequent myocardium necrosis. Hence, patients with acute ST-segment elevation myocardial infarction (STEMI) need to receive primary percutaneous coronary intervention (PPCI) to revascularize the occluded coronary vessels and rescue the ischemic myocardium in an early manner. The time interval between hospital arrival and the first intracoronary balloon inflation is called door-to-balloon (D2B) time. Previous clinical observations have shown that longer D2B time is associated with worse prognosis and higher mortality rate. To further understand the correlation between D2B time and heart function, we used the Chest Pain Unit databank from China Medical University Hospital to study the correlation between D2B time and left ventricular diastolic function in STEMI patients who received PPCI. Besides, we further study if the quality improvement approaches such as on-site cardiologist strategy can really lead to the reduction of D2B time. By this study, we hope to provide more evidence-based guidance about the management of AMI to improve the clinical outcomes in these patients.
In summary, by basic and clinical researches mentioned as above, we can have a better understanding about the underlying mechanisms and clinical presentations of atherosclerotic vascular diseases. Based on these results, further studies in the future are anticipated for the development of more effective therapies to reduce and vascular mortalities and morbidities for our patients. |
