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  • 學位論文

心臟老化過程中其結構與QT變異改變的危險因子探討

Risk Factors Evaluation for Changes of Cardiac Structure and QT Dispersion in Ageing Heart

指導教授 : 許勝雄

摘要


台灣地區由於經濟繁榮,人民生活水準提高,以及醫療衛生事業發展,國民普遍對健康的重視,使國民健康情形改善,致平均壽命延長。民國八十二年底台灣地區六十五歲以上人口上升到7.1﹪已達到世界衛生組織所謂之「高齡化社會」之標準,九十五年底台灣地區六十五歲以上人口已上升到10.0﹪。伴隨年齡增長而來的健康醫療問題及慢性病長期照護問題,已越來越受重視。根據中華民國九十一年臺閩地區老人狀況調查,六十五歲以上國民罹患慢性疾病或重大疾病前三項以循環系統疾病者最多占33.26%。由此可知心臟血管循環系統的疾病對老年人口的健康問題扮演重要角色。心臟血管循環系統在人體老化中扮演重要的一環,也是我國健保就診人數之大宗,與心血管疾病相關之死因,例如:腦血管疾病、心臟疾病、糖尿病和高血壓,分別占台灣地區老年人口主要死因之前幾名。因此臨床醫師必須具備心臟老化相關的知識及了解導致加重心臟老化的危險因子。 心臟血管循環系統在老化的過程中會產生許多變化,包括心臟的瓣膜會退化造成結構改變及支撐力下降產生瓣膜閉鎖不全的問題,進而產生心臟擴大與心臟衰竭。此外血管會漸漸失去彈性及產生硬化,進而產生高血壓,如此造成心臟在收縮時負擔增加。長久下來會使左心室代償性增厚及左心室質量(left ventricular mass, LVM)增加,進而造成心肌間質纖維化及左心室肥厚(left ventricular hypertrophy, LVH) ,最後可能產生心臟擴大與心臟衰竭。心肌的纖維化會造成心臟傳導的改變,進而產生心律不整的危險性。 心臟的瓣膜在老化的過程中會產生變厚及產生鈣化,研究顯示老化伴隨心內膜下結締組織的改變及支撐組織橫切面會減少,這些變化能一同導致心臟瓣膜閉鎖不全的問題。雖然二尖瓣膜閉鎖不全是一個很少需要外科手術治療的常見內科疾病。但是由Corvisart等人首先描述的二尖瓣膜腱索斷裂所導致的二尖瓣膜閉鎖會造成嚴重的臨床症狀且是一種進展的疾病造成最終需要外科手術治療。這些患者以內科治療會有高的死亡率(一年百分之6.3)。早期發現這個情況和找出危險因素能增加存活率。據我們所知,至今沒有報告來調查二尖瓣膜腱索斷裂的危險因素。因此我們第一個研究即是從事橫向性(cross-sectional)的研究在由二維心臟超音波確診為腱索斷裂的病人病歷上找尋有可能的危險因子,並探討年齡是否為一危險因子。 我們利用在台灣一醫學中心的病人經由分析病歷資料我們收集98位二尖瓣腱索斷裂的病人並將其分為兩群,68(69%)位病人無致病因子(原發群)及30位(31%)有已知致病因子(次發群)。63(64%)位病人是男性。整體平均年齡是57.5±1.5歲。後葉二尖瓣較易發生腱索斷裂(64%)。次發群中已知的誘發因子包括二尖瓣脫垂病史,感染性心內膜炎病史及風濕性心臟病病史。原發群病人的年齡較大(59.9±1.6 vs. 52.1±3.1; p=0.029),較易有高血壓(56% vs. 30%; p=0.003)且較易有呼吸困難的情形 (82% vs. 53%, p = 0.003)。利用多變項回歸分析發現高血壓(p = 0.048,OR = 2.717,95% CI = 1.008至7.326)及年齡(p = 0.039,OR = 1.039,95% CI = 1.002至1.077)仍然在原發群病人中扮演明顯角色。因此我們的研究發現年齡與高血壓對原發性二尖瓣腱索斷裂是一獨力危險因子。 我們第二,三部份的研究是利用一個社區的縱向性研究(老年病學研究實驗室 : 老化的縱向研究)而來。此研究被設計來探討在健康老年人身上在老化過程中許多生理功能和結構的變化。健康年長老人的收錄標準包括: (1)年紀大於等於60歲; (2)老人能自主自由活動,日常生活中沒有受限; (3)沒有先前被診斷為糖尿病、高血壓、缺血性心臟病或腦血管事件的病史,(4)沒有顯著心電圖及心臟超音波的異常其中包括心房顫動和心肌梗塞和(5)無服用任何慢性藥物。 左心室肥厚(LVH)為心臟標的器官(target organ)受損的證據且已知為一重要的心血管疾病的預後因子。有左心室肥厚的病人有較高的心血管事件發生率及總死亡率。然而之前心臟老化的橫向性(cross-sectional)研究對年齡與左心室質量間的關係產生不一致的結果。年齡與左心室質量間的關係有研究顯示正相關,亦有研究發現無相關甚至負相關。這些年齡和左心室質量指標之間的不一致結果可能歸因於個別研究設計上的差變和橫向性研究的先天性限制。我們第二部份的研究主要探討在無明顯結構病變的心臟上,探討老化是否伴隨左心室質量(left ventricular mass, LVM),左心室形態(left ventricular geometry)與左心室肥厚(LVH)的變化。此外我們也探討是否有其他相關因子會影響上述因子的改變。 許多神經荷爾蒙的營養(trophic)作用會刺激心肌細胞成長, 進而參與左心室肥厚的發展。胰島素(Insulin)本身被認為是營業激素(trophic hormone),胰島素藉由作用在胰島素生長因子受器和刺激細胞增生能導致心臟肥厚。與高胰島素有關的非胰島素依賴型糖尿病(non-insulin dependent diabetes mellitus, NIDDM)已被證明是左心室肥厚發展的危險因素。所以與胰島素濃度和糖尿病緊密相關的空腹血糖值,也可能與左心室質量與左心室肥厚相關,因此我們第二部份的研究主要探討空腹血糖值是否為左心室質量(LVM)與左心室肥厚(LVH)發展的危險因素。 我們進行以一固定族群為主的4年縱向性研究。藉由高雄醫學大學公共衛生研究所及高雄醫學大學附設醫院之內科和家庭醫學科共同合作,從高雄市老人活動中心篩選了1500個老人,其中105個無糖尿病、高血壓或心血管疾病的老人收錄至本研究中。所有受試者在初期、第二年和第四年皆接受二維心臟超音波和空腹血糖的檢查。當左心室質量大於122.4 gm/m2或51 gm/height2.7被定義為左心室肥厚。年齡範圍從60到81歲(平均71.7?b3.9),基礎血糖數值範圍從83到118 mg/dl (平均99.7?b7.9 mg/dl)。左心室質量在4年後顯著的增加(97.5?b24.9 到 104.5?b27.5 g/m2和44.2?b12.1到47.2?b13.4 g/m2.7,兩者p值皆小於0.05)。左心室肥厚比率亦顯著的增加(16到32%和25到39%,兩者p值皆小於0.01)。基礎血糖數值與4年的左心室質量變化相關(兩者p值皆小於0.02)。在第四年時使用邏輯回歸分析,基礎血糖數值是左心室質量及左心室肥厚的一個顯著預測因子。因此我們的結論為由於基礎血糖值是左心室質量及左心室肥厚的一個顯著預測因子,在非糖尿病的健康老年人身上,當評估心臟疾病與左心室質量時應同時注意空腹血糖值。 腎素血管緊縮素系統(renin-angiotensin system, RAS)被顯示影響許多心血管疾病,包括高血壓,狹心症,心肌梗塞,心臟衰竭,心律不整及猝死。但是橫向(cross-sectional)性研究探討腎素血管緊縮素系統的基因多形性(polymorphism)與左心室質量指標(left ventricular mass index, LVMI)產生不一致的結果。因此我們以縱向性的研究來測試左心室質量指標(LVMI)和左心室幾何形態(left ventricular geometry)與腎素血管緊縮素系統基因多形性之間的關係。 我們進行一縱向研究來調查血管緊縮素轉化酵素(angiotensin converting enzyme, ACE) 插入/刪除(insertion/deletion, I/D),血管緊縮素原(angiotensinogen, AGT) M235T 和血管緊縮素II 第一類型接受器(angiotensin II type 1 receptor, AT1R) A1166C 的基因多形性對左心室質量指標和幾何形態的影響。一共篩選了1500個老人,其中110個無糖尿病、正常血壓的老人收錄至本研究中。他們在初期,第二和第四年皆接受二維心臟超音波的檢查。受試者沒有結構性心臟病或服用任何慢性藥物的病史。基因多形性以聚鏈脢反應分析。年齡為71.9?b3.9歲(範圍60-81歲)。同心重塑(concentric remodeling)、偏心肥大(eccentric hypertrophy)和同心肥大(concentric hypertrophy)的比率與左心室質量指標在4年以後顯著的增加 (所有p值皆小於0.05)。這些改變和左心室質量指標的增加在帶血管緊縮素轉化酵素刪除(D)偶子的受試者比帶非D偶子的受試者有顯著統計上的變化 (所有p值皆小於0.05)。使用多變異回歸分析這個關係依舊存在(p小於0.02)。相同的分析對血管緊縮素II第一類型接受器(AT1R) A1166C顯示臨界的相關但對血管緊縮素原(AGT)M235T基因多形性無相關。這項縱向研究顯示老化過程伴隨左心室質量指標的增加與左心室幾何形態的變動。腎素血管緊縮素系統的基因多形性,特別是血管緊縮素轉化酵素(ACE)刪除(D)偶子的基因多形性,在中國人身上可能調節這些變化。這對評估和決定老年人左心室結構的心臟病疾病提供進一步知識。 QT間隔與QT變異(QT interval and dispersion)為臨床上評估病人是否易發生心律不整的指標,病人若伴隨延長的QT間隔或變異較易發生心律不整與猝死。在有心肌梗塞,心臟衰竭,心律不整或猝死的病人身上亦發現有較長QT間隔與QT變異。然而之前心臟老化的橫向(cross-sectional)研究探討年齡是否為QT變異長短的危險因子之文獻產生不一致的結果。因此我們第三部份的研究主要探討在無明顯結構病變的心臟上,以縱向(longitudinal)的研究探討老化是否伴隨QT間隔與QT變異的延長。此外我們也探討是否有其他相關因子會影響上述因子的改變,這包括會影響許多心血管疾病的腎素血管緊縮素系統(renin-angiotensin system, RAS)的基因多形性(polymorphism)。 由於沒有前瞻性(prospective)的研究來調查血管緊縮素轉換酵素(ACE)插入/刪除(I/D)與血管緊縮素原(AGT) M235T的基因多形性與再極化參數的關係,例如QT變異(QTd)及T波峰頂到結尾的間隔時間(the peak and the end of the T wave interval, Tpe) 。我們進行一縱向研究來調查血管緊縮素轉化酵素(ACE) 插入/刪除(I/D) 和血管緊縮素原 (AGT) M235T的基因多形性對QT變異及T波峰頂到結尾的間隔時間的影響。在初期,第二和第四年110個老人接受心電圖的檢查。我們計算修正的QT間隔(corrected QT intervel, QTc)、 QT變異(QT dispersion, QTd),修正的QT變異(corrected QT dispersion, QTcd)及T波峰頂到結尾的間隔時間。年齡72.7?b4.1歲(範圍62-81歲)。QT變異,修正的QT變異及T波峰頂到結尾的間隔時間隨老化明顯的延長(在第2和第4年,所有p值小於0.001)。在第4年時QT變異(p等於0.001)及修正的QT變異(p等於0.002)的延長強度但非T波峰頂到結尾的間隔時間的延長強度在帶血管緊縮素轉換酵素(ACE)刪除(D)偶子的受試者比帶非D偶子的受試者有顯著統計上的增加。使用多變異回歸分析這個關係依舊存在(對QT變異及修正的QT變異p小於0.001 及 p等於0.001)。血管緊縮素原(AGT) M235T的基因多形性與再極化參數無明顯的關係。這項縱向研究顯示老化過程伴隨QT變異,修正的QT變異及T波峰頂到結尾的間隔時間的延長。在中國老人身上帶血管緊縮素轉換酵素刪除(D)偶子的受試者有較高的QT變異延長的強度。 展望未來,伴隨年齡增長而來的身體各器官系統之老化問題會接踵而至。目前五十歲以上國民罹患慢性疾病以循環系統疾病者最多占,由此可知心臟血管循環系統的疾病對老年人口的健康問題扮演重要的角色,因此臨床醫師必須具備心臟老化相關的知識及了解導致加重心臟老化的危險因子。此外根據九十四年國人十大死亡排行榜的報告,心臟疾病已高居第三位,其不僅危害許多人寶貴的生命,也造成醫護人員和社會醫療資源沉重負擔。古人說: 「醫已病者為下醫,醫欲病者為中醫,醫未病者為上醫。」。因此我們必須避免或嚴謹控制心血管疾病危險因子,如血壓,血糖及血脂肪變化,多運動,不吸煙,才能減少發生心血管疾病的機會。此外我們希望本研究針對心臟老化過程中其結構(包括二尖瓣膜,心臟質量,形態與心臟肥厚)及QT變異的變化所發現的危險因子可幫助臨床醫師早期針對帶有特定危險因子的高危險病人族群從事介入性預防與治療,以減少病人心血管疾病發生的危險性。

並列摘要


Because of low birth rate and relatively increased ageing population, the percentage of Taiwan people aged 65 years old rises up to 7.1% in 1993, which had achieved the World Health Organization so-called "the advanced age society". Therefore, our society should pay more attention to the health problems on the elders. According to the national health survey, the cardiovascular problem is the leading chronic disease in the people aged 50 years and older. Ageing-related structure changes, including vlave, cardiac chambers and QT parameter, may predispose to future development of cardiovascular events. Clinical physcians should have knowledge about the risk factors aggravating the heart problems. Mitral regurgitation from chordae tendinae rupture (CTR) may cause severe clinical symptoms and is a progressive disease eventually resulting in the need for mitral valve surgery. Early recognition of CTR and identification of risk factors are important because early intervention increases the chances of survival. Ageing is associated valvular degeneration and hypertension may increase mitral valve complex mechanical strain and cause the chordae tendinae to rupture. Using a cross-sectional study of medical files in one medical center in Taiwan, we enrolled 98 patients with mitral CTR and classified them into two groups: 68 (69%) without obvious predisposing factors (primary group) and 30 (31%) with known predisposing causes (secondary group). Sixty-three (64%) of the patients were men with a mean age of 57.5?b1.5 years old. The posterior mitral leaflet was most commonly involved (64%). The known predisposing factors in secondary group include mitral valve prolapse, infective endocarditis, and rheumatic heart disease. The patients who had primary CTR were older (59.9?b1.6 vs. 52.1?b3.1 years, p = 0.029), had a higher prevalence of hypertension (56% vs. 30%, p = 0.018) and complained more often of dyspnea (82% vs. 53%, p = 0.003) than the patients in the secondary group. Using binary logistic regression analyses, the variation in primary group was found to be independently explained by age (P = 0.039, OR = 1.039, 95% CI = 1.002 to 1.077) and hypertension (P = 0.048, OR = 2.717, 95% CI = 1.008 to 7.326). Therefore, we conclude that age and hypertension were independent predictors for primary CTR in this study. Left ventricular hypertrophy (LVH), as measured by M-mode echocardiography, is a potent, independent predictor of cardiovascular events. Trophic effect of insulin is believed to stimulate myocardial cell growth, and thus take part in the development of LVH. Non-insulin-dependent diabetes mellitus, which is related to hyperinsulinemia, has been shown to be a risk factor for left ventricular hypertrophy. Therefore fasting glucose, which is closely related with insulin level and diabetes, may be associated with the left ventricular mass (LVM) and LVH. To test the association between fasting glucose level and LVM and LVH in people aged 60 and older. We conducted a population-based prospective study with 4-year follow-up from the department of internal medicine and family medicine, Kaohsiung medical university Hospital and graduate institute of public health. Of 1500 people screened, 105 participants without symptoms or signs of diabetes, hypertension or cardiovascular disease were recruited from senior activity centers in the Kaohsiung city. All received two-dimensional echocardiography and fasting glucose examination at baseline, the second and fourth year follow-up. LVH was defined as a LVM index (LVMI) greater than 122.4 g/m2 or 51 g/height2.7. Age ranged from 60 to 81 (mean 71.7?b3.9) years old. Baseline glucose ranged from 83 to 118 mg/dl (mean 99.7?b7.9 mg/dl). LVMI was significantly increased at the 4-year follow-up (97.5?b24.9 to 104.5?b27.5 g/m2 and 44.2?b12.1 to 47.2?b13.4 g/m2.7, both p < 0.01) as well as the occurrence of LVH (16 to 32% and 25 to 39 %, both p < 0.01). Baseline glucose correlates with 4-year change of LVMI (both p < 0.02). In the fourth year, baseline glucose was a significant predictor of LVMI (both p < 0.01) and LVH (p = 0.034 in g/m2 definition) using logistic regression analysis. Because fasting glucose is an independent predictor for increased LVM and for development of LVH, it should be considered in assessment of cardiac disease and LVM in non-diabetic healthy elders. Cross-sectional studies investigated the impact of renin-angiotensin system (RAS) gene polymorphism on left ventricular mass index (LVMI) with conflict results. We conduct a longitudinal study to investigate the influence of the angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms on the LVMI and geometry. Of 1500 people screened, 110 non-diabetic normotensive elderly Chinese were recruited and received echocardiography at the baseline, at the second and fourth year follow-up. No subjects had history of organic heart disease or chronic medication. The gene polymorphisms were analyzed by the polymerase chain reaction. Age was 71.9?b3.9 years old (ranges 60-81). The prevalence of concentric remodeling, eccentric hypertrophy and concentric hypertrophy was significantly increased as well as LVMI after 4 years (all p < 0.05). These changes and the magnitude of LVMI increase were significantly higher in subjects carrying the ACE D allele than non-D-allele carriers (all p < 0.05). This association was still significant in multivariate analyses (p ≦ 0.02). The similar analysis showed a borderline significance in the AT1R but not in the AGT gene polymorphism. This longitudinal study showed aging process was associated with increase of LVMI and changes of geometry. The RAS system gene polymorphism, especially the ACE D-allele, might modulate these changes in the Chinese. This provides further knowledge essential in the assessment of cardiac disease and determination of the left ventricular structure in the older subjects. There was no longitudinal investigation of the influence of angiotensin converting enzyme (ACE) insertion/deletion (I/D) and angiotensinogen (AGT) M235T gene polymorphisms on repolarization parameters, such as QT dispersion (QTd) and the peak and the end of the T wave interval (Tpe). ECGs were recorded from 106 elderly Chinese at baseline, second and fourth year follow-ups. The QTc (corrected QT), QTd, QTc dispersion (QTcd) and Tpe were manually calculated. Age was 72.7?b4.1 years old (ranges 62-81). QTd, QTcd and Tpe were significantly prolonged (all p < 0.001 at the 2nd and 4th year). At the 4th year the magnitude of QTd prolongation but not Tpe was significantly higher in subjects carrying the ACE D allele than non-D-allele carriers (p = 0.001) as well as QTcd (p = 0.002). This association was still significant in multivariate analyses (p < 0.001 and p = 0.001 for QTc and QTcd, respectively). No significant correlation was found between repolarization parameters and AGT genotype. This longitudinal study showed ageing process was associated with prolongation of QTd, QTcd and Tpe after 4 years follow-up. These subjects with ACE D-allele have higher magnitude of QTd and QTcd prolongation in elderly Chinese. Accoding the above four studies, we found ageing is associated with significant cardiovascular modification and changes. Ageing may predispose to the development of chordae tendinae rupture and is associated with increased LVM, geometry changes and QT dispersion prolongation. Furthermore, fasting glucose is an independent predicotor for future LVM increase and occurrence of LVH. The RAS system gene polymorphism, especially the ACE D-allele, might modulate LVM, geometry and QT parameters changes in the Chinese. In the future, we hope that our study findings may help doctor to stratify the high-risk population and prevent the disease progression.

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