脂質與其相關的賀爾蒙,維他命D,分別在急性心肌梗塞與代謝症候群的角色

The roles of lipid and its relevant hormone, vitamin D, in AMI and metabolic syndrome

鄭凱鴻(Kai-Hung Cheng)

指導教授 ： 賴文德

高雄醫學大學/醫學院/醫學研究所博士班/博士(2016年)

摘要

荷爾蒙(hormone)，包括女性荷爾蒙(estradiol)和維他命 D，與脂質代謝影響著代謝症候群和心血管疾病甚鉅。但是單獨針對男性的部分，女性荷爾蒙(estradiol)和具真正生理活性的維他命 D－1,25(OH)2D3，對代謝症候群的影響卻尚未知悉。另外，對於維他命 D新陳代謝的基因，是否在特殊位置的單核苷酸多型性（Single-nucleotide polymorphism, SNP）跟代謝症候群和特殊脂肪激素(adiponectin和leptin)有其影響，這是我們想去瞭解的。另外，我們知道高血脂對心血管疾病是危險因子，但是，在急性心肌梗塞的急性期，是否也是如此呢？反向思考，血脂也是重要的營養來源，對心臟細胞的營養供應，亦相當重要。在生死存亡高代謝的急性心肌梗塞的急性期，其角色到底是如何？這也是我們想要瞭解的，所以研究主題就圍繞這三個主題上：
主題一， 女性荷爾蒙(estradiol)和活性的維他命 D3(1,25(OH)2D3) 對中年台灣男性的影響。
除了脂肪激素外, 女性荷爾蒙(E2) 和維他命 D 已被報導會影響胰島素敏感性、血糖穩定性和體重。但是，有關於E2和維他命 D對於代謝症候群的影響的研究仍然乏善可陳。 本研究的目的就是來釐清循環中的E2和維他命 D 在台灣中年男性對代謝症侯群的影響。總共有655男性自願者加入研究，包括243位有代謝症侯群(平均年齡: 56.7 ± 5.8 歲) 和412正常男性(平均年齡: 55.1 ± 3.6 歲) 納入評估。相對正常者，代謝症侯群的人明顯有比較低的血中 E2, 1,25(OH)2D3, 和 adiponectin 以及比較高的 leptin (P < 0.001)。 E2和 1,25(OH)2D3 和其中的4個代謝症侯群的因子明顯相關；比adiponectin 和 leptin 還多，因adiponectin 和 leptin只和其中的3個因子明顯相關。在多變數分析中，回歸adiponectin 和 leptin後， E2 (beta = -0.216, P < 0.001) 和 1,25(OH)2D3 (beta = 0.067, P = 0.045)仍然是代謝症侯群獨立因子。但之後，仍然仰賴大型研究來證實我的結果和釐清相關的機轉。

主題二，維他命 D3代謝基因CYP27多型性對中年台灣男性與脂肪激素adiponectin/leptin比值和代謝症候群的關係。
代謝症侯群會增加心血管疾病的危險。維他命 D 和 脂肪激素(特別是 adiponectin 和 leptin) 兩者對心血管疾病和代謝症侯群有很大的影響。在維他命 D3 的代謝中，維他命 D3 25-hydroxylase (CYP27A1) 和 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) 是兩個關鍵的酵素。本研究主要就是檢視維他命 D3 CYP27 單核苷多變異 (SNPs) 對 adipocytokines 和 代謝症侯群的影響。我們從694位男性(年齡 55.7±4.7 歲)自願者收集齊相關資料和DNA 檢體。從HapMap project中，我們選取兩個tagging SNPs 分別為 CYP27A1 rs4674344 和 CYP27B1 rs10877012。 代謝症侯群明顯與 CYP27A1 rs4674344 SNP 相關 (p=0.04) 而 adiponectin/leptin 比 (A/L 比) 跟 CYP27A1 rs4674344 SNP最相關，其值在 T-carriers 明顯比 AA 的人低 (3.7±4.0 vs. 5.1±6.0, p=0.001) 且在校正後明顯呈現負相關的關係。對於代謝症侯群的各項目與CYP27A1 rs4674344 SNP相關中，除了血壓外，A/L 比明顯在臨床期前呈現負相關。 總結，CYP27A1 rs4674344 SNP, A/L 比 和代謝症侯群明顯相關，而T-carriers 有比較高的危險性會變成代謝症侯群，因為在臨床期前其A/L 比是比較低的。

主題三，脂質在心肌梗塞急性期－與30天院內死亡率的關係。
客觀事物: 低密度膽固醇(LDL-C)和三酸甘油脂(TG) 升高對於冠狀動脈疾病是主要的危險因子。但是，來自TG.的脂肪酸是主要的能量來源，而 LDL-C 對於細胞膜的製造是相當重要的；兩者對細胞的存活都是不可或缺的。本研究是想要釐清急性心肌梗塞患者其血脂和Killip 分類與30天死亡率的關係。
設計: 一非侵入性的觀察性研究。.
環境地點: 單一大學醫院的心臟加護病房.
病患: 724位急性心肌梗塞參與國健局的冠狀動脈照護計畫
干預措施: 無
結果: LDL-C 和TG 濃度在高Killip (III + IV)與30天內死亡的患者明顯的比低Killip (I + II) 與30天內存活的患者低 ( p <0.001)。 經過調整危險因子後， LDL-C <62.5 mg/dl 和 TG <110 mg/dl分別是對於預測30天死亡率之最好的閥值，其 hazard ratios 分別是1.65 (95% CI: 1.18-2.30) 和 5.05 (95% CI: 1.75-14.54) 而其真實死亡率分別是在23% 於低 LDL, 6% 於高 LDL, 14%於低TG 和3%於高TG 。其加成作用可見於當 低TG和 低 LDL遇到高Killip 時，其危險度逐步地增加 。高Killip 的患者比低Killip ，經過調整，有2.5倍的危險性; 但同時為低TG 和LDL 患者比同時為高TG 和LDL 患者，經過調整，卻有 10.9倍的危險性。這 lipid paradox 也可以改善原來Killip 與 TIMI scores對原來 AMI 的短期預後的預測性。
結論: 低 LDL-C, 低TG, 和高 Killip 嚴重度在急性心肌梗塞明顯有較高的30天院內死亡率。急性心肌梗塞患者剛住院的血脂資料也因此是重要的預測指標。

關鍵字

女性荷爾蒙(E2) ； 維他命 D3 ； 代謝症候群 ； 男性 ； 脂肪激素 ； CYP27A1 ； 多型性 ； 膽固醇 ； 肌梗塞 ； 低密度膽固醇 ； 三酸甘油脂 ； Killip分級 ； 死亡率

並列摘要

Hormones, including estradiol (E2) and vitamin D as well as lipid metabolism are significantly associated with metabolic syndrome (MetS) and cardiovascular diseases. Metabolic syndrome confers increased risks of cardiovascular disease (CVD). However, studies about the impact of E2 and really bioactive form of vitamin D (1,25(OH)2D3) on MetS are still limited, esp. for the pure male population. Since both vitamin D3 and adipocytokines (especially adiponectin and leptin) have a great impact on CVD and MetS and, in vitamin D3 metabolism, the vitamin D3 25-hydroxylase (CYP27A1) and 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) are two key enzymes. This is important to know the influence of vitamin D3 CYP27 single nucleotide polymorphisms (SNPs) on adipocytokines and MetS. As to lipid, we know that elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) are major risk factors for coronary artery disease. However, fatty acids from TG are a major energy source, LDL-C is critical for cell membrane synthesis, and both are critical for cell survival. This study was designed to clarify the relationship between lipid profile, morbidity as assessed by Killip classification, and 30-day mortality in patients with acute myocardial infarction (AMI). Therefore, studies are focused on these three topics:

1. The Impact of Estradiol and 1,25(OH)2D3 on Metabolic Syndrome in Middle-Aged Taiwanese Males
In addition to adipocytokines, estradiol (E2) and vitamin D have been reported to affect insulin sensitivity, glucose homeostasis and body weight. However, studies about the impact of E2 and vitamin D on metabolic syndrome (MetS) are still limited. The aim of this study is to clarify the roles of circulating E2 and vitamin D on the risk of MetS in middle-aged Taiwanese males. A total of 655 male volunteers, including 243 subjects with MetS (mean age: 56.7 ± 5.8 years) and 412 normal controls (mean age: 55.1 ± 3.6 years), were evaluated. Subjects with MetS had significantly lower circulating E2, 1,25(OH)2D3, and adiponectin, and higher leptin than those without MetS (P < 0.001 for all comparisons). E2 and 1,25(OH)2D3 were significantly associated with 4 individual components of MetS; more than adiponectin and leptin that were only associated with 3 individual components. In multivariate regression analysis, E2 (beta = -0.216, P < 0.001) and 1,25(OH)2D3 (beta = 0.067, P = 0.045) were still significant predictors of MetS independent of adiponectin and leptin. Further large studies are needed to confirm our preliminary results and elucidate the possible mechanism.

2. The associations of novel vitamin D3 metabolic gene CYP27A1 polymorphism, adiponectin/leptin ratio and metabolic syndrome in middle-aged Taiwanese males
Metabolic syndrome (MetS) confers increased risks of cardiovascular disease (CVD). Both vitamin D3 and adipocytokines (especially adiponectin and leptin) have a great impact on CVD and MetS. In vitamin D3 metabolism, the vitamin D3 25-hydroxylase (CYP27A1) and 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) are two key enzymes. This study aimed to examine the influence of vitamin D3 CYP27 single nucleotide polymorphisms (SNPs) on adipocytokines and MetS. Cross-sectional data and DNA samples were collected from male volunteers (n=649, age 55.7±4.7 years). Two tagging SNPs, CYP27A1 rs4674344 and CYP27B1 rs10877012, were selected from the HapMap project. MetS was significantly associated with the CYP27A1 rs4674344 SNP (p=0.04) and the ratio of adiponectin/leptin (A/L ratio) was most correlated to the CYP27A1 rs4674344 SNP, showing significantly lower in T-carriers than in AA subjects (3.7±4.0 vs. 5.1±6.0, p=0.001) and significantly negatively associated after adjustment. For each MetS component associated with the CYP27A1 rs4674344 SNP, the A/L ratios were significantly negative in preclinical stage (condition not meeting the individual criteria), except the blood pressure. In conclusion, CYP27A1 rs4674344 SNP, A/L ratio and MetS are signfiantly associated and T-carriers might have a higher risk of developing MetS due to low A/L ratios in the preclinical stage.

3. Lipid paradox in acute myocardial infarction - the association with 30-day in-hospital mortality
Objective: Elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) are major risk factors for coronary artery disease. However, fatty acids from TG are a major energy source, LDL-C is critical for cell membrane synthesis, and both are critical for cell survival. This study was designed to clarify the relationship between lipid profile, morbidity as assessed by Killip classification, and 30-day mortality in patients with acute myocardial infarction (AMI).
Design: A noninterventional Observational study.
Setting: Coronary care unit in a university hospital.
Patients: 724 patients with AMI in the coronary care program of the Bureau of Health Promotion were analyzed.
Interventions: None.
Results: LDL-C and TG levels were significantly lower in high-Killip (III + IV) patients compared to low-Killip (I + II) patients and in and those who died compared to those who survived beyond 30 days (both p <0.001). After adjustment for risk factors, LDL-C <62.5 mg/dl and TG <110 mg/dl were identified as optimal threshold values for predicting 30-day mortality and were associated with hazard ratios of 1.65 (95% CI: 1.18-2.30) and 5.05 (95% CI: 1.75-14.54) and the actual mortality rates were 23% in low LDL, 6% in high LDL, 14% in low TG and 3% in high TG groups, respectively. The synergic effect was noted as risk increased stepwise when low TG and low LDL incorporated with high-Killip. While patients with high-Killip had a 2.5-fold higher adjusted risk of mortality than patients with low-Killip, patients with both low TG and LDL had a a 10.9-fold higher adjusted risk of mortality than patients with both high TG and LDL.The lipid paradox also improved AMI short-term outcomes prediction on original Killip and TIMI scores.
Conclusions: Low LDL-C, low TG, and high Killip severity were associated with significantly higher 30-day in-hospital mortality in patients presenting with AMI. The initial lipid profile of AMI patients may therefore hold prognostic value.

並列關鍵字

estradiol (E2) ； vitamin D3 ； metabolic syndrome ； male ； adipocytokines ； CYP27A1 ； polymorphism ； cholesterol ； myocardial infarction ； LDL-C ； TG ； Killip classification ； mortality

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