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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李啟明(Chii-Ming Lee) | |
dc.contributor.author | Yu-Wen Wnag | en |
dc.contributor.author | 王妤文 | zh_TW |
dc.date.accessioned | 2021-06-13T00:29:15Z | - |
dc.date.available | 2008-08-08 | |
dc.date.copyright | 2007-08-08 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-25 | |
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Dobre D, van Veldhuisen DJ, Mordenti G, et al. Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial. Am Heart J 2007;154(1):109-15. 70. Metra M, Torp-Pedersen C, Swedberg K, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J 2005;26(21):2259-68. 71. Dobre D, DeJongste MJ, Lucas C, et al. Effectiveness of beta-blocker therapy in daily practice patients with advanced chronic heart failure; is there an effect-modification by age? Br J Clin Pharmacol 2007;63(3):356-64. 72. Sin DD, McAlister FA. The effects of beta-blockers on morbidity and mortality in a population-based cohort of 11,942 elderly patients with heart failure. Am J Med 2002;113(8):650-6. 73. Cintron G, Johnson G, Francis G, Cobb F, Cohn JN. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87(6 Suppl):VI17-23. 74. Cho GY, Park WJ, Han SW, et al. Myocardial systolic synchrony measured by Doppler tissue imaging as a role of predictor of left ventricular ejection fraction improvement in severe congestive heart failure. J Am Soc Echocardiogr 2004;17(12):1245-50. 75. Massie BM, Nelson JJ, Lukas MA, et al. Comparison of outcomes and usefulness of carvedilol across a spectrum of left ventricular ejection fractions in patients with heart failure in clinical practice. Am J Cardiol 2007;99(9):1263-8. 76. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27(1):65-75. 77. Curtis JP, Sokol SI, Wang Y, et al. 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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28913 | - |
dc.description.abstract | 背景:東方心臟衰竭病患對於β-腎上腺素受體拮抗劑之耐受劑量較西方國家為低。先前研究指出此差異性並非肇因於β1-腎上腺素受體基因密碼子49及389對偶基因分佈之差異,亦無發現新的β1-腎上腺素受體基因多型性,無法解釋耐受度較低之表現。近來有許多研究指出G蛋白偶合受體激酶第二型的表現量在心臟衰竭病患體內會逐漸升高,且其表現受β-腎上腺素受體拮抗劑所調控。
目的:本研究欲探討台灣心臟衰竭病患長期使用β-腎上腺素受體拮抗劑之耐受度及療效,與其可能相關之預測因子。同時探討G蛋白偶合受體激酶第二型之基因多型性與台灣心臟衰竭病患使用β-腎上腺素受體拮抗劑表現之相關性。 方法:我們回溯性地收集目前正在使用,或曾經使用carvedilol,metoprolol succinate或bisoprolol之心臟衰竭患者開始服用β-腎上腺素受體拮抗劑之前,調整至第一次及第二次穩定劑量後的各種臨床參數(例如:病史、心臟衰竭原因、併用藥物、左心室射出分率等)進行分析。此外,我們同時對病患之血液樣本進行G蛋白偶合受體激酶第二型之基因多型性之定序分析。 結果:共有72位心臟衰竭病患納入分析。長期使用β-腎上腺素受體拮抗劑使左心室射出分率顯著改善(39.9±16.4%升高至45.2±15.1%,p = 0.004),但第二年改善的程度有限(45.2±15.1%,相較於第一年:46.2±15.1%,p = 0.489)。對於β-腎上腺素受體拮抗劑耐受度高之病患相較於無法耐受之病患,第二年左心室射出分率顯著改善(1.0±8.2%與﹣7.03±16.0%,p = 0.014),且存活分析顯示耐受度高之病患相較於無法耐受之病患,較少發生死亡或需要接受心臟移植(94.3%與68.4%,p = 0.0074)。多元逐步迴歸分析顯示體重(B = 0.226,p = 0.006)與擴張性心肌病變(B = 4.884,p = 0.040)為第二年β-腎上腺素受體拮抗劑劑量之顯著預測因子;而長期使用口服降血糖藥物(B = ﹣7.753,p = 0.030)與第一年左心室射出分率改善程度(B = ﹣0.586,p < 0.001)、心跳(B = 0.321,p = 0.011)、β-腎上腺素受體拮抗劑穩定劑量(B = 0.417,p = 0.022)為第二年左心室射出分率改善之顯著預測因子。我們並未發現G蛋白偶合受體激酶第二型部分功能區域之的基因多型性與臨床β-腎上腺素受體拮抗劑耐受度或療效間之相關性。 結論:長期使用低劑量β-腎上腺素受體拮抗劑對於台灣心臟衰竭族群有其助益。且對於無法使用較高劑量(12.5 毫克/天以上)之心臟衰竭病患,其死亡率明顯上升,第二年左心室射出分率之改善亦較少。G蛋白偶合受體激酶第二型部分功能區域之的基因多型性與臨床β-腎上腺素受體拮抗劑耐受度或療效間並無相關性。 | zh_TW |
dc.description.abstract | Background: The tolerated doses of β-blockers in the Asian heart failure patients were lower than those widely used in the Western countries. Our previous study failed to demonstrate the association between the poor tolerability to β-blockers and the gene polymorphism of β1-adrenergic receptor. Recent studies indicated that the expression of G-protein-coupled receptor kinase 2 (GRK2) increased in patients with heart failure and the level of GRK2 was modulated by β-blockers.
Objective: This study is aimed to examine the tolerability and efficacy of long-term β-blocker therapy, and the related predictors in Taiwanese population with heart failure. We also analyzed the relationship between gene polymorphism of GRK2 and the tolerability to β-blockers. Methods: Patients who had the diagnosis of chronic heart failure and were using, or have used, one of the three β-blockers carvedilol, metoprolol succinate, and bisoprolol were included. Clinical parameters before the initiation of β-blocker, reach the stable dose in the first and the second year, were retrieved from the medical record or from the inquiries into the patients. We also did nucleotide sequencing for the analysis of GRK2 gene polymorphism. Results: Seventy-two heart failure patients were analyzed. The improvement of LVEF from baseline persisted to the second year of follow-up (39.9 ± 16.4% and 45.2 ± 15.1%, respectively, p = 0.004), but the LVEF increment during the second year is not significant (from 46.2 ± 15.1% to 45.2 ± 15.1%, p = 0.489). Patients tolerable to β-blocker therapy, compared with those who were intolerable, had better LVEF improvement within the second year (ΔLVEF12-24) (1.0 ± 8.2% versus -7.03 ± 16.0%, p = 0.014) and higher rate of free from mortality or heart transplantation (94.3% versus 68.4%, p = 0.0074). In stepwise multiple regression analysis, body weight (B = 0.226, p = 0.006) and the etiology of dilated cardiomyopathy (B = 4.884, p = 0.040) were the predictors of β-blocker stable dose in the second year. The use of oral hypoglycemic agents before the initiation of β-blocker therapy (B = -7.753, p = 0.030), LVEF improvement within the first year (ΔLVEF0-12) (B = -0.586, p < 0.001), heart rate at the first year (B = 0.321, p = 0.011) and β-blocker stable dose reached in the first year (B = 0.417, p = 0.022) were the predictors of ΔLVEF12-24. In the nucleotide sequence analyses of functional domains of GRK2, we did not reveal novel variant and failed to prove an association between the allele distribution and the tolerability or therapeutic efficacy. Conclusion: Low dose β-blocker therapy has beneficial effect through a 2-year period and carvedilol at the dose of 12.5 mg per day may be critical for better outcome in HF patients. We fail to demonstrate the relationship between the poor tolerability or efficacy of β-blocker therapy in our population and the gene polymorphism of GRK2. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:29:15Z (GMT). No. of bitstreams: 1 ntu-96-R94451009-1.pdf: 561420 bytes, checksum: 313d1ab2c8093f1bc2c2506181a33467 (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | Contents
中文摘要 i Abstract iii Contents vi Table Contents ix Figure Contents x Chapter 1 Introduction 1 SECTION 1 LITERATURE REVIEW 1 1 β1-Adrenergic Receptor Signal Transduction and G Protein-Coupled Receptor Kinase Position 1 2 Chronic Heart Failure and the Role of GRK2 2 3 Chronic Heart Failure and β-Blocker Treatment 4 4 Pattern of β-Blocker Treatment in Eastern HF Patients 4 5 Relationship between GRK2 and β-Blocker Therapy 6 SECTION 2 STUDY PURPOSES 8 Chapter 2 Materials and Methods 9 SECTION 1 STUDY POPULATION 9 SECTION 2 STUDY DESIGN 9 SECTION 3 DNA PREPARATION 11 SECTION 4 POLYMERASE CHAIN REACTIONS (PCR) 12 SECTION 5 PCR PRODUCTS PURIFICATION 15 SECTION 6 SEQUENCE ANALYSES 16 SECTION 7 STATISTICAL ANALYSES 16 Chapter 3 Results 18 SECTION 1 STUDY POPULATION 18 SECTION 2 TOLERABILITY 18 1 β-Blocker Stable Dose as a Categorical Value 18 2 β-Blocker Stable Dose as a Continuous Variable 19 SECTION 3 RESPONSE 21 1 Relationship between HF Etiologies and the Improvement of LVEF from Baseline to the Second Year 21 2 Tolerability to β-Blocker Predicts the Improvement of LVEF 21 3 Dose Escalation of β-Blocker in the Second Year did not Further Improve LVEF 22 4 Regression Analyses by Using LVEF Improvement in the Second Year (ΔLVEF12-24 ) as the Dependent Variable 23 SECTION 4 SURVIVAL ANALYSES 24 1 Relationship between Tolerability and Survival Rate 24 2 Relationship between Response and Survival Rate 24 SECTION 5 GRK2 GENE POLYMORPHISM 26 Chapter 4 Discussion 27 SECTION 1 TOLERABILITY 27 1 Relationship between HF Etiologies and β-Blocker Stable Dose 27 2 Body Weight as a Predictor of β-Blocker Stable Dose 28 SECTION 2 RESPONSE 30 1 β-Blocker Stable Dose Is Not a Predictor of LVEF Improvement in the Second Year of Follow-up (ΔLVEF12-24) 30 2 Comparison with MOCHA Trial 31 3 Predictors of LVEF Improvement in the Second Year (ΔLVEF12-24) 32 (1) The use of oral hypoglycemic agents (OHA) at baseline 32 (2) β-blocker stable dose in the first year 33 SECTION 3 SURVIVAL ANALYSES 34 SECTION 4 RELATIONSHIP BETWEEN GENE POLYMORPHISM AND CLINICAL OBSERVATION 35 Chapter 5 Limitations 37 Chapter 6 Conclusions 38 References 55 Table Contents Table 1 Single nucleotide polymorphisms of GRK2 reported 39 Table 2 Primers for PCR reaction and their targets 40 Table 3 Primers for sequence analysis 41 Table 4 Demographic characteristics stratified by tolerability 42 Table 5 Regression analysis of carvedilol stable dose in the second year 44 Table 6 Response to the carvedilol therapy stratified by tolerability 45 Table 7 Response of the second year of follow-up to the carvedilol therapy stratified by tolerability 46 Table 8 Characteristics of patients increasing carvedilol stable dose to 12.5 mg/day or higher in the second year 47 Table 9 Regression analysis of ΔLVEF of the second year (ΔLVEF12-24) as dependent variable 48 Table 10 Allele distribution of SNPs of GRK2 49 Table 11 Comparison of the tolerability and response to carvedilol between the present study and MOCHA trial27 50 Figure Contents Figure 1 Carvedilol stable dose in the second year between CAD, DCMP and VHD groups 51 Figure 2 LVEF improvement from baseline to the second year between CAD, DCMP and VHD groups 52 Figure 3 Survival analysis according to tolerability 53 Figure 4 Survival analysis according to different LVEF improvement from baseline to the second year of follow-up 54 | |
dc.language.iso | en | |
dc.title | G蛋白偶合受體激酶第二型之基因多型性對心衰竭病患使用乙型拮抗劑耐受度及療效之影響 | zh_TW |
dc.title | Influence of G Protein-Coupled Receptor Kinase 2 Genetic Polymorphisms on the Tolerability and Effectiveness of β-Blockers in Heart Failure Patients in Taiwan | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳燕惠,賴凌平 | |
dc.subject.keyword | 心臟衰竭,拮抗劑,β1-腎上腺素受體,基因多型性,耐受度,療效, | zh_TW |
dc.subject.keyword | Heart failure,β-blocker,β1-adrenoceptor,gene polymorphism,tolerability,therapeutic response, | en |
dc.relation.page | 64 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-26 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床藥學研究所 | zh_TW |
顯示於系所單位: | 臨床藥學研究所 |
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檔案 | 大小 | 格式 | |
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ntu-96-1.pdf 目前未授權公開取用 | 548.26 kB | Adobe PDF |
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