甲状腺功能影响心血管疾病患者心肌损害和远期预后的研究

发布时间：2018-09-09 16:46

【摘要】：甲状腺功能影响急性心肌梗死患者心肌损害及远期预后的研究背景：既往认为重症疾病状态下甲状腺激素水平的下调是人体进行自我保护的反馈调节。对于急性心肌梗死(acute myocardial infarction, AMI)患者,尚没有证据表明甲状腺功能下调究竟是对心肌具有保护作用还是加重心肌损害。本研究旨在评估甲状腺激素水平与AMI患者心肌损害、他汀药物负荷后血脂水平的相关性,以及甲状腺功能异常对AMI患者长期预后的影响。方法：本研究为前瞻性队列研究研究,原始队列入选2010年1月至2012年12月间以“急性心肌梗死”诊断入院的患者1757例,根据入选排除标准纳入1112例患者进入分析集。心肌损害的程度以CKMB阳cTnI的最高值来评估,取对数值以获得正态分布,分别表示为log-CKMB和1og-cTnI。将他汀治疗强度分为低、中等、高三个不同等级,在不同强度他汀治疗背景下探索甲状腺激素水平与他汀负荷后血脂指标的相关性。主要研究终点为主要不良心脏事件(major adverse cardiac events, MACE)(包括院内全因死亡、心肌梗死、住院期间的再次血运重建)。结果：1112例AMI患者根据其FT3水平分为5个组(1.79pg/mL; 1.80-2.42 pg/mL; 2.43-2.67 pg/mL; 2.68-2.95 pg/mL;2.96 pg/mL)共计有222例患者(20%)出现各种类型的甲状腺功能异常,其中以单纯FT3下降为表现的“低T3综合征”是最为常见的类型(90人,8.1%),其次是以TSH下降而T3、T4正常为特征的“亚临床甲状腺功能亢进”(73人,6.6%),以TSH升高而T3、T4正常为特征的“亚临床甲状腺功能减退”(51人,4.6%)和临床甲状腺功能减退(8人,0.7%)。FT3与log-CKMB (r=-0.251, P0.001)和log-cTnI (r=-0.287, P0.001)存在明显负相关。另外,FT3还与代表炎症反应状态的高敏C反应蛋白存在较强程度的相关性(r=-0.469,P0.001)。LVEF作为心功能指标,与FT3存在正相关(r=0.191,P0.001)。其他甲状腺激素(FT4和TSH)则未发现与上述指标存在相关性。在中、高强度他汀治疗背景下,FT3与总胆固醇(中等剂量：Liner Coeff=-0.105, P=0.031;高剂量：Liner Coeff=-0.172,P=0.029)及低密度脂蛋白胆固醇(中等剂量：Liner Coeff=-0.082, P=0.001;高剂量：Liner Coeff=-0.113, P=0.005)存在显著相关性。在低强度他汀治疗背景下,未发现甲状腺激素与血脂指标的相关性。在两年随访中,较低水平的FT3 (1.79pg/mL(?)1.80-2.42pg/mL两组)是MACE独立预测因子(HR:3.37,95%CI:1.66-6.85; HR: 2.28,95%CI:1.23-4.20)。根据TSH水平进行生存分析发现,TSH升高组(TSH4.78 IU/L)的患者MACE风险显著增加(HR:2.133,95%CI:1.22-3.72),而TSH下降组(TSH0.55IU/L)的患者死亡风险没有统计学意义上的升高(HR:1.545,95%CI: 0.91-2.61)。结论：急性心肌梗死患者FT3水平与患者心肌损害标记物和炎症标记物负相关,而与患者心功能呈正相关。在中、高强度他汀治疗负荷后,急性心肌梗死患者FT3下降与总胆固醇和低密度脂蛋白胆固醇水平升高有关。在长期随访中,低FT3和高TSH均是心血管不良事件的独立危险因素。甲状腺功能对扩张型心肌病患者心功能及远期预后的影响背景：心衰中常并存的甲状腺激素水平异常受到广泛关注。甲状腺激素的水平随着心衰程度的加重而更低,并且,甲状腺激素水平低下的心衰患者的预后也更差。现有关于甲状腺功能异常与心衰的临床证据存在诸多局限性。首先,没有对心衰病因进行细化,而心衰的不同病因是影响预后的重要混杂因素。另外,已有的研究多集中关注于某一项甲状腺功能指标,而没有对各种类型甲功异常的预后价值进行探讨,从而使不同类型甲功异常在心衰中的预后意义存在争议。方法：本研究为前瞻性队列研究,原始队列入选2010年1月至2011年10月就诊于阜外医院的532例扩张型心肌病患者,经过入选排除标准筛选后,最终由458例患者进入随访分析。主要研究终点为全因死亡,定义为任何原因导致的自然死亡。次要研究终点为心源性死亡,定义为猝死、心衰导致的死亡、恶性心律失常导致的死亡以及心梗引起的死亡。采用Kaplan-Meier图、单因素和多因素Cox模型分析FT3水平、TSH水平及甲状腺功能状态对患者预后的影响。结果：根据患者的甲功水平,458例扩张型心肌病患者被分为6组,其中,临床甲亢组因人数过少而剔除(n=3)。发生率最高的甲功异常为亚临床甲减(n=41,占9%),其次为亚临床甲亢(n=35,占7%)、低T3综合征(n=17,占4%)及临床甲减(n=12,占3%)。NYHA Ⅲ-Ⅳ的患者相对于NYHA Ⅰ-Ⅱ的患者fT3水平显著降低(2.89+0.45vs 2.68±0.54,P=0.05)而log-TSH显著升高(2.18±0.36 vs 2.30±0.45,P=0.02)。两组间的fT4没有显著差异。log-TSH水平升高和FT3水平下降均是心功能恶化的独立预测因子；采用Stepwise法筛选单因素分析中P值小于0.05者进入多因素分析,结果显示,og-TSH (HR:2.189,95%CI:1.217-3.938)、fT3 (HR:0.483,95%CI: 0.301-0.775)以及肾功能不全(HR:2.045,95%CI:1.077-3.882)是心功能恶化的独立预测因子。低FT3是全因死亡的显著预测因子(HR 3.18,95%CI:1.96-5.16, P0.001;见表3)。TSH升高是死亡的强预测因子(HR:2.828,95%CI:1.902-4.206), TSH降低对全因死亡没有显著影响(HR:0.883,95%CI:0.426-1.827)。多因素分析中,全因死亡的最强的预测因子为临床甲减(HR:4.189,95%CI:2.118-8.283),其余依次为低T3综合征(HR:3.147,95%CI:1.558-6.355)和亚临床甲减(HR: 2.869,95%CI:1.817-4.532).亚临床甲亢对全因死亡没有显著影响(HR:0.973, 95%CI:0.469-2.018)。结论：在原发性扩张型心肌病患者中,FT3水平降低和TSH水平升高均与患者心功能恶化存在相关性。甲状腺功能异常(低T3综合征、亚临床甲减、临床甲减)是原发性扩张型心肌病患者全因死亡和心源性死亡的独立危险因素。甲状腺功能对原发性扩张型心肌病患者肌纤维化和心肌灌注/代谢损害的影响背景：甲状腺激素水平与心衰患者心功能有显著相关性,同时也是远期不良预后的重要危险因素。目前关于甲功异常影响扩张型心肌病进展的机制研究仅停留在动物实验水平,人体层面的证据尚不充足,从而导致临床上对于该类患者是否需要补充甲状腺素治疗无法达成共识。目前的临床实践中,已经可以应用心脏核磁共振(Cardiac magnetic resonance imaging, cardiac MRI)来检测心肌纤维化程度,应用单光子发射计算机断层成像术(Single-Photon Emission Computed Tomography, SPECT)和正电子发射断层成像术(Positron Emission Tomography, PET)评估心肌灌注/代谢的方法也已逐步在临床推广。本研究利用心脏核磁共振和心肌核素显像手段,探讨甲状腺激素水平与心肌纤维化和灌注/代谢异常的相关性。方法：入选2010年1月至2011年10月就诊于阜外医院的71例原发性扩张型心肌病患者。采用心脏磁共振延迟强化(late gadolinium enhancement, LGE)评估心肌纤维化,采用99mTc-MIBI SPECT显像评估心肌灌注,采用18F-FDG PET显像评估心肌代谢。磁共振及核素影像利用17节段模型进行半定量分析,将心肌分为6个基底段、6个中段和5个心尖节段。根据灌注/代谢图像的不同特点将心肌节段分为4组：正常灌注/代谢,灌注/代谢不匹配,灌注/代谢轻中度匹配,灌注/代谢完全匹配。LGE类型分为三组：无延迟强化、壁间强化(延迟强化位于心肌壁内,呈线状或斑片状,未累及心肌全层)和透壁强化(延迟强化累及心肌全层)。主要研究终点为全因死亡,次要研究终点为心源性死亡。结果：将所有患者按照FT3四分位划分为以下四组：Quartile1组(2.53pg/mL,n=20); Quartile2组(2.53 pg/mL-2.76 pg/mL, n=16); Quartile3组(2.77 pg/mL-3.19 pg/mL, n=18); Quartile4组(≥3.19 pg/mL, n=17)。从Quartile1到Quartile4,随着FT3水平的升高,LGE节段的比例出现显著的下降趋势(23.53%,16.54%,5.22%,3.11%；P0.001),灌注异常节段的比例也存在下降趋势(20.88%,16.54%,14.05%,9.69%；P0.001)。对于代谢异常节段而言,Quartile3的发生比例显著低于Quartile1和Quartile2(8.82%,7.35%vs 1.63%；P=0.032)。Quartile4的代谢异常节段相对于Quartile3略有升高,但没有统计学意义(4.84%vs 1.63%；P=0.83)。Logistic回归分析中,FT3是患者出现LGE强化的唯一的危险因素(OR:0.180,95%CI:0.059-0.550)。对于心肌灌注异常,FT3在单因素模型中的OR值为0.38(95%CI：0.146-0.991),多因素模型中为0.172(95%CI：0.040-0.738)。对于心肌代谢异常,FT3是多因素模型中唯一有意义的预测因素(OR:0.338,95%CI:0.126-0.910)生存分析中,根据患者是否存在LGE强化以及FT3水平(中位数2.77 pg/mL),将或按着分为以下四组：LGE阴性+FT3≥2.77,LGE阴性+FT32.77,LGE强化+FT3≥2.77,LGE强化+FT32.77。LGE强化+FT3≥2.77(HR：4.966,1.851-8.658)和LGE强化+FT32.77(HR:8.623,95%CI:3.626-16.438)是死亡的独立危险因素。结论：在原发性扩张型心肌病患者中,FT3水平下降与心室心肌节段纤维化和心肌灌注/代谢异常的比例存在显著相关。低FT3和LGE阳性均是原发性扩张型心肌病患者远期死亡率的危险因素,两者联合可更好的预测死亡风险
[Abstract]:Background: Thyroid function affects myocardial damage and long-term prognosis in patients with acute myocardial infarction (AMI). It has been previously thought that the reduction of thyroid hormone levels in patients with severe illness is a feedback regulation of human self-protection. There is no evidence of thyroid function in patients with acute myocardial infarction (AMI). The purpose of this study was to assess the relationship between thyroid hormone levels and myocardial damage in patients with AMI, serum lipid levels after statin loading, and the effect of thyroid dysfunction on long-term prognosis in patients with AMI. From January 2010 to December 2012, 1 757 patients with acute myocardial infarction were enrolled in the study. 1112 patients were enrolled in the analysis set according to the exclusion criteria. The degree of myocardial damage was assessed by the highest value of CKMB positive cTnI, and logarithmic value was used to obtain normal distribution, which was expressed as log-CKMB and og-cTnI respectively. The primary endpoint was major adverse cardiac events (MACE) (including in-hospital all-cause death, myocardial infarction, and revascularization weight during hospitalization). Results: 1112 patients with AMI were divided into 5 groups according to their FT3 levels (1.79 pg/mL; 1.80-2.42 pg/mL; 2.43-2.67 pg/mL; 2.68-2.95 pg/mL; 2.96 pg/mL). A total of 222 patients (20%) had various types of thyroid dysfunction, and the most common type was low T3 syndrome (90 cases, 8.1%). Subclinical hyperthyroidism (73 cases, 6.6%) characterized by decreased TSH but normal T3 and T4, subclinical hypothyroidism (51 cases, 4.6%) and clinical hypothyroidism (8 cases, 0.7%) characterized by elevated TSH and normal T3 and T4, FT3 and log-CKMB (r =-0.251, P 0.001) and log-cTnI (r =-0.287, P 0.001) were significantly negatively correlated. In addition, there was a strong correlation between FT3 and high-sensitivity C-reactive protein (r = - 0.469, P 0.001). LVEF, as a cardiac function index, was positively correlated with FT3 (r = 0.191, P 0.001). Other thyroid hormones (FT4 and TSH) were not found to be correlated with the above indicators. There was a significant correlation between total cholesterol (moderate dose: Liner Coeff = - 0.105, P = 0.031; high dose: Liner Coeff = - 0.172, P = 0.029) and low density lipoprotein cholesterol (moderate dose: Liner Coeff = - 0.082, P = 0.001; high dose: Liner Coeff = - 0.113, P = 0.005). During the two-year follow-up, lower levels of FT3 (1.79 pg/mL (?) 1.80-2.42 pg/mL) were independent predictors of MACE (HR: 3.37, 95% CI: 1.66-6.85; HR: 2.28, 95% CI: 1.23-4.20). There was no statistically significant increase in the risk of death in patients with decreased SH (TSH 0.55IU/L) (HR: 1.545, 95% CI: 0.91-2.61). Conclusion: FT3 levels in patients with AMI were negatively correlated with myocardial damage markers and inflammatory markers, but positively correlated with cardiac function. Low FT3 and high TSH were independent risk factors for cardiovascular adverse events during long-term follow-up. The impact of thyroid function on cardiac function and long-term prognosis in patients with dilated cardiomyopathy Background: Abnormal thyroid hormone levels, which are common in heart failure, are affected. Extensive attention. Thyroid hormone levels are lower as heart failure progresses, and the prognosis of heart failure patients with low thyroid hormone levels is worse. In addition, previous studies focused on a certain thyroid function index, but did not explore the prognostic value of various types of thyroid dysfunction, so that different types of thyroid dysfunction in heart failure prognostic significance is controversial. Methods: This study was a prospective cohort study, the original cohort included in 2010. 532 patients with dilated cardiomyopathy hospitalized in Fuwai Hospital from January 2001 to October 2011 were screened by exclusion criteria, and 458 patients were followed up. The primary endpoint was all-cause death, defined as natural death from any cause. The secondary endpoint was cardiac death, defined as sudden death and death from heart failure. Death, death from malignant arrhythmias, and death from myocardial infarction. Kaplan-Meier diagram, univariate and multivariate Cox model were used to analyze the effect of FT3, TSH and thyroid function on prognosis. Results: According to thyroid function, 458 patients with dilated cardiomyopathy were divided into 6 groups, including hyperthyroidism. The highest incidence of thyroid dysfunction was subclinical hypothyroidism (n = 41, 9%), followed by subclinical hyperthyroidism (n = 35, 7%), hypothyroidism (n = 17, 4%) and clinical hypothyroidism (n = 12, 3%). There was no significant difference in fT4 between the two groups. The increase of log-TSH and the decrease of FT3 were independent predictors of deterioration of cardiac function. Stepwise method was used to screen those whose P value was less than 0.05 in univariate analysis and entered multivariate analysis. The results showed that og-TSH (HR: 2.189, 95% CI: 1.217-3.938), fT3 (HR: 0.483, 95% CI: 1.217-3.938), and fT3 (HR: 0.483, F3). 95% CI: 0.301-0.775) and renal insufficiency (HR: 2.045, 95% CI: 1.077-3.882) were independent predictors of deterioration of cardiac function. Low FT3 was a significant predictor of all-cause mortality (HR 3.18, 95% CI: 1.96-5.16, P 0.001; see Table 3). Elevated TSH was a strong predictor of death (HR: 2.828, 95% CI: 1.902-4.206), and decreased TSH had no significant effect on all-cause mortality. In multivariate analysis, the strongest predictors of all-cause mortality were clinical hypothyroidism (HR: 4.189, 95% CI: 2.118-8.283), followed by low T3 syndrome (HR: 3.147, 95% CI: 1.558-6.355) and subclinical hypothyroidism (HR: 2.869, 95% CI: 1.817-4.532). I:0.469-2.018). Conclusion: In patients with primary dilated cardiomyopathy, the decrease of FT3 and the increase of TSH levels are associated with the deterioration of cardiac function. Abnormal thyroid function (hypothyroidism, subclinical hypothyroidism, clinical hypothyroidism) is an independent risk factor for all-cause and cardiac death in patients with primary dilated cardiomyopathy. Background: Thyroid hormone levels are significantly associated with cardiac function in patients with heart failure, and are also an important risk factor for long-term adverse prognosis. At the animal level, there is insufficient evidence at the human level, leading to clinical consensus on the need for thyroid hormone therapy in these patients. The methods of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for evaluating myocardial perfusion/metabolism have also been widely used in clinic. Methods: 71 patients with primary dilated cardiomyopathy were enrolled in Fuwai Hospital from January 2010 to October 2011. Myocardial fibrosis was assessed by late gadolinium enhancement (LGE) and myocardium was assessed by 99mTc-MIBI SPECT. Myocardial perfusion was assessed by 18F-FDG PET imaging. Magnetic resonance imaging and radionuclide imaging were performed with 17-segment model. The myocardium was divided into 6 basal segments, 6 middle segments and 5 apical segments. LGE types were divided into three groups: no delayed enhancement, intermural enhancement (delayed enhancement in the myocardial wall, linear or patchy, not involving the whole myocardial layer) and transmural enhancement (delayed enhancement involving the whole myocardial layer). The primary endpoint was all-cause death, and the secondary endpoint was cardiac death. All patients were divided into four groups according to FT3 quadrant: Quartile 1 group (2.53 pg/mL, n=20); Quartile 2 group (2.53 pg/mL-2.76 pg/mL, n=16); Quartile 3 group (2.77 pg/mL-3.19 pg/mL, n=18); Quartile 4 group (> 3.19 pg/mL, n=17). From Quartile 1 to Quartile 4, the proportion of LGE segments decreased significantly with the increase of FT3 level. Potential (23.53%, 16.54%, 5.22%, 3.11%; P 0.001), the proportion of abnormal perfusion segments also showed a downward trend (20.88%, 16.54%, 14.05%, 9.69%; P 0.001). For abnormal metabolic segments, the incidence of Quartile 3 was significantly lower than that of Quartile 1 and Quartile 2 (8.82%, 7.35% vs 1.63%; P = 0.032). In logistic regression analysis, FT3 was the only risk factor for LGE enhancement (OR: 0.180, 95% CI: 0.059-0.550). For myocardial perfusion abnormalities, the OR value of FT3 in single-factor model was 0.38 (95% CI: 0.146-0.991) and in multivariate model was 0.172 (95% CI: 0.040-0.738). For myocardial metabolic abnormalities, FT3 was the only significant predictor in the multivariate model (OR: 0.338, 95% CI: 0.126-0.910). According to the presence of LGE enhancement and FT3 level (median 2.77 pg/mL), patients were divided into four groups: LGE negative + FT3 (> 2.77), LGE negative + FT32.77, LGE enhancement + FT3 (> 2.77), LGE enhancement + FT3 (> 2.77), LGE enhancement + FT3 (> 3.77), LGE enhancement + FT3 (%) 3 (> 2.77). 2.77. LGE enhancement + FT3 (> 2.77) (HR: 4.966, 1.851 - 8.658) and LGE enhancement + FT32.77 (HR: 8.623, 95% CI: 3.626 - 16.438) were independent risk factors for death. Conclusion: In patients with primary dilated cardiomyopathy, the decrease of FT3 level was significantly associated with the proportion of ventricular segmental fibrosis and abnormal myocardial perfusion / metabolism. Both are risk factors for long-term mortality in patients with primary dilated cardiomyopathy, and the combination of both can better predict the risk of death.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R542.22

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