心肌能量代谢及自身免疫与慢性心力衰竭关系的初步研究
|
摘要
背景:
近年来,尽管对慢性心力衰竭的治疗已经得到了很大的改善,但是其发病率与死亡率仍然居高不下,其主要原因是慢性心衰的发病机制尚未完全阐明。遗传因素、免疫系统激活、心肌能量耗竭和神经体液因子等在慢性心力衰竭的病理过程中起重要作用。
早在70年前,Herrmann和Decherd提出慢性心力衰竭时存在心肌能量耗竭的假说,此后慢性心力衰竭心肌能量代谢变化的临床和基础实验研究不断增多,有学者认为磷酸肌酸/三磷酸腺苷是较左室射血分数和纽约心功能分级更能反应慢性心衰患者预后的指标。研究显示直接改善心肌能量代谢药物曲美他嗪能够提高缺血性和非缺血性心力衰竭患者运动耐力、生活质量和左心功能、减少利尿剂和洋地黄的应用、降低血清中BNP含量。未来心衰治疗的一个目标就是改善心肌的能量代谢。
自身免疫反应参与了慢性心力衰竭的发生发展,在扩张型心肌病患者血清中发现心脏自身抗体增高,包括抗肾上腺素能受体抗体、抗肌球蛋白抗体、抗胆碱能受体抗体等。临床研究发现,心脏自身抗体增高的患者在接受免疫吸附治疗后,其心功能可得到改善。有学者提出自身抗体可能通过直接或间接途径造成心肌损伤、心功能减退。心肌肌钙蛋白Ⅰ(cTnI)是心脏特异性蛋白质,心肌损伤后释放入血,可激活免疫系统产生cTnI自身抗体,后者长期存在于患者血清中。虽已有文献报道其可以导致心肌损害,腹腔注射可以诱导小鼠发生心力衰竭,但是不同病因的心力衰竭患者cTnI自身抗体滴度是否有差异?cTnI自身抗体对慢性心衰患者预后是否有影响等问题尚待阐明。
第一部分:慢性心力衰竭大鼠心肌能量代谢变化及药物干预研究
目的:研究异丙肾上腺素(ISO)所致慢性心力衰竭大鼠心肌能量代谢变化及曲美他嗪、培哚普利和丹参益气浸膏对其影响。
方法:
1.96只雄性SD大鼠,体重201.86±6.68g,随机分为对照组(18只)和CHF组(78只),模型制备采用皮下多点注射ISO法,以每天20、10和5mg/kg递减剂量连续注射3天,再以每天3mg/kg剂量连续注射9天。
2.4周后分别随机取8只对照组和模型组大鼠进行二维超声心动图检查,确定模型制备成功。再随机分为未治疗组和曲美他嗪组(10 mg·kg~(-1)·d~(-1))、培哚普利组(0.42 mg·kg~(-1)·d~(-1))、芪参益气浸膏组(39.1 mg·kg~(-1)·d~(-1))三个治疗组。
3.平均治疗5周后行心脏超声检查和病理形态学观察,并测定心肌组织高能磷酸化合物的含量和肌浆网Ca~(2+)依赖型ATP酶(SERCA)活性。
结果:
1.皮下注射异丙肾上腺素4周后,与对照组比较,模型组大鼠EF和FS显著降低,IVS、LVPW明显减小,LVS、LVD明显增大。
2.与对照组比较,未治疗组大鼠心肌ATP、AMP、TAN和乳酸含量显著降低。
3.与未治疗组比较,药物治疗5周后,曲美他嗪治疗组大鼠EF和FS分别提高了6.5%和11.6%,心肌ATP/ADP升高了19.6%,AMP含量和SERCA活性明显增加;芪参益气浸膏治疗组大鼠心肌ATP、ADP、TAN含量和SERCA活性均显著增高;培哚普利治疗组大鼠心肌AMP含量显著升高。芪参益气浸膏治疗组、曲美他嗪治疗组和培哚普利治疗组大鼠心肌光镜与电镜结果均较未治疗组有改善。
结论:异丙肾上腺素导致的慢性心力衰竭大鼠心功能和心肌能量代谢恶化,曲美他嗪、培哚普利和芪参益气浸膏均能不同程度的改善慢性心力衰竭大鼠心肌的能量代谢和形态学变化。
第二部分:慢性心力衰竭患者心肌肌钙蛋白Ⅰ自身抗体的研究
目的:观察失代偿性慢性心力衰竭患者血清cTnI自身抗体水平及其与临床预后和患者生活质量的关系,初步探讨cTnI自身抗体在慢性心力衰竭中的临床意义。
方法:
1.收集59例慢性失代偿性心力衰竭患者血清标本,所有患者均参照2007年中国慢性心力衰竭诊断指南,NYHA分级为Ⅲ～Ⅳ级。收集40例健康体检者血清标本作为对照。
2.以人cTnI为抗原包被微孔板,以鼠抗人IgG为第二抗体,建立检测血清cTnI自身抗体的间接ELISA方法。通过检测不同样本和不同浓度的cTnI抗体对本实验室已建立的cTnI自身抗体间接ELISA测定法批间和批内差异进行评价。
3.检测慢性心力衰竭患者及健康体检者血清cTnI自身抗体,以超过对照组(?)+3SD为阳性。
4.对慢性心力衰竭患者进行平均6个月随访,观察患者再入院率、是否行器械及心脏移植、是否死亡和通过SF-36评价患者生活质量。
结果:
1.4.5ng/ml的cTnI抗体作为样品检测批间和批内差异分别为12%和6%,9.0ng/ml的cTnI抗体作为样品检测批间和批内差异分别为10%和12%,对4例不同患者样本cTnI自身抗体检测批间差异分别为23%、22%、15%和24%,批内差异分别为21%、9%、9%和9%。
2.对照组cTnI自身抗体检测平均值为0.46±0.07,慢性心衰患者cTnI自身抗体检测平均值为0.55±0.24,59例慢性心力衰竭患者中cTnI自身抗体检出阳性9例,其中15例缺血性心肌病患者3例cTnI自身抗体阳性、27例扩张型心肌病患者3例cTnI自身抗体阳性、17例其它原因引起的慢性心力衰竭患者3例cTnI自身抗体阳性。
3.对慢性心力衰竭患者出院后随访6个月,7例cTnI自身抗体阳性患者死亡3例,27例cTnI自身抗体阴性患者死亡2例;生活质量比较,cTnI自身抗体阳性组患者生活质量各指标均较阴性组患者有所降低。
结论:
1.在慢性失代偿性心力衰竭患者血清中可检测到cTnI自身抗体。
2.慢性失代偿性心力衰竭患者cTnI自身抗体增高可能预示患者预后不良和生活质量降低。
Background:
Despite recent improvements in therapy, both incidence and mortality of the chronic heart failure patients are still very high. The main problem is its heterogeneous etiology. So far, four factors have been identified to be potentially important: neurohumour factors, immune mechanism, energy metabolism and genetic factors.
The concept that the failing heart is an energy-starved engine that has run out of fuel is decades old. It was proposed in 1939 by Herrmann and Decherd, who, in their article entitled "The Chemical Nature of Heart Failure", described a significantly reduced creatine content in failing myocardium. Over the next 20 years, the energy-depletion hypothesis was pursued by various groups, and nowadays, energy metabolism in the heart—myocardial energetics—is a topic of considerable interest. In heart failure patients, a low myocardial phosphocreatine :ATP level predicts mortality better than left ventricular ejection fraction and New York Heart Association classes. And some studies demonstrated treatment with trimetazidine, an inhibitor of fatty acid oxidation, improved exercise tolerance, quality of life, left ventricular function and reduced diuretic/digitalis application in patients with heart failure of ischemic or nonischemic origin. Stephan et al presumed targets for future interventions in the chronic heart failure including energy imbalance.
Many cardiac autoantibodies can be found elevated in the serum of dilated cardiomyopathy patients. As we know now, they are anti-adrenoceptor autoantibodies, myosin autoantibodies, anti-M_2 acetylcholine receptor autoantibodies and so on. It has been suggested that clinical improvements in patients with high cardiac autoantibodies titers are related to the disappearance of antibodies by immunoadsorption therapy. It is presumed now that these autoantibodies can damage the cardiomyocytes by some mechanisms and take part in the pathophysiological process of myocardial damage and myocardium dysfunction. Cardiac troponin I (cTnI), a regulatory protein unique to heart muscle, is released to the bloodstream after myocardial necrosis. These findings suggested that antibodies to cTnI induced heart dysfunction and dilatation in mice. But many questions need further investigation. Such as whether there is a relationship between cTnI autoantibodies titers and origins of the CHF? And whether there is a relationship between the cTnI autoantibodies level and prognosis in the CHF patient?
Section 1 The changes and the intervention of the drugs on myocardial energy metabolism in chronic heart failure rats
AIM:
To investigate the changes and the intervention of the drugs, including trimetazidine, perindopril and QiShenYiQiJinGao, on myocardial energy metabolism in isoproterenol-induced heart failure rats.
METHODS:
1. ninety six male SD rats (body weight 201.86±6.68g) were enrolled in this study. Firstly they were randomly divided into two groups, one was normal control group(n=18), the other was CHF group(n=78). Rats in CHF group were injected subcutaneously with isopreteronol(ISO) at a dose of 20mg/Kg at the first day of this study, 10mg/Kg at the second day, 5mg/Kg at the third day and 3mg/Kg at the following nine day.
2. Four weeks later, in order to confirm whether the CHF model were successful, 8 rats from the control group and the model group were selected at random respectively performed 2-Dimensional echocardiography (2-DE). Then the survived rats in CHF group were randomly re-divided into four groups, which were untreated group(Group M) , trimetazidine treated group(Group T, 10 mg·kg~(-1)·d~(-1)), perindopril treated group(Group P, 0.42 mg·kg~(-1)·d~(-1)) QiShenYiQi treated group(Group Q, 39.1 mg·kg~(-1)·d~(-1)).
3. After an average treatment for five weeks, echocardiography and myocardial pathology were performed to assess the cardiac function and structure changes of these rats. And the level of ATP, ADP , AMP, lactic acid(LA) and sarcoplasmic reticulum Ca~(2+)-ATPase(SERCA) activity in myocardium were determined by enzymatic analyses.
RESULTS:
1. Four weeks later, model group showed a significant decrease in LVPW,IVS, EF, FS and increase in LVS, LVD as compared with the control value.
2. Compared with the control group, the level of myocardial ATP, AMP, TAN and LA showed a significant decrease in group M.
3. As compared with the group M values, the level of myocardial ATP , ADP, TAN and myocardial SERCA activity had a significant increase in Group Q; EF , FS and ATP/ADP of Group T were increased by 6.5%, 11.6% and 19.6% respectively, and the level of myocardial AMP and the myocardial SERCA activity showed a significant increase; the level of myocardial AMP had a significant increase in Group P. The microscope and electronic microscope analysis showed that the myocardial injury from the rats in Group T , Group P and Group Q was ameliorated in comparison with those from rats in Group M.
CONCLUSION:
In this study, the myocardial energy metabolism and heart function were to getworse in isoproterenol-induced heart failure rats. Trimetazidine, Perindopriland QiShenYiQiJinGao can improve myocardial energy metabolism, patho-and ultrastructure , but they do not enhance the cardiac function inisopreteronol-induced HF rats.
Section 2 The preliminary study on cTnI autoantibodies in chronic heart failure
AIM:
To evaluate the serum cTnI autoantibodies level in the chronic uncompensated heart failure patients, discuss the relationship between the cTnI autoantibodies level and prognosis. To elucidate the pathological roles of human cTnI autoantibodies in the chronic heart failure(CHF) patients.
METHODS:
1. Enrolled the testees of 59 CHF patients and 40 healthy participants from the outpatient clinic. The CHF patients was diagnosed according to the CHF guideline of Chinese Medical Association and the NYHA of the CHF patients were III～IV.
2. A sandwich ELISA method detecting cTnI autoantibodies was established with human cTnI and mouse anti-human IgG. Tested the interassay coefficient of variation and the intraassay coefficient of variation of a sandwich ELISA method detecting cTnI autoantibodies by detecting mouse anti-human antibodies of different concentrations and different samples.
3. All the serum cTnI autoantibodies of the testees (CHF group and healthy control group) were measured by ELISA. Set the mean±3SD obtained from the healthy control to define positive for each group.
4. Follow-up for discharged CHF patients was 6 months. Follow-up index included mortality rate, readmission rate, mechanical therapy rate, heart transplantation rate and the quality of life.
RESULTS:
1. The interassay coefficient of variation and the intraassay coefficient of variation of this method were about 10% by detecting mouse anti-human antibodies of different concentrations, while which were 9%-24% by different samples.
2. The mean value of the serum cardiac troponin I autoantibodies of the CHF group was 0.55±0.24, while the healthy control group was 0.46±0.07. 9 patients were identified as positive in the CHF group. We found that three patients from the 15 having ICM, three patients from the 27 having DCM and three patients from 17 having other origins had cTnI autoantibodies.
3. After 6 months of follow-up, the mortality rate of cTnI autoantibodies positive patients had a trend to increase as compared with the negative group. Compared with the negative group, the indexes of the quality of life also had a trend to decrease in cTnI autoantibodies positive patients.
CONCLUSIONS:
1. The cTnI autoantibodies can be detected in the serum of chronic uncompensated heart failure patients.
2. The elevated serum cTnI autoantibodies of some chronic uncompensated heart failure patients may be correlated with unfavorable prognosis and quality of life.
近年来,尽管对慢性心力衰竭的治疗已经得到了很大的改善,但是其发病率与死亡率仍然居高不下,其主要原因是慢性心衰的发病机制尚未完全阐明。遗传因素、免疫系统激活、心肌能量耗竭和神经体液因子等在慢性心力衰竭的病理过程中起重要作用。
早在70年前,Herrmann和Decherd提出慢性心力衰竭时存在心肌能量耗竭的假说,此后慢性心力衰竭心肌能量代谢变化的临床和基础实验研究不断增多,有学者认为磷酸肌酸/三磷酸腺苷是较左室射血分数和纽约心功能分级更能反应慢性心衰患者预后的指标。研究显示直接改善心肌能量代谢药物曲美他嗪能够提高缺血性和非缺血性心力衰竭患者运动耐力、生活质量和左心功能、减少利尿剂和洋地黄的应用、降低血清中BNP含量。未来心衰治疗的一个目标就是改善心肌的能量代谢。
自身免疫反应参与了慢性心力衰竭的发生发展,在扩张型心肌病患者血清中发现心脏自身抗体增高,包括抗肾上腺素能受体抗体、抗肌球蛋白抗体、抗胆碱能受体抗体等。临床研究发现,心脏自身抗体增高的患者在接受免疫吸附治疗后,其心功能可得到改善。有学者提出自身抗体可能通过直接或间接途径造成心肌损伤、心功能减退。心肌肌钙蛋白Ⅰ(cTnI)是心脏特异性蛋白质,心肌损伤后释放入血,可激活免疫系统产生cTnI自身抗体,后者长期存在于患者血清中。虽已有文献报道其可以导致心肌损害,腹腔注射可以诱导小鼠发生心力衰竭,但是不同病因的心力衰竭患者cTnI自身抗体滴度是否有差异?cTnI自身抗体对慢性心衰患者预后是否有影响等问题尚待阐明。
第一部分:慢性心力衰竭大鼠心肌能量代谢变化及药物干预研究
目的:研究异丙肾上腺素(ISO)所致慢性心力衰竭大鼠心肌能量代谢变化及曲美他嗪、培哚普利和丹参益气浸膏对其影响。
方法:
1.96只雄性SD大鼠,体重201.86±6.68g,随机分为对照组(18只)和CHF组(78只),模型制备采用皮下多点注射ISO法,以每天20、10和5mg/kg递减剂量连续注射3天,再以每天3mg/kg剂量连续注射9天。
2.4周后分别随机取8只对照组和模型组大鼠进行二维超声心动图检查,确定模型制备成功。再随机分为未治疗组和曲美他嗪组(10 mg·kg~(-1)·d~(-1))、培哚普利组(0.42 mg·kg~(-1)·d~(-1))、芪参益气浸膏组(39.1 mg·kg~(-1)·d~(-1))三个治疗组。
3.平均治疗5周后行心脏超声检查和病理形态学观察,并测定心肌组织高能磷酸化合物的含量和肌浆网Ca~(2+)依赖型ATP酶(SERCA)活性。
结果:
1.皮下注射异丙肾上腺素4周后,与对照组比较,模型组大鼠EF和FS显著降低,IVS、LVPW明显减小,LVS、LVD明显增大。
2.与对照组比较,未治疗组大鼠心肌ATP、AMP、TAN和乳酸含量显著降低。
3.与未治疗组比较,药物治疗5周后,曲美他嗪治疗组大鼠EF和FS分别提高了6.5%和11.6%,心肌ATP/ADP升高了19.6%,AMP含量和SERCA活性明显增加;芪参益气浸膏治疗组大鼠心肌ATP、ADP、TAN含量和SERCA活性均显著增高;培哚普利治疗组大鼠心肌AMP含量显著升高。芪参益气浸膏治疗组、曲美他嗪治疗组和培哚普利治疗组大鼠心肌光镜与电镜结果均较未治疗组有改善。
结论:异丙肾上腺素导致的慢性心力衰竭大鼠心功能和心肌能量代谢恶化,曲美他嗪、培哚普利和芪参益气浸膏均能不同程度的改善慢性心力衰竭大鼠心肌的能量代谢和形态学变化。
第二部分:慢性心力衰竭患者心肌肌钙蛋白Ⅰ自身抗体的研究
目的:观察失代偿性慢性心力衰竭患者血清cTnI自身抗体水平及其与临床预后和患者生活质量的关系,初步探讨cTnI自身抗体在慢性心力衰竭中的临床意义。
方法:
1.收集59例慢性失代偿性心力衰竭患者血清标本,所有患者均参照2007年中国慢性心力衰竭诊断指南,NYHA分级为Ⅲ～Ⅳ级。收集40例健康体检者血清标本作为对照。
2.以人cTnI为抗原包被微孔板,以鼠抗人IgG为第二抗体,建立检测血清cTnI自身抗体的间接ELISA方法。通过检测不同样本和不同浓度的cTnI抗体对本实验室已建立的cTnI自身抗体间接ELISA测定法批间和批内差异进行评价。
3.检测慢性心力衰竭患者及健康体检者血清cTnI自身抗体,以超过对照组(?)+3SD为阳性。
4.对慢性心力衰竭患者进行平均6个月随访,观察患者再入院率、是否行器械及心脏移植、是否死亡和通过SF-36评价患者生活质量。
结果:
1.4.5ng/ml的cTnI抗体作为样品检测批间和批内差异分别为12%和6%,9.0ng/ml的cTnI抗体作为样品检测批间和批内差异分别为10%和12%,对4例不同患者样本cTnI自身抗体检测批间差异分别为23%、22%、15%和24%,批内差异分别为21%、9%、9%和9%。
2.对照组cTnI自身抗体检测平均值为0.46±0.07,慢性心衰患者cTnI自身抗体检测平均值为0.55±0.24,59例慢性心力衰竭患者中cTnI自身抗体检出阳性9例,其中15例缺血性心肌病患者3例cTnI自身抗体阳性、27例扩张型心肌病患者3例cTnI自身抗体阳性、17例其它原因引起的慢性心力衰竭患者3例cTnI自身抗体阳性。
3.对慢性心力衰竭患者出院后随访6个月,7例cTnI自身抗体阳性患者死亡3例,27例cTnI自身抗体阴性患者死亡2例;生活质量比较,cTnI自身抗体阳性组患者生活质量各指标均较阴性组患者有所降低。
结论:
1.在慢性失代偿性心力衰竭患者血清中可检测到cTnI自身抗体。
2.慢性失代偿性心力衰竭患者cTnI自身抗体增高可能预示患者预后不良和生活质量降低。
Background:
Despite recent improvements in therapy, both incidence and mortality of the chronic heart failure patients are still very high. The main problem is its heterogeneous etiology. So far, four factors have been identified to be potentially important: neurohumour factors, immune mechanism, energy metabolism and genetic factors.
The concept that the failing heart is an energy-starved engine that has run out of fuel is decades old. It was proposed in 1939 by Herrmann and Decherd, who, in their article entitled "The Chemical Nature of Heart Failure", described a significantly reduced creatine content in failing myocardium. Over the next 20 years, the energy-depletion hypothesis was pursued by various groups, and nowadays, energy metabolism in the heart—myocardial energetics—is a topic of considerable interest. In heart failure patients, a low myocardial phosphocreatine :ATP level predicts mortality better than left ventricular ejection fraction and New York Heart Association classes. And some studies demonstrated treatment with trimetazidine, an inhibitor of fatty acid oxidation, improved exercise tolerance, quality of life, left ventricular function and reduced diuretic/digitalis application in patients with heart failure of ischemic or nonischemic origin. Stephan et al presumed targets for future interventions in the chronic heart failure including energy imbalance.
Many cardiac autoantibodies can be found elevated in the serum of dilated cardiomyopathy patients. As we know now, they are anti-adrenoceptor autoantibodies, myosin autoantibodies, anti-M_2 acetylcholine receptor autoantibodies and so on. It has been suggested that clinical improvements in patients with high cardiac autoantibodies titers are related to the disappearance of antibodies by immunoadsorption therapy. It is presumed now that these autoantibodies can damage the cardiomyocytes by some mechanisms and take part in the pathophysiological process of myocardial damage and myocardium dysfunction. Cardiac troponin I (cTnI), a regulatory protein unique to heart muscle, is released to the bloodstream after myocardial necrosis. These findings suggested that antibodies to cTnI induced heart dysfunction and dilatation in mice. But many questions need further investigation. Such as whether there is a relationship between cTnI autoantibodies titers and origins of the CHF? And whether there is a relationship between the cTnI autoantibodies level and prognosis in the CHF patient?
Section 1 The changes and the intervention of the drugs on myocardial energy metabolism in chronic heart failure rats
AIM:
To investigate the changes and the intervention of the drugs, including trimetazidine, perindopril and QiShenYiQiJinGao, on myocardial energy metabolism in isoproterenol-induced heart failure rats.
METHODS:
1. ninety six male SD rats (body weight 201.86±6.68g) were enrolled in this study. Firstly they were randomly divided into two groups, one was normal control group(n=18), the other was CHF group(n=78). Rats in CHF group were injected subcutaneously with isopreteronol(ISO) at a dose of 20mg/Kg at the first day of this study, 10mg/Kg at the second day, 5mg/Kg at the third day and 3mg/Kg at the following nine day.
2. Four weeks later, in order to confirm whether the CHF model were successful, 8 rats from the control group and the model group were selected at random respectively performed 2-Dimensional echocardiography (2-DE). Then the survived rats in CHF group were randomly re-divided into four groups, which were untreated group(Group M) , trimetazidine treated group(Group T, 10 mg·kg~(-1)·d~(-1)), perindopril treated group(Group P, 0.42 mg·kg~(-1)·d~(-1)) QiShenYiQi treated group(Group Q, 39.1 mg·kg~(-1)·d~(-1)).
3. After an average treatment for five weeks, echocardiography and myocardial pathology were performed to assess the cardiac function and structure changes of these rats. And the level of ATP, ADP , AMP, lactic acid(LA) and sarcoplasmic reticulum Ca~(2+)-ATPase(SERCA) activity in myocardium were determined by enzymatic analyses.
RESULTS:
1. Four weeks later, model group showed a significant decrease in LVPW,IVS, EF, FS and increase in LVS, LVD as compared with the control value.
2. Compared with the control group, the level of myocardial ATP, AMP, TAN and LA showed a significant decrease in group M.
3. As compared with the group M values, the level of myocardial ATP , ADP, TAN and myocardial SERCA activity had a significant increase in Group Q; EF , FS and ATP/ADP of Group T were increased by 6.5%, 11.6% and 19.6% respectively, and the level of myocardial AMP and the myocardial SERCA activity showed a significant increase; the level of myocardial AMP had a significant increase in Group P. The microscope and electronic microscope analysis showed that the myocardial injury from the rats in Group T , Group P and Group Q was ameliorated in comparison with those from rats in Group M.
CONCLUSION:
In this study, the myocardial energy metabolism and heart function were to getworse in isoproterenol-induced heart failure rats. Trimetazidine, Perindopriland QiShenYiQiJinGao can improve myocardial energy metabolism, patho-and ultrastructure , but they do not enhance the cardiac function inisopreteronol-induced HF rats.
Section 2 The preliminary study on cTnI autoantibodies in chronic heart failure
AIM:
To evaluate the serum cTnI autoantibodies level in the chronic uncompensated heart failure patients, discuss the relationship between the cTnI autoantibodies level and prognosis. To elucidate the pathological roles of human cTnI autoantibodies in the chronic heart failure(CHF) patients.
METHODS:
1. Enrolled the testees of 59 CHF patients and 40 healthy participants from the outpatient clinic. The CHF patients was diagnosed according to the CHF guideline of Chinese Medical Association and the NYHA of the CHF patients were III～IV.
2. A sandwich ELISA method detecting cTnI autoantibodies was established with human cTnI and mouse anti-human IgG. Tested the interassay coefficient of variation and the intraassay coefficient of variation of a sandwich ELISA method detecting cTnI autoantibodies by detecting mouse anti-human antibodies of different concentrations and different samples.
3. All the serum cTnI autoantibodies of the testees (CHF group and healthy control group) were measured by ELISA. Set the mean±3SD obtained from the healthy control to define positive for each group.
4. Follow-up for discharged CHF patients was 6 months. Follow-up index included mortality rate, readmission rate, mechanical therapy rate, heart transplantation rate and the quality of life.
RESULTS:
1. The interassay coefficient of variation and the intraassay coefficient of variation of this method were about 10% by detecting mouse anti-human antibodies of different concentrations, while which were 9%-24% by different samples.
2. The mean value of the serum cardiac troponin I autoantibodies of the CHF group was 0.55±0.24, while the healthy control group was 0.46±0.07. 9 patients were identified as positive in the CHF group. We found that three patients from the 15 having ICM, three patients from the 27 having DCM and three patients from 17 having other origins had cTnI autoantibodies.
3. After 6 months of follow-up, the mortality rate of cTnI autoantibodies positive patients had a trend to increase as compared with the negative group. Compared with the negative group, the indexes of the quality of life also had a trend to decrease in cTnI autoantibodies positive patients.
CONCLUSIONS:
1. The cTnI autoantibodies can be detected in the serum of chronic uncompensated heart failure patients.
2. The elevated serum cTnI autoantibodies of some chronic uncompensated heart failure patients may be correlated with unfavorable prognosis and quality of life.
引文
Cohn JN.The management of chronic heart failure.N Engl J Med,1996,335:490-498.
2 Miller LW,Missov ED.Epidemiology of heart failure.Cardiol Clin,2001,19:547-555.
3 Hunt SA,Abraham WT,Chin MH,et al.ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure):developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation:endorsed by the Heart Rhythm Society.Circulation JT -Circulation,2005,112:e154-235.
4 McMurray JJ,Pfeffer MA.Heart failure.Lancet JT - Lancet,2005,365:1877-1889.
5 顾东风,黄广勇,吴锡桂,等.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003,31:3-6.
6 Neubauer S.The failing heart--an engine out of fuel.N Engl J Med,2007,356:1140-1151.
7 von Haehling S,Doehner W,Anker SD.The roles of immunity and autoimmunity in chronic heart failure.Ernst Schering Res Found Workshop,2006:155-168.
8 Neubauer S,Horn M,Cramer M,et al.Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy.Circulation,1997,96:2190-2196.
9 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
10 Matsui S,Fu ML,Shimizu M,et al.Dilated cardiomyopathy defines serum autoantibodies against G-protein-coupled cardiovascular receptors.Autoimmunity,1995,21:85-88.
11 Felix SB,Staudt A,Landsberger M,et al.Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption.J Am Coll Cardiol, 2002, 39: 646-652.
12 Staudt A, Schaper F, Stangl V, et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation, 2001, 103: 2681-2686.
13 Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med, 2003,9:1477-1483.
14 Goser S, Andrassy M, Buss SJ, et al. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation, 2006,114:1693-1702.
1 OLSON RE.Myocardial metabolism in congestive heart failure.J Chronic Dis,1959,9:442-464.
2 OLSON RE,SCHWARTZ WB.Myocardial metabolism in congestive heart failure.Medicine(Baltimore),1951,30:21-41.
3 St Cyr JA,Schneider JR.A sugar that benefits failing hearts.Int J Cardiol,2007:1-2.
4 Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-145.
5 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
6 Reuter H.Calcium channel modulation by neurotransmitters,enzymes and drugs.Nature,1983,301:569-574.
7 Teerlink JR,Pfeffer JM,Pfeffer MA.Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats.Circ Res,1994,75:105-113.
8 李为民,甘润韬,孙桂芳.肿瘤坏死因子拮抗剂对异丙肾上腺素诱导大鼠心力衰竭的治疗作用.中华心血管病杂志,2002,30:747-750.
9 沈雁,曹洪欣.温心胶囊对心力衰竭大鼠心肌基质金属蛋白酶组织抑制物1mRNA表达的干预效应.中国临床康复,2005,9:85-87.
10 贾月霞,曹军,齐永芬,等.APelin对异丙基肾上腺素诱导的大鼠心肌缺血性损伤的影响.中国病理生理杂志,2005,21:2289-2294.
11 Manning WJ,Wei JY,Katz SE,et al.In vivo assessment of LV mass in mice using high-frequency cardiac ultrasound:necropsy validation.Am J Physiol,1994,266:H1672-675.
12 RONA G,CHAPPEL CI,BALAZS T,et al.An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat.AMA Arch Pathol,1959,67:443-455.
13 Grimm D,Elsner D,Schunkert H,et al.Development of heart failure following isoproterenol administration in the rat:role of the renin-angiotensin system.Cardiovasc Res,1998,37:91-100.
1 吴伟康,侯灿,罗汉川,等.四逆汤改善缺血心肌能量代谢的作用及其机制探讨.中国病理生理杂志,1998,6:634-636.
2 Chandler MP,Kerner J,Huang H,et al.Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation.Am J Physiol Heart Circ Physiol,2004,287:H1538-543.
3 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
4 Kantor PF,Lucien A,Kozak R,et al.The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.Circ Res,2000,86:580-588.
5 Manning WJ,Wei JY,Katz SE,et al.In vivo assessment of LV mass in mice using high-frequency cardiac ultrasound:necropsy validation.Am J Physiol,1994,266:H1672-675.
6 张寄南 杨国平 苏恩本,等.乌拉地尔干预急性心肌缺血的细胞机制.中华心血管病杂志,1999,27:388-390.
7 祝宝华,张寄南,马文珠.肌浆网钙调节蛋白在心肌肥厚病理中的作用.东南大学学报:医学版,2002,21:49-51.
8 Huss JM,Kelly DP.Mitochondrial energy metabolism in heart failure:a question of balance.J Clin Invest,2005,115:547-555.
9 Ventura-Clapier R,Mettauer B,Bigard X.Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure.Cardiovasc Res,2007,73:10-18.
10 Stanley WC,Recchia FA,Lopaschuk GD.Myocardial substrate metabolism in the normal and failing heart.Physiol Rev,2005,85:1093-1129.
11 惠海鹏,李小鹰,刘秀华,等.腺相关病毒介导心肌肌浆网Ca2+-ATPase 2a基因转导治疗大鼠慢性心力衰竭.中华心血管病杂志,2006,34:357-362.
12 Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-145.
13 Fragasso G,Perseghin G,De Cobelli F,et al.Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure.Eur Heart J,2006,27:942-948.
14 Fragasso G,Palloshi A,Puccetti P,et al.A randomized clinical trial of trimetazidine,a partial free fatty acid oxidation inhibitor,in patients with heart failure.J Am Coll Cardiol,2006,48:992-998. Zhou Z,Liao YH,Wei Y,et al.Cardiac remodeling after long-term stimulation by antibodies against the alphal-adrenergic receptor in rats.Clin Immunol,2005,114:164-173.
2 Felix SB,Staudt A,Friedrich GB.Improvement of cardiac function after immunoadsorption in patients with dilated cardiomyopathy.Autoimmunity,2001,34:211-215.
3 Muller J,Wallukat G,Dandel M,et al.Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy.Circulation,2000,101:385-391.
4 Cummins P,Perry SV.Troponin I from human skeletal and cardiac muscles.Biochem J,1978,171:251-259.
5 Eriksson S,Halenius H,Pulkki K,et al.Negative interference in cardiac troponin I immunoassays by circulating troponin autoantibodies.Clin Chem, 2005,51: 839-847.
6 Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med, 2003, 9: 1477-1483.
7 Staudt A, Schaper F, Stangl V, et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation, 2001,103: 2681-2686.
8 Dorffel WV, Wallukat G, Baumann G, et al. Immunoadsorption in dilated cardiomyopathy. Ther Apher, 2000, 4: 235-238.
9 Felix SB, Staudt A, Landsberger M, et al. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J Am Coll Cardiol, 2002, 39:646-652.
10 Muller-Tasch T, Peters-Klimm F, Schellberg D, et al. Depression is a major determinant of quality of life in patients with chronic systolic heart failure in general practice. J Card Fail, 2007,13:818-824.
11 Shmilovich H, Danon A, Binah O, et al. Autoantibodies to cardiac troponin I in patients with idiopathic dilated and ischemic cardiomyopathy. Int J Cardiol, 2007, 117: 198-203.
12 Goser S, Andrassy M, Buss SJ, et al. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation, 2006, 114: 1693-1702.
13 Moraru M,Roth A,Keren G,et al.Cellular autoimmunity to cardiac myosin in patients with a recent myocardial infarction.Int J Cardiol,2006,107:61-66.
14 刘尊齐,崔连群.慢性心力衰竭患者血清肌钙蛋白I与心肌重构的相关性研究.中华心血管病杂志,2006,34:437-439.
1 Hunt SA,Abraham WT,Chin MH,et al.ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure):developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation:endorsed by the Heart Rhythm Society.Circulation JT-Circulation,2005,112:e154-235.
2 McMurray JJ,Pfeffer MA.Heart failure.Lancet JT - Lancet,2005,365:1877-1889.
3 顾东风,黄广勇,吴锡桂,等.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003,31:3-6.
4 Cleland JG,Daubert JC,Erdmann E,et al.The effect of cardiac resynchronization on morbidity and mortality in heart failure.N Engl J Med,2005,352:1539-1549.
5 Chandler MP,Kemer J,Huang H,et al.Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation.Am J Physiol Heart Circ Physiol,2004,287:H1538-1543.
6 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
7 苏苹,郭庆亩,尹昭.心力衰竭的代谢与治疗.医学综述,2007,13:299-301.
8 Neubauer S.The failing heart--an engine out of fuel.N Engl J Med,2007,356:1140-1151.
9 Carvajal K,Moreno-Sanchez R.Heart metabolic disturbances in cardiovascular diseases.Arch Med Res,2003,34:89-99.
10 Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-45.
11 OLSON RE.Myocardial metabolism in congestive heart failure.J Chronic Dis,1959,9:442-464.
12 OLSON RE,SCHWARTZ WB.Myocardial metabolism in congestive heart failure.Medicine(Baltimore),1951,30:21-41.
13 St Cyr JA,Schneider JR.A sugar that benefits failing hearts.Int J Cardiol,2007,8:1-2.
14 Davila-Roman VG,Vedala G,Herrero P,et al.Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy.J Am Coll Cardiol,2002,40:271-277.
15 Stanley WC,Recchia FA,Lopaschuk GD.Myocardial substrate metabolism in the normal and failing heart.Physiol Rev,2005,85:1093-1129.
16 Taylor M, Wallhaus TR, Degrado TR, et al. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure. J Nucl Med, 2001,42:55-62.
17 Razeghi P, Young ME, Alcorn JL, et al. Metabolic gene expression in fetal and failing human heart. Circulation, 2001,104:2923-2931.
18 Ide T, Tsutsui H, Hayashidani S, et al. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res, 2001,88:529-535.
19 Ning XH, Zhang J, Liu J, et al. Signaling and expression for mitochondrial membrane proteins during left ventricular remodeling and contractile failure after myocardial infarction. J Am Coll Cardiol, 2000,36:282-287.
20 Quigley AF, Kapsa RM, Esmore D, et al. Mitochondrial respiratory chain activity in idiopathic dilated cardiomyopathy. J Card Fail, 2000,6:47-55.
21 Lewandowski ED. Cardiac carbon 13 magnetic resonance spectroscopy: on the horizon or over the rainbow?. J Nucl Cardiol, 2002,9:419-428.
22 Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet, 2004,364:1786-1788.
23 Starling RC, Hammer DF, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Mol Cell Biochem, 1998,180:171-177.
24 Beer M, Seyfarth T, Sandstede J, et al. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol, 2002,40:1267-1274.
25 Ten Hove M, Chan S, Lygate C, et al. Mechanisms of creatine depletion in chronically failing rat heart. J Mol Cell Cardiol, 2005,38:309-313.
26 Liao R, Nascimben L, Friedrich J, et al. Decreased energy reserve in an animal model of dilated cardiomyopathy. Relationship to contractile performance. Circ Res, 1996,78:893-902.
27 Liu J, Wang C, Murakami Y, et al. Mitochondrial ATPase and high-energy phosphates in failing hearts. Am J Physiol Heart Circ Physiol, 2001,281:H1319-326.
28 Neubauer S, Krahe T, Schindler R, et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation, 1992,86:1810-1818.
29 Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation, 1997,96:2190-2196.
30 Barger PM, Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J Clin Invest, 2000,105:1723-1730.
31 Sack MN, Rader TA, Park S, et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation, 1996,94:2837-2842.
32 Huss JM, Kelly DP. Nuclear receptor signaling and cardiac energetics. Circ Res, 2004,95:568-578.
33 Arany Z, Novikov M, Chin S, et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1 alpha. Proc Natl Acad Sci U S A, 2006,103:10086-10091.
34 Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart, 2005,91:161-165.
35 Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation, 2005,112:3280-3288.
36 Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci (Lond), 2000,99:27-35.
37 Hermann HP, Pieske B, Schwarzmuller E, et al. Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet, 1999,353:1321-1323.
38 Nikolaidis LA, Elahi D, Hentosz T, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation, 2004,110:955-961.
39 Liao R, Jain M, Cui L, et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation, 2002,106:2125-2131.
40 Omran H, Illien S, MacCarter D, et al. D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study. Eur J Heart Fail JT - European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology, 2003,5:615-619.
41 Wallis J, Lygate CA, Fischer A, et al. Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice. Circulation, 2005,112:3131-3139.
2 Miller LW,Missov ED.Epidemiology of heart failure.Cardiol Clin,2001,19:547-555.
3 Hunt SA,Abraham WT,Chin MH,et al.ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure):developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation:endorsed by the Heart Rhythm Society.Circulation JT -Circulation,2005,112:e154-235.
4 McMurray JJ,Pfeffer MA.Heart failure.Lancet JT - Lancet,2005,365:1877-1889.
5 顾东风,黄广勇,吴锡桂,等.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003,31:3-6.
6 Neubauer S.The failing heart--an engine out of fuel.N Engl J Med,2007,356:1140-1151.
7 von Haehling S,Doehner W,Anker SD.The roles of immunity and autoimmunity in chronic heart failure.Ernst Schering Res Found Workshop,2006:155-168.
8 Neubauer S,Horn M,Cramer M,et al.Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy.Circulation,1997,96:2190-2196.
9 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
10 Matsui S,Fu ML,Shimizu M,et al.Dilated cardiomyopathy defines serum autoantibodies against G-protein-coupled cardiovascular receptors.Autoimmunity,1995,21:85-88.
11 Felix SB,Staudt A,Landsberger M,et al.Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption.J Am Coll Cardiol, 2002, 39: 646-652.
12 Staudt A, Schaper F, Stangl V, et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation, 2001, 103: 2681-2686.
13 Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med, 2003,9:1477-1483.
14 Goser S, Andrassy M, Buss SJ, et al. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation, 2006,114:1693-1702.
1 OLSON RE.Myocardial metabolism in congestive heart failure.J Chronic Dis,1959,9:442-464.
2 OLSON RE,SCHWARTZ WB.Myocardial metabolism in congestive heart failure.Medicine(Baltimore),1951,30:21-41.
3 St Cyr JA,Schneider JR.A sugar that benefits failing hearts.Int J Cardiol,2007:1-2.
4 Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-145.
5 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
6 Reuter H.Calcium channel modulation by neurotransmitters,enzymes and drugs.Nature,1983,301:569-574.
7 Teerlink JR,Pfeffer JM,Pfeffer MA.Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats.Circ Res,1994,75:105-113.
8 李为民,甘润韬,孙桂芳.肿瘤坏死因子拮抗剂对异丙肾上腺素诱导大鼠心力衰竭的治疗作用.中华心血管病杂志,2002,30:747-750.
9 沈雁,曹洪欣.温心胶囊对心力衰竭大鼠心肌基质金属蛋白酶组织抑制物1mRNA表达的干预效应.中国临床康复,2005,9:85-87.
10 贾月霞,曹军,齐永芬,等.APelin对异丙基肾上腺素诱导的大鼠心肌缺血性损伤的影响.中国病理生理杂志,2005,21:2289-2294.
11 Manning WJ,Wei JY,Katz SE,et al.In vivo assessment of LV mass in mice using high-frequency cardiac ultrasound:necropsy validation.Am J Physiol,1994,266:H1672-675.
12 RONA G,CHAPPEL CI,BALAZS T,et al.An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat.AMA Arch Pathol,1959,67:443-455.
13 Grimm D,Elsner D,Schunkert H,et al.Development of heart failure following isoproterenol administration in the rat:role of the renin-angiotensin system.Cardiovasc Res,1998,37:91-100.
1 吴伟康,侯灿,罗汉川,等.四逆汤改善缺血心肌能量代谢的作用及其机制探讨.中国病理生理杂志,1998,6:634-636.
2 Chandler MP,Kerner J,Huang H,et al.Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation.Am J Physiol Heart Circ Physiol,2004,287:H1538-543.
3 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
4 Kantor PF,Lucien A,Kozak R,et al.The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.Circ Res,2000,86:580-588.
5 Manning WJ,Wei JY,Katz SE,et al.In vivo assessment of LV mass in mice using high-frequency cardiac ultrasound:necropsy validation.Am J Physiol,1994,266:H1672-675.
6 张寄南 杨国平 苏恩本,等.乌拉地尔干预急性心肌缺血的细胞机制.中华心血管病杂志,1999,27:388-390.
7 祝宝华,张寄南,马文珠.肌浆网钙调节蛋白在心肌肥厚病理中的作用.东南大学学报:医学版,2002,21:49-51.
8 Huss JM,Kelly DP.Mitochondrial energy metabolism in heart failure:a question of balance.J Clin Invest,2005,115:547-555.
9 Ventura-Clapier R,Mettauer B,Bigard X.Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure.Cardiovasc Res,2007,73:10-18.
10 Stanley WC,Recchia FA,Lopaschuk GD.Myocardial substrate metabolism in the normal and failing heart.Physiol Rev,2005,85:1093-1129.
11 惠海鹏,李小鹰,刘秀华,等.腺相关病毒介导心肌肌浆网Ca2+-ATPase 2a基因转导治疗大鼠慢性心力衰竭.中华心血管病杂志,2006,34:357-362.
12 Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-145.
13 Fragasso G,Perseghin G,De Cobelli F,et al.Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure.Eur Heart J,2006,27:942-948.
14 Fragasso G,Palloshi A,Puccetti P,et al.A randomized clinical trial of trimetazidine,a partial free fatty acid oxidation inhibitor,in patients with heart failure.J Am Coll Cardiol,2006,48:992-998. Zhou Z,Liao YH,Wei Y,et al.Cardiac remodeling after long-term stimulation by antibodies against the alphal-adrenergic receptor in rats.Clin Immunol,2005,114:164-173.
2 Felix SB,Staudt A,Friedrich GB.Improvement of cardiac function after immunoadsorption in patients with dilated cardiomyopathy.Autoimmunity,2001,34:211-215.
3 Muller J,Wallukat G,Dandel M,et al.Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy.Circulation,2000,101:385-391.
4 Cummins P,Perry SV.Troponin I from human skeletal and cardiac muscles.Biochem J,1978,171:251-259.
5 Eriksson S,Halenius H,Pulkki K,et al.Negative interference in cardiac troponin I immunoassays by circulating troponin autoantibodies.Clin Chem, 2005,51: 839-847.
6 Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med, 2003, 9: 1477-1483.
7 Staudt A, Schaper F, Stangl V, et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation, 2001,103: 2681-2686.
8 Dorffel WV, Wallukat G, Baumann G, et al. Immunoadsorption in dilated cardiomyopathy. Ther Apher, 2000, 4: 235-238.
9 Felix SB, Staudt A, Landsberger M, et al. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J Am Coll Cardiol, 2002, 39:646-652.
10 Muller-Tasch T, Peters-Klimm F, Schellberg D, et al. Depression is a major determinant of quality of life in patients with chronic systolic heart failure in general practice. J Card Fail, 2007,13:818-824.
11 Shmilovich H, Danon A, Binah O, et al. Autoantibodies to cardiac troponin I in patients with idiopathic dilated and ischemic cardiomyopathy. Int J Cardiol, 2007, 117: 198-203.
12 Goser S, Andrassy M, Buss SJ, et al. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation, 2006, 114: 1693-1702.
13 Moraru M,Roth A,Keren G,et al.Cellular autoimmunity to cardiac myosin in patients with a recent myocardial infarction.Int J Cardiol,2006,107:61-66.
14 刘尊齐,崔连群.慢性心力衰竭患者血清肌钙蛋白I与心肌重构的相关性研究.中华心血管病杂志,2006,34:437-439.
1 Hunt SA,Abraham WT,Chin MH,et al.ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure):developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation:endorsed by the Heart Rhythm Society.Circulation JT-Circulation,2005,112:e154-235.
2 McMurray JJ,Pfeffer MA.Heart failure.Lancet JT - Lancet,2005,365:1877-1889.
3 顾东风,黄广勇,吴锡桂,等.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003,31:3-6.
4 Cleland JG,Daubert JC,Erdmann E,et al.The effect of cardiac resynchronization on morbidity and mortality in heart failure.N Engl J Med,2005,352:1539-1549.
5 Chandler MP,Kemer J,Huang H,et al.Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation.Am J Physiol Heart Circ Physiol,2004,287:H1538-1543.
6 von Haehling S,Doehner W,Anker SD.Nutrition,metabolism,and the complex pathophysiology of cachexia in chronic heart failure.Cardiovasc Res,2007,73:298-309.
7 苏苹,郭庆亩,尹昭.心力衰竭的代谢与治疗.医学综述,2007,13:299-301.
8 Neubauer S.The failing heart--an engine out of fuel.N Engl J Med,2007,356:1140-1151.
9 Carvajal K,Moreno-Sanchez R.Heart metabolic disturbances in cardiovascular diseases.Arch Med Res,2003,34:89-99.
10 Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-45.
11 OLSON RE.Myocardial metabolism in congestive heart failure.J Chronic Dis,1959,9:442-464.
12 OLSON RE,SCHWARTZ WB.Myocardial metabolism in congestive heart failure.Medicine(Baltimore),1951,30:21-41.
13 St Cyr JA,Schneider JR.A sugar that benefits failing hearts.Int J Cardiol,2007,8:1-2.
14 Davila-Roman VG,Vedala G,Herrero P,et al.Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy.J Am Coll Cardiol,2002,40:271-277.
15 Stanley WC,Recchia FA,Lopaschuk GD.Myocardial substrate metabolism in the normal and failing heart.Physiol Rev,2005,85:1093-1129.
16 Taylor M, Wallhaus TR, Degrado TR, et al. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure. J Nucl Med, 2001,42:55-62.
17 Razeghi P, Young ME, Alcorn JL, et al. Metabolic gene expression in fetal and failing human heart. Circulation, 2001,104:2923-2931.
18 Ide T, Tsutsui H, Hayashidani S, et al. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res, 2001,88:529-535.
19 Ning XH, Zhang J, Liu J, et al. Signaling and expression for mitochondrial membrane proteins during left ventricular remodeling and contractile failure after myocardial infarction. J Am Coll Cardiol, 2000,36:282-287.
20 Quigley AF, Kapsa RM, Esmore D, et al. Mitochondrial respiratory chain activity in idiopathic dilated cardiomyopathy. J Card Fail, 2000,6:47-55.
21 Lewandowski ED. Cardiac carbon 13 magnetic resonance spectroscopy: on the horizon or over the rainbow?. J Nucl Cardiol, 2002,9:419-428.
22 Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet, 2004,364:1786-1788.
23 Starling RC, Hammer DF, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Mol Cell Biochem, 1998,180:171-177.
24 Beer M, Seyfarth T, Sandstede J, et al. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol, 2002,40:1267-1274.
25 Ten Hove M, Chan S, Lygate C, et al. Mechanisms of creatine depletion in chronically failing rat heart. J Mol Cell Cardiol, 2005,38:309-313.
26 Liao R, Nascimben L, Friedrich J, et al. Decreased energy reserve in an animal model of dilated cardiomyopathy. Relationship to contractile performance. Circ Res, 1996,78:893-902.
27 Liu J, Wang C, Murakami Y, et al. Mitochondrial ATPase and high-energy phosphates in failing hearts. Am J Physiol Heart Circ Physiol, 2001,281:H1319-326.
28 Neubauer S, Krahe T, Schindler R, et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation, 1992,86:1810-1818.
29 Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation, 1997,96:2190-2196.
30 Barger PM, Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J Clin Invest, 2000,105:1723-1730.
31 Sack MN, Rader TA, Park S, et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation, 1996,94:2837-2842.
32 Huss JM, Kelly DP. Nuclear receptor signaling and cardiac energetics. Circ Res, 2004,95:568-578.
33 Arany Z, Novikov M, Chin S, et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1 alpha. Proc Natl Acad Sci U S A, 2006,103:10086-10091.
34 Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart, 2005,91:161-165.
35 Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation, 2005,112:3280-3288.
36 Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci (Lond), 2000,99:27-35.
37 Hermann HP, Pieske B, Schwarzmuller E, et al. Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet, 1999,353:1321-1323.
38 Nikolaidis LA, Elahi D, Hentosz T, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation, 2004,110:955-961.
39 Liao R, Jain M, Cui L, et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation, 2002,106:2125-2131.
40 Omran H, Illien S, MacCarter D, et al. D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study. Eur J Heart Fail JT - European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology, 2003,5:615-619.
41 Wallis J, Lygate CA, Fischer A, et al. Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice. Circulation, 2005,112:3131-3139.