Cardiomyocyte apoptosis and progression of heart failure to transplantation

BACKGROUND: Cardiomyocyte apoptosis has been found in congestive heart failure, but its clinical significance has been difficult to study. We compared the occurrence of cardiomyocyte apoptosis in explanted hearts with the progression of severe heart failure until the need for transplantation. DESIGN: Using the TUNEL assay, apoptotic cardiomyocytes were quantified in explanted failing hearts from patients with either idiopathic dilated cardiomyopathy (n = 21) or ischaemic heart disease (n = 14). The percentage was compared with the clinical severity and progression of endstage heart failure. Samples obtained at autopsy and during open heart surgery served as controls. RESULTS: The number of apoptotic cardiomyocytes was significantly increased in failing hearts regardless of aetiology (medians 0.075% in ischaemic heart disease and 0.119% in dilated cardiomyopathy) compared with control myocardium. In patients with dilated cardiomyopathy, apoptotic cardiomyocytes were more numerous in subjects with a rapidly deteriorating clinical course (0.192%, n = 10) than in patients with intermediate (0.093%, n = 6, P = 0.03) or slow (0.026%, n = 5, P = 0.003) progression. No such association was observed in patients with ischaemic heart disease, in whom we found significantly increased cardiomyocyte apoptosis adjacent to scars of previous infarctions (0.576%) in contrast to the diffuse distribution seen in dilated cardiomyopathy. Expression of Bcl-2, an antiapoptotic protein, was increased in all failing hearts by immunohistochemistry. CONCLUSION: Cardiomyocyte apoptosis is a consistent feature of end-stage heart failure in man and appears to be quantitatively related to the clinical severity of deterioration in dilated cardiomyopathy. Increased expression of Bcl-2 in cardiomyocytes indicates activation of an antiapoptotic response. These observations suggest that cardiomyocyte apoptosis is a clinically relevant and potentially modifiable pathophysiological phenomenon in severe heart failure.     

Serum neopterin, tumor necrosis factor-alpha and soluble tumor necrosis factor receptor II (p75) levels and disease activity in Egyptian female patients with systemic lupus erythematosus

OBJECTIVE: To determine the clinical value of assaying serum levels of neopterin, tumor necrosis factor-alpha (TNF-alpha) and soluble tumor necrosis factor receptor II (p75) (sTNFRII) in patients with systemic lupus erythematosus (SLE), manifested clinically with lupus nephritis (LN), neuropsychiatric lupus erythematosus (NPLE), and/or vasculitis compared with established parameters (complements C3 and C4). PATIENTS AND METHODS: Serum concentrations of neopterin, TNF-alpha and sTNFRII were studied in 40 female patients with SLE at various degrees of disease activity and in 10 healthy controls, matched for age and sex, using an ELISA kit. Disease activity was assessed by the SLE disease activity index (SLEDAI) score. Thirty-five, 30 and 28 of our patients presented with LN, NPLE and/or vasculitis, respectively, as the main clinical manifestation. RESULTS: Serum levels of neopterin, TNF-alpha and sTNFRII were significantly increased, while the TNF-alpha/sTNFRII ratio, C3 and C4 levels of SLE patients were significantly lower than those of healthy controls. Neopterin and sTNFRII were the only parameters that showed significantly higher levels in SLE patients with mild activity compared to normal subjects and were the only parameters that showed a significant elevation in membranous nephritis and in mild NPLE compared to patients without nephritis and NPLE. Patients with vasculitis had significant elevation of serum neopterin, TNF-alpha and sTNFRII levels compared to patients without vasculitis. We found significant correlations between all measured variables and the SLEDAI score. Also, serum neopterin levels showed significant positive correlation with serum TNF-alpha, sTNFRII and TNF-alpha/sTNFRII levels. Serum neopterin and sTNFRII could be used to identify SLE patients from normals with a sensitivity and specificity of 100%. Multivariate linear regression analysis showed that serum sTNFRII was the only significant independent variable among parameters for prediction of SLE disease activity. CONCLUSION: We suggest that serum sTNFRII and neopterin are more sensitive markers of disease activity than TNF-alpha, C3 or C4. However, sTNFRII may be a clinically useful independent marker for prediction of SLE disease activity and to differentiate normal subjects from those having mild SLE.     

Metabolic alterations in end-stage and less severe heart failure--myocardial carnitine decrease

Severe tissue carnitine deficiency impairs fatty acid oxidation. In explanted hearts from patients with end stage heart failure a 57% carnitine decrease was found in comparison with healthy donor hearts (p less than 0.05). The reduction of myocardial carnitine levels affected all areas of the explanted hearts to a comparable extent. Carnitine decreases in patients with dilated cardiomyopathy or coronary artery disease were similar. Endomyocardial biopsies from patients with less severe heart failure due to cardiomyopathy (n = 28) or other myocardial diseases (n = 8) showed a 42% decrease of total myocardial carnitine (in nmol/mg non-collagen protein) in comparison with biopsies from patients with normal cardiac function (controls) (heart failure: 5.7, confidence interval 4.2-7.0; controls 9.3, confidence interval 7.6-12.0, p less than 0.005). Free myocardial carnitine in heart failure was also different from controls (heart failure: 4.2, confidence interval 3.7-5.3; controls 10.3, confidence interval 7.5-12.2, p less than 0.001). The decrease of free and total myocardial carnitine was comparable in dilated cardiomyopathy and heart failure due to other diseases. Alterations in myocardial carnitine content represent therefore non-specific biochemical markers in heart failure with yet unknown consequences for myocardial function.     

影响老年充血性心力衰竭患者血清CA125的相关因素分析

目的 探讨老年冠心病慢性充血性心力衰竭(CHF)患者血清CA125水平与心功能等相关因素之间的关系.方法 测定178例老年冠心病CHF患者血清肿瘤标志物CA125、癌胚抗原(CEA)、甲胎蛋白(AFP)、CA199、CA15-3、CA724以及肝肾功能和N末端脑钠肽(NT-proBNP);超声心动图测定二尖瓣舒张早期E峰最大流速(Ve)、舒张晚期A峰最大流速(Va)、Ve/Va、左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)及左心室射血分数(LVEF)、左心室射血时间.所有患者根据NYHA分为Ⅰ+Ⅱ、Ⅲ、Ⅳ级3组;统计其胸腔积液、外周水肿、心房颤动的发生率.结果 (1)178例患者中血清CA125≤35 U/ml 91例,CA125中位数9.9(3.4～33.7)U/ml;＞35 U/ml 87例,中位数64.4(20.2～462.1)U/ml.CA125＞35 U/ml组NYHA心功能Ⅲ+Ⅳ级82例,Ⅰ+Ⅱ级5例;≤35 U/ml组Ⅲ+Ⅳ级7例,Ⅰ+Ⅱ级84例,组间心功能差异有统计学意义(x2=133.3,P＜0.001).CA125增高组胸腔积液、心房颤动、外周水肿的发生率高于CA125≤35 U/ml组[32.2%(28/87)、5.5%(5/91),51.7%(45/87)、9.9%(9/91),78.2%(68/87)、19.8%(18/91),P均＜0.01],NT-proBNP、LVESD、LVEF、左心室射血时间比较差异均有统计学意义[2524.0(104.0～19 308.0)、356.0(32.0～5201.1)ng/L,35(27～55)、32(26～53)mm,49%(23%～66%)、59%(42%～69%),268(210～312)、290(260～340)ms,P均＜0.05].(2)直线回归显示:血清CA125与血浆NT-proBNP、尿素氮呈正相关(r=0.3326、P=0.002,r=0.3430、P=0.002),与LVEF、左心室射血时间呈负相关(r=-0.3016、P=0.006,r=-0.3336、P=0.004).结论 老年冠心病CHF患者血清CA125随着心功能分级恶化而升高,并且与血浆NT-proBNP水平、LVEF、左心室射血时间以及有无胸腔积液、心房颤动、外周水肿等因素有关.

Abstract：

Objective To assess the association between serum levels of carbohydrate antigen 125 (CA125) and the heart function in the elderly with congestive heart failure (CHF). Methods CA125, carcinoembryonic antigen (CEA) ,alpha-fetoprotein ( AFP), CA199, CA15-3, CA724, liver and kidney function and NT-proBNP were measured in 178 patients with heart failure. Ve, Va, Ve/Va, left ventricular end-diastolic diamete ( LVEDD), left ventricular end-systolic diamete ( LVESD ), left ventricular ejection fraction ( LVEF ) and time were measured using echocardiograph. All patients were classified as Ⅰ + Ⅱ , Ⅲ and Ⅳ level according to the criteria of New York Heart Assocation ( NYHA), and the incidence of pleural effusion, peripheral edema,atrial fibrillation were observed. Results Among the 178 patients,serum CA125 were ≤35 U/ml in 91 patients with median of 9.9( 3.4 - 33.7 ) U/ml, ＞ 35 U/ml in 87 patients with median of 64. 4 ( 20. 2 - 462. 1 ) U/ml.Among those patients with CA125 ＞ 35 U/ml ,heart function was classified as level Ⅲ + Ⅳ in 82 patients,and level Ⅰ + Ⅱ in 5 patients. Among the patients with CA125 ≤35 U/ml,heart function was classified as level Ⅲ + Ⅳin 7 patients,and level Ⅰ + Ⅱ in 84 patients. Heart function was significantly different between the two CA125 groups( x2= 133. 3 ,P ＜0. 001 ). The incidence of pleural effusion,atrial fibrillation ,peripheral edema in the higher CA125 group were 32. 2%, 51.7% and 78. 2%, respectively, which were significantly higher than those in the normal CA 125 group ( 5.5 %, 9. 9% and 19. 8 %, repactively ) ( P ＜ 0. 01 ). NT-proBNP, LVESD,LVEF and time in the higher CA125 group were 2524. 0( 104.0 - 19 308. 0) ng/L,35 (27 -55) mm,49% (23%-66% ) and 268 (210 -312)ms, which were significantly differenct from those in the normal CA125 group [356.0 ( 32.0 - 5201.0) ng/L, 32 ( 26 - 53 ) mm, 59% ( 42% - 69% ) and 290 ( 260 - 340 ) ms, respectively](Ps ＜0. 05). The linear regression showed that serum CA125 was positively correlated with NT-ProBNP and urea nitrogen ( BUN ) ( r= 0. 3326 and 0. 3430, Ps= 0. 002 ) , as well as negtively correlated with LVEF and time (r= -0. 3016,P =0. 006;r = -0. 336,P =0. 004). Conclusion Serum CA125 in the elderly with congestive heart failure increased with the worsing of heart function, and correlated with the level of NT-proBNP, LVEF and time,as well as pleural effusion, atrial fibrillation, peripheral edema.     

Uric acid--a marker for systemic inflammatory response in patients with congestive heart failure?

Congestive heart failure is associated with hyperuricemia and elevations in the levels of circulating markers for inflammation. The purpose of this study was to assess the relationship between levels of serum uric acid, activity of the renin-angiotensin-aldosterone system and TNF-alpha in heart failure patients with respect to the extent of left ventricular dysfunction. Circulating uric acid, TNF-alpha, plasma renin activity and concentrations of aldosterone were measured in 30 patients with congestive heart failure, divided into subgroups according to their NYHA class (II-IV). We found a significant step-by-step increase in TNF-alpha among the subgroups. Significant differences among the subgroups were found for the values of uric acid and the values of plasma renin and aldosterone. Serum uric acid correlated significantly with TNF-alpha concentrations (r = 0.36, P < 0.05) leukocytes (r = 0.38, P = 0.03) and ejection fraction (r = 0.64, P < 0.01). No significant correlation was found between the activity of the renin-angiotensin-aldosterone system and uricemia (r = 0.34). In a multivariate model, uric acid concentration was predicted significantly by the ejection fraction and blood leukocytes, this relationship being independent of serum creatinine, treatment modality, age and gender. We conclude that serum uric acid may reflect the severity of systolic dysfunction and the activation of an inflammatory reaction in patients with congestive heart failure.     

Experimental studies on the influence of ouabain on ATP, calcium and magnesium in the failing human heart

Abstract. 1. ATP, Ca, Mg determinations from arterial and coronary-venous blood were carried out during routine cardiac catheterization. 2. 10 patients with chronic left heart failure and 10 patients with normal left ventricles were tested. An additional 10 patients with chronic left heart failure were tested only for ATP in arterial and coronary-venous blood. 3. The blood specimens were taken at rest and during physical exertion as well as before and after the administration of ouabain. 4. In coronary-venous blood of chronically failing human hearts ATP is increased during physical exertion (arterial = 0.756 μmol ATP/ml whole blood; coronary-venous = 0.796 μmol ATP/ml whole blood. p < 0.005). The results were reproduced in a second group of 10 patients with left heart failure (arterial = 0.654 μmol ATP/ml whole blood; coronary-venous = 0.693 μmol ATP/ml whole blood. p < 0.0005). 5. After the administration of ouabain this effect is no longer detectable in the same patients. 6. The chronically failing human myocardium absorbs essentially more Ca during physical exertion than the normal myocardium does (arterial = 107.4 μg/ml serum; coronary-vonous = 113.4 μ/ml serum. p < 0.0005). 7. In chronic heart failure there was no uptake of Ca after the administration of ouabain. 8. Differences in Mg uptake and release could not be determined in the failing human heart.     

Decreased serum lipoprotein levels as a guide for clinical severity in patients with idiopathic dilated cardiomyopathy

Hyperlipidemia is a cardiovascular risk factor. In patients with idiopathic dilated cardiomyopathy (IDC), prognostic roles of endogenous lipoproteins are not fully clarified. It has been known that there is a direct relationship between the levels of cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6 [IL-6]) and deteriorating functional classes of heart failure and mortality. The present study compared the levels of circulating TNF-alpha, IL-6, lipoproteins, and apolipoproteins in patients with stable IDC (n = 28) with those of patients with unstable IDC (n = 26) and controls (n = 24). Mean serum total cholesterol (TC) was significantly lower in stable IDC patients than controls (p < 0.05). In unstable IDC patients, mean serum TC was also lower than controls but not statistically significant. The IDC patients had significantly higher concentrations of IL-6 and TNF-alpha than the controls (p < 0.01). Serum IL-6 and Apo AI levels were significantly different between stable and unstable IDC patients (p = 0.021 and p = 0.012, respectively). Increased levels of IL-6 were associated with decreased levels of TC (r = -0.266, p = 0.019), LDL-C (r = -0.376, p = 0.001) and apolipoprotein AI (apo AI) (r = -0.495, p < 0.001) in all IDC patients. TNF-alpha was also inversely related to apo AI (r = -0.455, p < 0.001) and LDL-C (r = -0.364, p = 0.001) in all patients. Thus, elevated serum levels of cytokines in patients with IDC are associated with decreased lipoprotein concentrations, which may indicate impaired prognosis.     

Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart.

To elucidate the expression of the atrial natriuretic polypeptide (ANP) gene in the ventricle of the human failing heart, we have measured ANP and ANP messenger RNA (ANPmRNA) levels in left ventricular aneurysm obtained at operation, biopsy specimens of left ventricles from dilated cardiomyopathy (DCM) and autopsy samples of old myocardial infarction (OMI) and DCM hearts, and compared the levels with those in the normal ventricle. The ANP level (mean +/- SE) was 17.5 +/- 6.9 ng/g in the normal ventricle, and increased to 660.3 +/- 122.2 ng/g in the left ventricular aneurysm tissues and to 3,138.6 +/- 1,642.1 ng/g in the biopsy specimens of the DCM ventricle. These levels were approximately 40 and 200 times higher than in the normal ventricle. The increase of ANP levels was observed in both infarcted and noninfarcted regions of the OMI heart, and in the entire ventricle of the DCM heart. A significant positive correlation was found between the ANP level in aneurysm tissues and pulmonary capillary wedge pressure (r = 0.85). The ANPmRNA level in the left ventricular aneurysm showed about a 10-fold increase compared with that in the normal heart and reached 23% of that in the atrium of the same heart. A similar increase in the ANPmRNA level was observed in the entire ventricle of DCM. These data clearly indicate that the expression of the ANP gene in the ventricle is augmented in the failing heart in accordance with the severity of heart failure. In the atrium of the failing heart, ANP and ANPmRNA levels were only two times higher than those in the normal atrium. Thus, the augmentation in the expression of the ANP gene was more prominent in the ventricle than in the atrium. Taking tissue weight into account, the total content of ANPmRNA in the ventricle of the failing heart is much the same as that in the normal atrium. The ratio of the ANP level to the ANPmRNA level in the ventricle is much smaller than that in the atrium. These results suggest more rapid secretion of ANP after synthesis in the ventricle. These findings demonstrate that the expression of the ANP gene is augmented in the human ventricle of the failing heart and suggest that the ventricle becomes a substantial source of circulating ANP in congestive heart failure.     

Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure

Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS)     

Therapeutic plasma exchange a potential strategy for patients with advanced heart failure

Background: Previous reports had emphasized the importance of humoral immunity in heart failure in humans, primarily determined by the presence of circulating antibodies. However, there is little or no information about the frequency of anticardiac antibodies present in failing human myocardium. Methods: Clinical data and myocardial tissue samples were analyzed to determine the role of humoral immunity in patients with chronic heart failure (CHF) in different settings. Results: Anticardiac antibodies were found present in failing hearts but not in normal control hearts. Further, the level of expression of these anticardiac antibodies changed with the severity of the disease state; and in patients with acute heart failure, we found selective activation of B cells. Finally, treatment of CHF patients with therapeutic plasma exchange, a strategy that removes circulating antibodies, resulted in a reduction in anticardiac antibody deposition and improvements in cardiac function. Conclusion: These data collectively suggest a role of humoral immunity in the progression of heart failure. J. Clin. Apheresis, 2010. © 2010 Wiley‐Liss, Inc.     

骨髓增生异常综合征患者T细胞异常极化导致的负性造血调控

目的研究骨髓增生异常综合征（MDS）患者骨髓T细胞极化状况及其与骨髓上清液中促凋亡因子TNF—α、INF-γ水平及造血细胞凋亡的关系。方法采用流式细胞术检测34例MDS患者骨髓T细胞极化亚群状况，用ELISA法检测骨髓上清液TNF—α、INF-γ水平，并用TdT介导的dUTP缺口末端标记法（TUNEL）检测骨髓造血细胞凋亡状况，分析三者间的相关性。结果①MDS患者骨髓，Th1细胞百分比[（10．1±1．6）％]和Tc1细胞百分比[（24．0±3．6）％]以及Tc1／Tc2值（50．0±11．1）明显高于正常对照[分别为（4．0±0．5）％，（5．8±0．6）％和13．4±2．7]；MDS患者骨髓上清液INF．1浓度[（58．6±21．7）μg／L]和TNF—α浓度[（15．7±3．8）μg／L]较正常对照[分别为0和（0．3±0．2）μg／L]明显升高；MDS患者骨髓造血细胞凋亡指数[（7．8±1．5）％]明显高于正常对照[（2．1±0．3）％，P〈0．05]。骨髓Th1细胞数与骨髓上清液INF-γ和TNF—α浓度呈正相关（r值分别为0．38和0．39，P〈0．05），并与造血细胞凋亡指数呈正相关（r=0．33，P〈0．05）。骨髓上清液INF-γ，和TNF—α浓度与造血细胞凋亡也呈正相关（r值分别为0．74和0．73，P〈0．01）。②难治性血细胞减少伴多系发育异常（RCMD）组（18例）Th1、Tc1细胞百分比，Tc1／Tc2值较正常对照明显升高（P值均〈0．01），T细胞向Ⅰ型反应极化；RCMD伴环形铁粒幼细胞增多（RCMD—RS）（4例）、RAEB—1（5例）、RAEB-2组（7例）T细胞未显示异常极化。③IPSS低危组病例Th1细胞百分比、Tc1细胞百分比及Tc1／Tc2值均较正常升高，而高危组T细胞未见异常极化。④染色体核型正常的RCMD患者骨髓Th1细胞百分比、Tc1细胞百分比及Tc1／Tc2值均较正常对照明显升高。而核型异常组T细胞未见异常极化。结论MDS患者骨髓中Th1、Tc1细胞比例增高，Th1／Th2、Tc1／Tc2平衡向Ⅰ型反应极化，其中以RCMD组、IPSS低危组和染色体核型正常组患者的T细胞I型反应极化明显。骨髓造血细胞过度凋亡与Th1细胞以及INF-γ和TNF—α水平呈正相关，提示Th1细胞通过分泌INF-γ和TNF-α导致造血细胞过度凋亡。     

急性脑损伤后血儿茶酚胺与血糖浓度变化及其意义

测定４８例急性重型脑外伤患者伤后７天内血儿茶酚胺（ＣＡ）及伤后６小时内血糖含量，并与３５例正常人血ＣＡ含量值作对照。结果表明：外伤组血ＣＡ含量显著高于对照组；伤后７天内血去甲肾上腺素（ＮＥ）、肾上腺素（Ｅ）含量及其变化与格拉斯哥昏迷评分（ＧＣＳ）和预后均密切相关；入院时病情越重，ＧＣＳ评分越低，血ＮＥ、Ｅ含量越高；死亡组患者血ＮＥ、Ｅ含量明显高于存活组（Ｐ均＜０．０５），其与伤后２４小时内血ＮＥ、Ｅ含量分别显著正相关（ｒ＝０．５７４，Ｐ＜０．０５和ｒ＝０．４１０，Ｐ＜０．０５），而与ＧＣＳ和预后分别显著负相关（ｒ＝０．７８１，Ｐ＜０．０１和ｒ＝０．７０８，Ｐ＜０．０１）。     

应激性高糖血症与胰岛素抵抗的相关因素研究

目的探讨危重病应激状态与高糖血症相关的发病环节及致病因素。方法采用放射免疫分析或双抗体夹心酶联免疫吸附法测定47例应激性高糖血症(SHG)危重患者和15名正常人的血糖(BG)、胰岛素(INS)、C-肽(C-P)、胰高血糖素(Gluc)、生长激素释放抑制因子(SS)、皮质醇(Cor)、肿瘤坏死因子-α(TNF-α)、人可溶性TNF受体(sTNFR)和sTNFR,并计算胰岛素敏感指数(ISI)。结果147例SHG患者中存活36例,死亡11例;入重症监护室(ICU)24h内的急性生理学与慢性健康状况评分系统(A-PACHE)为(13.89±6.29)分,住ICU时间为(5.5±6.3)d,机械通气(MV)时间为(51.49±66.01)h。2SHG组的各项检测结果均明显高于正常对照组,除SS外,余各指标差异均有显著性(P<0.05或P<0.01)。3随着BG增高,反映胰腺β细胞功能的C-P浓度增高,ISI越差。4对不同APACHE评分分组比较显示,BG并不随病情危重程度的增加而升高,但MV时间、Cor、Gluc、SS、TNF-α、sTNFR和sTNFR均随病情的危重程度而增加,差异均有显著性。5SHG对MV时间的影响差异有显著性(F=10.438,P<0.01),而对年龄、预后、住ICU时间的影响差异均无显著性。6应激状态下影响BG升高的主要相关因素为:INS(r=0.674,P<0.01),C-P(r=0.552,P<0.01),ISI(r=-0.787,P<0.01),APACHE(r=0.267,P<0.05),sTNFR(r=0.465,P<0.01)。结论SHG的主要发病环节是胰岛素抵抗。受体前急性应激激素与SHG的调节关系不明确;sTNFR对SHG有介导作用,而TNF-α、sTNFR过度释放与SHG病情程度有关。BG水平与MV时间有关,与年龄、预后和住ICU时间无关。探讨治疗和预防SHG策略的重点应放在组织对BG的利用障碍方面,提高和增强组织对INS的敏感性。     

Synthesis of atrial natriuretic polypeptide in human failing hearts. Evidence for altered processing of atrial natriuretic polypeptide precursor and augmented synthesis of beta-human ANP

To elucidate the synthesis of atrial natriuretic polypeptide (ANP) in the failing heart, 20 human right auricles obtained at cardiovascular surgery were studied. The concentration of alpha-human ANP-like immunoreactivity (alpha-hANP-LI) in human right auricles ranged from 13.8 to 593.5 micrograms/g, and the tissue alpha-hANP-LI concentration in severe congestive heart failure (CHF) (New York Heart Association [NYHA] functional class III and class IV) (235.4 +/- 57.2 micrograms/g) was much higher than that in mild CHF (NYHA class I and class II) (52.5 +/- 15.6 micrograms/g). Atrial alpha-hANP-LI levels were significantly correlated with plasma concentrations of alpha-hANP-LI in these patients (r = 0.84, P less than 0.01). High performance gel permeation chromatography and reverse phase high performance liquid chromatography coupled with radioimmunoassay for ANP revealed that the alpha-hANP-LI in the human auricle consisted of three major components of ANP, gamma-human ANP (gamma-hANP), beta-human ANP (beta-hANP) and alpha-human ANP (alpha-hANP). Comparing percentages of gamma-hANP, beta-hANP, and alpha-hANP in alpha-hANP-LI in severe CHF with those in mild CHF, the predominant component of alpha-hANP-LI was gamma-hANP in mild CHF, whereas beta-hANP and/or alpha-hANP were prevailing in severe CHF and, especially, beta-hANP was markedly increased in human failing hearts. These results demonstrate that the total ANP concentration in the atrium of the human heart is increased in severe CHF and that the increase of ANP in the human failing heart is mainly due to the increase of small molecular weight forms of ANP, beta-hANP, and alpha-hANP, especially beta-hANP, and indicate that the processing of ANP precursor, or gamma-hANP, in the human failing heart differs from that in the normal heart, suggesting that the failing heart augments synthesis and secretion of ANP as one of its own compensatory responses.     

Defective lipid metabolism in the failing heart

The metabolism of long chain fatty acids was investigated in the failing heart of guinea pigs with chronic constriction of the ascending aorta. Homogenates prepared form failing hearts exhibited (a) a decreased capacity to oxidize palmitic acid (failure = 0.50 +/- 0.06 mumole/g of protein per 20 min; control = 1.09 +/- 0.10); (b) a reduced level of carnitine, a myocardial constituent which serves to control the oxidation rate of long chain fatty acids in the heart (failure = 0.91 +/- 0.10 mumole/g wet weight; control = 1.69 +/- 0.10); and (c) an increased rate of palmitate incorporation into triglycerides and lecithin. Exogenous carnitine effected a restoration of the defective palmitate metabolism of the homogenates towards normal. In contrast to long chain fatty acid oxidation, glucose oxidation by the failing heart was not impaired. As a consequence of this selective lesion in energy substrate utilization, the failing heart might be forced to rely on substrates other than long chain fatty acids for its major energy supply.     

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.     

肾功能与N末端B型钠尿肽原的关系及其在慢性心力衰竭诊断中的应用

目的通过观察人血清预测肾小球滤过率(eGFR)与N末端B型钠尿肽原(NT-proBNP)之间的关系,比较慢性心力衰竭(简称心衰)患者不同eGFR水平NT-proBNP的诊断界值(cut-off值),研究肾功能对NT-proBNP应用于心衰诊断的影响。方法选择我院2003年10月至2004年4月明确诊断为心衰的住院患者106例(心衰组)以及同期正常对照191名(对照组)。采用电化学发光法测定受试者血清NT-proBNP浓度,应用Levey改良的饮食校正公式计算eGFR。结果肾功能异常者[eGFR<60ml·(min·1·73m2)-1]的NT-proBNP中位数水平显著高于肾功能正常者[eGFR≥60ml·(min·1·73m2)-1],无论是在心衰组(829·1ng/Lvs·227·2ng/L,P<0·01)还是对照组(85·5ng/Lvs·50·4ng/L,P<0·01)。将NT-proBNP与eGFR进行对数转换后,二者呈负相关(心衰组r=-0·271,P<0·01;对照组r=-0·353,P<0·01)。NT-proBNP诊断肾功能正常心衰患者的cut-off值为162·3ng/L,敏感度为68·3%,特异度为98·1%,阳性预测值(PPV)为94·9%,阴性预测值为(NPV)85·3%,AUC为0·901;而诊断肾功能异常心衰患者的cut-off值明显升高,为238·8ng/L,敏感度为70·8%,特异度为100%,PPV为100%,NPV为84·1%,AUC为0·863。结论肾功能与NT-proBNP呈微弱相关,肾功能异常时NT-proBNP诊断心衰的cut-off值升高,可以作为合并肾功能不全心衰的诊断指标。     

Tumor necrosis factor-alpha and kidney damage in rheumatoid arthritis

AIM: To investigate clinical significance of tumor necrosis factor-alpha (TNF-alpha) and kidney damage in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: 94 patients (84 women and 10 men, mean age 45.2 +/- 11.9 years and the disease duration 7.5 +/- 6.5 years) with RA and 20 donors were examined. In 37(39.4%) and 57(60.6%) patients radiological stages I-II and III-IV, respectively, were determined. TNF-alpha and C-reactive protein (CRP) were measured by ELISA. RESULTS: Serum levels of TNF-alpha in patients with RA appeared significantly higher than in donors (10.9 +/- 22.1 pg/ml vs 0.6 +/- 2.0 pg/ml, p < 0.001). 33 (35.1%) of 94 patients had TNF-alpha levels above 6.6 pg/ml. High serum levels of TNF-alpha correlated significantly with the presence of nephrotic syndrome (r = 0.22, p = 0.03) caused by secondary amyloidosis. There were no correlations between high levels of TNF-alpha and sex, age, disease duration, stages and clinical activity in patients with RA. Positive correlation was found between high levels of TNF-alpha and ESR (r = 0.30, p = 0.003), CRP (r = 0.37, p = 0.0001). CONCLUSION: Thus, TNF-alpha may be involved in pathogenesis of amyloidosis in RA.     

Fenofibrate reduces tumor necrosis factor-alpha serum concentration and adipocyte secretion of hypercholesterolemic rabbits

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is produced by cells of the macrophage-monocyte lineage and by adipocytes. It may provide the link between inflammation and atherosclerosis. The aim of this study was to evaluate the effect of fenofibrate on serum TNF-alpha concentration and TNF-alpha secretion by adipocytes from hypercholesterolemic rabbits. METHODS: Ten male New Zealand white rabbits were fed with high-cholesterol diet for 8 weeks, and were randomly divided into two groups: (1) high cholesterol group: maintained cholesterol diet for 4 weeks; and (2) fenofibrate treated group: the same cholesterol diet supplemented with fenofibrate (30 mg/kg/day) for 4 weeks. Control group was fed with normal diet for 12 weeks. Subcutaneous adipose was collected for adipocytes culture. TNF-alpha concentrations in serum and adipocytes culture supernatant were measured by ELISA. RESULTS: Rabbits fed with high-cholesterol diet showed higher serum levels of total cholesterol, low density lipoprotein cholesterol than those fed with normal diet (P<0.001). Fenofibrate treatment did not change serum lipid levels during the feeding period, but decreased high cholesterol diet-induced increases in body weight by 19% and serum TNF-alpha concentration by 44.7% in fenofibrate treated group compared with high cholesterol group (P<0.05). The decreased levels of TNF-alpha correlated with the weight loss (r=0.35, P<0.05). Fenofibrate (10 to 100 micromol/l) significantly reduced release of TNF-alpha in adipocytes (P<0.05). Meanwhile serum TNF-alpha concentration were significantly correlated with TNF-alpha secretion in adipocytes (r=0.51, P<0.05). CONCLUSIONS: Our study indicated that fenofibrate reduced tumor necrosis factor-alpha serum concentration and adipocyte secretion of hypercholesterolemic rabbits. This effect of fenofibrate might contribute to its benefits on the prevention and treatment of atherosclerosis.     

Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy

BACKGROUND: Impaired energy metabolism in the failing human heart could be an important mechanism of functional deterioration. The purpose of this study was to assess the changes of myocardial energy metabolism in the human heart at end-stage heart failure. MATERIALS AND METHODS: The left ventricular myocardium of patients undergoing heart transplantation due to dilated (DCM, n = 14) or hypertrophic cardiomyopathy (HCM, n = 5) and non-diseased donor heart samples (n = 4) were analysed for citrate synthase (CS), enzymes of the glycolytic pathway as well as concentrations of phosphocreatine (PCr), creatine (Cr), adenine and guanine nucleotides. RESULTS: Total creatine levels (phosphocreatine + creatine) were significantly decreased (P < 0.05) in both groups of diseased hearts (3.87 +/- 0.57 in DCM, 5.09 +/- 1.23 in HCM compared with control 10. 7 +/- 3.5 micromol g-1 wet weight). There was a trend for higher guanine nucleotide content in failing hearts, but no significant differences were observed in total adenine nucleotides and total NAD content. CS was markedly reduced (P < 0.05) in both groups of diseased hearts: in the DCM to 13.8 +/- 1.3 micromol min-1 g-1 wet weight, and in HCM to 11.9 +/- 2.4 compared with the control 29.2 +/- 2.2. Glycolytic enzymes were decreased compared with the control, and this decrease was greater in DCM than in HCM. Echocardiographic indices of contractility were considerably better in hypertrophic cardiomyopathy. CONCLUSION: Despite the different mechanisms of cardiac failure and the differences in contractility of the heart we have observed, metabolic changes are very similar in hypertrophic and dilated cardiomyopathy. Depletion of the creatine pool suggests an alteration in the intracellular energy reserves and transfer, whereas the decrease in citrate synthase activity suggests reduced oxidative capacity in both dilated and hypertrophic cardiomyopathy.