摘要
目的首先对顽固性感染性休克病人相关心功能不全进行临床及血流动力学研究,之后评价不同的心功能指标尤其应力和应变关系在犬内毒素性休克心功能不全时的作用,其次研究心肌解偶连蛋白(UCP2)在内毒素休克犬心功能不全发病机制中的作用
方法回顾性调查北京协和医院加强医疗科(ICU)收治的放置肺动脉导管的顽固性感染性休克70例,根据目标指导治疗指标(GDT)达标情况分达标组和不达标组;两组中分别根据28天生存状态分死亡组和存活组。记录血流动力学指标、APACHEⅡ评分、动脉乳酸(Lac)、24小时乳酸清除率(Clac%)和诊断后第28天生存状况,结果用统计学软件分析。之后应用经肺动脉导管缓慢推注2mg/kg大肠杆菌内毒素建立杂犬内毒素休克模型,随机分两组,A组(n=6)—对照组(观察6小时)和B组(n=7)—内毒素休克(观察6小时)组。联合应用肺动脉导管技术(PAC)和脉搏指示剂持续心排量(PICCO)监测系统测量血流动力学指标;同时应用经食道心脏超声(TEE)及组织多普勒等技术测量,以LAPLACE公式为核心的临床应用公式计算心室壁应力,均为连续监测同时每小时记录结果,每2时检测静脉心肌损伤的生化指标。将心功能指标分三个层次,着重以心室壁应力和应变以及应力和应变关系为主的指标评价心脏功能。其次,将杂犬26只随机分为4组,A组(n=6)—对照组;B2组(n=6)--休克2小时组,2小时高动力状态组;B4组(n=6)--休克4小时组,4小时心功能不全组;B6组(n=7)--休克6小时组,6小时失代偿的心功能不全组,建立内毒素性休克不同阶段心功能不全模型,亦联合应用肺动脉导管技术和PICCO监测系统并应用心脏超声进行血流动力学综合评估,每组规定时间末处死动物并取心脏标本。对心肌标本应用高效液相色谱法(HPLC)检测心肌能量代谢并进行UCP2的免疫荧光、western—blotting、RT-PCR检测。结合第二部分进一步分析UCP2与心功能的关系。
结果(1)临床研究中顽固性感染性休克病人37%不达标,死亡率65%,达标组56%;不达标组年龄大于对照组,中心静脉压(CVP)、肺动脉阻塞压(PAOP/PAWP)、肺动脉压(PAP)、体循环阻力指数(SVRI)、肺循环阻力指数(PVRI)、氧摄取率(O2ext)明显高于对照组,差异具有统计学意义;心输出量(CO)、心脏指数(CI)、氧输送(DO2I)、混合静脉血氧饱和度(SVO2)明显低于达标组,差异具有统计学意义;SVO2与CI具有明显的相关性,r=0.680,P=0.000;CI和DO2I相关性好,r=0.859.P=0.000;在达标组的病人中,乳酸(Lac),ApacheⅡ、心率(HR)在死亡组高于存活组;24小时乳酸清除率(Clac%)死亡组低于存活组,差异有统计学意义(P＜0.05);在不达标组病人中,ApacheⅡ在死亡组高于存活组(P＜0.01);Clac%和氧消耗(VO2I)死亡组低于存活组,差异有统计学意义(P＜0.05)。(2)从整体心脏功能到心肌功能分析,与对照组比,CO和每搏输出量(SV)在6小时后才有差异,射血分数(EF)等在5小时时有差异,平均圆周纤维缩短速度(mVCF)在4小时有差异,心肌收缩速度(Sm)4小时有差异,应变率(SR)在4小时有差异,结合应力与应变部分,包括SR指标在3小时有差异而mVCF/心率纠正的mVCF(RVCF)在4小时有差异。在内毒素休克平均动脉压及SVR低时,每分收缩期应力总量没有明显下降,心率与射血时间是代偿CO的主要因素,但心率的增加与射血时间不变会增加左室收缩期应力总量,早期SV的维持与收缩期应力下降有关;有关生化指标的研究:心肌型肌酸激酶同功酶(CKMB)在B组可以看到明显上升的趋势,但与A组比,各时间点总体平均值均无统计学差异P＞0.05。心肌肌钙蛋白Ⅰ(cTnⅠ)在B组可以看到明显上升的趋势,与A组比,2,4,6时间点及两组总体平均值均有差异P＜0.05。心肌氮末端脑钠素前体(NTproBNP)在B组可以看到明显上升的趋势,与A组比,2,6时间点及两组总体平均值均有差异P＜0.05。相关性分析发现:在B组CKMB与CO,SV,EF,mVCF,Sm,SR等均没有明显相关性。cTnI与CO,SV比较均没有相关性,但与EF呈负相关,而与mVCF,Sm,SR等有明显负相关性。NTproBNP与CO,SV,EF比较均没有相关性,但与mVCF,Sm,SR有明显负相关性见表。与各种力学指标的相关分析:与CVP,全心舒张末容积(GEDV),左室舒张末容积(LVEDV)无相关性,与收缩期径向心室壁应力(WSsm)和环周向心室壁应力(WSsc)没有任何相关性,仅与PAWP有一般相关性,r=0.468.P=0.033。(3)心肌能量代谢研究的结果提示腺苷二磷酸(ADP)有增加趋势,各组比较无统计学差异;三磷酸腺苷(ATP)减少趋势,各组比较也无统计学差异:磷酸肌酸(PCr)有下降趋势,ATP/ADP比值下降趋势有增加,无统计学差异;PCr/ATP有明显下降趋势,第6小时与对照组相比有差异。有关UCP2的研究结果为:UCP2的组织免疫荧光定位,定性结果提示UCP2存在于细胞浆中,同时与对照组单纯手术组)相比,第4,6小时的表达明显增强。Western blotting的结果提示:UCP2蛋白的表达从2小时即开始有增加,而4,6小时时明显增加。而与之相比UCP2信使核糖核酸(UCP2mRNA)的表达有增加趋势,仅4,6小时组与对照比更为明显。结合上部分分析本部分研究结果时,最早在3小时时发现了内在心肌的收缩功能异常,而UCP2的表达异常,无论蛋白水平还是转录水平,均在2小时时已经有了异常。与普通心脏收缩功能指标或心脏泵血功能指标发现心功能异常的时间相比,UCP2的表达异常更早。相关性分析发现,UCP2的蛋白水平与各个层次的心功能指标比负相关趋势明显,没有统计学差异,心肌的内在机能指标,包括Sm和sR与UCP2mRNA的负相关性非常明显,有统计学差异。UCP2的蛋白水平及转录水平均与心肌能量合成水平呈负相关。
结论顽固性感染性性休克在复苏过程中,心功能不全是目标指导治疗不达标的主要原因,并且可能是死亡率居高不下的原因;感染性休克时,应力与应变及两者关系可以早期发现心肌收缩性下降同时,提示尽管外周阻力低下而心肌本身应力总量是没有下降的,会进一步造成心肌功能的损害;感染性休克时心肌的能量合成是低下的,UCP2的表达增强早于心肌收缩功能异常,且与能量物质合成及心肌功能呈负相关,因此本研究期望有助于临床实现早期发现和合理治疗,以减低感染性休克死亡率。
Objective To research and analysis the clinical and hemodynamic status of refractory septic shock associated cardiac dysfunction,then to assess the role of different administrative level parameters of cardiac function in evaluating the endotoxic shock induced cardiac dysfunction,especially the role of relationship between the stress and strain;furthermore,to research the role of UCP2 in the mechanism of endotoxic shock induced cardiac dysfunction.Methods(1)70 refractory septic shock patients were studied.In the duration of hemodynamic optimization,the patients were divided into observation group who achieved the goals(CVP≥8mmHg,MAP≥65mmHg and SvO2≥65%)of goal-directed therapy(GDT)and controll group who had not achieved the goals.Every patient was placed a pulmonary artery catheter.Before it and 24hours later, hemodynamic parameters,lactate concentration and APACHEⅡscores were obtained.All the abtained values were analysised by statistics method.(2) 15 pentobarbital anesthetized and mechanically ventilated mongrel dogs were randomize divided into 2 groups:(A group) no injection of LPS(control group,n=6) and(B group) with LPS injection(n=7);Every dog was placed a pulmonary artery catheter and a Picco system. A single bolus injection of LPS(2mg/kg) through pulmonary aterial lumen of PAC was adopted to make endotoxic shock model.Hemodynamic parameters、transesophageal echocardiographic and Tissue Doppler Image(TDI)data are recorded every hour in the 6-hours duration of research.All the abtained values were analysised by statistics mcthod.(3) 26 pentobarbital anesthetized and mechanically ventilated mongrel dogs were randomize divided into 4 groups:(A group) no injection of LPS(control group,n=6); (B2group) 2 hours after LPS injection(n=6);(B4group) 4 hours after LPS injection (n=6);and(B6group) 6 hours after LPS injection(n=7).A single bolus injection of LPS(2mg/kg) through pulmonary aterial lumen of PAC was adopted to make endotoxic shock model.Hemodynamic parameters,transesophageal echocardiographic and Tissue Doppler Image(TDI)data are recorded to evaluate the cardiac function and myocardial function in the duration of research.Myocardial samples of every group are incised and studied by HPLC、western blots and RT-PCR.Results(1) 37%refractory septic shock patients had not acheived the goals of EGT.Age of observation group patients is significantly higher than patients of control group;CVP、PAOP、PAP、SVRI、PVRI、O2ext in observation group were significantly different from those in control group,CO、CI、D02I、SVO2 were significantly lower than patients of control group,SVO2 had a strong correlation with CI.If patients were regrouped by nonsurvivors and survivors,in patients complicated with cardiac dysfunction(observation group),ApacheⅡscores of nonsurvivors were significantly higher than survivors;Clac%(median 22%) of nonsurvivors were significantly lower than survivors(median -25%),P＜0.05.(2)CO、SV in endotoxic shock group were significantly different from those in control group at 6 hour,EF in endotoxic shock group were significantly different from those in control group at 5 hour,mVCF、Sm、SR in endotoxic shock group were significantly different from those in control group at 4 hour,the stress-strain characteristics of left ventricular myocardium in endotoxic shock group were significantly different from those in control group at 3 hour;cTnI have an negative corelation with EF and an strong correlation with mVCF、Sm and SR,NTproBNP have an negative an strong correlation with mVCF、Sm、SR and have an correlation with PAWP.(3) In endotoxic shock dogs,myocardial ATP,PCr are decreased and ADP are increase,ATP/ADP are decreased,PCr/ATP are decreased significantly; UCP2 expression are increased and UCP2 proteins are increased too;both are increased before the onset of myocardial dysfunction.Conclusion(1) In refractory septic shock patients,cardiac dysfunction was the main reason of not achieving the goals of GDT and maybe the reason leading to the bad outcome.Higher CVP and PAOP and lower SVO2 indicate the onset of cardiac dysfunction.The patients with significantly higher initial Lac and lower Clac%had bad outcome.(2) The different administrative level parameters of cardiac function,especially the stress and strain relation play a important role in evaluating and early discovering the endotoxic shock induced cardiac dysfunction,some cardiac biochemical marker:cTnI and BNP have a promising role to discover the endotoxie shock induced cardiac dysfunction(3) UCP2 have important impact in the mechanism of endotoxic shock induced cardiac dysfunction,UCP2 are increased before the onset of myocardial dysfunction.
引文
1.Annane D,Aegerter P,Jars-Guincestre MC,et al.Current epidemiology of septic shock:The CUB-Rea Network.Am J of Respir Crit Care Med,2003,168(2):165-172.
2.Angus DC,Linde-Zwirble WT,Lidicker J,et al.Epidemiology of severe sepsis in the United States:analysis of incidence,outcome,and associated costs of care.Crit Care Med,2001,29:1303-1310.
3.Moss M.The Epidemiology of Sepsis in the United States from 1979through 2000.N Engl J Med,2003,348:1546-1554
4. Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock. Crit Care Clin,2000,16:251-287,
5. Levy RJ, Deutschman CS. Evaluating myocardial depression in sepsis. Shock, 2004,22:lY10.
6. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med, 2001, 345:1368-1377.
7. Rabuel C, Mebazaa A. Septic shock: a heart story since the 1960s Intensive Care Med, 2006,32:799-807
8. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med, 1992, 20(6): 864-874.
9. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005, 365(1): 63-78.
10. Vincent JL, Gris P, Coffernils M, et al. Myocardial depression characterizes the fatal course of sepsic shock. Surgery 1992,111:660-667
11. Dellinger RP. Cardiovascular management of septic shock. Crit Care Med, 2003, 31(3):946-955
12. Levy MM, Fink MP, Marshall JC, et al. SCCM/ESICM/ACCP/ATS/SIS2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med, 2003,31:1250-1256
13. Leonardo D, Gregg C, et al. Acute heart failure syndrome: clinical scenarios and pathophysiologic target for therapy. Heart Fail Rev, 2007,12:97-104
14. William T, Patrick M. The pulmonary artery catheter in critical care. Seminars in Dialysis, 2006,19:480-491
(1) Angus DC,Walter T,Jeffrey Lidicker,et al.Epidemiology of severe sepsis in the United States:Analysis of incidence,outcome,and associated costs of care.Critical Care Medicine,2001,29:1303-1310
(2) Moss M.The Epidemiology of Sepsis in the United States from 1979 through 2000.N Engl J Med,2003,348:1546-1554
(3)Dombrovskiy VY,Martin AA,Sunderram J,Paz HL.Rapid increase in hospitalization and mortality rates for severe sepsis in the United States:a trend analysis from 1993 to 2003.Crit Care Med,2007,35(5):1244-50.
(4)Bφyum A,Tennfjord VA,Gran C,et al.Bioactive cytidine deaminase,an inhibitor of granulocyte-macrophage colony-forming cells,is massively released in fulminant meningococcal sepsis.J Infect Dis,2000,182(6):1784-7.
(5) Vincent JL,Gris P,Coffemils M,et al.Myocardial depression characterizes the fatal course of septic shock.Surgery,1992,111:660-667
(6) Parrillo JE,Parker MM,Natanson C,et al.Septic shock in humans.Advances in the understanding of pathogenesis,cardiovascular dysfunction,and therapy.Ann Intern Med,1990,113,227-242.
(7) Levy RJ,Deutschman CS.Evaluating myocardial depression in sepsis.Shock,2004,22:1-10.
(8) Rabuel C,Mebazaa A.Septic shock:a heart story since the 1960s Intensive Care Med,2006,32:799-807
(9) MacLean LD,Mulligan WG,McLean AP,et al.Patterns of septic shock in man-a detailed study of 56 patients.Ann Surg,1967,166(4):543-62
(10) Wilson RF,Thal AP,Kindling PH,et al. Hemodynamic measurements in septic shock. Arch Surg, 1965,91:121-129.
(11) Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock. Crit Care Clin,2000,16:251-287.
(12) Packman MI, Rackow EC: Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic shock. Crit Care Med,1983, 11:165-169.
(13) Serial cardiovascular variables in survivors and non-survivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med, 1987,15:923-929.
(14) Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med, 1984, 100:483-490.
(15) Raper RF, Sibbald WJ, Driedger AA, et al. Relative myocardial depression in normotensive sepsis. J Crit Care, 1989,4:9-18.
(16)Ognibene FP, Parker MM, Natanson C, et al. Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest, 1988,93:903-910
(17) Jones AE, Craddock PA, Tayal VS, et al. Diagnostic accuracy of left ventricular function for identifying sepsis among emergency department patients with nontraumatic symptomatic undifferentiated hypotension. Shock, 2005, 24:513-517
(18) Jardin F, Fourme T, Page B, et al. Persistent preload defect in severe sepsis despite fluid loading: A longitudinal echocardiographic study in patients with septic shock. Chest, 1999, 116:1354-1359
(19)Charpentier J, Luyt C-E, Fulla Y, et al. Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med, 2004, 32:660-665
(20)Curtis JP, Sokol SI, Wang Y, et al. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol, 2003, 42:736-742
(21) Wang TJ, Evans JC, Benjamin EJ, et al. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation, 2003, 108:977-982
(22) Dittoe N, Stultz D, Schwartz BP, et al.Quantitative left ventricular systolic function: from chamber to myocardium. Crit Care Med, 2007, 35(8 Suppl):S330-9.
(23) Arts T, Bovendeerd PH, Prinzen FW,et al.Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall.Biophys J,1991,59(1):93-102.
(24) 王鸿儒,文宗曜:血液循环力学[M]1北京:北京医科大学、中国协和医科大学联合出版社,1983:59-78
(25) Yuanzhen Feng,Biomechanics,1.st.ed.Science Press,Peking,1983
(26) Brodie BR,Melaurin L P,Grossman W.Combined hemodynamic Ultrasonic method for studing left ventricular wall stress[J].Am J Cardiol,1976,37(6):8642870.
(27) Quinones MA,Mokotoff DM,Nouri S,et al.Noninvasive quantification of left ventricular wall stress:Validation of method and application to assessment of chronic pressure overload[J].AmJ Cardiol,1980,45(4):7822790.
(28)Gilman G,Khandheria BK,Hagen ME,et al.Strain rate and strain:A step-by-step approach in image and data acquisition.J Am Soc Echocardiogr,2004,17:1011-1020
(29)Hoffmann R,Altiok E,Nowark,et al.Strain rate measurements by Doppler echocardiography allows improved assessment of myocardial viability in patients with depressed left ventricular function.J Am Coll Cardiol,2002,39:443-449
(30)Greenberg NL,Firstenberg MS,Castro PL,et al.Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility.Circulation,2002,105(1):99-105.
(31)Wang M,Yip GW,Wang AY,et al.Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value.J Am Coll Cardiol,2003,41:820-826
(32)Ashford Jr MW,Liu W,Lin SJ,et al.Occult Cardiac Contractile Dysfunction in Dystrophin-Deficient Children Revealed by Cardiac Magnetic Resonance Strain Imaging.Circulation,2005,112(16):2462-2467.
(33) Nagueh SF:Tissue Doppler imaging for the pre-clinical diagnosis of cardiomyopathy Eur.Heart J,2004,25(21):1865-1866.
(34) Neilan TG,Jassal DS,Perez-Sanz TM,et al.Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury.Eur.Heart J,2006,27(15):1868-1875.
(35) Varpula M,Pulkki K,Karlsson S,FINNSEPSIS Study Group.Predictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock.Crit Care Med,2007,35(5):1277-83.
(36) Metha NJ,Khan IA,Gupta V,et al.Cardiac troponin predicts myocardial dysfunction and adverse outcome in septic shock.Int J Cardiol,2004,95:13-17
(37) Maeder M,Fehr T,Rickli H,Ammann P.et al.Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic peptides. Chest, 2006,129(5): 1349-66.
(38) Cunha-Goncalves D, Perez-de-Sa V, Dahm P, Grins E, et al. Cardiovascular effects of levosimendan in the early stages of endotoxemia. Shock, 2007, 28(1):71-7.
(39)Pinto BB, Rehberg S, Ertmer C, Westphal M. Role of levosimendan in sepsis and septic shock. Curr Opin Anaesthesiol, 2008, 21(2): 168-77.
(40) Bernard GR, Vincent JL, Laterre PF, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group Efficacy and safety of recombinant human activated protein c for severe sepsis.N Engl J Med, 2001, 344: 699-709
(41) Kanji S, Perreault MM, Chant C, et al.Evaluating the use of Drotrecogin a!fa activated in adult severe sepsis: a Canadian multicenter observational study. Intensive Care Med, 2007, 33: 517-523
(42) TF Moriarty The law of Laplace. Its limitations as a relation for diastolic pressure, volume, or wall stress of the left ventricle. Circ. Res, 1980, 46:321-331
(43) Pellerin D, Sharma R, Elliott P, et al. Tissue Doppler, strain, and strain rate echocardiography for the assessment of left and right systolic ventricular function. Heart, 2003, 89 Suppl 3:iii9-17.
(44) Slama M, Maizel J. Echocardiographic measurement of ventricular function. Curr Opin Crit Care, 2006, 12(3):241-8.
(45) Marwick TH: Should we be evaluating the ventricle or the myocardium? Advances in tissue characterization. J Am Soc Echocardiogr, 2004, 17:168-172
(46) Dom GW Jr, Robbins J, Ball N, et al. Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice. Am J Physiol, 1994, 267(1 Pt 2):H400-H405
(47) Gulati VK, Katz WE, Follansbee WP, et al. Mitral annular descent velocity by tissue Doppler echocardiography as an index of global left ventricular function. Am J Cardiol, 1996, 77:979-84.
(48) Pai RG, Bodenheimer MM, Pai SM, Koss JH, et al. Usefulness of systolic excursion of the mitral anulus as an index of left ventricular systolic function. Am J Cardiol, 1991,67:222-4.
(49) Rushmer RF, Crystal DK, Wagner C. The functional anatomy of ventricular contraction. Circ Res, 1952, 1:162-170.
(50) Nagueh SF, Bachinski LL, Meyer D, et al.Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation, 2001, 104:128-130
(51) Yu C, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with 'isolated'diastolic heart failure and diastolic dysfunction. Circulation, 2002, 105: 1195 -1201.
(52) Hartley CJ, Latson LA, Michael LH et al. Doppler measurement of myocardial thickening with a single epicardial transducer. Am J Physiol, 1983, 245 (6):H1066-72.
(53) Jones CJ H , Rapeso L , Gibson DG, et al. Functional importance of the long axis dynamics of the human left ventricle [J ]. British Heart Journal, 1990, 63 (4) :215.
(54) Edvardsen T , Gerber BL , Garot J , et al. Quantitative assessment of intrinsic regional myocardial Deformation by Doppler Strain Rate. Echocardiography in humans [J ] .Circulation, 2002, 106(1):50255.
(55) Greenberg NL, Firstenberg MS, Castro PL, et al.Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility. Circulation, 2002, 105 (1):99-105.
(56) Donal E, Raud-Raynier P, Coisne D, Tissue Doppler echocardiographic quantification. Comparison to coronary angiography results in Acute Coronary Syndrome patients. Cardiovasc Ultrasound, 2005,8:3-10.
(57) Tanaka H, Kawai H, Tatsumi K, et al. Relationship between regional and global left ventricular systolic and diastolic function in patients with coronary artery disease assessed by strain rate imaging. Circ J, 2007, 71(4):517-23.
(58) Segar DS, Moran M, Ryan T. End-systolic regional wall stress-length and stress-shortening relations in an experimental model of normal, ischemic and reperfused myocardium. J Am Coll Cardiol, 1991 ,17(7): 1651-60.
(59) Colan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load-independent index of myocardial contractility. J Am Coll Cardiol, 1984, 4(4):715-24.
(60) Preiser JC, Sun Q, Vincent JL et al. Differential effects of a selective inhibitor of soluble guanylyl cyclase on global and regional hemodynamics during canine endotoxic shock. Shock, 2003, 20(5):465-8.
(61) Wu AH Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med, 2001, 27:959-961
(1) Neubauer S.The failing heart-an engine out of fuel.N Engl J Med,2007,15,(11):1140-51.
(2) Ingwall JS,Weiss RG.Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res,2004,95:135-45.
(3) Taegtmeyer H.Metabolism-the lost child of cardiology.J Am Coll Cardiol,2000,36:1386-8.
(4) Korvald C,Elvenes OP,Myrmel T:Myocardial substrate metabolism influences left ventricular energetics in vivo.Am J Physiol Heart Circ Physiol,2000,278:H 1345-H1351
(5) Stanley WC,Recchia FA,Lopaschuk GD.Myocardial substrate metabolism in the normal and failing heart.Physiol Rev,2005,85:1093-129.
(6) 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:H 1538-H 1543.
(7) Osorio JC,Stanley WC,Linke A,et al.Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation, 2002, 106:606-12.
(8) Razeghi P, Young ME, Alcorn JL, et al.Metabolic gene expression in fetal and failing human heart. Circulation, 2001, 104: 2923-31.
(9) Casademont J, Miro O. Electron transport chain defects in heart failure. Heart Fail Rev, 2002,7:131-9.
(10) Lewandowski ED. Cardiac carbon 13 magnetic resonance spectroscopy: on the horizon or over the rainbow? J Nucl Cardiol, 2002, 9:419-28.
(11) Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet, 2004, 364:1786-1788
(12) Ye Y, Gong G, Ochiai K, et al. High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model. Circulation, 2001,103:1570- 6.
(13) Weiss RG, Gerstenblith G, Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A, 2005, 102: 808 - 13.
(14) 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.
(15) Perseghin G, Lattuada G, De Cobelli F Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology, 2008,47(1):51-8.
(16) Prysiazhna OD, Sahach VF. The role of mitochondrial uncoupling proteins in the development of changes of endothelium-dependent reactions of the heart and vessels in experimental diabetes mellitus.Fiziol Zh, 2008,54(1): 10-6. Ukrainian.
(17) An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol, 2006,291(4):H1489-506.
(18) Idem. Cardiac metabolism as a target for the treatment of heart failure. Circulation, 2004,110:894-6.
(19) Stanley, W.C., and Chandler, M.P. 2002. Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail,Rev. 7:115-130.
(20) Brand MD, Esteves TC: Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab,2005,2:85-93
(21) Christiansen EN, Pedersen JI, Grav HJ. Uncoupling and recoupling of oxidative phosphorylation in brown adipose tissue mitochondria. Nature, 1969, 222(196): 857 -860.
(22) Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet,1997, 15(3): 269-272.
(23)Boss O, Samec S, Paoloni-Giacobino A, et al. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett, 1997, 408(1): 39-42.
(24) Mattiasson G, Sullivan PG.The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid Redox Signal, 2006, 8(1-2): 1-38.
(25) Fink BD, Hong YS, Mathahs MM. UCP2-dependent proton leak in isolated mammalian mitochondria. J Biol Chem, 2002, 8;277(6):3918-25.
(26) Mao W, Yu XX, Zhong A, et al. UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett, 1999, 443 (3) :326-330.
(27) Ishioka K, Kanehira K, Sasaki N et al.Canine mitochondrial uncoupling proteins: structure and mRNA expression of three isoforms in adult beagles. Comp Biochem Physiol B Biochem Mol Biol, 2002, 131(3):483-9.
(28) Roshon MJ, Kline JA, Thornton LR, et al. Cardiac UCP2 expression and myocardial oxidative metabolism during acute septic shock in the rat. Shock , 2003, 19: 570 -576
(29) Levy RJ, Deutschman CS. Evaluating myocardial depression in sepsis. Shock, 2004,22(1):l-10.
(30) Gellerich FN, Trumbeckaite S, Hertel K, et al. Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain. Shock, 1999, 11:336-341.
(31) Tavakoli H, Mela L. Alterations of mitochondrial metabolism and protein concentrations in subacute septicemia. InfectImmunity, 1982, 38:536-541.
(32) Crouser ED, Julian MW, Blaho DV, et al. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med, 2002, 30: 276 -284.
(33) Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med , 2007, 35 (6): 1599-608.
(34) Krauss S, Zhang C-Y, Lowell BB: The mitochondrial uncoupling-protein homologues. Nat Rev, 2005, 6:248-261
(35) Echtay KS. Mitochondrial uncoupling proteins—What is their physiological roles? Free Radical Biology & Medicine, 2007,43,1351-1371
(36) Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet, 1997,15(3): 269-272.
(37) Jaburek M, Varecha M, Gimeno RE, et al. Transport function and regulation of mitochondrial uncoupling proteins 2 and 3. J Biol Chem, 1999, 274 (37): 26003 -26007.
(38) Monemdjou S, Kozak LP, Harper ME. Mitochondrial proton leak in brown adipose tissue mitochondria of Ucpl-deficient mice is GDP insensitive. Am J Physiol, 1999, 276(6 Pt 1): E1073-E1082.
(39) Chan CB, De Leo D, Joseph JW,et al. Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes, 2001,50(6): 1302-10.
(40) Chavin KD, Yang S, Lin HZ, et al.Obesity induces expression ot uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.J Biol Chem, 1999, 274 (9): 5692-700.
(41) Evans ZP, Ellett JD, Chavin KD et al.Mitochondrial uncoupling protein-2 mediates steatotic liver injury following ischemia/reperfusion. J Biol Chem, 2008, 283(13):8573-9.
(42) Stuart J A, Harper JA, Brindle KM, et al. Physiological levels of mammalian uncoupling protein 2 do not uncouple yeast mitochondria. J Biol Chem, 2001, 276 (21):18633-18639.
(43) Chan CB, Saleh MC, Koshkin V, et al .Uncoupling Protein 2 and Islet Function. Diabetes, 2004,53(90001): S136 - 142.
(44) Zhang CY, Baffy G, Perret P, et al.Cell, 2001,105(6):745-755.
(45) Kassis N, Bernard C, Pusterla A,et al.Int J Exp Diabetes Res, 2000, 1 (3): 185 -193.
(46) Saleh MC, Wheeler MB, and Chan CB, et al. Endogenous islet uncoupling protein-2 expression and loss of glucose homeostasis in ob/ob mice. J Endocrinol, 2006, 190(3): 659-667.
(47) Affourtit C, Brand MD. On the role of uncoupling protein-2 in pancreatic beta cells. Biochim Biophys Acta, 2008,1777(7-8):973-9.
(48) Affourtit C, Crichton PG, Brand MD et al. Novel uncoupling proteins.Novartis Found Symp, 2007,287:70-80.
(49) Lambert AJ, Brand MD. Research on mitochondria and aging, 2006-2007. Aging Cell, 2007 , 6(4):417-20.
(50) Mills EM, Banks ML, Sprague JE, et al.Pharmacology: uncoupling the agony from ecstasy. Nature, 2003 ,426(6965):403-4.
(51) Mills EM, Weaver K.L, Abramson E, et al.Influence of dietary fats on Ecstasy-induced hyperthermia.Br J Pharmacol, 2007, 151(7):1103-8..
(52) Zhang CY, Parton LE, Ye CP,Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets.Cell Metab, 2006, 3(6):417-27.
(53) Boehm EA, Jones BE. Radda GK, et al.Increased uncoupling proteins and decreased efficiency in palmitate-perfused hyperthyroid rat heart.Am J Physiol Heart Circ Physiol,2001,280:H977-H983.
(54) Boudina S, Sena S,Theobald H,et al. Mitochondrial Energetics in the Heart in Obesity-Related Diabetes: Direct Evidence for Increased (55)Uncoupled Respiration and Activation of Uncoupling Proteins. Diabetes, 2007, 56 (10): 2457-2466.
(56) Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda), 2006, 21:250-8.
(57) Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet, 2004, 364: 1786—1788.
(58) Cortez-Pinto H, Yang SQ, Lin HZ, et al. Bacterial lipopolysaccharide induces uncoupling protein-2 expression in hepatocytes by a tumor necrosis factor-alpha-dependent mechanism.Biochem Biophys Res Commun,1998, 251: 313 -319.
(59) Faggioni R, Shigenaga J, Moser A, et al. Induction of UCP2 gene expression by LPS: a potential mechanism for increased thermogenesis during infection. Biochem Biophys Res Commun, 1998,244:75-78.
(60) Yu XX, Barger JL, Boyer BB: Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics. Am J Physiol Endocrinol Metab, 2000, 279(2):E433-46.
(61) McLeod CJ , Aziz A, Hoyt RF J r, et al. Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia [ J ]. J Biol Chem, 2005, 280: 33470 -33476.
(62) Somoza B, Guzman R, Cano V, et al.Induction of cardiac uncoupling protein-2 expression and adenosine 5'-monophosphate-activated protein kinase phosphorylation during early states of diet-induced obesity in mice.Endocrinology, 2007,148(3):924-31.
(63) Pedersen SB , Lund S , Buhl ES. Insulin and cont raction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal muscle in vit ro. Biochem Biophys Res Commun, 2001, 283(1):19 - 25.
(64) Pecqueur C, Alves-Guerra MC, Gelly C, et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation.J Biol Chem, 2001, 276:8705-8712.
(65) Cinel I, Dellinger RP.Advances in pathogenesis and management of sepsis.Curr Opin Infect Dis, 2007, 20:345-352.
(66) Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature, 2002, 415:96-99
(67) Goglia F, Skulachev VP.A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. FASEB J, 2003, 17(12): 1585-91.
(68) Jaburek M, Miyamoto S, Di Mascio PHydroperoxy fatty acid cycling mediated by mitochondrial uncoupling protein UCP2. J Biol Chem,2004, 279(51):53097-102.
(69) Blanc J, Alves-Guerra MC, Esposito B, et al.Protective role of uncoupling protein 2 in atherosclerosis. Circulation, 2003, 28; 107 (3):388-90.
(70)Mallat Z, Hugel B, Ohan J, et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation, 1999, 99: 348-353.
(71) Hang T, Jiang S, Wang C, et al. Apoptosis and expression of uncoupling protein-2 in pressure overload-induced left ventricular hypertrophy. Acta Cardiol, 2007, 62 (5): 461-5.
1.Martin GS,Mannino DM,Eaton S,Moss M.The epidemiology of sepsis in the United States from 1979 through 2000.N Engl J Med.2003;348:1546-1554.
2.Vincent JL,Sakr Y,Sprung CL,et al.Sepsis in European intensive care units:results of the SOAP study.Crit Care Med.2006;34:344-353.
3.Charpentier J,Luyt C-E,Fulla Y,et al.Brain natriuretic peptide:A marker of myocardial dysfunction and prognosis during severe sepsis.Crit Care Med 2004;32:660-665
4.Vincent JL,Gris P,Coffernils M,et al.Myocardial depression characterizes the fatal course of septic shock.Surgery 1992;111:660-667
5.Parrillo JE,Parker MM,Natanson C,et al.Septic shock in humans.Advances in the understanding of pathogenesis,cardiovascular dysfunction,and therapy.Ann Intern Med 113:227-242,1990.
6.Levy MM,Fink MP,Marshall JC,et al.SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Crit Care Med,2003,31:1250-1256
7.Dellinger RP,Carlet JM,Masur H,et al.Surviving Sepsis Campaign Management Guidelines Committee(2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.Crit Care Med 32:858-873
8.Court O,Kumar A,Parrillo JE,et al.Myocardial depression in sepsis and septic shock.Crit Care 2002;6:500-507
9.Rivers E,Nguyen B,Havstad S,et al the Early Goal-Directed Therapy Collaborative Group(2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock.N Engl J Med 345:1368-1377
10. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 348:138-150, 2003.
11. Kumar A, Haery C, Parrillo JE: Myocardial dysfunction in septic shock. Crit Care Clin 16:251-287, 2000.
12. Ceneviva G, Paschall JA, Maffei F, Carcillo JA: Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics 102:el9, 1998
13. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE: Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100:483-490, 1984.
14. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE (1986) The coronary circulation in human septic shock. Circulation 73:637-644
15. Dhainaut JF, Huyghebaert MF, Monsallier JF, et al. (1987) Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation 75:533-541
16. Lanone S, Mebazaa A, Heymes C, et al. (2000) Muscular contractile failure in septic patients: role of the inducible nitric oxide synthase pathway. Am J Respir Crit Care Med 162:2308-2315
17. Wu AH (2001) Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med 27:959-961
18. Wangensteen SL, Geissinger WT, Lovett WL et al. (1971) Relationship between splanchnic blood flow and a myocardial depressant factor in endotoxin shock. Surgery 69:410-418
19. Parrillo JE, Burch C, Shelhamer JH, et al. (1985) A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest 76:1539-1553
20. Finkel MS, Oddis CV, Jacob TD, et al (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387-389
21. Kumar A, Thota V, Dee L, et al. (1996) Tumor necrosis factor alpha and interleukin lbeta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med 183:949-958
22. Tavernier B, Mebazaa A, Mateo P, S et al. (2001) Phosphorylation-dependent alteration in myof ilament ca2+ sensitivity but normal mitochondrial function in septic heart. Am J Respir Crit Care Med 163:362-367
23. Mebazaa A, De Keulenaer GW, Paqueron X, et al. (2001) Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy. role of endothelin, prostaglandins, and nitric oxide. Circulation 104:3137-3144
24. Tavernier B, Li JM, El-Omar MM, et al. (2001) Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J 15:294-296
25. Ingalls R , Heine H , Linen E , et al . Lipopolysaccharide recognition CD14 and lipopolysaccharide receptors. Infect Dis Clin North Am , 1999 , 13 : 341 - 353.
26. Katz Z , Chen K, Chen S , et al . Potent CD14 mediated signalling of human leukocytes by Escherichia coli can be mediated by interaction of whole bacteria and host cells without extensive prior release of endotoxin. Immun , 1996 , 64 : 3592 - 3600.
27. Hamann L , Schumann R , Flad H, et al . Binding of lipopolysaccharide (1PS) to CHO cells does not correlate with LPS2induced NF-kappaB activation. Eur J Immunnol , 2000 , 30 : 211 - 216.
28. Hamann L , Stamme C , Ulmer A J . Inhibition of LPS induced activation of alveolar macrophages by high concentrations of LPS-binding protein[J] . Biochem Biophys Res Commun ,2002,295(2) : 553 - 560.
29. Pang L , Kno X. Synergistic inhibition by bete (2)agonists and corticosteroids on tumor necrosis factor2alpha2induced inter-leukin28 release from cultured human airway smooth2muscle cells[J] . Am J Respir Cell Mol Biol , 2000 , 23 (1) : 7985.
30. Luo C , Zheng L. Independent evolution of Toll and related genes in insect and mammals [J] . Immunogenetics,2000, 51(2) : 92 - 98.
31. Quershi S , Lariviere L, Leveque G, et al . Endotoxin tolerant mice have mutations in Toll21ike receptor ( TLR4) [J] . J Exp Med , 1999 , 189 : 615 - 625.
32.AkashiS, SaitohS, Wakabayashi Y. Lipopolysaccharide interaction with cell surface Toll21ike receptor 42MD22 : higher affinity than that with MD22 or CD14 .J Exp Med, 2003, 198(7) : 1035 - 1042.
33. Takeuchi 0 , Hoshinl K, Kawai T , et al . Differential role of TLR 2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components [J] . Immunity , 1999, 11:433 - 451.
34. Poltorak A , He X , Smirnova I , et al . Defective L PS signaling in C3H/ HeJ and C57B1/ lOScCr mice : mutations in Tlr4 gene. Science , 1998 , 282 : 2085 - 2088.
35. GuhaM, Mackman N. L PS induction of gene expression in human monocytes. Cell Signal, 2002 , 13 (2) : 85 - 94.
36. Medzhitov R , Preston2Hurlburt P , Janeway C. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature , 1997 , 388 - 397.
37. Dispersyn GD, Borgers M: Apoptosis in the heart: about programmed cell death and survival. News Physiol Sci 16:41-47, 2001.
38. Haunstetter A, Izumo S: Apoptosis: basic mechanisms and implications for cardiovascular disease. Circulation 82:1111-1129, 1998.
39. McDonald TE, Grinman MN, Carthy CM, et al. Endotoxin infusion in rats induces apoptotic and survival pathways in hearts. Am J Physiol Heart Circ Physiol 279:H2053-H2061, 2000.
40. Rossi MA, Celes MR, Prado CM, et al. Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction. Shock 2007; 27:10-18
41. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230-1248
42. Fauvel H, Marchetti P, Chopin C, et al. Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis. Am J Physiol Heart Circ Physiol 280:H1608-H1614, 2001.
43. Carlson DL, Willis MS, White DJ, et al. Tumor necrosis factor-alpha-induced caspase activation mediates endotoxin related cardiac dysfunction. Crit Care Med 200b; 33:1021-1028
44. Lancel S, Joulin 0, Favory R, et al. Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction. Circulation 2005; 111 :2596-2604
45. Kvasnicka T. NO (nitric oxide) and its significance in regulation of vascular homeostasis. Vnitr Lek , 2003 , 49 ( 4) : 291 -296.
46. Ullrich R , Scherrer2Crosbie M , Bloch K, et al . Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice . Circulation , 2000, 102 (12) : 1440 - 1446.
47. Ichinose F, Buys ES, Neilan TG, et al. Cardiomyocytc-specific overcxpression of nitric oxide synthase 2 prevents myocardial dysfunction in murine models of septic shock. Circ Res 2007; 100:130-139
48. Barouch LA, Harrison RW, Skaf MW, et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 2002; 416:337-339
49. Nisoli E, Clementi E, Paolucci C, et al. Mitochondrial biogenesis: The role of endogenous nitric oxide. Science 2003; 299:896-899
50. Nisoli E, Falcone S, Tonello C, et al. Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc Natl Acad Sci U S A 2004; 101:16507-16512
51. Opie LH: Receptors and signal transduction. In: Heart Physiology: From Cell to Circulation. Fourth Edition. Opie LH (Ed). London, Lippincott Williams & Wilkins, 2004, pp 186-220
52. Hahn PY, Wang P, Tait SM, et al. Sustained elevation in circulating catecholamine levels during polymicrobial sepsis. Shock 1995; 4:269-273
53. Macarthur H, Westfall TC, Riley DP, et al. Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A 2000; 97:9753-9758
54. Gulick TS, Chung MK, Pieper SJ, et al. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci USA 1989; 86:6753-6757
55. Matsuda N, Hattori Y, Akaishi Y, et al. Impairment of cardiac _-adrenoceptor cellular signaling by decreased expression of Gs_ in septic rabbits. Anesthesiology 2000; 93: 1465-1473
56. Bhm M, Kirchmayr R, Gierschik P, et al. Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan fai lure. Am J Med 1995; 98:183-186
57. Wu L-L, Yang S-L, Yang R-C, et al. G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis. Shock 2003; 19:533-537
58. Barth E, Radermacher P, Thiemermann C, et al. Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock. Crit Care Med 2006; 34:307-313
59. Buckley JF, Singer M, Clapp LH: Role of KATP channels in sepsis. Cardiovasc Res 2006; 72:220-230
60. Dong LW, Wu LL, Ji Y, et al. Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. Shock 2001; 16:33-39
61. Cohen RI, Wilson D, Liu SF: Nitric oxide modifies the sarcoplasmic reticular calcium release channel in endotoxemia by both guanosine-3', 5' (cyclic) phosphate-dependent and independent pathways. Crit Care Med 2006; 34:173-181
62. Rudiger A, Singer M: Mechnism of sepsis-induced cardiac dysfunction. Crit Care Med 2007; 35: 1599-1608
63. Joshi MS, Julian MW, Huff JE, et al. Calcineurin regulates myocardial function during acute endotoxemia. Am J Respir Crit Care Med 2006; 173:999-1007
64. Wang W, Schulze CJ, Suarez-Pinzon WL, et al. Intracellular action of matrix metalloproteinase- 2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 2002; 106:1543-1549
65. Gao CQ, Sawicki G, Suarez-Pinzon WL, et al. Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction. Cardiovasc Res 2003; 57:426-433
66. Chen HW, Hsu C, Lu TS, et al. Heat shock pretreatment prevents cardiac mitochondrial dysfunction during sepsis. Shock 20:274-279,2003.
67. Kregel KC: Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 92: 2177-2186, 2002.
68. Meng X, Harken AH: The interaction between Hsp70 and TNF- expression:a novel mechanism for protection of the myocardium against post-injury depression. Shock 17-345-353, 2002.
69. Chi S-H, Mestril R: Stable expression of a human HSP70 gene in a rat myogenic cell line confers protection against endotoxin. Am J Physiol Cell Physiol 270:C1017-C1021, 1996.
70. Raeburn CD, Calkins CM, Zimmerman MA, et al. Vascular cell adhesion molecule-1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction. Surgery 130:319-325, 2001.
71. Raeburn CD, Calkins CM, Zimmerman MA, et al. ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation. Am J Physiol Regul Integr Comp Physiol 283:R477-R486, 2002.
72. Stanley WC, Recchia FA, Lopaschuk GD: Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005; 85:1093-1129
73. Cunnion RE, Schaer GL, Parker MM, et al. The coronary circulation in human septic shock. Circulation 1986; 73:637-644
74. Dhainaut J-F, Huyghebaert M-F, Franois MJ, et al. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketoncs in patients with septic shock. Circulation 1987; 75:533-541
75. Boekstegers P, Weidenhfer S, Pilz G, et al. Peripheral oxygen availability within skeletal muscle in sepsis and septic shock: Comparison to limited infection and cardiogenic shock. Infection 1991; 19:317-323
76. Boekstegers P, Weidenhfer S, Kapsner T, et al. Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 1994; 22:640-650
77. Richard J. Levy and Clifford S: evaluating myocardial depression in sepsis SHOCK, 2004 Vol. 22, No. 1, pp. 1-10,
78. Crouser ED: Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 2004; 4: 729-741
79. GellerichFN, Trumbeckaite S, OpalkaJR, et al. Mitochondrial dysfunction in sepsis: Evidence from bacteraemic baboons and endotoxaemic rabbits. Biosci Rep 2002; 22: 99-113
80. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360:219-223
81. Watts JA, Kline JA, Thornton LR, et al. Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J Mol Cell Cardiol 2004; 36:141-150
82. Suliman HB, Welty-Wolf KE, Carraway MS, et al. Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc Res 2004; 64:279-288
83. Krauss S, Zhang OY, Lowell BB: The mitochondrial uncoupling-protein homologues. Nat. Rev 2005; 6:248-261
84. Brand MD, Esteves TC: Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2005; 2:85-93
85. Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet 2004; 364:1786-1788
86. Roshon MJ, Kline JA, Thornton LR, et al. Cardiac UCP2 expression and myocardial oxidative metabolism during acute septic shock in the rat. Shock 2003; 19:570-576
87. Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002; 415:96-99
88. Larche J, Lancel S, Hassoun SM, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 2006; 48:377-385
89. Hotchkiss RS, Karl IE: Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA 1992; 267:1503-1510
90. Hotchkiss RS, Rust RS, Dence CS, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F] fluoromisonidazole. Am J Physiol Regul Integr Comp Physiol 1991; 261:R965-R972
91. Mebazaa A, De Keulenaer GW, Paqueron X, et al. Activation of cardiac endothelium as a compensatory component in endotoxin induced cardiomyopathy: Role of endothelin, prostaglandins, and nitric oxide. Circulation 2001; 104:3137-3144
92. Jacobs H, Mink SN, Duke K, et al. Characterization of membrane N-glycan binding sites of lysozyme for cardiac depression in sepsis. Intensive Care Med 2005; 31:129-137
93. Madorin WS, Rui T, Sugimoto N, et al. Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: Role of platelet-activating factor and the chemokines LIX and KC. Circ Res 2004; 94:944-951
94. Sharshar T, Gray F, Lorin de la, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 2003; 362:1799-1805
95. Azimi G, Vincent J-L: Ultimate survival from septic shock. Resuscitation 1986; 14:245-253
96. Heusch G, Schulz R, Rahimtoola SH: Myocardial hibernation: A delicate balance. Am J Physiol Heart Circ Physiol 2005; 288: 984-999
97. Levy RJ, Piel DA, Acton PD, et al. Evidence of myocardial hibernation in the septic heart. Crit Care Med 2005; 33:2752-2756 69.
98. Kreymann G, Jean-Pierre Quenot, Gwnal Le Teuff: Myocardial Injury in Critically I11 Patients: Relation to Increased Cardiac Troponin I and Hospital Mortality Chest 2005;128;2758-2764
99. Fink MP, Heard SO: Laboratory models of sepsis and septic shock. J Surg Res 49:186-196, 1990.
100. Schultz MJ, van der Poll T: Animal and human models for sepsis. Ann Med 34:573-581, 2002.
101. Walvatne CS, Johnson AS, Wojcik LJ, Cerra FB: Cardiovascular response to acute and chronic endotoxemia in an awake, volume-resuscitated, canine model Shock 3:299-306, 1995.
102. Cervenkova K, Belejova M, Vesely J, et al. Cell suspensions, cell cultures, and tissue slices: important metabolic in vitro systems. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 145:57-60, 2001.
103. Colan SD: Assessment of ventricular and myocardial performance. In Fyler DC (ed.) : Nadas' Pediatric Cardiology. Philadelphia, PA: Hanley & Belfus, Inc., 1992, pp 225-248.
104. Goldfarb RD: Cardiac mechanical performance in circulatory shock: a critical review of methods and results. Circ Shock 9:633-653, 1982.
105. 王鸿儒,文宗曜:血液循环力学[M]1 北京:北京医科大学、中国协和医科大学联合出版社, 1983: 59278
106. Sutherland FJ, Hearse DJ: The isolated blood and perfusion fluid perfused heart. Pharmacol Res 41:613-627, 2000.
107. Parker JL, Adams HR: Development of myocardial dysfunction in endotoxin shock. Am J Physiol 248:H818-H826, 1985.
108. Yasuda S, Lew WY: Angiotensin II exacerbates lipopolysaccharide-induced contractile depression in rabbit cardiac myocytes. Am J Physiol 276:H1442-H1449, 1999.
109. Michard F, Alaya S, Zarka V, et al. Global end-diastolic volume as an indicator of cardiac preload in patients with septic shock. Chest, 2003, 124:1900-1908.
110.Dittoe N, Stultz D,Schwartz,BP et al. Quantitative left ventricular systolic function: From chamber to myocardium Crit Care Med 2007;35:s330-s335
111. Pinsky MR, Payen D. Functional hemodynamic monitoring. Crit Care 2005; 9 :566-572.