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1、1 Inflammation in hInflammation in heart failureeart failure Liao Yu-HuaLiao Yu-Hua Institute of CardiologyInstitute of Cardiology Union HospitalUnion Hospital Huazhong University of Science and Huazhong University of Science and Technology, Wuhan ChinaTechnology, Wuhan China 2 Cognitive process of
2、pathophysiology and therapy in haert failure Fluid retention Hemodynamic abnormity Neurohormone abnormity Cytokines 40-60 era 70-80 era80-90 era90 era Neurohormone antagonist Expand vessel /cardiotonic Diuretic ？ 3 InflammationInflammation and Heart failure and Heart failure 1. Interaction between n
3、euroendocrine and cytokines in heart failure 2. therapy between inflammation and heart failure 4 -adrenergic stimulation induces proinflammatory cytokine expression in myocardium mRNA expression by Northern blottingprotein levels by Western blotting *P0.01, *P0.0001 vs saline-treated animals. Murray
4、 et al. Circulation. 2000;101:2338-2341. In control myocardium, TNF-a,IL-1b and IL-6 were not detected. Isoproterenol infusion significantly increased expression of all 3 cytokines, indicating that chronic -adrenergic stimulation was associated with proinflammatory cytokine expression. 5 Causal rela
5、tionship between Ang II and TGF-1 in cardiac hypertrophy Schultz JEJ, et al. J Clin Invest 2002;109:787 96 The lack of the TGF1 gene fully prevented the development of cardiac hypertrophy induced by subpressor doses of Ang II that was observed in wild type mice Ang II-induced cardiac hypertrophy is
6、mediated by TGF-1 6 Evidence for a connection between Ang II and TGF-1 in cardiac tissue Stephan Rosenkranz.Cardiovascular Research 2004; 63:423 432 Some studies indicate that Ang II and TGF-1 act in an auto-/paracrine manner, and suggest cross-talk between the various myocardial cell types and comp
7、artments 7 Angiotensin II-induced myocardial TNF biosynthesis in the adult heart TNF mRNA expression Kalra D, et al. Circulation 2002; 105:2198 205. Treatment with Ang II resulted in a rapid increase in TNF mRNA synthesis in isolated buffer perfused hearts 8 Angiotensin II induced activation of NF-B
8、 Kalra D, et al. Circulation 2002; 105:2198 205. Stimulation with Ang II lead to a rapid increase in NF-B binding activity in isolated buffer perfused hearts, the finding suggest a possible pathway in Ang II mediated TNF biosynthesis 9 Cross-regulation between the renin- angiotensin system and infla
9、mmatory mediators K. Sekiguchi et al. Cardiovascular Research 2004； 63： 433442 There is a complicated network in heart failure between neuroendocrine system and immune system Ang II provokes inflammatory responses in the heart through an NF-B dependent pathway, whereas TNF provoke activation of the
10、RAS in the heart through increased ACE activity. Both of these pathways converge on overlapping MAPK signal transduction pathways 10 InflammationInflammation and Heart failure and Heart failure 1. Interaction between neuroendocrine and cytokines in heart failure 2. therapy between inflammation and h
11、eart failure 11 Autoimmune response after AMI Liao YH. Autoimmunity in myocardial infarction. Int J Cardiol, 2006; 112:21-26 MI area of post-MI non-MI area of post-MI 12 New field of therapy in inflammation and heart failure Problem of Immunosuppresion therapy Problem of anti-cytokine therapy Immuor
12、egulatory effect of -blockers on inflammation after AMI Immuoregulatory effect of statins on inflammation after AMI Liao YH. Autoimmunity in myocardial infarction. Int J Cardiol, 2006; 112:21-26 13 Myocardial inflammation should be suppressed or regulated after AMI? A clinical study using methylpred
13、nisolone in patients with AMI, which resulted in catastrophic results, increased the incidence of ventricular arrhythmias and extending infarct size Subsequent investigations suggested that corticosteriods inhibit the inflammatory process decreasing the number of infiltrating leukocytes, but also de
14、lay healing and collagen deposition Roberts R, DeMello V, Sobel BE. Circulation. 1976;204-206. Kloner RA, Fishbein MC, Lew H, et al. Circulation. 1978;1:56-63. 14 New field of therapy in inflammation and heart failure Problem of Immunosuppresion therapy Problem of anti-cytokine therapy Immuoregulato
15、ry effect of -blockers on inflammation after AMI Immuoregulatory effect of statins on inflammation after AMI Targeted anticytokine therapy has been given great expectation, but the results from large scale clinical trials were not satisfying Liao YH. Autoimmunity in myocardial infarction. Int J Card
16、iol, 2006; 112:21-26 15 RENEWAL trial Mann DL, et al. Circulation 2004;109:1594-1602 Etanercept is a soluble TNF antagonist, which can lower the serum level of TNF in patients with heart failure, but the results of RENEWAL rule out a clinically relevant benefit on the rate of death or hospitalizatio
17、n due to chronic heart failure 16 Explanations by designer Proinflammation cytokines do not play a deleterious role in the pathophysiology of chronic heart failure The doses of etanercept were not sufficient to neutralize TNF- The targeted approach that was taken was not sufficient to disrupt the ne
18、twork of inflammatory mediators that are activated in heart failure Etanercept also has intrinsic biological activity and can act as agonists for the cytokine that they bind Mann DL, et al. Circulation 2004;109:1594-1602 17 ATTACH trial Infliximab is a recombinant TNF- monoclonal antibody that speci
19、fically and potently binds to TNF- Although it can lower the levels of circulatory CRP and IL-6, the short-term infliximab treatment cannot improve and high doses (10 mg/kg) adversely affect the clinical condition of patients with chronic heart failure Chung ES, et al. Circulation 2003;107:313340 18
20、 ATTACH trial results Chung ES, et al. Circulation 2003;107:313340 Death or CHF Hospitalization Placebo (n=49) 5mg/kg (n=50) 10mg/kg (n=51) 0-14 wks2(4%)2(4%)8(21%) 0-28 wks5(10%)4(8%)13(26%)* *P=0.043 vs placebo Infliximab 19 The activation of TNF- may not play a deleterious role in heart failure T
21、he toxicity of TNF- might be also enhanced if treatment with infliximab caused circulating levels of TNF- to rebound When exposed to cells expressing transmembrane TNF-, infliximab can cause cell lysis in the presence of complement Explanations by designer Chung ES, et al. Circulation 2003;107:31334
22、0 20 Expression of cytokines in myocardium after AMI Zhang JY, Cheng X, Liao YH, et al. Cardiovasc Drug Ther. 2005;19:13-21 MI rat SH rat TNF-IL-1IL-6IL-10 Our study show the cytokines might be secreted by means of an autocrine and paracrine in myocardium after AMI 21 RENEWAL trial: The doses of eta
23、nercept may be sufficient to neutralize circulating TNF-, but not sufficient to neutralize myocardial TNF- ATTACH trial: Infliximab is directly cytotoxic to cells expressing TNF- on the myocardium. So high doses of infliximab (10mg/kg) adversely affected the clinical condition of patients with chron
24、ic heart failure. The anti-cytokine therapy is aborted because the cytokines might be secreted by means of an autocrine and paracrine in myocardium Explanations by our experiment 22 New field of therapy in inflammation and heart failure Problem of Immunosuppresion therapy Problem of anti-cytokine th
25、erapy Immuoregulatory effect of -blockers on inflammation after AMI Immuoregulatory effect of statins on inflammation after AMI Liao YH. Autoimmunity in myocardial infarction. Int J Cardiol, 2006; 112:21-26 23 Carvedilol Carvedilol reducedreduced cardiac cytokine protein expression in AMI rats after
26、 therapy 4w MIMI-CSH TNF- IL-1 IL-6 TGF1 IL-10 TNF-/IL-10 TNF- IL-1 IL-6 IL-10 TGF-1TNF-/IL-10 Li B, Liao YH, et al. Natl Med J China,2005,85(6):416-418 Li B, Liao YH, et al. Chin Hosp Pharm J, 2004;24(11):659-661 *Compared with sham-operated group, P0.01; Compared with MI group, P0.01 24 Carvedilol
27、Carvedilol decreased myocardial MMP-2 and MMP-9 expression in AMI rats *Compared with sham-operated group, P0.01; Compared with MI group, P0.01 Li B, Liao YH, et al. Natl Med J China,2005,85(6):416-418 Li B, Liao YH, et al. Chin Hosp Pharm J, 2004;24(11):659-661 25 CarvedilolCarvedilol decreased myo
28、cardial type and collagens expression in AMI rats (200) SHMI MI-C Li B, Liao YH, et al. Natl Med J China,2005,85(6):416-418 Li B, Liao YH, et al. Chin Hosp Pharm J, 2004;24(11):659-661 26 Metoprolol regulates cytokines protein production of LV myocardium post-MI *P 0.01 vs. Sham group. # P 0.05 vs.
29、MI group A Cheng X, Liao YH, et al. Chin J Cardiol, 2005;33(5):448-452 B 27 Localization of cytokines immunoreactivity in myocardium SH: S group, I: infarcted zone of MI group, B-I: infarcted zone of MI -B group, N: noninfarcted zone of MI group, B-N: noninfarcted zone of MI-B group (400) TNF-IL-1IL
30、-6IL-10 I B-I N B-N SH Cheng X, Liao YH, et al. Chin J Cardiol, 2005;33(5):448-452 28 New field of therapy in inflammation and heart failure Problem of Immunosuppresion therapy Problem of anti-cytokine therapy Immuoregulatory effect of -blockers on inflammation after AMI Immuoregulatory effect of st
31、atins on inflammation after AMI Liao YH. Autoimmunity in myocardial infarction. Int J Cardiol, 2006; 112:21-26 29 Atorvastatin inhibits Th1 response in AMI patients B * A *P0.05 vs. AMI-C1 Cheng X, Liao YH, et al. Circulation. 2004;110 (17) Supplement III: 696-697 but atorvastatin has no effect on T
32、h2 response in patients with AMI, which may be one of the mechanisms that atorvastatin prevents heart failure after AMI. 30 Atorvastatin inhibits Th1 response in vitro the effect can be reversed by Mevalonate A B * * # A B *P0.05 vs. cultured without atorvastatin group # P0.05 vs. cultured with ator
33、vastatin (3mol/L) group Cheng X, Liao YH, et al. Circulation. 2004;110 (17) Supplement III: 696-697 31 Simvastatin reduces TNF- expression in myocardium Zhang JY, Cheng X, Liao YH, et al. Cardiovasc Drug Ther. 2005;19:13-21 MI MI-S Non MI areaMI area 32 *P0.01 vs Sham # P0.01 vs MI-C Simvastatin mod
34、ulate cytokines protein expression after AMI Zhang JY, Cheng X, Liao YH, et al. Cardiovasc Drug Ther. 2005; 19(1): 13-21 33 Heart function improved in AMI rats after simvastatin treatment GroupsnLVEDd (mm)EF (%)FS (%) Sham 104.50.385.23.751.63.1 MI-C127.50.4*41.44.3*20.52.5* MI-S 125.90.3#51.84.3#25
35、.42.7# ShamMI-CMI-S ED ES Compared with sham group, *p0.01 Compared with MI -C,#p0.05 Simvastatin animal trial after AMI Zhang JY, Cheng X, Liao YH, et al. Cardiovasc Drug Ther. 2005; 19(1): 13-21 34 Summary(1) Inflammatory mechanism in heart failure 1.Isoproterenol induced proinflammatory cytokine
36、expression in myocardium 2.Ang II-induced myocardial TNF- biosynthesis in heart 3.Network between Ang II and TGF-1 in mediating cardiac hypertrophy via auto- /paracrine mechanisms 35 Summary(2) Inflammatory intervention in heart failure 1.Immunosuppression and anti-cytokine therapy were not satisfyi
37、ng 2.TNF- isnt therapy target in heart failure because TNF- expressed on the myocardial cells with heart failure Beta-blockers and Statins could regulate inflammation and improve heart function after AMI 36 Cognitive process of pathophysiology and therapy in haert failure Fluid retention Hemodynamic
38、 abnormity Neurohormone abnormity Cytokines 40-60 era 70-80 era80-90 era90 era Neurohormone antagonist Expand vessel /cardiotonic Diuretic Regulate of the immune function may become a new targeted therapy for the prevention of heart failure ？ Immune regulation 37 1980 武汉协和医院 心血管病研究所 Acknowledgement The grant supported by NSFC Prof. Wang Zhao-Hui Accessory-prof. Wang Zhaohui Dr.Cheng Xiang Dr. Li Bin Dr. Zhang Jinying Dr.Tao Rong Dr. Ge Hong-Xia Dr. Liu Ying Researcher. Wang Min Dr. Guo Zhang-Qiang