心衰中的炎症-课件,幻灯,PPT (英文).ppt
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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
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