| Recent studies have identified the importance of TNF-αin the development and progression of heart failure. TNF-αexerts its effects via TNF-αreceptors(TNFR),which are expressed by almost all nucleated cells.There are two types of TNFR,including TNFR -1(p55) an TNFR -2(p75).Thease two TNFR have been so far indentified. TNFR-1 is more abundantly expressed and appears to be the main signaling receptor.The majority of deleterious effects caused by TNFR seem to be mediated via this receptor,whereas TNFR-2 appears to have a more protected role in the heart. It is now known that every nucleated cell type in the myocardium, including the cardiac myocyte, is able to secrete TNF-αin response to various forms of stress/injury. Experimentally,a model of pressure and/or volume overload of heart demonstrated the expression of mRNA for TNF-α.It also demonstrated that the insufficient human myocardium ,but not the normal human myocardium express TNF-α. In addition, increased bowel wall edema causes translocation of bacterial endotoxin from the gut which yields TNF-αproduction by monocytes in the bloodstream and possibly other tissues. The observation that TNF-αcan modulate LV function was firstly reported in a series of important experimental studies showing that direct injection of TNF would produce hypotention, metabolic acidosis,and even death within minutes,thus mimicking the cardiac response seen during in the endotoxin-induced sepsis shock.The effect of TNF-αon cardiac contraction are typically divdided into immediate response and delayed response. The immediate response occurs within minutes and can be stimulatory or depressant, depending on experimental conditions,and mediated by activating of the neutral sphingomyelinase pathyway. The delayed response, lasting hours to days, is always cardiodepressant and is modulated by NO-mediated blunting ofβ-adrenergic signaling.TNF-αhave a number of important effects that may play an important role in the process of LV remodeling, including myocyte hypertrophy, alterations in fetal gene expression and progressive myocyte loss through apoptosis. In addition to the above effects, there are several lines of evidence suggesting that TNF-αmay promote LV remodeling through alterations in the extracellular matrix. The content of fibrillar collagen depends on the ratio of MMP activity to TIMP levels.During the early stage of inflammation ,there is an increase in the ratio that fosters LV dilation.However,with the chronic inflammation signaling ,there is a time-dependent increase in TIMP level,with a resultant decrease in the ratio of MMP activity to TIMP activity and a subsequent increase in myocardial fibrillar collagen cotent. TNF-αhas also an important role in the prognosis value of heart failure. As reported in a number of studies , the cytokines are activated earlier in heart failure (ie, NYHA class II) than the classic neurohormones, which tend to be activated in the latter stages of heart failure. SOLVD Test demonstrates that there was a progressive increase in serum TNF-a levels in direct relation to decreasing functional heart failure classification .Moreover,VEST test has demonstrated that TNF-αand its soluble receptor (sTNFR)can predict adverse cardiovascular events .Beacause heart failure remain a progressive process disease despite the optimal therapy with ACEI andβ-blockers . So anti-inflammatory therapy by various agents such as pentoxifylline should be a promising future treatment for heart failure.
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