TY - JOUR
T1 - Inflammatory mediators and the failing heart
T2 - A translational approach
AU - Diwan, Abhinav
AU - Tran, Tony
AU - Misra, Arunima
AU - Mann, Douglas L.
PY - 2003/3
Y1 - 2003/3
N2 - Recent studies have identified the importance of proinflammatory mediators in regulating cardiac structure in health and disease. Recent studies suggest that cytokines that are expressed within the myocardium in response to a environmental injury, namely tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and the interleukin-6 (IL-6) family of cytokines play an important role in initiating and integrating homeostatic responses within the heart. However, these "stress-activated" cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Indeed, there is now a growing appreciation that these molecules may play an important role in mediating disease progression in the failing heart. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in pre-clinical and clinical heart failure models culminated in a series of multicenter clinical trials that utilized "targeted" approaches to neutralize tumor necrosis factor (TNF) in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.
AB - Recent studies have identified the importance of proinflammatory mediators in regulating cardiac structure in health and disease. Recent studies suggest that cytokines that are expressed within the myocardium in response to a environmental injury, namely tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and the interleukin-6 (IL-6) family of cytokines play an important role in initiating and integrating homeostatic responses within the heart. However, these "stress-activated" cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Indeed, there is now a growing appreciation that these molecules may play an important role in mediating disease progression in the failing heart. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in pre-clinical and clinical heart failure models culminated in a series of multicenter clinical trials that utilized "targeted" approaches to neutralize tumor necrosis factor (TNF) in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.
KW - Clinical trials
KW - Etanercept
KW - Inflammatory mediators
KW - Infliximab
KW - Tumor necrosis factor
KW - [110] congestive heart failure
KW - [147] growth factors/cytokines
UR - http://www.scopus.com/inward/record.url?scp=0037333873&partnerID=8YFLogxK
U2 - 10.2174/1566524033361537
DO - 10.2174/1566524033361537
M3 - Review article
C2 - 12630562
AN - SCOPUS:0037333873
SN - 1566-5240
VL - 3
SP - 161
EP - 182
JO - Current Molecular Medicine
JF - Current Molecular Medicine
IS - 2
ER -