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J Am Coll Cardiol, 2006; 48:556-558, doi:10.1016/j.jacc.2006.05.005
(Published online 11 July 2006). © 2006 by the American College of Cardiology Foundation |
Center for Translational Medicine, Jefferson Medical College, Philadelphia, Pennsylvania.
* Reprint requests and correspondence: Dr. Thomas Force, Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, College Building Room 316, Philadelphia, Pennsylvania 19107. (Email: thomas.force{at}jefferson.edu).
)-induced depression of contractile function of the heart is mediated by a specific intracellular signaling pathway, the p38 mitogen-activated protein kinase (MAPK) pathway. Why is this important? Numerous studies have identified proinflammatory cytokines, including TNF-, as potential mediators of the progression of congestive heart failure (CHF). Levels of TNF- were first found to be increased in patients with markedly advanced heart failure and later found to correlate with prognosis (2,3). Following these initial discoveries, Mann et al. (4) and Feldman et al. (5), working with mouse models over-expressing either TNF- or its receptors in the heart, respectively, found that activation of TNF- signaling recreated many of the key pathologies of heart failure: myocyte hypertrophy, remodeling of the extracellular matrix with increased fibrosis, and apoptosis. In addition, of direct relevance to Bellahcene et al. (1), injection of TNF- produced a deleterious hemodynamic response similar to that seen in septic shock (6), and administration of TNF to volunteers depressed left ventricular function, resulting in hypotension (7). These and many other studies raised the hypothesis that TNF- played a significant role in the progression of heart failure.
This hypothesis was tested in recent clinical trials in patients with heart failure with agents targeting TNF-, either by a decoy approach (i.e., preventing interaction of TNF- with the native receptor; etanercept), or by neutralizing TNF- with an intravenously administered monoclonal antibody (infliximab). Results of the trials were, to say the least, disappointing, showing either no benefit or worsened outcomes (8). At the moment, agents targeted to neutralize TNF- are in use for rheumatoid arthritis, inflammatory bowel disease, and psoriasis, but physicians are recommended to exercise caution in using etanercept in patients with CHF, and use of greater than a 5 mg/kg dose of infliximab is contraindicated in patients with New York Heart Association functional class III/IV CHF.
There are several possible explanations for the lack of benefit of these agents in the treatment of heart failure. These include complement fixation on the myocyte cell membrane following infliximab administration or a stabilizing effect of etanercept on TNF-, leading to elevated circulating levels of the cytokine (8). Alternatively, progression of CHF may be due to multiple cytokines and not just TNF-, because, for example, interleukin (IL)-6 levels are also highly correlated with a poor prognosis (3). Another possibility is that TNF- may have beneficial as well as deleterious effects on the heart. Supporting this concept, studies in mice with both TNF receptors knocked out showed that ischemic injury was increased (9).
Tumor necrosis factor- activates 4 key pathways in the cell (Fig. 1). These are: 1) a proapoptotic pathway leading to activation of caspase 8; 2) the c-Jun-N-terminal kinase (JNK) pathway that enhances matrix remodeling and, if persistently activated, apoptosis; 3) the nuclear factor-
B (NF-B) pathway, which indirectly (via JNK inhibition) and directly (via induction of antiapoptotic factors) suppresses apoptosis, thus serving as a counter-regulator; and 4) the p38 pathway which depresses contractility and enhances matrix remodeling and the inflammatory state. Therefore targeting specific pathways, in theory, might provide a more selective approach to treating heart failure than targeting TNF- signaling at the TNF-/TNF receptor level, because cytoprotective NF-B signaling would not be impaired yet the inflammatory state and matrix remodeling might be reduced and contractility improved. This, of course, is entirely speculative in the absence of any data in patients with heart failure.
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The first clear evidence that p38 activation produced negative inotropic effects in vivo was provided by Wang et al. (reviewed in reference 12). Subsequent studies in vitro showed that adenovirus-mediated gene transfer of an activated mutant of MKK3, a kinase that directly activates p38, led to decreased contractility, and, conversely, pharmacologic blockade of p38 enhanced contractility in cultured cardiac myocytes (17). Importantly, this study suggested that the negative inotropic effect of p38 is mediated by altering myofilament sensitivity to intracellular calcium concentration. The negative inotropic effects of p38 have since been confirmed in both in vitro and in vivo models.
Bellahcene et al. (1) now show that either genetic inhibition of p38, achieved by knocking out MKK3, an upstream activator of p38 (Fig. 1), or pharmacologic inhibition of p38 (with a small molecule inhibitor) attenuate TNF-–induced contractile depression in an isolated perfused mouse heart model (thereby eliminating contributions from the periphery, which can obviously be quite profound with TNF-). Importantly, they go even further down the pathway to demonstrate that knocking out the p38 target, MK2, also largely prevents the negative inotropic response induced by TNF-, although the authors point out that this could be due to the fact that MK2 knockout mice have reduced p38 levels in their hearts. Of note, whereas the current study focuses on early effects of TNF- on cardiac contractility, data from numerous in vitro and ex vivo studies concur that TNF- and other cytokines produce a negative inotropic response with early effects within 30 min and prolonged effects for up to 48 to 72 h (7). The mechanisms of the late effects are not known.
Most of the clinical trials of small molecule inhibitors of p38 target inflammatory diseases or multiple myeloma. Preclinical studies in models of cardiovascular diseases suggest that inhibition of p38 might have applications in ischemic diseases, including acute coronary syndromes (ACS), because, as noted, various strategies to block p38 (and MK2) activation in MI models were protective (13–15,18). Inhibitors of p38 are currently in clinical trials for treatment of stroke (SCIO323) and acute coronary syndrome (VX702). In the latter study, patients going to percutaneous coronary intervention were treated for 5 days with VX702 versus placebo. There was no increase in adverse events, and serum levels of C-reactive protein (CRP) were reduced by VX702, possibly consistent with an antiinflammatory effect in ACS. Intriguingly, CRP levels remained reduced 4 weeks after the drug had been stopped.
Is there any rationale for the use of p38 inhibitors in heart failure patients besides the fact that p38 activity is increased in the hearts of these patients (10,11)? We believe the answer to this question may be a very cautious "yes." In addition to studies supporting beneficial effects on contractile function and matrix remodeling in animal models, Kyoi et al. (19) recently reported that inhibition of p38 with either of 2 small molecule inhibitors, SB203580 and FR167653, reduced apoptosis, fibrosis, hypertrophy, and left ventricular dilatation and increased ejection fraction and left ventricular contractility in the cardiomyopathic hamster model. Of note, the proinflammatory effects of p38 are likely mediated by several inflammatory cytokines in addition to TNF-, including IL-1-ß and IL-6 which are hypothesized to play roles in progression of heart failure. Thus, if the anti-TNF- heart failure studies failed, in part, because cytokines in addition to TNF are involved, p38 inhibition might address that issue more effectively. To our knowledge, only 1 clinical trial of a p38 inhibitor in patients with heart failure has been initiated (with semapimod), but this trial was apparently stopped when the results of the TNF--targeted heart failure trials were reported. However, p38 inhibition, if able to be tolerated long term, may have the potential to not only increase contractility (1) but also to reduce matrix remodeling. Clearly, though, there is a need for much more preclinical work in this area before proceeding to trials in this complex and fragile patient population.
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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