Developing a new treatment for heart failure caused by meningococcal infection
Professor Michael Levin, Imperial College London
Dr Levin and his team tried to examine the causes for heart failure during meningococcal septicaemia and to find new ways of treating this condition.
Heart failure is a major occurrence in children with meningococcal septicaemia, who often die as a result. Heart failure caused by meningococcal septicaemia is often resistant to current supportive treatments and, prior to this study, there were no specific treatments for heart failure caused by meningococcal septicaemia.
This study aimed to look at what exactly causes heart failure in children with meningococcal septicaemia and the best way to treat children who are suffering from this.
The results of this study could lead to improved treatment options for children suffering from heart failure as a consequence of meningococcal septic shock, potentially saving lives through better treatment.
This project is now complete - see the outcomes tab for more information.
Professor Levin and his team established that heart failure in meningococcal septicaemia is caused by the presence of a protein called interleukin-6 in the blood of children with the disease.
This discovery means that it is now possible to develop treatments to block the effects of interleukin-6 on the heart and prevent heart failure. Such treatments will be a major step in improving the chances of survival in children with the disease.
Development of a novel therapy for myocardial depression in meningococcal septic shock inhibition of a small protein called interleukin 6 (IL6)
Professor Michael Levin, Imperial College London
Dr Levin and his team tried to examine the causes for heart failure during meningococcal septicaemia and to find new ways of treating this condition.
Myocardial depression as a consequence of meningococcal septic shock is a major occurrence in children. Treatment options are limited as the exact mechanisms leading to myocardial depression are unclear. It has been suggested that a cytokine called IL-6 might play an important role in the process.
It is necessary to define the exact mechanisms underlying myocardial depression during meningococcal septic shock to design more promising treatment options than are currently available.
The researchers examined the mechanisms responsible for myocardial depression using an in vitro model of cardiac function: the isolated adult rat ventricular myocyte. In particular, they used pharmacological blockers in an attempt to identify the signalling pathways involved in the mechanism of action of IL-6 mediated muscle weakening.
They also examined muscle weakening leading to cardiac depression through IL-6 in an in vivo mouse model.
In view of the clinical importance of IL-6 as the principal mediator of myocardial depression in meningococcal disease, the team also investigated the role of the IL-6 receptor (sIL6-R). They then examined changes in the IL-6 / IL-6 receptor axis in meningococcal sepsis, as a potential site for blockade of IL-6 activity in septic shock.
This project is now complete - see the outcomes tab for more information.
The group around Dr Levin showed that the muscle weakening action of IL-6 would seem to involve the p38 MAPK signalling pathway and possibly share a common pathway with the Gi G protein to promote myocardial depression.
Data obtained during this project also point to a possible separate mechanism of IL-6 action on basal contraction and on iso-stimulated contraction. This information could have important consequences given that positive inotropes, which strengthen the muscle, are often given in the early stages of sepsis to correct the observed myocardial dysfunction.
The results demonstrate that the IL-6/sIL-6R axis is significantly altered in sepsis, but recovers to normal in survivors. Together with the association between IL-6, sIL-6R and clinical markers of disease severity, the data suggest that these proteins play an important role in the occurrence of myocardial dysfunction in meningococcal septic shock.
The results of this study confirm the importance of IL-6 and its receptor in myocardial depression and will lead the way for new treatment options that target the muscle weakening action of this cytokine to prevent heart failure.
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