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Protein discovery could be key to preventing heart complications of sepsis

Proteins in the blood called histones, which are released from damaged tissues during sepsis, can cause life-threatening heart failure according to new research from the University of Liverpool funded by the British Heart Foundation (BHF) and published in the journal Critical Care Medicine. The finding that histones affect the heart’s ability to pump, points the way toward a new treatment against the deadly effects of a septic infection.

Sepsis is a life-threatening condition caused by the body’s response to an infection. It leads to more than 100,000 people being admitted to hospital in the UK each year. Over a third (around 37,000) of people admitted with sepsis die, more than from any single type of cancer1. While antibiotics are often effective at treating the infection, the body’s response and toxins released by dead cells or from bacteria can be deadly as blood pressure and heart function drop significantly.

Previous research also funded partly by the BHF and published in Critical Care Medicine, showed a link between elevated levels of histones in the blood and heart damage or dysfunction in septic patients. But it was not clear how histones were harmful to the heart. The Liverpool team, led by Professor Cheng-Hock Toh and Dr Guozheng Wang and also funded by the Medical Research Council and the National Institute of Health Research, have now found in mice how histones affect the heart.

Histones are usually found in the cell’s nucleus, its ‘command centre’, which contains all of its genetic material. They act like spools around which the DNA winds so it can be tightly packaged and fit inside the nucleus. Once large numbers of cells die, the histones are released into the blood causing harmful effects.

The researchers have now found that histones affect the left and right side of the heart differently, dependent on the levels of histone in the blood. Higher doses of histone were found to be more damaging but the left side of the heart was affected by even moderate doses.

The Liverpool team is planning a systemic investigation of common proteins released by cell death and bacteria that are toxic to the heart. They will find out their basic structures and how they interact at a molecular level, as well as developing ways to detect them and therapeutic drugs to target them. This could ultimately lead to better clinical management of people who suffer from septic shock.

Dr Guozheng Wang, a lead researcher on the study at the University of Liverpool, said:

“We learnt that histones have a damaging effect on the levels of calcium in heart muscle cells, which affects heart rhythm and the cells ability to beat properly. Importantly we also found that an ‘anti-histone treatment’ cancelled out the toxic effects of the histones on heart cells suggesting we could develop a drug to successfully treat some of the damaging effects of sepsis on the heart.

“Our team is now looking at what levels of histone cause damage on the heart during sepsis before we begin looking further at testing new treatments, which could ultimately help save the lives of thousands of people.”

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which helped fund the research, said:

“Treatments for the effects of sepsis on the heart and blood vessels are urgently needed and they will only come through research such as this.

“Although at an early stage, these findings point to a promising way to target and treat the heart damage associated with sepsis. These results, along with the team’s earlier work, also offer the possibility of developing a test, measuring histone levels, which could be used to identify the patients suffering from sepsis who are at greatest risk of heart problems.”

Paul Cornhill, aged 55 from Tamworth in Staffordshire, suffered sepsis and septic shock in 2012 and spent nearly five weeks in hospital as a result of the condition.

Paul survived this traumatic experience but he still feels debilitated by the after effects. The researchers hope new treatments based on their findings will not only save lives but reduce the long term complications caused by sepsis.

“I’m so grateful to be alive but it’s three years later and I still feel the effects of what I went through. I am getting stronger but I often struggle to climb stairs without feeling weak or breathless. We need new, more effective treatments for sepsis that save lives and also mean people recover quicker from the condition.

“I was ill in hospital for a long time and my recovery has been even longer, but with the support of Good Hope Hospital, the Sepsis Trust, my wife and daughter, I’m finally beginning to feel like myself again.”