'Heart attack jab' still needs more work

Scientists have developed a “new heart attack jab” that is “even more effective than statins”, The Daily Telegraph has reported. The newspaper says that a simple jab given to patients up to 12 hours after a heart attack or stroke “could reduce their devastating effects by more than a half”.

This news story is based on animal research that investigated the use of an antibody to block the action of MASP-2, which causes inflammatory response when blood flow returns to tissues that have been starved of oxygen. This phenomenon, known as reperfusion injury, occurs in heart muscle following a heart attack. In mice, the antibody jab reduced the injury when the blood flow to their heart and gut was temporarily stopped. Importantly, though, this injection was given to mice several hours before the blood flow was stopped, meaning that it has not been tested after an injury occurred in the mice.

This research was well conducted and used genetically modified mice to understand further the immune pathways that may cause damage following disruption of blood to the heart. However, this was very early stage animal research and, therefore, should not be considered to have immediate implications for treating heart attack in humans, as some newspapers have mistakenly reported.

Where did the story come from?

The study was carried out by researchers from The University of Leicester and was funded by The Wellcome Trust, The Medical Research Council and the US National Institutes of Health. It was published in the peer-reviewed journal Proceedings of the National Academy of Sciences of the United States of America.

This story was covered poorly by The Daily Telegraph and the Daily Mail. Although both newspapers did say that human trials were expected to start in the next two years, the fact that this was basic animal research was not emphasised. Additionally, the study made no comparisons between statins and the MASP-2 antibody tested in this study. Statins are a long-term medication given to lower cholesterol levels in order to help reduce the risk of having a heart attack or stroke. They are usually given alongside the management of other cardiovascular risk factors, such as high blood pressure. Statins have no role in preventing reperfusion injury after a heart attack or stroke and, therefore, newspapers’ comparison between statins and the experimental antibody injection does not seem to be valid as the two have completely different applications.

What kind of research was this?

This was animal research that used a mouse model of heart attack. The researchers were interested in factors that affect reperfusion injury, a type of tissue injury that can occur when blood returns to the heart after a heart attack.

The researchers were particularly interested in using animal models to explore what might happen if they blocked part of the body’s immune response called the complement immune response following an induced heart attack. They focused on one part of the complement system called the lectin pathway. One enzyme involved in the lectin pathway is called the mannan-binding lectin-associated serine protease 2 (MASP-2). They looked at reperfusion after induced injury in normal mice and in mice who were genetically modified so that they did not produce MASP-2. They also tested the effects of MASP-2 antibodies which blocked the action of MASP-2 in the normal mice.

What did the research involve?

The researchers produced a strain of genetically modified mice that did not produce MASP-2. They checked in their mouse model that MASP-2 activity was completely removed by taking blood from these mice and showing that it could not act upon the proteins that MASP-2 would normally affect. They further showed that in this mouse model the lectin pathway was removed but all other pathways involved in the complement immune system were left intact.

To model a heart attack the researchers clamped one of the heart arteries for 30 minutes. They then allowed the blood to flow back into the heart for two hours. They looked at the extent of the damaged heart tissue and the size of a “risk zone”, which is an area of tissue surrounding the heart that is at risk of suffering delayed damage after reperfusion. The researchers compared the damage in the genetically modified mice and their normal littermates. A similar surgical technique was used to stop blood flow to the intestine to look at the reperfusion injury in the gut.

The researchers then used an antibody that acted against MASP-2 to block its activity. Normal non-genetically modified mice were injected with the anti-MASP-2 antibody, a salt solution (control) or a control antibody (that did not inhibit MASP-2 activity) 18 hours prior to the surgery to block their blood supply. They then looked at the reperfusion damage after surgery.

What were the basic results?

The researchers found that the genetically engineered mice that lacked MASP-2 had significantly less heart damage after the induced heart attack than their normal littermates. They showed that if they took hearts from the genetically engineered mice and the normal mice and perfused them with only blood plasma rather than whole blood, there was no difference in the amount of reperfusion in the two hearts. This showed that it was the enzyme content of the animal’s blood that was responsible for the effects, rather than because the hearts of the genetically engineered mice were intrinsically less susceptible to damage.

The researchers also found that, compared with the normal mice, there was also less damage to the gut tissue of mice who lacked MASP-2 following reperfusion after intestinal injury.

The researchers found that if they inhibited MASP-2 with an antibody before surgery, they reduced the damage more than twofold compared with animals that had received the control antibody. Although tissue damage following reperfusion was not completely avoided, a significant reduction in damage was seen with the antibody.

How did the researchers interpret the results?

The researchers said that their experiments demonstrated that “lectin pathway activity is an essential component of the inflammatory process leading to loss of myocardial [heart] tissue”. They suggest that the importance of MASP-2 lies in its role in the lectin pathway, but they do not exclude the possibility that MASP-2 may have other roles, for example in clot formation.

The researchers also say that the lectin pathway can be blocked in the short term and in a sustained manner by using an MASP-2-specific antibody. They say that such a transient inhibition of MASP-2 activity may provide an attractive therapeutic approach for treating a wide range of ischaemia-induced inflammatory diseases (conditions in which interrupted blood flow causes a potentially damaging immune response when blood flow is restored).

Conclusion

This was well conducted basic animal research that showed the importance of MASP-2 in reperfusion injuries, which can occur in the heart and intestinal tissue when blood flow is returned to them after an interruption. It highlighted that it may be a potential therapeutic target following more research to see whether the findings of this study are relevant to humans.

The newspapers suggested that, on the basis of this research, a jab to protect against injury following stroke and heart attack could be developed, implying that this jab would be effective if given to people within nine hours of their heart attack or stroke. The research study gave the antibody injection to mice 18 hours before their gut injury had been induced and so did not look at whether the antibody would be able to protect this area from subsequent damage if given after the blood flow had returned. Additionally, although newspapers have suggested an application in stroke treatment, this animal study did not look at whether MASP-2 was involved in brain damage subsequent to an experimentally induced stroke.

Although this was good scientific research, the immediate implications of it have been exaggerated. Extensive further research is needed to see whether MASP-2 is a viable and safe drug target after someone has had a stroke or heart attack to prevent further damage taking place.

It remains important that people know the signs of stroke and heart attack. This is so that treatment to restore blood flow can be given as soon as possible, to limit the extent of tissue damage.