Heart injection tested in mice

A “new jab could help repair heart damage and prevent future attacks”, reported the Daily Mail . It said that new cells were ‘kick-started’ into growing when researchers injected a protein called neuregulin 1 into the hearts of adult mice and rats. The newspaper reports that further tests of the injection will be needed before it can be used in humans, including tests on larger animals such as pigs.

This animal research has identified a protein that may be useful in treating some heart disease. Although the news reports suggest that neuregulin 1 (NRG1) treatment might reduce the risk of a second heart attack, this possibility has not been tested in this study, which looked specifically at the effects of the treatment on the recovery after a first simulated heart attack in mice.

The results of this study are promising but as the newspaper suggests, more research will be needed to determine the safety and effectiveness of this protein for treating heart damage before it could move on to testing in humans, and this research will take time.

Where did the story come from?

This research was carried out by Dr Kevin Bersell and colleagues from the Children’s Hospital Boston and Harvard Medical School. The study was funded by the Department of Cardiology at Children’s Hospital Boston, the Charles Hood Foundation, and the American Heart Association. One of the authors is reported as being the founder of an organisation called CardioHeal but no further details are provided. The study was published in the peer-reviewed scientific journal, Cell .

What kind of scientific study was this?

In this study in rats and mice, the researchers investigated whether they could develop a technique to make fully developed adult heart muscle cells divide and form new cells. Such a technique could potentially be used to heal damaged heart muscle, without the need for using stem cells.

The researchers started by trying to identify proteins that could cause fully developed adult heart cells to divide. They were particularly interested in the proteins fibroblast growth factor1 (FGF1), periostin, and neuregulin1 (NRG1). These proteins prompt foetal heart cells to divide and form new cells, and the researchers wanted to see whether the proteins would have the same effect on adult rat heart cells. To do this they grew adult rat cells in the presence of these different proteins and looked at whether the proteins prompted the cells to start making more DNA so that they could divide.

These experiments found that all three proteins prompted adult rat cells in the laboratory to begin making more DNA. As FGF1 and periostin were already known to have this effect, the researchers looked at NRG1 in more detail in a large number of related experiments, some of which are described further here.

Most cells in the body have one nucleus (mononucleate), a structure that contains the majority of genetic material of the cell (DNA). However, some adult heart muscle cells have two nuclei (binucleate) or more (multinucleate). The researchers investigated whether NRG1 prompted cell division in mono- or binucleate heart cells.

The researchers used biochemical methods to see whether the proteins ErbB2 and ErbB4 were needed for NRG1 to have its effects, as they were known to interact with NRG1. They then genetically engineered mice so that they could ‘switch off’ the action of ErbB4 two to four days after the mice were born. These mice had normal heart development up to this point. The researchers looked at the effects that this ‘switching off’ had on the mice’s hearts at 19 days after birth.

The researchers also looked at the effects of injecting NRG1 into three-month-old normal mice. They carried out various tests to see whether any cell division occurred in fully developed (differentiated) adult heart muscle cells rather than undifferentiated progenitor cells.

To look at the effects of NRG1 on damaged hearts, the researchers blocked off one of the coronary arteries on the left side of the heart in two-month-old mice to mimic the effects of a heart attack. One week later, they started injecting some of the mice with NRG1 daily for 12 weeks followed by two weeks without injections, while other mice did not receive any injections (control mice). The researchers then looked at the effects on the structure and function of the heart.

What were the results of the study?

The researchers found that the proteins FGF1, periostin and NRG1 prompted adult rat cells in the laboratory to begin the process that leads to cell division. They then showed that NRG1 prompted about 0.6% of the adult rat heart cells to divide in the laboratory, and these cells lived for the entire duration of the experiment (up to 163 hours). All of the cells that divided were originally mononucleate heart cells; some of these heart cells underwent division of their nucleus and became binucleate cells without dividing.

Further experiments showed that NGF1 needed the proteins ErbB2 and ErbB4 to have this effect. If the researchers stopped the ErbB4 protein from working in genetically engineered mice after birth, they found that at day 19 none of the heart muscle cells were dividing, while in normal mice, about 5% of the heart muscle cells were dividing. The hearts of the 19-day-old mice lacking ErbB4 had fewer cells than normal mice.

The researchers found that injecting three-month-old normal mice with NRG1 led to a proportion of heart muscle cells to divide and this process required the ErbB4 protein. There was no evidence of the heart muscle cells dividing in normal mice that had not been injected with NRG1. Tests suggested that NRG1 caused fully developed (differentiated) adult heart muscle cells to divide rather than undifferentiated progenitor cells.

In control mice that were given a simulated heart attack, there was an enlargement of the volume of one of the lower chambers of the heart (the left ventricle), as well as a thickening of the walls of this chamber 15 weeks later. Tests also showed reduced heart function. These changes are similar to those that occur during the development of heart failure after a heart attack in humans. However, mice treated with NRG1 injections for 12 weeks did not show significant enlargement of the left ventricle or thickening of the walls of this chamber, and had improved heart function compared to untreated mice. NRG1-treated mice were also found to have less scarring of the heart muscle compared to the untreated mice at 15 weeks. Tests showed that the treated mice showed more heart muscle cell division than untreated mice.

What interpretations did the researchers draw from these results?

The researchers concluded that they have identified “major elements of a new approach to promote [heart muscle] regeneration”. They say that their findings suggest that stimulating fully developed heart muscle cells to divide may be an alternative to stem cell-based approaches to promoting heart muscle regeneration in mammals.

What does the NHS Knowledge Service make of this study?

This animal research has identified a protein that may be useful in treating heart disease. Although the news reports suggest that NRG1 treatment might reduce the risk of a second heart attack, this possibility has not been tested in this study, which looked specifically at the effects of the treatment on the recovery after a first simulated heart attack in mice.

The results of this study are promising but more research will be needed to determine the safety and effectiveness of this protein for treating heart damage before it is tested in humans.