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Sick hearts as instructors

Diseases are possibly one-way streets, at least this is what many scientists and physicians believe in the case of chronic cardiac insufficiency. Therefore, only the symptoms of this disease are treated. However, under certain conditions, some hearts manage to partially recover on their own. In a joint project with heart surgeons from Freiburg, pharmacologist Professor Dr. Lutz Hein and his team at the University of Freiburg, are working to uncover the mystery of spontaneous self-healing. Initial results suggest the involvement of genetic mechanisms, amongst other things.

In Germany, acute and chronic cardiac insufficiency is responsible for 23 percent of all deaths. This number will increase in a constantly ageing population. High blood pressure, alterations of the cardiac valves as well as frequent cardiac infarctions can lead to cardiac insufficiency. The heart gets weaker and is no longer able to pump efficiently. The body reacts to this situation with stress symptoms, noradrenalin is released along with hormones such as aldosterone, angiotensin and renin. These substances lead to elevated blood pressure. The heart beats faster and inflates, leading to cracks and scar tissue. This can have long-term consequences, resulting in cardiac arrhythmia and eventually heart failure. Physicians usually prescribe drugs that block the stress hormone system or the renin-angiotensin system, meaning that they are only treating the symptoms. “We hope that our project, which we are conducting in cooperation with the Cardiovascular Centre at the University Medical Centre in Freiburg, will open up new methods of treatment,” said Professor Dr. Lutz Hein from the Institute for Experimental and Clinical Pharmacology and Toxicology at the University of Freiburg.

Healthy (top row) and sick (bottom row) mouse hearts: cardiohypertrophy leads to the enlargement of the heart muscle (bottom row, left picture), the cavity expands (bottom, central picture) and cracks and scars develop in the muscle tissue. © Work group Hein

The heart will manage on its own

The scientists led by Hein and the heart surgeon Professor Dr. Friedhelm Beyersdorf from the Cardiovascular Centre hope to get the heart “out of the one-way street and enable it to drive longer distances.” They are hoping to be able to work out how to do this by carrying out experiments on hearts that have regained the ability to work autonomously. Observations of patients who have been given artificial pumps to compensate chronic heart insufficiency, show that about ten percent of them no longer need the pump after a short while. Their hearts have recovered. But the question remains, how did this happen? “The cells of the hearts in question must have switched on mechanisms that induce normalisation,” said Hein. “We hope to understand these mechanisms in order to be able to induce or strengthen them specifically at some stage in the future.”

In order to find out more, Hein and his team of researchers are investigating genes that are activated and switched off in human heart tissue samples obtained from healthy, sick and spontaneously recovered patients. The problem is that human samples are rare, and they cannot be genetically manipulated as the researchers require. Therefore, the researchers use another trick. They manipulate healthy mouse hearts. A thread is knotted around the aortic bow, which leads to aortic constriction and reduces the supply of blood. As a result, the mouse heart has to beat quicker and more strongly. This is exactly what occurs in people with chronic heart insufficiency. After the typical symptoms of hypertrophy (i.e. the enlargement of the heart) have appeared, the researchers loosen the knot and simulate an artificial pump which eases the pressure on the mouse heart. The researchers closely monitor which genes are being switched on or off.

Artificial cardiohypertrophy: A thread tied around the aortic bow of a mouse heart (centre) limits the supply of blood and causes the heart to become inflated. © Work group Hein

Cell memory beyond DNA

Methyl groups and a complex consisting of MeCP2 and HDAC block and silence the DNA (left). The lack of methyl groups and proteins leads to the transcription of the DNA (right). © Work group Hein

Hein and his team have found a large number of such genes. But it is still not clear which ones have the required function. Many more experiments will have to be carried out. One candidate is of particular interest to the researchers. This is the gene coding for the protein MeCP2, which binds to DNA that has methyl groups attached to it. DNA sequences with small methyl molecules attached to them cannot be transcribed and subsequently translated into a protein. Proteins that transcribe these sequences and produce mRNA are no longer able to approach the DNA. The genes in such regions are silenced. MeCP2 directs proteins that mediate the silencing of the genes, to methylated DNA stretches.

"DNA methylation is part of what is referred to as epigenetic programming," said Hein. In the cell, epigenetic mechanisms provide information that, in addition to information encoded by the DNA itself, determines which proteins are produced in a cell. This information can also be passed on to subsequent cell generations. Therefore, epigenetic programming is a kind of memory. "It is very interesting to note that chronic heart insufficiency involves molecules that affect the epigenetic memory of the heart cells," said Hein. "It may be that cells in a hypertrophic heart could have an epigenetic programme forced on them, obliging them to behave in a particular way." Such phenomena are also known in the case of cancer cells where epigenetic modifications cause tumour cells to inherit their ability to divide incessantly to their daughter cells. Researchers are now trying to reprogramme tumour cells.

Further information:
Prof. Dr. Lutz Hein
Institute for Experimental and Clinical Pharmacology and Toxicology
University of Freiburg
Albertstraße 25
D-79104 Freiburg i. Br.
Tel.: +49 (0)761/203 5314
Fax: +49 (0)761/203 5318
E-mail: lutz.hein(at)pharmakol.uni-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/sick-hearts-as-instructors