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An active substance that could help fill your failing heart – New Treatment

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Shortness of breath and fatigue are common in patients with Heart Failure. They frequently complain about water retention, palpitations of the heart, and dizziness.

A combination of high blood pressure, diabetes, and kidney disease, as well as acute events like heart attacks or infections, can cause the condition. Because the number of risk factors increases as people age, heart failure primarily affects the elderly, particularly women.

Despite the fact that the symptoms are identical, there are a number of causes. The heart’s pumping function is impaired in one form of the condition. However, a medication that is freely available can help. In the other case, the heart pumps with sufficient force, but the heart’s chambers – the ventricles – fail to fill correctly due to thicker or stiffened ventricular walls.

This type of heart failure currently has no effective treatment. A team led by Professor Michael Gotthardt of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has developed a therapeutic agent to improve the treatment of heart failure with preserved ejection fraction in collaboration with colleagues from Heidelberg University and the California-based company Ionis Pharmaceuticals.

In the journal Science Translational Medicine, the researchers detail their novel therapeutic method.

The giant protein titin influences heart elasticity

The heart’s mechanics are reliant on titin, an elastin-like large protein. It’s made by cardiac muscle cells in a variety of variations or isoforms with varying degrees of flexibility. While extremely elastic titin proteins predominate in infants, stiffer titin isoforms are synthesized later in life as growth and remodeling are completed, increasing pumping efficiency. Thickened heart walls, intercalated connective tissue, and stiffer titin filaments may result in poorer ventricular filling in heart failure with intact ejection fraction.

Adult heart muscle cells are virtually incapable of self-renewal. The constant pumping activity of the heart muscle, on the other hand, places such a pressure on titin that it must be broken down and replenished every three to four days.

“The mechanical properties of titin proteins are difficult to adjust,” said Gotthardt.

Artificial heart tissues

“But we can now intervene in the process preceding protein synthesis – that is alternative splicing.”

Alternative splicing is a brilliant mechanism designed by nature to produce a number of similar proteins from a single gene, including several forms of titin. Splicing factors are in charge of this procedure.

“One of these, the master regulator RBM20, is a suitable target that we can address therapeutically,” explained Gotthardt.

Antisense agent deactivates RBM20

The elastic, contractile, and electrical properties of the heart chambers are determined by RBM20. Preliminary trials with mice that can only produce half as much RBM20 as normal animals due to a deletion demonstrated that it is definitely the deciding factor: There was a shift to more elastic titin isoforms in the lacking mice. The scientists began exploring for a strategy to impact RBM20 with the help of the Ionis researchers.

“We were surprised at how easily this could be done,” said Gotthardt – namely with antisense oligonucleotides (ASOs).

These are synthetically manufactured short chains of single-stranded nucleic acids. They attach to the complementary RNA sequence, which is the blueprint for the targeted protein, and thereby prevent its creation.

Artificial heart tissues

The ASOs were initially successfully tested in mice with stiffer heart walls, according to Dr. Michael Radke, one of the study’s lead authors. The heart muscle cells produced from human stem cells were subsequently grown into artificial heart tissue by his colleague Victor Badillo Lisakowski.

When the tiny 3D structures find resistance, they can be encouraged to contract and relax, simulating the heart’s pumping motion. This artificial heart tissue also demonstrated the treatment’s impact: The researchers were able to show that the ASO molecules do indeed permeate cells and cause the intended response.

“These tests on artificial heart tissue were an important step, because the primary sequences for titin are not identical in mice and humans,” said Radke.

A weekly injection?

Antisense oligonucleotides have been successfully employed to influence alternative splicing in cardiac illness for the first time. The Ionis researchers were able to stabilize the sensitive molecule so that it can reach the striated muscles in the mouse model without being destroyed in the blood, liver, or kidneys. The majority of it is absorbed by the heart, with some reaching the skeletal muscle.

“In the mouse model, however, we observed that it has no disruptive effect if increased amounts of elastic titin are formed in skeletal muscle,” stressed Radke.

Heart failure is a chronic condition that demands long-term care.

“So we treated our mice over a longer period of time and were able to see lasting treatment effects,” said Gotthardt.

“An improvement over a weekly injection, which many patients are already familiar with from insulin or heparin, would be oral administration,” he said.

Source: 10.1126/scitranslmed.abe8952

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