Heart failure occurs when the heart loses its ability to pump blood effectively. Current treatments can slow or stop the disease getting worse, but they can’t regress it. Now, scientists have designed a molecule that could not only curb heart failure but also improve the heart’s blood pumping ability.
The researchers in Brazil and the United States who developed and tested the experimental drug have named it “SAMβA,” which is short for “selective antagonist of mitofusin 1-β2PKC association.”
When the researchers gave it to rats with heart failure, the molecule not only stopped the disease from progressing but also reduced its severity by improving the ability of heart muscle to contract.
“The drugs in current use,” says first study author Julio C. B. Ferreira, who is a professor in the Biomedical Science Institute at the University of São Paulo in Brazil, “halt [the] progression of the disease but never make it regress.”
SAMβA works by blocking a specific interaction between the proteins mitofusin 1 (Mfn1) and beta II protein kinase C (β2PKC) whose association impairs mitochondria in heart muscle cells, causing the cells to die. Mitochondria are tiny compartments inside cell bodies that make the chemical energy cells need to function and live.
“We showed that by regulating this specific interaction, we could both halt [the] progression and make the disease regress to a less severe stage,” Prof. Ferreira explains.
According to the most recent figures from the Centers for Disease Control and Prevention (CDC), in 2016 there were around 5.7 million people in the United States living with heart failure.
The body’s organs and tissues require a constant supply of oxygen- and nutrient-rich blood to function and stay in good health.
Heart failure arises when the heart’s ability to pump blood does not match the body’s needs.
In a healthy heart, the heart muscle contracts and pumps freshly oxygenated blood into the aorta from where it travels to the rest of the body.
In a person with heart failure, the heart muscle is weak or damaged and does not fully contract, leaving some blood left to pool inside the organ.
People with heart failure often feel tired and fatigued and may experience shortness of breath as they go about their everyday lives. They can also struggle to breathe when they lie down, and they can put on weight due to swelling in the stomach, ankles, feet, or legs.
Failing hearts overproduce the protein β2PKC. Previous work by some of the researchers in Brazil had shown that blocking the protein improved heart function in people with heart failure.
However, while the β2PKC inhibitor that they used improved heart function, it also stopped the protein from doing other things that help the heart.
What the new study shows is that SAMβA “is more selective.” It only blocks one specific interaction, and that is the one that β2PKC has with Mfn1 — the one that affects the function of mitochondria. It does not affect β2PKC’s other interactions.
To show this, the team carried out a series of tests in cells, rodents, and samples of heart tissue from people with heart failure.
It reveals that β2PKC builds up on the outer wall of mitochondria and chemically alters the function of Mfn1 by adding a phosphate group to it. This leads to “buildup of fragmented and dysfunctional mitochondria in heart failure,” note the study authors.
Scientists call the process through which β2PKC alters Mfn1 phosphorylation, and it is one of the “most common” mechanisms in cells for altering the function of proteins.
The team experimented with various compounds to find candidate molecules that could block this interaction between β2PKC and Mfn1 to prevent the ensuing damage to mitochondria.
They identified six molecules that could block the β2PKC-Mfn1 interaction, but of these, only SAMβA did it in a way that did not affect β2PKC’s other interactions.
Tests using human heart cells showed that, like the drugs already in use for the treatment of heart failure, SAMβA could curb the progression of the disease.
However, unlike conventional treatments, many of which have been around since the 1980s, SAMβA went a step further: it enhanced the ability of heart cells to contract, which is essential for effective pumping of blood.
The researchers observed that SAMβA also reduced a marker of oxidative stress in the heart cells. Oxidative stress can trigger cell death if the cell cannot defend itself against it.
In a final set of tests, the team induced heart failure in rats by provoking a heart attack. Unlike the rats that received a placebo, those that received SAMβA stopped showing signs of heart failure and showed improvement in heart function.
To make progress toward a clinical treatment, other teams now need to test the molecule independently. There is also a need to check its compatibility with other heart failure drugs.
“Validation and reproduction of our findings by other groups are critical to the process of developing SAMβA for use in treating heart failure. We will be seeking partners in the private and public sectors for this purpose.”
Prof. Julio C. B. Ferreira