Shutting down a protein found in cardiac muscle could be a new mechanism to treat post-heart attack heart failure, according to research led by the University of Cambridge.
New drugs are needed to improve the heart’s pumping ability after damage from a heart attack. Drugs that strengthen the contraction of failing heart muscle have been deemed unsafe, leaving a gap in the heart attack and heart failure armamentarium.
Researchers now believe that they might have identified a new drug target—a protein called MARK4.
In research funded by the British Heart Foundation (BHF), Cambridge scientists found levels of MARK4 were elevated in mouse hearts after a heart attack. When they compared mice with and without MARK4 in the heart, they found hearts lacking the protein pumped blood 57% more efficiently. This protective effect was seen 24 hours after a heart attack and persisted over the entire follow-up period of four weeks.
The team was first in identifying that MARK4 fine-tunes a structural network within the heart muscle cell—called the microtubule network—that attaches to the machinery governing heart muscle cells contraction and relaxation. When MARK4 levels were increased after a heart attack, microtubules were tightly anchored onto the contractile machinery in the heart, increasing resistance and hindering normal function. When MARK4 levels were reduced, microtubules were loosely anchored, making contraction and relaxation easier.
Following a heart attack the speed of contraction in MARK4-lacking muscle cells increased by 42 percent and the speed of relaxation increased by 47 percent, compared to muscle cells from mice that had the MARK4 protein. They were also almost on par with healthy heart muscle performance, attesting to the power of reducing MARK4.
Based on these findings, the researchers suggested that drugs to switch off MARK4 could be a new way to improve recovery and help the heart to pump blood more efficiently in people with failing hearts.
Dr Xuan Li, BHF Intermediate Research Fellow at University of Cambridge BHF Centre of Research Excellence, said: “After years of research we’ve revealed an entirely new and promising way that could help the recovery of failing hearts.
“It’s early days, and we now need to test the longer-term effects of switching off MARK4. But if drugs to do that prove successful, the life-changing benefits could be seen in people with other types of heart disease as well as those who’ve had a heart attack and developed heart failure.”
Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said: “Heart attacks are a major cause of disability worldwide—people who’ve had a major heart attack are at much greater risk of developing chronic heart failure. There are around 920 000 people living with heart failure in the UK, and we desperately need drugs to drastically improve the heart’s function in these patients.
“These findings are a positive step forward. Further research is needed to refine and test drugs that can target MARK4 before we’ll see them given to people who’ve had a heart attack and develop heart failure.”
Source: University of Cambridge