An international research team have pinpointed a hidden culprit that leads to dilated cardiomyopathy--a dangerous condition that accounts for 20 per cent of all cases of heart failure--which opens the door to potential new treatments that could help counter the threat.

The team identified a key molecule named PI3K alpha that binds to gelsolin--an enzyme that can destroy filaments that help make up the structure of the heart's cells--and suppresses it.

The researchers believe the molecule holds great promise as a possible therapeutic target, offering a possible path forward to personalized and precision medicine for patients with dilated cardiomyopathy.

The condition decreases the heart's ability to pump blood because its main pumping chamber, the left ventricle, is enlarged and weakened. Researchers studied the condition at the molecular level in animal models and in explanted human hearts, and found that the pathway leading to dilated cardiomyopathy is common in all species. According to the senior author, the condition is caused by biomechanical stress, which activates the gelsolin enzyme.

Loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. 

"You need some gelsolin, but when it gets out of control, it destroys things. The molecule chews up the filaments and you get really bad heart failure," said the senior author. "But we have also shown that when you suppress this molecule, you preserve your heart function. It's intact."

According to the senior author, there are currently no specific treatments for patients with heart failure. The same medications are used for all patients.

"But if we can now identify patients that have problems with this type of remodelling (dilated cardiomyopathy), we can target them specifically," the senior author explained. "That's where we're heading down the road. And to take this research right from the molecule to our patients, it's very rewarding."

https://www.folio.ca/researchers-discover-a-hidden-culprit-in-heart-failure/
 
https://www.nature.com/articles/s41467-018-07812-8

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fpi3k-945-regulated&filter=22