A new treatment for heart failure could soon be on the cards, according to a new study. A research team – including scientists from Johns Hopkins Medicine – claims to have discovered an enzyme that triggers the condition, and medications that block this enzyme are already being tested for other diseases.
Senior investigator Dr. David Kass – professor of medicine at the Heart and Vascular Institute at Johns Hopkins University School of Medicine – and colleagues publish their findings in the journal Nature.
More than 5 million Americans have heart failure. The condition occurs when the heart is no longer able to pump enough blood and oxygen around the body to fuel other organs.
For the heart to function normally, the team explains, two signaling pathways need to be in working order. The chemicals nitric oxide and natriuretic peptide stimulate each pathway to produce a signaling molecule called cGMP, which activates a protein called PKG – the protector of the heart muscle. A breakdown in both of the signaling pathways is a cause of most heart failure cases.
Past research from Dr. Kass and colleagues found that an enzyme called PDE-5 is responsible for the breakdown in the first of the heart’s signaling pathways. In this latest study, the team found that an enzyme called PDE-9 is responsible for the breakdown in the second signaling pathway.
Earlier research revealed that an excess of PDE-5 causes damage in the first of the heart’s signaling pathways by interfering with the signaling molecule cGMP and the protein PKG.
In this latest study, the team found that too much PDE-9 triggers heart failure by specifically interfering with the type of cGMP produced by the second heart signaling pathway.
In detail, PDE-9 speeds up the breakdown of cGMP, which reduces PKG production. This leaves the heart cells susceptible to defects, which can lead to scarring and damage in the heart muscle.
Commenting on the discovery, lead investigator Dong Lee, a cardiology research associate at Johns Hopkins University School of Medicine, says:
“Like a play with multiple characters, heart muscle function is the result of a complex but perfectly synchronized interaction of several proteins, enzymes and hormones.
Our findings reveal that, like two subplots that converge in the end of the play, PDE-5 and PDE-9 are independent rogue operators, each leading to heart muscle damage but doing so through different means.”
The team notes that medications that block PDE-9 activity are currently undergoing testing for Alzheimer’s disease – another condition in which the enzyme is believed to play a part – suggesting it may not be too long before the drugs can be used to treat heart failure.
On testing such medications on mouse models of heart failure, the researchers found they halted enlargement and scarring of the heart muscle. What is more, the drugs almost reversed the condition completely.
“We believe the identification of PDE-9 puts us on the cusp of creating precision therapies that target the second pathway or developing combined therapies that avert glitches in both pathways,” says Dr. Kass.
In another experiment, the team gave mice with heart failure either a PDE-5 inhibitor, a PDE-9 inhibitor or a placebo for 4 weeks. They found that mice treated with the PDE-5 inhibitor or the PDE-9 inhibitor showed significant improvements in heart muscle size and function, and the drugs nearly restored the heart’s pumping ability to normal.
Next, the researchers gave half of the treated mice a chemical that deactivated the signaling pathway regulated by PDE-5. On treating these mice with PDE-5 inhibitors, the team found the drugs had no effect on heart function. Treating mice with a PDE-9 inhibitor, however, led to significant improvements in heart function.
These findings, the researchers say, support the idea that heart failure is triggered by faults in two separate signaling pathways, with one regulated by PDE-5 and the other regulated by PDE-9.
“In practical terms,” adds Dr. Kass, “this affirms that preserving the function in one pathway can avert clinical disease, even if the other one goes bad.”
Medical News Today recently reported on a study published in The Lancet Diabetes and Endocrinology, which suggested that drugs used to manage type 2 diabetes may put patients at higher risk of heart failure.