Researchers from Johns Hopkins Medicine are currently testing a drug that is in clinical trials to treat Parkinson’s disease for the possibility that it could also treat heart failure.
The drug—ITI-214—is a member of a class of compounds called phosphodiesterase (PDE) type I inhibitors, and has shown promising effects on both dog and rabbit hearts, as well as on isolated rabbit heart cells. It has demonstrated the ability to increase the strength of the heart muscle’s contractions.
“Our results are intriguing because so far it’s been largely uncharted territory to come up with a way of increasing contractility that doesn’t ultimately hurt patients,” David Kass, MD, the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine and principal investigator of the study, said in a statement.
PDEs are known to break down one or both of cAMP and cGMP—molecules that serve as molecular messengers inside cells. Each PDE has very specific features, including the type of cell they exist in and their location inside that cell, allowing them to adjust cAMP and/or cGMP very precisely.
PDE inhibitors stop the breakdown of the two molecules, causing them to build up so they can influence proteins to alter the cell.
The researchers found that PDE1 inhibitors shrunk abnormally thick heart muscles in mice caused by high blood pressure and dilate blood vessels. In mice, the heart mostly has a different form of the PDE1 enzyme than found in humans, so PDE1 inhibitors likely affect mice differently than humans.
However, dogs and rabbits have a PDE1 composition more similar to humans.
The researchers used six dogs surgically outfitted with sensors and heart pacemakers and tested the drug’s effects on them before and after they were induced with heart failure, by running the pacemaker rapidly for about three weeks.
The drug was tested at different doses, both orally and intravenously. The dogs were given at least a day between tests.
When given at an oral dose of 10 milligrams for every kilograms via a peanut butter-covered pill, ITI-214 increased the amount of blood pumped out by the heart each minute by 50 percent in the healthy hearts and by 32 percent in the failing hearts.
According to Kass, the drug increased the strength of the heart’s contractions by almost 30 percent and by dilating the blood vessels.
Intravenous administration of the drug resulted in similar, but more rapid, effects.
“We were pretty agnostic about what we would find and didn’t necessarily expect anything that novel,” Kass said. “To my knowledge, no study had reported increased heart contraction strength from a PDE1 inhibition before. But then, all of the prior studies where this might have been tested had used mice, and we knew that a different PDE1 form was found in larger mammals and humans. So, we just had to try it, and the results were very interesting.”
However, in healthy dogs the drug increased the heart rate by about 40 beats per minute, which can prove to be dangerous for patients with heart failure, while the dogs with failing hearts saw no significant difference in heart rate.
Despite promise, the researchers are worried about potential fatal complications.
“This was the boogeyman in the room,” Kass said. “The new drug produced many of the same heart and artery changes that PDE3 inhibitors do, so we naturally worried whether it worked in a similar way and might also have complications. So we tested them side by side.”
Here the researchers found that ITI-214 caused the cell to contract strongly, but the cell’s calcium levels did not ultimately rise.
This indicates that ITI-214 increases muscle contractions through a different mechanism than the PDE3 inhibitors.
“Our results show that inhibiting PDE1 produces different changes than blocking PDE3, and so we hope that we can bypass the calcium-mediated and potentially deadly arrhythmias that have plagued PDE3 inhibitors,” Grace Kim, a lead co-author and a postdoctoral fellow in Kass’ lab, said in a statement. “We are anticipating similar positive benefits on heart function but with much less toxicity.”
According to the Centers for Disease Control and Prevention, heart failure affects about 5.7 million U.S. adults and contributes to an estimated one in nine deaths.
ITI-214 is now in early clinical trials and is being tested in heart failure patients at Johns Hopkins Medicine and Duke University. It has already passed phase I safety trials in healthy individua
