In enzyme's isoforms, hope for developing heart drugs that improve contractility, prevent SCD

Nov 18, 2013

Drugs known as PDE3 inhibitors save many lives by helping failing hearts do a better job of pumping blood. But those same medications come with a sometimes deadly cost when taken for long periods: an increased risk for sudden cardiac death.

The drugs work by inhibiting PDE3A, an enzyme that regulates how the heart pumps blood. When PDE3A is inhibited, the heart contracts more forcefully, pumping more blood.

Developing a medication that has the benefits of current drugs but doesn't increase the risk for associated has eluded researchers. But an international collaboration led by two Utah researchers is a key first step in finding out whether such a drug may one day be developed.

The research, funded by the Department of Veterans Affairs, was published in the Proceedings of the National Academy of Sciences (PNAS) online the week of Nov. 18, 2013. Matthew A. Movsesian, M.D., professor of medicine at the University of Utah School of Medicine and a cardiologist at the George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City, is the senior author. Fabrice Vandeput, Ph.D., a postdoctoral fellow in cardiology at the University of Utah and the VA Medical Center, is first author.

PDE3A comes in three types, or isoforms. PDE3A inhibitors work by inhibiting all three isoforms of the enzyme. Working with colleagues from the United States and Scotland, Vandeput and Movsesian made an important discovery: two of those isoforms, PDE3A1 and PDE3A2, are regulated individually and interact with different proteins in a cell.

"If those isoforms are regulated differently, this tells us they probably are doing different things in cells. And if they interact with different proteins, this means there are molecules that bind to one isoform and not the other," Movsesian says.

That could make it possible to develop a drug that targets one or other of the isoforms to inhibit PDE3A without upping the risk of sudden . Years of work must be done before such a drug could be developed and available to patients. Researchers need to learn much more about the isoforms to understand their roles in how the heart contracts to pump blood (called contractility). They also need to know whether either form of PDE3A contributes to sudden cardiac death in those taking current drugs.

It's also possible that research could determine neither of the isoforms would be a good target for drugs, according to Movsesian, also a professor of pharmacology and toxicology.

"We don't know for certain if these isoforms will ultimately prove to be good targets for drugs," he says. "But we now have reason to believe we could target one or the other."

About 5.7 million people in the United States have heart failure, according to the Centers for Disease Control and Prevention (CDC), with more than 55,000 deaths directly attributed to the condition annually. In 2008, heart failure was a contributing cause in 280,000 deaths, according to the CDC.

PDE3 inhibitors can be taken for shorter periods, when someone has a heart attack and needs help recovering, for example, or for a year or more, such as when a patient with heart failure waits for a transplant or can't survive without the drug. In patients who take them for longer periods, an increase in the mortality rate from sudden cardiac death may outweigh the benefits of increasing cardiac contractility, according to Movsesian.

Explore further: NIH and CDC launch registry for sudden death in the young

More information: Selective regulation of cyclic nucleotide phosphodiesterase PDE3A isoforms, www.pnas.org/cgi/doi/10.1073/pnas.1305427110

Related Stories

NIH and CDC launch registry for sudden death in the young

Oct 24, 2013

A registry of deaths in young people from conditions such as heart disease and epilepsy is being created to help researchers define the scope of the problem and set future research priorities. The National Institutes of Health ...

New research takes aim at heart's 'safe zone'

Oct 28, 2013

Sudden cardiac arrest is the leading cause of death in the industrialized world. However, it's not well understood and is challenging to both predict and effectively prevent, according to Alain Karma, Arts and Sciences Distinguished ...

Patients with heart failure need specialist care

Nov 01, 2013

(Medical Xpress)—New research from Karolinska Institutet in Sweden shows that patients with heart failure have high mortality and often are undertreated. According to a study, published in the scientific periodical JACC, ...

Recommended for you

Chemical biologists find new halogenation enzyme

Sep 15, 2014

Molecules containing carbon-halogen bonds are produced naturally across all kingdoms of life and constitute a large family of natural products with a broad range of biological activities. The presence of halogen substituents ...

Protein secrets of Ebola virus

Sep 15, 2014

The current Ebola virus outbreak in West Africa, which has claimed more than 2000 lives, has highlighted the need for a deeper understanding of the molecular biology of the virus that could be critical in ...

Protein courtship revealed through chemist's lens

Sep 15, 2014

Staying clear of diseases requires that the proteins in our cells cooperate with one another. But, it has been a well-guarded secret how tens of thousands of different proteins find the correct dancing partners ...

Decoding 'sweet codes' that determine protein fates

Sep 15, 2014

We often experience difficulties in identifying the accurate shape of dynamic and fluctuating objects. This is especially the case in the nanoscale world of biomolecules. The research group lead by Professor Koichi Kato of ...

User comments : 0