MAR 25, 2015 9:41 AM PDT

'Missing Culprit' in Heart Failure

WRITTEN BY: Judy O'Rourke
Working with lab animals and human heart cells, scientists from Johns Hopkins and other institutions have identified what they describe as "the long-sought culprit" in the mystery behind a cell-signaling breakdown that triggers heart failure. The condition, which affects nearly 6 million Americans and 23 million people worldwide, is marked by progressive weakening and stiffening of the heart muscle and the organ's gradual loss of blood-pumping ability.

The research results, described recently in the journal Nature, reveal that an enzyme called PDE-9 interferes with the body's natural "braking" system needed to neutralize stress on the heart.
Ultrasound images of mouse hearts: Absence of PDE-9 protects the heart from the deleterious effects of pressure overload as seen in image, lower right corner. By contrast, mice with intact PDF-9 genes developed enlarged, dilated hearts captured here by walls that are stretched far apart from each other, shown in lower left corner.
The experiments demonstrate that the enzyme wreaks mischief by gobbling up a signaling molecule, cGMP, which normally stimulates the production of a heart-protective protein called PKG, known to shield the heart muscle from the ravages of disease-causing stress, such as long-standing high blood pressure.

Naturally found in the gut, kidneys, and brain, PDE-9 is already a prime suspect in neurodegenerative conditions such as Alzheimer's, the researchers say.

But the new study shows the enzyme's footprints are also present in heart cells and markedly elevated in patients with heart failure - evidence that PDE-9 is a multitasking "offender" and a key instigator of heart muscle demise, the researchers say.

To understand the enzyme's role, the scientists exploited the knowledge that heart muscle health is safeguarded by two separate mechanisms, or signaling pathways. Activated by two different chemicals - nitric oxide and natriuretic peptide - each pathway produces cGMP, which in turn stimulates the all-important heart muscle protector PKG. Most cases of heart failure, the researchers say, are fueled by breakdowns in both.

"The existence of two separate pathways with overlapping but distinct functions is nature's insurance policy, a fail-safe redundancy to ensure that should one pathway falter, the other one can compensate and maintain heart muscle function," says senior investigator David Kass, MD, professor of medicine at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute.

Nearly a decade ago, a team led by Kass identified the culprit responsible for breakdown in one of the signaling pathways, an enzyme called PDE-5 - also known to cause erectile dysfunction - and ever since then scientists have searched for the second "offender" that causes glitches in the other pathway. The discovery of PDE-9 provides that long-sought "break in the case," the team 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," says lead investigator Dong Lee, MS, PhD, a cardiology research associate at the Johns Hopkins University School of Medicine. "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."

Kass' earlier studies showed that PDE-5, like its newly identified accomplice PDE-9, inflicts damage by feeding on heart-protective cGMP and PKG. But the new findings reveal an important difference - PDE-9 has an appetite for the form of cGMP stimulated by the second signaling pathway.

In other words, Kass says, too much PDE-9 can interfere with the second of the two heart-protective systems by speeding up the breakdown of cGMP, which in turn reduces levels of PKG, rendering heart cells prone to malfunction and the heart muscle vulnerable to scarring and damage.

The research team also notes that heart failure treatments blocking the activity of PDE-9 may be right around the corner, with drugs that inhibit PDE-9 already being tested for use in people with Alzheimer's disease.

In the current study, such PDE-9 blockers not only stopped heart muscle enlargement and scarring in mice with heart failure, but they nearly reversed the effects of the disease.

"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," Kass says.

The new findings could be even more relevant for the nearly one-half of all heart failure patients with an especially recalcitrant form of the disease known as heart failure with preserved ejection fraction - a treatment-defying condition in which the heart appears to pump normally but is, in fact, scarred and hardened. Heart cells obtained from people with this form of the disease showed PDE-9 levels six times higher than normal hearts, suggesting that people with that form of the disease have far less heart-protective PKG, the researchers note.

[Source: Johns Hopkins Medicine]
About the Author
  • Judy O'Rourke worked as a newspaper reporter before becoming chief editor of Clinical Lab Products magazine. As a freelance writer today, she is interested in finding the story behind the latest developments in medicine and science, and in learning what lies ahead.
You May Also Like
JUN 18, 2019
Cardiology
JUN 18, 2019
New Noninvasive Method For Controlling Atrial Fibrillation
Atrial fibrillation or Afib is a condition in which the heartbeat is irregular. Often the pulse is rapid in Afib patients as the heart attempts to maintain...
JUN 24, 2019
Cardiology
JUN 24, 2019
Performance Enhancing Bacteria?
Attempts by athletes to increase their performance occasionally goes too far. This is the case in endless doping scandals across all types of elite athleti...
JUL 29, 2019
Drug Discovery & Development
JUL 29, 2019
Medications Used for Atrial fibrillation May Increase Falls
Falls among older adults are a growing health concern that often lead to injury, hospitalization, and other severe complications. Older adults are even at...
AUG 01, 2019
Cardiology
AUG 01, 2019
Preventing Sarcopenia In Older Adults
The loss of muscle mass associated with aging, called sarcopenia, begins at about age 30 and continues throughout an individual's lifespan. This muscle...
SEP 11, 2019
Cardiology
SEP 11, 2019
Better Sleep, Brought To You By Exercise
Regular difficulty falling or staying asleep, called chronic insomnia, is the most common sleep disorder among adults. In the search for better, more restf...
JAN 04, 2020
Cardiology
JAN 04, 2020
New Protein Therapy Improves Heart Attack Survival Rates
Heart disease is the top killer in the Western world. This is partially because, if one manages to survive an initial heart attack, oftentimes the scar tis...
Loading Comments...