'Missing culprit' in heart failure identified

Scientists have identified what they describe as "the long-sought culprit" behind a cell-signalling breakdown that triggers heart failure.

Working with lab animals and human heart cells, scientists from Johns Hopkins University School of Medicine and colleagues found that an enzyme called PDE-9 interferes with the body's natural "braking" system needed to neutralise stress on the heart.

The experiments demonstrated that the enzyme gobbles up a signalling molecule, cGMP, which normally stimulates the production of a heart-protective protein called PKG.

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

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 said.

To understand the enzyme's role, the scientists exploited the knowledge that heart muscle health is safeguarded by two separate mechanisms, or signalling 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 said, are fuelled by breakdowns in both.

Senior investigator David Kass, professor of medicine at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute, nearly a decade ago, identified the culprit responsible for breakdown in one of the signalling pathways.

The culprit was identified as 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 said.

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 pointed out an important difference - PDE-9 has an appetite for the form of cGMP stimulated by the second signalling pathway.

In other words, Kass said, 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 noted 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, researchers said.

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