By David N. Leff

Heart failure means just what it says: The heart falls down on its job of pumping blood around the body to meet that body's ever-changing needs for oxygen and nutrients.

This doesn't spell an automatic sentence of sudden death, though. Heart failure, the commonest form of cardiac disease, is often a drawn-out chronic ailment, marked by bouts of fatigue, breathlessness, palpitations and extreme sensitivity to cold.

As the ability of a failing heart to pump blood goes down, the level of an enzyme known as BARK goes up. BARK stands for "beta-adrenergic receptor kinase." It sits on the surface of cardiac tissue cells.

Severe attenuation of this enzyme's receptor marks chronic human heart failure. It results from diminished receptor number and function.

Beta-adrenergic receptors grab onto neurotransmitters, especially epinephrine (adrenaline), the hormone famously known for its action to cope with the "three-F" fight-flight-or-fornicate rush of energy. (See BioWorld Today, April 17, 1995, p. 1.) Such stressful episodes make sudden, severe demands on a heart's pumping force and speed of beat. If the cardiac organ isn't up to the challenge, heart failure ensues.

The BARK enzyme uncouples — that is, turns off — cardiac beta-adrenergic receptors, so there are fewer of these molecules to recruit neurotransmitters. The enzyme may mean well, metabolically, as a feedback mechanism to keep those stresses from hitting the heart too hard, but when that heart is in failure, shouldn't BARK be leashed?

That notion led cardiologist Howard Rockman at the University of North Carolina, in Chapel Hill, to prevent mice born prone to heart failure from developing their lurking disease. He and his collaborators pulled off this feat by blocking BARK.

Their report in the current Proceedings of the National Academy of Sciences (PNAS), dated June 9, 1998, bears this title: "Expression of a ß-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice."

It took three strains of transgenic mice to make this in vivo therapy work.

The first group of animals came into the world equipped with more than 100 times the normal number of beta-adrenergic receptors on their cardiac cells. A second murine contingent carried built-in genetic inhibitors of the enzyme. Rockman and his co-authors created both types of transgenic rodents.

The team mated each of the two BARK-silencing strains with a third transgenic contingent — mice genetically constructed elsewhere, which develop cardiac failure marked by heart enlargement and decreased contraction. Their third-generation progeny cross-bred to BARK-blocked mice grew up free of these heart-failure hallmarks.

"Whether they're young animals or old animals," Rockman said, "age six months or a year, we totally prevented heart failure."

Hanging over this accomplishment is a teasing question: Did the experiment merely prevent inborn heart failure from emerging, or did it cure heart failure that had already developed?

"We're actually involved in studies," Rockman revealed, "to determine if it is possible to reverse heart failure in mice after it has already developed, by turning on this enzyme inhibitor later in life."

His paper concluded: "That the inhibition of a single molecule (ßARK) can have such a dramatic effect on a cardiac phenotype caused by a structural abnormality [incipient heart failure] is surprising and indicates that ßARK1 inhibition may offer a novel therapeutic target in heart failure." *