Jefferson researchers find potential biomarker for heart failure

August 19, 2005

Signs of heart failure may be in the blood. Cardiac researchers at Jefferson Medical College have found an enzyme in the blood that could be a potential marker for heart failure.

A team of scientists led by Walter Koch, Ph.D., director of the Center for Translational Medicine in the Department of Medicine in Jefferson Medical College of Thomas Jefferson University in Philadelphia, previously showed that an enzyme called GRK2 or beta-adrenergic kinase (ßARK1) is critically important in heart function. It is increased in failing human hearts and contributes to the loss of the heart's contractile strength during the development of heart failure. Decreasing or inhibiting the enzyme reversed heart failure in laboratory tests.

Now, Dr. Koch, who is W.W. Smith Professor of Medicine at Jefferson Medical College, and his co-workers have shown, using tissue samples from heart failure patients, that they could track heart levels of GRK2 in the blood.

"We can track levels of this kinase with a simple blood test," he says. "It appears that consistent with the numerous animal studies we have done. When GRK2 is elevated in the blood, patients have more severe heart failure.

"It's a potential biomarker for heart failure," he says.

The researchers reported their findings July 29 in an online article in advance of print in the European Heart Journal.

In the study, Dr. Koch's team compared tissue samples from a group of 24 patients in heart failure who needed transplants to 58 patients who were not as sick, though had various stages of left ventricular malfunction. They found that the sicker patients had higher levels of GRK2 in the heart and in the blood.

Dr. Koch would like to eventually perform large human trials to specifically look at levels of GRK2 to see if they can predict responses to drugs such as beta-blockers or other treatments for heart failure. "We want to see in our proposed clinical trial if GRK2 can be a biomarker that can predict response to various therapies," he says. "In animal models, we've shown that when we lower GRK2 levels, the animal does better. We think that if a drug lowers GRK2 levels, the patient should benefit."

According to Dr. Koch, researchers have known from animal studies that the expression of GRK2 appears to be regulated by hormones called catecholamines, which include norepinephrine and epinephrine, message-carrying neurotransmitters in the sympathetic nervous system.

In heart failure, the sympathetic nervous system is in overdrive, and levels of these hormones are high. Dr. Koch says that they probably are responsible for increasing GRK2 levels in the heart in heart failure. "Circulating white blood cells and cardiac cells bathed in blood are both exposed to levels of these hormones," he explains.

In congestive heart failure, the beta-adrenergic receptor system fails to work properly. Such receptors "drive the heart - both by rate and force of contraction," Dr. Koch says.

One of the functions of GRK2 or beta-adrenergic kinase (ßARK1) is to turn off beta-adrenergic receptors. "In heart failure, beta adrenergic receptor density is decreased, ßARK is increased and both together cause dysfunctional beta receptor signaling," Dr. Koch says. "A failing heart then has little capacity to respond to exercise or stress because there are fewer receptors, and remaining receptors are more or less turned off."

Congestive heart failure affects nearly 5 million Americans, many of whom have poor long-term prognoses, despite recent therapeutic advances.

Other authors on the paper include Guido Iaccarino, Emanuele Barbato, Ersilia Cipolletta, Vincenzo De Amicis, Dario Leosco and Bruno Trimarco, Federico II University, Naples, Italy; and Kenneth B. Margulies, Temple University Medical Center, Philadelphia.
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Thomas Jefferson University

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