Jefferson Researchers Find Potential Biomarker For Heart Failure

A teamof scientists led by Walter Koch, Ph.D., director of the Center forTranslational Medicine in the Department of Medicine in JeffersonMedical 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 infailing human hearts and contributes to the loss of the heart’scontractile strength during the development of heart failure.Decreasing or inhibiting the enzyme reversed heart failure inlaboratory tests.

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

“We can track levels of thiskinase with a simple blood test,” he says. “It appears that consistentwith the numerous animal studies we have done. When GRK2 is elevated inthe 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.

Inthe study, Dr. Koch’s team compared tissue samples from a group of 24patients in heart failure who needed transplants to 58 patients whowere not as sick, though had various stages of left ventricularmalfunction. They found that the sicker patients had higher levels ofGRK2 in the heart and in the blood.

Dr. Koch would like toeventually perform large human trials to specifically look at levels ofGRK2 to see if they can predict responses to drugs such asbeta-blockers or other treatments for heart failure. “We want to see inour proposed clinical trial if GRK2 can be a biomarker that can predictresponse to various therapies,” he says. “In animal models, we’ve shownthat when we lower GRK2 levels, the animal does better. We think thatif a drug lowers GRK2 levels, the patient should benefit.”

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

Inheart failure, the sympathetic nervous system is in overdrive, andlevels of these hormones are high. Dr. Koch says that they probably areresponsible for increasing GRK2 levels in the heart in heart failure.“Circulating white blood cells and cardiac cells bathed in blood areboth exposed to levels of these hormones,” he explains.

Incongestive heart failure, the beta-adrenergic receptor system fails towork properly. Such receptors “drive the heart – both by rate and forceof contraction,” Dr. Koch says.

One of the functions of GRK2 orbeta-adrenergic kinase (ßARK1) is to turn off beta-adrenergicreceptors. “In heart failure, beta adrenergic receptor density isdecreased, ßARK is increased and both together cause dysfunctional betareceptor signaling,” Dr. Koch says. “A failing heart then has littlecapacity to respond to exercise or stress because there are fewerreceptors, and remaining receptors are more or less turned off.”
Congestiveheart failure affects nearly 5 million Americans, many of whom havepoor long-term prognoses, despite recent therapeutic advances.

Otherauthors on the paper include Guido Iaccarino, Emanuele Barbato, ErsiliaCipolletta, Vincenzo De Amicis, Dario Leosco and Bruno Trimarco,Federico II University, Naples, Italy; and Kenneth B. Margulies, TempleUniversity Medical Center, Philadelphia.