Philadelphia, PA - Italian and American researchers have identified an enzyme in the blood known as G protein-coupled receptor kinase 2 (GRK2) that correlates with cardiac GRK2 levels. As GRK2 is responsible for turning off -adrenergic receptors in the heart, researchers say the easily measured GRK2 activity in white blood cells could be used as surrogate for cardiac GRK2 levels in failing hearts.

"In our previous animal work, we saw that elevated GRK2 levels in the heart are bad and lower levels are good," said senior investigator Dr Walter Koch (Thomas Jefferson University, Philadelphia, PA). "Our thinking was that if we could somehow monitor GRK2 levels in the heart, it could possibly serve as a biomarker for the heart's function. In this paper, we were able to show that it is possible to track cardiac levels of this kinase in white blood cells."

The study is published in the September 2005 issue of the European Heart Journal, with Dr Guido Iaccarino (Federico II University, Napoli, Italy) as first author.

Koch told heartwire that GRK2 is one of seven kinases of the G-protein coupled receptor family. GRK2 is most abundant in the heart and specifically targets the -adrenergic receptors, the pivotal molecules in control of cardiac function through sympathetic nervous system activity. In heart failure, the deterioration of ventricular function is associated with a reduction in -receptor density as well as increased expression of GRK2, which acts to shut down remaining receptors so that the heart is unable respond to exercise or stress, said Koch.

In this study, the investigators obtained left ventricular tissue samples from 24 patients undergoing cardiac transplant due to severe deterioration of cardiac function. They found a significant inverse correlation between GRK activity and -adrenergic receptor responsiveness, noting that when GRK2 activity is higher, -receptor signaling is depressed.

To test the hypothesis that GRK2 activity in white blood cells could be used as a surrogate for cardiac GRK2 levels in failing hearts, the researchers measured GRK2 expression in the atrial appendages and lymphocytes of 10 NYHA class 1-3 heart failure patients undergoing cardiac surgery. They found a direct correlation between myocardial and lymphocyte GRK2 expression (r²=0.568, p=0.011), suggesting that levels of GRK2 in white blood cells "mirror" cardiac expression. Extending their findings to a larger group of patients with different degrees of cardiac function, they also observed a stepwise increase in GRK activity with NYHA functional class and higher GRK activity levels in patients with lower ejection fractions (p<0.001).

"In the end, what we mainly want to communicate is that we can track GRK2 levels in the blood, and these findings also hint at the ability of detecting more severe heart failure," said Koch.

In an editorial accompanying the published study, Dr Stephen Liggett (University of Cincinnati College of Medicine, OH) writes that, given the complexity of heart failure and the small sample size, the correlation is "reasonable." He points out that the range of expression is approximately sixfold, writing that "it would be interesting to know about the clinical status of those with the highest expression vs those with the lowest, as well as the range of lymphocyte GRK2 expression or function found in normal individuals."

Liggett also adds that some of the deleterious effects of elevated GRK levels might not be related to its direct effect of -adrenergic receptor function, pointing out that GRK activity, via phosphorylation, also provides a substrate for other signaling pathways.

"Despite these caveats, this commendable work now sets the stage for larger studies, potentially providing for a new and desperately needed biomarker for heart-failure status," Liggett concludes.