Even for those without a heart condition, it's a peculiar feeling when your heart "races" in response to stress. That pacing change happens in part because of how the enzyme calcium/calmodulin-dependent protein kinase II (CaM kinase II) is called into action by the body's 'fight or flight' stress response, University of Iowa researchers have found.

The finding challenges traditional concepts of the heart's peacemaking function and adds support to the idea that finding ways to inhibit CaM kinase II could help control heart rate problems in people with arrhythmias and other heart conditions. The study results appeared March 10 in the online Early Edition of the Proceedings of the National Academy of Sciences.

Previous understanding of the heart's pacemaking functions was focused on beta-adrenergic receptors, said Yuejin Wu, PhD, the study's lead investigator and a research scientist in internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine.

Fight or Flight

"Beta-adrenergic receptor stimulation during stress ultimately increases activity of the 'pacemaker channel.” Our current treatments for fast heart rates involve drugs that directly inhibit these beta-adrenergic receptors," Wu said. "In fact, we found that a significant part of the 'fight or flight' heart rate response depends on activation of the enzyme CaM kinase II during beta-adrenergic stimulation."

In a recent study from Germany, a mouse model that was missing the gene for the pacemaker ion channel surprisingly responded normally to the drug isoproterenol. Similar to adrenaline, isoproterenol can increase heart rate. This response meant that the ion channel, by itself, does not explain the physiological "fight or flight" heart rate response.

Based on this observation, Wu and other colleagues in the lab of the paper's senior author, Mark Anderson, MD, PhD, head of the UI Division of Cardiovascular Medicine, developed mice in which the CaM kinase II function was inhibited in heart cells. When these mice were exposed to the adrenaline-like agent isoproterenol, the stimulant's effect did not occur. As a result, the mice without CaM kinase II function had much slower heart rates than mice that had normal CaM kinase II function. The finding underscored that CaM kinase II activation can increase heart rates.

"In a person whose heart beats at a normal rate, you would not want to inhibit CaM kinase II function," Wu said. "But our findings suggest that in people with rapid heart rates, it could be beneficial to inhibit the enzyme's function. When the heart beats too fast, it does not pump well, and if a fast heart rate persists, it can damage the heart's muscle."

Yuejin Wu, PhD

For more information:

Mark Anderson, MD, PhD

UI Heart and and Vascular Center

UI Roy J. and Lucille A. Carver College of Medicine