Key events in the development of atrial fibrillation
Atrial fibrillation (AF) is characterized by rapid, irregular, unsynchronized contractions of the atria, the top chambers of the heart. AF is the most common cardiac arrhythmia among adults, affecting more than 2 million people in the U.S., and is an important cause of stroke.
A critical step in the development of AF seems to be a disruption in how calcium is handled in atrial cells. The signal for a cardiac cell to contract is an influx of calcium into the cell. This influx triggers a complementary release of calcium from the sarcoplasmic reticulum, a calcium storage compartment inside the cell, via the ryanodine receptor type 2 (RyR2). The activity of RyR2 is itself regulated by the calmodulin-dependent protein kinase II (CaMKII): phosphorylation (the attachment of a phosphate group) of RyR2 by CaMKII increases its release of calcium.
In atrial cells from patients with AF, the normally tightly regulated flow of calcium is disturbed, and calcium leaks out of the sarcoplasmic reticulum inappropriately. Investigators from two Transatlantic Networks, the Alliance for Calmodulin Kinase Signaling in Heart Disease (Drs. Mark E. Anderson and Xander H.T. Wehrens) and the European North American Atrial Fibrillation Research Alliance (Drs. Dobromir Dobrev and Ulrich Schotten), along with others from the United States and Europe, aimed to clarify the contributions of RyR2 and CaMKII to the development of AF. The results of this collaborative work were published in the July 2009 issue of the Journal of Clinical Investigation.
To test the theory that abnormal RyR2 activity could cause AF, the investigators compared normal mice with mice carrying a mutation in the RyR2 gene that increases its leakiness. Interestingly, the mutant mice did not develop AF spontaneously. However, when subjected to rapid atrial pacing, an external means of increasing the heart rate, the mutant mice developed AF.
The investigators then sought to explain how rapid atrial pacing could trigger AF. They found that rapid pacing causes a dramatic increase in the activity of the CaMKII enzyme, in both normal and mutant mice. The observation that only the mutant mice developed AF suggests that changes in both RyR2 and CaMKII activity were necessary. On the other hand, the investigators found that inhibition of CaMKII activity, whether using a drug or expression of a blocking protein, abolished the calcium leak from the sarcoplasmic reticulum, decreased CaMKII-mediated phosphorylation of RyR2, and, most significantly, attenuated the development of AF in the mutant mice.
To determine the clinical implications of these findings, the investigators evaluated the levels of CaMKII activity and CaMKII-mediated phosphorylation of RyR2 in atrial biopsies from patients undergoing cardiac surgery. Sure enough, both were increased in patients with AF patients compared to those without AF. Increased CaMKII activity and CaMKII-mediated phosphorylation of RyR2 were similarly found in a goat model of AF.
These findings suggest that two conditions are required for the development of AF: 1) susceptibility to AF, such as increased calcium leakiness from a mutation in RyR2, and 2) increased CaMKII activity, as might occur with an increased heart rate. Understanding the roles of RyR2 and CaMKII will hopefully lead to novel treatment strategies for AF.
Click on the title to access the article in the Journal of Clinical Investigation: Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice.