Abstract
In myocardial tissue, Ca2+ release from the sarcoplasmic reticulum (SR) that occurs via the ryanodine receptor (RyR2) channel complex. Ca2+ release through RyR2 can be either stimulated by an action potential (AP) or spontaneous. The latter is often associated with triggered afterdepolarizations, which in turn may lead to sustained arrhythmias. It is believed that some synchronization mechanism exists for afterdepolarizations and APs in neighboring myocytes, possibly a similarly timed recovery of RyR2 from refractoriness, which enables RyR2s to reach the threshold for spontaneous Ca2+ release simultaneously. To investigate this synchronization mechanism in absence of genetic factors that predispose arrhythmia, we examined the generation of triggered activity in multicellular cardiac preparations. In myocardial trabeculae from the rat, we demonstrated that in the presence of both isoproterenol and caffeine, neighboring myocytes within the cardiac trabeculae were able to synchronize their diastolic spontaneous SR Ca2+ release. Using confocal Ca2+ imaging, we could visualize Ca2+ waves in the multicellular preparation, while these waves were not always present in every myocyte within the trabeculae, we observed that, over time, the Ca2+ waves can synchronize in multiple myocytes. This synchronized activity was sufficiently strong that it could trigger a synchronized, propagated contraction in the whole trabecula encompassing even previously quiescent myocytes. The detection of Ca2+ dynamics in individual myocytes in their in situ setting at the multicellular level exposed a synchronization mechanism that could induce local triggered activity in the heart in the absence of global Ca2+ dysregulation.
Highlights
The sarcoplasmic reticulum (SR) Ca2+ release complex comprises more than a dozen proteins, with the ryanodine receptor (RyR2) as the core channel
To investigate the effect of both isoproterenol and caffeine on the incidence of extra-systolic contractions (ESCs) in trabeculae, we monitored the contractile activity in these muscles while electrically pacing at 1 Hz
The control, untreated muscle showed no signs of ESCs following relaxation (Figure 2A); after 1 min of perfusion with 100 nM isoproterenol and 0.5 mM caffeine the trabeculae displayed ESCs between successive twitches (Figure 2B)
Summary
The sarcoplasmic reticulum (SR) Ca2+ release complex comprises more than a dozen proteins, with the ryanodine receptor (RyR2) as the core channel. Some acquired or genetic defects found in both RyR2 or its regulatory proteins can lead to a state of “perceived” SR Ca2+ overload, where there is a decrease in the threshold for SR Ca2+ release that leaves the RyR2 hyperactive (Gyorke and Carnes, 2008). Both of these scenarios can lead to triggered arrhythmias
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
