Late Ca2+ Sparks and Ripples During the Systolic Ca2+ Transient in Heart Muscle Cells
Rationale: The development of a refractory period for Ca2+ spark initiation after Ca2+ release in cardiac myocytes, should inhibit further Ca2+ release during the action potential (AP) plateau. However, Ca2+ release sites that did not initially activate, or which have prematurely recovered from refractoriness might release Ca2+ later during the AP and alter the cell-wide Ca2+ transient.
Objective: To investigate the possibility of late Ca2+ spark (LCS) activity in intact isolated cardiac myocytes using fast confocal line scanning with improved confocality and signal to noise.
Methods and Results: We recorded Ca2+ transients from cardiac ventricular myocytes isolated from rabbit hearts. APs were produced by electrical stimulation and rapid solution changes were used to modify the L-type Ca2+ current. After the upstroke of the Ca2+ transient, late Ca2+ sparks (LCS) were detected which had increased amplitude compared to diastolic Ca2+ sparks. LCS are triggered by both L-type Ca2+ channel activity during the action potential plateau, as well as by the increase of cytosolic Ca2+ associated with the Ca2+ transient itself. Importantly, a mismatch between SR load and L-type Ca2+ trigger can increase the number of LCS. The likelihood of triggering a LCS also depends on recovery from refractoriness that appears after prior activation. Consequences of LCS include a reduced rate of decline of the Ca2+ transient and, if frequent, formation of microscopic propagating Ca2+ release events (Ca2+ ripples). Ca2+ ripples resemble Ca2+ waves in terms of local propagation velocity but spread for only a short distance due to limited regeneration.
Conclusions: These new types of Ca2+ signalling behaviour extend our understanding of Ca2+ mediated signalling. LCS may provide an arrhythmogenic substrate by slowing the Ca2+ transient decline as well as by amplifying maintained Ca2+ current effects on intracellular Ca2+ and consequently Na+/Ca2+ exchange current.
- Received October 19, 2017.
- Revision received December 15, 2017.
- Accepted December 24, 2017.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.