UC Merced

The heart is the central organ in the circulatory system. It pumps blood to the entire body with a controlled rhythmicity. At elevated heart rates (HR) the organ gets into a dynamic regime called tachycardia. During tachycardia, the function of the heart can be seriously impaired due to the emergence of serious arrhythmogenic events. In order for cardiac arrhythmias to be developed, a specific functional and morphological scenario needs to be present. In particular, bimodal beat-to-beat alternations in the amplitude of electrical and mechanical activity of the heart can lead to ventricular arrhythmias. It has been already shown that electrical and mechanical alternans can be related between them through alternations in the intracellular Ca2+ dynamics. Unfortunately, the exact cause-effect relationship between intracellular Ca2+ alternans and action potential (AP) alternans is still not clear. This relationship was studied at elevated HRs by recording of Ca2+ and electrical activity simultaneously; Ca2+ was measured with the fluorescent dye Rhod-2AM by means of Pulsed Local Field Fluorescence Microscopy (PLFFM). Additionally, the intracellular electrical activity was assessed using sharp microelectrode techniques. All experiments were conducted on mouse hearts. Additionally, to specifically test the idea that the intracellular Ca2+ dynamics is the one responsible for electrical alternanses, we used a transgenic murine model where the organellar Ca2+ buffering has been modified. Specifically, the major sarcoplasmic reticulum (SR) Ca2+ binding protein, Calsequestrine (Casq), was deleted. At low HR, comparison of results between genotypes revealed no difference in the measured parameters: Ca2+ kinetics, dyadic delay, AP kinetics, frequency dependence of action potential duration, or frequency dependence of the relationship between Ca2+ and AP. On the contrary, at higher HR several kinetic parameters between genotypes were statistically different. For example, WT mice display a more pronounced and statistically significant “negative staircase” relationship between intracellular [Ca2+] and HR. Additionally, KO mice displayed a statistically significant shift in its frequency dependence of Ca2+ and AP alternans. Since Casq2 is a protein found exclusively in the SR, its deletion caused a specific change in the SR release. Consequently, the shift in the frequency dependence of Ca2+ transient alternans caused the shift in frequency dependence of AP alternans. Thus, the conclusion of this study is that Ca2+ alternans are the ones driving AP repolarization alternans.