Atrial Excitation-Contraction Coupling and Ca Wave Propagation in Normal and Failing Hearts

Abstract

We compared excitation-contraction coupling and Ca wave propagation in normal and heart failure (HF) rabbit atrial myocytes. Cytosolic Ca transients (Fluo-4 or Rhod-2), sarcoplasmic reticulum (SR) [Ca] (Fluo-5N) and mitochondrial localization (Mitotracker Red) were recorded by confocal microscopy. SEA and Ru360 were used to inhibit sarcolemmal Na/Ca exchange (NCX) or mitochondrial Ca uptake, respectively. In normal and HF rabbit atrial myocytes transverse tubules are missing, and the peripheral junctional SR (j-SR) is separated from the central non-junctional SR (nj-SR) by a 1-2 µm wide gap that is largely devoid of mitochondria and SR structures. During action potential (AP) stimulation SR Ca release initiated from the j-SR and propagated in centripetal direction via Ca-induced Ca release (CICR) from nj-SR. The centripetal Ca propagation velocity was highest across the gap between j-SR and nj-SR, slowed during propagation across the nj-SR and increased after Ru360 application. In HF, the centripetal propagation velocity was higher and mitochondrial density was decreased. Spontaneous Ca waves propagated with a leading wave front located to the cell periphery, i.e. arising from j-SR Ca release. Nearly half of all Ca waves in normal cells, but <10% in normal cells pretreated with SEA and none in ventricular cells triggered an AP, followed by a whole-cell Ca transient (termed here 'arrhythmogenic Ca waves'). The incidence of spontaneous Ca waves, the fraction of arrhythmogenic Ca waves and NCX activity were significantly increased in HF. In summary, the lack of mitochondria in the gap between j-SR and nj-SR enables rapid propagation of CICR from the j-SR to the nj-SR. Decreased mitochondrial Ca uptake in HF contributes to an increased centripetal Ca propagation velocity. Atrial myocytes are prone to develop NCX-dependent arrhythmogenic Ca waves, which is further accentuated in HF.