Abstract
The pulmonary vein, which returns oxygenated blood to the left atrium, is ensheathed by a population of unique, myocyte-like cells called pulmonary vein sleeve cells (PVCs). These cells autonomously generate action potentials that propagate into the left atrial chamber and cause arrhythmias resulting in atrial fibrillation; the most common, often sustained, form of cardiac arrhythmia. In mice, PVCs extend along the pulmonary vein into the lungs, and are accessible in a lung slice preparation. We exploited this model to study how aberrant Ca2+ signaling alters the ability of PVC networks to follow electrical pacing. Cellular responses were investigated using real-time 2-photon imaging of lung slices loaded with a Ca2+-sensitive fluorescent indicator (Ca2+ measurements) and phase contrast microscopy (contraction measurements). PVCs displayed global Ca2+ signals and coordinated contraction in response to electrical field stimulation (EFS). The effects of EFS relied on both Ca2+ influx and Ca2+ release, and could be inhibited by nifedipine, ryanodine or caffeine. Moreover, PVCs had a high propensity to show spontaneous Ca2+ signals that arose via stochastic activation of ryanodine receptors (RyRs). The ability of electrical pacing to entrain Ca2+ signals and contractile responses was dramatically influenced by inherent spontaneous Ca2+ activity. In PVCs with relatively low spontaneous Ca2+ activity (<1 Hz), entrainment with electrical pacing was good. However, in PVCs with higher frequencies of spontaneous Ca2+ activity (>1.5 Hz), electrical pacing was less effective; PVCs became unpaced, only partially-paced or displayed alternans. Because spontaneous Ca2+ activity varied between cells, neighboring PVCs often had different responses to electrical pacing. Our data indicate that the ability of PVCs to respond to electrical stimulation depends on their intrinsic Ca2+ cycling properties. Heterogeneous spontaneous Ca2+ activity arising from stochastic RyR opening can disengage them from sinus rhythm and lead to autonomous, pro-arrhythmic activity.
Highlights
Throughout a typical human lifetime, a coordinated ‘cardiac cycle’ of atrial and ventricular contraction is repeated over a billion times [1]
To explore Ca2+ signaling mechanisms within pulmonary vein sleeve cells (PVCs), lung slices were loaded with the Ca2+-sensitive indicator Oregon Green BAPTA-1 and examined with real-time 2-photon microscopy
These observations indicate that PVCs and atrial myocytes have a different propensity for spontaneous Ca2+ signaling
Summary
Throughout a typical human lifetime, a coordinated ‘cardiac cycle’ of atrial and ventricular contraction is repeated over a billion times [1]. The SA node generates action potentials (APs) that sweep over the atrial and ventricular chambers to cause them to contract and pump blood [2]. This contraction is mediated by Ca2+ increases within cardiac myocytes via the well-known process of ‘excitation-contraction coupling’ (EC-coupling). Membrane depolarisation opens voltage-operated Ca2+ channels (VOCCs) to allow Ca2+ influx into the ‘dyadic’ cleft between the sarcolemma and the sarcoplasmic reticulum (SR; the myocyte Ca2+ store) This Ca2+ signal is amplified by Ca2+-induced Ca2+ release via ryanodine receptors (RyRs) on the SR, causing a global Ca2+ signal that triggers actin-myosin filament interaction and myocyte contraction [3].
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