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Synchronization of stochastic Ca²(+) release units creates a rhythmic Ca²(+) clock in cardiac pacemaker cells.

ABSTRACT: In sinoatrial node cells of the heart, beating rate is controlled, in part, by local Ca²(+) releases (LCRs) from the sarcoplasmic reticulum, which couple to the action potential via electrogenic Na(+)/Ca²(+) exchange. We observed persisting, roughly periodic LCRs in depolarized rabbit sinoatrial node cells (SANCs). The features of these LCRs were reproduced by a numerical model consisting of a two-dimensional array of stochastic, diffusively coupled Ca²(+) release units (CRUs) with fixed refractory period. Because previous experimental studies showed that ?-adrenergic receptor stimulation increases the rate of Ca²(+) release through each CRU (dubbed I(spark)), we explored the link between LCRs and I(spark) in our model. Increasing the CRU release current I(spark) facilitated Ca²(+)-induced-Ca²(+) release and local recruitment of neighboring CRUs to fire more synchronously. This resulted in a progression in simulated LCR size (from sparks to wavelets to global waves), LCR rhythmicity, and decrease of LCR period that parallels the changes observed experimentally with ?-adrenergic receptor stimulation. The transition in LCR characteristics was steeply nonlinear over a narrow range of I(spark), resembling a phase transition. We conclude that the (partial) periodicity and rate regulation of the "Calcium clock" in SANCs are emergent properties of the diffusive coupling of an ensemble of interacting stochastic CRUs. The variation in LCR period and size with I(spark) is sufficient to account for ?-adrenergic regulation of SANC beating rate.

SUBMITTER: Maltsev AV

PROVIDER: S-EPMC3021664 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Synchronization of stochastic Ca²(+) release units creates a rhythmic Ca²(+) clock in cardiac pacemaker cells.

Maltsev Anna V AV Maltsev Victor A VA Mikheev Maxim M Maltseva Larissa A LA Sirenko Syevda G SG Lakatta Edward G EG Stern Michael D MD

Biophysical journal 20110101 2

In sinoatrial node cells of the heart, beating rate is controlled, in part, by local Ca²(+) releases (LCRs) from the sarcoplasmic reticulum, which couple to the action potential via electrogenic Na(+)/Ca²(+) exchange. We observed persisting, roughly periodic LCRs in depolarized rabbit sinoatrial node cells (SANCs). The features of these LCRs were reproduced by a numerical model consisting of a two-dimensional array of stochastic, diffusively coupled Ca²(+) release units (CRUs) with fixed refract ...[more]

PMID: 21244823

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Project description:The use of temporary cardiac pacing is frequent in critical care units for severe bradycardia or electrical storm, but may be associated with frequent and potentially severe complications, especially when indwelling for several days. In some cases, transient indication or ongoing contraindication for a permanent pacemaker justifies prolonged temporary pacing. In that case, the implantation of an active-fixation lead connected to an externalized pacemaker represents a valuable option to increase safety and patient comfort. Yet, evidence remains scarce. We aimed to describe the population receiving prolonged temporary cardiac pacing (PTCP) and their outcomes. We retrospectively included all consecutive patients, admitted to our hospital from 2016 to 2021, who underwent PTCP. We collected in-hospital and six-month outcomes. Forty-six patients (median age of 73, 63% male) were included, and twenty-nine (63%) had prior heart disease. Indications for PTCP were found: seventeen (37%) potentially reversible high-grade conduction disorders, fourteen (30%) indications for permanent pacemaker but ongoing infection, seven (15%) cardiac implantable electronic device infections requiring extraction in pacing-dependent patients, seven (15%) severe vagal hyperreactivity in prolonged critical care hospitalizations, and one (2%) recurrent sustained ventricular tachycardia requiring overdrive pacing. The median PTCP duration was nine (5-13) days. Ten (22%) patients exhibited at least one complication during hospitalization. Twenty-six (56.5%) patients required definite device implantation (twenty-five pacemakers and one cardioverter-defibrillator) and twenty (43.5%) did not (fifteen PTCP device removal for recovery and five deaths under PTCP). At six months, two (5%) deaths and two (5%) new infections of a definite implanted device occurred, all in patients with initial active infection. The use of prolonged temporary cardiac pacing, with an active -fixation lead connected to an externalized pacemaker, is possible and reasonable; this would allow for the possible recovery or resolution of contraindication for definite device implantation.

Project description:There is an intense interest in differentiating embryonic stem cells to engineer biological pacemakers as an alternative to electronic pacemakers for patients with cardiac pacemaker function deficiency. Embryonic stem cell-derived cardiocytes (ESCs), however, often exhibit dysrhythmic excitations. Using Ca(2+) imaging and patch-clamp techniques, we studied requirements for generation of spontaneous rhythmic action potentials (APs) in late-stage mouse ESCs. Sarcoplasmic reticulum (SR) of ESCs generates spontaneous, rhythmic, wavelet-like Local Ca(2+)Releases (LCRs) (inhibited by ryanodine, tetracaine, or thapsigargin). L-type Ca(2+)current (I(CaL)) induces a global Ca(2+) release (CICR), depleting the Ca(2+) content SR which resets the phases of LCR oscillators. Following a delay, SR then generates a highly synchronized spontaneous Ca(2+)release of multiple LCRs throughout the cell. The LCRs generate an inward Na(+)/Ca(2+)exchanger (NCX) current (absent in Na(+)-free solution) that ignites the next AP. Interfering with SR Ca(2+) cycling (ryanodine, caffeine, thapsigargin, cyclopiazonic acid, BAPTA-AM), NCX (Na(+)-free solution), or I(CaL) (nifedipine) results in dysrhythmic excitations or cessation of automaticity. Inhibition of cAMP/PKA signaling by a specific PKA inhibitor, PKI, decreases SR Ca(2+) loading, substantially reducing both spontaneous LCRs (number, size, and amplitude) and rhythmic AP firing. In contrast, enhancing PKA signaling by cAMP increases the LCRs (number, size, duration) and converts irregularly beating ESCs to rhythmic "pacemaker-like" cells. SR Ca(2+) loading and LCR activity could be also increased with a selective activation of SR Ca(2+) pumping by a phospholamban antibody. We conclude that SR Ca(2+) loading and spontaneous rhythmic LCRs are driven by inherent cAMP/PKA activity. I(CaL) synchronizes multiple LCR oscillators resulting in strong, partially synchronized diastolic Ca(2+) release and NCX current. Rhythmic ESC automaticity can be achieved by boosting "coupling" factors, such as cAMP/PKA signaling, that enhance interactions between SR and sarcolemma.

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Synchronization of stochastic Ca²(+) release units creates a rhythmic Ca²(+) clock in cardiac pacemaker cells.

Publications

Synchronization of stochastic Ca²(+) release units creates a rhythmic Ca²(+) clock in cardiac pacemaker cells.

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