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Published on: September 10, 2015
Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes
Vyacheslav M Shkryl1, Joshua T Maxwell, Timothy L Domeier
1Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612, USA.
Abstract:
Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden cardiac death. At the cellular level, Ca(2+) alternans appears as cytosolic Ca(2+) transients of alternating amplitude at regular beating frequency. Cardiac alternans is a multifactorial process but has been linked to disturbances in intracellular Ca(2+) regulation. In atrial myocytes, we tested the role of voltage-gated Ca(2+) current, sarcoplasmic reticulum (SR) Ca(2+) load, and restitution properties of SR Ca(2+) release for the occurrence of pacing-induced Ca(2+) alternans. Voltage-clamp experiments revealed that peak Ca(2+) current was not affected during alternans, and alternans of end-diastolic SR Ca(2+) load, evaluated by application of caffeine or measured directly with an intra-SR fluorescent Ca(2+) indicator (fluo-5N), were not a requirement for cytosolic Ca(2+) alternans. Restitution properties and kinetics of refractoriness of Ca(2+) release after activation during alternans were evaluated by four different approaches: measurements of 1) the delay (latency) of occurrence of spontaneous global Ca(2+) releases and 2) Ca(2+) spark frequency, both during rest after a large and small alternans Ca(2+) transient; 3) the magnitude of premature action potential-induced Ca(2+) transients after a large and small beat; and 4) the efficacy of a photolytically induced Ca(2+) signal (Ca(2+) uncaging from DM-nitrophen) to trigger additional Ca(2+) release during alternans. The results showed that the latency of global spontaneous Ca(2+) release was prolonged and Ca(2+) spark frequency was decreased after the large Ca(2+) transient during alternans. Furthermore, the restitution curve of the Ca(2+) transient elicited by premature action potentials or by photolysis-induced Ca(2+) release from the SR lagged behind after a large-amplitude transient during alternans compared with the small-amplitude transient. The data demonstrate that beat-to-beat alternation of the time-dependent restitution properties and refractory kinetics of the SR Ca(2+) release mechanism represents a key mechanism underlying cardiac alternans.
Insights
Cardiac alternans, a risk factor for sudden death, involves alternating calcium transient amplitudes. Our study reveals that altered calcium release properties, not calcium load, drive this cellular phenomenon in atrial myocytes.
Area of Science:
- Cardiology
- Cellular Physiology
- Biophysics
Background:
- Cardiac alternans is a cellular electrical instability linked to arrhythmia and sudden cardiac death.
- It manifests as alternating amplitudes of intracellular calcium transients during regular heartbeats.
- Disturbances in intracellular calcium regulation are implicated in cardiac alternans.
Purpose of the Study:
- To investigate the roles of voltage-gated calcium current, sarcoplasmic reticulum (SR) calcium load, and SR calcium release restitution in pacing-induced calcium alternans in atrial myocytes.
- To elucidate the underlying cellular mechanisms driving cardiac alternans.
Main Methods:
- Utilized voltage-clamp experiments in atrial myocytes.
- Assessed SR calcium load via caffeine application and direct measurement using fluo-5N.
- Evaluated SR calcium release restitution properties through measurements of spontaneous calcium release latency, calcium spark frequency, premature action potential-induced calcium transients, and responses to photolytically induced calcium release.
Main Results:
- Peak voltage-gated calcium current remained unaffected during alternans.
- Alternations in end-diastolic SR calcium load were not required for cytosolic calcium alternans.
- Prolonged latency of spontaneous SR calcium release and decreased calcium spark frequency were observed after large calcium transients.
- Restitution properties of SR calcium release lagged after large-amplitude transients, indicating altered refractory kinetics.
Conclusions:
- Beat-to-beat alternation in the time-dependent restitution properties and refractory kinetics of SR calcium release is a key mechanism underlying cardiac alternans.
- These findings highlight the critical role of SR calcium release dynamics in cellular alternans.
- The study provides novel insights into the cellular basis of cardiac alternans, distinct from calcium load variations.
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