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Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

Christopher Y Ko1, Michael B Liu1, Zhen Song1

  • 1Division of Cardiology, Department of Medicine, UCLA Cardiovascular Research Laboratory, University of California, Los Angeles, California.

Biophysical Journal
|May 13, 2017
PubMed

Insights

Spontaneous calcium waves in heart cells cause delayed afterdepolarizations (DADs) that trigger arrhythmias. Increased calcium synchrony and sarcoplasmic reticulum load, not initiation sites, drive DADs in cardiac tissue.

Area of Science:

  • Cardiovascular Physiology
  • Computational Biology
  • Cardiac Electrophysiology

Background:

  • Spontaneous calcium (Ca) waves in cardiac myocytes are linked to delayed afterdepolarizations (DADs), a key mechanism triggering cardiac arrhythmias.
  • The precise mechanisms by which subcellular and cellular Ca events translate to tissue-level DADs sufficient to initiate action potentials remain incompletely understood, particularly concerning source-sink dynamics.

Purpose of the Study:

  • To quantitatively assess how subcellular (Ca wave initiation sites), cellular (sarcoplasmic reticulum (SR) Ca load), and tissue-scale (Ca release synchrony) factors influence DAD characteristics in cardiac tissue.
  • To elucidate the relative importance of these factors in promoting DADs that trigger cardiac arrhythmias.

Main Methods:

  • Utilized a combined experimental and computational modeling approach with isolated rabbit ventricular myocytes and a ventricular tissue model.
  • Experimentally induced diastolic Ca waves and subthreshold DADs by rapid pacing under elevated extracellular Ca and isoproterenol.
  • Quantified SR Ca content, Ca wave initiation sites, Ca transients, DAD amplitude/duration, and latency using Fluo-4 imaging and caffeine pulses.

Main Results:

  • Increased pacing led to higher SR Ca content, more Ca wave initiation sites, larger/shorter Ca transients and DADs, and shortened/more synchronous Ca wave latencies.
  • In silico analysis demonstrated that reduced latency variance (increased synchrony) and higher SR Ca load were the primary drivers of larger DADs and triggered activity.
  • The number of Ca wave initiation sites per myocyte had a less significant impact on DAD generation compared to synchrony and SR Ca load.

Conclusions:

  • Increased intracellular Ca promotes DAD-mediated triggered activity in cardiac tissue.
  • This promotion is mainly driven by enhanced synchrony of Ca waves across myocytes and increased SR Ca load.
  • While Ca wave initiation sites contribute, synchrony and SR Ca load are more critical determinants for DADs triggering arrhythmias.

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