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Circ Arrhythm Electrophysiol. 2015 Jun;8(3):703-12. doi: 10.1161/CIRCEP.114.002214. Epub 2015 Feb 26.

Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2.

Author information

1
From the Department of Bioengineering (J.J.K., G.S.), and Department of Medicine, Heart and Vascular Institute (J.J.K., J.N., Q.L., G.S.), University of Pittsburgh, PA; and Tsinghua University School of Medicine, China (Q.L).
2
From the Department of Bioengineering (J.J.K., G.S.), and Department of Medicine, Heart and Vascular Institute (J.J.K., J.N., Q.L., G.S.), University of Pittsburgh, PA; and Tsinghua University School of Medicine, China (Q.L). gsalama@pitt.edu.

Erratum in

Abstract

BACKGROUND:

Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca(2+)-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias.

METHODS AND RESULTS:

Optical maps of action potentials and Ca(2+)-transients from Langendorff rabbit hearts were measured at low (150×150 μm(2)/pixel) and high (1.5×1.5 μm(2)/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca(2+)-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca(2+-)waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca(2+-)elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca(2+) (40%-60% of peak-Ca(2+)-transients), appeared first in small islands (0.5×0.5 mm(2)) that enlarged and spread throughout the epicardium. Synchronous systolic Ca(2+-)elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca(2+)-transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca(2+)-dynamics (multiple chaotic Ca(2+)-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca(2+)-elevations and arrhythmias.

CONCLUSIONS:

The results indicate that systolic and diastolic Ca(2+)-elevations emanate from sarcoplasmic reticulum Ca(2+)-release and systolic Ca(2+)-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca(2+), which overcomes source-sink mismatch to trigger arrhythmias in intact hearts.

KEYWORDS:

action potential; electrophysiology; high-resolution subcellular optical mapping; long QT syndrome; sarcoplasmic reticulum

PMID:
25722252
PMCID:
PMC4472565
DOI:
10.1161/CIRCEP.114.002214
[Indexed for MEDLINE]
Free PMC Article

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