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


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.
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).
Jong J
JJ
Kim
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).
Jan
J
Němec
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).
Qiao
Q
Li
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.
Guy
G
Salama
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D010627:Phenethylamines; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides; D013841:Thiazepines / Q000494:pharmacology; D013997:Time Factors; D056969:Voltage-Sensitive Dye Imaging
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D013841:Thiazepines; C109183:K201 compound; C063533:dofetilide
action potential; electrophysiology; high-resolution subcellular optical mapping; long QT syndrome; sarcoplasmic reticulum