Correction for Fowler et al., Arrhythmogenic late Ca2+sparks in failing heart cells and their control by action potential configuration

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early afterdepolarizations (EADs) are triggered in failing heart cells. To examine EAD initiation, high-sensitivity intracellular Ca2+ measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca2+ release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca2+ release events (“late” Ca2+ sparks) during phase 2–3 of the action potential. These late Ca2+ sparks prolong the Ca2+ transient that activates contraction and can trigger propagating microscopic Ca2+ ripples, larger macroscopic Ca2+ waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca2+ sparks and their (subsequent) spatiotemporal summation into Ca2+ ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca2+ sparks provide a mechanism for EAD initiation. Computer simulations confirmed that this forms the basis of a strong oscillatory positive feedback system that can act in parallel with other purely voltage-dependent ionic mechanisms for EAD initiation. In failing heart cells, restoration of the action potential to a nonfailing phase 1 configuration improved the synchrony of excitation–contraction coupling, increased Ca2+ transient amplitude, and suppressed late Ca2+ sparks. Therapeutic control of late Ca2+ spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death.

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Correlation between iron uptake, lipid peroxidation and action potential duration in cultured heart cells

Journal of Molecular and Cellular Cardiology ◽

10.1016/s0022-2828(87)80168-2 ◽

1987 ◽

Vol 19 ◽

pp. S54-S54

Author(s):

G LINK ◽

P ATHIAS ◽

A GRYNBERG ◽

C HERSHKO ◽

A PINSON

Keyword(s):

Lipid Peroxidation ◽

Action Potential ◽

Action Potential Duration ◽

Iron Uptake ◽

Heart Cells ◽

Cultured Heart Cells

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Phase-locked rhythms in periodically stimulated heart cell aggregates

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.254.1.h1 ◽

1988 ◽

Vol 254 (1) ◽

pp. H1-H10 ◽

Cited By ~ 5

Author(s):

M. R. Guevara ◽

A. Shrier ◽

L. Glass

Keyword(s):

Action Potential ◽

Classification Scheme ◽

Stimulation Frequency ◽

Heart Cell ◽

Heart Cells ◽

Complete Suppression ◽

Intrinsic Frequency ◽

Low Frequencies ◽

High Frequencies ◽

Biological Oscillators

We have studied the effect of injecting a periodic train of current pulses into spontaneously beating aggregates of embryonic chick ventricular heart cells. Over a range of stimulation frequencies around the intrinsic frequency of an aggregate we find one action potential for each stimulus with a fixed latency from each stimulus to the subsequent action potential. For a stimulation frequency higher (lower) than the intrinsic frequency, this corresponds to overdrive (underdrive). At high frequencies of stimulation dropped beats occur leading to complex rhythms analogous to various Wenckebach rhythms observed clinically. At higher stimulation frequencies one can obtain a complete suppression of action potential generation. At low frequencies of stimulation, there are rhythms containing escape beats. Almost every rhythm seen bears a striking resemblance to some cardiac arrhythmia. We present a simple classification scheme that predicts the order of appearance of all the classes of rhythms experimentally observed as one changes the stimulation frequency. We propose that this scheme can be used generally to describe the behavior of other biological oscillators.

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Development of electrical coupling and action potential synchrony between paired aggregates of embryonic heart cells

The Journal of Membrane Biology ◽

10.1007/bf01869344 ◽

1979 ◽

Vol 51 (1) ◽

pp. 75-96 ◽

Cited By ~ 39

Author(s):

Dirk L. Ypey ◽

David E. Clapham ◽

Robert L. DeHaan

Keyword(s):

Action Potential ◽

Electrical Coupling ◽

Embryonic Heart ◽

Heart Cells

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Inhibition of rest potentiation in canine ventricular muscle by BAY K 8644: comparison with caffeine

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.2.h399 ◽

1989 ◽

Vol 257 (2) ◽

pp. H399-H406

Author(s):

L. V. Hryshko ◽

R. Bouchard ◽

T. Chau ◽

D. Bose

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Calcium Uptake ◽

Calcium Influx ◽

Bay K 8644 ◽

Contractile Apparatus ◽

Peak Tension ◽

Time To Peak ◽

Configuration Changes ◽

Action Potential Configuration

Rest potentiation, believed to be due to increased utilization of sarcoplasmic reticular calcium, was converted to rest depression by BAY K 8644 (1 microM). Plateau height and duration of the postrest beat were enhanced by BAY K 8644, suggesting an enhancement of extracellular calcium entry. Caffeine (3 mM) also produced depression at all rest intervals, although to a lesser extent than BAY K 8644. Compared with BAY K 8644, treatment with caffeine resulted in an elevation of plateau amplitude and a shortening of action potential duration. Action potential configuration changes induced by rest were unaltered by caffeine despite reduction in rest potentiation. Caffeine-induced rest depression was associated with an increase in the time to peak tension. This was not observed with BAY K 8644. Treatment with both caffeine (3 mM) and BAY K 8644 (1 microM) greatly prolonged time to peak tension. Action potential duration and plateau height were either maintained or increased. Less rest depression was observed with the combination than with either agent alone. These results suggest that 1) BAY K 8644 and caffeine inhibit rest potentiation by different mechanisms, and 2) caffeine-induced inhibition of calcium uptake by the sarcoplasmic reticulum may enhance the effect of BAY K 8644-induced increase in calcium influx on the contractile apparatus.

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Electrical uncoupling and impulse propagation in isolated sheep Purkinje fibers

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.1.h179 ◽

1989 ◽

Vol 257 (1) ◽

pp. H179-H189 ◽

Cited By ~ 6

Author(s):

J. Jalife ◽

S. Sicouri ◽

M. Delmar ◽

D. C. Michaels

Keyword(s):

Action Potential ◽

Electrical Coupling ◽

Conduction Delay ◽

Heart Cells ◽

Hypertonic Solution ◽

Purkinje Fibers ◽

One Dimensional ◽

Action Potential Propagation ◽

Electrical Uncoupling ◽

Impulse Propagation

Alterations in electrical coupling may have a major role in the development of cardiac rhythm and conduction disturbances. We have used microelectrodes and linear Purkinje fibers to analyze the relative importance of cell-to-cell coupling on action potential propagation and to study the changes in the relationship between conduction velocity (theta) and upstroke velocity (Vmax) induced by three agents (heptanol, hypertonic solution, and ouabain) known to alter gap junction resistance. Heptanol superfusion (1.5–3.0 mM) reversibly led to a major decrease in theta and ultimately to block at a time when Vmax had been reduced by approximately 38%. Conduction delay was closely correlated with an increase in intracellular resistance (Ri), calculated as the sum of myoplasmic and junctional resistances, assuming a one-dimensional cable model. Qualitatively similar results were obtained by superfusion with 0.1–0.5 mM ouabain or hypertonic Tyrode solution (up to 600 mM sucrose added) instead of heptanol. In contrast, when the Vmax vs. theta relationship was studied by changing the KCl from 4 to 20 mM, decreases in Vmax correlated well with changes in theta. No significant effects on Ri were observed during KCl superfusion. Finally, we developed a computer model of action potential propagation along a one-dimensional strand of 90 electrically coupled heart cells. By changing systematically the degree of electrical coupling or the maximum sodium conductance in the model and by studying the effects of these changes on propagation and Vmax, we obtained strong evidence supporting the validity of our experimental results. The overall data provide testable predictions regarding the role of electrical uncoupling on abnormal impulse propagation.

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Acetate-induced depression of electrical and contractile activity in normoxic and hypoxic guinea pig papillary muscle

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-118 ◽

1989 ◽

Vol 67 (7) ◽

pp. 734-739

Author(s):

Hideharu Hayashi ◽

Hajime Terada ◽

Alexander Kholopov ◽

Terence F. McDonald

Keyword(s):

Guinea Pig ◽

Action Potential ◽

Action Potential Duration ◽

Contractile Activity ◽

High Energy ◽

Factors Affecting ◽

Resting Tension ◽

Tension Increase ◽

Action Potential Shortening ◽

Action Potential Configuration

The action potential configuration, developed tension, and resting tension were monitored in normoxic and hypoxic guinea pig papillary muscles superfused with solutions containing no substrate, glucose, or acetate (1–10 mM). In normoxic muscle, acetate provoked a concentration-dependent transient depression of the action potential duration and force of contraction, depression was maximal after 10–30 min, and recovery was complete after 90–120 min. In hypoxic muscle, acetate accelerated functional rundown (action potential shortening, decline of developed tension, increase in resting tension). Because rundown in hypoxic muscle was sensitive to factors affecting glycolysis (moderated by external glucose; accentuated by 2-deoxyglucose), the accentuated rundown with acetate may be accounted for by a partial block of glycolysis. However, block of glycolysis cannot explain the acetate-induced transient depression in normoxic muscle, since the depression was enhanced in normoxic muscle with 2-deoxyglucose-blocked glycolysis. We suggest that the transient depression is due to a transient depression of high energy nucleotides with consequent effects on ionic currents.Key words: acetate, action potential duration, 2-deoxyglucose, hypoxia, ATP.

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