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Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling.

Lau E, Kossidas K, Kim TY, Kunitomo Y, Ziv O, Song Z, Zhen S, Taylor C, Schofield L, Yammine J, Liu G, Peng X, Qu Z, Koren G, Choi BR - PLoS ONE (2015)

Bottom Line: Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05).Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+.Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.

ABSTRACT

Background: Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (IKs), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of Iks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome.

Methods and results: LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo telemetry demonstrated steepening of the QT/RR slope in LQT1 with TICM (LQT1-TICM; pre: 0.26±0.04, post: 0.52±0.01, P<0.05). In vivo electrophysiology showed that LQT1-TICM had higher incidence of VF than LMC-TICM (6 of 11 vs. 3 of 11, respectively). Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05). LQT1-TICM developed spatially discordant alternans (DA), which caused conduction block and higher-frequency VF (15±1 Hz in LQT1-TICM vs. 13±1 Hz in LMC-TICM, p<0.05). Ca2+ DA was highly dynamic and preceded voltage DA in LQT1-TICM. Ryanodine abolished DA in 5 out of 8 LQT1-TICM rabbits, demonstrating the importance of Ca2+ in complex DA formation. Computer simulations suggested that HF remodeling caused Ca2+-driven alternans, which was further potentiated in LQT1-TICM due to the lack of IKs.

Conclusions: Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+. Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.

No MeSH data available.


Related in: MedlinePlus

Computer simulations of APD and Ca2+ alternans under different conditions.(A) Vm (upper) and whole-cell Ca2+ concentration (lower) versus time for the control condition at CL = 280 ms. (B) Vm and whole-cell Ca2+ concentration versus time for the HF condition. (C) Vm and whole-cell Ca2+ concentration versus time for the same condition as in B but with zero IKs. (D) Peak whole-cell Ca2+ concentrations of two consecutive beats versus CL for the three conditions. (E) APD of the same two consecutive beats as in D versus CL for the three conditions.
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pone.0122754.g006: Computer simulations of APD and Ca2+ alternans under different conditions.(A) Vm (upper) and whole-cell Ca2+ concentration (lower) versus time for the control condition at CL = 280 ms. (B) Vm and whole-cell Ca2+ concentration versus time for the HF condition. (C) Vm and whole-cell Ca2+ concentration versus time for the same condition as in B but with zero IKs. (D) Peak whole-cell Ca2+ concentrations of two consecutive beats versus CL for the three conditions. (E) APD of the same two consecutive beats as in D versus CL for the three conditions.

Mentions: Fig 6 shows the results of a computer model of ventricular myocytes, which includes a detailed spatiotemporal Ca2+ cycling system (details are provided in S1 File). Under the control condition, both APD and Ca2+ exhibited very small amplitudes of alternans at rapid pacing rates. However, under HF conditions, large-amplitude alternans of APD and Ca2+ occurred when the pacing cycle length was shorter than 320 ms. Alternans in the HF condition was caused mainly by changes in Ca2+ cycling properties from the control condition, i.e., Ca2+ cycling was the major origin of alternans [58]. With further reduction of IKs from the HF condition to mimic the LQT1-TICM condition, alternans occurred at pacing cycle length shorter than 360 ms, and the amplitudes of APD and Ca2+ alternans were further increased. In other words, alternans was further potentiated by the lack of IKs in addition to remodeling of Ca2+ cycling in HF. This supports the experimental observation that LQT1-TICM rabbits had a higher propensity to alternans and arrhythmias than LMC-TICM rabbits.


Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling.

Lau E, Kossidas K, Kim TY, Kunitomo Y, Ziv O, Song Z, Zhen S, Taylor C, Schofield L, Yammine J, Liu G, Peng X, Qu Z, Koren G, Choi BR - PLoS ONE (2015)

Computer simulations of APD and Ca2+ alternans under different conditions.(A) Vm (upper) and whole-cell Ca2+ concentration (lower) versus time for the control condition at CL = 280 ms. (B) Vm and whole-cell Ca2+ concentration versus time for the HF condition. (C) Vm and whole-cell Ca2+ concentration versus time for the same condition as in B but with zero IKs. (D) Peak whole-cell Ca2+ concentrations of two consecutive beats versus CL for the three conditions. (E) APD of the same two consecutive beats as in D versus CL for the three conditions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430457&req=5

pone.0122754.g006: Computer simulations of APD and Ca2+ alternans under different conditions.(A) Vm (upper) and whole-cell Ca2+ concentration (lower) versus time for the control condition at CL = 280 ms. (B) Vm and whole-cell Ca2+ concentration versus time for the HF condition. (C) Vm and whole-cell Ca2+ concentration versus time for the same condition as in B but with zero IKs. (D) Peak whole-cell Ca2+ concentrations of two consecutive beats versus CL for the three conditions. (E) APD of the same two consecutive beats as in D versus CL for the three conditions.
Mentions: Fig 6 shows the results of a computer model of ventricular myocytes, which includes a detailed spatiotemporal Ca2+ cycling system (details are provided in S1 File). Under the control condition, both APD and Ca2+ exhibited very small amplitudes of alternans at rapid pacing rates. However, under HF conditions, large-amplitude alternans of APD and Ca2+ occurred when the pacing cycle length was shorter than 320 ms. Alternans in the HF condition was caused mainly by changes in Ca2+ cycling properties from the control condition, i.e., Ca2+ cycling was the major origin of alternans [58]. With further reduction of IKs from the HF condition to mimic the LQT1-TICM condition, alternans occurred at pacing cycle length shorter than 360 ms, and the amplitudes of APD and Ca2+ alternans were further increased. In other words, alternans was further potentiated by the lack of IKs in addition to remodeling of Ca2+ cycling in HF. This supports the experimental observation that LQT1-TICM rabbits had a higher propensity to alternans and arrhythmias than LMC-TICM rabbits.

Bottom Line: Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05).Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+.Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.

ABSTRACT

Background: Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (IKs), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of Iks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome.

Methods and results: LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo telemetry demonstrated steepening of the QT/RR slope in LQT1 with TICM (LQT1-TICM; pre: 0.26±0.04, post: 0.52±0.01, P<0.05). In vivo electrophysiology showed that LQT1-TICM had higher incidence of VF than LMC-TICM (6 of 11 vs. 3 of 11, respectively). Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05). LQT1-TICM developed spatially discordant alternans (DA), which caused conduction block and higher-frequency VF (15±1 Hz in LQT1-TICM vs. 13±1 Hz in LMC-TICM, p<0.05). Ca2+ DA was highly dynamic and preceded voltage DA in LQT1-TICM. Ryanodine abolished DA in 5 out of 8 LQT1-TICM rabbits, demonstrating the importance of Ca2+ in complex DA formation. Computer simulations suggested that HF remodeling caused Ca2+-driven alternans, which was further potentiated in LQT1-TICM due to the lack of IKs.

Conclusions: Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+. Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.

No MeSH data available.


Related in: MedlinePlus