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Isoprenaline increases the slopes of restitution trajectory in the conscious rabbit with ischemic heart failure

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Abstract

Roughly speaking, restitution is the dependence of recovery time of cardiac electrical activity on heart rate. Increased restitution slope is theorized to be predictive of sudden death after heart injury such as from coronary artery occlusion (ischemia). Adrenaline analogs are known to increase restitution slope in normal hearts, but their effects in failing hearts are unknown. Twenty-six rabbits underwent coronary ligation (n = 15) or sham surgery (n = 11) and implantation of a lead in the heart for recording electrocardiograms. Eight weeks later, unanesthetized rabbits were given 0.25–2.0 ml of 1 μmol/L isoprenaline intravenously, which increased heart rate. Heart rate was quantified by time between QRS peaks (RR) and heart activity duration by R to T peak time (QTp). Ligated rabbits (n = 6) had lower ejection fraction than sham rabbits (n = 7, p < 0.0001) indicative of heart failure, but similar baseline RR (269 ± 15 vs 292 ± 23 ms, p = 0.07), QTp (104 ± 17 vs 91 ± 9 ms, p = 0.1), and isoprenaline-induced minimum RR (204 ± 11 vs 208 ± 6 ms, p = 0.4). The trajectory of QTp vs TQ plots displayed hysteresis and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 ± 0.66) and <1 in sham rabbits (0.35 ± 0.14, p = 0.004). The absolute value of the negative slope was greater in ligated rabbits (− 0.81 ± 0.52 vs − 0.35 ± 0.14, p = 0.04). Isoprenaline increased heart rate and slopes of restitution trajectory in failing hearts. The dynamics of restitution trajectory may hold clues for sudden death in heart failure patients.

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Notes

  1. Ventricular fibrillation is an irregular rhythm of the heart which is a major cause of sudden death. Ventricular tachycardia is a fast periodic rhythm that frequently leads to ventricular fibrillation.

  2. Adrenaline is one of the naturally occurring hormones in the body that causes heart rate to increase by stimulating receptors in the heart, one of which is the beta-adrenergic receptor. Ischaemia means lack of blood flow, such as from clogged arteries. Ischaemia stresses or injures tissue.

  3. To apply nonlinear dynamical theory, restitution slope must be calculated using the diastolic interval as the independent variable, and not beat to beat interval. That said, in steady state pacing experiments, the choice of independent variable does not affect the slope value because the restitution curve is merely shifted horizontally by a constant.

Abbreviations

ECG:

electrocardiogram

RR:

time from R peak to R peak on electrocardiogram

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Acknowledgements

The experimental portion of this research project was conducted at Glasgow Royal Infirmary, with the financial support of British Heart Foundation Project Grant PG/02/155 and Stuart M. Cobbe. The analytical portion of this research project was conducted at St. Louis University School of Medicine. TK received salary support from Sankyo Co, Ltd., Shizuoka, Japan. The authors thank Robert F. Gilmour Jr. and Paul Belk for expert advice concerning the manuscript.

Conflict of Interest

The authors have no conflicts of interest to disclose.

Author contributions

All authors contributed to the study: TK and NN in the analysis and interpretation of data, MNH and MD in the conception and design of the study and in conducting the experiments, SMC in the conception and design of the study, and MAW in all of the above and in writing the computer program for data analysis. All authors also read the manuscript critically and approved the final version, with the exception of MNH, who passed away before the study was completed.

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Authors and Affiliations

  1. Internal Medicine Department, St. Louis University School of Medicine, St. Louis, USA

    Tomofumi Kimotsuki & Mari Alford Watanabe

  2. Developmental Biology Department, Washington University School of Medicine, St. Louis, USA

    Noriko Niwa

  3. Cardiology Department, Glasgow Royal Infirmary, Glasgow, UK

    Martin N. Hicks, Michael Dunne, Stuart M. Cobbe & Mari Alford Watanabe

  4. Cardiology Division, Internal Medicine Department, St. Louis University Hospital, 3635 Vista Avenue at Grand Avenue, St. Louis, MO, 63110-0250, USA

    Mari Alford Watanabe

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  1. Tomofumi Kimotsuki
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Correspondence to Mari Alford Watanabe.

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Kimotsuki, T., Niwa, N., Hicks, M.N. et al. Isoprenaline increases the slopes of restitution trajectory in the conscious rabbit with ischemic heart failure. J Biol Phys 36, 299–315 (2010). https://doi.org/10.1007/s10867-009-9185-5

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