Higher-Order Dynamics Beyond Repolarization Alternans in Ex-Vivo Human Ventricles are Independent of the Restitution Properties

• Type of Material: Article
• Authors: Shahriar Iravanian, Emory University; Ilija Uzelac, Georgia Institute of Technology; Anand D. Shah, Emory University; Mikael J. Toye, Georgia Institute of Technology; Michael S Lloyd, Emory University; Michael Anthony Burke, Emory University; Mani Ali Daneshmand, Emory University; Tamer S. Attia, Emory University; David Vega, Emory University; Mikhael F El Chami, Emory University; Faisal M Merchant, Emory University; Elizabeth M. Cherry, Georgia Institute of Technology; Neal Kumar Bhatia, Emory University; Flavio H. Fenton, Georgia Institute of Technology
• Language: English
• Date: 2023-08-21
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1101%2F2023.08.16.23293853
• Title of Journal or Parent Work: medRxiv
• Grant/Funding Information: This study was partly supported by the NIH under grant 1R01HL143450-01 and the NSF under CMMI-1762553.
• Keywords: Repolarization alternans; higher-order periodicities
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: Repolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., periods 4, 6, 8,...) are expected but have minimal experimental evidence. Methods: We studied explanted human hearts obtained from recipients of heart transplantation at the time of surgery. Optical mapping of the transmembrane potential was performed after staining the hearts with voltage-sensitive fluorescent dyes. Hearts were stimulated at an increasing rate until VF was induced. Signals recorded from the right ventricle endocardial surface prior to induction of VF and in the presence of 1:1 conduction were processed using the Principal Component Analysis and a combinatorial algorithm to detect and quantify higher-order dynamics. Results were correlated to the underlying electrophysiological characteristics as quantified by restitution curves and conduction velocity. Results: A prominent and statistically significant global 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local (pixel-wise) analysis revealed the spatially heterogeneous distribution of periods 4, 6, and 8, with the regional presence of periods greater than two in all the hearts. There was no significant correlation between the underlying restitution properties and the period of each pixel. Discussion: We present evidence of higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex-vivo human hearts. We infer from the independence of the period to the underlying restitution properties that the oscillation of the excitation-contraction coupling and calcium cycling mechanisms is the primary mechanism of higher-order dynamics. These higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation and may provide targets for substrate-based ablation of VF.