Beyond Alternans: Detection of Higher-Order Periodicity in Ex-Vivo Human Ventricles Before Induction of Ventricular Fibrillation

Abstract

Background: Repolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, is one of the cornerstones of cardiac electrophysiology as it provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., period-4, period-8,...) are expected but have very limited experimental evidence.

Methods: We studied explanted human hearts, obtained from the recipients of heart transplantation at the time of surgery, using optical mapping technique with transmembrane voltage-sensitive fluorescent dyes. The hearts were stimulated at an increasing rate until VF was induced. The signals recorded from the right ventricle endocardial surface just before the 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: A prominent and statistically significant 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local analysis revealed the spatiotemporal distribution of higher-order periods. Period-4 was localized to temporally stable islands. Higher-order oscillations (period-5, 6, and 8) were transient and primarily occurred in arcs parallel to the activation isochrones.

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 before VF induction. This result is consistent with the period-doubling route to chaos as a possible mechanism of VF initiation, which complements the concordant to discordant alternans mechanism. The presence of higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation.

Figure 1.. The schematics of global analysis.

Spatiotemporally processed signals recorded over a line, showing staggered action potentials upstrokes consistent with wavefront propagation (A). Same signals as A shifted to align the upstrokes (B). The first principle component $\left(W_1\right)$, displaying alternans (C). Spectrogram of C, showing a 1:2 peak of alternans (D). The second principle component $\left(W_2\right)$, displaying more pronounced alternans larger than C (E). Spectrogram of E, showing a prominent 1:2 peak of alternans (F). The bar in A depicts 200 ms.

Figure 2.. Comparison of baseline and pre-VF spectrograms using global analysis.

The blue spectrograms are the baseline (stimulation cycle length of 500 ms except for H4 at 800 ms) and the orange spectrograms are obtained just prior to VF induction. H1, H2 (A and B) exhibit prominent 1:4 peaks (the red arrows), while no discernable 1:4 peak is seen for H6 (D). H4 has a ~0.18 peak (the green arrow), corresponding to mainly period-6 activity (C), which is discussed in the text. The baseline signals are multiplied by 0.1 to offset the signals for better visualization.

Figure 3.. Local analysis of heart H1.

The predominant periodicity of the pixels (color coded) superimposed on an activation map (red isochrones)(A). A frame from Movie S1, showing the instantaneous period of each pixel (B). The representative signals from points c (period-2), and e and g (period-4)(C, E, G) with the corresponding APD trends (D, F, H). Note that stable period-4 is localized to a few discrete regions. The isochronous lines are 10 ms apart and the bar in C is 100 ms long.

Figure 4.. Local analysis of heart H2.

The predominant periodicity of the pixels (color coded) superimposed on an activation map (red isochrones)(A). A frame from Movie S2, showing the instantaneous period of each pixel (B). The representative signals from points c (period-2), e (period-4) and g (period-6)(C, E, G) with the corresponding APD trends (D, F, H). Period-6 areas seem disjoint from period-4 regions. The isochronous lines are 10 ms apart and the bar in C is 100 ms long.

Figure 5.. Local analysis of heart H4.

The predominant periodicity of the pixels (color coded) superimposed on an activation map (red isochrones)(A). A frame from Movie S3, showing the instantaneous period of each pixel (B). The representative signals from points c (period-2), and e (period-5) and g (period-6)(C, E, G) with the corresponding APD trends (D, F, H). No significant regions with period-4 are seen in this heart that lacks a 1:4 peak in global analysis. The isochronous lines are 10 ms apart and the bar in C is 100 ms long.