Characterization of the Electrophysiologic Remodeling of Patients With Ischemic Cardiomyopathy by Clinical Measurements and Computer Simulations Coupled With Machine Learning

Figures

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  FIGURE 1. (A) ARI over DI in patients with SNLV (blue) and ICMP (red). Points represent mean values and error bars represent 95% confidence intervals. ARI, activation recovery interval in ms; DI, diastolic interval in ms. (B) Box-plots demonstrating the distribution of clinically obtained APDR intercept (in ms) and slope (unitless) in patients with SNLV (blue) and ICMP (red). Box-plots summarize the intercept and slope of the clinically obtained APDR curve fitted at each UniEGM recording of each patient. p-values are derived from mixed model analysis as described in the main text. (C) Box-plots of the clinically obtained APDR slope in each individual SNLV and ICMP patient, demonstrating the within- and between-subject variability of clinically obtained APDR slope.

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  FIGURE 2. (A) Action potential waveform of the SNLV and ICMP models. (B) Fast inward current waveform of the SNLV and ICMP models. (D) Slow inward current waveform of the SNLV and ICMP models. (E) Slow outward current waveform of the SNLV and ICMP models. Waveforms in (A,B,D,E) are derived from cell-level simulations during pacing at 500 ms. Bold blue and red lines represent the waveforms of the best fit models, while light blue and red lines represent the wavefronts using the centroids of the six highest clusters. Jitter has been applied to the waveforms using the centroids of the six highest clusters to facilitate visualization. (C) Fold-difference of the parameters of SNLV (blue) and ICMP (red) compared to the endocardial parameter set of the baseline BOFC model. The parameter τw1− of SNLV and ICMP models is 16.6- and 16.7-fold higher than the baseline BOFC model but the bar chart has been truncated at 8 for better visualization of the remaining parameters. (F) Fold-difference of the parameters of ICMP compared to SNLV models.

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  FIGURE 3. (A) Cell-level simulations of the best-fit GA-derived SNLV (blue) and ICMP (red) model. The first row demonstrates the APDR. The pink line is the patient derived average APDR curve. These plots demonstrate good fit of the models to patient data. The second row demonstrates bifurcation plots for SNLV and ICMP models. The onset of APD alternans (development of bifurcation) is annotated. APD alternans occur at slower cycle lengths in the ICMP model compared to SNLV suggesting a more proarrhythmic behavior. (B) Tissue-level simulation using a conductivity of 0.009 S/m and S1S2 interval of 330 ms for the SNLV model and 295 ms for the ICMP model. Non-sustained functional re-entry was induced in the SNLV model while sustained functional re-entry was induced in the ICMP. Upper row: snapshot of the simulation, color represents transmembrane voltage in arbitrary units. Lower row: activation isochrone maps for simulations using SNLV and ICMP models; each isochrone represents 10 ms. (C) Range of functional re-entry inducibility of the SNLV (blue) and ICMP (red) best-fit models. X-axis represents different tissue conductivity values in Siemens/m and Y-axis represents S1S2 coupling intervals…

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  FIGURE 4. Cell-level simulations in the 2 and 4 highest level clusters of (A) SNLV and (B) ICMP models. In the center of each sub-plot we show the four highest-level clusters of the dendrogram produced by AHC. The two highest-level clusters are noted as 2/1 and 2/2 and the four highest level clusters are noted as 4/1, 4/2, 4/3, and 4/4. Note that ICMP clusters 2/2 and 4/4 are identical since no bifurcation of the dendrogram occurs at this level. The bifurcation plots surrounding the dendrograms are labeled after the cluster that they have been created from (X-axis is pacing cycle length in ms and Y-axis is APD in ms). For all clusters, onset of alternans occurred at ICMP models at longer cycle length intervals compared to SNLV models (385–400 ms vs 355 ms).

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  FIGURE 5. Tissue-level simulations in the two and four highest-level clusters of (A) SNLV and (B) ICMP models. In the center of each sub-plot we show the four highest-level clusters of the dendrogram produced by AHC. The two highest-level clusters are noted as 2/1 and 2/2 and the four highest clusters are noted as 4/1, 4/2, 4/3, and 4/4. Note that for ICMP clusters 2/2 and 4/4 are identical since no bifurcation of the dendrogram occurs at this level. Each plot surrounding the dendrogram shows the S1–S2 coupling intervals that resulted in sustained functional re-entry for different conductivity values and is labeled after the cluster that it has been created from (X-axis represents different tissue conductivity values in mS/m and Y-axis represents S1–S2 coupling intervals that resulted in sustained functional re-entry). For all clusters, ICMP models developed sustained functional re-entry over a wider range of S1–S2 coupling intervals for the entire range of conductivity values, compared to SNLV.