# Non-Invasive and Quantitative Estimation of Left Atrial Fibrosis Based on P Waves of the 12-Lead ECG—A Large-Scale Computational Study Covering Anatomical Variability

^{*}

## Abstract

**:**

## 1. Introduction

## 2. Materials and Methods

#### 2.1. Database

#### 2.2. Modeling Methodology of Fibrotic Tissue

#### 2.3. Electrophysiological Simulations

#### 2.4. ECG Analysis and Feature Extraction

#### 2.5. Regression Using Neural Networks

## 3. Results

#### 3.1. Influence of Geometries, Rotation Angles and Electrode Positions on P wave Features

#### 3.2. Effect of the Fibrotic LA Volume Fraction on P Wave Features

#### 3.3. Estimating the Amount of Fibrosis with Neural Networks

## 4. Discussion

## 5. Conclusions

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Conflicts of Interest

## Abbreviations

AF | atrial fibrillation |

AR | anisotropy ratio |

CV | conduction velocity |

ECG | electrocardiogram |

FAM | fibrotic atrial cardiomyopathy |

LA | left atrium |

LAT | local activation time |

MRI | magnetic resonance imaging |

NN | neural network |

PTF V1 | P wave terminal force in lead V1 |

PWD | P wave duration |

RMSE | root mean square error |

SR | sinus rhythm |

## Appendix A. Calculation of the PWD

**Figure A1.**One exemplary simulated P wave of the 12-lead ECG. The P wave ending automatically calculated with different thresholds is indicated by the blue lines. The last activation time extracted from the simulation is shown in green.

**Figure A2.**Comparison between the maximum activation time extracted from the simulation results and the automatically calculated PWDs based on the 12-lead ECG with a threshold of (

**a**) 1.5 $\times {10}^{-4}$ mV (top) and (

**b**) 3 $\times {10}^{-3}$ mV (bottom).

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**Figure 1.**Exemplary volumetric atrial model with labels for different anatomical structures (left column) that define the heterogeneous conduction velocity setup (Section 2.3). Rule-based fiber orientation (middle column) and exemplary fibrosis distribution representing 30% left atrium (LA) fibrotic volume fraction (right column) are depicted aside. The point of view on the atrial models is indicated by the red human body schematics on the left.

**Figure 2.**Representation of eigenmodes of the upper body statistical shape model. The first eigenmode (

**top**row) reflects in a change of the torso size predominantly in the abdominal region, the second one (

**bottom**row) in the chest region.

**Figure 3.**Representation of the different model combinations leading to 540,000 simulated P waves from a virtual patient cohort with fibrosis covering different volume fractions of the atrial tissue.

**Figure 4.**Definition of the spatial distribution of fibrotic tissue. The atrial geometry was first separated into 6 subregions for the left and 2 subregions for the right atrium as reported by Akoum et al. [24] and Higuchi et al. [26] indicated by the black separation lines. The stage of fibrosis to be modeled was then set (15% in this example) and the number of seed points and radii around them were chosen pseudo-randomly by ensuring that within each of these subregions, the total volume of fibrotic elements accumulated to the spatial fibrosis distribution found in clinical studies [24,26]. 80% of the cells in these candidate regions were defined as fibrotic (middle column) and this process was repeated for all subregions (right column).

**Figure 5.**Effect of atrial geometry, thoracic geometry, atrial rotation angles, V1 electrode placement and the fibrotic LA volume fraction on (

**a**) P wave terminal force in lead V1 (PTF V1, top left), (

**b**) P wave duration (PWD, top right), (

**c**) P wave amplitude in V6 (bottom left) and (

**d**) P wave dispersion (bottom right). The vertical line in (

**a**) indicates the common PTF threshold value of 4 mV·ms. The colored sample points indicate one major change resulting from a variation of the respective influencing factor which consist of the total LA volume (small to large LA volume from light to dark blue), the torso diameter in anterior-posterior direction (small to large diameter from light to dark red), the rotation angle around the z-axis (small to large angle from light to dark orange), the position of the V1 electrode along the inferior-superior direction (inferior to superior direction from light to dark purple) and the fibrotic LA volume fraction (0–45% from light to dark turquoise).

**Figure 6.**Effect of LA volume fraction infiltrated with fibrosis on (

**a**) PTF V1 (top), (

**b**) PWD (middle) and (

**c**) P wave dispersion (bottom). Each box contains all torso and atrial geometries and rotation angles.

**Figure 7.**Difference of the peak-to-peak amplitudes in each lead between the healthy baseline case and the mean of each fibrotic model cohort. Each cohort comprised all torso sizes, atrial geometries and rotation angles.

**Figure 8.**Network performance for predicting the volume fraction of atrial fibrosis (

**a**) only based on P wave derived features (top) and (

**b**) by also including other non-invasive anatomical measures for atrial and thoracic size (bottom). The color code represents the LA volume of each individual sample point (light: small volume; dark: high volume). The allocation of the different model cohorts into four Utah stages and into healthy vs. fibrotic atrial cardiomyopathy (FAM) is indicated by the vertical lines in the bottom plot.

**Table 1.**Volume fraction of fibrosis in the right atrium as reported by Akoum et al. [24]. LA, left atrium; RA, right atrium.

Utah Stage | Fibrotic LA Volume Fraction | Fibrotic RA Volume Fraction |
---|---|---|

Utah I | 0–5% | 1.27 ± 0.38% |

Utah II | 5–20% | 4.65 ± 0.70% |

Utah III | 20–35% | 9.40 ± 2.16% |

Utah IV | >35% | 12.66 ± 3.0% |

Tissue Region | CV${}_{\perp}$ in m/s | Anisotropy Ratio (AR) |
---|---|---|

Bulk right and left atrium | 0.591 | 2.090 |

Crista terminalis | 0.591 | 2.843 |

Pectinate muscles | 0.461 | 3.780 |

Inter-atrial connections | 0.645 | 3.339 |

Inferior isthmus | 0.540 | 1 |

Fibrosis (non-conductive) | 0 | NA |

Fibrosis (slow conducting) | 0.2 × CV${}_{\perp}$ | 2.5 × AR |

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**MDPI and ACS Style**

Nagel, C.; Luongo, G.; Azzolin, L.; Schuler, S.; Dössel, O.; Loewe, A. Non-Invasive and Quantitative Estimation of Left Atrial Fibrosis Based on P Waves of the 12-Lead ECG—A Large-Scale Computational Study Covering Anatomical Variability. *J. Clin. Med.* **2021**, *10*, 1797.
https://doi.org/10.3390/jcm10081797

**AMA Style**

Nagel C, Luongo G, Azzolin L, Schuler S, Dössel O, Loewe A. Non-Invasive and Quantitative Estimation of Left Atrial Fibrosis Based on P Waves of the 12-Lead ECG—A Large-Scale Computational Study Covering Anatomical Variability. *Journal of Clinical Medicine*. 2021; 10(8):1797.
https://doi.org/10.3390/jcm10081797

**Chicago/Turabian Style**

Nagel, Claudia, Giorgio Luongo, Luca Azzolin, Steffen Schuler, Olaf Dössel, and Axel Loewe. 2021. "Non-Invasive and Quantitative Estimation of Left Atrial Fibrosis Based on P Waves of the 12-Lead ECG—A Large-Scale Computational Study Covering Anatomical Variability" *Journal of Clinical Medicine* 10, no. 8: 1797.
https://doi.org/10.3390/jcm10081797