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Observational Study
. 2025 Sep 16;14(18):e040517.
doi: 10.1161/JAHA.124.040517. Epub 2025 Sep 11.

Fibrosis Entropy Is Associated With Life-Threatening Arrhythmia in Nonischemic Cardiomyopathy

Daniel J Hammersley  1   2   3   4 , Hassan A Zaidi  5 , Richard E Jones  3   4   6   7 , Suzan Hatipoglu  3 , Emmanuel Androulakis  1   2   3 , Gabriel Balaban  8 , Lukas Mach  3   4 , Amrit S Lota  3 , Zohya Khalique  3 , Antonio De Marvao  2   9   10 , Aleksandra Lopuszko  3 , Laura Lazzari  3 , Andrew Ravendren  3 , Ankur Gulati  11 , Resham Baruah  3 , Kaushik Guha  12 , Upasana Tayal  3   4 , Francisco Leyva  13   14 , A John Baksi  3 , James S Ware  3   4   10 , Pablo Lamata  5 , Dudley J Pennell  3   4 , Brian P Halliday  3   4 , Martin J Bishop  5 , Sanjay K Prasad  3   4
Affiliations
Observational Study

Fibrosis Entropy Is Associated With Life-Threatening Arrhythmia in Nonischemic Cardiomyopathy

Daniel J Hammersley et al. J Am Heart Assoc. .

Abstract

Background: Greater precision is required for arrhythmic risk stratification of patients with nonischemic cardiomyopathy (NICM). We sought to evaluate whether fibrosis entropy, a measure of scar texture heterogeneity derived from late gadolinium enhancement cardiovascular magnetic resonance, has incremental utility to fibrosis presence for arrhythmic risk prediction in NICM.

Methods: In this prospective observational cohort study, fibrosis entropy was calculated for patients with NICM and fibrosis (late gadolinium enhancement positive, LGE+), including regions of core fibrosis, gray zone fibrosis and combined core and gray zone fibrosis. Patients with NICM and no fibrosis (LGE-) were included as a comparator group. Adjudicated follow-up for life-threatening arrhythmia included sudden cardiac death, aborted sudden cardiac death, or sustained ventricular tachycardia.

Results: Of 291 patients with LGE+ NICM, 38 (13.1%) experienced life-threatening arrhythmia over a median follow-up of 6.3 years. Core fibrosis entropy (per-SD hazard ratio [HR], 1.77 [95% CI, 1.25-2.52]; P=0.001), gray zone fibrosis entropy (HR, 1.97 [95% CI, 1.20-2.54]; P=0.004), and combined fibrosis entropy (HR, 1.98 [95% CI, 1.30-3.02]; P=0.004) were each associated with life-threatening arrhythmia after adjustment for variables used to determine implantable cardioverter-defibrillator candidacy in clinical practice (left ventricular ejection fraction ≤35% and New York Heart Association class >1) and remained associated after accounting for core and gray zone fibrosis mass. Left ventricular ejection fraction ≤35% was not associated with life-threatening arrhythmia (HR, 1.45 [95% CI, 0.77-2.74]; P=0.250). Integration of fibrosis presence with fibrosis entropy classified patients into low-, intermediate-, and high-arrhythmic-risk groups.

Conclusions: Deeper phenotypic characterization of scar using fibrosis entropy offers incremental utility to left ventricular ejection fraction and fibrosis presence for arrhythmic risk stratification in NICM.

Keywords: arrhythmic risk stratification; entropy; fibrosis; nonischemic cardiomyopathy.

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Conflict of interest statement

R.B. has received honoraria from AstraZeneca, Vifor, and Medtronic. K.G. has received honoraria from Bayer, Pfizer, Novartis, AstraZeneca, and Servier Laboratories; a previous unrestricted educational grant from Biotronik; and previous travel assistance from Abbott Laboratories, Medtronic, Biotronik, and Boston Scientific. F.L. is a consultant with and has received research funding from Medtronic Inc., Boston Scientific, Abbott, Microport, and Biotronik. J.S.W. has acted as a consultant for MyoKardia, Foresite Labs, Pfizer, Health Lumen, and Tenaya Therapeutics. D.J.P. has received research funding from Siemens. The remaining authors have no disclosures to report.

Figures

Figure 1
Figure 1. Fibrosis entropy quantification.
Quantification of myocardial fibrosis entropy from late gadolinium enhancement cardiovascular magnetic resonance. A, LGE CMR short‐axis stack; (B) single LGE short‐axis slice; (C) classification of core fibrosis (red) and gray zone fibrosis (pink); (D) visual representation of pixel signal intensity for region of core fibrosis with corresponding signal intensity histogram. CMR indicates cardiovascular magnetic resonance; and LGE, late gadolinium enhancement.
Figure 2
Figure 2. Study cohort.
Flowchart illustrating the assembly of the study cohort. CMR indicates cardiovascular magnetic resonance; LGE, late gadolinium enhancement; LVEDVi, indexed left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction; and NICM, nonischemic cardiomyopathy.
Figure 3
Figure 3. Fibrosis entropy and LVEF in relation to the primary end point.
Cumulative incidence curves for life‐threatening arrhythmia stratified by (A) combined fibrosis entropy above median; and (B) LVEF ≤35%. Combined fibrosis entropy greater than median was associated with increased cumulative incidence of life‐threatening arrhythmia; LVEF ≤35% was not associated with increased cumulative incidence of LTA. LTA indicates life‐threatening arrhythmia; and LVEF, left ventricular ejection fraction.
See this image and copyright information in PMC

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