A Novel Translational Porcine Large Animal Model for Arrhythmia-Induced Cardiomyopathy (AiCM): Bridging Pathomechanisms to Therapeutic Innovations

M. Harder (Heidelberg)¹, F. Wiedmann (Heidelberg)¹, A. Erkal (Heidelberg)¹, A. Paasche (Heidelberg)¹, L. Weirauch (Heidelberg)¹, M. Kraft (Heidelberg)¹, M. Stelzle (Heidelberg)¹, M. Prüser (Heidelberg)¹, M. A. Waibel (Heidelberg)¹, A. Garrido (Mannheim)², N. Frey (Heidelberg)¹, J. Heineke (Mannheim)², C. Schmidt (Göttingen)^1
1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; ²Medizinische Fakultät Mannheim der Universität Heidelberg Kardiovaskuläre Physiologie Mannheim, Deutschland

Background: Arrhythmia-induced cardiomyopathy (AiCM) is an increasingly recognized cause of heart failure (HF), yet its pathophysiology remains underexplored, and the absence of clear diagnostic criteria hampers clinical management. Establishing a robust translational large animal model for AiCM is crucial for understanding the underlying molecular mechanisms and developing therapeutic interventions. This study presents a novel porcine model of AiCM that simulates human disease, providing a platform for investigating pathomechanisms and testing novel therapeutic approaches.

Methods: Six male pigs (36 ± 2 kg) were implanted with dual-chamber pacemakers. Atrial fibrillation (AF) was induced through right atrial burst pacing over 21 days, using a feedback algorithm that suppressed pacing when endogenous AF propagation occurred. Comprehensive diagnostic assessments, including ECG, echocardiography, blood sampling, right heart catheterization, and electrophysiological (EP) studies, were conducted at baseline, and day 21. Echo and ECG was repeated on d10.

Results: AF burden progressively increased from 46 ± 11% on day 10 to 69 ± 11% by day 21. While surface ECG values showed no significant changes, left ventricular ejection fraction (LVEF) decreased significantly from 64% at baseline to 42% (P = 0.0024) on day 10 and to 37% (P = 0.001) by day 21. Echocardiography further revealed marked biventricular dilatation, with a 50.4% increase in right ventricular diameter (P = 0.013) and a 45.7% increase in left ventricular end-diastolic diameter (P = 0.040). Atrial dilation, impaired diastolic function, reduced global longitudinal strain (GLS), and atrioventricular valve regurgitation were observed. Hemodynamic measurements showed a 46.7% increase in pulmonary artery pressure (P = 0.039) and an 80% increase in central venous pressure, indicative of congestive right heart failure. EP studies revealed trends toward prolonged atrial and ventricular effective refractory periods (AERP, VERP), though these did not reach statistical significance.

Conclusion: This novel porcine model successfully replicates the key features of AiCM, highlighting its potential as a translational tool to facilitate the development of pharmacological, device-based, and gene therapies for AiCM and advancing their implementation into clinical practice.