Myocardial Tug-of-War Is a Determinant of Left Ventricular Function and Failure

Background: Heart failure with reduced ejection fraction is a leading cause of death worldwide, characterized by impaired left ventricular systolic function. Contractile, structural, and electrophysiological changes underpin this impairment, but how these changes collectively determine ventricular function remains unclear. We hypothesize that their integrated action involves a complex mechanical interplay at the myocardial mesoscale level, intermediate between individual cardiomyocytes and the global left ventricle. Methods: We acquired high-resolution magnetic resonance images of healthy individuals and patients with myocardial infarction, and developed an analytical method to characterize in vivo contraction patterns in millimeter-sized myocardial units (i.e., at the mesoscale). Furthermore, we employed computational models to examine how mesoscale contraction patterns relate to the contraction mechanism, structure, and electrophysiology of the left ventricle. Results: At the left ventricular mesoscale, we observed that weakly contracting myocardial units are transiently elongated by the contraction of adjacent, more strongly contracting units. These mesoscale interactions generate a ?tug-of-war? that pervades the left ventricle in healthy hearts and becomes particularly prominent following myocardial infarction. This behavior is macroscopically invisible as the contraction patterns of opposing units cancel each other out, but it nevertheless shapes the efficiency of mechanical performance. In the healthy heart, recruitment of more uniformly contracting units (i.e., reduction in tug-of-war) supports augmented contractility during acute stress. However, following myocardial infarction, excessive tug-of-war contributes to impaired contractile efficiency and performance. Computational modelling showed that the ventricular contraction mechanism, structure, and electrophysiology underpin this behavior in healthy hearts and exacerbate it in disease. Conclusion: Left ventricular systolic function is characterized by a myocardial tug-of-war at the mesoscale, which contributes to the heart's adaptability in health and its vulnerability in disease. These findings introduce a new concept for understanding left ventricular function and a novel analytical approach for investigating its failure.