LVAD or no LVAD: biomechanical signatures of mechanical unloading

Abstract Background The left ventricular assist device (LVAD) is a life-saving therapy for patients with end-stage heart failure (HF), often used as a bridge to cardiac transplantation. Mechanical unloading by an LVAD has been associated with structural and molecular reverse remodeling, including partial restoration of ventricular geometry, calcium cycling, and metabolic function. In some patients, such reverse remodeling can progress sufficiently to enable successful LVAD explantation without the need for transplantation, underscoring the clinical importance of understanding unloading-induced myocardial recovery. However, direct functional assessment of human ventricular myocardium after LVAD unloading remains limited. Living myocardial slices (LMS) offer a promising translational platform to directly interrogate how mechanical unloading affects contractility, refractoriness and remodeling features at the tissue level, providing functional insight that is not accessible through imaging techniques or molecular profiling alone. Aim To assess the effects of mechanical unloading on tissue-level function in human ventricular myocardium using a biomimetic LMS model. Methods Ventricular tissue was obtained from explanted hearts of patients undergoing cardiac transplantation, with or without prior LVAD support. LMS were prepared using our optimized protocol and maintained in biomimetic chambers under isotonic loading (1 mN) and continuous electrical pacing (1 Hz) to mimic in vivo conditions. Contractile metrics, including peak force (Fmax), time to peak (TTP), time to relaxation (TTR), and refractory period (RP), were quantified using MyoDish software. Statistical analysis was performed using linear mixed-effects models. Results A total of 274 ventricular slices (106 LVAD, 168 non-LVAD) from 46 patients (19 LVAD, 27 non-LVAD) were analysed. LVAD patients were older, predominantly male and had lower preoperative left ventricular ejection fraction. During the acute stabilization phase (day 0–3), LVAD and non-LVAD slices displayed comparable contractile profiles. In the chronic culture phase (day 4–7), LVAD slices generated higher Fmax (1602.6 vs 868.5 µN, p=0.04), longer TTP (279.2 vs 226.4 ms, p=0.04), and trends toward prolonged TTR (438.0 vs 339.4 ms, p=0.07) and greater contractile work (478.8 vs 248.3 µN·s, p=0.12). Fmax showed a positive, albeit non-significant, association with LVAD support duration. RP remained comparable between groups. Conclusion Mechanical unloading by LVAD support is associated with enhanced contractile performance in human ventricular tissue after the initial stabilization period. These long-term LMS data provide direct functional evidence of unloading-induced recovery in end-stage HF. Future work will include paired pre/post-LVAD tissue analyses, pharmacological testing of new agents to augment reverse remodeling, alongside calcium imaging and work-loop assessments to advance understanding of myocardial recovery during LVAD support.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.