Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy

Abstract

Cardiac resynchronization therapy (CRT) has emerged as one of the few effective and safe treatments for heart failure. However, identifying patients that will benefit from CRT remains controversial. The dependence of CRT efficacy on organ and cellular scale mechanisms was investigated in a patient-specific computer model to identify novel patient selection criteria. A biophysically based patient-specific coupled electromechanics heart model has been developed which links the cellular and sub-cellular mechanisms which regulate cardiac function to the whole organ function observed clinically before and after CRT. A sensitivity analysis of the model identified lack of length dependence of tension regulation within the sarcomere as a significant contributor to the efficacy of CRT. Further simulation analysis demonstrated that in the whole heart, length-dependent tension development is key not only for the beat-to-beat regulation of stroke volume (Frank-Starling mechanism), but also the homogenization of tension development and strain. In individuals with effective Frank-Starling mechanism, the length dependence of tension facilitates the homogenization of stress and strain. This can result in synchronous contraction despite asynchronous electrical activation. In these individuals, synchronizing electrical activation through CRT may have minimal benefit.