Frank-Starling Mechanism, Fluid Responsiveness, And Length-Dependent Activation: Unravelling The Multiscale Behaviors With An In Silico Analysis

Author summaryIt is commonly admitted that the length-dependent activation is the cellular property underlying the Frank-Starling mechanism. However, it is challenging to assess the cardiac cell length in vivo, and to link it to system-level variables. In this study, we investigated the relationship between length-dependent activation (LDA), the Frank-Starling mechanism, and vascular filling therapy using a multiscale model of the cardiovascular system. We showed that the Frank-Starling mechanism is a multiscale, dynamical and LDA-driven phenomenon involving essential connections between the three cellular, ventricular and cardiovascular scales. We also demonstrated that the response to vascular filling therapy is similarly multiscale and LDA-driven, and that afterload is an important factor to account for when trying to predict the system fluid responsiveness.

The Frank-Starling mechanism is a fundamental regulatory property which underlies the cardiac output adaptation to venous filling. Length-dependent activation is generally assumed to be the cellular origin of this mechanism. At the heart scale, it is commonly admitted that an increase in preload (ventricular filling) leads to an increased cellular force and an increased volume of ejected blood. This explanation also forms the basis for vascular filling therapy. It is actually difficult to unravel the exact nature of the relationship between length-dependent activation and the Frank-Starling mechanism, as three different scales (cellular, ventricular and cardiovascular) are involved. Mathematical models are powerful tools to overcome these limitations. In this study, we use a multiscale model of the cardiovascular system to untangle the three concepts (length-dependent activation, Frank-Starling, and vascular filling). We first show that length-dependent activation is required to observe both the Frank-Starling mechanism and a positive response to high vascular fillings. Our results reveal a dynamical length dependent activation-driven response to changes in preload, which involves interactions between the cellular, ventricular and cardiovascular levels and thus highlights fundamentally multiscale behaviors. We show however that the cellular force increase is not enough to explain the cardiac response to rapid changes in preload. We also show that the absence of fluid responsiveness is not related to a saturating Frank-Starling effect. As it is challenging to study those multiscale phenomena experimentally, this computational approach contributes to a more comprehensive knowledge of the sophisticated length-dependent properties of cardiac muscle.