In silico analysis of the Frank-Starling mechanism

The Frank-Starling mechanism (FS) is an essential feature of the heart, which
allows for a beat-to-beat adaptation of cardiac output to hemodynamic conditions.
This intrinsic adaptative mechanism to preload variations lies in the cellular
components that make up the cardiac muscle. It is believed that lengthdependent
activation (LDA), a cardiac cellular property, is responsible for the FS
mechanism observed at the heart scale. However, LDA is essentially highlighted
in cellular experiments that do not reproduce the in vivo conditions of a beating
heart. The connexion between LDA and the FS mechanism is actually difficult
to unravel experimentally, as two very different scales (cellular and ventricular)
are involved.
This thesis is devoted to the analysis of this connexion between a cellular mechanism
(LDA) and its manifestation at the cardiovascular scale (FS mechanism).
This analysis is performed in silico with a multiscale model of the cardiovascular
system (CVS), where ventricular contraction is described at the cellular scale.
Such models help overcome the experimental difficulties of linking two different
scales, while providing a formal framework to integrate the experimental
observations coming from both scales.
Our multiscale model is first used to study the relevance of some cardiac contractility
indices. Then, an analysis of the FS mechanism is proposed. Attention
is paid to providing rigorous definitions and numerical protocols so that the
correlation between LDA and the FS can be established without any ambiguity.
LDA is shown to underlie the macroscopic (ventricular) response to preload
variations, but in a highly dynamical way, in contrast with what is generally
presented in the literature. In addition to these physiological considerations, the
relationship between the FS mechanism and clinical therapies is also addressed.
The FS mechanism is commonly presented as the founding principle for vascular
filling, but we challenge this theory and introduce the concept of lengthdependent
fluid response (LDFR). We show that LDA underlies LDFR, but it is
not the only factor that drives the macroscopic (ventricular) response to fluid
infusions. The afterload also comes into play and the global CVS response results
from a balance between a cellular LDA-driven mechanism and a hemodynamic
resistance to blood ejection. Finally, the role of the FS mechanism regarding
stroke volumes equilibrium is also investigated.
We conclude that LDA indeed underlies the FS mechanism in vivo, but in a
way that implies a complex dynamical interaction of cellular and hemodynamical
variables. The FS mechanism is thus really a multiscale phenomenon, where
the cellular variables and the hemodynamic variables influence each other during
the whole heartbeat. It is hoped that our multiscale CVS model could be
developed and used for further studies that aim at linking cellular properties
and organ behaviors, either in healthy or in pathological conditions.