Exploring the Heart: from Genetic Mutations to Tissue Function

The heart is a fascinatingly efficient pump with intricate design criteria. While many aspects of
heart function remain a mystery, investigations through the prism of mechanics, physics, and
mathematics can provide invaluable insights – presented as three examples in this talk. First, we
consider the problem of automatically characterizing cardiac tissue architecture over multiple
length-scales. Through, the use of existing and creation of new order parameters, multiple
discoveries were made such as the existence of consistently sized spontaneous patches of
organization in isotropic cardiac tissues. Second, we explore the relationship between cell
organization and tissue force generation. Through a tissue engineering trick, the global (~1mm)
and local (~100 microns) architecture effects were separated, and it was discovered that the
reduction in developed force due purely to changes in global tissue architecture can be predicted
by an astonishingly simple physical model, while local changes trigger complex biological
responses. Third, we investigate the relationship among genetic mutations to the nuclear lamina
protein, Lamin A/C (LMNA), detrimental consequences to cellular architecture, and cardiac
function. LMNA mutations can lead to a devastating early aging disease (progeria) or have a
subtler effect with patients presenting only with heart disease symptoms. However, the
mechanisms by which the LMNA mutation emerges in the heart muscle are unknown. Thus far
we have uncovered a relationship between nuclear defects in patient-specific cells and the age at
which these patients present with heart disease symptoms. Additionally, we have found that the
pathology that takes decades to develop in patients can be recapitulated in a dish within a few
weeks. Through all three of these examples, we will also explore newly generated mysteries that
can again be elucidated in the future through the application of physical principles.