Myoarchitectural Basis of Heart Failure - ABSTRACT
Heart failure linked to coronary artery disease remains a major source of morbidity, mortality, and cost
in the setting of American health care. Despite considerable efforts in the past several decades to understand
the molecular underpinnings of heart failure, major gaps continue to exist in the understanding of how the
structure and function of myofilament proteins contribute to the organization of cardiac myocytes in the
ventricular wall, a multi-scale formulation termed cardiac myoarchitecture. The current project defines heart
failure in architectural terms, reflective of underlying defects of the cardiac sarcomere, but, at the same time,
predictive of whole organ physiology. Normal cardiac myoarchitecture represents the distribution of cardiac
myocytes in the ventricular wall, and may be portrayed as ordered patterns that provide a template for
physiological force generation during cardiac ejection, whereas pathological myoarchitecture manifests varying
degrees of myofiber disarray that provides a structural basis for impaired force generation and heart failure.
Our laboratory has developed techniques that display the multi-scale myoarchitecture of the intact heart in
terms of spatially restricted proton diffusion, a method termed generalized Q-space imaging (GQI). We
propose to employ this approach to study the effects of molecular perturbations that occur in a critical
sarcomere scaffold protein, myosin binding protein C (MYBPC3), during normal and ischemic conditions. Our
core concept is that the phosphoregulation of MYBPC3 affects critical protein-protein interactions that modify
sarcomere morphology, and in turn, affect ventricular myoarchitecture and mechanics. In support of this
concept, we have shown that 1) Constitutive de-phosphorylation of MYBPC3 is associated with changes of
sarcomere morphology that underlie the loss of transmural myofiber helicity and left ventricular distensibility,
and 2) constitutive phosphorylation of MYBPC3 protects the cardiac wall from architectural damage associated
with ischemic injury. The proposed research will study the mechanism by which impaired phosphorylation of
MYBPC3 modulates sarcomere morphology, transmural fiber helicity, and ventricular wall mechanics.
Accordingly, we propose to carry out the following specific aims: Specific Aim 1: Assess the relationship
between altered 3D sarcomere morphology resulting from impaired MYBPC3 phosphorylation and ventricular
wall myoarchitecture and mechanics. Specific Aim 2: Determine the mechanism by which phosphorylation of
MYBPC3 protects against architectural disarray linked to ischemia-reperfusion (I-R) injury. We propose to
demonstrate an architectural conceptualization of heart failure that links MYBPC3 phospho-regulation, sarcomere
morphology, and ventricular wall organization in order to track the natural history of cardiomyopathy and to assess
the impact of novel molecular treatments directed at defects of the cardiac sarcomere.
