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.
The proposed research will study how variations in the regulation of myosin binding protein C (MYBPC3) affect muscle structure and function in the wall of the heart following ischemic injury. We will create an architectural model of heart failure that links MYBPC3 phosphorylation with sarcomere morphology and the alignment of cardiac myocytes distributed across the ventricular wall, thus depicting the multi-scale organization in the normal and the failing heart. We propose that the loss of MYBPC3 phosphorylation alters interactions of MYBPC3 with myofilament proteins and results in a profound effect on the architectural integrity of the ventricular wall. We will depict through this research an architectural formulation of heart failure that links MYBPC3 phospho-regulation, sarcomere morphology, and muscular anatomy in order to track the natural history of cardiomyopathy and to assess the impact of molecular treatments directed at defects of the cardiac sarcomere.