Pregnancy-Induced Remodeling of Heart Valves

Abstract

Although many cardiovascular tissues have been shown to remodel when exposed to chronic changes in hemodynamic stresses, little is known about the capacity of heart valves to adapt in a non-disease state such as pregnancy. In this context, pregnancy is an ideal in vivo model, producing dramatic hemodynamic changes to the maternal circulation and resulting in enlargement of the heart and valve orifices. The aim of the following work was to (i) investigate pregnancy-induced alterations in valve leaflet biomechanics, and (ii) perform detailed structural studies defining the material basis for these changes. Using a bovine pregnancy model, leaflets from all four heart valves were harvested from non-pregnant and pregnant cows, from a local abattoir. Gross leaflet structure was characterized by leaflet dimensions. Small-angle light scattering was used to assess changes in internal fiber architecture. ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and crosslinking state was assessed using denaturation and hydrothermal isometric tension tests. We have reported rapid and extensive remodeling in pregnancy, similar across all of the maternal valves: alterations to leaflet geometry, fiber architecture, composition, biomechanics, and cellularity. All the valves expanded in pregnancy, via an increase in the production of collagen, with associated changes in the biochemical makeup of the ECM and the structure of the collagen network (i.e. loss of crimp, crosslink maturation, and reduction in thermal stability). This thesis is the first to present a comprehensive investigation of physiological heart valve remodeling. Taken together, these studies provide irrefutable evidence of physiological remodeling of bovine heart valve leaflets. This work has expanded our understanding of maternal cardiovascular physiology as well as providing valuable insight into the structure/function relationships at play in these tissues. The ability of the heart to adapt to pregnancy, a non-disease state, without failure is remarkable. Understanding the valvular adaptations to pregnancy may be fundamental both to developing interventions and treatments for valve disease and heart failure, as well as recognizing the implications of pregnancies on maternal long-term vascular risk.