Pregnancy-induced remodeling of heart valves

Abstract

Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and 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 cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. HEART VALVES ARE COMPLEX and dynamic biological structures. They play important roles toward efficient cardiac pumping, ensuring unidirectional blood flow while opening and closing 3 billion times in a lifetime. The extent and the mechanisms via which the valves may adapt to changing loading conditions in either physiology or pathology remain unclear. Many investigations of valve adaptation have focused on physiological development (8,20,(51)(52)(53) or pathological conditions such as left ventricular (LV) dysfunction (10), mitral valve regurgitation (58), myxomatous degeneration (19), or heart failure (17). Recent studies from our laboratory, however, have demonstrated the capacity of maternal heart valve leaflets to remodel under the altered hemodynamics of pregnancy, a nonpathological condition (38,39,60). Pregnancy is accompanied by an increase in blood volume and cardiac output of ϳ50%, as the maternal circulation accommodates the developing fetoplacental unit. This volume overload produces cardiac enlargement (21, 45, 60) with expansion of valve orifices (areas increasing from 12-53% in humans; see Refs. 9 and 43). These changes in geometry then elevate...

A functionally graded material model for the transmural stress distribution of the aortic valve leaflet

“…Beyond demonstrating that there are large differences between the conventionally defined three layers, the stress distribution we inferred suggests that there is also considerable variation within each layer. From a biological perspective, this result could have significant implications, since VICs are known to deform in vivo and remodel their surrounding matrix in manners highly specific to the mechanical properties of their microenvironment (Lee et al, 2015a; Pierlot et al, 2014; Pierlot et al, 2015). Efforts to understand local valve tissue maintenance, growth, and adaptation to deviations in physiological function (e.g.…”

“…While this notion has been exploited in the past to bioengineer scaffolds and other medical materials (Erisken et al, 2008; Pompe et al, 2003), it has generally not been adopted in the study of native tissues, perhaps due to the high-resolution data required. Quantifying continuous transmural variations in structure and stress could have a substantial impact on our understanding of heart valve mechanobiology, since the deformation and biosynthetic behavior of valve interstitial cells (VICs) have been shown to depend on local extracellular matrix (ECM) mechanical properties (Lee et al, 2015a; Pierlot et al, 2014; Pierlot et al, 2015). In the present study, we developed a FGM structural constitutive model for the AV leaflet to infer a more realistic transmural stress distribution under physiological deformation.…”

Mitral valve leaflet remodelling during pregnancy: insights into cell-mediated recovery of tissue homeostasis

“…Note that mass fractions of collagen and elastin were not included in the set of estimated parameters, and were instead prescribed from previous biochemical assay results [5,14]. Mass fraction data were re-analysed to identify potential timedependent trends, and appropriate values for f c and f e were assigned to each specimen accordingly.…”

A noninvasive method for the determination of in vivo mitral valve leaflet strains

“…The present study builds upon over a century of investigations into MV mechanics and owes much to recent achievements in the development of high‐fidelity computational models of the MV . Moreover, the overarching objective of devising noninvasive methods to estimate MV strains in vivo is motivated by an increasingly compelling body of evidence that supports hypotheses of bidirectional causal links between tissue‐level deformations and cell‐mediated growth and remodeling events . It is thus strongly believed that accounting for these interconnected phenomena is paramount to the accurate prediction of clinical events, such as post‐MI MV/ventricular remodeling and postsurgical MV repair outcomes .…”

“…This is because IMR is not caused by defects in the MV apparatus itself but is rather a result of changes to the geometry of the left ventricle post‐MI. Such alterations place the MV in a nonphysiological loading state, leading to valvular tissue growth and remodeling . In light of this, recent studies have begun to elucidate links between MV function at the organ level and the mechanobiological responses of the underlying MV interstitial cells, which ultimately drive remodeling .…”