Reconstituting electrical conduction in soft tissue: the path to replace the ablationist.

Cardiac arrhythmias are a leading cause of morbidity and mortality in the developed world. A common mechanism underlying many of these arrhythmias is re-entry, which may occur when native conduction pathways are disrupted, often by myocardial infarction. Presently, re-entrant arrhythmias are most commonly treated with antiarrhythmic drugs and myocardial ablation, although both treatment methods are associated with adverse side effects and limited efficacy. In recent years, significant advancements in the field of biomaterials science have spurred increased interest in the development of novel therapies that enable restoration of native conduction in damaged or diseased myocardium. In this review, we assess the current landscape of materials-based approaches to eliminating re-entrant arrhythmias. These approaches potentially pave the way for the eventual replacement of myocardial ablation as a preferred therapy for such pathologies.

Poly(ethylene glycol)-Based Coatings for Bioprosthetic Valve Tissues: Toward Restoration of Physiological Behavior.

Bioprosthetic valves (BPVs) have a limited lifespan in the body necessitating repeated surgeries to replace the failed implant. Early failure of these implants has been linked to various surface properties of the valve. Surface properties of BPVs are significantly different from physiological valves because of the fixation process used when processing the xenograft tissue. To improve the longevity of BPVs, efforts need to be taken to improve the surface properties and shield the implant from the bodily interactions that degrade it. Toward this goal, we evaluated the use of hydrogel coatings to attach to the BPV tissue and impart surface properties that are close to physiological. Hydrogels are well characterized for their biocompatibility and highly tunable surface characteristics. Using a previously published coating method, we deposited hydrogel coatings of poly(ethylene glycol)diacrylate (PEGDA) and poly(ethylene glycol)diacrylamide (PEGDAA) atop BPV samples. Coated samples were evaluated against the physiological tissue and uncoated glutaraldehyde-fixed tissue for deposition of hydrogel, surface adherence, mechanical properties, and fixation properties. Results showed both PEGDA- and PEGDAA-deposited coatings were nearly continuous across the valve leaflet surface. Further, the PEGDA- and PEGDAA-coated samples showed restoration of physiological levels of protein adhesion and mechanical stiffness. Interestingly, the coating process rather than the coating itself altered the material behavior yet did not alter the cross-linking from fixation. These results show that the PEG-based coatings for BPVs can successfully alter surface properties of BPVs and help promote physiological characteristics without interfering with the necessary fixation.

Age-related changes in aortic valve hemostatic protein regulation.

OBJECTIVE: Although valvular endothelial cells have unique responses compared with vascular endothelial cells, valvular regulation of hemostasis is not well-understood. Heart valves remodel throughout a person's lifetime, resulting in changes in extracellular matrix composition and tissue mechanical properties that may affect valvular endothelial cell hemostatic function. This work assessed valvular endothelial cell regulation of hemostasis in situ and in vitro as a function of specimen age. APPROACH AND RESULTS: Porcine aortic valves were assigned to 1 of 3 age groups: Young (YNG) (6 weeks); Adult (ADT) (6 months); or Elderly (OLD) (2 years). Histological examination of valves showed that secreted thrombotic/antithrombotic proteins localize at the valve endothelium and tissue interior. Gene expression and immunostains for von Willebrand factor (VWF), tissue factor pathway inhibitor, and tissue plasminogen activator in YNG porcine aortic valve endothelial cells were higher than they were for OLD, whereas plasminogen activator inhibitor 1 levels in OLD were higher than those for YNG and ADT. Histamine-stimulated YNG porcine aortic valve endothelial cells released higher concentrations of VWF proteins than OLD, and the fractions of VWF-140 fragments was not different between age groups. A calcific aortic valve disease in vitro model using valvular interstitial cells confirmed that VWF in culture significantly increased valvular interstitial cell nodule formation and calcification. CONCLUSIONS: Hemostatic protein regulation in aortic valve tissues and in valvular endothelial cells changes with age. The presence of VWF and other potential hemostatic proteins increase valvular interstitial cell calcification in vitro. Therefore, the increased capacity of elderly valves to sequester the hemostatic proteins, together with age-associated loss of extracellular matrix organization, warrants investigation into potential role of these proteins in the formation of calcific nodules.

Perinatal changes in mitral and aortic valve structure and composition.

At birth, the mechanical environment of valves changes radically as fetal shunts close and pulmonary and systemic vascular resistances change. Given that valves are reported to be mechanosensitive, we investigated remodeling induced by perinatal changes by examining compositional and structural differences of aortic and mitral valves (AVs, MVs) between 2-day-old and 3rd fetal trimester porcine valves using immunohistochemistry and Movat pentachrome staining. Aortic valve composition changed more with birth than the MV, consistent with a greater change in AV hemodynamics. At 2 days, AV demonstrated a trend of greater versican and elastin (P  =  0.055), as well as greater hyaluronan turnover (hyaluronan receptor for endocytosis, P  =  0.049) compared with the 3rd-trimester samples. The AVs also demonstrated decreases in proteins related to collagen synthesis and fibrillogenesis with birth, including procollagen I, prolyl 4-hydroxylase, biglycan (all P ≤ 0.005), and decorin (P  =  0.059, trend). Both AVs and MVs demonstrated greater delineation between the leaflet layers in 2-day-old compared with 3rd-trimester samples, and AVs demonstrated greater saffron-staining collagen intensity, suggesting more mature collagen in 2-day-old compared with 3rd-trimester samples (each P < 0.05). The proportion of saffron-staining collagen also increased in AV with birth (P < 0.05). The compositional and structural changes that occur with birth, as noted in this study, likely are important to proper neonatal valve function. Furthermore, normal perinatal changes in hemodynamics often do not occur in congenital valve disease; the corresponding perinatal matrix maturation may also be lacking and could contribute to poor function of congenitally malformed valves.

Functional characterization of fibronectin-separated valve interstitial cell subpopulations in three-dimensional culture.

BACKGROUND AND AIM OF THE STUDY: Myxomatous mitral valves (MVs) contain elevated proportions of myofibroblasts, a valve interstitial cell (VIC) subpopulation that may be important in disease pathogenesis. A novel technique was recently developed for the isolation of VIC myofibroblasts using time-dependent adhesion to fibronectin (FN). Cells that adhere rapidly to FN ('FAST') demonstrate myofibroblast cell phenotype markers, in contrast to cells that fail to adhere after a longer time ('SLOW'). The study aim was to characterize the functionality of these subpopulations using three-dimensional (3D) collagen constructs. METHODS: The VICs were harvested from porcine mitral valve posterior leaflets. FAST and SLOW subpopulations, as well as unseparated VIC populations grown on FN and tissue culture plastic (TCP) (UNSEP FN, UNSEP TCP), were seeded within 3D collagen gels and cultured for three weeks. Collagen gel contraction was assessed throughout the culture duration; the mechanical properties of the resultant collagen constructs were assessed using uniaxial tensile testing. RESULTS: FAST cells demonstrated a greater contraction of collagen gels compared to SLOW cells, particularly after 10 days (p < 0.05). Interestingly, the collagen gel contraction by both FN-separated VIC subpopulations (FAST and SLOW) was greater than for gels seeded with UNSEP TCP VICs (p < 0.05). Further, the contraction of UNSEP FN gels was greater than UNSEP TCP throughout the culture duration (p < OR = 0.002), suggesting that the subculture of VICs on FN potentiated these phenotypic changes. Finally, the collagen constructs seeded with FAST cells were stiffer than those seeded with SLOW, followed by UNSEP TCP (p < 0.001). The same pattern was found for failure stress (p = 0.006). CONCLUSION: Time-dependent adhesion to FN produced a VIC subpopulation (FAST), the function of which in 3D culture was consistent with that of myofibroblasts; FN exposure alone also caused VICs to function similarly to myofibroblasts. This novel isolation method may prove valuable in future studies of myofibroblasts in valve disease.