Structural and Functional Characterization of the Aorta in Hypertrophic Obstructive Cardiomyopathy.

Background: Changes in the phenotype and genotype in hypertrophic cardiomyopathy (HCM) are thought to involve the myocardium as well as extracardiac tissues. Here, we describe the structural and functional changes in the ascending aorta of obstructive patients with HCM.

Methods: Changes in the aortic wall were studied in a cohort of 101 consecutive patients with HCM undergoing myectomy and 9 normal controls.

Structural aortic wall abnormalities following the Nikaidoh operation, which could be reversible and include a healing process.

The Nikaidoh operation continues to be used for patients with transposition of the great arteries, ventricular septal defect and left ventricular outflow tract obstruction. We recently reported structural and functional changes in the aortic root during the follow-up of a patient who underwent the Nikaidoh operation. These changes necessitated re-operation.

Valvulogenesis of a living, innervated pulmonary root induced by an acellular scaffold.

Heart valve disease is a major cause of mortality and morbidity worldwide with no effective medical therapy and no ideal valve substitute emulating the extremely sophisticated functions of a living heart valve. These functions influence survival and quality of life. This has stimulated extensive attempts at tissue engineering "living" heart valves.

Multiscale structure and function of the aortic valve apparatus.

Whereas studying the aortic valve in isolation has facilitated the development of life-saving procedures and technologies, the dynamic interplay of the aortic valve and its surrounding structures is vital to preserving their function across the wide range of conditions encountered in an active lifestyle. Our view is that these structures should be viewed as an integrated functional unit, here referred to as the aortic valve apparatus (AVA). The coupling of the aortic valve and root, left ventricular outflow tract, and blood circulation is crucial for AVA's functions: unidirectional flow out of the left ventricle, coronary perfusion, reservoir function, and support of left ventricular function.

Profiling Genome-Wide DNA Methylation Patterns in Human Aortic and Mitral Valves.

Cardiac valves exhibit highly complex structures and specialized functions that include dynamic interactions between cells, extracellular matrix (ECM) and their hemodynamic environment. Valvular gene expression is tightly regulated by a variety of mechanisms including epigenetic factors such as histone modifications, RNA-based mechanisms and DNA methylation. To date, methylation fingerprints of non-diseased human aortic and mitral valves have not been studied.

Atypical Expression of Smooth Muscle Markers and Co-activators and Their Regulation in Rheumatic Aortic and Calcified Bicuspid Valves.

Objective: We have previously reported that human calcified aortic cusps have abundant expression of smooth muscle (SM) markers and co-activators. We hypothesised that cells in bicuspid aortic valve (BAV) cusps and those affected by rheumatic heart valve (RHV) disease may follow a similar phenotypic transition into smooth muscle cells, a process that could be regulated by transforming growth factors (TGFs).

Aims: Cusps from eight patients with BAV and seven patients with RHV were analysed for early and late SM markers and regulators of SM gene expression by immunocytochemistry and compared to healthy aortic valves from 12 unused heart valve donors.

Nine days extended release of adenosine from biocompatible MOFs under biologically relevant conditions.

Adenosine is a small molecule directly involved in maintaining homeostasis under pathological and stressful conditions. Due to its rapid metabolism, delivery vehicles capable of exhibiting extended release of adenosine are of paramount interest. Herein, we demonstrate a superior long-term (9 days) release profile of adenosine from biocompatible MOFs in a physiologically relevant environment.

Biocompatibility and Application of Carbon Fibers in Heart Valve Tissue Engineering.

The success of tissue-engineered heart valves rely on a balance between polymer degradation, appropriate cell repopulation, and extracellular matrix (ECM) deposition, in order for the valves to continue their vital function. However, the process of remodeling is highly dynamic and species dependent. The carbon fibers have been well used in the construction industry for their high tensile strength and flexibility and, therefore, might be relevant to support tissue-engineered hearts valve during this transition in the mechanically demanding environment of the circulation.

Design and characterization of an in vivo injectable hydrogel with effervescently generated porosity for regenerative medicine applications.

Injectable hydrogels that polymerize directly in vivo hold significant promises in clinical settings to support the repair of damaged or failing tissues. Existing systems that allow cellular and tissue ingrowth after injection are limited because of deficient porosity and lack of oxygen and nutrient diffusion inside the hydrogels. Here is reported for the first time an in vivo injectable hydrogel in which the porosity does not pre-exist but is formed concomitantly with its in situ injection by a controlled effervescent reaction.

Severe degeneration of a sub-coronary pulmonary autograft in a young adult.

The pulmonary autograft is currently the best valve substitute in terms of longevity and performance. However, there is no agreement about the optimal method of insertion (sub-coronary position or freestanding root). We sought to examine the clinical status, detailed imaging and morphometric changes in an explanted pulmonary autograft 22 years after sub-coronary implantation.

Microstructure of the juvenile sheep aortic valve hinge region and the trilamellar sliding hypothesis.

The aortic valve mechanism performs extremely sophisticated functions which depend on the microstructure of its component parts. The hinge mechanism of the aortic leaflets plays a crucial part in the overall function. However, the detailed microstructure and its relation to function has not been adequately studied.

Expression and function of mechanosensitive ion channels in human valve interstitial cells.

Background: The ability of heart valve cells to respond to their mechanical environment represents a key mechanism by which the integrity and function of valve cusps is maintained. A number of different mechanotransduction pathways have been implicated in the response of valve cells to mechanical stimulation. In this study, we explore the expression pattern of several mechanosensitive ion channels (MSC) and their potential to mediate mechanosensitive responses of human valve interstitial cells (VIC).

Long-term adaptive versus maladaptive remodelling of the pulmonary autograft after the Ross operation.

Objectives: Following the Ross operation, the pulmonary autograft undergoes structural changes (remodelling). We sought to determine the extent, nature and possible determinants of long-term remodelling in the different components of the pulmonary autograft.

Methods: Ten pulmonary autografts and 12 normal control valves (6 pulmonary and 6 aortic) were examined by conventional histology, immunocytochemistry and electron microscopy.

Knitting for heart valve tissue engineering.

Knitting is a versatile technology which offers a large portfolio of products and solutions of interest in heart valve (HV) tissue engineering (TE). One of the main advantages of knitting is its ability to construct complex shapes and structures by precisely assembling the yarns in the desired position. With this in mind, knitting could be employed to construct a HV scaffold that closely resembles the authentic valve.

A Strategy to Enhance Secretion of Extracellular Matrix Components by Stem Cells: Relevance to Tissue Engineering.

The ability of cells to secrete extracellular matrix proteins is an important property in the repair, replacement, and regeneration of living tissue. Cells that populate tissue-engineered constructs need to be able to emulate these functions. The motifs, KTTKS or palmitoyl-KTTKS (peptide amphiphile), have been shown to stimulate production of collagen and fibronectin in differentiated cells.

Aortic calcified particles modulate valvular endothelial and interstitial cells.

Background: Normal and calcified human valve cusps, coronary arteries, and aortae harbor spherical calcium phosphate microparticles of identical composition and crystallinity, and their role remains unknown.

Objective: The objective was to examine the direct effects of isolated calcified particles on human valvular cells.

Method And Results: Calcified particles were isolated from healthy and diseased aortae, characterized, quantitated, and applied to valvular endothelial cells (VECs) and interstitial cells (VICs).

Hypoxia-mediated regulation of the secretory properties of mitral valve interstitial cells.

The sophisticated function of the mitral valve depends to a large extent on its extracellular matrix (ECM) and specific cellular components. These are tightly regulated by a repertoire of mechanical stimuli and biological pathways. One potentially important stimulus is hypoxia.

Robust Generation of Quiescent Porcine Valvular Interstitial Cell Cultures.

Background: Valvular interstitial cells (VICs) in the healthy aortic valve leaflet exhibit a quiescent phenotype, with <5% of VICs exhibiting an activated phenotype. Yet, in vitro culture of VICs on tissue culture polystyrene surfaces in standard growth medium results in rapid transformation to an activated phenotype in >90% of cells. The inability to preserve a healthy VIC phenotype during in vitro studies has hampered the elucidation of mechanisms involved in calcific aortic valve disease.

Effect of Side-Specific Valvular Shear Stress on the Content of Extracellular Matrix in Aortic Valves.

Responses of valve endothelial cells (VECs) to shear stresses are important for the regulation of valve durability. However, the effect of flow patterns subjected to VECs on the opposite surfaces of the valves on the production of extracellular matrix (ECM) has not yet been investigated. This study aims to investigate the response of side-specific flow patterns, in terms of ECM synthesis and/or degradation in porcine aortic valves.

Alginate for cardiac regeneration: From seaweed to clinical trials.

Heart failure is a growing endemic in the aging Western population with a prevalence of over 20 million people worldwide. Existing heart failure therapies are unable to reverse heart failure and do not address its fundamental cause, the loss of cardiomyocytes. In order to induce myocardial regeneration for the myocardium and the heart valve, facilitate self-repair, improve tissue salvage, reduce or reverse the adverse-remodeling and ultimately achieve long-term functional stabilization and improvement in the heart function, novel strategies for therapeutic regeneration are being developed which are aiming to compensate for the insufficient and low intrinsic regenerative ability of the adult heart.

Modulation of human valve interstitial cell phenotype and function using a fibroblast growth factor 2 formulation.

Valve interstitial cells (VICs) are fibroblastic in nature however in culture it is widely accepted that they differentiate into a myofibroblastic phenotype. This study assessed a fibroblast culture media formulation for its ability to maintain the phenotype and function of VICs as in the intact healthy valve. Normal human VICs were cultured separately in standard DMEM and in fibroblast media consisting of FGF2 (10 ng/ml), insulin (50 ng/ml) and 2% FCS for at least a week.

The living aortic valve: From molecules to function.

The aortic valve lies in a unique hemodynamic environment, one characterized by a range of stresses (shear stress, bending forces, loading forces and strain) that vary in intensity and direction throughout the cardiac cycle. Yet, despite its changing environment, the aortic valve opens and closes over 100,000 times a day and, in the majority of human beings, will function normally over a lifespan of 70-90 years. Until relatively recently heart valves were considered passive structures that play no active role in the functioning of a valve, or in the maintenance of its integrity and durability.

Expression of smooth muscle cell markers and co-activators in calcified aortic valves.

Aims: Similar risk factors and mediators are involved in calcific aortic stenosis (CAS) and atherosclerosis. Since normal valves harbour a low percentage of smooth muscle cells (SMCs), we hypothesize that the SMC phenotype participates in the pathogenesis of CAS.

Method And Results: We analysed 12 normal and 22 calcified aortic valves for SMC markers and the expression of co-activators of SMC gene expression, myocardin and myocardin-related transcription factors (MRTF-A/B).

The potential of anisotropic matrices as substrate for heart valve engineering.

Cells environment is increasingly recognized as an important function regulator through cell-matrix interactions. Extracellular matrix (ECM) anisotropy being a key component of heart valves properties, we have devised a method to create highly porous anisotropic nanofibrillar scaffolds and studied their suitability as cell-support and interactions with human adipose derived stem cells (hADSCs) and human valve interstitial cells (hVICs). Anisotropic nanofibrillar scaffolds were produced by a modified jet-spraying method that allows the formation of aligned nanofibres (600 nm) through air-stream diffraction of a polymer solution (poly (ε-caprolactone, PCL) and collection onto a variably rotating drum.