Keynote Speakers
Keynote Speakers
Frank Baaijens, Ph.D.Professor, Biomedical Engineering, Eindhoven University of Technology
Heart valve tissue engineering
Although existing valve prostheses generally have resulted in enhanced survival and quality of life, they have serious drawbacks that limit their long-term efficacy. These include thrombo-embolic complications requiring lifelong anticoagulation in case of mechanical valves, limited durability due to calcification and structural failure in case of bioprostheses and structural deterioration and shortage of donor material when using a homograft. Besides, the inability to grow restricts the application of currently available prostheses in pediatric patients. Importantly, assuming that no valve-related complications occur, the life expectancy of patients after aortic valve replacement is substantially lower than that of an age matched, healthy individual living in the same environment, especially when the aortic valve is replaced at relatively young age. Tissue Engineering seeks to overcome these drawbacks by creating living substitutes. By using autologous cells, immunologic problems may be avoided and by application of (rapidly) degrading scaffolds the graft may be able to grow, repair and remodel in response to functional changes in demand. Tissue engineering aims at the creation of ‘one valve for life’, with minimum complications and maximum quality of life. Critical issues include cell source, scaffold material and design, in-vitro bioreactor culture protocol and implantation technology, and in vivo tissue response.
José Luis de la Pompa, Ph.D.Senior Scientist, Cardiovascular Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares
Concerted activity of Notch and BMP2 during cardiac valve development
Despite the prevalence of cardiac valve disease, little is known about the molecular circuitry regulating valve morphogenesis. We show that Notch is one key signal that acts with BMP2 to establish a valve-forming field between two chamber developmental domains. This occurs via restricted atrioventricular canal (AVC) activation of endocardial epithelial-to-mesenchymal-transition (EMT). Mice with constitutive Notch1 endocardial expression activate a mesenchymal gene program in ventricles (including Snail1, Snail2, Twist2 and TGFß2) and display partial (non-invading) ectopic EMT in vitro. BMP2 induces complete EMT in ventricular explants and snail1, TGFß2 or Notch inhibition reduces ventricular transformation and invasion, indicating that these molecules participate in the BMP2-triggered EMT. In endothelial cells, BMP2 mediates GSK3-ß inhibition, favoring snail1 stability and promoting cell invasiveness. BMP2 myocardial deletion attenuates Notch1 signaling, while Notch1 myocardial activation causes ectopic Hey1 expression in AVC, BMP2 repression and EMT impairment. We suggest that a conserved Notch1/BMP2 interplay promoting snail1 expression and activity regulates the extent of EMT in prospective valve territory.
Volkmar Falk, M.D.Professor, Department of Cardiovascular Surgery, University of Zürich
Transapical aortic Valve Implantation – Patient selection, Imaging, Results and Future directions
Transapical aortic valve implantation /TAVI) has evolved as a routine procedure in many centers. Up to now TAVI has been exclusively applied in a high risk population for standard aortic valve replacement. Early and mid-term results are encouraging despite the fact that new procedure related complications occur. Ongoing randomized trials are likely to demonstrate equal safety as with standard surgical techniques and TAVI is likely to develop as a true alternate approach for aortic valve replacement. The increasing number of reports demonstrating the feasibility of a valve in valve concept may further promote the use of biological valve implants in a younger population. A number of different valve designs are currently undergoing preclinical trials or have just entered the clinical arena. Enhanced Imaging and Modelling as well as augmented reality techniques will help to select the best possible implant based on individual anatomic and morphologic data and facilitate the process of implantation in the near future.
K. Jane Grande-Allen, Ph.D.Associate Professor of Bioengineering, Rice University
Heterogeneity of Cell Phenotypes, Extracellular Matrix, and Tissue Function in the Mitral Valve
The mitral valve is one of the most complicated connective tissue structures in the human body. Although many aspects of its anatomy and microstructure are well characterized, other features are still coming to light. For example, new evidence demonstrates the potential for functional tissue adaption by the valvular interstitial cells and other microstructural components across varying time scales. There is also profound phenotypic heterogeneity across different regions of the mitral valve leaflets and chordae with new appreciation for regional behavior valvular cells and non-fibrillar extracellular matrix components such as proteoglycans. These heterogeneities are driven by and reinforced by the diversity of pericellular environments and mechanical loading experienced by the mitral valve cells and tissues.
Professor of Cardiology and Director of “L’institut du Thorax,” Nantes, France
Genetics: a new approach for the understanding of valvular diseases
An increase number of information are in favor of the implication of the genetic background in the development of idiopathic or degenerative valvular diseases including myxomatous valve diseases and calcific aortic stenosis. The recent developments in genetics will probably play a major role for the understanding of the pathophysiology of these diseases and the identification of new therapeutic targets. The keynotes lecture will synthesize the actual knowledge in this field and describe the strategies that should rapidly improve or understanding of the molecular mechanisms leading to these diseases.
Director, Cardiovascular Developmental Biology Center, Medical University of South Carolina
Developmental Mechanisms of Adult Cardiovascular Remodeling Diseases: Valvular Heart Diseases (VHD)
VHD is a common medical condition that increases with age and despite improvements in treatment options, mortality and morbidity rates remain high. New strategies are needed which include stimulating endogenous repair pathways including formation of new progenitor cells. To do so, will require, in part, understanding how the mechanisms of valvulogenesis relate to how adult valves adapt to physiologic and pathologic states including myocardial infarction or hypertrophic cardiomyopathy (HCM). Valvulogenesis is a complex process involving temporal “waves” of progenitor cells (including circulating cells and extracardiac mesenchyme) joining with those initially derived from the process of endocardium-mesenchyme transformation (EMT) to form prevalvular “cushions”. The regulatory genes of the EMT process have been well characterized and include members of the TGF supergene family and their downstream targets. The genes regulating the post-EMT processes whereby the cushions are subsequently molded (or remodeled) into mature valve leaftets are less understood. Genes encoding matricellular proteins like periostin, have been implicated as candidates for regulating post-EMT remodeling. Periostin through integrin signaling pathways promotes differentiation of cushion mesenchyme into valve interstitial fibroblasts and collagen fibrillogenesis. Mice with targeted deletion of periostin or a downstream target, filamin-A, generate a myxomatous AV valve phenotype seen in age-related or inherited degenerative forms of human VHD. Conversely, a 5-8 fold upregulation of periostin occurs in transgenic HCM mice which correlates with abnormal elongation and cooptation of AV valve leaflets often leading to mitral regurgitation. The changes in engraftment of circulating bone marrow-derived stem cells that express periostin into adult murine valves following myocardial injury also support a role for periostin in pathophysiological, adaptive remodeling of the leaflets. Collectively, these findings suggest that developmental mutations in secreted extracellular proteins (like periostin) or transducers of their signaling (e.g. filamin A) or postnatal adaptive responses to environmental changes (e.g. HCM) can contribute, over time, to dystrophic adult valves. Supported by HL 33756 and a Leducq Foundation Transatlantic Network Grant (MITRAL).
Abhay Pandit, Ph.D.Director, Network of Excellence for Functional Biomaterials, NUI Galway
Designing Functionalised Biomaterials Platforms
Biomaterials are no longer considered innate structures and using functionalisation strategies to modulate a desired response whether it be a host or implant responsive is currently an important focus in current research paradigms. Examples of functionalisation strategies that have utilised enzymatic and dendrimeric linkers we have been able to link biomolecules to different structural moieties. Biomolecules include designed peptide motifs, growth factors and a multitude of gene vector systems. Structural moieties have taken multitude of different forms such as nanofibers and nanoparticulate. Functionalisation on a microscale and macroscale has also been successfully attempted. Such strategies with examples from in vitro and in vivo studies will be illustrated. Development of complex geometrical structures and quantification of these geometries that have aided these investigations will be exemplified.
Assistant Professor, Mechanical and Biomedical Engineering, University of Toronto
Mechanobiology of valve stem cells and calcific aortic valve disease
Calcific aortic valve disease occurs through multiple mechanisms that are mediated by fibroblast-like cells within the valve matrix. We have identified and characterized a large subpopulation of mesenchymal stem cells within the aortic valve that can differentiate to osteoblast and myofibroblast lineages, and are presumably responsible for the calcific and fibrotic changes that occur with disease progression. Our recent findings indicate that differentiation of valve stem cells to distinct pathological phenotypes is regulated by complex interplay between local mechanical signals from the extracellular matrix and specific paracrine signals from valve endothelial cells, which themselves are hemodynamically regulated. By elucidating the mechanobiological determinants of valve calcification, we aim not only to identify therapeutic targets to prevent and treat CAVD, but also to improve fundamental understanding of the mechanobiology of mesenchymal stem cells and their role in disease.