Artificial heart valves such as mechanical valves and tissue valves are generally used in patients with a dysfunctional heart valve. These have their pros and cons. Durability of current tissue valves is limited, as they do not consist of living tissue that can adapt and repair itself. Although mechanical valves can in principle function for a long time, they require life-long anticoagulation therapy and cannot adapt to changes in body environment or requirements. This restricts the use of valve replacements in paediatric patients, who need multiple reoperations to accommodate somatic growth. TEHVs have growth and remodelling potential but their use in patients, especially in children, is limited by the poorly understood tissue growth and remodelling processes in the heart. This has become evident in many pre-clinical studies where TEHVs lost their functionality over time due to adverse tissue remodelling. The goals of the G-Valve project were to understand the mechanisms of growth and remodeling in natural human heart valves, and to use this insight to predict the growth potential of TEHVs. The mechanobiological (biological processes stimulated by mechanical factors), mechanisms associated with valve adaptation were explored by integrating advanced continuum mechanics and cell biology. This allowed the development of predictive models of valve growth. Modelling cardiovascular adaptation "For our investigation of native heart valve adaptation, we had access to a very unique experimental data set containing the geometrical and material properties of human aortic and pulmonary heart valves of various ages," says Dr Loerakker, G-Valve project coordinator. Using computational analysis involving mathematical models and computer simulations, partly in collaboration with Prof. Ellen Kuhl from Stanford University, it was discovered that all these valves appeared to be subjected to a similar degree of mechanical stretch under age- and location-specific haemodynamic loading conditions. Importantly, this result suggested that native human heart valves adapt to preserve a certain state of stretch throughout life, which serves as a homeostatic mechanical parameter. G-Valve further developed a computational model of the Notch signaling pathway, which plays an essential role in cardiovascular development and adaptation. "The development of this computational model was more challenging than expected and required considerably more time than anticipated," adds Dr Loerakker. Using experimental data that demonstrated the sensitivity of Notch proteins to mechanical cues (mechanosensitivity) as input, the model predicted that tissue homeostasis could emerge or disappear suddenly upon certain changes in tissue geometry. This finding provided an explanation for why and how cardiovascular tissues can start or stop growing depending on mechanosensitive cell-cell communication. The results of this study were published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS). TEHvs with long-term growth and functionality – The future G-Valve has produced computational data with regard to mechanosensitive cell-cell signaling processes in tissue development and adaptation. These developments have provided a starting point for a whole new research direction. The research team is confident that this will enable the rational design of engineered cardiovascular tissues that can grow and remodel in line with the patient’s demands. This will in turn boost European excellence and competitiveness in the fields of biomechanics and tissue engineering and will result in the long-term use of engineered cardiovascular tissues in general and TEHVs in particular.
G-Valve, heart valves, tissue-engineered heart valves (TEHVs), cardiovascular tissues, growth and remodeling, computational model, tissue engineering, mechanical stretch