The living aortic valve

Abstract

Aortic valve disease represents a leading cause of morbidity and mortality for patients with cardiovascular disease. The number of patients requiring aortic valve replacement is in fact expected to triple within the next 40 years. To date, surgical valve replacement represents the only option for patients with aortic valve disease. No treatments exist to slow down or reverse the disease process. This is in large part due to the fact that for a long time, aortic valves were thought to be passive flaps which open and close in responses to changes in transvalvular pressures. However, recent data suggests that aortic valves are dynamic structures with a complex, yet well-preserved macro- and microstructure and unique features which differentiate it from surrounding structures. In light of these findings, we sought to further evaluate the intricate structure and function of the aortic valve. Our hypothesis was that as a living organ, aortic valves will have the capacity to modulate their own properties, to regulate structural changes within them, thus affecting their overall function. The aims of this work were to investigate the structural complexity of the aortic valve at a cellular level, to evaluate the role of aortic valve endothelium in actively regulating valve calcification and modulating valve mechanical properties. We will also seek to evaluate the adaptive properties of heart valves in response to their biomechanical and biochemical environment and the role of a living valve substitute on aortic root flow dynamics. Finally, the clinical implications of a living valve will be highlighted through results of a clinical trial evaluating outcomes following the Ross procedure, the only operation which guarantees long-term viability of the aortic valve. Our findings support the notion that the aortic valve is a dynamic and living structure. Its unique location which exposes it to a variety of side specific hemodynamic and mechanical stresses leads to significant structural and functional adaptive responses on either side of the valve. These responses are operative in physiological conditions but also appear to affect pathological processes within the valve, which could partly explain the pathophysiology of aortic valve disease. In addition, our findings show that aortic valves adapt to their environment by modifying their mechanical properties, in particular their overall stiffness. This could have a major impact on the patterns of flow within the aortic root and stress distribution on the cusps. Using patient-specific computational modelling of aortic root flow dynamics, we show that a living aortic valve following aortic valve replacement such as with the Ross procedure, results in a pattern of flow which closely resembles that of normal subjects. In contrast, non-living valve substitutes such as homografts and xenografts do not provide similar results. Clinically, these differences play an important role as shown in a randomized clinical trial comparing autografts to homografts showing improved survival following autograft root replacement, along with other clinically-relevant endpoints. In conclusion, the aortic valve is a living, dynamic organ with unique features and intricate complexity which allows it to adapt to its complex hemodynamic and biomechanical environment and ensure adequate function. The clinical relevance of a living valve substitute in patients requiring aortic valve replacement is confirmed and highlights the importance of developing tissue-engineered heart valve substitutes. Additional work is required to further understand the molecular complexity of heart valves and understand their immediate impact in the body through new in vivo functional imaging techniques