The living aortic valve

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

Side-Specific Endothelial-Dependent Regulation of Aortic Valve Calcification Interplay of Hemodynamics and Nitric Oxide Signaling

Arterial endothelial cells maintain vascular homeostasis and vessel tone in part through the secretion of nitric oxide (NO). In this study, we determined how aortic valve endothelial cells (VEC) regulate aortic valve interstitial cell (VIC) phenotype and matrix calcification through NO. Using an anchored in vitro collagen hydrogel culture system, we demonstrate that three-dimensionally cultured porcine VIC do not calcify in osteogenic medium unless under mechanical stress. Co-culture with porcine VEC, however, significantly attenuated VIC calcification through inhibition of myofibroblastic activation, osteogenic differentiation, and calcium deposition. Incubation with the NO donor DETA-NO inhibited VIC osteogenic differentiation and matrix calcification, whereas incubation with the NO blocker l-NAME augmented calcification even in 3D VIC–VEC co-culture. Aortic VEC, but not VIC, expressed endothelial NO synthase (eNOS) in both porcine and human valves, which was reduced in osteogenic medium. eNOS expression was reduced in calcified human aortic valves in a side-specific manner. Porcine leaflets exposed to the soluble guanylyl cyclase inhibitor ODQ increased osteocalcin and α-smooth muscle actin expression. Finally, side-specific shear stress applied to porcine aortic valve leaflet endothelial surfaces increased cGMP production in VEC. Valve endothelial-derived NO is a natural inhibitor of the early phases of valve calcification and therefore may be an important regulator of valve homeostasis and pathology

Scanning ion conductance microscopy: a convergent high-resolution technology for multi-parametric analysis of living cardiovascular cells

Cardiovascular diseases are complex pathologies that include alterations of various cell functions at the levels of intact tissue, single cells and subcellular signalling compartments. Conventional techniques to study these processes are extremely divergent and rely on a combination of individual methods, which usually provide spatially and temporally limited information on single parameters of interest. This review describes scanning ion conductance microscopy (SICM) as a novel versatile technique capable of simultaneously reporting various structural and functional parameters at nanometre resolution in living cardiovascular cells at the level of the whole tissue, single cells and at the subcellular level, to investigate the mechanisms of cardiovascular disease. SICM is a multimodal imaging technology that allows concurrent and dynamic analysis of membrane morphology and various functional parameters (cell volume, membrane potentials, cellular contraction, single ion-channel currents and some parameters of intracellular signalling) in intact living cardiovascular cells and tissues with nanometre resolution at different levels of organization (tissue, cellular and subcellular levels). Using this technique, we showed that at the tissue level, cell orientation in the inner and outer aortic arch distinguishes atheroprone and atheroprotected regions. At the cellular level, heart failure leads to a pronounced loss of T-tubules in cardiac myocytes accompanied by a reduction in Z-groove ratio. We also demonstrated the capability of SICM to measure the entire cell volume as an index of cellular hypertrophy. This method can be further combined with fluorescence to simultaneously measure cardiomyocyte contraction and intracellular calcium transients or to map subcellular localization of membrane receptors coupled to cyclic adenosine monophosphate production. The SICM pipette can be used for patch-clamp recordings of membrane potential and single channel currents. In conclusion, SICM provides a highly informative multimodal imaging platform for functional analysis of the mechanisms of cardiovascular diseases, which should facilitate identification of novel therapeutic strategies

Formal consensus study on surgery to replace the aortic valve in adults aged 18-60 years

Objective: There is uncertainty about surgical procedures for adult patients aged 18-60 years undergoing aortic valve replacement (AVR). Options include conventional AVR (mechanical, mAVR; tissue, tAVR), the pulmonary autograft (Ross) and aortic valve neocuspidisation (Ozaki). Transcatheter treatment may be an option for selected patients. We used formal consensus methodology to make recommendations about the suitability of each procedure. Methods: A working group, supported by a patient advisory group, developed a list of clinical scenarios across seven domains (anatomy, presentation, cardiac/non-cardiac comorbidities, concurrent treatments, lifestyle, preferences). A consensus group of 12 clinicians rated the appropriateness of each surgical procedure for each scenario on a 9-point Likert scale on two separate occasions (before and after a 1-day meeting). Results: There was a consensus that each procedure was appropriate (A) or inappropriate (I) for all clinical scenarios as follows: mAVR: total 76% (57% A, 19% I); tAVR: total 68% (68% A, 0% I); Ross: total 66% (39% A, 27% I); Ozaki: total 31% (3% A, 28% I). The remainder of percentages to 100% reflects the degree of uncertainty. There was a consensus that transcatheter aortic valve implantation is appropriate for 5 of 68 (7%) of all clinical scenarios (including frailty, prohibitive surgical risk and very limited life span). Conclusions: Evidence-based expert opinion emerging from a formal consensus process indicates that besides conventional AVR options, there is a high degree of certainty about the suitability of the Ross procedure in patients aged 18-60 years. Future clinical guidelines should include the option of the Ross procedure in aortic prosthetic valve selection

The Ross procedure: total root technique

We describe our technique for the Ross procedure using a total root technique without any foreign material for autograft support. We insist on technical principles, based on the surgical anatomy of the aortic and pulmonary root, aimed at optimizing aortic root dynamics while ensuring long-term stability of the autograft root

Lights and shadows on the Ross procedure: biological solutions for biological problems

The Ross procedure represents a valid option for aortic valve replacement in young adults and was repeatedly shown to restore survival to that of the age- and sex-matched general population. However, its major drawback relies in the risk of pulmonary autograft (PA) dilation, negative histological remodeling and need for reoperation. Several techniques and materials to reinforce the PA have been proposed. They mainly include Dacron, personalized external aortic root support with a polyethylene terephthalate mesh system, autologous aortic tissue and bioresorbable materials. Synthetic materials, despite widely used in cardiac surgery, have significant biocompatibility issues with the PA and their interaction with this living structure translates into negative remodeling phenomena and disadvantageous biomechanical behaviors. Conversely, biomaterials with tailored degradable profiles might be able to reinforce while integrating with the PA and enhance its remodeling capabilities. The recent advancement in this field are here discussed