A calcified polymeric valve for valve-in-valve applications
Introduction
According to epidemiological studies, aortic valve stenosis affects 2–7% of the elderly population (Nkomo et al., 2006). Calcification is by far the major cause of aortic valve stenosis (more than 80%), and among the affected patients, some have certain types of triggering congenital heart defects such as bicuspid valve or a history of rheumatic heart disease (Rayner et al., 2014). Calcific aortic valve stenosis is a progressive disease, which is irreversible and can be fatal if left untreated. Pharmacotherapy cannot currently prevent valvular calcification or help repair a damaged valve, since the valve tissue is unable to spontaneously regenerate. Thus, aortic valve replacement/repair is the only current available treatment.
The introduction of transcatheter aortic valve replacement (TAVR) has revolutionized heart valve replacement procedures by offering minimally invasive treatment options for patients with high-risk who have been considered unfit for traditional open-heart surgery (Kheradvar et al., 2015a) and more recently for patients with moderate-risk (Leon et al., 2016). A narrow range of FDA-approved transcatheter valves is currently being used in patients with calcific aortic valve stenosis (Kheradvar et al., 2015a). Contrary to the surgically-implantable aortic valves, transcatheter valves are not sewn within the aortic annulus but their stent expands within the native calcific aortic valve and the roughness due to the calcific nodules on the native leaflets provides means to hold the stented valve in place. The patterns of calcific nodules developed on the leaflets are completely random and vary in every patient (Goldbarg et al., 2007).
Calcific aortic valve stenosis is mainly a disease of the human and has not ever reported to naturally occur in animals. Very few attempts have been made to develop animal models with calcific aortic valve stenosis that were mainly mouse models, (Cheek et al., 2012, Miller et al., 2011, Zhang et al., 2014) and no large animal model of calcific aortic valve stenosis is yet available. Lack of such an animal model makes the research and development studies related to prosthetic heart valves very difficult and costly. Almost all the technologies related to transcatheter repair/replacement of aortic valve require a calcified heart valve in animals to show their feasibility. Currently, the preclinical studies related to TAVR have been performed on ovine or swine models with normal aortic valve (Emmert et al., 2014, Emmert et al., 2012, Kheradvar et al., 2015b, Wendt et al., 2013). However, the experiments do not closely represent the actual clinical situation, since these animals possess normal aortic valves without any trace of calcification. Therefore, not only a successful implant in sheep does not guarantee that a transcatheter valve can similarly perform in a patient with calcific aortic valve but also a failed experiment due to lack of anchoring in the animal does not necessarily imply that the tested transcatheter valve will fail in a patient with calcific aortic valve stenosis. Furthermore, since the calcific patterns in human aortic valve is remarkably heterogeneous, design and development of the TAVR systems suitable for most patients is extremely difficult due to the lack of a proper experimental model.
Here, we introduce a novel polymeric valve concept whose leaflets possess calcium hydroxyapatite inclusions immersed in them. These valves can be produced to replicate different grades of calcification to test transcatheter aortic valve implantation in vitro and may eventually be used for short-term in vivo experiments. The present work discusses the performance of these valves in vitro.
Section snippets
Heart flow simulator
We used a heart pulsed flow simulator as previously described for these experiments (Falahatpisheh and Kheradvar, 2012, Groves et al., 2014, Kheradvar and Gharib, 2009a, Kheradvar and Gharib, 2009b, Kheradvar et al., 2006). The system׳s modular build allows addition of a transparent patient-specific ventricle. The ventricular sac is suspended over the Plexiglas atrium, free-floating inside a rigid water-filled container. The system is connected and actuated by a pulsatile pump system (Superpump
Calcified aortic valves
We successfully made and used two polymeric valves of 23 mm according to the shape of the reported native calcified aortic valves (Baumgartner et al., 2009, Novaro et al., 2007) using randomly distributed hydroxyl-appetite inclusions replicating a severely-stenotic and a moderately-stenotic aortic valves (Fig. 2B and C, respectively).
Aortic valve area
Fig. 4 shows the aortic valve area (AVA) of all the studied aortic valves. The moderately- and severely-stenotic valve׳s AVA were measured as 1.40 cm2 and 0.91 cm2,
Discussion
In the past few years, the development of more advanced TAVR systems is enthusiastically progressing but no aortic valve stenosis model is yet available to properly test the implantation procedures. To the best of our knowledge, this is the first report on conception of a polymeric valve with calcium hydroxyapatite inclusions replicating a stenotic aortic valve.
Conclusion
For the first time, we have developed polymeric calcified valve prototypes that replicate moderately- and severely-stenotic valve conditions. The feasibility of these valves was validated for studies related to transcatheter heart valve implantation in vitro. Through multiple experiments, we showed that these calcified valves can suitably mimic the function of a native calcified stenotic aortic valve and can be used for valve-in-valve studies. Finally, we corroborate that using this novel
Conflict of interest
Prof. Kheradvar is a co-founder of Folda LLC that makes FoldaValve™. He also has an equity interest in Folda LLC, a company that may potentially benefit from the research results. The terms of this arrangement have been reviewed and approved by the University of California, Irvine in accordance with its conflict of interest policies. The other authors have no conflicts of interest to declare.
Acknowledgement
This study is funded by a grant from American Heart Association (16IRG27250078) to Prof. Kheradvar.
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