Investigation of heart valve transcatheter therapies - from an experimental platform to a new therapy concept

Background The aging of society and associated comorbidities are major stimulators for the spread of valvular transcatheter therapies. This sets new challenges for clinicians, researchers and device developers. The need for new valvular treatments or improvement of existing ones is related to poor clinical outcomes of current state-of-the-art therapies, especially in case of functional mitral and tricuspid regurgitation, which showed high pathology recurrence rate in long-term. Moreover, tricuspid regurgitation treatment specifically has been neglected surgically until recent years and the available options for tricuspid valve treatment are limited. The quest for new, more durable and less invasive strategies for tricuspid and mitral valves treatment can be assisted with realistic preclinical evaluation. We hypothesize that reliable experimental platforms tailored for transcatheter therapies and featuring models of valvular pathologies could be of help in accelerating the development of new therapies and in defining new directions for heart valve treatments. The valvular transcatheter procedures demand from the cardiologists new, previously not acquired skills encompassing manual navigation of a device solely based medical imaging. The procedural error can lead to life-threatening conditions and suboptimal procedural results can worsen long-term outcomes. The therapies presented a learning curve which currently is gained purely in clinical settings. Therefore, a possibility for hand-on high-fidelity training could help to potentially reduce the occurrence of procedural errors and improve the initial phase of the learning curve. Aims and objectives In this context, the aim of this dissertation was to facilitate current transformations in valvular therapies from the experimental point of view. Firstly, we developed novel passive beating heart platforms tailored for transcatheter valvular therapies assessment. Secondly, using the developed instruments and specifically designed testing protocols we assessed new valvular treatments for tricuspid and mitral valve. Finally, we adopted the platform and applied it for high-fidelity clinicians’ training. Experimental toolbox tailored for transcatheter therapies Within this PhD project experimental models of functional tricuspid regurgitation and functional mitral regurgitation were developed and incorporated into passive beating heart platforms. A mock circulation loop of pulmonary circulation was designed, manufactured and assessed. The platform housed whole right porcine heart passively actuated under pulsatile flow conditions. The incorporated experimental model of functional tricuspid regurgitation was reversible, easily manageable and yielded stable hemodynamic conditions over simulated typical procedure time. We tackled the challenges related with the management of cyclically pressurized compliant-wall right ventricle and control of the tricuspid regurgitation state in an experimental setup. The developed platform enables systematic preclinical assessment of novel treatments under repeatable and controllable setting, which is not possible to be obtained in real clinical scenario. An experimental approach to induce functional mitral regurgitation conditions in a cyclically actuated healthy porcine left ventricle was explored. The proposed method was based on mechanical dilation of mitral annulus and displacement of left ventricular papillary muscles using ad-hoc designed and 3D-printed devices. This strategy provided a realistic, repeatable and reversible ex-vivo pathological model, featuring two lesions clinically associated with the pathology in terms of hemodynamics, valve morphology and kinematics (type I and IIIb as with Carpentier classification). It is the first experimental approach which reproduced actual main determinants of functional mitral regurgitation in whole heart sample under pulsatile flow conditions. Novel treatments assessment The developed experimental instruments were further employed for preclinical assessment of (i) an unconventional concept for tricuspid valve therapy based on approximation of right ventricular papillary muscles and (ii) a new design of transcatheter device for edge-to-edge mitral and tricuspid regurgitation treatment. The tricuspid regurgitation is conventionally treated at valve-level only. However, papillary muscle displacement is, next to annular dilation, the main determinant of the tricuspid regurgitation. Concomitant treatment at valve and subvalvular level for mitral regurgitation demonstrated superior long-term outcomes, comparing to annuloplasty alone. In case of tricuspid valve, much less is known. Right ventricular papillary muscle approximation was comprehensively assessed in an ex-vivo model of functional tricuspid regurgitation under tight control of the direction and level of the approximation with the support of computational 3D morphology reconstructions. The treatment caused a significant reduction of the tricuspid regurgitation, tricuspid valve tenting volume and dimensions of tricuspid annulus. Moreover, low baseline cardiac output and low baseline dimensions of the tricuspid annulus were identified as the predictors of treatment success. Considering commonly observed severe dilation of the tricuspid annulus in patients with tricuspid regurgitation (van Rosendael et al., 2015), a follow-up study was performed where the pathology was treated at valve and subvalvular level. We demonstrated that the greatest reductions in regurgitation and morphological anomalies of the tricuspid valve were obtained after the concomitant treatment (valvular and subvalvular level). Comparing with valve-level treatments performed alone, the concomitant treatments were less sensitive to simulated pulmonary hypertension, one of the causes of tricuspid regurgitation recurrence, which bears a promise for their more durable performance. Possible approaches of translating the papillary muscles approximation concept into an interventional device were defined. Next, in cooperation with a leading industrial player in the biomedical field, we investigated the hemodynamic effects of a new design of a transcatheter edge-to-edge device, featuring a long-arms clip. A standard-length clip is widely used commercially, whereas the long-arm clip could ease grasping procedure, however the impact on the hemodynamics was unknown (specifically in terms of possible increase of transvalvular pressure drop). In the experimental models of functional and degenerative mitral regurgitation and functional tricuspid regurgitation, the long-arm clip treatment improved overall hemodynamic conditions without inducing significant increase of transvalvular pressure drop across mitral and tricuspid valve. We demonstrated that tricuspid valve clip-based therapy was successful when septal leaflet was grasped along with either anterior or posterior one. It confirmed initial clinical observations and previous experimental study of our group with standard-length clip. Moreover, we found that left atrial pressure monitoring could be used as an additional indicator of procedure success. The treatment assessment studies not only demonstrated usefulness of the developed experimental instruments and specifically developed testing protocols, but also provided clinically valuable insights and set new directions for transcatheter devices development. Hands-on training The last objective of this dissertation was the adaptation of the experimental platforms for simulation-based clinicians’ training in transcatheter therapies. The training-oriented platform was employed for various training purposes. It facilited the definition of training strategies in transcatheter edge-to-edge treatment of tricuspid regurgitation and providing visual data (fiberscopic, echocardiographic and fluoroscopic images) for training materials. Moreover, it served as demonstrative and training tool during cardiological congresses across Europe in transcatheter mitral and tricuspid edge-to-edge repair, transcatheter mitral valve replacement, transcatheter aortic valve replacement and transseptal puncture. This work demonstrated a possible spin-off application of platforms initially intended for research purposes.

L’invecchiamento della società e le malattie ad essa associate sono i più grandi stimoli per la diffusione delle terapie riguardanti le valvole trans-catetere. Questo scenario definisce nuove sfide che includono la necessità di nuovi trattamenti valvolari e piattaforme sperimentali per i test preclinici e per il training realistico degli operatori che le utilizzeranno. L’obiettivo di questo lavoro è quello di favorire lo sviluppo dei nuovi trattamenti valvolari dal punto di vista sperimentale. Noi abbiamo sviluppato una nuova piattaforma, che si basa sull’utilizzo del beating heart passivo, per la valutazione e l’analisi e delle terapie trans-catetere valvolari. Noi siamo riusciti a generare in-vitro, modelli patologici delle valvole, come ad esempio i modelli funzionali di valvola mitrale e tricuspide. Inoltre, usando gli strumenti sviluppati e specificamente progettati per definire il protocollo dei test, noi abbiamo valutato nuovi trattamenti sia per la valvola mitrale sia per quella tricuspide. Nello specifico, abbiamo valutato l’effetto e l’efficacia dell’approssimazione dei muscoli papillari e di un nuovo design del device trans-catetere per il trattamento edge-to-edge del rigurgito mitraico o tricuspideo. Infine, abbiamo utilizzato la piattaforma sviluppata per il traning realistico dei clinici.