Animal Experiment And Early Clinical Results Of Transcatheter Tricuspid Valve Replacement Device Via Right Atrial Approach-the Lux-Valve

BackgroundValvular heart disease is one of the most common heart diseases.Tricuspid valve(TV)is often considered as a forgotten valve in cardiovascular community because of the initial clinical symptoms are easy to be ignored.Clinically,tricuspid regurgitation(TR)is more common than isolated stenosis,and the number of this group is huge.It has been reported that there are about 1.6 million patients with moderate or severe TR in the United States,and more than 80% of them are functional tricuspid regurgitation(FTR).Incomplete,such disease often secondary to left heart valve replacement and cardiac pacemaker electrode implantation,associating with high risk factors such as cardiac dysfunction,atrial fibrillation and pulmonary hypertension,which is induced by dilation of right ventricle and tricuspid annulus(TA).Eventually,the tricuspid valve leaflets are not firmly engaged.In the early stage of TR,the right heart system has a strong adaptability to the change of over-load volume,subsequently clinical symptoms were mild.A small amount of diuretics can alleviate clinical symptoms and cannot be taken seriously by patients.As the disease progresses and the progression of TR is aggravated,eventually decompensated right heart dysfunction will occur,leading to a series of symptoms including congestive liver disease,severe ascites,and peripheral edema,At present,the traditional surgical treatment includes tricuspid valvuloplasty(TVP)and tricuspid valve replacement(TVR).Clinically,TVP is performed in more patients than TVR.However,Navia et al.reported that for patients with moderate to severe FTR,the residual TR was 34% 3 months postoperatively after undergoing TVP,and the 10-year survival rate was only 44%,which seriously affected the long-term survival rate.In China,about 22%-30% of patients with left valvular disease have FTR.Even in patients undergoing TVP in the left heart valve,the incidence of tricuspid regurgitation is still high in the long term.Such patients often require secondary surgical repair or valve replacement under cardiopulmonary bypass.However,about half of the patients have contraindications for cardiopulmonary bypass due to aging,low cardiac function,a history of secondary surgery or a serious comorbidity.This undoubtedly affects the quality of life and has become one of hot issue in clinical practice.At present,transcatheter aortic valve replacement(TTVR)and mitral valve repair technology has achieved leap-forward development,and two domestically developed interventional aortic valve products have also been approved by the State Food and Drug Administration(CFDA).Although the technique of transcatheter intervention for tricuspid valve is still in its infancy,it has become one of the research hotspots in this field.Some foreign scholars have tried to use the existing aortic valve interventional stent valve for this technique and obtained certain effects.Since the fixation of this device depends on the support of its own valve annulus,it is only suitable for patients with tricuspid valves bioprosthetic replacement or implantation of a tricuspid annuloplasty ring.Therefore,the clinical indications are very limited,and the function and early clinical effect of this kind of device are not perfect.We cooperate with zhejiang ningbo jianshi biotechnology co.,LTD.According to the shape of the tricuspid annulus and its clinical situation,we have developed a novel transcatheter TV replacement device via right atrial approach-the LuX-Valve.It is expected to promote the development of interventional treatment of tricuspid valve technology and bring benefits to more patients.ObjectivesTo evaluate the feasibility,efficacy and safety of self-developed transcatheter tricuspid replacement device--LuX-Valve via right atrial approach implantation in situ tricuspid annulus for experimental goats,as well as the early clinical results in humans.Methods1.Transcatheter tricuspid replacement device via right atrial approach--LuX-Valve device development:In cooperation with Zhejiang Ningbo Jianshi Biotechnology Co.,Ltd.,we designed a transcatheter interventional stent tricuspid device LuX-Valve,which was mainly consist of nickel-titanium stent,bovine pericardial leaflet,avoid paravalvular leakage ring,two anterior leaflet-grasping clips,anchor and delivery system.The main body stent was made up of nickel-titanium alloy,which consist of a circle tread on right atrium side and a barrel-shaped wave-like valve segmented structure after the process of cutting,stent shaping and polishing;The trileaflet prosthetic valve was made of bovine pericardial tissue through cross-linking and glutaraldehyde processing.According to the valve model profile,they were sutured to the nickel-titanium stent,closely fitting with the surface;The avoid paravalvular leakage ring was woven into a skeleton by a single titanium-nickel wire and sewn with PET film.As a whole,the design conforms to the D-shaped skirt,partially bulging at the junction of the anterior-septal leaflet.The fixed anchor and the main body stent were integrally cut from a nickel-titanium material,which consist of an anchor needle and a bird tongue-shaped ventricle septum anchor;Anterior leaflet-grasping clips were connected to the exterior wall of the cylinder,and orientated toward the atrial disc,which bring the functions to assist in clamping and fixing the positioning of the leaflets and tricuspid annulus.Delivery system mainly consists of inner sheath,outer sheath and core and adopts an end curved corner design.2.Percutaneous establishment of tricuspid regurgitation with chordae tendinease cutter in animals via an incision from right atrium:TR model was established in 6 goats with a self-made tricuspid valve chordae tendineae cutter to sever as a chronic model in the future and allow investigation of transcatheter interventional device.The goats were positioned in a left lateral decubitus and procedure was performed via a right minimal anterior lateral thoracotomy in the fourth intercostal.Under the guidance of ultrasound and angiography,the chordae tendineae of anterior leaflet was repeatedly cutted until moderate to severe regurgitation was confirmed.Echocardiography and laboratory examinations were performed preoperatively,immediately after surgery and 3 months.Additionally,all goats were sacrificed to clarify pathological changes of tricuspid regurgitation.3.Animal experiment of transcatheter tricuspid replacement device-LuX-Valve via right atrial approach:Under the guidance of ultrasound and angiography,LuX-Valve devices were implanted in 17 healthy adult male goats(weighing40±5kg)via a right minimal anterior lateral thoracotomy,of which 5 animals(group A)were sacrificed after the first postoperative echocardiography for evaluation on the advice immediately after the procedure,and 12 animals(group B)were randomly selected for anatomy at 30 days and 180 days respectively.Hemodynamics and geometry were characterized by echocardiography,and hematology laboratory tests were conducted every month during following-up.4.The first-in-man clinical outcomes with LuX-Valve: We designed a clinical trial for the purpose of rescue treatment,which could verify the early clinical results of LuX-Valve and provide experience for further clinical research and application of this product.Following a rigorous inclusion criteria,exclusion criteria and endpoint,the LuX-Valve as a catheter-based device was performed in one patient with severe TR and surgical contraindication for the first time.Result:1.We designed the LuX-Valve as a catheter-based device comprising a stent bioprosthesis and a delivery system.Structurally,the stent bioprosthesis consists of four parts:(1)a trileaflet prosthetic valve made of bovine pericardial tissue;(2)a skirt-shaped self-expandable nitinol valve stent covered with a layer of expanded polytetrafluoroethylene(ePTEE);(3)a bird tongue-shaped ventricle septum anchoring component,and(4)two anterior leaflet-grasping clips.The edges of the atrial disc are designed to be everted with has a diameter of 40 mm.The atrial disc was 10 mm higher than the annular ring.Pericardium was treated with glutaraldehyde and biochemical,the flexibility and the mechanical strength were obviously improved,whic was closely adhered to the nickel-titanium stent after suturing.By the way,we designed a tough tip head in the front of the Delivery device.The diameter of the delivery system is 32 Fr.Outer sheath in Delivery system has a flexural performing range of the distal portion up to 45,which could support a post-releasing fine adjustment of the orientation and position of the stent valve device,and the entire process is easier and faster.2.TR was successfully established in 6 goats with a self-made tricuspid valve chordae tendineae cutter.The right atrium pressure increased from 5.1 mmHg to 9.2 mmHg immediately after surgery(p<0.05).During a follow-up of 3 months,the progression of TR was aggravated(p=0.003),and the annular diameter was increase from a mean of 2.15±0.23 cm to 2.65±0.2cm.Overall,there were no statistically significant changes in transvalvular gradient and velocity before the surgery,as was the laboratory examinations.Autopsy evaluation demonstrated obviously chordae tendineae transection of the anterior leaflet in five sheep,while anterior and posterior chordae were all damaged in one sheep.3.Implantations of the LuX-Valve were successful in 16 goats with no technical difficulties during prostheses deployment.In group B(n=12),the follow-up monitoring lasted 30(n=3)and 180(n=6)days before euthanasia.In group A(n=5),after successful implantation,experienced massive bleeding from the right atrial rupture during tightening the suture in one case.No animals(n=16)died secondary to a cardiac or non-cardiac complications.In all animals,the stent valve device played correct dynamic functions after fluoroscopy and echocardiography-guided accurate alignments and anchoring in secure.Perioperative echocardiography was conducted before,during,and after implantation.During the follow-up period,the same evaluations were performed monthly until euthanasia.In the animals of successful implantation(n=16),perioperative evaluation confirmed 12 goats without paravalvular leakage or central TR,while 3 cases showed mild and 1 showed moderate paravalvular leakage.There were no statistically significant changes in transvalvular gradient and velocity before the surgery.During a follow-up of 6 months,all 16 implanted prosthesis were immobilized in secure and functioned normally without evidence of fracture or displacement.All animals had normal right ventricular function.Laboratory examination included blood routine and so on,which was not significantly different from preoperative.According to the anatomical examination of randomly selected goats at the planned stage,the correct position of the stent valve was confirmed.Calcification and embolization were not found between the stent and the original annulus,There is no significant thickening of the RA wall,while septal-anterior junction has no myocardial compensatory thickening.Pathological examination in all stages showed no embolism in all organs under HE staining.4.LuX-Valve was successfully implanted in a patient with severe TR at a predetermined anchor position.The right ventricular angiography showed a significant improvement in regurgitation.TEE showed only a small amount of paravalvular leakage from the side of the atrial septum.There were no complications occurred such as arrhythmia and perforation of ventricular septum during operation.However,pleural effusion increased within 24 hours after surgery with hypotension,and the emergency thoracotomy hemostasis was used.After 7 days,the ultrasound indicated LuX-Valve was fixed firmly and functioned normally,at the time there were moderate paravalvular leakage could be observed.The patient recovered successfully and discharged.Conclusion:Transcatheter TV replacement device LuX-Valve via right atrial approach was successfully implanted into the original tricuspid annulus of the goat.The hemodynamics,echocardiography and anatomical were satisfactory during follow-up.The first-in-man clinical outcomes with LuX-Valve indicated anchor was fixed firmly and the stent valve device played correct dynamic functions,which had significant improvement in regurgitation and enhanced patients’ life quality.The feasibility and safety of the LuX-Valve were further determined,which could be used as an alternative treatment for patients with contraindication of cardiac surgery,laying a foundation for multi-center clinical trials in the future.