Midterm Experience with the Self-Expandable Venus P-Valve ™ for Percutaneous Pulmonary Valve Replacement in Large Right Ventricular Outflow Tracts

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Introduction
Residual or reoccurring right ventricular outfow tract (RVOT) dysfunction after the repair of congenital heart disease results in signifcant morbidity and mortality and represents one of the most frequent causes of reoperation [1,2].Owing to the pioneering work of Bonhoefer and colleagues, the concept of transcatheter pulmonary valve replacement (PPVI) has been established as a safe and effective minimally invasive alternative option by now [3][4][5].
PPVI has become an integral element of the lifetime management of patients with RVOT lesions.It reduces the number of required open heart surgeries in afected patients and has excellent results comparable to surgical valve replacement while showing lower complication and mortality rates and favourable cost-efectiveness [4][5][6][7][8].
To date, the Melody ® transcatheter pulmonary valve (Medtronic Inc., Minneapolis, MN, USA) and the Edwards SAPIEN ™ Valve (Edwards Lifesciences, Irvine, CA, USA) have been the most commonly percutaneously implanted valves in the pulmonary position [9,10].Both are balloonexpandable and intended for the treatment of dysfunctional RVOT conduits or bioprosthetic valves [4].Te available range of sizes is limited, and it has become evident that there are a considerable number of patients with RVOT dysfunction having unsuitably large dimensions for PPVI with balloon-expandable valves, in particular patients with native outfow tracts and predominant pulmonary valve regurgitation, as frequently observed in patients after tetralogy of Fallot repair [11,12].Moreover, in combination with large diameters and highly variable morphology, outfow tracts in these patients often are very distensible and compliant, precluding the safe implantation of balloon-expandable valves [13].
To address these limitations, the concept of using largediameter self-expanding stents for PPVI stimulated the development of a new generation of devices.Several selfexpanding devices have been introduced such as the Harmony ™ Valve (Medtronic Inc., Minneapolis, USA), the Venus P-Valve ™ (Venus MedTech Inc., Hangzhou, China), and the Pulsta ™ Valve (Taewoong Medical Co., Ltd., Gyeonggi-do, South Korea) as self-expanding valves for PPVI or the Alterra Adaptive Prestent ™ (Edwards Life- sciences, Irvine, USA), designed to serve as a self-expanding landing zone within the ROVT to accommodate the SAPIEN ™ Valve [14-17].While the Harmony ™ Valve and Alterra ™ devices received Food and Drug Administration approval in the USA in 2021, the Venus P-Valve ™ is the frst and currently only CE-marked valve designed for PPVI in large-dimension native RVOT.
Worldwide, a considerable number of patients have been successfully treated with the Venus P-Valve ™ during the past years, with encouraging early and midterm results [18][19][20][21].Nevertheless, the clinical experience is still limited as marketing and increasing use in Europe only began recently after CE certifcation in 2022.We therefore sought to summarize our initial experience and early and midterm outcomes with the self-expandable Venus P-Valve ™ for PPVI in patients with large RVOT.

Study Cohort.
We performed a retrospective study including all patients who had received PPVI with a Venus P-Valve ™ in our institution.Demographic, clinical, imaging, and hemodynamic and procedural data were retrieved from electronic medical charts.If available, data from the last follow-up examinations were also recorded.

Percutaneous Pulmonary Valve Implantation.
Cardiac catheterization was generally performed under sedation/analgesia with spontaneous breathing according to our routine institutional protocol.Two patients were submitted to general anaesthesia: one had severe scoliosis with restrictive lung function and one had a history of relevant allergic reactions during previous analgosedation, respectively.Vascular access was femoral in all cases and included two venous sheaths (6-7F) and one arterial sheath (5-6F).Heparin was administered to achieve an activated clotting time of 200-220 seconds; cefazolin (30 mg/kg) was administered as antibiotic prophylaxis.In addition to angiography (Figure 1(c)), the RVOT was sized with a 34 mm Amplatzer ™ sizing balloon (Abbott, Plymouth, USA) or occasionally with a Z-MED II ™ balloon (28−30 mmm;   Numed Inc., Hopkinton, USA).Dual antiplatelet inhibition was initiated on the second postprocedural day and maintained for 6 months followed by continuous antiplatelet therapy with aspirin alone.

Statistics.
Statistical analyses were performed using SPSS (version 25; IBM Corp., Armonk, USA).Data distribution was tested using the D'Agostino-Pearson test, and most variables displayed normal distribution.Categorical variables are expressed as fgures (percentages); continuous variables are expressed as the mean ± standard deviation for normal distribution or median (interquartile range, IQR) for non-normal distribution, respectively.Comparisons between baseline and follow-up parameters were performed with the paired t-test.P values <0.05 were considered statistically signifcant.  c-f ) Implantation of the Venus P-Valve ™ (same patient as Figure 1).Slow and controlled deployment with gradual release of the valve and gentle pullback of the delivery system and the valve to the designated landing zone (c, d).
Final valve confguration after release (e) and fnal angiography after removal of the delivery system (f ) showing excellent valve function. 4 Journal of Interventional Cardiology

Results
3.1.Patients.Patient characteristics are displayed in Table 1.A total of 20 patients underwent PPVI with a Venus P-Valve ™ in our institution.Five of these procedures were performed between 2017 and 2018 within the CE certifcation study (EUDAMED CIV-15-04-013524); 15 patients were treated after certifcation and market release in 2022.Te majority of the patients were adults, while fve were children of 13-17 years of age, respectively.All patients had moderate-to-severe pulmonary valve regurgitation and RV dilatation documented by magnetic resonance imaging and angiography.No relevant pressure gradient across the RVOT was observed.Tere was a fair overall concordance of the smallest RVOT dimensions assessed by magnetic resonance imaging and angiography (Tables 1 and 2); individually, however, diferences of up to 6 mm were noted.Patients displayed considerable compliance of the RVOT with a mean diference of 2.8 ± 1.5 mm of the smallest dimensions between angiography and balloon sizing (Table 2).
All patients reported reduced physical capacity to some extent; however, advanced heart failure was uncommon and most patients were in NYHA functional class ≤II.Several patients had a history of arrhythmias prior to PPVI (Table 1).A history of ventricular tachycardia (VT) was noted in three patients (15%).Of these, two had electrophysiological studies with successful ablation prior to PPVI due to recurrent nonsustained VT.One patient had experienced a single episode of torsades de pointes tachycardia thought to be medication-induced during chemotherapy for colon cancer, and she had no further documented VT after the conclusion of chemotherapy.

Immediate Outcome.
All procedures were successful, and procedural details are presented in Table 2.All valves were implanted in an annular position.Valves were deployed via the left pulmonary artery in the majority of cases, and only in one patient, deployment was performed via the right pulmonary artery.Deployment was uneventful in all but one patient.A partial infolding of the distal aspect of the valve limited control of deployment and placement in that patient.During the deployment of the last third of the valve, it eventually unfolded and slid distally towards the bifurcation, well beyond the intended implantation site.As it was still partially hooked to the delivery catheter, it could be successfully repositioned by traction.
Final intraprocedural angiograms showed excellent valve function in all patients, and there were no valvar regurgitations or paravalvular leakages.Invasive pressure recordings documented unobstructed fow after PPVI.No compromise of coronary perfusion was observed.
One major procedural complication occurred, which, however, was unrelated to the Venus P-Valve ™ .Te patient experienced a presumable perforation of the peripheral pulmonary artery by the stif guidewire during balloon sizing.He showed acute haemoptysis during the procedure and was intubated.No extravasation was observed in the pulmonary angiography, and intrabronchial bleeding seemed to have stopped; therefore, the procedure was continued with successful PPVI.On the frst postinterventional day, a signifcant haematothorax was noted requiring thoracotomy for evacuation.Te majority of patients had a transiently increased burden of premature ventricular complexes (PVCs) observed by telemetry, which had generally ceased until discharge.In 5 patients, short episodes of nonsustained VT were detected by telemetry during the frst 2-3 days after PPVI.At discharge, Holter monitoring showed a low burden of PVC in 8 patients and short nonsustained VT in three patients.A new antiarrhythmic medication was initiated in four patients with either ß-blocker (n � 2) or amiodarone (n � 2).One patient with frequent short episodes of VT and preexisting sinus node dysfunction became symptomatically bradycardic with the initiated antiarrhythmic; a dualchamber implantable cardioverter-defbrillator (ICD) was implanted before discharge as he displayed additional risk factors for ventricular arrhythmias such as advanced age and reduced systolic RV function.One patient complained of severe chest pain after PPVI and possible causes such as coronary artery compression or pulmonary artery dissection were ruled out by a computed tomography scan and laboratory analyses.Chest pain resolved with analgesic medication within a few days.Te hospital course was uneventful in all other patients.

Midterm Outcome.
Median follow-up was 0.5 (IQR 0.1-4.1)years.Valve function was excellent in all patients.Two patients showed mild pulmonary valve regurgitation in echocardiography after 6.2 and 6.6 years of follow-up, respectively, while all the other patients had no or only trivial regurgitation.No relevant valve stenosis was observed with a mean gradient of 12 ± 4 mmHg in echocardiography.Right ventricular dimensions had signifcantly decreased (Table 3).Symptoms and physical capacity improved signifcantly, and the majority were in NYHA functional class I at the last follow-up (Table 3).Eleven patients had chest radiograms after a median of 0.6 (IQR 0.5-3.1)years of follow-up, and only one patient showed a stent fracture of a single strut without compromise of stent integrity or valve function.
In two patients, relevant ventricular dysrhythmias occurred during follow-up.One patient experienced a sustained VT one month after PPVI.It degenerated to ventricular fbrillation while being treated in an emergency department; he was defbrillated to sinus rhythm after a short episode of cardiopulmonary resuscitation.After a subsequent electrophysiological study with ablation, he underwent ICD implantation.Te second patient had sinus bradycardia and recurrent episodes of nonsustained VT during follow-up Holter monitoring despite antiarrhythmic therapy; therefore, implantation of an ICD was decided.No relevant ventricular arrhythmias were observed in the remaining patients.Of the four patients with newly initiated antiarrhythmic treatment, medication could be discontinued during follow-up in two and switched from amiodarone to ß-blocker in one patient, respectively.In one additional patient, discontinuation of ß-blocker is intended after repeated Holter.
A haemodynamically relevant femoral arteriovenous fstula requiring surgical treatment was diagnosed in one patient during follow-up.No further complications were observed.

Discussion
Here, we report excellent results from our initial experience with the Venus P-Valve ™ for PPVI in patients with large RVOT.Procedural success in our cohort was 100%, and implanted valves showed excellent function without relevant regurgitation or stenosis during follow-up of up to 6.6 years.
Te development of PPVI has revolutionized the treatment of a huge number of patients with RVOT dysfunction after the repair of congenital heart disease.Balloonexpandable valves for PPVI valves have shown very good short-and long-term results; however, their limitations in size exclude a substantial number of patients with unsuitably large RVOT dimensions from treatment [9,10,12].Currently, the Venus P-Valve ™ is the only CE-certifed valve intended for PPVI in large-dimension native RVOT available in Europe.It covers a wide size range of 28−36 mm diameter in 2 mm increments and allows percutaneous treatment of RVOT dimensions up to 33−34 mm, considering a safety margin for required oversizing.Tus, the Venus P-Valve ™ considerably expands the options of PPVI providing a feasible alternative for patients not amenable to PPVI with hitherto available valves.Of note, critical evaluation of the RVOT morphology, comparable to PPVI with balloon-expandable valves, is paramount for the successful implantation of the Venus P-Valve ™ .While preprocedural magnetic resonance imaging is crucial in assessing RVOT  Valve ™ , size measurements may difer substantially be- tween imaging and angiography, as also seen in some patients in our cohort.Moreover, the dilated RVOT may be unpredictably compliant [13].For the ultimate decision on PPVI and appropriate selection of valve size, balloon sizing of the RVOT is therefore to be recommended.Deployment and implantation of the valve were safe and generally uneventful in our cohort and in previous studies [18][19][20][21].Only in one case, we experienced a partial infolding of the self-expandable stent limiting controlled deployment.Complete infolding of the valve stent, requiring balloon dilatation, has been previously described but seems to be a rare phenomenon [23].No particular device-related procedural complications were observed in our cohort.One major complication occurred; however, this was caused by guidewire perforation of the pulmonary artery during balloon sizing and was not related to the valve.
We did observe one case of stent fracture during follow-up (9% of patients with follow-up chest radiograms).Interestingly, stent fractures were found in up to 27% of the patients in a previous report after a mean follow-up of 25 months [18].Tese, however, did not compromise valve function.Concordant with our fndings, stent fractures were infrequent in various other studies [19][20][21].Additional long-term follow-up data will be required to determine the causes and signifcance of stent fractures of the Venus P-Valve ™ .
Consistent with the limited previous experience with the Venus P-Valve ™ , patients in our cohort improved in the NYHA functional class and experienced marked right ventricular remodeling [18,21].Te systolic right ventricular function did not improve in our patients, but was in general only mildly impaired before PPVI.Various studies reported no improvement in right ventricular ejection fraction despite remodeling after pulmonary valve replacement, suggesting that regurgitation should be remediated before relevant deterioration of function becomes evident [24].However, the optimal time point for pulmonary valve replacement in patients with moderate-to-severe regurgitation is still a matter of controversy.Inconsistent results from studies and meta-analyses foremost indicate essential knowledge gaps [24][25][26][27].
One particular concern of self-expandable valves and devices for PPVI is the possible increase in the risk of ventricular arrhythmias.In addition to the overall increased risk in patients with tetralogy of Fallot, mechanical irritation by the foreign body protruding into the RVOT might facilitate the provocation of malignant arrhythmias such as VT.Moreover, arrhythmogenic substrates in the RVOT might become inaccessible after PPVI [28].However, while a transient increase in the burden of PVC was observed in the majority of our patients, only a few showed persisting relevant ventricular arrhythmias at discharge.Nonetheless, one of our patients experienced a serious arrhythmic event with a sustained VT subsequently deteriorating to ventricular fbrillation; he had shown no relevant arrhythmias prior to discharge.Ventricular arrhythmias including VT have also been documented after PPVI with other self-expanding devices such as the Harmony ™ and the Alterra ™ but also with balloon-expandable valves [16,29,30].While regular monitoring for arrhythmias is the standard of care in these patients and particularly essential before and after PPVI, there are currently no guildeline recommendations concerning preemptive electrophysiological studies to detect and ablate latent arrhythmogenic substrates, as recently advocated [28].In the hitherto reported experience with the Venus P-Valve ™ , no overt risk of signifcant ventricular arrhythmias has been observed [18][19][20][21].Appropriate risk stratifcation to guide arrhythmia screening and possible preemptive treatment will be an objective for future studies.

4.1.
Limitations.Limitations of this study are inherent to its retrospective design, for which consistency of follow-up examinations and data acquisition is not given.Our study is restricted to a single institution, and results may not be generalizable.Moreover, our cohort is small and rare procedural complications may not have been detected.Importantly, our follow-up is limited and does not allow confdent conclusions concerning the long-term performance of the valve or late complications such as infective endocarditis.

Conclusions
Early and midterm results with the Venus P-Valve ™ are excellent.Te self-expandable valve considerably extends the interventional options for PPVI and provides an alternative to surgical valve replacement in patients with large RVOT not amenable to PPVI with balloon-expandable valves.Larger multi-institutional studies with longer follow-up duration are required to reliably assess the long-term performance and possible long-term complications of the Venus P-Valve ™ .Medtronic; consulting fees, travel expenses, and research support from Abbott; and consulting fees from Venus MedTech Europe.P.D. has received consulting fees and travel expenses from Venus MedTech Europe.None of the other authors have conficts of interest to declare.
Stop fow was ascertained by pressure recordings documenting arterial pressure drop and right ventricular angiography (Figure 1(d)).Coronary compression or displacement was ruled out by simultaneous angiography of the left coronary artery.Te valve diameter (28−36 mm) was chosen to comply with a safety margin of at least 1-2 mm of oversizing the valve in relation to the smallest waist diameter determined by balloon sizing, and length was chosen according to distance from the annular 2 Journal of Interventional Cardiology level to the bifurcation.While in the early experience the longer 30 mm valve length was often preferred due to concerns of stable positioning, currently the shorter 25 mm valve is generally favoured to minimise the protrusion of the valve's proximal fared end into the RVOT.For valve implantation, an extra-stif guidewire (Lunderquist ® ; Cook Medical, Bloomington, USA; or E-Wire; Artivion, Kennesaw, USA) was placed in the peripheral pulmonary artery and a 24F-26F GORE ® DrySeal Flex Introducer Sheath (W.L. Gore & Associates, Inc., Flagstaf, USA) was advanced.Te Venus P-Valve ™ (Figures 2(a) and 2(b)) was crimped and mounted to the delivery catheter according to the manufacturer's instructions.Te delivery catheter was then advanced through the sheath into the proximal branch of the pulmonary artery, where valve deployment was initiated (Figure 2(c)).During slow and controlled deployment with gradual release of the valve, the delivery system was gently pulled back to the designated landing zone, controlled by repeated RVOT angiograms (Figure 2(d)).After the release of the valve (Figure 2(e)) and extraction of the delivery system, pressure recordings and fnal angiograms were performed to document valve function and position (Figure 2(f )).

Figure 1 :
Figure 1: Preprocedural imaging and measurements in a patient with subsequent Venus P-Valve ™ implantation.3D reconstruction (a) and assessment of RVOTdimensions (b) from preprocedural MRI.(c) Angiography of the pulmonary artery/RVOT with simultaneous coronary angiogram of the left coronary artery.(d) Balloon sizing of the RVOT with simultaneous RV angiogram demonstrating complete occlusion.MRI: magnetic resonance imaging; RV: right ventricle; RVOT: right ventricular outfow tract.

Figure 2 :
Figure 2: (a, b) Design of the Venus P-Valve ™ . (c-f) Implantation of the Venus P-Valve ™ (same patient as Figure1).Slow and controlled
Data are presented as the mean ± standard deviation or frequencies (percentages).Right ventricular functional parameters and minimum RVOT diameter were analyzed from MRI, and RVEDD was analyzed from echocardiography.RVEDD was measured as a maximal transversal dimension in the basal part of RV infow at the end diastole in the four-chamber view.* More than one type of arrhythmia has been observed in some patients.TOF: tetralogy of Fallot; PV: pulmonary valve; PVC: premature ventricular complex; PVR: pulmonary valve replacement; RVEDD: right ventricular end-diastolic diameter; RVEDVi: indexed right ventricular end-diastolic volume; RVEF: right ventricular ejection fraction, RF: regurgitation fraction; RVOT: right ventricular outfow tract; RVESVi: indexed right ventricular end-systolic volume.

Table 3 :
Comparison of baseline and follow-up data.Data are presented as the mean ± standard deviation or frequencies (percentages).Right ventricular functional parameters were analyzed from MRI, and RVEDD was analyzed from echocardiography.Statistically signifcant p values are highlighted in bold. *