Novel Ring for Tricuspid Annuloplasty: A Feasibility Study in Animal Model

doi:10.21203/rs.3.rs-3895775/v1

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Novel Ring for Tricuspid Annuloplasty: A Feasibility Study in Animal Model

https://doi.org/10.21203/rs.3.rs-3895775/v1

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Background

Tricuspid regurgitation (TR) is the most common disease of the tricuspid valve, and tricuspid valvuloplasty is the main treatment method. Currently, most tricuspid annuloplasty rings are incomplete and rigid and can easily cause myocardial tear and prosthesis dehiscence. Therefore, we developed a novel tricuspid annuloplasty ring and evaluated its effectiveness.

Methods

In this study, eight adult pigs were selected, and implanted the novel rings (N = 4) and the commercial Edwards MC3 rings (N = 4) respectively, through median thoracotomy. The perioperative echocardiographic data were recorded, and a 6-month follow-up was completed to evaluate the effectiveness and safety of the novel rings.

Results

The average weight of the pigs was 70.06 kg. A total of five pigs successfully underwent tricuspid valvuloplasty and completed follow-up. The diameter of the native tricuspid annulus ranged from 25 to 29 mm. Three pigs experienced the decline of tricuspid regurgitation grade after surgery. The average tricuspid transvalvular gradients at one month and six months after the operation were 4.28 mmHg and 4.26 mmHg, respectively. No serious complications related to surgery, such as bleeding, infective endocarditis, or pericardial effusion, were found during the follow-up period. Autopsy confirmed that the tricuspid valves had good morphology and function, and the valve leaflets were completely closed. No deformation of the tricuspid annuloplasty rings was observed.

Conclusions

The novel tricuspid valvuloplasty ring was confirmed to be feasible in this animal model. During the six-month follow-up, the rings showed good effects without significant complications.

Tricuspid valve

Tricuspid regurgitation

Valvuloplasty

Animal model

Tricuspid regurgitation (TR) is a common heart valve disease with an incidence rate of 65–85%. It is usually secondary or functional, and the main pathological features are leaflet abnormalities and annular dilation [1, 2]. Untreated TR may increase the load on the right ventricle, causing ventricular remodeling and right heart failure [3]. Therefore, some studies recommend that tricuspid valve surgery be performed at the same time as left valve surgery to treat severe TR, but whether to address moderate or mild TR is still controversial [4, 5]. Compared with suture annuloplasty, the implantation of a tricuspid annuloplasty ring to remodel the tricuspid valve annulus has better efficacy and durability and is currently the main surgical method for the treatment of TR [6, 7]. Due to the distinct bimodal or saddle-shaped three-dimensional structure of the tricuspid valve annulus [8], most of the current tricuspid annuloplasty rings cannot match well [9], possibly resulting in deformation of the tricuspid annulus, which can easily cause myocardial tear and impair heart function. In addition, most surgical tricuspid annuloplasty rings are incomplete and rigid, which may bring difficulties to future transcatheter tricuspid valve-in-ring (TVIR) implantation [10]. Therefore, we developed a novel tricuspid annuloplasty ring to reduce TR and improve the safety profile and success rate of subsequent TVIR to treat recurrent TR. In this study, we investigated the feasibility of a novel tricuspid annuloplasty rings in a porcine model.

2.1. Design and description of the valvuloplasty ring

We developed a novel tricuspid C-shaped stereoscopic annuloplasty ring. The C-shaped stereoscopic ring included a first free-end segment, a posterior leaflet ring segment, an anterior ring segment and a second free-end segment (Fig. 1A). Compared with the previous C-shaped stereoscopic ring used for tricuspid annuloplasty, the free end segment of the novel shaped ring was softened and shortened, the length was shortened to 10 ± 0.5 mm, and the stereoscopic height was reduced to 7 ± 2 mm. The novel annuloplasty rings were produced by Beijing PERMED Biomedical Engineering Co., Ltd., and passed the performance test. The C-shaped stereoscopic ring is an integrated structure, including an internal metal core bracket, a silicone tube and an external polyester fabric. The metal core bracket was made of hollow nickel-titanium striated tube, nickel-titanium wire and liquid silica gel. The nickel-titanium wire runs through the hollow nickel-titanium striated tube and was welded to both ends. The cavity of the nickel-titanium striated tube was filled with liquid silica gel. The soft and elastic medical polyester fabric on the surface not only ensures the best attachment of the ring to the tricuspid annulus but also has excellent biocompatibility. Suture marking lines are designed at the junction of the valve leaflets, which is convenient for determining the position of the tricuspid annuloplasty ring during surgery. In addition, we designed a novel tricuspid O-shaped stereoscopic annuloplasty ring on this basis, connecting the first free-end segment of the C-shaped ring to the second free-end segment (Fig. 1B). The connecting area was made of silicone and polyester cloth to maintain overall connectivity and better flexibility. The absence of metal stents in the connection area prevents the sensitive cardiac conduction system from being affected and further dilation of the ring from occurring. Detailed data on the different types of novel tricuspid annuloplasty rings are shown in Fig. 1C.

2.2. Preparation of animals

Between November 2021 and May 2022, eight adult pigs weighing 65–86 kg were enrolled in the study and divided into an experimental group (n = 4) and a control group (n = 4). Pigs in the experimental group were implanted with two novel C-shaped rings and two novel O-shaped rings, while pigs in the control group were implanted with conventional commercial tricuspid annuloplasty rings (MC3 rings, Edwards Lifesciences, LLC, Irvine, CA, USA). The follow-up time was six months, and echocardiography was performed at the first and sixth months after surgery. The overall experimental data were analyzed to evaluate the efficacy of the novel tricuspid annuloplasty ring in large animals. All animals received humane care in compliance with the Ministry of Science and Technology of the People’s Republic of China Guide for the Care and Use of Laboratory Animals and the principles of Laboratory Animal Care (NIH publication No. 86 − 23, revised 1985). This animal experiment was approved by the Silver Snake Medical Technology Co., LTD ethics committee (approval number: SS-2021-ZSYSJB1).

2.3. Surgical details and perioperative management

All procedures were performed in the supine position. Arterial blood pressure was monitored by catheterization through the right femoral artery, venous access was established through the right femoral vein, central venous pressure was monitored through the right internal jugular vein, and limb lead electrocardiogram, transcutaneous oxygen saturation, and nasopharyngeal temperature were monitored throughout the procedure. Ketamine (10 mg/kg) and midazolam (0.2–0.5 mg/kg) were used for induction of anesthesia. Isoflurane 2.5% was used for maintenance anesthesia. Cefradine (25 mg/kg) was infused intravenously before the operation. After routine thoracotomy through median sternotomy, perfusion tubes were inserted into the aorta and superior and inferior vena cava to establish cardiopulmonary bypass (CPB). Heparin was administered for anticoagulation therapy to maintain the activated clotting time above 400 seconds. The right atrium was incised along the long axis of the right atrial appendage to expose the tricuspid valve. The appropriate tricuspid annuloplasty ring was selected according to the size of the tricuspid annular. After the artificial tricuspid annulus was implanted, the atriotomy was closed, and the animal was weaned from CPB. The blood pressure of the animals was monitored for 24 h after the operation to maintain stable circulation, and vasoactive drugs were used when necessary. After the six-month follow-up period, all animals were sacrificed by intravenous injection of 2mmol/L potassium chloride under anesthesia.

2.4. Echocardiography evaluation

All animals underwent careful clinical evaluation before the procedure. The degree of paravalvular leak, diameter of the tricuspid annulus, tricuspid transvalvular pressure gradient and TR were measured by transthoracic echocardiography to evaluate the function of the implanted ring at 1 month and 6 months after the procedure.

We prepared eight pigs for surgery and divided them into an experimental group (n = 4) and a control group (n = 4). Table 1 summarizes the general condition and examination results of the animals. The mean weight of the pigs was 70.06 kg. The diameter of the native tricuspid annulus ranged from 25 to 29 mm. Five animals were successfully implanted and followed up for 6 months, including 1 in the control group and 4 in the experimental group. The sixth pig died on the third day after surgery, and the cause of death was considered to be heart failure. The seventh pig died during anesthesia induction preoperative. The eighth pig had sudden ventricular fibrillation during chest closure and died after ineffective rescue. The three pigs above were all from the control group. The intraoperative implantation results for the C-shaped ring and O-shaped ring are shown in Fig. 2A and Fig. 2B. The novel tricuspid valvuloplasty ring fitted well with the native tricuspid annulus, and the valve leaflets were completely closed. No severe operation-related complications, such as bleeding, infective endocarditis or pericardial effusion, were found in the remaining animals during the 6-month follow-up.

Table 1

Baseline characteristics and surgical information of the experimental animals
Pig	Body weight (kg)	Ring type	Ring size	Result	Tricuspid valve diameter (mm)	Left ventricular ejection fraction, %	Pulmonary artery diameter, mm	HR (beats/min)	Blood pressure (mmHg)	CVP mean (mmHg)
1	65	C-shaped	28	Sacrificed	25	73	31	93	115/78	9
2	86	O-shaped	32	Sacrificed	29	75	28	98	108/73	8
3	66.5	O-shaped	30	Sacrificed	26	76	26	105	123/81	10
4	67	C-shaped	30	Sacrificed	27	74	28	110	109/69	11
5	69	Edwards MC3	30	Sacrificed	27	78	30	116	106/72	8
6	72	Edwards MC3	28	Died of heart failure	25.5	76	29	118	120/76	9
7	65	NA	NA	Died of anesthesia induction	28	75	31	121	111/76	10
8	70	Edwards MC3	32	Died of ventricular fibrillation	29	74	30	119	114/80	8
NA, not applicable; HR, Heart rate; CVP, Central venous pressure

The results of echocardiographic assessment of tricuspid valve function at 1 month and 6 months after implantation are shown in Table 2. Two pigs had grade two TR before surgery, and two pigs had grade one TR. Three of these pigs experienced the decline of grades. Before sacrifice, echocardiography showed that three pigs had no TR, and two pigs had grade one TR. There was no perivalvular leakage or valvular dysfunction, as shown by echocardiography, during the follow-up period (Fig. 3). The mean tricuspid transvalvular gradient was 4.28 mmHg at 1 month and 4.26 mmHg at 6 months. The autopsy results showed that the tricuspid valves of five pigs had good morphology and function, and the valve leaflets were completely closed. No deformation of the tricuspid annuloplasty rings was observed.

Table 2

Echocardiographic evaluations of tricuspid valve function
Pig	Tricuspid regurgitation grades			Tricuspid valve velocity, m/s			Tricuspid transvalvular gradient, mmHg			Perivalvular leakage
	Baseline	1-month	6-month	Baseline	1-month	6-month	Baseline	1-month	6-month	Baseline	1-month	6-month
1	2+	0	0	0.81	0.93	0.92	2.6	3.5	3.4	NA	0	0
2	0	0	0	0.85	0.94	0.95	2.9	3.5	3.6	NA	0	0
3	1+	1+	1+	1.06	1.15	1.14	4.5	5.3	5.2	NA	0	0
4	1+	0	0	0.91	1.08	1.07	3.3	4.7	4.6	NA	0	0
5	2+	1+	1+	0.89	1.05	1.06	3.2	4.4	4.5	NA	0	0
NA, not applicable

There are many commercial types of tricuspid annuloplasty prostheses according to their 3-dimensional shape and material properties; these prostheses can be divided into planar or nonplanar, rigid, partially rigid, semi-rigid or flexible, and complete or incomplete. In our hospital, the main prostheses used for tricuspid valvuloplasty were Edwards MC3 rings, which are incomplete rigid rings. However, due to the hard material and high three-dimensional height, it does not match the tricuspid annulus well and can easily cause myocardial tear during implantation, increasing the risk of early prosthesis dehiscence. Therefore, we developed a novel tricuspid stereoscopic annuloplasty ring, which included C-shaped and O-shaped rings. By softening and shortening the two ends of the rings, the stereoscopic height can be reduced to alleviate the compression and wear of the forming ring on the fibrous trigone, prevent myocardial tear, and reduce the impact on cardiac function. The rings were proven to be safe and effective in short-term follow-up animal experiments. Echocardiography revealed that the TR of the experimental animals was generally reduced, cardiac function was good, and there was no paravalvular leakage or tricuspid valve dysfunction.

Except for congenital tricuspid valve disease, most cases of TR are secondary to left ventricular disease, such as mitral valve or aortic valve disease [1]. Left heart valve dysfunction increases the volume load of the right ventricle, leading to right ventricular enlargement and tricuspid annular dilatation. Untreated TR can lead to right heart failure [3]. Patients with severe TR have lower long-term survival rates and poorer functional status [4]. Simultaneous repair of the tricuspid valve at the time of left-sided heart surgery has not previously been recommended unless TR is severe because of the belief that once the major left-sided valve problem is eliminated, the TR should also disappear [5]. However, current research suggests that correction of the left-sided valve dysfunction alone may not complete reversely remodel the dilated right ventricle, reduce the size of the tricuspid annulus, and reliably eliminate TR [11, 12]. Conversely, the tricuspid annulus may be further enlarged if left untreated [4].

The normal tricuspid valve annular appears as a distinct bimodal or saddle-shaped three-dimensional structure with 2 high points and 2 low points. During the development of TR, the tricuspid annulus changes from a normal bimodal-elliptical shape to a more dilated, planar, and circular shape. This not only increases the annular area but also may alter the normal papillary muscle to leaflet and annulus relationship [8]. For this type of TR, tricuspid valvuloplasty is currently preferred to tricuspid valve replacement. The greatest advantage of this approach is that valve function can be restored by narrowing the dilated annulus. There is no need to worry about the threat of many complications after surgery, such as mechanical valve replacement, or about the possibility of valve replacement, such as for a biological valve. The main methods of tricuspid valvuloplasty are Key's annuloplasty, DeVega annuloplasty, and ring annuloplasty. Ring annuloplasty gets more and more applications, because of its less late TR recurrence and better durability [13, 14].

In order to obtain good long-term results, tricuspid annuloplasty rings should not only meet the needs of reversing right ventricular remodeling and maintaining 3D geometry of the native annulus but also preserve annular dynamic parameters as much as possible [15]. We improved the manufacturing process and structural design of tricuspid annular prostheses to reduce the risk of recurrent TR, prosthesis dehiscence and paravalvular leakage. First, the material used for the front-ends of the current commercial C-shaped rings is relatively hard and long. During the implantation process, the terminal of the ring often turns up to the right atrial side and does not fit the tricuspid annulus well, which may increase suture pressure and cause myocardial tear. Considering this problem, we performed targeted optimization of the novel rings. The main body material of the novel rings is rigid, but the front and back ends have been softened and shortened, which makes the rings have a phased hardness change, and at the same time, the height is reduced. The rings can better match the tricuspid annulus, reducing the risk of myocardial tearing and prosthesis dehiscence. Second, tricuspid annuloplasty is often combined with mitral and aortic valve surgery, such as mitral or aortic valve replacement. The presence of bilateral prostheses may squeeze and wear the fibrous trigone and influence the cardiac conduction system. Our novel C-shaped annuloplasty rings were modified by softening and shortening the front and back ends of the rings to enlarge the septal leaflet gap and alleviate compression on the conduction system. Third, unlike the stationary fibrous anterior mitral annulus, the tricuspid annulus dynamically changes during the cardiac cycle, mainly in the septal region of the tricuspid annulus [15]. The wrapped flexible material and increased gap can preserve the contractile motion and dynamic parameters of the physiologic annulus. Moreover, the presence of a metal stent ensures the effect of remodeling the tricuspid annulus. The novel ring metal stent is smaller and shorter than other rigid rings, which reduces the high risk of prosthesis dehiscence with rigid rings [16].

At present, compared to redoing tricuspid surgery to treat tricuspid annuloplasty ring failure, TVIR implantation is considered to be an attractive treatment option and has a high success rate and safety [10]. However, in order to minimize the impact on the conduction system, most of the current tricuspid annuloplasty valve rings are incomplete rigid rings. The gap can easily lead to paravalvular leakage and recurrent regurgitation, reducing the treatment efficacy [17]. Moreover, the oval shape of the rigid ring does not match the shape of the transcatheter heart valve, and there is a risk of prosthesis dehiscence. We fully considered this factor and designed a novel O-shaped tricuspid annuloplasty ring, which supplemented the gap of the C-shaped ring with flexible material to fit the annulus and reduce the impact on the conduction system. At the same time, the O-shaped ring can be more adaptable to transcatheter heart valves and reduce the risk of complications.

Limitations

This study has several limitations. First, with a relatively short follow-up of 6 months, we cannot determine the long-term effects of the novel valvuloplasty ring. Second, the research animals were healthy, and no pathological changes were found in the tricuspid valve. Although the novel tricuspid valvuloplasty rings were successfully implanted and reduced the degree of regurgitation, this study cannot fully validate the clinical effect of the rings. Finally, we did not conduct further studies of TVIR, and further research is needed to validate the function of this aspect.

This animal study showed that the novel tricuspid valvuloplasty ring had good efficacy and high safety and preserved physiologic annular dynamic parameters without causing paravalvular leakage or cardiac conduction in a pig model.

Tricuspid regurgitation

transcatheter tricuspid valve-in-ring

TVIR

cardiopulmonary bypass

CPB

Heart rate

Central venous pressure

CVP

Not applicable

Ethics approval and consent to participate

All methods were carried out in accordance with relevant guidelines and regulations. All methods are reported in accordance with ARRIVE guidelines. This animal experiment was approved by the Silver Snake Medical Technology Co., LTD ethics committee (approval number: SS-2021-ZSYSJB1).

Funding

This study was supported by the National Key Research and Development Program of Guangzhou [Grant number: 202103000014] and the National Natural Science Foundation of China [Grant numbers: 82370271; 82070297].

Conflict of interest statement

No potential conflicts of interest were reported by the authors.

Author contributions

All the authors have made substantial and intellectual contributions to this study. ZW, JH, and SY contributed to the conception and design of the study. SH, JC, ML, QL, KF, and ZW contributed to the animal surgery. JW, JH, SH, WL, and LS contributed to the analysis and interpretation of the data. JW, SH and GC drafted the article, and ZW critically revised the article for important intellectual content. All the authors have approved the version to be submitted.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgements

Not applicable

Consent for publication

Not applicable

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

Novel Ring for Tricuspid Annuloplasty: A Feasibility Study in Animal Model

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

1. Background

2. Methods

2.1. Design and description of the valvuloplasty ring

2.2. Preparation of animals

2.3. Surgical details and perioperative management

2.4. Echocardiography evaluation

3. Results

4. Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1