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Table of Contents   
ORIGINAL ARTICLE  
Year : 2021  |  Volume : 14  |  Issue : 1  |  Page : 35-41
Melody valve to replace the mitral valve in small children: Lessons learned


Children's Heart Centre and Children's Research Centre, University Children's Hospital, Zurich, Switzerland

Click here for correspondence address and email

Date of Submission16-Apr-2020
Date of Decision22-Jun-2020
Date of Acceptance18-Sep-2020
Date of Web Publication04-Jan-2021
 

   Abstract 


Objective: Infants requiring mitral valve replacement have few viable options. Recently, stented bovine jugular vein graft (Melody) has been surgically implanted in such cases. Herein, we report our experience, elaborating on evolution of implantation technique, pitfalls, as well as long-term outcome (including late dilatability).
Methods: Seven Melody valves were implanted (2013–2019). The median patient age and weight were 6.7 (1.8–30.5) months and 5.8 (4.6–9.5) kg, respectively. The indications for implantation were mitral stenosis and/or regurgitation postatrioventricular septal defect (AVSD) repair (5), congenital mitral valve dysplasia (1), and Shone's complex (1). Operative technique involved shortening the valve and creating a neo-sewing ring at 2/3 (atrial)–1/3 (ventricular) junction. Implantation was followed by intraoperative balloon dilatation.
Results: Five out of seven patients survived the perioperative period (one death due to technical failure and the other due to acute respiratory distress syndrome postcardiopulmonary bypass). Two out of five medium-term survivors got transplanted (1) or died due to acute myeloid leukemia (1). No valves were replaced. The mean echo gradient at discharge was a median 4 (2–6) mmHg. None of the patients showed left ventricular outflow tract or pulmonary venous obstruction. Two Melody valves were dilated late (5 months and 3 years postoperatively), resulting in decreasing mean gradients from 6 to 1 and from 17 to 4 mmHg. At last follow-up, surviving Melody had a mean gradient of 4 (1–9) mmHg.
Conclusions: Mitral valve replacement with a Melody valve is feasible in infants, is reproducible, shows good immediate results, and offers the possibility of later dilatation. This technique offers a better solution compared to the existing alternatives for infants requiring a prosthetic mitral valve.

Keywords: Bioprosthesis, complete atrioventricular septal defect, congenital valvular disease, Melody valve, mitral valve replacement in infants and children

How to cite this article:
Dranseika V, Pretre R, Kretschmar O, Dave H. Melody valve to replace the mitral valve in small children: Lessons learned. Ann Pediatr Card 2021;14:35-41

How to cite this URL:
Dranseika V, Pretre R, Kretschmar O, Dave H. Melody valve to replace the mitral valve in small children: Lessons learned. Ann Pediatr Card [serial online] 2021 [cited 2021 Apr 15];14:35-41. Available from: https://www.annalspc.com/text.asp?2021/14/1/35/306113





   Introduction Top


Options to replace irreparable mitral valves in infants are limited. Mechanical valves are often too big, especially for infants. They pose challenges to implantation technique, unhindered function, effective anticoagulation, and pannus formation, in addition to predestining them to multiple reoperations. Bioprosthesis do not need anticoagulation, but are hard to get (especially in small sizes), and degenerate quickly, thus necessitating replacements.[1],[2] Several groups have proposed the use of stented biological valves considering their potential for catheter dilatation as the child grows.[3] One such valve is the Melody® (Medtronic Inc., Minneapolis, USA) valve, a stented bovine jugular vein graft, developed for use as a transcatheter pulmonary valve substitute. We have pursued an “off-label” surgical-hybrid implantation of the Melody valve in mitral position for small children since 2013.[4] Herein, we describe our 6-year experience of 7 Melody implantations in mitral position.[5]


   Methods Top


Patient and public involvement

Based on ethical approval for reporting this technique as a part of a multicentric study (15), written informed consent for off-label use of Melody valve as a life-saving strategy was obtained preoperatively from parents of the children. The Cantonal Ethics Committee of Zürich waived the need for ethical approval for an assimilated report of a small number of such procedures (when not performed or published as a systematic study)

Patients

Melody valve was implanted using a surgical-hybrid approach in 7 patients (2013-2019). The first patient received an 18 mm Melody model; all others received a 20 mm Melody model. The choice was not deliberate but rather on the logistics of availability. The median age and weight were 6.6 (1.7-30.5) months and 5.1 (4.6-9.5) kg, respectively. The indications for implantation were severe left atrioventricular (henceforth referred to as mitral) valve regurgitation and/or stenosis (5 patients) following repair of complete atrioventricular septal defect (AVSD), congenital mitral dysplasia (1 patient), and Shone's complex (1 patient). A mitral valve repair was always attempted, and a replacement was considered when the repair was unsatisfactory and unlikely to achieve a satisfactory clinical outcome. Valve function (gradient and regurgitation), pulmonary veins, and left ventricular outflow tract (LVOT) were analyzed intraoperatively with transesophageal echocardiography and postoperatively with transthoracic echocardiography at regular intervals. Follow-up was complete at a median of 11 (4-58) months (excluding 1 death on the table due to technical failure and 1 death on postoperative day 11 due to acute respiratory distress syndrome (ARDS) unrelated to Melody).

Surgical technique

Since the description of surgical Melody implantation,[5] the technique has evolved. While describing our technique, we shall refer to the potential pitfalls, which we have learned to avoid using certain modifications.

Once the decision to replace the valve is made (sometimes intraoperatively after a failed repair), the atriotomy can be quickly closed and the heart can be allowed to be perfused (kept beating). Rarely, a decision to replace can be made beforehand, allowing valve preparation before instituting cardiopulmonary bypass.

Preparing the valve

The high profile of the Melody poses the first challenge when considering the small infants, where this valve is likely to be used most often. The Melody is shortened from 28-30 to about 20 mm, by bending the distal and proximal stent struts backward, thus facilitating implantation in the left heart, which is not yet enlarged, to the extent seen in bigger children or adults with chronic mitral regurgitation (MR) [Figure 1]a. Caution is warranted to avoid distortion of the valve at the commissures as well as at the scallops. A water test of the valve confirms the competence of the valve. We now routinely suture a sewing ring made of a strip of xenopericardium on the outer surface of the Melody [Figure 1]b. One should be careful while stitching the sewing ring to the thin-walled conduit, in order to avoid stitching through the leaflets. In view of the small size of the patients, we have of late exclusively created this neo-sewing ring at the premarked junction of distal 1/3 and proximal 2/3 of the valve. However, this may be modified depending on the confidence of accommodating ventricular part of the valve without causing LVOT obstruction (LVOTO).
Figure 1: (a) Foreshortened Melody valve by turning back the struts. (b) Creation of a neo-sewing ring at the junction of proximal 2/3rd and distal 1/3rd of Melody® valve

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Implantation

At this stage, cardioplegia is accomplished. We have effectively used trans-septal as well as left atriotomy (Waterston's groove) approaches for the implantation, depending on how dilated the left atrium is. The body of the native valve tissue is resected in its entirety. In one of our first cases where subvalvular apparatus was completely resected, we encountered an early LV dysfunction, which eventually recovered. Hence, we do consider preserving the subvalvular apparatus whenever possible. Islands of tissue hosting primary chordae of the anterior leaflet are retained and easily incorporated in the annular Ticron mattress stitches. If the posterior leaflet tissue is thin, and does not occupy annular space, it can be completely retained. Retaining both the anterior and the posterior subvalvular apparatus has not hindered the ventricular part of the Melody, thanks to only about 5 mm ventricular profile of the Melody in our technique. Pledgeted 5-0 Ticron stitches are placed first at the mitral annulus in horizontal mattress fashion with pledgets placed at the atrial side. The Melody valve is crimped by circumferential finger pressure on a 5 ml syringe and positioned into the annulus. Thereafter, preplaced mitral annular sutures are pierced and tied onto the sewing ring. Placing sutures on the sewing ring first and then parachuting it down may lead to entangling of sutures around the struts, leading to significant valve dysfunction (encountered in one of our early patients).

Balloon dilatation and septal fenestration

A partial dilatation of the valve may be performed before tying the sutures, if necessary. Once tied, Melody valve is progressively dilated to 14 or 16 mm, considering patients' expected valve size as well as the size of the available annulus. Although not encountered by us, overzealous dilatation can cause AV block or stretching/compression of the left circumflex artery. For the same reasons, the placement of stitches at the 2 o'clock position as well as along the posterior annulus (especially in infants) should be carefully titrated. The valve and the subvalvular ventricular cavity are inspected and valve competence is confirmed. A 3 mm opening in the fossa ovalis is created with a punch at a preferably posterior location, thus facilitating future catheter access of the left atrium and balloon dilatation of the Melody. The left atrium or the interatrial septum, as the case may be, is often enlarged with a xenopericardial patch to increase left atrial volume. A brief inspection of both sided pulmonary veins ensures unhindered flow into the valve.

Postoperative management

All patients received therapeutic anticoagulation after mitral valve replacement (MVR). Considering the challenges of managing Coumadin anticoagulation in infancy, crystalline heparin therapy was started immediately postoperatively. This was replaced by therapeutic enoxaparin subcutaneously after discharge from the intensive care unit. In older infants, enoxaparin gave way to Coumadin with a target INR of 2-3. For lack of systematic studies and the high valve profile in the left atrium, we plan therapeutic anticoagulation for 12 months and aim to replace it thereafter with aspirin. Despite this protocol, the oldest child with Melody at 5 years underwent therapeutic anticoagulation on insistence of the parents.


   Results Top


Implantation was successful in all but 1 case. [Table 1] depicts the demographics and outcome of the patient cohort.
Table 1: Patient characteristics

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Mortality and transplantation

A 1.7-month-old child with congenital mitral dysplasia (mixed lesion) as well as tricuspid dysplasia suffered LVOTO during Melody implantation. Intraoperative attempt to correct this led to LV rupture and death on the table. A 2.4-month-old child undergoing complete AVSD repair developed severe MR and shock lung requiring postoperative Extra Corporeal Membrane Oxygenation (ECMO). Despite a successful salvage MVR with Melody, the child succumbed to ARDS on ECMO (day 11). One child was diagnosed with acute myeloid leukemia after a successful AVSD repair. He developed late Mitral dysfunction at 30.5 months of age, which was successfully treated with MVR using a Melody. Despite well-functioning Melody, the child succumbed to sepsis, 11 months postimplantation at a district hospital. One child with Shone's complex (status post-Ross-Konno operation) underwent MVR with Melody at 6.6 months of age and was successfully transplanted at 8.5 months due to LV diastolic dysfunction. Three children with Melody in situ are alive and free from replacement or transplantation.

Pulmonary vein and left ventricular outflow tract obstruction

None of the acute survivors showed Melody-induced pulmonary venous obstruction. The first implantation (nearly half of the valve protruding in the ventricular cavity) developed an initial LVOT gradient (maximum 40-60 mmHg); this reduced spontaneously after cessation of adrenaline and better preloading. None of the other patients where the ventricular part was about 7 mm developed any such gradient [Figure 2].
Figure 2: Left ventricular angiogram demonstrating an unobstructed left ventricular outflow tract at 3.1 years postimplantation

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Melody function

In situ duration of Melody in acute survivors was 11 (4-58) months. None of the valves needed replacement. None of the valves suffered more than trivial/mild regurgitation. Mean postoperative gradients were a median of 4 (2-6) mmHg at discharge and of 4 (1-9) mmHg at follow-up. [Figure 3]a and [Figure 3]b depicts the two-dimensional echo as well as color Doppler flow profile through the longest surviving Melody valve in situ for 5 years.
Figure 3: (a) Two-dimensional echo and (b) color Doppler image of the Melody valve in mitral position at 61 months postimplantation

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Late dilatation

Late balloon dilatation was successfully performed in 2 patients (5 months and 3 years postoperatively). In the former, balloon dilatation was undertaken intraoperatively during re-repair of a de novo pulmonary vein ostial stenosis, existing before Melody implantation (unrelated to the Melody®) [Figure 4]. In the second case, successful transfemoral balloon dilatation (16 mm) could be performed through a trans-septal access to the left atrium [Figure 5]. This resulted in an immediate decrease in mean gradient from 6 to 1 mmHg and from 17 to 4 mmHg, respectively. The z value dynamics of the mitral valve from the time of MVR to follow-up are depicted in [Table 2]. Notable is the fact that while the median weight of the cohort increased by nearly 20%, the median z value of the Melody remained normal (change from 0.8 at implant to 0.4 at follow-up), thanks to the possibility of secondary balloon dilatation.
Figure 4: De novo left pulmonary vein ostial stenosis (red arrow) in patient 5; preceding mitral valve replacement

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Figure 5: Melody valve balloon dilatation: (a) before (b) during (c) after dilatation

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Table 2: Impact of secondary balloon dilatation on the Z value of the Melody valve

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   Discussion Top


Surgically implanted Melody is a viable and life-saving option for infants needing mitral valve replacement. They offer good immediate results and can be re-dilated using transvenous catheter technique as the child grows. This being a new operation, several aspects of Melody in mitral position are still evolving.

Surgical considerations

The Melody valve construct

Most groups working with Melody follow similar principles. The length of the valve needs to be decreased either by bending the stent struts backward[6],[7] or by trimming the outermost parts of the valve.[8] We avoided any resection of stent struts so as to avoid impairing the integrity of the stent valve and thereby its radial and longitudinal stability. We have not resorted to cutting away the LVOT facing sinus, as it may destabilize the valve geometry, and exact positioning may be difficult. We have instead used less ventricular profiling to avoid LVOTO.

Presently, we are convinced about the advantages of creating a neo-sewing ring. A prestitched sewing ring facilitates putting the stitches as well as tying them efficiently. It minimizes the risk of paravalvular leak.[4],[6],[7],[9]

Profile of the valve in the atrium versus the ventricle

Differences exist in the positioning of the sewing ring and hence the valve profile in the mitral inflow. It involves finding a balance between the requirement of good pulmonary venous return on the atrial side and the risk of LVOTO on the ventricular side. Positioning the valve entirely in the atrium[6] or even supra-annularly[7] has been described when LVOTO is feared. It appears attractive when the atrium is hugely dilated, as is the case in older children. Supra-annular placement has been associated with increased early mortality in conventional valves, possibly due to consequences of impaired disc motion.[10] Melody valve, in contrast, does not carry the risks of hindrance to disc motion and pannus formation. Positioning the sewing cuff half-way or at 2/3rd (atrial)-1/3rd (ventricular) junction of the Melody appears to ensure[4],[9] unhindered pulmonary venous return as well as unobstructed LVOT. With this approach, we have not found it necessary to place a ventricular stitch to drag the valve toward the interventricular septum and away from the LVOT.[8] Considering the relatively short exposure to MR (median 3.5 months in our cohort), in small infants (median 5.8 kg), some sort of left atrial/interatrial septal enlargement is usually performed to increase LA volume.[6],[7]

Preservation of the subvalvular apparatus

Preservation of the subvalvular apparatus during MVR has been shown to positively influence LV function both in the short and long term.[3],[11] However, interaction of the small LV cavities, high profile Melody valve, and its impact on LVOT in infants has attracted caution. Acceptable results have been published despite subvalvular apparatus resection.[6] Since experiencing short-term LV dysfunction in one of our first patients, we now pursue at least partial preservation of subvalvular apparatus. We believe that subvalvular preservation prevents systolic tilting of the Melody into the LVOT.

Anticoagulation

Usually, biological valves do not require long-term therapeutic anticoagulation. Considering the long experience with Melody in mitral position, risk of thromboembolism due to Melody per se seems to be low.[12] Recommendations of anticoagulation for Melody in mitral position are evolving. This reflects in variation in practice from aspirin monotherapy to aspirin plus clopidogrel[6],[7],[8] and enoxaparin.[13] Considering the high profile of valve we leave in the atrium, the small and short-term experience, we have been cautious in favor of therapeutic anticoagulation for 1 year. Thereafter, we recommend the use of aspirin monotherapy once echocardiographic result of valve and LV function remain favorable.

Dilatability

Future dilatability lies at the heart of attractiveness of this concept. Leaving a small fenestration in the atrial septum has been practiced by most groups.[1],[5],[8] A multicenter study showed that 24 out of 59 patients underwent balloon dilatation at a median of 6.9 months postimplantation, 10 of them undergoing multiple interventions. Similar to other groups, balloon dilatation in 2 of our patients achieved a significant reduction in transvalvular gradient without experiencing new regurgitation.[12] Fortunately, we did not encounter any of the reported complications such as distortion of valve (ventricular end) and hemodynamic collapse.[4]

Valve degeneration/longevity

Considering our own experience with the Contegra valve in pulmonary position, we believe that Contegra valve leaflets have continued to function well beyond 10 years in vivo.[14] The Melody concept is a value addition of the Contegra, where the leaflets (the biggest asset of Contegra) are retained and a dilatability is bestowed upon. Some question the ability of the venous valves to withstand systemic pressures. Considering the short follow-up, it is too early to predict the longevity of Melody in mitral position. Histological analysis of postmortem specimen in one of our patients (dying of leukemia 13 months postimplantation) demonstrated good biocompatibility, neo-endothelialization, and minimal neo-intima formation. The cusps remained thin, pliable, and intact.[15] The only multicenter study showed that 16/59 Melody valves underwent replacement at 23 months of follow-up. Reasons included stenosis, endocarditis, structural valve deterioration (without infection), stent fracture, and paravalvular leak.[12] Considering the 55% freedom from death, transplant, structural valve degeneration, or valve replacement reported in this series,[12] our experience of no structural valve degeneration, death, replacement, and severe regurgitation stands favorably in comparison.

Alternatives

A possible alternative to the Melody is the Sapien 3® valve (a stented bovine transcatheter valve); however, we have no personal experience with surgical implantation of the Sapien valve.[8],[16],[17]

Mechanical valves, by virtue of their known poor prognosis in infants, lend itself to no comparison. In addition to high risk of mortality, significant morbidity including permanent pacemaker implantations, paravalvular leaks, valve thrombosis, as well as the significant loss of “quality of life” rightfully has fuelled the drive for better solutions.[10],[18],[19] A recent Dutch experience with the smallest 15 mm mechanical mitral valve implanted in 3 neonates reported perioperative death in 1, the other two requiring one or two re-replacements before adolescence.[18],[19] In contrast, older children have a better prognosis. Children <2 years reportedly have a 26% inhospital mortality compared to 4% in older children.[20]

Biological valves are attractive as they require no anticoagulation; however, they degenerate faster in young children.[21] The median time to replacement ranges from 2.5 to 5 years. In addition, they pose the same size issues as the mechanical valves, especially since some models have even higher profiles compared to their mechanical counterparts.[1],[2] The Ross II procedure (pulmonary autograft in mitral position) offers the benefits of biological valves. However, since 2 valves are potentially jeopardized, it has hardly found acceptance.[1] In the midst of this outlook, Melody in mitral presents itself as a concept with a new ray of hope for infants needing MVR. Only time will tell how far this hope turns into reality.


   Conclusion Top


Mitral valve replacement in infants remains extremely challenging. Conventional valves are marred by significant morbidity and mortality. Melody valve implantation has opened up new avenues to treat infants needing a prosthetic mitral valve. Melody implantation in mitral position is feasible and safe and the dilatability to accommodate child growth is a reality. Although not a life-long solution, it provides a ray of hope for infants and small children, in the least to bridge the gap, until other options become a viable option.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Henaine R, Roubertie F, Vergnat M, Ninet J. Valve replacement in children: A challenge for a whole life. Arch Cardiovasc Dis 2012;105:517-28.  Back to cited text no. 1
    
2.
Günther T, Mazzitelli D, Schreiber C, Wottke M, Paek SU, Meisner H, et al. Mitral-valve replacement in children under 6 years of age. Eur J Cardiothorac Surg 2000;17:426-30.  Back to cited text no. 2
    
3.
Quiñonez LG, Breitbart R, Tworetsky W, Lock JE, Marshall AC, Emani SM. Stented bovine jugular vein graft (Melody valve) for surgical mitral valve replacement in infants and children. J Thorac Cardiovasc Surg 2014;148:1443-9.  Back to cited text no. 3
    
4.
Sullivan PM, Wong PC, Kim R, Ing FF. Further percutaneous dilation of a Melody® valve in the mitral position to accommodate somatic growth in a small child: Lessons learned. Cardiol Young 2019;29:235-7.  Back to cited text no. 4
    
5.
Hofmann M, Dave H, Hübler M, Kretschmar O. Simplified surgical-hybrid Melody valve implantation for paediatric mitral valve disease. Eur J Cardiothorac Surg 2015;47:926-8.  Back to cited text no. 5
    
6.
Langer NB, Solowiejczyk D, Fahey JT, Torres A, Bacha E, Kalfa D. Modified technique for Melody valve implantation in the mitral position. J Thorac Cardiovasc Surg 2018;156:1190-1.  Back to cited text no. 6
    
7.
Stephens EH, Tannous P, Nugent AW, Hauck AL, Forbess JM. Supra-annular mitral implantation of melody valve: minimizing left ventricular outflow tract obstruction. World J Pediatr Congenit Heart Surg 2019;10:235-8.  Back to cited text no. 7
    
8.
Emani SM, Piekarski BL, Zurakowski D, Baird CA, Marshall AC, Lock JE, et al. Concept of an expandable cardiac valve for surgical implantation in infants and children. J Thorac Cardiovasc Surg 2016;152:1514-23.  Back to cited text no. 8
    
9.
González Rocafort Á, Aroca Á, Abelleira C, Carnicer H, Labrandero C, Villagrá S. Stented bovine jugular vein graft (melody valve) in mitral position. could be an alternative for mechanical valve replacement in the pediatric population? Rev Esp Cardiol (Engl Ed) 2017;70:675-7.  Back to cited text no. 9
    
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Kanter KR, Kogon BE, Kirshbom PM. Supra-annular mitral valve replacement in children. Ann Thorac Surg 2011;92:2221-7.  Back to cited text no. 10
    
11.
Athanasiou T, Chow A, Rao C, Aziz O, Siannis F, Ali A, et al. Preservation of the mitral valve apparatus: Evidence synthesis and critical reappraisal of surgical techniques. Eur J Cardiothorac Surg 2008;33:391-401.  Back to cited text no. 11
    
12.
Pluchinotta FR, Piekarski BL, Milani V, Kretschmar O, Burch PT, Hakami L, et al. Surgical atrioventricular valve replacement with melody valve in infants and children. Circ Cardiovasc Interv 2018;11:e007145.  Back to cited text no. 12
    
13.
Abdullah I, Ramirez FB, McElhinney DB, Lock JE, del Nido PJ, Emani S. Modification of a stented bovine jugular vein conduit (melody valve) for surgical mitral valve replacement. Ann Thorac Surg 2012;94:e97-8.  Back to cited text no. 13
    
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Dave H, Mueggler O, Comber M, Enodien B, Nikolaou G, Bauersfeld U, et al. Risk factor analysis of 170 single-institutional contegra implantations in pulmonary position. Ann Thorac Surg 2011;91:195-302.  Back to cited text no. 14
    
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Schmiady M, Kretschmar O, Hübler M, Sigler M. Histopathological workup of a hybrid implanted Melody® valve in mitral valve position. Eur Heart J 2017;38:2788.  Back to cited text no. 15
    
16.
Chai PJ, George I, Nazif TM, Kalfa DM, Kodali SK, Torres AJ, et al. Use of stented bovine pericardial valve for surgical mitral valve replacement in infants. J Thorac Cardiovasc Surg 2016;151:e51-2.  Back to cited text no. 16
    
17.
Trezzi M, Cetrano E, Iacobelli R, Carotti A. Edwards Sapien 3 Valve for Mitral Replacement in a Child After Melody Valve Endocarditis. Ann Thorac Surg 2017;104:e429-30.  Back to cited text no. 17
    
18.
Eltayeb OM, Readdy WJ, MongÁ© MC, Forbess JM, Sarwark AE, Patel A, et al. Mitral Valve Replacement in Infants Using a 15-mm Mechanical Valve. Ann Thorac Surg 2019;108:552-7.  Back to cited text no. 18
    
19.
IJsselhof RJ, Slieker MG, Hazekamp MG, Accord R, van Wetten H, Haas F, et al. Mitral valve replacement with the 15-mm mechanical valve: A 20-year multicenter experience. Ann Thorac Surg 2020;110:956-61.  Back to cited text no. 19
    
20.
Alsoufi B, Manlhiot C, Al-Ahmadi M, McCrindle BW, Kalloghlian A, Siblini G, et al. Outcomes and associated risk factors for mitral valve replacement in children. Eur J Cardiothorac Surg 2011;40:543-51.  Back to cited text no. 20
    
21.
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Correspondence Address:
Prof. Dr. Hitendu Dave
Congenital Cardiovascular Surgeon, Children's Heart Centre and Children's Research Centre, University Children's Hospital, Zurich
Switzerland
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/apc.APC_74_20

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

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