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\begin{document}

\title{Aortic Valve Neocuspidization using glutaraldehyde-treated autologous
pericardium: A literature review}



\author[1]{Jeremy Chan}%
\author[2]{Ayan Basu}%
\author[2]{Gabriela Di Scenza}%
\author[3]{Jack bartlett}%
\author[4]{Ka Siu Fan}%
\author[5]{Shwe Oo}%
\affil[1]{Bristol Medical School}%
\affil[2]{St George's University of London}%
\affil[3]{Swansea University Medical School}%
\affil[4]{University of London}%
\affil[5]{Bristol Royal Infirmary}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Aortic Valve Neocuspidization using glutaraldehyde-treated
autologous pericardium was first performed by Ozaki et al. in 2007. This
technique has become an alternative to tissue and mechanical valve as
long-term anticoagulation is not required and shows promising midterm
results and durability. Method: A comprehensive search was performed on
the major database using search terms ``Ozaki technique'' AND ``Aortic
Valve Neocuspidization'' AND ``AV Neocuspidization'' AND ``Autologous
pericardium'' AND ``glutaraldehyde-treated autologous pericardium''.
Articles up to 1st of August 2020 were included in this study. Results:
A total of 9 studies with a total of 1342 patients were included. The
mean age was 67.36 and 54.23\% were male. 66.32\% and 23.92\% of
patients had aortic stenosis and aortic regurgitation, respectively.
66\% of patients had a native tricuspid aortic valve and 31.37 \%
patients' native aortic valve was bicuspid. Three studies reported their
experience performing Aortic Valve Neocuspidization via mini sternotomy.
Conclusion: Aortic Valve Neocuspidization is an alternative to
biological and mechanical prostheses for surgical aortic valve
replacement. The short and mid-term outcome are comparable without the
need for long term oral anticoagulation. Long term follow-up data is
required for this novel approach to be widely adopted.%
\end{abstract}%



\sloppy


Aortic Valve Neocuspidization using glutaraldehyde-treated autologous
pericardium: A literature review

Jeremy Chan\textsuperscript{1}, Ayan Basu\textsuperscript{2}, Gabriela
Discenza\textsuperscript{3}, Jack Bartlett\textsuperscript{4}, Ka Siu
Fan\textsuperscript{5}, Shwe Oo\textsuperscript{6}

1: MB BCh BAO, PgDip (ClinEd), Bristol Medical School, University of
Bristol, Bristol, United Kingdom

2: MSc, BSc, MBBS, St George's University of London, London, United
Kingdom

3: St George's University of London, London, United Kingdom

4: MSc, BSc, Swansea University Medical School, Swansea, United Kingdom

5: BSc, St. George's University of London, London, United Kingdom

6: MRCS, PgCert (ClinEd), Department of Cardiothoracic Surgery, Bristol
Royal Infirmary, Bristol, United Kingdom

Corresponding author

Dr Jeremy Chan MB BCh BAO, PgDip (ClinEd) Bristol Medical School
University of Bristol, Bristol, United Kingdom
Email:\emph{jeremychan@doctors.org.uk}

Keywords: Aortic Valve Neocuspidization, Ozaki technique, Literature
review

Word Count:

Funding: (None)

Disclosure: Nil

Acknowledgement: Nil

Presentation: Nil

Abstract

Background: Aortic Valve Neocuspidization using glutaraldehyde-treated
autologous pericardium was first performed by Ozaki \emph{et al.} in
2007. This technique has become an alternative to tissue and mechanical
valve as long-term anticoagulation is not required and shows promising
midterm results and durability.

Method: A comprehensive search was performed on the major database using
search terms ``Ozaki technique'' AND ``Aortic Valve Neocuspidization''
AND ``AV Neocuspidization'' AND ``Autologous pericardium'' AND
``glutaraldehyde-treated autologous pericardium''. Articles up to
1\textsuperscript{st} of August 2020 were included in this study.

Results: A total of 9 studies with a total of 1342 patients were
included. The mean age was 67.36 and 54.23\% were male. 66.32\% and
23.92\% of patients had aortic stenosis and aortic regurgitation,
respectively. 66\% of patients had a native tricuspid aortic valve and
31.37 \% patients' native aortic valve was bicuspid. Three studies
reported their experience performing Aortic Valve Neocuspidization via
mini sternotomy.

Conclusion: Aortic Valve Neocuspidization is an alternative to
biological and mechanical prostheses for surgical aortic valve
replacement. The short and mid-term outcome are comparable without the
need for long term oral anticoagulation. Long term follow-up data is
required for this novel approach to be widely adopted.

\textbf{Introduction}

Severe Aortic stenosis affects an estimated 3.4\% of adults over 75 in
North America and Europe. (1) This number is set to increase due to the
strong association between advanced age and valvular heart disease. The
current gold standard treatment for aortic stenosis is aortic valve
replacement, either via surgical or transcatheter approach. The current
replacement valve options often present a dilemma for young adults.
Mechanical prostheses have been shown to have excellent function and
durability. However, but due to their non-organic materials, lifelong
anticoagulation often in the form of warfarin is required. (2) This can
no doubt increases the risk of haemorrhage, adverse effects, and drug
interaction. The current alternative to is the biological tissue valve,
usually produced from bovine or porcine tissue, minimising the need for
warfarin. However, in younger patients, this presents a significant risk
due to degeneration requiring a re-do open-heart surgery and/or
valve-in-valve transcatheter aortic valve replacement in a later stage.

AV Neocuspidization (AV Neo) using glutaraldehyde-treated autologous
pericardium may be the solution to this dilemma. The technique was
originally trialled in the 1960s but fell out of favour due to the lack
of standardised procedure and reproducible results. This was
revolutionised by Ozaki \emph{et al.} using standardised modelling to
size the cusps and allowed reproducibly in other centres. (3) This
relatively new technique involves harvesting of patient's own
pericardium that is subsequently treated with Glutaraldehyde. The tissue
is then shaped to form cusps measured precisely using sizing and
templating tools. (3) These new cusps are then used for aortic valve
reconstruction. This technique has become an alternative to biological
and mechanical valve with multiple centres reporting their promising
early (and mid-term) outcomes.(4)

Method

A comprehensive search was performed on PubMed, Ovid, SCOPUS, EMBASE,
Cochrane library and Google Scholar. The search terms included ``Ozaki
technique'' AND ``Aortic Valve

Neocuspidization'' AND ``AV Neocuspidization'' AND ``Autologous
pericardium'' AND ``glutaraldehyde-treated autologous pericardium''.
Articles published prior to 31\textsuperscript{st} of August 2020 were
included in this study. All articles including outcomes on Ozaki
procedure were reviewed. Only full, original articles were included for
review. Case reports, expert opinion, editorials, duplicates studies,
and conference abstracts were excluded. The literature search was
performed independently by two reviewers (SO and KSF). The final review
was performed by the third reviewer (JC).

Results:

The literature search yielded 9 eligible studies with a total 1342
patients. The mean age was 67.36 and 54.23\% were male. 66.32\%,
23.92\%,3.58\% and 6.18\% of patients had aortic stenosis, aortic
regurgitation, infective endocarditis and mixed aortic stenosis and
regurgitation, respectively. 66.0\% of patients had a native tricuspid
aortic valve and 31.37 \% patients' native aortic valve was bicuspid.
Demographics for all patients enrolled in the 9 studies are shown in
Table 1.

Intra-operative outcome

Total procedure time was reported by 3 papers with an average of 217.43
minutes (3 hours and 37 minutes) All studies reported their mean
cardiopulmonary bypass (143.75 mins) and aortic cross-clamp time (104.54
mins) with isolated AV Neo. 53.41\% of the study population received an
isolated AV Neo. Overall, 98.14\% of patients underwent AV Neo via a
median sternotomy. Three studies with a total of 25 patients had their
operation via mini-sternotomy. The intra-operative outcomes are included
in Table 2.

Post-operative outcome

All studies included their outcomes on the following: a) Moderate and
severe aortic valve regurgitation, b) Mortality, c) Postoperative
infective endocarditis and d) Reintervention rate. Additionally, 5
studies included their incidence on patients developed stroke
post-operatively. The results of the above categories are included in
table 3. The mean mortality rate reported was 2.68\%. 1.64\% of patients
had infective endocarditis postoperatively and 5.15\% of patients had
moderate or greater aortic regurgitation on their first follow up
echocardiogram. Overall, 2.16\% of patients required reintervention with
either a biological or mechanical prosthesis.

Discussion

The average age of population is on the rise, and so is the incidence of
valvular disease. (3) Aortic stenosis (AS) is the commonest disease of
the aortic valve, commonly due to age-related calcifying degeneration.
(5) Current European guideline indicates surgical aortic valve
replacement (SAVR) in severe AS in patients with low surgical risk
(EuroScore I \textless{}10\%), young (Age \textless{}75), in need of
concomitant procedures and for aortic regurgitation (AR). (6) Mechanical
valves are preferred in patients less than 50 years old because of a
longer durability, and biological valves are utilised with the main
advantages of its low thrombogenicity and lack of obligatory long-term
anticoagulation. (7) The increasingly popular transcatheter aortic valve
replacement (TAVR) has been promising for high risk for open-heart
surgery but may not be suitable for the extreme size of aortic annuli
and long-term data are currently lacking. (6) All aortic valve
bioprostheses are prone to structural degeneration secondary to
calcification and stiffening.

Alternative to tissue and mechanical valve

Aortic Valve Neocuspidization (AV Neo) using glutaraldehyde-treated
autologous pericardium with the aim to reconstruct the aortic valve
using patients' own tissue. AV Neo provided an alternative to the
biological and mechanical valve. First performed and reported by
Professor Ozaki and his team in 2007, reconstructing the aortic valve
using autologous pericardium. AV Neo allows surgeons to preserve natural
aortic root expansion in systole with maximal orifice area, and to
replace the valve as one complete structure. (3) Due to the lack of
foreign materials, no long-term oral anticoagulation is required.
Avoiding long term anticoagulation have no doubt being advantageous in
both the short and long run. Moreover, avoiding the use of warfarin can
be particularly useful in young women who wished to be pregnant in the
future due to its teratogenicity nature. Maternal warfarin
administration could lead to foetal warfarin syndrome causing multiple
facial, physical, and intellectual disabilities. This was also noted
despite a reduced regime was trailed.

Clinical outcome of AV Neo

Ongoing, full follow-up by Ozaki \emph{et al.} including 850 patients
showed positive short- and medium-term outcomes up to 11 years after
initial AV Neo. (3) Mourad \emph{et al.} showed good reproducibility of
AV Neo procedure with an initial cohort of 52 patients in Germany. (8)
They reported several positive findings including safety, reliability,
low re-intervention rate, low permanent pacemaker rate and low incidence
of valve thrombosis. Additionally, most patients were discharged with no
or trace AR or AS and low aortic valve gradients in follow up
echocardiogram. (8) Similar results were reported by several other
centres suggesting this procedure are reproducible across different
centres and surgical teams. (9-11)

Krane \emph{et al.} demonstrated the effectiveness of this technique in
a younger population and compared the haemodynamic performance with
virtually implanted Trifecta Bioprostheses. They reported a
significantly lower mean pressure gradient as well as a higher mean
effective orifice area in AV Neo. It was also stable at one-year follow
up with a 96.1\% freedom from reoperation. (12)

An alternative to autologous pericardium such as bovine pericardium was
trialled by Sheng \emph{et al.} (13) The authors reported a comparable
early and mid-term outcomes to autologous tissue. This eliminates the
drawback of poor quality of patients' own autologous pericardium as well
as shorten the procedure time as by eliminating the process of handling
and preparing the autologous pericardium with glutaraldehyde solution.
The bovine pericardium was also treated with hydroxychromium which was
shown to further increase its durability in animal models. (13)

Surgical approach

Several systematic reviews had also reported minimally invasive SAVR
(either via right anterior mini-thoracotomy or upper J Ministernotomy)
reduced intra-operative blood loss, a small increase in post-operative
pulmonary function and a small reduction on intensive care unit stay
with comparable Intra- and postoperative outcomes compared with
conventional SAVR via median sternotomy. (8, 14) Minimally invasive
technique could potentially be translated and adapted to AV Neo.
Nguyen\emph{et al.} have reported their experience in performing the AV
Neo via mini sternotomy with thoracoscopic harvesting of the
pericardium. (15) They concluded that the AV Neo via minimally invasive
technique is feasible with low mortality and morbidity, potentially
beneficial in younger populations. (15)

The da Vinci Robotic Surgical System has been used in cardiac surgery
since its approval from the Food and Drug Administration in 2000. (16)
Robotic mitral valve surgery for mitral regurgitation (MR) has been
explored. While its efficacy is still being explored, early and midterm
outcomes are promising. Incidence of recurrence of MR and reoperation
rate remains low. (15) Robotic AV Neo could be a prospect. However, the
drawbacks of robotic surgery such as high cost, the size of equipment,
and extensive training required must not be forgotten.

Limitations

Due to the novel nature of the AV Neo, limited studies are available to
fully evaluate the early, mid and long-term outcomes. Long term outcome
and durability remains unknown. This remains an important issue as the
operation mainly aims to avoid long term anticoagulation for the young
population group. One of the major advantages for AV Neo, avoiding long
term anticoagulation seems to be diminished when compared to biological
SAVR or TAVR in the elderly population group. Furthermore, due to its
novelty, there is no doubt a significant learning curve, suggesting an
initial longer cardiopulmonary bypass (CPB) and cross-clamp (CC) time.
Similar results are shown in minimally invasive aortic valve surgery
using a tissue or mechanical valve, suggesting that average 40-50 cases
are required to achieve a stable CBP and CC time.(17, 18)

To harvest the pericardium for the procedure, most surgeons would
perform the procedure via a sternotomy, hence limiting its popularity.
Lately, an upper mini-sternotomy incision with harvesting the
pericardium via thoracoscopic technique has been reported but again, a
significant learning curve may arise. Moreover, an extra 20 minutes of
CPB is normally required for harvesting the pericardium via
thoracoscopic technique in order to decompress the heart. (15) A
practical difficulty may also arise that the glutaraldehyde substance
required to prepared autologous pericardium may not be readily available
due to local restrictions. (19)

The procedure is currently performed only by selected surgeons, limiting
the availability of data to ascertain its effectiveness. To date, there
is no study directly compare the outcomes between conventional aortic
valve replacement with biological or mechanical valve with AV Neo. The
availability of data on the specific groups of patients (E.g. high-risk
patients) are also limited, restricting its use widely.

Conclusion

AV Neo offers an effective alternative to conventionally established
tissue and mechanical prostheses. Mid-term outcomes of the procedure
have been positive, demonstrating a large haemodynamic improvement in
valve function with low rates of adverse events. However, long-term, and
large-scale studies are still in progress and the lack of randomised
controlled trials may limit its use in a bigger scale.

1. Osnabrugge RL, Mylotte D, Head SJ, Van Mieghem NM, Nkomo VT, LeReun
CM, et al. Aortic stenosis in the elderly: disease prevalence and number
of candidates for transcatheter aortic valve replacement: a
meta-analysis and modeling study. J Am Coll Cardiol.
2013;62(11):1002-12.

2. Thoren O. Blood flow patterns of the forearm of critically ill
post-traumatic patients. A plethysmographic study. Acta Chir Scand
Suppl. 1974;443:1-59.

3. Ozaki S, Kawase I, Yamashita H, Uchida S, Nozawa Y, Takatoh M, et al.
A total of 404 cases of aortic valve reconstruction with
glutaraldehyde-treated autologous pericardium. J Thorac Cardiovasc Surg.
2014;147(1):301-6.

4. Ozaki S, Kawase I, Yamashita H, Uchida S, Takatoh M, Kiyohara N.
Midterm outcomes after aortic valve neocuspidization with
glutaraldehyde-treated autologous pericardium. J Thorac Cardiovasc Surg.
2018;155(6):2379-87.

5. Marathe SP, Chavez M, Sleeper LA, Marx G, Del Nido PJ, Baird CW.
Modified Ozaki Procedure Including Annular Enlargement for Small Aortic
Annuli in Young Patients. Ann Thorac Surg. 2020;110(4):1364-71.

6. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al.
2017 ESC/EACTS Guidelines for the management of valvular heart disease.
Eur Heart J. 2017;38(36):2739-91.

7. Dvir D, Bourguignon T, Otto CM, Hahn RT, Rosenhek R, Webb JG, et al.
Standardized Definition of Structural Valve Degeneration for Surgical
and Transcatheter Bioprosthetic Aortic Valves. Circulation.
2018;137(4):388-99.

8. Mourad F, Shehada SE, Lubarski J, Serrano M, Demircioglu E, Wendt D,
et al. Aortic valve construction using pericardial tissue: short-term
single-centre outcomes. Interact Cardiovasc Thorac Surg.
2019;28(2):183-90.

9. Reuthebuch O, Koechlin L, Schurr U, Grapow M, Fassl J, Eckstein FS.
Aortic valve replacement using autologous pericardium: single centre
experience with the Ozaki technique. Swiss Med Wkly. 2018;148:w14591.

10. Iida Y, Fujii S, Akiyama S, Sawa S. Early and mid-term results of
isolated aortic valve neocuspidization in patients with aortic stenosis.
Gen Thorac Cardiovasc Surg. 2018;66(11):648-52.

11. Arutyunyan V, Chernov I, Komarov R, Sinelnikov Y, Kadyraliev B,
Enginoev S, et al. Immediate Outcomes of Aortic Valve Neocuspidization
with Glutaraldehyde-treated Autologous Pericardium: a Multicenter Study.
Braz J Cardiovasc Surg. 2020;35(3):241-8.

12. Krane M, Boehm J, Prinzing A, Ziegelmueller J, Holfeld J, Lange R.
Excellent Hemodynamic Performance After Aortic Valve Neocuspidization
Using Autologous Pericardium. Ann Thorac Surg. 2020.

13. Sheng W, Zhao G, Chao Y, Sun F, Jiao Z, Liu P, et al. Aortic Valve
Replacement with Bovine Pericardium in Patients with Aortic Valve
Regurgitation. Int Heart J. 2019;60(6):1344-9.

14. Kirmani BH, Jones SG, Malaisrie SC, Chung DA, Williams RJ. Limited
versus full sternotomy for aortic valve replacement. Cochrane Database
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15. Nguyen DH, Vo AT, Le KM, Vu TT, Nguyen TT, Vu TT, et al. Minimally
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16. Intuitive. da vinci surgery: Intuitive; 2020 {[}Available from:
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17. Masuda T, Nakamura Y, Ito Y, Kuroda M, Nishijima S, Okuzono Y, et
al. The learning curve of minimally invasive aortic valve replacement
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2020;68(6):565-70.

18. Murzi M, Cerillo AG, Gilmanov D, Concistre G, Farneti P, Glauber M,
et al. Exploring the learning curve for minimally invasive sutureless
aortic valve replacement. J Thorac Cardiovasc Surg. 2016;152(6):1537-46
e1.

19. Koechlin L, Schurr U, Miazza J, Imhof S, Maurer M, Erb J, et al.
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2020;44(9):3175-81.

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