\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Surgical reconstruction of the right ventricular outflow tract -- The
clock is still ticking}



\author[1]{Filippo  Rapetto}%
\author[1]{Massimo Caputo}%
\author[2]{Gianni Angelini}%
\affil[1]{University of Bristol}%
\affil[2]{Bristol University}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Editorial commentary}

\textbf{Surgical reconstruction of the right ventricular outflow tract
-- The clock is still ticking}

Filippo Rapetto MD, Massimo Caputo MD, Gianni D Angelini MD*

Bristol Heart Institute, University of Bristol, United Kingdom

\textbf{Conflict of interest statement}

The authors have no conflict of interest to declare

\textbf{*Corresponding Author}

Gianni D Angelini

Bristol Heart Institute

Bristol Royal Infirmary

Bristol BS2 8HW

United Kingdom

Tel +441173423165

Email address: g.d.angelini@bristol.ac.uk

The optimal device for heart valve replacement is yet to be developed.
If this is certainly true for adult patients with acquired pathologies,
the need for better materials is even more pressing in the setting of
congenital heart disease, where any valve replacement activates
a\emph{ticking clock} towards the next procedure.

In this issue of the \emph{Journal of Cardiac Surgery} , Selcuk and
coworkers report their single center experience with the BioIntegral
Biopulmonic Conduit?, implanted as a right ventricle-to-pulmonary artery
(RV-PA) conduit in 48 pediatric patients over a period of 13
months\textsuperscript{1}. This is a stentless porcine heart valve
covered with a 10 cm-long porcine pericardial sleeve, and it is
available in relatively small sizes (starting from 15 mm). The conduit
is initially treated with formaldehyde and glutaraldehyde and then
detoxified with the No-React\selectlanguage{ngerman}® treatment, with the aim of reducing the
risk of endocarditis and structural degeneration \textsuperscript{2}.

The No-React® is just one of several different treatments that
bioproshtesis producers have developed over the last few decades; all of
them released with promises of improved durability, freedom from
structural deterioration and infection. Despite unquestionable
innovations in engineering and treatment of the available biomaterials,
with the current technology, surgical reconstruction of the right
ventricular outflow tract (RVOT) in the pediatric population still
exposes patients to a cumulative risk of multiple interventions,
morbidity and potentially mortality \textsuperscript{3}.

The study by Selcuck and colleagues is the first to focus on the use of
the BioIntegral Biopulmonic Conduit\selectlanguage{english}? on pediatric patients. The Authors'
main finding is a high incidence of fever in the early postoperative
period (\textgreater{}30\%), not previously described in the literature.
The pathophysiology of the fever in these patients was not clarified. No
clinical or echocardiographic evidence of prosthetic endocarditis was
found in those who experienced fever; however, the Authors point out
that this triggered potentially inappropriate antibiotic use and caused
prolonged hospital stay. Furthermore, there seems to be a correlation
between fever and early conduit stenosis.

To put these findings into the correct perspective, a few aspects must
be mentioned. This is a retrospective, single center study with no
control group and a relatively small number of patients; the indirect
evidence that no patient had fever after switching to bovine jugular
vein conduit does not come from a statistical analysis and it must be
considered at best as speculative. Comparison with the current
literature is not straightforward, as the only published paper focusing
on the use of this particular conduit on congenital patients is the
study from Marianeschi and colleagues from 2001 \textsuperscript{4}; all
previous papers investigating BioIntegral devices mainly concentrated on
mid-term rather than short-term results \textsuperscript{5--9}. Finally,
the median follow-up of 14.5 months is short and a trend towards higher
gradients in patients who experienced fever is the only follow-up
information provided by the Authors.

However, other aspects must also be considered, and the Authors'
concerns regarding the Biopulmonic Conduit\selectlanguage{english}? performance should not come
as a surprise. Even though the literature is highly heterogeneous in
terms of patient population, device used, and study protocols, a few
common key points can be identified. This is not the first study raising
questions about early deterioration and early infection of devices
treated with the No-React(r) protocol. Multiple papers focusing on the
aortic BioIntegral Bioconduit\selectlanguage{english}? in the adult population or on similar
devices implanted in the pulmonary position with a long enough
follow-up, reported significant rates of adverse valve-related
events\textsuperscript{5--9}. Moreover, bioprostheses typically
degenerate earlier in pediatric patients compared to adult patients, and
a similar trend can be expected even in devices undergoing the No-React(r)
treatment. This is even more relevant if we consider that in the present
study, all conduits were implanted in extra-anatomic position (i.e. in a
non-Ross setting), which is a recognized risk factor for early
structural deterioration \textsuperscript{10,11}. Finally, even if fever
does not always correlate with infection, it always correlates with
inflammation, which has been strongly linked to structural deterioration
of bioprostheses \textsuperscript{12}.

Where do we go from here? Better quality research (both pre-clinical and
clinical) in congenital cardiac surgery is needed: a significant
proportion of our clinical practice still derives from single center
experiences and suboptimal observational studies. Outcomes for the
available biological conduits for RVOT reconstruction are rather
unsatisfactory \textsuperscript{13--15}. This, combined with the limited
availability of small size homografts, is the main reason that pushes
our interest towards new devices when they become available. However,
valve replacement in the pediatric age is the ultimate task for any
biomaterial: size, anatomy and metabolism all plot together against
durability. If there are concerns regarding the performance of a
biomaterial in the adult population, it is very likely that results in
children will be worse.

One may argue that continuing with the current approaches will only
provide small improvements. The future is more likely to come from
development on the use of biomaterials which act as scaffolds, and which
we can re-populated with the patient's own cells. Theoretically, this
would be expected to improve durability, but also be the biological
substrate for growth, and ultimately reduce morbidity, reoperations and
mortality. Tissue engineering technologies and regenerative medicine
have expanded considerably over the last decade, and it may not be long
before the translation of this knowledge into clinical practice.

Regretfully till then, after every pediatric RVOT operation, the clock
will start ticking.

\textbf{References}

1. Selcuck A, Kilic Y, Korun O, et al. High incidence of fever in
patients after biointegral pulmonic valved conduit implantation. \emph{J
Card Surg.} DETAILS TO BE CONFIRMED

2. Abolhoda A, Yu S, Oyarzun JR, McCormick JR, Bogden JD, Gabbay S.
Calcification of bovine pericardium: Glutaraldehyde versus No-React
biomodification. \emph{Ann Thorac Surg} . 1996;62(1):169-174.
doi:10.1016/0003-4975(96)00277-9

3. Raissadati A, Nieminen H, Haukka J, Sairanen H, Jokinen E. Late
Causes of Death After Pediatric Cardiac Surgery. \emph{J Am Coll
Cardiol} . 2016;68(5):487-498. doi:10.1016/j.jacc.2016.05.038

4. Marianeschi SM, Iacona GM, Seddio F, et al. Shelhigh No-React porcine
pulmonic valve conduit: A new alternative to the homograft. \emph{Ann
Thorac Surg} . 2001;71(2):619-623. doi:10.1016/S0003-4975(00)02456-5

5. Grohmann J, Hohn R, Fleck T, et al. No-React(r) Injectable
BioPulmonic\textsuperscript{TM} valves re-evaluated: Discouraging
follow-up results. \emph{Interact Cardiovasc Thorac Surg} .
2015;21(5):657-665. doi:10.1093/icvts/ivv214

6. Ishizaka T, Ohye RG, Goldberg CS, et al. Premature failure of
small-sized Shelhigh No-React porcine pulmonic valve conduit model
NR-4000. \emph{Eur J Cardio-thoracic Surg} . 2003;23(5):715-718.
doi:10.1016/S1010-7940(03)00080-0

7. Sahin A, Muggler O, Sromicki J, et al. Long-term follow-up after
aortic root replacement with the Shelhigh(r) biological valved conduit: A
word of caution! \emph{Eur J Cardio-thoracic Surg} .
2016;50(6):1172-1178. doi:10.1093/ejcts/ezw167

8. Reineke DC, Kaya A, Heinisch PP, et al. Long-term follow-up after
implantation of the Shelhigh(r) No-React(r) complete biological aortic
valved conduit. \emph{Eur J Cardio-thoracic Surg} . 2016;50(1):98-104.
doi:10.1093/ejcts/ezv452

9. Kaya A, Heijmen RH, Kelder JC, Schepens MA, Morshuis WJ. Stentless
biological valved conduit for aortic root replacement: Initial
experience with the Shelhigh BioConduit model NR-2000C. \emph{J Thorac
Cardiovasc Surg} . 2011;141(5):1157-1162.
doi:10.1016/j.jtcvs.2010.07.009

10. Tweddell JS, Pelech AN, Frommelt PC, et al. Factors affecting longer
of homograft valves used in right ventricular outflow tract
reconstruction for congenital heart disease. \emph{Circulation} .
2000;102(19). doi:10.1161/01.cir.102.suppl\_3.iii-130

11. Niwaya K, Knott-Craig CJ, Lane MM, et al. Cryopreserved homograft
valves in the pulmonary position: Risk analysis for intermediate-term
failure. \emph{J Thorac Cardiovasc Surg} . 1999;117(1):141-147.
doi:10.1016/S0022-5223(99)70479-4

12. Kostyunin AE, Yuzhalin AE, Rezvova MA, Ovcharenko EA, Glushkova T
V., Kutikhin AG. Degeneration of Bioprosthetic Heart Valves: Update
2020. \emph{J Am Heart Assoc} . 2020;9(19):e018506.
doi:10.1161/JAHA.120.018506

13. Mery CM, Guzman-Pruneda FA, De Leon LE, et al. Risk factors for
development of endocarditis and reintervention in patients undergoing
right ventricle to pulmonary artery valved conduit placement Read at the
95th Annual Meeting of the American Association for Thoracic Surgery,
Seattle, Washington, April 25-29, 2015. In: \emph{Journal of Thoracic
and Cardiovascular Surgery} . Vol 151. Mosby Inc.; 2016:432-441.e2.
doi:10.1016/j.jtcvs.2015.10.069

14. Beckerman Z, De Leon LE, Zea-Vera R, Mery CM, Fraser CD. High
incidence of late infective endocarditis in bovine jugular vein valved
conduits. \emph{J Thorac Cardiovasc Surg} . 2018;156(2):728-734.e2.
doi:10.1016/j.jtcvs.2018.03.156

15. Groning M, Tahri NB, Sondergaard L, Helvind M, Ersboll MK, Orbaek
Andersen H. Infective endocarditis in right ventricular outflow tract
conduits: A register-based comparison of homografts, Contegra grafts and
Melody transcatheter valves. \emph{Eur J Cardio-thoracic Surg} .
2019;56(1):87-93. doi:10.1093/ejcts/ezy478

\textbf{Acknowledgement:} \emph{This study was supported by the British
Heart Foundation and the NIHR Biomedical Research Centre at University
Hospitals Bristol and Weston NHS Foundation Trust and the University of
Bristol.}

\selectlanguage{english}
\FloatBarrier
\end{document}

