\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[T2A]{fontenc}
\usepackage[ngerman,polish,english]{babel}
\usepackage{CJKutf8}



\usepackage{float}








\begin{document}

\title{Mitral valve disease: A view on pathophysiology and management of the
most common valve disease in the world}



\author[1]{Bianca  Botezatu }%
\author[1]{Sahil Kakar}%
\author[1]{MoLiu  Ren}%
\author[1]{Manasi Shirke}%
\author[2]{Kellan Masharani }%
\author[2]{Kiran Pillai }%
\author[3]{Amer Harky}%
\affil[1]{Queen's University Belfast Faculty of Medicine Health and Life Sciences}%
\affil[2]{University of Liverpool}%
\affil[3]{Liverpool Heart and Chest Hospital NHS Foundation Trust}%


\vspace{-1em}



  
  \date{May 22, 2024}


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





\selectlanguage{english}
\begin{abstract}
Objectives: Mitral valve disease is increasingly prevalent. Timely
diagnosis and the choice of the right intervention are very important in
the early stages, as valvular dysfunction often leads to cardiac failure
and even sudden death. The focus of this paper is on the various
pathologies of the mitral valve, their etiology, and clinical
management. Methods: Mitral regurgitation (MR) can be managed
surgically, percutaneously or medically. Treatment methods for primary
MR include percutaneous mitral valve (MV) repair, MV replacement,
minimally invasive mitral valve surgery (MIMVS), and more recently,
robotics. Additionally, conventional sternotomy has been used for both
MR and mitral stenosis. Nonetheless, ongoing clinical trials are a clear
indicator that the management of valve diseases is continuously
evolving. Results: Multiple studies favour MV repair via MIMVS, over
conventional sternotomy or percutaneous approach. However, more data is
needed to optimize patient selection. Robot assisted repair is a new
alternative, but attention should be given to the steep learning curve
and medical training of professionals wishing to perform this
intervention. Cost effectiveness and possible side effects should be
explored by clinical trials as well. While guidelines are fairly
straightforward for primary MR, there is insufficient evidence to
suggest that surgical treatment is advantageous for secondary MR.
Management is usually pharmaceutical and aims to treat symptoms rather
than cause. Conclusion: Mitral valve disease remains a medical
challenge, but numerous research and clinical trials have been embarked
upon to refine old methods and discover new ones to improve treatment
success and procedural safety.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Mitral valve disease affected approximately 5.8 million adults in the
United States in 2016, with 5.49 million suffering from mitral
regurgitation and 323 127 suffering from mitral stenosis. Mitral valve
disease is prevalent across all age groups; however, it increases with
age and affects 5.1\% of elderly aged 65 and
above.\textsuperscript{1-3}The mitral valve has the most complex anatomy
out of the four valves of the heart. It is also the valve most
frequently causing disease. The three most common diseases of the mitral
valve include mitral stenosis, mitral regurgitation, and mitral valve
collapse.\textsuperscript{4} Out of these, mitral regurgitation (MR) is
by far the most frequently diagnosed and accounts for approximately
9.3\% of over 75-year old, whereas mitral stenosis accounts for around
0.2\%.\textsuperscript{5}

Mitral regurgitation consists of two types: primary and secondary.
Primary MR is a pathology of the mitral valve apparatus whereas
secondary MR is a pathology of the left atrium or ventricle that
ultimately affects the function of the mitral valve. Secondary MR can be
further classified into ischemic or non-ischemic, depending on the
cause, which will require different treatment plans.\textsuperscript{6}
Common causes of MR include annular calcification in the elderly,
rheumatic fever, infective endocarditis, and left ventricular dilatation
in functional mitral regurgitation. On the other hand, typical causes of
mitral stenosis include rheumatic fever and congenital
causes.\textsuperscript{7} In order to treat mitral valve diseases, a
surgical attempt is the golden standard and aims to either restore
function or to replace the valve. Where surgery is contraindicated, the
transcatheter approach has proved to be a reliable option, especially
for secondary mitral regurgitation.\textsuperscript{8,9}

\textbf{Understanding~Mitral Valve Disease}

\emph{Mitral Annulus Anatomy}

Understanding mitral valve anatomy provides the foundation to appreciate
its intrinsic valvular abnormalities. Continuing advancements in cardiac
imaging allow for visualization over three
dimensions.\textsuperscript{10}

The mitral annulus is a junctional region between the left ventricle and
the left atrium. It is saddle-shaped and will experience dynamic changes
throughout the cardiac cycle (see Figure 1 for mitral valve
anatomy).\textsuperscript{11,12}

Annular diameter correlates with function and has shown to be impaired
secondary to valve pathologies such as myxomatous disease and
cardiomyopathies. With respect to myxomatous disease, the mitral annulus
will dilate in all planes. The increase in diameter will inhibit
regurgitation prevention mechanisms. In comparison, there is an isolated
anterior-posterior enlargement with ischemic cardiomyopathy. Annular
remodeling will vary depending on the pathophysiology of the underlying
disease process.\textsuperscript{13}

Physiological degrees of mitral annular incoherence have been isolated
in ``normal'' patients and whether this represents early signs of
dysfunction or a mere physiological variant is yet to be determined.
However, it is important to appreciate that, histologically, the annulus
is a non -- continuous structure and its thickness will vary depending
on the density of collagen.\textsuperscript{14}

\emph{Mitral Stenosis}

The physiological mitral orifice extent is between
4cm\textsuperscript{2} to 6cm\textsuperscript{2}, the valve will open
throughout the ventricular diastole to facilitate the blood filling of
the left ventricle. Constriction less than 2cm\textsuperscript{2} can
cause an impediment of blood flow to the ventricle thereby resulting in
increased pressure exerted on the walls of the left
atrium.\textsuperscript{15} The main etiology of this constriction is
rheumatic fever, where a group A beta-hemolytic streptococcus infects
the patient in early life. The initial pharyngeal infection promotes the
innate immune system to activate T and B cells. CD4+ T cells will
promote the production of complementary IgG and IgM antibodies. However,
the structural resemblance between the infectious material and human
proteins results in tissue damage. From a cardiovascular perspective,
antibody binding and dissemination of T cells will cause
carditis.\textsuperscript{16}

Genetic susceptibility to the development of acute rheumatic fever was
initially considered in 1986. A 2011 systematic review seemed to confirm
this hypothesis, suggesting heritability of 60\%. Some studies have
reported associations to class 2 HLA whilst other studies have discussed
an association to non-HLA proteins, but a definite link is yet to be
confirmed.\textsuperscript{17-19}

Clinically, mitral stenosis will cause massive rises in left atrial
pressure thereby resulting in reactive pulmonary hypertension. As the
pressure remains elevated the atrium will begin to dilate in an attempt
to accommodate the increasing volumes of blood. This dilation puts the
patient at risk of atrial arrhythmias. This sequence of events will
eventually result in congestive heart failure which is measurable via
the New York Heart Association (NYHA)
Classification.\textsuperscript{15}

\emph{Mitral Regurgitation}

Mitral regurgitation (MR) is a common valvular anomaly occurring in
approximately 10\% of the populace.\textsuperscript{20} The disease can
be divided into primary and secondary MR. Primary MR is the predominant
form that will occur following myxomatous degeneration -- which is the
predominant aetiology, accounting for 2.5\% of the world's population.
Throughout the developing world, rheumatic heart disease remains
widespread.\textsuperscript{6}

Retrograde flow from the left ventricle into the left atrium results in
a cyclic increase in left ventricular volume. Ultimately, ventricular
remodeling occurs in an attempt to maintain cardiac output. Over time,
as the ventricle hypertrophies, the actin-myosin cross-bridges will
stretch, eventually derailing from the point of optimal contractility,
therefore, resulting in a gradual decrease in ejection fraction. As the
ejection fraction deteriorates, the patient will experience heart
failure symptoms.\textsuperscript{21} Table 1 is a summary of the
different types of mitral disease and their classification.

\textbf{Endocarditis and its effects on mitral valve}

Before the discovery of antibiotics, infective endocarditis was
invariably fatal. Even with advancements in diagnosis and treatment, the
in-hospital mortality rate for infective endocarditis is still high at
20\% to 25\%.\textsuperscript{22} Studies have shown that early and late
mortality rates were lower and event-free survival was greater in
patients who went through mitral valve repair to treat acute
endocarditis, as compared to those who underwent mitral valve
replacement.\textsuperscript{23} There is also a lower incidence of
recurrent infections associated with mitral valve repair as compared to
mitral valve replacement.\textsuperscript{24} Therefore, patients with
mitral valve endocarditis should be offered mitral valve repair whenever
possible.\textsuperscript{23} 89\% of endocarditis patients who
underwent mitral valve surgery are free from re-surgery at 5 years. This
value decreases to 72\% at 10 years post-operation. Patients who
received mechanical valve replacements have a higher or equal rate of
freedom from re-operation at 10 years compared with those who received
biological valve replacements.\textsuperscript{25} Native mitral valve
endocarditis is relatively responsive to antibiotic treatment, therefore
is likely to be cured pharmacologically. Prosthetic mitral valve
endocarditis is, however, linked with poorer
prognosis.\textsuperscript{26}

\textbf{Approaches for Treatment of Mitral Valve Disease}

\begin{enumerate}
\tightlist
\item
  Percutaneous Mitral Valve Repair
\item
  Percutaneous Transluminal Mitral Valvuloplasty
\item
  Transcatheter Mitral Valve Replacement
\item
  Minimally Invasive Mitral Valve Surgery
\item
  Conventional Sternotomy
\end{enumerate}

\emph{Percutaneous Mitral Valve Repair}

Percutaneous mitral valve repair using the MitraClip (Abbott
Laboratories, Menlo Park, California, USA) has been approved in 2008 in
Europe and 2013 in the United States. Is one of the most common
procedures performed today for patients with primary severe mitral
regurgitation (MR) who are deemed unfit for surgery. This is usually the
case for older patients with multiple co-morbidities.\textsuperscript{7,
27-31}

The MitraClip device has 2 essential components: the clip delivery
system and a guide catheter.\textsuperscript{30} It enters the
circulation through the femoral vein and is directed towards the heart.
Transseptal puncture allows the advancement of the MitraClip to the left
atrium. Moving through the mitral valve (MV), the apparatus reaches the
left ventricle. The clip will grasp the leaflets, bringing them
together, connecting the middle segment of the anterior leaflet to the
one of the posterior leaflet. The MitraClip technology is based on
Alfieri's surgical technique, thus creating a `double orifice' MV.
Before releasing the clip, assessment of the procedure via
transesophageal echocardiogram (TEE) is required, as the MitraClip can
be reopened and repositioned. This step also allows re-evaluation of
mitral valve defect (if still present) and
re-grading.\textsuperscript{27,30-32}

After the operation, patients receive clopidogrel for 30 days and
aspirin for the next 6 to12 months.\textsuperscript{27} Procedural
success is highly dependent on patient factors. TEE along with
transthoracic echocardiography is used for patient screening and ensures
that anatomic requirements are met for a feasible MitraClip repair.
Calcification of more than 80\% of leaflet area, short leaflets, and low
baseline MV area are common disqualifiers from the procedure, while
orifice area greater than 70.8 mm\textsuperscript{2} or mitral valve
area less than 3 cm\textsuperscript{2} were indicators of clip
failure.\textsuperscript{33}

Although considered safer than surgical treatment for severe primary MR,
percutaneous repair still has its risks. Common postoperative
complications include atrial fibrillation and acute kidney injury, as
well as partial detachment of the clip. Mitral stenosis or full
displacement of the clip have occurred in less than 5\% of cases. The
EVEREST II trial, which proved the efficacy of MitraClip in 2010 and
gained its approval in the US, also highlighted that nearly 20\% of
patients needed another operation within a year.\textsuperscript{27,32}

Since 2019, the MitraClip has been approved in the USA for secondary
functional MR as well.\textsuperscript{27~} Ongoing clinical trials in
Europe (RESHAPE-HF2) and Canada~ (EVOLVE-MR) are considering the
effectiveness of promoting this treatment for functional MR, after
another two anticipated clinical trials, COAPT and MITRA-FR, had
conflicting results (mainly due to different selection
criteria).\textsuperscript{34-36} Cardioband (Edwards Lifesciences,
Irvine, California) percutaneous annuloplasty procedure is currently
used in Europe for the treatment of this condition.\textsuperscript{33}

Nevertheless, the first line of management of secondary MR remains
pharmacological therapy: angiotensin-converting enzyme inhibitors,
beta-blockers, and diuretics, providing symptom
relief.\textsuperscript{37} Tsang et al. paper on recent advances in the
management of mitral valve disease argued that doctors are more reticent
in offering interventional therapy such as mitral valve repair or
replacement, in the absence of clear guidelines (in the US, replacement
is still favored, sparing the sub-valvular apparatus, while in Europe
repair is considered first). This could adversely affect outcomes for
patients.\textsuperscript{13}~Case studies are expected to be published
in the coming years (especially from the USA) and careful documentation
of medical decisions and considerations would be advisable. Over time,
the conduction of longitudinal studies should also shed some light on
the issue.

PASCAL Transcatheter mitral valve repair system is a newer device that
is used for percutaneous repair of MR. It hopes to fill in the gap left
by the MitraClip and help patients who do not meet the anatomic criteria
for the procedure. PASCAL is still developing, although an initial
clinical trial including 23 patients has yielded favourable results. The
CLASP study was shortly commenced, which gained CE marking approval
after 98\% out of the 62 patients had an MR grade of two or under at 6
months follow-up. More randomized controlled trials are needed before
the procedure becomes widely available.\textsuperscript{13,38,39}

\emph{Percutaneous Transluminal Mitral Valvuloplasty}

Percutaneous transluminal mitral valvuloplasty (PTMV) changed the
approach of cardiothoracic surgeons to mitral stenosis. The technique
was developed by Inoue in 1984 but has since been refined. Anatomically,
PTMV is of greatest use in patients with the pliability of the mitral
valve, clear of substantial calcification or
fibrosis.\textsuperscript{40,41.} Suitability of this technique for
mitral stenosis can be determined through the application of Abascal's
echocardiographic scoring system. Also known as the Wilkins score, it is
essential in its application as it can predict mitral regurgitation
following an intervention. The criteria evaluate four key aspects to
valvular morphology outlined in Table 2. With respect to the Wilkins
criteria, a higher score specifies a more progressed disease and a
reduced chance of success with this technique. Surgical mitral valve
replacement is recommended for patients in those in which PTMV is not
anatomically optimal.\textsuperscript{42} The surgical basis is via
balloon valvuloplasty, this balloon is applied crossing the mitral valve
thereby improving leaflet excursion and orifice diameter. The operation
is critical in the treatment of rheumatic heart disease as it fractures
the rheumatic fusion that has developed. It is also a reliable therapy
management option for pregnant women.\textsuperscript{43}

The 1984 paper by Inoue and colleagues was revolutionary as the
technique developed allowed mitral commissurotomy without thoracotomy.
Post-operative complications following thoracotomy, in patients who are
already cardiopulmonary compromised, create a very vulnerable situation
for the patient. The initial study consisted of six patients, five of
which were successfully managed with this new technique. The procedure
was unable to be performed in the remaining patient due to technical
difficulties. Interestingly, the Wilkins score was only implemented in
1990, 6 years following this study.\textsuperscript{44}

The balloon is introduced through the saphenous vein and will ascend
into the mitral orifice. Across the mitral orifice, the balloon is
partially inflated, when fully expanded the balloon will separate the
fused commissures via expansile propulsion. Surgically, the balloon is
buoyed via a nylon micromesh and changes shape in three stages,
depending on the degree of inflation. The micromesh is essential for the
shape adaptation that the balloon
experiences.\textsuperscript{44}Despite medical advances, the basic
premise of this technique has remained the same. As of 2016 Adhikari and
colleagues described a similar approach.\textsuperscript{45} In selected
patients, PTMV is now the treatment of choice and is associated with
less than a 1\% mortality. With any operation, the risk of embolism is
always appreciable. However, pre-operative application of
transesophageal echocardiography aids in the identification of left
atrial thrombi and therefore has limited risk of embolic stroke to 1.1\%
- 5.4\%.\textsuperscript{46}

Furthermore, a review conducted by Satya and colleagues highlighted how
PTMV resulted in an estimated doubling of the mitral valve area coupled
with a 50\% decrease in the transmitral gradient. Long term follow-up
highlighted continued functional enhancement with survival rates
\textgreater{}80\% at 10 years post-operation.\textsuperscript{47}

A randomized controlled trial completed by Reyes and colleagues compared
open mitral commissurotomy to PTMV. The study focused upon sixty
patients with severe mitral stenosis, none of which were lost to follow
up. Even though long-term results were similar and both techniques
maintained a desired mitral valve area three years post-intervention,
more desirable results were achieved through PTMV (2.4 \selectlanguage{ngerman}±0.6
cm\textsuperscript{2}, vs. 1.8 ±0.4 cm\textsuperscript{2}). Restenosis
rates were similar in both groups and less than 40\% had cardiovascular
symptoms three years post-operation. The trial emphasized the potential
complications with PTMV, but also noted superior hemodynamic results and
faster recovery due to the eradication of the need for a thoracotomy.
This led to a suggestion that those who are anatomically favorable
should undergo PTMV rather than open commissurotomy.\textsuperscript{48}

\emph{Transcatheter Mitral Valve Replacement}

Multiple studies acknowledge that surgical repair of the MV is the
preferred method of management in both primary and secondary MR,
however, not all patients qualify for it.\textsuperscript{7,13,27,31.}

Transcatheter mitral valve replacement (TMVR) is a relatively new
therapy, a little over 500 patients receiving it to date worldwide. It
is not as advanced as transcatheter aortic valve replacement due to the
complexity of the MV and its anatomical structure: asymmetric annulus,
intricate subvalvular apparatus, and located in close proximity to the
left ventricle, subsequently being affected by changes in the left
ventricular function.\textsuperscript{49}

Similar to transcatheter MV repair, TMVR is accomplished using TEE
guidance. In early studies, a left mini-thoracotomy was required to gain
access to the left ventricle. Once inside, the device is directed up to
the left atrium and aligned over the mitral annulus. A specific target
area is identified and the new valve will be deployed, while the
delivery system will be retracted.\textsuperscript{50} Most of TMVR
procedures still use this technique, as only 4 reported devices were
technically successful using a transfemoral-transseptal approach, the
first-in-human trial using the Sapien M3 valve publishing its results in
2019. Ten patients received the procedure and success was recorded in
nine of them (one patient reported recurrent MR due to paravalvular
leak).\textsuperscript{51,52}

The valves can be mechanical or bioprosthetic and around 70\% of
patients who undergo mitral valve replacement will receive a
bioprosthetic valve. Conversely, mechanical valves are believed to be
more resilient as multiple studies report a much lower mortality rate,
despite the need for anticoagulation
therapy.\textsuperscript{31,53,54}The same studies, however, highlighted
the worryingly high rates of complications and postoperative mortality.
Systematic reviews place the mortality rate anywhere between 10 to 60\%
after one year, while the risk of developing heart failure can be as
high as 31\%.\textsuperscript{49,51,53,55} ~Tendyne prosthesis (Abbott
Structural, Santa Clara the US) is the first TMVR device to gain CE
approval in January 2020, but the evolution of TMVR systems is far from
rapid, due to the strict selection criteria of ongoing clinical trials,
which affect results by diminishing the external validity of the studies
and their transferability to real-life clinical scenarios
.\textsuperscript{49,51}

\emph{Minimally Invasive Surgery}

Surgical mitral valve repair is the gold standard for treating primary
MR and around 95\% of patients being treated in designated centres while
the remaining 5\% who are not suited for surgery, will be considered for
one of the aforementioned transcatheter interventions. Its effectiveness
on secondary MR is still disputed and current European guidelines
encourage pharmacological management.\textsuperscript{56}

Traditionally, surgical repair/replacement of the mitral valve was done
via median sternotomy. In order to minimise mortality and morbidity,
various minimally invasive approaches have been developed, but
undoubtedly the most common approach is right
minithoracotomy.\textsuperscript{56-58} A small incision is made in the
4\textsuperscript{th} intercostal space, providing access to the heart.
The intervention requires access to femoral vessels for peripheral
cannulation and connection to a cardiopulmonary bypass machine (CPB).
TEE is used for guidance. Wolfe et al present in great detail the
surgical technique and the four pillars of a successful minimally
invasive mitral valve surgery (MIMVS): adequate cannulation and
perfusion, good view of the mitral valve, thorough cardiac protection
and procedure match to specific pathology and aetiology of MV
defect.\textsuperscript{58}

For correction of degenerative MR, one of the most prevalent MV
pathologies, great results have been recorded using a non-resectional
repair technique and implantation of new chordae using the loop
technique, accompanied by ring annuloplasty for better resilience in the
long-term. MV repair in the case of endocarditis is based on the removal
of infected tissue and the use of a pericardial patch or repair using
primary suturing, along with artificial chordae implant and ring
annuloplasty. Annuloplasty with a closed, undersized ring is also used
in the operation for ischemic MR.\textsuperscript{57, 59,60}

Less perioperative complications (especially blood loss), decreased
chances of surgical wound infection, as well as a shorter recovery
period, have been the main advantages of
MIMVS.\textsuperscript{57,61,62} Operative survival rate in multiple
retrospective studies has been 100\% and mortality rate at 30-day follow
up is between 0.2 to 4.8\%, depending on patient profile, higher
mortality being recorded for patients undergoing MIMVS with concomitant
tricuspid valve repair or coronary artery bypass
grafting.\textsuperscript{60,63,64} Disadvantages of MIMVS, compared to
standard sternotomy, include longer CPB time and increased risk of
stroke during or immediately after intervention (almost 2.6\% of
patients have reported ischemic strokes).\textsuperscript{59}

\emph{Conventional Sternotomy}

Median sternotomy has been the preferred approach in mitral valve
surgery for many years. It involves an incision due to complications
such as inevitable blood loss, transfusion, and a higher risk of
surgical site infections, MIMVS has gained ground as a first choice
instead.\textsuperscript{65,66} Sundermann et al. meta-analysis reports
similar rates of mortality, but a clear advantage of MIMVS over
conventional sternotomy when it comes to postoperative care and hospital
stay.\textsuperscript{66} Nonetheless, some surgeons argue that median
sternotomy allows for better exposure and possibly even fewer
complications.\textsuperscript{67}

All in all, the efficacy of conventional sternotomy is comparable to
that of MIMVS and ongoing clinical trials are still trying to provide
the medical community with a definite answer.\textsuperscript{68}

\textbf{Future directions}

This paper focused on percutaneous mitral valve repair with the
MitraClip device, which is the only percutaneous technology accepted by
the US Food and Drug Administration (FDA). However, there are other
approaches to edge-to-edge mitral valve repair under development, such
as PASCAL, valve clamp, and mitral stitch. The PASCAL mitral valve
repair system adopts a transseptal approach. It involves a 22-French
guide with a maneuverable catheter and an implanted catheter. It
achieves its best position via a central spacer created to occupy the
regurgitant orifice area, along with two paddles and two clasps that
hold separate valve leaflets.\textsuperscript{1,2} Such techniques,
which aim to resolve the challenges posed by existing techniques, are
currently being studied.\textsuperscript{3}

The various advantages of minimally invasive surgery over conventional
techniques have made minimally invasive surgery thrive in the past few
years. However, there are still many difficulties associated with it,
such as the restricted field of view, decreased maneuverability of the
instruments, increased skill requirement, and higher costs.

Robots have been used in an attempt to solve some of the aforementioned
challenges, and some success has been seen with the da Vinci SP
(Intuitive Surgical, Sunnyvale, California, USA) robotic
system.\textsuperscript{69} However, the utility of robotic systems is
still unable to prove significant improvements clinically. One study
comparing robotic approach against minimally invasive surgery, found
that robotic intervention had higher rates of transfusion (15\% compared
to 5\% rates in MIMVS), as well as higher chances of developing atrial
fibrillation post-surgery. Moreover, it is immensely expensive, which
further strains the resources of the NHS.\textsuperscript{70}

Ways to enhance the success of minimally invasive surgery and reduce its
postoperative complications need to be explored further. The paper by
Gillinov et al. analysing robotic mitral valve repair in 1000 patients
described a decrease in stroke risk (which is originally linked to long
CPB time) after the first 500 cases, from 2\% to 0.8\%. This sheds a
light on the importance of the learning curve among surgeons and how
this may pose an impediment in adopting robotic mitral valve surgery as
a conventional approach.\textsuperscript{71}

\textbf{Conclusion}

Understanding the management of mitral valve diseases is ever-evolving
with satisfactory outcomes through minimally invasive and percutaneous
approaches. Future studies, perhaps, could focus on long term results of
such approaches and patient selection methods.

\textbf{Human Studies: No ethical approval required as no patient
information was shared}

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Alliance for Aging Research. The Silver Book: Valve Disease. 2018;11.
  Available at:
  https://www.agingresearch.org/document/the-silver-book-valve-disease/
  (Accessed: 15 August 2020)
\item
  Fadi G, Jad O 'Percutaneous Mitral Valve Therapies: The Old, Current,
  and Future', American College of Cardiology. Available at:
  https://www.acc.org/latest-in-cardiology/articles/2020/07/31/08/28/percutaneous-mitral-valve-therapie.
  (Accessed: 20 August 2020)
\item
  Khan F, Winkel M, Ong G, et al. Percutaneous Mitral Edge-to-Edge
  Repair: State of the Art and a Glimpse to the Future. Front Cardiovasc
  Med. 2019;6:122. DOI:10.3389/fcvm.2019.00122
\item
  Gallegos RP, Bolman RM. Heart Valve Disease. In: Iaizzo P.A. (eds)
  Handbook of Cardiac Anatomy, Physiology, and Devices. Humana Press.
  2005. Available at: https://doi.org/10.1007/978-1-59259-835-9\_27
\item
  Brinkley DM, Gelfand EV. Valvular heart disease: Classic teaching and
  emerging paradigms. Am J Med. 2013;126(12):1035--42. Available at:
  http://dx.doi.org/10.1016/j.amjmed.2013.05.022
\item
  Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of
  mitral-valve prolapse. N Engl J Med. 1999;341(1):1-7.
  DOI:10.1056/NEJM199907013410101
\item
  El Sabbagh A, Reddy YNV, Nishimura RA. Mitral Valve Regurgitation in
  the Contemporary Era: Insights Into Diagnosis, Management, and Future
  Directions. \emph{JACC Cardiovasc Imaging} . 2018;11(4):628-643.
  DOI:10.1016/j.jcmg.2018.01.009
\item
  Wilkinson IB, Raine T, Wiles K et al. Oxford Handbook of Clinical
  Medicine, 10th edn. Oxford University Press. 2017 Doi:
  10.1093/med/9780199689903.001.0001
\item
  Nielsen SL. Current status of transcatheter mitral valve repair
  therapies - From surgical concepts towards future directions. Scand
  Cardiovasc J. 2016;50(5-6):367-376. DOI:10.1080/14017431.2016.1248482
\item
  Ben Zekry S, Lang RM, Sugeng L, et al. Mitral annulus dynamics early
  after valve repair: preliminary observations of the effect of
  resectional versus non-resectional approaches. J Am Soc Echocardiogr.
  2011;24(11):1233-1242. doi:10.1016/j.echo.2011.08.010
\item
  Veronesi F, Corsi C, Sugeng L, et al. A study of functional anatomy of
  aortic-mitral valve coupling using 3D matrix transesophageal
  echocardiography. Circ Cardiovasc Imaging.
  2009;2(1):24-31.doi:10.1161/CIRCIMAGING.108.785907
\item
  Asgar AW, Mack MJ, Stone GW. Secondary mitral regurgitation in heart
  failure: pathophysiology, prognosis, and therapeutic considerations. J
  Am Coll Cardiol. 2015;65(12):1231-1248. doi:10.1016/j.jacc.2015.02.009
\item
  Tsang W. Recent advances in understanding and managing mitral valve
  disease. F1000Res. 2019;8:F1000 Faculty Rev-1686.
  doi:10.12688/f1000research.16066.1
\item
  Rahman S, Eid N, Murarka S, Heuser RR. Remodeling of the mitral valve
  using radiofrequency energy: review of a new treatment modality for
  mitral regurgitation. Cardiovasc Revasc Med. 2010;11(4):249-259.
  doi:10.1016/j.carrev.2009.10.004
\item
  Maeder MT, Weber L, Buser M, et al. Pulmonary Hypertension in Aortic
  and Mitral Valve Disease. Front Cardiovasc Med. 2018;5:40.
  doi:10.3389/fcvm.2018.00040
\item
  Kaplan EL. Pathogenesis of acute rheumatic fever and rheumatic heart
  disease: evasive after half a century of clinical, epidemiological,
  and laboratory investigation. Heart. 2005;91(1):3-4.
  doi:10.1136/hrt.2004.034744
\item
  Bryant P, Robins-Browne R, Carapetis J, Curtis N.Some of the People,
  Some of the Time. \emph{Circulation} . 2009;119(5), pp.742-753.
\item
  Anastasiou-Nana MI, Anderson JL, Carlquist JF, Nanas JN. HLA-DR typing
  and lymphocyte subset evaluation in rheumatic heart disease: a search
  for immune response factors. Am Heart J. 1986;112(5):992-997.
  doi:10.1016/0002-8703(86)90311-x
\item
  Engel ME, Stander R, Vogel J, Adeyemo AA, Mayosi BM. Genetic
  susceptibility to acute rheumatic fever: a systematic review and
  meta-analysis of twin studies. PLoS One. 2011;6(9):e25326.
  doi:10.1371/journal.pone.0025326
\item
  Wu S, Chai A, Arimie S, et al. Incidence and treatment of severe
  primary mitral regurgitation in contemporary clinical practice.
  Cardiovasc Revasc Med. 2018;19(8):960-963.
  doi:10.1016/j.carrev.2018.07.021
\item
  Maganti K, Rigolin VH, Sarano ME, Bonow RO. Valvular heart disease:
  diagnosis and management. Mayo Clin Proc. 2010;85(5):483-500.
  doi:10.4065/mcp.2009.0706
\item
  Gammie JS, O'Brien SM, Griffith BP, Peterson ED. Surgical treatment of
  mitral valve endocarditis in North America. Ann Thorac Surg.
  2005;80(6):2199-2204. doi:10.1016/j.athoracsur.2005.05.036
\item
  Sternik L, Zehr KJ, Orszulak TA, Mullany CJ, Daly RC, Schaff HV. The
  advantage of repair of mitral valve in acute endocarditis. J Heart
  Valve Dis. 2002;11(1):91-98.
\item
  Toyoda N, Itagaki S, Egorova NN, et al. Real-world outcomes of surgery
  for native mitral valve endocarditis. J Thorac Cardiovasc Surg.
  2017;154(6):1906-1912.e9. doi:10.1016/j.jtcvs.2017.07.077
\item
  de Kerchove L, Vanoverschelde JL, Poncelet A, et al. Reconstructive
  surgery in active mitral valve endocarditis: feasibility, safety, and
  durability {[}published correction appears in Eur J Cardiothorac Surg.
  2007 Sep;32(3):557{]}. Eur J Cardiothorac Surg. 2007;31(4):592-599.
  doi:10.1016/j.ejcts.2007.01.002
\item
  Aranki SF, Adams DH, Rizzo RJ, et al. Determinants of early mortality
  and late survival in mitral valve endocarditis. Circulation. 1995;92(9
  Suppl):II143-II149. doi:10.1161/01.cir.92.9.143
\item
  Shah M, Jorde UP. Percutaneous Mitral Valve Interventions (Repair):
  Current Indications and Future Perspectives. \emph{Front Cardiovasc
  Med} . 2019;6:88. Published 2019 Jul 12. doi:10.3389/fcvm.2019.00088
\item
  Kelley C, Lazkani M, Farah J, Pershad A. Percutaneous mitral valve
  repair: A new treatment for mitral regurgitation. \emph{Indian Heart
  J} . 2016;68(3):399-404. doi:10.1016/j.ihj.2015.08.025
\item
  Pepe M, De Cillis E, Acquaviva T, et al. Percutaneous Edge-to-Edge
  Transcatheter Mitral Valve Repair: Current Indications and Future
  Perspectives. \emph{Surg Technol Int} . 2018;32:201-207.
\item
  Jilaihawi H, Hussaini A, Kar S. MitraClip: a novel percutaneous
  approach to mitral valve repair. \emph{J Zhejiang Univ Sci B} .
  2011;12(8):633-637. doi:10.1631/jzus.B1101009
\item
  Mangieri A, Laricchia A, Giannini F, et al. Emerging Technologies for
  Percutaneous Mitral Valve Repair. \emph{Front Cardiovasc Med} .
  2019;6:161. Published 2019 Nov 6. doi:10.3389/fcvm.2019.00161
\item
  Shamoun FE, Craner RC, Seggern RV, Makar G, Ramakrishna H.
  Percutaneous and minimally invasive approaches to mitral valve repair
  for severe mitral regurgitation-new devices and emerging
  outcomes.\emph{Ann Card Anaesth} . 2015;18(4):528-536.
  doi:10.4103/0971-9784.166462
\item
  Khalique OK, Hahn RT. Percutaneous Mitral Valve Repair: Multi-Modality
  Cardiac Imaging for Patient Selection and Intra-Procedural Guidance.
  Front Cardiovasc Med. 2019;6:142. Published 2019 Sep 20.
  doi:10.3389/fcvm.2019.00142
\item
  U.S National Library of Medicine-ClinicalTrials.gov (2020) A Clinical
  Evaluation of the Safety and Effectiveness of the MitraClip System in
  the Treatment of Clinically Significant Functional Mitral
  Regurgitation (Reshape-HF2), Available
  at:https://clinicaltrials.gov/ct2/show/NCT02444338?term=mitraclip\&cond=Mitral+Regurgitation\&draw=2\&rank=8\#moreinfo
  (Accessed: 6 August 2020).
\item
  U.S National Library of Medicine-ClinicalTrials.gov (2020) MitraClip
  for the Treatment of Moderate Functional Mitral Regurgitation:
  EVOLVE-MR (EVOLVE-MR)\emph{,} Available at:
  https://clinicaltrials.gov/ct2/show/NCT03705312?term=mitraclip\&cond=Mitral+Regurgitation\&draw=2\&rank=16
  (Accessed: 6 August 2020).
\item
  Grayburn PA, Sannino A, Packer M. Proportionate and Disproportionate
  Functional Mitral Regurgitation: A New Conceptual Framework That
  Reconciles the Results of the MITRA-FR and COAPT Trials. JACC
  Cardiovasc Imaging. 2019;12(2):353-362. doi:10.1016/j.jcmg.2018.11.006
\item
  Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of
  the 2014 AHA/ACC Guideline for the Management of Patients With
  Valvular Heart Disease: A Report of the American College of
  Cardiology/American Heart Association Task Force on Clinical Practice
  Guidelines. Circulation. 2017;135(25):e1159-e1195.
  doi:10.1161/CIR.0000000000000503
\item
  Praz F, Spargias K, Chrissoheris M, et al. Compassionate use of the
  PASCAL transcatheter mitral valve repair system for patients with
  severe mitral regurgitation: a multicentre, prospective,
  observational, first-in-man study. Lancet. 2017;390(10096):773-780.
  doi:10.1016/S0140-6736(17)31600-8
\item
  Corpataux N, Winkel MG, Kassar M, Brugger N, Windecker S, Praz F. The
  PASCAL Device-Early Experience with a Leaflet Approximation Device:
  What Are the Benefits/Limitations Compared with the MitraClip?. Curr
  Cardiol Rep. 2020;22(8):74. Published 2020 Jun 27.
  doi:10.1007/s11886-020-01305-1
\item
  Mitral Stenosis: Percutaneous Transvenous Mitral Commissurotomy - The
  Cardiology Advisor {[}Internet{]}. The Cardiology Advisor. 2020.
  Available from:
  https://www.thecardiologyadvisor.com/home/decision-support-in-medicine/cardiology/mitral-stenosis-percutaneous-transvenous-mitral-commissurotomy/
  (Accessed: 13 August 2020)
\item
  Saccocci M, Taramasso M, Maisano F. Percutaneous mitral valvuloplasty
  in the modern era. Kardiol Pol. 2018;76(5):819-820.
  doi:10.5603/KP.2018.0095
\item
  Farman MT, Khan N, Sial JA, et al. Predictors of successful
  percutaneous transvenous mitral commissurotomy using the Bonhoeffer
  Multi-Track system in patients with moderate to severe mitral
  stenosis: Can we see beyond the Wilkins score?. Anatol J Cardiol.
  2015;15(5):373-379. doi:10.5152/akd.2014.5466
\item
  Firouzi A, Samiei N, Ahmadi S, et al. Percutaneous Transluminal Mitral
  Commissurotomy in Pregnant Women with Severe Mitral Stenosis. J Tehran
  Heart Cent. 2019;14(1):12-17.
\item
  Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical
  application of transvenous mitral commissurotomy by a new balloon
  catheter. The Journal of Thoracic and Cardiovascular Surgery.
  1984;87(3):394-402.
\item
  Adhikari CM, Malla R, Rajbhandari R, et al. Percutaneous transvenous
  mitral commissurotomy in juvenile mitral stenosis. Cardiovasc Diagn
  Ther. 2016;6(1):20-24. doi:10.3978/j.issn.2223-3652.2015.12.07
\item
  Harrison JK, Wilson JS, Hearne SE, Bashore TM. Complications related
  to percutaneous transvenous mitral commissurotomy. Cathet Cardiovasc
  Diagn. 1994;Suppl 2:52-60.
\item
  Murthy Jayanthi Sriram SN, Venkata BJ, Sadagopan T, Ramamurthy MT.
  Immediate, intermediate and long term clinical outcomes of
  percutaneous transvenous mitral commissurotomy. Int J Cardiol Heart
  Vasc. 2015;6:66-70. Published 2015 Jan 15.
  doi:10.1016/j.ijcha.2015.01.006
\item
  Reyes VP, Raju BS, Wynne J, et al. Percutaneous balloon valvuloplasty
  compared with open surgical commissurotomy for mitral stenosis. N Engl
  J Med. 1994;331(15):961-967. doi:10.1056/NEJM199410133311501
\item
  Walther C, Fichtlscherer S, Holubec T, Vasa-Nicotera M, Arsalan M,
  Walther T. New developments in transcatheter therapy of mitral valve
  disease. J Thorac Dis. 2020;12(4):1728-1739.
  doi:10.21037/jtd.2019.12.137
\item
  Bapat V, Rajagopal V, Meduri C, et al. Early Experience With New
  Transcatheter Mitral Valve Replacement. J Am Coll Cardiol.
  2018;71(1):12-21. doi:10.1016/j.jacc.2017.10.061
\item
  Del Val D, Ferreira-Neto AN, Wintzer-Wehekind J, et al. Early
  Experience With Transcatheter Mitral Valve Replacement: A Systematic
  Review. J Am Heart Assoc. 2019;8(17):e013332.
  doi:10.1161/JAHA.119.013332
\item
  Webb JG, Murdoch DJ, Boone RH, et al. Percutaneous Transcatheter
  Mitral Valve Replacement: First-in-Human Experience With a New
  Transseptal System. J Am Coll Cardiol. 2019;73(11):1239-1246.
  doi:10.1016/j.jacc.2018.12.065
\item
  Báez-Ferrer N, Izquierdo-Gómez MM, Marí-López B, et al. Clinical
  manifestations, diagnosis, and treatment of ischemic mitral
  regurgitation: a review. J Thorac Dis. 2018;10(12):6969-6986.
  doi:10.21037/jtd.2018.10.64
\item
  Schnittman SR, Itagaki S, Toyoda N, Adams DH, Egorova NN, Chikwe J.
  Survival and long-term outcomes after mitral valve replacement in
  patients aged 18 to 50 years. \emph{J Thorac Cardiovasc Surg} .
  2018;155(1):96-102.e11. doi:10.1016/j.jtcvs.2017.08.018
\item
  Winkel MG, Praz F, Wenaweser P. Mitral and Tricuspid Transcatheter
  Interventions Current Indications and Future Directions. \emph{Front
  Cardiovasc Med} . 2020;7:61. Published 2020 May 15.
  doi:10.3389/fcvm.2020.00061
\item
  De Bonis M, Al-Attar N, Antunes M, et al. Surgical and interventional
  management of mitral valve regurgitation: a position statement from
  the European Society of Cardiology Working Groups on Cardiovascular
  Surgery and Valvular Heart Disease. Eur Heart J. 2016;37(2):133-139.
  doi:10.1093/eurheartj/ehv322
\item
  Van Praet KM, Stamm C, Sündermann SH, et al. Minimally Invasive
  Surgical Mitral Valve Repair: State of the Art Review {[}published
  correction appears in Interv Cardiol. 2018 May;13(2):99{]}. Interv
  Cardiol. 2018;13(1):14-19. doi:10.15420/icr.2017:30:1
\item
  Wolfe JA, Malaisrie SC, Farivar RS, et al. Minimally Invasive Mitral
  Valve Surgery II: Surgical Technique and Postoperative Management.
  Innovations (Phila). 2016;11(4):251-259.
  doi:10.1097/IMI.0000000000000300
\item
  Marin Cuartas M, Javadikasgari H, Pfannmueller B, et al. Mitral valve
  repair: Robotic and other minimally invasive approaches. Prog
  Cardiovasc Dis. 2017;60(3):394-404. doi:10.1016/j.pcad.2017.11.002
\item
  Axtell AL, Moonsamy P, Dal-Bianco JP, Passeri JJ, Sundt TM,
  Melnitchouk S. Minimally Invasive Nonresectional Mitral Valve Repair
  Can Be Performed With Excellent Outcomes. Ann Thorac Surg.
  2020;109(2):437-444. doi:10.1016/j.athoracsur.2019.07.029
\item
  Kastengren M, Svenarud P, Ahlsson A, Dalén M. Minimally invasive
  mitral valve surgery is associated with a low rate of complications. J
  Intern Med. 2019;286(6):614-626. doi:10.1111/joim.12974
\item
  Grant SW, Hickey GL, Modi P, Hunter S, Akowuah E, Zacharias J.
  Propensity-matched analysis of minimally invasive approach versus
  sternotomy for mitral valve surgery. Heart. 2019;105(10):783-789.
  doi:10.1136/heartjnl-2018-314049
\item
  Sakaguchi T, Totsugawa T, Kuinose M, et al. Minimally Invasive Mitral
  Valve Repair Through Right Minithoracotomy\begin{CJK}{UTF8}{gbsn}　- \end{CJK}\selectlanguage{english}11-Year Single Institute
  Experience. Circ J. 2018;82(6):1705-1711. doi:10.1253/circj.CJ-17-1319
\item
  N\selectlanguage{polish}ě\selectlanguage{english}mec P, Ondr\selectlanguage{ngerman}á\selectlanguage{polish}š\selectlanguage{english}ek J. Surgical treatment of mitral
  regurgitation.\emph{Cor et Vasa} 2017; 59(1): 92-96.
  doi:10.1016/j.crvasa.2017.01.017
\item
  Liu J, Chen B, Zhang YY, et al. Mitral valve replacement via minimally
  invasive totally thoracoscopic surgery versus traditional median
  sternotomy: a propensity score matched comparative study. Ann Transl
  Med. 2019;7(14):341. doi:10.21037/atm.2019.07.07
\item
  S\selectlanguage{ngerman}ündermann SH, Sromicki J, Rodriguez Cetina Biefer H, et al. Mitral
  valve surgery: right lateral minithoracotomy or sternotomy? A
  systematic review and meta-analysis. J Thorac Cardiovasc Surg.
  2014;148(5):1989-1995.e4. doi:10.1016/j.jtcvs.2014.01.046
\item
  Ding C, Jiang DM, Tao KY, et al. Anterolateral minithoracotomy versus
  median sternotomy for mitral valve disease: a meta-analysis. J
  Zhejiang Univ Sci B. 2014;15(6):522-532. doi:10.1631/jzus.B1300210
\item
  ISRCTN Registry (2020) Minimally invasive thoracoscopically-guided
  right minithoracotomy versus conventional sternotomy for mitral valve
  repair: a multicentre randomised controlled trial (UK Mini Mitral).,
  Available at: http://www.isrctn.com/ISRCTN13930454 (Accessed: 1
  September 2020).
\item
  Tonutti M, Elson DS, Yang GZ, Darzi AW, Sodergren MH. The role of
  technology in minimally invasive surgery: State of the art, recent
  developments and future directions. Postgrad Med J.
  2017;93(1097):159--67.
\item
  Hawkins RB, Mehaffey JH, Mullen MG, et al. A propensity matched
  analysis of robotic, minimally invasive, and conventional mitral valve
  surgery. Heart. 2018;104(23):1970-1975.
  doi:10.1136/heartjnl-2018-313129
\item
  Gillinov AM, Mihaljevic T, Javadikasgari H, et al. Early results of
  robotically assisted mitral valve surgery: Analysis of the first 1000
  cases. J Thorac Cardiovasc Surg. 2018;155(1):82-91.e2.
  doi:10.1016/j.jtcvs.2017.07.037
\end{enumerate}

\textbf{Hosted file}

\verb`MVD Tables and Figures.docx`  available at \url{https://authorea.com/users/356774/articles/479583-mitral-valve-disease-a-view-on-pathophysiology-and-management-of-the-most-common-valve-disease-in-the-world}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/MVDFigure-1/MVDFigure-1}

\end{center}
\end{figure}

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

