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\begin{document}

\title{Analysis of clinical outcome and postoperative organ function effects in
a propensity-matched comparison between conventional and minimally
invasive mitral valve surgery}



\author[1]{Sophie Missault}%
\author[1]{Jerome Van Causenbroeck}%
\author[1]{Korneel Vandewiele}%
\author[1]{Jens Czapla}%
\author[1]{Tine Philipsen}%
\author[2]{Katrien François}%
\author[3]{Thierry Bove}%
\affil[1]{University Hospital Ghent}%
\affil[2]{University of Ghent}%
\affil[3]{University Hopsital of Ghent}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Minimally invasive mitral valve(MV) surgery(MIVT) is
increasingly performed with excellent clinical outcome, despite longer
procedural times. This study analyzes clinical outcome and secondary
organ function effects in a propensity-matched comparison with
conventional MV surgery. Methods and Results: Out of 439 patients
undergoing MV surgery from January 2005 to May 2017, 345 patients were
included after propensity-matching: 95 sternotomy patients and 250 MIVT
patients. Endpoints focused on survival, quality of MV repair and organ
function effects through analysis of biomarkers and functional
parameters. Despite longer cardiopulmonary bypass(sternotomy:
96.0(IQR34)min -- MIVT:134.0(IQR42)min, p\textless{}0.001) and
cardioplegic arrest times(sternotomy: 61.0(IQR26)min --
MIVT:87.0(IQR34)min, p\textless{}0.001), no differences in survival nor
complication rate were found. Effect on renal function(creatinine,
p=0.751 -- ureum, p=0.538 - glomerular filtration, p=0.848), myocardial
damage by troponine I level (sternotomy:1.8\selectlanguage{ngerman}±3.9ng/ml --
MIVT:1.2±1.3ng/ml, p=0.438) and ventilatory support \textgreater{} 24
hours(sternotomy:5.5\% - MIVT:9.5\%, p=0.240) were comparable. Systemic
inflammatory reaction by postoperative CRP count was markedly lower for
MIVT(p\textless{}0.001). Increased rhadomyolysis was found after MIVT
surgery, based on significant elevation of creatinine-kinase
levels(sternotomy: 431±237U/L -- MIVT: 701±595U/L, p\textless{}0.001).
Conclusion: Despite an inherent learning curve, minimally invasive MV
surgery guarantees a clinical outcome and MV repair quality, at least
non-inferior to those of MV surgery via sternotomy. Notwithstanding
longer cardiopulmonary bypass and cardiac arrest times, the impact on
secondary organ function is negligible, excepted for a lower systemic
inflammatory response. The postoperative increase of CK-enzymes
suggestive for enhanced rhabdomyolysis needs to be accounted when
procedural times tend to exceed the critical time threshold for severe
limb ischemia.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Analysis of clinical outcome and postoperative organ function
effects in a propensity-matched comparison between conventional and
minimally invasive mitral valve surgery}

Sophie Missault MD.\textsuperscript{1*}, J\selectlanguage{ngerman}érôme Van Causenbroeck
MD.\textsuperscript{1*}, Korneel Vandewiele MSc.\textsuperscript{2},
Jens Czapla MD.\textsuperscript{1}, Tine Philipsen
MD.\textsuperscript{1}, Katrien François MD.PhD.\textsuperscript{1},
Thierry Bové MD.PhD.\textsuperscript{1}

\textsuperscript{1}Department of Cardiac Surgery\textsuperscript{1} and
Perfusion\textsuperscript{2}

University Hospital of Ghent, Ghent, Belgium

*Both authors contributed equally in the submission of this manuscript

\emph{Corresponding author:}

Thierry Bové MD. PhD.

Department of Cardiac Surgery

University Hospital Gent

Corneel Heymanslaan 10, 9000 Gent, Belgium

Phone: +32-93323925

E-mail: thierry.bove@ugent.be

\emph{Funding:} None

\emph{Short running title:} Port-access Mitral Valve Surgery

\emph{Word count:}

Abstract: 250 - Manuscript: 4495

\emph{Abstract}

\emph{Background:}

Minimally invasive mitral valve(MV) surgery(MIVT) is increasingly
performed with excellent clinical outcome, despite longer procedural
times. This study analyzes clinical outcome and effect on secondary
organ functions in a propensity-matched comparison with conventional MV
surgery.

\emph{Methods and Results:}

Out of 439 patients undergoing MV surgery from January 2005 to May 2017,
345 patients were included after propensity-matching: 95 sternotomy
patients and 250 MIVT patients. Endpoints focused on survival, quality
of MV repair and organ function effects through analysis of biomarkers
and functional parameters.

Regardless of longer cardiopulmonary bypass(sternotomy: 96.0(IQR34)min
-- MIVT:134.0(IQR42)min, p\textless{}0.001) and cardioplegic arrest
times(sternotomy: 61.0(IQR26)min -- MIVT:87.0(IQR34)min,
p\textless{}0.001), no differences in survival nor complication rate
were found. Effect on renal function(creatinine, p=0.751 -- ureum,
p=0.538 - glomerular filtration, p=0.848), myocardial damage by
troponine I level (sternotomy:1.8±3.9ng/ml -- MIVT:1.2±1.3ng/ml,
p=0.438) and prolonged ventilatory support \textgreater{} 24
hours(sternotomy:5.5\% - MIVT:9.5\%, p=0.240) were comparable. Systemic
inflammatory reaction by postoperative CRP count was markedly lower for
MIVT(p\textless{}0.001). Increased rhadomyolysis was found after MIVT
surgery, based on significant elevation of creatinine-kinase
levels(sternotomy: 431±237U/L -- MIVT: 701±595U/L, p\textless{}0.001).

\emph{Conclusion:}

Despite an inherent learning curve, minimally invasive MV surgery
guarantees a clinical outcome and MV repair quality, at least
non-inferior to those of MV surgery via sternotomy. Notwithstanding
longer cardiopulmonary bypass and cardiac arrest times, the impact on
secondary organ function is negligible, excepted for a lower systemic
inflammatory response. The postoperative increase of CK-enzymes
suggestive for enhanced rhabdomyolysis needs to be accounted when
procedural times tend to exceed the critical time threshold for severe
limb ischemia.

\emph{Introduction}

The concept of a minimally invasive approach for mitral valve(MV)
surgery has been initiated in the nineties by Cosgrove et al., and was
primarily based on attempts to reduce the surgical invasiveness by
limiting the incision length and avoiding a full
sternotomy\textsuperscript{1,2}. Encouraged by advances in thoracic and
abdominal surgery, an endoscopic approach with thoracoscopic
visualization and use of peripheral cardiopulmonary bypass, aided to
minimize the surgical trauma\textsuperscript{3}\emph{.} Meanwhile, this
`port-access' surgery has become the preferred technique for mitral
and/or tricuspid valve surgery in many centers. Several studies pointed
repetitively to the obvious benefits as an improved cosmetic result, a
shorter hospital stay, quicker socio-economic reintegration and
decreased need for blood products, whilst the main surgical end-points
in terms of quality of mitral repair and morbidity as mortality were
commonly maintained once the inevitable learning curve has been
surpassed\textsuperscript{4-11}. Hence, even in experienced hands,
port-access MV surgery is associated with longer duration of
cardiopulmonary bypass and aortic cross-clamp time, known of having an
adverse effect on postoperative morbidity and mortality due to secondary
organ dysfunction\textsuperscript{5,6,8}.

The purpose of this study is to compare the clinical outcome of MV
surgery performed through port-access and conventional sternotomy in a
propensity-matched cohort, with additional focus on secondary organ
function by analysis of organ-specific biomarkers and/or other
functional outcome parameters.

\emph{Material and methods}

This study was approved by the ethical committee of the University
Hospital of Ghent, waiving patient's informed consent by the
retrospective study design and the use of anonymized data (reference
B67201732290/91).

\emph{Surgical technique of minimally invasive videoscopic MV surgery
(MIVT)}

The MIVT program at our institution started in 2008, and has been
applied to all patients presenting for elective MV surgery since then.
Patients were omitted during the early phase of the program in case of
previous cardiac surgery, extensive annular calcifications and
precarious vascular access. Preoperative screening for MIVT
systematically included angiographic imaging of the complete aorta to
femoral vessels, to rule out severe atherosclerotic disease. Patients
were routinely intubated with a double-lumen endotracheal tube to allow
single lung ventilation. Surgical access was obtained through a right
anterior thoracotomy at the 4\textsuperscript{th} intercostal space, via
a 5-6 cm skin incision. Cardiopulmonary bypass was installed through
cannulation of the femoral vein and artery via Seldinger technique, and
correct positioning of the cannulas under guidance of transesophageal
echocardiography. Cardioplegic arrest was achieved by antegrade
administration of cold crystalloid cardioplegia in the aortic root after
aortic clamping with Chitwood clamp or endoaortic balloon occlusion
(IntraClude, Edwards Lifesc., Irvine, CA, USA). MV repair was done
according to classical techniques.

MV surgery through sternotomy was used as standard approach before the
end of 2008, and was still used later on for patients requiring
concomitant procedures like aortic valve surgery or coronary artery
bypass grafting, patients with extensive mitral annular calcifications,
or those presenting with fulminant lung edema in need for preoperative
respiratory support, prohibiting single lung ventilation.

\emph{Patient data}

From January 2005 to May 2017, 439 patients underwent MV surgery at our
department. A MIVT procedure was done in 250 patients between July 2008
and May 2017, and 189 patients were operated through conventional
sternotomy between January 2005 and December 2014. Pre-, intra- and
postoperative data were retrospectively retrieved from the patient's
medical records. Organ-specific biomarkers were obtained preoperatively
and per 24 hour on ICU concerning assessment of liver, kidney and
myocardial damage, while lung and brain function were based on clinical
parameters such as ventilation time and stroke incidence respectively.
Evaluation of systemic inflammatory response was based on CRP values,
obtained preoperatively and at the first and second day after surgery.
Use of blood products, postoperative blood loss and hematological
assessment were additionally included.

The clinical follow-up ended in November 2017, considering the endpoints
survival, reoperation free-survival and late MV function.

\emph{Statistical Analysis}

Statistical analysis was performed using SPSS Statistics 25.0 (IBM SPSS
Statistics for Windows, Version 25.0, Armonk, NY).

Since both surgical procedures were performed consecutively over time
yielding only a limited time overlap during the learning phase of MIVT,
this study is inherently biased. Therefore, a propensity-score matched
analysis with a tolerance of 0.05 and without replacement was executed
for the patient characteristics having a baseline significant
difference. Adjustment was performed for differences in preoperative
NYHA class and previous cardiac surgery to match both study groups.

Data distribution is verified for normality by the Shapiro-Wilk test.
Categorical variables are expressed by number and percentage. Continuous
variables are noted as mean and standard deviation or as median and
interquartile range, depending on the distribution normality of the
data. Categorical variables were compared between groups by Chi-square
or Fisher's exact test. Comparison of continuous data was done by the
unpaired t-test or Mann-Whitney U-test.

To examine significant between-group differences in biomarker evolution
over time points, an repeated ANOVA-analysis was used. Significance was
based on Wilk's-Lambda or Greenfeld-Houser testing depending on
Mauchly's sphericity preservation of the data. Survival analysis was
performed by the Kaplan--Meier estimation method with log-rank testing
of the difference between both procedures. All tests were performed
2-tailed and considered as statistically significant for a p-value
\textless{} 0.05.

\emph{Results}

\emph{Patient demographics}

In the entire cohort of 439 patients, the sternotomy group (n=189)
showed a higher NYHA class (p\textless{}0.001) and underwent more
frequently prior cardiac surgery (sternotomy: 26.5\% vs. MIVT: 4.8\%,
p\textless{}0.001). After propensity-score matching for these variables,
345 patients were retained for analysis, respectively 95 in the
sternotomy group and 250 patients in the MIVT group, showing comparable
demographics(Table 1).

\emph{Operative characteristics}

The operative data are shown in table 2. Regarding the etiology of MV
disease, isolated annular dilation was noticed more frequently in the
MIVT group(28.5\% versus 8.7\%, p\textless{}0.001), in contrast to the
incidence of degenerative MV disease slightly in favor of the sternotomy
group (sternotomy: 72.8\% versus MIVT: 59.4\%, p=0.054)(figure 1).
Accordingly, the number of mitral valve replacements was higher in the
sternotomy group, while isolated annuloplasty was performed more
frequently in the MIVT group. No significant differences were found
regarding the use of neochordae and the performance of concomitant AF
ablation or tricuspid surgery. Duration of cardiopulmonary bypass and
aortic cross-clamp time were significantly longer in the MIVT group.

\emph{Postoperative morbidity and mortality}

There was no difference in major complications rate in terms of stroke
rate, pulmonary complications, and acute renal failure and/or need for
dialysis. New-onset atrial fibrillation occurred in 4.1\% of MIVT
patients versus 7.8\% of the sternotomy patients (p=0.259), after
exclusion of the confounding effect of concomitant ablation therapy. A
significantly shorter hospital stay was noticed in the MIVT group
(median: 13(IQR 4) d vs. 14(IQR 4) d, p=0.016), while ICU stay was
comparable for both groups (sternotomy: 1.4(IQR 1.8) d vs. MIVT:
1.3(IQR1.7) d, p=0.366).

Seven MIVT patients needed intra-operative conversion to median
sternotomy for respectively traumatic laceration of the left atrial
appendage by the Chitwood clamp(n=2), retrograde aortic dissection(n=1),
bleeding of the right ventricle during pacemaker wire insertion(n=1),
circumflex artery occlusion(n=1), and final need for mitral valve
replacement after prolonged attempts of MV repair(n=2).

In-hospital mortality was similar for both groups: MIVT: n=5(2.0\%)
patients versus sternotomy: n=1(1.1\%)(p=1.000).

\emph{Late outcomes}

Clinical follow-up was complete for 302(87.5\%) patients of the whole
cohort (sternotomy: 75.8\% versus MIVT: 92.0\%, p\textless{}0.001).
Median follow-up duration was 3.1(IQR 4.2)y, and significantly longer in
the sternotomy group (sternotomy: 6.5(IQR 6)y versus MIVT: 2.5(IQR
4.3)y, p\textless{}0.001). The cumulative patient follow-up time was 962
patient/years.

Kaplan-Meier analysis showed no significant survival difference between
the groups (p=0.472)(Figure 2). At last follow-up, sternotomy patients
showed a higher NYHA class (p=0.015) and appeared to develop more
frequently atrial fibrillation (Sternotomy: 3.8\% vs. MIVT: 15.7\%,
p=0.002).

Echocardiographic assessment of MV function at last follow-up showed a
similar quality of MV repair for the 2 groups, in terms of freedom from
regurgitation(figure 3) as well as transmitral gradient (mean gradient:
sternotomy 4.0(2.0) mmHg versus MIVT 4.0 (2.0) mmHg, p=0.810); max
gradient: sternotomy 10.0(6.8) mmHg versus MIVT 10.0(5.4) mmHg,
p=0.957).

Late reoperation for recurrent MV dysfunction was necessary in 8(8.6\%)
sternotomy patients vs. 11(4.4\%) MIVT patients (p=0.130), revealing a
comparable freedom from MV-related reoperation of 90.8±3.6\% and
90.8±3.6\% in the sternotomy group versus 93.9±2.0\% and 90.7±3.0\% in
the MIVT group at respectively 3 and 5 years (logrank p=0.529)(Figure
4).

\emph{Organ-specific biomarker analysis (Table 4)}

Analysis of liver function biomarkers showed an AST count increase in
both groups, but significantly higher in MIVT, together with raised ALT
counts. In contrast, LDH levels increased significantly more in the
sternotomy group compared to MIVT group.

Renal function biomarkers increased similarly in both groups as shown in
Figure 5, corresponding with a decrease of GRF, but without reaching a
statistically significant difference.

Myocardial damage assessed by troponin I and creatine kinase(CK) and
creatine kinase MB(CK-MB) counts revealed no difference of postoperative
troponin levels between MIVT and sternotomy. However, CK counts
increased significantly more in the MIVT group than in the sternotomy
group (MIVT: 89.74 to 933.02 U/l vs. sternotomy: 73.92 to 89.74 U/l;
p=0.002). In contrast, CK-MB levels increased postoperatively in both
groups, albeit based on samplings of only 44 patients.

Non-specific systemic inflammation was considered by leukocyte counts
and C-reactive protein(CRP) levels. Leukocyte counts increased
significantly more in MIVT compared to sternotomy. However, CRP counts
raised significantly more from the first to second postoperative day in
the sternotomy compared to the MIVT group(p\textless{}0.001)(Figure 6).
Other hematologic biomarkers are listed in Table 4.

As red blood cell derivatives are confounded by intra- and postoperative
transfusion, only the latter parameters are analyzed. Mediastinal
drainage loss during the first 12 and 48 hours was higher in the MIVT
group. No significant difference was found in the number of blood
transfusions nor total blood transfusion volume.

The impact of the surgical approach on lung function was represented by
the length of mechanical ventilation. No difference between groups was
found concerning mechanical ventilation longer than 24 hours.

\emph{Discussion}

Port-access MV surgery is nowadays a valid approach to treat all kinds
of MV disease according to contemporary techniques, resulting in a
clinical outcome equal to the conventional sternotomy approach. This
technique has been implemented in our department since more than 10
years now for the surgical management of most MV pathologies, with or
without the need for additional treatment of associated lesions as
atrial fibrillation and tricuspid valve dysfunction. Even after
including the obligatory learning phase, the clinical outcome as well as
the quality of MV procedure itself appeared to be non-inferior to that
of the standard MV surgery. Hence, the effect of the learning period
during the adoption of a new approach is not negligible. In a large
volume center, Holzhey et al. demonstrated that approximately 75 to 125
operations are required to achieve optimal results with MIVT,
characterized by a net decrease of bleeding complications, reoperation
for early valve failure and a nearly obsolete conversion
rate\textsuperscript{12}.

Moreover, some complications are typically related to the surgical
approach. The risk of stroke is often estimated to be increased due to
the retrograde systemic perfusion and the potential risk for aortic
dissection, inadequate aortic de-airing and the deficient tactile
manipulation of the ascending aorta, regardless of the mode of aortic
clamping\textsuperscript{13-14}. The incidence of major neurological
injury in our study was similar to others, revealing only one case of
retrograde aortic dissection. Here, we underscore the importance of
examining the vascular access -- specifically the arterial side --
rigorously to limit such devastating complication as much as possible.

Considering the lower traumatic impact of a mini-thoracotomy on the
thorax compared to a sternotomy, one would expect a favorable effect on
respiratory dynamics and so, shorter ventilation time. In this
propensity-matched comparison, the ventilation times were identical as
well as the ICU stay duration. In an equivalent study design comparing
350 port-access patients and 365 sternotomy patients, Suri et al. found
a slight decrease of ventilatory support duration despite of
significantly longer procedural times\textsuperscript{15}. However, it
is commonly known that the criteria for extubation may vary in-between
centers, and that even in one single center, the decision for extubation
may vary among ICU physicians, advancing thereby the subjective aspect
of this parameter.

A recurrent finding of many studies on this topic is the notification of
longer aortic cross-clamp and cardiopulmonary bypass
times\textsuperscript{5-11}. The adverse relationship between these
factors and secondary organ dysfunction is well-known in the field of
cardiac surgery\textsuperscript{16-17}. Through analysis of specific
organ function biomarkers, routinely sampled at the postoperative stage,
we found no significantly different effect between both approaches.
Biomarkers of myocardial and liver origin increased similarly in both
groups, but one has to consider that, through lack of specificity, it is
difficult to know what the real impact of each procedure on respectively
myocardial and liver function is. Interestingly, the creatinine-kinase
level was significantly increased after port-access surgery. Bearing in
mind that this count also represents global muscle damage, one can
relate this to a condition of relative limb ischaemia initiated by the
cannulation of the femoral artery and vein. As the duration of
cardiopulmonary bypass is rarely exceeding the critical duration
threshold for irreversible ischemia and rhabdomyolysis, it generally
remains clinically insidious. However, this issue needs to be accounted
for optimization of the peripheral cannulation strategy, by using
specifically designed arterial cannulas allowing distal leg perfusion or
by avoiding combined ipsilateral femoral artery and vein cannulation.

Kidney biomarkers are both specific and sensitive to renal function. Our
study demonstrated a rise of creatinine and ureum level, together with a
decrease of glomerular filtration, during the early postoperative
period, but independent of the used surgical approach. Nevertheless, the
incidence of effective kidney failure, requiring renal replacement
therapy, was low. Data on this organ-specific outcome are controversial,
some showing a clear advantage for the minimally invasive technique,
while others were not able to found any effect\textsuperscript{15,18}.
One part of this confounding is related to the use of different study
designs including selection bias and other statistical methods to
analyze renal outcome.

Regarding the systemic inflammatory reaction, CRP counts remained
largely inferior during the first 48 hours after port-access MV surgery
than after conventional sternotomy. This suggests that the MIVT
technique is associated with a significant trauma reduction to the body,
with less activation of inflammatory mediators. Watt et al. reported
similar results in a systematic review on CRP post-surgery, and
identified that CRP counts were higher after bigger, more invasive
surgical procedures like thoracic surgery compared to smaller surgeries
such as cholecystectomy\textsuperscript{19}. The results of Paparella et
al. confirmed that CRP and interleukine-6 counts were lower after MIVT
compared to sternotomy MV surgery\textsuperscript{20}.

The lack of detrimental effect of longer duration of cardiopulmonary
bypass and cardiac arrest on secondary organ function, as observed after
port-access MV surgery, points to eventual intra-operative measures,
directly related to the management of cardiopulmonary bypass. The
conduct of cardiopulmonary bypass during MIVT surgery is commonly facing
flow restrictions, due to the use of smaller caliber cannulas via
peripheral vascular access, which on top of it, need to be properly
positioned, depending on adequate guidance via intra-operative
transesophageal echocardiography. Using kidney function as most robust
organ function endpoint, our group recently demonstrated that an
equivalent organ-specific as well as clinical outcome between MIVT and
conventional MV surgery is achievable through targeting an minimal
oxygen delivery during the duration of cardiopulmonary bypass. However,
in order to cope with the frequent inferences of intra-operative flow
restrictions over a longer procedural time during MIVT, other means need
to be applied as the tolerance of lower body temperature, the pursuit of
a higher intra-operative hematocrit level and the use of blood
preserving measures\textsuperscript{21}. Moreover, operative times may
probably be less decisive for patient outcomes, as long as they are not
excessively long.

\emph{Limitations}

The limitations of this study are linked to its retrospective design,
yielding missing data and incomplete follow-up. Regarding the validity
of biomarkers to represent organ function, the low specificity of some
biomarkers might impede clear interpretation of some data, as for
example, liver enzymes AST, ALT and LDH are known to have other tissue
sources. Therefore, this study would have been favored by a prospective
design, incorporating the follow-up of organ-specific markers.

Since MIVT was used consecutively for MV surgery since 2009, with a
short time overlap to cover the learning phase, there is a historical
difference between the study groups. This might include some selection
bias, where patients with more complex MV pathology were preferably
operated through conventional approach during the transit period. As we
found it mandatory to include the learning period, propensity-matching
was performed for patient-related conditions but not for MV disease.
However, we feel confident that even in a fully 1:1-matched cohort, the
clinical outcome and organ function results would be comparable,
demonstrating that the port-access approach allows to achieve a
qualitatively identical outcome despite longer procedural times.

\emph{Conclusion}

Minimally invasive port-access surgery is an equivalent alternative to
the conventional median sternotomy approach for the treatment of
all-kind of MV diseases, but offers an improved cosmetic result and
faster postoperative recovery as most important advantage. Despite an
inherent learning curve, this technique provides to achieve the same
results in terms of valve repair quality and clinical outcome.
Notwithstanding the commonly longer cardiopulmonary bypass and cardiac
arrest times, the impact on secondary organ function is comparable to
conventional median sternotomy, excepted for the lower systemic
inflammatory response by CRP counts. Hence, the postoperative increase
of CK-enzymes suggestive for enhanced rhabdomyolysis needs to be
accounted when procedural times tend to exceed the critical time
threshold for severe limb ischemia.

Therefore, MIVT should be offered as a first-line technique to all
patients with significant mitral valve disease, even with the need for
concomitant treatment of tricuspid valve dysfunction and atrial
fibrillation, guaranteeing that a clinical outcome and valve repair
quality can be accomplished, at least non-inferior to that of the
conventional approach through sternotomy.

\emph{Tables}

Table 1.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& \textbf{Unmatched Patients (n = 439)} & \textbf{Unmatched Patients (n
= 439)} & \textbf{Unmatched Patients (n = 439)} & \textbf{Matched
Patients (n = 345)} & \textbf{Matched Patients (n = 345)} &
\textbf{Matched Patients (n = 345)}\tabularnewline
\midrule
\endhead
& \emph{Sternotomy} & \emph{MIVT} & \emph{p-value} & \emph{Sternotomy} &
\emph{MIVT} & \emph{p-value}\tabularnewline
\textbf{Number} & 189 & 250 & & 95 & 250 &\tabularnewline
\textbf{Age (years)} & 70.0(19.0) & 68.0(16.0) & 0.850 & 72.0(14.0) &
68.0(16.0) & 0.081\tabularnewline
\textbf{Gender (male)} & 72(38.1) & 117(46.8) & 0.068 & 37(38.9) &
117(46.8) & 0.225\tabularnewline
\textbf{Weight (kg)} & 69.0(17.3) & 70.0(20.8) & 0.319 & 70.0(17.0) &
70.0(20.8) & 0.063\tabularnewline
\textbf{BSA (m\textsuperscript{2})} & 1.8(0.3) & 1.8(0.3) & 0.334 &
1.8(0.2) & 1.8(0.3) & 0.069\tabularnewline
\textbf{Diabetes} & 21(12.6) & 18(7.2) & 0.065 & 11(11.6) & 18(7.2) &
0.197\tabularnewline
\textbf{CVA/TIA} & 12(6.3) & 10(4.0) & 0.182 & 5(5.3) & 10(4.0) &
0.567\tabularnewline
\textbf{Chronic renal disease} & 8(4.2) & 2(1.2) & 0.191 & 5(5.2) &
2(1.2) & 0.108\tabularnewline
\textbf{Heart rhythm} & & & 0.626 & & & 0.443\tabularnewline
Sinus rhythm & 101(61.6) & 164(65.9) & & 59(62.1) & 164(65.9)
&\tabularnewline
Atrial fibrillation & 60(36.6) & 82(32.9) & & 36(37.9) & 82(32.9)
&\tabularnewline
PM rhythm & 3(1.8) & 3(1.2) & & 0(0) & 3(1.2) &\tabularnewline
\textbf{Prior MV surgery} & 50(26.5) & 12(4.8) & \textless{}0.001 &
9(9.5) & 12(4.8) & 0.129\tabularnewline
\textbf{NYHA class} & & & \textless{}0.001 & & & 0.137\tabularnewline
NYHA 1 & 7(4.6) & 26(12.4) & & 6(6.3) & 26(12.4) &\tabularnewline
NYHA 2 & 59(39.1) & 113(53.8) & & 45(47.4) & 113(53.8) &\tabularnewline
NYHA 3 & 70(46.4) & 63(30.0) & & 39(41.1) & 63(30.0) &\tabularnewline
\textbf{NYHA 4} & 15(9.9) & 8(3.8) & & 5(5.3) & 8(3.8) &\tabularnewline
\textbf{LV function (EF)} & & & 0.187 & & & 0.795\tabularnewline
[?]30\% & 4(2.6) & 4(1.6) & & 2(2.1) & 4(1.6) &\tabularnewline
30-60\% & 33(21.4) & 38(15.2) & & 17(17.9) & 38(15.2) &\tabularnewline
[?] 60\% & 117(76.0) & 208(83.2) & & 76(80.0) & 208(83.2) &\tabularnewline
\bottomrule
\end{longtable}

\emph{Data :} dichotomous data are given by n(\%); continuous data are
given by median(IQR)

\emph{Legend:} BSA=body surfance area; CVA=cerebrovascular accident;
TIA=transient ischemic attack; PM=pacemaker; LV=left ventricular;
EF=ejection fraction

Table 2. Operative data\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \emph{Sternotomy (n=95)} & \emph{MIVT(n=250)} & \emph{p
value}\tabularnewline
\midrule
\endhead
\textbf{Cardiopulmonary bypass time (min)} & 96.0(34) & 134.0(42) &
\textless{}0.001\tabularnewline
\textbf{Aortic Cross-clamp time (min)} & 61.0(26) & 87.0(34) &
\textless{}0.001\tabularnewline
\textbf{MV repair} & & &\tabularnewline
Posterior leaflet & 30(33.0) & 120(48.0) & 0.031\tabularnewline
Anterior leaflet & 5(5.5) & 12(4.8) & 0.823\tabularnewline
Both leaflets & 13(14.3) & 21(8.4) & 0.188\tabularnewline
Neochordae & 11(12.0) & 18(7.2) & 0.161\tabularnewline
Isolated annuloplasty & 12(13.2) & 70(28.0) & 0.010\tabularnewline
\textbf{MV replacement} & 31(34.1) & 27(10.8) &
\textless{}0.001\tabularnewline
\textbf{Additional tricuspid surgery} & 34(36.2) & 45(18.0) &
\textless{}0.001\tabularnewline
\textbf{AF Ablation} & 14(15.1) & 50(20.0) & 0.296\tabularnewline
\bottomrule
\end{longtable}

\emph{Data :} dichotomous data are given by n(\%); continuous data are
given by median(IQR)

\emph{Legend:} AF=atrial fibrillation

Table 3. Organ-specific biomarkers\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \emph{Sternotomy (n=95)} & \emph{MIVT (n=250)} & \emph{Wilk's-Lamda
p-value}\tabularnewline
\midrule
\endhead
\emph{Liver} & & &\tabularnewline
\textbf{AST (U/l)} & & & 0.047\tabularnewline
Preop & 25.6\selectlanguage{ngerman}±10.2 & 26.0\selectlanguage{ngerman}±14.3 &\tabularnewline
Day 1 & 67.1\selectlanguage{ngerman}±40.0 & 81.4\selectlanguage{ngerman}±53.4 &\tabularnewline
\textbf{ALT (U/l)} & & & 0.035\tabularnewline
Preop & 26.5\selectlanguage{ngerman}±16.9 & 26.9\selectlanguage{ngerman}±21.5 &\tabularnewline
Day 1 & 23.5\selectlanguage{ngerman}±20.8 & 30.2\selectlanguage{ngerman}±28.4 &\tabularnewline
\textbf{LDH (U/l)} & & & \textless{}0.001\tabularnewline
Preop & 350.7\selectlanguage{ngerman}±119.9 & 253.1\selectlanguage{ngerman}±106.5 &\tabularnewline
Day 1 & 514.7\selectlanguage{ngerman}±174.6 & 357.6\selectlanguage{ngerman}±145.3 &\tabularnewline
\emph{Heart} & & &\tabularnewline
\textbf{Creatine kinase (U/l)} & & & 0.002\tabularnewline
Preop & 73.9\selectlanguage{ngerman}±54.6 & 89.7\selectlanguage{ngerman}±61.7 &\tabularnewline
Day 1 & 608.3\selectlanguage{ngerman}±634.1 & 933.0\selectlanguage{ngerman}±795.4 &\tabularnewline
\textbf{CKMB (mg/l)} & & & 0.733\tabularnewline
Preop & 15.9\selectlanguage{ngerman}±17.8 & 13.3\selectlanguage{ngerman}±4.61 &\tabularnewline
Day 1 & 57.1\selectlanguage{ngerman}±55.9 & 47.0\selectlanguage{ngerman}±16.7 &\tabularnewline
\textbf{Troponin (ng/ml)} & & & 0.438\tabularnewline
Day 1 & 1.8\selectlanguage{ngerman}±3.9 & 1.2\selectlanguage{ngerman}±1.3 &\tabularnewline
\emph{Inflammation and Hematology} & & &\tabularnewline
\textbf{CRP (mg/l)} & & & \textless{}0.001\tabularnewline
Preop & 1.4\selectlanguage{ngerman}±1.9 & 1.3\selectlanguage{ngerman}±4.0 &\tabularnewline
Day 1 & 5.3\selectlanguage{ngerman}±2.8 & 4.5\selectlanguage{ngerman}±5.4 &\tabularnewline
Day 2 & 177.1\selectlanguage{ngerman}±75.3 & 17.9\selectlanguage{ngerman}±18.4 &\tabularnewline
\selectlanguage{greek}\textbf{Leukocytes (10\textsuperscript{3} μL)}\selectlanguage{english} & & &
0.010\tabularnewline
Preop & 7.1\selectlanguage{ngerman}±3.2 & 6.8\selectlanguage{ngerman}±2.2 &\tabularnewline
Day 1 & 10.4\selectlanguage{ngerman}±3.3 & 11.2\selectlanguage{ngerman}±3.5 &\tabularnewline
\selectlanguage{greek}\textbf{Trombocytes (10\textsuperscript{3} μL)}\selectlanguage{english} & & &
0.501\tabularnewline
Preop & 229.3\selectlanguage{ngerman}±68.1 & 234.1\selectlanguage{ngerman}±69.2 &\tabularnewline
Day 1 & 149.2\selectlanguage{ngerman}±46.7 & 158.4\selectlanguage{ngerman}±49.6 &\tabularnewline
\textbf{Protrombin activity (\%)} & & & 0.006\tabularnewline
Preop & 89.9\selectlanguage{ngerman}±11.3 & 96.9\selectlanguage{ngerman}±13.9 &\tabularnewline
Day 1 & 68.1\selectlanguage{ngerman}±9.9 & 71.2\selectlanguage{ngerman}±10.8 &\tabularnewline
\textbf{APTT (s)} & & & 0.045\tabularnewline
Preop & 35.9\selectlanguage{ngerman}±5.2 & 34.8\selectlanguage{ngerman}±5.7 &\tabularnewline
Day 1 & 40.0\selectlanguage{ngerman}±8.9 & 37.2\selectlanguage{ngerman}±5.3 &\tabularnewline
\textbf{Fibrinogen (mg/dl)} & & & 0.105\tabularnewline
Preop & 401.9\selectlanguage{ngerman}±107.9 & 379.1\selectlanguage{ngerman}±85.7 &\tabularnewline
Day 1 & 293.4\selectlanguage{ngerman}±80.2 & 287.5\selectlanguage{ngerman}±72.0 &\tabularnewline
\emph{Lung function} & & &\tabularnewline
Mechanical ventilation & & &\tabularnewline
\textgreater{} 24 hours & 5(5.5\%) & 23(9.5\%) & 0.240\tabularnewline
\textgreater{} 48 hours & 2(2.2\%) & 13(5.4\%) & 0.372\tabularnewline
\emph{Blood loss and drainage} & & &\tabularnewline
Mediastinal loss at 12 hours(ml) & 350\selectlanguage{ngerman}±270 & 400\selectlanguage{ngerman}±250 &
0.030\tabularnewline
Mediastinal loss at 24 hours(ml) & 510\selectlanguage{ngerman}±305 & 575\selectlanguage{ngerman}±370 &
0.038\tabularnewline
Blood transfusions(units) & 0(0-9) & 0(0-4) & 0.492\tabularnewline
Blood transfusion volume(ml) & 600\selectlanguage{ngerman}±600 & 300\selectlanguage{ngerman}±300 & 0.148\tabularnewline
\bottomrule
\end{longtable}

\emph{Data:} dichotomous data are given by n(\%); continuous data are
given by mean \selectlanguage{ngerman}± standarddeviation

\emph{Legend:} AST=aspartate transaminase; ALT=alanine transaminase;
LDH=lactate dehydrogenase; CRP=c-reactive protein; aPTT=activated
prothrombin time

\emph{Figures}

Figure 1. Distribution of MV disease per group

Figure 2. Survival plot for MIVT and sternotomy

Figure 3. Mitral regurgitation at last echocardiographic follow-up

Figure 4. Freedom from MV-related reoperation per group

Figure 5. Evolution of renal function biomarkers

Creatinine -- b) Ureum -- c) Glomerular filtration rate

\emph{p-value represents the Wilk's-Lamda test}

Figure 6. Evolution of CRP

\emph{p-value represents the Wilk's-Lamda test}

\emph{Author contributions}

\emph{Sophie Missault:} concept, data acquisition and analysis,
statistics, drafting manuscript

\emph{Jérôme Van Causenbroeck:} concept, data acquisition and analysis,
statistics, drafting manuscript

\emph{Korneel Vandewiele:} data acquisition and analysis, revision of
article

\emph{Jens Czapla:} data acquisition and analysis, revision of article

\emph{Tine Philipsen:} data acquisition and analysis, revision of
article

\emph{Katrien François:} data acquisition and analysis, revision of
article

\emph{Thierry Bové:} concept, data acquisition and analysis, statistics,
revision of manuscript

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Interact Cardiovasc Thorac Surg. 2020, 31(1):48-55.\selectlanguage{english}
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