\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{Accuracy of The Single Beat Method for Assessment of Mitral Valve
Stenosis Severity in Atrial Fibrillation}



\author[1]{Tengku Ardini}%
\author[2]{Amiliana Soesanto}%
\author[2]{Rina Ariani}%
\author[2]{Estu Rudiktyo}%
\author[2]{Ario Kuncoro}%
\affil[1]{Rumah Sakit Umum Pusat Haji Adam Malik Medan}%
\affil[2]{University of Indonesia Faculty of Medicine}%


\vspace{-1em}



  
  \date{May 03, 2024}


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





\selectlanguage{english}
\begin{abstract}
\textbf{Purpose}: In mitral stenosis (MS) patients, determining stenosis
severity in atrial fibrillation (AF) is time-consuming by averaging
measurement by multiple cardiac cycles. Whether a single beat method can
be used to measure the mitral valve area (MVA) and transmitral gradient
for stenosis severity assessment in AF is still uncertain.
\textbf{Methods}: Forty-eight MS patients with AF (mean age 46.8+8.6
years) underwent routine echocardiographic study. The MVA by pressure
half time (PHT) and transmitral mean gradient were measured by four
methods: the standard approach (averaging multiple beats), single short
R-R cycle, single long R-R cycle, and single beat RRp/RRpp = 1. 2D and
3D planimetry MVA were measured at the mitral orifice. \textbf{Results}:
The single beat RRp/RRpp = 1 showed no significant difference in MVA PHT
measurement compared with standard approach (0.8 (0.3 -- 2.7 vs 0.9 +
0.3 cm \textsuperscript{2} ) cm \textsuperscript{2}, \emph{P} = 0.472),
whereas there was a significant difference in MVA by PHT when short R-R
cycle (1.0 (0.4 -- 2.7) cm \textsuperscript{2}, \emph{P} = 0.0001) and
long R-R cycle (0.8 (0.3 -- 1.7) cm \textsuperscript{2}, \emph{P} =
0.013) were selected. There was a significant difference in mean MVG
measurement when short R-R cycle (12.1 + 3.9 mmHg, \emph{P} = 0.001) ,
long R-R cycle (10.1 + 4.0 mmHg, \emph{P} = 0.007), and single beat
RRp/RRpp = 1 (12.2 + 4.4 mmHg, \emph{P} = 0.0001) were selected.
Correlation coefficients for MVA PHT calculated by single beat RRp/RRpp
= 1 compared with MVA PHT measured by standard approach are \emph{r} =
0.87 ( \emph{P} \textless{} 0.001). There is weak correlation in
measurement MVA between PHT single beat RRp/RRpp = 1 and 3D planimetry (
\emph{r} = 0.316, \emph{P} = 0.044). \textbf{Conclusion}: In AF, the
single beat method RRp/RRpp = 1 for measurement MVA by PHT in MS has a
high correlation with the current standard approach by averaging
multiple beats. Compared with MVA by 3D planimetry as the reference
measurement of MVA, measurement of MVA by PHT standard approach and
single beat RRp/RRpp = 1 have a weak correlation in AF patients. MVA by
planimetry especially 3D planimetry, is considered as a reference
measurement, but MVA by PHT single beat RRp/RRpp =1 can be an
alternative, especially when MVA by planimetry is not feasible.%
\end{abstract}%



\sloppy


\textbf{TITLE PAGE}

Title : \textbf{Accuracy of The Single Beat Method for Assessment of
Mitral Valve Stenosis Severity in Atrial Fibrillation}

Authors : \textbf{Tengku W Ardini\textsuperscript{1*}, Amiliana M
Soesanto\textsuperscript{2}, Rina Ariani\textsuperscript{2} , Estu
Rudiktyo\textsuperscript{2} , Ario S Kuncoro\textsuperscript{2}}

\textsuperscript{1}Department of Cardiology and Vascular Medicine,
Faculty of Medicine, Sumatera Utara University, General Hospital of Haji
Adam Malik, Medan, Indonesia.

List of Authors :\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Title * (Dr/Mr/Mrs/Ms/Miss/Prof)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
First Name*\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Middle Name\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Last Name*\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
E-mail\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Affiliation* (Institution, City, Country)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dr\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Tengku\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Winda\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ardini\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
tengkuwinda@gmail.com\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{1}Department of Cardiology and Vascular Medicine,
Faculty of Medicine, Sumatera Utara University, General Hospital of Haji
Adam Malik, Medan, Indonesia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dr\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Amiliana\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mardiani\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Soesanto\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
amiliana14@gmail.com\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{2}Department of Cardiology and Vascular Medicine,
Faculty of Medicine, University of Indonesia, National Cardiovascular
Center of Harapan Kita, Jakarta, Indonesia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dr\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Rina\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ariani\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Rina.ariani@yahoo.com\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{2}Department of Cardiology and Vascular Medicine,
Faculty of Medicine, University of Indonesia, National Cardiovascular
Center of Harapan Kita, Jakarta, Indonesia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dr\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Estu\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Rudiktyo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
esturudi@gmail.com\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{2}Department of Cardiology and Vascular Medicine,
Faculty of Medicine, University of Indonesia, National Cardiovascular
Center of Harapan Kita, Jakarta, Indonesia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Dr\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ario\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Soeryo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Kuncoro\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
arioskoe@yahoo.com\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{2}Department of Cardiology and Vascular Medicine,
Faculty of Medicine, University of Indonesia, National Cardiovascular
Center of Harapan Kita, Jakarta, Indonesia\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{*Corresponding Author:} Tengku Winda Ardini, MD. Department of
Cardiology and Vascular Medicine, Faculty of Medicine, Sumatera Utara
University, General Hospital of Haji Adam Malik, Medan, Indonesia.
Email: \emph{tengkuwinda@gmail.com} ORCID iD: 0000-0003-1715-5984.

\textbf{Data Availability Statement :} The authors confirm that the data
supporting the findings of this study are available within the article.

\textbf{Funding Statement:} This research did not receive any specific
grant from funding agencies in the public, commercial, or not-for-profit
sectors.

\textbf{Conflict of Interest Disclosure :} The authors report no
conflicts of interest. The authors alone are responsible for the content
and writing of this article. This research did not receive any financial
support.

\textbf{Ethics Approval Statement:} Ethical clearance was obtained from
The Committee on Instutional Review Board/Health Reasearch Ethics of
National Cardiac Center ``Harapan Kita'' Hospital.

\textbf{Author's contribution:} Data gathering, and ideas, study design,
writing, submitting of manuscript, editing and approval of final draft,
were all events conducted by the authors.

\textbf{Patient Consent Statement} : written consent obtained from every
participant.

\textbf{Permission to Reproduce Material from Other Source} : not
applicable.

\textbf{Clinical Trial Registration:} N/A



\textbf{INTRODUCTION}

Echocardiography plays an important role in assessing valve anatomy,
stenosis severity, and its consequences in mitral stenosis (MS) {[}1{]}.
Doppler has a principal part in quantitation stenosis severity. In
patients with atrial fibrillation (AF), Doppler assessment is limited by
the variability in cycle length {[}2{]}. It should be calculated as the
average of at least five cycles with the least variation of R--R
intervals and as close as possible to normal heart
rate\textsuperscript{1}. This method of calculating stenosis severity in
AF is time-consuming and may still lead to inaccurate area assessment
depending on the R-R intervals included in the calculations {[}3{]}.

In patients with MS and irregular ventricular rate due to AF, beat to
beat variations in the filling of the left ventricle take place due to
alterations in the duration of the filling period. It was considered
that if Starling's law of the MS, the characteristic of each left
ventricular (LV) contraction should appear to be a function of the
previous end-diastolic fiber length {[}4{]}. Beat to beat variation in
LV performance shows not only changes in contractility but changes in
preload {[}5{]}. Previous end-diastolic fiber length defined as the
preceding R-R interval (RRp) and pre-preceding R-R interval (RRpp).
Previous studies reported a significant positive linear relationship
between LV pressure and the ratio of preceding R-R to pre-preceding R-R
(RRp/RRpp). Some studies reported the value at RRp/RRpp =1 has the
linear regression line that could estimate stable LV performance
{[}6-10{]}. Previous studies reported the single long cycle length
method of calculating valvular stenosis could be used instead of
averaging multiple cardiac cycles {[}3{]}.

This study aims to determine whether a single beat method can be used
for severity assessment of MS compared with averaging at least five
cycle method as the standard approach and mitral valve area (MVA) by 3D
planimetry as the reference measurement in MVA when the patients have
AF.

\textbf{MATERIAL AND METHODS}

The study population consists of 48 patients with MS and AF, 18-55 years
old, who were undergone transthoracic or transoesophageal
echocardiography at National Cardiovascular Center Harapan Kita in
Jakarta from September 2019 until January 2020. Baseline characteristics
were recorded for all patients, including age, body surface area (BSA),
heart rate, systolic and diastolic blood pressure, and echocardiography
data (Table 1). The heart rate must be between 60 and 100 bpm. Patients
were excluded if they had significant mitral regurgitation, significant
aortic valve abnormality, and concomitant congenital heart disease. The
study was approved by the institutional review board on human research.

\textbf{Echocardiography Analysis}

All patients underwent complete transthoracic and transesophageal
echocardiographic evaluation using GE Vivid E9 system (GE Vingmed
Ultrasound AS, Horten, Norway) with a 1.4-4.6 MHz for trans-thoracal and
3-8 MHz for transesophageal transducer. All data were analyzed in a
workstation (EchoPAC PC; GE Vingmed Ultrasound AS). MS severity is
evaluated based on the 2009 EAE/ASE Recommendations Echocardiographic of
Assessment of Valve Stenosis for Clinical Practice and met the world
heart federation criteria for diagnosis of rheumatic MS {[}1,11{]}. 2D
and 3D planimetry MVA was measured at the mitral orifice.

Continuous-wave Doppler (CWD) was used to derive transmitral velocity,
and Doppler gradient was assessed using the apical window as it parallel
alignment of the ultrasound beam and mitral inflow. Pressure half time
(PHT) and mean mitral valve gradient (MVG) were measured and averaged
over five beats as a standard method at speed 66.6 m/s.

R-R interval is measured immediately preceding (RRp) and pre-preceding
(RRpp) the selected transmitral Doppler velocity. The short and long R-R
cycle define relative to the average heart rate. Transmitral gradient
and PHT was measured for a short R-R cycle and a long R-R cycle. Single
beat transmitral gradient and PHT was measured when RRp/RRpp = 1 (Figure
1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Fig. 1} . Measurement methods. Examples of measurement single
continuous-wave Doppler across a stenotic mitral valve (\emph{red
asterisk} ) are shown: short RR cycle (A), long RR cycle (B), single
beat RRp/RRpp = 1 (C).

\textbf{Statistical Analysis}

Statistical analyses were made using IBM SPSS Statistics for Windows,
version 23 (IBM Corp., Armonk, N.Y., USA). Normally distributed
variables were expressed as mean \selectlanguage{ngerman}± standard deviation (SD). Shapiro-Wilk
test was used for the normality test. For non-normally distributed
variables, the Wilcoxon rank-sum test was used to calculate
\emph{P}values. Spearman correlation coefficients calculated to
determine correlations between MVA PHT standard approach and single beat
methods.\emph{P} values \textless{} 0.05 were considered statistically
significant. Interclass correlation coefficients (ICCs) were used to
assess interobserver and intraobserver variability. The interobserver
and intraobserver variability was assessed from 18 studies.

\textbf{RESULTS}

\textbf{Baseline characteristic}

Forty-eight patients that have MS and AF, 18 were male, and 30 were
female. The mean age of the patients was 46.8\emph{+} 8.6 years, with
BSA 1.5\emph{+} 0.2 m\textsuperscript{2}. The median heart rate of the
patients was 85 (60-100) beats/min. MVA by planimetry 0.7 (0.4-1.8)
cm\textsuperscript{2}, MVA by PHT 0.8 (0.4-1.7) cm\textsuperscript{2},
and mean MVG 11 \emph{+} 4.1 mmHg. Detail baseline characteristics and
echocardiography data of 48 patients are shown in Table 1.

Table 1. Clinical Characteristics in All Patients (n = 48)\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Variable & N = 48\tabularnewline
\midrule
\endhead
Age (yrs) & 46.8 \emph{+} 8.6\tabularnewline
BSA (m\textsuperscript{2}) & 1.5 \emph{+} 0.2\tabularnewline
Sex (Male/Female) & 18/30\tabularnewline
HR (bpm) & 85 (60 -- 100)\tabularnewline
Systolic blood pressure (mmHg) & 120.3 \emph{+} 16.9\tabularnewline
Diastolic blood pressure (mmHg) & 79.3 \emph{+} 11.6\tabularnewline
Echocardiography data &\tabularnewline
LV ejection fraction (\%) & 56.5 \emph{+} 11.4\tabularnewline
LVOT diameter (cm) & 1.86 \emph{+} 0.23\tabularnewline
End diastolic LV dimension (mm) & 46.9 \emph{+} 6.1\tabularnewline
End systolic LV dimension (mm) & 33.2 \emph{+} 6.1\tabularnewline
LA volume index (ml/m\textsuperscript{2}) & 110 (50 --
408)\tabularnewline
MVA planimetry (cm\textsuperscript{2}) & 0.7 (0.4 -- 1.8)\tabularnewline
TVG (mmHg) & 51.3 \emph{+} 24\tabularnewline
TAPSE (mm) & 15.4 \emph{+} 3.4\tabularnewline
Wilkins score & 6 (4 -- 13)\tabularnewline
IVC dimension (mm) & 17.6 \emph{+} 5.4\tabularnewline
MVA PHT (cm\textsuperscript{2}) & 0.9 \emph{+} 0.3\tabularnewline
Mean MVG (mmHg) & 11 \emph{+} 4.1\tabularnewline
LVOT VTI (cm) & 14.3 \emph{+} 3.0\tabularnewline
Stroke Volume (ml) & 39 \emph{+} 12.1\tabularnewline
\bottomrule
\end{longtable}

BSA = body surface area; HR = heart rate; LV = left ventricle; LVOT =
left ventricle outflow track; LA = left atrium; MVA = mitral valve area;
TVG = tricuspid valve gradient; TAPSE = tricuspid annular plane systolic
excursion; IVC = inferior vena cava; PHT = pressure half time; MVG =
mitral valve gradient; VTI = velocity time integral.

\textbf{MVA PHT and mean MVG}

The average of MVA PHT measured by the standard approach was 0.9\emph{+}
0.3 cm\textsuperscript{2}. By the single beat method, there was a
significant difference in MVA PHT when short R-R cycle (1.0 (0.4-2.7)
cm\textsuperscript{2}, \emph{P} = 0.0001) and long R-R cycle (0.8
(0.3-1.7) cm\textsuperscript{2}, \emph{P} = 0.013) were selected. When
single beat RRp/RRpp = 1 were used, there was no significant difference
in MVA PHT measurement compared with the standard approach (0.8
(0.3-2.7) cm\textsuperscript{2}, \emph{P} = 0.472). The average of mean
MVG measured by the standard approach was 11.0\emph{+} 4.1 mmHg. There
was a significant difference in mean MVG measurement when short R-R
cycle (12.1\emph{+} 3.9 mmHg, \emph{P} = 0.001) , long R-R cycle
(10.1\emph{+} 4.0 mmHg, \emph{P} = 0.007), and single beat RRp/RRpp = 1
(12.2\emph{+} 4.4 mmHg, \emph{P} = 0.0001) were selected (Table 2).

Table 2. MVA PHT and mean MVG variables measured by different methods\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Variable & Standard approach (a) & Single-cycle short RR (b) &
Single-cycle long RR (c ) & Single beat RRp/RRpp = 1 (d) & \emph{P}
value a vs b & \emph{P} value a vs c & \emph{P} value a vs
d\tabularnewline
\midrule
\endhead
MVA PHT & 0.9 \emph{+} 0.3 & 1.0 (0.4 -- 2.7) & 0.8 (0.3 -- 1.7) & 0.8
(0.4 -- 2) & 0.0001 & 0.013 & 0.472\tabularnewline
Mean MVG & 11.0 \emph{+} 4.1 & 12.1 \emph{+} 3.9 & 10.1 \emph{+} 4.0 &
12.2 \emph{+} 4.4 & 0.001 & 0.007 & 0.0001\tabularnewline
\bottomrule
\end{longtable}

MVA = mitral valve area; PHT = pressure half time; MVG = mitral valve
gradient.

\textbf{Correlation of MVA PHT Measured by Standard Approach versus
Single Beat RRp/RRpp =1}

Correlation coefficients for MVA PHT calculated by single beat RRp/RRpp
= 1 compared with MVA PHT measured by standard approach are \emph{r} =
0.87 (\emph{P} \textless{} 0.001). There was a strong positive
correlation between MVA PHT standard approach and single beat RRp/RRpp =
1. Figure 2 shows a good agreement when comparing MVA PHT standard
approach method with the single beat RRp/RRpp = 1 method.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Fig. 2} . Bland-Altman plots assessing differences in MVA PHT
measurement for standard approach method and single beat RRp/RRpp = 1
method.

\textbf{MVA PHT Single Beat RRp/RRpp = 1 Method and MVA 3D Planimetry}

Forty-one patients underwent 3D TEE MVA planimetry. There was a weak
correlation between MVA PHT single beat RRp/RRpp = 1 and 3D planimetry
(\emph{r} = 0.316, \emph{P} = 0.044). Figure 3 shows a good agreement
when comparing MVA 3D planimetry with the PHT single beat RRp/RRpp = 1
method.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Fig. 3} . Bland-Altman plot assessed differences in MVA
measurement for 3D planimetry and PHT single beat RRp/RRpp = 1 method.

\textbf{Intra- and Interobserver Variability for MVA PHT Single Beat
RRp/RRpp = 1 Method}

The interclass correlation coefficients (ICC) for interobserver
variability for MVA PHT single beat RRp/RRpp = 1 method was 0.94 (95\%
CI, 0.70 -- 0.98). The ICC for intraobserver variability was 0.91 (95\%
CI, 0.56-0.97).

\textbf{DISCUSSION}

Multiple measurements in AF patients is a tedious task, especially in
high volume echocardiography laboratory. The single beat measurement can
be an alternative to the standard method by averaging at least five
cycles. Esquitin et al. reported the use of a single long cycle length
method that has the highest correlation with the current standard
approach of averaging multiple beats for calculation of EOA (effective
orifice area) in aortic stenosis and AF patients {[}3{]}. For
transmitral flow, Kusunose et al. reported the single beat preceding RR
interval (RRp)/pre-preceding RR interval (RRpp) = 1 has a good positive
linear relationship compared with the standard method by averaging
multiple beats for E/e' lateral measurement in AF and preserved systolic
function patients {[}10{]}. Some studies reported the value at RRp/RRpp
=1 has the linear regression line that could estimate stable LV
performance {[}6-10{]}. In this study, we try to determine whether
single short R-R cycle, long R-R cycle, and single beat RRp/RRp = 1 can
be used for the severity assessment of MS.

Beat to beat variation in ventricular performance associates with
variations in the length of the preceding heart period. It was
consistent with the Frank-Starling mechanism. During regular rhythm,
there is a simple relationship between the constant ventricular cycle
length (VCL) and the heart rate (HR), namely HR (bpm) = 60.000/VCL (ms).
According to the equation, a prolongation of VCL is equivalent to a
slower heart rate. Otherwise, the shortening of VCL is equivalent to a
faster heart rate. Previous study has shown that faster AF or short R-R
cycle correlates with less maximum LV power, dP/dtmin, and the time
constant of relaxation (t). Otherwise, slower AF or long R-R cycle
showed an increase in maximum LV power and dP/dtmin, while t decreased
i.e. the relaxation improved {[}6{]}. It was consistent with MVA by PHT
measurement. It was smaller when the long R-R cycle, and larger when
short R-R cycle. A short time interval makes a shorter PHT due to a
faster decline of the velocity of diastolic transmitral blood flow. The
long-time-interval makes a longer PHT due to the slower decline of the
transmitral flow. PHT is inversely proportional to MVA {[}1{]}. This
explanation applies to the transmitral gradient; the short R-R cycle has
an association with a higher gradient and long R-R cycle with a lower
gradient. Shortened diastole in faster AF has an association with a
higher transmitral gradient {[}12{]}.

The main finding of this study is the measurement of MVA PHT by single
beat RRp/RRpp = 1 method results in a high correlation and good
agreement with the standard method of MVA by PHT for AF patients whereas
short R-R cycle and long R-R cycle have a significant difference
compared with the standard method. The previous study reported that
using a long R-R cycle in AF patients is the most accurate method for
assessing EOA {[}3{]}. EOA calculation using left ventricular outflow
tract (LVOT) velocity time integral (VTI) measurement reflects stroke
volume in systolic phase that influenced by previous end-diastolic fiber
length or preceding R-R cycle {[}4{]}. Studies have shown that
myocardial contractility and LV function are also directly related to
the ratio of preceding interval (RRp) to the pre-preceding interval
(RRp/RRpp). Different from AS severity calculation, measuring MVA by PHT
is from transmitral inflow in diastolic phase. Kusunose et al., reported
clinical utility single beat RRp/RRpp = 1 of transmitral flow for the
evaluation of LV diastolic function {[}10{]}. This is the first study
that evaluated the usefulness of the single beat RRp/RRpp = 1 MVA PHT
compared with standard approach in MS and AF patients.

The severity assessment of rheumatic MS should rely mostly on the valve
area. MVA by PHT and MVA by planimetry have level 1 recommendation to
assess stenosis severity. MVA by planimetry is a direct measurement of
MVA, unlike other methods, does not involve any hypothesis regarding
flow conditions, cardiac chamber compliance, or associated valvular
lesion. It has been shown to have the best correlation with the
anatomical valve area {[}1{]}. Real-time three-dimensional (3D)
echocardiography reported as a feasible, accurate, and highly
reproducible technique for assessing MVA in MS patients {[}13{]}. This
study also analyzed the correlation between MVA PHT single beat RRp/RRpp
=1 method with MVA 3D planimetry as reference measurement. There was a
weak correlation in measurement MVA between PHT single beat RRp/RRpp = 1
and 3D planimetry. Since MVA planimetry has the best correlation with
anatomical MVA and does not influence by multiple factors, measurement
of MVA PHT single beat RRp/RRpp = 1 should not be the decisive parameter
when assessing MVA in MS and AF patients. MVA by planimetry, especially
3D planimetry, is considered as reference measurement of MVA. In some
conditions, planimetry measurement may not be feasible when there is a
poor acoustic window or severe distortion of valve anatomy, in
particular with severe valve calcifications of the leaflet tips {[}1{]}.
Especially in an industrialized country like Indonesia, the percentage
of significant elderly MS patients might be higher in whom planimetry is
not feasible. This method can be an alternative when planimetry MVA is
not feasible.

The mean gradient of transmitral flow is the relevant hemodynamic
findings. Although reliably assessed by Doppler, it is not the best
marker for MS severity {[}1{]}. In this study, there was a significant
difference in mean MVG measurement for single short R-R cycle, long R-R
cycle, and single beat RRp/RRpp = 1 compared with the standard approach
by averaging multiple beats (Table 2). The values of mean gradient
influenced by multiple factors and only a supportive sign and cannot be
considered as a surrogate indicator of the severity of MS. Mean gradient
can be a supportive sign at heart rates between 60 and 80 bpm in sinus
rhythm patients, and considered cannot be a supportive sign in AF
patients {[}1{]}. Sabbagh et al. reported low flow low gradient MS which
define as mean MVA planimetry less than 1.5 cm\textsuperscript{2} but
mean transmitral gradient \textless{}10 mmHg and stroke volume index
\textless{}35 mL/m\textsuperscript{2}. Presence of low gradient MS in
patients with severe MS associated with high arterial afterload,
prevalent AF, and decreased LV compliance {[}14{]}.

Our center is a national referral center whose patients from all regions
in Indonesia. Most patients in our center have significant to severe MS,
which is prepared for percutaneous balloon mitral valvuloplasty or
mitral valve surgery. Non-significant or mild MS were not represented in
this study.

\textbf{CONCLUSION}

In AF, the single beat method RRp/RRpp = 1 for measurement MVA by PHT in
MS has a high correlation with the current standard approach by
averaging multiple beats. Compared with MVA by 3D planimetry as the
reference measurement of MVA, measurement of MVA by PHT standard
approach and single beat RRp/RRpp = 1 have a weak correlation in AF
patients. MVA by planimetry, especially 3D planimetry, is considered as
a reference measurement, but MVA by PHT single beat RRp/RRpp =1 can be
an alternative, especially when MVA by planimetry is not feasible.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Baumgartner H, Hung J, Bermejo J, Chambers J, Evangelista A, Griffin
  BP, et al. (2009) Echocardiographic assessment of valve stenosis:
  EAE/ASE recommendation for clinical practice. European Journal of
  Echocardiography 10:1-25.
\item
  Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T,
  et al. (2016) Recommendation for the evaluation of left ventricular
  diastolic function by echocardiography: an update from American
  Society of Echocardiography and the European Association of
  Cardiovascular Imaging. J Am Soc Echocardiography 29:277-314.
\item
  Esquitin KA, Khalique OK, Liu Q, Kodali SK, Marcoff L, Nazif TM, et
  al. (2019) Accuracy of the single cycle length method for calculation
  of aortic effective orifice area in irregular heart rhythms. J Am Soc
  Echocardiogr 32:344-50.
\item
  Braundwald E, Frye RL, Aygen MM, Gilbert JW (1960) Studies on
  Starling's law of the heart, observation in patient with mitral
  stenosis and atrial fibrillation on the relationship between left
  ventricular end diastolic segment length, filling pressure, and the
  characteristic of ventricular contraction. J Clin Invest
  39(12):1874-84.
\item
  Nakamura Y, Konishi T, Nonogi H, Sakurai T, Sasayama S, Chuichi K
  (1986) Myocardial relaxation in atrial fibrillation. J Am Coll Cardiol
  7:68-73.
\item
  Popovic ZB, Mowrey KA, Zhang Y, Zhuang S, Tabata T, Wallick DW, et al.
  (2003) Slow rate during AF improves ventricular performance by
  reducing sensitivity to cycle length irregularity. Am J Physiol Heart
  Circ Physiol 283(6):2706-13.
\item
  Tabata T, Grimm RA, Greenberg NL, Agler DA, Mowrey KA, Wallick DW, et
  al. (2001) Assessment of LV systolic function in atrial fibrillation
  using an index of preceding cardiac cycles. Am J Physiol Heart Circ
  Physiol 281:573-80.
\item
  Suzuki S, Araki J, Morita T, Mohri S, Mikane T, Yamaguchi H, et al.
  (1998) Ventricular contractility in atrial fibrillation is predictable
  by mechanical restitution and potentiation. Am J Physiol Heart Circ
  Physiol 275(44):1513-19.
\item
  Yamaguchi H, Takaki M, Ito H, Tachibana H, Lee S, Suga H (1997)
  Pressure interval relationship characterized left ventricular
  irregular beat contractilities and their mean level during atrial
  fibrillation. Japanese Journal of Physiology 47:101-10.
\item
  Kusunose K, Yamada H, Nishio S, Tomita N, Niki T, Yamaguchi K, et al.
  (2009) Clinical utility of single beat E/e' obtained by simultaneous
  recording of flow and tissue Doppler velocities in atrial fibrillation
  with preserved systolic function. J Am Coll Cardiol Img 2:1147-56.
\item
  Rem\selectlanguage{ngerman}ényi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al.
  (2012) World heart federation criteria for echocardiographic diagnosis
  of rheumatic heart disease -- an evidence-based guideline. Nat Rev
  Cardiol 9:297--309.
\item
  Rahimtoola SH, Durairaj A, Mehra A, Nuno I (2002) Current evaluation
  and management of patients with mitral stenosis. Circulation
  106:1183-8.
\item
  Zamorano J, Cordeiro P, Sugeng L, Isla LP, Weinert L, Macaya C, et al.
  (2004) Real-time three-dimensional echocardiography for rheumatic
  mitral valve stenosis evaluation -- an accurate and novel approach. J
  Am Coll Cardioll 43:2091- 6.
\item
  Sabbagh AE, Reddy YNV, Gomes SB, Borlaug BA, Miranda WR, Pislaru SV,
  et al. (2019) Low-gradient severe mitral stenosis: hemodynamic
  profiles, clinical characteristics, and outcomes. J Am Heart Assoc
  8:e010736.
\end{enumerate}

\textbf{List of Tables}

\textbf{Table 1.} Clinical Characteristics

\textbf{Table 2.} MVA PHT and mean MVG variables measured by different
methods

\textbf{List of Figures}

\textbf{Fig. 1} . Measurement methods. Examples of measurement single
continuous-wave Doppler across a stenotic mitral valve (\emph{red
asterisk} ) are shown: short RR cycle (A), long RR cycle (B), single
beat RRp/RRpp = 1 (C).

\textbf{Fig. 2} . Bland-Altman plots assessing differences in MVA PHT
measurement for standard approach method and single beat RRp/RRpp = 1
method

\textbf{Fig. 3} . Bland-Altman plot assessed differences in MVA
measurement for 3D planimetry and PHT single beat RRp/RRpp = 1 method.

\textbf{ABSTRACT}

\textbf{Purpose} : In mitral stenosis (MS) patients, determining
stenosis severity in atrial fibrillation (AF) is time-consuming by
averaging measurement by multiple cardiac cycles. Whether a single beat
method can be used to measure the mitral valve area (MVA) and
transmitral gradient for stenosis severity assessment in AF is still
uncertain.

\textbf{Methods} : Forty-eight MS patients with AF (mean age
46.8\emph{+} 8.6 years) underwent routine echocardiographic study. The
MVA by pressure half time (PHT) and transmitral mean gradient were
measured by four methods: the standard approach (averaging multiple
beats), single short R-R cycle, single long R-R cycle, and single beat
RRp/RRpp = 1. 2D and 3D planimetry MVA were measured at the mitral
orifice.

\textbf{Results} : The single beat RRp/RRpp = 1 showed no significant
difference in MVA PHT measurement compared with standard approach (0.8
(0.3 -- 2.7 vs 0.9 \emph{+} 0.3 cm\textsuperscript{2} )
cm\textsuperscript{2}, \emph{P} = 0.472), whereas there was a
significant difference in MVA by PHT when short R-R cycle (1.0 (0.4 --
2.7) cm\textsuperscript{2}, \emph{P} = 0.0001) and long R-R cycle (0.8
(0.3 -- 1.7) cm\textsuperscript{2}, \emph{P} = 0.013) were selected.
There was a significant difference in mean MVG measurement when short
R-R cycle (12.1 \emph{+} 3.9 mmHg, \emph{P} = 0.001) , long R-R cycle
(10.1 \emph{+} 4.0 mmHg, \emph{P} = 0.007), and single beat RRp/RRpp = 1
(12.2 \emph{+} 4.4 mmHg, \emph{P} = 0.0001) were selected. Correlation
coefficients for MVA PHT calculated by single beat RRp/RRpp = 1 compared
with MVA PHT measured by standard approach are \emph{r} = 0.87
(\emph{P}\textless{} 0.001). There is weak correlation in measurement
MVA between PHT single beat RRp/RRpp = 1 and 3D planimetry (\emph{r} =
0.316,\emph{P} = 0.044).

\textbf{Conclusion} : In AF, the single beat method RRp/RRpp = 1 for
measurement MVA by PHT in MS has a high correlation with the current
standard approach by averaging multiple beats. Compared with MVA by 3D
planimetry as the reference measurement of MVA, measurement of MVA by
PHT standard approach and single beat RRp/RRpp = 1 have a weak
correlation in AF patients. MVA by planimetry especially 3D planimetry,
is considered as a reference measurement, but MVA by PHT single beat
RRp/RRpp =1 can be an alternative, especially when MVA by planimetry is
not feasible.

\textbf{Keywords} : Mitral stenosis, mitral valve area, pressure half
time, planimetry, mean gradient, atrial fibrillation.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/RR=1/RR=1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/long/long}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/short/short}

\end{center}
\end{figure}

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

