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\begin{document}

\title{Factors Contributing to Energy Loss in Left Ventricle during Diastolic
and Systolic Phases in Elderly Patients.}



\author[1]{Shutaro Futami}%
\author[1]{Joji Ishikawa}%
\author[1]{Teppei Maeda}%
\author[1]{Masuyo Kawano}%
\author[1]{Chieko Sakurayama}%
\author[1]{Kazumasa Harada}%
\affil[1]{Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology}%


\vspace{-1em}



  
  \date{June 12, 2024}


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





\selectlanguage{english}
\begin{abstract}
Background: The change of left ventricular function deteriorated with
age because of gradual increases of blood pressure may result in
increased energy loss (EL) in left ventricle (LV). The present study
investigated EL in LV among hypertensive elderly patients and examined
factors contributing to EL. Methods: A single-center retrospective study
was performed on elderly hypertensive outpatients (?65 years) who
underwent echocardiography (N=105). EL in the LV was measured using an
vector flow mapping system, and factors affecting peak EL during the
early diastolic phase (ED-EL), late diastolic phase (LD-EL), and
systolic phase (Sys-EL) were evaluated. Result: Mean age was 79.9\selectlanguage{ngerman}±6.4
years (male 43\%). Mean ED-EL, LD-EL, and Sys-EL were 42.1±46.7,
75.6±60.2, and 40.4±40.2 mJ/N/s. In a stepwise regression analysis, the
E wave peak velocity of transmitral flow (unstandardized B=0.002, 95\%CI
0.001 to 0.002, standardized \selectlanguage{greek}β\selectlanguage{english}=0.547, p\textless{}0.001) and stroke
volume in the LV outflow tract (LVOT) (B=0.001, 95\%CI 0.000 to 0.001,
\selectlanguage{greek}β\selectlanguage{english}=0.190, p=0.034) were identified as factors affecting ED-EL. The
factors affecting LD-EL were the E/A ratio (B=-0.122, 95\%CI -0.180 to
-0.064, \selectlanguage{greek}β\selectlanguage{english}=-0.451, p\textless{}0.001) and peak velocity in LVOT
(unstandardized B=0.001, 95\%CI 0.0001 to 0.001, \selectlanguage{greek}β\selectlanguage{english}=0.339, p=0.003). The
factors influencing Sys-EL were peak velocity in LVOT (B=0.001, 95\%CI
0.001 to 0.001, \selectlanguage{greek}β\selectlanguage{english}=0.619, p\textless{}0.001) and the E/A ratio (B=-0.050,
95\%CI -0.087 to -0.013, \selectlanguage{greek}β\selectlanguage{english}=-0.241, p=0.008). Conclusion: Peak EL in the
LV was higher during diastolic phase than systolic phase among elderly
hypertensive patients. Peak EL during each phase was affected by
systolic blood flow in LVOT and LV transmitral flow.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Aging increases cardiovascular stiffness and structural changes due to
cardiomyopathy, hypertension, ischemia, or valvular diseases, resulting
in left ventricular (LV) diastolic dysfunction (1) (2) (3) (4).
Hypertension is one of the most common problems in the elderly and
regarded as one of the most important cardiovascular risk factors (5).

Hypertension in the elderly often progresses to arteriosclerosis and
cardiovascular diseases, which changes LV myocardial tissue, such as
structural remodeling or impaired function (6). These changes cause LV
diastolic dysfunction, which leads to heart failure (HF) with diastolic
disfunction despite preserved LV ejection fraction (LVEF) (7). The
mortality rates are higher in patients with than in those without LV
diastolic dysfunction even when HF is not indicated (8). Therefore, the
diagnosis of LV diastolic dysfunction is important. However, the
assessment of LV diastolic dysfunction is complicated (9).

Vector flow mapping (VFM) can visualize intraventricular blood flow with
velocity vectors (10, 11). This new technology is also used to calculate
hemodynamic parameters, such as flow energy loss (EL) and shear stress,
based on actual measurements. Regarding EL in the LV, three main peaks
are observed in one cardiac cycle: in the early diastolic phase (ED),
late diastolic phase (LD), and systolic phase (Sys) (12). Previous
studies evaluated EL in the LV of healthy adults (29.5 \selectlanguage{ngerman}± 4.8 years old)
(12) and children (13) using VFM. Recent study also showed VFM could be
considered as an important supplementary tool to quantitatively evaluate
the impaired blood flow efficiency and LV diastolic function in patients
with various diastolic dysfunction(14).

LV function deteriorates with age because of gradual increases of blood
pressure (BP) and the mass of the LV (9). Therefore, the change of LV
function caused by aging and increased blood pressure might have the
effect to EL in the LV. However, the standard data in the elderly
remains unknown and the factors responsible have not yet been
identified. The present study was conducted to measure EL in the LV
using VFM among elderly patients with hypertension and identify the
factors contributing to peak EL during each phase.

\textbf{Method}

\textbf{Study population}

A single-center retrospective analysis of echocardiographic data
obtained between September 1st 2015 and December 31st 2018 was
performed. Data were collected on elderly outpatients with hypertension
(\selectlanguage{english}[?]65 years) who underwent echocardiography using Profound F 75 Premier
(Hitachi Ltd., Tokyo, Japan) (N=105). Hypertension was defined as
BP\selectlanguage{english}[?]140/90 mmHg or the use of antihypertensive medication. Exclusion
criteria were as follows: (1) atrial fibrillation at the time of
echocardiography, (2) severe valvular diseases, (3) local LV wall motion
abnormalities, (4) current decompensated HF, (5) a history of myocardial
infarction, and (6) a history of cardiac surgery. The present study was
approved by the Ethics Committee of Tokyo Metropolitan Geriatric
Hospital (R18-44). Informed consent was not obtained from patients
because this was a retrospective analysis of conventional clinical
practice data; therefore, information on the opt-out policy was provided
on the hospital website.

\textbf{Data collection}

Data were obtained on clinical history, and venous blood samples at the
time of echocardiography. In the hospital, values for eGFR, a measure of
glomerular filtration function, were calculated using the Chronic Kidney
Disease Epidemiology Collaboration Formula, and serum brain natriuretic
peptide (BNP) levels were measured by an enzyme immunoassay (E test
TOSOH II (BNP), TOSOH Corporation, Tokyo, Japan) with a coefficient of
variation \textless{}15\%.

\textbf{Echocardiography}

Echocardiographic data obtained using the ultrasound device Profound F
75 Premier (Hitachi Ltd, Tokyo, Japan) with a 1-5 MHz sector probe
(UST-52105) were analyzed. Echocardiography was performed by experienced
sonographers (T.M., M.K., and C.S.) Standard 2D resting echocardiography
was conducted in the lateral decubitus position. Conventional
echocardiographic data were collected in accordance using the method
recommended by the American Society of Echocardiography (9) (15) (16).
The modified Simpson's biplane method was used to calculate LVEF and the
left atrial volume index (LAVI). Transmitral E and A wave peak
velocities were obtained in the apical three-chamber view. Diastolic
mitral annular velocities (e' and a') were obtained using Doppler tissue
imaging at the septal side of the mitral annulus from the apical
four-chamber view. Peak velocities in the LV outflow tract (LVOT),
aortic valve, and tricuspid valve were assessed using continuous Doppler
imaging.

Cine loop color images from the apical three-chamber view were acquired
for use in the VFM analysis. The colored area of this movies is set to
include the entire LV area, LV inflow tract, and LVOT during all cardiac
cycles. The Doppler area were optimized in order to achieve the highest
frame rate. The Nyquist limit set for 2D color Doppler imaging was 69.3
cm/s.

\textbf{Analysis by VFM}

Optimized two-dimensional ultrasound color movies of the apical
three-chamber view were transferred to a computer with the VFM software
DAS-RS1 (Hitachi Ltd., Tokyo, Japan). Each image of one cardiac cycle
was selected using electrocardiography. All aliasing phenomena were
checked, and the aliasing area was manually corrected. The LV
endocardial boundary was initially traced manually and was then traced
automatically throughout the remaining frames. The software used
calculated intracardiac EL in one cardiac cycle from VFM images.

By echocardiography and electrocardiography, one cardiac cycle was
separated into the following three phases: ED, LD and Sys. ED was
defined as the phase from the opening of the mitral valve to before the
start of atrial contraction. LD was defined as the phase from the start
of atrial contraction to the closing of the mitral valve. Peak EL in
each phase was collected as a parameter. An example of the VFM analysis
in the present study is shown in Figure 1.

\textbf{Statistical analysis}

Data were shown as means +- standard deviations for continuous variables
and percentages for categorical variables. Pearson's correlation
coefficients were used to assess relationships between peak EL in ED,
LD, and Sys (ED-EL, LD-EL, and Sys-EL, respectively) and age, height,
weight, sex, comorbidities, heart rate (HR), BP, laboratory data, and
echocardiographic parameters. A stepwise multivariate linear regression
was performed to analyze independent variables that correlated with
ED-EL, LD-EL, and Sys-EL. All statistical analyses were performed using
SPSS software version 20 (IBM Inc., Chicago, IL, USA). A P value less
than 0.05 was considered to be significant.

\textbf{Results}

\textbf{Patient characteristics}

Patient characteristics are shown in Table 1 (N=105). Mean age was
79.9+-6.4 years, and 43\% were male. In total, 9\% of patients had a
history of paroxysmal atrial fibrillation, but had sinus rhythm at the
time of echocardiography. HR and BP were controlled (HR 63.2+-10.9
beats/min, systolic BP 125.8+-17.3 mmHg, and diastolic BP 65.4+-11.1
mmHg). The mean serum BNP level was 65.8+-83.2 pg/ml.

Echocardiographic parameters in the present study are shown in Table 2.
Patients mostly had preserved LVEF (67.3+-5.6\%) and diastolic
dysfunction. The average E wave was 59.3 cm/s, A wave 84.6 cm/s, and E/A
ratio 0.72. Most patients exhibited LA dilatation (LAVI 35.6+-32.4
ml/m\textsuperscript{2}).

\textbf{EL in each phase}

Table 3 shows EL in each phase. ED-EL and LD-EL were higher than Sys-EL,
while LD-EL was higher than ED-EL. No significant differences were
observed in peak EL between males and females.

\textbf{Relationships between peak EL during each phase and other
parameters (univariate analysis)}

Table 4 shows the correlation coefficients of peak EL to other
variables. Figure 2 shows a scatter plot of peak EL during each phase
and some variables.

Age, systolic BP, and mean BP did not correlate with peak EL during any
phase. Diastolic BP correlated with ED-EL (r=-0.251, p=0.011). The LV
mass index (LVMI) and LAVI did not correlate with peak EL during any
phase.

ED-EL correlated with the indices of diastolic function (E wave peak
velocity, A wave peak velocity, E/A, E/e' in the septal side, and E/e'
in the lateral side; p\textless{}0.05). LD-EL also correlated with A
wave peak velocity (r=0.513, p\textless{}0.001) and the E/A ratio
(r=-0.358, p\textless{}0.001). ED-EL and LD-EL both correlated with the
parameters of LVOT (diameter, peak velocity, and the time velocity
integral (TVI); p\textless{}0.05).

Sys-EL correlated with EF (r=0.342, p=0.001) and the parameters of LVOT
(diameter, peak velocity, and TVI; p\textless{}0.05). It also correlated
with the A wave peak velocity (r=0.233, p=0.017) and the E/A ratio
(r=-0.240, p=0.014).

\textbf{Multivariate analysis of relationships between EL and other
parameters}

Table 5 shows the correlation coefficients of peak EL during each phase
to a number of parameters. Factors contributing to ED-EL were
transmitral flow E wave peak velocity and stroke volume in LVOT, while
those correlated to LD-EL were transmitral flow A wave peak velocity and
peak velocity of LVOT. Sys-EL correlated with peak velocity in LVOT and
E/A.

\textbf{Discussion}

The present study assessed peak EL in three major phases of the cardiac
cycle in elderly patients with hypertension. The results obtained showed
that age and LVMI did not correlate with peak EL in these patients and
that the indices of transmitral flow and LVOT parameters were associated
with ED-EL, LD-EL, and Sys-EL.

Three peaks were observed in EL in the LV cavity of elderly outpatients
in the present study, which is consistent with previous findings (12)
(13) (14) (17). In the present study, ED-EL and LD-EL were higher than
Sys-EL, while LD-EL was higher than ED-EL. These results were in
contrast to the findings obtained from children and young healthy
volunteers, showing that ED-EL was more likely to be higher than LD-EL
(12) (13).

In the present study, a direct correlation was not observed between EL
and age; however, EL correlated with the parameters of diastolic
function. Diastolic function in the LV decreases with age (1). Aging is
associated with cardiovascular stiffness and structural changes due to
cardiomyopathy, ischemia, or ventricular dysfunction, resulting in LV
diastolic dysfunction. Diastolic function in the LV involves relaxation
and compliance. Regarding echocardiographic parameters, reduced LV
relaxation generally decreases the E/A ratio and e', leading to an
impaired relaxation pattern (9). The JAMP (The Japanese Normal Values
for Echocardiographic Measurements Project) study previously reported
normal values for echocardiographic parameters in a healthy Japanese
population and showed that the age at which E wave and A wave heights
are reversed in a healthy population is approximately 60 years old (18).
Patients in the present study were older than 60 years (between 66 and
97 years), and all had hypertension; therefore, LV diastolic dysfunction
of varying severities was more prevalent in this group than in children
and a young healthy population. The differences observed in EL patterns
between the elderly patients in the present study and children or a
young healthy population in previous studies were attributed to LV
diastolic dysfunction.

In the present study, a higher E wave velocity positively correlated
with higher ED-EL. Due to the age of this study group, very few patients
had normal diastolic function. Therefore, the higher E wave velocity in
this study reflected the severity of LV diastolic dysfunction, resulting
in higher ED-EL. Wang et al. previously examined LV diastolic
dysfunction and EL in chronic kidney diseases patients with preserved
LVEF (LVEF\selectlanguage{english}>50\%) and sinus rhythm based on blood fluid dynamics using
VFM (7). The findings obtained revealed that ED-EL and LD-EL were higher
in patients with grade II or III diastolic dysfunction than in those
with grade \selectlanguage{english}I, and were also higher in patients with grade I diastolic
dysfunction than in the control group. The majority of patients in the
present study had grade \selectlanguage{english}I or II diastolic dysfunction, and the peak
diastolic EL pattern observed was similar to that reported previously.
Therefore, this suggested that LV diastolic dysfunction caused by aging
and hypertension increased ED-EL and LD-EL in the LV cavity.

The proportion of patients with HF and preserved EF (HFpEF) is high in
the elderly (16) (14, 19). HFpEF often necessitates the evaluation of LV
diastolic function. Diastolic dysfunction is assessed by combining
various measurements obtained from echocardiography (9); however, this
method is complex. The present results and previous findings indicated a
relationship between EL in LV and LV diastolic function (14) (20).
Therefore, the evaluation of LV EL in each phase, which is simpler than
existing methods, has potential as a useful and comprehensive parameter
for assessing diastolic function.

Sys-EL correlated with peak velocity in LVOT and the E/A ratio. Peak
velocity in LVOT showed a positive correlation. Based on patient
backgrounds and exclusion criteria, the patient population examined in
the present study had relatively stable cardiac function and none had
more than moderate valvular diseases. Therefore, it is considered that
morphological changes in LVOT, such as sigmoid septum or hypertensive
hypertrophy, which are often observed in elderly patients, affected LVOT
parameters. These morphological factors need to be considered in future
research. The E/A ratio negatively correlated with Sys-EL. The E/A ratio
is a comprehensive index of LV diastolic function and is used to
evaluate left ventricular relaxation ability, LV filling pressure, and
atrial function (9) (21). In elderly patients, a higher E/A ratio
reflects more severe diastolic dysfunction of LV and often accompanies
LV systolic dysfunction. Therefore, a higher E/A ratio is associated
with lower Sys-EL. The results obtained on the E/A ratio in the present
study suggested that diastolic function affected not only diastolic, but
also systolic blood flow. Previous studies reported that the incidence
of isolated diastolic HF was low and many patients with diastolic HF
exhibited subclinical systolic function (22) ((23), which was consistent
with the present results on the E/A ratio in Sys.

LVOT TVI and flow velocity positively correlated with ED-EL and LD-EL
(Figure 2), suggesting that LVOT blood flow affected LV diastolic
function. Blood is viscous and generates frictional heat due to its
viscosity at sites at which turbulent flow and vortexes occur. The
energy of this frictional heat is called EL in blood flow. EL increases
at sites at which large vortexes occur locally and is smaller at those
with laminar flow (7) (8) (20). In the present study, LVOT parameters
related to vector positively correlated with EL in the LV during ED, LD,
and Sys. The morphology of the LVOT affects the formation of LV blood
flow. Therefore, the morphology of the LVOT might be associated to
intraventricular vector change, not only during Sys, but also ED and LD.
Previous studies investigated vortexes in the LV cavity and their
contribution to EL (14, 20) (24). The present study did not assess the
formation of vortexes. The LVOT diameter did not correlate with EL in
this study. Therefore, other factors affecting the morphology of LVOT,
such as the angle between LVOT and LV inflow or sigmoid septum, may
contribute to EL. In future studies, it is necessary to investigate the
effects of these left ventricular outflow tract morphology-related
factors on left ventricular blood flow and vortex formation.

\textbf{Limitations}

The present study was performed at a single center and the number of
subjects was small. Accordingly, the results obtained need to be
confirmed in a larger number of subjects. Furthermore, it was not
possible to evaluate VFM in 3D fields. Blood flow is affected by the
structure of the LV. Therefore, evaluations of blood flow in 3D fields
will be more precise than those in 2D fields. This is a technical
limitation that will be overcome with technological advances in VFM.
Another limitation was the severity of diastolic dysfunction. The
results of the present study showed diastolic dysfunction may affect
peak EL in ED, LD, and Sys. The grading of LV diastolic dysfunction and
comparisons of peak EL in each phase may result in more detailed
assessments. Therefore, the relationship between EL and the grade of
diastolic dysfunction needs to be investigated in more detail in future
studies. The present study also did not evaluate vortexes, which need to
be assessed in each phase.

\textbf{Conclusion}

Among elderly patients with hypertension, peak EL in the LV was higher
during ED and LD than during Sys, and peak EL in the LV during the three
phases was affected by systolic blood flow in LVOT and LV transmitral
flow. It also suggested that diastolic dysfunction may be an important
factor influencing EL.

\textbf{Disclosures}

None.



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\textbf{Figure Legends}

Figure 1: An example VFM analysis of three phases.

Peak energy loss in the left ventricle in one cardiac cycle was observed
in the following three phases: the early-diastolic phase, late-diastolic
phase, and systolic phase.

LA, left atrium; LV, left ventricle; Ao, Ascending Aorta.

Figure 2: A scatter plot of peak energy loss during each phase versus
variables.

EL, energy loss; ED, early-diastolic phase; TMF, transmitral flow; LVOT,
left ventricular outflow tract; TVI, time velocity integral; LD,
late-diastolic phase; E/A, peak velocity of the transmitral E wave to
that of the A wave.

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\textbf{Hosted file}

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