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\begin{document}

\title{Myocardial recruitment and the systolic efficiency slope; how do they
relate to exercise performance in healthy young adults?}



\author[1]{Jet van Zalen}%
\author[1]{Sveeta Badiani}%
\author[2]{Andrew d'Silva}%
\author[3]{Anish Bhuva}%
\author[1]{Nikhil Patel}%
\author[4,5]{Alun Hughes}%
\author[3]{Charlotte Manisty}%
\author[2]{Sanjay Sharma}%
\author[3]{James Moon}%
\author[3]{Guy Lloyd}%
\affil[1]{Eastbourne District General Hospital}%
\affil[2]{St George's University of London}%
\affil[3]{Saint Bartholomew's Hospital Barts Heart Centre}%
\affil[4]{University College London}%
\affil[5]{UCL}%


\vspace{-1em}



  
  \date{May 10, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aims The extent to which augmentation of heart function mirrors the
increased metabolic demands of the peripheral musculature is not well
characterised. The details of ventricular augmentation may provide
insight into determinants of cardiac efficiency for optimal exercise
performance. The aims were to establish how much of the variability in
exercise performance could be explained by myocardial recruitment, and
which parameter of systolic function was most closely related to
exercise performance. Methods and results Untrained volunteers were
recruited prior to training for the London Marathon. All performed a
cardiopulmonary exercise test combined with stress echocardiography.
Systolic and diastolic longitudinal velocities (S' and E'), ejection
fraction (LVEF), stroke volume (SV) and strain were obtained throughout
exercise. Continuous S' showed a strong correlation with absolute VO2
(rho=0.83;p\textless{}0.0001). Only SV and S' were predictive of
VO2peak. LVEF and E' as well as both global longitudinal and
circumferential strain showed no correlation. The systolic efficiency
slope (SES) was calculated by determining the individual regression
lines for VO2 and S'. A moderate relationship between the SES and
VO2peak was observed for both septal S'; r=0.57;p\textless{}0.001 and
lateral S', r=0.53;p\textless{}0.001). Conclusion A detailed description
of myocardial function is described; linear for S' and E' and a plateau
for EF and GLS. S' during exercise is a better predictor of exercise
performance than LVEF, SV or GLS. The SES slope was able to predict
VO2peak suggesting the process driving systolic velocity and its
augmentation is a key determinant of exercise ability.%
\end{abstract}%



\sloppy


\textbf{Keywords}

Cardiopulmonary exercise test

Stress echocardiography

Myocardial augmentation slope



\textbf{Introduction}

The relationship between resting echocardiographic measures of cardiac
function and exercise capacity is weak \textsuperscript{1--4}. At peak
exercise, left ventricular (LV) function, especially longitudinal
motion, is better correlated with maximum exercise
capacity\textsuperscript{5}. The shape of the relationship, as well as
the relative contribution of various measurable facets of heart function
is not known. Amongst athletes with phenotypically abnormal hearts,
augmentation of left ventricular ejection fraction (LVEF) by more than
10\% differentiates those with adaptive rather than cardiomyopathic
hearts \textsuperscript{6,7}. Understanding the shape to the
relationship between contractile reserve and exercise attainment is
vital to understand the physiology, and to establish target parameters
that might be useful when investigating disease states. We therefore
hypothesized that detailed measures of exercise myocardial recruitment
would explain individual exercise performance, and that longitudinal
function would be the primary adaptive strategy. This was achieved by
recording oxygen uptake (VO\textsubscript{2}) and echocardiography
simultaneously across an incremental exercise protocol in a cohort of
healthy volunteers.



\textbf{Methods}

Full details of the protocol have been previously
published\textsuperscript{8} and this was a pre-planned ancillary
analysis. Healthy participants were recruited in 2016 prior to
undertaking training their first marathon (Virgin Money London).
Inclusion criteria age was less than 35 years at recruitment, no past
significant medical history and no previous marathon running experience.
All procedures were in accordance with the principles of the Helsinki
declaration. All participants gave written informed consent and the
study was approved by the London-Queen Square National Research Ethics
Service Committee (15/LO/0086).

All measurements were conducted before training started over a
three-week period (three consecutive weekends after ballot place
announcement), six months prior to the marathon.

\subsection*{Data acquisition and
analysis}

{\label{data-acquisition-and-analysis}}

Cardiopulmonary exercise testing (CPET) was performed according to
exercise testing guidelines \textsuperscript{9}. Protocols were
individually determined with work rate (15-30 W) increased every minute
until voluntary exhaustion, aiming for 10 minutes of exercise. To permit
concurrent transthoracic echocardiography, studies were performed using
a semi-recumbent cycle ergometer (ERG 911 S/L, Schiller, Baar,
Switzerland). A 1-minute rest period was included followed by a 3-minute
warm up. Heart rate (HR), blood pressure and oxygen saturation were
monitored throughout. VO\textsubscript{2} was continuously measured
using a calibrated breath-by-breath analyser (Cosmed Quark CPET, Rome,
Italy). Participants were verbally encouraged to exercise until maximal
exertion. VO\textsubscript{2}peak was expressed as the highest value
from an average of 30 seconds during the final stage of the exercise
test. To fully assess submaximal efforts, the oxygen uptake efficiency
slopes (OUES) was calculated automatically from
VO\textsubscript{2}against the logarithm of V\textsubscript{E}
(logV\textsubscript{E})\textsuperscript{10}.

Echocardiography was performed using a GE Vivid E95 platform
(Vingmed-General Electric, Horten, Norway) equipped with a phased-array
transducer (1.4-4.6 MHz). A detailed protocol was collected at rest, at
5 minutes into exercise (excluding the 3-minute warm-up period), and
when the respiratory exchange ratio (RER) was above 1.0. This included
the apical 4-chamber view (with and without tissue velocity imaging
(TVI), the apical two-chamber, apical long axis view, parasternal short
axis view at the base and apical level, and a PW at the level of the
Left ventricular outflow tract (LVOT) (one centimetre below the aortic
valve). An abbreviated protocol was obtained every 1 minute and 15
seconds and included the apical 4-chamber view (with and without TVI).
As part of the protocol 12-lead ECG and cardiac magnetic resonance was
undertaken but not included in this analysis.

\textbf{Echocardiographic analysis}

All analyses were carried out offline using the GE Echopac software
(version 113). S' was derived from colour-derived TVI images where the
sample volume was placed at the annulus of the septal and lateral walls.
S' was defined as the highest velocity during systole after the end of
isovolumetric contraction. Three cardiac cycles were obtained and S' was
averaged for each time point. During the full protocol Simpson's biplane
was measured (in the apical 4-and 2-chamber view), global longitudinal
strain (GLS) in the three apical views and the LVOT velocity time
integral (VTI). Speckle-tracking strain analysis was accepted when the
software and visual inspection indicated adequate tracking. If tracking
was inadequate, manual adjustments were made or the analysis was
excluded from overall analyses. GLS was obtained from the apical
4-chamber view (basal septum, mid septum, apical septum, basal lateral,
mid lateral, and apical lateral), the apical 2-chamber view (basal
inferior, mid inferior, apical inferior, basal anterior, mid anterior,
apical anterior) and the apical long axis view (basal posterior, mid
posterior, basal anteroseptal, mid anteroseptal). If data was of
insufficient quality it was excluded from analyses. This was defined as
poor TVI tracing, exclusion of the mitral valve annulus (for colour TVI
measurements), or poor endocardial border definition (for biplane).
Eleven participants were excluded from analysis.

\textbf{Statistical analyses}

All data are expressed as mean \selectlanguage{ngerman}± standard deviation (SD) for continuous
variables. Categorical data are expressed as absolute values and
percentages. All data was tested for normality using the
Kolmogorov-Smirnov statistical test. Pearson's correlation coefficients
(r) or Spearman's coefficients (rho) were used to determine
relationships between haemodynamic and echocardiographic responses.
VO\textsubscript{2} was averaged every 10 seconds and were linked with
corresponding S' values every minute. E', LVEF, GLS and circumferential
strain values were linked with corresponding S' values at rest, 5
minutes and when the RER was over 1. Values at rest, at 5 minutes and
when RER was over 1 were compared using one-way ANOVA and Tukey post-hoc
analyses to determine differences between groups. A scatter plot with
95\% confidence interval was plotted. The augmentation curve was
investigated in more detail (LVEF, systolic and diastolic volumes, LVOT
VTI and GLS) and correlated with corresponding VO\textsubscript{2}peak
values. Inter- and intraobserver measurement variability was performed
for 5 randomly selected participants for echocardiographic parameters
and for 15 randomly selected participants for CPET parameters. Two BSE
accredited operators (JVZ, SB) with extensive experience in performing
CPET simultaneously with echocardiography performed the inter- and
intra-observer measurements. The intraclass correlation coefficient
(ICC) and 95\% confidence intervals was used to quantify
reproducibility. All statistical analyses were performed using the
Statistical Package for the Social Sciences (SPSS version 20.0; SPSS,
Inc). A P-value of \textless{} 0.05 was considered statistically
significant.



\textbf{Results}

\textbf{Population}

Of the 68 patients recruited 11 were excluded (nine studies were off
insufficient image quality for meaningful analysis and 2 studies did not
have TDI switched on during exercise). Fifty-seven participants were
included in the final analysis. Thirty-two (56\%) were male, aged 29.2~±
3.3 years, weight of 71.6 ± 12.9 kg and height of 175~±~10.3 cm.
Baseline LVEF, end-diastolic (EDV) and end-systolic volumes (ESV) were
within normal ranges (LVEF: 61.0 ± 2.8 \%; EDV: 120 ± 30.2 mL; ESV; 46.9
± 13.3 mL) (table 1 and 2).

\textbf{Exercise performance}

Peak RER was 1.23 ± 0.09 with 56 (98\%) of participants achieving an RER
of \textgreater{} 1.10 (1 participant reached a peak RER of 1.08).
Absolute VO\textsubscript{2}peak was 2.8 ± 0.7
L·min\textsuperscript{-1}and relative VO\textsubscript{2}peak was 38.7 ±
6.5 mL·kg\textsuperscript{-1}·min\textsuperscript{-1}. OUES was 2936 ±
749
(mL·min\selectlanguage{english}\textsuperscript{-1})*(L*min\selectlanguage{english}\textsuperscript{-1})\textsuperscript{-1}(table
1).

\textbf{Mechanical augmentation}

All parameters with the exception of EDV significantly augmented after 5
minutes of exercise (table 2). EF increased by 13+-7.2\%, stroke volume
by 22+-17 \%, GLS by 22+-15\% and septal S' and lateral S' by 52+-24 and
61+-27\% respectively. At RER\textgreater{}1 only longitudinal velocities
(systolic and diastolic, septal and lateral) continued to show
statistically significant augmentation. All other parameters
demonstrated an augmentation plateau (Table 2; Figure~1).

\textbf{Longitudinal contractile reserve -
VO\textsubscript{2}relationship}

The augmentation of longitudinal velocity showed a strong correlation
with VO\textsubscript{2} throughout exercise for the septal S' (rho=
0.86, p\textless{}0.0001), the lateral S' (rho=0.78, p\textless{}0.0001)
and for the average S' (rho=0.83, p\textless{}0.0001) throughout
exercise (Figure 2). Diastolic velocities also demonstrated a good
relationship with VO\textsubscript{2} (septal E'; rho=0.8,
p\textless{}0.0001; lateral~E';~rho=0.78) (Table 2). The relationship
was stronger with the septum than the lateral wall (Table 3).

On multivariate testing only stroke volume and systolic velocities
(especially at RER\textgreater{} 1 in the septum) were predictive of
VO\textsubscript{2}peak. Diastolic parameters, ejection fraction as well
as both global longitudinal and circumferential strain showed no
correlation with VO\textsubscript{2}peak (Table 4).

\textbf{Systolic efficiency slope (SES) - the S'/
VO\textsubscript{2}relationship}

We took advantage of the linear augmentation pattern of systolic
velocity and its close relationship with VO\textsubscript{2} to derive
individual regression lines for VO\textsubscript{2} and S'. This new
parameter represents the amount of S' associated with a 1 unit increase
in VO\textsubscript{2} and therefore a measure of myocardial efficiency.
A relationship between the SES slope was observed for
VO\textsubscript{2}peak and septal S'; r = 0.57; p\textless{}0.001 and
lateral~S'; r = 0.53; p\textless{}0.001) (Figure 3). We also confirmed
the validity of these findings by creating models for OUES, a submaximal
measures shown to predict total cardiopulmonary
capacity\textsuperscript{10,11}. A significant relationship was found
between SES slope and the OUES (septal r~=~0.54; p\textless{}0.001,
lateral r = 0.52; p=0.001).

I\textbf{nter- and intraobserver reproducibility}

There was excellent inter- and intra-observer reproducibility for all
measurements by CPET (VO\textsubscript{2}peak and OUES). For
echocardiography parameters there was good to excellent inter- and
intraobserver reproducibility for S' and E' at rest and exercise. There
was lower inter- and intraobserver reproducibility seen for LVEF and GLS
both at rest and exercise (Appendix 1).



\textbf{Discussion}

There are significant gaps in the understanding of myocardial
augmentation and its relationship with exercise performance. This study
addresses these by demonstrating that systolic and (to a lesser extent)
diastolic myocardial velocities increase incrementally as exercise work
rate increases in a linear fashion, in contrast to parameters that are
measured throughout systole (LVEF, SV, GLS) which show a plateau after
low intensity exercise. We provide ranges for the expected augmentation
in healthy young adults both at low intensity and at peak exercise. We
demonstrate that systolic velocities are very closely linked to
VO\textsubscript{2} throughout exercise and, in our study, systolic
velocities during exercise are a better predictor of exercise
performance than LVEF, SV or GLS; and we define a new parameter (SES)
equivalent to the slope of this relationship that can predict exercise
capacity.

Although the augmentation of normal and pathological heart function has
been measured this is usually at the start, at some fixed point, during
or after the cessation of exercise. This makes comparison complex. We
found a 14\% increase in LVEF during exercise with the majority of the
increase happening during the initial bout of exercise which is very
comparable with the existing literature which suggests that LVEF beyond
the ventilatory threshold show a slightly plateau
response\textsuperscript{12}. In normal individuals, in an upright
position, EDV slightly increases with incremental exercise, with either
no change or small decrease in ESV \textsuperscript{13,14}. However body
position effects the change in EDV and ESV during exercise. In a
recumbent position EDV remains unchanged during exercise and an increase
in seen in ESV \textsuperscript{15}. We used a semi-recumbent cycle
ergometer and found a similar response to volumes.

GLS is a more advanced method of measuring LV function. Wang et
al.(2014)\textsuperscript{16} showed a significantly increase in GLS and
S' during exercise in healthy control patients, our data showed a 25\%
increase in GLS and 89\% increase in S', which is a similar. However GLS
is more problematic to measure at peak exercise because high heart rates
may lead to speckle misregistration, although anecdotally higher than
recommended heart rates are tolerated by the software. Cifra \emph{et
al.} , (2016) described a linear relationship between HR and GLS during
exercise and showed that S' obtained using colour Doppler tissue imaging
showed excellent inter-and intra-observer variability. GLS measurements
were more challenging to obtain during exercise due to lung interference
and more excessive cardiac motion. However although peak systolic strain
values showed higher interobserver variability it was still considered
acceptable for clinical use \textsuperscript{17}.

There is limited data on the relationship between myocardial
augmentation and exercise performance. We have previously published that
peak systolic velocity and VO\textsubscript{2} are closely correlated
across a very wide range of diagnoses \textsuperscript{5,18}. This data,
while an interesting proof of concept, does not resolve the question of
whether the heart is behaving differently, or whether those with less
severe disease are simply achieving more exercise and hence more
myocardial augmentation. This central weakness, the confounding effect
of exercise ability, runs through much of the contractile reserve
literature. Attempts to resolve this by imaging at submaximal exercise
are vulnerable to an incomplete understanding of the pattern of
augmentation for each measured parameter.

The use of a semi-recumbent cycle ergometer allows the combination with
CPET and echocardiography to be combined, providing additional insight
into any observed changes in heart function. There have been limited
attempts to relate changes on myocardial function on echocardiography
with changes in VO\textsubscript{2}. In a study of 31 patients (12 with
HF, 15 with preserved LVEF and 16 with reduced LVEF and 15 controls);
they demonstrated an increase in S' and E' from baseline, to the
ventilatory threshold up to maximal effort, a result similar to the data
in a healthy cohort. GLS and LVEF also augmented but the relationship
was weaker, as did the additional measures of the RV and circumferential
strain \textsuperscript{19}. Resting LVEF is not able to predict
VO\textsubscript{2}peak \textsuperscript{4,20,21}. However obtaining
LVEF during exercise does have incremental prognostic value. HF patients
who are able to increase LVEF by more than 5\% have a better prognosis
than those we do not \textsuperscript{22}. Evaluating GLS at rest is an
independent and incremental prognostic tool regarding long-term risk in
cardiovascular morbidity and mortality \textsuperscript{23}. However GLS
at exercise requires more investigation.

In our study, we selected S' as our principle long axis evaluation
parameter as it is a reproducible measurement during
exercise\textsuperscript{2}. Mechanistically longitudinal S' has
previously shown to be an early indicator for ventricular dysfunction,
as it is one of the principle engines of systole, and a fall often
precedes a subsequent fall in LVEF\textsuperscript{24} during disease;
unlike other parameters of both volumetric and longitudinal function S'
augmentation remained linear during exercise. In the analysis S' was
more predictive of VO\textsubscript{2}peak than EF or GLS both at 5
minutes of exercise, when all parameters showed augmentation and at peak
exercise, when EF and GLS had plateaued. It is easily forgotten that
strain and velocity measure different aspects of systolic performance
and cannot be considered interchangeable. Work by Gu \emph{et al.}
(2017) looking at the first phase EF, during which with, normal
activation, peak velocity is reached, has demonstrated that within
systole the initial phase of contraction is the most
important\textsuperscript{25}. This provides a rationale for the
superiority of systolic velocity over the whole systolic measures EF and
GLS. Our study confirms the very tight relationship between
VO\textsubscript{2} and S' throughout the whole of exercise, making it a
very useful surrogate for VO\textsubscript{2} and suggesting that the
processes that increase myocardial velocity are central to determine
exercise function.

By inference therefore variation in, or changes to, cardiac function
would result in different relationships between VO\textsubscript{2} and
S'. This is important because of the potential that augmentation of S'
is simply reflecting a longer exercise time or greater workload making
the relationship tautological. To understand the relationship between
VO\textsubscript{2} and S' in greater detail we hypothesised that the
individual ratios of S' to VO\textsubscript{2} (the amount of myocardial
augmentation required to increase VO\textsubscript{2} by a single unit)
would be able to predict VO\textsubscript{2}peak values. We devised the
term the Systolic Efficiency Slope (SES) to describe this. There was a
relationship between the SES and VO\textsubscript{2}peak suggesting that
this relationship may be important. But given that peak exertion can be
heavily effort dependent we also looked at OUES (a well validated
submaximal measure known to be highly related to
VO\textsubscript{2}peak). Again there was a significant relationship.
This contraction / metabolic coupling relationship has not been
previously described in this way. The SES slope; a slope that does not
require a pre-specified heart rate or maximal exercise to be achieved.
While the data is not strong enough to suggest this as a clinical tool,
we propose these may be suitable methods for future research.



\textbf{Limitations}

Our population was young and verified to be without cardiac disease and
despite this 11 patients were excluded mainly due to insufficient image
quality. Only participants with analysable image quality were included.
The imaging protocol was arduous, however the findings (threshold values
for EF and GLS / continuous augmentation of S') would allow
simplification in future studies that would also be more clinically
achievable. Non invasive blood pressure was measured as part of the
protocol, however the sampling from the automatic detection devices was
consistently poor resulting in less than 50\% evaluable data. Analysis
requiring blood pressure was therefore not performed. These findings may
not apply to a disease population or those from other age groups. TVI
measurements were optimised for perpendicular septal measurements.
Lateral wall TVI may have been off axis which can introduce error.
Transmitral Doppler was not recorded because of the technical challenge
of obtaining these values at high rate show complete E/A fusion making
detection of the true Doppler E wave and hence an unreliable E/E'. The
GLS measured by speckle tracking may not be accurate at the higher heart
rate. Our data would have permitted the evaluation of myocardial work,
but this did not form part of the original protocol and is vendor
specific, therefore this analysis has not been undertaken.



\textbf{Conclusion}

We have described in detail the augmentation of a variety of systolic
parameters during exercise in fit young adults demonstrating two
patterns of augmentation; linear for S' and E' and a plateau for EF and
GLS. The magnitude of the augmentation (14\% for EF / 89\% for S' is in
line with previous research. The study describes the relationship
between longitudinal function (as expressed by S') and
VO\textsubscript{2} throughout exercise. Systolic velocity, which
represents early and mid-systolic function, is more important than whole
systolic parameters such as ejection fraction including GLS in
predicting exercise performance. The SES described for the first time
shows that the regressive relationship between S' /
VO\textsubscript{2}predicts peak exercise tolerance which proves that
the relationship is more than simply collinearity. It also offers a
novel research opportunity to evaluate disease states where this
relationship may be different. We abandon the past at our peril, and
this data suggests a move from velocity to strain may not be justified
or helpful in evaluating myocardial performance during exercise.

Acknowledgements

We thank the study participants for their time and taking part in the
study. We are also grateful to Virgin London Marathon for their support
in recruitment of participants. We are grateful to the entire marathon
study team performing investigations. In addition to the authors of this
manuscript, The Marathon Study group included the following staff from
St George's University of London, University College London, Bart's
Health Trust and other organizations.

Funding

The Marathon Study was funded by the British Heart Foundation
(FS/15/27/31465), Cardiac Risk in the Young, and the Barts
Cardiovascular Biomedical Research Centre. The study received support
from COSMED (Rome, Italy) through the provision of cardiopulmonary
exercise testing equipment and technical support.

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with systolic heart failure. \emph{Echo Res Pract}2015;\textbf{2}
:19--27.

19. Shimiaie J, Sherez J, Aviram G, \emph{et al.} Determinants of Effort
Intolerance in Patients With Heart Failure. \emph{JACC: Heart
Failure}2015;\textbf{3} :803--14.

20. Benge W, Litchfield RL, Marcus ML. Exercise capacity in patients
with severe left ventricular dysfunction.
\emph{Circulation}1980;\textbf{61} :955--9.

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peak exercise oxygen consumption, cardiothoracic ratio, ventricular
arrhythmias, and plasma norepinephrine as determinants of prognosis in
heart failure. The V-HeFT VA Cooperative Studies
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value of ejection fraction changes during dobutamine-atropine stress
echocardiography. \emph{Coron Artery Dis} 2005;\textbf{16} :309--13.

23. Biering-Sorensen T, Biering-Sorensen SR, Olsen FJ, \emph{et
al.}Global Longitudinal Strain by Echocardiography Predicts Long-Term
Risk of Cardiovascular Morbidity and Mortality in a Low-Risk General
Population: The Copenhagen City Heart Study. \emph{Circ Cardiovasc
Imaging} 2017;\textbf{10} .

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New Prognosticator for Cardiovascular Diseases. \emph{Journal of the
American College of Cardiology} 2007;\textbf{49} :1903--14.

25. Gu H, Li Y, Fok H, \emph{et al.} Reduced First-Phase Ejection
Fraction and Sustained Myocardial Wall Stress in Hypertensive Patients
With Diastolic Dysfunction: A Manifestation of Impaired Shortening
Deactivation That Links Systolic to Diastolic Dysfunction and Preserves
Systolic Ejection Fraction. \emph{Hypertension}2017;\textbf{69}
:633--40.

Table 1: Baseline characteristics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
& All participants (n=57)\tabularnewline
\midrule
\endhead
Height (cm) & 175 \selectlanguage{ngerman}± 10.3\tabularnewline
Weight (kg) & 71.6 \selectlanguage{ngerman}± 12.9\tabularnewline
Age (years) & 29.2 \selectlanguage{ngerman}± 3.3\tabularnewline
Male (\%) & 32 (56\%)\tabularnewline
VO\textsubscript{2}peak (L\selectlanguage{ngerman}·min\textsuperscript{-1}) & 2.8 \selectlanguage{ngerman}±
0.7\tabularnewline
VO\textsubscript{2}peak
(mL·kg\textsuperscript{-1}·min\textsuperscript{-1}) & 38.7 \selectlanguage{ngerman}±
6.5\tabularnewline
Predicted VO\textsubscript{2} (\%) & 107 \selectlanguage{ngerman}± 17\tabularnewline
WR peak (Watts) & 226 \selectlanguage{ngerman}± 55\tabularnewline
HR peak (beats · min\textsuperscript{-1}) & 168 \selectlanguage{ngerman}± 17.5\tabularnewline
Peak RER & 1.23 \selectlanguage{ngerman}± 0.09\tabularnewline
OUES
(mL·min\selectlanguage{english}\textsuperscript{-1})*(L*min\selectlanguage{english}\textsuperscript{-1})\textsuperscript{-1}
& 2936 \selectlanguage{ngerman}± 749\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

VO\textsubscript{2}peak-- peak oxygen uptake; WR -- work rate; HR --
heart rate; RER -- Respiratory Exchange Ratio; OUES -- oxygen uptake
efficiency slope

Table 2: Haemodynamic and echocardiographic responses at baseline and
exercise (mean~± SD)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& Rest & 5 minutes & RER \textgreater{} 1.0 & \% change from rest to 5
minutes & \% change from rest to RER \textgreater{} 1\tabularnewline
\midrule
\endhead
Septal S' (cm \selectlanguage{ngerman}·s\textsuperscript{-1}) & 7.2\selectlanguage{ngerman}±1.4 &
11.3\selectlanguage{ngerman}±1.8\textsuperscript{*} & 13.7\selectlanguage{ngerman}±1.8\textsuperscript{§} & 61\selectlanguage{ngerman}±27 &
96\selectlanguage{ngerman}±45\tabularnewline
Lateral S' (cm ·s\textsuperscript{-1}) & 8.4\selectlanguage{ngerman}±1.6 &
12.5\selectlanguage{ngerman}±1.6\textsuperscript{*} & 14.9\selectlanguage{ngerman}±1.7\textsuperscript{§} & 52\selectlanguage{ngerman}±24 &
81\selectlanguage{ngerman}±39\tabularnewline
Septal E' (cm ·s\textsuperscript{-1}) & 10.1\selectlanguage{ngerman}±1.4 &
15.3\selectlanguage{ngerman}±2.8\textsuperscript{*} & 18.1\selectlanguage{ngerman}±2.7\textsuperscript{§} & 54\selectlanguage{ngerman}±29 &
78\selectlanguage{ngerman}±31\tabularnewline
Lateral E' (cm ·s\textsuperscript{-1}) & 12.8\selectlanguage{ngerman}±2.0 &
17.0\selectlanguage{ngerman}±2.7\textsuperscript{*} & 18.8\selectlanguage{ngerman}±2.5\textsuperscript{§} & 35\selectlanguage{ngerman}±23 &
49\selectlanguage{ngerman}±31\tabularnewline
LVEF (\%) & 61.0\selectlanguage{ngerman}±2.8 & 68.8\selectlanguage{ngerman}±3.6\textsuperscript{*} & 69.9\selectlanguage{ngerman}±3.9 & 13\selectlanguage{ngerman}±7.2 &
14\selectlanguage{ngerman}±7.5\tabularnewline
EDV (mL) & 120\selectlanguage{ngerman}±30.2 & 113\selectlanguage{ngerman}±38.0 & 112\selectlanguage{ngerman}±25.8 & -2.1\selectlanguage{ngerman}±14 &
-6\selectlanguage{ngerman}±15\tabularnewline
ESV (mL) & 46.9\selectlanguage{ngerman}±13.3 & 36.7\selectlanguage{ngerman}±11.5\textsuperscript{*} & 34.3\selectlanguage{ngerman}±9.2 & -21\selectlanguage{ngerman}±14
& -25\selectlanguage{ngerman}±16\tabularnewline
SV (mL) & 67.4\selectlanguage{ngerman}±14.9 & 81.1\selectlanguage{ngerman}±17.0\textsuperscript{*} & 84.6\selectlanguage{ngerman}±19.1 & 22\selectlanguage{ngerman}±17 &
27\selectlanguage{ngerman}±18\tabularnewline
HR (beats ·min\textsuperscript{-1}) & 68.6\selectlanguage{ngerman}±10.6 &
130\selectlanguage{ngerman}±14.8\textsuperscript{*} & 151\selectlanguage{ngerman}±14.0\textsuperscript{§} & 93\selectlanguage{ngerman}±32 &
128\selectlanguage{ngerman}±34\tabularnewline
GLS (\%) & -18.0\selectlanguage{ngerman}±2.4 & -21.4\selectlanguage{ngerman}±3.1\textsuperscript{*} & -21.8\selectlanguage{ngerman}±2.7 & -22\selectlanguage{ngerman}±15
& -25\selectlanguage{ngerman}±26\tabularnewline
Circumferential strain (\%) & -20.1\selectlanguage{ngerman}±4.7 & -23.2\selectlanguage{ngerman}±4.3 & -23.3\selectlanguage{ngerman}±4.3 & -16\selectlanguage{ngerman}±25
& -16\selectlanguage{ngerman}±25\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

* Baseline vs. 5 minutes; p \textless{}0.05; §; 5 minutes vs. RER
\textgreater{} 1.0; p \textless{}0.05

HR -- heart rate; S' -- systolic velocity; E' -- diastolic velocity;
LVEF -- left ventricular ejection fraction; EDV -- end diastolic volume;
ESV- end systolic volume; GLS -- global longitudinal strain; SV --
stroke volume

Table 3: Correlations between V0\textsubscript{2} measures of myocardial
function throughout exercise\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
& VO\textsubscript{2} (L\selectlanguage{ngerman}·min\textsuperscript{-1})\tabularnewline
\midrule
\endhead
Sep S' (cm·s\textsuperscript{-1}) & 0.86*\tabularnewline
Lat S'(cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.80*\tabularnewline
Sep E'(cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.78*\tabularnewline
Lat E'(cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.70*\tabularnewline
LVEF (\%) & 0.66*\tabularnewline
ESV (mL) & -0.17\tabularnewline
SV (mL) & 0.56\tabularnewline
GLS (\%) & -0.46\tabularnewline
\bottomrule
\end{longtable}

*P\textless{}0.05

S' -- Systolic longitudinal velocity; E' -- diastolic
velocity;\(\dot{\mathrm{V}}\mathrm{O}_{\mathrm{2}}\) -- oxygen uptake; LVEF -- Left ventricular
ejection fraction; ESV -- end systolic volume; SV -- stroke volume; GLS
-- global longitudinal strain

Table 4: Correlations between measures of myocardial function and
VO\textsubscript{2}peak at baseline low intensity and peak intensity
exercise\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& VO\textsubscript{2}peak (L\selectlanguage{ngerman}·min\textsuperscript{-1}) &
VO\textsubscript{2}peak (L\selectlanguage{ngerman}·min\textsuperscript{-1}) &
VO\textsubscript{2}peak (L\selectlanguage{ngerman}·min\textsuperscript{-1})\tabularnewline
\midrule
\endhead
& Rest & 5 min & RER \textgreater{} 1\tabularnewline
Sep S' (cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.48* & 0.27* & 0.60*\tabularnewline
Lat S' (cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.33* & 0.13 & 0.24\tabularnewline
Mean S' (cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.49* & 0.26 & 0.39*\tabularnewline
Sep E' (cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.15 & -0.13 & 0.17\tabularnewline
Lat E' (cm\selectlanguage{ngerman}·s\textsuperscript{-1}) & 0.10 & 0.04 & -0.02\tabularnewline
LVEF (\%) & -0.11 & 0.03 & -0.01\tabularnewline
SV (mL) & 0.59* & 0.62* & 0.64*\tabularnewline
GLS (\%) & -0.09 & 0.05 & -0.14\tabularnewline
Circumferential strain (\%) & -0.06 & -0.1 & -0.09\tabularnewline
\bottomrule
\end{longtable}

*P\textless{}0.05

S' -- Systolic longitudinal velocity; E' -- diastolic velocity;
VO\textsubscript{2}-- oxygen uptake; LVEF -- Left ventricular ejection
fraction; SV -- stroke volume; GLS -- global longitudinal strain

Figure legends:

Figure 1: Mechanical augmentation for S', E', LVEF, GLS throughout
exercise

(S' -- systolic velocity; E' -- diastolic velocity; LVEF -- left
ventricular ejection fraction; GLS -- global longitudinal strain;
VO\textsubscript{2} -- oxygen consumption)

Figure 2: S' -- VO\textsubscript{2} relationship throughout exercise

(S' -- systolic velocity; VO\textsubscript{2} -- oxygen consumption)

Figure 3: Systolic efficiency slope (SES) -- S' --
VO\textsubscript{2}relationship

(S' -- systolic velocity; VO\textsubscript{2} -- oxygen consumption; sep
-- septal; lat - lateral)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-1-600DPI/figure-1-600DPI}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2-600DPI/figure-2-600DPI}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-3-600DPI/figure-3-600DPI}

\end{center}
\end{figure}

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

