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\begin{document}

\title{Relationship between the strain measures of left atrial function and
heart failure worsening}



\author[1]{Massimo Iacoviello}%
\author[1]{Davide Diomede}%
\author[1]{Erica Terazzi}%
\author[1]{Nicolangelo Diomede}%
\author[1]{Gianmarco Alcidi}%
\author[1]{Rosanna Pugliese}%
\author[1]{Sara Ioannoni}%
\author[1]{Matteo Romano}%
\author[2]{Michele Granatiero}%
\author[2]{Vito Di Terlizzi}%
\author[1]{Michele Correale}%
\author[1]{Matteo Di Biase}%
\author[1]{Natale Daniele Brunetti}%
\affil[1]{Universita degli Studi di Foggia Dipartimento di Scienze Mediche e Chirurgiche}%
\affil[2]{Azienda Ospedaliera Universitaria Foggia}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background.} Two-dimensional speckle tracking evaluation
(2D-STE) is a useful tool to evaluate the complexity of atrial function
by the analysis of the different phases of atrial deformation and by the
combination with Doppler measurements of diastolic function. \textbf{Aim
of the study.} To evaluate the role of the left atrial (LA) strain
parameters to predict worsening chronic heart failure (CHF).
\textbf{Methods.} We enrolled outpatients affected by CHF referred to
our heart failure unit. Each patient underwent a medical visit, an
electrocardiogram (ECG), and an echocardiographic examination. LA
function was assessed by 2D-STE. The three phases of LA strain -- i.e.
the reservoir (LAr), the conduit (LAcd), and the contraction (LAct) --
were evaluated. Moreover, the ratio between LAr and that of septal
(LAr/Ees), lateral (LAr/Eel), and septal-lateral (LAr/Eem) E/e' were
evaluated. During follow-up, the worsening of heart failure was
evaluated. \textbf{Results.} Two hundred twenty-eight patients were
enrolled. During a mean follow-up of 14\selectlanguage{ngerman}±7 months, 47 patients showed at
least one event related to heart failure worsening (40 hospitalisations,
5 heart transplantations, and 19 cardiovascular deaths). During
univariate Cox regression analysis, LAr, LAcd, LAct, LAr/Ees, LAr/Eel,
and LAr/Eem were all associated with events related to heart failure
worsening, but during multivariate regression analysis, only LAr (HR:
0.94; 95\% CI: 0.91--0.98; p: 0.007), LAr/Ees (HR: 0.49; 95\% CI:
0.30--0.78; p: 0.002), and LAr/Eem (HR: 0.65; 95\% CI: 0.47--0.89; p:
0.008) remained significantly associated with the events. Finally,
LASr/Ee's showed accuracy in predicting outcomes greater than LASr
(C-index 0.78 vs. 0.72, respectively). \textbf{Conclusions.} In CHF
patients, the measure of the LA reservoir by 2D-STE is independently
associated with heart failure worsening, but the accuracy in predicting
the events is even greater when the reservoir is combined with the
Doppler measures of diastolic function.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

While left atrial (LA) function could play a significant role in
patients affected by cardiovascular diseases, it is poorly studied in
several pathological conditions and is frequently considered a passive
bystander of these pathophysiologic alterations {[}1{]}. However, the LA
is a complex and active chamber which modulates left ventricle filling
during ventricular systole through its reservoir function and during
ventricular diastole as a conduit and booster pump functions {[}1--3{]}.
Moreover, the interplay between LA and left ventricular (LV) functions
throughout the cardiac cycle is crucial in several pathophysiological
conditions {[}3, 4{]}.

Recently, using two-dimensional spackle tracking evaluation (2D-STE),
the significance of LA function impairment in heart failure has been
demonstrated {[}5, 6{]}. However, the predictive value of the different
phases of atrial function -- i.e. reservoir, conduit, and contraction --
still needs to be clarified. Moreover, the combination between the LA
reservoir and Doppler measures of diastolic function has been
demonstrated to be more accurate in detecting the presence of high LV
filling pressure {[}7{]}, but its association with heart failure outcome
has not been investigated.

The aim of this study was to evaluate the role of the LA strain
parameters reflecting the reservoir, conduit, and contraction as well as
the combination with Doppler measurements of atrial function in
predicting worsening chronic heart failure (CHF).

\textbf{Methods}

We enrolled patients affected by CHF who were referred to the Heart
Failure Outpatients Clinic of the Cardiology Unit of the Polyclinic
University Hospital Riuniti of Foggia, Italy, between October 2020 and
January 2023. All the patients were enrolled in the Daunia registry,
which was approved by the Institutional Ethics Committee of the
Polyclinic University Hospital of Foggia, Italy (Protocol Code 68/CE/20,
approved on 26 May 2020), and all provided written informed consent to
participate.

The following inclusion criteria were considered: history of heart
failure of any origin with recommended medical therapy at the time of
the enrolment and in clinically stable condition for at least 30 days
(e.g. no significant changes in hemodynamic status or medical therapy).
Patients diagnosed with atrial fibrillation were enrolled if a regular
ventricular paced rhythm was present, whereas they were excluded if an
irregular rhythm was observed.

At the time of enrolment, each participant underwent a medical
evaluation, including an electrocardiogram (ECG) and two-dimensional
echocardiography.

\emph{Medical examination and electrocardiogram.} Each participant's
full medical history was collected. A physical examination and a 12-lead
ECG were performed. Any evidence of ischemic cardiomyopathy, arterial
hypertension, atrial fibrillation, diabetes mellitus, and/or
dyslipidaemia was documented together with any history of chronic kidney
disease and dialysis. New York Heart Association (NYHA) classes,
anthropometric data, systolic and diastolic arterial pressures, and
heart rhythms were also recorded. If available, the most recent routine
blood chemistries were also documented. In particular, by serum
creatinine, the glomerular filtration rate was calculated using the
abbreviated CKD-EPI formula (GFR-EPI, ml/min/1.73 m\textsuperscript{2})
{[}8{]}.

\emph{Echocardiographic evaluation.} Two-dimensional echocardiographic
imaging and Doppler acquisition were performed using an EPIQ CVx system
(Philips, Amsterdam, the Netherlands) with an S5-1 transducer. At the
baseline, five cycles of ECG-guided standard parasternal long- and
short-axis, apical two-, three-, and four-chamber, and subcostal views
were acquired. The LV end-diastolic diameter (LVEDD) and
interventricular septum and LV posterior wall thicknesses were measured;
the LV mass indexed for body surface area was calculated based on
current recommendations {[}9{]}. Additionally, to analyse the tricuspid
annular plane systolic excursion, an RV-focused four-chamber view was
obtained. The LV end-diastolic volume (LVEDV), LV end-systolic volume
(LVESV), and LV ejection fraction (LVEF) were calculated using Simpson's
rule. The LA volume was also calculated using Simpson's rule and indexed
for body surface area (LAVI). Using colour Doppler, mitral (MR) and
tricuspid (TR) regurgitation were evaluated semi-quantitatively and
assigned arbitrary units ranging from 0 to 4. The maximum
trans-tricuspid valve pressure gradient was assessed using
continuous-wave Doppler. Pulmonary systolic arterial pressure (PASP) was
estimated based on the vena cava diameter. Peaks of early wave velocity
at the mitral valve (E) were measured using pulsed Doppler. Furthermore,
the early diastolic velocity peaks (e') at the level of the septal (e's)
and lateral (e'l) mitral annulus were measured using pulsed and tissue
Doppler imaging (TDI) {[}9{]}. Then the means of e's and e'l (e'm) as
well as the ratios between E and e's (Ee's) and E and e'm (Ee'm) were
calculated.

The AutoStrain application of the Philips EPIQ CVx ultrasound systems
was used for the `off-cart' analysis of strain from stored examinations.
Values for LV global longitudinal strain (LV-GLS) were obtained from the
analysis of two-, three-, and four-chamber views. The software
automatically generated curves representing longitudinal strain; LV-GLS
was calculated by averaging values obtained in all the segments. In this
study, reduced systolic strain is indicated by values that are less
negative than those determined at the baseline. The global longitudinal
strain of the right ventricle (RVGLS) and that of the free wall (RVfwLS)
were also calculated automatically from the values obtained in an
RV-focused four-chamber view. In this study, reduced ventricular
systolic strain is indicated by values that are less negative than those
determined at the baseline.

By the standard four-chamber view, the AutoStrain application of the
Philips EPIQ CVx ultrasound systems was also used for the `off-cart'
analysis of LA strain from stored examinations. As shown in Figure 1,
the LA strain of \emph{reservoir} (LAr), including those
of\emph{conduit} (LAcd) and \emph{contraction} (LAct), were calculated
(D.D., E.T.). Finally, the ratios between LAr and E/e's (LAr/Ees) and
LAr and E/e'l (LAR/Eel) and that between LAr and E/e'm (LAr/Eem) were
evaluated {[}7{]}.

\emph{Follow-up}

The patients were followed up as outpatients in the heart failure unit.
The primary endpoint was heart failure progression defined as heart
failure hospitalisation, heart transplantation, and/or cardiovascular
death caused by heart failure worsening. The cause of death was verified
by means of hospital records or the testimony of relatives and defined
as being cardiovascular (death caused by heart failure worsening, acute
coronary syndrome, and sudden death) or non-cardiovascular. Sudden death
was defined as death within one hour after the onset of symptoms in a
previously medically stable patient, death during sleep, or unwitnessed
death.

\emph{Statistical analysis}

The continuous variables are expressed as mean values \selectlanguage{ngerman}± SD. The intra-
and inter-observer reproducibility of the LA strain measures were
evaluated in 20 patients by two operators (M.I., N.D.) by means of the
intraclass correlation coefficient (ICC), which measures the strength of
the association between the two baseline recordings. The data were
considered reproducible if the ICC was \textgreater{}0.60, and the
reproducibility was considered almost perfect if the ICC was between
0.81 and 1.00 {[}10{]}.

Pearson's linear correlations were used to assess the relationship
between atrial strain measures and the other variables studied. Cox's
proportional hazard model was used to verify the associations between
the variables and the endpoints. Hazard ratios (HRs) are given with
their 95\% confidence intervals (CIs) and refer to a unit increase in
the variable. The variables used in the forward stepwise multivariable
models were selected based on their statistical significance during
univariate analysis and the most relevant risk parameters for HF
patients. Discrimination of the univariate and multivariate models was
determined using a modified concordance statistic (C-index) for censored
data.

Receiver operating characteristic (ROC) curves and the area under the
curve (AUC) of the ROC were calculated to determine the associations
between the studied variables and 1-year events. The best cut-off values
for the analysed events were defined based on the highest sum of
sensitivity and specificity. The event-free curves were based on
Kaplan--Meier analysis stratified by the best cut-offs of LASr and
LASr/Ees and were compared using a log-rank test. The proportional
hazards assumption was formally assessed. Statistical analyses were
performed using STATA, version 12 (StataCorp, College Station, Texas,
USA), or Statistica 6.1 (StatSoft Inc., Tulsa, Oklahoma, USA).\emph{P}
-values~\textless{}0.05 were considered statistically significant.

\textbf{Results}

Out of the 274 patients, LA strain analysis was not evaluable in 39
because of the presence of atrial fibrillation with irregular rhythm and
in 7 because of poor quality of imaging. The clinical and
echocardiographic characteristics of the remaining 228 are shown in
Table 1. Among the patients enrolled, 17 presented atrial fibrillation
with regular ventricular paced rhythm; 31 (13.6\%) were in KDOQI Class
1, 111 (48.7\%) in Class 2, 43 (18.9\%) in Class 3a, 34 (14.9\%) in
Class 3b, 8 (3.5\%) in Class 4, and 1 in Class 5.

\emph{Left atrial strain measures' reproducibility.} A high degree of
intra-observer and intra-observer reproducibility was observed for LAr
(average ICC = 0.93; 95\% CI: 0.84--0.97 and ICC: 0.87; 95\% CI:
0.71--0.95, respectively) as well as for LAcd (ICC: 0.93; 95\% CI:
0.84--0.97 and ICC: 0.86; 95\% CI: 0.68--0.94, respectively) and LAct
(ICC: 0.89; 95\% CI: 0.76--0.96 and ICC: 0.80; 95\% CI: 0.56--0.91,
respectively).

\emph{Clinical and echocardiographic correlates of left atrial strain
measures.} As shown in Supplementary Table 1, LAr was significantly and
positively correlated with GFR-EPI, LVEF, TAPSE, e's, e'l, and e'm and
significantly and negatively correlated with age, NYHA class, heart
rate, LVEDV, LVESV, LAVi, MR, TR, E/e's, E/e'm, LV-GLS, RV-GLS, and
RVfwLS. LAcd was significantly and positively correlated with age, NYHA
class, heart rate, LVEDV, LVESV, LAVi, TR, E/e's, E/e'm, LV-GLS, RV-GLS,
and RVfwLS and significantly and negatively correlated with GFR-EPI,
LVEF, TAPSE, e's, e'l, and e'm. LAct was significantly and positively
correlated with NYHA class, heart rate, LVEDV, LVESV, LAVi, MR, TR,
E/e's, E/e'm, LV-GLS, RV-GLS, and RVfwLS and significantly and
negatively correlated with GFR-EPI, LVEF, and TAPSE. LAr/Eel, LAr/Ees,
and LAr/Eem were significantly and positively correlated with SAP,
GFR-EPI, LVEF, TAPSE, e's, e'l, and e'm and significantly and negatively
correlated with age, NYHA class, heart rate, LVESV, LAVi, MR, TR, E/e's,
E/e'm, LV-GLS, RV-GLS, and RVfwLS.

\emph{Left atrial strain measures and heart failure worsening.} During a
mean follow-up of 14±7 months, at least one event related to heart
failure worsening (40 hospitalisations caused by acute decompensated
heart failure, 5 heart transplantations, and 19 cardiovascular deaths)
occurred in 47 patients. As shown in Table 2, during univariate Cox
regression analysis, LAr, LAcd, and LAct were all associated with events
related to heart failure worsening. In forward stepwise Cox regression
analysis, LAr (HR: 0.94; 95\% CI: 0.91--0.98; p: 0.006) and LAct (HR:
1.05; 95\% CI: 1.00--1.10; p: 0.043) but not LAcd remained associated
with events after correction for NYHA class, heart rate, age, MR, TR,
LVEF, GFR-EPI, and TAPSE.

Analogously, LAr/Eel, LAr/Rrs, and LAr/Eem were associated with events
during univariate analysis, but only LAr/Ees and LAr/Eem remained
significantly associated with them during multivariate analysis (HR:
0.49; 95\% CI: 0.30--0.78; p: 0.002 and HR: 0.65; 95\% CI: 0.47--0.89;
p: 0.008, respectively) after correction for NYHA class, heart rate,
age, MR, TR, LVEF, GFR-EPI, and TAPSE. As shown in Figure 2, the
presence of a reduced or mildly reduced/preserved LVEF did not influence
the prognostic value of all the LA strain measures as well as of those
derived by the combination with Doppler measures.

\emph{ROC curves.} As shown in Supplementary Figure 1, among the LA
measures derived by strain analysis, LASr/Ees (AUC 0.76; 95\% CI:
0.67--0.85) showed the greater ROC AUC, followed by LASr/Eem (AUC 0.75;
95\% CI: 0.65--0.84), LASr (AUC 0.71; 95\% CI: 0.63--0.80), LASct (AUC
0.70; 95\% CI: 0.61--0.78), and LAScd (AUC 0.60; 95\% CI: 0.52--0.69).
For LASr, the best cut-off was 17\% (sensitivity of 72\% and specificity
of 60\%), for LASr/Ees 1.28 (sensitivity of 80\% and specificity of
64\%), and for LASr/Eem 1.60 (sensitivity of 77\% and specificity of
59\%). Figure 3 shows the Kaplan--Meier curves of the patients
dichotomised according to the best cut-off of LASr (Panel A) and
LASr/Ees (Panel B).

\textbf{Discussion}

The main result of this study is that in CHF outpatients, the LA
reservoir, a 2D-STE measure of atrial function, is independently
associated with worsening heart failure. Moreover, the integration of
the LA reservoir with the ratio between mitral early diastolic peak
velocity at pulsed Doppler and TDI provides a measure reflecting the
interaction between atrial and ventricular function which is even more
accurate to stratifying prognosis.

LA function is often considered only a passive bystander of LV
dysfunction. However, several studies have shown that LA contractile
function is determined by intrinsic LA contractility, LV compliance, LV
filling pressures (LA afterload), and pulmonary vascular capacitance
{[}1{]}. Atrial function improves ventricular filling by storing blood
during ventricular systole while the atrioventricular valves are closed
(reservoir function), as a passive conduit and emptying during early
ventricular filling (conduit function), and providing additional
ventricular filling with active contraction before atrioventricular
valve closure (booster pump function). The interplay between LA and LV
functions throughout the cardiac cycle (LA--LV coupling) is crucial in
several pathophysiological conditions {[}3{]}. In this
pathophysiological setting 2D-STE could represent a useful tool not only
to evaluate the LV and RV functions {[}11-13{]} but also to provide
measures reflecting the atrial function {[}14{]}. In particular, it
allows the study of the complexity of the atrial deformation by
analysing three sequential phases, i.e. the reservoir, the conduit, and
the contraction.

The reservoir phase begins at the closure of the atrio-ventricular
valves and ends with their opening at the end of isovolumic ventricular
relaxation. In this phase, the atrial pressure quickly rises while
receiving blood from the veins, and the atria stretch to their maximum
capacity. The greater the atrial stretch, the greater the value of the
reservoir. The other two phases of atrial function are reciprocal to the
reservoir. The first is the conduit phase, which is related to the first
half of ventricular diastole, after the opening of the atrioventricular
valves. During this phase, the atria quickly unload in the ventricles
the blood accumulated in the reservoir phase (passive atrial emptying),
and the strain analysis will register a negative deflection of the
curve, followed by a plateau which corresponds to the diastasis, when
the blood directly flows from the veins to the ventricles. This phase is
influenced by the compliance of the ventricles and the diastolic
function {[}14{]}. The last phase is the contraction phase,
corresponding to the atrial systole. This phase reflects the contractile
capacity of the atria, along with the ventricular stiffness and the
ventricular end diastole filling pressures {[}14{]}.

Previous studies have demonstrated the role of peak atrial strain in
predicting heart failure prognosis {[}5, 6{]}. However, different from
these studies, we attempted to evaluate the prognostic role of all the
phases of the atrial function. Interestingly, all the measures were
associated with heart failure worsening, but only LASr remained
independently associated with the occurrence of events during
multivariate regression analyses. This evidence could be related to the
ability of the reservoir to reflect a global atrial dysfunction.
Consequently, although the conduit and contraction phases could help to
define more clearly the mechanisms responsible for atrial dysfunction,
the reservoir, being the expression of both the other phases, is
associated with more important prognostic information.

This hypothesis is supported by the studies demonstrating the close
relationship between a reduced LASr and the pathophysiological
mechanisms underlying atrial dysfunction {[}14--16{]}, i.e. the
increased LV filling pressure, the LA remodelling, and the loss of
contractile capacity. For this reason, the impairment of LASr could
precede anatomical alterations {[}15{]}, thus allowing a more accurate
identification of diastolic dysfunction than conventional echo
variables, such as LA volume index or E/e' {[}17-20{]}. Moreover, the
therapeutic strategies able to improve LV function can be associated
with the improvement of atrial function {[}21{]}.

The relevance of our study is also related to the demonstration that the
combination of the strain measure of LA function, LASr, and that of LV
filling pressure based on pulsed Doppler and TDI, E/e', is characterised
by even greater prognostic accuracy in predicting heart failure
worsening. In previous studies, the ratio between LASr and E/e' showed
greater accuracy in detecting high filling pressure {[}7, 22{]}, but
this measure should also be considered as a parameter that can better
reflect the relationship between LA and LV functions. In fact, LV
function worsening could cause an increase in LV end-diastolic
pressures, which can then cause LA wall stiffening, thereby resulting in
decreased LA relaxation and decreased LA strain peak during LV systole.
Conversely, the decreased LA function could further favour the increase
in LV filling pressure, thus leading to a vicious circle responsible for
heart failure progression. Consequently, lower ratio between LASr and
E/e' corresponds to worse interaction between LA and LV functions, i.e.
greater LV filling pressure and worse LA function, thus allowing to
provide a significant parameter of prognostic stratification.

In conclusion, 2D-STE is an echocardiographic technique able to provide
measures of atrial function independently associated with heart failure
worsening. Among these measures, the reservoir shows greater accuracy in
predicting the events. Moreover, this accuracy is even greater when the
strain measure of the reservoir is combined with the Doppler measures
related to LV filling pressure. These data further strengthen the
possible usefulness of 2D-STE in providing information about both
ventricular and atrial functions.

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\end{enumerate}

\textbf{Figure legends}

\textbf{Figure 1.} Left atrial strain measures, Doppler measures of
diastolic function, and combined atrial/Doppler measurements.

E: peaks of early wave velocity at the mitral valve by pulsed Doppler;
e': early diastolic velocity peaks at tissue Doppler imaging; e's:
septal e'; e'l: lateral e'; e'm: mean septal-lateral e'; LAr: left
atriale reservoir; LAcd: left atrial conduit; LAct: left atrial
contraction.

\textbf{Figure 2.} Cox univariate regression analyses for all the left
atrial measures , according with the presence of a reduced or not left
ventricular ejection fraction.

CI: confidence interval; HR: hazard ratio; LAcd: left atrial conduit;
LAct: left atrial contraction; LAr: left atrial reservoir; LAr/Eel:
ratio between LAr and the ratio between peak of E at pulsed Doppler and
mitral lateral e' at lateral Tissue Doppler Imaging; LAr/Eem: ratio
between LAr and the ratio between peak of E at pulsed Doppler and mean
mitral septal and lateral e' at Tissue Doppler Imaging; LAs/Ees: ratio
between LAr and the ratio between peak of E at pulsed Doppler and mitral
septal e' at Tissue Doppler Imaging.

\textbf{Figure 3.} Kaplan Meier curves according to the best cut-offs of
LASr and LASr/Ees.

LAr: left atriale reservoir; LAr/Ees: ratio between LAr and the ratio
between E (peaks of early wave velocity at the mitral valve by pulsed
Doppler) and septal e' (early diastolic velocity peaks at septal mitral
tissue Doppler imaging).

\textbf{Supplementary Figure 1.} ROC curves of left atrial strain
derived measures for one year events related to heart failure worsening.

LAcd: left atrial conduit; LAct: left atrial contraction; LAr: left
atrial reservoir; LAr/Eel: ratio between LAr and the ratio between peak
of E at pulsed Doppler and mitral lateral e' at lateral Tissue Doppler
Imaging; LAr/Eem: ratio between LAr and the ratio between peak of E at
pulsed Doppler and mean mitral septal and lateral e' at Tissue Doppler
Imaging; LAs/Ees: ratio between LAr and the ratio between peak of E at
pulsed Doppler and mitral septal e' at Tissue Doppler Imaging.\selectlanguage{english}
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\textbf{Hosted file}

\verb`Tables.docx`  available at \url{https://authorea.com/users/605712/articles/635068-relationship-between-the-strain-measures-of-left-atrial-function-and-heart-failure-worsening}

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