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\begin{document}

\title{Comparative analysis of phasic left atrial strain and left ventricular
posterolateral strain pattern to discriminate Fabry cardiomyopathy from
other forms of left ventricular hypertrophy}



\author[1]{David Frumkin}%
\author[1]{Isabel Mattig}%
\author[1]{Maamoun Al-Daas}%
\author[1]{Nina-Maria Laule}%
\author[1]{Sima Canaan-kühl}%
\author[1]{Fabian Knebel}%
\author[2]{Karl Stangl}%
\author[3]{Anna Brand}%
\affil[1]{Charité Universitätsmedizin Berlin}%
\affil[2]{Charité-Universitätsmedizin Berlin}%
\affil[3]{Charite Universitätsmedizin Berlin, Campus Charite Mitte}%


\vspace{-1em}



  
  \date{June 14, 2024}


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





\selectlanguage{english}
\begin{abstract}
Background `Classical' echocardiographic signs of Fabry cardiomyopathy
(FC), such as left ventricular hypertrophy (LVH), posterolateral strain
deficiency (PLSD) and papillary muscle hypertrophy may have a limited
diagnostic accuracy in clinical practice. Our aim was to evaluate the
diagnostic value of left atrial (LA) strain impairment compared to
`classical' echocardiographic findings to discriminate FC. Methods In
standard echocardiographic assessments, we retrospectively analyzed the
diagnostic value of the ``classical'' red flags of FC as well as LA
strain in 20 FC patients and in 20 subjects with other causes of LVH.
Receiver operating characteristic (ROC) curve analysis was performed to
assess the respective diagnostic accuracy. Results FC was confirmed in
20 patients by genetic testing. In the LVH group, 12 patients were
classified by biopsy to have hypertrophic cardiomyopathy, two had
hypertensive heart disease, and six LVH combined with borderline
myocarditis. Global and regional left ventricular (LV) strain was not
significantly different between groups while LA strain was significantly
impaired in FC (Left atrial reservoir strain (LASr) 19.1\%\selectlanguage{ngerman}±8.4 in FC and
25.6\%±8.9 in LVH, p=0.009; left atrial conduction strain (LAScd)
-8.4\%±4.9 in FC and -15.9\%±8.4 in LVH, p\textless{}0.01). LAScd, with
an area under the curve (AUC) of 0.81 {[}95\% confidence interval (CI)
0.66-0.96{]} showed the highest diagnostic accuracy to discriminate FC.
The PLSD pattern showed an AUC of 0.49, quantification of papillary
muscle hypertrophy an AUC of 0.47. Conclusion Adding LA strain analysis
to a comprehensive echocardiographic work-up of unclear LVH may be
helpful to identify FC as a possible cause.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


Comparative analysis of phasic left atrial strain and left ventricular
posterolateral strain pattern to discriminate Fabry cardiomyopathy from
other forms of left ventricular hypertrophy

David Frumkin\textsuperscript{1,2},M.D., Isabel
Mattig\textsuperscript{1},M.D., Nina Laule\textsuperscript{1}, Maamoun
Al Daas\textsuperscript{1}, Sima Canaan-K\selectlanguage{ngerman}ühl \textsuperscript{3},M.D.,
Fabian Knebel\textsuperscript{1,2},M.D., Karl
Stangl\textsuperscript{1,2},M.D., Anna Brand\textsuperscript{1,2},M.D.

1 Charite\selectlanguage{english} -- Universita\selectlanguage{english}tsmedizin Berlin, corporate member of Freie
Universita\selectlanguage{english}t Berlin and Humboldt- Universita\selectlanguage{english}t zu Berlin, Campus Mitte,
Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie

2 DZHK (German Centre for Cardiovascular Research), partner site Berlin,
Germany.

3 Charite -- \selectlanguage{english}Universita\selectlanguage{english}tsmedizin Berlin, corporate member of Freie
Universita\selectlanguage{english}t Berlin and Humboldt- Universita\selectlanguage{english}t zu Berlin, Campus Virchow
Klinikum, Medizinische Klinik mit Schwerpunkt Nephrologie und
Internistische Intensivmedizin~

Short title: Left atrial strain to discriminate Fabry cardiomyopathy

\textbf{Corresponding author:}

David Frumkin, M.D.

Charit\selectlanguage{ngerman}é - Universitätsmedizin Berlin \textbar{}~Campus Charité Mitte

Medizinische Klinik m. S. Kardiologie und Angiologie

Charitéplatz 1

10117 Berlin

Germany

\emph{Telephone: 0049 30 450 613194}

\emph{Email: david.frumkin@charite.de}

Abstract:

\emph{Background}

`Classical' echocardiographic signs of Fabry cardiomyopathy (FC), such
as left ventricular hypertrophy (LVH), posterolateral strain deficiency
(PLSD) and papillary muscle hypertrophy may have a limited diagnostic
accuracy in clinical practice.

Our aim was to evaluate the diagnostic value of left atrial (LA) strain
impairment compared to `classical' echocardiographic findings to
discriminate FC.

\emph{Methods}

In standard echocardiographic assessments, we retrospectively analyzed
the diagnostic value of the ``classical'' red flags of FC as well as LA
strain in 20 FC patients and in 20 subjects with other causes of LVH.
Receiver operating characteristic (ROC) curve analysis was performed to
assess the respective diagnostic accuracy.

\emph{Results}

FC was confirmed in 20 patients by genetic testing. In the LVH group, 12
patients were classified by biopsy to have hypertrophic cardiomyopathy,
two had hypertensive heart disease, and six LVH combined with borderline
myocarditis.

Global and regional left ventricular (LV) strain was not significantly
different between groups while LA strain was significantly impaired in
FC (Left atrial reservoir strain (LASr) 19.1\%±8.4 in FC and 25.6\%±8.9
in LVH, p=0.009; left atrial conduction strain (LAScd) -8.4\%±4.9 in FC
and -15.9\%±8.4 in LVH, p\textless{}0.01). LAScd, with an area under the
curve (AUC) of 0.81 {[}95\% confidence interval (CI) 0.66-0.96{]} showed
the highest diagnostic accuracy to discriminate FC. The PLSD pattern
showed an AUC of 0.49, quantification of papillary muscle hypertrophy an
AUC of 0.47.

\emph{Conclusion}

Adding LA strain analysis to a comprehensive echocardiographic work-up
of unclear LVH may be helpful to identify FC as a possible cause.

\textbf{Keywords: Fabry Disease, cardiomyopathy, speckle tracking
echocardiography, left atrial strain, left atrial deformation imaging,
left ventricular strain}

Introduction

Fabry Disease (FD) is a rare, X-linked lysosomal storage disease that
leads to a deficient activity of the enzyme \selectlanguage{greek}α-\selectlanguage{english}galactosidase and
consequently progressive accumulation of sphingolipids in multiple
organs, including the heart. This results in progressive concentric left
ventricular (LV) hypertrophy (LVH) \textsuperscript{1}, making
cardiovascular death the leading cause of mortality in patients with
FD\textsuperscript{2,3}. The prevalence of Fabry disease has been
reported to be around 1\% in hypertrophic cardiomyopathy population and
1:117.000 in general population based on clinical data
\textsuperscript{4,5}, although underdiagnosis is common and the true
prevalence may be significantly higher \textsuperscript{6}. Enzyme
replacement therapy (ERT) and novel chaperone-based therapy is available
for FD patients\textsuperscript{7} and several treatments including
modified enzymes, substrate reduction therapy and gene therapy are in
development. Studies have demonstrated a benefit when ERT is initiated
early in the course of disease, but efficacy is uncertain when started
after the development of advanced cardiomyopathy \textsuperscript{8}.
Early diagnosis of cardiac involvement as well as timely and effective
treatment are crucial to prevent irreversible cardiomyopathy. Guidelines
currently suggest strict eligibility criteria of ERT, such as
significant LVH, diastolic dysfunction, and increased indexed left
atrial volume (LAVI)\textsuperscript{9-11}. In late stages of FD,
reduced longitudinal systolic deformation, assessed by myocardial
strain, could be predominately detected in the basal and mid
posterolateral left ventricular (LV) segments combined with a
progressive local myocardial thinning seen by magnetic resonance imaging
(MRI) \textsuperscript{12}. This increase in myocyte mass, which
subsequently causes LVH, is thought to be a combination of the
intracellular accumulation of lipid and neurohormonal activation
promoting hypertrophic activation\textsuperscript{1,13}. Increase in
myocyte mass is not only thought to affect ventricular walls but also
the papillary muscles, causing a prominent papillary muscle often linked
with FD. A prominent papillary muscle in FD becomes particularly obvious
in the presence of a small left cavity due to
hypertrophy\textsuperscript{14}.

Impairment of phasic left atrial strain (LAS) compared to healthy
controls was previously shown in FD \textsuperscript{15,16} as well as
in other storage diseases featuring increased myocardial wall thickness,
such as cardiac amyloidosis (CA) \textsuperscript{17}. These findings
suggest that FD may not only cause LVH and left ventricular fibrosis but
may also impact on the thin-walled left atrium (LA) with consecutive
impairment of LA mechanics. However, data investigating LA function and
comparing its diagnostic value to parameters of regional LV function in
FD, such as the posterolateral strain deficiency (PLSD) pattern, are
sparse.

In this study we aimed to describe variations in phasic LA and regional
LV strain in patients with FD compared to other causes of LVH and to
assess their respective diagnostic accuracy in discriminating patients
with FD.

Methods

Study population

We retrospectively screened 51 patients with FD or LVH of other cause
from our registry at the Department of cardiology at Charit\selectlanguage{ngerman}é --
Universitätsmedizin Berlin. FD was confirmed by mutation analysis
genetic testing and leukocyte \selectlanguage{greek}α-\selectlanguage{english}galactosidase activity. 20 patients had
confirmed diagnosis of FD. Fabry patients were compared with a group of
bioptically confirmed LVH due to other causes (n=20). LVH was defined as
a septal or posterior wall thickness \textgreater{}11 mm according to
the European Society of Cardiology (ESC) guidelines\textsuperscript{18}.
All patients with LVH in the control group underwent endomyocardial
biopsy to exclude infiltrative disease. All patients obtained a
standardized transthoracic echocardiographic assessment between February
2013 and July 2020. Exclusion criteria were age \textless{}18 years or
insufficient imaging of the LA, such as foreshortening or bad acoustic
window. 11 patients had to be excluded due to insufficient imaging
quality. Finally, we retrospectively analyzed clinical and
echocardiographic data of 20 patients diagnosed with FD and of 20
patients in the LVH group. The collection of pseudonymized medical
records and the conduction of the study were approved by the
institutional ethics committee (registration number EA2/194/18).

Echocardiography

A standardized transthoracic echocardiographic assessment was performed
in 40 patients using a Vivid E9 (GE Vingmed, Horton, Norway) with an M5S
1.5--4.5 MHz transducer. LV dimensions, LV ejection fraction (LVEF),
left ventricular global longitudinal strain (LVGLS), and LA volume index
(LAVI) were analyzed in accordance with the recent recommendations of
the American Society of Echocardiography (ASE) and the European
Association of Cardiovascular Imaging (EACVI) \textsuperscript{18}.

Analysis of phasic LA and regional LV strain

Phasic LAS was retrospectively analyzed from a standard 2D apical four
chamber

view (offline analysis, EchoPAC PC, GE Vingmed, Horton, Norway),
following the recent recommendations on standardization of left atrial
deformation imaging \textsuperscript{19}. LAS data was obtained as
previously described \textsuperscript{17}: In a QRS-triggered strain
curve, with LAS set to zero at the beginning of QRS, global average LA
reservoir, conduit, and contraction strain were defined as specific
points: LA reservoir strain (LASr) was represented by the highest
average LAS value, LA conduit strain (LAS during passive LV filling,
LAScd) was calculated by average LAS value at the onset of the p-wave
minus LASr. LA contraction strain (LAS during peak atrial contraction,
LASct) was calculated by LAS value following maximum LA contraction
minus LAS at the onset of the p-wave. In patients with atrial
fibrillation (n=5), only LASr and LAScd were obtained, as proposed by
the recent recommendations of the EACVI \textsuperscript{19}. As
proposed by the same recommendations, the arithmetic mean of three valid
measurements was determined.

LVGLS was calculated offline as the average peak systolic longitudinal
LV strain basing on LV strain analyses from three apical chamber views
(17 segment LV model; EchoPAC software, GE, Vingmed, Horton, Norway).
PLSD was obtained by the mean of deformation values in basal posterior
and lateral segments as proposed by Kramer et al. \textsuperscript{12}.

Papillary muscle area to LV area ratio (PM/LV-ratio) was obtained at a
transthoracic short axis view at end diastole and the areas were
manually traced as proposed by Nieman et al.\textsuperscript{14}.
Patients in whom only one papillary muscle was seen at this view were
excluded, this applied to 16 patients.

Statistical analysis

Statistical analyses were performed using SPSS (IBM Corp. Released 2020.
IBM SPSS Statistics for Macintosh Version 27.0. Armonk, NY: IBM Corp).
Data were expressed as mean \selectlanguage{ngerman}± standard deviation for continuous
variables or in percentage for categorical variables. Significance of
differences in clinical and echocardiographic data was calculated using
the non-parametric Mann--Whitney U test for continuous variables, and
the Fisher's exact test for categorical variables. Receiver operating
characteristic curve (ROC) analyses were performed to compare the
diagnostic value of phasic LAS and the PLSD.

Results

Clinical and echocardiographic characteristics

Of the 40 patients analyzed, 20 had FD proven by genetic testing. In the
LVH group, twelve patients were classified by endomyocardial biopsy to
have hypertrophic cardiomyopathy, two had hypertensive heart disease,
and six expressed the pattern of LV hypertrophy combined with borderline
myocarditis/myocardial inflammation. Possible confounders such as age,
gender and Body mass index (BMI) showed homogenous distribution between
the groups without significant differences. LV and LA geometry as well
as LVEF were not different between groups. LV filling parameters such as
E/A and E/e' showed slightly more advanced impairment in the LVH group.
PM/LV-ratio showed no significant difference between groups
(Figure\textbf{1} ). All clinical and echocardiographic characteristics
can be inspected in Tables 1 and 2.

Regional LV function and phasic LA strain

Global and regional LV function (LVGLS and PLSD) were not significantly
different between groups (Table 2 and Figure 1). In contrast, LAS of all
three phases of the atrial cycle was significantly reduced in FD
compared to the LVH group (Table 2 and Figure 1). Figure 2 shows
representative examples of regional LVGLS and phasic LAS analysis in a
patient with FD and a patient of the LVH group.

Diagnostic value of phasic LA strain in FD

A higher diagnostic accuracy could be shown for phasic LAS impairment in
discriminating FD compared to parameters such as LVGLS and PLSD in ROC
analyses (Table 3 and Figure 3). LAScd and LASr, with an area under the
curve (AUC) of 0.81 {[}95\% confidence interval (CI) 0.66-0.96{]} for
LAScd; and 0.76 {[}95\% CI 0.58-0.94{]} for LASr respectively, showed
the highest diagnostic accuracy. The PLSD, in contrast, showed an AUC of
0.49. LAVI also showed a poor diagnostic value to discriminate FD with
an AUC of 0.58 (95\% CI 0.35-0.81; p = 0.486).

Discussion

In this study, we provide a comparative assessment of phasic LAS and LV
mechanics, such as LVGLS and the PLSD pattern, in patients with FD and a
group with LVH due to other causes. Results showed a significantly
reduced phasic LAS in patients with FD compared to the LVH groups.
Beyond that, we describe a higher diagnostic value of LAS assessment,
compared to that of LVGLS or PLSD, in discriminating patients with FD.

Pichette et al \textsuperscript{15} published an extensive description
of LAS alterations in FD and showed a significant impairment of phasic
LAS in 50 patients with FD compared to 50 healthy controls. In contrast
to these findings, we compared data of FD patients to those with LVH due
to other causes; infiltrative disease was excluded by endomyocardial
biopsy in all patients in the LVH group, a fact that is of growing
importance due to the probable underreporting of infiltrative
cardiomyopathy in patients with LVH during the past
years\textsuperscript{20,21}. Furthermore, we compared phasic LAS to
more specific LV deformation parameters in FD since studies on this
topic are yet scarce in cardiomyopathies, particularly in FD.

LVGLS impairment was earlier described in FD by echocardiography and
MRI. Subsequently, Kramer et al. \textsuperscript{12} described the
phenomenon of PLSD in FD cardiomyopathy, concordant with posterolateral
myocardial fibrosis seen in MRI; a finding which is since then thought
to be the classic echocardiographic phenotype of FD
cardiomyopathy\textsuperscript{10}. Our study, however, showed a high
diagnostic accuracy of phasic LAS impairment in discriminating FD, but a
surprisingly low diagnostic accuracy for regional LVGLS and PM/LV-ratio,
a fact that could be linked to power issues of our study on the one
hand, and to the inclusion of patients featuring different staged FD
forms with incomplete PLSD pattern combined with unspecific PLSD pattern
in the LVH group on the other hand. These findings confirm the need for
more reproducible research of such `classical' appearing phenotypes in
comparison with other entities of LVH. Similarly, other LA parameters
recommended for echocardiographic assessment in FD by the recent expert
consensus recommendation \textsuperscript{10}, such as LAVI, failed to
discriminate FD as well, despite their proven correlation with phasic
LAS \textsuperscript{22}.

Another ``classical'' echocardiographic sign in FD, the
PM/LV-ratio\textsuperscript{14}, also failed to discriminate FD in our
cohort.

In a widely underdiagnosed but treatable disease such as FD with proven
benefit of treatment in early stages of disease, echocardiographic
parameters yielding a higher diagnostic accuracy than the
echocardiographic standard approach are urgently needed. Since Fabry
disease is a systemic disease and sphingolipid accumulation is
histologically proven to exceed the LV, it may be reasonable to
integrate echocardiographic parameters exceeding LV geometry and
function, such as impairment of LAS, into the diagnostic algorithm
(Figure \textbf{4} ).

The mechanisms of the significant impairment of LAS in FD patients shown
in our study are yet not thoroughly explained. The previously described
pattern of PLSD is also matter of debate; previous data by Weidemann et
al and Kramer et al \textsuperscript{8,12} strongly suggest that
impaired regional LV function may be caused by posterior and
inferolateral LV wall thinning due to fibrosis following sphingolipid
accumulation. Regarding the left atrium, impairment of LAS in many
cardiomyopathies and thus also in FD could be partially explained by
impaired diastolic LV function and consecutively elevated LV filling
pressures, a hypothesis that was previously confirmed when assessing LA
mechanics in general \textsuperscript{23} and in
FD\textsuperscript{15,16}. However, phasic LAS showed significant
reductions in the FD group while, in contrast, other parameters of LV
systolic and diastolic function, i.e. LVGLS, LAVI, E/e', were not
different between groups. Furthermore, NTproBNP was significantly higher
in the LVH group. These findings suggest that intrinsic LA dysfunction,
rather than high filling pressures imposing on LA function, may be the
leading cause of LAS impairment in this FD cohort.

There was further only a weak correlation of LV systolic and diastolic
parameters with LA reservoir and conduit function, a finding that is
well in line with the hypothesis of phasic LAS reductions due to
intrinsic rather than secondary LA function. Next to our study, also
data by Pichette et al suggest intrinsic LAS impairment in FD in a
longitudinal speckle-tracking study \textsuperscript{15} showing that
after initiation of ERT therapy LA mechanics improved, whereas LVGLS
remained stable. Similarly, \textsuperscript{17} in another `thick heart
pathology', i.e. CA, concomitant LA myopathy was previously considered
as well, questioning the isolated influence of systolic and diastolic LV
function on impaired LA function \textsuperscript{17}.

Boyd et al. previously suggested an additional atrial myopathy
irrespective of LVH \textsuperscript{16}, a suggestion we encourage with
our results since accumulation of sphingolipids in the LA wall have been
shown in autopsies\textsuperscript{24}. Future prospective studies,
however, assessing LA and LV dysfunction as well as tissue
characterization in FD are needed to investigate whether sphingolipid
accumulation into the thin-walled LA may be responsible for the observed
significant mechanical LA impairment.

Limitations

Our study was performed retrospectively, with all its inherent biases.
Furthermore, echocardiographic images focusing of the LA are needed for
LA strain analysis. However, this is neither part of standard
transthoracic image acquisition beyond LA volume and area analysis nor
feasible in all patients. Therefore, it contributes to the large number
of exclusions.This could be avoided in future by a prospective study
design with focus on LA image acquisition.

The relatively low number of studied subjects is comparable to other
Fabry disease studies \textsuperscript{15,16} due to the rare nature of
disease. Because the true prevalence of infiltrative disease is reported
to be strongly underestimated \textsuperscript{20,21}, we exclusively
included patients in the control group in which no findings of
infiltrative disease were detected by biopsy. Our results represent a
first explorative description; they need to be confirmed in larger,
prospective trials. Magnetic resonance imaging was not available in this
cohort but should be used in future studies for further understanding of
underlying pathophysiological mechanisms.

Author contributions:

David Frumkin, M.D.: Concept/design, Data analysis/interpretation,
Drafting article, Critical revision of article, Approval of article,
Statistics, Data collection

Isabel Mattig, M.D.: Data collection, Critical revision of article

Nina Laule: Data collection

Mamoun Al Daas: Data collection

Sima Canaan-Kühl, M.D.: Data collection

Fabian Knebel, M.D.: Concept/design, Data analysis/interpretation,
Critical revision of article, Approval of article,

Karl Stangl, M.D.: Critical revision of article, Approval of article

Anna Brand, M.D.: Concept/design, Data analysis/interpretation, Drafting
article, Critical revision of article, Approval of article, Statistics,
Data collection

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Figure legends:

\textbf{Figure 1} : Differences of LA reservoir (\emph{A} ), conduit
(\emph{B} ) strain, as well as of PLSD (C) and PM/LV-ratio (D) in
patients with FC and LVH. \emph{(*: p\textless{}0.05; \#: p=0.86; §:
p=0.93; LASr: Left atrial strain rate; LAScd: Left atrial conduit
strain; LA: left atrial; PLSD: posterolateral strain deficiency;
PM/LV-ratio: Ratio of papillary muscle area to left ventricular area;
FC: Fabry cardiomyopathy; LVH: left ventricular hypertrophy)}

\textbf{Figure 2} : Representative examples of LVGLS in a 17 segment
model and LAS analysis in two patients of the present cohort. (A)
Patient with FC featuring the PLSD pattern (yellow circle) and
impairment of LASr. (B) Patient with hypertrophic cardiomyopathy also
demonstrating PLSD, while LASr is less impaired. \emph{(LA: Left atrium;
LV: Left ventricle; LASr: Left atrial strain rate; LAScd: Left atrial
conduit strain; LASct: Left atrial contraction strain; PLSD:
posterolateral strain deficiency; FC: Fabry cardiomyopathy)}

\textbf{Figure 3} : ROC analysis of LASr and LAScd (A) as well as of
PLSD and PM/LV-ratio (B) to discriminate FC and LVH. \emph{(LASr: Left
atrial strain rate; LAScd: Left atrial conduit strain; PLSD:
posterolateral strain deficiency; PM/LV-ratio: Ratio of papillary muscle
area to left ventricular area; FC: Fabry cardiomyopathy; LVH: left
ventricular hypertrophy)}

\textbf{Figure 4} : \selectlanguage{english},Classical' echocardiographic findings when
examining patients with Fabry Cardiomyopathy. \emph{(LA: Left atrium;
LV: Left ventricle)}

\textbf{Hosted file}

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