<div>THE ADDED VALUE OF LEFT ATRIAL STRAIN IN CANCER-THERAPY-RELATED CARDIAC
DYSFUNCTION</div><div>By</div><div>Laura Romero, MD and Michele Nanna, MD</div><div>Albert Einstein Coll of Med/ Cardiac Care and Vascular Medicine, Bronx,
NY</div><div>Correspondence:</div><div>Michele Nanna, MD,</div><div>Associate Professor of Medicine, Albert Einstein College of Medicine/
Cardiac Care and Vascular Medicine</div><div>1461 Astor Ave, Bronx, NY 10469, USA</div><div>Email: mnannamd@cardiovascularcare.org</div><div>Cancer-therapy-related cardiac dysfunction (CTRCD) is an undesirable
side effect of chemotherapy that occurs in approximately 10% of the
patients [1]. Targeting early detection and advances in treatment
increases cancer survivors [2]. The American Society of
Echocardiography and the European Association of Cardiovascular Imaging
guidelines recommend the use of Speckle-Tracking-derived LV Global
Longitudinal Strain (LV-GLS) as a more objective and accurate method to
identify subclinical LV deterioration in patient undergoing chemotherapy
[3].</div><div>In cancer patients, assessment of Left Atrium (LA) function by Speckle
Tracking has emerged as a potential tool for predicting CTRCD and its
associated morbid arrhythmias such as atrial fibrillation (AF), a
frequent complication in this patient population [4-6].</div><div>Early research work used volumetric approaches to derive LA function
parameters. Volumetric parameters are widely used in standard clinical
practice and current guidelines assigns prognostic value to end-systolic
LA volume in patients with suspected LV diastolic dysfunction [3].
The relationship between LV filling and volumetric parameters is not
linear and reduction in LV filling pressures reduces but rarely
normalizes LA volumes. LA functional parameters, as measured by novel
methods of deformation analysis, more reliably detect reductions in LV
filling independent of LA volumes changes [7]. Speckle tracking
echocardiography–derived analysis of LA strain provides quantitative
parameters for all phases of LA function (reservoir, conduit, and
booster pump) and carries similar prognostic significance to that
provided by volumetric approaches, in different pathological conditions
including cancer patients[5,8].</div><div>Knowing the impact that LA functions has in detecting CTRCD the study by
Lassen and colleagues has tested LA strain in the evaluation of CTRCD as
a tool for early detection of myocardial damage induced by chemotherapy
[9].</div><div>In this retrospective cohort study a total of 170 women with HER2+
breast cancer (stage I-IV) undergoing treatment with trastuzumab were
studied at baseline, 3 months into treatment and 1 year since treatment
initiation. Of note, 77 (45.3%) of participants had prior exposure to
anthracycline. Also of note, during the 1- year follow-up, 23 (13.5%)
patients had trastuzumab held or stopped for either a decline in Left
Ventricular Ejection Fraction (LVEF) in 82.6% of cases or other
non-cardiac reasons in the remaining cases.</div><div>A total of 36 patients developed CTRCD during follow-up. At 3-month
follow-up, CTRCD patients had lower LVEF, LV-GLS, LA reservoir strain
(LA εres), and LA conduit strain rate (LAεcon-sr) compared to patients
that did not develop CTRCD. In the 36 patients developing CTRCD, there
was a decline in LVEF from baseline to 3-months follow-up with partial
recovery at 1-year follow- up. LV-GLS also declined at 3 months,
however, contrary to LVEF a recovery did not occur at 1 year follow up.
In the 134 patients who did not develop CTRCD during follow-up, LA
Volume Index increased from baseline to 3-month follow-up and then
modestly recovered at 1-year. LA strain parameters also declined during
follow-up but to a lesser degree than in the CTRCD group suggesting its
value as a more sensitive parameters of subtle functional changes. This
study is one of the largest studies in patients with breast cancer that
has assessed changes in LA strain parameters following treatment with
transtuzumab.</div><div>The new information provided by Lassen et al. is in demonstrating that
cancer and its treatment with Transtuzumab may negatively affect atrial
function and that measurements of LA strain can detect functional
changes related to cardiotoxic effects of chemotherapy. Other studies
also support the fact that cancer and chemotherapy can modified LA
function earlier than LV function. For example, Laufer-Perl et al.
identified that cancer itself caused LA εres to be 17% lower with a
further 10% relative reduction in LA εres or a decrease in LA εres
below 35% in half of a population of patients undergoing chemotherapy
with anthracycline. [10]. Park et al. demonstrated that while both
LA εres and LV-GLS were early markers in the detection of CTRCD, LA εres
reduction was more sensitive and specific than LV-GLS in predicting
CTRCD [6]. Similar abnormalities in LA function were demonstrated by
Tadic et al. who showed that LA reservoir and conduit function were
reduced, while booster pump function was increased in cancer patients
[11]. Combined with the observation by Laufer- Perl and colleagues,
this raises the question as to whether LV dysfunction is only the
consequence of anti- cancer therapy or if cancer itself leads to
abnormalities in function. Thus, both the pathology and the therapy for
that pathology can lead to LA functional impairment, which is associated
with a higher risk of AF, a frequent arrhythmia in cancer patients with
an impact on prognosis [4, 12].</div><div>Several limitations should be noted. CTRCD is a serious complication of
anticancer therapy that can be</div><div>classified into Type I exemplified by anthracyline- induced cardiac
dysfunction characterized by irreversible myocardial damage due to
cumulative administered dose and type II exemplified by</div><div>trastuzumab- induced cardiac dysfunction that is dose independent and
reversible. The mechanism of cardiac toxicity in both types is not well
defined. Current ACC/AHA guidelines recommend that patients who develop
Heart Failure (HF) while receiving potentially cardiotoxic therapies
should have these therapies discontinued while a diagnostic workup is
undertaken to ascertain the cause of HF [12, 13]. These guidelines
acknowledge that, particularly in patients receiving trastuzumab,
asymptomatic decreases in LVEF can occur in approximately 10% of
patients, yet, a high recovery rate is observed and discontinuation of
therapy is not always necessary. [13, 14].</div><div>Accordingly, trastuzumab is often continued in patients deemed low risk
while neurohormonal blockade</div><div>Is initiated usually with guideline directed medical therapy to improve
LV function such as beta blockers</div><div>and ACEi. While the authors report discontinuing or holding trastuzumab
in 23 (13.5%) patients, they do not mention adjuvant treatment with
neurohormonal blockade that might have influenced the results. Partial
improvement of some parameters (LA εres and LVEF) at 12 months follow-up
in patients who developed CTRCD raises the possibility that treatment
with adjuvant therapy might be responsible for the beneficial changes.
Another important limitation is the lack of additional echocardiographic
parameters potentially related to LA function. A significant association
exists between impaired LA strain and LV filling pressure (E/E′ ratio),
pulmonary pressure (tricuspid regurgitation velocity), and RV systolic
function (RVFAC) [15]. None of these parameters have been described
in the manuscript.</div><div>From a research perspective, future investigations should be mindful of
the association between reduction in LV filling pressure and improvement
in LA function as indicated by the improvement in LA strain and a more
holistic approach should be used reporting echocardiographic parameters
related to</div><div>LV filling (i.e. E/E′ ratio, LA stiffness index or E/E′/LA reservoir
strain). Although Strain and Strain Rate are increasingly used,
deformation analysis of the LA offers unique challenges. Anatomic
challenges as well as specific expertise and training required for
accurate data acquisition and processing remain a significant impediment
to a widespread clinical use. Advances in cardiac imaging in the field
of speckle tracking echocardiography, including machine learning
algorithms, may help overcome these obstacles and provide a more
reliable and fast functional assessment of the LA.</div><div>Despite the limitations the manuscript convincingly confirms previous
reports that have demonstrated the added value of LA strain in the
assessment of various pathologic conditions affecting LV function and
reinforces the need for further work to establish its role in clinical
applications such as risk stratification and decision-making strategies.</div><div>BIBLIOGRAPHY</div><div>1. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of
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