DEFINING NORMAL REFERENCE RANGES OF LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN AMONG DIFFERENT VENDORS: ARE WE THERE YET?Nanna Michele1 MD, Romero Acero Laura Marcela1 MD, Lee Pei-Lun 2 MDCardiac Care & Vascular Medicine / Albert Einstein College of MedicineJacobi Medical Center, Department of Medicine/Albert Einstein College of MedicineStrain and strain rate imaging have evolved significantly since their introduction two decades ago, providing an objective means to quantify both regional and global myocardial function [1]. Initially developed using tissue Doppler strain, strain imaging has largely transitioned to speckle-tracking echocardiography (STE), a technique that is angle-independent and offers improved feasibility and reproducibility. Left ventricular global longitudinal strain (LVGLS) has become an established measure of left ventricular (LV) systolic function with numerous clinical applications. However, despite its promise, LVGLS has not yet been widely adopted in real-world clinical practice. One major barrier is the variability across different echocardiographic vendors, which introduces inconsistency in measurements and complicates standardization efforts.Traditionally, left ventricular ejection fraction (LVEF) has been the most commonly used parameter for assessing LV systolic function and predicting outcomes. However, despite its widespread use, LVEF has notable limitations, including significant intra- and inter-observer variability, dependence on geometric assumptions, and susceptibility to technical artifacts such as endocardial dropout and foreshortening of the apex. Similar challenges exist for LVGLS, where accurate endocardial contour delineation and motion tracking are crucial for reliable assessment. Reproducibility of LVGLS using different vendors’ algorithm software remains controversial and has been described as acceptable by some [2] or shown to have significant discrepancies by others [3-5].Advancements in speckle-tracking echocardiography, including machine learning-driven algorithms, have improved strain analysis. However, a key limitation of strain imaging is that measurements remain dependent on proprietary software algorithms, leading to variability between vendors. Moreover, despite abundant literature, defining universal reference ranges remains a challenge, as different software platforms yield slightly different results. A proposed solution has been the use of intra-institutional vendor independent software capable of obtaining off line strain measurements. These vendor independent strain software packages have evolved but have not undergone rigorous external validation studies.The study by Arockiam et al. [6] addresses this gap by evaluating normal reference ranges for LVGLS using contemporary, vendor-neutral strain software in a cohort of healthy individuals. The authors examined 100 subjects across different age groups, using echocardiographic scans from General Electric (GE) and Philips systems. Four strain software packages—TomTec, EchoPAC, VVI, and Epsilon—were used to quantify LVGLS, enabling direct comparative and regression analyses. Their findings indicate that mean LVGLS values varied slightly across the four software packages, with EchoPAC producing the most negative strain values and VVI yielding the least negative values. Regression analyses identified sex, heart rate, LVEF, and the choice of strain software (particularly EchoPAC and VVI vs. TomTec) as significant contributors to LVGLS measurement variability. Despite differences across the four software platforms, the study provides reference ranges that may aid in defining normal, abnormal, and borderline LVGLS values for clinical application.Based on these results, the authors conclude that LVGLS measurements were feasible across all four strain software on both GE and Philips scans in this study. While acknowledging differences among the four strain software packages, by reporting LLNs and their 95%CI the authors provide helpful reference ranges to define normal, abnormal and borderline LVGLS values to enable clinical application. The results led the authors to cautiously recommend using the same strain software and their own respective reference ranges for interpreting and comparing LVGLS measurements.Importantly, the authors demonstrate that the inter-vendor variability of LVGLS is now comparable to, or even smaller than, the variability seen with LVEF. This marks a significant step toward the routine clinical application of LVGLS as an alternative or adjunct to LVEF. An increasing number of studies have suggested that GLS is superior to EF as a measure of LV function and as a predictor of mortality and cardiac events [7-10] . Previous reports have suggested that an absolute GLS of -12% represents severe systolic dysfunction and carries an adverse prognosis, and -15–16% identifies patients with relatively preserved EF at higher risk for future events. However, LVGLS reference range values associated with risk tiers have yet to be firmly established, in part due to lack of established lower limit of normal values.While the study represents a significant contribution to the field, some limitations should be acknowledged. The cohort predominantly comprised younger subjects, which may not reflect the typical age distribution seen in clinical practice. Since older patients often have more comorbidities affecting myocardial mechanics, the findings may not be fully generalizable. Most participants were white, limiting the applicability of the findings to ethnically diverse populations. A number of studies have provided reference ranges for specific ethnic groups. In the 2012 JUSTICE (Japanese Ultrasound Speckle Tracking of the Left Ventricle) study [5] of 817 healthy mostly male volunteers with average age 36 years, the overall mean full thickness, peak systolic GLS using GE equipment was reported as -21.3+ 2.1% . In a 2014 Italian study [11] of 260 Caucasian healthy mostly female volunteers with average age 44 years, the mean full-thickness, peak systolic GLS using GE equipment was reported as -21.5 +2.0% (lower limits of normal or average: 2 SD was 16.9% for men and 18.5% for women). Different values were obtained in a 2009 multicenter (Australian, European and American) study [12] of 242 healthy mostly female volunteers with average age 51 years in which mean full-thickness, peak systolic GLS using GE equipment was reported as -18.6+ 0.1%, with no significant differences among geographical regions. Given known ethnic differences in cardiac structure and function, further studies incorporating broader demographic diversity are needed.The study does not provide data on whether LVGLS measurements obtained from different ultrasound machines (GE vs. Philips) in the same patient yield consistent results across all vendor-neutral software platforms. This remains a crucial question for laboratories that use multiple echocardiographic systems. Additionally, the study focused solely on LVGLS and did not assess global circumferential strain, global radial strain, or strain rate measurements. These parameters are less commonly used in clinical practice due to their greater variability, but further investigations into their standardization remain necessary.Similarly, GLS is highest in the endocardium and lowest in the epicardium. To assess inter-vendor global strain differences the study results only apply to endocardial GLS, the only parameter that could be provided by all vendors. Results may not be valid if region of interest for GLS is set in the midwall, epicardial, or full thickness. Indeed, most companies now include software capable of mid/full wall tracking which preliminary data have shown to have similarly good inter-vendor bias and reproducibility as endocardial GLS [13].There is currently lack of reference values for segmental strain measurements in part due to suboptimal reproducibility and large inter-vendor measurement variability. The current study does not provide information regarding quantitative assessment of the magnitude of regional deformation. This leaves open the possibility that, inter-vendor differences for segmental strain values may be considerably higher than that reported for global values. The extent of spatial smoothing aimed at reducing noise in the regional tracking of speckles may vary in the different algorithms used by each vendor and may contribute to inter-vendor variability. This gap in knowledge relegates regional strain measurements to assessment of regional differences in polar strain maps rather than precise definition of numerical segment-specific strain values. While reductions in local strain may correctly identify areas of inflammation or fibrosis, the availability of reference values might enhance the ability to quantify regional abnormalities as compared to other imaging techniques.Thanks to continued collaboration between vendors and potential sharing of proprietary software has resulted in further reduction in inter-vendor variability. A recent report of the European Association of Cardiovascular Imaging (EACVI) Strain Standardization Task Force [13] aimed at comparing the current inter-vendor variability and reproducibility to the findings from their previous 2013 results evaluated 372 echocardiographic examinations performed in sixty-two subjects with a wide range of left ventricular (LV) function (ejection fraction from 30% to 64%) using ultrasound systems from six manufacturers.The results showed that both endocardial and mid/full-wall GLS measurements were comparable and within a very narrow range (maximum inter-vendor bias of 0.9% strain units) whereas in 2013, the maximum absolute difference was 3.7 % strain units, leading the authors to conclude that in contrast to the situation ten years earlier, a substantial improvement in inter-vendor bias has been accomplished. In addition, most companies now allow mid/full-wall tracking, which had similarly good inter-vendor bias and reproducibility as endocardial GLS.The study by Arockiam et al. [6] represents an important step toward the standardization of LVGLS measurements across different software platforms. By providing vendor-neutral reference ranges, the authors offer valuable insights that may facilitate the integration of strain imaging into routine clinical practice. However, persistent variability among independent vendors, albeit reduced, underscores the need for continued refinement in strain software and external validation in larger, more diverse populations. Moving forward, widespread adoption of vendor-neutral strain software, along with further multicenter studies, will be crucial for achieving true standardization. In the interim, clinicians should remain aware of the potential measurement discrepancies among software packages and ensure consistency by using the same strain analysis tool for serial patient evaluations.REFERENCES[1]. Sutherland GR, Di Salvo G, Claus P, et al. Strain and strain rate imaging: a new clinical approach to quantifying regional myocardial function. J Am Soc Echocardiogr. 2004;17(7):788-802.[2]. Manovel A, Dawson D, Smith B, et al. Assessment of left ventricular function by different speckle-tracking software. Eur J Echocardiogr. 2010;11(5):417-21.[3]. Biaggi P, Carasso S, Garceau P, et al. Comparison of two different speckle tracking software systems: does the method matter? Echocardiography. 2011;28(5):539-47.[4]. Nelson MR, Hurst RT, Raslan SF,et al. Echocardiographic measures of myocardial deformation by speckle-tracking technologies: the need for standardization? J Am Soc Echocardiogr. 2012;25(11):1189-94.[5]. Takigiku K, Takeuchi M, Izumi C, et al. Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study. Circ J. 2012;76(11):2623-32.[6]. Arockiam A D, Dong T, Agrawal A, et al. Reference ranges of left ventricular global longitudinal strain by contemporary vendor-neutral echocardiography software in healthy subjects. Echocardiography (in press).[7]. Ersbøll M, Valeur N, Mogensen UM, et al. Prediction of all-cause mortality and heart failure admissions from global left ventricular longitudinal strain in patients with acute myocardial infarction and preserved left ventricular ejection fraction. J Am Coll Cardiol. 2013;61(23):2365-73.[8]. Mignot A, Donal E, Zaroui A , et al. Global longitudinal strain as a major predictor of cardiac events in patients with depressed left ventricular function: a multicenter study. J Am Soc Echocardiogr. 2010;23(10):1019-24.[9]. Stanton T, Leano R, Marwick TH. Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring. Circ Cardiovasc Imaging. 2009;2(5):356-64.[10]. Haugaa KH, Grenne BL, Eek CH, et al. Strain echocardiography improves risk prediction of ventricular arrhythmias after myocardial infarction. JACC Cardiovasc Imaging. 2013;6(8):841-50.[11]. Kocabay G, Muraru D, Peluso D, et al. Normal left ventricular mechanics by two-dimensional speckle-tracking echocardiography. Reference values in healthy adults. Rev Esp Cardiol (Engl Ed). 2014;67(8):651-8.[12]. Marwick TH, Leano RL, Brown J, et al. Myocardial strain measurement with 2-dimensional speckle-tracking echocardiography: definition of normal range. JACC Cardiovasc Imaging. 2009;2(1):80-4.[13]. Balinisteanu A E, Duchenne J, Puvrez A,et al. Inter-vendor variability in two-dimensional speckle tracking strain: a ten-year follow-up on the strain standardization task force inter-vendor comparison study. Eur. Heart J. Cardiovasc. Imaging. 2025; 26, Issue Supplement_1.

THE ADDED VALUE OF LEFT ATRIAL STRAIN IN CANCER-THERAPY-RELATED CARDIAC DYSFUNCTIONByLaura Romero, MD and Michele Nanna, MDAlbert Einstein Coll of Med/ Cardiac Care and Vascular Medicine, Bronx, NYCorrespondence:Michele Nanna, MD,Associate Professor of Medicine, Albert Einstein College of Medicine/ Cardiac Care and Vascular Medicine1461 Astor Ave, Bronx, NY 10469, USAEmail: mnannamd@cardiovascularcare.orgCancer-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].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].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].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].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.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.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].Several limitations should be noted. CTRCD is a serious complication of anticancer therapy that can beclassified into Type I exemplified by anthracyline- induced cardiac dysfunction characterized by irreversible myocardial damage due to cumulative administered dose and type II exemplified bytrastuzumab- 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].Accordingly, trastuzumab is often continued in patients deemed low risk while neurohormonal blockadeIs initiated usually with guideline directed medical therapy to improve LV function such as beta blockersand 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.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 toLV 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.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.BIBLIOGRAPHY1. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015; 131(22):1981-8.2. de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev. 2013; 22(4):561-70.3. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016; 29(4):277-314.4. Galderisi M, Esposito R, Sorrentino R, et al. Atrial Fibrillation, Cancer and Echocardiography. J Cardiovasc Echogr. 2020; 30(Suppl 1):S33-S7.5. Sarvari SI, Haugaa KH, Stokke TM, et al. Strain echocardiographic assessment of left atrial function predicts recurrence of atrial fibrillation. Eur Heart J Cardiovasc Imaging. 2016; 17(6):660-7.6. Park H, Kim KH, Kim HY, et al. Left atrial longitudinal strain as a predictor of Cancer therapeutics-related cardiac dysfunction in patients with breast Cancer. Cardiovasc Ultrasound. 2020; 18(1):28.7. Huynh QL, Kalam K, Iannaccone A,et al. Functional and Anatomic Responses of the Left Atrium to Change in Estimated Left Ventricular Filling Pressure. J Am Soc Echocardiogr. 2015; 28(12):1428-33.e1.8. Donal E, Behagel A, Feneon D. Value of left atrial strain: a highly promising field of investigation. Eur Heart J Cardiovasc Imaging. 2015; 16(4):356-7.9. M C Lassen, F Arya, T Biering-Sørensen, et al. Left Atrial Strain is Reduced Following Trastuzumab in Breast Cancer Patients. Echocardiography (InPress).10. Laufer-Perl M, Arias O, Dorfman SS, et al. Left Atrial Strain changes in patients with breast cancer during anthracycline therapy. Int J Cardiol.2021; 330:238-44.11. Tadic M, Genger M, Cuspidi C, et al. Phasic Left Atrial Function in Cancer Patients Before Initiation of Anti-Cancer Therapy. J Clin Med.2019; 8(4).12. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022; 79(17):e263-e421.13. Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol. 2006; 24(25):4107-15.14. Wang SY, Long JB, Hurria A, et al. Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival. Breast Cancer ResTreat. 2014; 146(2):411-9.15. Santos AB, Roca GQ, Claggett B, et al. Prognostic Relevance of Left Atrial Dysfunction in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2016; 9(4):e002763.