Association of Speckle Tracking Echocardiography with Acute Cellular Rejection in Cardiac Transplant Patients: A Systematic Review and Meta-Analysis

Association of Speckle Tracking Echocardiography with Acute Cellular Rejection in Cardiac Transplant Patients: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of Speckle Tracking Echocardiography with Acute Cellular Rejection in Cardiac Transplant Patients: A Systematic Review and Meta-Analysis Jesse Frye, Michael Tao, Simrat Dhaliwal, Matthew Raven, Jordan Price, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4046173/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Myocardial strain imaging by speckle tracking echocardiography (STE) has demonstrated prognostic utility in several disease states. However, the association of strain measurements with acute cellular rejection (ACR) after cardiac transplantation is not well established. This meta-analysis aims to evaluate the association of myocardial strain measurements with acute cellular rejection in cardiac transplant patients. Methods: A literature search was conducted using Ovid MEDLINE, EMBASE, and Web of Science for studies reporting on the association of left ventricular (LV) global longitudinal (GLS), radial (GRS), and circumferential (GCS) strain in cardiac transplant patients with and without acute cellular rejection. Subgroup analysis was performed by ISHLT standardized ACR grading to compare grade 1R versus Grade 2R and higher. Results: A total of 21 studies with 2502 transplant patients (1465 without ACR versus 1037 with ACR) were included. Patients with ACR had significantly lower GLS compared to patients without ACR on biopsy (MD 2.84, 95% CI 1.5-4.18; p<0.01). Patients with ACR grade ≥2R had significantly lower GLS compared to patients with ACR grade 1R (MD 2.36, 95% CI 1.49-3.23; p<0.01). Patients with ACR had a significantly lower GCS compared to patients without ACR and GCS was significantly lower in patients with ACR grade ≥2R compared to patients with ACR grade 1R (MD 2.29, 95% CI 1.08, 3.51; MD 2.83, 95% CI 0.08-5.59; p=0.04). Conclusions: Left ventricular GLS and GCS may represent useful markers to identify cardiac transplant patients with ACR. Speckle tracking echocardiography cardiac transplantation acute cellular rejection Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Orthotopic heart transplantation (OHT) is often the treatment of choice for individuals with stage D heart failure [1]. Over time, survival following transplant has improved with better patient selection, organ availability, and advances in immunosuppression strategies[2]. Despite these improvements, acute cellular rejection (ACR) is still a significant possible complication of OHT[3]. Though incidence has declined, it is still an important cause of mosrtality in the first year following ACR, complicating more than 12% of cases in the first year following transplant [4,5]. Prompt diagnosis and initiation of immunomodulators is essential for patient survival and preventing the progression of disease. Currently, histological sampling of diseased tissue is the gold standard for diagnosis. ACR can then be graded: Grade 1R is mild, grade 2R is moderate, and grade 3R is severe [6]. This procedure is invasive, costly, and associated with several complications [7, 8]. Thus, non-invasive imaging modalities could prove to be a useful alternative to endomyocardial biopsy (EMB) in diagnosis and prognosis. Speckle tracking echocardiography (STE) may be a reliable tool that holds prognostic potential. The use of STE has exhibited considerable prognostic utility across several disease states characterized by subclinical myocardial dysfunction [9-11]. Notably, it has shown sensitivity in detecting subtle changes in sub-endocardial tissues secondary to fibrotic or inflammatory states [12, 13]. Because of this, STE is a promising tool to allow for prompt diagnosis of ACR, though this has not yet been definitively established. This meta-analysis aims to evaluate the correlation between myocardial strain measurements via STE and ACR in orthotopic transplant patients. Methods Data Search and Collection We reviewed PubMed, EMBASE, and Web of Science for our literature search. The subject matter of interest was the association of left ventricular (LV) lobal longitudinal (GLS), radial (GRS), and circumferential (GCS) strain in cardiac transplant patients with and without ACR. The reviewers used the following search keywords: “speckle tracking,” “strain,” “heart transplant,” “cardiac transplant,” and “rejection.” Reviewers examined the full text of each relevant article to determine if it met inclusion criteria. Studies chosen compared patients with ACR on endomyocardial biopsy (EMB) to those without ACR on EMB, assessing LV strain measurements by transthoracic echocardiogram in these cohorts. LV strain measurements of interest were GLS, GCS, and GRS. The primary endpoint was acute cellular rejection. Studies reporting on antibody mediated rejection were excluded. Studies that did not confirm transplant rejection by EMB were excluded. Variables that were extracted from the studies included: Lead author, year of publication, study design, follow up duration, mean age, left ventricular ejection fraction, sex, presence of ACR, classification of ACR, GLS, GRS, and GCS. Statistics The statistical portion of the meta-analysis was done with the program “Cochrane Review Manager Version 5.4.” The association between GLS, GRS, and GCS with the presence of ACR on EMB was examined with a random effects model and presented as a mean difference with 95% confidence intervals and p-values. Subgroup analysis was performed according to the International Society for Heart & Lung Transplantation standardized ACR grading to compare grade 1R versus Grade 2R and higher. I2 values were used to measure heterogeneity. Statistical significance was defined as a p-value less than 0.05 on a two-sided test. Results Literature Search and Study Selection We identified 1377 potential studies from our literature search. After reviewing the full text of each of these studies, 21 studies were determined to be eligible for inclusion in the meta-analysis for the outcomes: GLS, GCS, GRS. This process of selection is summarized in (Figure 1). Study and patient characteristics This meta-analysis included prospective and retrospective studies (Table 1). A total of 2,502 patients with cardiac transplant met inclusion criteria. This included 1,465 patients without ACR and 1,037 patients with ACR. The average LV ejection fraction was 62%. Mean age was 48.3 years old. 71.6% were men. Mean follow-up duration was 12.7 months (ranging 4 – 24 months). Association of ACR with Strain Measurements Patients with ACR had significantly lower GLS compared to patients without ACR on biopsy (MD 2.84, 95% CI 1.5-4.18; p<0.01) (Figure 2). Patients with ACR had a significantly lower GCS compared to patients without ACR (MD 2.29, 95% CI 1.08, 3.51; P<0.01) (Figure 3). GRS measurements were not significantly different in patients with ACR compared to patients without ACR (MD -0.19, 95% CI -4.93 – 4.53; p = 0.94) (Figure 4). Subgroup Analysis Patients with ACR grade ≥2R had significantly lower GLS compared to patients with ACR grade 1R (MD 2.36, 95% CI 1.49-3.23; p<0.01) (Figure 5). GCS was significantly lower in patients with ACR grade ≥2R compared to patients with ACR grade 1R (MD 2.83, 95% CI 0.08-5.59, p = 0.04) (Figure 6). The association between ACR and GCS is weaker with a smaller effect size compared to GLS. Discussion This meta-analysis evaluated whether myocardial strain imaging by STE adequately predicts ACR in orthotopic heart transplant patients. We found that (a) patients with confirmed ACR on endomyocardial biopsy had significantly lower GLS and GCS than patients without ACR on biopsy regardless of grade of disease; whereas (b) GRS measurements were not significantly different between ACR and non-ACR patients; (c) GLS and GCS values were lower in ACR grade ≥2R compared to ACR grade 1R. The historical challenges posed by ACR have been mitigated by the effectiveness of various therapies, contributing to improved health outcomes and increased survival in orthotopic heart transplant patients. EMB remains standard of care for detecting ACR; however, it is invasive and associated with complications. In addition, false negative biopsies occur in approximately 20% of cases due to the heterogeneity of diseased tissue present in the myocardium [14, 15]. Moreover, ACR positive patients may be clinically asymptomatic or present with non-specific symptoms. These subtle presentations can often go unnoticed for an extended period, potentially leading to delays in the initiation of essential treatments and, consequently, contributing to unfavorable outcomes [16, 17]. Effective treatment modalities with early disease detection holds promise for further reducing the disease burden of ACR in orthotopic heart transplant patients, and STE, via the measurement of strain, may serve as a potential resource. ACR is characterized by cellular infiltrates and edema, which ultimately disrupt left ventricular contractility. Traditional transthoracic echocardiography can assess graft function through measurement of systolic and diastolic function. However, left ventricular ejection fraction (LVEF) is often preserved until late in the disease course, and other measures of systolic and diastolic function are not sufficiently sensitive [18]. On the other hand, STE allows for a unique assessment of left ventricular myocardial deformation in several directions (GLS, GCS and GRS), which may improve sensitivity. Our results suggest that GLS and GRS can help rule out significant ACR and serve as an important tool to diagnose rejection prior to the development of frank LV dysfunction. While symptomatic and more severe rejection is associated with significant GLS/GRS reduction, one study by Ambardekar et al. showed there were no changes in myocardial strain and strain rate as assessed by STE in patients with asymptomatic biopsy-proven rejection [19]. This brings forth a potential limitation to STE, and stresses the importance of future studies in this particular patient population. Our meta-analysis also investigated how the values of LVGLS and LVGCS compared between ACR Grade 1R and ≥2R rejection. Both LVGLS and LVGCS were significantly lower in ACR Grade ≥2R rejection. This can be partly explained by the degree of histopathologic injury. ACR Grade 1R demonstrates interstitial/perivascular infiltrates with up to one focus of myocyte damage; however, ACR Grade ≥2R represents at least 2 or more foci (at times even diffuse) associated with myocyte damage, with or without edema, hemorrhage, or vasculitis [6]. Thus, it comes as no surprise that as the degree of myocyte damage increases, the values for LVGLS and LVGCS decrease. It should be noted that segmental LV longitudinal strain has been shown to be most sensitive when assessing for lower grades of ACR; this can be partly explained by the patchy nature of ACR [17]. However, the scope of this paper did not assess the use of segmental strain values or directly compare prognostication abilities among the various forms of global strain. Conclusion/Future Direction Our findings demonstrate that STE has the potential to be a reliable prognostic modality for ACR in post-transplant patients, especially in symptomatic or higher-grade presentations. This is not to say that STE can replace EBM biopsy for rejection surveillance, but it may serve as an adjunctive tool. This is just one of many potential noninvasive tools available. The list also includes cell-free DNA, Allo-Maps, gene expression microarrays and cardiac MRI [20-23]. Additional studies would be useful in analyzing the combination of these techniques to predict ACR. Limitations: Despite its contributions to the field of research, certain limitations of our study must be acknowledged. The studies included in this paper excluded subjects with certain comorbidities, which greatly affects the generalizability of our results. The heterogeneity was considerably high, likely due to vendor-specific and user-dependent differences in strain measurements and STE lab protocols. To combat this limitation, a random-effects model and subgroup analysis may be beneficial. Lastly, the scope of our study focuses on ACR and left ventricular strain values only. Additional studies covering other strain measurements, such as right ventricular strain, as well as other cardiovascular outcomes can further elucidate the value of STE in this population. Abbreviations ACR: Acute Cellular Rejection EMB: Endomyocardial Biopsy GCS: Global Circumferential Strain GLS: Global Longitudinal Strain GRS: Global Radial Strain ISHLT: International Society for Heart and Lung Transplantation LV: Left Ventricular STE: Speckle Tracking Echocardiography Declarations Data Availability Statement: The data underlying this article will be shared on reasonable request to the corresponding author. Financial Disclosures: None Conflicts of Interest: None References Cameli M, Pastore MC, Campora A, Lisi M, Mandoli GE. Donor shortage in heart transplantation: How can we overcome this challenge? Front Cardiovasc Med, 2022. 9 : p. 1001002. Hsich E, Singh TP, Cherikh WS, et al. 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Usefulness of Two-Dimensional Strain Parameters to Diagnose Acute Rejection after Heart Transplantation. J Am Soc Echocardiogr. 2015 Oct;28(10):1149-56. Podrouzkova H, Bedanova H, Tretina M, et al. Decrease in longitudinal strain in heart transplant recipients is associated with rejection. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015 Dec;159(4):601-6. Ruiz Ortiz M, Peña ML, Mesa D, et al. Impact of asymptomatic acute cellular rejection on left ventricle myocardial function evaluated by means of two-dimensional speckle tracking echocardiography in heart transplant recipients. Echocardiography. 2015 Feb;32(2):229-37. Sade LE, Hazirolan T, Kozan H, et al. T1 Mapping by Cardiac Magnetic Resonance and Multidimensional Speckle-Tracking Strain by Echocardiography for the Detection of Acute Cellular Rejection in Cardiac Allograft Recipients. JACC Cardiovasc Imaging. 2019 Aug;12(8 Pt 2):1601-1614. Stavenchuk TV, Kosmachova ED, Shelestova IA. 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Tables Table 1: Demographic data of the included studies: ACR: Acute Cellular Rejection, LVEF: Left Ventricular Ejection Fraction Author Publication Year Type of Publication Follow-up Duration Mean Age LVEF No ACR LVEF ACR Gender (%male) No ACR Total ACR Total Ambardekar 19 2015 Retrospective 12 44.4 Not specified Not specified 77 14 30 Antoczyk 24 2018 Prospective 10 50.2 Not specified Not specified 88 190 30 Antoczyk 25 2018 Prospective 12 49.5 Not specified Not specified 80 15 15 Chamberlain 26 2022 Retrospective 12 48 62 64 Not specified Not applicable 96 Ciarka 27 2022 Retrospective 12 36 62 49 82.4 17 10 Clemmensen 28 2016 Prospective 12 45.48 64 65 66.7 20 16 Clemmensen 29 2015 Prospective 24 42.4 64 64 64.1 268 241 Clemmensen 30 2015 Prospective 24 54.44 64 62 78.6 Not applicable 119 Cruz 31 2021 Prospective 6 42.1 64 65 56.7 43 17 da Costa 32 2022 Retrospective 12 50.3 67 67 60.4 84 21 Du 33 2016 Prospective Not specified 51 49 51 Not specified 7 8 Eleid 34 2010 Prospective 12 52.6 62 59 75 18 13 Mancuso 35 2022 Prospective Not specified 54 62 63 Not specified 300 94 Marciniak 36 2007 Prospective 12 Not specified 63 59 75.7 21 10 Mingo-Santos 37 2015 Prospective 12 51.8 64 62 82.4 173 62 Otto 17 2022 Prospective 12 52 61 65 40.3 36 31 Podrouzkova 38 2015 Prospective 51.33 62 60 67 20 23 Ruiz-Ortiz 39 2014 Prospective 4 51.5 67 62 85 31 45 Sade 40 2019 Prospective 15.5 40 60 56 67.3 18 31 Stavenchuck 41 2016 Retrospective Not specified Not specified Not specified Not specified Not specified 150 100 Tseng 42 2018 Retrospective 12 51 65 64 70.8 40 25 Additional Declarations No competing interests reported. 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diagram depicting the study selection for inclusion in the meta-analysis according to the PRISMA statement for reporting systematic reviews and meta-analyses\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/727a08eda49ebb5d797f6547.jpg"},{"id":52542958,"identity":"ff68d7b3-160b-4d28-97cf-961d610c8bfa","added_by":"auto","created_at":"2024-03-12 17:46:57","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64047,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of GLS measurements with ACR\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/7bd1c86b63c08a0f5e0ccb21.jpg"},{"id":52542960,"identity":"e2c35c34-82e3-4f69-9433-125a030d1c1b","added_by":"auto","created_at":"2024-03-12 17:46:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52869,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of GCS measurements with ACR\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/63af68155d9233aff5610472.jpg"},{"id":52543393,"identity":"2f51d478-ca5f-4fe9-8fb0-7d063108ecc7","added_by":"auto","created_at":"2024-03-12 17:54:57","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":36457,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of GRS measurements with ACR\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/f714e17955a774346315bf71.jpg"},{"id":52542962,"identity":"1c86c399-e1a2-4c54-a0aa-e91e3b7c8118","added_by":"auto","created_at":"2024-03-12 17:46:58","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":36157,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of GLS measurements with ACR grade 1R versus ACR grade ≥2R\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/1bca75dac61b2214fe0e7ef1.jpg"},{"id":52543394,"identity":"dd918941-c395-4e21-a9d9-9c4b91a417dc","added_by":"auto","created_at":"2024-03-12 17:54:58","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":27222,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of GCS measurements with ACR grade 1R versus ACR grade ≥2R\u003c/p\u003e","description":"","filename":"Picture6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/70d7f9c39a705fc297ea9224.jpg"},{"id":52591700,"identity":"83971885-7264-447d-8c7f-9aebfc07d4c6","added_by":"auto","created_at":"2024-03-13 10:35:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":446033,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4046173/v1/663a7b08-0e8c-44de-9d6b-3760cac5aba8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of Speckle Tracking Echocardiography with Acute Cellular Rejection in Cardiac Transplant Patients: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOrthotopic heart transplantation (OHT) is often the treatment of choice for individuals with stage D heart failure\u0026nbsp;[1]. Over time, survival following transplant has improved with better patient selection, organ availability, and advances in immunosuppression strategies[2]. Despite these improvements, acute cellular rejection (ACR) is still a significant possible complication of OHT[3]. Though incidence has declined, it is still an important cause of mosrtality in the first year following ACR, complicating more than 12% of cases in the first year following transplant [4,5].\u003c/p\u003e\n\u003cp\u003ePrompt diagnosis and initiation of immunomodulators is essential for patient survival and preventing the progression of disease. Currently, histological sampling of diseased tissue is the gold standard for diagnosis. ACR can then be graded: Grade 1R is mild, grade 2R is moderate, and grade 3R is severe [6]. This procedure is invasive, costly, and associated with several complications\u0026nbsp;[7, 8]. Thus, non-invasive imaging modalities could prove to be a useful alternative to endomyocardial biopsy (EMB) in diagnosis and prognosis. Speckle tracking echocardiography (STE) may be a reliable tool that holds prognostic potential. The use of STE has exhibited considerable prognostic utility across several disease states characterized by subclinical myocardial dysfunction\u0026nbsp;[9-11]. \u0026nbsp;Notably, it has shown sensitivity in detecting subtle changes in sub-endocardial tissues secondary to fibrotic or inflammatory states\u0026nbsp;[12, 13]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBecause of this, STE is a promising tool to allow for prompt diagnosis of ACR, though this has not yet been definitively established. This meta-analysis aims to evaluate the correlation between myocardial strain measurements via STE and ACR in orthotopic transplant patients.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eData Search and Collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe reviewed PubMed, EMBASE, and Web of Science for our literature search. The subject matter of interest was the association of left ventricular (LV) lobal longitudinal (GLS), radial (GRS), and circumferential (GCS) strain in cardiac transplant patients with and without ACR. The reviewers used the following search keywords: \u0026ldquo;speckle tracking,\u0026rdquo; \u0026ldquo;strain,\u0026rdquo; \u0026ldquo;heart transplant,\u0026rdquo; \u0026ldquo;cardiac transplant,\u0026rdquo; and \u0026ldquo;rejection.\u0026rdquo; Reviewers examined the full text of each relevant article to determine if it met inclusion criteria.\u003c/p\u003e\n\u003cp\u003eStudies chosen compared patients with ACR on endomyocardial biopsy (EMB) to those without ACR on EMB, assessing LV strain measurements by transthoracic echocardiogram in these cohorts. LV strain measurements of interest were GLS, GCS, and GRS. The primary endpoint was acute cellular rejection. Studies reporting on antibody mediated rejection were excluded. Studies that did not confirm transplant rejection by EMB were excluded.\u003c/p\u003e\n\u003cp\u003eVariables that were extracted from the studies included: Lead author, year of publication, study design, follow up duration, mean age, left ventricular ejection fraction, sex, presence of ACR, classification of ACR, GLS, GRS, and GCS.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe statistical portion of the meta-analysis was done with the program \u0026ldquo;Cochrane Review Manager Version 5.4.\u0026rdquo; The association between GLS, GRS, and GCS with the presence of ACR on EMB was examined with a random effects model and presented as a mean difference with 95% confidence intervals and p-values. Subgroup analysis was performed according to the International Society for Heart \u0026amp; Lung Transplantation standardized ACR grading to compare grade 1R versus Grade 2R and higher. I2 values were used to measure heterogeneity. Statistical significance was defined as a p-value less than 0.05 on a two-sided test.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eLiterature Search and Study Selection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 1377 potential studies from our literature search. After reviewing the full text of each of these studies, 21 studies were determined to be eligible for inclusion in the meta-analysis for the outcomes: GLS, GCS, GRS. This process of selection is summarized in (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy and patient characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis included prospective and retrospective studies (Table 1). A total of 2,502 patients with cardiac transplant met inclusion criteria. This included 1,465 patients without ACR and 1,037 patients with ACR. The average LV ejection fraction was 62%. Mean age was 48.3 years old. 71.6% were men. Mean follow-up duration was 12.7 months (ranging 4 \u0026ndash; 24 months).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssociation of ACR with Strain Measurements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients with ACR had significantly lower GLS compared to patients without ACR on biopsy (MD 2.84, 95% CI 1.5-4.18; p\u0026lt;0.01) (Figure 2). Patients with ACR had a significantly lower GCS compared to patients without ACR (MD 2.29, 95% CI 1.08, 3.51; P\u0026lt;0.01) (Figure 3). GRS measurements were not significantly different in patients with ACR compared to patients without ACR (MD -0.19, 95% CI -4.93 \u0026ndash; 4.53; p = 0.94) (Figure 4).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSubgroup Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients with ACR grade \u0026ge;2R had significantly lower GLS compared to patients with ACR grade 1R (MD 2.36, 95% CI 1.49-3.23; p\u0026lt;0.01) (Figure 5). GCS was significantly lower in patients with ACR grade \u0026ge;2R compared to patients with ACR grade 1R (MD 2.83, 95% CI 0.08-5.59, p = 0.04) (Figure 6). The association between ACR and GCS is weaker with a smaller effect size compared to GLS.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis meta-analysis evaluated whether myocardial strain imaging by STE adequately predicts ACR in orthotopic heart transplant patients. We found that (a) patients with confirmed ACR on endomyocardial biopsy had significantly lower GLS and GCS than patients without ACR on biopsy regardless of grade of disease; whereas (b) GRS measurements were not significantly different between ACR and non-ACR patients; (c) GLS and GCS values were lower in ACR grade \u0026ge;2R compared to ACR grade 1R.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe historical challenges posed by ACR have been mitigated by the effectiveness of various therapies, contributing to improved health outcomes and increased survival in orthotopic heart transplant patients.\u0026nbsp;EMB remains standard of care for detecting ACR; however, it is invasive and associated with complications. In addition, false negative biopsies occur in approximately 20% of cases due to the heterogeneity of diseased tissue present in the myocardium\u0026nbsp;[14, 15]. Moreover, ACR positive patients may be clinically asymptomatic or present with non-specific symptoms. These subtle presentations can often go unnoticed for an extended period, potentially leading to delays in the initiation of essential treatments and, consequently, contributing to unfavorable outcomes [16, 17].\u0026nbsp;Effective treatment modalities with early disease detection holds promise for further reducing the disease burden of ACR in orthotopic heart transplant patients, and\u0026nbsp;STE, via the measurement of strain, may serve as a potential resource.\u003c/p\u003e\n\u003cp\u003eACR is characterized by cellular infiltrates and edema, which ultimately disrupt left ventricular contractility. Traditional transthoracic echocardiography can assess graft function through measurement of systolic and diastolic function. However, left ventricular ejection fraction (LVEF) is often preserved until late in the disease course, and other measures of systolic and diastolic function are not sufficiently sensitive [18]. On the other hand, STE allows for a unique assessment of left ventricular myocardial deformation in several directions (GLS, GCS and GRS), which may improve sensitivity. Our results suggest that GLS and GRS can help rule out significant ACR and serve as an important tool to diagnose rejection prior to the development of frank LV dysfunction. While symptomatic and more severe rejection is associated with significant GLS/GRS reduction, one study by Ambardekar et al. showed there were no changes in myocardial strain and strain rate as assessed by STE in patients with asymptomatic biopsy-proven rejection [19]. This brings forth a potential limitation to STE, and stresses the importance of future studies in this particular patient population.\u003c/p\u003e\n\u003cp\u003eOur meta-analysis also investigated how the values of LVGLS and LVGCS compared between ACR Grade 1R and \u0026ge;2R rejection. Both LVGLS and LVGCS were significantly lower in ACR Grade \u0026ge;2R rejection.\u0026nbsp;This can be partly explained by the degree of histopathologic injury. ACR Grade 1R demonstrates interstitial/perivascular infiltrates with up to one focus of myocyte damage; however, ACR Grade \u0026ge;2R represents at least 2 or more foci (at times even diffuse)\u0026nbsp;associated with myocyte damage, with or without edema, hemorrhage, or vasculitis\u0026nbsp;[6]. Thus, it comes as no surprise that as the degree of myocyte damage increases, the values for LVGLS and LVGCS decrease. It should be noted that segmental LV longitudinal strain has been shown to be most sensitive when assessing for lower grades of ACR; this can be partly explained by the patchy nature of ACR\u0026nbsp;[17]. However, the scope of this paper did not assess the use of segmental strain values or directly compare prognostication abilities among the various forms of global strain.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion/Future Direction","content":"\u003cp\u003eOur findings demonstrate that STE has the potential to be a reliable prognostic modality for ACR in post-transplant patients, especially in symptomatic or higher-grade presentations.\u0026nbsp;This is not to say that STE can replace EBM biopsy for rejection surveillance, but it may serve as an adjunctive tool. This is just one of many potential noninvasive tools available. The list also includes cell-free DNA, Allo-Maps, gene expression microarrays and cardiac MRI [20-23]. Additional studies would be useful in analyzing the combination of these techniques to predict ACR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite its contributions to the field of research, certain limitations of our study must be acknowledged.\u0026nbsp;The studies included in this paper excluded subjects with certain comorbidities, which greatly affects the generalizability of our results. The heterogeneity was considerably high, likely due to vendor-specific and user-dependent differences in strain measurements and STE lab protocols. To combat this limitation, a random-effects model and subgroup analysis may be beneficial. Lastly, the scope of our study focuses on ACR and left ventricular strain values only. Additional studies covering other strain measurements, such as right ventricular strain, as well as other cardiovascular outcomes can further elucidate the value of STE in this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACR: Acute Cellular Rejection\u003c/p\u003e\n\u003cp\u003eEMB: Endomyocardial Biopsy\u003c/p\u003e\n\u003cp\u003eGCS: Global Circumferential Strain\u003c/p\u003e\n\u003cp\u003eGLS: Global Longitudinal Strain\u003c/p\u003e\n\u003cp\u003eGRS: Global Radial Strain\u003c/p\u003e\n\u003cp\u003eISHLT: International Society for Heart and Lung Transplantation\u003c/p\u003e\n\u003cp\u003eLV: Left Ventricular\u003c/p\u003e\n\u003cp\u003eSTE: Speckle Tracking Echocardiography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData Availability Statement: The data underlying this article will be shared on reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003eFinancial Disclosures: None\u003c/p\u003e\n\u003cp\u003eConflicts of Interest: None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCameli M, Pastore MC, Campora A, Lisi M, Mandoli GE. \u003cem\u003eDonor shortage in heart transplantation: How can we overcome this challenge?\u003c/em\u003e Front Cardiovasc Med, 2022. \u003cstrong\u003e9\u003c/strong\u003e: p. 1001002.\u003c/li\u003e\n\u003cli\u003eHsich E, Singh TP, Cherikh WS, et al. \u003cem\u003eThe International thoracic organ transplant registry of the international society for heart and lung transplantation: Thirty-ninth adult heart transplantation report-2022; focus on transplant for restrictive heart disease.\u003c/em\u003e J Heart Lung Transplant, 2022. \u003cstrong\u003e41\u003c/strong\u003e(10): p. 1366-1375.\u003c/li\u003e\n\u003cli\u003eRaichlin E, Edwards BS, Kremers WK, et al. \u003cem\u003eAcute cellular rejection and the subsequent development of allograft vasculopathy after cardiac 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\u003cstrong\u003e12\u003c/strong\u003e(8 Pt 2): p. 1632-1641.\u003c/li\u003e\n\u003cli\u003eAntończyk K, Niklewski T, Antończyk R, Zakliczyński M, Zembala M, Kukulski T. \u003cem\u003eSpeckle-Tracking Echocardiography for Monitoring Acute Rejection in Transplanted Heart.\u003c/em\u003e Transplant Proc. 2018 Sep;50(7):2090-2094.\u003c/li\u003e\n\u003cli\u003eAntończyk K, Niklewski T, Antończyk R, Zakliczyński M, Zembala M, Kukulski T.\u003cem\u003e Evaluation of the Graft Mechanical Function Using Speckle-Tracking Echocardiography During the First Year After Orthotropic Heart Transplantation. \u003c/em\u003eAnn Transplant. 2018 Aug 8;23:554-560.\u003c/li\u003e\n\u003cli\u003eChamberlain R, Edwards NFA, Doyle SN, et al.\u003cem\u003e Prognostic Value of Left and right ventricular deformation strain analysis on Acute Cellular rejection in Heart Transplant recipients: A 6-year outcome study.\u003c/em\u003e Int J Cardiovasc Imaging. 2022 Nov;38(11):2271-2281.\u003c/li\u003e\n\u003cli\u003eCiarka A, Cordeiro F, Droogne W, Van Cleemput J, Voigt JU.\u003cem\u003e Speckle-tracking-based global longitudinal and circumferential strain detect early signs of antibody-mediated rejection in heart transplant patients. \u003c/em\u003eEur Heart J Cardiovasc Imaging. 2022 Oct 20;23(11):1520-1529.\u003c/li\u003e\n\u003cli\u003eClemmensen TS, L\u0026oslash;gstrup BB, Eiskj\u0026aelig;r H, Poulsen SH.\u003cem\u003e Serial changes in longitudinal graft function and implications of acute cellular graft rejections during the first year after heart transplantation. \u003c/em\u003eEur Heart J Cardiovasc Imaging. 2016 Feb;17(2):184-93.\u003c/li\u003e\n\u003cli\u003eClemmensen TS, L\u0026oslash;gstrup BB, Eiskj\u0026aelig;r H, Poulsen SH.\u003cem\u003e Changes in longitudinal myocardial deformation during acute cardiac rejection: the clinical role of two-dimensional speckle-tracking echocardiography. \u003c/em\u003eJ Am Soc Echocardiogr. 2015 Mar;28(3):330-9.\u003c/li\u003e\n\u003cli\u003eClemmensen TS, L\u0026oslash;gstrup BB, Eiskjaer H, H\u0026oslash;yer S, Poulsen SH.\u003cem\u003e The long-term influence of repetitive cellular cardiac rejections on left ventricular longitudinal myocardial deformation in heart transplant recipients. \u003c/em\u003eTranspl Int. 2015 Apr;28(4):475-84.\u003c/li\u003e\n\u003cli\u003eCruz CBBV, Hajjar LA, Bacal F, et al.\u003cem\u003e Usefulness of speckle tracking echocardiography and biomarkers for detecting acute cellular rejection after heart transplantation.\u003c/em\u003e Cardiovasc Ultrasound. 2021 Jan 9;19(1):6.\u003c/li\u003e\n\u003cli\u003eda Costa RCPL, Rodrigues ACT, Vieira MLC, et al,\u003cem\u003e Evaluation of the myocardial deformation in the diagnosis of rejection after heart transplantation. \u003c/em\u003eFront Cardiovasc Med. 2022 Oct 13;9:991016.\u003c/li\u003e\n\u003cli\u003eDu GQ, Hsiung MC, Wu Y, et al.\u003cem\u003e Three-Dimensional Speckle-Tracking Echocardiographic Monitoring of Acute Rejection in Heart Transplant Recipients. \u003c/em\u003eJ Ultrasound Med. 2016 Jun;35(6):1167-76.\u003c/li\u003e\n\u003cli\u003eEleid MF, Caracciolo G, Cho EJ, et al.\u003cem\u003e Natural history of left ventricular mechanics in transplanted hearts: relationships with clinical variables and genetic expression profiles of allograft rejection. \u003c/em\u003eJACC Cardiovasc Imaging. 2010 Oct;3(10):989-1000.\u003c/li\u003e\n\u003cli\u003eMancuso F, Fontana A, Messina M, Cipriani M, De Gregorio C. \u003cem\u003eGlobal Longitudinal Strain By Speckle Tracking Echocardiography In Sibclinical Orthotopic Heart Transplant Rejection.\u003c/em\u003e European Heart Journal Supplements, Volume 24, Issue Supplement_K, December 2022\u003c/li\u003e\n\u003cli\u003eMarciniak A, Eroglu E, Marciniak M, et al. \u003cem\u003eThe potential clinical role of ultrasonic strain and strain rate imaging in diagnosing acute rejection after heart transplantation. \u003c/em\u003eEuropean Journal of Echocardiography. 2007 8(3):213-221.\u003c/li\u003e\n\u003cli\u003eMingo-Santos S, Mo\u0026ntilde;ivas-Palomero V, Garcia-Lunar I, et al.\u003cem\u003e Usefulness of Two-Dimensional Strain Parameters to Diagnose Acute Rejection after Heart Transplantation. \u003c/em\u003eJ Am Soc Echocardiogr. 2015 Oct;28(10):1149-56.\u003c/li\u003e\n\u003cli\u003ePodrouzkova H, Bedanova H, Tretina M, et al.\u003cem\u003e Decrease in longitudinal strain in heart transplant recipients is associated with rejection.\u003c/em\u003e Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015 Dec;159(4):601-6.\u003c/li\u003e\n\u003cli\u003eRuiz Ortiz M, Pe\u0026ntilde;a ML, Mesa D, et al.\u003cem\u003e Impact of asymptomatic acute cellular rejection on left ventricle myocardial function evaluated by means of two-dimensional speckle tracking echocardiography in heart transplant recipients.\u003c/em\u003e Echocardiography. 2015 Feb;32(2):229-37.\u003c/li\u003e\n\u003cli\u003eSade LE, Hazirolan T, Kozan H, et al.\u003cem\u003e T1 Mapping by Cardiac Magnetic Resonance and Multidimensional Speckle-Tracking Strain by Echocardiography for the Detection of Acute Cellular Rejection in Cardiac Allograft Recipients.\u003c/em\u003e JACC Cardiovasc Imaging. 2019 Aug;12(8 Pt 2):1601-1614.\u003c/li\u003e\n\u003cli\u003eStavenchuk TV, Kosmachova ED, Shelestova IA.\u003cem\u003e Correlation between the parameters of myocardium deformation and the results of endomyocardial biopsy in recipients at the stage of subclinical heart transplant rejection. \u003c/em\u003eEuropean Heart Journal. 2016 37 (56) Supplement 1.\u003c/li\u003e\n\u003cli\u003eTseng AS, Gorsi US, Barros-Gomes S, et al.\u003cem\u003e Use of speckle-tracking echocardiography-derived strain and systolic strain rate measurements to predict rejection in transplant hearts with preserved ejection fraction.\u003c/em\u003e BMC Cardiovasc Disord. 2018 Dec 22;18(1):241.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u0026nbsp;\u003c/strong\u003eDemographic data of the included studies:\u003c/p\u003e\n\u003cp\u003eACR: Acute Cellular Rejection, LVEF: Left Ventricular Ejection Fraction\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"756\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAuthor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003ePublication Year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eType of Publication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eFollow-up Duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eMean Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eLVEF No ACR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eLVEF ACR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eGender (%male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNo ACR Total\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eACR Total\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAmbardekar\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e44.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAntoczyk\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e50.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAntoczyk\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e49.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eChamberlain\u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot applicable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eCiarka\u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e82.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eClemmensen\u003csup\u003e28\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e45.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e66.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eClemmensen\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e42.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e241\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eClemmensen\u003csup\u003e30\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e54.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e78.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot applicable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e119\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eCruz\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e42.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e56.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eda Costa\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e50.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e60.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDu\u003csup\u003e33\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eEleid\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e52.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eMancuso\u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eMarciniak\u003csup\u003e36\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e75.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eMingo-Santos\u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e51.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e82.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e173\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eOtto\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e40.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003ePodrouzkova\u003csup\u003e38\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e51.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRuiz-Ortiz\u003csup\u003e39\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e51.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eSade\u003csup\u003e40\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e67.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eStavenchuck\u003csup\u003e41\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eTseng\u003csup\u003e42\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e70.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Speckle tracking echocardiography, cardiac transplantation, acute cellular rejection","lastPublishedDoi":"10.21203/rs.3.rs-4046173/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4046173/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Myocardial strain imaging by speckle tracking echocardiography (STE) has demonstrated prognostic utility in several disease states. However, the association of strain measurements with acute cellular rejection (ACR) after cardiac transplantation is not well established. This meta-analysis aims to evaluate the association of myocardial strain measurements with acute cellular rejection in cardiac transplant patients.\u003c/p\u003e\n\u003cp\u003eMethods: A literature search was conducted using Ovid MEDLINE, EMBASE, and Web of Science for studies reporting on the association of left ventricular (LV) global longitudinal (GLS), radial (GRS), and circumferential (GCS) strain in cardiac transplant patients with and without acute cellular rejection. Subgroup analysis was performed by ISHLT standardized ACR grading to compare grade 1R versus Grade 2R and higher.\u003c/p\u003e\n\u003cp\u003eResults: A total of 21 studies with 2502 transplant patients (1465 without ACR versus 1037 with ACR) were included. Patients with ACR had significantly lower GLS compared to patients without ACR on biopsy (MD 2.84, 95% CI 1.5-4.18; p\u0026lt;0.01). Patients with ACR grade ≥2R had significantly lower GLS compared to patients with ACR grade 1R (MD 2.36, 95% CI 1.49-3.23; p\u0026lt;0.01). Patients with ACR had a significantly lower GCS compared to patients without ACR and GCS was significantly lower in patients with ACR grade ≥2R compared to patients with ACR grade 1R (MD 2.29, 95% CI 1.08, 3.51; MD 2.83, 95% CI 0.08-5.59; p=0.04).\u003c/p\u003e\n\u003cp\u003eConclusions: Left ventricular GLS and GCS may represent useful markers to identify cardiac transplant patients with ACR.\u003c/p\u003e","manuscriptTitle":"Association of Speckle Tracking Echocardiography with Acute Cellular Rejection in Cardiac Transplant Patients: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-12 17:46:52","doi":"10.21203/rs.3.rs-4046173/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ba51d211-6184-4105-bbe0-b58c0fd592ec","owner":[],"postedDate":"March 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-13T10:34:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-12 17:46:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4046173","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4046173","identity":"rs-4046173","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}