Right Ventricular Free Wall Strain to Predict Clinical Outcomes in Acute Pulmonary Embolism

Right Ventricular Free Wall Strain to Predict Clinical Outcomes in Acute Pulmonary Embolism | 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 Right Ventricular Free Wall Strain to Predict Clinical Outcomes in Acute Pulmonary Embolism Daniel Gorman, Mehrdad Ghahramani, Sibei Liu, Boyangzi Li, Mauricio Tellez, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7820966/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Submassive (intermediate risk) pulmonary embolism (PE) presents with heterogenous clinical outcomes. Critical management decisions are unclear and improved prognostication is needed. Right ventricular free wall longitudinal strain (RV FWS) is an echocardiographic finding that reflects the pathophysiologic changes in PE and therefore should provide prognostic value. Methods A retrospective cohort study was performed by reviewing the medical records of patients followed by the hospital pulmonary embolism response team (PERT). The primary outcome was in-hospital mortality or hemodynamic instability. Traditional qualitative and quantitative markers of RV function including tricuspid annular plane systolic excursion and velocity (TAPSE and S’) were collected for comparison to RV FWS. A total of 84 patients were included in the final cohort. Logistical regression analysis was performed to assess the primary outcome association with RV FWS, TAPSE, and S’. Multivariate logistic regression was performed adjusting for age, gender, and baseline medical comorbidities. Receiver operating characteristic (ROC) curves and Empiric cumulative distribution function (ECDF) plots were created for all three echocardiographic variables to assess diagnostic performance. Results The primary outcome occurred in 45.7% (n=38) and death occurred in 11.9% (n=10). RV FWS was associated with increased risk of the primary outcome (adjusted OR = 19.3; p=0.0003). RV FWS demonstrated good predictive performance with an area under the curve (AUC) of 70.7%. Significant inverse correlation was noted between the primary outcome and RV FWS when using empiric cumulative distribution function (ECDF). TAPSE additionally demonstrated positive predictive performance, albeit lower than RV FWS. Qualitative assessment of the RV as well as S’ did not demonstrate statistically significant association with primary outcome. Conclusions In this retrospective cohort study of patients with primarily submassive PE, RV FWS demonstrated good predictive performance in terms of death or hemodynamic instability. Further data is needed to validate these findings in a larger population. Pulmonary Embolism Echocardiography Vascular Diseases Hemodynamics Critical Care Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Despite advances in therapy for pulmonary embolism (PE), the estimated mortality rate remains high with minimal improvement over the last twenty years [ 1 , 2 ]. There exists a consensus regarding classification, however treatment recommendations are less clear. Challenging management decisions are based on severity, prognostic markers, and baseline characteristics [ 3 , 4 , 5 , 6 ]. PE is classified into three basic severity categories: low risk, submassive (intermediate-risk), and massive (high-risk) PE ( Supplement A ). Minor categorical criteria vary slightly in different clinical guidelines; however the general characteristics are in agreement [ 3 , 4 , 5 , 6 ]. Classification is made based on the presence of right ventricular (RV) dysfunction and elevated cardiac biomarkers. Massive (high-risk) PE is defined by the presence of hypotension (systolic blood pressure < 90mmHg). The presence of both RV dysfunction and elevated cardiac biomarkers classifies as submassive-high (intermediate-high) risk. The presence of RV dysfunction or elevated biomarkers, but not both, is classified as submassive-low (intermediate-low) risk. Low risk PE is defined by the absence of RV dysfunction and cardiac biomarker elevation. The submassive PE subgroup is heterogeneous in terms of clinical outcomes. As such, predicting which submassive PE patients will decompensate is challenging. Guidelines generally reflect the paucity definitive data [ 3 , 4 , 5 , 6 ]. Few studies have focused on defining which patients are at increased risk and therefore warrant aggressive management. There are no clear evidence-based echocardiographic findings that have been shown to consistently prognosticate clinically important outcomes. A better way of prognosticating these patients is needed to clarify management decisions that are often unclear. Right ventricular (RV) function is difficult to assess by transthoracic echocardiography (TTE). Qualitative estimation of RV size and function have been shown to have high observer variability with limited data on prognostic value [ 7 , 8 , 9 , 36 ]. Quantitative assessments of RV function include tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular plane systolic velocity (TAPSV, or S’). TAPSE is the linear distance the tricuspid annulus moves towards the apex during systole, measured using m-mode (Fig. 1 ). It is an indirect correlate of RV function and most literature supports the normal range above 1.7cm [ 10 ]. TAPSV, or S’, is a similar indirect measurement using tissue doppler velocity with normal values 11 cm/s or greater [ 11 ]. TAPSE and S’ are angle-dependent measures that can be unreliable in cases of regional RV dysfunction or altered loading conditions [ 12 ]. These variables do not directly assess RV function or the pathologic changes of PE. RV Free Wall Longitudinal Strain (RV FWS) is potentially a direct measurement of the pathophysiologic changes in PE. Strain is defined as the rate of change in myocardial length normalized to the original length [ 12 ]. When myocardial work exceeds perfusion relaxation is impaired resulting in a lower measured strain. Acute changes in afterload, such as acute PE, create increased myocardial work and this change should be reflected by lower measurements of strain. More research is needed, but RV FWS should accurately predict clinical outcomes in PE. The utility of RV FWS has been explored as it relates to aortic stenosis, tricuspid regurgitation, and pulmonary hypertension [ 37 , 38 , 39 ]. Previous research on RV FWS related to PE has demonstrated correlation to mortality, pulmonary vascular resistance, and correlation to traditional markers of RV function [ 13 , 14 , 15 ]. The addition of RV FWS addition to existing TTE parameters improves diagnostic yield of PE [ 16 ]. A 2020 meta-analysis demonstrated the lower limit of normal for RV FWS to be -18% [ 17 ]. Recent guidelines recommend incorporating RV strain analysis into the standard echocardiographic assessment of RV function, however data specific to PE is limited [ 35 ]. We aimed to explore the prognostic value of RV FWS in the evaluation of critically ill patients diagnosed with PE. We additionally compared the performance of RV FWS to traditional measurements of RV function including TAPSE, S’, and gross qualitative assessment. METHODS This was a retrospective cohort study of hospitalized patients who were evaluated by the Pulmonary Embolism Response Team (PERT). Patients were identified using the PERT consultation process. Clinical data was collected throughout the hospitalization during which the pulmonary embolism was diagnosed. Data was collected with waiver of consent approval by the institutional review board (University of Miami - IRB 20230013, Clinical Trial Number – N/A). The study was conducted at a single academic center which is additionally an inpatient affiliate of a national cancer institute (NCI) designated cancer center. Patients were enrolled during hospitalizations from January 2023 to April 2024. Patients were identified by the PERT consultation process which is generally limited to submassive PE, massive PE, or patients with high bleeding risk. Patients were required to be older than 18 years for inclusion. Patients were excluded if they received systemic thrombolysis (ST) or catheter directed therapy prior to formal TTE, did not have a confirmatory diagnosis of PE, or if the clinical outcome was determined to be unrelated to PE during the review process ( Supplement B ). A clinically indicated TTE was performed at the time of PE diagnosis as part of existing PERT protocol. Timing of TTE was dependent on risk stratification with urgent studies being done within 1 hour. Echocardiographic data including TAPSE, S’, gross RV size, gross RV function, and presence of McConnell’s sign was collected from the initial reviewing cardiologists who were blinded to this study ( Supplement C2 ). This data was confirmed by review of TTE images by two providers with echocardiography board certification (DG, KL). The two echocardiographic reviewers ensured validity of the reported measurements as well as qualitative variables. RV FWS was calculated using Phillips-TOMTEC™ software (Fig. 1 ). Using this software, strain calculation is performed by selecting the cardiac cycle and providing a tracing of the RV chamber including the free wall in either a dedicated RV or an apical four chamber view (Fig. 1 ). The resulting strain value was graphically and numerically reported for the basal, mid, and apical segments of the free wall, as well as a mean of the three segments. The RV septal wall was excluded for the purposes of this study. RV FWS calculation was performed using two different image series and an average value of the two mean values was reported for final analysis. For the purposes of comparison with other TTE variables; RV FWS was reported as an absolute value with smaller numbers being more pathologic. Echocardiographic review and RV FWS calculations were performed by the primary investigator prior to analyzing clinical outcome data to minimize bias. The second independent reviewer remained blinded to clinical outcomes throughout the study. Clinical outcome data was obtained through review of the electronic medical record (EMR). Data was collected throughout the hospitalization by the primary investigator and two independent reviewers (JM, MT). The two independent reviewers were blinded to the echocardiographic data throughout the study ( Supplement C1 ). The primary outcome was PE-related in hospital mortality or hemodynamic instability. Outcome was determined by multidisciplinary review and limited to the current hospitalization at time of diagnosis. Hemodynamic instability was defined as: a > 40mmHg systolic blood pressure (SBP) decrease, SBP < 90mmHg, tachyarrhythmias requiring chemical or electrical cardioversion, or vasopressor use. Secondary outcomes were intensive care unit (ICU) length of stay (LOS), acute kidney injury (AKI), and need for mechanical ventilation if not initially required at the time of PE diagnosis. Logistical regression analysis was performed to assess the outcome association with RV FWS, TAPSE, and S’. TTE variables were evaluated using abnormal cutoffs based off best available evidence (RV FWS < 18%, TAPSE < 1.7cm, S’ < 11cm/s). To adjust for cofounders, multivariate logistic regression was performed adjusting for age, gender, and baseline medical comorbidities. A Pearson’s Chi-squared test with Yates’ continuity correction was performed to evaluate outcome association with gross RV function, gross RV size, and the presence of McConnell’s sign. Receiver operating characteristic (ROC) curves were created for all three echocardiographic variables to assess diagnostic performance. Empirical cumulative distribution function (ECDF) plots comparing RV FWS, TAPSE, and S’ were created for both the presence and absence of primary outcome. The estimated sample size during study design was 60 patients to detect a 10% progression to the primary outcome with 90% power. A 12-month enrollment period was determined to be sufficient based on average monthly census and tracking statistics provided by the internal PERT registry. Enrollment continued for three additional months to account for patients who could potentially be excluded during the review process. RESULTS Upon completion of the enrollment period, January 2023 through April 2024, a total of 98 patients met the inclusion criteria. 8 patients were excluded after it was determined that the primary outcome was not related to PE. 3 patients were excluded for lack of definitive diagnosis of PE. 3 patients received catheter embolectomy prior to formal echocardiography and were excluded. A total of 84 patients were included in final statistical analysis ( Supplement B ). The mean age of participants was 63.5 years with the majority male ( Table 1 ). The most common comorbid condition was hypertension and nearly half of all participants had an active malignancy. A large majority, 85.7%, of patients enrolled had a PE that was initially classified in the Submassive subgroup. The composite primary outcome occurred in 45.2% (n=38) of patients and death occurred in 11.9% (n=10) of patients. The most common baseline comorbidity of those meeting the primary outcome was hypertension which was present in 58% of these patients. TAPSE was not calculated on 8 patients during initial TTE. Similarly, S’ was not calculated on 25 patients. This data was excluded from the analysis as these calculations cannot be retrospectively done unless appropriate ultrasound modes are obtained during the initial study (m-mode for TAPSE, and tissue doppler for S’). RV FWS can be retrospectively calculated if the RV free wall is adequately visualized and was obtained for all 84 patients. The Mean ICU LOS was noted to be 2 days with a high relative standard deviation. Acute kidney injury (AKI) occurred in 28.6% (n=24) of patients and 10.7% (n=9) of patients required mechanical ventilation for respiratory decline after initially not requiring ( Supplement D ). Demographic and objective data was compared between those meeting primary outcome and those who did not meet primary outcome ( Table 2 ). Of the 38 patients that met the primary outcome, the initial PE classification included 4 massive, 25 submassive-high risk, and 9 submassive-low risk. The average RV FWS of patients meeting primary outcome was found to be -9.8% (SD 4.9) and -17.53% (SD 6.6) for those not meeting primary outcome. The average values for TAPSE and S’ in patients meeting primary outcome were 1.69cm (SD 0.49) and 13.3 cm/s (SD 4.4). Qualitative assessment of RV size, RV function, and the presence of McConnell’s sign did not demonstrate statistically significant association with primary outcome ( Supplement E ). RV FWS was associated with the primary outcome (OR 15.4; p=0.0005) in unadjusted models ( Table 3 ). TAPSE was also associated with the primary outcome (OR 8.1; p=0.00015). S’ did not demonstrate statistical significance in univariate analysis (OR 2.3, p=0.134). Multivariate logistic regression analysis adjusting for age, sex, and baseline comorbidities demonstrated an association with the primary outcome for all three echocardiographic variables ( Table 3 ). The adjusted OR for RV FWS was 19.3 (CI 4.6-136.6). The adjusted OR for TAPSE was 12.9 (CI 3.9-54.6). S’ was not associated with the primary outcome in univariate analysis, however adjusted odds ratio was calculated to be 7.5 (CI 1.6-45.98). ROC curves were created comparing the three TTE variables to primary outcome ( Figure 2 ). RV FWS demonstrated good predictive performance with an area under the curve (AUC) of 70.7%. TAPSE additionally performed well with an AUC of 71.1%. S’ performed poorly in ROC analysis with AUC of 58.5%. Empirical cumulative distribution function (ECDF) and box plots were created comparing the three predictors with the presence and absence of primary outcome ( Figure 3 ). Significant inverse correlation was noted between the primary outcome and RV FWS as well as TAPSE. S’ was found to have significant overlap between the two groups. DISCUSSION We found RV FWS to be a strong predictor of death or hemodynamic instability in this cohort of primarily submassive and massive PE patients. RV FWS demonstrated stronger association with the primary outcome than TAPSE in terms of odds ratio in both univariate and multivariate analysis. Both RV FWS and TAPSE performed well in terms of AUC and linear regression analysis. A RV FWS less than or equal to 17% was the most sensitive echocardiographic marker at predicting death or hemodynamic instability. S’ was not associated with the primary outcome in most of the analysis. The value of quantitative markers of RV function over gross qualitative assessment is supported by this study. Qualitative assessment of RV size, function, and the presence of McConnel’s sign did not demonstrate a statistically significant association with the primary outcome. These findings emphasize the need for a more precise and quantitative evaluation of RV dysfunction when prognosticating patients with PE. Previous work has evaluated the performance of RV FWS as a predictive and diagnostic tool in management of PE [ 16 , 18 , 19 , 20 ]. Strengths of this study compared to previous literature include the acute clinical follow-up period, PE severity of the included cohort, and the primary outcome design. This study validates previous work with a focus on acute, critically ill patients. 90.5% of the included cohort were classified with either submassive or massive PE at time of diagnosis. Previous studies have focused on a lower risk population with more longitudinal outcomes that are less applicable to the acute phase of illness [ 18 , 20 ]. In 2019, Lee et al published an observational study of low-risk PE patients that demonstrated strong predictive performance of RV FWS compared to other echocardiographic markers of RV function [ 18 ]. Dahhan et al previously demonstrated that RV FWS is associated with 30-day mortality in a comparatively low-risk cohort [ 20 ]. This study focused on a higher risk cohort in the acute phase of illness to potentially help guide initial management. Management decisions become less clear in these higher risk subgroups and these patients require more useful prognostic tools. Similar cohort studies have included treatment modality as well as recurrence of PE in the primary composite outcome [ 18 , 19 ]. This type of design introduces confounding variables when evaluating the usefulness of RV FWS as a prognostic tool. Treatment indications are often not standardized, and such studies are subject to practice pattern variability. Recurrence of PE is often multifactorial and unrelated to severity of the acute event. A primary composite outcome that is isolated to acute, objective data increases the ability to evaluate RV FWS as a prognostic tool. This study demonstrated a strong negative predictive value of RV FWS relative to hemodynamic collapse. Only 2 of the 38 patients meeting the primary outcome had RV FWS in the normal range. Critically ill patients that are discovered to have PE frequently have multiple pathophysiologic processes contributing to hemodynamic instability. This data supports the potential of RV FWS to help the intensivist discern which process is the primary driver of hemodynamic collapse. Further data is needed to validate such potential as well as the overall prognostic value, however these results are promising. A major limitation in terms of generalizability is the baseline demographics of the included cohort. Nearly half of the patients had an active malignancy at the time of PE diagnosis (Table 1 ). While typical for this institution, further research is needed to validate our prognostic findings in a cohort more representative of the general population. The study protocol is reproducible assuming PE patients are followed consistently through their hospitalization when transitioning between services. Additionally, a formal TTE is required with included quantitative markers of RV function at the time of diagnosis. A protocol was previously in place at our institution and timely TTE for PE was part of standard clinical practice. Several studies were missing either a calculated TAPSE or S’ when the TTE was initially performed. As this is not able to be retroactively calculated, these studies were not included during statistical analysis of the missing variable. The three echocardiographic variables were analyzed independent of one another, as such a missing variable would not affect the analysis of other TTE variables on the same patient. One limitation in terms of feasibility is the interrater reliability of RV FWS calculations. Previous work on RV FWS has demonstrated good to excellent interrater reliability, however more data is needed [ 21 ]. In this current study, the two reviewers were blinded to one another during their calculations of RV FWS. Interobserver agreement for RV FWS was excellent, with an intraclass correlation coefficient (ICC[ 2 , 1 ]) of 0.93. Disagreement outside of one standard deviation occurred in only 3 of the 84 patients (3.6%) and categorical discordance (normal vs abnormal) occurred in two patients (2.4%). The degree of interrater reliability needs to be further explored and is likely to improve with advancing technology. The feasibility of incorporating RV FWS into PE prognostication is dependent on institutional echocardiographic capabilities. Obtaining a formal TTE in a timely manner is highly variable across healthcare institutions. After the study is completed, the TTE needs to be reviewed and interpreted by a provider board certified in echocardiography. It is worth noting the dramatic improvement in point of care ultrasound (POCUS) technology over the past decade. As technology continue to advance, this may allow strain to be more accessible [ 33 ]. Most of the literature to date supports the association of RV FWS and adverse outcomes from PE. This association has been validated by this study. The prognostic value of RV FWS appears to be increased when applied to the submassive and massive subgroups. The performance of RV FWS at predicting death or hemodynamic instability was superior to TAPSE and S’, however this finding needs to be validated in a larger cohort that is more representative of the general population. The feasibility of incorporating RV FWS into current practice will vary by health system, however as technology advances this will likely become more readily available. CONCLUSION RV FWS was a strong predictor of death or hemodynamic instability in patients with primarily submassive and massive PE. It performed favorably when compared to more conventional quantitative and qualitative markers of RV function. Further research is needed in a larger and more generalizable population to validate these findings. Abbreviations Acute kidney injury (AKI) Area under the curve (AUC) Electronic medical record (EMR) Empiric cumulative distribution function (ECDF) Intensive care unit (ICU) Length of stay (LOS) National Cancer Institute (NCI) Point of care ultrasound (POCUS) Pulmonary embolism (PE) Pulmonary Embolism Response Team (PERT) Receiver operative characteristic (ROC) Right ventricle (RV) Right ventricular free wall longitudinal strain (RV FWS) Systolic blood pressure (SBP) Systemic thrombolysis (ST) Transthoracic echocardiography (TTE) Tricuspid annular plane systolic excursion (TAPSE) Tricuspid annular plane systolic velocity (TAPSV, or S’) Declarations Ethics approval and consent to participate This study adhered to the Declaration of Helsinki ethical principles on human medical research. A waiver of consent to participate was requested due to observational, non-intervention design. The waiver of consent was approved by the institutional review board (University of Miami - IRB 20230013). Clinical Trial Number: Not applicable Consent for publication Consent for publication not required as manuscript does not contain any individual person’s data. Availability of Data & Materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests The authors declare no conflicts of interest and have no financial disclosures regarding this manuscript. Funding Funding for this study, in part, was provided by the University of Miami, Division of Pulmonary, Critical Care, and Sleep Medicine as a grant awarded within the division. No external funding was provided. Authors’ Contributions DG – project administration, conceptualization, data curation, formal analysis, investigation, methodology, validations, primary contributor in writing, editing, reviewing MG – writing, reviewing, editing, data curation SL – data curation, formal analysis BL – investigation, validation, data curation MT – investigation, validation, data curation JM – investigation, validation, data curation DK – conceptualization, investigation RD – investigation, methodology, editing, reviewing TS – conceptualization, investigation, methodology, major contributor in writing, reviewing, and editing Acknowledgements Not applicable References Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol. 1997 Nov 1;30(5):1165-71. doi: 10.1016/s0735-1097(97)00319-7. PMID: 9350909. 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Preoperative Right Ventricular Free-Wall Longitudinal Strain as a Prognosticator in Isolated Surgery for Severe Functional Tricuspid Regurgitation. J Am Heart Assoc. 2021 May 4;10(9):e019856. doi: 10.1161/JAHA.120.019856. Epub 2021 Apr 17. Erratum in: J Am Heart Assoc. 2021 Jun 15;10(12):e020842. doi: 10.1161/JAHA.121.020842. PMID: 33870734; PMCID: PMC8200727. Nabeshima Y, Kitano T, Node K, Takeuchi M. Prognostic value of right ventricular free-wall longitudinal strain in patients with pulmonary hypertension: systematic review and meta-analyses. Open Heart. 2024 Feb 7;11(1):e002561. doi: 10.1136/openhrt-2023-002561. PMID: 38325907; PMCID: PMC10860115. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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16:17:54","extension":"html","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":135608,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/83f0738c972dbce132ce03c2.html"},{"id":96453557,"identity":"eae09277-11bc-4e66-a6f7-10953d3d4098","added_by":"auto","created_at":"2025-11-21 10:00:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":469234,"visible":true,"origin":"","legend":"\u003cp\u003eTTE images demonstrating calculations of normal RV FWS (top left), borderline RV FWS (top right), reduced RV FWS (bottom right).\u003c/p\u003e\n\u003cp\u003eTAPSE measurement is obtained using m-mode to calculate the linear distance the tricuspid annulus moves towards the apex in systole (bottom left)\u003c/p\u003e\n\u003cp\u003eTAPSV or S' measurement is obtained using tissue doppler to calculate the velocity of the tricuspid annulus as it moves towards the apex in systole (bottom middle).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/1a1862e765c0239de89fc234.png"},{"id":96401958,"identity":"fb38511d-3081-44ef-b918-68c6324a4c73","added_by":"auto","created_at":"2025-11-20 16:17:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101698,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curve plots for RV FWS, TAPSE, and S' relative to the primary outcome.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/ffa5b8291974e40055f4e192.png"},{"id":96401960,"identity":"092de745-d7ad-4a7e-8ef2-356778fc11fb","added_by":"auto","created_at":"2025-11-20 16:17:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":88526,"visible":true,"origin":"","legend":"\u003cp\u003eEmpirical cumulative distribution function (ECDF) and box plots comparing RV FWS [%], TAPSE [cm], and S' [cm/s]. Presence of primary outcome (red) and lack of primary outcome (blue). RV FWS is reported as the absolute value with less than 17% being abnormal.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/522b68d637098734137f0141.png"},{"id":96456937,"identity":"87a423d0-5761-494e-94fa-72e1de739658","added_by":"auto","created_at":"2025-11-21 10:08:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1150506,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/5c685839-7e70-4634-ad51-72c247d586b2.pdf"},{"id":96454358,"identity":"21b30c5a-4332-47b7-a4d2-5dfadf3bb6fa","added_by":"auto","created_at":"2025-11-21 10:02:39","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":252497,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/4ffed624050f184672aede6b.docx"},{"id":96453553,"identity":"3a861be0-0b56-4fff-95b4-017df6f7ed4f","added_by":"auto","created_at":"2025-11-21 10:00:34","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":142106,"visible":true,"origin":"","legend":"","description":"","filename":"Table123.docx","url":"https://assets-eu.researchsquare.com/files/rs-7820966/v1/30edc58cbfb7dfe58b1ac901.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Right Ventricular Free Wall Strain to Predict Clinical Outcomes in Acute Pulmonary Embolism","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDespite advances in therapy for pulmonary embolism (PE), the estimated mortality rate remains high with minimal improvement over the last twenty years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There exists a consensus regarding classification, however treatment recommendations are less clear. Challenging management decisions are based on severity, prognostic markers, and baseline characteristics [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePE is classified into three basic severity categories: low risk, submassive (intermediate-risk), and massive (high-risk) PE (\u003cem\u003eSupplement A\u003c/em\u003e). Minor categorical criteria vary slightly in different clinical guidelines; however the general characteristics are in agreement [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Classification is made based on the presence of right ventricular (RV) dysfunction and elevated cardiac biomarkers. Massive (high-risk) PE is defined by the presence of hypotension (systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90mmHg). The presence of both RV dysfunction and elevated cardiac biomarkers classifies as submassive-high (intermediate-high) risk. The presence of RV dysfunction or elevated biomarkers, but not both, is classified as submassive-low (intermediate-low) risk. Low risk PE is defined by the absence of RV dysfunction and cardiac biomarker elevation.\u003c/p\u003e\u003cp\u003eThe submassive PE subgroup is heterogeneous in terms of clinical outcomes. As such, predicting which submassive PE patients will decompensate is challenging. Guidelines generally reflect the paucity definitive data [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Few studies have focused on defining which patients are at increased risk and therefore warrant aggressive management. There are no clear evidence-based echocardiographic findings that have been shown to consistently prognosticate clinically important outcomes. A better way of prognosticating these patients is needed to clarify management decisions that are often unclear.\u003c/p\u003e\u003cp\u003eRight ventricular (RV) function is difficult to assess by transthoracic echocardiography (TTE). Qualitative estimation of RV size and function have been shown to have high observer variability with limited data on prognostic value [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Quantitative assessments of RV function include tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular plane systolic velocity (TAPSV, or S\u0026rsquo;). TAPSE is the linear distance the tricuspid annulus moves towards the apex during systole, measured using m-mode (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). It is an indirect correlate of RV function and most literature supports the normal range above 1.7cm [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. TAPSV, or S\u0026rsquo;, is a similar indirect measurement using tissue doppler velocity with normal values 11 cm/s or greater [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. TAPSE and S\u0026rsquo; are angle-dependent measures that can be unreliable in cases of regional RV dysfunction or altered loading conditions [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These variables do not directly assess RV function or the pathologic changes of PE.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRV Free Wall Longitudinal Strain (RV FWS) is potentially a direct measurement of the pathophysiologic changes in PE. Strain is defined as the rate of change in myocardial length normalized to the original length [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. When myocardial work exceeds perfusion relaxation is impaired resulting in a lower measured strain. Acute changes in afterload, such as acute PE, create increased myocardial work and this change should be reflected by lower measurements of strain. More research is needed, but RV FWS should accurately predict clinical outcomes in PE.\u003c/p\u003e\u003cp\u003eThe utility of RV FWS has been explored as it relates to aortic stenosis, tricuspid regurgitation, and pulmonary hypertension [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Previous research on RV FWS related to PE has demonstrated correlation to mortality, pulmonary vascular resistance, and correlation to traditional markers of RV function [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The addition of RV FWS addition to existing TTE parameters improves diagnostic yield of PE [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A 2020 meta-analysis demonstrated the lower limit of normal for RV FWS to be -18% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Recent guidelines recommend incorporating RV strain analysis into the standard echocardiographic assessment of RV function, however data specific to PE is limited [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe aimed to explore the prognostic value of RV FWS in the evaluation of critically ill patients diagnosed with PE. We additionally compared the performance of RV FWS to traditional measurements of RV function including TAPSE, S\u0026rsquo;, and gross qualitative assessment.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis was a retrospective cohort study of hospitalized patients who were evaluated by the Pulmonary Embolism Response Team (PERT). Patients were identified using the PERT consultation process. Clinical data was collected throughout the hospitalization during which the pulmonary embolism was diagnosed. Data was collected with waiver of consent approval by the institutional review board (University of Miami - IRB 20230013, Clinical Trial Number \u0026ndash; N/A).\u003c/p\u003e\u003cp\u003eThe study was conducted at a single academic center which is additionally an inpatient affiliate of a national cancer institute (NCI) designated cancer center. Patients were enrolled during hospitalizations from January 2023 to April 2024.\u003c/p\u003e\u003cp\u003ePatients were identified by the PERT consultation process which is generally limited to submassive PE, massive PE, or patients with high bleeding risk. Patients were required to be older than 18 years for inclusion. Patients were excluded if they received systemic thrombolysis (ST) or catheter directed therapy prior to formal TTE, did not have a confirmatory diagnosis of PE, or if the clinical outcome was determined to be unrelated to PE during the review process (\u003cem\u003eSupplement B\u003c/em\u003e).\u003c/p\u003e\u003cp\u003eA clinically indicated TTE was performed at the time of PE diagnosis as part of existing PERT protocol. Timing of TTE was dependent on risk stratification with urgent studies being done within 1 hour. Echocardiographic data including TAPSE, S\u0026rsquo;, gross RV size, gross RV function, and presence of McConnell\u0026rsquo;s sign was collected from the initial reviewing cardiologists who were blinded to this study (\u003cem\u003eSupplement C2\u003c/em\u003e). This data was confirmed by review of TTE images by two providers with echocardiography board certification (DG, KL). The two echocardiographic reviewers ensured validity of the reported measurements as well as qualitative variables.\u003c/p\u003e\u003cp\u003eRV FWS was calculated using Phillips-TOMTEC\u0026trade; software (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Using this software, strain calculation is performed by selecting the cardiac cycle and providing a tracing of the RV chamber including the free wall in either a dedicated RV or an apical four chamber view (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The resulting strain value was graphically and numerically reported for the basal, mid, and apical segments of the free wall, as well as a mean of the three segments. The RV septal wall was excluded for the purposes of this study. RV FWS calculation was performed using two different image series and an average value of the two mean values was reported for final analysis. For the purposes of comparison with other TTE variables; RV FWS was reported as an absolute value with smaller numbers being more pathologic.\u003c/p\u003e\u003cp\u003eEchocardiographic review and RV FWS calculations were performed by the primary investigator prior to analyzing clinical outcome data to minimize bias. The second independent reviewer remained blinded to clinical outcomes throughout the study.\u003c/p\u003e\u003cp\u003eClinical outcome data was obtained through review of the electronic medical record (EMR). Data was collected throughout the hospitalization by the primary investigator and two independent reviewers (JM, MT). The two independent reviewers were blinded to the echocardiographic data throughout the study (\u003cem\u003eSupplement C1\u003c/em\u003e). The \u003cem\u003eprimary outcome\u003c/em\u003e was PE-related in hospital mortality or hemodynamic instability. Outcome was determined by multidisciplinary review and limited to the current hospitalization at time of diagnosis. Hemodynamic instability was defined as: a\u0026thinsp;\u0026gt;\u0026thinsp;40mmHg systolic blood pressure (SBP) decrease, SBP\u0026thinsp;\u0026lt;\u0026thinsp;90mmHg, tachyarrhythmias requiring chemical or electrical cardioversion, or vasopressor use. \u003cem\u003eSecondary outcomes\u003c/em\u003e were intensive care unit (ICU) length of stay (LOS), acute kidney injury (AKI), and need for mechanical ventilation if not initially required at the time of PE diagnosis.\u003c/p\u003e\u003cp\u003eLogistical regression analysis was performed to assess the outcome association with RV FWS, TAPSE, and S\u0026rsquo;. TTE variables were evaluated using abnormal cutoffs based off best available evidence (RV FWS\u0026thinsp;\u0026lt;\u0026thinsp;18%, TAPSE\u0026thinsp;\u0026lt;\u0026thinsp;1.7cm, S\u0026rsquo; \u0026lt; 11cm/s). To adjust for cofounders, multivariate logistic regression was performed adjusting for age, gender, and baseline medical comorbidities. A Pearson\u0026rsquo;s Chi-squared test with Yates\u0026rsquo; continuity correction was performed to evaluate outcome association with gross RV function, gross RV size, and the presence of McConnell\u0026rsquo;s sign. Receiver operating characteristic (ROC) curves were created for all three echocardiographic variables to assess diagnostic performance. Empirical cumulative distribution function (ECDF) plots comparing RV FWS, TAPSE, and S\u0026rsquo; were created for both the presence and absence of primary outcome.\u003c/p\u003e\u003cp\u003eThe estimated sample size during study design was 60 patients to detect a 10% progression to the primary outcome with 90% power. A 12-month enrollment period was determined to be sufficient based on average monthly census and tracking statistics provided by the internal PERT registry. Enrollment continued for three additional months to account for patients who could potentially be excluded during the review process.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eUpon completion of the enrollment period, January 2023 through April 2024, a total of 98 patients met the inclusion criteria. 8 patients were excluded after it was determined that the primary outcome was not related to PE. 3 patients were excluded for lack of definitive diagnosis of PE. 3 patients received catheter embolectomy prior to formal echocardiography and were excluded. A total of 84 patients were included in final statistical analysis (\u003cem\u003eSupplement B\u003c/em\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean age of participants was 63.5 years with the majority male (\u003cem\u003eTable 1\u003c/em\u003e). The most common comorbid condition was hypertension and nearly half of all participants had an active malignancy. A large majority, 85.7%, of patients enrolled had a PE that was initially classified in the Submassive subgroup.\u003c/p\u003e\n\u003cp\u003eThe composite primary outcome occurred in 45.2% (n=38) of patients and death occurred in 11.9% (n=10) of patients. The most common baseline comorbidity of those meeting the primary outcome was hypertension which was present in 58% of these patients. TAPSE was not calculated on 8 patients during initial TTE. Similarly, S\u0026rsquo; was not calculated on 25 patients. This data was excluded from the analysis as these calculations cannot be retrospectively done unless appropriate ultrasound modes are obtained during the initial study (m-mode for TAPSE, and tissue doppler for S\u0026rsquo;). RV FWS can be retrospectively calculated if the RV free wall is adequately visualized and was obtained for all 84 patients. The Mean ICU LOS was noted to be 2 days with a high relative standard deviation. Acute kidney injury (AKI) occurred in 28.6% (n=24) of patients and 10.7% (n=9) of patients required mechanical ventilation for respiratory decline after initially not requiring (\u003cem\u003eSupplement D\u003c/em\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDemographic and objective data was compared between those meeting primary outcome and those who did not meet primary outcome (\u003cem\u003eTable 2\u003c/em\u003e). Of the 38 patients that met the primary outcome, the initial PE classification included 4 massive, 25 submassive-high risk, and 9 submassive-low risk. The average RV FWS of patients meeting primary outcome was found to be -9.8% (SD 4.9) and -17.53% (SD 6.6) for those not meeting primary outcome. The average values for TAPSE and S\u0026rsquo; in patients meeting primary outcome were 1.69cm (SD 0.49) and 13.3 cm/s (SD 4.4). Qualitative assessment of RV size, RV function, and the presence of McConnell\u0026rsquo;s sign did not demonstrate statistically significant association with primary outcome (\u003cem\u003eSupplement E\u003c/em\u003e). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRV FWS was associated with the primary outcome (OR 15.4; p=0.0005) in unadjusted models (\u003cem\u003eTable 3\u003c/em\u003e). TAPSE was also associated with the primary outcome (OR 8.1; p=0.00015). S\u0026rsquo; did not demonstrate statistical significance in univariate analysis (OR 2.3, p=0.134).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMultivariate logistic regression analysis adjusting for age, sex, and baseline comorbidities demonstrated an association with the primary outcome for all three echocardiographic variables (\u003cem\u003eTable 3\u003c/em\u003e). The adjusted OR for RV FWS was 19.3 (CI 4.6-136.6). The adjusted OR for TAPSE was 12.9 (CI 3.9-54.6). S\u0026rsquo; was not associated with the primary outcome in univariate analysis, however adjusted odds ratio was calculated to be 7.5 (CI 1.6-45.98).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eROC curves were created comparing the three TTE variables to primary outcome (\u003cem\u003eFigure 2\u003c/em\u003e). RV FWS demonstrated good predictive performance with an area under the curve (AUC) of 70.7%. TAPSE additionally performed well with an AUC of 71.1%. S\u0026rsquo; performed poorly in ROC analysis with AUC of 58.5%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEmpirical cumulative distribution function (ECDF) and box plots were created comparing the three predictors with the presence and absence of primary outcome (\u003cem\u003eFigure 3\u003c/em\u003e). Significant inverse correlation was noted between the primary outcome and RV FWS as well as TAPSE. S\u0026rsquo; was found to have significant overlap between the two groups.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe found RV FWS to be a strong predictor of death or hemodynamic instability in this cohort of primarily submassive and massive PE patients. RV FWS demonstrated stronger association with the primary outcome than TAPSE in terms of odds ratio in both univariate and multivariate analysis. Both RV FWS and TAPSE performed well in terms of AUC and linear regression analysis. A RV FWS less than or equal to 17% was the most sensitive echocardiographic marker at predicting death or hemodynamic instability. S\u0026rsquo; was not associated with the primary outcome in most of the analysis.\u003c/p\u003e\u003cp\u003eThe value of quantitative markers of RV function over gross qualitative assessment is supported by this study. Qualitative assessment of RV size, function, and the presence of McConnel\u0026rsquo;s sign did not demonstrate a statistically significant association with the primary outcome. These findings emphasize the need for a more precise and quantitative evaluation of RV dysfunction when prognosticating patients with PE.\u003c/p\u003e\u003cp\u003ePrevious work has evaluated the performance of RV FWS as a predictive and diagnostic tool in management of PE [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Strengths of this study compared to previous literature include the acute clinical follow-up period, PE severity of the included cohort, and the primary outcome design.\u003c/p\u003e\u003cp\u003eThis study validates previous work with a focus on acute, critically ill patients. 90.5% of the included cohort were classified with either submassive or massive PE at time of diagnosis. Previous studies have focused on a lower risk population with more longitudinal outcomes that are less applicable to the acute phase of illness [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In 2019, Lee et al published an observational study of low-risk PE patients that demonstrated strong predictive performance of RV FWS compared to other echocardiographic markers of RV function [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Dahhan et al previously demonstrated that RV FWS is associated with 30-day mortality in a comparatively low-risk cohort [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This study focused on a higher risk cohort in the acute phase of illness to potentially help guide initial management. Management decisions become less clear in these higher risk subgroups and these patients require more useful prognostic tools.\u003c/p\u003e\u003cp\u003eSimilar cohort studies have included treatment modality as well as recurrence of PE in the primary composite outcome [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This type of design introduces confounding variables when evaluating the usefulness of RV FWS as a prognostic tool. Treatment indications are often not standardized, and such studies are subject to practice pattern variability. Recurrence of PE is often multifactorial and unrelated to severity of the acute event. A primary composite outcome that is isolated to acute, objective data increases the ability to evaluate RV FWS as a prognostic tool.\u003c/p\u003e\u003cp\u003eThis study demonstrated a strong negative predictive value of RV FWS relative to hemodynamic collapse. Only 2 of the 38 patients meeting the primary outcome had RV FWS in the normal range. Critically ill patients that are discovered to have PE frequently have multiple pathophysiologic processes contributing to hemodynamic instability. This data supports the potential of RV FWS to help the intensivist discern which process is the primary driver of hemodynamic collapse. Further data is needed to validate such potential as well as the overall prognostic value, however these results are promising.\u003c/p\u003e\u003cp\u003eA major limitation in terms of generalizability is the baseline demographics of the included cohort. Nearly half of the patients had an active malignancy at the time of PE diagnosis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). While typical for this institution, further research is needed to validate our prognostic findings in a cohort more representative of the general population.\u003c/p\u003e\u003cp\u003eThe study protocol is reproducible assuming PE patients are followed consistently through their hospitalization when transitioning between services. Additionally, a formal TTE is required with included quantitative markers of RV function at the time of diagnosis. A protocol was previously in place at our institution and timely TTE for PE was part of standard clinical practice.\u003c/p\u003e\u003cp\u003eSeveral studies were missing either a calculated TAPSE or S\u0026rsquo; when the TTE was initially performed. As this is not able to be retroactively calculated, these studies were not included during statistical analysis of the missing variable. The three echocardiographic variables were analyzed independent of one another, as such a missing variable would not affect the analysis of other TTE variables on the same patient.\u003c/p\u003e\u003cp\u003eOne limitation in terms of feasibility is the interrater reliability of RV FWS calculations. Previous work on RV FWS has demonstrated good to excellent interrater reliability, however more data is needed [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this current study, the two reviewers were blinded to one another during their calculations of RV FWS. Interobserver agreement for RV FWS was excellent, with an intraclass correlation coefficient (ICC[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]) of 0.93. Disagreement outside of one standard deviation occurred in only 3 of the 84 patients (3.6%) and categorical discordance (normal vs abnormal) occurred in two patients (2.4%). The degree of interrater reliability needs to be further explored and is likely to improve with advancing technology.\u003c/p\u003e\u003cp\u003eThe feasibility of incorporating RV FWS into PE prognostication is dependent on institutional echocardiographic capabilities. Obtaining a formal TTE in a timely manner is highly variable across healthcare institutions. After the study is completed, the TTE needs to be reviewed and interpreted by a provider board certified in echocardiography. It is worth noting the dramatic improvement in point of care ultrasound (POCUS) technology over the past decade. As technology continue to advance, this may allow strain to be more accessible [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMost of the literature to date supports the association of RV FWS and adverse outcomes from PE. This association has been validated by this study. The prognostic value of RV FWS appears to be increased when applied to the submassive and massive subgroups. The performance of RV FWS at predicting death or hemodynamic instability was superior to TAPSE and S\u0026rsquo;, however this finding needs to be validated in a larger cohort that is more representative of the general population. The feasibility of incorporating RV FWS into current practice will vary by health system, however as technology advances this will likely become more readily available.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eRV FWS was a strong predictor of death or hemodynamic instability in patients with primarily submassive and massive PE. It performed favorably when compared to more conventional quantitative and qualitative markers of RV function. Further research is needed in a larger and more generalizable population to validate these findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAcute kidney injury (AKI)\u003c/p\u003e\n\u003cp\u003eArea under the curve (AUC)\u003c/p\u003e\n\u003cp\u003eElectronic medical record (EMR)\u003c/p\u003e\n\u003cp\u003eEmpiric cumulative distribution function (ECDF)\u003c/p\u003e\n\u003cp\u003eIntensive care unit (ICU)\u003c/p\u003e\n\u003cp\u003eLength of stay (LOS)\u003c/p\u003e\n\u003cp\u003eNational Cancer Institute (NCI)\u003c/p\u003e\n\u003cp\u003ePoint of care ultrasound (POCUS)\u003c/p\u003e\n\u003cp\u003ePulmonary embolism (PE)\u003c/p\u003e\n\u003cp\u003ePulmonary Embolism Response Team (PERT)\u003c/p\u003e\n\u003cp\u003eReceiver operative characteristic (ROC)\u003c/p\u003e\n\u003cp\u003eRight ventricle (RV)\u003c/p\u003e\n\u003cp\u003eRight ventricular free wall longitudinal strain (RV FWS)\u003c/p\u003e\n\u003cp\u003eSystolic blood pressure (SBP)\u003c/p\u003e\n\u003cp\u003eSystemic thrombolysis (ST)\u003c/p\u003e\n\u003cp\u003eTransthoracic echocardiography (TTE)\u003c/p\u003e\n\u003cp\u003eTricuspid annular plane systolic excursion (TAPSE)\u003c/p\u003e\n\u003cp\u003eTricuspid annular plane systolic velocity (TAPSV, or S\u0026rsquo;)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study adhered to the Declaration of Helsinki ethical principles on human medical research. A waiver of consent to participate was requested due to observational, non-intervention design. The waiver of consent was approved by the institutional review board (University of Miami - IRB 20230013).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication not required as manuscript does not contain any individual person\u0026rsquo;s data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data \u0026amp; Materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest and have no financial disclosures regarding this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this study, in part, was provided by the University of Miami, Division of Pulmonary, Critical Care, and Sleep Medicine as a grant awarded within the division. No external funding was provided. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDG \u0026ndash; project administration, conceptualization, data curation, formal analysis, investigation, methodology, validations, primary contributor in writing, editing, reviewing\u003c/p\u003e\n\u003cp\u003eMG \u0026ndash; writing, reviewing, editing, data curation\u003c/p\u003e\n\u003cp\u003eSL \u0026ndash; data curation, formal analysis\u003c/p\u003e\n\u003cp\u003eBL \u0026ndash; investigation, validation, data curation\u003c/p\u003e\n\u003cp\u003eMT \u0026ndash; investigation, validation, data curation\u003c/p\u003e\n\u003cp\u003eJM \u0026ndash; investigation, validation, data curation\u003c/p\u003e\n\u003cp\u003eDK \u0026ndash; conceptualization, investigation\u003c/p\u003e\n\u003cp\u003eRD \u0026ndash; investigation, methodology, editing, reviewing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTS \u0026ndash; conceptualization, investigation, methodology, major contributor in writing, reviewing, and editing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J. 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PMID: 38741438; PMCID: PMC11022635.\u003c/li\u003e\n\u003cli\u003eMukherjee M, Rudski LG, Addetia K, Afilalo J, D\u0026apos;Alto M, Freed BH, Friend LB, Gargani L, Grapsa J, Hassoun PM, Hua L, Kim J, Mercurio V, Saggar R, Vonk-Noordegraaf A. Guidelines for the Echocardiographic Assessment of the Right Heart in Adults and Special Considerations in Pulmonary Hypertension: Recommendations from the American Society of Echocardiography. J Am Soc Echocardiogr. 2025 Mar;38(3):141-186. doi: 10.1016/j.echo.2025.01.006. Erratum in: J Am Soc Echocardiogr. 2025 Jul;38(7):641. doi: 10.1016/j.echo.2025.05.001. PMID: 40044341.\u003c/li\u003e\n\u003cli\u003eLing LF, Obuchowski NA, Rodriguez L, Popovic Z, Kwon D, Marwick TH. Accuracy and interobserver concordance of echocardiographic assessment of right ventricular size and systolic function: a quality control exercise. J Am Soc Echocardiogr. 2012 Jul;25(7):709-13. doi: 10.1016/j.echo.2012.03.018. Epub 2012 Apr 26. PMID: 22542275.\u003c/li\u003e\n\u003cli\u003eLee CY, Nabeshima Y, Kitano T, Parasca CA, Calin A, Popescu BA, Takeuchi M. Prognostic value of right ventricular free-wall longitudinal strain in aortic stenosis: A systematic review and meta-analysis. J Cardiol. 2024 Aug;84(2):80-85. doi: 10.1016/j.jjcc.2023.11.008. Epub 2023 Dec 2. PMID: 38043709.\u003c/li\u003e\n\u003cli\u003eKim M, Lee HJ, Park JB, Kim J, Lee SP, Kim YJ, Chang SA, Kim HK. Preoperative Right Ventricular Free-Wall Longitudinal Strain as a Prognosticator in Isolated Surgery for Severe Functional Tricuspid Regurgitation. J Am Heart Assoc. 2021 May 4;10(9):e019856. doi: 10.1161/JAHA.120.019856. Epub 2021 Apr 17. Erratum in: J Am Heart Assoc. 2021 Jun 15;10(12):e020842. doi: 10.1161/JAHA.121.020842. PMID: 33870734; PMCID: PMC8200727.\u003c/li\u003e\n\u003cli\u003eNabeshima Y, Kitano T, Node K, Takeuchi M. Prognostic value of right ventricular free-wall longitudinal strain in patients with pulmonary hypertension: systematic review and meta-analyses. Open Heart. 2024 Feb 7;11(1):e002561. doi: 10.1136/openhrt-2023-002561. PMID: 38325907; PMCID: PMC10860115.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pulmonary Embolism, Echocardiography, Vascular Diseases, Hemodynamics, Critical Care","lastPublishedDoi":"10.21203/rs.3.rs-7820966/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7820966/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubmassive (intermediate risk) pulmonary embolism (PE) presents with heterogenous clinical outcomes. Critical management decisions are unclear and improved prognostication is needed. Right ventricular free wall longitudinal strain (RV FWS) is an echocardiographic finding that reflects the pathophysiologic changes in PE and therefore should provide prognostic value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective cohort study was performed by reviewing the medical records of patients followed by the hospital pulmonary embolism response team (PERT). The primary outcome was in-hospital mortality or hemodynamic instability. Traditional qualitative and quantitative markers of RV function including tricuspid annular plane systolic excursion and velocity (TAPSE and S’) were collected for comparison to RV FWS. A total of 84 patients were included in the final cohort. Logistical regression analysis was performed to assess the primary outcome association with RV FWS, TAPSE, and S’. Multivariate logistic regression was performed adjusting for age, gender, and baseline medical comorbidities. Receiver operating characteristic (ROC) curves and Empiric cumulative distribution function (ECDF) plots were created for all three echocardiographic variables to assess diagnostic performance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome occurred in 45.7% (n=38) and death occurred in 11.9% (n=10). \u0026nbsp;RV FWS was associated with increased risk of the primary outcome (adjusted OR = 19.3; p=0.0003). RV FWS demonstrated good predictive performance with an area under the curve (AUC) of 70.7%. Significant inverse correlation was noted between the primary outcome and RV FWS when using empiric cumulative distribution function (ECDF). TAPSE additionally demonstrated positive predictive performance, albeit lower than RV FWS. Qualitative assessment of the RV as well as S’ did not demonstrate statistically significant association with primary outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study of patients with primarily submassive PE, RV FWS demonstrated good predictive performance in terms of death or hemodynamic instability. Further data is needed to validate these findings in a larger population.\u003c/p\u003e","manuscriptTitle":"Right Ventricular Free Wall Strain to Predict Clinical Outcomes in Acute Pulmonary Embolism","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-20 16:17:49","doi":"10.21203/rs.3.rs-7820966/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-25T10:30:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-24T07:54:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T15:12:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64206579268759061766605973748769368","date":"2025-11-13T13:21:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57312139117737269521273785759075651973","date":"2025-11-11T13:11:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284150800747173246125119060764117767938","date":"2025-11-11T08:07:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-10T19:49:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-29T09:42:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-24T15:45:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-24T14:23:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-10-24T14:20:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ee1df439-6173-480a-ae04-aed4148c5119","owner":[],"postedDate":"November 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-17T09:53:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-20 16:17:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7820966","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7820966","identity":"rs-7820966","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}