The impact of right bundle branch block and SIQIII-type patterns in determining risk levels in acute pulmonary embolism

Background: Electrocardiography (ECG) findings in acute pulmonary embolism (PE) are known to be related to various right ventricular (RV) alterations. These abnormalities are not included in risk stratification algorithms despite emerging evidence of their association with patient outcomes. We aimed to analyze the impact of right bundle branch block (RBBB) and/or SIQIII patterns as indicators for determining the level of risk in patients with PE. Methods: We performed a retrospective cohort study including all patients with confirmed acute PE hospitalized from January 2008 to December 2019 in two tertiary care cardiology departments. The first ECG taken at admission was selected and the analysis focused on the presence of a complete or an incomplete RBBB and SIQIII-type patterns. Results: A total of 255 patients were divided into two groups: Group I (47.8%, n=122) included patients with PE without RBBB nor SIQIII patterns, and Group II (52.2%, n=133) included patients with RBBB and/or SIQIII patterns. Patients in group II presented significantly more frequently with acute right heart symptoms (45.1% vs. 18%, p<0.001) and cardiogenic shock at admission (31.6 vs. 4.1%, p<0.001). Echocardiographic parameters indicating right heart injury also occurred more significantly in group II patients (p<0.001). By univariate analysis, patients in group II were found to be significantly associated with in-hospital mortality (22.6 vs. 6.1%, p=0.002) and major cardiovascular events (MACEs) during hospitalization (43.3 vs. 13.7%, p<0.001). Multivariate logistic regression analysis identified five independent factors predictive of MACEs: SIQIII and/or RBBB, renal failure, positive troponin levels, RV dysfunction and right heart failure symptoms during initial presentation. Kaplan-Meier survival analysis identified the inclusion in Group II and the presence of SIQIII pattern as predictors of overall mortality (p<0.001). Conclusions: Our study suggests an important and independent prognostic value of RBBB and SIQIII patterns and their usefulness in determining the outcome of PE patients.


Introduction
Pulmonary embolism (PE) is a common and potentially life-threatening medical condition.It is estimated that thromboembolism affects over 1,000,000 people in the United States each year and results in over 25,000 deaths annually. 1sk stratification is important in determining the likelihood of poor outcomes for patients with acute PE.It dictates the attitude towards patients with PE from early discharge to urgent care in intensive care units.Thus, recent risk stratification algorithms rely on various clinical, laboratory, and imaging factors to estimate the risk of complications and guide treatment decisions. 24][5] These changes are primarily related to right ventricular (RV) overload and reflect right ventricular dysfunction (RVD), injury and enlargement in patients with acute PE. [6][7][8][9] Furthermore, ECG abnormalities associated with acute PE are more likely to be present in patients with a confirmed diagnosis of PE. 2,10 Despite their potential prognostic value, none of these ECG changes are included in the current guidelines for PE risk stratification due to the lack of specificity. 2,11Encouraging evidence has emerged showing the relationship between the right bundle branch block (RBBB) and SIQIII patterns in acute PE events with poor outcomes. 10,12,13In addition, more research is needed to clarify the potential role of ECG abnormalities in the risk stratification of acute PE.By addressing these gaps in the literature, we can improve our ability to manage patients with this common and potentially life-threatening condition. 12,14m Our study aimed to examine the impact of RBBB and/or SIQIII-type patterns as indicators for determining the level of risk in patients with acute PE.

Ethical considerations
This study was a retrospective observational cohort study that did not involve human testing and did not challenge human rights.The ethical approval was obtained retrospectively as we did not initially believe that this study needed ethical approval.This issue has been a subject of debate inside our team and that belief has since been revised and updated.Data collection for our study began in January 2011 in two Tunisian tertiary care cardiology departments: Cardiology A Department, Fattouma Bourguiba University Hospital affiliated to the University of Monastir and the Cardiology Department of Kairouan affiliated to the University of Sousse.Our study was retrospectively approved by the Research Ethics Committee of the Faculty of Medicine of Monastir (an independent organization under the aegis of the Tunisian Ministry of Public Health) under the number IORG 0009738 N°114/OMB 0990-0279.We obtained this approval on the 16 th of March 2023.
The initial approval to start the study was obtained by consensus from both research teams under the supervision of both heads of the aforementioned departments at the University of Monastir and University of Sousse.The study was performed in compliance with the Declaration of Helsinki.We ensured that participants' privacy and confidentiality were maintained, and the study results were reported in a way that protected the participants' identities.
Oral informed consent was obtained from patients, whenever possible.This verbal consent was obtained during initial hospitalization.Each patient was informed that their anonymized data could serve for future research purposes.We did not conceptualize the content of this article at the time of information gathering and we could not obtain this consent in patients initially presenting with critical conditions and fatal outcomes.Verbal consent was approved retrospectively when we received ethical approval and deemed adequate by the ethics committee.

Study design
We conducted a retrospective cohort study.We included all patients with confirmed acute PE hospitalized from January 10 th , 2008, to December 31 st , 2019, in two Tunisian tertiary care cardiology departments: Cardiology A Department, Fattouma Bourguiba University Hospital affiliated to the University of Monastir and the Cardiology Department of Kairouan affiliated to the University of Sousse.The data were gathered by reviewing patients' hospital records from each hospitalization, supplemented with comprehensive in-hospital assessments and follow-up interviews conducted either in person or via telephone.PE was diagnosed primarily by either computed tomography (CT) or scintigraphic ventilation-perfusion (V/Q) scans.The CT pulmonary angiogram (CTPA) demonstrated the existence and the extension of a filling defect in the pulmonary artery system.In the cases where V/Q scintigraphic scanning was employed, the results were interpreted by a nuclear medicine specialist.A high-probability V/Q scan was considered sufficient for the diagnosis of acute PE.This examination showed the presence of at least two segmental perfusion defects without ventilatory or radiological abnormalities in the same territories. 2,15PE diagnosis was also assessed by a positive venous doppler ultrasound consistent with deep venous thrombosis (DVT) in patients with high clinical suspicion of PE and positive D-dimer values. 2 All CT, scintigraphy and venous doppler ultrasound scans were analyzed and interpreted by experienced specialists.

Definitions
Complete RBBB was identified according to the Minnesota Code criteria (7-2-1) as a QRS duration must be ≥120 ms in addition to R 0 wave>R wave in lead V1 and/or V2 in most beats of leads I, II, III, aVL, aVF; or a QRS complex being predominantly upright with an R-peak duration ≥60 ms in lead V1 and/or V2 or; an S wave duration > to R wave duration in all beats in lead I and/or II. 16,17complete RBBB was identified according to the Minnesota Code criteria (7-1) by a QRS duration in each of leads I, II, III, aVL, and aVF being <120 ms in addition to an R 0 >R wave in lead V1 and/or V2. 16,17 SIQIII-type ECG patterns were defined as a qualitative presence of S wave in lead I and Q wave in lead III.
Right ventricular dysfunction (RVD) was defined as a decreased systolic function of the RV (TAPSE <17 mm) and/or the presence of a paradoxical interventricular septal movement and/or a systolic pulmonary artery pressure ≥40 mmHg.
Major Adverse Cardiovascular Events (MACE) were defined as the presence of at least one of the following: death during hospitalization, cardiogenic shock in initial presentation or the presence of a thrombus in the right heart.
Renal failure was defined as an eGFR < 60 ml/min per 1.73 m 2 . 18sitive troponin levels were defined as any value above the 99th percentile of the upper reference limit. 19tients with PE with a systolic blood pressure (SBP) <90 mmHg at admission were classified as high-risk of mortality patients. 2e sex of each participant was defined based on self-report and assigned following external examination of body.

Inclusion criteria
Patients were eligible if: i) The diagnosis of PE was confirmed using one of the three diagnostic tools described above; ii) they were managed in Cardiology A Department, Fattouma Bourguiba University Hospital affiliated to the University of Monastir and the Cardiology Department of Kairouan affiliated to the University of Sousse; and iii) aged 18 years or above.
Exclusion criteria included: i) patients aged under 18 years and ii) if the diagnosis of acute PE was unclear.
A standard 12-lead ECG was assessed in the Emergency Department immediately upon initial contact.This first ECG taken at admission was selected for analysis.Both the ECG and echocardiography exams were performed and interpreted by experienced examiners.The retrospective analysis of ECG parameters focused on the existence of RBBB, either complete or incomplete, and SIQIII-type patterns.

Statistics
Data analysis was performed using IBM SPSS Statistics (RRID:SCR_016479) version 26.0.The mean AE standard deviation (SD) was used to describe the normally distributed data.The median and interquartile range (IQR) was used to describe the skewed distribution data.
Frequencies and percentages were used to present categorical variables.The comparison between frequencies was performed using the Chi-squared test (χ 2 test) or Fisher's exact test.Means were compared using the Student's t test for independent samples.A Kaplan-Meier survival analysis was performed to assess the association between the RBBB and/or SIQIII and overall mortality using the log-rank test.In order to identify the independent factors associated with the occurrence of MACEs, univariate and multivariate analyses were performed.First, covariates with a p-value less than or equal to 0.20 were retained in the multivariable model.Then, a binary logistic regression was performed for assessing the independent risk factors for MACEs.

Results
A total of 255 patients were included in the analysis.All of the medical reports for these patients included a usable ECG from the time of their acute PE episode.Patients were divided into two groups: i) Group I (n=122, 47.8%) included patients with PE without RBBB nor SIQIII patterns; and ii) group II (n=133, 52.2%) included patients with RBBB and/or SIQIII type patterns.Patients in both groups did not differ by age nor sex.The proportion of diabetes mellitus (DM), hypertension (HTN) and dyslipidemia were homogeneous between the two groups (Table 1). 25roup II patients had an active cancer (17.3% vs. 12.3%) more frequently but this difference did not reach statistical significance (p=0.29).Patients presenting with SIQIII pattern and/or RBBB were also significantly more likely to have history of systolic or diastolic heart failure (13.5% vs. 4.9%, p=0.03).
We analyzed the association between the presence of RBBB and/or SIQIII type pattern with PE severity and patient outcome.
Patients in group I had a significantly lower likelihood of positive Cardiac troponin I (cTnI) or high-sensitivity cardiac troponin (hs-cTn) levels (26.9 vs. 51.1%,p<0.001).
Negative T waves in leads V1-V3 were significantly more frequently associated with Group II patients in univariate analysis (p=0.01) (Table 1).
There were slightly more patients with atrial fibrillation (AF) in Group I patients, but this was not statistically significance (10.6 vs. 7.6%, p=0.4).

Discussion
Early and risk-oriented diagnosis and management of patients with acute PE are key for a better prognosis. 2In our study, RBBB and SIQIII-type patterns at admission were found to be associated with worsening clinical, echographic and biological profiles and with a poor clinical outcome.
Meta-analyses by Shopp et al., reported different ECG patterns, such as inverted T wave in leads V1-V4, a QR pattern in lead V1, SIQIII, complete or incomplete RBBB and ST elevation in lead aVR as being associated with increasing severity and poor outcomes. 4G scoring by Daniel et al., was notable for providing an applicable and reliable prognostic tool. 5However, recent studies indicate that there are several ECG abnormalities that can provide valuable prognostic information, but are not currently included in these scores. 9These ECG findings were also associated with early clinical deterioration. 20Despite these findings, ECG abnormalities were not included nor recommended in the latest guidelines for risk stratification of acute PE. 2 This is probably due to the lack of specificity as these changes can be encountered in acute and chronic cor pulmonale. 21e SIQIII pattern was found to be a strong independent predictor of in-hospital mortality, contrary to RBBB.Acute onset of SIQIII patterns mirror a longitudinal dextrorotation of the RV and appears to be more associated with poor hemodynamic outcomes than RBBB.RBBB alone was not found to be independently associated with in-hospital mortality The findings concerning RBBB were interpreted as follows: this characteristic can be observed in both acute pulmonary embolism (PE) and different conditions affecting the right ventricle (RV).Consequently, distinguishing between a new onset RBBB and a preexisting chronic RBBB is challenging.Furthermore, this challenge may be attributed to the limited sample size in various studies exploring the correlation between ECG abnormalities and risk assessment in acute PE.
New onset SIQIII and/or RBBB is likely to increase right heart failure, cardiogenic shock and intra-hospital mortality.These ECG changes seem to profoundly impact the overall survival as patients with SIQIII and/or RBBB patterns, and especially those with SIQIII, have significantly lower survival rates with curves diverging in less than a year.Parallel to the Pulmonary Embolism Severity Index (PESI) and to the simplified Pulmonary Embolism Severity Index (SPESI) scores, these findings suggest the importance of the RBBB and SIQIII patterns as important criteria in risk stratification of PE. 12 The recent onset of these patterns may improve its specificity especially if other causes of acute cor pulmonale are ruled out.
Given the predictive value of these parameters, it would be beneficial to integrate them into new and more accurate risk stratification scores for future guidelines.This would probably outperform guideline-backed risk scores. 22Furthermore, our study suggests that ECG alone is a useful tool in determining the outcome of PE, particularly in limited resources environments where advanced diagnostic tools are not available. 23,24nclusions Risk stratification is key for the management of patients with acute PE.New-onset RBBB and/or SIQIII and especially SIQIII patterns are likely to worsen patient outcomes.Our study suggests important and independent prognostic values of RBBB and SIQIII patterns and their usefulness in determining the outcome of acute PE patients.

Boris Dzudovic
Clinic -The inclusion of right heart thrombus as part of the MACE definition is debatable as it may not always lead to major cardiovascular events and can sometimes be asymptomatic.A clearer rationale for this inclusion or a standardized definition would enhance the robustness of the findings.

SPAP Calculation:
-The calculation of systolic pulmonary artery pressure (SPAP) when tricuspid annular plane systolic excursion (TAPSE) is <17 mm requires clarification.The potential underestimation of PAP using tricuspid regurgitation flow in these cases should be addressed, as it impacts the interpretation of right ventricular dysfunction.

Ethical Considerations:
-While the study is retrospective and received ethical approval, the initial lack of ethical approval and subsequent retrospective approval should be more transparently discussed, especially regarding the collection of verbal consent from critically ill patients.
Minor remarks: 1.The study provides valuable contributions to the field and has the potential to influence clinical practice by incorporating ECG findings into risk stratification models for PE.
2. The presentation of survival curves adds a significant dimension to understanding the prognostic implications of the ECG patterns studied.

Conclusion:
The article is a significant contribution to the literature on PE and its risk stratification.The findings support the integration of RBBB and SIQIII patterns into risk stratification algorithms, potentially improving patient management.Addressing the minor issues noted would further strengthen the study.

Recommendation:
Accept with minor revisions.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Yes

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Talel Trimech Rambouillet Hospital Center, Le Chesnay, France I found the article to be interesting.The exploration of ECG modifications and their correlation with acute pulmonary embolism risk stratification has been a matter of several debates.Using such simple methods, if proven accurate, might sharpen the sensibility of such predictive models.
The bicentric study design with a substantial number of patients adds considerable weight to the findings, enhancing the credibility of the study and positioning it as one of the most credible papers addressing the relationship between ECG modifications and risk stratification.The statistical analysis carried out in the study has solid standards, and the inclusion of survival curves added a valuable dimension to the interpretation of the data.
I therefore, have two minor remarks: The definition of MACE included the presence of a thrombus in the right heart.This can be asymptomatic and not leading to a major cardiovascular event.Although the definition of MACE has not been standardized, I think that the inclusion of such TTE findings might be a matter of discussion.Reviewer Expertise: Cardiovascular diseases, heart failure, pulmonary embolism I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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for Emergency Internal Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia Summary: The study investigates the prognostic significance of right bundle branch block (RBBB) and SIQIII patterns on the risk stratification and outcomes of patients with acute pulmonary embolism (PE).Conducted as a retrospective cohort study involving 255 patients over a period of 11 years, the research provides valuable insights into the association between these ECG patterns and clinical outcomes, emphasizing their potential utility in risk stratification.Review: Is the work clearly and accurately presented and does it cite the current literature?Yes.The manuscript is well-written and clearly presents its findings.It adequately references current and relevant literature, contextualizing its contributions within the existing of knowledge.Is the study design appropriate and is the work technically sound?Yes.The study design is appropriate for the research question.The use of a bicentric study design with a substantial patient cohort enhances the robustness of the findings.The methods, including statistical analyses, are solid and align with the study objectives.Are sufficient details of methods and analysis provided to allow replication by others?Yes.The methods section is detailed, allowing for reproducibility.The descriptions of ECG criteria, inclusion/exclusion criteria, and statistical methods are thorough and clear.If applicable, is the statistical analysis and its interpretation appropriate?Yes.The statistical analyses are appropriate, with a comprehensive use of univariate and multivariate logistic regression analyses to identify independent predictors of major adverse cardiovascular events (MACEs) and in-hospital mortality.Kaplan-Meier survival analyses further enrich the interpretation of the data.Are all the source data underlying the results available to ensure full reproducibility?Yes.The underlying data is available as cited, ensuring transparency and reproducibility.6. Are the conclusions drawn adequately supported by the results?Yes.The conclusions are well-supported by the data presented.The study effectively demonstrates the prognostic value of RBBB and SIQIII patterns in patients with acute PE.Specific Comments: Definition of MACE:

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How were the SPAP calculated when the TAPSE was <17 mm.Using the tricuspid regurgitation flow might underestimate the PAP values in such cases.○Overall,I commend the authors for their work in conducting this study and presenting the results in a clear and impactful manner.This research has the potential to influence clinical practice positively.Thank you for considering my feedback.Best regardsIs the work clearly and accurately presented and does it cite the current literature?YesIs the study design appropriate and is the work technically sound?YesAre sufficient details of methods and analysis provided to allow replication by others?YesIf applicable, is the statistical analysis and its interpretation appropriate?Yes Are all the source data underlying the results available to ensure full reproducibility?YesAre the conclusions drawn adequately supported by the results?YesCompeting Interests: No competing interests were disclosed.

Table 3 .
Independent predictors of in-hospital mortality.RVD, right ventricular dysfunction; OR, odds ratio; CI, confidence interval.