The role of the electrocardiogram in the recognition of cardiac transplant rejection: A systematic review and meta‐analysis

Abstract Background In cardiac transplant recipients, the electrocardiogram (ECG) is a noninvasive measure of early allograft rejection. The ECG can predict an acute cellular rejection, thus shortening the time to recognition of rejection. Earlier diagnosis has the potential to reduce the number and severity of rejection episodes. Methodology A systematic literature review was conducted to identify and select the original research reports on using electrocardiography in diagnosing cardiac transplant rejection in accordance with the PRISMA guidelines. Studies included reported sensitivity and specificity of ECG readings in heart transplant recipients during the first post‐transplant year. Data were analyzed with Review manager version 5.4. p‐value was used in testing the significant difference. Results After the removal of duplicates, 98 articles were eligible for screening. After the full‐text screening, a total of 17 papers were included in the review based on the above criteria. A meta‐analysis of five studies was done. Conclusion In heart transplant recipients, a noninvasive measure of early allograft rejection has the potential to reduce the number and severity of rejection episodes by reducing the time and cost of surveillance of rejection and shortening the time to recognition of rejection.

post-transplant. The most frequent cause of morbidity and rehospitalization in this patient population remains acute rejection. 2,3 The electrocardiogram (ECG) is a simple, cost-effective, and noninvasive tool used to evaluate the rhythm and electrical activity of the heart. Sensors attached to the skin are used to display the electrical signals generated by your heart on an easy to interpret grid paper. 4 Utilizing ECG readings in heart transplant recipients can predict an acute cellular rejection, thus shortening the time to recognize rejection. A recent study examined serial ECGs in 98 patients within the first-year post-heart transplantation. The most common abnormalities were associated with intraventricular conduction delays, with the right bundle branch block (RBBB) being the most prevalent. 5,6 In cardiac transplant recipients, a noninvasive measure of early allograft rejection can reduce the number and severity of rejection episodes.
ECG can reduce the time to detection and the cost of surveillance of rejection. 6 In this study, we summarize the diagnostic accuracy and criteria of the ECG in the detection of cardiac transplant rejection patients. Hashim, and Jaffer Sha, with disagreements being resolved by Joseph Varney. There was no restriction on participant's age, gender, or ethnicity, and no restrictions to language written. The references of selected papers were manually checked for additional relating studies. An analysis of the funnel plot was carried out to determine the possibility of bias in the publication in the Review Manager program version 5.4. Inclusion criteria for meta-analysis were studies that correlated the Endomyocardial biopsy grading to the ECG features.

| Data extraction
Details of the study design, ECG characteristics, endomyocardial biopsy grading, and outcome data, including the QT interval, QTc, QT dispersion, and QTc dispersion, were extracted. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment tool.

| Study inclusion
After a comprehensive search of the literature, 170 publications resulted and then became 96 after removal of duplicates. Of these, 51 were eligible for full-text screening. After the full-text screening, 18 studies were included in the systematic review and meta-analysis, as shown in F I G U R E 1 Flow chart of the study selection process HASHIM ET AL. | 259 ( Figure 1). Six studies were included in the meta-analysis. The included QT (ms), QTc, QT dispersion, and QTc dispersion outcomes in the metaanalysis were reported in 2, 3, and 5 studies. The summary of the included studies and risk of bias assessment are shown in Tables 1-3, respectively.

| Analyses
The total number of patients included in the meta-analysis in the no rejection or mild rejection group is 1733 patients, and the total number of patients in the moderate or severe rejection group is 264 patients.

| RESULTS
We used random effects due to heterogeneity observed among studies when we used fixed effects. In QT (ms) outcome, the pooled analysis between no or mild rejection and moderate or severe rejection was (MD = 3.80, 95% CI = −18.10 to 25.70, p-value = .73), we observed heterogeneity that was not solved by random effects, as shown in Figure 1  2 Patients While no rejection-specific ECG changes have been reported so far, the above-described changes that may represent actual hemodynamic anomalies may be a diagnostic tool for rejection.

E 7
Important changes in the high-frequency components (between 50 and 110 Hz) of the QRS complex and significant reductions in the low-frequency components (between 10 and 30 Hz).
-During acute rejection, improvements in the ECG properties of transplanted hearts were observed, with improvements in intraarticular and auriculoventricuir conduction and decreases in QRS voltage amplitude. These experimental findings should be considered in the development of new methods for detecting cardiac allograft rejection ECGs.

E 8
An expanded QTC interval in recipients of a heart transplant is linked to acute allograft rejection and death.
-In heart transplant recipients, a noninvasive measure of early allograft rejection has the ability to reduce the number and severity of rejection episodes by reducing the time and cost of monitoring of rejection and shortening the time to identification of rejection. In addition, other ECG parameters important to noninvasive allograft rejection monitoring must be identified to achieve the objectives of the current study and may provide evidence for a randomized controlled trial to assess the feasibility and cost-effectiveness of this form of noninvasive ECG monitoring as compared with normal EMB surveillance.

E 9
A decrease in the summed QRS voltage in the anterior chest leads and a turn to the right in the QRS frontal vector was also seen in humans and nonspecific repolarization shifts were also seen and drops in the evoked T wave amplitude.  We did subgroup analysis based on the duration of the follow-up.
The two subgroups were from 3 to 6 months and from hospital dis- No publication bias was observed among included studies, as shown in Figure S7. F I G U R E 2 Publication bias Table 1 describes the characteristics data for each study individually and their citations. Table 2 shows the data of patients and their characteristics, their ages, the type of study, and the duration of the study (the age and the duration are either mean or median). Table 3 shows the characteristics of the ECG recording and the outcomes of the studies (No. of rejections is the number of patients recognized with ECG).
The rejection was diagnosed with histology findings and biopsies and then compared with the findings of the ECG to give the definitive diagnosis ( Figure 2). Figure S7 shows the risk of biases and applicability concerns among the studies distributed as high risk, low risk, and unclear risk.

| DISCUSSION
We found no significant association between heart transplant rejection and QT changes of ECG. The studies included in this review report the rejection of the heart transplant after the surgery with either moderate or severe rejection. The results were assured by the biopsy to compare between the results of the ECG and the histology. A total of 957 patients were identified for heart transplant rejection, with 304 diagnosed by ECG (31.7%). The primary method used for diagnosis was the QRS interval and amplitude (see Table 3). Sensitivity and specificity varied widely between our studies (see Figure S3) We found no significant association between heart transplant rejection and QT changes of ECG. Although some studies reported significant association, other studies did not. There is heterogeneity among studies included in the meta-analysis, that does not provide conclusive results. More clinical trials are needed to give final conclusion about using ECG as a measure in detecting heart transplant rejections.

SUPPORTING INFORMATION
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