Troponin T Elevation After Percutaneous Left Atrial Appendage Occlusion

Background: Cardiac troponin T (cTNT) has been widely used in detecting cardiac damage. Elevated cTNT level has been reported to be associated with increased mortality in multiple cardiac conditions. It is not uncommon to observe an increased level of cTNT in patients after left atrial appendage occlusion (LAAO). The objective of the study is to study the incidence, significance, and factors associated with cTNT elevation after LAAO. Methods: We prospectively included patients who underwent LAAO from January 2019 to July 2020 in Fudan Zhongshan Hospital. Patients were divided into those with elevated cTNT after procedure and those with normal postprocedure cTNT. All individuals were followed up for 1 year. The primary outcome is major adverse cardiovascular events, which include myocardial infarction, heart failure, cardiac death, and stroke. The second outcome is periprocedure complication, including chest pain, tachycardia, cardiac tamponade, change of electrocardiograph, and atrial thrombus. Results: A total of 190 patients were enrolled. Of the patients, 85.3% had elevated cTNT after LAAO, while 14.7% of them did not. Exposure time, dosage of contrast, types of devices, shapes, and sizes of LAA could contribute to elevated postprocedure cTNT. We found that patients with a Watchman device were more likely to have elevated postprocedure cTNT than those with a Lambre device (89.2 vs. 76.7%, p = 0.029). LAAO shapes were associated with cTNT levels in patients with a Watchman device, while the diameter of the outer disc and LAA depth mattered for the Lambre device. There was no significant difference in the primary and second outcome between the two groups (p-value: 0.619, 0.674). Conclusion: LAAO was found to be commonly accompanied with cTNT elevation, which might not to be related to the complications and adverse cardiac outcomes within 1 year of follow-up. Moreover, eGFR at baseline, exposure time, dosage of contrast, types of LAAO device, and LAA morphology could contribute to cTNT elevation.

However, different procedures affect levels of cTNT differently. For cardiac procedures like PCI and CABG, elevated cTNT levels after procedure is associated with worse clinical outcomes (2)(3)(4)(5); however, for other cardiac procedures, increased postprocedure cTNT levels do not necessarily affect adverse clinical outcomes (8). It remains controversial whether increased cTNT values after cardiac procedure affect long-term adverse events.
Left atrial appendage occlusion (LAAO) has emerged as a new strategy to prevent stroke in patients with atrial fibrillation (AF) (14,15). It is applied in AF patients who have relative contraindication to oral anticoagulants (16). For LAAO, little remains unknown about the changes of cTNT and its effect on clinical outcomes after LAAO procedure.
The objective of the study is to study the incidence, significance, and factors associated with cTNT elevation after LAAO.

METHODS
Our study is a single-center, prospective study. Postoperative cTNT refers to cTNT 12-24 h after LAAO.

Study Population
Patients who underwent LAAO from January 2019 to July 2020 in Fudan Zhongshan Hospital were consecutively selected. Based on the cTNT levels, eligible patients were separated into elevated cTNT group and normal cTNT group. We further divided patients into two groups based on the LAAO devices: Watchman (Boston Scientific, Plymouth, MN, USA) and Lambre [Lifetech Scientific (Shenzhen) Co. Ltd., Shenzhen, China]. Within each group, we compared the LAA sizes and shapes.
Baseline characteristics of the patients included age, male, hypertension, diabetes, hyperlipidemia, history of cerebrovascular disease, coronary heart disease, structural heart disease, heart failure, history of radiofrequency ablation, history of malignant tumor, preprocedure cTNT, hemoglobin (HB), white blood cell (WBC), endogenous glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF). The intraoperative information included types of left atrial appendage, morphological characteristics of the left atrium, and diameter and depth of the left atrial appendage.
The study was approved by the Institutional Review Board of Zhongshan Hospital, Fudan University, Shanghai, China.

Clinical Outcomes and Definitions
The primary endpoint of this study is 1-year major adverse cardiovascular events, including myocardial infarction, heart failure, cardiac death, and stroke. The secondary endpoint is the perioperative adverse events, including chest pain, tachycardia, cardiac tamponade, change in electrocardiograph, and atrial thrombus. According to our hospital lab protocol, elevated cTNT is defined as the level of cTNT ≥0.03 µg/L, and normal cTNT is defined as cTNT <0.03 µg/L. Mild-elevated cTNT is defined as post-cTNT higher than 0.03 but lower than 0.09 µg/L. Severe-elevated post-cTNT is defined as ≥0.09 µ g/L. Myocardial infarction is defined by an elevation of cTn values >5 times of the 99th percentile URL in patients with normal baseline values. Patients with elevated preprocedural cTn values, in whom the preprocedural cTn level is stable (≤20% variation) or falling, must meet the criteria for a >5-or >10-fold increase and manifest a change from the baseline value of >20%. In addition, patients have at least one of the following: (1) new ischemic ECG changes (this criterion is related to type 4a MI only), (2) development of new pathological Q waves, (3) imaging evidence of loss of viable myocardium that is presumed to be new and in a pattern consistent with an ischemic etiology, and (4) angiographic findings consistent with a procedural flowlimiting complication such as coronary dissection, occlusion of a major epicardial artery or graft, side-branch occlusion thrombus, disruption of collateral flow, or distal embolization.

Statistical Analysis
We used t-test and chi-square test to compare variables between the positive cTNT group and the negative cTNT group. ANOVA analysis was used for the pairwise comparison among the three group. A time-to-event model was used to analyze the primary endpoint between the two groups. Log rank test was done to compare the significance of the Kaplan-Meier curve. All statistical analyses were performed using Stata 23.0 (Stata Corp, 2015).

RESULTS
A total of 190 patients were enrolled in the study. About 85.3% of the patients were in the group of elevated cTNT, while 14.7% of them were in the group of normal cTNT, among which 55.8% had a mild increase and 29.5% had a severe increase in cTNT (Figure 1). The median and quartile range of postprocedure cTNT was 0.037 µg/L (0.064-0.108 µg/L).

Baseline Characteristics
The baseline characteristics between the normal cTNT and elevated cTNT groups are presented in Table 1.  Other characteristics like age, sex, history of hyperlipidemia, coronary artery disease, and heart failure are distributed evenly between the two groups.

Intraoperative Information Between the Normal Cardiac Troponin T and the Elevated Cardiac Troponin T Group
We further analyzed the characteristics of the LAAO procedure between the two groups. The procedure length had no significant difference in the different cTNT group Times for changing LAAO devices, morphological characteristics of the left atrium, length and depth of atrial atrium, and heart rate had no statistical difference between the two groups ( Table 2).

Watchman Device and Lambre Device
In the patients receiving the Watchman device, we found that shapes of LAA were associated with elevated cTNT, among which chicken wing type was more likely to have a higher cTNT level (100 vs. 0%). We found no difference in the size of Watchman, compression ratio, size of atrial atrium, and residual regurgitation between the two groups ( Table 3).
For the patients receiving the Lambre device, a larger diameter of the outer disc of the device (35.04 ± 4.04 vs. 36.86 ± 1.88, p = 0.001) and deeper LAAs (31.31 ± 3.88 vs. 31.96 ± 8.01, p = 0.027) were more prevalent in the elevated cTNT group. Different shapes of the left atrium were distributed equally in the different cTNT groups ( Table 4).

Follow-Up Results
Regarding peri-procedural complications, there is no significant difference between the elevated cTNT group and the normal cTNT group, regardless of which device was used ( Table 5). There was also no difference in the incidence of 1-year cardiovascular events between the two groups (p-value: 0.619) (Figure 2).

DISCUSSION
Our study found that 85.3% (162/190) of LAAO patients had elevated cTNT after the procedure. This elevation might not be related to the complications of left atrial appendage occlusion and cardiac outcomes within 1 year of follow-up. Furthermore, eGFR at baseline, exposure time, dosage of contrast, type of LAAO device, and LAA morphology were found to be independently associated with cTNT elevation after the procedure. Our study is the first we know to explore the incidence, significance, and risk factors of elevated cTNT for patients after LAAO.
In our study, longer exposure time and higher dose of contrast were associated with higher levels of cTNT, indicating that the cTNT elevation in LAAO was probably related to the procedure itself, since patients with elevated cTNT had no evidence of chest pain, and hemodynamic or respiratory distress afterward (17). The cause of cTNT elevation in our study was likely by the implantation of a LAAO device, which was supported by the positive association between exposure time and cTNT elevation since longer exposure time often suggests more complexity of the procedure and more times of attempts to place a LAAO device, leading to more myocardial damage. However, the longer procedure time was not associated with higher cTNT levels in our study, and the reasons may be that procedure time have more confounding factors such as the puncture time, the skill of the operator, the team coordination, and so on. What is more, the types of LAAO device affected the level of cTNT. The post-cTNT in the Watchman group was higher than that of the Lambre group. Like other intra-cardiac procedures, LAAO could cause potential cardiac damage by anchoring in the myocardium, decompression of the device, and mechanical compression of the LAA (18). For the Watchman device, certain shapes of LAA correlates with the higher level of cTNT. However, for the Lambre device, the diameter of the outer disc of the device and the length of the left atrial appendage are associated with higher levels of cTNT. The reasons for those results were listed as follows. First, designs of the device could affect postprocedure cTNT levels. For example, the design of the transport system, release mechanism, and the way of the device binding to the left atrial appendage may explain the level of post-cTNT after LAAO. The Watchman has a barb, which is fixed in the left atrial appendage by relying on the barb, which will inevitably cause myocardial injury. In addition, it needs to be pulled before releasing the occlusion, and if the position is not proper, it will need to be adjusted repeatedly, which may increase the injury of the operation; The Lambre occluder is a disc occluder, which will not directly damage the myocardium in most cases, but repeated extrusion or friction may cause damage (18). Second, morphology of LAAs could affect postprocedure cTNT level. The shape of LAA mainly affects postprocedure cTNT in patients receiving the Watchman device. With regard to the Lambre device group, patients who had larger disc diameter and deeper LAA are more likely to have positive postprocedure cTNT. It is likely because the Watchman device requires more for the left atrial morphology, while the Lambre device does not (18)(19)(20)(21). The Watchman device becomes spherical after expansion, and when the atrial shape does not match the shape of the Watchman device, myocardial injury is likely to occur, which has been mentioned before. On the contrary, the Lambre device is highly adaptable to different LAA morphologies because of its disc occluder. It can be quite useful in patients with difficulty anatomies (21). The Lambre device is embedded in the atrial wall by hook and parachute, so the requirement of atrial morphology is not as high as that of the Watchman, but the outer disk size and atrial diameter of the Lambre device are accountable for the degree of myocardial injury. In our study, patients with lower eGFR were also found to be related to higher incidence of cTNT elevation after the procedure. Renal dysfunction is one of the major reasons for cTNT elevation except for acute myocardial infarction (22). cTNT elevation is common among patients with renal failure, indicating that cTNT was cleared by the kidneys (23). In addition, cTNT elevations in these patients could be due to increased cTNT release linked to cardiac stress, called the cardiorenal syndrome (24). Martens et al. found that eGFR was independently associated with cTNT levels, even when eGFR levels do not fulfill the CKD criteria (25). Our results were consistent with a previous study that eGFR was associated with cTNT elevation after LAAO in the condition that the means of eGFR of the two groups do not meet the eGFR criteria.
cTNT elevation has been associated with poor prognosis in many conditions (26,27). However, the mild and transient elevation of cTNT in our study did not contribute to the poor prognosis, indicating that the increase in cTNT is mostly transient myocardial injury caused by occluder implantation, which does not affect cardiac ejection function and ventricular survival area. Our results were consistent with previous studies (28,29). Similarly, all patients in our study were followed up for 1 year, and the cTNT elevation had no relation to the complications of the procedure or cardiac outcomes. Thus, it is demonstrated that cTNT elevation after LAAO was not associated with adverse clinical events and complications within 1 year follow-up in this relatively large cohort.

LIMITATIONS
The limitations of our analyses are listed as follows: First, the sample of this study is a little small, which decreases the reliability level of the conclusion. Second, our study is a single-center study, which may result in selection bias. Third, we were unable to rule out the influence of differing skill levels of different operators involved in the procedure on cTNT elevation.

CONCLUSION
LAAO was found to be commonly accompanied with cTNT elevation, which might not to be related to the complications and adverse cardiac outcomes within 1 year of follow-up. Moreover, eGFR at baseline, exposure time, dosage of contrast, types of LAAO device, and LAA morphology could contribute to cTNT elevation.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Institutional Review Board of Zhongshan Hospital, Fudan University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
XiaW, XC, YY, DZ, and QC conceptualized and designed the study. QC and DZ provided administrative support. XiaW and QC analyzed and interpreted the data. XiaW, YY, and QC wrote the manuscript. All authors gave the final approval of the manuscript and provided the study materials or patients and collected and assembled the data.