Clinical Significance of Cardiac Troponin I Elevation in Detecting Immune Checkpoint Inhibitor-Induced Myocarditis

Abstract

Background: Immune checkpoint inhibitors (ICIs) enhance T-cell activity against cancer, but can cause immune-related adverse events, including myocarditis, a rare yet potentially fatal complication. Cardiac troponin I (cTnI) is widely used for screening the development of myocarditis, but its efficacy remains uncertain.

Methods and Results: From January 2016 to June 2024, we conducted a single-center retrospective study of 468 cancer patients receiving ICI therapy. Serum cTnI levels were assessed at baseline, at 1, 3, 6, 9, 12 months, and every 4 months. During the follow-up period, 26 patients (5.6%) exhibited cTnI elevation. This group had a higher prevalence of breast cancer, higher baseline cTnI levels, lower estimated glomerular filtration rates, and a greater proportion of concomitant ipilimumab and nivolumab use. Multivariate analysis revealed that high baseline cTnI levels and concomitant ipilimumab and nivolumab use were independent predictors of cTnI elevation. Of the 26 patients with elevated cTnI, 4 developed myocarditis, requiring steroid therapy, and exhibited a progressive increase in cTnI levels, whereas the remaining 22 patients without myocarditis did not show such an increase.

Conclusions: Occasional cTnI elevation occurs during ICI therapy. However, a marked and sustained increase in cTnI levels may be a sign of the development of myocarditis.

Central Figure

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that inhibit the immunosuppressive mechanisms of T cells, enabling the agents to target and attack cancer cells. With the expansion of the approval of ICIs, many cancer types are now indicated for ICI therapy, and they have become an indispensable option in cancer treatment. However, immune-related adverse events (irAEs) are notable complications that can occasionally lead to life-threatening conditions. Among these, acute myocarditis is a particularly lethal complication associated with ICI therapy. The prevalence of ICI-induced myocarditis has been reported to be approximately 1%.^1,2 Mahmood et al. reported that ICI-induced myocarditis had a median onset of 34 days after initiating ICI, with cardiac troponin I (cTnI) elevation observed in 94% of cases.¹ The European Society of Cardiology Guidelines on cardio-oncology recommend that all patients undergoing ICI treatment should have an ECGm and cardiac troponin assay at baseline.³ Although the elevation of cTnI is a characteristic of myocarditis, non-significant cTnI elevations have been reported and low diagnostic accuracy is problematic for screening during ICI treatment.^4,5 In this study, we evaluated the utility and temporal characteristics of cTnI elevation for the detection of ICI-induced myocarditis.

Methods

Study Subjects and Protocol

This study was a single-center, retrospective study of patients receiving ICI treatment. From January 2016 to June 2024, we enrolled 686 consecutive cancer patients planned for ICI treatment in Fukushima Medical University Hospital. Patients were excluded if they were transferred to other hospitals within the 6-month follow-up period (n=150), no use of ICI due to protocol change (n=42), prior history of ICI use (n=14), and showing elevated cTnI levels ≥50 pg/mL prior to ICI therapy (n=12). These patients did not exhibit any cardiac symptoms or obvious findings of cardiovascular diseases. We excluded cases of unexplained cTnI elevation because such findings could complicate the interpretation of cTnI elevation potentially induced by ICI therapy. For the remaining 468 patients, we investigated ECG and serum cardiac troponin I levels for screening of ICI-induced myocarditis at baseline, at 1, 3, 6, 9, and 12 months, and every 4 months until the completion of ICI therapy. Patients who discontinued ICI treatment due to progressive disease and/or deteriorating condition were included, but cTnI assessments ceased after ICI discontinuation. The use of antidiabetic medications, statins, antiplatelets, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium-channel blockers was reviewed by medical chart. Radiation therapy was defined as irradiation of any site of the body for the treatment of cancer prior to ICI treatment. We investigated comorbid cardiovascular diseases, such as previous myocardial infarction, moderate or greater valvular disease, and cardiomyopathy, based on echocardiographic data and medical history. We defined ICI-induced myocarditis according to the JCS 2023 Japanese Guidelines on diagnosis and treatment of myocarditis.⁶

Ethics

We obtained approval from the Ethics Committee of Fukushima Medical University (approval number REC2023-098) that the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Because of the anonymous nature of the database, the requirement for informed consent was waived. An opt-out procedure was conducted.

Echocardiography

Transthoracic echocardiography was performed by a trained sonographer, and images were checked by another trained sonographer and an echocardiologist. We measured cardiac function using EPIQ 7G (Philips Healthtech, Best, The Netherlands). Left ventricular ejection fraction (LVEF) was calculated using the modified Simpson’s method according to the guideline from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.⁷ LV mass was calculated as:⁷ LVM = 0.8 [1.04 {(LV diastolic diameter + interventricular septum wall thickness + LV posterior wall thickness)³ − LV diastolic diameter³ }] + 0.6 g.

Blood Sampling

High-sensitivity cTnI was measured using an assay based on Luminescent Oxygen Channeling Immunoassay technology, and run on a Dimension EXL integrated chemistry system (Siemens Healthcare Diagnostics, Deerfield, IL, USA). We defined ≥cTnI 50 pg/mL as cTnI elevation based on the 99th percentile of cTnI levels. When TnI levels were elevated, a cardiologist assessed accompanying symptoms and ECG changes. The decision to either perform follow-up testing at the next outpatient visit or to withhold ICI treatment was made through discussion between the cardiologist and the oncologist. In all patients with elevated cTnI, repeat measurement of cTnI was performed within 1 month. If patients exhibited any cardiac symptoms, further evaluation was performed promptly.

Statistical Analysis

All statistical analyses were performed using Prism 10.4.1 (GraphPad Software, San Diego, LA, USA). We used the Shapiro-Wilk test to discriminate which variables were or were not normally distributed. Non-normally distributed variables were indicated by median with interquartile range. Categorical variables are shown as numbers and percentages. The Mann-Whitney U test was used for variables with non-normal distribution, and the χ-square test was used for categorical variables.

Logistic regression analysis was used to identify the variables that predict the occurrence of cTnI elevation. We selected variables related to the patients’ general condition and cardiac function, including age, sex, cancer therapy, daily medications, laboratory data, and echocardiographic and electrocardiographic parameters. The variables presenting P<0.1 in the univariable analysis were entered into the multivariable analysis. P≤0.05 was defined as significant.

Results

Our cohort included 468 consecutive patients, of whom 26 (5.6%) showed cTnI elevation during the follow-up period (Figure 1). Of them, the number of patients with elevated cTnI was 14 at 1 month, 6 at 2–3 months, 5 at 4–6 months, and 1 at 7–9 months (Figure 2). Figure 3 illustrates the rate of continuing ICI treatment. The median duration of ICI treatment continuation was 163 days. A considerable number of patients discontinued ICI treatment due to decrease in performance status, progressive disease status, change of chemotherapy, and irAEs.

Figure 1.

Flowchart of the incidence of cardiac troponin I elevation and myocarditis in patients receiving immune checkpoint inhibitor (ICI) treatment.

Figure 2.

Timing of cardiac troponin I elevation after starting immune checkpoint inhibitor (ICI) treatment.

Figure 3.

Continuation rate of immune checkpoint inhibitor (ICI) treatment.

Patient characteristics at baseline are presented in Table 1. The median age, sex distribution, and body mass index were similar between the normal cTnI group and the elevated cTnI group. However, the prevalence of breast cancer and the use of antidiabetes mellitus medication were higher in the elevated cTnI group. Laboratory data revealed lower estimated glomerular filtration rates (eGFR) and higher baseline cTnI levels in the elevated cTnI group. The proportion of patients receiving concomitant ipilimumab and nivolumab was higher in the elevated cTnI group. Echocardiographic and electrocardiographic findings were similar between groups.

Table 1.

Baseline Clinical Characteristics of Patients With and Without Elevated Cardiac Troponin I

Variable	Normal cTnI (n=442)	Elevated cTnI (n=26)	P value
Age, years	69 [61–74]	73 [66–77]	0.1246
Male, n (%)	293 (66)	19 (73)	0.4756
Body mass index, kg/m2	22.0 [19.4–24.6]	22.3 [20.7–23.9]	0.5908
Medical history
Old myocardial infarction, n (%)	6 (1)	0 (0)	0.5499
Valvular heart disease, n (%)	4 (1)	0 (0)	0.6261
Cardiac sarcoidosis, n (%)	1 (0)	0 (0)	0.8082
CTRCD, n (%)	1 (0)	0 (0)	0.8082
Post CABG, n (%)	1 (0)	0 (0)	0.8082
Cancer diagnosis
Head and neck, n (%)	27 (6)	0 (0)	0.1942
Breast, n (%)	18 (4)	4 (15)	0.0081
Gastrointestinal, n (%)	145 (33)	6 (23)	0.3024
Melanoma, n (%)	19 (4)	1 (4)	0.9117
Lung, n (%)	76 (17)	2 (8)	0.2064
Renal, n (%)	40 (9)	3 (12)	0.6694
Urinary tract and bladder, n (%)	41 (9)	5 (19)	0.0975
Hepatocellular carcinoma, n (%)	17 (4)	2 (8)	0.3342
Cholangiocarcinoma, n (%)	16 (4)	0 (0)	0.3236
Gynecologic, n (%)	36 (8)	2 (8)	0.9346
Other, n (%)	7 (2)	1 (4)	0.3871
Prior radiation or chemotherapy
Prior radiation, n (%)	101 (23)	5 (19)	0.6682
Prior anthracyclines, n (%)	17 (4)	3 (12)	0.0595
Pre-ICI medication
Diabetic medications, n (%)	66 (15)	9 (35)	0.0078
Statins, n (%)	88 (20)	4 (15)	0.5726
Antiplatelet medications, n (%)	34 (8)	0 (0)	0.1420
β-blockers, n (%)	38 (9)	2 (8)	0.8726
Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, n (%)	120 (27)	11 (42)	0.0943
Sodium-glucose cotransporter 2 inhibitors	14 (3)	2 (8)	0.2172
Mineralocorticoid receptor antagonists	10 (2)	1 (4)	0.6044
Calcium-channel blockers, n (%)	148 (34)	10 (39)	0.6020
Laboratory data
White blood cells	5,800 [4,500–7,400]	5,600 [4,050–6,975]	0.6737
Lymphocytes, %	22 [13–27]	22 [13–27]	0.8241
Aspartate aminotransferase, IU/L	20 [15–26]	17 [15–28]	0.6122
Alanine aminotransferase, IU/L	16 [10–26]	13 [9–20]	0.1824
eGFR, mL/min/1.73 m2	69 [57–83]	54 [40–78]	0.0141
Albumin, g/dL	3.7 [3.3–4.0]	3.8 [3.4–4.0]	0.5702
C-reactive protein, mg/dL	0.28 [0.05–1.33]	0.58 [0.11–2.64]	0.1369
Troponin I, pg/mL	5 [3–9]	8 [4–26]	0.0039
Echocardiography and electrocardiography
LVEF, %	64 [61–67]	63 [61–66]	0.4811
Interventricular septal thickness, mm	9.0 [8.0–10.0]	10.0 [8.8–11.3]	0.1243
Posterior wall thickness, mm	9.0 [8.0–10.0]	9.5 [8.0–10.0]	0.3759
Left ventricular diastolic diameter, mm	43 [40–46]	43 [39–46]	0.5956
Left ventricular mass index, g/m2	77 [64–92]	79 [69–99]	0.4023
Left ventricular hypertrophy, n (%)	35 (8)	1 (4)	0.4489
Sinus rhythm, n (%)	424 (96)	25 (96)	0.9547
Chronic atrial fibrillation, n (%)	16 (4)	1 (4)	0.9522
Heart rate, bpm	73 [65–85]	75 [63–84]	0.8040
Complete right bundle branch block, n (%)	35 (8)	1 (4)	0.4489
Complete left bundle branch block, n (%)	2 (1)	0 (0)	0.7310
QRS interval, ms	95 [89–103]	95 [89–100]	0.5622
QTc interval, ms	429 [415–446]	425 [419–446]	0.9432
T-wave changes, n (%)	18 (4)	0 (0)	0.2940
Type of ICI
Pembrolizumab, n (%)	154 (35)	10 (39)	0.7069
Nivolumab, n (%)	176 (40)	8 (31)	0.3586
Ipilimumab+nivolumab, n (%)	33 (8)	5 (19)	0.0328
Atezolizumab, n (%)	37 (8)	1 (4)	0.4117
Durvalumab, n (%)	35 (8)	2 (8)	0.9669
Durvalumab+tremelimumab	1 (0)	0 (0)	0.8082
Avelumab, n (%)	6 (1)	0 (0)	0.5499

CTRCD, cancer therapy-related cardiac dysfunction; CABG, coronary artery bypass graft; eGFR, estimated glomerular filtration ratio; ICI, immune checkpoint inhibitor; LVEF, left ventricular ejection fraction.

Table 2 shows the results of logistic regression analysis using potential parameters associated with cTnI elevation. Using parameters with a P value <0.1 as determined by univariate logistic analysis, multivariate analysis revealed that a diagnosis of breast cancer, the concomitant use of ipilimumab and nivolumab, low eGFR rate, and high baseline cTnI levels were independent predictive factors for cTnI elevation during ICI treatment.

Table 2.

Parameters Associated With the Elevation of Cardiac Troponin I

	Univariate		Multivariate
	OR (95% CI)	P value	OR (95% CI)	P value
Age, per 1 year	1.021 (0.984–1.063)	0.3006
Male	1.380 (0.592–3.600)	0.4772
Body mass index, per 1 kg/m2	0.997 (0.907–1.073)	0.9362
Prior radiation	0.804 (0.263–2.031)	0.6688
Prior anthracycline	3.261 (0.7252–10.610)	0.0741	1.504 (0.264–6.842)	0.6156
Breast cancer	4.622 (1.250–13.830)	0.011	12.390 (1.935–69.450)	0.0048
Combination of ICI and chemotherapy	0.502 (0.193–1.169)	0.1282
Dosing interval, per 1 week	1.161 (0.842–1.534)	0.3214
Nivolumab	0.672 (0.271–1.530)	0.3613
Atezolizumab	0.438 (0.024–2.161)	0.4245
Durvalumab	0.940 (0.147–3.346)	0.9346
Pembrolizumab	1.169 (0.501–2.603)	0.7072
Nivolumab+ipilimumab	2.951 (0.939–7.800)	0.0410	4.478 (1.292–13.830)	0.0115
Diabetic medication	3.016 (1.239–6.911)	0.0108	1.584 (0.484–4.574)	0.4152
Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker	1.968 (0.859–4.381)	0.0997	1.635 (0.601–4.278)	0.3200
Calcium-channel blocker	1.242 (0.532–2.767)	0.6026
Statin	0.731 (0.210–1.971)	0.5740
β-blocker	0.886 (0.139–3.145)	0.8726
Albumin, per 1 g/dL	1.265 (0.641–2.689)	0.5189
Aspartate aminotransferase, per 1 U/L	1.011 (0.992–1.025)	0.1822
Alanine aminotransferase, per 1 U/L	0.992 (0.963–1.011)	0.4895
eGFR, per 1 mL/min/1.73 m2	0.978 (0.961–0.995)	0.0106	0.971 (0.946–0.995)	0.0232
Cardiac troponin I at baseline, per 1 pg/mL	1.093 (1.054–1.135)	<0.0001	1.095 (1.047–1.146)	<0.0001
LVEF, per 1%	0.993 (0.932–1.069)	0.8405
Left ventricular diastolic diameter, per 1 mm	0.968 (0.898–1.039)	0.3807
Left ventricular mass index, per 1 g/m2	1.003 (0.985–1.020)	0.6971
Heart rate, per 1 beat/min	1.005 (0.975–1.034)	0.7349
QRS duration, per 1 ms	0.987 (0.954–1.014)	0.4020
QTc, ms	1.002 (0.984–1.019)	0.8543

eGFR, estimated glomerular filtration rate; ICI, immune checkpoint inhibitor (avelumab and tremelimumab were not included from the analysis due to small sample sizes).

Of the 26 patients with cTnI elevation, 4 received steroid therapy for ICI-induced myocarditis, and the remaining 22 showed no symptoms of myocarditis (Figure 1). The diagnostic process for the 4 patients who were diagnosed with myocarditis was as follows. Patients 1 and 2 were diagnosed by pathohistological analysis of endomyocardial biopsy. Patient 3 was diagnosed by cTnI elevation with MRI findings. Patient 4 was diagnosed by cTnI elevation with decline of LVEF with myositis. Patients 1–3 were ruled out for ischemic heart disease based on coronary angiography. Although patient 4 did not undergo coronary angiography, echocardiography demonstrated diffuse hypokinesis with findings of edematous LV, suggesting that ischemic heart disease was unlikely. All 4 patients underwent steroid pulse therapy after first detection of cTnI elevation at 3, 28, 28, and 43 days, respectively. Figure 4 illustrates temporal changes in cTnI levels among patients with elevated cTnI. Patients with myocarditis exhibited higher and more sustained cTnI levels than those without myocarditis, suggesting that persistent elevation of cTnI following the initial rise is a noteworthy finding in patients with cTnI elevation. Steroid therapy was effective for all 4 patients diagnosed as myocarditis because their cTnI levels normalized after the treatment.

Figure 4.

Temporal changes in cardiac troponin I (cTnI) levels in patients with elevated cTnI, with or without myocarditis. The Mann-Whitney U test was performed to compare cTnI levels at each time point. **P<0.001.

Discussion

In the present study, we investigated the clinical significance and predictive factors of cTnI elevation in patients treated with ICIs. First, of 468 consecutive patients, 26 (5.6%) exhibited cTnI elevation during ICI treatment; however, only 4/26 patients developed symptomatic myocarditis. Second, a high baseline cTnI level and the concomitant use of ipilimumab and nivolumab were identified as independent predictive factors for cTnI elevation during ICI treatment. Third, among patients with cTnI elevation, persistent elevation of cTnI may be associated with ICI-induced myocarditis requiring steroid treatment, highlighting its potential as an early marker for clinical monitoring (Central Figure).

The elevation of cardiac troponins is an essential diagnostic criterion for ICI-associated myocarditis. The ESC cardio-oncology guidelines recommend periodic screening of cardiac troponins for the early detection and treatment of myocarditis.³ Because cTnI is highly specific for myocardial injury, it is preferred for screening when myocarditis is suspected.⁸ Although cTnI is consistently elevated when myocarditis develops, the diagnostic accuracy of screening for myocarditis using cTnI elevation alone remains unclear. Waliany et al. reported that the positive predictive value of cTnI for diagnosing myocarditis was 12.5%.⁴ Tamura et al. showed that among 18 patients with cTnI elevation during ICI therapy, 6 developed myocarditis, with the remaining patients showing no evidence of myocarditis.⁵ Consistent with previous reports, in our cohort of 26 patients who exhibited cTnI elevation, only 4 developed myocarditis requiring steroid treatment. The reason for troponin elevation that does not reflect progression to clinically apparent myocarditis remains unclear. A clinical spectrum of myocarditis ranging from smoldering to fulminant has been reported.^9,10 In 28 cases of endomyocardial biopsy performed for suspected ICI myocarditis, the inflammatory state of the myocardium varied from no inflammatory cell infiltrate to a fulminant state, and in 4 cases of mild inflammation the patients were able to continue ICI therapy without immunosuppressive treatment.¹¹ Observational studies suggest that combination immunotherapy increases the incidence of all-grade myocarditis compared with monotherapy.¹² Our study also demonstrated that dual therapy with ipilimumab and nivolumab was a predictive factor for cTnI elevation, suggesting that a slight elevation of cTnI may indicate early-stage myocarditis. In addition, breast cancer and reduced eGFR also emerged as independent predictive factors. Although the exact mechanisms are unclear, some breast cancer patients had previous exposure to anthracyclines and/or anti-HER2 agents. Reduced eGFR may reflect underlying subclinical cardiovascular vulnerability, rendering the myocardium more susceptible to immune-mediated injury during ICI treatment. Furthermore, the prevalence of antidiabetic medication use was higher in patients with cTnI elevation, and we speculate that patients with diabetes may have had an increased risk of underlying ischemic heart disease. Theoretically, ICI therapy can induce coronary plaque inflammation through enhanced T-cell activation, as previously reported.^13,14 It is therefore possible that, in diabetic patients, activated T cells may have contributed to coronary plaque destabilization, resulting in troponin elevation. However, this remains speculative, as ECGs obtained on the first day of troponin I elevation showed no ischemic changes in those cases.

Several hypotheses of the mechanisms underlying ICI-induced myocarditis have been proposed. In 2 patients who developed fulminant ICI-induced myocarditis, common high-frequency T-cell receptor (TCR) sequences were identified in infiltrates from cardiac muscle, skeletal muscle, and tumors, suggesting that the same T-cell clones recognized shared antigens.⁹ Axelrod et al.¹⁵ reported that peripheral blood T cells from 3 patients with ICI-induced myocarditis expanded in response to α-myosin peptides. Moreover, those α-myosin-expanded T cells shared TCR clonotypes with those found in the heart and skeletal muscle, indicating that α-myosin may be a clinically important autoantigen in ICI-induced myocarditis. In contrast, a single-cell RNA sequencing analysis of cardiac cells from ICI-induced myocarditis showed that heart-expanded TCR clones did not recognize the cardiac autoantigens α-myosin, troponin I, or troponin T. Additionally, TCRs enriched in heart tissue largely did not overlap with those enriched in paired tumor tissue.¹⁶ Thus, the precise mechanisms underlying the development of myocarditis remain unclear.

The currently available guidelines for ICI-induced myocarditis do not clearly specify the management of cases, especially those in which only cardiac troponins are elevated. The ASCO guidelines recommend holding ICI treatment and rechecking troponin levels when G1 elevated troponin (G1: abnormal cardiac biomarker testing without symptoms and no ECG changes) is detected.¹⁷ The ESC cardio-oncology guidelines also recommend temporarily withholding ICI treatment.³ However, clear evidence is lacking on whether to discontinue ICI treatment, initiate steroid therapy, or resume ICI treatment. Further accumulation of evidence is needed to establish the appropriate approach. Prior literature reports that troponin elevation can be detected without clinically relevant myocarditis,^4,5 but few mention the importance of persistent troponin I elevation. In the present study, >5% of patients demonstrated troponin I elevation. However, because only a subset of them progressed to myocarditis, withholding ICI treatment in all cases with cTnI elevation could lead to unnecessary treatment interruptions in many patients. If patients exhibit troponin I elevation without other findings suggestive of myocarditis (i.e., cardiac symptoms, ECG changes, or echocardiographic abnormality), a watchful waiting approach might be a practical option. We found that sustained cTnI elevation was a notable finding associated with the development of clinically relevant myocarditis. When cTnI elevation occurs during ICI therapy, careful monitoring will be necessary to determine whether there is progression to clinically relevant myocarditis. Because treatment delay is a determinant of poor prognosis,¹⁸ the additional examinations recommended in the JCS 2023 guidelines for the diagnosis of myocarditis should be performed once myocarditis is suspected.⁶

Recent epidemiological and basic research has revealed that cancer and cardiovascular disease are interrelated, known as the “heart-cancer axis”.¹⁹ ICI-induced myocarditis suggests a mechanistic link between these disease groups via immune pathways, highlighting the need for further research in this field.

Study Limitations

First, this was a single-center retrospective study, and a multicenter prospective study is warranted. Second, the cTnI measurement interval was >1 month apart, the positivity rate may vary if the testing interval is shorter. Third, because this was a retrospective observational analysis, the intervals for re-evaluating cTnI were not consistent. Fourth, although all patients with isolated troponin I elevation exhibited no ECG abnormalities or clinical symptoms, the possibility of subclinical myocarditis cannot be entirely ruled out. To precisely assess the time-course changes in cTnI, a prospective observational study should be performed.

Conclusions

Occasional cTnI elevation occurs during ICI therapy. However, a marked and sustained increase in cTnI may be a sign of the development of myocarditis.

Acknowledgment

We thank members of ACiST (Active Care of irAE, Supportive Team) at Fukushima Medical University.

Sources of Funding

This work was supported by JSPS KAKENHI (Grant Number JP 23K07537).

Disclosures

None.

IRB Information

Ethics Committee of Fukushima Medical University (approval number REC2023-098)

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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