Summary
Coronavirus disease (COVID-19) causes myocardial injury by inducing a cytokine storm in severe cases. Studies have reported that myocardial injury persists for a prolonged period during COVID-19 recovery, and cardiac troponin is a useful indicator of myocardial injury. The interleukin-6 (IL-6) level is known to be associated with the morbidity and mortality of COVID-19, but this association has not been studied during recovery. The current study examined the association between IL-6 levels and myocardial damage during COVID-19 recovery. Four of 209 patients (1.9%) who recovered from COVID-19 had elevated IL-6 levels. All 4 patients tested positive for high-sensitivity troponin T, and 3 patients had subclinical left ventricular (LV) dysfunction according to echocardiography. Positivity for IL-6 during COVID-19 recovery suggests ongoing myocardial damage due to inflammation.
Keywords: COVID-19, interleukin-6, cardiac troponin, myocardial damage, echocardiography
Coronavirus disease (COVID-19) continues to be prevalent worldwide, and in severe cases, it induces a cytokine storm that causes myocardial damage. In addition, studies have reported that myocardial damage is prolonged even during the recovery period as a result of elevated troponin levels and abnormalities in cardiac imaging studies (1,2). However, no studies have reported an association between cytokines and myocardial injury in patients who have recovered from COVID-19. The current study examined the relationship between the level of interleukin-6 (IL-6) and myocardial damage during COVID-19 recovery.
Subjects were patients who participated in the COVIPLA study of convalescent plasma therapy in Japan from April to September 2020 (3). Patients who had recovered from COVID-19 underwent blood tests and echocardiography at least 3 weeks after the onset of infection. All data were retrospectively collected at the National Center for Global Health and Medicine. IL-6 and high-sensitivity troponin T (hsTnT) were measured in stored frozen serum. An IL-6 level ≥ 8 pg/mL and a hsTnT level ≥ 0.003 ng/mL were considered to be a positive result (Roche Diagnostics, Tokyo, Japan).
Echocardiography was performed using Canon Artida, and standard guidelines were used as a reference for abnormal values of left and right ventricular function (4). Tricuspid annular plane systolic excursion (TAPSE) of 17 mm or more was regarded as normal. Left ventricular global longitudinal strain (LVGLS) was determined from the average of the 4-chamber, 3-chamber, and 2-chamber views, and LVGLS was analyzed using TOMTEC. A LVGLS value of < -20 was regarded as abnormal (5).
This study complied with the Declaration of Helsinki and was approved by the Hospital Ethics Committee. Informed consent was obtained in an opt-out format.
Subjects were 209 patients from the COVIPLA registry who underwent echocardiography and blood tests between April and September 2020. IL-6 could not be measured in 3 patients due to insufficient sample volume. The mean age (± standard deviation) was 44 ± 12 years (range: 36-55 years), and the proportion of males was 51%. Of 74 patients (35.4%) with hsTnT below the limit of detection, all had an IL-6 level below the limit of detection. hsTnT levels were above the limit of detection (> 0.003 ng/mL) in 135 patients (64.6%), and the IL-6 level exceeded the sensitivity threshold in 4 patients (3.0%). Those 4 patients had high peak CRP levels of 10.03 mg/dL, 18.91 mg/dL, 17.24 mg/dL, and 8.99 mg/dL during their hospitalization for COVID-19 (Table 1).
Table 1. Patient characteristics including myocardial troponin T and echocardiographic data for IL-6-positive patients.
| Patients No. | Age (years) |
Sex | BMI (kg/m2) | Period from onset to testing (days) | COVID-19 severity during hospitalization | Medication for COVID-19 | Peak CRP during infection (mg/dL) | CRP during recovery (mg/dL) | IL-6 (pg/mL) | hsTnT (ng/mL) | Left ventricular function LVGLS | Right ventricular function TAPSE |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 57 | Male | 21.5 | 65 | Oxygen required | Remdesivir, steroid | 10.03 | 0.02 | 14 | 0.004 | -19.3% | 23.1 mm |
| 2 | 42 | Male | 27.2 | 27 | No oxygen therapy | Remdesivir | 18.91 | 0.06 | 14 | 0.004 | -18.9% | 16.7 mm |
| 3 | 53 | Male | 28.9 | 28 | Oxygen required | Remdesivir, steroid, Tocilizumab | 17.24 | 0.04 | 103 | 0.005 | -17.7% | 14.2 mm |
| 4 | 46 | Male | 29 | 24 | Intubation | Remdesivir, steroid | 9.0 | 0.43 | 12 | 0.004 | -20.0% | 18.4 mm |
BMI: body mass index; IL-6: interleukin-6; hsTnT: high-sensitivity troponin T; LVGLS: left ventricular global longitudinal strain; TAPSE: tricuspid annular plane systolic excursion.
Of the IL-6-positive patients, all 4 had no history of hypertension, diabetes, or cardiovascular disease, and their echocardiographic ejection fraction was greater than 50%. Patient 1 received oxygen therapy during hospitalization, with slightly reduced left ventricular function (LVGLS -19.3%) and normal right ventricular function (TAPSE 23.1 mm). Patient 2 did not need oxygen therapy and had slight left ventricular and right ventricular dysfunction (LVGLS -18.9%, TAPSE 16.7 mm). Patient 3 required oxygen and had the highest IL-6 level (103 pg/mL) during recovery. The patient had marked left ventricular and right ventricular dysfunction (LVGLS -17.7%, TAPSE 14.2 mm). Patient 4 had previously been on mechanical ventilation but had no left ventricular or right ventricular hypofunction (LVGLS -20.0%, TAPSE 18.4 mm). All 4 patients with elevated IL-6 during COVID-19 recovery were positive for hsTnT. Of the 4, 3 had impaired left ventricular function, 2 had impaired right ventricular function, and 2 had both impaired left and right ventricular function.
Previous studies have reported the presence of subclinical myocardial damage with positive hsTnT in about 70% of patients recovering from COVID-19 (1). A recent study in Japan reported that 65% of patients who recovered from COVID-19 had a hsTnT level exceeding the limit of detection (6), and another study reported that a hsTnT level is associated with decreased LVGLS (7).
In the current study, all 4 patients who were positive for IL-6 were also positive for hsTnT, and all of the CRP tests performed during recovery were negative, suggesting that myocardial injury due to different inflammatory mechanisms may occur during COVID-19 recovery.
A recent study found that significantly elevated IL-6 levels in patients hospitalized for COVID-19 were associated with worse clinical outcomes such as ICU admission and death (8). In an analysis of risk factors for ARDS and death by Wu et al. (9), IL-6 was significantly elevated in patients with COVID-19 who developed ARDS (median 7.4 pg/mL, IQR 5.6-10.9 vs. median 6.3 pg/mL, IQR 5.4-7.8, p = 0.03). Ruan et al. (10) found that IL-6 levels were significantly higher in patients who died of COVID-19 compared to those who survived (11.4 ± 8.5 pg/mL vs. 6.8 ± 3.6 pg/mL, p < 0.001).
Among the patients with elevated IL-6 who recovered from COVID-19, 3 had impaired left and right ventricular function, suggesting that cytokine-induced inflammatory mechanisms persist and may contribute to impaired cardiac function even during COVID-19 recovery. Patients positive for IL-6 and with impaired cardiac function should be carefully monitored for a further decline in cardiac function. Two limitations of this study were the lack of data on cytokine levels and the lack of echocardiography images during hospitalization.
Funding: This work was supported by a donation from the National Center for Global Health and Medicine and supported by the Health, Labour, and Welfare Policy Research Grants, Research on Emerging and Re-emerging Infectious Diseases and Immunization (grant number 20HA1006). The funders/sponsors have had no role in the design and/or implementation of the study.
Conflict of Interest
The authors have no conflicts of interest to disclose.
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