key: cord-0926539-44114vqr
authors: Huang, Lu; Zhao, Peijun; Tang, Dazhong; Zhu, Tong; Han, Rui; Zhan, Chenao; Liu, Weiyong; Zeng, Hesong; Tao, Qian; Xia, Liming
title: Cardiac involvement in recovered COVID-19 patients identified by magnetic resonance imaging
date: 2020-05-12
journal: JACC Cardiovasc Imaging
DOI: 10.1016/j.jcmg.2020.05.004
sha: 7d273b6786ff09629d5aaf2f3f165d3a074f98c3
doc_id: 926539
cord_uid: 44114vqr

Abstract Objective To evaluate cardiac involvement in recovered COVID-19 patients using cardiac MRI. Background Myocardial injury caused by COVID-19 was previously reported in hospitalized patients. It is unknown if there is sustained cardiac involvement after patients’ recovery from COVID-19. Methods Twenty-six recovered COVID-19 patients that reported cardiac symptoms and underwent MRI exams were retrospectively included. MRI protocols consisted of conventional sequences (cine, T2WI, LGE), and quantitative mapping sequences (T1, T2, and ECV mapping). Edema ratio and LGE were assessed in post-COVID-19 patients. Cardiac function, native T1/T2, and ECV were quantitatively evaluated and compared with controls. Results Fifteen patients (58%) had abnormal MRI findings on conventional MRI sequences: myocardial edema was found in 14 (54%) patients and LGE was found in 8 (31%) patients. Decreased RV functional parameters including EF, CI, and SV/ BSA were found in patients with positive conventional MRI findings. Using quantitative mapping, global native T1, T2, and ECV were all found to be significantly elevated in patients with positive conventional MRI findings, compared to patients without positive findings and controls (median [IQR], native T1 1271ms [1243-1298] vs 1237ms [1216-1262] vs 1224ms [1217-1245]; mean [SD], T2 42.7ms [3.1] vs 38.1ms [2.4] vs 39.1ms [3.1]; median [IQR], 28.2% [24.8-36.2] vs 24.8% [23.1-25.4] vs 23.7% [22.2-25.2]; p=0.002, p <0.001, and p =0.002, respectively). Conclusions Cardiac involvement was found in a proportion of the recovered COVID-19 patients. MRI manifestation included myocardial edema, fibrosis, and impaired RV function. Attention should be paid to the possible myocardial involvement in recovered COVID-19 patients with cardiac symptoms.

Coronavirus disease 2019 (COVID -19) has been a global outbreak since March 2020.(1) To date, more than 2,725,000 patients have been confirmed with SARS-CoV-2 infection in over 200 countries. Lung is the major organ involved in COVID-19, and angiotensin-converting enzyme 2 (ACE2) is the path for SARS-CoV-2 to attack pulmonary tissue.(2) ACE2 is located not only in lungs, but also in other organs, including the cardiovascular system. (3) Previous studies (4, 5) found that 12%-15% of COVID-19 patients had elevated high-sensitive cardiac troponin I (hs-cTnI) during hospitalization, which indicated myocardial injury, and that cardiac involvement in severe type patients was up to 31%. However, it is unknown if there is sustained cardiac involvement in patients after their recovery from COVID-19, especially those with moderate type.

Cardiac involvement in myocarditis, including myocardial fibrosis, edema, and pericarditis, (6) is associated with adverse events and poor prognosis; it is important to identify such involvement at an early stage for appropriate treatment. Magnetic resonance imaging (MRI) is the current gold standard to evaluate cardiac morphology and function, (7) and the recent MRI mapping techniques, including T1, T2, and extracellular volume (ECV), are unique tools to quantitatively assess myocardial diffuse fibrosis and edema. (8, 9) While hs-cTnI is highly specific for myocardial injury, MRI has reported higher sensitivity for detecting occult cardiac involvement. (10, 11) The purpose of our study is to evaluate cardiac involvement in recovered COVID-19 patients who reported cardiac symptoms, by cardiac MRI as a sensitive imaging tool.

This single-center, retrospective, observational study was performed at Tongji Hospital, Tongji Medical College, Wuhan, China. Consecutive patients since Mar 2020 who were initially referred to cardiac MRI examination due to cardiac complaints and met the following inclusion criteria were retrospectively included: (1) Patients were previously confirmed of SARS-CoV-2 infection by reverse transcription and polymerase chain reaction (RT-PCR) swab test(12); (2) patients were considered recovered by the discharging criteria (a. normal temperature lasting longer than 3 days; b. resolved respiratory symptoms; c. substantially improved acute exudative lesions on chest CT images; d. two consecutive negative RT-PCR test results separated by at least 24 hours) and was isolated for 14 days(13); (3) patients reported cardiac symptoms after being discharged, including chest pain, palpitation and chest distress. Exclusion criteria were: (1) a history of coronary artery disease or myocarditis; (2) contradictions to gadolinium contrast; (3) MRI image quality was not sufficient for analysis.

Healthy controls of similar age and sex distributions who previously underwent the same MRI exams in our hospital were also included. The controls were selected from a database of healthy subjects without cardiovascular disease or systemic inflammation. This study was approved by the institutional review board of Tongji Hospital, Tongji Medical College (TJ-IRB20200417). The requirement for informed patient consent was waived by the ethics committee for this retrospective study.

All patients underwent MRI examination on a 3T MR scanner (Skyra, Siemens, Healthineers, Germany). MRI scanning protocol included (1) conventional sequences:

short-axis and long-axis cine, T2-weighted imaging (T2WI), and late gadolinium enhancement (LGE), and (2) quantitative mapping sequences: native T1/T2 mapping, and post-contrast T1 mapping. The stack of short-axis slices covered the left ventricle (LV) from apex to mitral annulus. Steady state free precession (SSFP) was used for cardiac cine imaging with the following parameters: echo time (TE) = 1.4ms, repetition time (TR) = 37.7ms, field of view (FOV) = 360×360mm, matrix = 192×146, flip angle (FA) = 55°, slice thickness = 8mm, slice gap = 2mm. T2WI, native T1/T2 mapping, LGE and post-contrast T1 mapping had the same imaging plane as the short-axis cine.

T2WI, black blood T2-weight short tau inversion recovery (STIR) sequence was performed using TR = 2RR intervals, TE = 41ms, slice thickness = 8mm, FOV = 360mm×360mm.

Native and post-contrast T1 mapping was acquired using an ECG-gated single-shot modified 

Two radiologists (LH with 10 years' MRI diagnosis experience and PZ with 4 years' MRI diagnosis experience) evaluated all MRI images using a commercial software (cvi 42, v.5.3, Circle Cardiovascular Imaging, Calgary, Canada). Myocardial edema was evaluated on T2WI images (14) and divided into 16 AHA segments. Myocardial edema ratio (ER) was defined as the ratio between myocardial signal intensity (SI) to skeletal muscle SI.(7) An ER greater than 2.0 was considered as abnormal. 16 The location (16 segments of AHA), and pattern (epicardial, mid-wall, or transmural) of LGE lesions on the LGE images were assessed by two observers who reviewed all PSIR images independently. A senior observer (LX, with 20 years' experience in MRI) adjudicated any discrepancies between two observers. For each patient, the endo-and epicardial contours of LGE images were manually delineated, and LGE lesion was defined as SI >5SD above the mean SI of the remote reference myocardium. (15) Ratios between the LGE volume and the total LV myocardium volume (LGE/Myocardium) in the LGE-positive patients were calculated. Patients were further divided into two subgroups based on the presence or absence of positive conventional cardiac MRI findings, which were defined as increased myocardial edema ratio (>2.0) and/ or LGE presence.

Global T1/T2 values were computed by manually delineating the whole LV myocardium region (including regions of LGE lesion) on the T1/T2 map. To assess the remote myocardium, T1/T2 values were also measured in the AHA myocardium segments free of apparent LGE lesion. Native T1 and post-contrast T1 of myocardium and blood pool were used to derive ECV as described equation in previous study (16) .

LV and right ventricle (RV) function parameters were automatically calculated from endocardial and epicardial contours. Functional parameters included LV/RV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), cardiac output (CO), LV mass, and ejection fraction (EF). All volumes and mass were normalized by body surface area (BSA).

All statistical analysis was performed using SPSS (version 23.0, IBM statistics, Armonk, NY, USA) and GraphPad Prism (Version 8.1, GraphPad Software Inc). Categorical variables were expressed as counts (percentage), and continuous variable as mean ± SD or median (interquartile range). Normality of distribution was tested using Shapiro-Wilk test.

Comparison between two groups were performed by unpaired Student's t-test (for normal distribution) or Mann-Whitney U test (for non-normal distribution) with continuous variables, or χ 2 test with categorical variable. Comparison among three groups were performed by ordinary one-way Analyses of Variance (ANOVA) with Bonferroni corrected post-hoc comparisons (for normal distribution) or Kruskal-Wallis tests with post-hoc pairwise comparisons (for non-normal distribution), as appropriate. P < 0.05 was considered statistically significant.

Clinical characteristics and laboratory results of COVID-19 patients are reported in Table 1 

LV and RV morphological and functional parameters are summarized in Table 2 

In this study, we present an MRI study of 26 patients who had recovered from COVID-19 but reported cardiac symptoms. None of 26 patients selected for this retrospective analysis had known previous myocarditis or other heart diseases before COVID-19. However, fifteen The results therefore suggest existence of diffuse myocardial edema and fibrosis in patients with positive conventional MRI findings. We note that the range of ECV value in the healthy controls is lower than previously reported by Gottbrecht et al, (20) but close to that by Xu et al. (21) in a Chinese cohort.

Eleven of 26 recovered COVID-19 patients reported cardiac symptoms, but had no positive CMR findings either on conventional cardiac MRI sequences (cine, T2WI, and LGE) or quantitative mapping sequences (T1/T2/ECV mapping). There may be two reasons accounting for this phenomenon. First, it is possible that the chest symptoms were caused by the residual pulmonary disease, but further study is needed to confirm this. Second, as the median duration between clinical symptoms onset and MRI scan was as long as 50 days, the patients may have had acute myocarditis but were imaged at the sub-acute stage when edema already resolved. In either case, there is no sustained cardiac involvement in this patient subgroup.

It was previously reported that myocarditis and cardiac arrhythmias may be induced by COVID-19 associated with a high inflammatory burden. Previous studies have reported RV failure in acute lung injury and acute respiratory distress syndrome. (26, 27) As lung is the main target organ of SARS-CoV-2, RV may be more susceptible to impairment compared to LV.

In our cohort, LVEF was in the normal range for all patients except one. Previous studies suggested that myocardial tissue remodeling may precede functional remodeling in LV, (28, 29) and our results concord to the finding as abnormalities were identified mostly in myocardial tissue instead of LV function. This also indicates that the patients were in a relatively early stage of cardiac involvement, and need to be followed up in a longer run. Quantitative cardiac MRI is a sensitive tool for early detection of cardiac involvement, and can also be used to monitor further progress.

There are several limitations of the present study. First, the sample size was small, limited by the current capacity of medical resources in the epidemic area. Second, most included patients had moderate COVID-19 previously, therefore our report cannot reflect the full spectrum covering severe and critical COVID-19 patients. With both limitations, the reported proportion of cardiac involvement is limited to the present study and cannot be extrapolated to a larger population. Nevertheless, this study demonstrates the phenomenon of post-COVID-19 cardiac involvement, and the findings can be alerting as cardiac involvement may be more easily overlooked in patients of mild SARS-CoV-2 infection. Lastly, we only had a one-time point MRI examination, while longitudinal follow ups will be valuable to confirm if the cardiac involvement will progress or regress.

There may be sustained cardiac involvement in recovered COVID-19 patients, as demonstrated by our cardiac MRI study. Major MRI manifestation included edema, fibrosis, and impaired RV contractile function. The cardiac status of COVID-19 patients and survivors needs to be closely monitored; cardiac MRI can be a sensitive imaging tool in combination with laboratory tests for identifying cardiac involvement in COVID-19 patients.

Magnetic resonance imaging (MRI) is a sensitive and quantitative imaging tool to study early cardiac involvement. Our results showed that MRI was able to identify fibrosis and edema on the myocardium in a proportion of the recovered COVID-19 patients. Impaired RV function was also observed this patient subgroup.

Attention needs to be paid to the potential cardiac involvement and negative consequences in recovered COVID-19 patients. This is a relatively short-term small-cohort study; longitudinal follow-ups in a larger cohort are needed to confirm the prognosis value of cardiac MRI for recovered COVID-19 patients 

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We thank all colleagues who contributed to the present study. We are especially grateful to our front-line medical staff for their professionalism, dedication, and courage in the face of the COVID-19 outbreak.