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Clinical features, risk factors and survival in cardiac myxoma-related ischemic stroke: A multicenter case-control study

Open AccessPublished:December 06, 2022DOI:https://doi.org/10.1016/j.jns.2022.120517

      Highlights

      • This is a retrospective, multicenter, case-control study in patients with cardiac myxoma-related ischemic stroke (CM-IS). patients with CM-IS have mild-to-moderate neurologic deficits at the onset of the disease.
      • Narrower tumor width, tumors with high-mobility, thrombus on the tumor surface, and lower BNP levels are potential predictors of CM-IS development.
      • Prolonged symptoms to operation time (SOT) is a potential predictor of CM-IS recurrence.
      • Surgical removal of cardiac myxoma is safe, efficacious, and definitive in patients with CM-IS.

      Abstract

      Background

      Cardiac myxoma (CM) is an important etiology of stroke in young adults, but studies on CM-related ischemic stroke (CM-IS) are limited and conflicting. Hence, we investigated clinical characterizations, risk factors of CM-IS, and short-term survival after surgical resection.

      Methods

      We performed a retrospective analysis of data from all CM patients at three referral management centers and conducted follow-up examination.

      Results

      Among 414 CM patients, 402 were recruited for further analysis, including 54 patients with CM-IS and 348 patients with CM without stroke (Non-stroke). In the acute phase, patients presented with NIHSS 3 (interquartile range: 0–10) and clinical presentation comprising neurological, cardiac and constitutional symptoms. Multivariate analysis showed that the factors associated with an increased risk of CM-IS were tumor width < 30 mm [OR = 2.652, 95% CI: 1.061–6.627, P = 0.037], tumors with high-mobility (OR = 2.700, 95% CI: 1.357–5.371, P = 0.005), thrombus on the tumor surface (OR = 1.856, 95% CI: 1.003–3.434, P = 0.049), and lower B-type natriuretic peptide (BNP) levels (OR = 0.995, 95% CI: 0.989–0.999, P = 0.047). The overall three-year survival rate was 95.7% (95% CI: 94.9–96.5) in CM-IS patients who underwent surgery.

      Conclusions

      CM-IS patients had mild or moderate neurologic deficits with various presentations at disease onset. Narrower tumor width, tumors with high-mobility, thrombus on the tumor surface, and lower BNP levels are potential predictors of CM-IS development. Surgical removal of CM is safe and efficacious in patients with CM-IS.

      Graphical abstract

      Keywords

      Abbreviations:

      CM (cardiac myxoma), CM-IS (CM-related ischemic stroke), ICVE (ischemic cerebrovascular events), IQR (interquartile range), IS (ischemic stroke), MCA (middle cerebral artery), SOT (symptoms to operation time)

      1. Introduction

      As the most frequent primary benign tumor of the heart, cardiac myxoma (CM) is a slowly progressive tumor of endocardial origin [
      • Pinede L.
      • Duhaut P.
      • Loire R.
      Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases.
      ,
      • Johansson L.
      Histogenesis of cardiac myxomas. An immunohistochemical study of 19 cases, including one with glandular structures, and review of the literature.
      ]. Despite a low incidence of 0.5–1 per 1,000,000 individuals per year [
      • Keeling I.M.
      • Oberwalder P.
      • Anelli-Monti M.
      • Schuchlenz H.
      • Demel U.
      • Tilz G.P.
      • et al.
      Cardiac myxomas: 24 years of experience in 49 patients.
      ], CM is generally considered an important etiology for stroke in the young adults [
      • Sanya E.O.
      • Kolo P.M.
      • Adamu U.G.
      • Opadijo O.G.
      • Wahab K.W.
      • Mustapha A.F.
      • et al.
      Intracardiac tumor: a risk factor for stroke in the young--a case report.
      ], most commonly ischemic stroke [
      • Lee V.H.
      • Connolly H.M.
      • Brown R.D.
      Central nervous system manifestations of cardiac myxoma.
      ,
      • Yuan S.M.
      • Humuruola G.
      Stroke of a cardiac myxoma origin.
      ,
      • Zhang Y.
      • Ye Z.
      • Fu Y.
      • Zhang Z.
      • Ye Q.
      • Chen F.
      Characterizations of ischemic stroke compocations in complications in cardiac Myxoma patients at a single institution in eastern China.
      ]. However, the diagnosis of CM is often elusive in young stroke patients owing to its variable clinical manifestations, such as non-specific cardiac, embolic (approximately 50% cerebral embolism), and constitutional symptoms [
      • Gošev I.
      • Paić F.
      • Durić Z.
      • Gošev M.
      • Ivčević S.
      • Jakuš F.B.
      • et al.
      Cardiac myxoma the great imitators: comprehensive histopathological and molecular approach.
      ]. Moreover, the risk factors contributing to embolism in CM patients remain to be clearly identified [
      • Pinede L.
      • Duhaut P.
      • Loire R.
      Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases.
      ,
      • Elbardissi A.W.
      • Dearani J.A.
      • Daly R.C.
      • Mullany C.J.
      • Orszulak T.A.
      • Puga F.J.
      • et al.
      Embolic potential of cardiac tumors and outcome after resection: a case-control study.
      ,
      • He D.K.
      • Zhang Y.F.
      • Liang Y.
      • Ye S.X.
      • Wang C.
      • Kang B.
      • et al.
      Risk factors for embolism in cardiac myxoma: a retrospective analysis.
      ], since some important issues of embolism (i.e., size of tumor [
      • Elbardissi A.W.
      • Dearani J.A.
      • Daly R.C.
      • Mullany C.J.
      • Orszulak T.A.
      • Puga F.J.
      • et al.
      Embolic potential of cardiac tumors and outcome after resection: a case-control study.
      ,
      • Kalçık M.
      • Bayam E.
      • Güner A.
      • Küp A.
      • Kalkan S.
      • Yesin M.
      • et al.
      Evaluation of the potential predictors of embolism in patients with left atrial myxoma.
      ,
      • Dias R.R.
      • Fernandes F.
      • Ramires F.J.
      • Mady C.
      • Albuquerque C.P.
      • Jatene F.B.
      Mortality and embolic potential of cardiac tumors.
      ] and gender [
      • Pinede L.
      • Duhaut P.
      • Loire R.
      Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases.
      ,
      • He D.K.
      • Zhang Y.F.
      • Liang Y.
      • Ye S.X.
      • Wang C.
      • Kang B.
      • et al.
      Risk factors for embolism in cardiac myxoma: a retrospective analysis.
      ,
      • Lee S.J.
      • Kim J.H.
      • Na C.Y.
      • Oh S.S.
      Eleven years’ experience with Korean cardiac myxoma patients: focus on embolic complications.
      ]) as independent risk factors for embolism were controversial. More importantly, although the only curative treatment to prevent stroke recurrence is surgical CM resection, with an operative mortality rate of 0%–3% [
      • Jiang C.X.
      • Wang J.G.
      • Qi R.D.
      • Wang W.
      • Gao L.J.
      • Zhao J.H.
      • et al.
      Long-term outcome of patients with atrial myxoma after surgical intervention: analysis of 403 cases.
      ], the options and timing of treatment are still debatable, and the clinical outcomes are uncertain [
      • Yuan S.M.
      • Humuruola G.
      Stroke of a cardiac myxoma origin.
      ,
      • Zhang Y.
      • Ye Z.
      • Fu Y.
      • Zhang Z.
      • Ye Q.
      • Chen F.
      Characterizations of ischemic stroke compocations in complications in cardiac Myxoma patients at a single institution in eastern China.
      ,
      • Stefanou M.I.
      • Rath D.
      • Stadler V.
      • Richter H.
      • Hennersdorf F.
      • Lausberg H.F.
      • et al.
      Cardiac Myxoma and cerebrovascular events: a retrospective cohort study.
      ]. Therefore, this multicenter case-control study aimed to investigate clinical characterizations and risk factors of CM-related ischemic stroke (CM-IS) and examine the postoperative complications and short-term survival rate.

      2. Methods

      2.1 Study population

      A total of 414 patients with CM were identified in three referral management centers in Beijing, China between January 2010 and December 2020. The initial diagnosis of CM was made by echocardiography or subsequently confirmed by pathology. All patients with CM underwent 2D echocardiography using an EPIQ7c ultrasound imaging system (Philips Ultrasound, Bothell, WA, USA, probe: S5–1 or X5–1, 1.0–5.0MHz). Image loops (≥ 3 s) were digitally stored at three different gain settings (−10, 0, +10dB) to select the optimal image for subsequent off-line analysis using TomTec software (GE Healthcare, Chicago, IL, United States). Patients with ischemic stroke (IS) were diagnosed clinically and on computed tomography (CT) or magnetic resonance imaging (MRI) results, confirmed by two experienced neurologists. Patients with CM-IS were further divided into two subgroups: first-episode CM-IS subgroup (suffering from IS for the first time) and recurrent CM-IS subgroup (suffering from IS twice or more). Patients with transient ischemic attack (TIA), asymptomatic ischemic lesion revealed by brain CT or MRI, cerebral vascular aneurysm without stroke, or stroke caused by other cardiac tumors were excluded from this study. The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee of each participating institution. Written informed consent was obtained from all the patients.

      2.2 Clinical data extraction

      Data in the electronic medical records upon first hospital admission, including demographic information, medical history, clinical symptoms, brain and cardiac imaging using CT or MRI, echocardiography and electrocardiogram, operative reports, medicine use and pathological results, were collected.
      Regarding echocardiographic data, CM with high-mobility refers to highly mobile phenomena of myxoma mass on transthoracic or transesophageal echocardiography as described by previous literatures [
      • Lee V.H.
      • Connolly H.M.
      • Brown R.D.
      Central nervous system manifestations of cardiac myxoma.
      ,
      • Ha J.W.
      • Kang W.C.
      • Chung N.
      • Chang B.C.
      • Rim S.J.
      • Kwon J.W.
      • Jang Y.
      • Shim W.H.
      • Cho S.Y.
      • Kim S.S.
      • Cho S.H.
      Echocardiographic and morphologic characteristics of left atrial myxoma and their relation to systemic embolism.
      ]. In addition, we selected 30 mm as the threshold of the size of CM, since two distinct studies revealed that tumor diameter < 30 mm were more frequently seen in patients with CM complicated by cerebral infarction [
      • Cao G.F.
      • Bi Q.
      • Cao L.
      • Wang C.
      The clinical characteristics of stroke in young patients with cardiac myxoma.
      ].
      Independence in activities of daily living (ADL) was measured by Modified Barthel Index (mBI), which consists of 10 daily activity items and can be analyzed using a total score ranging from 0 to 100. Each item was scored on a 5-level scale, from 1 (completely dependent) to 5 (completely independent) [
      • Shah S.
      • Vanclay F.
      • Cooper B.
      Improving the sensitivity of the Barthel index for stroke rehabilitation.
      ]. Early neurological deterioration (END) is defined as an increase of NIHSS score ≥ 2 points within 72 h after admission [
      • Siegler J.E.
      • Martin-Schild S.
      Early neurological deterioration (END) after stroke: the END depends on the definition.
      ].

      2.3 Follow-up

      After hospital discharge, follow-ups were conducted by trained investigators via face-to-face interviews or phone calls. The main outcomes were complications and mortality, which were monitored for periods lasting 1 month to 10.1 years.

      2.4 Statistical analysis

      Statistical analyses were performed using SPSS (version 17.0; SPSS, Chicago, IL, USA). Continuous variables are presented as mean ± standard deviation or median [interquartile range (IQR)]. Categorical variables were expressed as percentages. Normally distributed data were analyzed using Student's t-test, and non-normally distributed data were analyzed using the Mann–Whitney U test. Categorical variables were analyzed using the chi-squared test. Binary logistic regression analysis was used to assess the variables associated with determining CM stroke and CM stroke recurrence. Variables demonstrating an association with the outcome at a level of ≤0.05 in univariate analysis were candidates for further multivariate analysis. The Kaplan–Meier method was used to estimate the survival rate after surgical resection of CM. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Statistical significance was set at P < 0.05.

      3. Results

      3.1 Patient selection

      A total of 414 consecutive patients with a diagnosis of CM were enrolled, of whom 66 were initially diagnosed with ischemic cerebrovascular events (ICVE) and 348 were histologically verified as CM without stroke (Non-stroke). Among the 66 cases with ICVE, their etiologies remain unidentified because the neurological deficits might be caused by transient ischemic attack or other non-CM-related etiologies. After further careful evaluation, one case was diagnosed with transient ischemic attack and 11 cases with other pathological mechanisms were excluded, including 10 cases caused by atherosclerosis and one cardiogenic cerebral embolism caused by atrial fibrillation. Of the remaining 54 cases, 51 with IS and histologically verified CM, and 3 with IS and suspected CM upon cardiac imaging were identified. Finally, after excluding 12 patients who did not meet inclusion criteria, 402 patients were included in the study for further analysis (Fig. 1).
      Fig. 1
      Fig. 1Flowchart describing the enrollment of patients with cardiac myxoma-related ischemic stroke (CM-IS).

      3.2 Clinical characteristics

      Half (50%) of patients with CM-IS (n = 54) were female in the present study. The mean age of the patients was 55.7 ± 12.2 years. In most cases (61.1%, 33/54), ICVE was the first and singular manifestation (i.e., hemiplegia, hypoesthesia, aphasia, conscious alteration, dysarthria, ataxia) of CM-IS, whereas sixteen (29.6%, 16/54) and two (3.7%, 2/54) cases demonstrated further cardiac (i.e., dyspnea, cheat tightness/pain, palpitations, cough, syncope) and constitutional (i.e., fever, asthenia, weight loss) symptoms, respectively. Six patients (11.1%, 6/54) had concomitant embolism to other parts of the body, including one patient (1.9%) with concomitant retinal artery ischemia, one (1.9%) with concomitant coronary embolism, one (1.9%) with concomitant pulmonary embolism, one (1.9%) with concomitant peripheral embolism to the right lower extremity, and two (3.7%) with previous peripheral embolism to the bilateral lower extremity or left upper extremity. Two patients (3.7%) showed secondary partial hemorrhagic transformation limited to isolated cortical and subarachnoid hemorrhagic lesions. In the acute phase, most patients (64.8%, 35/54) presented with relatively mild or moderate clinical deficits, as reflected by the NIHSS scores (3, interquartile range: 0, 10). Of the 54 patients, 45 (83.3%) had a history of one episode of stroke and 9 (16.7%) had recurrent stroke.
      Compared to Non-stroke patients (n = 348), patients with CM-IS had more coronary heart disease (16.7% vs. 6.6%, P = 0.011), history or tumor width < 30 mm (74.1% vs. 52.2%, P = 0.003), tumors with high-mobility (77.8% vs. 56.0%, P = 0.013), thrombus on the tumor surface (9.6% vs. 2.6%, P = 0.011), and hyperlipidemia (18.5% vs. 7.2%, P = 0.006), elevated platelet count (245.0 ± 102.5 109/L vs. 212.0 ± 84.7 109/L, P = 0.013) and hemoglobin concentration (120.5 ± 23.6 g/L vs. 109.9 ± 21.6 g/L, P = 0.001), as well as lower B-type natriuretic peptide (BNP) levels [100.3 (IQR: 67.0, 208.5) pg/ml vs. 133.7 (IQR: 57.6, 188.4) pg/ml, P = 0.024] compared to patients Non-stroke patients. The details of the comparisons between the two groups are shown in Table 1.
      Table 1Comparison of baseline characteristics between patients with cardiac myxoma-related ischemic stroke (CM-IS) and patients of cardiac myxoma without stroke (Non-stroke). Data are presented as mean ± standard deviation (SD) or Median [interquartile range (IQR)] for continuous variables, and number of subjects (n) and percentage (%), respectively, for categorical variables.
      CM-ISNon-strokeP Value
      (n = 54)(n = 348)
      Female (%)27 (50)231 (66.4)0.018
      Age (years)55.7 ± 12.254.3 ± 13.60.462
      Cigarette smoking (%)13 (24.1)65 (18.7)0.351
      Drinking alcohol (%)9 (16.7)37 (10.6)0.195
      Hypertension (%)17 (31.5)98 (28.2)0.615
      Diabetes mellitus (%)4 (7.4)39 (11.2)0.401
      Hyperlipidemia (%)10 (18.5)25 (7.2)0.006
      Coronary heart disease (%)9 (16.7)23(6.6)0.011
      Atrial fibrillation (%)1(1.9)9 (2.6)0.747
      Valvular heart disease (%)5(9.3)49 (14.1)0.334
      Left atrium diameter (mm)37.5 ± 5.637.4 ± 7.00.953
      Ejection fraction (%)63.1 ± 7.163.9 ± 5.90.407
      NYHA class (III/IV)12 (22.2)80 (23.0)0.986
      Tumor length <30 mm(%)12 (22.2)104(30.1)0.233
      Tumor width <30 mm(%)40(74.1)180(52.2)0.003
      Tumor stalk (%)40 (74.1)245 (70.4)0.565
      Irregular tumor surface (%)15 (27.8)103 (29.7)0.775
      Tumor with high-mobility (%)42 (77.80)195 (56.0)0.013
      Thrombosis on tumor surface (%)5 (9.6)9 (2.6)0.011
      Tumor in left atrium (%)51 (94.4)302 (86.8)0.109
      Antiplatelate drug use (%)6 (11.10)21 (6.0)0.166
      Anticougulate drug use (%)1 (1.9)4 (1.1)0.665
      Platelet count (109/L)245.0 ± 102.5212.0 ± 84.70.013
      Leukocyte count (109/L)8.8 ± 3.79.7 ± 4.40.16
      Hemoglobin (g/L)120.5 ± 23.6109.9 ± 21.60.001
      CRP (mg/L)42.5 (21.7,94.8)55.1 (20.8, 107.0)0.35
      BNP (pg/ml)100.3(67.0,208.5)133.7 (57.6, 188.4)0.024
      FDP (μg/ml)1.5(0.9,2.4)1.5 (0.8, 2.4)0.765
      DD (ng/ml)188.0(129.0,278.3)204.0 (131.0,322.0)0.765
      HCY (μmol/L)13.3 ± 7.913.0 ± 6.70.84
      BNP, B-type natriuretic peptide; CRP, C-reactive protein; DD, D-dimer; FDP, fibrinogen degradation product; HCY, homocysteine.
      In the acute stage of CM-IS, most patients were neurologically stable, while only 3 patients (5.6%, 3/54) suffered early neurological deterioration (END). Modified Barthel Index (mBI) scores were significantly lower in the CM-IS patients as compared with Non-stroke patients at 90 d (84.2 ± 17.2 vs. 95.7 ± 8.1, P = 0.000), and modified Rankin Scale (mRS) 0–1, 2–3 and 4–5 at 90 d was 70.4%, 24.1% and 5.5% in the CM-IS patients, respectively (Fig. 2).
      Fig. 2
      Fig. 2The comparison of modified Barthel Index (mBI) between patients with cardiac myxoma (CM)-related ischemic stroke (CM-IS) and CM without stroke (Non-stroke), as well as distribution of modified Rankin Scale (mRS) scores in patients with CM-IS. (A) mBI scores were significantly lower in the CM-IS patients as compared with Non-stroke patients at 90 d (84.2 ± 17.2 vs. 95.7 ± 8.1, P = 0.000), and (B) mRS 0–1, 2–3 and 4–5 at 90 d were 70.4%, 24.1% and 5.5% in the CM-IS patients, respectively.

      3.3 Brain imaging

      Among the 54 patients with CM-IS, the middle cerebral arteries (MCA) were the most commonly affected area (74.1%, 40/54), followed by the posterior cerebral arteries (37.0%, 20/54), anterior cerebral arteries (14.8%, 8/54), basilar arteries (11.1%, 6/54), and internal carotid arteries (1.9%, 1/54) (Table S1).
      There were 24 cases in the basal ganglion (24/54, 51.9%), 22 in the frontal lobe (22/54, 40.7%), 18 in the parietal lobe (18/54, 33.3%), 12 in the temporal lobe (12/54, 22.2%), 10 in the cerebellum (10/54, 18.5%), 6 in the thalamus (6/54, 11.1%), 6 in the occipital lobe (6/54, 11.1%), three in the brainstem (5.5%), and 2 in the insula (2/54, 3.7%) (Table S2).
      Multiple infarcts (53.7%, 29/54) were more frequently seen in patients with CM-IS than in those with a single infarct (46.3%, 25/54), and there were no significant differences between the left and right sides in either the anterior (χ2 = 0.987, P = 0.320) or posterior circulation (χ2 = 0.150, P = 0.699). Additionally, patients with CM-IS demonstrated more unilateral cerebral infarcts (78.8%, 42/54) than bilateral cerebral infarcts (22.2%, 12/54)), and there was no difference between the anterior and posterior circulations (χ2 = 0.229, P = 0.865) (Table S3).

      3.4 Risk factors of CM-related ischemic stroke

      Multiple variables, including basic characteristics, stroke risk factors, echocardiography findings (i.e., left atrium diameter, ejection fraction), laboratory results, tumor features, and medication, were compared between patients with and without CM-IS (Table 1). Of the 33 variables, nine were associated with CM-IS by univariate logistic regression: female [odds ratio (OR) = 0.233, 95% CI: 0.282–0.895, P = 0.001], hyperlipidemia [OR = 1.322, 95% CI: 1.136–6.523, P = 0.014], coronary heart disease [OR = 1.231, 95% CI: 1.038–6.489, P = 0.001], tumor width < 30 mm [OR = 2.085, 95% CI: 1.375–4.988, P = 0.000], tumor with high-mobility [OR = 2.215, 95% CI: 1.186–8.720, P = 0.001], thrombus on tumor surface [OR = 3.142, 95% CI: 1.262–12.198, P = 0.001], platelet count [OR = 1.004, 95% CI: 1.001–1.007, P = 0.015], hemoglobin concentration [OR = 1.022, 95% CI: 1.008–1.035, P = 0.001], and BNP levels [OR = 0.994, 95% CI: 0.990–0.999, P = 0.021].
      Four significant variables were retained in the final multivariate logistic regression model followed by backward stepwise variable selection. The factors associated with an increased risk of CM-IS were tumor width < 30 mm [OR = 2.652, 95% CI: 1.061–6.627, P = 0.037], tumors with high-mobility (OR = 2.700, 95% CI: 1.357–5.371, P = 0.005), thrombus on the tumor surface (OR = 1.856, 95% CI: 1.003–3.434, P = 0.049), and lower BNP levels (OR = 0.995, 95% CI: 0.989–0.999, P = 0.047) (Table 2).
      Table 2Risk factors of patients with cardiac myxoma-related ischemic stroke (CM-IS) : univariate and multivariate binary logistic regression analysis.
      CharacteristicsUnivariate analysisMultivariate analysis
      OR (95% CI)P valueOR (95% CI)P value
      Female0.233 (0.282–0.895)0.001
      Hyperlipidemia1.322 (1.136–6.523)0.014
      Coronary heart disease1.231 (1.038–6.489)0.001
      Tumor width < 30 mm2.085 (1.375–4.988)0.0002.652 (1.061–6.627)0.037
      Tumor with high-mobility2.215 (1.186–8.720)0.0012.700 (1.357–5.371)0.005
      Thrombosis on tumor surface3.142 (1.262–12.198)0.0011.856 (1.003–3.434)0.049
      Platelet count1.004 (1.001–1.007)0.015
      Hemoglobin1.022 (1.008–1.035)0.001
      BNP0.994 (0.990–0.999)0.0210.995(0.989–0.999)0.047
      BNP, B-type natriuretic peptide.

      3.5 Risk factors of CM-IS recurrence

      Similarly, multiple variables, including basic characteristics, stroke risk factors, echocardiography findings, laboratory results, tumor features, medication, treatment time, and NIHSS scores were also compared between patients with recurrent CM-IS and patients with first-episode CM-IS. Marked differences in fibrinogen degradation product [1.7 (IQR: 1.4, 2.8) μg/ml vs. 0.7 (IQR: 0.4,1.5) μg/ml, P = 0.007], D-dimer levels [207 (IQR: 131.0, 334.0) ng/ml vs. 169.0 (IQR: 53.0, 328.5) ng/ml, P = 0.019], symptoms to operation time (SOT) [25 (IQR: 4.2, 49.9) months vs. 1.1 (IQR: 0.4, 4.2) months, P = 0.002], and homocysteine levels (23.1 ± 11.9 μmol/L vs. 11.6 ± 4.9 μmol/L, P = 0.000) were found between these two CM-IS subgroups (Table S4).
      In univariate analyses, four baseline variables were associated with CM-IS recurrence (Table 3) but only SOT (OR = 1.098, 95% CI: 1.005–1.020, P = 0.038) was retained following backward-stepwise variable selection, in the final binary logistic regression model (Table 3).
      Table 3Risk factors of ischemic stroke recurrence in patients with cardiac myxoma-related ischemic stroke (CM-IS): univariate and multivariate binary logistic regression analyses.
      CharacteristicsUnivariate analysisMultivariate analysis
      OR (95% CI)P valueOR (95% CI)P value
      FDP1.460 (1.086–7.449)0.015
      DD1.022 (1.003–1.094)0.034
      HCY1.143 (1.027–1.272)0.015
      SOT1.046 (1.005–1.088)0.0291.098 (1.005–1.2)0.038
      DD, D-dimer; FDP, fibrinogen degradation product; HCY, homocysteine; SOT, symptoms to operation time.

      3.6 Intravenous thrombolysis and intra-arterial thrombectomy for acute CM-IS

      One patient received thrombolysis and endovascular therapy (EVT) at stroke onset two months before surgical resection, without residual neurological deficits. One patient received intravenous thrombolytic therapy with minimal residual neurological deficits, which did not deteriorate. No intracerebral hemorrhage transformation occurred in either patient.

      3.7 Postoperative complications

      There was no postoperative mortality in 393 patients with CM who underwent surgical resection, and 44 (11.2%) patients underwent postoperative complications, including 13 (25.5%, 13/51) patients in the CM-IS group and 31 (9.1%, 31/342) patients in the Non-stroke group. The most common complication related to surgery was pulmonary infection (5.1%, 20/393), followed by arrhythmia (2.3%, 9/393) and embolism (1.5%, 6/393). However, no marked difference was observed between CM-IS and Non-stroke groups in pulmonary infection [4 (7.8%) vs. 16 (4.7%), P = 0.337], arrhythmia [2 (3.9%) vs. 7 (2.0%), P = 0.404], and embolism [2 (3.9%) vs. 4 (1.2%), P = 0.135]. Additionally, pneumothorax occurred in four Non-stroke patients and valvular heart disease occurred in two CM-IS patients, whereas pulmonary hemorrhage, cerebral hemorrhagic transformation secondary to embolism, and nerve injury occurred in one CM-IS patient, respectively (Table 4).
      Table 4Comparisons of postoperative complications between patients with cardiac myxoma-related ischemic stroke (CM-IS) and patients of cardiac myxoma without stroke (Non-stroke).
      ComplicationsCM-IS

      (n = 51)
      Non-stroke

      (n = 342)
      P Value
      Pulmonary infection4160.337
      Arrhythmia270.404
       Atrial fibrillation04
       Atrial flutter12
       Cardiac arresttion01
      Embolism240.135
       Pulmonary12
       Cerebral11
       Limb01
      Pneumothorax04
      Valvular heart disease20
      Hemorrhage20
       Pulmonary10
       Cerebral10
      Nerve injury10

      3.8 Three-year survival

      Among 393 CM patients undergoing surgery, 125 were followed up after hospital discharge, including 23 patients with CM-IS and 102 Non-stroke patients. The median follow-up time was 22.2 (IQR: 6.4, 36.4) months. During the follow-up period, only one patient had a stroke in Non-stroke group, and CM recurred in three patients (3/125, 2.4%). Death was recorded in three patients (one CM-IS case, two Non-stroke cases), with overall one-year and three-year survival rates of 95.7% (95% CI: 94.9–96.5) and 95.7% (95% CI: 94.9–96.5) in CM-IS patients, and 100% and 95.8% (95% CI: 95.0–96.6) in Non-stroke patients, respectively (Fig. 3). Causes of death were heart failure (n = 1), massive cerebral embolism (n = 1), and lung infection (n = 1). We did not observe any significant differences in survival rates between patients with CM-IS and Non-stroke (log-rank P = 0.93). CM-related stroke did not increase the risk of mortality when adjusted for age, gender, and recurrent myxoma (hazard ratio = 1.787, 95% CI: 0.092–34.695, P = 0.701).
      Fig. 3
      Fig. 3Kaplan–Meier plot for survival rate in patients with cardiac myxoma-related ischemic stroke (CM-IS) and CM without stroke (Non-stroke). The overall one- and three-year survival rates were 95.7% [95% confidence interval (CI): 94.9–96.5)], 95.7% (95% CI: 94.9–96.5) in the CM-IS group, and 100%, 95.8% (95% CI: 95.0–96.6) in the Non-stroke group, respectively.

      4. Discussion

      To our knowledge, this is the first multicenter cohort study to determine the clinical features, risk factors, and short-term prognosis of patients with CM-IS. We found that CM-IS patients had mild or moderate neurological deficits with various presentations at the onset of the disease, but they had no characteristic neuroimaging feature. Tumor width < 30 mm, tumor with high-mobility, thrombus on tumor surface and lower BNP levels were significantly associated with increased risk of CM-IS, while prolonged SOT was associated with increased risk of CM-IS recurrence. CM-IS patients had an estimated three-year survival rate of 95.7%, and expired from heart failure, massive cerebral embolism, and lung infection.
      Stroke caused by cardiac myxoma is known to mainly affect young women in their third and sixth decades of life [
      • Yuan S.M.
      • Humuruola G.
      Stroke of a cardiac myxoma origin.
      ,
      • Lee S.J.
      • Kim J.H.
      • Na C.Y.
      • Oh S.S.
      Eleven years’ experience with Korean cardiac myxoma patients: focus on embolic complications.
      ,
      • Stefanou M.I.
      • Rath D.
      • Stadler V.
      • Richter H.
      • Hennersdorf F.
      • Lausberg H.F.
      • et al.
      Cardiac Myxoma and cerebrovascular events: a retrospective cohort study.
      ]. Our study showed no obvious female predominance, with a female-to-male ratio of 1:1. However, age was consistent with that of the CM populations, as reported in a previous study [
      • Pinede L.
      • Duhaut P.
      • Loire R.
      Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases.
      ]. Concomitant cerebrovascular risk factors, such as hyperlipidemia and coronary heart disease, are common among patients with CM-IS. The incidence of initial and singular ICVE (i.e., hemiplegia, hypoesthesia, aphasia, conscious alteration, dysarthria, and ataxia) in patients with CM-IS was relatively high (61.1%), and most patients had mild to moderate stroke, as reflected by their NIHSS scores; in accordance with two recently published studies [
      • Zhang Y.
      • Ye Z.
      • Fu Y.
      • Zhang Z.
      • Ye Q.
      • Chen F.
      Characterizations of ischemic stroke compocations in complications in cardiac Myxoma patients at a single institution in eastern China.
      ,
      • Stefanou M.I.
      • Rath D.
      • Stadler V.
      • Richter H.
      • Hennersdorf F.
      • Lausberg H.F.
      • et al.
      Cardiac Myxoma and cerebrovascular events: a retrospective cohort study.
      ]. Additionally, the incidence of END during the acute phase of disease is low and a favorable outcome remains at the 3-month follow-up visit, which implies a good prognosis in patients with CM-IS.
      To date, the association between tumor type, size, location, and mobility with embolism in patients with CM remains controversial [
      • Elbardissi A.W.
      • Dearani J.A.
      • Daly R.C.
      • Mullany C.J.
      • Orszulak T.A.
      • Puga F.J.
      • et al.
      Embolic potential of cardiac tumors and outcome after resection: a case-control study.
      ,
      • Kalçık M.
      • Bayam E.
      • Güner A.
      • Küp A.
      • Kalkan S.
      • Yesin M.
      • et al.
      Evaluation of the potential predictors of embolism in patients with left atrial myxoma.
      ,
      • Wen X.Y.
      • Chen Y.M.
      • Yu L.L.
      • Wang S.R.
      • Zheng H.B.
      • Chen Z.B.
      • et al.
      Neurological manifestations of atrial myxoma: a retrospective analysis.
      ]. In this study, significant differences in the proportion of tumor width < 30 mm, tumors with high-mobility and thrombus on the tumor surface were found between CM-IS patients and Non-stroke patients, instead of tumor location, or irregular tumor surface. Our findings are noteworthy, as previous studies reported that myxomas with high-mobility were related to an increased occurrence of cerebral embolism [
      • Liao W.H.
      • Ramkalawan D.
      • Liu J.L.
      • Shi W.
      • Zee C.S.
      • Yang X.S.
      • et al.
      The imaging features of neurologic complications of left atrial myxomas.
      ], and the embolic source may be tumor fragments or surface emboli [
      • Lee V.H.
      • Connolly H.M.
      • Brown R.D.
      Central nervous system manifestations of cardiac myxoma.
      ,
      • Wold L.E.
      • Lie J.T.
      Cardiac myxomas: a clinicopathologic profile.
      ]. Nevertheless, the relationship between CM morphology and stroke requires further investigation.
      Moreover, elevated platelet count and hemoglobin levels were observed separately in patients with CM-IS. Consistent with our results, previous studies have shown a relationship between platelet count or hemoglobin concentration and increased stroke onset [
      • He D.K.
      • Zhang Y.F.
      • Liang Y.
      • Ye S.X.
      • Wang C.
      • Kang B.
      • et al.
      Risk factors for embolism in cardiac myxoma: a retrospective analysis.
      ,
      • Kannel W.B.
      • Gordon T.
      • Wolf P.A.
      • McNamara P.
      Hemoglobin and the risk of cerebral infarction: the Framingham study.
      ,
      • Wannamethee G.
      • Perry I.J.
      • Shaper A.G.
      Haematocrit, hypertension and risk of stroke.
      ,
      • Panwar B.
      • Judd S.E.
      • Warnock D.G.
      • McClellan W.M.
      • Booth J.N.
      • Muntner P.
      • et al.
      Hemoglobin concentration and risk of incident stroke in community-living adults.
      ]. However, in a recently published meta-analysis by Liu et al., platelet count, white blood cells, and hemoglobin concentration were not associated with embolism in CM patients [
      • Liu Y.
      • Wang J.
      • Guo L.
      • Ping L.
      Risk factors of embolism for the cardiac myxoma patients: a systematic review and metanalysis.
      ]. Interestingly, lower serum levels of BNP, a well-known marker of cardiac damage and dysfunction, were also observed in patients with CM-IS, suggesting its potential use as a biomarker to differentiate between CM-IS and Non-stroke.
      Similar to the previous neuroimaging findings of CM-related stroke [
      • Yuan S.M.
      • Humuruola G.
      Stroke of a cardiac myxoma origin.
      ,
      • Zhang Y.
      • Ye Z.
      • Fu Y.
      • Zhang Z.
      • Ye Q.
      • Chen F.
      Characterizations of ischemic stroke compocations in complications in cardiac Myxoma patients at a single institution in eastern China.
      ,
      • Stefanou M.I.
      • Rath D.
      • Stadler V.
      • Richter H.
      • Hennersdorf F.
      • Lausberg H.F.
      • et al.
      Cardiac Myxoma and cerebrovascular events: a retrospective cohort study.
      ], we found that single cerebral vessels (mostly MCA) and multiple territory involvements were common in patients with CM-IS, thereby displaying no distinctive neuroimaging feature. Additionally, the most frequently affected areas involve the basal ganglion, frontal, parietal, temporal, and cerebellar regions. The predominantly affected cerebral vessels (MCA) and areas (the basal ganglion, cerebellum, and parietal and temporal regions) correspond well with the clinical presentation of hemiplegia, hypoesthesia, aphasia, conscious alteration, dysarthria, and ataxia. Therefore, we recommend that brain imaging should be performed in all patients with CM presenting with immediate neurological deficits.
      In the multivariate logistic model, we identified tumor width < 30 mm, tumors with high- mobility, thrombus on the tumor surface, and lower BNP as factors independently associated with CM-IS, and SOT was associated with CM-IS recurrence. The tumor mobility and morphology are strongly related to CM-related stroke and their prognostic value has been reported in various studies [
      • Lee V.H.
      • Connolly H.M.
      • Brown R.D.
      Central nervous system manifestations of cardiac myxoma.
      ,
      • Zhang Y.
      • Ye Z.
      • Fu Y.
      • Zhang Z.
      • Ye Q.
      • Chen F.
      Characterizations of ischemic stroke compocations in complications in cardiac Myxoma patients at a single institution in eastern China.
      ,
      • Liao W.H.
      • Ramkalawan D.
      • Liu J.L.
      • Shi W.
      • Zee C.S.
      • Yang X.S.
      • et al.
      The imaging features of neurologic complications of left atrial myxomas.
      ,
      • Wold L.E.
      • Lie J.T.
      Cardiac myxomas: a clinicopathologic profile.
      ]. So far no consensus reached yet on tumor size [
      • Zhang Y.
      • Ye Z.
      • Fu Y.
      • Zhang Z.
      • Ye Q.
      • Chen F.
      Characterizations of ischemic stroke compocations in complications in cardiac Myxoma patients at a single institution in eastern China.
      ,
      • Liu Y.
      • Wang J.
      • Guo L.
      • Ping L.
      Risk factors of embolism for the cardiac myxoma patients: a systematic review and metanalysis.
      ,
      • Wang Z.
      • Chen S.
      • Zhu M.
      • Zhang W.
      • Zhang H.
      • Li H.
      • et al.
      Risk prediction for emboli and recurrence of primary cardiac myxomas after resection.
      ], mostly on tumor diameter. In the present study we first adopted two different parameters (i.e., tumor length and tumor width), in an attempt to set up a new two-dimensional tumor size measurement for prediction of CM-IS. As a result, we found that the tumor width < 30 mm, instead of tumor length, was associated with the increased risk of CM-IS. The role of decreased BNP levels in CM-IS remains unclear. Of note, a recent meta-analysis revealed that better cardiac function (class I/II) was at a markedly increased risk of embolism than worse function (class III/IV) [
      • Liu Y.
      • Wang J.
      • Guo L.
      • Ping L.
      Risk factors of embolism for the cardiac myxoma patients: a systematic review and metanalysis.
      ]. Based on this finding, a plausible explanation is that most embolic groups were diagnosed after an acute embolic event, but the tumor blockage symptoms were relatively fewer, so the overall cardiac function was better than that of the non-embolic group. Indeed, our study demonstrated that the proportion of worse cardiac function (class III/IV) in patients with CM-IS was mildly lower than that in the Non-stroke patients. Moreover, the association of narrower tumor width (< 30 mm) with increased risk of CM-IS further supports our viewpoint. Intriguingly, we found that the risk of CM-IS recurrence increased with the time elapsed between IS and CM surgical resection. Our findings, in accordance with those of a previous study by Stefanou et al. [
      • Stefanou M.I.
      • Rath D.
      • Stadler V.
      • Richter H.
      • Hennersdorf F.
      • Lausberg H.F.
      • et al.
      Cardiac Myxoma and cerebrovascular events: a retrospective cohort study.
      ], substantiate the view that cardiac surgery should be performed as early as possible from the tumor diagnosis. However, these issues must be addressed further.
      Presently, for the acute treatment of CM-related stroke, several case series have reported the safety and efficacy of intravenous thrombolysis [
      • Kulkarni G.B.
      • Yadav R.
      • Mustare V.
      • Sailesh M.
      Intravenous thrombolysis in a patient with left atrial myxoma with acute ischemic stroke.
      ,
      • Sun M.C.
      • Tai H.C.
      • Lee C.H.
      Intravenous thrombolysis for embolic stroke due to cardiac Myxoma.
      ,
      • Vidale S.
      • Comolli F.
      • Tancredi L.
      • Campana C.
      • Arnaboldi M.
      Intravenous thrombolysis in a patient with left atrial myxoma.
      ,
      • Dong M.
      • Ge Y.
      • Li J.
      • Fu K.
      • Zhang L.
      • Teng W.
      • et al.
      Intravenous thrombolysis for pure pontine infarcts caused by cardiac myxoma: a case report and literature review.
      ,
      • Esmaeili S.
      • Shojaei S.F.
      • Bahadori M.
      • Mojtahed M.
      • Mehrpour M.
      Intravenous thrombolysis for acute ischemic stroke due to cardiac Myxoma, basic.
      ] and mechanical thrombectomy [
      • Bhatia V.
      • Jain C.
      • Ray S.
      • Gupta O.
      • Chatterjee D.
      • Kumar A.
      Mechanical Thrombectomy in embolic cardiac Myxoma: case report and literature review.
      ,
      • Zhou B.
      • Huang S.
      • Liu S.
      • Ren L.
      • Huang C.
      • Lian Z.
      Thrombectomy for stroke caused by cardiac Myxoma.
      ,
      • Chung Y.S.
      • Lee W.J.
      • Hong J.
      • Byun J.S.
      • Kim J.K.
      • Chae S.A.
      Mechanical thrombectomy in cardiac myxoma stroke: a case report and review of the literature.
      ,
      • Mikulenka P.
      • Stetkarova I.
      • Vasko P.
      • Peisker T.
      Left ventricle cardiac myxoma as a cause of ischaemic stroke in young patient treated by mechanical thrombectomy.
      ,
      • Vega R.A.
      • Chan J.L.
      • Anene-Maidoh T.I.
      • Grimes M.M.
      • Reavey-Cantwell J.F.
      Mechanical thrombectomy for pediatric stroke arising from an atrial myxoma: case report.
      ,
      • Tadi P.
      • Feroze R.
      • Reddy P.
      • Sravanthi P.
      • Fakhri N.
      • McTaggart R.
      • et al.
      Clinical reasoning: mechanical thrombectomy for acute ischemic stroke in the setting of atrial myxoma.
      ]. Based on the limited data, the AHA/ASA 2019 guidelines make weak recommendations (Class IIb) on the use of IV alteplase in the treatment of CM patients with severe disabling stroke [
      • Powers J.W.
      • Rabinstein A.A.
      • Ackerson T.
      • Adeoye O.M.
      • Adevoe M.O.
      • Bambakidis C.N.
      Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American heart association/American stroke association.
      ]. In this study, one patient received intravenous thrombolysis and another patient received intravenous thrombolysis, followed by thrombectomy, with various levels of improvement of neurological deficits. No signs of intracerebral hemorrhage transformation were observed in either patient. Ko et al. reported surgery for myxoma resection through the right anterolateral mini-thoracotomy approach in 1998 [
      • Ko P.J.
      • Chang C.H.
      • Lin P.J.
      • Chu J.J.
      • Tsai F.C.
      • Hsueh C.
      • et al.
      Video-assisted minimal access in excision of left atrial myxoma.
      ]. Minimally invasive surgical techniques have been gradually adopted for the treatment of cardiac tumors, such as [
      • Kenawy A.
      • Abdelbar A.
      • Zacharias J.
      Minimally invasive resection of benign cardiac tumors.
      ,
      • Luo C.
      • Zhu J.
      • Bao C.
      • Ding F.
      • Mei J.
      Minimally invasive and conventional surgical treatment of primary benign cardiac tumors.
      ]. Postoperative complications included IS, wound infection, arrhythmia, pulmonary infection, pleural effusion, deep venous thrombosis, and myocardial infarction7. In our study, minimally invasive resection was performed, and the most common complications were pulmonary infection (5.1%), arrhythmia (2.3%), and embolism (1.5%); implicative of safety and effectiveness of surgical resection for the treatment of CM-IS. Moreover, the lack of difference in postoperative complications between the two groups once again confirms that surgical excision is a relatively safe and efficacious procedure for treating CM, regardless of the stroke complications.
      Previous studies reported that CM patients had good long-term survival after surgical resection [
      • Jiang C.X.
      • Wang J.G.
      • Qi R.D.
      • Wang W.
      • Gao L.J.
      • Zhao J.H.
      • et al.
      Long-term outcome of patients with atrial myxoma after surgical intervention: analysis of 403 cases.
      ,
      • Lee K.S.
      • Kim G.S.
      • Jung Y.
      • Jeong I.S.
      • Na K.J.
      • Oh B.S.
      • et al.
      Surgical resection of cardiac myxoma-a 30-year single institutional experience.
      ], and a few patients expired from low cardiac output syndrome, pneumonia, or coronary sinus rupture [
      • Powers J.W.
      • Rabinstein A.A.
      • Ackerson T.
      • Adeoye O.M.
      • Adevoe M.O.
      • Bambakidis C.N.
      Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American heart association/American stroke association.
      ]. In this study, we observed that the three-year survival rate of CM-IS was 95.7%, which was better than the long-term (over five years) overall survival rate in the CM cohort after surgical resection [
      • Lee K.S.
      • Kim G.S.
      • Jung Y.
      • Jeong I.S.
      • Na K.J.
      • Oh B.S.
      • et al.
      Surgical resection of cardiac myxoma-a 30-year single institutional experience.
      ,
      • Shah I.K.
      • Dearani J.A.
      • Daly R.C.
      • Suri R.M.
      • Park S.J.
      • Joyce L.D.
      • et al.
      Cardiac Myxomas: a 50-year experience with resection and analysis of risk factors for recurrence.
      ]. The cause of death was heart failure, massive cerebral embolism, and pneumonia. Of note, in our data, three patients (2.4%, 3/125) had recurrence, consistent with the recurrence rate of <5% after myxoma resection reported in several previous studies [
      • Lee K.S.
      • Kim G.S.
      • Jung Y.
      • Jeong I.S.
      • Na K.J.
      • Oh B.S.
      • et al.
      Surgical resection of cardiac myxoma-a 30-year single institutional experience.
      ,
      • Bjessmo S.
      • Ivert T.
      Cardiac myxoma: 40 years’ experience in 63 patients.
      ,
      • Centofanti P.
      • Di Rosa E.
      • Deorsola L.
      • Dato G.M.A.
      • Patane F.
      • et al.
      Primary cardiac tumors: early and late results of surgical treatment in 91patients.
      ,
      • Garatti A.
      • Nano G.
      • Canziani A.
      Piervincenzo. Surgical excision of cardiac myxomas: twenty years experience at a single institution.
      ,
      • Jones D.R.
      • Warden H.E.
      • Murray G.F.
      • Jeong I.S.
      • Na K.J.
      • Oh B.S.
      • et al.
      Biatrial approach to cardiac myxomas: a 30-year clinical experience.
      ]. To address this, some clinicians have proposed that in cases of CM occurring at a relatively young age, with ventricular origin, family history, Carney complex, or multiple myxomas; full-layer wide resection is recommended because of the increased recurrence rate [
      • Shah I.K.
      • Dearani J.A.
      • Daly R.C.
      • Suri R.M.
      • Park S.J.
      • Joyce L.D.
      • et al.
      Cardiac Myxomas: a 50-year experience with resection and analysis of risk factors for recurrence.
      ,
      • Bjessmo S.
      • Ivert T.
      Cardiac myxoma: 40 years’ experience in 63 patients.
      ,
      • Garatti A.
      • Nano G.
      • Canziani A.
      Piervincenzo. Surgical excision of cardiac myxomas: twenty years experience at a single institution.
      ,
      • Jones D.R.
      • Warden H.E.
      • Murray G.F.
      • Jeong I.S.
      • Na K.J.
      • Oh B.S.
      • et al.
      Biatrial approach to cardiac myxomas: a 30-year clinical experience.
      ]. Nonetheless, further large-scale clinical trials are needed to confirm this hypothesis.

      5. Limitations

      The present study had some limitations. First, as a retrospective study, the data may be insufficient, for example, lack of known onset time for the myxoma and time interval from onset to physician consultation. Second, this study involved a small number of patients, particularly those with CM-IS. Considering the sample size and number of events, the study may fail to reach statistical power; hence, the findings should be interpreted with caution. Third, selection bias may have existed because of the disparity in patient enrollment between the three medical centers. Finally, the number of patients available for follow-up was small and the follow-up period was relatively short for most patients.

      6. Conclusions

      In conclusion, patients with CM-IS had mild or moderate neurologic deficits with various presentations at the onset of the disease, but they had no characteristic neuroimaging feature. Single cerebral vessels (mostly MCA) and multiple territory involvements are neuroimaging characteristics of CM-IS. Narrower tumor width, tumors with high-mobility, thrombus on the tumor surface, and lower BNP levels are potential predictors of CM-IS development, while prolonged SOT is a potential predictor of CM-IS recurrence. Surgical removal of CM is safe, efficacious, and definitive in either patients with CM-IS or CM without stroke. As such, our findings undoubtedly will help neurologists and cardiologists identify CM patients at high risk of IS and therefore, prevent the occurrence and recurrence of IS. Nevertheless, prospective randomized controlled studies in selected cases with longer follow-up periods are needed to validate our results.

      Funding support

      This work was supported by grants from National Natural Science foundation (NSF 81870951 and 82071342).

      Author disclosures

      All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

      Acknowledgments

      The authors thank all participants for their participation.

      Appendix A. Supplementary data

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