key: cord-0861593-0kss5r7u
authors: Deng, Qing; Hu, Bo; Zhang, Yao; Wang, Hao; Zhou, Xiaoyang; Hu, Wei; Cheng, Yuting; Yan, Jie; Ping, Haiqin; Zhou, Qing
title: Suspected myocardial injury in patients with COVID-19: Evidence from front-line clinical observation in Wuhan, China()
date: 2020-04-08
journal: Int J Cardiol
DOI: 10.1016/j.ijcard.2020.03.087
sha: 8266bf6f779e996da4d0ba2fb7733abbac7ca5e7
doc_id: 861593
cord_uid: 0kss5r7u

BACKGROUND: A novel coronavirus disease (COVID-19) in Wuhan has caused an outbreak and become a major public health issue in China and great concern from international community. Myocarditis and myocardial injury were suspected and may even be considered as one of the leading causes for death of COVID-19 patients. Therefore, we focused on the condition of the heart, and sought to provide firsthand evidence for whether myocarditis and myocardial injury were caused by COVID-19. METHODS: We enrolled patients with confirmed diagnosis of COVID-19 retrospectively and collected heart-related clinical data, mainly including cardiac imaging findings, laboratory results and clinical outcomes. Serial tests of cardiac markers were traced for the analysis of potential myocardial injury/myocarditis. RESULTS: 112 COVID-19 patients were enrolled in our study. There was evidence of myocardial injury in COVID-19 patients and 14 (12.5%) patients had presented abnormalities similar to myocarditis. Most of patients had normal levels of troponin at admission, that in 42 (37.5%) patients increased during hospitalization, especially in those that died. Troponin levels were significantly increased in the week preceding the death. 15 (13.4%) patients have presented signs of pulmonary hypertension. Typical signs of myocarditis were absent on echocardiography and electrocardiogram. CONCLUSIONS: The clinical evidence in our study suggested that myocardial injury is more likely related to systemic consequences rather than direct damage by the 2019 novel coronavirus. The elevation in cardiac markers was probably due to secondary and systemic consequences and can be considered as the warning sign for recent adverse clinical outcomes of the patients.

J o u r n a l P r e -p r o o f wall motion abnormality, or left ventricular wall thickening (>10mm) and/or presence of pericardial effusion (≥5mm); the abnormalities on ECG define as ST segment elevation/ST-T changes.

According to the guidelines of American Society of Echocardiography [14] and European Society of Cardiology [15] , signs of pulmonary hypertension defines as peak tricuspid regurgitation velocity >2.8m/s with echocardiographic signs including the changes of ventricles as right ventricle/left ventricle basal diameter ratio >1.0; or pulmonary changes as pulmonary acceleration time <105msec and/or mid-systolic notching; or signs of the increase of right atrial pressure as inferior cava diameter >21mm with decreased inspiratory collapse (<50 % with a sniff or <20 % with quiet inspiration). At least two different echocardiographic signs above should be present to determine higher probability of pulmonary hypertension.

Based on clinical demand, echocardiography, ECG and cardiac markers test and other laboratory tests may be performed at least one time or several times for each patient during hospitalization. The imaging findings and the laboratory results were recorded for the reflection of COVID-19 patients' condition during treatment and clinical management. In addition, the results of series cardiac marker and N-terminal pro brain natriuretic peptide (NT-pro BNP) tests were traced for the analysis of potential myocardial injury, myocarditis and cardiac dysfunction.

The composite endpoint of our study was the admission to intensive care unit (ICU), or mechanical ventilation, or extracorporeal membrane oxygenation (ECMO), or death. Clinical outcomes of the patients were followed up to March 11, 2020 . Patients with one of the following situations should be considered as responding to treatment in hospital: continuously decreased temperature; improved respiratory J o u r n a l P r e -p r o o f

The statistical analysis was performed with SPSS version 22.0 (IBM, Illinois, USA). Binary and ranked variables were described as counts and percentages. Continuous variables were expressed as the means and standard deviations or median, and interquartile range (IQR) values as appropriate. Continuous parameters were compared by independent-samples t-test when the data were normally distributed or otherwise the Mann-Whitney test, while binary and ranked data were analyzed by Wilcoxon rank sum test.

Cox proportional hazard ratio analysis of cardiac imaging findings and laboratory results was performed for the risk prediction of the death of COVID-19 patients adjusted with demographics, clinical symptoms and signs and co-existing conditions. Statistical significance for all analysis were defined as two-tailed p value less than 0.05.

The demographics and baseline clinical characteristics of COVID-19 patients were summarized in body mass index >28Kg/m 2 in severe and non-severe groups, respectively. There were no significant differences between patients in severe and non-severe groups with co-existing conditions. J o u r n a l P r e -p r o o f

Echocardiography has presented that cardiac chamber sizes, LVEF (representing left ventricular systolic function) and tricuspid anterior plane systolic excursion (representing right ventricular systolic function) were within the normal ranges [14, 16] and there were no significant differences of cardiac chamber sizes between patients in non-severe and severe groups (summarized in Table 2 ). There were 6 (5.4%) patients with LVEF <50% and no patients had LVEF <40%. The maximum depth of pericardial effusion was 6.2±1.1mm and there were more patients in severe group with this small amount of pericardial effusion (19 [28.3%] vs 3 [6.7%], p < 0.01). 15 (13.4%) patients have presented the signs of pulmonary hypertension however categorized as low probability (peak tricuspid regurgitation velocity <2.8m/s or no presence of at least two echocardiographic signs) [15] .

Cardiac troponin I were elevated (over 0.04ng/mL) in 42 (37.5%) patients and triple elevated (over 0.12ng/mL) in 32 (28.6%) patients during hospitalization. Compared with non-severe group, the peak significantly higher in severe group. There were also significant differences of lactose dehydrogenase and creatinine kinase between non-severe and severe groups (summarized in Table 2 ).

According to the definition, 14 (12.5%) COVID-19 patients possibly had myocarditis. The characteristics of these patients were summarized in Table 3 and Supplementary Table 1 . All the patients possibly with myocarditis had elevation in creatine kinase MB and NT-pro BNP. Of these patients, 10 (8.9%) and 2 (1.8%) had the abnormalities on echocardiography and electrocardiogram, respectively, and 2 (1.8%) had both the abnormalities. 6 patients were removed among the possible acute myocarditis because 5 patients had pre-existing cardiac disorders and 1 had an acute inferior myocardial infarction 4 days after hospitalization. For these 5 patients with pre-existing cardiac disorders, 4 patients were with history of CHD and heart failure and 3 of them presented reduced LVEF and segmental wall motion abnormality while the other one presented reduced LVEF; another patient with history of hypertrophic J o u r n a l P r e -p r o o f cardiomyopathy (HCM) has presented wall thickening. The patient with myocardial infarction after hospitalization presented reduced LVEF and segmental wall motion abnormality. Besides that, the abnormalities on echocardiography were mainly the presence of a small amount of pericardial effusion.

In our study, 37 (33.0%) patients recovered and discharged with median duration (from onset to discharge) of 32 days (IQR: 22.0-38.0). 31 (27.7%) patients have reached the composite endpoint. Of these patients, 26 (23.2%) were admitted to ICU; 28 (25.0%) and 3 (2.7%) required mechanical ventilation and ECMO, respectively. 14 (12.5%) patients died during hospitalization (summarized in Table 4 

J o u r n a l P r e -p r o o f specific for myocardial injury but more inclined to systemic causes. In addition, some patients have presented the signs of pulmonary hypertension and it was more likely because of the severe conditions in lungs and acute respiratory distress syndrome. ECG manifestations were also nonspecific for the patients.

ST-T changes is common and lacks specificity in older patients, especially those with co-existing cardiac conditions. Tachycardia was more common in patients reached the composite endpoint, which is more likely due to other reasons, such as severe hypoxia. For most of the time during hospitalization, the levels of cardiac troponin I and NT-pro BNP have not elevated. Even the condition of lungs became extremely severe, the changes of the heart were still not obvious for patients with COVID-19, indicating that the novel coronavirus has not presented direct aggression on the heart and it was less likely to be considered as the primary cause for myocardial injury.

Meanwhile, it is worth noting that the elevation in cardiac troponin I and NT-pro BNP peaked within one-week preceding death of the patients. Cardiac troponin I is a sensitive marker for myocardial injury[24] and NT-pro BNP is an optimal biomarker for heart failure [25] . Myocardial injury and heart failure presented before death may be attributed to other reasons, like severe hypoxia induced myocardial ischemia, management of mechanical ventilation or ECMO, multiple organ failure requiring kidney or liver replacement therapies, severe water and electrolyte unbalance or irreversible metabolic acidosis and coagulation dysfunction, which would cause severe systemic disorders in patients with COVID-19. All these conditions may have influences on the heart and cause secondary myocardial injury and heart failure. Though this was not the presence of the novel coronavirus directly attacking the heart, the elevation in cardiac markers should be considered as a warning sign, highly suggesting for recent adverse clinical outcomes of patients with COVID-19. Once the conditions of patients have become severe, such as the decline of blood oxygen saturation, the cardiac markers should be tested and monitored in order to improve clinical management and outcomes for these patients.

Our study has several limitations. First, cardiac magnetic resonance and myocardial biopsy were unavailable in this clinical setting to confirm myocardial injury and myocarditis. The exclusion of potential myocardial inflammation and injury caused by COVID-19 requires more evidence from the demonstration of pathophysiological mechanisms. Second, we have followed up the patients for over two months, however 61 patients (54.5%) are still hospitalized and the median time (from onset to the end of follow-up) of these patients were 46 days (IQR: 39.5-49.0; range: 24-66 days). Thus, the relationship between the study parameters and clinical outcomes remains to be further validated. Third, echocardiography, ECG and all the laboratory tests were based on clinical demand. Differences in the timing of the examinations and tests may lead to differences in the results. J o u r n a l P r e -p r o o f 

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The abnormalities on echocardiography define as reduced left ventricular ejection fraction (LVEF) (<50%), or segmental wall motion abnormality, or left ventricular wall thickening (>10mm) and/or presence of pericardial effusion (≥5mm); the abnormalities on ECG define as ST segment elevation/ST-T changes. LVEF: left ventricular ejection fraction. TAPSE: tricuspid annular plane systolic excursion