1 INTRODUCTION
In December 2019, an outbreak of coronavirus disease 2019 (COVID‐19) was firstly reported in Wuhan, China. The World Health Organization (WHO) declared COVID‐19 as a new coronavirus disease that mainly spread through asymptomatic transmission by respiratory droplets, aerosols, and close contact.1 Respiratory lesion is the main clinical feature, manifesting as fever, productive cough, sputum, chest tightness, and dyspnea resulting in hypoxemia. Meanwhile, COVID‐19 related myocardial injury was commonly observed, with the increasing or decreasing of myocardial biomarkers such as creatine kinase isoenzyme‐MB (CK‐MB), cardiac troponin I (cTnI), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). It is reported that around 7.2%–12% of COVID‐19 patients are accompanied with myocardial injury (COVID‐19 Clinical Guidance For the Cardiovascular Care Team, February 14, 2020); for severe or critical COVID‐19 patients, this proportion increases up to 23.1%.2 Although many studies reported the changes of myocardial markers related to the overall COVID‐19 population, the important role of myocardial injury in predicting prognosis in severe and critical COVID‐19 patients is yet to be investigated. This study aims to develop the risk predictors in myocardial injury to the prognosis of severe and critical patients with COVID‐19 disease, thus providing a basis for early intervention for myocardial injury in this population.
2 METHODS
2.1 Study design
Between February 10, 2020 and March 31, 2020, data on consecutive patients with a diagnosis of severe or critical COVID‐19 admitted to the intensive care unit (ICU) of Wuhan Tongji Hospital were collected. The diagnosis of COVID‐19 was confirmed according to the interim guidance from WHO and National Health Commission of China3, 4: positive result for a nasopharyngeal swab and respiratory pathogen nucleic acid test with high‐throughput sequencing or real‐time reverse transcriptase‐polymerase chain reaction.2 All patients have undergone chest computed tomographic scans and confirmed as viral pneumonia with characteristic changes of nodules, patchy areas of peribronchial ground‐glass opacity, or air‐space consolidation. To study the direct myocardial injury secondary to COVID‐19 disease, patients with a history of lung disease, myocardial infarction, or other cardiovascular diseases, cardiac surgery, or other previous end‐stage diseases including malignant tumors were excluded.
Demographic, epidemiological, and medical history data were collected by the researchers within the first 24 h admitted to ICU. The first intravenous blood sample was also collected in the first 24 h to evaluate the myocardial injury and inflammation, including creatine kinase isoenzyme‐MB (CK‐MB), cTnI, myoglobin (MYO), NT‐proBNP, interleukin‐6 (IL‐6), C‐reactive protein (CRP), and the myocardial injury was defined as the elevation of myocardial related enzymes. Prognostic data were collected before death or discharge from ICU, including mechanical ventilation (MV) time (including both noninvasive and invasive mechanical ventilation), the incidence of malignant arrhythmia (including ventricular fibrillation, complete atrioventricular block, ventricular tachycardia, and ventricular flutter), and the ICU mortality. Then the risk factors to adverse prognosis in myocardial injury and inflammation were explored.
2.2 Diagnosis of severe and critical COVID‐19 patients
Severe and critical patients were retrospectively enrolled in the study according to the guidance from the National Health Commission of China.3 Severe: (1) respiratory distress, the respiratory rate per min ≥30; or (2) mean oxygen saturation ≤93%; or (3) arterial blood oxygen partial pressure/oxygen concentration ≤300 mmHg; or (4) pulmonary focus of infection progress >50% in 24–48 h; or (5) age >60 years; or (6) noninvasive positive pressure ventilation. Critical: (1) with respiratory failure needing invasive mechanical ventilation; or (2) with shock; or (3) with multiple organ failure (MOF).
2.3 General treatments
All enrolled patients were treated according to protocols of Chinese severe and critical COVID‐19 diagnosis and treatment protocol (trial version 2), which consists of bed rest; hemodynamic monitoring; medication treatments including basic disease treatment, antiviral treatment, and immunotherapy treatment; calories and nutrients supporting; maintaining water, electrolyte and acid–base imbalances; preventing of venous thromboembolism and secondary infection; as well as oxygenation therapy and mechanical ventilation (detailed in the Supplementary Material).
2.4 Ethics approval
The study was approved and monitored by the Institutional Review Board of the Huashan Hospital, China (Grant No. 2020780A176). Written informed consent was obtained from all included patients for data to be used for research.
2.5 Statistical analysis
Continuous data were expressed as mean ± SD, and group comparisons were analyzed with the unpaired Student’s t‐test. Categorical variables were compared using the χ2 test or Fisher exact test. The significance of each clinical or experimental variates including age, heart rates, mean artery pressure (MAP), CK‐MB, cTnI, MYO, NT‐proBNP, IL‐6, CRP was assessed by univariate regression analysis and binary logistic regression analysis between Non‐Arrhythmia Group and Arrhythmia Group, and between Death Group and Survival Group to determine the predictors of prognostic risks. These variates were also assessed by multivariate linear regression analysis to determine the risk factors of the increased MV time. A value of p < .05 was considered to be significant. Admission data and prognostic data were separately studied by two researchers blindly to avoid selection bias.
3 RESULTS
3.1 General information
Ninety‐eight consecutive COVID‐19 patients were admitted in ICU and evaluated by the inclusion criteria, and 74 patients were included in the study (mean age of 67.2 ± 14.6 years, male of 66.2%), including 42 severe and 32 critical cases. Epidemiological history, clinical manifestation, vital signs, hematology, and serological results at admission were detailed in the Supplementary Material (Table S1). Twenty‐eight patients successfully discharged from ICU to the general ward, and 46 patients died in ICU, including 13 severe (mortality of 40.6%) and 33 critical (mortality of 75.0%) patients. The direct cause of death included arrhythmia, respiratory failure, low output syndrome, and MOF. Four patients avoided MV assistance due to relatively good respiratory conditions. Forty‐four patients experienced malignant arrhythmia and 30 patients presented no obvious arrhythmia. According to which, patients were retrospectively grouped as Arrhythmia Group (n = 44) versus Non Arrhythmia Group (n = 30); and Death Group (n = 46) versus Survival Group (n = 28).
3.2 Effect of myocardial injury on MV time
As was shown in Table 1, multivariate linear regression analysis results showed that CK‐MB (odds ratio = 5.895; p < .001; 95% confidence interval: 3.097–8.692) and IL‐6 (odds ratio = 0.379; p = .005; 95% confidence interval: 1.051–1.769) were independent risk factors of increased MV time. According to the results, the MV time increase is associated with the CK‐MB and IL‐6 elevation.
Multivariate linear regression analysis of MV time in severe and critical COVID‐19 patients
| Items | B value | SE value | Wald value | p Value | 95% CI |
|---|---|---|---|---|---|
| Age | −1.022 | 1.293 | 0.625 | .429 | −3.557 to 1.512 |
| Heart rates | −1.134 | 1.073 | 1.116 | .291 | −3.237 to 0.969 |
| MAP | 0.323 | 0.703 | 0.211 | .646 | −1.054 to 1.701 |
| cTnI | −0.017 | 0.016 | 1.233 | .267 | −0.048 to 0.013 |
| MYO | −0.195 | 0.071 | 7.473 | .056 | −0.335 to −0.055 |
| CK‐MB | 5.895 | 1.427 | 17.060 | <.001 | 3.097 to 8.692 |
| NT‐proBNP | 0.003 | 0.003 | 1.049 | .306 | −0.003 to 0.009 |
| IL ‐ 6 | 0.379 | 0.135 | 7.894 | .005 | 0.115 to 0.643 |
| CRP | 0.689 | 0.266 | 6.719 | .050 | 0.209 to −0.868 |
- Abbreviations: COVID‐19, coronavirus disease 2019; CI, confidence interval; CK‐MB, creatine kinase isoenzyme‐MB; CRP, C‐reactive protein; cTnI, cardiac troponin I; IL‐6, interleukin‐6; MAP, mean artery pressure; MYO, myoglobin; MV, mechanical ventilation; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; SE, standard error.
3.3 Effect of myocardial injury on incidence of malignant arrhythmia
The incidence of malignant arrhythmia in severe and critical COVID‐19 patients was 59.5% (n = 44). As was shown in Table 2, the MAP was associated with the incidence of malignant arrhythmia by univariate regression analysis (p = .049). Binary logistic regression analysis developed MYO (odds ratio = 7.710; p = .045; 95% confidence interval: 1.051–56.571) as the independent predictor of incidence of malignant arrhythmia (Table 3). It suggests that the incidence of malignant arrhythmia is independently associated with the elevation of MYO at admission. MAP is also potentially associated with malignant arrhythmia occurring.
Univariate regression analysis of the incidence of malignant arrhythmia in severe and critical COVID‐19 patients
| Characteristic | No arrhythmia (n = 30) | Arrhythmia (n = 44) | p Value |
|---|---|---|---|
| Age (years) | 61.00 ± 18.38 | 69.57 ± 11.93 | .063 |
| Heart rates (bpm) | 95.49 ± 13.44 | 96.32 ± 17.61 | .789 |
| MAP (mmHg) | 88.55 ± 40.76 | 107.54 ± 28.63 | .049 |
| cTnI (pg/ml) | 317.83 ± 1617.40 | 669.56 ± 2940.19 | .224 |
| MYO (ng/ml) | 274.86 ± 323.80 | 308.09 ± 341.26 | .260 |
| CK‐MB (ng/ml) | 6.66 ± 24.39 | 9.56 ± 45.58 | .657 |
| NT‐proBNP (pg/ml) | 2537.91 ± 2799.89 | 3543.99 ± 7997.60 | .913 |
| IL‐6 (pg/ml) | 58.83 ± 73.03 | 73.56 ± 164.53 | .912 |
| CRP (mg/L) | 104.42 ± 56.75 | 108.47 ± 78.18 | .846 |
- Abbreviations: COVID‐19, coronavirus disease 2019; CK‐MB, creatine kinase isoenzyme‐MB; CRP, C‐reactive protein; cTnI, cardiac troponin I; IL‐6, interleukin‐6; MAP, mean artery pressure; MYO, myoglobin; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.
Binary logistic regression analysis of the incidence of malignant arrhythmia in severe and critical COVID‐19 patients
| Items | B value | SE value | Wald value | p Value | OR value | 95% CI |
|---|---|---|---|---|---|---|
| Age | 0.034 | 0.025 | 1.843 | .175 | 1.035 | 0.985–1.086 |
| Heart rates | −0.007 | 0.020 | 0.115 | .734 | 0.993 | 0.956–1.032 |
| MAP | 0.018 | 0.014 | 1.753 | .185 | 1.018 | 0.991–1.046 |
| cTnI | −0.924 | 0.849 | 1.186 | .276 | 0.397 | 0.075–2.094 |
| MYO | 2.042 | 1.017 | 4.035 | .045 | 7.710 | 1.051–56.571 |
| CK‐MB | −1.270 | 1.203 | 1.115 | .291 | 0.281 | 0.027–2.968 |
| NT‐proBNP | 0.357 | 0.786 | 0.207 | .649 | 1.430 | 0.307–6.667 |
| IL ‐ 6 | 0.001 | 0.003 | 0.125 | .724 | 1.001 | 0.994–1.008 |
| CRP | 0.008 | 0.006 | 1.936 | .164 | 1.008 | 0.997–1.020 |
- Abbreviations: COVID‐19, coronavirus disease 2019; CI, confidence interval; CK‐MB, creatine kinase isoenzyme‐MB; CRP, C‐reactive protein; cTnI, cardiac troponin I; IL‐6, interleukin‐6; MAP, mean artery pressure; MYO, myoglobin; MV, mechanical ventilation; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; OR, odds ratio; SE, standard error.
3.4 Effect of myocardial injury on ICU mortality
The ICU mortality in severe and critical COVID‐19 patients was 62.2% (n = 46). As was shown in Table 4, age (p = .001), cTnI (p = .009), MYO (p = .023) and NT‐proBNP (p = .029) were associated with ICU mortality by univariate regression. Binary logistic regression analysis developed the age (odds ratio = 1.077; p = .009; 95% confidence interval: 1.019–1.139), MYO (odds ratio = 9.480; p = .032; 95% confidence interval: 1.211–78.188), and NT‐proBNP (odds ratio = 4.852; p = .047; 95% confidence interval: 0.956–24.627) as the independent predictors of ICU mortality (Table 5), suggesting that ICU mortality was associated with the increases of age, MYO, and NT‐proBNP levels.
Analysis of univariate regression of ICU mortality in severe and critical COVID‐19 patients
| Characteristic | Survival group (n = 28) | Death group(n = 46) | p Value |
|---|---|---|---|
| Age (years） | 59.32 ± 16.95 | 72.09 ± 9.94 | .001 |
| Heart rates (bpm) | 94.92 ± 15.21 | 96.81 ± 17.36 | .960 |
| MAP (mmHg) | 95.46 ± 37.29 | 106.63 ± 30.01 | .141 |
| cTnI (pg/ml) | 171.46 ± 1062.91 | 819.83 ± 3238.17 | .009 |
| MYO (ng/ml) | 225.65 ± 284.66 | 343.83 ± 357.45 | .023 |
| CK ‐ MB (ng/ml) | 5.75 ± 20.85 | 10.62 ± 49.30 | .111 |
| NT‐proBNP (pg/ml) | 1741.18 ± 2362.67 | 3543.99 ± 7997.60 | .029 |
| IL‐6 (pg/ml) | 56.17 ± 67.78 | 73.56 ± 164.53 | .744 |
| CRP (mg/L) | 91.29 ± 56.92 | 117.16 ± 79.75 | .260 |
- Abbreviations: COVID‐19, coronavirus disease 2019; CK‐MB, creatine kinase isoenzyme‐MB; CRP, C‐reactive protein; cTnI, cardiac troponin I; ICU, intensive care unit; IL‐6, interleukin‐6; MAP, mean artery pressure; MYO, myoglobin; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.
Analysis of multivariate regression of ICU mortality in severe and critical COVID‐19 patients
| Items | B value | SE value | Wald value | p Value | OR value | 95% CI |
|---|---|---|---|---|---|---|
| Age | 0.075 | 0.028 | 6.887 | .009 | 1.077 | 1.019–1.139 |
| Heart rates | 0.005 | 0.021 | 0.056 | .813 | 1.005 | 0.964–1.031 |
| MAP | 0.004 | 0.014 | 0.075 | .784 | 1.004 | 0.977–1.031 |
| cTnI | −0.344 | 0.856 | 0.162 | .688 | 0.709 | 0.132–3.796 |
| MYO | 2.249 | 1.050 | 4.591 | .032 | 9.480 | 1.211–74.188 |
| CK‐MB | −2.171 | 1.250 | 3.016 | .082 | 0.114 | 0.010–1.322 |
| NT‐proBNP | 1.579 | 0.829 | 3.631 | .047 | 4.852 | 0.956–24.627 |
| IL ‐ 6 | 0.001 | 0.003 | 0.261 | .609 | 1.001 | 0.996–1.007 |
| CRP | 0.012 | 0.006 | 3.355 | .067 | 1.012 | 0.999–1.025 |
- Abbreviations: COVID‐19, coronavirus disease 2019; CI, confidence interval; CK‐MB, creatine kinase isoenzyme‐MB; CRP, C‐reactive protein; cTnI, cardiac troponin I; ICU, intensive care unit; IL‐6, interleukin‐6; MAP, mean artery pressure; MYO, myoglobin; MV, mechanical ventilation; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; OR, odds ratio; SE, standard error.
4 DISCUSSION
Since the WHO listing COVID‐19 disease as a public health emergency with international concerns, this disease presented a global explosive trend. Until July 4, 2020, over 11 million cases have been diagnosed in 206 countries and regions, with total mortality as high as 4.71%. With the characteristics of high infectivity, potent pathogenicity, and rapid progression, around 15% of the patients progressed to a severe or critical degree, and the 28‐day mortality was 61.5%.5 Myocardial injury plays an important role in the poor prognosis of severe and critical COVID‐19 cases, presenting myocardial necrosis, inflammation, heart failure, and MOF.
In the present study, the majority of severe or critical patients were accompanied with abnormal biomarkers related to myocardial injury or heart failure at admission, which were related to adverse prognosis including increased MV time, malignant arrhythmia, and mortality. In this study, ventilation duration is related to the elevation of CK‐MB and IL‐6. To date, there existed many reports presenting cTnI and NT‐proBNP as surrogate markers of COVID‐19 related myocardial injury, however, as a common myocardial injury marker, CK‐MB is rarely mentioned. CK‐MB is widely used as a biomarker for myocardial injury for its primary source from the myocardium.6 In severe and critical patients, the increase in myocardial oxygen demand may result in aggravating myocardial degeneration and myocardial injury, which could further deteriorate cardiac and respiratory function and increase the demand for ventilation. IL‐6 is an important inflammation marker that suggests significant systemic inflammation response including heart and lung. There existed hypostasis that the myocardial injury is more likely related to systemic consequences rather than direct damage by the 2019 novel coronavirus.7
Malignant arrhythmia was a major cause of death in severe and critical COVID‐19 patients. This study demonstrated that the incidence of malignant arrhythmia was independently associated with elevated MYO levels at admission. MYO is commonly used as a biomarker of myocardial injury, which is a major protein sourcing from skeletal and cardiac muscles.8, 9 It releases quickly after myocardial ischemic events happening, peaking at 6–9 h and return to normal within 36 h.10 This is why it has been recognized as a very useful tool in the early diagnosis of acute myocardial ischemia.10, 11 High blood pressure was also found to be potentially associated with malignant arrhythmia occurring in ICU; it may be related to existing sympathetic excitation due to severe infection and stress after dyspnea.
Poor survival is the main challenge of severe and critical COVID‐19 patients, and the population consisting of this study is all in severe and critical degrees with high mortality. Myocardial injury and heart failure may play an important role in poor survival. In the present study, ICU mortality was independently associated with elevated MYO and NT‐proBNP. As mentioned above, MYO plays a key role in the oxidation function of cell membranes, suggesting myocardial injury, inflammation, and poor prognosis. NT‐proBNP has been recommended as the diagnostic indicator of heart failure by the European Cardiovascular Society and the American College of Cardiology.12, 13 It is recognized as a sensitive indicator of cardiac overload and could be elevated in diastolic left ventricular dysfunction or pulmonary hypertension. NT‐proBNP is also well known as a predictor of mortality, especially in a severely ill population.14 In the severe and critical COVID‐19 patients, severe dyspnea, pulmonary hypertension, and systemic inflammation may aggravate the myocardial injury and heart failure, and heart failure could also deteriorate lung lesions, causing MOF and deaths. Myocardial injury and heart failure may also be attributed to other reasons like severe hypoxia‐induced myocardial ischemia, mechanical ventilation, MOF requiring kidney or liver replacement therapies, severe water, and electrolyte unbalance or irreversible metabolic acidosis, which would cause severe systemic disorders in patients with COVID‐19.
The direct myocardial injury occurring in COVID‐19 patients involves many mechanisms. It is reported that the infection of the myocardium by new coronavirus could be dependent on the disruption of ACE‐2 receptors, leading to cardiac injury and heart failure,15 and myocardial inflammation and damage could be caused by the interaction between coronavirus and ACE‐2 in heart16 with increased Tumor necrosis factor‐α levels.15, 17 Other reports also discovered that activated TGF‐β signaling could induce lung fibrosis, which is a common pathway of damage and fibrosis in the myocardium.18 In patients with coronavirus, interferon‐mediated responses could also contribute to myocardial injury and dysfunction.19 Therefore, the possible mechanisms of myocardial injury in COVID‐19 could be direct damage to the cardiomyocytes, systemic inflammation, and hypoxia.
As was presented in this study, age portends poor prognosis in severe and critical COVID‐19 patients. The mortality obviously increased in the elderly patients, it is in accordance with other studies reporting poor prognosis of elderly patients with COVID‐19 disease.20 Elderly patients are less possibly to survive from a severe infection, MOF, heart and lung failure, as well as inflammatory storms leading to malignant arrhythmia, nutritional deficiencies, and electrolyte, and acid–base imbalances. Also, comorbidities greatly increase by age, including hypertension, chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease, and thrombotic disease, which also contribute to poor survival rates in elder COVID‐19 patients.21, 22 The characteristics of severe and critical COVID‐19 patients were significantly different from the mild and moderate degree cases, which is much more sensitive to myocardial injury‐causing heart failure and deaths. Furthermore, the diagnosis and management are more challenged to be performed in elderly patient cohorts, leading to delay and insufficiency in therapy. Early diagnosis and interventions of myocardial injury might improve the poor outcomes of severe and critical COVID‐19 patients, and active preventive treatments should be considered.
The study has several limitations. Firstly, as a limited study population to a severe and critical degree, only 74 patients were included. Secondly, our study is a single‐center retrospective study that lacks the insight of multi‐center studies, therefore cannot fully validate the myocardial injury on the prognosis. Further multi‐center studies with a large sample size will be needed to confirm our conclusions. Thirdly, as to the limitation of patient critical condition, the echocardiographic data including ejection fraction was not collected. Fourthly, as in all retrospective studies, the selection bias in this study cannot be fully avoided. Moreover, as to the staff saturation at the specific and urgent period, the postmortem examination was not performed, which is the gold standard and powerful tool for analyzing the causes and potential mechanisms of death. Finally, as to the limited study population, severe and critical COVID‐19 patients were studied as the entire population to reach the conclusions, which should be separately studied in further studies.
5 CONCLUSIONS
In severe and critical COVID‐19 patients, the obvious myocardial injury was observed. Increases of CK‐MB, MYO, NT‐proBNP, IL‐6 at admission, as well as age were independently associated with poor prognosis including increased ventilation duration, malignant arrhythmia, and ICU mortality. Early diagnosis and interventions of myocardial injury might improve the outcomes of severe and critical COVID‐19 patients.
ACKNOWLEDGMENTS
This study was supported by the National Natural Science Foundation of China (81601663), Shanghai Shen Kang Clinical Research Cultivation Project (SHDC12018X18), and Training Funding Program for Shanghai Yiyuan New Star and Youth Medical Talent. We also thank the help of the medical support team of Huashan Hospital to Wuhan in the urgent period of the COVID‐19 outbreak in February.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
