Cardiovascular involvement in patients with 2019 novel coronavirus disease

Myocardial injury

In most of the studies, the degree of myocardial injury was evaluated by the level of hs-cTnI.^{[40, 41]} The levels of hs-cTnI have been confirmed as an independent risk factor of poor prognosis in COVID-19 patients.^[11] In a report involving 671 severe COVID-19 patients, 15.8% of patients were found to have a myocardial injury.^[10] A subsequent study of 311 patients showed that myocardial injury was associated with a 17.66-fold increase of in-hospital mortality. In another report of 2068 COVID-19 patients in Wuhan, a total of 181 patients (8.8%) had elevated hs-cTnI levels.^[34] Compared with critically ill patients, non-critically ill patients had a lower level of hs-cTnI and lower incidence of hs-cTnI elevation. In non-critically ill patients, only 2.3% of patients were presented with a high hs-cTnI level. For most of non-critically ill patients, their myocardial biomarkers, including hs-cTnI, creatine kinase-MB (CK-MB) and NT-ProBNP, were within a normal range. However, in critically ill patients, the levels of myocardial biomarkers are significantly elevated. For critically ill patients, 30.3% of patients had elevated hs-cTnI level on admission, 93.8% of patients had elevated NT-proBNP level on admission, 11.1% of patients had elevated CK-MB level on admission, and 39.2% of patients had elevated myoglobin (Mb) level on admission. Compared with critically ill survivors, critically ill deaths had a higher level of hs-cTnI level at admission and throughout hospitalization. Moreover, the level of hs-cTnI and other myocardial biomarkers decreased on the third day after admission in critically ill survivors. Among critically ill deaths, the levels of myocardial biomarkers, especially for hs-cTnI level, continuously increase during the whole hospitalization. In this study, one per standard deviation (SD) increase of hs-cTnI on admission was associated with 1.31-fold risk of in-hospital mortality. After adjusted for baseline characteristics, the level of hs-cTnI was still independently associated with increased in-hospital mortality.

Acute coronary syndrome

In most of the COVID-19 patients, they were presented with fever, dyspnea, and diarrhea on admission, but some patients did not have the above symptoms when they were admitted to the hospital. For those without typical symptoms, chest pain is one of the initial symptoms. A report from Italy involving 28 COVID-19 patients with ST-segment elevation showed that 17 of patients need revascularization. More importantly, in 85.7% of patients (24/28), the first clinical symptoms was chest pain.^[42] In the study from Li et al., 3.1% of patients were presented with chest pain, although the incidence of chest pain in non-critically ill patients was not different from critically ill patients.^[34] The comparison of the incidence of ACS between COVID-19 period and pre-COVID-19 period has shown that the rate of hospitalization for ACS and percutaneous coronary intervention decrease with a 38%–48% reduction in Italy.^{[43, 44]} However, the incidence of ACS is underestimated. Due to the limited medical sources, very few patients take the examination of coronary angiography. Electrocardiogram (ECG) is, therefore, the most used technique to assess the degree of myocardial ischemia during COVID-19 outbreak. In the study from a Wuhan single-center, 22 patients performed ECG, and 14 of them had T-wave depression and inversion, ST-segment depression, or Q waves.^[41] In our study, the results showed that 118 patients had the findings of ECG. The elevation/ depression of ST segment accounted for 72.5%. Only three patients were diagnosed with myocardial infarction by coronary angiography.^[34] The mechanism of ACS underlying COVID-19 patients is suspected to result from systemic inflammation and cytokine storm that induced plaque rupture, microthrombosis, and coronary spasm.

Heart failure

Heart failure is one of the most common causes of death in COVID-19 patients. According to a report from Tongji hospital including 799 COVID-19 patients, they observed that 49.0% patients had an elevation of NT-proBNP (the cutoff was 285 pg/mL).^[45] In dead COVID-19 patients, this proportion increased to 85%. Similarly, the high incidence of NT-proBNP elevation was confirmed in another study that enrolled 2,068 patients.^[34] In this study, more than 64.3% of patients had elevated NT-proBNP on admission (the cutoff was 62.9 pg/mL). Especially, critically ill patients had a higher incidence of NT-proBNP elevation and NT-proBNP level, compared with non-critically ill patients. On the third day, the level and the elevated rate of NT-proBNP started to decrease to the normal range. Besides, the level of NT-proBNP is positively correlated with the level of inflammation biomarkers, such as IL-6, C-reactive protein (CRP), and interleukin-8 (IL-8), which showed an association of systemic inflammation with the incidence of heart failure. However, the application of echocardiography to evaluate the cardiac function of patients with elevated NT-proBNP is not feasible during the outbreak of COVID- 19. Therefore, whether the elevation of NT-proBNP is due to heart failure or hypoxia is not easy to differentiate. However, in a case series involving 100 patients with echocardiography examination,^[46] the findings showed that 39% patients had right ventricular dilatation and dysfunction, 16% of patients had left ventricular diastolic dysfunction, and 10% patients had left ventricular systolic dysfunction. The reasons for the high incidence of heart failure is still unknown. However, given that most of COVID-19 patients were older than 60 years old and complicated with cardiovascular comorbidities. Heart failure may be triggered by high fever, arrhythmia, and systemic inflammation. Additionally, acute myocardial injury can exacerbate pre-existing cardiovascular disease and induce heart failure. On the other hand, due to the overactivation of the immune system, stress-induced cardiomyopathy, or cytokine storm-induced myocardial dysfunction (inflammatory cardiomyopathy), sepsis-related cardiac dysfunction are also the possible mechanisms for the incidence of heart failure or cardiac dysfunction.

Arrhythmia

Arrhythmia is a common clinical cardiovascular manifestation in COVID-19 patients. In the early report involving 138 patients, 16.7% of patients had arrhythmias.^[31] In hospitalized patients in the intensive care unit (ICU), the incidence of arrhythmias is 44.4%, which was higher than non-ICU patients (6.9%). But, the specific type of arrhythmia in this study was not pointed out. Besides, palpitation is also one of the frequent clinical presentation, except for fever and cough, although the rate of palpitation was not significantly different between critically ill patients and non-critically ill patients.^[31] Moreover, the incidence of arrhythmias is associated with the degree of myocardial injury.^[34] A study with 2,068 COVID-19 patients demonstrates that the incidence of arrhythmia is higher in COVID-19 patients with elevated hs-cTnI on admission, compared with patients without elevated hs-cTnI admission. This association was still consistent when patients were stratified according to the hs-cTnI level during hospitalization. In patients with elevated hs-cTnI during hospitalization, the rate of arrhythmia was 47.1%. However, the rate of arrhythmias was 12.4% in patients without elevated hs-cTnI during hospitalization, suggesting some cardiac injury cannot be evident by its biomarkers such as hs-cTnI and NT-ProBNP. In this study, the types of arrhythmias were specified, including ventricular tachycardia, supraventricular tachycardia, atrial fibrillation, atrial flutter, second-degree (type 2) or third-degree atrioventricular block, and sick sinus syndrome. Except of rhythm disturbance, cardiac arrest also frequently occurred in COVID-19 patients. In 2,068 patients, 77 patients had experienced cardiac arrest. Importantly, cardiac arrest occurred only in critically ill patients. In critically ill victims, 1.7% of patients was cardiac arrest survivors. For critically ill deaths, the incidence rate of cardiac arrest was significantly increased. However, the real association of arrhythmia and COVID-19 remains unclear. The etiology of arrhythmia in COVID-19 patients can be multi-factor. For example, myocardial injury, sepsis, cytokine storm, systemic inflammation, and other application of antiviral and antibiotic medications.

Coagulopathy

Coagulopathy is disorders in coagulation function. Hypercoagulation is also frequently observed in COVID-19 patients. A study reported that the elevated D-dimer level on admission was associated with a worse clinical outcome.^[47] If the cutoff value is 0.5 ug/mL,^[35] 46.4% of patients had elevated D-dimer level, and 42.0% of patients had elevated D-dimer level in another study if the cut-off value was set to 1.0 ug/mL⁷. In the report of Tongji hospital, critically ill patients had a higher rate of hypercoagulation, indicated by elevated D-dimer, fibrinogen (Fbg), and international normalized ratio (INR). In a total of 2,068 patients, 58.6% of patients had elevated D-dimer, 58.0% patients had elevated Fbg (the cut-off value was 4.0 g/L), and 10.0% patients had abnormal INR (normal range 0.8–1.2). The rate of hypercoagulation was significantly increased in critically ill patients. In critically ill survivors, the median level of D-dimer on admission was 2 ug/mL, but decreased on the third day after admission. For critically ill deaths, the level of D-dimer attained to the peak on the seventh day. Except for the level of D-dimer, the level of platelet and prothrombin time are also the indicators of coagulation abnormalities. A study of 41 patients with COVID-19 from Wuhan observed a reduction of platelet counts and prolongation of prothrombin time, although the changes were modest.^[30] In this report, the rate of a low platelet count was 5%, and the time of prothrombin time was 11.1s in non-ICU patients; by contrast, the time of prothrombin time was 11.2 non-ICU patients. Consistently, another retrospective research studying liver dysfunction in COVID-19 patients also observed a modest but significant prolongation of prothrombin time.^[48] Thus, these retrospective data showed that hypercoagulation and also thrombosis, including microthrombosis, is a common complication in COVID-19 patients. Importantly, the level of D-dimer is independently associated with increased in-hospital mortality.^[34] The findings showed that 1 per SD increase in the level of D-dimer on admission 1.48-fold increase in the risk for in-hospital death, and 1 per SD increase in the level of D-dimer on the third day after admission was associated with 2.71 hazard ratio for in-hospital mortality, and 1 per SD increase in the level of D-dimer on the >14th day after admission was associated with a 3.05-fold risk for in-hospital mortality.^[34] When the dead patients were divided into two groups: deaths less than 7 days and deaths more than 7 days, similar observations were found that those who died within 7 days had a higher level of D-dimer, Fbg, and INR than those who died after 7 days. These suggested that the hypercoagulation status promoted the progression of COVID-19. For the investigation of the mechanism of hypercoagulation is still limited. However, in the study from Wuhan assessing the longitude dynamic changes of inflammation biomarkers and coagulation biomarkers, we found significant positive correlations of the level D-dimer, Fbg, INR, and the level of IL-6, CRP, which partially implied a systemic inflammation-inducing the hypercoagulation status. Another hypothesis is that some medications, such as antiviral drug, can arise hypercoagulation status.

Besides, venous thromboembolism was also commonly observed in COVID-19 patients.^[49] A report studying COVID-19 patients by echocardiography showed that deep vein thrombosis and pulmonary embolism were found in COVID-19 patients.^{[50, 51]} An autopsy study involving 12 patients revealed that seven of patients had deep vein thrombosis, and four of patients had a pulmonary embolism, but they were all not suspected as patients with venous thromboembolism before death.^{[49, 52, 53]} These implied that venous thromboembolism is a pivotal factor contributing to the death in COVID-19 patients, but it is not easy to be identified during the infection of COVID-19.

Given that most of COVID-19 patients were under hypercoagulation status. The efficiency of the anticoagulation drugs in treating COVID-19 patients is of interest to investigators. A retrospective study of 449 COVID-19 patients showed a reduction of in-hospital mortality after application of prophylactic heparin.^[54] The in-hospital mortality was 40.0% in patients with prophylactic heparin treatment group with sepsis-induced coagulopathy score ≥4, which was significantly lower than the mortality in patients without the prophylactic heparin treatment group with ≥4 (64.2%; p=0.029). However, in another study involving 2,773 patients, 28% of patients were treated with the anticoagulation drug.^[55] The overall in-hospital mortality was not significantly different between those treated with the anticoagulation drug and those without the anticoagulation drug. But, a prolongation of median survival time was observed in patients treated with the anticoagulation drug. The survival time was 21 days in patients with treatment of anticoagulation drug, which significantly longer than 14 days in patients without anticoagulation drug treatment. In the study involving 2,068 COVID-19 patients,^[34] 16.8% of patients received anticoagulation treatment during hospitalization. Of them, critically ill patients were more often treated with the anticoagulation drug than non-critically ill patients. However, among critically ill patients, the proportion of application of anticoagulation drug was 53.6% in critically ill survivors and 55.2% in critically ill deaths. No significant efficiency of the application of anticoagulation drugs on in-hospital mortality was observed in critically ill patients. In this study, the type of anticoagulation drug includes dabigatran, heparin, warfarin, rivaroxaban, and sulodexide. However, the potential confounding factors and the indications of the anticoagulation drug were not clarified in these studies. In future studies, the dose, the administration time, and the type of anticoagulation drug should be analyzed. Alternatively, prospective, double, randomized trials are encouraged to prospectively evaluate the efficiency of the anticoagulation drug in COVID-19 patients.

Myocarditis

Whether patients with elevated hs-cTnI level results from myocarditis is unclear. Given that few COVID-19 patients received echocardiography or magnetic resonance imaging (MRI) examination during the outbreak of COVID-19. According to the data from a retrospective study involving 112 COVID-19 patients, 37.5% of patients had an elevation of hs-cTnI, but there were no significant abnormalities in segmental wall motion and left ventricular ejection fraction on echocardiography.^[56] In the study of 2,068 COVID-19 patients from Wuhan,^[34] 49 of patients were examined by echocardiography. In COVID-19 patients, 10.2% of patients had reduced left ventricular ejection fraction (LVEF<40%), and 25.8% of patients had pericardial effusion. As a limited sample size, the comparisons between groups cannot be achieved. However, this evidence suggests a nature that myocardial injury may mostly result from systemic inflammation rather than the direct injury of SARS-CoV-2. Nevertheless, some sporadic cases reported that COVID-19 patients had typical symptoms of myocarditis. In a case report,^[57] a 53-year-old female admitted to the hospital presented with elevated myocardial biomarkers and elevated ST segment on the ECG. Echocardiography showed a significant reduction in LVEF. MRI thereafter also confirmed the diagnosis of acute myocarditis. A similar case was also reported by another team.^[58] They successfully saved COVID-19 patients with fulminant myocarditis by applying methylprednisolone. But, the supportive evidence for direct myocardial injury from histology is still limited. In an autopay of COVID-19 patients, there was no obvious evidence showing a direct impairment on heart, although this patient died because of cardiac arrest.^[59] But investigators found coronavirus particles and viral RNA from another endomyocardial biopsy of COVID-19 patients.^[60] Overall, there is no strong evidence support that myocarditis is the main consequence of the direct myocardial injury of SARS-CoV-2. It is more likely to be a secondary consequence of systemic inflammation.