2. Materials and Methods
A systematic literature search of Ovid MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews (from inception to August 2020) was conducted to identify studies evaluating the incidence/prevalence and clinical significance of myocardial injury among COVID-19-infected patients.
The systematic literature review was undertaken independently by two investigators (R.C. and N.P.) applying a search approach that incorporated the terms “COVID” or “coronavirus” or “SARS-CoV-2” and “myocardial injury’ or “clinical” (Online Supplementary Data
). No language limitation was applied.
Eligible studies included cross-sectional, case-control, or cohort studies that assessed the incidence/prevalence and clinical significance of myocardial injury in COVID-19-infected patients. Studies had to provide effect estimates for overall incidence, prevalence, and risk ratios with a 95% confidence interval (CI). Inclusion was not limited by study size. Retrieved articles were reviewed individually for their eligibility by the two investigators noted previously. Analyses were performed using STATA version 14.1. Adjusted point estimates from each study were consolidated using the generic inverse variance approach of DerSimonian and Laird, which designated the weight of each study based on its variance [3
]. Meta-regression was also performed to explore risk modifiers.
Our study highlighted that the incidence of COVID-19 myocardial injury has ranged from 16.1 to 23.8% (Table 2
). In comparison with previous epidermic Coronavirus, myocardial injury following COVID-19 seemed to be higher—likely due to underreported incidence of the previous diseases which did not reach pandemic state, suggested by higher mortality rates from those previous diseases limiting their spread. Of note, the diverse incidence of AMI could be explained by differences in demographic data and comorbidities which our study suggested. Despite several studies since the beginning of COVID-19 era, our insight into cardiovascular complications remains limited, warranting further data for better understanding.
Based on our meta-regression, our study also supported that older age, male, and comorbidities—particularly hypertension, diabetes, underlying coronary heart disease and chronic kidney disease—were associated with higher risk of myocardial injury incidence. This suggests that these factors may be casual in cardiac injury process. On the other hand, it was deemed primordial to conclude null impact from races and regions, given the paucity of data from countries other than China. Further studies are encouraged to investigate.
COVID-19 myocardial injury occurs through several mechanisms. One is direct cardiac injury on different parts of the heart by viral entry into the cardiomyocytes. The second is microvascular dysfunction as a consequence of severe inflammatory reaction to the virus. With this cascade come endothelial dysfunction and endothelitis, which further worsen cardiac function [2
]. This phenomenon may lead to several manifestations of myocardial injury, from myocarditis and arrhythmia, to Takotsubo cardiomyopathy [35
Intriguingly, the hypercoagulability state is one of the most unique pathophysiologies proposed in COVID-19, which leads to generalized arterial and venous thrombosis [36
]. Owing to the dysregulated immune system, especially in severe infection, several interplays between cytokine storm, platelet hyperactivation and altered microvascular permeability result in abnormal coagulation cascades which promote coronary thrombosis, plaque thrombosis, and even stent thrombosis [37
]. Recent studies provided data that support this theory, demonstrating massively elevated Von Willebrand factor, D-Dimer and abnormal procoagulant factors, and even the presence of antiphospholipid antibodies [38
Another mechanism is indirect involvement through imbalance between metabolic demand and cardiac reserve in patients with preexisting cardiac disease. Based on Choundry et al. [41
], we can infer that COVID-19 posed patients at higher risks for acute coronary events. Exaggerated inflammatory responses following the infection can stimulate acute plaque rupture, leading to demand-supply mismatch [42
]. As a result, acute myocardial infarction ensues, complicating the patient’s prognosis and clinical course. Nevertheless, data paucity has remained in regard to the true incidence between AMI by microvascular dysfunction and coronary thrombosis among COVID-19 patients, given the difficulty in designing such dedicated studies.
Given the consequent high fatality rate, several clinical trials have been investigated to treat and prevent its progression. Combined antibiotics with Azithromycin and Chloroquine, however, did not improve mortality outcomes but lengthened QT interval, posing significant arrhythmias [43
]. For novel therapies such as Remdesevir and IL-6 inhibitors, the data are still limited. Recently, Sheng et al. began a clinical trial using Canakinumab to minimize the risk of myocardial injury, which is currently in the enrolling state [44
]. At the moment, we do not have any effective treatments which reduce COVID-19 complications.
Though informative, our study has certain limitations. First, the statistical heterogeneity is sizable. Thus, meta-regression was performed elucidating the contributions from demographical data and patients’ comorbidities. Moreover, the lack of echocardiographic parameters is cumbersome, further precluding proper variable adjustment. However, the use of echocardiograms in COVID-19-infected patients remains limited due to the disease’s high transmission rate. Second, most studies were from China; thus, real-world incidence may be diverse. Nevertheless, our preliminary analysis suggested no significant difference in myocardial injury incidence. Many more studies from countries other than China are required to demonstrate such diversity. Lastly, true incidence could be overestimated, as most studies used troponin as a marker of cardiac injury, which is not specific to COVID-induced cardiac injury alone, but also to ACS, heart failure, arrhythmia, and so on. Thus, interpretation should be carefully discerned.