Our meta-analysis of the currently published data has demonstrated that: 1) a considerable amount of hospitalized COVID–19 patients developed cardiac injury (23.2%) and the incidence was significantly higher in patients who were sicker (58.5%); 2) hospitalized COVID–19 who developed cardiac injury exhibited significantly higher rates of mortality (75.1%) and poor outcomes (75.3%) compared to those without; and 3) hospitalized COVID–19 patients who were older and had co-morbidities including HTN, CAD, DM and COPD demonstrated increased risk of developing cardiac injury.
1. Incidence of cardiac injury in COVID–19 patients
Since the outbreak in China, increasing spotlight has been brought up on cardiac injury in COVID–19 patients who needed inpatient care. Hu et al described a 37 year-old male patient in Wuhan positive for COVID–19 who developed fulminant myocarditis after three days of chest pain and shortness of breath. He presented with hemodynamic instability, severely elevated cardiac biomarkers (Troponin T [TnT] >10,000 ng/L and NT-BNP >21,000 ng/L) and depressed ventricular systolic function (LVEF 27%). In Europe, Inciardi et al reported an otherwise healthy 53 year-old female positive for COVID–19 who developed acute myopericaridits. Similarly, she had elevated cardiac biomarkers as well as radiographic evidence of biventricular myocardial interstitial edema and diffuse late gadolinium enhancement on cardiac magnetic resonance imaging. Fortunately, both patients stabilized after undergoing aggressive treatment. These case reports should ring a bell on the potential involvement of the cardiovascular system in a wider range of COVID–19 patients worldwide.
More than a dozen studies have reported incidence of cardiac injury in hospitalized COVID–19 patients, ranging from 7% to 44%[2–4,11–17]. However, there is no consensus on the overall incidence of cardiac injury in these patients. Li et al performed a meta-analysis and attempted to determine the incidence of cardiac injury. However, they only analyzed two studies (179 patients) and presented the overall incidence of cardiac injury at 8% (15/179). Although two other studies with more patients were included, these studies only reported elevated creatine kinase levels, which was not specific for cardiac injury and hence could not represent true incidence.
With more evidence available, we included all of the current studies that reported cardiac injury and determined its incidence in hospitalized COVID–19 patients was 23.2% from a total of 1637 patients (380/1637). Moreover, we performed subgroup analyses and discovered a significantly higher incidence of cardiac injury (58.5%, 286/489) in patient with poor outcomes (death, ICU admission or critically ill). Although not included in our pooled analysis, Du et al’s investigation of 85 fatal cases reported that the incidence of cardiac injury in patient who died from COVID–19 was 44.7% (38/85). This was in stark contrast with patients who were not in the poor outcomes group as their incidence of cardiac injury was only 8.3% (95/1148). Although it can be expected that the incidence of cardiac injury would be higher in patients who were sicker, this marked difference requires more attention in our current battle with COVID–19. We believe the overall incidence rate presented in this pooled analysis is more representative due to the larger number of patients included.
2. Demographics and co-morbidities associated with cardiac injury
Age is perhaps the most talked about indicators of patient outcomes in this current COVID–19 outbreak as the general public often has the notion that this is a disease of the elderly. Whether there is a connection between age and the development of cardiac injury was also studied. Here, our pooled analysis was consistent with other studies that COVID–19 patients who developed cardiac injury were significantly older (mean difference = 15.98 years, 95% CI 11.80–20.15, P<0.00001). Besides age, the male gender has also been associated with poor outcomes in COVID–19 patients. A pre-print meta-analysis of 77,932 patients by Wei et al revealed that the male gender had significantly higher risks of developing severe cases (OR = 1.63, 95% CI 1.28–2.06) and death (OR = 1.71, 95% CI 1.51–1.93). However, although both Shi et al and Guo et al reported more male patients in the cardiac injury group[3,4], our pooled analysis of these two studies did not achieve statistical significance. Thus, whether male patients are more likely to develop cardiac injury still needs more evidence.
Several studies have looked into cardiovascular co-morbidities in COVID–19 patients. In Li et al’s meta-analysis of 6 studies, the incidence of HTN, DM and cardio-cerebral vascular diseases were 17.1% 9.7% and 16.4%. Chen T. et al reported that hospitalized COVID–19 patients with cardiovascular co-morbidities were more likely to develop cardiac complications. In the multivariate analysis carried out by Wang L. et al , a history of cardiovascular disease was an independent predictor for death. This was consistent with another multivariate analysis from Chen C. et al . On the other end of the spectrum, Guo et al  pointed out that a significant number of patient with these co-morbidities did not progress to cardiac injury and had relatively favorable outcomes. According to China CDC Weekly in February, 80.9% of all COVID–19 patients (hospitalized and non-hospitalized) with cardiovascular co-morbidities had only mild symptoms with no mortality, 13.8% severe symptoms and only 4.7% critically ill among 44,672 confirmed cases. To determine whether having cardiovascular co-morbidities affected the risk of developing cardiac injury, we looked at the combined effects of 603 patients in Guo et al and Shi et al. Consistent with previous reports, hospitalized COVID–19 patients with history of HTN (OR = 5.13, 95% CI 3.41–7.72, P<0.00001), CAD (OR = 8.94, 95% CI 3.83–20.87, P<0.00001), DM (OR = 3.07, 95% CI 1.64–5.75, P = 0.0004) and COPD (OR = 6.33, 95% CI 1.44–27.85, P = 0.01) were more likely to develop cardiac injury.
In addition to demographics and co-morbidities, we also observed substantially elevated levels of NT-proBNP in patients who developed cardiac injury (mean difference = 1113.44, 95% CI 256.94–1969.96, P = 0.01) during their hospitalization. This pointed to one possible explanation of the high mortality rate in patients with cardiac injury: acute decompensated heart failure. In the two case reports mentioned above, both patients developed heart failure and required inotropic support[9,10]. Zhou F. et al reported that 23% of hospitalized COVID–19 patients (44/191) developed heart failure symptoms. This ratio increased to 52% in those who died (28/54). Guo et al not only reported a positive correlation of TnT levels in COVID–19 patients with NT-proBNP (β = 0.613, P<0.001), but also showed a dynamic increase of NT-proBNP during the hospital course exclusively in patients who eventually died. Together with our analysis, these data proposed a new area of investigation of whether COVID–19 patients with cardiac injury died from heart failure.
3. Cardiac injury in hospitalized COVID–19 patients predicts poor outcomes and death
Not only is it important to know the association of cardiac injury with co-morbidities, whether it predicts prognosis is of more value. Some studies included in our review reported positive correlation of elevated cardiac biomarkers in patients who had poor outcomes. Both Shi et al and Chen C. et al performed multivariate regression analysis and both reported that cardiac injury was an independent predictor of mortality. However, in the multivariate analysis performed by Wang L et al, cardiac injury was only predictive of fatal outcomes in univariate analysis but failed to achieve significance in multivariate analysis. Lippi et al conducted a preliminary meta-analysis of troponin levels in COVID–19 patients and found that it was increased in COVID–19 patients with severe disease than in those without.
In our analysis, we integrated 10 studies to better look into how cardiac injury affected outcomes in hospitalized COVID–19 patients. We discovered that hospitalized COVID–19 patients with cardiac injury had a significantly increased mortality rate compared to those without, with an OR of 21.71. The mortality rate of hospitalized COVID–19 patients with cardiac injury was found to be 75.1% (251/334). This mortality rate was significantly higher than any mortality rates reported so far. Guo et al described a mortality rate of 69.44% (25/36) for patients who developed cardiac injury and also had underlying cardiovascular diseases and 37.50% (6/16) for those with cardiac injury but without cardiovascular co-morbidities. Shi et al reported a mortality rate of 51.2% (42/82) in patients with cardiac injury. This extremely high rate of mortality among patients with cardiac injury is alarming. Revisiting the studies included in our analysis, we discovered that in two studies by Zhou F. et al and Deng et al, death rate among patients with cardiac injury were particularly high: 97.0% (32/33) and 98.5% (65/66) respectively. These extreme rates may have skewed the overall mortality rate higher and needed to be considered with caution.
Since only 6 studies associated cardiac injury with mortality, we combined death, ICU admission and those who were critically ill as poor outcomes and investigated whether cardiac injury predicted overall poor prognosis in COVID–19 patients. With the rate of poor outcomes as high as 75.3% (286/380), patients with cardiac injury again had significantly elevated risk of being critically ill, needing ICU admission or even death compared to those without (OR = 22.18, 95% CI 11.68–42.10, P<0.00001). It is important to note that these high rates of mortality and poor outcomes were only associated with COVID–19 patients who were hospitalized and cannot be applied to those who do not require hospitalization.
4. Possible etiology of cardiac injury in COVID–19 patients
Currently several editorials and review articles have elaborated on the possible etiologies of cardiac injury. The mainstream hypotheses include 1) damage caused by cytokine storm triggered by the virus, 2) Type II demand ischemia due to hypoxemia caused by the dominating respiratory failure, and 3) direct myocardial injury by viral infiltration. As of now, no evidence was available to substantiate direct viral infiltration of cardiomyocytes. Only a few autopsy reports were available that described pathological involvement of the heart. Xu et a. observed the presence of interstitial mononuclear inflammatory infiltrates in the heart but no substantial tissue damage. Another Chinese pathology report by Yao et al described three patients who died of COVID–19 in Chongqing, China. They observed enlarged and necrotic cardiomyocytes with infiltrative phagocytes and rare CD4+ T cells in all three patients. Again, no virus was detected in the heart. More autopsy results are needed. Although Type II demand ischemia should always be kept in mind in patients with respiratory distress, there is hardly direct evidence pointing towards hypoxemia as the sole cause of cardiac injury. Moreover, in Inciardi et al’s  case report, the previously healthy 53 year-old female COVID–19 patient did not exhibit any signs and symptoms of pneumonia and had normal chest radiographic findings. It seemed like in her case, cardiac involvement was the only complication from her SARS-CoV–2 infection. This potentially reasoned against hypoxemia and Type II demand ischemia as the main cause of cardiac injury. Currently, the most convincing hypothesis of cardiac injury involves cytokine storm. This has been solidified by Huang et al, whose study revealed higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα in COVID–19 patients admitted to the ICU. Our analyses also agreed with this hypothesis by showing significantly elevated inflammatory markers including CRP (mean difference = 6.00, 95% CI 4.95–7.06, P<0.00001) and procalcitonin (mean difference = 0.18, 95% CI 0.13–0.23, P<0.00001) in patients with cardiac injury compared to those without. In order to further elucidate the cytokine storm hypothesis, more studies are needed to compare inflammatory marker between COVID–19 patients with or without cardiac injury.
5. Recommendations for managing hospitalized COVID–19 patients with cardiac injury
Given the high risk of mortality in hospitalized COVID–19 patients with cardiac injury, the authors recommend early screening with cardiac biomarkers, electrocardiograms, and echocardiograms in patients who are at higher risk of developing cardiac injury. These patients are older and often have history of HTN, DM, CAD, and COPD. We hope early detection with appropriate triage and support would help reduce the incidence of cardiac injury in hospitalized COVID–19 patients and the dangerously high rate of mortality and poor outcomes.