Reply to Tsolaki and Zakynthinos: Are Patients with COVID-19 Dying of or with Cardiac Injury?

From the Authors:

We appreciate the great interest in our paper in the Journal entitled “Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study” (1). Some insightful points were raised by Dr. Tsolaki and Dr. Zakynthinos.

In our study, the lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase levels analyzed were obtained on admission. In an isolation unit, where physical examination is difficult to perform because of donning of protective gear, laboratory findings and chest computed tomographic (CT) scans are crucial tools for disease monitoring and can help identify early risk factors for mortality in patients with coronavirus disease (COVID-19) (1, 2).

The question of how acute cardiac injury should be assessed is debatable. However, according to chapter 2 of the Fourth Universal Definition of Myocardial Infarction published in 2018, “Universal Definitions of Myocardial Injury and Myocardial Infarction,” myocardial injury is defined as elevated cardiac troponin values with at least one value above the 99th percentile upper reference limit (3). These are the same criteria used in similar recently published papers on COVID-19 (4, 5). The 44.7% of our patients with acute cardiac injury rely on TnI (troponin I) or TnT (troponin T) measured during patients’ hospitalization, whereas other biomarkers, such as CK-MB (creatine kinase MB isoform), NT-proBNP (N-terminal prohormone of brain natriuretic peptide), and BNP, are less sensitive and less specific. Acute cardiac injury was reported in 59% of nonsurvivors in Huang and colleagues’ report, which is consistent with our findings (5). It should be clear that cardiac injury is a depictive diagnosis, the spectrum of which ranges from mild injury to myocardial infarction. Various clinical entities may accompany these myocardial abnormalities, such as ventricular tachyarrhythmia, heart failure, kidney disease, hypotension and/or shock, hypoxemia, and anemia (3). Therefore, cardiac injury cannot always be considered as the main driver of death, which is why it was not included in Table 1 of our paper but instead as a complication reflected by TnI or TnT levels as shown in Table 5 of our paper.

The mechanism of cardiac injury in patients with COVID-19 is still unclear. There are several possibilities: 1) The role of cytokine storm has been previously shown, wherein IL-1β, IL-6, IL-12, IP-10 (IFN-γ–induced protein 10), and MCP-1 (monocyte chemoattractant protein 1) levels are increased in COVID-19 (5, 6). 2) Oudit and colleagues showed that downregulation of ACE2 (angiotensin-converting enzyme 2) is associated with the degree of macrophage infiltration after myocardial infection. It is speculated that downregulation of ACE2 expression secondary to viral infection may be related to cardiac insufficiency (7). 3) Long-term bed rest can lead to coagulation system activation, secondary intravascular microthrombosis, and pulmonary embolism. 4) Hypoxemia, pulmonary vasospasm, inflammation and hypercapnia, and secondary transient pulmonary hypertension can lead to right heart flow limitations. Cardiomyocyte ischemia or hypoxia leads to impaired left heart function and aggravates pulmonary congestion. 5) Fever, anorexia, and hypoproteinemia can lead to increased pulmonary exudation, rendering the patient vulnerable to secondary infection by other pathogens, inducing multiple organ dysfunction.

Echocardiographic abnormalities observed in patients with COVID-19 included reduced cardiac systolic and diastolic function, stress myocardiopathy, and right heart dysfunction, which can result from right heart volume and/or pressure load related to increased pulmonary resistance, inappropriate mechanical ventilation, or volume overload. However, patients with severe COVID-19 have rapid changes in echocardiographic findings.

Increased cardiac dimension on CT imaging is insufficient to diagnose myocarditis in patients with COVID-19. The standard Dallas pathological criteria for the definition of myocarditis require that an inflammatory cellular infiltrate with or without associated myocyte necrosis be present on conventionally stained heart-tissue sections (8). At present, there has not been autopsy evidence to indicate myocarditis, although a recent study showed the presence of few interstitial mononuclear inflammatory infiltrates. No other substantial myocardial damage has been found in the heart tissue of patients who died of COVID-19 (9).

Figure 1C of our paper is a CT image of a 23-year-old female patient who died of acute respiratory failure. The patient has a very small amount of right pleural effusion, but the CT image of the left lower pulmonary vessels is very clear, which does not show evidence of an increase in vascular pressure. There is no thickening of the blood vessels, and no perivascular exudation is seen. This patient had severe anemia with Hb 44 g/L but no increase in BNP. It is likely that the change in heart shadow seen on CT imaging is caused by anemia.

It should be noted that none of the patients had been on chloroquine, so this could not be the cause of the arrythmias observed in our patients. Perfusion markers such as low central venous oxygen saturation were not available for this study, but we agree that this would be useful information to obtain in future studies.

We thank Tsolaki and Zakynthinos again for their insightful comments.