In this cohort study of 80 critically ill COVID-19 patients, several ECG pathologies were associated with death in the univariate analysis, including both prior MI pattern and ST-T pathology. An ECG consistent with prior MI pattern or unspecific repolarization abnormalities was associated with death in multivariate analysis adjusting for SAPS 3. Both chronic and acute ECG pathology at ICU admission was associated with higher peak values of biomarkers of cardiac strain and damage, lactate and more frequent requirement for vasoactive treatment. This indicates that ECG at ICU admission may be an important prognostic tool in COVID-19.
Similar to our study, a cohort study of 756 patients with COVID-19 found that prior MI pattern, unspecific repolarization abnormalities and T-wave inversion at hospital admission were associated with death while sinus tachycardia was not. Further, patients with ST-T pathology at hospital admission have a higher risk of developing more severe disease . In one study of 850 patients with ECG recorded at presentation to the emergency department, and another study of 269 patients that analysed ECG at hospital admission and the seventh day of hospitalization found that ST-T-pathology were predictive of death and invasive ventilation[23, 33]. RBBB, AF, and LVH at hospital admission also have been reported to indicate higher risk of death in patients with COVID-19. These abnormalities were uncommon in our study and therefore lacked sufficient statistical power for analysis. Contrary to our findings, a study describing ECG findings at hospital admission in 431 patients who later died or underwent invasive ventilation reported abnormal ECG in 93% of patients, a high prevalence of AF (22%) and signs of right ventricular strain (30%). In their cohort, patients were older (74 vs 61 years) and had higher over-all mortality (46% vs 28%) compared to our study, and they did not report the proportion of patients who were not eligible for ICU admission which may account for some of the differences between our study and theirs.
Both ECG pathology and elevated troponin have previously been associated with death. There are several plausible explanations why severely ill COVID-19 patients develop ECG abnormalities and myocardial damage. Patients with pre-existing cardiovascular disease are more prone to develop secondary myocardial ischemia due to non-cardiac conditions  such as hypoxia. Consistent with this, we found that abnormalities associated with prior MI was associated with death and developed higher peak troponin-I and NT-pro-BNP values compared to patients with normal ECG. Patients with ST-T pathology in our study also had higher odds of death and developed higher peak values of cardiac biomarkers compared to patients with normal ECG, which may be caused by several different pathophysiological mechanisms, such as ischemia due to pre-existing coronary stenosis with oxygen supply-demand mismatch, acute coronary syndrome due to plaque rupture secondary, myocardial microthrombi due to complement activation or myocarditis. T-wave inversion, present in 16% of our cohort, may be present in up to 57% of patients with myocarditis. In a study of unselected patients recently recovered from COVID-19, 60% of patients had finding consistent with myocardial inflammation on magnetic resonance imaging. Myocarditis may be non-viral, as a part of the hyperinflammatory response reported in COVID-19, but also due to direct viral infiltration in myocardial cells[12, 39, 40]. Unspecific repolarization was found in 21% of patients and may be seen in myocarditis but is also associated with higher mortality due to cardiovascular disease in the general population.
Although patients with COVID-19 have high risk of pulmonary embolism and 11% of the patients in our cohort were diagnosed with pulmonary embolism, none of them had an ECG consistent with right ventricular strain. In a case series of 15 hospitalized patients with confirmed COVID-19 and pulmonary embolism, 33% had right ventricular strain pattern on ECG while two-thirds had non-specific ECG findings, such as sinus tachycardia. The absence of right ventricular strain pattern in our study could simply be due to the absence of pulmonary embolism at the time of the ECG-recording. However, critically ill patients with COVID-19 related pulmonary embolism may also have less clot burden compared to a general ICU population with pulmonary embolism, and right ventricular strain pattern may therefore not manifest on the ECG. Further, the incidence of pulmonary embolism was lower in our cohort than in other studies, possibly due to a higher dose low molecular weight heparin thromboprophylaxis at our ICU.
In a previous study, patients with an abnormal ECG developed higher peak plasma creatinine and had a higher incidence of continuous renal replacement therapy compared to patients with normal ECG. In our study, peak plasma creatinine was similarly higher in patients with prior MI pattern compared to those with normal ECG. Patients with ST-T pathology also developed higher peak plasma creatinine values compared to patients with normal ECG, but this finding was only borderline significant, likely due to low statistical power. Kidney injury in COVID-19 is likely multifactorial and may be caused by several mechanisms, in part common to those responsible for cardiac injury, including both direct viral pathophysiological effects, systemic inflammation, hypovolemia and cardiopulmonary instability related to the degree of illness severity[2, 34, 48]. Pre-existing cardiovascular risk factors are frequent in COVID-19 patients and may further contribute to the development of simultaneous cardiac and renal dysfunction.
Contrary to previous studies, where immune dysregulation has been proposed as a major mechanism for cardiac injury in COVID-19 and cardiac biomarkers have been positively associated with inflammatory biomarkers[49, 50], we found no statistically difference in CRP, ferritin and IL-6, between patients with prior MI pattern or ST-T pathology compared to patients with normal ECG in our study. Patients admitted to the ICU may represent a cohort of patients with severe inflammatory response regardless of myocardial injury which could explain the lack of difference in our study. Pathological ECG changes may thus not primarily be caused by more severe inflammation, but rather similar levels of inflammation causing ECG abnormalities and cardiac injury primarily in patients with pre-existing cardiac disease.
Strengths of this study included that ECG interpretation was conducted according to pre-specified criteria by two independent physicians blinded to patient outcomes. The study was conducted at a large tertiary referral centre with a large catchment area and all inhabitants in Sweden are covered by the public health insurance increasing generalizability of our study. Further, no patients were lost to follow up and there was minimal missing data.
There are also limitations of this study. The single centre design reduces generalizability and the small sample size hampers statistical power, especially in the multivariate analysis where only additional adjustment for SAPS 3 was feasible. Several patients did not have an ECG recorded at ICU admission, which may have led to selection bias if patients with pre-existing comorbidities or more severe disease were more likely to have ECG recorded. Even so, this study contains important new information for bedside clinicians and future studies. If confirmed, ECG findings presented herein may be used in prognostic tools for severe COVID-19 and the apparent lack of association between pathological ECG and inflammatory markers may further the understanding how COVID-19 affects the cardiovascular system.