Case-Control; Retrospective Cohort
Study population and setting
This case-control study assessed patterns of myocardial injury using multiparametric cardiovascular magnetic resonance (CMR) imaging in 148 patients who recovered from severe COVID-19 (e.g. all requiring hospital admission) and had troponin elevation during their hospitalization. Patients were recruited across six hospitals within the UK’s National Health Service network; CMR was performed at 3 sites. Case selection criteria included patients with a diagnosis of COVID-19 made by a positive reverse-transcriptase-polymerase chain reaction test for SARS-CoV-2, or positive for a triad of viral symptoms characteristic of COVID-19 illness, typical blood biomarkers, and findings of probable COVID-19 on chest radiography or by computed tomography. Eligible cases had to have an elevated high-sensitivity troponin level during admission, and were referred clinically for CMR because of the biomarker elevation. Discharges before June 20, 2020 were included. Case CMR scans were compared to research scans from a group of healthy volunteers (n=40) obtained prior to January 1, 2020 as well as a historical control group (n=40) obtained from stable outpatients prior to January 1, 2020 and matched for age, gender, diabetes, and hypertension but without suspicion for myocardial injury. Primary outcomes included presence, patterns, and extent of myocardial injury in recovered COVID patients compared to a control group and healthy volunteers.
Summary of Main Findings
Among case patients recovered from severe COVID-19 illness with elevated troponin, 30% (n=44) were female, average age was 64 years (+/- 12), and self-reported ethnicity was 50% white (n=75), 18% Afro-Caribbean (n=26), and 15% Asian (n=22). Case patients were imaged a median of 68 days following confirmed diagnosis (56 days from discharge). Cardiovascular risk factors were frequent among the cases (prior myocardial infarction in 7%, prior coronary revascularization in 12%, hypertension in 57%, diabetes in 34%, hypercholesterolemia in 46%, and smoking history in 24%). The control group was relatively well-matched, except for ethnicity and prior revascularization. Left ventricular (LV) function was normal in 89% with average case left ventricular ejection fraction (LVEF) at 67% +/- 11%, which was no different from matched controls (LVEF 67% +/- 9%, P=0.99) or healthy volunteers (LVEF 66% +/- 5%, P=0.55). In 54% (80/148) of case patients, there was evidence of late gadolinium enhancement (LGE), both ischemic and non-ischemic and/or ischemia on CMR (adenosine stress performed in a subset). Observed patterns of myocardial injury consisted of non-infarct myocarditis-like scar (26% [39/148]), ischemic heart related (infarction by LGE and/or ischemia) (22% [32/148]), non-ischemic non-specific scar (5% [7/148]), and dual ischemic and non-ischemic pathology (6% [9/148]). Myocardial infarction was found in 19% (28/148) of case patients, and inducible ischemia was found in 26% (20/76) of case patients undergoing stress perfusion. 66% (27/41) of patients with ischemic injury had no history of coronary artery disease. Among patients with non-ischemic, myocarditis-like injury, 30% (12/40) had active myocarditis with elevations in both T1 and T2, and 68% (27/40) had evidence of healed myocarditis, with only elevated native T1 values. The T1/T2 indices were not different in the remote regions between cases and matched controls, suggesting the absence of diffuse fibrosis and edema. For the LGE findings, there was a higher prevalence of the subepicardial LGE pattern among cases compared to controls, but no other differences in patterns with similar overall prevalence of any LGE (49% vs. 45% compared to 0% in the healthy volunteers). Peak troponin level was not predictive of myocarditis diagnosis. Extracardiac findings (pleural and pericardial effusions) were relatively infrequent (9% and 5%, respectively). Among those with a normal CMR scan, 51% underwent computed tomography pulmonary angiography during admission, of which 29% were diagnosed with pulmonary embolism, which could have contributed to the troponin elevation. However, among those with an abnormal CMR, the prevalence of pulmonary embolism was also high at 43% and hence, pulmonary embolus should not be assumed to be the only cause of troponin elevation. Right ventricular ejection fraction was lower and RV volumes higher among cases compared to controls (though still in normal range), perhaps attributable to the high prevalence of pulmonary emboli as well as the likely severe pulmonary involvement in these severely ill COVID patients.
This multicenter case-control study examined a high-risk cohort with elevated troponin (most at risk for cardiac injury) for post-COVD sequelae. Patients were enrolled across 6 hospitals in the UK and included an ethnically diverse cohort of subjects. There were comparison CMR scans from COVID-negative participants, including those from matched controls and normal volunteers, the latter to establish normal values of T1 and T2 indices as well as phantom standardization of the mapping sequences.
The total number of discharged patients with elevated troponins was not stated and hence, there could be selection bias in those electing to follow-up with post-discharge CMR. Inclusion of only discharged patients introduces survivorship bias; by only studying those with troponin elevation, this likely overestimates the prevalence of myocardial injury among the broader group of COVID patients. Troponin-negative COVID-19 patients were not included as a comparison group, reducing usefulness of control groups. There were no pre-hospitalization studies in the cases so it was unclear the extent to which the CMR findings are new. Post-contrast extracellular volume fraction was not assessed, which is generally more sensitive than native T1 for diffuse fibrosis. This study largely included the early pandemic period in the UK, a time with limited diagnostic resources and evolving therapies, which may have resulted in selection bias toward patients with the most severe and classic disease presentations. The extended period between discharge and CMR imaging may have contributed to underestimation of some disease presentations. As an observational study, confounding is likely to exist. There were no follow-up CMR scans to track temporal evolution of the CMR patterns.
This study is the largest reported CMR effort to date to comprehensively investigate myocardial injury in patients who have recovered from severe COVID-19 disease. It included appropriate COVID-negative controls and a quality assurance standardization protocol for the T1 and T2 mapping sequences.
This review was posted on: 22 March 2021