Prospective Case-Control Study of Cardiovascular Abnormalities 6 Months Following Mild COVID-19 in Healthcare Workers

Abstract

Objectives: The purpose of this study was to detect cardiovascular changes after mild severe acute respiratory syndrome-coronavirus-2 infection.

Background: Concern exists that mild coronavirus disease 2019 may cause myocardial and vascular disease.

Methods: Participants were recruited from COVIDsortium, a 3-hospital prospective study of 731 health care workers who underwent first-wave weekly symptom, polymerase chain reaction, and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post-infection, 74 seropositive and 75 age-, sex-, and ethnicity-matched seronegative control subjects were recruited for cardiovascular phenotyping (comprehensive phantom-calibrated cardiovascular magnetic resonance and blood biomarkers). Analysis was blinded, using objective artificial intelligence analytics where available.

Results: A total of 149 subjects (mean age 37 years, range 18 to 63 years, 58% women) were recruited. Seropositive infections had been mild with case definition, noncase definition, and asymptomatic disease in 45 (61%), 18 (24%), and 11 (15%), respectively, with 1 person hospitalized (for 2 days). Between seropositive and seronegative groups, there were no differences in cardiac structure (left ventricular volumes, mass, atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterization (T₁, T₂, extracellular volume fraction mapping, late gadolinium enhancement) or biomarkers (troponin, N-terminal pro-B-type natriuretic peptide). With abnormal defined by the 75 seronegatives (2 SDs from mean, e.g., ejection fraction <54%, septal T₁ >1,072 ms, septal T₂ >52.4 ms), individuals had abnormalities including reduced ejection fraction (n = 2, minimum 50%), T₁ elevation (n = 6), T₂ elevation (n = 9), late gadolinium enhancement (n = 13, median 1%, max 5% of myocardium), biomarker elevation (borderline troponin elevation in 4; all N-terminal pro-B-type natriuretic peptide normal). These were distributed equally between seropositive and seronegative individuals.

Conclusions: Cardiovascular abnormalities are no more common in seropositive versus seronegative otherwise healthy, workforce representative individuals 6 months post-mild severe acute respiratory syndrome-coronavirus-2 infection.

Keywords: COVID-19; SARS-CoV-2; cardiovascular magnetic resonance; late gadolinium enhancement; myocardial edema; myocarditis; troponin.

Graphical abstract

Figure 1

CONSORT Diagram The study design: a nested substudy of the parent COVIDsortium Bioresource. Ab = antibody; CMR = cardiac magnetic resonance; PCR = polymerase chain reaction.

Central Illustration

Summary of Findings Participants were recruited from COVIDsortium, a 3-hospital prospective study of 731 health care workers who underwent first-wave weekly symptom, polymerase chain reaction, and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post–mild severe acute respiratory syndrome coronavirus 2 infection, 74 seropositive and 75 age-, sex-, and ethnicity-matched seronegative health care workers underwent multiparametric cardiac magnetic resonance (CMR). This was phantom controlled, using artificial intelligence analytics with blinded human oversight. Our main finding was that there were no detectable cardiovascular differences in 5 primary and 5 secondary endpoints.

Figure 2

All Subjects With Reported LGE Outside of the RV Insertion Point There were 13 subjects with reported LGE outside of the RV insertion point. We show a single slice from all (i.e., no freedom to select cases). In total, 6 were found in seropositive cases (A to F), and 7 in seronegative cases (G to M). In addition to the low frequency of LGE abnormalities, the LGE was mainly small-volume, noninfarct pattern and nonspecific. Some may be normal (e.g., a likely septal perforator vessel visible in the anteroseptum) (A). In 2, the abnormality was 3 segments (M and J). For the rest of these subject results, see Figure 4. For LGE segmentation, see Supplemental Figure 1. LGE = late gadolinium enhancement; RV = right ventricular.

Figure 3

Dot Plots of the Pre-Specified Primary Endpoints There are no statistical differences in any between group comparisons. LGE is not drawn (as 136 were negative with 6 in the seropositive and 7 in the seronegative; p = NS – making it hard to graph). Septal T₁ and T₂ were pre-specified endpoints, but global T₁ and T₂ were also measured and are displayed here (also with no statistical differences). LGE = late gadolinium enhancement; LVEDVi = left ventricular end-diastolic volume indexed; LVEF = left ventricular ejection fraction.

Figure 4

Graphical Representation of Abnormalities in Blood and Imaging Within Individuals by Serostatus All 149 subjects ranked by age with the results of the 5 primary and 5 secondary endpoints, plus biomarkers. Each horizontal row (12 across) is a health care worker, with seropositives (left) and seronegatives (right). A green cell is a normal result, blue is 2 SDs abnormal or LGE present, red is 4 SDs abnormal or LGE ≥3 segments, and white is missing data. (A to M) Cross-reference the LGE images in Figure 2. Of the 1,776 results ([12 × 149] – 12 missing datapoints), abnormalities cluster in only a few (see the >55-year-old seronegative subject, a horizontal line of 6 abnormal results). Note that when T₁ and T₂ are abnormal (15 times), in no case were T₁ and T₂ abnormal at the same time. There is a single T₂ septal outlier (4 SD) considered on post hoc review to be erroneously from poor motion correction, but has been left in the pre-specified analyses. BNP = B-type natriuretic peptide; ECV = extracellular volume fraction; EDV = left ventricular end diastolic volume indexed; EF = ejection fraction; GLS = global longitudinal shortening; LAA = left atrial area indexed; LGE = late gadolinium enhancement; LVM = left ventricular mass index; TNT = troponin T.