Utilization of cardiovascular magnetic resonance (CMR) imaging for resumption of athletic activities following COVID-19 infection: an expert consensus document on behalf of the American Heart Association Council on Cardiovascular Radiology and Intervention (CVRI) Leadership and endorsed by the Society for Cardiovascular Magnetic Resonance (SCMR).

The global pandemic of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory suyndrome coronavirus 2 (SARS-CoV-2) is now entering its 4th year with little evidence of abatement. As of December 2022, the World Health Organization Coronavirus (COVID-19) Dashboard reported 643 million cumulative confirmed cases of COVID-19 worldwide and 98 million in the United States alone as the country with the highest number of cases. While pneumonia with lung injury has been the manifestation of COVID-19 principally responsible for morbidity and mortality, myocardial inflammation and systolic dysfunction though uncommon are well-recognized features that also associate with adverse prognosis. Given the broad swath of the population infected with COVID-19, the large number of affected professional, collegiate, and amateur athletes raises concern regarding the safe resumption of athletic activity (return to play, RTP) following resolution of infection. A variety of different testing combinations that leverage the electrocardiogram, echocardiography, circulating cardiac biomarkers, and cardiovascular magnetic resonance (CMR) imaging have been proposed and implemented to mitigate risk. CMR in particular affords high sensitivity for myocarditis but has been employed and interpreted non-uniformly in the context of COVID-19 thereby raising uncertainty as to the generalizability and clinical relevance of findings with respect to RTP. This consensus document synthesizes available evidence to contextualize the appropriate utilization of CMR in the RTP assessment of athletes with prior COVID-19 infection to facilitate informed, evidence-based decisions, while identifying knowledge gaps that merit further investigation.

Utilization of Cardiovascular Magnetic Resonance Imaging for Resumption of Athletic Activities Following COVID-19 Infection: An Expert Consensus Document on Behalf of the American Heart Association Council on Cardiovascular Radiology and Intervention Leadership and Endorsed by the Society for Cardiovascular Magnetic Resonance.

The global pandemic of COVID-19 caused by infection with SARS-CoV-2 is now entering its fourth year with little evidence of abatement. As of December 2022, the World Health Organization Coronavirus (COVID-19) Dashboard reported 643 million cumulative confirmed cases of COVID-19 worldwide and 98 million in the United States alone as the country with the highest number of cases. Although pneumonia with lung injury has been the manifestation of COVID-19 principally responsible for morbidity and mortality, myocardial inflammation and systolic dysfunction though uncommon are well-recognized features that also associate with adverse prognosis. Given the broad swath of the population infected with COVID-19, the large number of affected professional, collegiate, and amateur athletes raises concern regarding the safe resumption of athletic activity (return to play) following resolution of infection. A variety of different testing combinations that leverage ECG, echocardiography, circulating cardiac biomarkers, and cardiovascular magnetic resonance imaging have been proposed and implemented to mitigate risk. Cardiovascular magnetic resonance in particular affords high sensitivity for myocarditis but has been employed and interpreted nonuniformly in the context of COVID-19 thereby raising uncertainty as to the generalizability and clinical relevance of findings with respect to return to play. This consensus document synthesizes available evidence to contextualize the appropriate utilization of cardiovascular magnetic resonance in the return to play assessment of athletes with prior COVID-19 infection to facilitate informed, evidence-based decisions, while identifying knowledge gaps that merit further investigation.

Unsupervised machine learning demonstrates the prognostic value of TAPSE/PASP ratio among hospitalized patients with COVID-19.

BACKGROUND: The ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) is a validated index of right ventricular-pulmonary arterial (RV-PA) coupling with prognostic value. We determined the predictive value of TAPSE/PASP ratio and adverse clinical outcomes in hospitalized patients with COVID-19. METHODS: Two hundred and twenty-nine consecutive hospitalized racially/ethnically diverse adults (≥18 years of age) admitted with COVID-19 between March and June 2020 with clinically indicated transthoracic echocardiograms (TTE) that included adequate tricuspid regurgitation (TR) velocities for calculation of PASP were studied. The exposure of interest was impaired RV-PA coupling as assessed by TAPSE/PASP ratio. The primary outcome was in-hospital mortality. Secondary endpoints comprised of ICU admission, incident acute respiratory distress syndrome (ARDS), and systolic heart failure. RESULTS: One hundred and seventy-six patients had both technically adequate TAPSE measurements and measurable TR velocities for analysis. After adjustment for age, sex, BMI, race/ethnicity, diabetes mellitus, and smoking status, log(TAPSE/PASP) had a significantly inverse association with ICU admission (p = 0.015) and death (p = 0.038). ROC analysis showed the optimal cutoff for TAPSE/PASP for death was 0.51 mm mmHg-1 (AUC = 0.68). Unsupervised machine learning identified two groups of echocardiographic function. Of all echocardiographic measures included, TAPSE/PASP ratio was the most significant in predicting in-hospital mortality, further supporting its significance in this cohort. CONCLUSION: Impaired RV-PA coupling, assessed noninvasively via the TAPSE/PASP ratio, was predictive of need for ICU level care and in-hospital mortality in hospitalized patients with COVID-19 suggesting utility of TAPSE/PASP in identification of poor clinical outcomes in this population both by traditional statistical and unsupervised machine learning based methods.

C-reactive Protein Elevation Is Associated With QTc Interval Prolongation in Patients Hospitalized With COVID-19.

Background: The relationship between inflammation and corrected QT (QTc) interval prolongation is currently not well defined in patients with COVID-19. Objective: This study aimed to assess the effect of marked interval changes in the inflammatory marker C-reactive protein (CRP) on QTc interval in patients hospitalized with COVID-19. Methods: In this retrospective cohort study of hospitalized adult patients admitted with COVID-19 infection, we identified 85 patients who had markedly elevated CRP levels and serial measurements of an ECG and CRP during the same admission. We compared mean QTc interval duration, and other clinical and ECG characteristics between times when CRP values were high and low. We performed mixed-effects linear regression analysis to identify associations between CRP levels and QTc interval in univariable and adjusted models. Results: Mean age was 58 ± 16 years, of which 39% were women, 41% were Black, and 25% were White. On average, the QTc interval calculated via the Bazett formula was 15 ms higher when the CRP values were "high" vs. "low" [447 ms (IQR 427-472 ms) and 432 ms (IQR 412-452 ms), respectively]. A 100 mg/L increase in CRP was associated with a 1.5 ms increase in QTc interval [ß coefficient 0.15, 95% CI (0.06-0.24). In a fully adjusted model for sociodemographic, ECG, and clinical factors, the association remained significant (ß coefficient 0.14, 95% CI 0.05-0.23). Conclusion: An interval QTc interval prolongation is observed with a marked elevation in CRP levels in patients with COVID-19.

Real-Time Prediction of Mortality, Cardiac Arrest, and Thromboembolic Complications in Hospitalized Patients With COVID-19.

Background: COVID-19 infection carries significant morbidity and mortality. Current risk prediction for complications in COVID-19 is limited, and existing approaches fail to account for the dynamic course of the disease. Objectives: The purpose of this study was to develop and validate the COVID-HEART predictor, a novel continuously updating risk-prediction technology to forecast adverse events in hospitalized patients with COVID-19. Methods: Retrospective registry data from patients with severe acute respiratory syndrome coronavirus 2 infection admitted to 5 hospitals were used to train COVID-HEART to predict all-cause mortality/cardiac arrest (AM/CA) and imaging-confirmed thromboembolic events (TEs) (n = 2,550 and n = 1,854, respectively). To assess COVID-HEART's performance in the face of rapidly changing clinical treatment guidelines, an additional 1,100 and 796 patients, admitted after the completion of development data collection, were used for testing. Leave-hospital-out validation was performed. Results: Over 20 iterations of temporally divided testing, the mean area under the receiver operating characteristic curve were 0.917 (95% confidence interval [CI]: 0.916-0.919) and 0.757 (95% CI: 0.751-0.763) for prediction of AM/CA and TE, respectively. The interquartile ranges of median early warning times were 14 to 21 hours for AM/CA and 12 to 60 hours for TE. The mean area under the receiver operating characteristic curve for the left-out hospitals were 0.956 (95% CI: 0.936-0.976) and 0.781 (95% CI: 0.642-0.919) for prediction of AM/CA and TE, respectively. Conclusions: The continuously updating, fully interpretable COVID-HEART predictor accurately predicts AM/CA and TE within multiple time windows in hospitalized COVID-19 patients. In its current implementation, the predictor can facilitate practical, meaningful changes in patient triage and resource allocation by providing real-time risk scores for these outcomes. The potential utility of the predictor extends to COVID-19 patients after hospitalization and beyond COVID-19.

Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs.

BACKGROUND: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19. METHODS: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy. FINDINGS: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury. INTERPRETATION: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2. FUNDING: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health.

Improving risk prediction for pulmonary embolism in COVID-19 patients using echocardiography.

SARS-CoV-2 infection is associated with increased risk for pulmonary embolism (PE), a fatal complication that can cause right ventricular (RV) dysfunction. Serum D-dimer levels are a sensitive test to suggest PE, however lacks specificity in COVID-19 patients. The goal of this study was to identify a model that better predicts PE diagnosis in hospitalized COVID-19 patients using clinical, laboratory, and echocardiographic imaging predictors. We performed a cross-sectional study of 302 adult patients admitted to the Johns Hopkins Hospital (March 2020-February 2021) for COVID-19 infection who underwent transthoracic echocardiography and D-dimer testing; 204 patients had CT angiography. Clinical, laboratory and imaging predictors including, but not limited to, D-dimer and RV dysfunction were used to build prediction models for PE using logistic regression. Model discrimination was assessed using area under the receiver operator curve (AUC) and calibration using Hosmer-Lemeshow χ 2 statistic. Internal validation was performed. The prevalence of PE was 7.6%. The model with positive D-dimer above 5 mg/L, RV dysfunction on echocardiography, and troponin had an AUC of 0.77, and cross-validated AUC of 0.74. D-dimer (>5 mg/L) had a positive association with PE (adj odds ratio = 4.40; 95% confidence interval: [1.80, 10.78]). We identified a model including clinical, imaging and laboratory variables that predicted PE in hospitalized COVID-19 patients. Positive D-dimer >5, RV dysfunction on echocardiography, and troponin were important predictors for calculating likelihood of PE diagnosis. This approach may be useful to aid in clinical decision-making related to diagnostic imaging and treatment. Prospective studies are needed to evaluate impact on patient outcomes.

Cardiovascular Magnetic Resonance for Patients With COVID-19.

COVID-19 is associated with myocardial injury caused by ischemia, inflammation, or myocarditis. Cardiovascular magnetic resonance (CMR) is the noninvasive reference standard for cardiac function, structure, and tissue composition. CMR is a potentially valuable diagnostic tool in patients with COVID-19 presenting with myocardial injury and evidence of cardiac dysfunction. Although COVID-19-related myocarditis is likely infrequent, COVID-19-related cardiovascular histopathology findings have been reported in up to 48% of patients, raising the concern for long-term myocardial injury. Studies to date report CMR abnormalities in 26% to 60% of hospitalized patients who have recovered from COVID-19, including functional impairment, myocardial tissue abnormalities, late gadolinium enhancement, or pericardial abnormalities. In athletes post-COVID-19, CMR has detected myocarditis-like abnormalities. In children, multisystem inflammatory syndrome may occur 2 to 6 weeks after infection; associated myocarditis and coronary artery aneurysms are evaluable by CMR. At this time, our understanding of COVID-19-related cardiovascular involvement is incomplete, and multiple studies are planned to evaluate patients with COVID-19 using CMR. In this review, we summarize existing studies of CMR for patients with COVID-19 and present ongoing research. We also provide recommendations for clinical use of CMR for patients with acute symptoms or who are recovering from COVID-19.

Natriuretic Peptide Levels and Clinical Outcomes Among Patients Hospitalized With Coronavirus Disease 2019 Infection.

OBJECTIVES: There is increasing evidence of cardiovascular morbidity associated with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019). Pro-B-type natriuretic peptide is a biomarker of myocardial stress, associated with various respiratory and cardiac outcomes. We hypothesized that pro-B-type natriuretic peptide level would be associated with mortality and clinical outcomes in hospitalized coronavirus disease 2019 patients. DESIGN: We performed a retrospective analysis using adjusted logistic and linear regression to assess the association of admission pro-B-type natriuretic peptide (analyzed by both cutoff > 125 pg/mL and log transformed pro-B-type natriuretic peptide) with clinical outcomes. We additionally treated body mass index, a confounder of both pro-B-type natriuretic peptide levels and coronavirus disease 2019 outcomes, as an ordinal variable. SETTING: We reviewed hospitalized patients with coronavirus disease 2019 who had a pro-B-type natriuretic peptide level measured within 48 hours of admission between March 1, and August 31, 2020, from a multihospital U.S. health system. PATIENTS: Adult patients (≥ 18 yr old; n = 1232) with confirmed coronavirus disease 2019 admitted to the health system. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After adjustment for demographics, comorbidities, and troponin I level, higher pro-B-type natriuretic peptide level was significantly associated with death and secondary outcomes of new heart failure, length of stay, ICU duration, and need for ventilation among hospitalized coronavirus disease 2019 patients. This significance persisted after adjustment for body mass index as an ordinal variable. The adjusted hazard ratio of death for log transformed pro-B-type natriuretic peptide was 1.56 (95% CI, 1.23-1.97; p < 0.0001). CONCLUSIONS: Further investigation is warranted on the utility of pro-B-type natriuretic peptide for clinical prognostication in coronavirus disease 2019 as well as implications of abnormal pro-B-type natriuretic peptide in the underlying pathophysiology of coronavirus disease 2019-related myocardial injury.

Myocardial Work Efficiency, A Novel Measure of Myocardial Dysfunction, Is Reduced in COVID-19 Patients and Associated With In-Hospital Mortality.

Background: Although troponin elevation is common in COVID-19, the extent of myocardial dysfunction and its contributors to dysfunction are less well-characterized. We aimed to determine the prevalence of subclinical myocardial dysfunction and its association with mortality using speckle tracking echocardiography (STE), specifically global longitudinal strain (GLS) and myocardial work efficiency (MWE). We also tested the hypothesis that reduced myocardial function was associated with increased systemic inflammation in COVID-19. Methods and Results: We conducted a retrospective study of hospitalized COVID-19 patients undergoing echocardiography (n = 136), of whom 83 and 75 had GLS (abnormal >-16%) and MWE (abnormal <95%) assessed, respectively. We performed adjusted logistic regression to examine associations of GLS and MWE with in-hospital mortality. Patients were mean 62 ± 14 years old (58% men). While 81% had normal left ventricular ejection fraction (LVEF), prevalence of myocardial dysfunction was high by STE; [39/83 (47%) had abnormal GLS; 59/75 (79%) had abnormal MWE]. Higher MWE was associated with lower in-hospital mortality in unadjusted [OR 0.92 (95% CI 0.85-0.99); p = 0.048] and adjusted models [aOR 0.87 (95% CI 0.78-0.97); p = 0.009]. In addition, increased systemic inflammation measured by interleukin-6 level was associated with reduced MWE. Conclusions: Subclinical myocardial dysfunction is common in COVID-19 patients with clinical echocardiograms, even in those with normal LVEF. Reduced MWE is associated with higher interleukin-6 levels and increased in-hospital mortality. Non-invasive STE represents a readily available method to rapidly evaluate myocardial dysfunction in COVID-19 patients and can play an important role in risk stratification.

The role of sex and inflammation in cardiovascular outcomes and mortality in COVID-19.

OBJECTIVE: Higher mortality in COVID-19 in men compared to women is recognized, but sex differences in cardiovascular events are less well established. We aimed to determine the independent contribution of sex to stroke, myocardial infarction and death in the setting of COVID-19 infection. METHODS: We performed a retrospective cohort study of hospitalized COVID-19 patients in a racially/ethnically diverse population. Clinical features, laboratory markers and clinical events were initially abstracted from medical records, with subsequent clinician adjudication. RESULTS: Of 2060 patients, myocardial injury (32% vs 23%, p = 0.019), acute myocardial infarction (2.7% vs 1.6%, p = 0.114), and ischemic stroke (1.8% vs 0.7%, p = 0.007) were more common in men vs women. In-hospital death occurred in 160 men (15%) vs 117 women (12%, p = 0.091). Men had higher odds of myocardial injury (odds ratio (OR) 2.04 [95% CI 1.43-2.91], p < 0.001), myocardial infarction (1.72 [95% CI 0.93-3.20], p = 0.085) and ischemic stroke (2.76 [95% CI 1.29-5.92], p = 0.009). Despite adjustment for demographics and cardiovascular risk factors, male sex predicted mortality (HR 1.33; 95% CI:1.01-1.74; p = 0.041). While men had significantly higher markers of inflammation, in sex-stratified analyses, increase in interleukin-6, C-reactive protein, ferritin and d-dimer were predictive of mortality and myocardial injury similarly in both sexes. CONCLUSIONS: Adjusted odds of myocardial injury, ischemic stroke and all-cause mortality, but not myocardial infarction, are significantly higher in men compared to women with COVID-19. Higher inflammatory markers are present in men but associated similarly with risk in both men and women. These data suggest that adverse cardiovascular outcomes in men vs. women are independent of cardiovascular comorbidities.

Myocardial Injury in Severe COVID-19 Compared With Non-COVID-19 Acute Respiratory Distress Syndrome.

BACKGROUND: Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in coronavirus disease 2019 (COVID-19). We aimed to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared with acute respiratory distress syndrome (ARDS) unrelated to COVID-19. METHODS: We included intubated patients with COVID-19 from 5 hospitals between March 15 and June 11, 2020, with troponin levels assessed. We compared them with patients from a cohort study of myocardial injury in ARDS and performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. In addition, we performed linear regression to identify clinical factors associated with myocardial injury in COVID-19. RESULTS: Of 243 intubated patients with COVID-19, 51% had troponin levels above the upper limit of normal. Chronic kidney disease, lactate, ferritin, and fibrinogen were associated with myocardial injury. Mortality was 22.7% among patients with COVID-19 with troponin under the upper limit of normal and 61.5% for those with troponin levels >10 times the upper limit of normal (P<0.001). The association of myocardial injury with mortality was not statistically significant after adjusting for age, sex, and multisystem organ dysfunction. Compared with patients with ARDS without COVID-19, patients with COVID-19 were older and had higher creatinine levels and less favorable vital signs. After adjustment, COVID-19-related ARDS was associated with lower odds of myocardial injury compared with non-COVID-19-related ARDS (odds ratio, 0.55 [95% CI, 0.36-0.84]; P=0.005). CONCLUSIONS: Myocardial injury in severe COVID-19 is a function of baseline comorbidities, advanced age, and multisystem organ dysfunction, similar to traditional ARDS. The adverse prognosis of myocardial injury in COVID-19 relates largely to multisystem organ involvement and critical illness.

Multimodality Imaging for Cardiac Evaluation in Patients with COVID-19.

PURPOSE OF REVIEW: A growing number of cardiovascular manifestations resulting from the novel SARS-CoV-2 coronavirus (COVID-19) have been described since the beginning of this global pandemic. Acute myocardial injury is common in this population and is associated with higher rates of morbidity and mortality. The focus of this review centers on the recent applications of multimodality imaging in the diagnosis and management of COVID-19-related cardiovascular conditions. RECENT FINDINGS: In addition to standard cardiac imaging techniques such as transthoracic echocardiography, other modalities including computed tomography and cardiac magnetic resonance imaging have emerged as useful adjuncts in select patients with COVID-19 infection, particularly those with suspected ischemic and nonischemic myocardial injury. Data have also emerged suggesting lasting COVID-19 subclinical cardiac effects, which may have long-term prognostic implications. With the spectrum of COVID-19 cardiovascular manifestations observed thus far, it is important for clinicians to recognize the role, strengths, and limitations of multimodality imaging techniques in this patient population.

Prominent Longitudinal Strain Reduction of Basal Left Ventricular Segments in Patients With Coronavirus Disease-19.

BACKGROUND: Coronavirus disease-19 (COVID-19) has been associated with overt and subclinical myocardial dysfunction. We observed a recurring pattern of reduced basal left ventricular (LV) longitudinal strain on speckle-tracking echocardiography in hospitalized patients with COVID-19 and subsequently aimed to identify characteristics of affected patients. We hypothesized that patients with COVID-19 with reduced basal LV strain would demonstrate elevated cardiac biomarkers. METHODS AND RESULT: Eighty-one consecutive patients with COVID-19 underwent speckle-tracking echocardiography. Those with poor quality speckle-tracking echocardiography (n = 2) or a known LV ejection fraction of <50% (n = 4) were excluded. Patients with an absolute value basal longitudinal strain of <13.9% (2 standard deviations below normal) were designated as cases (n = 39); those with a basal longitudinal strain of ≥13.9% were designated as controls (n = 36). Demographics and clinical variables were compared. Of 75 included patients (mean age 62 ± 14 years, 41% women), 52% had reduced basal strain. Cases had higher body mass index (median 34.1; interquartile range 26.5-37.9 kg/m2 vs median 26.9, interquartile range, 24.8-30.0 kg/m2, P = .009), and greater proportions of Black (74% vs 36%, P = .0009), hypertensive (79% vs 56%, P = .026), and diabetic patients (44% vs 19%, P = .025) compared with controls. Troponin and N-terminal pro-brain natriuretic peptide levels trended higher in cases, but were not significantly different. CONCLUSIONS: Reduced basal LV strain is common in patients with COVID-19. Patients with hypertension, diabetes, obesity, and Black race were more likely to have reduced basal strain. Further investigation into the significance of this strain pattern is warranted.