COVID-19 and Myocarditis: Review of Clinical Presentations, Pathogenesis and Management.

There are four main myocarditis presentations identified in the context of severe acute respiratory coronavirus 2 (SARS-CoV-2): myocarditis associated with acute coronavirus disease 2019 (COVID-19) infection, post-acute COVID-19 syndrome, multisystem inflammatory syndrome, and vaccination-associated myocarditis. This article reviews the clinical features and current management strategies for each of these presentations. The overall prevalence of myocarditis is considered to be rare, although accurate estimation is affected by heterogeneity in diagnostic criteria and reporting, as well as infrequent use of gold-standard diagnostic endomyocardial biopsy. Severity of disease can range from mild symptoms to fulminant myocarditis. Therapeutic interventions are typically supportive and extrapolated from treatment for non-COVID-19 viral myocarditis. Several pathogenic mechanisms for the development of myocarditis have been proposed, and ongoing research is critical for elucidating disease pathogenesis and potentially identifying therapeutic targets. The long-term cardiovascular sequelae of SARS-CoV-2 infections and associated myocarditis require further elucidation and understanding.

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.

Ambulatory Management of Worsening Heart Failure: Current Strategies and Future Directions.

Heart failure (HF) is a highly prevalent and morbid disease in the USA. The chronic, progressive course of HF is defined by periodic exacerbations of symptoms, described as 'worsening heart failure' (WHF). Previously, episodes of WHF have required hospitalization for intravenous diuretics; however, recent innovations in care delivery models for patients with HF have allowed a transition from the acute care setting to the ambulatory setting. The development of remote monitoring strategies, including device-based algorithms and implantable haemodynamic monitoring systems, has facilitated more advanced surveillance of patients, aiming to prevent the clinical deterioration that leads to hospitalization. Additionally, the establishment of multidisciplinary HF clinics has provided the setting and resources for the outpatient treatment of WHF, specifically the administration of intravenous diuretics. Here we review the current state of ambulatory HF management, including mechanisms for patient monitoring and treatment, and outline future opportunities for outpatient management of this patient population.

High-value laboratory testing for hospitalized COVID-19 patients: a review.

We present here an evidence-based review of the utility, timing, and indications for laboratory test use in the domains of inflammation, cardiology, hematology, nephrology and co-infection for clinicians managing the care of hospitalized COVID-19 patients. Levels of IL-6, CRP, absolute lymphocyte count, neutrophils and neutrophil-to-lymphocyte ratio obtained upon admission may help predict the severity of COVID-19. Elevated LDH, ferritin, AST, and d-dimer are associated with severe illness and mortality. Elevated cardiac troponin at hospital admission can alert clinicians to patients at risk for cardiac complications. Elevated proBNP may help distinguish a cardiac complication from noncardiac etiologies. Evaluation for co-infection is typically unnecessary in nonsevere cases but is essential in severe COVID-19, intensive care unit patients, and immunocompromised patients.

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.

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.

Prevalence and Clinical Correlates of Echo-Estimated Right and Left Heart Filling Pressures in Hospitalized Patients With Coronavirus Disease 2019.

OBJECTIVES: The prevalence of elevated right and left heart filling pressures in coronavirus disease 2019 is not well characterized. We aimed to characterize the prevalence of pulmonary hypertension and concurrent elevated left heart filling pressure in hospitalized patients with coronavirus disease 2019. We hypothesized that a significant proportion of coronavirus disease 2019 patients has evidence of pulmonary hypertension associated with elevated left heart filling pressure on transthoracic echocardiography. DESIGN: Retrospective cohort study. SETTING: Academic tertiary-care center. PATIENTS: Hospitalized coronavirus disease 2019 patients who underwent clinical transthoracic echocardiography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure variable of interest was right ventricular systolic pressure, calculated using the American Society of Echocardiography guidelines. Pulmonary hypertension was defined as right ventricular systolic pressure greater than 40 mm Hg. Left heart filling pressure was estimated with Nagueh's method for pulmonary artery occlusion pressure using E/e' ratio, and normal was considered pulmonary artery occlusion pressure less than 16 mm Hg. Clinical characteristics and outcomes were compared between the patients with and without pulmonary hypertension. A total of 73 patients (median age 66 yr [57-75 yr]; 46% women) were included. Median right ventricular systolic pressure was 39 mm Hg (interquartile range, 32-50 mm Hg), and 36 patients (49.3%) had evidence of pulmonary hypertension. Patients with pulmonary hypertension were more likely to require ICU admission (86% vs 65%; p = 0.035) and have acute respiratory distress syndrome (72% vs 49%; p = 0.0053) than those without. In-hospital mortality was 26% for those with pulmonary hypertension compared with 14% for those without (p = 0.19). Patients with pulmonary hypertension had higher median-estimated pulmonary artery occlusion pressure (17.4 mm Hg [12.7-21.3 mm Hg] vs 12.1 mm Hg [10.0-14.1 mm Hg]; p = 0.0008), and elevated left heart filling pressure was present in 59% of those with pulmonary hypertension. CONCLUSIONS: Pulmonary hypertension is common in hospitalized patients with coronavirus disease 2019 and is associated with poor clinical outcomes. Left ventricular filling pressure is elevated in over half of those with pulmonary hypertension and may represent a target to reduce right ventricular afterload and potentially improve outcomes in coronavirus disease 2019.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).