COVID-19 and the heart.

BACKGROUND: There is evidence for a bi-directional relationship between COVID-19 and the cardiovascular (CV) system. SOURCE OF DATA: Published literature. AREAS OF AGREEMENT: Pre-existing heart failure (HF) increases the risk of mortality with COVID-19. CV complications are recognized, including increased rates of acute coronary syndromes, HF, arrhythmia and myocarditis. Drugs targeting the angiotensin system are safe and may provide prognostic benefit. AREAS OF CONTROVERSY: Vaccination as a cause of myocarditis remains a key area of contention. GROWING POINTS: As the pandemic progresses, we are gaining more data about the long-term effects of COVID-19 on the CV system: long COVID, and medium-to-long-term increases in CV risk. AREAS TIMELY FOR DEVELOPING RESEARCH: Large-scale longitudinal studies will shed light on long-term CV outcomes with COVID-19. Furthermore, the differential effects of COVID-19 variants on the CV system must be investigated.

Predictors of in-hospital mortality in critically ill patients with COVID-19: a large dual tertiary centre study.

OBJECTIVES: The aim of this study was to investigate the relationship of echocardiographic parameters, laboratory findings and clinical characteristics with in-hospital mortality in adult patients with COVID-19 admitted to the intensive care units (ICU) in two large collaborating tertiary UK centres. DESIGN: Observational retrospective study. SETTING: The study was conducted in patients admitted to the ICU in two large tertiary centres in London, UK. PARTICIPANTS: Inclusion criteria were: (1) patients admitted to the ICU with a COVID-19 diagnosis over a period of 16 weeks. and (2) underwent a transthoracic echocardiogram on the first day of ICU admission as clinically indicated.No exclusion criteria applied.Three hundred patients were enrolled and completed the follow-up. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome measure in this study was in-hospital mortality in patients admitted to the ICU with COVID-19 infection. RESULTS: Older age (HR: 1.027, 95% CI 1.007 to 1.047; p=0.008), left ventricular (LV) ejection fraction<35% (HR: 5.908, 95% CI 2.609 to 13.376; p<0.001), and peak C reactive protein (CRP) (HR: 1.002, 95% CI 1.001 to 1.004, p=0.001) were independently correlated with mortality in a multivariable Cox regression model. Following multiple imputation of variables with more than 5% missing values, random forest analysis was applied to the imputed data. Right ventricular (RV) basal diameter (RVD1), RV mid-cavity diameter (RVD2), tricuspid annular plane systolic excursion, RV systolic pressure, hypertension, RV dysfunction, troponin level on admission, peak CRP, creatinine level on ICU admission, body mass index and age were found to have a high relative importance (> 0.7). CONCLUSIONS: In patients with COVID-19 in the ICU, both severely impaired LV function and impaired RV function may have adverse prognostic implications, but older age and inflammatory markers appear to have a greater impact. A combination of echocardiographic and laboratory investigations as well as demographic and clinical characteristics appears appropriate for risk stratification in patients with COVID-19 who are admitted to the ICU.

Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective.

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.

Association of cardiometabolic microRNAs with COVID-19 severity and mortality.

AIMS: Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. METHODS AND RESULTS: We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. CONCLUSION: Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.

Cardiovascular Effects of COVID-19 - What Do We Know and Where Should We Go?

Amongst the many challenges of the global pandemic, understanding the effects of coronavirus disease 2019 (COVID-19) on the cardiovascular system has emerged as a key priority. Emerging data indicate possible roles for cardiac biomarkers and cardiac imaging in the prognostic assessment of these patients, as well as implications of the vascular endothelium in the pathogenesis of the condition. From a therapeutic perspective, early data suggest that the provision of well-established treatments for cardiovascular disease, whether with angiotensin-converting enzyme inhibitors or primary angioplasty, is likely to be beneficial. These early data are of limited quality however, and robust studies are needed to address many of the key remaining questions.

Pre-existing cardiovascular disease rather than cardiovascular risk factors drives mortality in COVID-19.

BACKGROUND: The relative association between cardiovascular (CV) risk factors, such as diabetes and hypertension, established CV disease (CVD), and susceptibility to CV complications or mortality in COVID-19 remains unclear. METHODS: We conducted a cohort study of consecutive adults hospitalised for severe COVID-19 between 1st March and 30th June 2020. Pre-existing CVD, CV risk factors and associations with mortality and CV complications were ascertained. RESULTS: Among 1721 patients (median age 71 years, 57% male), 349 (20.3%) had pre-existing CVD (CVD), 888 (51.6%) had CV risk factors without CVD (RF-CVD), 484 (28.1%) had neither. Patients with CVD were older with a higher burden of non-CV comorbidities. During follow-up, 438 (25.5%) patients died: 37% with CVD, 25.7% with RF-CVD and 16.5% with neither. CVD was independently associated with in-hospital mortality among patients < 70 years of age (adjusted HR 2.43 [95% CI 1.16-5.07]), but not in those ≥ 70 years (aHR 1.14 [95% CI 0.77-1.69]). RF-CVD were not independently associated with mortality in either age group (< 70 y aHR 1.21 [95% CI 0.72-2.01], ≥ 70 y aHR 1.07 [95% CI 0.76-1.52]). Most CV complications occurred in patients with CVD (66%) versus RF-CVD (17%) or neither (11%; p < 0.001). 213 [12.4%] patients developed venous thromboembolism (VTE). CVD was not an independent predictor of VTE. CONCLUSIONS: In patients hospitalised with COVID-19, pre-existing established CVD appears to be a more important contributor to mortality than CV risk factors in the absence of CVD. CVD-related hazard may be mediated, in part, by new CV complications. Optimal care and vigilance for destabilised CVD are essential in this patient group. Trial registration n/a.

SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.

First-Phase Ejection Fraction, a Measure of Preclinical Heart Failure, Is Strongly Associated With Increased Mortality in Patients With COVID-19.

Presence of heart failure is associated with a poor prognosis in patients with coronavirus disease 2019 (COVID-19). The aim of the present study was to examine whether first-phase ejection fraction (EF1), the ejection fraction measured in early systole up to the time of peak aortic velocity, a sensitive measure of preclinical heart failure, is associated with survival in patients hospitalized with COVID-19. A retrospective outcome study was performed in patients hospitalized with COVID-19 who underwent echocardiography (n=380) at the West Branch of the Union Hospital, Wuhan, China and in patients admitted to King's Health Partners in South London, United Kingdom. Association of EF1 with survival was performed using Cox proportional hazards regression. EF1 was compared in patients with COVID-19 and in historical controls with similar comorbidities (n=266) who had undergone echocardiography before the COVID-19 pandemic. In patients with COVID-19, EF1 was a strong predictor of survival in each patient group (Wuhan and London). In the combined group, EF1 was a stronger predictor of survival than other clinical, laboratory, and echocardiographic characteristics including age, comorbidities, and biochemical markers. A cutoff value of 25% for EF1 gave a hazard ratio of 5.23 ([95% CI, 2.85-9.60]; P<0.001) unadjusted and 4.83 ([95% CI, 2.35-9.95], P<0.001) when adjusted for demographics, comorbidities, hs-cTnI (high-sensitive cardiac troponin), and CRP (C-reactive protein). EF1 was similar in patients with and without COVID-19 (23.2±7.3 versus 22.0±7.6%, P=0.092, adjusted for prevalence of risk factors and comorbidities). Impaired EF1 is strongly associated with mortality in COVID-19 and probably reflects preexisting, preclinical heart failure.

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

Biological responses to COVID-19: Insights from physiological and blood biomarker profiles.

BACKGROUND: Understanding the spectrum and course of biological responses to coronavirus disease 2019 (COVID-19) may have important therapeutic implications. We sought to characterise biological responses among patients hospitalised with severe COVID-19 based on serial, routinely collected, physiological and blood biomarker values. METHODS AND FINDINGS: We performed a retrospective cohort study of 1335 patients hospitalised with laboratory-confirmed COVID-19 (median age 70 years, 56 % male), between 1st March and 30th April 2020. Latent profile analysis was performed on serial physiological and blood biomarkers. Patient characteristics, comorbidities and rates of death and admission to intensive care, were compared between the latent classes. A five class solution provided the best fit. Class 1 "Typical response" exhibited a moderately elevated and rising C-reactive protein (CRP), stable lymphopaenia, and the lowest rates of 14-day adverse outcomes. Class 2 "Rapid hyperinflammatory response" comprised older patients, with higher admission white cell and neutrophil counts, which declined over time, accompanied by a very high and rising CRP and platelet count, and exibited the highest mortality risk. Class 3 "Progressive inflammatory response" was similar to the typical response except for a higher and rising CRP, though similar mortality rate. Class 4 "Inflammatory response with kidney injury" had prominent lymphopaenia, moderately elevated (and rising) CRP, and severe renal failure. Class 5 "Hyperinflammatory response with kidney injury" comprised older patients, with a very high and rising CRP, and severe renal failure that attenuated over time. Physiological measures did not substantially vary between classes at baseline or early admission. CONCLUSIONS AND RELEVANCE: Our identification of five distinct classes of biomarker profiles provides empirical evidence for heterogeneous biological responses to COVID-19. Early hyperinflammatory responses and kidney injury may signify unique pathophysiology that requires targeted therapy.

A case-control and cohort study to determine the relationship between ethnic background and severe COVID-19.

BACKGROUND: People of minority ethnic backgrounds may be disproportionately affected by severe COVID-19. Whether this relates to increased infection risk, more severe disease progression, or worse in-hospital survival is unknown. The contribution of comorbidities or socioeconomic deprivation to ethnic patterning of outcomes is also unclear. METHODS: We conducted a case-control and a cohort study in an inner city primary and secondary care setting to examine whether ethnic background affects the risk of hospital admission with severe COVID-19 and/or in-hospital mortality. Inner city adult residents admitted to hospital with confirmed COVID-19 (n = 872 cases) were compared with 3,488 matched controls randomly sampled from a primary healthcare database comprising 344,083 people residing in the same region. For the cohort study, we studied 1827 adults consecutively admitted with COVID-19. The primary exposure variable was self-defined ethnicity. Analyses were adjusted for socio-demographic and clinical variables. FINDINGS: The 872 cases comprised 48.1% Black, 33.7% White, 12.6% Mixed/Other and 5.6% Asian patients. In conditional logistic regression analyses, Black and Mixed/Other ethnicity were associated with higher admission risk than white (OR 3.12 [95% CI 2.63-3.71] and 2.97 [2.30-3.85] respectively). Adjustment for comorbidities and deprivation modestly attenuated the association (OR 2.24 [1.83-2.74] for Black, 2.70 [2.03-3.59] for Mixed/Other). Asian ethnicity was not associated with higher admission risk (adjusted OR 1.01 [0.70-1.46]). In the cohort study of 1827 patients, 455 (28.9%) died over a median (IQR) of 8 (4-16) days. Age and male sex, but not Black (adjusted HR 1.06 [0.82-1.37]) or Mixed/Other ethnicity (adjusted HR 0.72 [0.47-1.10]), were associated with in-hospital mortality. Asian ethnicity was associated with higher in-hospital mortality but with a large confidence interval (adjusted HR 1.71 [1.15-2.56]). INTERPRETATION: Black and Mixed ethnicity are independently associated with greater admission risk with COVID-19 and may be risk factors for development of severe disease, but do not affect in-hospital mortality risk. Comorbidities and socioeconomic factors only partly account for this and additional ethnicity-related factors may play a large role. The impact of COVID-19 may be different in Asians. FUNDING: British Heart Foundation; the National Institute for Health Research; Health Data Research UK.

Predictive model of increased mortality and bed occupancy if thrombolysis becomes the initial treatment strategy for STEMI during the SARS-CoV-2 pandemic.

During the current SARS-CoV-2 pandemic the restructure of healthcare services to meet the huge increase in demand for hospital resource and capacity has led to the proposal that where necessary ST elevation myocardial infarction (STEMI) could be managed by intravenous thrombolysis in the first instance as a means of reducing the workforce requirements of a primary angioplasty service run at a heart attack centre. Our modelling, based on data from the UK, shows that contrary to reducing demand, the effect on both mortality and bed occupancy would be negative with 158 additional deaths per year for each 10% reduction in primary angioplasty and at a cost of ~8,000 additional bed days per year for the same reduction. Our analysis demonstrates that specialist services such as heart attack pathways should be protected during the COVID crisis to maximise the appropriate use of resource and prevent unnecessary mortality.