Immunothrombosis and its underlying biological mechanisms.

The evolutionary conserved link between coagulation and innate immunity is a biological process characterized by the thrombosis formation stimulus of immune cells and specific thrombosis-related molecules. In physiological settings, the relationship between the immune system and thrombosis facilitates the recognition of pathogens and damaged cells and inhibits pathogen proliferation. However, when deregulated, the interplay between hemostasis and innate immunity becomes a pathological process named immunothrombosis, which is at the basis of several infectious and inflammation-related thrombotic disorders, including coronavirus disease 2019 (COVID-19). In advanced stages, alterations in both coagulation and immune cell function due to extreme inflammation lead to an increase in blood coagulability, with high rates of thrombosis and mortality. Therefore, understanding underlying mechanisms in immunothrombosis has become decisive for the development of more efficient therapies to treat and prevent thrombosis in COVID-19 and in other thrombotic disorders. In this review, we outline the existing knowledge on the molecular and cellular processes involved in immunothrombosis, focusing on the role of neutrophil extracellular traps (NETs), platelets and the coagulation pathway. We also describe how the deregulation of hemostasis is associated with pathological conditions and can significantly aggravate a patient's condition, using COVID-19 as a clinical model.

Impaired Cardiac Sympathetic Activity Is Associated With Myocardial Remodeling and Established Biomarkers of Heart Failure.

BACKGROUND: 123Iodine-meta-iodobenzylguanidine scintigraphy is useful for assessing cardiac autonomic dysfunction and predict outcomes in heart failure (HF). The relationship of cardiac sympathetic function with myocardial remodeling and diffuse fibrosis remains largely unknown. We aimed to evaluate the cardiac sympathetic function of patients with HF and its relation with myocardial remodeling and exercise capacity. METHODS AND RESULTS: Prospectively enrolled patients with HF (New York Heart Association class II-III) were stratified into HF with preserved left ventricular ejection fraction [LVEF] ≥45%) and reduced LVEF. Ventricular morphology/function and myocardial extracellular volume (ECV) fraction were quantified by cardiovascular magnetic resonance, global longitudinal strain by echocardiography, cardiac sympathetic function by heart-to-mediastinum ratio from 123iodine-meta-iodobenzylguanidine scintigraphy. All participants underwent cardiopulmonary exercise testing. The cohort included 33 patients with HF with preserved LVEF (LVEF, 60±10%; NT-proBNP [N-terminal pro-B-type natriuretic peptide], 248 [interquartile range, 79-574] pg/dL), 28 with HF with reduced LVEF (LVEF, 30±9%; NT-proBNP, 743 [interquartile range, 250-2054] pg/dL) and 20 controls (LVEF, 65±5%; NT-proBNP, 40 [interquartile range, 19-50] pg/dL). Delayed (4 hours) 123iodine-meta-iodobenzylguanidine heart-to-mediastinum ratio was lower in HF with preserved LVEF (1.59±0.25) and HF with reduced LVEF (1.45±0.16) versus controls (1.92±0.24; P<0.001), and correlated negatively with diffuse fibrosis assessed by ECV (R=-0.34, P<0.01). ECV in segments without LGE was increased in HF with preserved ejection fraction (0.32±0.05%) and HF with reduced left ventricular ejection fraction (0.31±0.04%) versus controls (0.28±0.04, P<0.05) and was associated with the age- and sex-adjusted maximum oxygen consumption (peak oxygen consumption); (R=-0.41, P<0.01). Preliminary analysis indicates that cardiac sympathetic function might potentially act as a mediator in the association between ECV and NT-proBNP levels. CONCLUSIONS: Abnormally low cardiac sympathetic function in patients with HF with reduced and preserved LVEF is associated with extracellular volume expansion and decreased cardiopulmonary functional capacity.

Profile of serum microRNAs in heart failure with reduced and preserved ejection fraction: Correlation with myocardial remodeling.

Background and aims: Cardiomyocyte hypertrophy and interstitial fibrosis are key components of myocardial remodeling in Heart Failure (HF) with preserved (HFpEF) or reduced ejection fraction (HFrEF). MicroRNAs (miRNAs) are non-coding, evolutionarily conserved RNA molecules that may offer novel insights into myocardial remodeling. This study aimed to characterize miRNA expression in HFpEF (LVEF ≥ 45%) and HFrEF (LVEF < 45%) and its association with myocardial remodeling. Methods: Prospectively enrolled symptomatic HF patients (HFpEF:n = 36; HFrEF:n = 31) and controls (n = 23) underwent cardiac magnetic resonance imaging with T1-mapping and circulating miRNA expression (OpenArray system). Results: 13 of 188 miRNAs were differentially expressed between HF groups (11 downregulated in HFpEF). Myocardial extracellular volume (ECV) was increased in both HF groups (HFpEF 30 ± 5%; HFrEF 30 ± 3%; controls 26 ± 2%, p < 0.001). miR-128a-3p, linked to cardiac hypertrophy, fibrosis, and dysfunction, correlated positively with ECV in HFpEF (r = 0.60, p = 0.01) and negatively in HFrEF (r = -0.51, p = 0.04). miR-423-5p overexpression, previously associated HF mortality, was inversely associated with LVEF (r = - 0.29, p = 0.04) and intracellular water lifetime (τic) (r = -0.45, p < 0.05) in both HF groups, and with NT-proBNP in HFpEF (r = -0.63, p < 0.01). Conclusions: miRNA expression profiles differed between HF phenotypes. The differential expression and association of miR-128a-3p with ECV may reflect the distinct vascular, interstitial, and cellular etiologies of HF phenotypes.

Prognostic role of renal replacement therapy among hospitalized patients with heart failure in the Brazilian national public health system.

Introduction: Data on patients hospitalized with acute heart failure in Brazil scarce. Methods: We performed a cross-sectional, retrospective, records-based study using data retrieved from a large public database of heart failure admissions to any hospital from the Brazilian National Public Health System (SUS) (SUS Hospital Information System [SIHSUS] registry) to determine the in-hospital all-cause mortality rate, in-hospital renal replacement therapy rate and its association with outcome. Results: In total, 910,128 hospitalizations due to heart failure were identified in the SIHSUS registry between April 2017 and August 2021, of which 106,383 (11.7%) resulted in in-hospital death. Renal replacement therapy (required by 8,179 non-survivors [7.7%] and 11,496 survivors [1.4%, p < 0.001]) was associated with a 56% increase in the risk of death in the univariate regression model (HR 1.56, 95% CI 1.52 -1.59), a more than threefold increase of the duration of hospitalization, and a 45% or greater increase of cost per day. All forms of renal replacement therapy remained independently associated with in-hospital mortality in multivariable analysis (intermittent hemodialysis: HR 1.64, 95% CI 1.60 -1.69; continuous hemodialysis: HR 1.52, 95% CI 1.42 -1.63; peritoneal dialysis: HR 1.47, 95% CI 1.20 -1.88). Discussion: The in-hospital mortality rate of 11.7% observed among patients with acute heart failure admitted to Brazilian public hospitals was alarmingly high, exceeding that of patients admitted to North American and European institutions. This is the first report to quantify the rate of renal replacement therapy in patients hospitalized with acute heart failure in Brazil.

Thrombosis Occurrence in COVID-19 Compared With Other Infectious Causes of ARDS: A Contemporary Cohort.

Thrombosis occurrence in coronavirus disease 2019 (COVID-19) has been mostly compared to historical cohorts of patients with other respiratory infections. We retrospectively evaluated the thrombotic events that occurred in a contemporary cohort of patients hospitalized between March and July 2020 for acute respiratory distress syndrome (ARDS) according to the Berlin Definition and compared those with positive and negative real-time polymerase chain reaction results for wild-type severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) using descriptive analysis. The association between COVID-19 and thrombotic risk was evaluated using logistic regression. 264 COVID-19-positive (56.8% male, 59.0 years [IQR 48.6-69.7], Padua score on admission 3.0 [2.0-3.0]) and 88 COVID-19-negative patients (58.0% male, 63.7 years [51.2-73.5], Padua score 3.0 [2.0-5.0]) were included. 10.2% of non-COVID-19 and 8.7% of COVID-19 patients presented ≥ 1 clinically relevant thrombotic event confirmed by imaging exam. After adjustment for sex, Padua score, intensive care unit stay, thromboprophylaxis, and hospitalization length, the odds ratio for thrombosis in COVID-19 was 0.69 (95% CI, 0.30-1.64). We, therefore, conclude that infection-induced ARDS carries an inherent thrombotic risk, which was comparable between patients with COVID-19 and other respiratory infections in our contemporary cohort.

Immunothrombosis and its underlying biological mechanisms

Abstract The evolutionary conserved link between coagulation and innate immunity is a biological process characterized by the thrombosis formation stimulus of immune cells and specific thrombosis-related molecules. In physiological settings, the relationship between the immune system and thrombosis facilitates the recognition of pathogens and damaged cells and inhibits pathogen proliferation. However, when deregulated, the interplay between hemostasis and innate immunity becomes a pathological process named immunothrombosis, which is at the basis of several infectious and inflammation-related thrombotic disorders, including coronavirus disease 2019 (COVID-19). In advanced stages, alterations in both coagulation and immune cell function due to extreme inflammation lead to an increase in blood coagulability, with high rates of thrombosis and mortality. Therefore, understanding underlying mechanisms in immunothrombosis has become decisive for the development of more efficient therapies to treat and prevent thrombosis in COVID-19 and in other thrombotic disorders. In this review, we outline the existing knowledge on the molecular and cellular processes involved in immunothrombosis, focusing on the role of neutrophil extracellular traps (NETs), platelets and the coagulation pathway. We also describe how the deregulation of hemostasis is associated with pathological conditions and can significantly aggravate a patient's condition, using COVID-19 as a clinical model.