Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci.

Relationship Between Myocardial Injury During Index Hospitalization for SARS-CoV-2 Infection and Longer-Term Outcomes.

Background Myocardial injury in patients with COVID-19 is associated with increased mortality during index hospitalization; however, the relationship to long-term sequelae of SARS-CoV-2 is unknown. This study assessed the relationship between myocardial injury (high-sensitivity cardiac troponin T level) during index hospitalization for COVID-19 and longer-term outcomes. Methods and Results This is a prospective cohort of patients who were hospitalized at a single center between March and May 2020 with SARS-CoV-2.

Rare, Damaging DNA Variants in and Risk of Coronary Artery Disease: Insights From Functional Genomics and Large-Scale Sequencing Analyses.

Background: Corin is a protease expressed in cardiomyocytes that plays a key role in salt handling and intravascular volume homeostasis via activation of natriuretic peptides. It is unknown if Corin loss-of-function (LOF) is causally associated with risk of coronary artery disease (CAD).

Methods: We analyzed all coding variants in an Italian case-control study of CAD.

Chronic Thromboembolic Pulmonary Hypertension: the Bench.

Purpose Of Review: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary embolism (PE), in which the red, platelet-rich thrombus does not resolve but forms into an organized yellow, fibrotic scar-like obstruction in the pulmonary vasculature. Here we review the pathobiology of CTEPH.

Recent Findings: Our current knowledge has predominantly been informed by studies of human samples and animal models that are inherently limited in their ability to recapitulate all aspects of the disease.

A neutrophil activation signature predicts critical illness and mortality in COVID-19.

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of more than 3300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, hepatocyte growth factor, interleukin-8, and granulocyte colony-stimulating factor, which were the strongest predictors of critical illness.

A neutrophil activation signature predicts critical illness and mortality in COVID-19.

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of over 3,300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, HGF, IL-8, and G-CSF, as the strongest predictors of critical illness.

COVID-19 for the Cardiologist: Basic Virology, Epidemiology, Cardiac Manifestations, and Potential Therapeutic Strategies.

Coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has reached pandemic status. As it spreads across the world, it has overwhelmed health care systems, strangled the global economy, and led to a devastating loss of life. Widespread efforts from regulators, clinicians, and scientists are driving a rapid expansion of knowledge of the SARS-CoV-2 virus and COVID-19.

A Tight Squeeze: Focal Tamponade and Obstructive Shock From Esophageal Stenting.

Cardiac tamponade is a rare cause of shock in the medical intensive care unit. This paper describes the case of a focal cardiac tamponade caused by compression of the left atrium due to an esophageal stent. Echocardiography yielded a diagnosis when other diagnostic methods did not.

Publisher Correction: N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA-dependent neovascularization.

The original version of this Article contained errors in Figures 1, 3 and 4. In panels b and d of Figure 1, the labels 'Sdc4' were inadvertently replaced by 'Sdc4'. In panels c and d of Figure 3, the labels 'Sdc4' were replaced by 'Sdc2'.

N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA-dependent neovascularization.

The proteoglycan Syndecan-2 (Sdc2) has been implicated in regulation of cytoskeleton organization, integrin signaling and developmental angiogenesis in zebrafish. Here we report that mice with global and inducible endothelial-specific deletion of Sdc2 display marked angiogenic and arteriogenic defects and impaired VEGFA signaling. No such abnormalities are observed in mice with deletion of the closely related Syndecan-4 (Sdc4) gene.

Endothelial signaling and the molecular basis of arteriovenous malformation.

Arteriovenous malformations occur when abnormalities of vascular patterning result in the flow of blood from arteries to veins without an intervening capillary bed. Recent work has revealed the importance of the Notch and TGF-β signaling pathways in vascular patterning. Specifically, Notch signaling has an increasingly apparent role in arterial specification and suppression of branching, whereas TGF-β is implicated in vascular smooth muscle development and remodeling under angiogenic stimuli.

Endothelial RAF1/ERK activation regulates arterial morphogenesis.

Arterial morphogenesis is one of the most critical events during embryonic vascular development. Although arterial fate specification is mainly controlled by the Notch signaling pathway, arterial-venous patterning is modulated by a number of guidance factors. How these pathways are regulated is still largely unknown.

Endothelial ERK signaling controls lymphatic fate specification.

Lymphatic vessels are thought to arise from PROX1-positive endothelial cells (ECs) in the cardinal vein in response to induction of SOX18 expression; however, the molecular event responsible for increased SOX18 expression has not been established. We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1(S259A)) that is associated with Noonan syndrome. Expression of mutant RAF1(S259A) in ECs activated ERK and induced SOX18 and PROX1 expression, leading to increased commitment of venous ECs to the lymphatic fate.