Circulation September 22, 2020 Issue Circulation on the Run

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, our feature paper today talks about the risks of sudden cardiac death, something that we still grapple with, and do you know what, really highlights the important emerging role of biomarkers of myocardial stress, myocardial injury, or even subclinical inflammation in predicting this risk. A really important discussion coming right up.
But before we do that, let me tell you about a paper in today's issue that really provides novel mechanistic insights into atrial fibrillation pathogenesis. In fact, this is the first paper to demonstrate that decreased expression of a striated muscle preferentially expressed protein kinase, or SPEG in atria, is causally linked to altered diastolic calcium handling and human paroxysmal atrial fibrillation.
This is from corresponding author, Dr Wehrens and colleagues from Baylor College of Medicine. And they used phosphoproteomic studies to identify S2367 on ryanodine receptor type-2 as a novel kinase substrate of SPEG. Through the study of novel ryanodine receptor type-2 phospho-mutant mouse models, they revealed that in contrast to previously characterized phosphorylation sites on this receptor, S2367 phosphorylation inhibited diastolic calcium release from the receptor, while loss of phosphorylation of the site increased atrial fibrillation susceptibility.
Dr Greg Hundley: Wow, Carolyn. So the clinical implication is that normalizing S2367 phosphorylation in SPEG activity may provide novel therapeutic opportunities for the treatment of atrial fibrillation, right?
Dr Carolyn Lam: You bet, Greg. Too smart. And this is discussed in an accompanying editorial by Drs Knollmann and Blackwell from Vanderbilt University Medical Center.
Dr Greg Hundley: Very nice, Carolyn. Well, I've got a paper pertaining to COVID-19, and it comes to us from Dr Leo Nicolai from the Klinik der Universität München in Germany. Carolyn, I really enjoyed this article about COVID-19. I found it very intriguing, and the study addresses the mechanisms by which the SARS-CoV-2 infection, associated pneumonia or COVID-19, leads to subsequent respiratory failure, complicating renal and myocardial involvement, and the prothrombotic phenotype found in some patients with COVID-19.
62 subjects were included in the study, 38 patients with RT-PCR confirmed COVID-19 and 24 non-COVID-19 controls. The investigative team performed histopathological assessments of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet-neutrophil functions and coagulation tests.
Dr Carolyn Lam: Wow, that sounds like really sort of in-depth testing. And what did they find?
Dr Greg Hundley: Several things, Carolyn. First, the authors found evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. They found that in COVID-19 patients, inflammatory microvascular thrombi are present in the lung, kidney and heart, containing neutrophil extracellular traps associated with platelets and fibrin.
Second, they observed that COVID-19 patients also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood which changes with disease severity, whereas cases of intermediate severity show an exhausted platelet and hyperreactive neutrophil phenotype. This finding differs for severely affected individuals. Among severely affected COVID-19 patients, there is excessive platelet and neutrophil activation compared to healthy controls and non-COVID-19 pneumonia.
Finally, dysregulated immunothrombosis in SARS-CoV-2 pneumonia