This week, our very own Carolyn Lam is in the author role along with author Vlado Perkovic, Associate Editor Naveed Sattar, and Guest Editor John McMurray as they discuss the articles "Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial" and "Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: A Pooled Analysis of SUSTAIN 6 and LEADER Trials." Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam:             I have a confession. I am nervous because right after this, Dr. Greg Hundley is going to interview me and, thank goodness, not just me, but really, really interesting other authors and editors with feature papers, all about GLP-1 receptor agonists and the SGLT-2 inhibitors. Very, very, very hot topic. Do listen up! But for now, Greg, you're going to be nice, right? How would you start? Dr. Greg Hundley:           Well, thank you, Carolyn. I am really looking forward to that. Maybe we'll have a few quiz questions in there. Before we get started, how about we grab a cup of coffee? I am going to bring to our listeners a paper from the world of preclinical science. It's from Professor Vincent Christoffels from Amsterdam. Carolyn, there's a pathogenic variant in the fifth exon of TBX-5 entitled PG125R. It's found in a Dutch atypical Holt-Oram syndrome family with early onset atrial fibrillation. These investigators modeled this in a mouse. Carolyn, this is the first human pathogenic variant based on a patient family in this key cardiac transcription factor that's been explored in an in-vivo animal model. Dr. Carolyn Lam:             Wow, that's interesting. So, what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. The investigative team identified widespread electrophysiological transcriptional and epigenetic changes including coding and non-coding RNA, chromatin accessibility, and H3K27ac associations in the atria of TBX5-PG125R heterozygous mice distinct from the changes in the atria of TBX5 insufficient animals. Dr. Carolyn Lam:             Okay. Could you give us the clinical take home message, Greg? Dr. Greg Hundley:           Right, Carolyn. What these authors really have found is that the characterization of the TBX5-BG125R mouse model... it indicates that a patient-specific pathogenic variant in TBX5 induces changes in regulatory element activity, an altered balance in the regulatory network of atrial cardiomyocytes, and clinically relevant changes in cardiomyocyte function. So therefore, Carolyn, this work may provide insight into the epigenetic changes and transcriptional underpinning of arrhythmias in the general population caused by small increases in TBX5 expression also caused by common variants predisposing ones to atrial fibrillation. Dr. Carolyn Lam:             Wow. Thanks Greg. Well, guess what? I've got an interesting mouse model to share about as well. This next paper comes from co-corresponding authors, Drs. Chen, Fu, and Wu from UCSD. What they do is provide insights into possible underlying factors in a molecular mechanism responsible for left ventricular noncompaction cardiomyopathy. Now, we know this condition, but... It was discovered half a century ago, yet owing in part to the lack of a suitable mouse model that faithfully mirrors that selective left ventricular vulnerability in patients, the actual mechanisms underlying susceptibility of the left ventricle to dilatation dysfunction in this condition ac