This week’s episode includes author Jeffrey Testani and Associate Editor Justin Grodin as they discuss empagliflozin heart failure, including diuretic and cardio-renal effects. TRANSCRIPT: 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 Centre and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg. I'm the director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, the SGLT-2 inhibitors have really revolutionized heart failure treatment, but we still need to understand a bit better how they work. And today's feature paper is so important, talking about diuretic and cardio-renal effects of Empagliflozin. That's all I'm going to tell you though, because I want to talk about another paper in the issue very related. And it's from John McMurray from the University of Glasgow with insights from DAPA-HF. But maybe a question for you first. Have you ever wondered what to do about loop diuretics doses in patients with heart failure and whom you're thinking of initiating an SGLT-2 inhibitor, Greg? Dr Greg Hundley: Absolutely, Carolyn. That comes up all the time and how do you make that transition. Dr Carolyn Lam: Exactly. And so this paper is just so important, and Dr McMurray and his colleagues showed that in the DAPA-HF trial, the SGLT-2 inhibitor, dapagliflozin, first, just as a reminder, reduce the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. And in the current paper, they examined the efficacy and tolerability that dapagliflozin falls in relation to background diuretic treatment and change in diuretic therapy, following randomization to dapagliflozin or placebo. They found that 84% of patients randomized were treated with a conventional diuretic, such as the loop or thiazides diuretic. The majority of patients did not change their diuretic dose throughout follow-up. And the mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization. Although a decrease in diuretic dose was more frequent with dapagliflozin than with placebo, the between-group differences were small. So treatment with dapagliflozin is safe and effective regardless of diuretic dose or diuretic use. Dr Greg Hundley: Very nice, Carolyn. That's such a nice practical article. I really enjoyed your presentation of that. My next article comes from Professor Karlheinz Peter, and it's investigating the reduction of shear stress and how that might impact monocyte activation in patients that undergo TAVI. So this group hypothesized that the large shear forces exerted on circulating cells, particularly in the largest circulating cells, monocytes, while passing through stenotic aortic valves results in pro-inflammatory effects that could be resolved with TAVI. So to address this, the investigative team implemented functional essays, calcium imaging, RNA gene silencing and pharmacologic agonist and antagonist to identify the key mechanical- receptor mediating the shear stress sensitivity of the monocytes. In addition, they stained for monocytes in explanted, stenotic, aortic human valves. Dr Carolyn Lam: Lots of work done in a very translational study. So what did they find Greg? Dr Greg Hundley: They found monocyte accumulation at the aortic side of the leaflets in the explanted aortic valves. That was the human subject study. In addition, they demonstrated that high shear stress activates multiple monocyte functions and identify PZ1 as the main responsible mechanoreceptors representing, therefore, a potentially druggable target. So reducing the shear stress from a stenotic valve promotes an anti-inflammatory effect and, therefore, could serve as a novel therapeutic benefit of those undergoing TAVI procedures. Dr Carolyn Lam: Really nice, Greg. Thanks. We're going to switch tracks a bit, Gre