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 cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                In just a moment, we will be discussing further results from the CREDENCE trial. That's canagliflozin in patients with type 2 diabetes and chronic kidney disease, this time focusing on the cardiovascular outcomes as well as both primary and secondary prevention groups. Really exciting stuff, huh, Greg? Dr Greg Hundley:             Absolutely, Carolyn. Got any papers you want to have a coffee chat about? Dr Carolyn Lam:                Absolutely. So my first pick really tells us that allele-specific RNA silencing of human alleles may be effective in treating inherited cardiomyopathies. Want to hear more? Dr Greg Hundley:             You bet. Dr Carolyn Lam:                So, this is a study from Dr Ashley and colleagues from Stanford University School of Medicine who performed a selective allele-specific silencing of the human restrictive cardiomyopathy, a specific mutation of asparagine to lysine in the regulatory light chain, which is encoded by MYL2. So they did this in a humanized transgenic mouse model using an adeno-associated virus RNA interference approach. Using this approach, they showed that an interfering RNA treatment ameliorated disease phenotypes by specifically reducing the cardiac expression of the mutated allele, hypertrophic carb biomarkers and intramyocardial fibrosis. In fact, isolated cardiomyocytes from the treated animals showed normalization of contraction and relaxation dynamics with partial restoration of calcium re-uptake dynamics. Dr Greg Hundley:             Boy, Carolyn, sounds like improvement in cardiovascular function, but were there any adverse effects? Dr Carolyn Lam:                Great question. Well, they also performed cardiac genome-wide transcriptome profiling, which showed a reduction in the hypertrophic program without significant off-target effects, so that's important. So in summary, these results show the feasibility, efficacy, and safety of RNA interference therapeutics directed at human restrictive cardiomyopathy. A really promising step towards targeted therapy for a prevalent disease. Dr Greg Hundley:             Very nice. Carolyn. So I'm going to start my discussion also with a basic science paper that's going to focus on ischemia reperfusion injury and looking at the mechanism by which mitochondrial dysfunction can be avoided. So, the paper emanates from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital Medical University in Beijing. The study from Dr Li identifies an important mechanism of this myocardial ischemia-reperfusion injury in a mouse model and found, in human subjects, a biomarker that was predictive of adverse cardiovascular events after those individuals had sustained an MI. Dr Carolyn Lam:                Oh, interesting. So tell us more, Greg. Dr Greg Hundley:             Yeah, so the authors utilized a dynamic transcriptome analysis of mouse hearts exposed to various myocardial ischemia-reperfusion periods to identify a new inflammatory molecule that they termed S100A8/A9, and it was an early mediator. And then they measured this new inflammatory molecule level in patients, human subjects, after myocardial infarction, before and after they had undergone percutaneous intervention. So this S100A8/A9 was identified as the most significantly up-regulated gene during the early reperfusion stage and knockout of that molecule markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of the molecule exacerbated myocardial ischemia-reperfusion injury.