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. Today's feature discussion revolves around important hemodynamic and echo data from the reprise three trial, comparing the lotus and core valve transcatheter aortic valves in patients with high surgical risk. Can't wait? Well it's coming right up after these summaries.                                                 The first original paper this week provide experimental data showing that the endothelium controls cardiomyocyte metabolism and function via notch signaling. Corresponding author, Dr. Fischer, from German Cancer Research Center in Heidelberg, Germany, and colleagues, studied fatty acid transport in cultured endothelial cells and transgenic mice with endothelial specific notch inhibition, or wild type mice treated with neutralizing antibodies against the Notch ligand. They showed that notch signaling in the endothelium controlled blood vessel formation and fatty acid transport in the adult mouse heart. Inhibition of Notch signaling in the vasculature led to expansion of the cardiac vasculature and impairment of fatty acid transport to cardiomyocytes. This resulted in metabolic reprogramming and heart failure.                                                 Together, these data provide compelling evidence for a central role of Notch signaling at the coordination of nutrient transport processes in the heart. These findings help to explain how pharmacological inhibition of Notch signaling, for example, in oncology could lead to heart failure. The findings also help to identify the signals and molecules involved in endothelial transport capacity and show how these could offer new targets for the treatment of heart failure.                                                 The next paper raises the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure. Ischemic injury to the myocardium is known to trigger a robust, inflammatory response, which is an integral part of the healing process, although much effort has been directed at tempering the inflammatory response in hopes of achieving clinical gain. Major efforts have focused on individual cytokines, the complement cascade, and antibodies to adhesion molecules preventing leukocyte invasion.                                                 In contrast, relatively little effort has focused on macrophages. Although macrophage transformation is known to be crucial to myocardial repair, the events governing this transformation are poorly understood. In today's paper, co-corresponding authors of the trial in Hill, from UT Southwestern Medical Center, performed an elegant series of experiments and showed that release of DNA from necrotic tissue during myocardial infarction, triggered in macrophages a recently described innate immune response known as the GMP-AMP synthase-stimulator of interferon genes pathway or cGAS-STING pathway.                                                 This response in turn promoted an inflammatory macrophage phenotype. Suppression of the pathway promoted emergence of reparative macrophages, thereby mitigating pathological ventricular remodeling. These results therefore reveal for the first time, that the cytosolic DNA receptor, GMP-AMP synthase, functions during cardio ischemia as a pattern recognition receptor in the sterile immune response.                                                 Furthermore, this pathway governs macrophage transformation, thereby regulating post injury cardiac repair. As modulators of this pathway are currently in clinical use, these findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.                                                 Cigarette smoki