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. Our featured paper today provides important trial evidence that will guide interventional management of symptomatic femoral artery disease, but first, here's your summary of this week's journal.                                                 The first paper sheds light on the interaction between left ventricular dysfunction and mesenchymal stromal cell activation. First author, Dr. Naftali-Shani. Corresponding author, Dr. Leor and colleagues from Neufeld Cardiac Research Institute in Israel isolated mesenchymal stromal cells from cardiac and subcutaneous fat tissues of mice with left ventricular dysfunction, 28 days after myocardial infarction or sham operation. They further injected mesenchymal stromal cells or saline into the infracted myocardium of mice and evaluated left ventricular remodeling 28 days after myocardial infarction. They found that left ventricular dysfunction switched cardiac mesenchymal stromal cells towards an inflammatory phenotype and that these pro-inflammatory mesenchymal stromal cells contributed to adverse left ventricular remodeling and dysfunction. The inflammatory polarization of cardiac mesenchymal stromal cells by left ventricular dysfunction was mediated by toll-like receptor four. Finally, toll-like receptor four deficiency in mesenchymal stromal cells attenuated their pro-inflammatory activation, improved their reparative properties, graft survival, infarct repair and left ventricular remodeling.                                                 In summary, the environment of the failing and infarcted myocardium drove resident and transplanted mesenchymal stromal cells towards a pro-inflammatory phenotype that restricted their survival and reparative effects in a mechanism mediated by toll-like receptor four. Targeting toll-like receptor four in mesenchymal stromal cells could improve the safety and efficacy of cell therapy in heart failure.                                                 The next study provides evidence that fractional flow reserve or FFR is a useful index for decision-making in real life daily cath lab practice. First author, Dr. Ahn, corresponding author, Dr. Park and colleagues from Heart Institute Asan Medical Center in South Korea, evaluated the prognosis of deferred and revascularized coronary stenosis after FFR measurement in the IRIS-FFR registry of 5,848 prospectively enrolled patients. This large prospective registry showed that the FFR was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR of less than 0.75 was associated with better outcomes than deferral, while for a stenosis with a high FFR of greater than 0.76, medical treatment would be a reasonable and safe strategy. Thus, the authors concluded that FFR may be considered a clinical prognostic index in addition to a physiological quantification for flow-limiting stenosis. These and other issues are discussed in an accompanying editorial by Doctors De Bruyne, Fournier and Barbato.                                                 The next study sheds important insights into a potential disease modifier in pulmonary arterial hypertenstion, and that is vascular endothelial growth factor receptor three, or VEGF receptor three. First author, Dr. Hwangbo, Co-corresponding authors Dr. Chun and Dr. Jin from Yale Cardiovascular Research Center in Connecticut, used a combination of experimental animal models, human patient cells and detailed signaling studies to demonstrate the importance of a novel interaction between bone morphogenetic protein type two receptors, or BMPR2 and VEGF receptor three in regulating the robustness of endothelial bone morphogenic protein sign