The death of heart-muscle tissue caused by heart attacks all too often leads to heart failure. The heart’s fibroblasts synthesize extracellular matrix (ECM) that provides structural support for the heart and its cells. But heart failure triggers fibroblasts to deposit large amounts of ECM proteins, which can precipitate deadly heart rhythm abnormalities and also increase the stiffness of the heart. A stiff heart fails to relax properly, leading to pressure overload (increased pressure in the heart’s chambers) that contributes to shortness of breath. Nikolaos Frangogiannis, M.D., and colleagues have found that expression of the protein transglutaminase-2 (TG2) greatly increases in failing hearts and that TG2 is a major mediator of effects that occur during heart failure. The United States Army has awarded Dr. Frangogiannis a three-year, $2 million grant to examine how TG2 influences the two most common situations associated with heart failure: heart attacks that lead to heart failure by killing cardiac muscle, and the pressure overload that causes heart failure in patients with high blood pressure. The research may provide insights into the pathogenesis of heart failure and may identify TG2 inhibition as a new heart-failure therapy. Dr. Frangogiannis is professor of medicine and microbiology & immunology and the Edmond J. Safra/Republic National Bank of New York Chair in cardiovascular medicine at Einstein.