Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared to wild-type controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.
Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, Daniel P. Kelly
Background: Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models but the clinical effect of targeting extracellular PDI in humans has not been studied. Methods: We conducted a multi-center phase 2 trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, N=28) or 1000 mg (cohort B, N=29) daily for 56 days with laboratory assays performed at baseline and end-of-study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis. Results: The administration of isoquercetin 1000 mg decreased D-dimer plasma concentrations by a median of -21.9% (P=0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, N=25, P<0.001; 73.3% in cohort B, N=22, P<0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P=0.007; cohort B median decrease -57.2%, P=0.004) and circulating soluble P-selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P<0.0001). Conclusions: Isoquercetin represents first-in-class inhibitor of PDI demonstrating efficacy in improving markers of coagulation in advanced cancer patients. Trial Registration: Clinicaltrials.gov NCT02195232
Jeffrey I. Zwicker, Benjamin L. Schlechter, Jack D. Stopa, Howard Liebman, Anita Aggarwal, Maneka Puligandla, Thomas Caughey, Kenneth A. Bauer, Nancy Kuemmerle, Ellice Wong, Ted Wun, Marilyn McLaughlin, Manuel Hidalgo, Donna Neuberg, Bruce Furie, Robert Flaumenhaft
No posts were found with this tag.