Despite the myriad major advances in cardiology, the prognosis for patients with severe, medically refractive heart failure (HF) is exceedingly poor. Approximately 287,000 deaths occur annually in patients with HF who have endured an impaired quality of life often accompanied by significant economic and personal losses due to recurrent hospitalizations. At least 58,000 of these deaths were directly related to severe heart failure. Because the number of available heart donors (~2,200/year) has not increased over the last decade, there is an enormous and expanding gap between medical need for transplant and the woefully low supply of hearts. Today's axial and centrifugal flow left ventricular assist devices (LVAD) have reduced size and power requirements, allowing LVADs to become a therapeutic options as a bridge-to-transplantation (BTT) and increasingly for destination-therapy (DT). Unfortunately the life-saving benefit of LVADs is offset by potential life-threatening complications and costly hospital readmissions for bleeding, infection, and thrombosis. Prophylactic anticoagulation to prevent intra-pump thrombus with warfarin (in addition to an anti-platelet drug) exacerbates inherent bleeding complications induced by the high shear high blood flow conditions of the pumps. Multicenter efforts to reduce anticoagulation guidelines tripled the incidence of pump thrombotic complications. LDH, a nonspecific marker of RBC lysis, is currently used as the best surrogate indicator for pump thrombosis. But, given clinical results to date, LDH is only an insensitive probably late biomarker of LVAD fibrin accumulation. We have innovated and demonstrated a very high avidity nuclear probe prototype, 99mTc-F4A, in vitro, in excised LVADs operated ex vivo, and in rodent models, which sensitively localizes thrombus accumulation in LVADs. In Phase 1 of this Fast-track proposal the effectiveness of 99mTc-F4A will be demonstrated in a large animal model, calves (70kg), using reimplanted human LVADs (70Kg) and a clinical gamma camera. In Phase 2 the analytical, chemical process, and regulatory development and documentation required to transfer the product candidate (FibroScint) to contract research organizations for GMP toll manufacturing, stability testing, and GLP toxicology will be completed. FibroScint is anticipated to refine and individualize LVAD clinical management to reduce bleeding events, thromboembolic complications and pump exchanges.
