Sacubitril/Valsartan as a Cardiac Radioprotector

PURPOSE: The role of the natriuretic peptides in radiation heart injury (RHI) has not been thoroughly examined. Pharmacologic modulation of the natriuretic peptide system with sacubitril/valsartan (sac/val) has led to improvements in heart failure therapy, and preliminary data suggest that RHI is associated with decreased atrial natriuretic peptide (ANP). In this study, we assessed sac/val as a radioprotector in a partial-heart irradiation mouse model and explored preliminary trends in patients receiving thoracic irradiation. METHODS AND MATERIALS: Female 8-10-week-old C57BL/6J mice were randomly assigned to receive sham irradiation, with or without sac/val, or irradiation with or without sac/val. The superior two-thirds of the heart was exposed to 20 Gy of x-rays using a small animal radiation research platform. Cardiac function was assessed at 10-week intervals over 30 weeks by transthoracic echocardiography and electrocardiography. Plasma levels of ANP were analyzed at 30 weeks. Small retrospective clinical series were undertaken in patients undergoing thoracic radiation therapy, to assess ANP dynamics and sac/val safety. RESULTS: At 30 weeks, irradiated mice that received sac/val exhibited a marked improvement in structural remodeling, systolic longitudinal strain, diastolic function, and electrophysiological parameters, compared with irradiated animals that did not receive sac/val. Functional sparing with sac/val was detectable as early as 10 weeks postirradiation by global longitudinal strain. Animals and patients tolerated the combination of sac/val with radiation without additional adverse effects. NT-proANP levels generally decreased among patients during thoracic radiation therapy and posttreatment NT-proANP changes were dose dependent. There was no effect on tolerability or efficacy of (chemo)radiation for patients on sac/val concurrently for heart failure. CONCLUSIONS: Sac/val attenuated structural and functional aspects of RHI and was well tolerated in animals when given with radiation. Clinical data suggest that ANP changes dynamically during radiation therapy and that sac/val is safe to take concurrently. Further investigation of sac/val as a cardiac radioprotector is warranted.