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Inorganic Nitrate Supplementation Improves Diastolic Function in Cancer Survivors treated with Anthracycline Chemotherapy

Cancer survivors treated with anthracycline‐based chemotherapy have an increased risk of cardiotoxicity, resulting in the development of cardiac complications up to 10 years after chemotherapy cessation. Thus, cardiovascular events and heart failure are the second leading cause of morbidity and mortality in these women. Notably, the increased generation of reactive oxygen species relative to antioxidant defenses in the cardiomyocyte with anthracyclines results in lipid peroxidation and peroxynitrate formation, at the consequence of a decreased nitric oxide (NO) bioavailability, which over time results in ventricular systolic and diastolic dysfunction. Recently, orally ingested inorganic nitrates (NO3−), which increase NO bioavailability via the nitrate‐nitrite‐nitric oxide pathway and high antioxidant capacity, have shown to improve cardiac function in mice given anthracycline chemotherapy. Therefore, we hypothesized that inorganic NO3− administration would improve of left ventricular (LV) systolic and diastolic function, arterial stiffness, and ventricular‐arterial coupling in human cancer survivors with a history of anthracycline chemotherapy. Ten cancer survivors, 9 with breast cancer and 1 with lymphoma, participated in this randomized, double blind, crossover study comparing a week of daily doses NO3− rich beetroot juice with a nitrate‐depleted placebo. Standard and Tissue Doppler echocardiography were used to assess LV and carotid artery function during systole and diastole. NO3− supplementation significantly improved parameters of LV diastolic function, specifically strain rate in early filling (1.07±0.17 versus 0.80±0.29 1/s; P<0.5), early mitral septal wall annular velocity (0.07±0.02 versus 0.06±0.02 m/s; P=0.02, and mitral A‐wave velocity (0.65±0.23 versus 0.52±0.17 cm/s; P=0.009). There were no differences in LV systolic parameters; ejection fraction (P=0.2) ventricular‐arterial coupling (P =0.10), systolic strain rate (P =0.49). Arterial stiffness (P =0.38) was not different between conditions. These findings suggest that decrease in NO bioavailability may have a mechanistic role in determining LV diastolic function in cancer survivors treated with anthracycline‐based chemotherapy. This is critical information that can be used to developed therapeutic strategies targeting NO‐dependent changes in left ventricular function that occur following anthracycline chemotherapy.