Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy.

Aims: Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro‐fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive. Methods and results: Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long‐term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow‐up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6‐min walking distance. MPO inhibitor‐related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort. Conclusions: Myeloperoxidase predicts long‐term outcome in HFrEF and its inhibition elicits systemic anti‐inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF. [ABSTRACT FROM AUTHOR]