Low Plasma Carnosinase-1 Activity in Patients with Left Ventricular Systolic Dysfunction: Implications for Carnosine Therapy in Heart Failure

Therapeutic efficacy of histidyl dipeptides such as carnosine is hampered by circulating carnosinase-1 (CN1), which catalyzes carnosine's hydrolysis and degradation. Prior reports suggest that oral carnosine may improve cardiometabolic parameters in patients with heart failure (HF), but whether CN1 activity is affected by HF is unknown. Here, we measured CN1 content and carnosine degradation rate (CDR) in preoperative plasma samples from a cohort of patients (<i>n</i> = 138) undergoing elective cardiac surgery to determine whether plasma CN1 and/or CDR varied with left ventricular (LV) systolic dysfunction. CN1 content was normally distributed in the cohort, but plasma CDR displayed a quasi-bimodal distribution into high- (>2 nmol/(h*μL)) and low-activity (≤2 nmol/(h*μL)) clusters. Multivariable analysis confirmed female sex, diabetes and LV systolic dysfunction was associated with the low-activity CDR cluster. Although CN1 content did not differ, logistic regression analysis revealed that CDR and CN1-specific activity (CDR/CN1 content) was significantly lower in patients with both moderate (ejection fraction, EF ≥ 35 to <50%) and severe LV systolic dysfunction (EF < 35%) compared with patients in the normal range (EF ≥ 50%). These findings suggest that plasma CN1 activity is regulated by factors independent of expression, and that a decline in LV systolic function is associated with low CN1 activity. Further studies are needed to delineate specific mechanisms controlling CN1 expression and activity, which will facilitate the development of carnosine and other histidyl dipeptide therapies for cardiometabolic disorders such as HF.