Increased arginase levels in heart failure represent a therapeutic target to rescue microvascular perfusion

Heart failure (HF) is defined as the incapability of the heart to serve the tissues adequately with blood. This includes changes in microvascular perfusion. A mechanism aggravating perfusion disturbances in HF is endothelial dysfunction by reduced bioavailability of nitric oxide (NO). A mechanism possibly contributing to low NO bioavailability is the upregulation of arginase. Therefore, we investigated circulating arginase levels in patients with HF and its consequences for microvascular perfusion.

A first group consisted of eighty patients with chronic HF. Patients were characterized by echocardiography and laboratory values. Arginase 1 levels were determined using a commercially available ELISA. A second experimental group included eight patients with severe heart failure. Using sidestream darkfield intravital microscopy sublingual microcirculation was quantified before and after the topical incubation of nor-NOHA as arginase inhibitor and L-NMMA as NO synthase inhibitor.

Circulating arginase-1 levels were significantly higher in patients with heart failure compared to controls (p < 0.001). Patients with severe heart failure (NYHA III/IV) had significantly higher arginase-1 levels compared to patients with mild heart failure (p < 0.01, NYHA I/II). Sublingual perfused capillary density increased significantly (p < 0.01) following incubation with nor-NOHA. However, this effect was abolished when nor-NOHA was co-incubated with L-NMMA.

In conclusion, circulating arginase 1 levels are elevated in patients with HF. A topical inhibition of arginase in these patients leads to improved microcirculation by a NO dependent mechanism. Inhibition of arginase is a possible therapeutic target to rescue microcirculation in patients with HF.