Aim: Endothelial dysfunction and altered nitric oxide (NO) metabolism are considered causal factors in heart failure with preserved ejection fraction (HFpEF). NO synthase activity depends on the availability of arginine and its derivatives. Thus, we analysed arginine, associated metabolites, arginine-metabolizing enzymes and NO turnover in lean (L-ZSF1) and obese ZSF1 rats (O-ZSF1) with and without HFpEF, respectively.

Methods and results: Serum, urine and lysates of liver, kidney and heart of 20-week-old female L-ZSF1 and O-ZSF1 rats were analysed. We observed a 5.8-fold higher arginase 1 expression in serum and >4-fold increased cardiac macrophage invasion in O-ZSF1. There were significantly lower lysine (-28%), arginine (-31%) and most prominently homoarginine (-72%) levels in O-ZSF1 rats. Ornithine (+60%) and citrulline (+20%) levels were higher. Similar results were found in the heart. Expression of arginine consuming enzymes in liver and kidney were similar. We found lower serum concentrations of nitrite and increased granulocyte derived serum arginase 1 and more macrophages in cardiac sections of O-ZSF1 when compared to L-ZSF1 rats (49±23 vs. 12±8 cells per section, p<0.001).

Conclusions: We conclude that inflammatory cells in blood and heart consume arginine and probably homoarginine via arginase 1 and inducible NO synthase and release ornithine and citrulline into the circulation. In combination with evidence for decreased NO turnover in O-ZSF1 rats, we assume lower arginine bioavailability to endothelial NO synthase.

Translational Perspective: The detection and control of systemic and cardiac inflammation and the restoration of arginine metabolism homeostasis may be an interventional target in HFpEF. Selected markers from this context may help to monitor HFpEF diagnosis and prognosis in clinic.