Resynchronization reduces arginase activity in red blood cells of heart failure patients with dyssynchrony

Abstract Background Heart failure with reduced ejection fraction (HFrEF) is a complex disease, where dyssynchronic HFrEF (DysHF) makes up a specific phenotype with a worse prognosis and a specific treatment, cardiac resynchronization therapy (CRT). Endothelial dysfunction is common in DysHF, but the mechanism is unknown. It was recently shown that increased arginase activity in the red blood cells (RBCs) play a pivotal role in diseases related to heart failure, i.e. Diabetes Mellitus type 2 (DM2). We hypothesized that this mechanism contributes to the endothelial dysfunction in DysHF and that arginase activity is reduced following CRT implantation. Purpose To explore RBC arginase activity levels in HFrEF patients and whether this is affected by specific heart failure treatment. Methods We included 15 patients with DysHF who received and responded to CRT. Patients with newly diagnosed synchronous HFrEF (SynHF; QRS120ms) starting up guideline directed medical therapy (GDMT) served as controls (n=14). An additional healthy control group was included for comparison (n=14). Patients were evaluated at baseline (before CRT or GDMT), three and six months. Endothelial function was estimated using pulse amplitude tonometry in the fingertip following reactive hyperemia and expressed as reactive hyperemia index (RHI). RBCs were isolated from peripheral blood and analysed for arginase activity with a colorimetric enzymatic assay. Results Six months with CRT resulted in an improvement of ejection fraction (EF) from 37% ± 10 to 46% ± 13 (p0.01) and end-systolic volume (ESV) from 110 ml ± 59 to 65 ml ± 28 (p0.01) for DysHF. SynHF similarly improved with GDMT, EF 33% ± 8 to 48 ± 8 (p0.01) and ESV 126 ml ± 51 to 74 ml ± 41 (p0.01). At baseline the majority of patients had endothelial dysfunction defined as RHI1.67, DysHF 67% and SynHF 71%. RHI did not differ between groups or improve over the study period. At baseline, arginase activity was 48% higher in DysHF (p0.05) compared to healthy controls, SynHF did not differ from healthy controls (Fig.1A). RBC arginase activity was reduced after CRT in DysHF (Fig.1B, n=12) but unchanged in SynHF after GDMT (Fig.1C, n=9). DM2 was present in 40% with DysHF and 14% with SynHF (p=0.12). However, our results remained unchanged when the diabetic patients were excluded. Conclusion Arginase activity in RBCs is elevated in DysHF, but not SynHF, regardless of the presence of DM2, and resynchronization reverses this. Resynchronization reduces arginase activity in DysHF as opposed to GDMT in SynHF, despite similar response in terms of reverse remodeling. Our findings suggest that increased RBC arginase activity represent a DysHF-specific mechanism underlying endothelial dysfunction, potentially distinguishing it from SynHF, and that CRT may help normalize this activity over time. Further studies are needed to establish the functional role of increased RBC arginase activity as a potential pathophysiological driver in DysHF.