Gliflozin therapy is associated with reduced monocyte activation and plasma-induced oxidative stress in endothelial cells and cardiomyocytes of patients with hypertrophic cardiomyopathy.
A Mroueh, W Fakih, D S Gong, H Muzammel, J Tse Sik Sun, F Sauer, J J Von Hunolstein, M Riou, E Galli, V Schini-KerthAbstract
Background
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and a leading cause of morbidity and mortality. It is characterised by myocardial hypertrophy, microvascular impairment and endothelial dysfunction, contributing to reduced myocardial perfusion and adverse cardiac remodelling. Systemic inflammation, endothelial dysfunction and myocyte metabolic dysregulation further exacerbate disease progression. Activated circulating monocytes are key contributors of this process through oxidative stress, endothelial injury and inflammatory signalling. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, improve HF outcomes, but their effects on monocyte activation, endothelial dysfunction and metabolic stress in HCM remain incompletely understood.
Methods
40 HCM patients (63±years, 53% men) receiving guideline-directed pharmacological treatment (56% betablockers, 3% disopyramide, 59% ACE-inhibitors, 3% mavacamten, 20% gliflozins) and 10 healthy donors were enrolled. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from EDTA-treated blood samples. PBMCs oxidative stress levels and glucose uptake were assessed. Human microvascular endothelial cells and cardiomyocytes were stimulated with 20% plasma for 24 h, and thereafter the level of oxidative stress was evaluated.
Results
PBMCs from 32 (80%) HCM patients showed approximately 2-fold higher levels of oxidative stress compared to healthy controls, whereas the remaining 8 HCM patients showed similar levels. This latter subgroup of HCM patients corresponded to those receiving chronic gliflozin therapy. Ex vivo treatment with losartan, eplerenone or empagliflozin reduced the increased pro-oxidant level of PBMC by 40-50% in HCM patients non-receiving gliflozin. PBMCs from these patients also exhibited an increased glucose uptake, which was strongly correlated with oxidative stress levels and was inhibited by empagliflozin by about 60%. In contrast, PBMCs of gliflozin-treated HCM patients showing lower ROS levels were unaffected by the pharmacological inhibitors, and exhibited glucose uptake comparable to that of healthy donors. Finally, plasma from HCM patients not receiving gliflozins increased oxidative stress in endothelial cells (about 3-fold) and cardiomyocytes (about 2-fold) compared with healthy plasma. Ex vivo treatment with losartan, eplerenone and empagliflozin attenuated this response by 27%, 34% and 49%, respectively. Of interest, plasma from gliflozin-treated HCM patients did not increase ROS levels in either cell type.
Conclusion
HCM showed pro-oxidant responses in monocytes and a stimulatory pro-oxidant effect of plasma on endothelial cells and cardiomyocytes involving the local angiotensin-aldosterone-SGLT2 pro-oxidant pathway, which was significantly reduced in the case of gliflozin treatment. These results suggest that SGLT2 inhibition is a promising therapy to mitigate pro-inflammatory and metabolic pathways in HCM.