Myocardial sodium–glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO‐AS study

Abstract

AimCardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Our study aimed to evaluate the expression of sodium–glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow‐low gradient (LF‐LG) AS and its association with cardiac functional impairments.Methods and resultsGene expression and protein levels of main biomarkers of cardiac fibrosis (galectin‐3, sST2, serpin‐4, procollagen type I amino‐terminal peptide, procollagen type I carboxy‐terminal propeptide, collagen, transforming growth factor [TGF]‐β), inflammation (growth differentiation factor‐15, interleukin‐6, nuclear factor‐κB [NF‐κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium–hydrogen exchanger, peroxisome proliferator‐activated receptor [PPAR]‐α, PPAR‐γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. Our study showed SGLT2 gene and protein hyper‐expression in patients with LF‐LG AS, compared to controls and HG AS (p < 0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: (i) TGF‐β (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF‐κB (r = 0.36, p < 0.01) and myocardial interleukin‐6 (r = 0.68, p < 0.001) as markers of inflammation: (iii) SOD2 (r = −0.38, p < 0.006) as a marker of oxidative stress; (iv) GLUT4 (r = 0.33, p < 0.02) and PPAR‐α (r = 0.36, p < 0.01) as markers of cardiac metabolism.ConclusionIn patients with LF‐LG AS, SGLT2 gene and protein were hyper‐expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress.