Pitt, B. | Search bioRxiv

bioRxiv2025

Targeting Metabolic Dysfunction and Inflammation with Sotagliflozin Reverses Diastolic Dysfunction in Experimental HFpEF

BackgroundHeart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and strongly associated with cardiometabolic comorbidities including obesity, hypertension, and metabolic dysfunction. While SGLT2 inhibitors have demonstrated clinical benefits in HFpEF, the mechanisms underlying dual SGLT1/2 inhibition remain incompletely understood. MethodsWe utilized a murine model of cardiometabolic HFpEF induced by high-fat diet combined with L-NAME administration. Following disease establishment, mice received sotagliflozin (30 mg/kg) or vehicle for 10 weeks. Comprehensive assessments included echocardiography, indirect calorimetry, cardiac metabolomics, bulk RNA sequencing with cell-type deconvolution, and high-dimensional immune profiling by flow cytometry and CyTOF. ResultsSotagliflozin significantly attenuated weight gain and improved glucose tolerance without normalizing blood pressure. Metabolic cage analyses revealed a sustained reduction in respiratory exchange ratio, indicating enhanced fatty acid oxidation, corroborated by elevated cardiac acylcarnitine intermediates including palmitoylcarnitine and dodecanoylcarnitine. Echocardiography demonstrated that sotagliflozin protected against diastolic dysfunction, normalizing isovolumic relaxation time and E/e ratio while reducing left ventricular mass and myocardial fibrosis. Transcriptomic profiling revealed upregulation of mitochondrial fatty acid {beta}-oxidation pathways and suppression of inflammatory signaling cascades including IL-1 processing and TLR pathways. Flow cytometric analysis demonstrated reduced cardiac infiltration of neutrophils, CCR2+ inflammatory monocytes/macrophages, and IL-1{beta}-expressing immune cells. Splenic immune cell expansion characteristic of systemic inflammation was similarly attenuated. ConclusionsDual SGLT1/2 inhibition with sotagliflozin exerts coordinated cardiometabolic benefits in experimental HFpEF through metabolic reprogramming toward enhanced lipid utilization and suppression of cardiac and systemic inflammation. These findings establish that sotagliflozin targets the intertwined metabolic-inflammatory axis central to HFpEF pathogenesis, providing mechanistic insight into the therapeutic efficacy of dual SGLT inhibition in cardiometabolic heart failure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/691021v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@146dfbforg.highwire.dtl.DTLVardef@ba784org.highwire.dtl.DTLVardef@122ecfcorg.highwire.dtl.DTLVardef@1f49a1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Mineralocorticoid Receptor Antagonism Reduces Atrial Arrhythmias Post-Cardiac Surgery and Attenuates Atrial Stress Responses to Cardioplegic Arrest

BackgroundNew postoperative atrial fibrillation (POAF) occurs in about 40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We examined the impact of preoperative MRA use on POAF and also examine the atrial cell type impacted by MRA treatment during cold cardiac preservation. MethodsRetrospective study of 19,042 patients who underwent cardiac surgery at Mayo Clinic in Minnesota, and performed 1:3 propensity matching to obtain 298 patients on preoperative MRA matched to 894 who were not. We also separately matched patients using preoperative diuretics. Single-nuclei RNA sequencing (snRNA-seq) examined MRAs effects on different atrial cell types in canrenone (water soluble MRA) treated human donor hearts undergoing cold preservation followed by ex-vivo reperfusion and compared gene expression to the atria of patients with AF. ResultsPropensity matched preoperative MRA group had less new onset POAF (19.8% vs 31.5%, P<0.001). To account for the possibility that preoperative diuretic use and volume reduction may impact POAF, we propensity matched 298 preop diuretic users that included MRA use to another 894 patients who used a non-MRA diuretic preoperatively. Those who used preoperative MRA similarly had a lower incidence of POAF (19.8% vs 33.2%, P<0.001). No survival difference was present between the propensity matched groups that used preoperative diuretics (P=0.079). Preoperative MRA use also reduced the development of paroxysmal and chronic AF at 6 years of follow up. From our snRNA-seq data, we identified a subpopulation of atrial cardiomyocytes (CM2) that had high MR expression where canrenone suppressed the increase in MR target gene expression associated with cold preservation-reperfusion. These MR targets were conversely elevated in patients with chronic AF. Canrenone also suppressed other cardiac preservation associated genes that show elevated expression in atrial macrophages and pericytes from chronic AF atria. ConclusionsOur studies show that preoperative MRA use is associated with 40% reduction in POAF as well as lowering long standing AF development by about 41%. Our cold cadiac preservation-reperfusion model showed that canrenone reduced expression of MR target genes associated with chronic AF, particular in cardiomyocytes with important roles in electrical conduction. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThis study shows that preoperative use of mineralocorticoid receptors antagonists (MRA) is associated with a reduced incidence of new onset perioperative atrial fibrillation after cardiac surgery utilizing cardiopulmonary bypass. C_LIO_LIWe show that preoperative MRA use is associated with a lower incidence of developing more chronic paroxymal or sustained atrial fibrillation. C_LIO_LIAddition of canrenone, a clinically utilized water soluble MRA, to cardioplegia solution used during cardiac preservation can attenuate atrial inflammatory reponses and reduce signaling through molecular pathways that promote atrial fibrillation. C_LI What are the clinical implications?O_LIPerioperative use of MRAs may be considered to reduce early postoperative atrial fibrillation as well as lowering the risk of developing more chronic atrial arrhythmias. C_LIO_LIThese findings support pursuing a clinical trial to determine the impact of MRA use on atrial arrhythmias following cardiac surgery in the setting of cardiopulmonary bypass with cold cardiac preservation. C_LI

molecular biology↗