GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE277nnn/GSE277623/primaryOK200TranscriptomicsRattus norvegicusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE277623GEOGSEfalseCo-Treatment with Empagliflozin and Pirfenidone Improves Cardiac Functions and Reverses Hypertrophic Remodeling in Heart Failure with Preserved Ejection Fraction in a Two-Hit Rat ModelHeart failure with preserved ejection fraction (HFpEF) is a life-threatening condition that affects more than half of all heart failure patients. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) showed promising improvements in cardiovascular death or heart failure among HFpEF patients. This study aimed to test if cotreatment of Empagliflozin and Pirfenidone can improve the therapeutic outcome HFpEF by addressing the underlying cardiac fibrosis. We induced HFpEF in Sprague-Dawley rats using N-nitro-L-arginine methyl ester and a high-fat diet for 5 weeks, then treated them with EMPA, PFD, or both (EMPA+PFD) for 4 weeks. Echocardiography showed that EMPA+PFD significantly improved left ventricular ejection fraction (LVEF, p<0.0001), fractional shortening (FS, p=0.0427), stroke volume (SV, p=0.0019), and cardiac output (CO, p=0.0016) compared to the untreated group. These improvements were superior to PFD treatment alone (LVEF, p = 0.0131; CO, p = 0.040) and were absent in the EMPA group. Also, the late diastolic transmitral flow velocity and isovolumic relaxation time were much better with EMPA+PFD (p<0.0001) than with EMPA or PFD alone. PFD alone greatly reduced cardiac fibrosis in the subendocardial region. However, when EMPA and PFD were combined, the amount of fibrosis was significantly reduced in both the subendocardium (p<0.0001) and myocardium (p=0.0140). Myocyte cross-sectional area was significantly lower in both PFD-treated and EMPA+PFD-treated groups (p<0.001). However, only the EMPA+PFD group showed a significant reduction in left ventricular weight index (p = 0.0008), while the EMPA-treated group did not show these effects. Greater exercise capacity in HFpEF rats after EMPA+PFD treatment reflected the improvement in cardiac function, outperforming both EMPA and PBS-treated control. In conclusion, cotreatment with PFD and EMPA improves cardiac functions and reverses hypertrophic remodeling, suggesting a better strategy for treating HFpEF. Further investigation to decipher the cellular changes in ventricular CM may provide insights into the mechanism underlying the benefit of treatment combinations.2026/05/26GSE277623GSM8526585GSM8526574GSM8526586GSM8526575GSM8526587GSM8526576GSM8526577GSM8526578GSM8526579GSM8526569GSM8526580GSM8526570GSM8526581GSM8526582GSM8526571GSM8526583GSM8526572GSM8526573GSM852658431008277623Rattus norvegicus