Type 2 diabetes worsens the outcome of ischemia/reperfusion in female STEMI patients and female db/db mice with HFpEF cardiometabolic phenotype

Background Heart failure with preserved ejection fraction (HFpEF) poses a significant global health challenge, disproportionately affecting women. Diabetic women with HFpEF represent a high-risk subgroup, particularly after experiencing ST-segment elevation myocardial infarction (STEMI), exhibiting increased mortality compared to men. While prolonged door-to-balloon (DTB) times, reflecting delayed reperfusion, are a critical factor in STEMI outcomes, they alone do not fully capture the observed outcome variability in diabetic women. Using an integrated clinical and pre-clinical approach this study aimed to investigate the relative contributions of metabolic dysfunction and coronary artery disease (CAD) in type 2 diabetes (T2D) to STEMI outcomes in women, beyond the impact of DTB time. Methods A retrospective case-control study analysed female STEMI patients undergoing primary percutaneous coronary intervention (pPCI, n=40 T2D, n=40 non-diabetic controls), comparing clinical characteristics, treatment strategies, and early outcomes. A preclinical model (female db/db mice) assessed cardiac function via echocardiography, Langendorff perfusions, and ischemia-reperfusion protocols. Metabolome of heart, liver, and skeletal muscle was assessed by ¹H NMR spectroscopy Results Our study reveals significantly higher mortality, impaired left ventricular function post-PCI, and increased implantable cardioverter-defibrillator (ICD) implantation rates in diabetic STEMI patients, irrespective of DTB time, when compared to non-diabetic controls. Elevated inflammatory markers, acute hyperglycaemia and evidence of cardio-hepatic damage were identified in T2D patients. db/db mice exhibited analogous T2D-associated pathophysiology, including increased ischemia-reperfusion injury exacerbated by metabolic disturbances in the myocardium, liver, and skeletal muscle versus non-diabetic controls Conclusions In diabetic women, multiple factors beyond reperfusion delays exacerbate acute myocardial injury. This necessitates the development of sex-specific strategies to manage the cardiovascular complications of diabetic HFpEF. The db/db mouse model provides a relevant preclinical tool for future research as mimics human T2D-associated HFpEF and STEMI outcome.