A Multimodality Imaging Investigation of Diabetic Heart Failure with Preserved Ejection Fraction (HFpEF) and Obstructive Sleep Apnoea (OSA) in Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Therapy

Abstract

Concurrent Heart failure with preserved ejection fraction (HFpEF) diagnosis with diabetes mellitus (diabetic HFpEF) is of escalating contemporary research interest due to incidence augmentation, in line with global obesity and ageing elevations.

This Thesis aimed to examine pathophysiological mechanisms and wider CV-associated clinical implications of diabetic HFpEF and OSA, with additional assessment of potential cardioprotective effects of SGLT2i and association of gender-specific variation, with added focus on gender-specific prevalence, cardiac structural and functional consideration, as well as LGE distribution pattern type upon late gadolinium enhancement-cardiac magnetic resonance (LGE-CMR) imaging.

This research indicates significantly elevated CV risk profiles in HFpEF, particularly diabetic HFpEF. Concurrent LVH and LV myocardial fibrosis diagnosis further compounded adverse clinical event risk upon long-term follow-up of a diabetic cohort, reinforcing a poorer prognosis in diabetic HFpEF patients with adverse cardiac remodelling. Diabetic HFpEF patients also demonstrated endothelial dysfunction and elevated atherosclerosis, through flow-mediated dilatation (FMD) and left carotid intima-media thickness (CIMT), respectively.

However, comparison amongst diabetic HFpEF patients revealed those administered SGLT2i therapy demonstrated significantly improved cardiac structural and functional parameters upon LGE-CMR and echocardiographic imaging. OSA severity was also reduced in SGLT2i-administered diabetic HFpEF patients, further associated with reduced endothelial dysfunction and arteriosclerosis. Additionally, plasma pro and anti -inflammatory cytokine expression was also reduced and elevated, respectively in diabetic HFpEF patients on an SGLT2i. These findings were also reinforced in a murine model of diabetic HFpEF (SGLT2i-/+), further strengthening the cardioprotective benefit of SGLT2 inhibition and consequently, its clinical usage in diabetic HFpEF.