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Diabetes mellitus type II (DM) is an important risk factor for developing heart failure (HF). Within the HF syndrome, we distinguish HF patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Overall, DM is equally prevalent among patients with HFrEF and HFpEF. Yet, there is evidence that DM affects cardiac geometry differently in HFrEF and HFpEF. Indeed, diabetic cardiomyopathy (DMCMP) with HFrEF is associated with more eccentric cardiac hypertrophy, while DMCMP with HFpEF is associated with more concentric cardiac hypertrophy.
It has become increasingly clear that also on a cellular level, DMCMP presents as two distinct diseases with a HFrEF and HFpEF phenotype. Early evidence suggests that in the DMCMP HFpEF phenotype collagen and advanced glycation end-products (AGEs) deposition are increased. In contrast, cardiomyocytes in patients with the DMCMP HFrEF phenotype show an overall loss of sarcomeres.
Unfortunately, limited information is available on differences between DMCMP with HFrEF and HFpEF. Elucidating these differences will aid in our understanding of the underlying pathophysiological differences of DMCMP with HFrEF and HFpEF and provide for novel treatment targets. Additionally, it has become increasingly clear that particular DM medications might have beneficial effects in patients with HF. Results from the EMPA-REG trial showed that sGLT2 inhibitors might possible aid in reducing the number of HF hospital readmissions. Novel targets on DMCMP patients with HFrEF and HFpEF will aid in identifying HF patients potentially benefitting from existing treatment for DM.
The overall aim of this proposal is to elucidate the differences between patients with DMCMP presenting with a HFrEF or HFpEF phenotype. We will then investigate mechanistic implications of patient specific treatment targets in in-vitro and in-vivo models.
To approach the above stated aim, we propose four sub aims using a translational approach:
Creating a better understanding of DMCMP with HFrEF and HFpEF will lead to potential novel patient specific treatment targets for these patients. Furthermore, by measuring novel targets in patients with HF, we will identify patients benefiting from a personalized medicine approach (sub aim 4) using existing DM treatments.
This proposal is linked to the following ProminenT domains: