Matrix modulation in degenerative aortic valve disease due to metabolically-independent insulin action?

• Applicant: Dr. Mareike Barth
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421961956

Fibrotic changes are substantial during development of degenerative aortic valve disease. Diabetic disorders initiate and aggravate further pathogenesis even during moderate elevation of insulin levels independently from mechanisms regulating metabolism. Ageing, development of pre-diabetic states and cardiac pathologies represent major health care expenditures and mortality risk factors world-wide. Thus, early rebalancing, prevention and additional intervention is of vital interest in the context of individual healthcare and socioeconomic calculations. We found that even short-term hyperinsulinemia severely disturbs insulin-sensitivity in interstitial cells. We therefore will identify mitogenic pathways leading to fibrotic changes associated to insulin-receptor mediated signaling. These will be new and additive targets for an early clinical intervention in pre-diabetic states. We will analyze expression and functional addressability of insulin-related downstream signaling in isolated interstitial cells from sheep aortic valves and in sheep aortic valve cusps. Translational relevance will be clarified in human aortic valve cusps from non-diabetic patients. We hypothesize that insulin leads to pathological alterations of extracellular matrix in degenerative aortic valve disease through mitogenic pathways independently from glucose metabolism.

• DFG Programme: Research Grants