P103Impact of diabetes mellitus on myofilaments phosphorylation and calcium sensitivity is aortic stenosis patients

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Background: Diabetes mellitus (DM) is an independent risk factor for progression of aortic valve stenosis (AS) and significantly impacts longterm outcome after valve replacement. Our aim was to clarify myofilamentary changes induced by DM on AS patients.

Methods and Results: Patients with severe isolated AS (n=20) and AS plus type-II diabetes patients (AS-DM+, n=16) with preserved left ventricular (LV) ejection fraction and no clinical or angiographic signs of coronary artery disease were studied. Doppler echocardiographic data was used to compare in vivo LV function. Biopsies were used to isolate and permeabilize cardiomyocytes allowing to assess active force (Factive), resting force (Fpassive) and calcium sensitivity (pCa50) before and after incubation with PKA as well as to measure phosphorylation of myofilamentary proteins.

Compared to AS patients, AS-DM+ patients presented aggravated diastolic dysfunction, increased myofilaments pCa50 and a higher PKA-induced drop of pCa50 which was correlated with higher baseline levels of PKA-induced phosphorylation of Troponin I.

Conclusions: We have shown that myofilamentary changes induced by DM in AS patients are related to PKA-mediated hyperphosphorylation status of troponin I. This study highlights the need for earlier therapeutic interventions in order to prevent these myofilamentary alterations that fasten the progression of diastolic dysfunction in diabetic AS patients.

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