Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling

Type 2 diabetes mellitus (T2D) is one of the prominent risk factors for the development and progression of calcific aortic valve disease. Nevertheless, little is known about molecular mechanisms of how T2D affects aortic valve (AV) remodeling. In this study, the influence of hyperinsulinemia and hyperglycemia on degenerative processes in valvular tissue is analyzed in intact AV exposed to an either static or dynamic 3D environment, respectively. The complex native dynamic environment of AV is simulated using a software-governed bioreactor system with controlled pulsatile flow. Dynamic cultivation resulted in significantly stronger fibrosis in AV tissue compared to static cultivation, while hyperinsulinemia and hyperglycemia had no impact on fibrosis. The expression of key differentiation markers and proteoglycans were altered by diabetic conditions in an environment-dependent manner. Furthermore, hyperinsulinemia and hyperglycemia affect insulin-signaling pathways. Western blot analysis showed increased phosphorylation level of protein kinase B (AKT) after acute insulin stimulation, which was lost in AV under hyperinsulinemia, indicating acquired insulin resistance of the AV tissue in response to elevated insulin levels. These data underline a complex interplay of diabetic conditions on one hand and biomechanical 3D environment on the other hand that possesses an impact on AV tissue remodeling.

Aortic stenosis in patients with kidney failure: Is there an advantage for a PD-first policy?

Aortic stenosis (AS) is the most common valvular disease. It is twice as prevalent in patients with kidney failure as compared to the general population. In addition, AS progresses at a faster rate and is associated with a higher risk of death and poorer quality of life in patients on dialysis. Chronic kidney disease–mineral and bone disorder (CKD-MBD), inflammation, and hemodynamic disturbances contribute to the pathophysiology and progression of AS. Whether the type of dialysis modality, that is, hemodialysis (HD) versus peritoneal dialysis (PD), has a differential impact on the development and progression of AS in patients with kidney failure remains debated. Recent data indicate that the prevalence of valvular calcifications might be lower and the development of AS delayed in PD patients, as compared to those treated with HD. This could be accounted for by several mechanisms including reduced valvular shear stress, better preservation of residual kidney function (with better removal of protein-bound uremic toxins and CKD-MBD profile), and lower levels of systemic inflammation. Given the high morbidity and mortality rates related to interventional procedures in the population with kidney failure, surgical and transcatheter aortic valve replacement should be considered in selected patients with severe AS. Strategies slowing down the progression of aortic valve remodeling should remain the cornerstone in the management of individuals with kidney failure and mild to moderate AS. This review explores the potential benefits of PD in patients with kidney failure and AS and provides some clues to help clinicians in the decision-making process when options for kidney replacement therapy are considered in patients with AS.