Towards Personalized Therapy of Aortic Stenosis

Calcific aortic stenosis (CAS) is the most common cause of acquired valvular heart disease in adults with no available pharmacological treatment to inhibit the disease progression to date. This review provides an up-to-date overview of current knowledge of molecular mechanisms underlying CAS pathobiology and the related treatment pathways. Particular attention is paid to current randomized trials investigating medical treatment of CAS, including strategies based on lipid-lowering and antihypertensive therapies, phosphate and calcium metabolism, and novel therapeutic targets such as valvular oxidative stress, coagulation proteins, matrix metalloproteinases, and accumulation of advanced glycation end products.

Calcific Aortic Stenosis—A Review on Acquired Mechanisms of the Disease and Treatments

Calcific aortic stenosis is a progressive disease that has become more prevalent in recent decades. Despite advances in research to uncover underlying biomechanisms, and development of new generations of prosthetic valves and replacement techniques, management of calcific aortic stenosis still comes with unresolved complications. In this review, we highlight underlying molecular mechanisms of acquired aortic stenosis calcification in relation to hemodynamics, complications related to the disease, diagnostic methods, and evolving treatment practices for calcific aortic stenosis.

Expression of tissue inhibitors of metalloproteinases type 1 and type 2 in the leaflets of explanted bioprosthetic heart valves: a new pathogenetic parallel between structural valve degeneration and calcific aortic stenosis

Objective: to study cellular and lipid infiltration, as well as the expression of tissue inhibitors of metalloproteinases (TIMP) types 1 and 2 in biological prosthetic heart valves (BPHVs) explanted due to dysfunction.Material and Methods. We examined 17 leaflets from 6 BPHVs, dissected from the aortic and mitral positions during valve replacement. For microscopic analysis, fragments of the BPHV leaflets were frozen and serial sections were made using a cryotome. In order to study cellular infiltration and the degree of degenerative changes in the prosthetic biomaterial, the sections were stained with Gill’s hematoxylin and eosin; Oil Red O stain was used to assess lipid deposition. Immunohistochemistry was used for cell typing and detection of TIMP-1/-2. The stained samples were analyzed by light microscopy.Results. Cellular and lipid infiltration of xenogeneic tissues was detected in all BPHV flaps studied. Recipient cells coexpressed pan-leukocyte and macrophage markers PTPRC/CD45 and CD68. Positive staining for TIMP-1/-2 co-localized with cell clusters but was absent in acellular sections.Conclusion. Cells infiltrating xenogeneic BPHV tissues express TIMP-1/-2. This suggests that BPHV immune rejection pathophysiology is partially similar to that of calcific aortic stenosis.

A Coupled Multiscale Approach to Modeling Aortic Valve Mechanics in Health and Disease

Mechano-biological processes in the aortic valve span multiple length scales ranging from the molecular and cell to tissue and organ levels. The valvular interstitial cells residing within the valve cusps sense and actively respond to leaflet tissue deformations caused by the valve opening and closing during the cardiac cycle. Abnormalities in these biomechanical processes are believed to impact the matrix-maintenance function of the valvular interstitial cells, thereby initiating valvular disease processes such as calcific aortic stenosis. Understanding the mechanical behavior of valvular interstitial cells in maintaining tissue homeostasis in response to leaflet tissue deformation is therefore key to understanding the function of the aortic valve in health and disease. In this study, we applied a multiscale computational homogenization technique (also known as “FE2”) to aortic valve leaflet tissue to study the three-dimensional mechanical behavior of the valvular interstitial cells in response to organ-scale mechanical loading. We further considered calcific aortic stenosis with the aim of understanding the likely relationship between the valvular interstitial cell deformations and calcification. We find that the presence of calcified nodules leads to an increased strain profile that drives further growth of calcification.