Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - RvD3-RAVIS (Novel Resolvin D3: its Role and Actions in the Resolution of Aortic Valvular Inflammation and Stenosis)

Teaser

Aortic valve stenosis is the most common cause of valvular heart disease and the third most common cardiovascular pathology after ischemic heart disease and hypertension, with the primary risk factor being increased age. It is a progressive disease driven by chronic...

Summary

Aortic valve stenosis is the most common cause of valvular heart disease and the third most common cardiovascular pathology after ischemic heart disease and hypertension, with the primary risk factor being increased age. It is a progressive disease driven by chronic inflammation that results in calcification and obstruction of the aortic valve with poor prognosis if left untreated. Most of the clinical trials have failed to stop the progression of aortic valve stenosis, and for that reason, the only available treatments are invasive surgical replacements and transcatheter interventions. Therefore new therapeutic strategies are needed but development of effective and targeted therapies that limit or prevent the progression of the diseases has been challenging and conceptual innovations are of uttermost importance. Hence the overall objectives of this project were to elucidate endogenous resolution programs in aortic valve stenosis and define the role and action of Resolvin D3 in aortic valve inflammation and calcification.

Work performed

In this project we employed and developed new tools to investigate inflammation-resolution mechanisms in aortic valve inflammation and calcification that included functional and phenotypic studies of human primary cells, receptor knockout mice and developing a new transgenic mouse model. Furthermore, LC-MS-MS based lipid mediator metabololipidomics profiling was employed for identification of resolution phase mediators. Primary human cells and preclinical models were used to assess the molecular mechanism and therapeutic actions of Resolvin D3 and its receptor ALX/FPR2 and GPR32 in aortic valve inflammation and calcification, which also extended to other cardiovascular diseases such as atherosclerosis.

Final results

No medical treatment has hitherto proved to be efficacious in slowing down valvular calcification, which further highlights the unmet medical needs in this disease. The project findings introduce a novel concept for therapeutic approaches of aortic valve stenosis, and in a broader context cardiovascular inflammation, that is focused on turning on resolution programs that may partly contribute to further palliate the incidence of the disease and the associated healthcare costs. This is particularly relevant in today’s society due to the increased life expectancy, as age is a major risk factor for aortic valve stenosis, as well as other cardiovascular and chronic inflammatory diseases, and thus their incidences are projected to rise significantly in the coming decades.

Identifying endogenous protective mechanisms to slow down the progression of aortic valve stenosis is novel and innovative. The implications of the findings from the present project are anticipated to go beyond aortic valve inflammation and calcification, since several other cardiovascular conditions may result from failed resolution, such as atherosclerosis. Turning on the resolution programs may hence emerge as a ground breaking novel therapeutic approach for cardiovascular prevention.