DeCure for Aortic valve disease 2

Aortic valve stenosis: an active atheroinflammatory process

AbstractPURPOSE OF REVIEW: To summarize the current understanding of the pathobiology of aortic valve stenosis and portray the major advances in this field. RECENT FINDINGS: Stenotic aortic valves are characterized by atherosclerosis-like lesions, consisting of activated inflammatory cells, including T lymphocytes, macrophages, and mast cells, and of lipid deposits, calcific nodules, and bone tissue. Active mediators of calcification and cells with osteoblast-like activity are present in diseased valves. Extracellular matrix remodeling, including collagen synthesis and elastin degradation by matrix metalloproteinases and cathepsins, contributes to leaflet stiffening. In experimental animals, hypercholesterolemia induces calcification and bone formation in aortic valves, which can be inhibited by statin treatment. The potential of statins to retard progression of aortic valve stenosis has also been recognized in clinical studies; however, further prospective trials are needed. Angiotensin II-forming enzymes are upregulated in stenotic valves. Angiotensin II may participate in profibrotic progression of aortic valve stenosis and may serve as a possible therapeutic target. SUMMARY: Recent findings regarding the interaction of inflammatory cells, lipids, mediators of calcification, and renin-angiotensin system in stenotic valves support the current opinion of aortic valve stenosis being an actively regulated disease, potentially amenable to targeted molecular therapy. Evidence from prospective clinical studies is eagerly awaited.

Molecular genetics of aortic valve disease

AbstractPURPOSE OF REVIEW: Bicuspid aortic valve is the most common type of cardiac malformation and predisposes to aortic valve calcification, which is the third leading cause of heart disease in adults. These seemingly temporally disparate diseases have been described as having genetic influences but limited data exist on the precise genetic causes in humans. Several advances in the molecular genetics of aortic valve formation and calcification have recently been identified and are described here. RECENT FINDINGS: A large family with autosomal-dominant aortic valve disease consisting of bicuspid aortic valve and aortic valve calcification was studied using genome-wide linkage analysis. This led to the identification of a nonsense mutation in NOTCH1 in affected individuals. This finding was supported by the discovery of a NOTCH1 frameshift mutation in an unrelated family with similar aortic valve disease, suggesting that NOTCH1 haploinsufficiency was a genetic cause of aortic valve malformations and calcification. The NOTCH signaling pathway was linked to a molecular pathway for aortic valve calcification, as NOTCH1 was found to repress activation of Runx2 - a transcription factor critical for osteoblast cell fate that is up-regulated in calcified human aortic valves. SUMMARY: The recent genetic and biochemical findings provide novel insights into the molecular and genetic basis for aortic valve dysmorphogenesis and calcification. Future studies focusing on the identification of additional disease-causing and susceptibility genes will aid in the development of prevention strategies. Ultimately, it will be the careful dissection of these molecular pathways that will hopefully lead to novel therapeutic options.

Transcriptomic Signatures of Calcific Aortic Valve Stenosis Severity in Human Tricuspid and Bicuspid Aortic Valves

AbstractThere is currently no medical therapy for calcific aortic valve stenosis. We aimed to identify transcriptomic signatures of the disease severity. We performed mRNA sequencing from explanted human aortic valves of 500 individuals who underwent aortic valve replacement (n = 440) or a heart transplant (n = 60). We performed differential gene expression analyses according to hemodynamic severity, valve morphology, calcification grade, and age of onset, and we estimated immune cell proportions. We identified immune response, inflammation, and adipocyte metabolism as predominant pathways associated with calcific aortic valve stenosis severity, offering new perspectives for the development of pharmacological treatments.

Can the Results of Aortic Valve Repair Equal the Results of a Biologic Aortic Valve Replacement?

AbstractAortic valve replacement (AVR) has been the default procedure for the surgical management of aortic valve disease, with repair techniques heterogeneously and infrequently used. However, surgical aortic valve repair has evolved with improved techniques. Yet many questions remain regarding the ideal techniques and real-world applicability and effectiveness of valve repair. The AORTA Great Debate highlighted and discussed the controversies regarding the surgical management of aortic valve disease.

An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis

AbstractAortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFlt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.

AbstractAortic valve replacement (AVR) has been the default procedure for the surgical management of aortic valve disease, with repair techniques heterogeneously and infrequently used. However, surgical aortic valve repair has evolved with improved techniques. Yet many questions remain regarding the ideal techniques and realworld applicability and effectiveness of valve repair. The AORTA Great Debate highlighted and discussed the controversies regarding the surgical management of aortic valve disease.

THE ROLE OF VALVE INTERSTITIAL CELLS IN THE PATHOGENESIS OF CALCIFIC AORTIC VALVE DISEASE

AbstractCalcific aortic valve disease (CAVD) is the most common etiology of acquired aortic valve disease. The early stage is characterized by thickening of the leaflets and none or marginal effect on the?mechanical properties of the valve, while the end stage disease is associated with impaired leaflet motion and resistances to blood flow. These conditions are known as aortic valve sclerosis (AVSc) and calcific aortic valve stenosis (AVS), respectively. AVSc is present in 25?30% of patients over 65 years of age and?in up to 40% of those over 75 years of age. Moreover, since AVSc hemodynamics are comparable to healthy controls, the presentation of the?disease is largely asymptomatic and almost 10% of these patients will progress to AVS within 10 years from the?diagnosis. Patients with severe AVS have a life expectancy of less than 10 years if untreated. Currently the main indication for AVS is aortic valve replacement (AVR). Over the last decade several clinical trials have been performed to halt the progression of CAVD with contradictory results. The early enthusiastic findings documenting a reduction in the progression of CAVD have been questioned by later randomized studies, which show substantial equivalence between treatments and placebo. It has been proposed that CAVD therapy may have been initiated too late in the course of the disease to have the desired effect. In conclusion, there is currently no definitive therapy supported by prospective and randomized studies to halt or delay the progression of CAVD, leaving AVR the treatment of choice. Therefore, the identification of high-risk patients at early stages of degeneration will open new perspectives for the appropriate timing of therapeutic intervention on future clinical trials. We implemented in vitro and ex vivo experiments to better characterize the early asymptomatic stage of CAVD and to evaluate osteopontin (OPN) as a potential biomarker in the progression of this degenerative disease. Moreover, we focused on OPN role in valve endothelial cells (VEC) migration, as well as valve interstitial cells (VIC) osteoblastic-like activation and biomineralization. Our results supported the correlation between CAVD progression and increased OPN levels in aortic valve tissue and blood. Interestingly, in advance stages of calcification, we demonstrated that the overexpressed OPN had different post-translational modification compared to healthy controls. Moreover, we analyzed bone morphogenetic protein 4 (BMP4) pathway and mechanical tensile stretch as cause of VIC osteogenic-like transdifferentiation and calcium accumulation.

Long-term durability and resilient tissue: ‘the future end of valve in valve!’

AbstractCurrent research focuses on new preservation technologies for xeno-pericardial prostheses with the aim of improving long-term durability, lowering the age threshold for bio-prosthetic valve implantation and thus reducing the side effects of long-lasting anticoagulation [1]. The increasing shift of an indicated age threshold for bio-prosthetic valve implantation towards younger patients may also lead to new long-term complementary treatment concepts, especially in times of success of the transcatheter aortic valve implantation (TAVI). We read with great interest the article ‘Final 5-year outcomes following aortic valve replacement with a RESILIA™ tissue bioprosthesis’ by Bartus et al., the authors present a prospective, non-randomized, single-arm study of 133 patients implanted with a RESILIA aortic with clinical outcomes and haemodynamic performance assessed annually for 5 years post-implant [2]. This study concluded that the bioprosthesis with RESILIA tissue demonstrated a good safety profile with excellent haemodynamic performance over 5 years of follow-up [3]. Aortic valve-in-valve is a less-invasive alternative to surgical redo in the treatment of failed bioprosthetic valves. In this context, we present our reflection, if the long-term results on RESILIA tissue continue to be promising in the next studies, it could be legitimate to think of a RESILIA treatment on TAVI; this would change the paradigm by extinguishing the valve-in-valve approach in degenerative processes on surgical bio-prosthetic valves and TAVI. Conflict of interest: none declared.