Pathophysiology of Aortic Stenosis and Mitral Regurgitation

Perrucci, Gianluca Lorenzo; Zanobini, Marco; Gripari, Paola; Songia, Paola; Alshaikh, Bayan; Tremoli, Elena; Poggio, Paolo

doi:10.1002/cphy.c160020

Cited by 21 publications

(12 citation statements)

References 203 publications

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“…Valvular interstitial cells (VICs) distributed throughout the three extracellular matrix (ECM) layers are the predominant population of cells in the aortic valve (AV) and play a role in the progression of CAVS [10]. The tissue is surrounded by a monolayer of valvular endothelial cells (VECs), which also seem to be involved in disease development [11].…”

Section: Pathophysiology Of Cavsmentioning

confidence: 99%

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

Donato

Ferri

Lupo

et al. 2020

IJMS

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Calcific aortic valve stenosis (CAVS), the most common heart valve disease, is characterized by the slow progressive fibro-calcific remodeling of the valve leaflets, leading to progressive obstruction to the blood flow. CAVS is an increasing health care burden and the development of an effective medical treatment is a major medical need. To date, no effective pharmacological therapies have proven to halt or delay its progression to the severe symptomatic stage and aortic valve replacement represents the only available option to improve clinical outcomes and to increase survival. In the present report, the current knowledge and latest advances in the medical management of patients with CAVS are summarized, placing emphasis on lipid-lowering agents, vasoactive drugs, and anti-calcific treatments. In addition, novel potential therapeutic targets recently identified and currently under investigation are reported.

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Section: Pathophysiology Of Cavsmentioning

confidence: 99%

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

Donato

Ferri

Lupo

et al. 2020

IJMS

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“…Although MMV has been largely described at clinical, functional and histological levels, the cellular and molecular mechanisms underlying the pathological ECM remodeling are still elusive. Pathogenesis of MMV has been related to biological mediators such as serotonin [8,9], angiotensin II [10] and activation of the TGFβ pathway [11,12]. Mechanistic knowledge was also gained from studies of the syndromic forms of MMV, such as Marfan and Loeys-Dietz syndromes [13,14] characterized by an activated TGFβ signaling.…”

Section: Introductionmentioning

confidence: 99%

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways

Blomme

Deroanne

Hulin

et al. 2019

Journal of Molecular and Cellular Cardiology

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The mitral valve is a complex multilayered structure populated by fibroblast-like cells, valvular interstitial cells (VIC) which are embedded in an extracellular matrix (ECM) scaffold and are submitted to the mechanical deformations affecting valve at each heartbeat, for an average of 40 million times per year. Myxomatous mitral valve (MMV) is the most frequent heart valve disease characterized by disruption of several valvular structures due to alterations of their ECM preventing the complete closure of the valve resulting in symptoms of prolapse and regurgitation. VIC and their ECM exhibit reciprocal dynamic processes between the mechanical signals issued from the ECM and the modulation of VIC phenotype responsible for ECM homeostasis of the valve. Abnormal perception and responsiveness of VIC to mechanical stress may induce an inappropriate adaptative remodeling of the valve progressively leading to MMV. To investigate the response of human VIC to mechanical strain and identify the molecular mechanisms of mechano-transduction in these cells, a cyclic equibiaxial elongation of 14% at the cardiac frequency of 1.16 Hz was applied to VIC by using a Flexercell-4000 T™ apparatus for increasing time (from 1 h to 8 h). We showed that cyclic stretch induces an early (1 h) and transient over-expression of TGFβ2 and αSMA. CTGF, a profibrotic growth factor promoting the synthesis of ECM components, was strongly induced after 1 and 2 h of stretching and still upregulated at 8 h. The mechanical stress-induced CTGF up-regulation was dependent on RhoC, but not RhoA, as demonstrated by siRNA-mediated silencing approaches, and further supported by evidencing RhoC activation upon cell stretching and suppression of cell response by pharmacological inhibition of the effector ROCK1/2. It was also dependent on the MEK/Erk1/2 pathway which was activated by mechanical stress independently of RhoC and ROCK. Finally, mechanical stretching induced the nuclear translocation of myocardin related transcription factor-A (MRTF-A) which forms a transcriptional complex with SRF to promote the expression of target genes, notably CTGF. Treatment of stretched cultures with inhibitors of the identified pathways (ROCK1/2, MEK/ Erk1/2, MRTF-A translocation) blocked CTGF overexpression and abrogated the increased MRTF-A nuclear translocation. CTGF is up-regulated in many pathological processes involving mechanically challenged organs, promotes ECM accumulation and is considered as a hallmark of fibrotic diseases. Pharmacological targeting of MRTF-A by newly developed inhibitors may represent a relevant therapy for MMV.

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“…CAVS is the most frequent valvular heart disease in the Western world. No medical therapy is currently available ( 21 ) even if multiple studies have been performed to elucidate the molecular and cellular mechanisms underlining the progression of this debilitating and fatal disease ( 22 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis

et al. 2022

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BackgroundAortic stenosis (AS) is the most common valve disorder characterized by fibro-calcific remodeling of leaflets. Recent evidence indicated that there is a sex-related difference in AS development and progression. Fibrotic remodeling is peculiar in women’s aortic valves, while men’s leaflets are more calcified. Our study aimed to assess aortic valve fibrosis (AVF) in a severe AS cohort using non-invasive diagnostic tools and determine whether sex-specific pathological pathways and cell types are associated with severe AS.Materials and MethodsWe have included 28 men and 28 women matched for age with severe AS who underwent echocardiography and cardiac contrast-enhanced computed tomography (CT) before intervention. The calcium and fibrosis volumes were assessed and quantified using the ImageJ thresholding method, indexed calcium and fibrosis volume were calculated by dividing the volume by the aortic annular area. For a deeper understanding of molecular mechanisms characterizing AS disorder, differentially expressed genes and functional inferences between women and men’s aortic valves were carried out on a publicly available microarray-based gene expression dataset (GSE102249). Cell types enrichment analysis in stenotic aortic valve tissues was used to reconstruct the sex-specific cellular composition of stenotic aortic valves.ResultsIn agreement with the literature, our CT quantifications showed that women had significantly lower aortic valve calcium content compared to men, while fibrotic tissue composition was significantly higher in women than men. The expression profiles of human stenotic aortic valves confirm sex-dependent processes. Pro-fibrotic processes were prevalent in women, while pro-inflammatory ones, linked to the immune response system, were enhanced in men. Cell-type enrichment analysis showed that mesenchymal cells were over-represented in AS valves of women, whereas signatures for monocytes, macrophages, T and B cells were enriched men ones.ConclusionsOur data provide the basis that the fibro-calcific process of the aortic valve is sex-specific, both at gene expression and cell type level. The quantification of aortic valve fibrosis by CT could make it possible to perform population-based studies and non-invasive assessment of novel therapies to reduce or halt sex-related calcific aortic valve stenosis (CAVS) progression, acting in an optimal window of opportunity early in the course of the disease.

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Pathophysiology of Aortic Stenosis and Mitral Regurgitation

Cited by 21 publications

References 203 publications

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways

Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis

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