Aortic Regurgitation Is Associated With Ascending Aortic Remodeling in the Nondilated Aorta

Objective: The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas ( P =0.005) but not AS-aortas ( P =0.23). This pathological remodeling included mucoid extracellular matrix accumulation ( P =0.005), elastin loss ( P =0.003), elastin fragmentation ( P =0.008), and decreased expression of fibrillin ( P =0.003) and collagen ( P =0.008). Furthermore, eNOS (endothelial nitric oxide synthase) expression was decreased in the intima ( P =0.0008) and in vasa vasorum ( P =0.004) of AR-aortas but not AS-aortas (all P >0.05). Likewise, subendothelial apoptosis was increased in AR-aortas ( P =0.03) but not AS-aortas ( P =0.50). Conclusions: AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic Abstract: A graphic abstract is available for this article.

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Platelet membrane-coated nanoparticles target sclerotic aortic valves in ApoE−/− mice by multiple binding mechanisms under pathological shear stress

European Heart Journal ◽

10.1093/ehjci/ehaa946.1863 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Yang ◽

Y Song ◽

Z Huang ◽

J Qian ◽

Z Pang ◽

...

Keyword(s):

Shear Stress ◽

Aortic Valve ◽

Aortic Valve Disease ◽

Binding Capacity ◽

Platelet Membrane ◽

Valve Disease ◽

Funding Source ◽

Aortic Valves ◽

Coated Nanoparticles

Abstract Background Aortic valve disease is the most common valvular heart disease leading to valve replacement. The efficacy of pharmacological therapy for aortic valve disease is limited by the high mechanical stress at the aortic valves impairing the binding rate. We aimed to identify nanoparticle coating with entire platelet membranes to fully mimic their inherent multiple adhesion mechanisms and target the sclerotic aortic valve of apolipoprotein E-deficient (ApoE−/−) mice based on their multiple sites binding capacity under high shear stress. Methods Considering the potent interaction of platelet membrane glycoproteins with components present in sclerotic aortic valves, platelet membrane-coated nanoparticles (PNPs) were synthetized and the binding capacity under high shear stress was evaluated in vitro and in vivo. Results Compared with PNPs bound intensity in the static station, 161%, 59%, and 39% of attached PNPs remained adherent on VWF-, collagen-, and fibrin-coated surfaces under shear stress of 25dyn/cm2 respectively. PNPs demonstrated effectively adhering to von Willebrand factor, collagen and fibrin under shear stresses in vitro. In an aortic valve disease model established in ApoE−/− mice, PNPs group exhibited significant increase of accumulation in the aortic valves compared with PBS and control NP group. PNPs displayed high degrees of proximity or co-localization with vWF, collagen and fibrin, which exhibited good targeting to sclerotic aortic valves by mimicking platelet multiple adhesive mechanisms. Conclusion PNPs could provide a promising platform for the molecular diagnosis and targeting treatment of aortic valve disease. Targeting combination Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China

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Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1619667114 ◽

2017 ◽

Vol 114 (7) ◽

pp. 1631-1636 ◽

Cited By ~ 45

Author(s):

Qingchun Zeng ◽

Rui Song ◽

David A. Fullerton ◽

Lihua Ao ◽

Yufeng Zhai ◽

...

Keyword(s):

Aortic Valve ◽

High Fat Diet ◽

Aortic Valve Disease ◽

Valve Disease ◽

High Fat ◽

Calcific Aortic Valve Disease ◽

Aortic Valves ◽

Valve Interstitial Cells ◽

Valve Lesions ◽

Osteogenic Factors

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

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Associations between aortic regurgitation severity and risk of incident myocardial infarction and stroke among patients with degenerative aortic valve disease: insights from a large Chinese population-based cohort study

BMJ Open ◽

10.1136/bmjopen-2020-046824 ◽

2021 ◽

Vol 11 (8) ◽

pp. e046824

Author(s):

Guangxiao Li ◽

Tan Li ◽

Yanli Chen ◽

Xiaofan Guo ◽

Zhao Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Cohort Study ◽

Aortic Valve ◽

Prospective Study ◽

Aortic Regurgitation ◽

Northeast China ◽

Aortic Valve Disease ◽

Valve Disease ◽

Stroke Mortality

ObjectivesFew studies have explored whether the risk of myocardial infarction (MI) or stroke varies among patients with degenerative aortic valve disease (DAVD) with different severity of aortic regurgitation (AR) or not. Thus, a prospective study was conducted to elucidate the causal relationship between AR severity and risk of incident MI and stroke among patients with DAVD recruited from a general population in Northeast China.DesignProspective cohort study.SettingCommunity-based study carried out in rural areas of Northeast China.MethodsThere were 3675 patients with DAVD aged ≥45 years eligible for the prospective study. During a median follow-up time of 4.64 years, 99 participants lost to follow-up. Cox regression analyses were used to investigate the association between baseline AR severity and the risk of incident MI or stroke.ResultsIn the final cohort of 3576 patients with DAVD, there were 3153 patients without AR (88.2%), 386 patients with mild AR (10.8%) and 37 patients with moderate or severe AR (1.0%). Multivariate analyses showed that, compared with participants without AR, those with moderate/severe AR were associated with 8.33 and 6.22-fold increased risk of MI and MI mortality, respectively. However, no significant associations between AR and the risk of stroke or stroke mortality were observed.ConclusionsAs compared with no AR, moderate/severe AR but not mild AR was an independent predictor for the risk of MI and MI mortality. AR was not significantly associated with stroke or stroke mortality, irrespective of AR severity. Secondary prevention strategies should be taken to delay the progression of DAVD and thus reduce the incidence of MI.

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Abstract 6147: A Tissue Stem Cell Niche Regulates Bicuspid Aortic Valve Disease

Circulation ◽

10.1161/circ.118.suppl_18.s_1071 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Nalini M Rajamannan

Keyword(s):

Stem Cell ◽

Aortic Valve ◽

Bicuspid Aortic Valve ◽

Cross Talk ◽

Aortic Valve Disease ◽

Stem Cell Niche ◽

Ex Vivo ◽

Valve Disease ◽

Aortic Valves ◽

Cell Niche

Bicuspid aortic valve disease is the most common congenital cardiac malformation and indication for surgery for aortic valve patients. The age of onset for the development of stenosis is earlier in bicuspid aortic valves than tricuspid aortic valves. Understanding the cellular mechanisms of this valve lesion, will help to develop novel approaches towards slowing disease progression. This study hypothesizes that bicuspid aortic valve disease develops secondary to a tissue stem cell niche to activate a cross-talk mechanism which induces Notch1 cleavage and Lrp5 mediated bone formation specific to the bicuspid aortic valve. Human ex vivo bicuspid valves versus control aortic valves were tested for Notch1 expression by RTPCR, Western Blot and Immunohistochemistry. eNOS null bicuspid mice: control (n=20), cholesterol (n=20), cholesterol + Atorvastatin (n=20), were tested for the development of aortic stenosis by Visual Sonics Echo, Immunohistochemistry for Notch1, Wnt, Lrp5, Osteocalcin, PCNA and RTPCR for Notch1, Lrp5, Cbfa1, Osteocalcin. In vitro studies were performed to characterize Wnt secretion from aortic valve endothelial cells and gene expression for Notch1, Lp5 and osteocalcin from the valve myofibroblast cells. This study characterizes the secretion of Wnt3a (>300-fold, p<0.01) from aortic valve endothelium in the presence of abnormal nitric oxide regulation and lipids as measured by eNOS enzymatic activity and tissue nitrite levels. Osteoblastogenesis in the adjacent myofibroblast cell is activated via Notch1 cleavage(p<0.001) and upregulation of the Wnt3a/Lrp5 receptor. Human ex vivo valves express Notch1 cleavage as compared to normal valves from heart transplant(p<0.01). Cholesterol treated eNOS mice develop severe stenosis with cleavage of Notch1, increase in Lrp5, Wnt3a, cyclin, Cbfa1, and Osteopontin,(3-fold increase(p<0.01) which was not present in the controls and normalized in the statin treated valves. Targeting the Notch1/Wnt3a/Lrp5 pathway in bicuspid valvular calcification presents a novel approach towards treating this disease. The importance of this cross talk mechanism is demonstrated in three models of aortic valve disease and will have important clinical implications. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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Asymmetric medial degeneration of the intrapericardial aorta in aortic valve disease

International Journal of Cardiology ◽

10.1016/s0167-5273(01)00526-5 ◽

2001 ◽

Vol 81 (1) ◽

pp. 37-41 ◽

Cited By ~ 10

Author(s):

Maurizio Cotrufo ◽

Luca S De Santo ◽

Salvatore Esposito ◽

Attilio Renzulli ◽

Alessandro Della Corte ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Valve Disease ◽

Valve Disease ◽

Medial Degeneration

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Superimposed Tissue Formation in Human Aortic Valve Disease: Differences between Regurgitant and Stenotic Valves

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8070079 ◽

2021 ◽

Vol 8 (7) ◽

pp. 79

Author(s):

Boudewijn P. T. Kruithof ◽

Aniek L. van Wijngaarden ◽

Babak Mousavi Gourabi ◽

Jesper Hjortnaes ◽

Meindert Palmen ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Valve Disease ◽

Body Part ◽

Free Edge ◽

The Body ◽

Valve Disease ◽

Matrix Composition ◽

Aortic Dilatation ◽

Aortic Valves ◽

Highly Active

The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation as a major contributor to valve thickening and possibly as a result of increased mechanical stresses. However, little is known whether SIT formation also occurs in aortic valve disease. We therefore performed histological analyses to assess SIT formation in aortic valve leaflets (n = 31) from patients with aortic stenosis (n = 17) or aortic regurgitation due to aortic dilatation (n = 14). SIT was observed in both stenotic and regurgitant aortic valves, both on the ventricular and aortic sides, but with significant differences in distribution and composition. Regurgitant aortic valves showed more SIT formation in the free edge, leading to a thicker leaflet at that level, while stenotic aortic valves showed relatively more SIT formation on the aortic side of the body part of the leaflet. SIT appeared to be a highly active area, as determined by large populations of myofibroblasts, with varied extracellular matrix composition (higher collagen content in stenotic valves). Further, the identification of the SIT revealed the presence of foldings of the free edge in the diseased aortic valves. Insights into SIT regulation may further help in understanding the pathophysiology of aortic valve disease and potentially lead to the development of new therapeutic treatments.

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Early Aberrant Angiogenesis Due to Elastic Fiber Fragmentation in Aortic Valve Disease

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8070075 ◽

2021 ◽

Vol 8 (7) ◽

pp. 75

Author(s):

Robert B. Hinton ◽

Amy L. Juraszek ◽

Amy M. Opoka ◽

Benjamin J. Landis ◽

J. Michael Smith ◽

...

Keyword(s):

Aortic Valve ◽

Marfan Syndrome ◽

Early Onset ◽

Aortic Valve Disease ◽

Late Onset ◽

Elastic Fiber ◽

Valve Disease ◽

Aortic Valves ◽

Valve Tissue ◽

Fiber Fragmentation

Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and neovascularization has been identified as a late finding related to inflammation. We sought to characterize the relationship between early EFF and aberrant angiogenesis. To examine disease progression, regional anatomy and pathology of aortic valve tissue were assessed using histochemistry, immunohistochemistry, and electron microscopy from early-onset (<40 yo) and late-onset (≥40 yo) non-syndromic AVD specimens. To assess the effects of EFF on early AVD processes, valve tissue from Williams and Marfan syndrome patients was also analyzed. Bicuspid aortic valve was more common in early-onset AVD, and cardiovascular comorbidities were more common in late-onset AVD. Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of elastic fiber components surrounded early-onset AVD neovessels, including increased emilin-1 and decreased fibulin-5. Different types of EFF were present in Williams syndrome (WS) and Marfan syndrome (MFS) aortic valves; WS but not MFS aortic valves demonstrated angiogenesis. Aberrant angiogenesis occurs in early-onset AVD in the absence of inflammation, implicating EFF. Elucidation of underlying mechanisms may inform the development of new pharmacologic treatments.

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Decreased Glucagon-Like Peptide-1 Is Associated With Calcific Aortic Valve Disease: GLP-1 Suppresses the Calcification of Aortic Valve Interstitial Cells

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.709741 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fan Xiao ◽

Qing Zha ◽

Qianru Zhang ◽

Qihong Wu ◽

Zhongli Chen ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Valve Disease ◽

Interstitial Cells ◽

Valve Disease ◽

Dependent Manner ◽

Calcific Aortic Valve Disease ◽

Aortic Valves ◽

Valve Interstitial Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Objectives: This study explores the concentration and role of glucagon-like peptide-1 (GLP-1) in calcific aortic valve disease (CAVD).Background: Calcific aortic valve disease is a chronic disease presenting with aortic valve degeneration and mineralization. We hypothesized that the level of GLP-1 is associated with CAVD and that it participates in the calcification of aortic valve interstitial cells (AVICs).Methods: We compared the concentration of GLP-1 between 11 calcific and 12 normal aortic valve tissues by immunohistochemical (IHC) analysis. ELISA was used to measure GLP-1 in serum of the Control (n = 197) and CAVD groups (n = 200). The effect of GLP-1 on the calcification of AVICs and the regulation of calcific gene expression were also characterized.Results: The GLP-1 concentration in the calcific aortic valves was 39% less than that in the control non-calcified aortic valves. Its concentration in serum was 19.3% lower in CAVD patients. Multivariable regression analysis demonstrated that GLP-1 level was independently associated with CAVD risk. In vitro, GLP-1 antagonized AVIC calcification in a dose- and time-dependent manner and it down-regulated RUNX2, MSX2, BMP2, and BMP4 expression but up-regulated SOX9 expression.Conclusions: A reduction in GLP-1 was associated with CAVD, and GLP-1 participated in the mineralization of AVICs by regulating specific calcific genes. GLP-1 warrants consideration as a novel treatment target for CAVD.

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Abstract 15192: Leptin Effects on Osteoblast Differentiation of Human Valvular Interstitial Cells: New Insight Into Calcific Aortic Valve Disease

Circulation ◽

10.1161/circ.132.suppl_3.15192 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Mickael Rosa ◽

Rodrigo Lorenzi ◽

Madjid Tagzirt ◽

Francis Juthier ◽

Antoine Rauch ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Valve Disease ◽

Osteoblast Differentiation ◽

Interstitial Cells ◽

Valve Disease ◽

Calcium Deposition ◽

Valvular Interstitial Cells ◽

Calcific Aortic Valve Disease ◽

Aortic Valves ◽

Alp Activity

Introduction: Calcific aortic valve disease (CAVD) affects 2% to 6% of the population over 65 years and results from dysregulated processes such as calcification, supported in part by the osteoblast differentiation of valvular interstitial cells (VIC), the most prevalent cell type in the human aortic valves. Leptin has recently been linked to aortic valve calcification in ApoE-/- mice. Hypothesis: Our hypothesis is that leptin could play a role in the calcifying processes implicated in CAVD via direct effects on human VIC. Methods: Patients who underwent aortic valve replacement for severe CAVD (n=43) or with coronary artery disease (CAD) but without CAVD (n=129) were included in this study. Presence of leptin was analyzed in human explanted calcified aortic valves and blood samples. Leptin receptors expression was analyzed in aortic valves and VIC isolated from aortic valves. Leptin effects on osteoblast differentiation of VIC in presence or not of Akt and ERK inhibitors were investigated by alizarin red staining, alkaline phosphatase (ALP) activity, and RT-qPCR analysis for osteopontin, ALP, bone morphogenetic protein BMP-2, and RUNX2. Results: Patients with CAVD have significant higher serum leptin concentration than CAD patients (p=0.002). The presence of leptin was observed by immunochemistry in human calcified aortic valves, with higher concentrations in calcified vs non-calcified zones (p=0.01). Both short and long leptin receptor isoforms were expressed in VIC. Chronic leptin stimulation of VIC enhanced ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. This treatment led to a higher, dose dependent, ALP activity and calcium deposition in VIC. Inhibiting Akt or ERK during leptin stimulation led to a reduced calcification by bringing the expression of calcification genes to the control levels. Conclusions: Together, these novel findings depict the potential role of leptin in the process of CAVD by triggering calcification processes in human VIC.

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