Abstract 43: SIRT1 Enhances Oxidized Low-density Lipoprotein Induced Autophagy in Human Valve Interstitial Cells

Objectives: Sirt1, an NAD + -dependent class III deacetylase, has been shown to regulate autophagy during cardiac remodeling. Its role in calcific aortic valve disease has not been studied. Methods: Aortic valve samples were collected from patients with calcific aortic valve diseases complicated with hyper-lipidemia (at the time of heart valve replacement) (CAVD group), and from patients with dilated cardiomyopathy with non-calcified valves and a normal blood lipid profile (at the time of heart transplantation) (control group); the expression and distribution of calcification and Sirt1 in the aortic valves were analyzed by immuno-histochemical staining and Western blotting. In addition, primary human valvular intersititial cells (VICs) were isolated from normal valves in control group, and their response to DiI-ox-LDL treatments was analyzed in the presence of adenovirus-mediated Sirt1 over-expression (Ad-SIRT1) and Sirt1 inhibitor EX527, followed by assessments of the levels of reactive oxygen species (ROS), autophagy, apoptosis and calcification with biochemical methods. Results: The H&E, Masson, Von Kossa and α-SMA immuno-fluorescence staining showed that the aortic valves in CAVD group were thickened by excessive elastin, collagen expression and calcium deposition, which was associated with an elevated expression of osteocalcin and a reduced expression of Sirt1, as compared to control group. In vitro, the primary VICs were incubated with different concentrations (25, 50 and 100μg/mL) of ox-LDL for 48 h. ROS levels increased in an ox-LDL dose dependent manner. In addition, ox-LDL treatment led to a slight increase in the level of LC3 and Beclin-1, autophagic death-related hMOF and acetyl-histone H4, and a significant decrease in the level of Sirt1 through Western blotting. Interestingly, co-treatment of VICs with EX527 further increased ROS generation and expression of Caspase 3, Bax, and β-Catenin, while Sirt1 over-expression by Ad-SIRT1 resulted in increased expression of LC3 and Beclin-1, decreased expression of Caspase 3, Bax, Wnt3a and β-Catenin and reduced ROS generation. Conclusion: Our data suggest that Sirt1 may play a protective role in ox-LDL-induced VIC autophagy and heart valve calcification.

Download Full-text

P4662Advanced glycation end products accumulate in aortic valve tissue during calcification development in the absence of diabetes mellitus. A spectroscopic study

European Heart Journal ◽

10.1093/eurheartj/ehz745.1044 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

N Anousakis-Vlachochristou ◽

K Toutouzas ◽

M Kyriakidou ◽

E Varela ◽

A Kapelouzou ◽

...

Keyword(s):

Aortic Valve ◽

Control Group ◽

Aortic Valve Calcification ◽

Aortic Valves ◽

Valve Calcification ◽

Valve Tissue ◽

Glycation End Products ◽

End Products ◽

Ft Ir

Abstract Background Advanced glycation end products (AGPs) promote human aortic smooth muscle cell calcification in vitro. Moreover, reduction of AGPs levels and inhibition of RAGE signaling decrease vascular calcification in vivo in animal studies. The role of AGPs in aortic valve calcification has not been investigated. Purpose We sought to investigate the role of AGPs in aortic valve calcification, in the absence of diabetes mellitus (DM). Methods We used human and animal cohorts. Firstly, we obtained aortic valves from patients without DM that underwent aortic valve replacement due to aortic valve stenosis. We studied the valves with Fourier-Transformed Infrared spectroscopy (FT-IR, Nicolet 6700 spectrometer, with Attenuated Total Reflection-ATR accessory, each spectrum consisted of 120 co-added spectra) in order to evaluate chemical changes. In the animal cohort, New Zealand male rabbits where randomized in calcification diet (normal chow+cholesterol 0,5%+3500 IU ergocalciferol/kg daily) and control group and sacrificed at 2, 4, 6, 8 10 and 12 weeks. The valves were longitudinally assessed with FT-IR. Results A total of 200 human aortic valves were studied (age 64–78). All patients demonstrated characteristic vibrations at the area about 1165 cm-1, where the C-O-C bonds absorb, attributed to AGPs. Thirty six rabbit valves were used, 3 per group. Glucose levels were within normal range and did not differ between groups. The FT-IR spectra of the rabbit aortic valves showed increasing intensity of the C-O-C band at 1165 cm-1 in experimental group in comparison to control group. The band at 1744 cm-1 is attributed to aldehyde formation due to oxidative stress and inflammation. Shifts and shape changes were detected at the bands of amide I and II at 1650 cm-1 and 1550 cm-1, respectively, concerning protein misfolding, fiber formation and sclerosis. The bands in the region 1299–900 cm-1 correspond to phosphate groups of phospholipidsand the formed calcium phosphate salts and non-biological hydroxyapatite Ca3(PO4)2 formation. All vibrations increased significantly longitudinally during experimental diet period. Representative FT-IR spectra of valves Conclusions Advanced glycation end products are detected in human calcified aortic valves irrespectively of DM. Moreover, AGPs correlate with presence and gradual development of aortic valve calcification in experimental rabbit model, along with acidosis, oxidation and protein secondary misfolding. Accumulation of AGPs in valve tissue is implicated in mechanisms of disease development.

Download Full-text

Valve-in-Valve-in-Valve: Degenerated Transcatheter Heart Valve within Degenerated Surgical Bioprosthetic Aortic Valve Treated with Second Transcatheter Heart Valve

Reports ◽

10.3390/reports3020007 ◽

2020 ◽

Vol 3 (2) ◽

pp. 7

Author(s):

Muhammad Ajmal ◽

Sridhar Reddy ◽

Ranjith Shetty ◽

Toshinobu Kazui ◽

Kapildeo Lotun

Keyword(s):

Cardiopulmonary Bypass ◽

Aortic Valve ◽

Heart Valve ◽

Rare Case ◽

Aortic Valves ◽

Safety And Efficacy ◽

Hemodynamic Support ◽

Transcatheter Aortic Valve ◽

Transcatheter Heart Valve ◽

Valve In Valve

Currently, transcatheter aortic valve replacements within degenerated surgical bioprosthetic aortic valves (valve in valve) are increasing in frequency with studies supporting their safety and efficacy. We present the rare case of a patient requiring a second transcatheter bioprosthetic aortic valve placed within a previously placed degenerated transcatheter aortic valve, which was implanted in a degenerated surgical bioprosthetic aortic valve. The procedure was performed using a percutaneous cardiopulmonary bypass with TandemLife for hemodynamic support.

Download Full-text

JNK pathway promotes hepatocyte apoptosis by inhibiting Bcl-2 and upregulating expressions of Bim, caspase-3 and caspase-9 after cardiopulmonary bypass

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i3.9 ◽

2020 ◽

Vol 19 (3) ◽

pp. 519-524

Author(s):

Haibin Yu ◽

Haojie Zhang ◽

Yan Cheng ◽

Xian’en Fa ◽

Fangtao Zhu ◽

...

Keyword(s):

Cardiopulmonary Bypass ◽

Protein Expression ◽

Caspase 3 ◽

Control Group ◽

Hepatocyte Apoptosis ◽

Caspase 9 ◽

Jnk Pathway ◽

Expression Levels ◽

Over Expression ◽

Mrna Expression Levels

Purpose: To study the effect of Jun N-terminal kinase (JNK) signaling pathway on hepatocyte apoptosis in vivo and in vitro, and to elucidate the mechanism of action. Methods: TdT-mediated dUTP Nick-End Labeling (TUNEL) method was used to determine apoptosis in control and cardiopulmonary bypass (CPB) groups at 0, 3 and 6 hours after rat surgery. The expressions of JNK and p-c-Jun in liver tissues at 0, 3 and 6 h after surgery, and the levels of p-c-Jun, Bcl-2 and Bim following overexpression of JNK, were determined using Western blot assay. Human liver cell line HL-7702 was cultured and transfected with over-expressed JNK plasmid and empty plasmid. Proliferation of HL-7702 cells after JNK over-expression was assessed by Cell Counting Kit-8 (CCK-8), while quantitative real-time polymerase chain reaction (RT-qPCR) was employed to evaluate mRNA expression levels of caspase-3 and caspase-9 mRNA after JNK over-expression. Apoptosis of the cells was determined by flow cytometry (FC) after JNK over-expression. Results: FC results showed that the number of apoptotic hepatocytes increased after JNK overexpression in hepatocytes while TUNEL assay results demonstrated that hepatocyte apoptosis increased in CPB group, when compared to control group; furthermore, the number of apoptotic cells gradually increased within 6 h after surgery. The expressions of JNK and p-c-Jun were higher in CPB group than in control group, and increased gradually in both groups within 6 h after surgery. Overexpression of JNK decreased the proliferation of hepatocytes, and also lowered protein expression levels of p-c-Jun and Bim; on the other hand, the protein expression levels of Bcl-2 fell, while mRNA expression levels of caspase-3 and caspase-9 mRNA increased. Conclusion: JNK pathway promotes hepatocyte apoptosis after cardiopulmonary bypass by inhibiting Bcl-2 pathway and promoting the expressions of Bim caspase-3 and caspase-9. Keywords: Cardiopulmonary bypass, Apoptosis, JNK pathway, Bim, caspase-3 and caspase-9

Download Full-text

Down-regulation of XIAP enhances the radiosensitivity of esophageal cancer cells in vivo and in vitro

Bioscience Reports ◽

10.1042/bsr20170711 ◽

2017 ◽

Vol 37 (5) ◽

Cited By ~ 5

Author(s):

Xin Wen ◽

Xin-Rui Han ◽

Shao-Hua Fan ◽

Zi-Feng Zhang ◽

Lu Chen ◽

...

Keyword(s):

Esophageal Cancer ◽

Gene Silencing ◽

Cell Survival ◽

Cell Lines ◽

Western Blotting ◽

Nude Mice ◽

Caspase 3 ◽

Control Group ◽

Caspase 9 ◽

Blank Control Group

The study investigated the effects of X-chromosome-linked inhibitor of apoptosis (XIAP) gene silencing on the radiosensitivity of esophageal cancer (EC) cells. Western blotting was used to select EC cell lines with XIAP overexpression. Selected EC9706 and KYSE30 cell lines were both divided into four groups: the blank control group, the negative control (NC) group (transfected with pBSHH1), the siRNA-enhanced group (transfected with pBSHH1-XIAP1-siRNA), and the siRNA-decreased group (transfected with pBSHH1-XIAP2-siRNA). Expressions of XIAP were measured by reverse-transcription quantitative PCR (RT-qPCR) and Western blotting, cell survival and viability by MTT assay and colony formation assay, and cell apoptosis by flow cytometry, respectively. Caspase-3 and caspase-9 activity were detected using caspase-3 and caspase-9 activity detection kits. A nude mice model of EC9706 cell line was established to measure tumorigenesis ability. Compared with the NC group, XIAP mRNA and protein expressions were decreased, caspase-3 and caspase-9 activity and apoptosis were up-regulated, and cell survival rate and colony-forming efficiency were lower in the siRNA-enhanced and siRNA-decreased groups in both the cell lines; while the opposite trends were found in the siRNA-decreased group compared with the siRNA-enhanced group. Tumor weight and volume of nude mice were decreased in the siRNA-enhanced and siRNA-decreased groups than those in the NC group, and were elevated in the siRNA-decreased group compared with the siRNA-enhanced group. These results indicate that XIAP gene silencing would strengthen the radiosensitivity of EC9706 cells, which provides a novel target for the treatment of EC.

Download Full-text

Emulsified isoflurane alleviates rat islet beta cell RIN-m5F apoptosis induced by glucose via inhibiting endoplasmic reticulum stress

10.21203/rs.2.11437/v1 ◽

2019 ◽

Author(s):

Wenyan Dong ◽

Zhenkun Yang ◽

Jingjing Zhao ◽

Jie Sun ◽

Min Yao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Beta Cell ◽

Beta Cells ◽

Western Blotting ◽

High Glucose ◽

Caspase 3 ◽

Control Group ◽

Group Culture ◽

Islet Beta Cell

Abstract Background Diabetes mellitus (DM) is a critical disease that considered a detriment to the health of people all over the world. Endoplasmic reticulum stress (ERS) is the response cause by endoplasmic reticulum misfolded and unfolded protein aggregation, which induces cell apoptosis. Our previous work showed that EIso could alleviate ERS in lung reperfusion injury. This study aimed to elucidate whether Emulsified isoflurane (EIso) could alleviate apoptosis induced by glucose in rat islet beta cell RIN-m5F via inhibiting ERS. Methods RIN-m5F cells were divided into five groups: Control group, cultured in 0.1M glucose for 24h (0.1G group), culture in 0.3M glucose for 24h (0.3G group), culture in 0.3M glucose with 57uM EIso for 24h (0.3G+57E group), and culture in 0.3M glucose with 76uM EIso for 24h (0.3G+76E group). First, the cellular proliferation was measured by MTT assay, and the level of insulin secretion was measured with ELISA kit. Second, the expression of Bax and Bcl-2 were detected by Western blotting. The level of caspase-3 activity was assessed by colorimetric method. Finally, the CHOP and GRP78 expression were detected by Western blotting. The level of ATF6, Xbp1 and eIF2α mRNA were assessed by qRT-PCR after treated with EIso for 24h. Results High glucose induced significant loss of RIN-m5F cell viability, and stimulated the secretion of insulin; EIso improved the survival and protected the function of RIN-m5F. Compare to 0.3G group, treatment with EIso inhibited the activity of caspase-3, decreased the expression of Bax and increased the expression of Bcl-2. The expression of CHOP and GRP78 were inhibited by EIso at 24 h after treatment, and decrement of CHOP and GRP78 expression were correlated with EIso concentration. The level of ATF6, Xbp1 and eIF2α mRNA of RIN-m5F were enhanced culture with high glucose, but only eIF2α mRNA was decreased by EIso treatment. Conclusion High glucose induces rat islet beta cell RIN-m5F apoptosis and aggravates the function of beta cells. EIso protects beta cells from glucose-induced apoptosis, and anti-apoptosis is mediated, at least in part, by inhibiting ERS.

Download Full-text

New Contributions to Asarum Powder on Immunology Related Toxicity Effects in Lung

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/1054032 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Yamin Li ◽

Lintao Han ◽

Chunhua Huang ◽

Wangqiang Dai ◽

Guangyu Tian ◽

...

Keyword(s):

Western Blotting ◽

Caspase 3 ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Inflammatory Factors ◽

Control Group ◽

Intragastric Administration ◽

Go Analysis ◽

Immune Related Genes ◽

Insight Into

Objective. Asarum is widely used in clinical practice of Chinese medicine in the treatment of respiratory diseases. Many toxic ingredients (safrole, etc.) had been found in Asarum that show multiple visceral toxicities. In this study, we performed systematic investigation of expression profiles of genes to take a new insight into unclear mechanism of Asarum toxicities in lung. Methods. mRNAs were extracted from lungs of rats after intragastric administration with/without Asarum powders, and microarray assays were applied to investigate gene expression profiles. Differentially expressed genes with significance were selected to carry out GO analysis. Subsequently, quantitative PCRs were performed to verify the differential expression of Tmprss6, Prkag3, Nptx2, Antxr11, Klk11, Rag2, Olr77, Cd7, Il20, LOC69, C6, Ccl20, LOC68, and Cd163 in lung. Changes of Ampk, Bcl2, Caspase 3, Il1, Il20, Matriptase2, Nfκb, Nptx2, and Rag2 in the lung on protein level were verified by western blotting and immunohistochemistry. Results. Compared with control group, the estimated organ coefficients were relatively increased in Asarum group. Results of GO analysis showed that a group of immune related genes in lung were expressed abnormally. The result of PCRs showed that Ccl20 was downregulated rather than other upregulated genes in the Asarum group. Western blotting and immunohistochemistry images showed that Asarum can upregulate the expression of Ampk, Caspase 3, Il1, Il20, Matriptase2, Nfκb, and Rag2 and downregulate the expression of Bcl2 in lung. Conclusion. Our data suggest that expressions of immune related genes in lung were selectively altered by Asarum. Therefore, inflammatory response was active, by regulating Caspase 3, Il1, Il20, Matriptase2, Nfκb, Rag2, Tmprss6, Prkag3, Nptx2, Antxr1, Klk11, Olr77, Cd7, LOC69, C6, LOC68, Cd163, Ampk, Bcl2, and Ccl20. Our study indicated that inflammatory factors take effect in lung toxicity caused by Asarum, which provides a new insight into molecular mechanism of Asarum toxicities in lung.

Download Full-text

Fluorochloridone Induces Autophagy in TM4 Sertoli Cells:Involvement of ROS-mediated AKT-mTOR Signaling Pathway

10.21203/rs.3.rs-140373/v1 ◽

2021 ◽

Author(s):

Zhijing Ni ◽

Weiqi Sun ◽

Rui Li ◽

Mingjun Yang ◽

Fen Zhang ◽

...

Keyword(s):

Signaling Pathways ◽

Sertoli Cells ◽

Reproductive Toxicity ◽

Cell Activity ◽

Mtor Signaling ◽

Beclin 1 ◽

Control Group ◽

Ros Generation

Abstract BackgroundFluorochloridone (FLC), a selective pyrrolidone herbicide, had medium persistence in soil and groundwater, indicating that its environmental fate was highly correlated with mammals and human health. FLC has been recognized as a potential endocrine disruptor and reported to induce male reproductive toxicity, but the underlying mechanism is largely unclear. MethodsAdult C57BL/6 mice were raised to divided into one control group (0.5% sodium carboxymethyl cellulose), and four FLC-treated groups (3,15,75,375 mg/kg). The animals (ten mice per group) received gavage for a period of 28 days. After treatment, histological analysis, sperm parameters, the microstructure of autophagy and the expression of autophagy-associated proteins in testis were evaluated. Furthermore, to explore the autophagy mechanism, TM4 Sertoli cells were treated with FLC (0,40,80,160μM) in vitro for 24 h. Cell activity and cytoskeletal changes were measured by MTT assay and F-actin immunofluorescence staining. The formation of autophagosome, accumulation of reactive oxygen species and expression of AKT, mTOR were detected.ResultsIn vivo, it showed that FLC exposure caused testicular injuries, abnormality in epididymal sperm. Moreover, FLC increased the formation of autophagosomes, the accumulation of LC3, Beclin-1 and the expression of P62 protein, which is related to the degradation of autophagy. In vitro, the upregulation of TM4 cells autophagy was confirmed by FLC increased the formation of autophagosomes and upregulation of autophagy marker proteins (LC3, Beclin-1 and P62) levels. In addition, FLC induced ROS production and inhibited the activities of AKT and mTOR kinases. The Inhibition of AKT/mTOR signaling pathways and the activation of autophagy induced by FLC could be efficiently reversed by pretreatment of ROS generation by N-acetylcysteine. SC79, AKT agonist, could restore the autophagy induced by FLC in TM4 cells. Intriguingly, FLC-induced autophagy could be inhibited through AKT agonists, which indicated that FLC-induced autophagy may be pro-death. ConclusionTaken together, our study provided the evidence that FLC promoted autophagy in TM4 Sertoli cells and that this process may involve ROS-mediated AKT/mTOR signaling pathways.

Download Full-text

Impact of Ciprofloxacin With Autophagy on Acute Kidney Injury

10.21203/rs.3.rs-210236/v1 ◽

2021 ◽

Author(s):

Woo Yeong Park ◽

Sun-Ha Lim ◽

Yaerim Kim ◽

Jin Hyuk Paek ◽

Kyubok Jin ◽

...

Keyword(s):

Acute Kidney Injury ◽

Caspase 3 ◽

Kidney Injury ◽

Underlying Mechanism ◽

Beclin 1 ◽

Control Group ◽

Renal Tubules ◽

Tubular Injury ◽

Renal Tubular Cells ◽

Renal Tubular

Abstract Renal tubular injury caused by oxidative stress and inflammation results in acute kidney injury. Recent research reported that antibiotics may restore deteriorated renal tubules, but the underlying mechanism remains unclear. Therefore, we investigated the efficacy and mechanism of action of antibiotics against renal tubular injury. We screened ciprofloxacin, ceftizoxime, minocycline, and netilmicin and selected ciprofloxacin to examine further because of its low toxicity towards renal tubular cells. We evaluated the effect of ciprofloxacin on cell survival by analyzing apoptosis and autophagy. TUNEL assay results showed that the ciprofloxacin group had less apoptotic cells than the control group. The ratio of cleaved caspase 3 to caspase 3, the final effector in the apoptosis process, was decreased, but the ratio of Bax to Bcl-2 located upstream of caspase 3 was not decreased in the ciprofloxacin group. Therefore, apoptosis inhibition does not occur via Bax/Bcl-2. Conversely, the levels of phosphorylated Bcl-2, and Beclin-1, an autophagy marker, were increased, and that of caspase-3 was decreased in the ciprofloxacin group. This indicates that ciprofloxacin enhanced autophagy, increasing the amount of free Beclin-1 via phosphorylated Bcl-2, and inhibited caspase activity. Therefore, ciprofloxacin might increase renal cell viability through the autophagy activation in acute kidney injury.

Download Full-text

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.

Download Full-text

Ultrastructural Pathology of Atherosclerosis, Calcific Aortic Valve Disease, and Bioprosthetic Heart Valve Degeneration: Commonalities and Differences

International Journal of Molecular Sciences ◽

10.3390/ijms21207434 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7434 ◽

Cited By ~ 1

Author(s):

Alexander Kostyunin ◽

Rinat Mukhamadiyarov ◽

Tatiana Glushkova ◽

Leo Bogdanov ◽

Daria Shishkova ◽

...

Keyword(s):

Aortic Valve ◽

Heart Valve ◽

Aortic Valve Disease ◽

Circulatory System ◽

Valve Disease ◽

Calcium Deposition ◽

Bioprosthetic Heart Valve ◽

Calcific Aortic Valve Disease ◽

Ultrastructural Pathology ◽

Structural Valve Deterioration

Atherosclerosis, calcific aortic valve disease (CAVD), and bioprosthetic heart valve degeneration (alternatively termed structural valve deterioration, SVD) represent three diseases affecting distinct components of the circulatory system and their substitutes, yet sharing multiple risk factors and commonly leading to the extraskeletal calcification. Whereas the histopathology of the mentioned disorders is well-described, their ultrastructural pathology is largely obscure due to the lack of appropriate investigation techniques. Employing an original method for sample preparation and the electron microscopy visualisation of calcified cardiovascular tissues, here we revisited the ultrastructural features of lipid retention, macrophage infiltration, intraplaque/intraleaflet haemorrhage, and calcification which are common or unique for the indicated types of cardiovascular disease. Atherosclerotic plaques were notable for the massive accumulation of lipids in the extracellular matrix (ECM), abundant macrophage content, and pronounced neovascularisation associated with blood leakage and calcium deposition. In contrast, CAVD and SVD generally did not require vasculo- or angiogenesis to occur, instead relying on fatigue-induced ECM degradation and the concurrent migration of immune cells. Unlike native tissues, bioprosthetic heart valves contained numerous specialised macrophages and were not capable of the regeneration that underscores ECM integrity as a pivotal factor for SVD prevention. While atherosclerosis, CAVD, and SVD show similar pathogenesis patterns, these disorders demonstrate considerable ultrastructural differences.

Download Full-text