scholarly journals Plasma Metabolomic Profiling Associates Bicuspid Aortic Valve Disease and Ascending Aortic Dilation with a Decrease in Antioxidant Capacity

2020 ◽  
Vol 9 (7) ◽  
pp. 2215
Author(s):  
Neus Martínez-Micaelo ◽  
Carme Ligero ◽  
Borja Antequera-González ◽  
Alexandra Junza ◽  
Oscar Yanes ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Antioxidant Capacity ◽  
Bicuspid Aortic Valve ◽  
Plasma Levels ◽  
Density Lipoprotein ◽  
Endothelial Damage ◽  
Alpha Tocopherol ◽  
Paraoxonase 1 ◽  
Aortic Dilation ◽  
Increased Risk

Background: The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV. Methods: Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and/or aortic stenosis (n = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism. Results: We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve. Discussion: Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.

scholarly journals The Development of the Ascending Aortic Wall in Tricuspid and Bicuspid Aortic Valve: A Process from Maturation to Degeneration

2020 ◽  
Vol 9 (4) ◽  
pp. 908
Author(s):  
Nimrat Grewal ◽  
Adriana C. Gittenberger-de Groot ◽  
Jan von der Thusen ◽  
Lambertus J. Wisse ◽  
Margot M. Bartelings ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Young Child ◽  
Bicuspid Aortic Valve ◽  
Aortic Wall ◽  
Age Groups ◽  
Intimal Thickening ◽  
Aortic Dilation ◽  
Future Studies ◽  
Increased Risk ◽  
Two Phases

Background: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in the tricuspid aortic valve (TAV) and the BAV populations as a reference for future studies on aortopathy and related syndromes. Methods: Non-dilated TAV and BAV ascending aortic wall samples were collected, including 60 TAV (embryonic–70 years) and 32 BAV specimens (fetal–72 years, categorized in eight age groups. Results: In TAV, intimal development starts in the neonatal phase. After birth, the thickness of the medial layer increases significantly by increase of elastic lamellae up to and including the “young child” phase stabilizing afterwards. The BAV shows already prenatal intimal thickening becoming significantly thinner after birth subsequently stabilizing. In BAV, increase in elastic lamellae is seen between the young child and the adolescent phases, stabilizing afterwards. Conclusions: Vascular development in TAV is described in three phases: maturation, stabilization, and degeneration. For BAV, the development can be described in two phases: maturation (already prenatally) and degeneration. After birth, the development of the aorta is characterized by degeneration, leading to weakening of the ascending aortic wall and increasing the risk of aortopathy.

Impaired Antiatherogenic Functions of High-density Lipoprotein in Patients with Ankylosing Spondylitis

2015 ◽  
Vol 42 (9) ◽  
pp. 1652-1660 ◽  
Author(s):  
Christina Gkolfinopoulou ◽  
Efstratios Stratikos ◽  
Dimitris Theofilatos ◽  
Dimitris Kardassis ◽  
Paraskevi V. Voulgari ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
High Density Lipoprotein ◽  
Antioxidant Capacity ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
High Density ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Akt Kinase ◽  
Increased Risk

Objective.Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with increased risk of cardiovascular disease (CVD). High-density lipoprotein (HDL) exerts a series of antiatherogenic properties and protects from CVD. We evaluated whether HDL antiatherogenic properties are impaired in patients with AS.Methods.HDL (apoB-depleted serum) was isolated from 35 patients with AS and 35 age- and sex-matched controls. We measured the antioxidant capacity of HDL, the ability of HDL to induce cholesterol efflux, the activity of HDL-associated enzymes paraoxonase-1 (PON1) and myeloperoxidase (MPO), as well as the ability of HDL to induce Akt kinase activation.Results.HDL from patients with AS had decreased antioxidant capacity and decreased ability to promote cholesterol efflux from macrophages compared to controls. HDL-associated PON1 activity was lower and HDL-associated MPO activity higher in patients with AS compared to controls. Higher MPO activity correlated positively with lower antioxidant capacity of HDL in patients with AS. In addition, HDL from patients with AS had impaired endothelial Akt kinase activating properties that were inversely correlated with the MPO/PON1 ratio and positively correlated with the cholesterol efflux capacity of HDL.Conclusion.HDL from patients with AS displays impaired antiatherogenic properties. Attenuation of HDL properties may constitute a link between AS and CVD.

scholarly journals Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy

2020 ◽  
Vol 13 (9) ◽  
pp. dmm044990
Author(s):  
Joshua C. Peterson ◽  
Lambertus J. Wisse ◽  
Valerie Wirokromo ◽  
Tessa van Herwaarden ◽  
Anke M. Smits ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Neural Crest Cell ◽  
Ascending Aorta ◽  
Aortic Aneurysms ◽  
Aortic Dilation ◽  
Elastic Fibres ◽  
Increased Risk

ABSTRACTPatients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3−/− mice, a model with congenital BAV formation. A combination of histological examination and in vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3−/− mice. Moreover, cell lineage analysis and single-cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3−/− mice. Spontaneous aortic dissections were found in ascending aortas located at the sinotubular junction in ∼13% of Nos3−/− mice. Moreover, Nos3−/− mice were prone to developing aortic dilations in the proximal and distal ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3−/− mice, as well as incomplete coverage of the aortic inner media by neural crest cell (NCC)-derived VSMCs. VSMCs of Nos3−/− mice showed downregulation of 15 genes, of which seven were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that, in addition to congenital BAV formation, disrupted endothelial-mediated nitric oxide (NO) signalling in Nos3−/− mice also causes aortic dilation and dissection, as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta.

scholarly journals Fate of mild-to-moderate bicuspid aortic valve disease untreated during ascending aorta replacement

2020 ◽  
Author(s):  
Alessandro Verzini ◽  
Marta Bargagna ◽  
Guido Ascione ◽  
Alessandra Sala ◽  
Davide Carino ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Ascending Aorta ◽  
Term Survival ◽  
Kaplan Meier ◽  
Aortic Root Surgery ◽  
Increased Risk ◽  
Aorta Replacement ◽  
Ascending Aorta Replacement

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect and it is responsible for an increased risk of developing aortic valve and ascending aorta complications. In case of mild to moderate BAV disease in patients undergoing supracoronary ascending aorta replacement, it is unclear whether a concomitant aortic valve replacement should be performed. Methods: From June 2002 to January 2020, 75 patients with mild-to-moderate BAV regurgitation (± mild-to-moderate stenosis) who underwent isolated supracoronary ascending aorta replacement were retrospectively analyze. Clinical and echocardiographic follow-up was 100% complete (mean: 7.4±3.9 years, max 16.4). Kaplan Meier estimates were employed to analyze long-term survival. Cumulative incidence function for time to re-operation, recurrence of aortic regurgitation (AR)≥3+ and aortic stenosis (AS) greater than moderate, with death as competing risk, were computed. Results: There was no hospital mortality and no cardiac death occurred. Overall survival at 12 years was 97.4±2.5%, 95% CI [83.16-99.63]. At follow-up there were no cases of aortic root surgery whereas 3 patients underwent AV replacement. At 12 years the CIF of reoperation was 2.6±2.5%, 95% CI [0.20-11.53]. At follow up, AR 3+/4+ was present in 1 pt and AS greater than moderate in 3. At 12 years the CIF of AR>2+/4+ was 5.1±4.98% and of AS>moderate 6.9±3.8%. Conclusions: In our study mild to moderate regurgitation of a BAV did not significantly worse at least up to 10 years after isolated supracoronary ascending aorta replacement.

Abstract 349: Outcomes Among Women With Bicuspid Aortic Valve and/or Bicuspid Aortopathy During Pregnancy

2020 ◽  
Vol 13 (Suppl_1) ◽  
Author(s):  
Sarina Meikle ◽  
Jenny Wu ◽  
David Bach ◽  
Marion Hofmann Bowman ◽  
Mark Norris ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Dissection ◽  
Bicuspid Aortic Valve ◽  
Gestational Age ◽  
Beta Blockers ◽  
Post Partum ◽  
Inclusion Criteria ◽  
Vaginal Deliveries ◽  
Increased Risk ◽  
Aortic Dissections

Background: Bicuspid aortic valve (BAV) is associated with an increased risk of aortic dissection, but little is known about pregnancy-associated outcomes. Methods: ICD codes and a text recognition program (EMERSE) were used to identify women with BAV and pregnancy (2000-2018) at a single center. Charts were manually reviewed to confirm the diagnoses, echocardiographic data, co-morbidities, and outcomes. Inclusion criteria were congenital BAV pathology and pregnancy. Primary endpoints included expansion of aortic aneurysm and aortic dissection during pregnancy and up to 6 weeks post-partum. Results: We identified 622 women with diagnoses of BAV and pregnancy. After detailed review, 72 women (87 pregnancies) met inclusion criteria. Mean gestational age at delivery was 36.9 weeks. Ten (11.5%) patients had hypertensive disorders of pregnancy, 7 (8.0%) had gestational diabetes, and 25 (28.7%) were treated with beta-blockers. Two (2.3%) pregnancies had intra-uterine growth restriction. Vaginal deliveries occurred in 56.5% and cesarean section in 36.3%. No Type A or B aortic dissections occurred. During pregnancy, there were no significant changes in the aortic dimensions. Prior to pregnancy, 6 women had aortic measurements > 40mm (mean pre-pregnancy 40.8 ± 3.2 mm; mean post-pregnancy 42.5 ± 3.9 mm). In this higher-risk group, mean gestational age was 38.7 weeks, 4 (66.7%) had vaginal delivery, 1 (16.7%) had preeclampsia, 4 (66.7%) were treated with beta-blockers, and all breastfed. There were no delivery complications, no aortic dissections, and no maternal or fetal deaths. Conclusions: Women with BAV appear to be at relatively low risk for acute aortic dissection during pregnancy.

scholarly journals Bicuspid aortic valve patients show specific epigenetic tissue signature increasing extracellular matrix destruction

2019 ◽  
Vol 29 (6) ◽  
pp. 937-943 ◽  
Author(s):  
Josephina Haunschild ◽  
Isabel N Schellinger ◽  
Sarah J Barnard ◽  
Konstantin von Aspern ◽  
Piroze Davierwala ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Epigenetic Regulation ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Aortic Tissue ◽  
Tissue Inhibitor ◽  
Tissue Samples ◽  
Increased Risk

Abstract OBJECTIVES Patients with a bicuspid aortic valve (BAV) have an increased risk for developing thoracic aortic aneurysm, which is characterized by the destruction of the elastic media of the aortic wall. Several important enzymes have been characterized to play key roles in extracellular matrix homeostasis, namely matrix metalloproteinases (MMPs). In this study, we investigated MMP-2 levels and their epigenetic regulation via the miR-29 family. METHODS Aortic tissue samples from 58 patients were collected during cardiac surgery, of which 30 presented with a BAV and 28 with a tricuspid aortic valve. Polymerase chain reaction, western blot analysis and immunohistochemistry were performed to analyse MMP-2. In addition, enzyme-linked immunosorbent assay measurements were carried out to investigate both MMP-2 and tissue inhibitor of metalloproteinase-2 levels. To examine the epigenetic regulation of aortic extracellular matrix homeostasis, we furthermore studied the expression levels of miR-29 via qRT-PCR. RESULTS Patients with a BAV were significantly younger at the time of surgery, presented significantly less frequently with arterial hypertension and displayed more often with an additional valvular disease. On a molecular level, we found that MMP-2 is increased on gene and protein level in BAV patients. Tissue inhibitor of metalloproteinase-2 levels do not differ between the groups. Interestingly, we also found that only miR-29A is significantly downregulated in BAVs. CONCLUSIONS Our findings highlight the importance of MMP-2 in the context of extracellular matrix destruction in BAV patients. We present new evidence that miR-29A is a crucial epigenetic regulator of these pathomechanistic processes and might hold promise for future translational research.

scholarly journals Influence of Aortic Dilation on the Regional Aortic Stiffness of Bicuspid Aortic Valve Assessed by 4-Dimensional Flow Cardiac Magnetic Resonance

2019 ◽  
Vol 12 (6) ◽  
pp. 1020-1029 ◽  
Author(s):  
Andrea Guala ◽  
Jose Rodriguez-Palomares ◽  
Lydia Dux-Santoy ◽  
Gisela Teixido-Tura ◽  
Giuliana Maldonado ◽  
...  
Keyword(s):  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Stiffness ◽  
Aortic Dilation ◽  
Dimensional Flow

scholarly journals Paraoxonase 1 Phenotype and Protein N-Homocysteinylation in Patients with Rheumatoid Arthritis: Implications for Cardiovascular Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 899
Author(s):  
Jolanta Parada-Turska ◽  
Grażyna Wójcicka ◽  
Jerzy Beltowski
Keyword(s):  
Rheumatoid Arthritis ◽  
Protein Concentration ◽  
Serum Proteins ◽  
Density Lipoprotein ◽  
Cardiovascular Complications ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Phenyl Acetate ◽  
Control Subjects ◽  
Increased Risk

Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the development of atherosclerosis by metabolizing lipid peroxidation products as well as hydrolyzing proatherogenic metabolite of homocysteine (Hcy), Hcy thiolactone, which otherwise reacts with lysine groups of proteins, thus forming N-Hcy-protein in a process referred to as protein N-homocysteinylation. Rheumatoid arthritis (RA) is the chronic inflammatory autoimmune disease associated with increased risk of cardiovascular complications, but the underlying mechanisms are incompletely understood. We examined PON1 status and N-homocysteinylation of serum proteins in patients with RA. Blood was collected from 74 RA patients and 70 control subjects. PON1 activity was measured toward synthetic (paraoxon, phenyl acetate) and natural (Hcy thiolactone) substrates. PON1 protein concentration was measured by ELISA. Total Hcy as well as N-Hcy-protein were measured in serum as well. PON1 activity toward Hcy thiolactone was lower in RA patients than in control subjects which was accompanied by increased concentration of N-Hcy-protein despite normal total Hcy concentration. PON1 protein concentration was unchanged in the RA group, but the specific enzyme activity was reduced. When RA patients were categorized according to the DAS28-ESR score, PON1 concentration and enzymatic activity were lower whereas N-Hcy-protein was higher in those with high disease activity. PON1 activity and Hcy thiolactone were correlated with DAS28-ESR score and myeloperoxidase concentration. In conclusion, RA is associated with deficiency of PON1 activity and increased protein N-homocyseinylation which may contribute to accelerated development of cardiovascular diseases.

Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: Mendelian randomization in the Copenhagen General Population Study

2020 ◽  
Vol 41 (24) ◽  
pp. 2288-2299 ◽  
Author(s):  
Morten Kaltoft ◽  
Anne Langsted ◽  
Børge G Nordestgaard
Keyword(s):  
Aortic Valve ◽  
General Population ◽  
Aortic Valve Stenosis ◽  
Population Study ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
General Population Study ◽  
Plasma Triglycerides ◽  
Increased Risk ◽  
Remnant Cholesterol

Abstract Aims We tested the hypothesis that higher levels of plasma triglycerides and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis. Methods and results We included 108 559 individuals from the Copenhagen General Population Study. Plasma triglycerides, remnant cholesterol (total cholesterol minus low-density lipoprotein and high-density lipoprotein cholesterol), and 16 genetic variants causing such increased or decreased levels were determined. Incident aortic valve stenosis occurred in 1593 individuals. Observationally compared to individuals with triglycerides <1 mmol/L (<89 mg/dL), the multifactorially adjusted hazard ratio for aortic valve stenosis was 1.02 [95% confidence interval (CI) 0.87–1.19] for individuals with triglycerides of 1.0–1.9 mmol/L (89–176 mg/dL), 1.22 (1.02–1.46) for 2.0–2.9 mmol/L (177–265 mg/dL), 1.40 (1.11–1.77) for 3.0–3.9 mmol/L (266–353 mg/dL), 1.29 (0.88–1.90) for 4.0–4.9 mmol/L (354–442 mg/dL), and 1.52 (1.02–2.27) for individuals with triglycerides ≥5 mmol/L (≥443 mg/dL). By age 85, the cumulative incidence of aortic valve stenosis was 5.1% for individuals with plasma triglycerides <2.0 mmol/L (77 mg/dL), 6.5% at 2.0–4.9 mmol/L (177–442 mg/dL), and 8.2% for individuals with plasma triglycerides ≥5.0 mmol/L (443 mg/dL). The corresponding values for remnant cholesterol categories were 4.8% for <0.5 mmol/L (19 mg/dL), 5.6% for 0.5–1.4 mmol/L (19–57 mg/dL), and 7.4% for ≥1.5 mmol/L (58 mg/dL). Genetically, compared to individuals with allele score 13–16, odds ratios for aortic valve stenosis were 1.30 (95% CI 1.20–1.42; Δtriglycerides +12%; Δremnant cholesterol +11%) for allele score 17–18, 1.41 (1.31–1.52; +25%; +22%) for allele score 19–20, and 1.51 (1.22–1.86; +51%; +44%) for individuals with allele score 21–23. Conclusion Higher triglycerides and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.

ALTERATION OF ELASTIC PROPERTIES IN CONGENITAL/INHERITED AORTIC DISEASES: MRI STUDY IN MARFAN SYNDROME AND BICUSPID AORTIC VALVE

2006 ◽  
Vol 06 (01) ◽  
pp. 47-53
Author(s):  
LUIGI LOVATO ◽  
PAOLO SBARZAGLIA ◽  
SILVIA MAGI ◽  
VINCENZO RUSSO ◽  
ROMANO ZANNOLI ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Marfan Syndrome ◽  
Elastic Properties ◽  
Bicuspid Aortic Valve ◽  
Aortic Distensibility ◽  
Control Group ◽  
Aortic Dilation ◽  
Aortic Diseases ◽  
Magnetic Resonance Imaging Mri ◽  
Mri Study

Marfan Syndrome and Bicuspid Aortic Valve (BAV) are characterized by the congenital/inherited alteration of the fibrillin proteins of aortic wall extracellular matrix, with higher incidence of aortic dissection/rupture even without aortic dilation. Therefore, early identification and treatment of aortic involvement could improve prognosis. The purpose of this study was to evaluate aortic elastic properties of BAV and Marfan Syndrome patients to identify an index of early aortic involvement. Methods: A Magnetic Resonance Imaging (MRI) study was performed on 38 BAV patients, 20 Marfan patients and 14 healthy volunteers as a control group. A high-resolution gradient-echo sequence was applied in the axial plane at the level of pulmonary artery bifurcation to evaluate aortic distensibility. Results: Aortic distensibility was significantly different among the three groups (ANOVA, p = 0.0001) and was sensibly reduced in BAV (0.0056 ± 0.0048 versus 0.025 ± 0.006 control group) and Marfan (0.0085 ± 0.006 versus 0.025 ± 0.006 control group). Intraobserver and interobserver reproducibility for diastolic measurements were 1.2% and 0.4% respectively and for systolic measurements, they were 1.1% and 0.3% respectively. Conclusion: In BAV or Marfan Syndrome patients, MRI evaluation of abnormal distensibility may provide a reliable index of early aortic involvement, even before aortic dilation occurs.

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