Dissolving cholesterol crystals reduces aortic valve stenosis development in mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.T Niepmann ◽  
M Lenart ◽  
N Willemsen ◽  
P Duewell ◽  
D Luetjohann ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Serum Cholesterol ◽  
Cholesterol Metabolism ◽  
Therapeutic Option ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Aortic Valves ◽  
Cholesterol Crystals

Abstract Background Aortic valve stenosis (AS) is the most common valve disease worldwide and is associated with a very high morbidity and mortality. Until today, aortic valve replacement is the only therapeutic option available. Analysis of explanted human aortic valves has shown that atherosclerosis-like lesions, that contain cholesterol crystals (CC), are present in stenotic aortic valve cusps. It has been demonstrated that CCs can activate the NLRP3 inflammasome and hereby trigger a complex, IL-1b driven, inflammatory response. 2-hydroxypropyl-β-cyclodextrin (CD) is a cyclic oligosaccharide that can increase the solubility of CCs, which results in a reduction of CC-load and therefore could inhibit the pro-inflammatory immune response. Methods Severe AS was induced in 10 weeks old C57BL/6-J (WT) and Apolipoprotein-E-deficient (ApoE) mice. Acoronary springwire was used to induce an endothelial injury under echocardiographic guidance. AS development was confirmed via ultrasound examinations. ApoE mice were fed a cholesterol-rich western diet and concomitantly received daily injections of 2g/kg/d CD via subcutaneous injection. CCs were visualized with laser reflection confocal microscopy. Serum cholesterol analysis were performed via mass GC-MS-SIM. Results In order to evaluate whether hyperlipidemia aggravates AS development, WT and ApoE mice were fed a cholesterol-rich diet and subjected to our model of wire-induced AS. Trans-aortic valve peak velocity levels of ApoE mice were significantly increased six weeks after injury compared to WT mice. Histological analysis of these mice showed large CC-deposits in the aortic valves of ApoE mice. Next, CC solubility was increased in a group of ApoE mice, control mice only received PBS injections. Interestingly, mice treated with CD displayed a significantly reduced peak blood velocity over the aortic valve compared to PBS mice. Left ventricular ejection fraction remained unchanged. Serum cholesterol analysis was performed to analyze the effect of CD on cholesterol metabolism. 27-hydroxycholesterol, an endogenous oxysterol of cholesterol metabolism, which reduces the potential for the conversion of free cholesterol into crystals was significantly increased in CD treated mice. The levels of cholesterol precursors were unchanged, indicating that CD doesn't influence de-novo synthesis of cholesterol. Intestinal absorption of cholesterol was also not affected by CD, as assessed by quantification of phytosterols in the serum of CD and PBS treated mice. Conclusion These results underline the importance of hyperlipidemia in the pathogenesis of AS. Particularly CCs seem to act as an important inflammatory trigger in the development of AS. Increasing the solubility of cholesterol through CD reduces AS development in mice and could, as it is already considered safe in human, act as a possible therapeutic option. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DFG, German Research Foundation

Presence of adipose tissue in aortic valves from aortic regurgitation patients: pathophysiological role and clinical implications

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Sadaba Cipriain ◽  
A.M Navarro Echeverria ◽  
C.R Tiraplegui Garjon ◽  
A Garcia De La Pena Urtasun ◽  
V Arrieta Paniagua ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Aortic Valve ◽  
Aortic Regurgitation ◽  
Systolic Function ◽  
Statistical Significance ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Funding Source ◽  
Matrix Remodeling ◽  
Aortic Valves

Abstract Introduction Adipose tissue is a common constituent of the heart and it is located, without great clinical relevance, frequently in the pericardium. The presence of adipose tissue in the aortic valve is rare, with unknown significance on valve structural properties and function. Aortic regurgitation (AR) is the third most prevalent valve disease, although it is uncommon to find it in isolation. Myxoid degeneration may be the cause or result of AR, although the pathophysiology remains poorly understood. Purpose To describe and characterize the presence of adipose tissue in the aortic valves from a cohort of AR patients. Methods 116 patients undergoing aortic valve replacement due to severe AR were enrolled. We classified them in two groups according to the histological results showing presence or absence of adipose tissue in the aortic valves. In the valve tissue molecular analysis were performed by RT-PCR, Western Blot and ELISA to analyze markers of adipocytes (leptin, adiponectin, resistin), inflammation (Rantes, interleukin-6, interleukin-1β), extracellular matrix remodeling (metalloproteinases-1, -2 and -9), proteoglycans (aggrecan, hyaluronan, lumican, syndecan-1, decorin) and fibrosis (collagens, fibronectin). Results Adipose tissue was found in 63% of the aortic valves analyzed. Baseline characteristics (age, hypertension, dyslipidemia, diabetes, smoking, left ventricular telediastolic diameter, left ventricular systolic function, ascending aorta) were similar in patients presenting valve adipose tissue as compared with patients without valve adipose tissue. Valves containing adipocytes exhibited a higher leptin content (p<0.001), fibronectin (p<0.01), decorin (p<0,0001), hyaluronan (p=0.03), aggrecan (p=0.04) and metalloproteinase 1 (p=0.03). Interestingly, the presence of adipocytes in the valve was positively correlated with valve thickness measured by echocardiogram (Pearson chi2 statistical significance = 26.3345 p<0.001). Conclusion To our knowledge, this is the first study that describes the presence of adipose cells in aortic valves from a cohort of AR patients. Aortic valves containing adipocytes were thicker and exhibited significant higher levels of proteoglycans, suggesting that adipocytes could contribute to the myxomatous degeneration process. Our results propose that the valve adipose tissue could play a role in the pathophysiology of AR. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Gobierno de Navarra

scholarly journals Poster Session 3The imaging examination and quality assessmentP626Value of mitral and tricuspid annular displacement to assess the interventricular systolic relationship in severe aortic valve stenosis : a Pilot studyP627Follow-up echocardiography in asymptomatic valve disease: assessing the potential economic impact of the European and American guidelines in a dedicated valve clinic, compared to standard care.P628The tricuspid valve: identification of optimal view for assessing for prolapseP629Right atrial volume by two-dimensional echocardiography in healthy subjectsP630Disturbance of inter and intra atrial conduction assessed by tissue doppler imaging in patients with medicaly controlled hypertension and prehypertension.P631Liver stiffness by shear wave elastography, new noninvasive and quantitative tool for acute variation estimation of central venous pressure in real-time?P632Weak atrial kick contribution is associated with a risk for heart failure decompensationP633Usefulness of wave intensity analysis in predicting the response to cardiac resynchronization therapyP634Early subclinical left ventricular systolic and diastolic dysfunction in gestational hypertension and preeclampsiaP635Clinical comparison of three different echocardiographic methods for left ventricular ejection fraction and LV end diastolic volume measurementP636Assessment of right ventricular-arterial coupling parameters by 3D echocardiography in patients with pulmonary hypertension receiving specific vasodilator therapyP637Prediction of right ventricular failure after left ventricular assist device implant: assessing usefulness of standard and strain echocardiographyP638Kinematic analysis of diastolic function using the novel freely available software Echo E-waves - feasibility and reproducibilityP639Evaluation of coronary flow velocity by Doppler echocardiography in the treatment of hypertension with the ARB: correlation to the histological cardiac fibrosisP640The clinical significance of limited apical ischaemia and the prognostic value of stress echocardiography - A contemporary study from a high volume centerP641Effects of intermediate stenosis of left anterior descending coronary artery on survival in patients with chronic total occlusion of right coronary arteryP642Left ventricular remodeling after a first myocardial infarction in patients with preserved ejection fraction at dischargeP643Left atrial size and acute coronary syndromes. Let is make simple.P644Influence of STEMI reperfusion strategy on systolic and diastolic functionP645Aortic valve resistance risk-stratifies low-gradient severe aortic stenosisP646Does permanent pacemaker implantation complicate the prognosis of patients after transcatheter aortic valve implantation?P647Influence of metabolic syndrome and diabetes on progression of calcific aortic valve stenosis - The COFRASA - GENERAC StudyP648Low referral for aortic valve replacement accounts for worse long-term outcome in low versus high gradient severe aortic stenosis with preserved ejection fractionP649The impact of right ventricular function from aortic valve replacement: A randomised study comparing minimally invasive aortic valve surgery and conventional open heart surgery

2016 ◽  
Vol 17 (suppl 2) ◽  
pp. ii122.1-ii130
Author(s):  
T. Ota ◽  
DNS Senaratne ◽  
NK. Preston ◽  
F. Ferrara ◽  
D. Djikic ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Ejection Fraction ◽  
Aortic Valve Replacement ◽  
Right Ventricular ◽  
Valve Replacement ◽  
Aortic Valve Stenosis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Long Term Outcome

scholarly journals Higher Acceleration/Ejection Time Ratio Predicts Impaired Outcome in Aortic Valve Stenosis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Eigir Einarsen ◽  
Dana Cramariuc ◽  
Edda Bahlmann ◽  
Helga Midtbo ◽  
John B. Chambers ◽  
...  
Keyword(s):  
Heart Failure ◽  
Aortic Valve ◽  
Ejection Fraction ◽  
Aortic Valve Stenosis ◽  
Cardiovascular Death ◽  
Left Ventricular ◽  
Hazard Ratio ◽  
Left Ventricular Ejection ◽  
Heart Failure Hospitalization ◽  
Ejection Time

Background: Acceleration time (AT)/ejection time (ET) ratio is a marker of aortic valve stenosis (AS) severity and predicts outcome in moderate-severe AS. Methods: We explored the association of increased AT/ET ratio on prognosis in 1530 asymptomatic patients with presumably mild-moderate AS, normal ejection fraction, and without known diabetes or cardiovascular disease. Patients were part of the SEAS study (Simvastatin Ezetimibe Aortic Stenosis). Patients were grouped according to the optimal AT/ET ratio threshold to predict cardiovascular death and heart failure hospitalization. Low-gradient severe AS was identified as combined valve area ≤1.0 cm 2 and mean gradient <40 mm Hg. Outcome was assessed in Cox regression analyses, and results are reported as hazard ratio and 95% CI. Results: Higher AT/ET ratio was significantly associated with lower systolic blood pressure, lower left ventricular ejection fraction, lower stress-corrected midwall shortening, low flow, and with higher left ventricular mass and higher peak aortic jet velocity. AT/ET ratio ≥0.32 provided the optimal cutoff for predicting incident cardiovascular death and heart failure hospitalization in the total study sample. In patients with low-gradient severe AS, this threshold was >0.32. AT/ET ratio ≥0.32 had a 79% higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 1.79 [95% CI, 1.20–2.68]). In patients with low-gradient severe AS, AT/ET ratio >0.32 was associated with a 2-fold higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 2.15 [95% CI, 1.22–3.77]). Conclusions: In asymptomatic nonsevere AS and low-gradient severe AS, higher AT/ET ratio was associated with increased cardiovascular morbidity and mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00092677.

Procedural and clinical outcomes of type 0 versus type 1 bicuspid aortic valve stenosis treated with transcatheter valve replacement: insights from the BEAT international collaborative registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Ielasi ◽  
E Moscarella ◽  
A Mangieri ◽  
D Tchetche ◽  
W Kim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Clinical Outcomes ◽  
Valve Replacement ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transvalvular Gradient

Abstract Background Transcatheter aortic valve replacement (TAVR) is an established therapy for symptomatic severe aortic stenosis. Bicuspid aortic valves (BAV) were generally excluded from randomized trials due to anatomic features that may challenge TAVR (valve morphology, annulus geometry and size and severe calcifications). Nevertheless real-world registries have shown that a consistent number of BAV has been treated with TAVR. Whether BAV phenotype may affect acute or long-term outcomes following TAVR still remains unclear. Purpose Evaluate the impact of BAV phenotype on procedural and clinical outcomes after TAVR with new generation valves. Methods Patients included in the BEAT (Balloon vs Self-Expandable valve for the treatment of bicuspid Aortic valve sTenosis) registry were classified according to the BAV phenotype. Procedural and clinical outcomes of type 0 (2 cusps, 1 commissure, no raphe) vs type 1 (1 raphe) BAV are here reported. Primary endpoint was post-procedural device success, according to Valve Academic Research Consortium–2 (VARC-2) criteria. Secondary endpoints included procedural complications, rate of permanent pacemaker (PM) implantation and assessment of clinical outcomes at 30-day and 1-year follow-up. Results BAV 0 phenotype was present in 25 (7.1%) cases, and BAV 1 in 218 (61.8%). 3 (0.9%) patients with BAV 2 phenotype and 105 (29.8%) patients in whom BAV phenotype was undeterminable were excluded. Baseline characteristics of the two populations were well balanced. Mean STS score tended to be lower in type 0 vs type 1 BAV (3.35% ±1.8 vs 4.5% ± 3.0, p=0.062). Mean transvalvular gradient, aortic valve area (AVA), and left ventricular ejection fraction didn't differ between groups. According to CT findings moderate-severe aortic valve calcifications were less frequently present in type 0 vs type 1 (52% vs 71.1%, p=0.01). TAVR was performed under conscious sedation in most patients (89.7%), no differences were noted in terms of valve type, valve size, pre and postdilation between groups. There was no significant difference in any peri-procedural complication including pericardial tamponade, second valve implantation, valve embolization, annular rupture, aortic dissection, coronary occlusion, conversion to open surgery, and need of PM between groups however VARC-2 success tended to be lower in type 0 BAV versus type 1 (72% vs 86.7%; p=0.07). A higher rate of mean transvalvular gradient&gt;20 mmHg was observed in the type 0 vs type 1 groups (respectively 24% vs 6%, p=0.007), while no differences were reported in the rate of moderate-severe aortic regurgitation. At 30-day and 1-year follow-up we did not find differences in clinical outcomes. Conclusions Our study confirms the feasibility of TAVR in both type 0 and type 1 BAV, however despite a lower rate of moderate-severe calcifications, a trend toward a lower VARC device success and a higher rate of mean transvalvular gradient &gt;20 mmHg was observed in type 0 vs type 1 BAV. Funding Acknowledgement Type of funding source: None

P3632Prognostic impact of aortic valve stenosis in patients with acute myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Mizutani ◽  
T Kurita ◽  
S Kasuya ◽  
T Mori ◽  
H Ito ◽  
...  
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
All Cause Mortality

Abstract Background Aortic valve stenosis (AS) is associated with the presence and severity of coronary artery disease independently of clinical risk factors, which leads to increased cardiovascular mortality. However, the prevalence of AS and its prognostic value among patients with acute myocardial infarction (AMI) remain unknown. Purpose The purpose of this study was to investigate the prevalence and prognostic impact of AS in AMI patients. Methods We studied 2,803 AMI patients using data from Mie ACS registry, a prospective and multicenter registry. Patients were divided into subgroups according to the presence and severity of AS based on maximal aortic flow rate by Doppler echocardiography before hospital discharge: non-AS <2.0 m/s, 2.0 m/s≤mild AS <3.0 m/s, 3.0 m/s≤moderate AS <4.0m/s and severe AS≥4.0 m/s. The primary outcome was defined as 2-year all-cause mortality. Results AS was detected in 79 patients (2.8%) including 49 mild AS, 23 moderate AS and 6 severe AS. AS patients were significantly older (79.9±9.8 versus 68.3±12.6 years), and higher killip classification than non-AS patients (P<0.01, respectively). However, left ventricular ejection fraction, and prevalence of primary PCI was similar between the 2 groups. During the follow-up periods (median 725 days), 333 (11.9%) patients experienced all-cause death. AS patients demonstrated the higher all-cause mortality rate compared to that of non-AS patients during follow up (47.3% versus 11.3%, P<0.0001, chi square). Kaplan-Meier curves showed that the probability of all-cause mortality was significantly higher among AS patients than non-AS patients, and was highest among moderate and severe AS (See figure A and B). Cox regression analyses for all-cause mortality demonstrated that the severity of AS was the strongest and independent poor prognostic factor (HR 1.71, 95% CI 1.30–2.24, P<0.001, See table). Cox hazard regression analysis Hazard ratio 95% Confidential interval P-value Severity of aortic valve stenosis 1.71 1.30–2.24 <0.001 Killip classification 1.63 1.46–1.82 <0.001 Age 1.07 1.06–1.09 <0.001 Serum creatinine level 1.05 1.03–1.08 <0.001 Max CPK level 1.00 1.00–1.01 <0.001 Left ventricular ejection fraction 0.96 0.95–0.97 <0.001 Primary percutaneous coronary intervention 0.67 0.47–0.96 0.03 CPK suggests creatinine phosphokinase. All cause mortality Conclusions The presence of AS of any severity contributes to worsening of patients' prognosis following AMI independently of other known risk factors. Acknowledgement/Funding None

Abstract 288: Mice With Disruptive Egfr Signaling In The Aortic Valves Develop Calcific Aortic Valve Stenosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Bin Zhou ◽  
Bingruo Wu
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Clinical Importance ◽  
Interstitial Cells ◽  
Left Ventricular ◽  
Specific Gene ◽  
Egfr Signaling ◽  
Aortic Valves ◽  
Major Health Problem ◽  
Mesenchymal Transition

Calcific aortic valve stenosis is a major health problem. Despite its clinical importance, the pathogenesis of this condition remains illusive. Aortic valves are made of endothelial cells and interstitial cells, both are derived from the endocardial cells of the heart during development. We have developed a new mouse model, Nfatc1-Cre, to specifically study the biology of the valve cells during valve development. In this study, we deleted epidermal growth factor receptor (Egfr) in the aortic valves using the Nfatc1-Cre and showed by histological and biochemical analyses that this deletion caused a spectrum of pathological characteristics of human calcific aortic valve stenosis. They include increased proliferation and dedifferentiation of the valve interstitial cells, abnormal deposition of extracellular matrix, bone-like formation and calcification. The null mice eventually developed the left ventricular dysfunction, presumably secondary to the stenotic aortic valves. We also revealed by immunohistochemistry and quantitative RT-PCR the changes in gene expression involved in the epithelial-to-mesenchymal transition or osteogenic activities. Altogether, these results demonstrate that Egfr signaling in the valve endothelial and interstitial cells regulates the homeostasis of the aortic valves and suggest that patients with mutations or medications affecting the Egfr signaling may be at the risk to develop calcific aortic valve stenosis. Our study also provides the proof-of-principle data showing that the Nfatc1-Cre is a useful genetic tool to elucidate the valve-specific gene function involved in the valve homeostasis and disease.

scholarly journals Prognostic value of secondary cardiac alterations in patients with moderate aortic valve stenosis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Stoebe ◽  
J Kandels ◽  
M Metze ◽  
K Lenk ◽  
C Kuehne ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Prognostic Value ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Rapid Progression ◽  
Current Guideline ◽  
Ventricular Ejection Fraction ◽  
Cardiac Alterations

Abstract Purpose Echocardiographic characteristics that predict the progression of moderate aortic valve stenosis (mAS) are lacking. The aim of the present study was to evaluate the prognostic value of left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and pulmonary artery hypertension (PAH) in patients with mAS. Methods A total of 137 patients with asymptomatic mAS (age 72±10 years; females: 51 (37%); Blood Pressure: 143±21 / 78±13 mmHg) were included. Echocardiography was performed at baseline and at follow-up every six or/and twelve months. Patients with concomitant valvular defects, hypertrophic cardiomyopathy or chronic obstructive pulmonary disease were excluded. mAS was defined by current guideline criteria. Left ventricular ejection fraction (LVEF), LVH (LV mass index, males: &gt;115g/m2, females: &gt;95 g/m2), DD (E/e' &gt;14) and PAH (maximum regurgitant velocity of tricuspid valve (TRVmax) &gt;2.8m/s) were assessed. mAS patients were divided into 4 subgroups based on the number of secondary cardiac alterations: (0) no; (1) one; (2) two; (3) three cardiac alterations. The primary endpoint was progression to severe AS with indication for treatment (effective aortic orifice area (EOA) by continuity equation &lt;1 cm2/&lt;0.6 cm2/m2) or the onset of symptoms. Results mAS patients showed (0) no secondary cardiac alterations in 20% (n=28), (1) one in 40% (n=55), (2) two in 26% (n=35) and (3) three in 14% (n=19). Among mAS subgroups, no significant differences were observed for age and comorbidities. Echocardiographic parameters are summarised in Tab.1. In general, mAS patients with ≥ two cardiac alterations showed significantly smaller EOA ((0): 1.32±0.19 vs. 1.29±0.19, p&gt;0.05; (1): 1.26±0.21 vs. 1.18±0.21, p&gt;0.05; (2): 1.29±0.20 vs. 1.01±0.20, p&lt;0.01; (3): 1.31±0.16 vs. 1.06±0.25, p&lt;0.01) and higher mean pressure gradients (PGmean) ((0): 19.8±6.64 vs. 21.8±6.32, p&gt;0.05; (1): 20.0±9.26 vs. 22.3±9.94, p&gt;0.05; (2): 22.7±9.32 vs. 30.5±12.61, p&lt;0.01 (3): 25.0±8.87 vs. 29.4±10.67, p&lt;0.01) between baseline and follow-up (mean follow-up 20±9 months). Further, decrease of EOA/days was significantly higher in these patients ((0) −0.003; (1) −0.006; (2) −0.016; (3) −0.028; p&lt;0.01, Fig. 1). As shown in Kaplan-Meier curve, mAS with ≥ two cardiac alterations showed rapid progression of moderate to severe AS (Fig. 2). Conclusions In 40% of patients with mAS ≥ two secondary cardiac alterations (LV hypertrophy, DD and PAH) were observed. The presence of ≥ two of these secondary cardiac alterations is associated with rapid progression of mAS. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Sign in / Sign up

Export Citation Format

Share Document