Stenotic Aortic Valve Research Articles

Clinical impact of pathology-proven etiology of severely stenotic aortic valves on mid-term outcomes in patients undergoing surgical aortic valve replacement.

The use of transcatheter or surgical aortic valve replacement (AVR) for severe aortic stenosis (AS) has considerably increased in recent years. However, the association between AS etiology and mid-term clinical outcomes after surgical AVR has not been fully investigated. We retrospectively included 201 patients (mean age, 75 years; 43%, men) who underwent surgical AVR for severe native AS (aortic valve area ≤1.0 cm2 on preoperative transthoracic echocardiography examination). The following valve etiologies were postoperatively identified on pathological examination: post-inflammatory (n = 28), congenital (n = 35), and calcific/degenerative (n = 138). The median follow-up interval was 4.1 years following surgical AVR. Of the 201 patients, 27% were asymptomatic, 40% had a history of heart failure, and 11% underwent previous heart surgery. The cumulative incidence of cardiac events (all-cause death, aortic valve deterioration requiring repeated AVR, and hospitalization for heart failure) and combined adverse events, which included non-fatal stroke, unplanned coronary revascularization, pacemaker implantation, and gastrointestinal bleeding along with cardiac events, was significantly higher in the calcific/degenerative group (p = 0.02 and p = 0.02, respectively). In multivariate analysis adjusted for age, sex, renal function, heart failure, atrial fibrillation, concomitant surgical procedures, and EuroSCORE II, AS etiology was independently associated with an increased risk of combined adverse events (congenital vs. post-inflammatory: hazard ratio [HR], 4.13; p = 0.02 and calcific/degenerative vs. post-inflammatory: HR, 5.69; p = 0.002). Pathology-proven AS etiology could aid in predicting the mid-term outcomes after surgical AVR, supporting the importance of accurate identification of severe AS etiology with or without postoperative pathological examination.

Transcatheter Aortic Valve Implantation: Transseptal Approach Using a Femoral Veno- Arterial Loop

After successful introduction of transcatheter aortic valve implantation (TAVI) in 2002, TAVI has become an increasingly accepted therapy for the treatment of severe aortic stenosis in patients judged to be at high risk for open heart surgery. We describe anterograde transseptal access for TAVI in a patient where transfemoral access alone was impossible to achieve due to a heavily calcified stenotic aortic valve. It is an interesting and alternative approach to achieve TAVI.

Simulation study of transcatheter heart valve implantation in patients with stenotic bicuspid aortic valve.

Bicuspid aortic valve (BAV) anatomy has routinely been considered an exclusion in the setting of transcatheter aortic valve implantation (TAVI) because of the large dimension of the aortic annulus having a more calcified, bulky, and irregular shape. The study aims to develop a patient-specific computational framework to virtually simulate TAVI in stenotic BAV patients using the Edwards SAPIEN 3 valve (S3) and its improved version SAPIEN 3 Ultra and quantify stent frame deformity as well as the severity of paravalvular leakage (PVL). Specifically, the aortic root anatomy of n.9 BAV patients who underwent TAVI was reconstructed from pre-operative CT imaging. Crimping and deployment of S3 frame were performed and then followed by fluid-solid interaction analysis to simulate valve leaflet dynamics throughout the entire cardiac cycle. Modeling revealed that the S3 stent frame expanded well on BAV anatomy with an elliptical shape at the aortic annulus. Comparison of predicted S3 deformity as assessed by eccentricity and expansion indices demonstrated a good agreement with the measurement obtained from CT imaging. Blood particle flow analysis demonstrated a backward blood jet during diastole, whereas the predicted PVL flows corresponded well with those determined by transesophageal echocardiography. This study represents a further step towards the use of personalized simulations to virtually plan TAVI, aiming at improving not only the efficacy of the implantation but also the exploration of "off-label" applications as the TAVI in the setting of BAV patients. Graphical abstract Computational frameworks of TAVI in patients with stenotic bicuspid aortic valve.

Network Analysis of Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement for Stenotic Bicuspid Aortic Valves According to Valve Type

BackgroundIt is currently unknown if outcomes after transcatheter aortic valve replacement (TAVR) differ according to the prosthetic valve deployed in patients with bicuspid aortic valves (BAV). ObjectivesThis study evaluated valve-specific outcomes post-TAVR in patients with BAV. MethodsLiterature search was performed using the Cochrane databases, PubMed, ClinicalTrials, SCOPUS and EMBASE databases from inception until July 2018. We computed risk ratios and their 95% confidence intervals for all outcomes of interest. For each outcome, the data were pooled using a multivariate random-effects meta-analysis including multiple treatment as well as direct and indirect comparisons. ResultsTen studies enrolling a total of 1547 BAV patients undergoing TAVR using 6 different prosthetic valve types were analyzed. There were no significant differences in 30-day all-cause mortality, life-threatening bleeding and device success among the diverse prosthetic valve types implanted. However, 2nd generation balloon-expandable valves had consistently lower risk of moderate-to-severe prosthetic valve regurgitation. ConclusionIn patients with BAV, there were no significant differences in 30-day all-cause mortality after TAVR among the various prosthetic valve types.

P190 Chest pain and syncope in Turner"s syndrome: going beyond the obvious to not miss the critical diagnosis. Role of multimodality imaging approach

Abstract Clinical Presentation: a 18-year-old woman with Turner’s syndrome (TS), with history of hypothyroidism treated with L-thyroxin, asymptomatic moderately stenotic bicuspid aortic valve (AV) and without any known cardiovascular risk factor, was admitted to our emergency department (ED) because of syncope and typical chest pain after dinner associated with dyspnea. Chest pain lasted for an hour with spontaneous regression. In the ED the patient (pt) was normotensive. An ECG showed sinus rhythm (88 bpm), nonspecific repolarization anomalies (T wave inversion) in the inferior and anterior leads. Myocardial necrosis biomarkers were negative. A 3D transthoracic echocardiography showed normal biventricular systolic function with left ventricular hypertrophy, dilatation of the ascending aorta, unicuspid AV with severe aortic stenosis (peak/mean gradient 110/61 mmHg, aortic valve area 0,88 cm2-0,62 cm2/m2), mild pericardial effusion (Figure Panel A, B, C). Five days after, the pt had a new episode of typical chest pain without ECG changes. A computerized tomography (CT) was performed to rule out the hypothesis of aortic dissection and showed a dilation of the ascending aorta and pericardial effusion localized in the diaphragmatic wall, no signs of dissection or aortic hematoma. However, CT was of suboptimal quality because of sinus tachycardia (120 bpm) and so the pt underwent a coronary angiography and aortography that ruled out coronary disease, confirmed the dilatation of ascending aorta (50 mm) and showed images of penetrating atherosclerotic ulcer of the ascending aorta (Figure panel D). The pt underwent urgent transesophageal echocardiography (TOE) that confirmed the severely stenotic unicuspid AV and showed a localized type A aortic dissection (Figure Panel E, F, G). The pt underwent urgent AV and ascending aorta replacement (Figure Panel H). Learning points Chest pain and syncope are challenging symptoms in pts presenting in ED. AV pathology and aortic dissection should be always suspected and ruled out. TS is associated with multiple congenital cardiovascular abnormalities and is the most common established cause of aortic dissection in young women. 30% of Turner’s pts have congenitally AV abnormalities, and dilation of the ascending aorta is frequently associated. However, unicuspid AV is a very rare anomaly, usually stenotic at birth and requiring replacement. The presence of pericardial effusion in a pt with chest pain and syncope should raise the suspicion of aortic dissection, even if those symptoms usually accompany severe aortic stenosis. Even if CT is the gold standard imaging technique to rule out aortic dissection, the accuracy of a test is critically related to the image quality. When the suspicion of dissection is high and the reliability of the reference test is low, it’s reasonable to perform a different test to rule out the pathology. Aortography and TOE were pivotal to identify the limited dissection of the ascending aorta. Abstract P190 Figure.

Persistent left superior vena cava and double-lumen aortic arch in a patient with a stenotic unicuspid aortic valve

Persistent left superior vena cava and double-lumen aortic arch in a patient with a stenotic unicuspid aortic valve

Persistent left superior vena cava and double-lumen aortic arch in a patient with a stenotic unicuspid aortic valve

Persistent left superior vena cava and double-lumen aortic arch in a patient with a stenotic unicuspid aortic valve

Calcium Pattern Assessment in Patients with Severe Aortic Stenosis Via the Chou's 5-Steps Rule.

Progression of aortic valve calcifications (AVC) leads to aortic valve stenosis (AS). Importantly, the AVC degree has a great impact on AS progression, treatment selection and outcomes. Methods of AVC assessment do not provide accurate quantitative evaluation and analysis of calcium distribution and deposition in a repetitive manner. We aim to prepare a reliable tool for detailed AVC pattern analysis with quantitative parameters. We analyzed computed tomography (CT) scans of fifty patients with severe AS using a dedicated software based on MATLAB version R2017a (MathWorks, Natick, MA, USA) and ImageJ version 1.51 (NIH, USA) with the BoneJ plugin version 1.4.2 with a self-developed algorithm. We listed unique parameters describing AVC and prepared 3D AVC models with color pointed calcium layer thickness in the stenotic aortic valve. These parameters were derived from CT-images in a semi-automated and repeatable manner. They were divided into morphometric, topological and textural parameters and may yield crucial information about the anatomy of the stenotic aortic valve. In our study, we were able to obtain and define quantitative parameters for calcium assessment of the degenerated aortic valves. Whether the defined parameters are able to predict potential long-term outcomes after treatment, requires further investigation.

Predictions of hypertrophy and its regression in response to pressure overload.

Mechanics-based cardiac growth models can now predict changes in mass, chamber size, and wall thickness in response to perturbations such as pressure overload (PO), volume overload, and myocardial infarction with a single set of growth parameters. As these models move toward clinical applications, many of the most interesting applications involve predictions of whether or how a patient's heart will reverse its growth after an intervention. In the case of PO, significant regression in wall thickness is observed both experimentally and clinically following relief of overload, for example following replacement of a stenotic aortic valve. Therefore, the objective of this work was to evaluate the ability of a published cardiac growth model that captures forward growth in multiple situations to predict growth reversal following relief of PO. Using a finite element model of a beating canine heart coupled to a circuit model of the circulation, we quantitatively matched hemodynamic data from a canine study of aortic banding followed by unbanding. Surprisingly, although the growth model correctly predicted the time course of PO-induced hypertrophy, it predicted only limited growth reversal given the measured unbanding hemodynamics, contradicting experimental and clinical observations. We were able to resolve this discrepancy only by incorporating an evolving homeostatic setpoint for the governing growth equations. Furthermore, our analysis suggests that many strain- and stress-based growth laws using the traditional volumetric growth framework will have similar difficulties capturing regression following the relief of PO unless growth setpoints are allowed to evolve.

Candesartan Treatment Associates With Reduced Expression of Collagen and Matrix Metalloproteinase Genes in Severely Stenotic Human Aortic Valves: A Prospective, Placebo-controlled, Randomized, Double-blinded Clinical Trial

Introduction: Calcific aortic valve stenosis (AS) is a progressive disease resulting from long-lasting inflammatory, fibrotic, and calcifying processes in the aortic valve leaflets. The renin-angiotensin-aldosterone system (RAAS) has been demonstrated to be active in human stenotic aortic valves. In experimental animals, administration of an angiotensin II type 1 receptor blocker has exerted both anti-inflammatory and antifibrotic effects on stenotic aortic leaflets. In human aortic smooth muscle cells, angiotensin II increases the expression of matrix metalloproteinase. The migration of vascular smooth muscle cells (VSMCs) is an early event of atherosclerosis. Indeed, angiotensin II increases matrix metalloproteinase 13 (MMP13)'s expression in aortic smooth muscle cells (SMCs) and the silencing or inhibition of MMP13 results in reduced SMCs' migration. Here were examined whether candesartan would beneficially affect the major pathogenic valvular mechanisms active in severe AS. Methods: In this placebo-controlled, randomized, double-blinded, prospective study a total of 43 AS patients were randomized to receive candesartan (target dose: 16 mg/d) or placebo for an average of about 5 months (164 ± 67 days) before undergoing aortic valve replacement surgery. In the explanted valves, the mRNA levels of markers for fibrosis were assessed using an mRNA assay panel and quantitative polymerase chain reaction (qPCR). Moreover, markers of fibrosis, inflammation, and neovascularization were analyzed immunohistologically. Results: In the candesartan group, the mRNA expression levels of Collagen Type X Alpha 1 Chain (Col10a1) (p = 0.003), Col11a1 (p = 0.002), Col12a1 (p = 0.016), and of MMP8 (p = 0.024) and MMP13 (p = 0.007) were lower than in the placebo group. During this short intervention period, immunohistological analysis did not show differences in fibrosis, calcification, neovascularization, or inflammation of the valves. Conclusion: In the present study, we found the potential mechanism for candesartan to interact with the progression of aortic valve stenosis by modeling the mRNA expressions of collagens and matrix metalloproteinases. Provided these potentially beneficial antifibrotic effects candesartan could retard the progression of AS. However, additional longer interventional studies are needed to prove possible beneficial clinical effects of candesartan in AS. Disclosure: Nothing to disclose

Pacemaker Implantation and Dependency After Transcatheter Aortic Valve Replacement in the REPRISE III Trial

BackgroundAs transcatheter aortic valve replacement expands to younger and/or lower risk patients, the long‐term consequences of permanent pacemaker implantation are a concern. Pacemaker dependency and impact have not been methodically assessed in transcatheter aortic valve replacement trials. We report the incidence and predictors of pacemaker implantation and pacemaker dependency after transcatheter aortic valve replacement with the Lotus valve.Methods and ResultsA total of 912 patients with high/extreme surgical risk and symptomatic aortic stenosis were randomized 2:1 (Lotus:CoreValve) in REPRISE III (The Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System—Randomized Clinical Evaluation) trial. Systematic assessment of pacemaker dependency was pre‐specified in the trial design. Pacemaker implantation within 30 days was more frequent with Lotus than CoreValve. By multivariable analysis, predictors of pacemaker implantation included baseline right bundle branch block and depth of implantation; diabetes mellitus was also a predictor with Lotus. No association between new pacemaker implantation and clinical outcomes was found. Pacemaker dependency was dynamic (30 days: 43%; 1 year: 50%) and not consistent for individual patients over time. Predictors of pacemaker dependency at 30 days included baseline right bundle branch block, female sex, and depth of implantation. No differences in mortality or stroke were found between patients who were pacemaker dependent or not at 30 days. Rehospitalization was higher in patients who were not pacemaker dependent versus patients without a pacemaker or those who were dependent.ConclusionsPacemaker implantation was not associated with adverse clinical outcomes. Most patients with a new pacemaker at 30 days were not dependent at 1 year. Mortality and stroke were similar between patients with or without pacemaker dependency and patients without a pacemaker.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier NCT02202434.

P5988Non-classical Ly6C-low monocytes contribute to aortic valve stenosis development in mice

Abstract Introduction Aortic valve stenosis (AS) is one of the most common valvular diseases in the western world. Once patients with AS develop symptoms mortality increases up to 50% over two years. For many years AS was believed to be a passive degenerative process. Recent findings suggest a more complex pathomechanism with a strict molecular and cellular regulation involving local inflammation and invasion of immune cells. Specifically, pro-inflammatory macrophages have been shown to play an important role in disease progression. On the other hand, monocyte counts in the peripheral blood of patients with severe AS are significantly decreased and there is an inverse correlation between valve orifice area and circulating monocyte count. In order to elucidate the exact function of pro-inflammatory classical (Ly6C-high) and non-classical (Ly6C-low) monocytes in disease initiation processes, we conducted a series of experiments in a model of murine AS. Methods In this study 10–12 weeks old male C57BL6/J or CX3CR1-deficient mice were investigated. For AS induction, a coronary springwire was introduced into the left ventricle, pushed and rotated over the aortic valve under echocardiographic guidance. In sham operated mice the wire was only inserted into the left carotid artery without manipulation of the aortic valve. Development of AS was confirmed via weekly ultrasound examinations. Immune cells in the aortic valve were quantified using flow cytometry and immunofluorescence microscopy. Results Ultrasound analysis after two weeks confirmed the development of AS in the injured wildtype mice. Transaortic peak velocity levels were significantly increased compared to sham operated mice. Flow cytometry of explanted aortic valves showed a strong cellular immunoreaction in the stenotic valves. The amount of anti-inflammatory Ly6C-low monocytes was significantly increased compared to sham-mice, whereas the number of pro-inflammatory Ly6C-high monocytes remained stable. Interestingly CD-4 positive T-cells were augmented in stenotic aortic valves. Immunofluorescence confirmed Ly6C-low monocytes infiltration in the valve, in close proximity to the endothelial cells on the ventricular and the aortic side. The expression of recruitment and adhesion markers CD11b and CX3CR1 were significantly increased on the surface of the Ly6C-low monocytes of AS mice. To investigate the role of Ly6C-low monocytes in AS development, CX3CR1 deficient mice, which are not able to recruit non-classical monocytes via CX3CR1, were subjected to aortic valve wire injury. After two weeks, peak velocity levels in CX3CR1−/− mice remained nearly unchanged and were significantly decreased compared to wildtype mice. Conclusion Our data suggest that non-classical Ly6Clow monocytes play a crucial role in AS development in mice. Therefore, they may be targets for future therapeutic interventions. Acknowledgement/Funding S.T.N. was funded by Else-Kröner-Fresenius-Foundation of the Medical Faculty of the University of Bonn

Mid-term outcome in patients with bicuspid aortic valve stenosis following transcatheter aortic valve replacement with a current generation device: A multicenter study.

To perform clinical and echocardiographic follow-up beyond 1 year in consecutive patients with severe bicuspid aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) with a current generation balloon-expandable valve. Treatment of bicuspid aortic valve disease with TAVR remains controversial and late follow-up data is still scarce. We collected baseline characteristics, procedural data, 30-day and mid-term clinical follow-up findings from six centers in Europe and Canada from patients with bicuspid AS treated with TAVR using the SAPIEN 3 valve. Seventy-nine patients underwent TAVR. Mean age was 76 ± 9 years; median STS risk score for mortality was 3.8% (interquartile range 2.3-5.5%). Median follow-up was 390 days (interquartile range 138-739 days). Device success was achieved in 95% of patients. Postimplantation mean aortic gradient decreased from 50.2 ± 16.2 to 8.8 ± 4.4 mmHg and no patient had more than mild aortic regurgitation. At last follow-up, there was persistent good valve performance. At 30 days and 1 year, the rates of all-cause mortality were 3.8 and 7.7%, stroke 1.2 and 1.2%, and the rate of new pacemakers 18 and 18%. Our data confirm that treating patients with stenotic bicuspid aortic valves is safe, effective, and has favorable valve performance over time.

Hot topics in interventional cardiology: Proceedings from the Society for Cardiovascular Angiography and Interventions (SCAI) 2019 Think Tank.

The society for cardiovascular angiography and interventions (SCAI) think tank is a collaborative venture that brings together interventional cardiologists, administrative partners, and select members of the cardiovascular industry community for high-level field-wide discussions. The 2020 think tank was organized into four parallel sessions reflective of the field of interventional cardiology: (a) coronary intervention, (b) endovascular medicine, (c) structural heart disease, and (d) congenital heart disease (CHD). Each session was moderated by a senior content expert and co-moderated by a member of SCAI's emerging leader mentorship program. This document presents the proceedings to the wider cardiovascular community in order to enhance participation in this discussion, create additional dialogue from a broader base, and thereby aid SCAI and the industry community in developing specific action items to move these areas forward.

Does clinical data quality affect fluid-structure interaction simulations of patient-specific stenotic aortic valve models?

Numerical models are increasingly used in the cardiovascular field to reproduce, study and improve devices and clinical treatments. The recent literature involves a number of patient-specific models replicating the transcatheter aortic valve implantation procedure, a minimally invasive treatment for high-risk patients with aortic diseases. The representation of the actual patient’s condition with truthful anatomy, materials and working conditions is the first step toward the simulation of the clinical procedure.The aim of this work is to quantify how the quality of routine clinical data, from which the patient-specific models are built, affects the outputs of the numerical models representing the pathological condition of stenotic aortic valve.Seven fluid–structure interaction (FSI) simulations were performed, completed with a sensitivity analysis on patient-specific reconstructed geometries and boundary conditions. The structural parts of the models consisted of the aortic root, native tri-leaflets valve and calcifications. Ventricular and aortic pressure curves were applied to the fluid domain.The differences between clinical data and numerical results for the aortic valve area were less than 2% but reached 12% when boundary conditions and geometries were changed. The difference in the aortic stenosis jet velocity between measured and simulated values was less than 11% reaching 27% when the geometry was changed. The CT slice thickness was found to be the most sensitive parameter on the presented FSI numerical model.In conclusion, the results showed that the segmentation and reconstruction phases need to be carefully performed to obtain a truthful patient-specific domain to be used in FSI analyses.

Biomechanical modeling of transcatheter aortic valve replacement in a stenotic bicuspid aortic valve: deployments and paravalvular leakage.

Calcific aortic valve disease (CAVD) is characterized by stiffened aortic valve leaflets. Bicuspid aortic valve (BAV) is the most common congenital heart disease. Transcatheter aortic valve replacement (TAVR) is a treatment approach for CAVD where a stent with mounted bioprosthetic valve is deployed on the stenotic valve. Performing TAVR in calcified BAV patients may be associated with post-procedural complications due to the BAV asymmetrical structure. This study aims to develop refined computational models simulating the deployments of Evolut R and PRO TAVR devices in a representative calcified BAV. The paravalvular leakage (PVL) was also calculated by computational fluid dynamics simulations. Computed tomography scan of severely stenotic BAV patient was acquired. The 3D calcium deposits were generated and embedded inside a parametric model of the BAV. Deployments of the Evolut R and PRO inside the calcified BAV were simulated in five bioprosthesis leaflet orientations. The hypothesis of asymmetric and elliptic stent deployment was confirmed. Positioning the bioprosthesis commissures aligned with the native commissures yielded the lowest PVL (15.7 vs. 29.5mL/beat). The Evolut PRO reduced the PVL in half compared with the Evolut R (15.7 vs. 28.7mL/beat). The proposed biomechanical computational model could optimize future TAVR treatment in BAV patients. Graphical abstract.

Two-Minute k-Space and Time-accelerated Aortic Four-dimensional Flow MRI: Dual-Center Study of Feasibility and Impact on Velocity and Wall Shear Stress Quantification.

To investigate the two-center feasibility of highly k-space and time (k-t)-accelerated 2-minute aortic four-dimensional (4D) flow MRI and to evaluate its performance for the quantification of velocities and wall shear stress (WSS). This cross-sectional study prospectively included 68 participants (center 1, 11 healthy volunteers [mean age ± standard deviation, 61 years ± 15] and 16 patients with aortic disease [mean age, 60 years ± 10]; center 2, 14 healthy volunteers [mean age, 38 years ± 13] and 27 patients with aortic or cardiac disease [mean age, 78 years ± 18]). Each participant underwent highly accelerated 4D flow MRI (k-t acceleration, acceleration factor of 5) of the thoracic aorta. For comparison, conventional 4D flow MRI (acceleration factor of 2) was acquired in the participants at center 1 (n = 27). Regional aortic peak systolic velocities and three-dimensional WSS were quantified. k-t-accelerated scan times (center 1, 2:03 minutes ± 0:29; center 2, 2:06 minutes ± 0:20) were significantly reduced compared with conventional 4D flow MRI (center 1, 12:38 minutes ± 2:25; P < .0001). Overall good agreement was found between the two techniques (absolute differences ≤15%), but proximal aortic WSS was significantly underestimated in patients by using k-t-accelerated 4D flow when compared with conventional 4D flow (P ≤ .03). k-t-accelerated 4D flow MRI was reproducible (intra- and interobserver intraclass correlation coefficient ≥0.98) and identified significantly increased peak velocities and WSS in patients with stenotic (P ≤ .003) or bicuspid (P ≤ .04) aortic valves compared with healthy volunteers. In addition, k-t-accelerated 4D flow MRI-derived velocities and WSS were inversely related to age (r ≥-0.53; P ≤ .03) over all healthy volunteers. k-t-accelerated aortic 4D flow MRI providing 2-minute scan times was feasible and reproducible at two centers. Although consistent healthy aging- and disease-related changes in aortic hemodynamics were observed, care should be taken when considering WSS, which can be underestimated in patients.© RSNA, 2019See also the commentary by François in this issue.

Modeling of the Instantaneous Transvalvular Pressure Gradient in Aortic Stenosis.

The simplified and modified Bernoulli equations break down in estimating the true pressure gradient across the stenotic aortic valve due to their over simplifying assumptions of steady and inviscid conditions as well as the fundamental nature in which aortic valves are different than idealized orifices. Nevertheless, despite having newer models based on time-dependent momentum balance across an orifice, the simplified and modified Bernoulli continue to be the clinical standard because to date, they remain the only models clinically implementable. The objective of this study is to (1) illustrate the fundamental considerations necessary to accurately model the time-dependent instantaneous pressure gradient across a fixed orifice and (2) propose empirical corrections when applying orifice based models to severely stenotic aortic valves. We introduce a general model to predict the time-dependent instantaneous pressure gradient across an orifice that explicitly model the Reynolds number dependence of both the steady and unsteady terms. The accuracy of this general model is assessed with respect to previous models through pulse duplicator experiments on a round orifice model as well as an explanted stenotic surgical aortic valve both with geometric areas of 0.6cm2 (less than 1cm2 which is the threshold for stenosis determination) over cardiac outputs of 3 and 5L/min and heart rates of 60, 90 and 120bpm. The model and the raw experimental data corresponding to the orifice showed good agreement over a wide range of cardiac outputs and heart rates (R2 exceeding 0.91). The derived average and peak transvalvular pressure gradients also demonstrated good agreement with no significant differences between the respective peaks (p > 0.09). The new model proposed holds promise with its physical and closed form representation of pressure drop, however accurate modeling of the time-variability of the valve area is necessary for the model to be applied on stenotic valves.

Identification of miR-143 as a Major Contributor for Human Stenotic Aortic Valve Disease.

Calcification of aortic valves leads to aortic stenosis mainly in elderly individuals, but the underlying molecular mechanisms are still not understood. Here, we studied microRNA (miR, miRNA) expression and function in healthy and stenotic human aortic valves. We identified miR-21, miR-24, and miR-143 to be highly upregulated in stenotic aortic valves. Using luciferase reporter systems, we found direct binding of miR-143 to the 3'UTR region of the matrix gla protein (MGP), which in turn is a key factor to sustain homeostasis in aortic valves. In subsequent experiments, we demonstrated a therapeutic potential of miRNA regulation during calcification in cardiac valvular interstitial cells. Collectively, our data provide evidence that deregulated miR expression contributes to the development of stenotic valve disease and thus form novel therapeutic opportunities of this severe cardiovascular disease.

Potential Role of H-Ferritin in Mitigating Valvular Mineralization.

Objective- Calcific aortic valve disease is a prominent finding in elderly and in patients with chronic kidney disease. We investigated the potential role of iron metabolism in the pathogenesis of calcific aortic valve disease. Approach and Results- Cultured valvular interstitial cells of stenotic aortic valve with calcification from patients undergoing valve replacement exhibited significant susceptibility to mineralization/osteoblastic transdifferentiation in response to phosphate. This process was abrogated by iron via induction of H-ferritin as reflected by lowering ALP and osteocalcin secretion and preventing extracellular calcium deposition. Cellular phosphate uptake and accumulation of lysosomal phosphate were decreased. Accordingly, expression of phosphate transporters Pit1 and Pit2 were repressed. Translocation of ferritin into lysosomes occurred with high phosphate-binding capacity. Importantly, ferritin reduced nuclear accumulation of RUNX2 (Runt-related transcription factor 2), and as a reciprocal effect, it enhanced nuclear localization of transcription factor Sox9 (SRY [sex-determining region Y]-box 9). Pyrophosphate generation was also increased via upregulation of ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase-2). 3H-1, 2-dithiole-3-thione mimicked these beneficial effects in valvular interstitial cell via induction of H-ferritin. Ferroxidase activity of H-ferritin was essential for this function, as ceruloplasmin exhibited similar inhibitory functions. Histological analysis of stenotic aortic valve revealed high expression of H-ferritin without iron accumulation and its relative dominance over ALP in noncalcified regions. Increased expression of H-ferritin accompanied by elevation of TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1β) levels, inducers of H-ferritin, corroborates the essential role of ferritin/ferroxidase via attenuating inflammation in calcific aortic valve disease. Conclusions- Our results indicate that H-ferritin is a stratagem in mitigating valvular mineralization/osteoblastic differentiation. Utilization of 3H-1, 2-dithiole-3-thione to induce ferritin expression may prove a novel therapeutic potential in valvular mineralization.