Patients with severe aortic stenosis, undergoing transcatheter aortic valve replacement (TAVR), are more likely to develop thrombotic complications. However, the definite mechanisms underlying the hypercoagulation state remain unclear to date. Our objectives were to explore whether and how neutrophil extracellular traps (NETs) play a procoagulant role in patients after TAVR alone or TAVR with percutaneous coronary intervention within 1 year and further to evaluate their interactions with platelets and endothelial cells.

The levels of plasma NETs, platelets, and endothelial cell activation markers were analyzed by ELISA. NET formation was observed by immunofluorescence. Procoagulant activity was measured by clotting time, fibrin, and TAT (thrombin-antithrombin) complex generation assays. Phosphatidylserine exposure on cells was assessed by flow cytometry.

Compared with pre-TAVR, controls, or severe aortic stenosis without TAVR patients, the plasma NET levels in patients after TAVR alone, especially TAVR with percutaneous coronary intervention, increased from 7 days, peaking at 3 months, and then gradually decreased until the 12th month. Furthermore, neutrophils and plasma from patients post-TAVR are more prone to promote NET formation; NETs from these patients markedly decreased clotting time and increased fibrin and TAT generation. Additionally, a high concentration of NETs induced platelet aggregation and exerted a strong cytotoxic effect on endothelial cells and transformed them into a procoagulant phenotype.

These results lead us to believe that NETs contribute to the hypercoagulability in patients post-TAVR. Our study may provide a new target for preventing thrombotic complications in patients post-TAVR by blocking NET generation.

Aortic valve replacements, both surgical and transcatheter, are nowadays widely employed treatments. Although clinically effective, these procedures are correlated with potentially severe clinical complications which can be associated with the non-physiological haemodynamics that they establish. In this work, the fluid dynamics changes produced by surgical and transcatheter aortic valve replacements are analysed and compared with an ideal healthy native valve configuration, employing advanced fluid-structure interaction (FSI) simulations. The aim of the study is to investigate how existing treatments may affect the aortic valve function, and giving indications about how to improve current therapies. Simulations were performed using the commercial software LS-DYNA, where the FSI strategy is based on the coupling of a Lagrangian approach for the structures and a Eulerian approach for the fluid, whilst the coupling between the two domains is reached through a hybrid arbitrary-Lagrangian-Eulerian algorithm. Idealised geometries are used for the aortic root and leaflets. The aortic wall was modelled as linear elastic material, whilst leaflets were modelled as hyperelastic incompressible, using an Ogden's constitutive model. A combination of physiological flow velocity and pressure differences are applied as boundary conditions to model realistically the whole cardiac cycle. Results are analysed throughout the cardiac cycle in terms of leaflets kinematics, flow dynamics, pressure and valve performance parameters. Globally, surgical valves presented worse performance than transcatheter counterparts (reduced effective orifice area, increased transvalvular pressure drop and increased opening and closing times). The clinical parameters of transcatheter devices were improved and closer to those of the healthy native valve, although the vortical activity within the Valsalva's sinuses was substantially altered. Here, the presence of the partition obstructed the washing out, resulting in higher degree of blood stasis and potential blood damage. The implantation of prosthetic devices produces major haemodynamic changes which alters the valve dynamics and leads to diminished performance. Currently, the design of these substitutes is not optimised to mimic realistic native conditions, particularly in terms of valve opening behaviour. Although transcatheter devices provide systolic performance similar to that estimated for the healthy native aortic model, none of the prosthetic solutions appeared to be able to fully restore healthy physiological conditions.

Over a decade of randomized controlled trial data demonstrate excellent outcomes with transcatheter aortic valve replacement or surgical aortic valve replacement for patients with symptomatic severe aortic stenosis regardless of surgical risk. The 2020 American College of Cardiology/American Heart Association guidelines recommend both options for low-risk AS patients aged 65 to 80 years. However, the fastest growing population of patients receiving transcatheter aortic valve replacement in the United States is <65 years old, with little data to support the practice. The American College of Cardiology's Cardiac Surgery Team Section Leadership and Interventional Cardiology Councils, a multidisciplinary collaboration of cardiologists and cardiac surgeons, sought to summarize the relevant data into a decision-making tool for heart valve teams. A literature review was completed, and guidelines, randomized controlled trials, and large observational studies were summarized into a pragmatic decision-making approach to treating young and low-risk patients with AS.

Transcatheter aortic valve replacement (TAVR) has emerged as a pivotal intervention for patients with severe aortic stenosis who are at high or prohibitive surgical risk. Although TAVR is a minimally invasive procedure, it is linked to serious hematological problems, most notably thrombosis and bleeding. Numerous factors, such as procedural features, patient comorbidities, and anticoagulation management techniques, contribute to these complications. Bleeding complications can be major, minor, or life-threatening. They can be caused by problems with the vascular access site, anticoagulation medication, or coexisting conditions like renal dysfunction and frailty. Hemoglobin drop, overt bleeding, and hematoma signs must all be closely watched to identify bleeding. Careful selection and modification of anticoagulation medication, the use of vascular closure devices, and timely attention to bleeding sites are examples of management techniques. Thrombotic consequences, which include cerebrovascular accidents and valve thrombosis, are caused by endothelial injury, stent implantation, and patient hypercoagulability. Imaging modalities such as computed tomography and transesophageal echocardiography are used in the crucial process of detection. The goal of preventive care is to maximize anticoagulation regimens that are customized to each patient's risk profile, frequently striking a balance between the risk of thrombosis and bleeding. A multidisciplinary strategy that integrates surgical, hematological, and cardiology expertise is necessary for the effective management of these hematological complications. To improve patient outcomes, ongoing research attempts to improve risk stratification and create safer anticoagulation protocols. This review emphasizes how critical it is to identify bleeding and thrombotic events as soon as possible and treat them promptly to reduce the risk of negative outcomes for TAVR patients.

Transcatheter aortic valve (TAV) thrombosis may manifest as subclinical leaflet thrombosis (SLT) and clinical valve thrombosis. SLT is relatively common (10%-20%) after transcatheter aortic valve replacement, but clinical implications are uncertain. Clinical valve thrombosis is rare (1.2%) and associated with bioprosthetic valve failure, neurologic or thromboembolic events, heart failure, and death. Treatment for TAV thrombosis has been understudied. In principle, anticoagulation may prevent TAV thrombosis. Non-vitamin K oral anticoagulants, as compared to antiplatelet therapy, are associated with reduced incidence of SLT, although at the cost of higher bleeding and all-cause mortality risk. We present an overview of existing literature for management of TAV thrombosis and propose a rational treatment algorithm. Vitamin K antagonists or non-vitamin K oral anticoagulants are the cornerstone of antithrombotic treatment. In therapy-resistant or clinically unstable patients, ultraslow, low-dose infusion of thrombolytics seems effective and safe and may be preferred over redo-transcatheter aortic valve replacement or explant surgery.

Subclinical bioprosthetic valve thrombosis (BPVT) is a relatively common finding in asymptomatic patients during follow-up imaging. However, its clinical significance is unclear. Data from registries associate BPVT with elevated valve gradients, thromboembolic complications, recurrence, and valve degeneration. Given the dynamic nature of the disease process, management is challenging. The duration of anticoagulation is unpredictable, and the need for frequent monitoring of BPVT, even in subclinical scenarios, is unclear. Our report is shedding the light on the clinical implications BPVT.

Subclinical leaflet thrombosis (SLT) develops in 15% of patients undergoing trans-catheter aortic valve replacement (TAVR). TAVR is a procedure in which a faulty aortic valve is replaced with a mechanical one. An aortic valve replacement can be done with open-heart surgery; this is called surgical aortic valve replacement (SAVR). A significant problem is defining the best course of treatment for asymptomatic individuals with SLT post-TAVR, including the use of oral anticoagulation (OAC) in it.

Systematic review.

The most pertinent published research (original papers and reviews) in the scientific literature were searched for and critically assessed using the online, internationally indexed databases PubMed, Medline, and Cochrane Reviews. Keywords like "Transcatheter valve replacement" and "Subclinical leaflet thrombosis" were used to search the papers. Selected studies were critically assessed for inclusion based on predefined criteria.

The review examined the prevalence and characteristics of SLT after TAVR. To note, the incidence of SLT is seen to be higher in TAVR compared SAVR. Dual antiplatelet therapy, which is utilized in antithrombotic regimens post-TAVR, can possibly hasten SLT progression which could result in the impaired mobility of leaflets and the worsening of pressure gradients.

The use of dual antiplatelet drugs in routine antithrombotic therapy tends to accelerate initial subclinical leaflet thrombosis after TAVI, which results in a developing restriction of leaflet mobility and an increase in pressure differences.

Transcatheter aortic valves (TAVs) are susceptible to leaflet thrombosis which may lead to thromboembolic events, and early detection and intervention are believed to be the key to avoiding such adverse outcomes. An embedded sensor system installed on the valve stent, coupled with an appropriate machine learning-based continuous monitoring algorithm can facilitate early detection to predict severity of reduced leaflet motion (RLM) and avoid adverse outcomes.

We present a data-driven, in silico, proof-of-concept analysis of a pressure microsensor based system for quantifying RLM in TAVs. We generate a dataset of 21 high-fidelity transvalvular flow simulations with healthy and mildly stenotic TAVs to train a logistic regression model to correlate individual leaflet mobility in each simulation with principal components of corresponding hemodynamic pressure recorded at strategic locations of the TAV stent. A separate test dataset of 7 simulations is also generated for prospective assessment of model performance.

An array of 6 sensors embedded on the TAV stent, with two sensors tracking individual leaflet, successfully correlates leaflet mobility with recorded pressure. The sensors are placed along leaflet centerlines, one in the sinus, and the other at the sino-tubular junction. The regression model is tuned using cross-validation to achieve high accuracy on both training (R² = 0.93) and test (R² = 0.77) sets.

Discrete blood pressure recordings on TAV stents can be successfully correlated with individual leaflet mobility. Further development of this technology can enable longitudinal monitoring of TAVs and early detection of valve failure.

This work intends to study the effect of aortic annulus eccentricity and leaflet rigidity on the performance, thrombogenic risk and calcification risk in bioprosthetic aortic valve replacements (BAVRs). To address these questions, a two-way immersed fluid-structure interaction (FSI) computational model was implemented in a high-performance computing (HPC) multi-physics simulation software, and validated against a well-known FSI benchmark. The aortic valve bioprosthesis model is qualitatively contrasted against experimental data, showing good agreement in closed and open states. Regarding the performance of BAVRs, the model predicts that increasing eccentricities yield lower geometric orifice areas (GOAs) and higher normalized transvalvular pressure gradients (TPGs) for healthy cardiac outputs during systole, agreeing with in vitro experiments. Regions with peak values of residence time are observed to grow with eccentricity in the sinus of Valsalva, indicating an elevated risk of thrombus formation for eccentric configurations. In addition, the computational model is used to analyze the effect of varying leaflet rigidity on both performance, thrombogenic and calcification risks with applications to tissue-engineered prostheses. For more rigid leaflets it predicts an increase in systolic and diastolic TPGs, and decrease in systolic GOA, which translates to decreased valve performance. The peak shear rate and residence time regions increase with leaflet rigidity, but their volume-averaged values were not significantly affected. Peak solid stresses are also analyzed, and observed to increase with rigidity, elevating risk of valve calcification and structural failure. To the authors' knowledge this is the first computational FSI model to study the effect of eccentricity or leaflet rigidity on thrombogenic biomarkers, providing a novel tool to aid device manufacturers and clinical practitioners.

The number of trans-catheter aortic valve replacement (TAVR) procedure is increasing; However, the incidence of leaflet thrombosis is higher in TAVR than in surgical aortic valve replacement (SAVR). In this study, the risk factors for leaflet thrombosis after TAVR and its effects on hemodynamics and clinical course were investigated.

Multidetector computed tomography (MDCT) was performed at 1year after TAVR in 94 patients from January 2015 to October 2020 at Samsung Medical Center in South Korea. Among the 94 patients, subclinical leaflet thrombosis occurred in 20 patients, and risk factors were analyzed. In addition, the difference in aortic valve (AV) hemodynamics between the two groups was examined and clinical outcomes compared. Indexed mean sinus of Valsalva (SOV) diameter, AV calcium volume, and post-procedure effective orifice area (EOA) were predictive of subclinical leaflet thrombosis with the area under the curve (AUC) value of 0.670 (P-value = 0.020), 0.695 (P-value = 0.013), and 0.665 (P-value = 0.031), respectively. In echocardiography performed at the time of follow-up CT, the value of AV max velocity and AV mean pressure gradient were higher in the thrombosis group and the EOA and Doppler velocity index values were lower in the thrombosis group than in the no thrombosis group. Clinical outcome was not significantly different between the two groups (log-rank P-value = 0.26).

Larger indexed SOV diameter, higher AV calcium volume, and smaller post-procedure AV EOA were risk factors for subclinical leaflet thrombosis after TAVR. Subclinical leaflet thrombosis has a benign course when properly managed.

Leaflet thrombosis is a potentially fatal complication after transcatheter aortic valve replacement (TAVR). Blood flow stagnation in the neo-sinus and aortic sinuses are associated with increased thrombus severity. Native aortic leaflet modification may be a potential strategy to improve the neo-sinus and aortic sinus fluid dynamics. However, limited data exist on the effect of leaflet geometry modification on the flow within the neo-sinus and aortic sinus regions. We evaluate the effect of aortic leaflet modification on the neo-sinus and aortic sinus flow stagnation after simulated TAVR.

Particle image velocimetry measurements were performed under nominal (5 LPM) and low (2.5 LPM) cardiac output conditions for an intact leaflet (control) case, and 3 modified leaflet geometries. Aortic leaflet geometry modification via leaflet splay was simulated with increasing splay geometry (leaflet splay distance: 5 mm-narrow, 10 mm-medium, and 20 mm-wide).

Leaflet geometry modification influenced flow features throughout the cardiac cycle, at both cardiac outputs, and allowed for flow communication between the neo-sinus and aortic sinus regions compared to the control. In the aortic sinus, flow stagnation reduced by over 64% at 5LPM, and over 36% at 2.5LPM for all simulated modified leaflet geometries compared to the control. However, only the medium and wide splay geometries enabled a reduction in neo-sinus flow stagnation compared to the control case.

These findings suggest that aortic leaflet geometry modification (of at least 10 mm leaflet splay distance) may reduce flow stasis and potentially decrease valve thrombosis risk.

With the extended indications of transcatheter aortic valve (TAV) replacement (TAVR) to lower-risk patients, there is an increasing number of patients requiring surgical explantation of failed TAV. We sought to describe macroscopic and microscopic features of surgically explanted percutaneous aortic valve prostheses.

Preoperative and surgical characteristic of patients undergoing surgical explantation of TAV were retrospectively analyzed from 2007 to 2020. Surgical and pathologic features of these valves, and outcomes of the surgical valve replacement were described.

Out of 1764 patients who underwent a TAVR procedure, 21 were operated for TAV failure. Isolated or combined indications for surgery included: significant paravalvular leak (n = 15), delayed prosthesis migration (n = 5), significant increase of trans-TAV gradients (n = 6), and endocarditis (n = 3). Mean time elapsed between TAVR and explantations was 674.9 ± 803.9 days. Macroscopic lesions found on explanted percutaneous valves were severe adhesions to the aorta (n = 10), calcifications (n = 7), leaflet thrombosis (n = 4), and vegetations (n = 3). Except for patients with endocarditis, one or more pathological lesions were found in 15 patients. Pathology analyses on these valves showed fibro-calcific degenerations (n = 12), pannus formation (n = 9), and chronic inflammation (n = 3). One patient (4.8%) died after surgical explantation, and 13 (61.9%) had concomitant procedures. The survival rate at 1 year was 94.4%.

Microscopic findings of fibro-calcific leaflet degeneration, and pannus formation in addition to macroscopic calcification and thrombosis present early, (within a mean of 2 years) after TAVR. Further investigation with a higher number of patients and echocardiographic follow-up is warranted.

Pregnancy in individuals with a mechanical heart valve has been classified as very high risk because of a substantially increased risk of maternal mortality or severe morbidity. Lifelong therapeutic anticoagulation is a principal component of the medical management of mechanical heart valves to prevent valve thrombosis. Anticoagulation regimens indicated outside of pregnancy for patients with mechanical valves should be continued during pregnancy with the possibility of modifications based on the type of valve, the trimester of pregnancy, individual risk tolerance, and circumstances around the time of delivery. The purpose of this document is to provide recommendations regarding the management of anticoagulation for common cardiac conditions complicating pregnancy, including mechanical heart valves, atrial fibrillation, systolic heart failure, and congenital heart disease.

Hypoattenuated leaflet thickening (HALT), identified on functional cardiac computed tomography (CTA), can affect valve function and clinical outcomes. The objective of this study was to assess the impact of HALT on clinical outcomes in patients treated with transcatheter aortic valve replacement (TAVR).

In July 2015, Minneapolis Heart Institute implemented prospective screening of HALT at 30-day post-TAVR with CTA. Patients with evidence of HALT were recommended to initiate anticoagulation for 3 to 6 months with warfarin. Echocardiographic, ischemic, and bleeding outcomes were compared between HALT+ and HALT- patients. Survival rates were compared between HALT+ and HALT- patients using log-rank test, with Cox regression analysis used to identify variables independently associated with long-term death landmarked at time of CTA. This analysis included patients treated from July 1, 2015 to October 31, 2019.

Of 856 patients undergoing TAVR during the study period, 638 (75%) underwent CTA post-TAVR (median time 31 [30-37] days). HALT+ was evident in 79 (12.3%). HALT+ patients were more likely prescribed warfarin at 1, 3, and 12 months (all P<0.001) and had similar gradients compared with HALT- patients. After a median follow-up of 2.2 years (1.5-3.2), HALT+ patients had increased mortality (30% versus 20%; P=0.001). In Cox regression analysis, presence of HALT (hazard ratio, 1.83 [95% CI, 1.13-2.97]; P=0.014) remained independently associated with long-term mortality.

In a large, real-world cohort of patients receiving TAVR followed by systematic screening with CTA 30-days post-procedure, HALT was found in 12% of patients and independently associated with long-term mortality. Findings of this nonrandomized, observational cohort study require independent validation.

Objective: We aimed to compare non-vitamin K oral anticoagulants (NOACs) with a traditional antithrombotic such as vitamin K antagonist (VKA) and antiplatelet agents in patients after transcatheter aortic valve replacement (TAVR). Methods: We conducted a search in PubMed, EMBASE, and the Cochrane Library until November 2021 for studies involving comparisons of any type of NOACs, including dabigatran, apixaban, rivaroxaban, and edoxaban, with VKA or antiplatelet agents after TAVR. A comparison of NOACs versus VKA was performed in patients with an indication for oral anticoagulation. In addition, we compared NOACs versus antiplatelet in patients without such indication. We calculated the hazard ratios with 95% confidence intervals (CIs) to determine long-term outcomes. The primary outcome was a combined endpoint consisting of all-cause mortality, stroke, major bleeding, or any related clinical adverse events. Secondary outcomes were all-cause mortality, major bleeding, and stroke, respectively. Results: A total of 10 studies including 10,563 patients after TAVR were included in this meta-analysis. There were no significant differences in any of the long-term outcomes between the NOAC and VKA groups. Although there were no significant differences in the combined endpoint, major bleeding, or stroke, a significant difference was observed in the all-cause mortality (HR 1.74, 95% CI 1.25-2.43, p = 0.001) between the NOAC and antiplatelet groups. Conclusion: For patients with an indication for oral anticoagulation after TAVR, NOACs seem to be associated with noninferior outcomes compared with VKA therapy. However, for patients without an indication for oral anticoagulation, NOACs appear to be associated with a higher risk of all-cause death as compared with antiplatelet treatment. Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42020155122.

Bicuspid aortic valve (BAV) disease is the most common congenital heart defect worldwide. When severe, symptomatic aortic stenosis ensues, the treatment has increasingly become transcatheter aortic valve replacement (TAVR). The purpose of this review is to identify BAV classification and imaging methods, outline TAVR outcomes in BAV anatomy, and discuss how computational modeling can enhance TAVR treatment in BAV patients.

TAVR use in BAV patients, when compared to use in tricuspid aortic valves, showed lower device success rate, and there remains no long-term randomized trial data. It has been reported that BAV patients with severe calcification increase the rate of complications. Additionally, the asymmetrical morphology of BAVs often results in asymmetric stent geometries which have implications for increased thrombosis risk and decreased durability. These adverse outcomes are currently very difficult to predict from routine pre-procedural imaging alone. Recently developed patient specific experimental and computational techniques have the potential to assist in filling knowledge gaps in the mechanisms of these complications and provide more information during preclinical planning for better TAVR selection in low surgical risk BAV patients. Efficacy of TAVR for irregular BAV anatomies remains concerning due to the lack of a long-term randomized trial data, their increased rate of short-term complications, and signs that long-term durability could be an issue. More knowledge on identifying which BAV anatomies are at greater risk for these adverse outcomes can potentially improve patient selection for TAVR versus SAVR in low surgical risk BAV patients.

Leaflet thrombosis is a significant adverse event after transcatheter aortic valve (TAV) replacement (TAVR). The purpose of our study was to present a semi-empirical, mathematical model that links patient-specific anatomic, valve, and flow parameters to predict likelihood of leaflet thrombosis.

The two main energy sources of neo-sinus (NS) washout after TAVR include the jet flow downstream of the TAV and NS geometric change in volume due to the leaflets opening and closing. Both are highly dependent on patient anatomic and hemodynamic factors. As rotation of blood flow is prevalent in both the sinus of Valsalva and then the NS, we adopted the vorticity flux or circulation (Г) as a metric quantifying overall washout. Leaflet thrombus volumes were segmented based on hypo-attenuating leaflet thickening (HALT) in post-TAVR patient's gated computed tomography. Г was assessed using dimensional scaling as well as computational fluid dynamics (CFD) respectively and correlated to the thrombosis volumes using sensitivity and specificity analysis.

Г in the NS, that accounted for patient flow and anatomic conditions derived from scaling arguments significantly better predicted the occurrence of leaflet thrombus than CFD derived measures such as stasis volumes or wall shear stress. Given results from the six patient datasets considered herein, a threshold Г value of 28.0 yielded a sensitivity and specificity of 100% where patients with Gamma < 28 developed valve thrombosis. A 10% error in measurements of all variables can bring the sensitivity specificity down to 87%.

A predictive model relating likelihood of valve thrombosis using Г in the NS was developed with promising sensitivity and specificity. With further studies and improvements, this predictive technology may lead to alerting physicians on the risk for thrombus formation following TAVR.

Patients who receive transcatheter aortic valve replacement are at risk for leaflet thrombosis-related complications, and can benefit from continuous, longitudinal monitoring of the prosthesis. Conventional angiography modalities are expensive, hospital-centric and either invasive or employ potentially nephrotoxic contrast agents, which preclude their routine use. Heart sounds have been long recognized to contain valuable information about individual valve function, but the skill of auscultation is in decline due to its heavy reliance on the physician's proficiency leading to poor diagnostic repeatability. This subjectivity in diagnosis can be alleviated using machine learning techniques for anomaly detection. We present a computational and data-driven proof-of-concept analysis of a novel, auscultation-based technique for monitoring aortic valve, which is practical, non-invasive, and non-toxic. However, the underlying mechanisms leading to physiological and pathological heart sounds are not well-understood, which hinders development of such a technique. We first address this by performing direct numerical simulations of the complex interactions between turbulent blood flow in a canonical ascending aorta model and dynamic valve motion in 29 cases with healthy and stenotic valves. Using the turbulent pressure fluctuations on the aorta lumen boundary, we model the propagation of heart sounds, as elastic waves, through the patient's thorax. The heart sound may be recorded on the epidermal surface using a stethoscope/phonocardiograph. This approach allows us to correlate instantaneous hemodynamic phenomena and valve motion with the acoustic response. From this dataset we extract "acoustic signatures" of healthy and stenotic valves based on principal components of the recorded sound. These signatures are used to train a linear discriminant classifier by maximizing correlation between recorded heart sounds and valve status. We demonstrate that this classifier is capable of accurate prospective detection of anomalous valve function and that the principal component-based signatures capture prominent audible features of heart sounds, which have been historically used by physicians for diagnosis. Further development of such technology can enable inexpensive, safe and patient-centric at-home monitoring, and can extend beyond transcatheter valves to surgical as well as native valves.

Transcatheter aortic valve implantation (TAVI) has become an established and increasingly used approach for management of severe symptomatic aortic stenosis, showing similar or even superior outcomes compared with standard surgical aortic valve replacement (SAVR). Stroke after TAVI is a relatively rare, but serious complication, associated with potential prolonged disability and increased mortality.

The overall incidence of 30-day stroke in TAVI patients is 3%-4%, but varies between different trials. Initial data suggested a higher risk of stroke after TAVI when compared with SAVR. The association between subclinical leaflet thrombosis and cerebral embolism, presented as stroke, transient ischemic accident, or silent cerebral ischemia is not entirely elucidated yet. Moreover, TAVI for severe bicuspid aortic stenosis is a relatively new issue, bicuspid anatomy being initially excluded from the pivotal clinical trials investigating TAVI procedure. Efficient stroke prevention strategies are under investigation.

In the present manuscript, we used the available published data from the most relevant clinical trials, registries, and meta-analysis of patients from different risk categories who underwent TAVI or SAVR.

Predictors of acute stroke are mainly procedure related. Technological development, improvements in bioprosthesis valve delivery catheters, and implantation technique may explain the decrease of stroke over the years since the beginning of TAVI procedures.

The overall evidences confirm similar or lower rate of stroke in TAVI versus SAVR. Risk predictors for acute stroke after TAVI are generally related to procedural factors, whereas late stroke is mainly associated with patient characteristics, with a variable impact on cognitive function. The optimal choice for the antithrombotic treatment in TAVI for stroke prevention is yet to be determined. Current data do not support routine use of cerebral embolic protection devices during TAVI.

Patients receiving transcatheter aortic valve replacement (TAVR) can benefit from continuous, longitudinal monitoring of valve prosthesis to prevent leaflet thrombosis-related complications. We present a computational proof-of-concept study of a novel, non-invasive and non-toxic valve monitoring technique for TAVs which uses pressure measurements from microsensors embedded on the valve stent. We perform a data-driven analysis to determine the signal processing and machine learning required to detect reduced mobility in individual leaflets.

We use direct numerical simulations to describe hemodynamic differences in transvalvular flow in ascending aorta models with healthy and stenotic valves. A Cartesian-grid flow solver and a reduced-order valve model simulate the complex dynamics of blood flow and leaflet motion, respectively. The two-way fluid-structure interaction coupling is achieved using a sharp interface immersed boundary method.

From a dataset of 21 simulations, we show leaflets with reduced mobility result in large, asymmetric pressure fluctuations in their vicinity, particularly in the region extending from the aortic sinus to the sino-tubular junction (STJ). We train a linear classifier algorithm by correlating sinus and STJ pressure measurements on the stent surface to individual leaflet status. The algorithm was shown to have >90% accuracy for prospective detection of individual leaflet dysfunction.

We demonstrate that using only two discrete pressure measurements, per leaflet, on the TAV stent, individual leaflet status can be accurately predicted. Such a sensorized TAV system could enable safe and inexpensive detection of prosthetic valve dysfunction.

Thromboembolic events remain clinically unresolved after transcatheter aortic valve implantation (TAVI). The use of direct oral anticoagulant (DOAC) to reduce thrombosis associated with TAVI remains controversial. This study aimed at investigating the periprocedural change in blood coagulation and thrombolysis parameters in 199 patients undergoing transfemoral TAVI. Prothrombin activation fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), soluble fibrin monomer complex (SFMC), and fibrin/fibrinogen degradation product (FDP) levels were measured before and 1 hour after TAVI and 1, 2, and 7 days postoperatively. Of the 199 patients, 49 were treated with DOAC (apixaban in 32, edoxaban in 10, and rivaroxaban in 7). The F1 + 2 and TAT levels immediately increased 1 hour after TAVI and then gradually decreased in both groups. The SFMC level also significantly increased with a peak on day 1. The FDP level gradually increased, peaking on day 2. The values of F1 + 2, TAT, SFMC, and FDP in patients who used DOAC were significantly lower than those who did not use DOAC at 1 hour after TAVI in F1 + 2 (600 [452 to 765] vs 1055 [812 to 1340] pmol/L; p < 0.001), TAT (21.4 [16.2 to 37.0] vs 38.7 [26.4 to 58.7] μg/mL; p < 0.001) and on day 1 in SFMC (18.2 [9.4 to 57.9] vs 113.4 [70.9 to 157.3] μg/mL; p < 0.001) and day 2 in FDP (6.0 [4.7 to 10.0] vs 12.6 [8.2 to 17.4] μg/mL; p < 0.001). Ischemic stroke within 30 days after TAVI occurred in 3 patients (1.5%), who were not treated with DOAC. Coagulation cascade activation was observed after TAVI. DOAC could reduce transient hypercoagulation following TAVI.

The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.

Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.

Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

This executive summary of the valvular heart disease guideline provides recommendations for clinicians to diagnose and manage valvular heart disease as well as supporting documentation to encourage their use.

A comprehensive literature search was conducted from January 1, 2010, to March 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected database relevant to this guideline. Structure: Many recommendations from the earlier valvular heart disease guidelines have been updated with new evidence and provides newer options for diagnosis and treatment of valvular heart disease. This summary includes only the recommendations from the full guideline which focus on diagnostic work-up, the timing and choice of surgical and catheter interventions, and recommendations for medical therapy. The reader is referred to the full guideline for graphical flow charts, text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in developing these guidelines.

Transcatheter aortic valve replacement (TAVR) is an established alternative to surgery for patients with severe symptomatic aortic stenosis. Adjunctive antithrombotic therapy used to mitigate thrombotic risks in patients undergoing TAVR must be balanced against bleeding complications, since both are associated with increased mortality.

Stroke risk associated with TAVR is lower than that associated with surgical aortic valve replacement in recent trials including patients at intermediate or low risk, but it is constant beginning at the time of implant and accrues over time based on patient risk factors. Patients with aortic stenosis undergoing TAVR also have a sizable risk of life-threatening or major bleeding. Although dual antiplatelet therapy for 3 to 6 months after TAVR is the guideline-recommended regimen, this practice is not well supported by current evidence. In patients with no indication for oral anticoagulation, current registry-based evidence suggests that single antiplatelet therapy may be safer than dual antiplatelet therapy. Similarly, oral anticoagulation monotherapy appears superior to anticoagulation plus antiplatelet therapy in those where oral anticoagulant use is indicated. To date, no risk prediction models have been established to guide antithrombotic therapy.

Despite the growing volume of TAVR procedures to treat patients with severe aortic stenosis, evidence for adjunctive antithrombotic therapy remains rather scarce. Ongoing clinical trials will provide better understanding to guide antithrombotic therapy.

Transcatheter aortic valve (TAV) leaflet thrombosis is a clinical risk with potentially fatal consequences. Studies have identified neo-sinus flow stasis as a cause of leaflet thrombosis. Flow stasis is influenced by the TAV leaflets, which affect the local fluid dynamics in the aortic sinus and neo-sinus. This study evaluated the effects of TAV leaflet features on the neo-sinus flow as a measure of leaflet thrombosis risk. Five TAVs of varied leaflet length and insertion height were tested in a simulator. Hydrodynamics and leaflet kinematics through en-phase imaging were quantified. Velocity fields were assessed using high-speed particle image velocimetry. Regions of flow stasis and particle residence times (PRTs) were quantified. TAVs with shorter leaflet length exhibited larger orifice areas and lower transvalvular pressure gradients. Shorter leaflet length and increased leaflet insertion TAVs additionally exhibited lower neo-sinus PRTs (0.44 ± 0.21 vs 2.83 ± 0.48 cycles, p < 0.05) and higher neo-sinus peak velocities (0.15 ± 0.009 vs 0.07 ± 0.005 m/s, p < 0.05) than TAVs with longer leaflet length and lower leaflet insertion. The average neo-sinus volume positively correlated with PRT(r = 0.810, p < 0.001), and extent of flow stasis (r = 0.682, p < 0.05). These results suggest that a small neo-sinus volume may reduce flow stagnation and particle residence, potentially reducing the risk of leaflet thrombosis. We propose that leaflet design features might be proactively controlled in the design of future transcatheter aortic valves.

Thrombosis in post-transcatheter aortic valve replacement (TAVR) patients has been correlated with flow stasis in the neo-sinus. This study investigated the effect of the post-TAVR geometry on flow stasis. Computed tomography angiography of 155 patients who underwent TAVR using a SAPIEN 3 were used to identify patients with and without thrombosis, and quantify thrombus volumes. Six patients with 23-mm SAPIEN 3 valves were then selected from the cohort and used to create patient-specific post-TAVR computational fluid dynamic models. Regions of flow stasis (%Vol_stasis, velocities below 0.05 m/s) were identified. The results showed that all post-TAVR anatomical measurements were significantly different in patients with and without thrombus, but only sinus diameter had a linear correlation with thrombus volume (r = 0.471, p = 0.008). A linear correlation was observed between %Vol_stasis and thrombus volume (r = 0.821, p = 0.007). The combination of anatomy and valve deployment created a unique geometry in each patient, which when combined with patient-specific cardiac output, resulted in distinct flow patterns. While parametric studies have shown individual anatomical or deployment metrics may relate to flow stasis, the combined effects of these metrics potentially contributes to the biomechanical environment promoting thrombosis, therefore hemodynamic studies of TAVR should account for these patient-specific factors.

Leaflet thrombosis (LT) has been claimed as a potential cause of hemodynamic dysfunction or bioprosthetic valve degeneration of transcatheter heart valves. Sparse and contrasting evidence exists, however, regarding LT occurrence, prevention and treatment. MEDLINE, ISI Web of Science and SCOPUS databases were searched for studies published up to January 2020. Only studies reporting data on incidence and outcomes associated to the presence/absence of clinical or subclinical LT, detected or confirmed with a multidetector computed tomography exam were included. The study was designed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) requirements. Two reviewers independently screened articles for fulfillment of inclusion criteria. Data were pooled using a random-effect model. The primary end point was the incidence of LT. Secondary outcomes included: stroke and transient ischemic attacks and mean transvalvular gradients at different time-points in patients with and without LT. Of the initial 200 studies, 22 were finally included with a total of 11,567 patients. LT overall incidence was 8% (95% Confidence Interval [CI]: 5% to 13%, I² = 96.4%). LT incidence in patients receiving only antiplatelets was 13% (95% CI: 7% to 23%, p <0.0001); patients discharged on oral anticoagulants had a reported incidence of 4% (95% CI: 2% to 8%, p <0.0001). Patients with LT, either clinical or subclinical, were not at increased risk of stroke (OR 1.06, 95% CI: 0.75 to 1.50, p = 0.730, I² = 0.0%) or transient ischemic attacks (Odds Ratio 1.01, 95% CI: 0.40 to 2.57, p = 0.989, I² = 0.0%). LT was associated with higher mean transvalvular gradients compared with patients without LT at 30 days post-transcatheter implantation, but not at discharge or at 1 year. LT is a relatively common event that, even when clinically manifest, is not associated with an increased risk of cerebrovascular events. Although patients on anticoagulants appear to be at lower risk of LT, the available evidence does not allow formulation of recommendations for prophylactical anticoagulation nor routine computed tomography after transcatheter aortic valve replacement.

A 67-year-old postmenopausal African American woman presented with biventricular takotsubo cardiomyopathy (TTC)-evidenced by transthoracic echocardiography (TTE) showing apical akinesis of both left and right ventricles in the absence of obstructive coronary artery disease on left heart catheterisation. On the 4th hospital day, she experienced acute left facial droop, dysarthria and dysphagia. CT of the head showed a wedge infarct of the right middle cerebral artery territory. Cardioembolism was presumed after intracranial and extracranial sources of thromboembolism were ruled out. Intravenous tissue plasminogen activator (tPA) was administered with resolution of symptoms. She was later discharged without neurological deficits. Crucially, repeat TTE after tPA infusion revealed a left ventricular mass concerning for thrombus. TTE 150 min prior to stroke onset was devoid of a mass. This case uniquely illustrates the potential for rapid thrombus formation and embolism in patients with TTC. As such, it emphasises the high index of suspicion required for management of these patients.

Transcatheter aortic valve replacement (TAVR) has emerged as a widely used therapy for aortic valve diseases. With TAVR, flow hemodynamics may change leading to areas of flow stagnation prone to thrombosis risk. The neo-sinus, created by introducing a prosthesis inside the diseased native valve, may prompt leaflet thrombosis due to areas of flow stasis. This study attempted to understand the effect of different prosthesis implant depths on the flow field within the neo- and native sinus and on the coronary perfusion. Experiments were performed inside an in vitro pulse duplicator producing physiological conditions according to ISO 5840-1:2015 standard. Flow fields were obtained for two cardiac outputs (CO) using particle image velocimetry (PIV). Washout was calculated as a measure of flow stasis. The two main results are: a lower implant position and a lower CO/frequency led to better native sinus washout, but worsened neo-sinus washout. In contrast, a higher implant position led to higher coronary flow (for higher CO/frequency). No significant effect of implant depth on coronary flow was observed for lower CO/frequency. In summary, a higher implant position using this self-expanding prosthesis is associated with reduced neo-sinus flow stasis. Hereby, washout of the native sinus, as well as coronary flow, are dependent on cardiac output.

The recent unexpected discovery of thrombosis in transcatheter heart valves (THVs) has led to increased concerns of long-term valve durability. Based on the clinical evidence combined with Virchow's triad, the primary hypothesis is that low-velocity blood flow around the valve could be a primary cause for thrombosis. However, due to limited optical access in such unsteady three-dimensional biomedical flows, measurements are challenging. In this study, for the first time, we employ a novel single camera volumetric velocimetry technique to investigate unsteady three-dimensional cardiovascular flows. Validation of the novel volumetric velocimetry technique with standard planar particle image velocimetry (PIV) technique demonstrated the feasibility of adopting this new technique to investigate biomedical flows. This technique was used to quantify the three-dimensional velocity field in the vicinity of a validated, custom developed, transparent THV in a bench-top pulsatile flow loop. Large volumetric regions of flow stagnation were observed in the neo-sinus throughout the cardiac cycle, with stagnation defined as a velocity magnitude lower than 0.05 m s^-1. The volumetric scalar viscous shear stress quantified via the three-dimensional shear stress tensor was within the range of low shear-inducing thrombosis observed in the literature. Such high-fidelity volumetric quantitative data and novel imaging techniques used to obtain it will enable fundamental investigation of heart valve thrombosis in addition to providing a reliable and robust database for validation of computational tools.

Computer modeling and simulation is a powerful tool for assessing the performance of medical devices such as bioprosthetic heart valves (BHVs) that promises to accelerate device design and regulation. This study describes work to develop dynamic computer models of BHVs in the aortic test section of an experimental pulse-duplicator platform that is used in academia, industry, and regulatory agencies to assess BHV performance. These computational models are based on a hyperelastic finite element extension of the immersed boundary method for fluid-structure interaction (FSI). We focus on porcine tissue and bovine pericardial BHVs, which are commonly used in surgical valve replacement. We compare our numerical simulations to experimental data from two similar pulse duplicators, including a commercial ViVitro system and a custom platform related to the ViVitro pulse duplicator. Excellent agreement is demonstrated between the computational and experimental results for bulk flow rates, pressures, valve open areas, and the timing of valve opening and closure in conditions commonly used to assess BHV performance. In addition, reasonable agreement is demonstrated for quantitative measures of leaflet kinematics under these same conditions. This work represents a step towards the experimental validation of this FSI modeling platform for evaluating BHVs.

There is a significant increase in transvalvular gradients after transcatheter aortic valve implantation (TAVI) in some patients; however, mechanisms underlying the greater than expected gradients are unknown. We sought to determine the incidence and mechanisms of greater than expected gradients post-TAVI. A total of 424 patients who underwent TAVI at our institution between November 2008 and August 2015 and had at least 1 follow-up echocardiogram were included in the study. Greater than expected gradients were defined as mean systolic Doppler gradients ≥20 mm Hg. The primary end-point was incidence and mechanisms of mean systolic Doppler gradients ≥20 mm Hg. A total of 36 (8%) patients had mean systolic Doppler gradients ≥20 mm Hg. The mechanisms of mean systolic Doppler gradients ≥20 mm Hg were: patient prosthesis mismatch in 15 (42%) patients, high cardiac output in 13 (36%), prosthetic and periprosthetic regurgitation in 11 (31%), stenosis in 5 (14%), and multiple mechanisms in 8 (22%). Patients with mean systolic Doppler gradients ≥20 mm Hg had higher cardiac re-hospitalization rate, but no difference in mortality or major cardiovascular events when compared with the normal gradient group. Smaller prosthetic valve size (p <0.0001) and larger body mass index (p = 0.02) were associated with mean systolic Doppler gradients ≥20 mm Hg; warfarin therapy at discharge had no effect on gradients. In conclusion, about 8% patients had mean systolic Doppler gradients ≥20 mm Hg following TAVI, and patient-prosthesis mismatch was the most common mechanism. The mean systolic Doppler gradients ≥20 mm Hg after TAVI are not benign and warrant careful surveillance.

The transcatheter aortic valve replacement (TAVR) procedure was developed to provide patients with severe aortic stenosis an alternative to the surgical aortic valve replacement. Since the approval of the original SAPIEN the technology has rapidly evolved. While several approaches can be used for valve deployment, as delivery systems have become smaller and more flexible, the transfemoral approach has become the dominant technique for valve deployment. One hundred and forty five patients undergoing TAVR receiving one of four valve types (Sapien, Sapien XT, Sapien3 or CoreValve) via the femoral artery were included in this study. Platelet count, white blood cells count (WBC), Interleukin-6 (IL-6), and Serum Amyloid A (SAA) were determined before and after TAVR. Platelet counts declined after the procedure regardless of the valve type and were dependent upon the baseline platelet count. Use of conscious sedation blunted the decline in platelet count. With the newer generation valves, the rise in WBC post-TAVR was lower than observed with the Sapien, in keeping with less systemic inflammation. Consistent with WBC, IL-6 levels were lower following deployment of the newer generation valves. Elevations in plasma SAA, which occur following myocardial injury, were not reduced with the newer valves. Evolution of the TAVR technology has occurred rapidly over the last 5 years. The newer devices and smaller delivery systems are associated with less systemic inflammation, as reflected in WBC and plasma IL-6 levels. However, the acute phase reactant SAA remains unchanged, possibly reflecting different triggers for SAA following TAVR.

TAVR has become the standard treatment in patients at increased surgical risk (STS or EuroSCORE II ≥4% or logistic EuroSCORE I ≥ 10% or other risk factors not included in these scores such as frailty, porcelain aorta, sequelae of chest radiation) and it is increasingly being performed in patients at intermediate to low (STS or EuroSCORE II <4% or logistic EuroSCORE I < 10%) surgical risk. Although non-inferiority has been demonstrated in intermediate and low-risk patients, several challenges need to be addressed before expansion to younger patients. Current trends, trials results, and remaining challenges are summarized and discussed in this review.