Embedding and Backscattered Scanning Electron Microscopy (EM-BSEM) Is Preferential over Immunophenotyping in Relation to Bioprosthetic Heart Valves.

Hitherto, calcified aortic valves (AVs) and failing bioprosthetic heart valves (BHVs) have been investigated by similar approaches, mostly limited to various immunostaining techniques. Having employed multiple immunostaining combinations, we demonstrated that AVs retain a well-defined cellular hierarchy even at severe stenosis, whilst BHVs were notable for the stochastic degradation of the extracellular matrix (ECM) and aggressive infiltration by ECM-digesting macrophages. Leukocytes (CD45+) comprised ≤10% cells in the AVs but were the predominant cell lineage in BHVs (≥80% cells). Albeit cells with uncertain immunophenotype were rarely encountered in the AVs (≤5% cells), they were commonly found in BHVs (≥80% cells). Whilst cell conversions in the AVs were limited to the endothelial-to-mesenchymal transition (represented by CD31+α-SMA+ cells) and the formation of endothelial-like (CD31+CD68+) cells at the AV surface, BHVs harboured numerous macrophages with a transitional phenotype, mostly CD45+CD31+, CD45+α-SMA+, and CD68+α-SMA+. In contrast to immunostaining, which was unable to predict cell function in the BHVs, our whole-specimen, nondestructive electron microscopy approach (EM-BSEM) was able to distinguish between quiescent and matrix-degrading macrophages, foam cells, and multinucleated giant cells to conduct the ultrastructural analysis of organelles and the ECM, and to preserve tissue integrity. Hence, we suggest EM-BSEM as a technique of choice for studying the cellular landscape of BHVs.

Echocardiographic Assessment of Prosthetic Valves.

Prosthetic valves are increasingly encountered in clinical practice. A grasp of the intricacies of the assessment and management of prosthetic valves is thus a crucial skillset for the practicing cardiologist. Echocardiography is the imaging modality of choice for the anatomic and functional evaluation of prosthetic valve. This document reviews the general features of prosthetic valves, echocardiographic identification of normally functioning and dysfunctional prosthetic valves as well as echocardiographic diagnosis of specific prosthetic valvular abnormalities.

Computed tomography predictors of structural valve degeneration in patients undergoing transcatheter aortic valve implantation with balloon-expandable prostheses.

OBJECTIVES: Computed tomography (CT) provides excellent anatomy assessment of the aortic annulus (AoA) and is utilized for pre-procedural planning of transcatheter aortic valve implantation (TAVI). We sought to investigate if geometrical characteristics of the AoA determined by CT may represent predictors of structural valve degeneration (SVD) in patients undergoing TAVI with balloon-expandable valves. METHODS: This is a retrospective study on 124 consecutive patients (mean age: 79 ± 7 years; female: 61%) undergoing balloon-expandable TAVI prospectively enrolled in a registry. AoA maximum diameter (Dmax), minimum diameter (Dmin), and area were assessed using pre-procedural CT. SVD was identified during follow-up with transthoracic echocardiography documenting structural prosthetic valve abnormalities with or without hemodynamic changes. RESULTS: The mean follow-up was 5.9 ± 1.7 years. SVD was found in 48 out of 124 patients (38%). AoA Dmax, Dmin, and area were significantly smaller in patients with SVD compared to patients without SVD (25.6 ± 2.2 mm vs. 27.1 ± 2.8 mm, p = 0.012; 20.5 ± 2.1 mm vs. 21.8 ± 2.1 mm, p = 0.001 and 419 ± 77 mm2 vs. 467 ± 88 mm2, p = 0.002, respectively). At univariable analysis, female sex, BSA, 23-mm prosthetic valve size, Dmax < 27.1 mm, and a Dmin < 19.9 mm were associated with SVD, whereas at multivariable analysis, only Dmin < 19.9 mm (OR = 2.873, 95% CI: 1.191-6.929, p = 0.019) and female sex (OR = 2.659, 95% CI: 1.095-6.458, p = 0.031) were independent predictors of SVD. CONCLUSIONS: Female sex and AoA Dmin < 19.9 mm are associated with SVD in patients undergoing TAVI with balloon-expandable valves. When implanting large prostheses in order to avoid paraprosthetic regurgitation, caution should be observed due to the risk of excessive stretching of the AoA Dmin, which may play a role in SVD. KEY POINTS: • Long-term durability is a concern for transcatheter aortic valve bioprosthesis. • CT provides an excellent assessment of the aortic annulus's geometrical characteristics for prosthesis sizing before transcatheter aortic valve implantation (TAVI). • Female sex and a small minimum aortic annulus diameter measured with CT are independent predictors of structural valve degeneration in patients undergoing TAVI with balloon-expandable valves.

Macroscopic and microscopic features of surgically explanted transcatheter aortic valve prostheses.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Trifecta versus perimount bioprosthesis for surgical aortic valve replacement; systematic review and meta-analysis.

OBJECTIVE: Recent studies suggested higher rates of early structural valve degeneration or reintervention for the Trifecta valve compared to other valves. Thus, we conducted a systematic review and meta-analysis comparing the outcomes of the Trifecta valve and the Perimount valves in patients who underwent a surgical aortic valve replacement (SAVR). METHODS: All randomized control trials and observational studies which investigated the outcomes of the Trifecta valve and Perimount valves were identified with PubMed and EMBASE. The endpoints were the rates of reintervention and all-cause mortality. Hazard ratios (HRs) for reintervention and all-cause mortality were combined with the random-effects model. RESULTS: Our search identified 6 eligible observational studies which enrolled a total of 11,135 patients who underwent SAVR with either the Trifecta valve (n = 4932) or Perimount (n = 6203). Pooled analyses demonstrated that the reintervention rates were significantly higher with the Trifecta valve compared with Perimount valves (HR [95% confidence interval {CI}] = 3.16 [1.83-5.46]; p < .0001; I2 = 40%). In contrast, all-cause mortality was not significantly different between the two groups (HR [95% CI] = 1.09 [0.75-1.58]; p = .32, I2 = 12%). CONCLUSION: Our analysis showed that AVR with the Trifecta valve was associated with higher rates of reintervention compared for that with the Perimount valve. Although further long-term randomized trials are warranted, surgeons need to be cautious when choosing a bioprosthetic valve for patients undergoing SAVR.

Structural valve degeneration in the transcatheter mitral valve implantation era.

Structural valve degeneration of biological valves continues to be a persistent problem and has assumed greater importance with the advent of transcatheter valve implantation techniques. Considerable variability exists among different studies in reporting the incidence of structural valve degeneration and differentiation with nonstructural valve degeneration and bio-prosthetic valve failures is important. Moreover, the pathological basis of structural valve degeneration is still not completely understood. Theoretically, trans-catheter implanted valves may be more prone to degeneration compared to surgically implanted biological valves. Measures to reduce structural valve degeneration are imperative, irrespective of the technique of valve implantation.

Utility of CT in the diagnosis of prosthetic valve abnormalities.

BACKGROUND: Patients with prosthetic heart valves (PHV) are at an increased risk of endocarditis and dysfunction. Knowledge about the etiology of dysfunction and extent of endocarditis can have distinct treatment implications. Echocardiography has limitations due to PHV-related artifacts. We hypothesized that computed tomography (CT) will have incremental value over echocardiography for evaluation of PHV abnormalities with surgical findings as the reference standard. METHODS: Consecutive patients with PHV that had a reoperation for valve replacement, had a contrast chest CT and echocardiogram within 1 year of the reoperation, between 2010 and 2018 at a single academic center formed the study cohort. CTs and echocardiograms were assessed for potential etiologies of dysfunction (valve degeneration, pannus and thrombus); and for extent of endocarditis (vegetation, abscess, and pseudoaneurysm). RESULTS: Seventy-three patients (65.8% male, mean age 62.1 ± 16.5 years) formed the study cohort. The indication for reoperation was PHV dysfunction in 51 and PHV endocarditis in 22. Compared to echocardiography, CT diagnosed the etiology of PHV dysfunction in 17 (33.3%) more patients (9 valve degeneration, 8 pannus). In the PHV endocarditis cohort, CT failed to detect one vegetation and one abscess, whereas echocardiography failed to detect 1 abscess. In combination, CT and echocardiography demonstrated all the vegetations and abscesses. CONCLUSION: CT may provide superior characterization in comparison to echocardiography for the identification of the cause of prosthetic valve dysfunction, and complementary information to echocardiography for the evaluation of prosthetic valve endocarditis.

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

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

Patient Risk Factors for Bioprosthetic Aortic Valve Degeneration: A Systematic Review and Meta-Analysis.

The choice of valve type for aortic valve replacement surgery is sometimes challenging. The main risk for bioprostheses is structural valve degeneration (SVD); however, little is known about what the most important risk factors are. We conducted a systematic review and meta-analysis to identify the risk factors and estimate their pooled effect sizes to aid the prosthesis choice for replacement. We followed PRISMA guidelines and systematically searched three electronic databases (PubMed, Scopus, and Web of Science) using appropriate key terms: 'aortic valve', 'bioprosthesis', 'degeneration', 'durability', 'prosthesis failure', etc. Hazard ratio (HR) and odds ratio (OR) and associated 95% confidence intervals (CI) were extracted. Pooled risk estimates were calculated using a random-effects model. Twenty-nine (29) observational studies were included with a total of 25,490 patients, 981 of whom developed SVD over a mean follow-up time of 18.5 years. Four (4) factors influencing bioprosthetic SVD were identified: increasing age was a protective factor (per 1-yr increase, HR: 0.91 [95% CI 0.89, 0.94], p<0.0001), whereas increased body surface area (HR 1.77 [1.04, 3.01], p=0.034), patient-prosthesis mismatch (HR 1.95 [1.56, 2.43], p<0.001), and smoking (HR 2.28 [1.37, 3.79], p=0.0015) were risk factors for SVD. We found younger age, patient-prosthesis mismatch, body surface area, and smoking, as risk factors for aortic SVD, which should be considered for valve selection. This study generates a further hypothesis that accelerated flow across the valve is a shared key component in the pathophysiology of SVD, thus future research should consider other high cardiac output states.

Rate, Timing, Correlates, and Outcomes of Hemodynamic Valve Deterioration After Bioprosthetic Surgical Aortic Valve Replacement.

BACKGROUND: The incidence of structural valve deterioration after bioprosthesis (BP) aortic valve replacement (AVR) established on the basis of reoperation may substantially underestimate the true incidence. The objective is to determine the rate, timing, correlates, and association between hemodynamic valve deterioration (HVD) and outcomes assessed by Doppler echocardiography after surgical BP AVR. METHODS: A total of 1387 patients (62.2% male, 70.5±7.8 years of age) who underwent BP AVR were included in this retrospective study. Baseline echocardiography was performed at a median time of 4.1 (1.3-6.5) months after AVR. All patients had an echocardiographic follow-up ≥2 years after AVR (926 at least 5 years and 385 at least 10 years). HVD was defined by Doppler assessment as a ≥10 mm Hg increase in mean gradient or worsening of transprosthetic regurgitation ≥1/3 class. HVD was classified according to the timing after AVR: "very early," during the first 2-years; "early," between 2 and 5 years; "midterm," between 5 and 10 years; and "long-term," >10 years. RESULTS: A total of 428 patients (30.9%) developed HVD. Among these patients, 52 (12.0%) were classified as "very early," 129 (30.1%) as "early," 158 (36.9%) as "midterm," and 89 (20.8%) as "long-term" HVD. Factors independently associated with HVD occurring within the first 5 years after AVR were diabetes mellitus ( P=0.01), active smoking ( P=0.01), renal insufficiency ( P=0.01), baseline postoperative mean gradient ≥15 mm Hg ( P=0.04) or transprosthetic regurgitation ≥mild ( P=0.04), and type of BP (stented versus stentless, P=0.003). Factors associated with HVD occurring after the fifth year after AVR were female sex ( P=0.03), warfarin use ( P=0.007), and BP type ( P<0.001). HVD was independently associated with mortality (hazard ratio, 2.18; 95% CI, 1.86-2.57; P<0.001). CONCLUSIONS: HVD as identified by Doppler echocardiography occurred in one third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes mellitus and renal insufficiency were associated with early HVD, whereas female sex, warfarin use, and stented BPs (versus stentless) were associated with late HVD.

Transcatheter aortic valve implantation in degenerative sutureless perceval aortic bioprosthesis.

Sutureless aortic bioprostheses (SAB) are increasingly being used to provide shorter cross-clamp time. Valve-in-valve transcatheter aortic valve replacement (VIV-A) is shown to be effective and safe in the vast majority of patients with degenerated bioprosthetics, yet its' use in SAB failure is infrequent. We present a case of balloon-expandable VIV-A in an 80-year-old woman who suffered severe symptomatic aortic regurgitation in a failed Perceval S 21-mm valve. Computed tomography scan demonstrated a deformed valve. Our heart team favored a percutaneous VIV-A over reoperation due to the patients' high surgical risk. An Edwards-Sapien XT 23 mm was successfully deployed with excellent results. The patient remained asymptomatic following 6 months. As other bioprosthesis, some sutureless valves are condemned to structural valve degeneration. Because VIV-A is being established for managing degenerative bioprosthesis in high risk patients, it is cardinal to identify its role in novel degenerative sutureless valves. SAB were introduced to the clinical market only 5-7 years ago. The absence of sutures may theoretically impose risk for valve instability when adding a transcatheter sutureless valve inside the first one. Our successful experience was very reassuring. We report its feasibility because we believe it should provide support for further investigation on VIV-A within novel SAV. © 2016 Wiley Periodicals, Inc.

Lp-PLA2 is associated with structural valve degeneration of bioprostheses.

OBJECTIVES: In this study, we sought to determine the metabolic markers associated with structural valve degeneration (SVD). BACKGROUND: Structural valve degeneration (SVD) is the major cause of bioprosthetic valve failure leading to bioprostheses (BPs) stenosis or regurgitation. We hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the SVD of BPs. METHODS: We included 197 patients who underwent aortic valve replacement with a bioprosthetic valve and had echocardiographic follow-up to evaluate valve function. Moreover, explanted BPs (n = 39) were analysed by immunohistochemistry for the expression of Lp-PLA2. RESULTS: After a mean follow-up of 7·9 ±0·2 years, forty-one patients (21%) were identified as developing SVD. Patients with SVD had significantly higher plasma level of Lp-PLA2 mass (151·8 ± 9·2 ng/mL vs. 133·2 ± 3·4 ng/mL, P = 0·03) and activity (27·6 ± 0·9 nmol/min/mL vs. 25·0 ± 0·4 nmol/min/mL, P = 0·005). Multivariate analysis revealed that Lp-PLA2 activity (OR: 1·09, 95% CI: 1·01-1·18; P = 0·03) was the strongest independent predictor of SVD. Immunohistochemistry studies of explanted BP showed that 77% of explanted BPs had the expression of Lp-PLA2, which correlated with the density of macrophages (CD68), and ox-LDL levels in bioprosthetic tissues. CONCLUSIONS: Increased blood plasma activity of Lp-PLA2 is associated with higher prevalence of SVD. These findings open new avenues for the identification of patients at risk for SVD and for the development of pharmacotherapy aiming at the prevention of SVD.

Early and mid-term outcomes after aortic valve replacement using a novel tissue bioprosthesis: a systematic review.

OBJECTIVES: While current data show a clear trend towards the use of bioprosthetic valves during aortic valve replacement (AVR), durability of bioprosthetic valves remains the most important concern. We conducted a 1st systematic review of all available evidence that analysed early and mid-term outcomes after AVR using the Inspiris RESILIA™ bioprosthesis. METHODS: A systematic literature search was performed to identify all relevant studies evaluating early and mid-term outcomes after AVR using the Inspiris RESILIA bioprosthesis and including at least 20 patients with no restriction on the publication date. Subgroup meta-analysis was performed to compare Inspiris RESILIA and PERIMOUNT Magna Ease bioprosthesis and to pool the early postoperative mortality and stroke rates. RESULTS: A total of 416 studies were identified, of which 15 studies met the eligibility criteria. The studies included a total of 3202 patients with an average follow-up of up to 5.3 years. The average age of patients across the studies was 52.2-75.1 years. Isolated AVR was performed in 39.0-86.4% of patients. In-hospital or 30-day postoperative mortality was 0-2.8%. At the mid-term follow-up, freedom from all-cause mortality was up to 85.4%. Among studies with mid-term follow-up, trace/mild paravalvular leak was detected in 0-3.0%, while major paravalvular leak was found only in up to 2.0% of patients. No statistically significant differences in terms of mortality (P = 0.98, odds ratio 1.02, 95% confidence interval 0.36-2.83) and stroke (P = 0.98, odds ratio 1.01, 95% confidence interval 0.38-2.73) between the Inspiris RESILIA bioprosthesis and PERIMOUNT Magna Ease bioprosthesis were observed in the subgroup meta-analysis. CONCLUSIONS: Mid-term data on the safety and haemodynamic performance of the novel aortic bioprosthesis are encouraging. Further comparative studies with other bioprostheses and longer follow-up are still required to endorse durability and safety of the novel bioprosthesis.

Calcification of surgical aortic bioprostheses and its impact on clinical outcome.

AIMS: Aortic valve calcification (AVC) of surgical valve bioprostheses (BPs) has been poorly explored. We aimed to evaluate in vivo and ex vivo BP AVCs and its prognosis value. METHODS AND RESULTS: Between 2011 and 2019, AVC was assessed using in vivo computed tomography (CT) in 361 patients who had undergone surgical valve replacement 6.4 ± 4.3 years earlier. Ex vivo CT scans were performed for 37 explanted BPs. The in vivo CT scans were interpretable for 342 patients (19 patients [5.2%] were excluded). These patients were 77.2 ± 9.1 years old, and 64.3% were male. Mean in vivo AVC was 307 ± 500 Agatston units (AU). The AVC was 562 ± 570 AU for the 183 (53.5%) patients with structural valve degeneration (SVD) and 13 ± 43 AU for those without SVD (P < 0.0001). In vivo and ex vivo AVCs were strongly correlated (r = 0.88, P < 0.0001). An in vivo AVC > 100 AU (n = 147, 43%) had a specificity of 96% for diagnosing Stage 2-3 SVD (area under the curve = 0.92). Patients with AVC > 100 AU had a worse outcome compared with those with AVC ≤ 100 AU (n = 195). In multivariable analysis, AVC was a predictor of overall mortality (hazard ratio [HR] and 95% confidence interval = 1.16 [1.04-1.29]; P = 0.006), cardiovascular mortality (HR = 1.22 [1.04-1.43]; P = 0.013), cardiovascular events (HR = 1.28 [1.16-1.41]; P < 0.0001), and re-intervention (HR = 1.15 [1.06-1.25]; P < 0.0001). After adjustment for Stage 2-3 SVD diagnosis, AVC remained a predictor of overall mortality (HR = 1.20 [1.04-1.39]; P = 0.015) and cardiovascular events (HR = 1.25 [1.09-1.43]; P = 0.001). CONCLUSION: CT scan is a reliable tool to assess BP leaflet calcification. An AVC > 100 AU is tightly associated with SVD and it is a strong predictor of overall mortality and cardiovascular events.

Rates and Predictors of Structural Valve Degeneration and Failure of Trifecta Bioprosthetic Valve Over a 5-year Follow-up Period: A Single-center Experience.

Introduction: The Trifecta bioprosthetic valve has been commonly used for surgical aortic valve replacement (SAVR). Multiple studies have been done to define the rate of structural valve degeneration (SVD) and failure (SVF), but the outcomes are still debatable. Therefore, we aim to conduct this single-center study to estimate the rate and predictors of SVD/SVF. Methodology: This retrospective observational cohort single-center study was conducted between 2014 and 2019 among Trifecta SAVR patients. Data were patient's characteristics collected from electronic medical records at baseline and follow-up (3-5 years). Statistical analysis was performed with a significance level of P ≤ 0.05. Results: A total of 271 eligible patients were identified. Most of our sample were males (57.9%), with a mean age of 71.1 ± 10.6 years. The mean baseline preoperative ejection fraction (EF) was 53.0%, with no change (P = 0.88) in the immediate postoperative EF (53.6%). A most recent follow-up EF revealed a significant increase of EF (55.2%), P = 0.01. Furthermore, there was a significant increase from peak velocity to PVMRE (mean difference [MD] ± standard error of mean (SEM) [0.15 ± 0.04], P < 0.01), an increase in pressure gradient (PGIPE) to PGMRE (MD ± SEM [1.70 ± 0.49], P < 0.01), and a decrease in Doppler velocity index (DVIIPE) to DVIMRE (MD ± SEM [-0.037 ± 0.01], P = 0.01). Regarding the SVF rate, 13 (4.8%) patients had failed valves requiring replacement throughout the study period. Conclusions: Over a 5-year follow-up period, 4.8% had SVF with an SVD of 23.2%, with the majority of SVD not being clinically significant except in six patients. These results corroborate with a previously published study suggesting a bad clinical outcome of Trifecta valve placement.

Genetically engineered sheep: A new paradigm for future preclinical testing of biological heart valves.

BACKGROUND: Heart valve implantation in juvenile sheep to demonstrate biocompatibility and physiologic performance is the accepted model for regulatory approval of new biological heart valves (BHVs). However, this standard model does not detect the immunologic incompatibility between the major xenogeneic antigen, galactose-α-1,3-galactose (Gal), which is present in all current commercial BHVs, and patients who universally produce anti-Gal antibody. This clinical discordance leads to induced anti-Gal antibody in BHV recipients, promoting tissue calcification and premature structural valve degeneration, especially in young patients. The objective of the present study was to develop genetically engineered sheep that, like humans, produce anti-Gal antibody and mirror current clinical immune discordance. METHODS: Guide RNA for CRISPR Cas9 nuclease was transfected into sheep fetal fibroblasts, creating a biallelic frame shift mutation in exon 4 of the ovine α-galactosyltransferase gene (GGTA1). Somatic cell nuclear transfer was performed, and cloned embryos were transferred to synchronized recipients. Cloned offspring were analyzed for expression of Gal antigen and spontaneous production of anti-Gal antibody. RESULTS: Two of 4 surviving sheep survived long-term. One of the 2 was devoid of the Gal antigen (GalKO) and expressed cytotoxic anti-Gal antibody by age 2 to 3 months, which increased to clinically relevant levels by 6 months. CONCLUSIONS: GalKO sheep represent a new, clinically relevant advanced standard for preclinical testing of BHVs (surgical or transcatheter) by accounting for the first time for human immune responses to residual Gal antigen that persists after current BHV tissue processing. This will identify the consequences of immune disparity preclinically and avoid unexpected past clinical sequelae.

Durability of bioprosthetic aortic valve replacement in patients under the age of 60 years - 1-year follow-up from the prospective INDURE registry.

OBJECTIVES: We report 1-year safety and clinical outcomes in patients <60 years undergoing bioprosthetic surgical aortic valve intervention. METHODS: The INSPIRIS RESILIA Durability Registry is a prospective, multicentre registry to assess clinical outcomes of patients <60 years. Patients with planned SAVR with or without concomitant replacement of the ascending aorta and/or coronary bypass surgery were included. Time-related valve safety, haemodynamic performance and quality of life (QoL) at 1 year were assessed. RESULTS: A total of 421 patients were documented with a mean age of 53.5 years, 76.5% being male and 27.2% in NYHA class III/IV. Outcomes within 30 days included cardiovascular-related mortality (0.7%), time-related valve safety (VARC-2; 5.8%), thromboembolic events (1.7%), valve-related life-threatening bleeding (VARC-2; 4.3%) and permanent pacemaker implantation (3.8%). QoL was significantly increased at 6 months and sustained at 1 year. Freedom from all-cause mortality at 1 year was 98.3% (95% confidence interval 97.1; 99.6) and 81.8% were NYHA I versus 21.9% at baseline. No patient developed structural valve deterioration stage 3 (VARC-3). The mean aortic pressure gradient was 12.6 mmHg at 1 year and the effective orifice area was 1.9 cm2. CONCLUSIONS: The 1-year data from the INSPIRIS RESILIA valve demonstrate good safety and excellent haemodynamic performance as well as an early QoL improvement. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT03666741.

Serum lipoprotein(a) and bioprosthetic aortic valve degeneration.

AIMS: Bioprosthetic aortic valve degeneration demonstrates pathological similarities to aortic stenosis. Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for incident aortic stenosis and disease progression. The aim of this study is to investigate whether serum Lp(a) concentrations are associated with bioprosthetic aortic valve degeneration. METHODS AND RESULTS: In a post hoc analysis of a prospective multimodality imaging study (NCT02304276), serum Lp(a) concentrations, echocardiography, contrast-enhanced computed tomography (CT) angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) were assessed in patients with bioprosthetic aortic valves. Patients were also followed up for 2 years with serial echocardiography. Serum Lp(a) concentrations [median 19.9 (8.4-76.4) mg/dL] were available in 97 participants (mean age 75 ± 7 years, 54% men). There were no baseline differences across the tertiles of serum Lp(a) concentrations for disease severity assessed by echocardiography [median peak aortic valve velocity: highest tertile 2.5 (2.3-2.9) m/s vs. lower tertiles 2.7 (2.4-3.0) m/s, P = 0.204], or valve degeneration on CT angiography (highest tertile n = 8 vs. lower tertiles n = 12, P = 0.552) and 18F-NaF PET (median tissue-to-background ratio: highest tertile 1.13 (1.05-1.41) vs. lower tertiles 1.17 (1.06-1.53), P = 0.889]. After 2 years of follow-up, there were no differences in annualized change in bioprosthetic hemodynamic progression [change in peak aortic valve velocity: highest tertile [0.0 (-0.1-0.2) m/s/year vs. lower tertiles 0.1 (0.0-0.2) m/s/year, P = 0.528] or the development of structural valve degeneration. CONCLUSION: Serum lipoprotein(a) concentrations do not appear to be a major determinant or mediator of bioprosthetic aortic valve degeneration.

Comparison of modes of failure and clinical outcomes between explanted porcine and bovine pericardial bioprosthetic valves.

OBJECTIVE: To compare pathological and hemodynamic modes of failure and operative outcomes between explanted porcine and bovine pericardial bioprosthetic valves. METHODS: Patients who underwent explantation of their bioprosthetic valves at Toronto General Hospital from 2007 to 2019 were identified. Retrospective chart review was conducted to attain demographic information, operative outcomes, and echocardiography and pathology reports. RESULTS: A total of 278 patients underwent explantation of their porcine (n=183) or bovine pericardial (n=95) valves. A greater proportion of the porcine group had severe regurgitation, compared to the bovine group (45.3% vs. 19.8%, p<.001). Porcine valves had higher rates of cusp flail (19.4% vs. 3.3%, p<.001). The rates of moderate or worse stenosis were higher among bovine pericardial valves (37.9% vs. 15.8%, p<.001). On pathologic examination, the porcine valves exhibited more cusp tears (67.6% vs. 50.5%, p=.006), while higher incidences of calcification were found in the bovine group (p<.001). Rate of stroke was higher during the explantation procedure of the bovine valves (5.3% vs. 0.5%, p=.040). CONCLUSIONS: The primary mode of failure was regurgitation in porcine valves due to cusp tears and stenosis in bovine valves due to calcification. Establishing a clear understanding of failure modes based on valve material may improve design and guide valve selection at the time of surgery.