Optimization of Enzymatic and Chemical Decellularization of Native Porcine Heart Valves for the Generation of Decellularized Xenografts.

One of the most important medical interventions for individuals with heart valvular disease is heart valve replacement, which is not without substantial challenges, particularly for pediatric patients. Due to their biological properties and biocompatibility, natural tissue-originated scaffolds derived from human or animal sources are one type of scaffold that is widely used in tissue engineering. However, they are known for their high potential for immunogenicity. Being free of cells and genetic material, decellularized xenografts, consequently, have low immunogenicity and, thus, are expected to be tolerated by the recipient's immune system. The scaffold ultrastructure and ECM composition can be affected by cell removal agents. Therefore, applying an appropriate method that preserves intact the structure of the ECM plays a critical role in the final result. So far, there has not been an effective decellularization technique that preserves the integrity of the heart valve's ultrastructure while securing the least amount of genetic material left. This study demonstrates a new protocol with untraceable cells and residual DNA, thereby maximally reducing any chance of immunogenicity. The mechanical and biochemical properties of the ECM resemble those of native heart valves. Results from this study strongly indicate that different critical factors, such as ionic detergent omission, the substitution of Triton X-100 with Tergitol, and using a lower concentration of trypsin and a higher concentration of DNase and RNase, play a significant role in maintaining intact the ultrastructure and function of the ECM.

Tricuspid Regurgitation and TAVR: Outcomes, Risk Factors and Biomarkers.

Background. The significance of concomitant tricuspid regurgitation (TR) in the context of transcatheter aortic valve replacement (TAVR) remains unclear. This study aimed to analyze the severity of TR before and after TAVR with regard to short- and long-term survival and to analyze the influencing factors. Methods. In our retrospective analysis, TR before and after TAVR was examined and patients were classified into groups accordingly. Special attention was paid to patients with post-interventional changes in TR. Mortality after TAVR was considered the primary endpoint of the analysis and major complications according to the Valve Academic Research Consortium 3 (VARC3) were compared. Moreover, biomarkers and risk factors for worsening or improvement of TR through TAVR were analyzed. Results. Among 775 patients who underwent TAVR in our center between January 2009 and December 2019, 686 patients (89%) featured low- and 89 patients (11%) high-grade TR. High-grade pre-TAVR TR was associated with worse short- (30-day), mid- (2-year) and long-term survival up to 8 years. Even though in nearly half of the patients with high-grade TR the regurgitation improved within seven days after TAVR (n = 42/89), this did not result in a survival benefit for this subgroup. On the other hand, a worsening of low-grade TR was seen in more than 10% of the patients (n = 73/686), which was also associated with a worse prognosis. Predictors of worsening of TR after TAVR were adipositas, impaired right ventricular function and the presence of mild TR. Age, atrial fibrillation, COPD, impaired renal function and elevated cardiac biomarkers were risk factors for mortality after TAVR independent from the grade of TR. Conclusions. Not only pre-interventional, but also post-TAVR high-grade TR is associated with a worse prognosis after TAVR. TAVR can change concomitant tricuspid regurgitation, but improvement does not have any impact on short- and long-term survival. Worsening of TR after TAVR is possible and impairs the prognosis.

Impact of Smoking on Coronary Volume-to-Myocardial Mass Ratio: An ADVANCE Registry Substudy.

Purpose To examine the relationship between smoking status and coronary volume-to-myocardial mass ratio (V/M) among individuals with coronary artery disease (CAD) undergoing CT fractional flow reserve (CT-FFR) analysis. Materials and Methods In this secondary analysis, participants from the ADVANCE registry evaluated for suspected CAD from July 15, 2015, to October 20, 2017, who were found to have coronary stenosis of 30% or greater at coronary CT angiography (CCTA) were included if they had known smoking status and underwent CT-FFR and V/M analysis. CCTA images were segmented to calculate coronary volume and myocardial mass. V/M was compared between smoking groups, and predictors of low V/M were determined. Results The sample for analysis included 503 current smokers, 1060 former smokers, and 1311 never-smokers (2874 participants; 1906 male participants). After adjustment for demographic and clinical factors, former smokers had greater coronary volume than never-smokers (former smokers, 3021.7 mm3 ± 934.0 [SD]; never-smokers, 2967.6 mm3 ± 978.0; P = .002), while current smokers had increased myocardial mass compared with never-smokers (current smokers, 127.8 g ± 32.9; never-smokers, 118.0 g ± 32.5; P = .02). However, both current and former smokers had lower V/M than never-smokers (current smokers, 24.1 mm3/g ± 7.9; former smokers, 24.9 mm3/g ± 7.1; never-smokers, 25.8 mm3/g ± 7.4; P < .001 [unadjusted] and P = .002 [unadjusted], respectively). Current smoking status (odds ratio [OR], 0.74 [95% CI: 0.59, 0.93]; P = .009), former smoking status (OR, 0.81 [95% CI: 0.68, 0.97]; P = .02), stenosis of 50% or greater (OR, 0.62 [95% CI: 0.52, 0.74]; P < .001), and diabetes (OR, 0.67 [95% CI: 0.56, 0.82]; P < .001) were independent predictors of low V/M. Conclusion Both current and former smoking status were independently associated with low V/M. Keywords: CT Angiography, Cardiac, Heart, Ischemia/Infarction Clinical trial registration no. NCT02499679 Supplemental material is available for this article. © RSNA, 2024.

Redo-TAVI with the ACURATE neo2 and Prime XL for balloon-expandable transcatheter heart valve failure.

BACKGROUND: There are limited data regarding treatment for failed balloon-expandable transcatheter heart valves (THVs) in redo-transcatheter aortic valve implantation (TAVI). AIMS: We aimed to assess THV performance, neoskirt height and expansion when performing redo-TAVI with the ACURATE platform inside a SAPIEN 3 (S3) compared to redo-TAVI with an S3 in an S3. METHODS: Redo-TAVI was performed on the bench using each available size of the S3, the ACURATE neo2 (ACn2) and the next-generation ACURATE Prime XL (AC XL) implanted at 2 different depths within 20 mm/23 mm/26 mm/29 mm S3s serving as the "failed" index THV. Hydrodynamic testing was performed to assess THV function. Multimodality assessment was performed using photography, X-ray, microcomputed tomography (micro-CT), and high-speed videos. RESULTS: The ACURATE in S3 combinations had favourable hydrodynamic performance compared to the S3 in S3 for all size combinations. In the 20 mm S3, redo-TAVI with the ACn2 had lower gradients compared to the S3 (mean gradient 16.3 mmHg for the ACn2 vs 24.7 mmHg for the 20 mm S3 in 20 mm S3). Pinwheeling was less marked for the ACURATE THVs than for the S3s. On micro-CT, the S3s used for redo-TAVI were underexpanded across all sizes. This was also observed for the ACURATE platform, but to a lesser extent. CONCLUSIONS: Redo-TAVI with an ACn2/AC XL within an S3 has favourable hydrodynamic performance and less pinwheeling compared to an S3 in S3. This comes at the price of a taller neoskirt.

Age- and Sex-Specific Nomographic CT Quantitative Plaque Data From a Large International Cohort.

BACKGROUND: With growing adoption of coronary computed tomographic angiography (CTA), there is increasing evidence for and interest in the prognostic importance of atherosclerotic plaque volume. Manual tools for plaque segmentation are cumbersome, and their routine implementation in clinical practice is limited. OBJECTIVES: The aim of this study was to develop nomographic quantitative plaque values from a large consecutive multicenter cohort using coronary CTA. METHODS: Quantitative assessment of total atherosclerotic plaque and plaque subtype volumes was performed in patients undergoing clinically indicated coronary CTA, using an Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis tool. RESULTS: A total of 11,808 patients were included in the analysis; their mean age was 62.7 ± 12.2 years, and 5,423 (45.9%) were women. The median total plaque volume was 223 mm3 (IQR: 29-614 mm3) and was significantly higher in male participants (360 mm3; IQR: 78-805 mm3) compared with female participants (108 mm3; IQR: 10-388 mm3) (P < 0.0001). Total plaque increased with age in both male and female patients. Younger patients exhibited a higher prevalence of noncalcified plaque. The distribution of total plaque volume and its components was reported in every decile by age group and sex. CONCLUSIONS: The authors developed pragmatic age- and sex-stratified percentile nomograms for atherosclerotic plaque measures using findings from coronary CTA. The impact of age and sex on total plaque and its components should be considered in the risk-benefit analysis when treating patients. Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis work flows could provide context to better interpret coronary computed tomographic angiographic measures and could be integrated into clinical decision making.

Producing and Testing Prototype Tissue-Engineered 3D Tri-Leaflet Valved Stents on Biodegradable Poly-ε-Caprolactone Scaffolds.

Transcatheter pulmonary valve replacement is a minimally-invasive alternative treatment for right ventricular outflow tract dysfunction and has been rapidly evolving over the past years. Heart valve prostheses currently available still have major limitations. Therefore, one of the significant challenges for the future is the roll out of transcatheter tissue engineered pulmonary valve replacement to more patients. In the present study, biodegradable poly-ε-caprolactone (PCL) nanofiber scaffolds in the form of a 3D leaflet matrix were successfully seeded with human endothelial colony-forming cells (ECFCs), human induced pluripotent stem cell-derived MSCs (hMSCs), and porcine MSCs (pMSCs) for three weeks for the generation of 3D tissue-engineered tri-leaflet valved stent grafts. The cell adhesion, proliferation, and distribution of these 3D heart leaflets was analyzed using fluorescence microscopy and scanning electron microscopy (SEM). All cell lineages were able to increase the overgrown leaflet area within the three-week timeframe. While hMSCs showed a consistent growth rate over the course of three weeks, ECFSs showed almost no increase between days 7 and 14 until a growth spurt appeared between days 14 and 21. More than 90% of heart valve leaflets were covered with cells after the full three-week culturing cycle in nearly all leaflet areas, regardless of which cell type was used. This study shows that seeded biodegradable PCL nanofiber scaffolds incorporated in nitinol or biodegradable stents will offer a new therapeutic option in the future.

Impact of Coronary CT Angiography-derived Fractional Flow Reserve on Downstream Management and Clinical Outcomes in Individuals with and without Diabetes.

Purpose: To compare the clinical use of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) in individuals with and without diabetes mellitus (DM). Materials and Methods: This secondary analysis included participants (enrolled July 2015 to October 2017) from the prospective, multicenter, international The Assessing Diagnostic Value of Noninvasive CT-FFR in Coronary Care (ADVANCE) registry (ClinicalTrials.gov identifier, NCT02499679) who were evaluated for suspected coronary artery disease (CAD), with one or more coronary stenosis ≥30% on CCTA images, using CT-FFR. CCTA and CT-FFR findings, treatment strategies at 90 days, and clinical outcomes at 1-year follow-up were compared in participants with and without DM. Results: The study included 4290 participants (mean age, 66 years ± 10 [SD]; 66% male participants; 22% participants with DM). Participants with DM had more obstructive CAD (one or more coronary stenosis ≥50%; 78.8% vs 70.6%, P < .001), multivessel CAD (three-vessel obstructive CAD; 18.9% vs 11.2%, P < .001), and proportionally more vessels with CT-FFR ≤ 0.8 (74.3% vs 64.6%, P < .001). Treatment reclassification by CT-FFR occurred in two-thirds of participants which was consistent regardless of the presence of DM. There was a similar graded increase in coronary revascularization with declining CT-FFR in both groups. At 1 year, presence of DM was associated with higher rates of major adverse cardiovascular events (hazard ratio, 2.2; 95% CI: 1.2, 4.1; P = .01). However, no between group differences were observed when stratified by stenosis severity (<50% or ≥50%) or CT-FFR positivity. Conclusion: Both anatomic CCTA findings and CT-FFR demonstrated a more complex pattern of CAD in participants with versus without DM. Rates of treatment reclassification were similar regardless of the presence of DM, and DM was not an adverse prognostic indicator when adjusted for diameter stenosis and CT-FFR.Clinical trial registration no. NCT 02499679Keywords: Fractional Flow Reserve, CT Angiography, Diabetes Mellitus, Coronary Artery Disease Supplemental material is available for this article. See also the commentary by Ghoshhajra in this issue.© RSNA, 2023.

Case Report: Stretching the limits-late valvuloplasty for THV dysfunction following redo mitral valve-in-valve implantation.

Late balloon valvuloplasty can be used to treat under-expansion-related transcatheter heart valve (THV) dysfunction. Whether this can be performed following redo-THV implantation is unknown. Herein, we report a case of a 72-year-old male presenting with symptomatic gradient elevation following redo mitral valve-in-valve implantation. The patient was successfully treated with late balloon valvuloplasty with gradient improvement. In conclusion, late valvuloplasty is effective even with several layers of valves. However, larger studies are required to clarify the role of this approach further.

Restoration of flow in the aorta: a novel therapeutic target in aortic valve intervention.

Aortic blood flow patterns are closely linked to the morphology and function of the left ventricle, aortic valve and aorta. These flow patterns demonstrate the exceptional adaptability of the cardiovascular system to maintain blood circulation under a broad range of haemodynamic workloads and can be altered in various pathophysiological states. For instance, normal ascending aortic systolic flow is predominantly laminar, whereas abnormal aortic systolic flow is associated with increased eccentricity, vorticity and flow reversal. These flow abnormalities result in reduced aortic conduit function and increased energy loss in the cardiovascular system. Emerging evidence details the association of these flow patterns with loss of aortic compliance, which leads to adverse left ventricular remodelling, poor tissue perfusion, and an increased risk of morbidity and death. In this Perspective article, we review the evidence for the link between aortic flow-related abnormalities and cardiovascular disease and how these changes in aortic flow patterns are emerging as a therapeutic target for aortic valve intervention in first-in-human studies.

TAVR in TAVR: Where Are We in 2023 for Management of Failed TAVR Valves?

PURPOSE OF REVIEW: As TAVR is increasingly performed on younger patients with a longer life expectancy, the number of redo-TAVR procedures is likely to increase in the coming years. Limited data is currently available on this sometimes challenging procedure. We provide a summary of currently published literature on management of patients with a failed transcatheter aortic valve. RECENT FINDINGS: Recent registry data have increased the clinical knowledge on redo-TAVR. Additionally, numerous bench studies have provided valuable insights into the technical aspects of redo-TAVR with various combinations of valve types. Redo-TAVR can be performed safely in selected cases with a high procedural success and good short-term outcomes. However, at present, the procedure remains relatively infrequent and many patients are not eligible. Bench testing can be useful to understand important concepts such as valve expansion, neoskirt, leaflet overhang, and leaflet deflection as well as their potential clinical implications.

Transcatheter Aortic Valve Implantation by Intercostal Access: Initial Experience with a No-Touch Technique.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is now a well-established therapeutic option in an elderly high-risk patient cohort with aortic valve disease. Although most commonly performed via a transfemoral route, alternative approaches for TAVI are constantly being improved. Instead of the classical mini-sternotomy, it is possible to achieve a transaortic access via a right anterior mini-thoracotomy in the second intercostal space. We describe our experience with this sternum- and rib-sparing technique in comparison to the classical transaortic approach. METHODS: Our retrospective study includes 173 patients who were treated in our institution between January 2017 and April 2020 with transaortic TAVI via either upper mini-sternotomy or intercostal thoracotomy. The primary endpoint was 30-day mortality, and secondary endpoints were defined as major postoperative complications that included admission to the intensive care unit and overall hospital stay, according to the Valve Academic Research Consortium 3. RESULTS: Eighty-two patients were treated with TAo-TAVI by upper mini-sternotomy, while 91 patients received the intercostal approach. Both groups were comparable in age (mean age: 82 years) and in the proportion of female patients. The intercostal group had a higher rate of peripheral artery disease (41% vs. 22%, p = 0.008) and coronary artery disease (71% vs. 40%, p < 0.001) with a history of percutaneous coronary intervention or coronary artery bypass grafting, resulting in significantly higher preinterventional risk evaluation (EuroScore II 8% in the intercostal vs. 4% in the TAo group, p = 0.005). Successful device implantation and a reduction of the transvalvular gradient were achieved in all cases with a significantly lower rate of trace to mild paravalvular leakage in the intercostal group (12% vs. 33%, p < 0.001). The intercostal group required significantly fewer blood transfusions (0 vs. 2 units, p = 0.001) and tended to require less reoperation (7% vs. 15%, p = 0.084). Hospital stays (9 vs. 12 d, p = 0.011) were also shorter in the intercostal group. Short- and long-term survival in the follow-up showed comparable results between the two approaches (30-day, 6-month- and 2-year mortality: 7%, 23% and 36% in the intercostal vs. 9%, 26% and 33% in the TAo group) with acute kidney injury (AKI) and reintubation being independent risk factors for mortality. CONCLUSIONS: Transaortic TAVI via an intercostal access offers a safe and effective treatment of aortic valve stenosis.

Redo-TAVI with SAPIEN 3 in SAPIEN XT or SAPIEN 3 - impact of pre- and post-dilatation on final THV expansion.

BACKGROUND: When a balloon-expandable transcatheter heart valve (THV) is chosen to treat a failed balloon-expandable THV, there is a risk of underexpansion with a potential impact on performance. AIMS: We aimed to assess the impact of pre- and post-dilatation on the expansion of balloon-expandable THVs after redo-transcatheter aortic valve implantation (TAVI). METHODS: Redo-TAVI was performed on the bench with a 23 mm SAPIEN 3 (S3) implanted within a 23 mm SAPIEN XT (SXT) or a 23 mm S3, both of which served as the "failed" THVs. Pre- and/or post-dilatation was performed using a 23 mm non-compliant TRUE balloon. Expansion of the index and redo-THVs were assessed before and after pre-/post-dilatation using microcomputed tomography (micro-CT), and THV hydrodynamic testing was conducted. RESULTS: Without pre- or post-dilatation, the S3 was underexpanded, for all combinations, particularly in the mid-portion of the THV (18.6 mm and 19.7 mm representing 81% and 86% of the nominal diameter inside the SXT and S3, respectively). Pre- and post-dilatation had an additive effect on diameter expansion of the redo-THV, which remained constrained in most combinations. The only combination to achieve nominal expansion was the S3 in S3 when both pre- and post-dilatation were performed. The S3 remained underexpanded inside the SXT despite pre- and post-dilatation (93% in the mid-portion). Improved redo-THV expansion was accompanied by 2.7 mm (12%) overexpansion of the index THV. While all samples had acceptable hydrodynamic performance, the underexpanded samples had worse leaflet pinwheeling. CONCLUSIONS: When performing redo-TAVI with a 23 mm S3 inside a 23 mm SXT or S3, only the S3 in S3 with the use of pre- and post-dilatation reached full expansion. This underlines the importance of CT assessment of THV expansion and the role of pre-/post-dilatation.

Predicted vs Observed Valve to Coronary Distance in Valve-in-Valve TAVR: A Computed Tomography Study.

BACKGROUND: Preprocedural computed tomography (CT) workup with assessment of virtual transcatheter heart valve-to-coronary ostia (VTC) distance and transcatheter heart valve-to-sinus (VTS) distances is recommended to assess the risk of coronary obstruction following valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR). OBJECTIVES: The authors sought to investigate the agreement of predicted VTC and VTS distances and observed post-TAVR anatomy on CT and their relationship with transcatheter heart valve (THV) expansion and deployment conditions. METHODS: Fifty-one patients who underwent a balloon-expandable ViV procedure were included in this study. The expansion of the THV stent frame was evaluated at 4 levels: THV inflow, surgical heart valve (SHV) sewing ring, SHV outflow, and THV outflow. Assessment of the VTC/VTS distances was performed on the pre-TAVR CT, and THV-to-coronary ostia and THV-to-sinus distances were assessed on the post-TAVR CT. RESULTS: Following the ViV procedure, the THV stent frame flared toward the outflow but was generally underexpanded at all levels, particularly at the SHV sewing ring level. Postdilatation impacted the extent of THV expansion, resulting in greater expansion than nominal balloon filling at all 4 THV levels (P < 0.001). Observed THV-to-coronary ostia distances were systematically larger than predicted by the VTC distance (mean difference 1.25 ±1.28 mm) in patients with nominal balloon filling but systematically smaller in case of postdilatation (mean difference -0.45 ± 0.52 mm). A similar relationship was observed between VTS and THV-to-sinus distance measurements. CONCLUSIONS: With nominal balloon filling, VTC and VTS distances underestimate postprocedural distances due to THV frame underexpansion. However, postdilatation may lead to distances smaller than predicted due to THV overexpansion at the outflow level.

Bioprosthetic Valve Remodeling in Nonfracturable Surgical Valves: Impact on THV Expansion and Hydrodynamic Performance.

BACKGROUND: There are limited data on the effect of bioprosthetic valve remodeling (BVR) on transcatheter heart valve (THV) expansion and function following valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) in a nonfracturable surgical heart valve (SHV). OBJECTIVES: This study sought to assess the impact of BVR of nonfracturable SHVs on THVs after VIV implantation. METHODS: VIV TAVR was performed using 23-mm SAPIEN3 (S3, Edwards Lifesciences) or 23/26-mm Evolut Pro (Medtronic) THVs implanted in 21/23-mm Trifecta (Abbott Structural Heart) and 21/23-mm Hancock (Medtronic) SHVs with BVR performed with a noncompliant TRUE balloon (Bard Peripheral Vascular Inc). Hydrodynamic assessment was performed, and multimodality imaging including micro-computed tomography was performed before and after BVR to assess THV and SHV expansion. RESULTS: BVR resulted in limited improvement of THV expansion. The largest gain in expansion was observed for the S3 in the 21-mm Trifecta with up to a 12.7% increase in expansion at the outflow of the valve. Minimal change was observed at the level of the sewing ring. The Hancock was less amenable to BVR with lower final expansion dimensions than the Trifecta. BVR also resulted in notable surgical post flaring of up to 17.6°, which was generally more marked with the S3 than with the Evolut Pro. Finally, BVR resulted in very limited improvement in hydrodynamic function. Severe pinwheeling was observed with the S3, which improved slightly but persisted despite BVR. CONCLUSIONS: When performing VIV TAVR inside a Trifecta and Hancock SHV, BVR had a limited impact on THV expansion and resulted in SHV post flaring with unknown consequences on coronary obstruction risk and long-term THV function.