Impact of left ventricular outflow tract calcium on valve geometry in self-expanding transcatheter aortic-valve replacement.

OBJECTIVES: Evaluate transcatheter heart valve (THV) geometry according to left ventricular outflow tract (LVOT) calcium degree and its impact on hemodynamics and outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) with a contemporary self-expanding THV. BACKGROUND: LVOT calcium remains challenging for contemporary THVs. LVOT calcium location and degree may affect THV deployment and impact flow patterns and shear stress, accelerating THV degeneration. METHODS: EPROMPT (CoreValve Evolut Pro Prospective Registry; NCT03423459) is a prospective, investigator-initiated, multicenter registry of patients undergoing TAVR using CoreValve Evolut PRO/PRO + THVs. A total of 107 patients were enrolled in EPROMPT's computed tomography (CT) cohort between January 2018 and October 2021. These patients underwent follow-up CT scan 30 days post-TAVR. We analyzed THV geometry and its interaction with the aortic root following deployment using 30-day post-TAVR CT in patients with none/mild versus moderate/severe LVOT calcium. RESULTS: Thirty-day THV inflows were less eccentric in the short axis in patients with none/mild versus moderate/severe LVOT calcium (1.16 ± 0.09 vs. 1.21 ± 0.12; p = 0.007). THV became more circular and was similar between both cohorts at the THV waist (1.08 ± 0.06 vs. 1.09 ± 0.11; p = 0.551), leaflet tips (1.03 ± 0.04 vs. 1.05 ± 0.09; p = 0.299), and THV outflow (1.04 ± 2.2 vs. 1.03 ± 2.7; p = 0.143). Thirty-day > mild paravalvular leak was low in both cohorts (1.5% vs. 2.4%; p = 0.724); mean gradients were similar (7.7 ± 3.6 vs. 7.7 ± 3.4 mmHg; p = 0.955). CONCLUSIONS: Despite inflow deformities observed in patients with moderate/severe LVOT calcium, Evolut PRO/PRO + conforms to elliptical aortic annuli, maintaining circularity and proper function at the leaflets and outflow, even in patients with moderate/severe LVOT calcium.

Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb.

BACKGROUND: Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion. METHODS: Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 µL injection of saline (n = 9) or 6 µg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 µg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers. RESULTS: Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03). CONCLUSIONS: Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.

Isolation and trans-differentiation of mesenchymal stromal cells into smooth muscle cells: Utility and applicability for cell-sheet engineering.

BACKGROUND: Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) have shown potential to differentiate into various cell types, including smooth muscle cells (SMCs). The extracellular matrix (ECM) represents an appealing and readily available source of SMCs for use in tissue engineering. In this study, we hypothesized that the ECM could be used to induce MSC differentiation to SMCs for engineered cell-sheet construction. METHODS: Primary MSCs were isolated from the BM of Wistar rats, transferred and cultured on dishes coated with 3 different types of ECM: collagen type IV (Col IV), fibronectin (FN), and laminin (LM). Primary MSCs were also included as a control. The proportions of SMC (a smooth muscle actin [aSMA] and SM22a) and MSC markers were examined with flow cytometry and Western blotting, and cell proliferation rates were also quantified. RESULTS: Both FN and LM groups were able to induce differentiation of MSCs toward smooth muscle-like cell types, as evidenced by an increase in the proportion of SMC markers (aSMA; Col IV 42.3 ± 6.9%, FN 65.1 ± 6.5%, LM 59.3 ± 7.0%, Control 39.9 ± 3.1%; P = 0.02, SM22; Col IV 56.0 ± 7.7%, FN 74.2 ± 6.7%, LM 60.4 ± 8.7%, Control 44.9 ± 3.6%) and a decrease in that of MSC markers (CD105: Col IV 64.0 ± 5.2%, FN 57.6 ± 4.0%, LM 60.3 ± 7.0%, Control 85.3 ± 4.2%; P = 0.03). The LM group showed a decrease in overall cell proliferation, whereas FN and Col IV groups remained similar to control MSCs (Col IV, 9.0 ± 2.3%; FN, 9.8 ± 2.5%; LM, 4.3 ± 1.3%; Control, 9.8 ± 2.8%). CONCLUSIONS: Our findings indicate that ECM selection can guide differentiation of MSCs into the SMC lineage. Fibronectin preserved cellular proliferative capacity while yielding the highest proportion of differentiated SMCs, suggesting that FN-coated materials may be facilitate smooth muscle tissue engineering.

Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.

RATIONALE: After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. OBJECTIVE: To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. METHODS AND RESULTS: Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). CONCLUSIONS: The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

Protein Corona Influences Cell-Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds.

Biomaterials are extensively used to restore damaged tissues, in the forms of implants (e.g. tissue engineered scaffolds) or biomedical devices (e.g. pacemakers). Once in contact with the physiological environment, nanostructured biomaterials undergo modifications as a result of endogenous proteins binding to their surface. The formation of this macromolecular coating complex, known as 'protein corona', onto the surface of nanoparticles and its effect on cell-particle interactions are currently under intense investigation. In striking contrast, protein corona constructs within nanostructured porous tissue engineering scaffolds remain poorly characterized. As organismal systems are highly dynamic, it is conceivable that the formation of distinct protein corona on implanted scaffolds might itself modulate cell-extracellular matrix interactions. Here, we report that corona complexes formed onto the fibrils of engineered collagen scaffolds display specific, distinct, and reproducible compositions that are a signature of the tissue microenvironment as well as being indicative of the subject's health condition. Protein corona formed on collagen matrices modulated cellular secretome in a context-specific manner ex-vivo, demonstrating their role in regulating scaffold-cellular interactions. Together, these findings underscore the importance of custom-designing personalized nanostructured biomaterials, according to the biological milieu and disease state. We propose the use of protein corona as in situ biosensor of temporal and local biomarkers.

Normalization of postinfarct biomechanics using a novel tissue-engineered angiogenic construct.

BACKGROUND: Cell-mediated angiogenic therapy for ischemic heart disease has had disappointing results. The lack of clinical translatability may be secondary to cell death and systemic dispersion with cell injection. We propose a novel tissue-engineered therapy, whereby extracellular matrix scaffold seeded with endothelial progenitor cells (EPCs) can overcome these limitations using an environment in which the cells can thrive, enabling an insult-free myocardial cell delivery to normalize myocardial biomechanics. METHODS AND RESULTS: EPCs were isolated from the long bones of Wistar rat bone marrow. The cells were cultured for 7 days in media or seeded at a density of 5 × 10(6) cells/cm(2) on a collagen/vitronectin matrix. Seeded EPCs underwent ex vivo modification with stromal cell-derived factor-1α (100 ng/mL) to potentiate angiogenic properties and enhance paracrine qualities before construct formation. Scanning electron microscopy and confocal imaging confirmed EPC-matrix adhesion. In vitro vasculogenic potential was assessed by quantifying EPC cell migration and vascular differentiation. There was a marked increase in vasculogenesis in vitro as measured by angiogenesis assay (8 versus 0 vessels/hpf; P=0.004). The construct was then implanted onto ischemic myocardium in a rat model of acute myocardial infarction. Confocal microscopy demonstrated a significant migration of EPCs from the construct to the myocardium, suggesting a direct angiogenic effect. Myocardial biomechanical properties were uniaxially quantified by elastic modulus at 5% to 20% strain. Myocardial elasticity normalized after implant of our tissue-engineered construct (239 kPa versus normal=193, P=0.1; versus infarct=304 kPa, P=0.01). CONCLUSIONS: We demonstrate restoration and normalization of post-myocardial infarction ventricular biomechanics after therapy with an angiogenic tissue-engineered EPC construct.

Spatially oriented, temporally sequential smooth muscle cell-endothelial progenitor cell bi-level cell sheet neovascularizes ischemic myocardium.

BACKGROUND: Endothelial progenitor cells (EPCs) possess robust therapeutic angiogenic potential, yet may be limited in the capacity to develop into fully mature vasculature. This problem might be exacerbated by the absence of a neovascular foundation, namely pericytes, with simple EPC injection. We hypothesized that coculturing EPCs with smooth muscle cells (SMCs), components of the surrounding vascular wall, in a cell sheet will mimic the native spatial orientation and interaction between EPCs and SMCs to create a supratherapeutic angiogenic construct in a model of ischemic cardiomyopathy. METHODS AND RESULTS: Primary EPCs and SMCs were isolated from Wistar rats. Confluent SMCs topped with confluent EPCs were spontaneously detached from the Upcell dish to create an SMC-EPC bi-level cell sheet. A rodent ischemic cardiomyopathy model was created by ligating the left anterior descending coronary artery. Rats were then immediately divided into 3 groups: cell-sheet transplantation (n=14), cell injection (n=12), and no treatment (n=13). Cocultured EPCs and SMCs stimulated an abundant release of multiple cytokines in vitro. Increased capillary density and improved blood perfusion in the borderzone elucidated the significant in vivo angiogenic potential of this technology. Most interestingly, however, cell fate-tracking experiments demonstrated that the cell-sheet EPCs and SMCs directly migrated into the myocardium and differentiated into elements of newly formed functional vasculature. The robust angiogenic effect of this cell sheet translated to enhanced ventricular function as demonstrated by echocardiography. CONCLUSIONS: Spatially arranged EPC-SMC bi-level cell-sheet technology facilitated the natural interaction between EPCs and SMCs, thereby creating structurally mature, functional microvasculature in a rodent ischemic cardiomyopathy model, leading to improved myocardial function.

Sustained release of engineered stromal cell-derived factor 1-α from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction.

BACKGROUND: Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction. METHODS AND RESULTS: Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls. CONCLUSIONS: We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

Bioengineered stromal cell-derived factor-1α analogue delivered as an angiogenic therapy significantly restores viscoelastic material properties of infarcted cardiac muscle.

Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

The impact of cusp overlap on permanent pacemaker requirement following self-expanding transcatheter aortic valve replacement.

BACKGROUND/PURPOSE: The cusp overlap technique has standardized implantation for self-expanding valves with the goal of achieving more consistent implantation depths and lowering permanent pacemaker (PPM) implantation rates. We retrospectively compared short-term outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) with a self-expanding valve implanted using the cusp overlap technique vs. the traditional coplanar technique in a large tertiary referral center. METHODS: We conducted a retrospective study among PPM-naïve patients who underwent TAVR using the CoreValve Evolut PRO/PRO+. We compared in-hospital PPM rates in patients who underwent TAVR using the cusp overlap technique vs. the coplanar technique. Additional outcomes included in-hospital all-cause mortality, stroke, major vascular complications, annular rupture, and >mild paravalvular leak. Furthermore, we compared outcomes over time to see whether there was evidence of a learning curve. RESULTS: Of the 528 patients included, 270 underwent TAVR using the coplanar technique and 258 underwent TAVR using the cusp overlap technique. The rate of new PPM implantation did not differ between cohorts (17.0 % vs. 16.7 %; p = 0.910). Additionally, rates of in-hospital all-cause mortality (0.0 % vs. 0.4 %; p = 0.328), stroke (3.7 % vs. 1.6 %; p = 0.124), major vascular complications (0.7 % vs. 1.2 %; p = 0.617), annular rupture (0.4 % vs. 0.0 %; p = 0.328) and >mild paravalvular leak (0.0 % vs. 0.4 %; p = 0.444) were similar. Our secondary analysis did not identify any evidence of a learning curve. CONCLUSIONS: The cusp overlap technique may not yield a reduction in PPM rates when compared with the coplanar technique. Other confounders should be explored to further minimize in-hospital PPM rates.

Continuous flow left ventricular assist device implant significantly improves pulmonary hypertension, right ventricular contractility, and tricuspid valve competence.

BACKGROUND: Continuous flow left ventricular assist devices (CF LVAD) are being implanted with increasing frequency for end-stage heart failure. At the time of LVAD implant, a large proportion of patients have pulmonary hypertension, right ventricular (RV) dysfunction, and tricuspid regurgitation (TR). RV dysfunction and TR can exacerbate renal dysfunction, hepatic dysfunction, coagulopathy, edema, and even prohibit isolated LVAD implant. Repairing TR mandates increased cardiopulmonary bypass time and bicaval cannulation, which should be reserved for the time of orthotopic heart transplantation. We hypothesized that CF LVAD implant would improve pulmonary artery pressures, enhance RV function, and minimize TR, obviating need for surgical tricuspid repair. METHODS: One hundred fourteen continuous flow LVADs implanted from 2005 through 2011 at a single center, with medical management of functional TR, were retrospectively analyzed. Pulmonary artery pressures were measured immediately prior to and following LVAD implant. RV function and TR were graded according to standard echocardiographic criteria, prior to, immediately following, and long-term following LVAD. RESULTS: There was a significant improvement in post-VAD mean pulmonary arterial pressures (26.6 ± 4.9 vs. 30.2 ± 7.4 mmHg, p = 0.008) with equivalent loading pressures (CVP = 12.0 ± 4.0 vs. 12.1 ± 5.1 p = NS). RV function significantly improved, as noted by right ventricular stroke work index (7.04 ± 2.60 vs. 6.05 ± 2.54, p = 0.02). There was an immediate improvement in TR grade and RV function following LVAD implant, which was sustained long term. CONCLUSION: Continuous flow LVAD implant improves pulmonary hypertension, RV function, and tricuspid regurgitation. TR may be managed nonoperatively during CF LVAD implant.

Rare case of infective endocarditis from invasive aspergillosis encasing the pulmonary valve: a case report.

Background: Aspergillus endocarditis is a rare cause of infective endocarditis and requires high index of suspicion for diagnosis. Case summary: We describe a case of a 50-year-old man with history of metastatic thymoma on immunosuppression (gemcitabine and capecitabine) who presented with progressive dyspnoea. Echocardiography and computed tomography (CT) of chest showed filling defect in the pulmonary artery. The initial differential diagnosis was of pulmonary embolism and metastatic disease. The mass was subsequently excised, which revealed a diagnosis of Aspergillus endocarditis of the pulmonary valve. Unfortunately, he passed away despite medical treatment with antifungal therapy after surgery. Discussion: Aspergillus endocarditis should be suspected in immunosuppressed hosts with negative blood cultures and large vegetations on echocardiography. Diagnosis is made by tissue histology but may be difficult or delayed. Optimal treatment involves aggressive surgical debridement and prolonged antifungal therapy; prognosis is poor with high mortality.

Management of Mechanical Prosthetic Heart Valve Thrombosis: JACC Review Topic of the Week.

Mechanical prosthetic heart valves, though more durable than bioprostheses, are more thrombogenic and require lifelong anticoagulation. Mechanical valve dysfunction can be caused by 4 main phenomena: 1) thrombosis; 2) fibrotic pannus ingrowth; 3) degeneration; and 4) endocarditis. Mechanical valve thrombosis (MVT) is a known complication with clinical presentation ranging from incidental imaging finding to cardiogenic shock. Thus, a high index of suspicion and expedited evaluation are essential. Multimodality imaging, including echocardiography, cine-fluoroscopy, and computed tomography, is commonly used to diagnose MVT and follow treatment response. Although surgery is oftentimes required for obstructive MVT, other guideline-recommended therapies include parenteral anticoagulation and thrombolysis. Transcatheter manipulation of stuck mechanical valve leaflet is another treatment option for those with contraindications to thrombolytic therapy or prohibitive surgical risk or as a bridge to surgery. The optimal strategy depends on degree of valve obstruction and the patient's comorbidities and hemodynamic status on presentation.

TAVR in 2023: Who Should Not Get It?

Since the first transcatheter delivery of an aortic valve prosthesis was performed by Cribier et al in 2002, the picture of aortic stenosis (AS) therapeutics has changed dramatically. Initiated from an indication of inoperable to high surgical risk, extending to intermediate and low risk, transcatheter aortic valve replacement (TAVR) is now an approved treatment for patients with severe, symptomatic AS across all the risk categories. The current evidence supports TAVR as a frontline therapy for treating severe AS. The crucial question remains concerning the subset of patients who still are not ideal candidates for TAVR because of certain inherent anatomic, nonmodifiable, and procedure-specific factors. Therefore, in this study, we focus on these scenarios and reasons for referring selected patients for surgical aortic valve replacement in 2023.

Coronary Artery Bypass at a Drug-Eluting Resorbable Magnesium Scaffold Site in a Porcine Model.

BACKGROUND/PURPOSE: Coronary artery bypass graft (CABG) in the presence of metallic permanent stents may be challenging. We explored the feasibility of performing CABG in 1-year Magmaris resorbable scaffold implants in healthy Yucatan pigs. METHODS/MATERIALS: One animal received Magmaris 3.0 × 20.0-mm scaffolds in the left anterior descending (LAD), left circumflex (LCx), and right coronary arteries (RCA) under fluoroscopy. After 376 days, the animal underwent off-pump CABG at the scaffold site, including a single "end-to-side" anastomosis involving the right internal mammary artery (RIMA) to the LAD. The LAD was grafted in the territory of the previous scaffold as demonstrated by angiogram and the D1 and D2 landmarks. RESULTS: Digital radiography of the intact heart showed all degraded scaffolds widely expanded and uniformly positioned in the vessel wall in their expected locations. The proximal and distal radiopaque markers were clearly visible. The anastomosis was clearly identified by titanium branch clips, and the RIMA bypass was surrounded by connective tissue, which was further dissected before micro-computed tomography (CT) imaging. On the micro-CT images, calcification of the device was rare. The anastomosis site appeared intact, and the LAD at treatment site was widely open. CONCLUSIONS: Our limited early feasibility study in a healthy animal demonstrates the practicality of CABG in a Magmaris scaffold after 1 year despite the persistence of visible degradation product, suggesting that the prior coronary device implant does not preclude future coronary surgery.

Stromal cell-derived factor-1alpha activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis.

BACKGROUND: Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPCs) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1α (SDF), known to be the most potent EPC chemokine. We hypothesized that implantation of a tissue-engineered extracellular matrix (ECM) scaffold seeded with EPCs primed with SDF could induce borderzone neovasculogenesis, prevent adverse geometric remodeling, and preserve ventricular function after myocardial infarction. METHODS AND RESULTS: Lewis rats (n=82) underwent left anterior descending artery ligation to induce myocardial infarction. EPCs were isolated, characterized, and cultured on a vitronectin/collagen scaffold and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular wall, which included the region of ischemia. Control animals received sutures but no EPCM. Additional groups underwent application of the ECM alone, ECM primed with SDF (ECM+SDF), and ECM seeded with EPCs but not primed with SDF (ECM+SDF). At 4 weeks, borderzone myocardial tissue demonstrated increased levels of vascular endothelial growth factor in the EPCM group. When compared to controls, Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 versus 6.2 vessels/high-powered field; P<0.001), and microvascular perfusion measured by lectin microangiography was enhanced 4-fold (0.7% versus 2.7% vessel volume/section volume; P=0.04). Comparisons to additional groups also showed a significantly improved vasculogenic response in the EPCM group. Ventricular geometry and scar fraction assessed by digital planimetric analysis of sectioned hearts exhibited significantly preserved left ventricular internal diameter (9.7 mm versus 8.6 mm; P=0.005) and decreased infarct scar formation expressed as percent of total section area (16% versus 7%; P=0.002) when compared with all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure-volume conductance, and Doppler flow. CONCLUSIONS: Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction.

Single-Center Experience With the LOTUS Edge Transcatheter Heart Valve.

BACKGROUND: Before its voluntary recall, the mechanically expandable LOTUS Edge transcatheter heart valve (THV) offered a number of unique features, notably sealing against paravalvular leak (PVL) and the ability to be fully deployed, re-captured, and re-deployed. METHODS: We performed a detailed review of all patients at our institution who underwent transcatheter aortic valve replacement (TAVR) using the LOTUS Edge THV from 2019 to 2020. We describe procedural and in-hospital outcomes. RESULTS: In brief, 59 patients underwent TAVR using the LOTUS Edge, of whom 18 were high-risk (most of whom had moderate or severe left ventricular outflow tract [LVOT] calcium), 36 were intermediate-risk enrolled in the REPRISE IV trial (one of whom had a bicuspid valve), and 5 were low-risk bicuspid patients enrolled in the LRT trial. Conduction disturbances were common (new left bundle branch block in 64.4%), with high rates of new permanent pacemaker (PPM) implantation across all risk groups (16.9%). Overall, stroke occurred in 11.9% of patients, and in 3/5 low-risk bicuspid patients, but occurred less frequently in patients with cerebral embolic protection. CONCLUSIONS: In our experience, in patients with heavy LVOT calcium burden and/or bicuspid valves, the LOTUS Edge THV offered excellent seal against PVL. However, the high rates of periprocedural stroke and new PPM implantation were a concern.

Transcatheter Versus Surgical Aortic Valve Replacement in Young, Low-Risk Patients With Severe Aortic Stenosis.

Transcatheter aortic valve replacement (TAVR) is approved for all patient risk profiles and is an option for all patients irrespective of age. However, patients enrolled in the low- and intermediate-risk trials were in their 70s, and those in the high-risk trials were in their 80s. TAVR has never been systematically tested in young (<65 years), low-risk patients. Unanswered questions remain, including the safety and effectiveness of TAVR in patients with bicuspid aortic valves; future coronary access; durability of transcatheter heart valves; technical considerations for surgical transcatheter heart valve explantation; management of concomitant conditions such as aortopathy, mitral valve disease, and coronary artery disease; and the safety and feasibility of future TAVR-in-TAVR. The authors predict that balancing these questions with patients' clear preference for less invasive treatment will become common. In this paper, the authors consider each of these questions and discuss risks and benefits of theoretical treatment strategies in the lifetime management of young patients with severe aortic stenosis.

Preventing Coronary Obstruction During Transcatheter Aortic Valve Replacement: Results From the Multicenter International BASILICA Registry.

OBJECTIVES: This study sought to determine the safety of the BASILICA (bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction) procedure. BACKGROUND: Transcatheter aortic valve replacement causes coronary artery obstruction in 0.7% of cases, with 40% to 50% mortality. BASILICA is a procedure to prevent coronary obstruction. Safety and feasibility in a large patient cohort is lacking. METHODS: The international BASILICA registry was a retrospective, multicenter, real-world registry of patients at risk of coronary artery obstruction undergoing BASILICA and transcatheter aortic valve replacement. Valve Academic Research Consortium-2 definitions were used to adjudicate events. RESULTS: Between June 2017 and December 2020, 214 patients were included from 25 centers in North America and Europe; 72.8% had bioprosthetic aortic valves and 78.5% underwent solo BASILICA. Leaflet traversal was successful in 94.9% and leaflet laceration in 94.4%. Partial or complete coronary artery obstruction was seen in 4.7%. Procedure success, defined as successful BASILICA traversal and laceration without mortality, coronary obstruction, or emergency intervention, was achieved in 86.9%. Thirty-day mortality was 2.8% and stroke was 2.8%, with 0.5% disabling stroke. Thirty-day death and disabling stroke were seen in 3.4%. Valve Academic Research Consortium-2 composite safety was achieved in 82.8%. One-year survival was 83.9%. Outcomes were similar between solo and doppio BASILICA, between native and bioprosthetic valves, and with the use of cerebral embolic protection. CONCLUSIONS: BASILICA is safe, with low reported rates of stroke and death. BASILICA is feasible in the real-world setting, with a high procedure success rate and low rates of coronary artery obstruction.

Acute myocardial rescue with endogenous endothelial progenitor cell therapy.

PURPOSE: Post-myocardial infarction heart failure is a major health concern with limited therapy. Molecular revascularisation utilising granulocyte-macrophage colony stimulating factor (GMCSF) mediated endothelial progenitor cell (EPC) upregulation and stromal cell derived factor-1α (SDF) mediated myocardial EPC chemokinesis, may prevent myocardial loss and adverse remodelling. Vasculogenesis, viability, and haemodynamic improvements following therapy were investigated. PROCEDURES: Lewis rats (n=91) underwent LAD ligation and received either intramyocardial SDF and subcutaneous GMCSF or saline injections at the time of infarction. Molecular and haemodynamic assessments were performed at pre-determined time points following ligation. FINDINGS: SDF/GMCSF therapy upregulated EPC density as shown by flow cytometry (0.12±0.02% vs. 0.06±0.01% circulating lymphocytes, p=0.005), 48hours following infarction. A marked increase in perfusion was evident eight weeks after therapy, utilising confocal angiography (5.02±1.7×10(-2)µm(3)blood/µm(3)myocardial tissue vs. 2.03±0.710(-2)µm(3)blood/µm(3)myocardial tissue, p=0.00004). Planimetric analysis demonstrated preservation of wall thickness (0.98±0.09mm vs. 0.67±0.06mm, p=0.003) and ventricular diameter (7.81±0.99mm vs. 9.41±1.1mm, p=0.03). Improved haemodynamic function was evidenced by echocardiography and PV analysis (ejection fraction: 56.4±18.1% vs. 25.3±15.6%, p=0.001; pre-load adjusted maximal power: 6.6±2.6mW/µl(2) vs. 2.7±1.4mW/µl(2), p=0.01). CONCLUSION: Neovasculogenic therapy with GMCSF-mediated EPC upregulation and SDF-mediated EPC chemokinesis maybe an effective therapy for infarct modulation and preservation of myocardial function following acute myocardial infarction.