Alternative Access Transcatheter Aortic Valve Replacement in Nonagenarians versus Younger Patients.

BACKGROUND: Numerous studies have documented the safety of alternatives access (AA) transcatheter aortic valve replacement (TAVR) for patients who are not candidates for transfemoral or surgical approach. There is a scarcity of studies relating use of AA TAVR in nonagenarian patients, a high-risk, frail group. Our study sought to investigate the clinical outcomes of nonagenarians who underwent AA TAVR for aortic stenosis, with comparison of nonagenarians age ≥90 years with patients age <90 years. METHODS: A cohort study of 171 consecutive patients undergoing AA TAVR (transapical [TA, n = 101, 59%], transaxillary [TAX, n = 56, 33%], transaortic [TAO, n = 11, 6%], and transcarotid [TC, n = 3, 2%]) from 2012 to 2019 was analyzed. Baseline, operative, and postoperative characteristics, as well as actuarial survival outcomes, were compared. RESULTS: AA TAVR patients had decreased aortic valve gradients with no difference detected in nonagenarians and younger patients. Operative mortality was 8% (n = 14; nine TA, three TAO, and two TAX). Compared to younger patients, significantly more nonagenarians were recorded to have new onset atrial fibrillation (7 vs. 5%, p < 0.01*). No significant difference in mortality or postoperative complications, such as stroke, pacemaker requirements, was detected. Actuarial survival at 1 and 5 years was 86 versus 87% (nonagenarians vs younger patients) and 36 versus 22%, respectively, with log-rank = 0.97. CONCLUSION: AA TAVR in nonagenarian patients who are not candidates for transfemoral approach can be efficaciously performed with comparable clinical outcomes to younger patients, age <90 years. Furthermore, some access sites should be avoided when possible; notably TA was associated with increased mortality, stroke, and new onset atrial fibrillation.

Outcomes of Urgent Transcatheter Aortic Valve Replacement in Patients With Acute Decompensated Heart Failure: A Single-Center Experience.

Background Data on urgent transcatheter aortic valve replacement (TAVR) as rescue therapy for acute decompensated heart failure (ADHF) due to severe aortic stenosis (AS) are limited. We sought to investigate the outcomes of patients who underwent urgent transcatheter aortic valve replacement (TAVR) in a single institution. Methods This is a retrospective cohort study of 602 patients with a history of heart failure (HF) due to AS who underwent TAVR between April 2012 and July 2017. We stratified patient cohort into urgent (n=139) and elective (n=463) TAVR. Urgent TAVR was defined as patients who were admitted for ADHF and underwent TAVR during the same hospitalization. Patients that underwent urgent TAVR for other reasons were excluded. Results Rates of postoperative intra-aortic balloon pump requirement, atrial fibrillation, dialysis requirement, vascular complications, and stroke were similar between the two groups. Compared with elective TAVR, patients undergoing urgent TAVR had a higher rate of cardiac arrest (5.7% vs 1.3%, p=0.005), longer length of stay (LOS) (11 vs. 5, p<0.001), and significant 30-day mortality (8.6% vs 4.1%, HR 2.1, 95% CI 1.04-4.22). Patients who underwent urgent TAVR were also associated with long-term mortality (Log-rank p = 0.0162). Conclusions In our study, urgent TAVR for ADHF was associated with both short-term and long-term mortality as compared to elective TAVR. Further randomized studies are needed to investigate the appropriate management of this population.

The utility of pulmonary function testing in the preoperative risk stratification of patients undergoing transcatheter aortic valve replacement.

BACKGROUND: The role of pulmonary function testing (PFT) as a predictor of clinically relevant endpoints in transcatheter aortic valve replacement (TAVR) is unclear. OBJECTIVE: To determine the utility of PFT in the preoperative risk stratification of patients undergoing TAVR. METHODS: An evaluation of PFT (i.e., FEV1), arterial blood gases (i.e., PO2), the diagnosis of chronic obstructive lung disease (COPD) by the Global Initiative for COPD (GOLD), and the diagnosis of chronic lung disease (CLD) by the Society of Thoracic Surgeons (STS) was performed to determine whether a relationship exists among these parameters and clinically relevant outcomes, including all-cause 30-day and 1-year mortality. RESULTS: A total of 513 patients underwent TAVR between March 2013 and December 2016. Per STS criteria, 269/513 (52%) had CLD with a mean FEV1 of 55.4 ± 12%. Per GOLD criteria, 158/513 (30%) of patients had COPD with a mean FEV1/forced vital capacity of 61.8 ± 8.2%. The severity of CLD was affected by changes in ejection fraction, albumin, creatinine, and B-type natriuretic peptide levels (p = .009, p < .001, p < .001, and p < .001, respectively), whereas the severity of COPD was not affected by these same variables, (p = .302, .079, .137, and .102, respectively). An increased A-a gradient (p = .035), increased PCO2 (p = .016), and decreased PO2 (p = <.001) demonstrated increased risk of 30-day mortality. Neither classification (COPD or CLD), nor PFT changes, showed association with 30-day and 1-year mortality (p = NS). CONCLUSION: This study suggests that isolated abnormalities in spirometry are a poor indicator of clinically relevant outcomes in TAVR. When classified correctly, COPD does not predict clinically relevant postoperative outcomes.

Predictors and outcomes of stroke after transcatheter aortic valve replacement.

OBJECTIVES: Stroke is a devastating complication of transcatheter aortic valve replacement (TAVR). Many studies have investigated risk factors for postoperative stroke, but reliable predictors are not yet well-established. The objective of this study was to further characterize the predictors and outcomes of stroke after TAVR. METHODS: This is a retrospective cohort study of 1022 patients who underwent TAVR at a single institution between 2012 and 2018. Multivariable logistic regression analysis was used to identify independent predictors of postoperative stroke and Kaplan-Meier method to compare 1-year survival in patients with and without postoperative stroke. RESULTS: Postoperatively, 36 patients experienced a stroke (3.5%) with most developing multiple (63.9%, N = 23), and often bilateral infarcts (50.0%, N = 18). Stroke patients more commonly had peripheral arterial disease (P = .032) and carotid stenosis (P = .013) and were less likely to receive predeployment balloon aortic valvuloplasty (P = .005). Alternative access approach (odds ratio [OR], 2.322; 95% confidence interval [CI]: 1.067-5.054) and history of transient ischemic attack (OR, 2.373; 95% CI: 1.026-5.489) were identified as independent predictors of postoperative stroke. Stroke patients more frequently developed postoperative complications, including prolonged ventilation (P < .001), major vascular complications (P < .001), and new-onset dialysis (P < .001). Operative mortality was greater in stroke patients (19.4% vs 3.7%; P < .001), and 1-year Kaplan-Meier estimates revealed worsened survival (log-rank P = .002). CONCLUSIONS: Alternative access approach and a history of transient ischemic attack emerged as independent predictors of postoperative stroke. Patients with stroke suffered more complications and had worse survival, underscoring the importance of characterizing the stroke risk in these patients.

Predictors and outcomes of patient-prosthesis mismatch after transcatheter aortic valve replacement.

BACKGROUND: Patient-prosthesis mismatch (PPM) has been shown to be associated with adverse outcomes after surgical aortic valve replacement. There is limited data on its risk and impact after transcatheter aortic valve replacement (TAVR), especially with the newer generation heart valves. OBJECTIVES: The objective of this study is to investigate the incidence, predictors, and clinical outcomes of PPM after TAVR. METHODS: This is a retrospective study of 991 consecutive patients who underwent TAVR procedure at a tertiary referral center, between April 2012 and February 2019. Patients were stratified by the presence or absence of PPM, defined as an effective orifice area/body surface area ratio ≤0.85 cm2 /m2 . Multivariable logistic regression analysis was used to determine independent predictors of PPM. Kaplan-Meier survival estimates were used to determine overall 5-year survival. RESULTS: PPM was encountered in 27.6% of patients. In multivariable analysis, age less than 70 years (P = .062), body mass index (BMI) more than 30 (P = .0057), history of atrial fibrillation (P = .0004), black race (P = .0078), and Sapien 3 sizes 20 and 23 mm (P < .0001)emerged as independent predictors of PPM. Sapien 3 valve size 20/23 mm was associated with higher risk of PPM compared to other valve types. Patients with PPM had comparable postoperative outcomes and overall 5-year survival. There was no significant difference in postoperative complications between patient groups. PPM was not associated with worse overall survival (56% for both PPM and no-PPM patients, log-rank P = .80). CONCLUSIONS: Younger age, atrial fibrillation, black race, higher BMI were predictors of PPM. Smaller sizes balloon-expandable valves had a higher risk of PPM.

Early Experience With Embolic Protection Devices During Transcatheter Aortic Valve Replacement.

OBJECTIVES: Embolic protection devices (EPDs) have been employed to combat the risk of cerebrovascular events during transcatheter aortic valve replacement (TAVR). The use of EPD has been shown in some studies to decrease periprocedural stroke incidence when compared with non-EPD TAVR. Our study aimed to compare the postoperative outcomes of TAVR with versus without EPD. METHODS: Thirty-three patients who underwent TAVR with EPD at our institution between October 2018 and February 2019 were compared with a contemporaneous control group of 50 patients who underwent TAVR during the same time period without EPD. Baseline characteristics, operative characteristics, and postoperative outcomes were compared between groups. Exclusion criteria for utilization of EPD included arch vessel tortuosity, calcified arch branches, and size discrepancy between the device and host arteries. RESULTS: The non-EPD group had a higher Society of Thoracic Surgeons risk score (6.8% vs 3.3% in the EPD group; P<.01) and more frequently had a prior diagnosis of diabetes mellitus (52% vs 21% in EPD patients; P<.01). Intraoperative characteristics were comparable, without significant differences in access site used, valve type (Sapien 3 vs Evolut), utilization of rapid pacing, or utilization of balloon aortic valvuloplasty. CONCLUSION: EPD was used in lower-risk patients, possibly related to lower incidence of vessel calcification in those patients that may preclude EPD use. Although postoperative outcomes between groups were comparable, current EPD design use precludes its utilization in higher-risk patients.

Alternative Access Versus Transfemoral Transcatheter Aortic Valve Replacement in Nonagenarians.

OBJECTIVES: Previous studies suggest that alternative access (AA) such as transapical (TA) approach to transcatheter aortic valve replacement (TAVR) is inferior to transfemoral (TF) approach. However, there is a paucity of data characterizing these outcomes, and studies often do not consider transaortic (TAO) and transaxillary (TAX) TAVR approaches. Therefore, the purpose of this study was to compare the outcomes of nonagenarians undergoing AA-TAVR compared to TF-TAVR. METHODS: A concurrent cohort study of 148 consecutive nonagenarian patients (≥90 years old) undergoing TAVR from April 2012 to July 2017 was carried out. We stratified the patient cohort into two groups based on access approach: TF-TAVR (n = 112); and AA-TAVR (n = 36), which included TA (n = 24), TAX (n = 8), and TAO (n = 4) approaches. Preoperative, operative, and postoperative outcomes and 5-year actuarial survival rates were analyzed. RESULTS: Compared to TF-TAVR, patients undergoing AA-TAVR were more likely to require blood transfusions (28% vs 69%; P<.001) and readmission (16% vs 58%; P<.001). AA-TAVR also resulted in significantly higher rates of postoperative complications, such as stroke (1% vs 8%; P=.02) and atrial fibrillation (19% vs 36%; P=.03). There was no significant difference in aortic valve gradients (P>.05), operative mortality rate (6% vs 8%; P=.66), or actuarial 5-year survival rate (68% vs 44%, log-rank P=.10). CONCLUSION: There is a higher risk of adverse events following AA-TAVR compared with TF-TAVR. Therefore, TF-TAVR is recommended when feasible, with AA approach as a viable back-up option in nonagenarians.

Transcatheter aortic valve in valve implantation with bioprosthetic valve fracture.

Valve-in-valve transcatheter aortic valve replacement (VIV TAVR) has emerged as a preferable option for high surgical risk patients requiring redo aortic valve replacement. However, VIV TAVR may restrict flow, especially in small native aortic valves. To remedy this, bioprosthetic valve fracture has been utilized to increase the effective orifice area and improve hemodynamics. We present three cases in which bioprosthetic valve fracture was used to increase hemodynamic flow in VIV TAVR procedures.

Japan-United States of America Harmonized Assessment by Randomized Multicentre Study of OrbusNEich's Combo StEnt (Japan-USA HARMONEE) study: primary results of the pivotal registration study of combined endothelial progenitor cell capture and drug-eluting stent in patients with ischaemic coronary disease and non-ST-elevation acute coronary syndrome.

Aims: Harmonized Assessment by Randomized Multicentre Study of OrbusNEich's Combo StEnt (HARMONEE) (NCT02073565) was a randomized pivotal registration trial of the Combo stent, which combined sirolimus and an abluminal bioabsorbable polymer with a novel endoluminal anti-CD34+ antibody coating designed to capture endothelial progenitor cells (EPC) and promote percutaneous coronary intervention (PCI) site healing. Methods and results: Clinically stabilized PCI subjects were randomized 1:1 to receive Combo or everolimus-eluting stents (EES). Between February 2014 and June 2016, 572 subjects with 675 coronary lesions underwent 1-year angiography and fractional flow reserve, with optical coherence tomography (OCT) in the first 140 patients. The primary clinical endpoint was non-inferior 1-year target vessel failure (TVF). The primary mechanistic endpoint of EPC capture activity was superior strut coverage by OCT. Target vessel failure occurred in 7.0% Combo (20/287) vs. 4.2% EES (12/285), a 2.8% [95% confidence interval (95% CI) -1.0%, 6.5%] difference, meeting the non-inferiority hypothesis (P = 0.02). There were no cardiac deaths, with one stent thrombosis observed in the EES group. Quantitative coronary angiography late loss with Combo was equivalent to EES. Optical coherence tomography strut coverage at 1 year was superior with Combo vs. EES [91.3% (95% CI 88.7%, 93.8%) vs. 74.8% (95% CI 70.0%, 79.6%), P < 0.001], with homogeneous tissue in 81.2% vs. 68.8%, respectively. Conclusion: Combo stent demonstrated non-inferior 1-year TVF and late loss in a randomized comparison to EES, with superior strut-based tissue coverage by OCT as a surrogate of EPC capture technology activity.

Successful Coronary Protection during TAVI in Heavily Calcified Aortic Leaflets in Patient with Short and Low Left Coronary System.

Transcatheter aortic valve replacement has been recently approved for patients who are high or intermediate risk for surgical aortic valve replacement. The procedure is associated with several known complications including coronary related complications. Coronary obstruction is rare but disastrous complication, and it is associated with a high mortality rate. Coronary protection technique has emerged as a preemptive technique to avoid this complication. We present a case of successful coronary protection during TAVR in severely calcified left cusp in patient with short and low left ostium.

Eosinophil depletion suppresses radiation-induced small intestinal fibrosis.

Radiation-induced intestinal fibrosis (RIF) is a serious complication after abdominal radiotherapy for pelvic tumor or peritoneal metastasis. Herein, we show that RIF is mediated by eosinophil interactions with α-smooth muscle actin-positive (α-SMA+) stromal cells. Abdominal irradiation caused RIF especially in the submucosa (SM) of the small intestine, which was associated with the excessive accumulation of eosinophils in both human and mouse. Eosinophil-deficient mice showed markedly ameliorated RIF, suggesting the importance of eosinophils. After abdominal irradiation, chronic crypt cell death caused elevation of extracellular adenosine triphosphate, which in turn activated expression of C-C motif chemokine 11 (CCL11) by pericryptal α-SMA+ cells in the SM to attract eosinophils in mice. Inhibition of C-C chemokine receptor 3 (CCR3) by genetic deficiency or neutralizing antibody (Ab) treatment suppressed eosinophil accumulation in the SM after irradiation in mice, suggesting a critical role of the CCL11/CCR3 axis in the eosinophil recruitment. Activated α-SMA+ cells also expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate eosinophils. Transforming growth factor-ß1 from GM-CSF-stimulated eosinophils promoted collagen expression by α-SMA+ cells. In translational studies, treatment with a newly developed interleukin-5 receptor α-targeting Ab, analogous to the human agent benralizumab, depleted intestinal eosinophils and suppressed RIF in mice. Collectively, we identified eosinophils as a crucial factor in the pathogenesis of RIF and showed potential therapeutic strategies for RIF by targeting eosinophils.

Severe aortic stenosis in dextrocardia with situs invertus and anomalous single coronary ostium treated with transcatheter aortic valve replacement.

Dextrocardia with situs inversus presents a unique anatomy with right-sided vascular system that may be associated with a number of additional cardiac and vascular malformations. A rare association is the presence of a single coronary artery ostium. To our knowledge, this is the first reported case of transcatheter aortic valve replacement using Edwards SAPIEN S3 valve in Dextrocardia patient with single coronary artery take off.

Automation of cell-based drug absorption assays in 96-well format using permeable support systems.

Cell-based drug absorption assays, such as Caco-2 and MDCK-MDR1, are an essential component of lead compound ADME/Tox testing. The permeability and transport data they provide can determine whether a compound continues in the drug discovery process. Current methods typically incorporate 24-well microplates and are performed manually. Yet the need to generate absorption data earlier in the drug discovery process, on an increasing number of compounds, is driving the use of higher density plates. A simple, more efficient process that incorporates 96-well permeable supports and proper instrumentation in an automated process provides more reproducible data compared to manual methods. Here we demonstrate the ability to perform drug permeability and transport assays using Caco-2 or MDCKII-MDR1 cells. The assay procedure was automated in a 96-well format, including cell seeding, media and buffer exchanges, compound dispense, and sample removal using simple robotic instrumentation. Cell monolayer integrity was confirmed via transepithelial electrical resistance and Lucifer yellow measurements. Proper cell function was validated by analyzing apical-to-basolateral and basolateral-to-apical movement of rhodamine 123, a known P-glycoprotein substrate. Apparent permeability and efflux data demonstrate how the automated procedure provides a less variable method than manual processing, and delivers a more accurate assessment of a compound's absorption characteristics.

Closed system cell culture protocol using HYPERStack vessels with gas permeable material technology.

Large volume adherent cell culture is currently standardized on stacked plate cell growth products when microcarrier beads are not an optimal choice. HYPERStack vessels allow closed system scale up from the current stacked plate products and delivers >2.5X more cells in the same volumetric footprint. The HYPERStack vessels function via gas permeable material which allows gas exchange to occur, therefore eliminating the need for internal headspace within a vessel. The elimination of headspace allows the compartment where cell growth occurs to be minimized to reduce space, allowing more layers of cell growth surface area within the same volumetric footprint. For many applications such as cell therapy or vaccine production, a closed system is required for cell growth and harvesting. The HYPERStack vessel allows cell and reagent addition and removal via tubing from media bags or other methods. This protocol will explain the technology behind the gas permeable material used in the HYPERStack vessels, gas diffusion results to meet the metabolic needs of cells, closed system cell growth protocols, and various harvesting methods.

Recombinant human FIZZ3/resistin stimulates lipolysis in cultured human adipocytes, mouse adipose explants, and normal mice.

Human FIZZ3 (hFIZZ3) was identified as an ortholog of mouse resistin (mResistin), an adipocyte-specific secreted factor linked to insulin resistance in rodents. Unlike mResistin, hFIZZ3 is expressed in macrophages and monocytes, but is undetectable in adipose tissue. The profound macrophage infiltration of adipose that occurs during obesity suggests that hFIZZ3 may play an important role in adipocyte biology. Using a recombinant protein produced in Escherichia coli, we report here that chronic treatment of cultured human adipocytes with hFIZZ3 results in hypotropic cells with smaller lipid droplets. Recombinant hFIZZ3 facilitates preadipocyte proliferation and stimulates adipocyte triglyceride lipolysis, whereas recombinant mResistin inhibits adipocyte differentiation, with no detectable effect on proliferation or lipolysis. In addition, insulin-stimulated glucose uptake and Akt phosphorylation are not altered in hFIZZ3-treated adipocytes, indicating an intact insulin response. In mouse adipose explants, hFIZZ3 accelerates simultaneously triglyceride lipolysis and fatty acid reesterification, as assessed by measurement of glycerol and fatty acid release. Consistent with the in vitro findings, acute administration of recombinant hFIZZ3 into normal mice caused a significant increase in serum glycerol concentration with no elevation in free fatty acid at 45 min post injection. Taken together, the data suggest that recombinant hFIZZ3 can influence adipose metabolism by regulating preadipocyte cell number, adipocyte lipid content, and energy expenditure via accelerating the fatty acid/triglyceride futile cycle.