Impact of paravalvular leak on left ventricular remodeling and global longitudinal strain 1 year after transcatheter aortic valve replacement.

Background: New mild or persistent moderate paravalvular leak (PVL) is a known predictor of poor outcomes after transcatheter aortic valve replacement (TAVR). Its impact on left ventricular (LV) remodeling and global longitudinal strain (GLS) has not been well studied. Materials & methods: We collected echocardiographic data in 99 TAVR patients. LV remodeling and GLS were compared between patients with and without PVL. Results: Patients without PVL (n = 84) had significant LV ejection fraction, wall thickness and LV mass improvement compared with patients with PVL (n = 15; p < 0.001 for all). Diastolic function worsened in patients with PVL. Baseline GLS improved significantly regardless of PVL (p = 0.016 and p = 0.01, respectively) and was not predictive of LV ejection fraction or LV mass improvement when analyzed in tertiles. Conclusion: PVL impedes reverse LV remodeling but not GLS improvement 1-year after TAVR. Baseline GLS was not a predictor of LV remodeling.

Use of supercritical carbon dioxide technology for fabricating a tissue engineering scaffold for anterior cruciate ligament repair.

Tissue-engineered grafts may be useful in Anterior Cruciate Ligament (ACL) repair and provide a novel, alternative treatment to clinical complications of rupture, harvest site morbidity and biocompatibility associated with autografts, allografts and synthetic grafts. We successfully used supercritical carbon dioxide (Sc-CO2) technology for manufacturing a "smart" biomaterial scaffold, which retains the native protein conformation and tensile strength of the natural ACL but is decellularized for a decreased immunogenic response. We designed and fabricated a new scaffold exhibiting (1) high tensile strength and biomechanical properties comparable to those of the native tissue, (2) thermodynamically-stable extra-cellular matrix (ECM), (3) preserved collagen composition and crosslinking, (4) a decellularized material milieu with potential for future engineering applications and (5) proven feasibility and biocompatibility in an animal model of ligament reconstruction. Because of the "smart" material ECM, this scaffold may have the potential for providing a niche and for directing stem cell growth, differentiations and function pertinent to new tissue formation. Sc-CO2-related technology is advanced and has the capability to provide scaffolds of high strength and durability, which sustain a lifetime of wear and tear under mechanical loading in vivo.

Development of novel machine learning model for right ventricular quantification on echocardiography-A multimodality validation study.

PURPOSE: Echocardiography (echo) is widely used for right ventricular (RV) assessment. Current techniques for RV evaluation require additional imaging and manual analysis; machine learning (ML) approaches have the potential to provide efficient, fully automated quantification of RV function. METHODS: An automated ML model was developed to track the tricuspid annulus on echo using a convolutional neural network approach. The model was trained using 7791 image frames, and automated linear and circumferential indices quantifying annular displacement were generated. Automated indices were compared to an independent reference of cardiac magnetic resonance (CMR) defined RV dysfunction (RVEF < 50%). RESULTS: A total of 101 patients prospectively underwent echo and CMR: Fully automated annular tracking was uniformly successful; analyses entailed minimal processing time (<1 second for all) and no user editing. Findings demonstrate all automated annular shortening indices to be lower among patients with CMR-quantified RV dysfunction (all P < .001). Magnitude of ML annular displacement decreased stepwise in relation to population-based tertiles of TAPSE, with similar results when ML analyses were localized to the septal or lateral annulus (all P ≤ .001). Automated segmentation techniques provided good diagnostic performance (AUC 0.69-0.73) in relation to CMR reference and compared to conventional RV indices (TAPSE and S') with high negative predictive value (NPV 84%-87% vs 83%-88%). Reproducibility was higher for ML algorithm as compared to manual segmentation with zero inter- and intra-observer variability and ICC 1.0 (manual ICC: 0.87-0.91). CONCLUSIONS: This study provides an initial validation of a deep learning system for RV assessment using automated tracking of the tricuspid annulus.

Prognostic role of diastolic dysfunction in patients undergoing transcatheter aortic valve replacement.

OBJECTIVES: Prior studies have shown that left ventricular diastolic dysfunction (DD) is associated with increased mortality after surgical aortic valve replacement but studies on transcatheter aortic valve replacement (TAVR) are limited and have not taken into account mitral annular calcification (MAC), which limits the use of mitral valve annular tissue Doppler imaging. We performed a single-center retrospective analysis to better evaluate the role of baseline DD on outcomes after TAVR. METHODS: After excluding patients with atrial fibrillation, mitral valve prostheses and significant mitral stenosis, 359 consecutive TAVR patients were included in the study. Moderate-to-severe MAC was present in 58% of the patients. We classified patients into severe versus nonsevere DD based on the evaluation of elevated left ventricular filling pressure. The outcome measure was all-cause mortality or heart failure hospitalization. RESULTS: Over a mean follow-up time of 13 months, severe DD was associated with an increased risk for the outcome measure (HR 2.02 [1.23-3.30], p = .005). However, this association was lost in a propensity-matched cohort. In multivariate analysis, STS score was the only independent predictor of all cause mortality of heart failure hospitalization (HR 1.1 [1.05-1.15], p < .001). CONCLUSIONS: We evaluated the role of baseline DD on outcomes after TAVR by taking into account the presence of MAC. Severe DD was associated with increased all-cause mortality or heart failure hospitalization but not independently of other structural parameters and known predictors of the outcome measure.

Comparison of transesophageal and transthoracic echocardiography under moderate sedation for guiding transcatheter aortic valve replacement.

The optimal periprocedural imaging strategy during transcathether aortic valve replacement (TAVR) performed under moderate sedation is debated. Transthoracic echocardiography (TTE) provides suboptimal views due to poorer resolution and patient positioning, whereas use of transesophageal echocardiography (TEE) under moderate sedation is not widely utilized. The aim of our study was to compare the value of TTE in comparison with TEE guidance under moderate sedation during TAVR. The study population included 144 consecutive patients (mean age 83 ± 11 years, 78 (54%) females) who had TAVR under moderate sedation using either a TTE (n = 96) or TEE (n = 48). We compared procedural outcomes using propensity score matching. There were no significant inter-group differences in age, sex, ejection fraction, aortic valve area, pressure gradients, creatinine or type of valve used. The procedural time was significantly shorter in the TEE group (P < 0.001) and associated with a lower need for periprocedural aortograms (7.7 ± 1.9 vs 8.2 ± 1.9, P = 0.022) and a lower occurrence of acute kidney injury (1 vs 11, P = 0.047). The 1:1 propensity score matching also showed a lower procedural time (P = 0.032), number of aortograms (P = 0.014) and a trend toward lower acute kidney injury in the TEE group (P = 0.077). TAVR guidance using TEE is associated with a lower fluoroscopic time, a lower need for additional aortograms and trend in lower occurrence of post-TAVR acute kidney injury.

Anterior cruciate ligament surgery in the rabbit.

BACKGROUND: Various methods regarding allograft knee replacements have been described. The animal models, which are generally used for this purpose include sheep, dogs, goats, and pigs, and accrue significant costs for study protocols. The authors herein describe an efficient and cost-effective model to study either native or tissue-engineered allografts for anterior cruciate ligament (ACL) replacement in a New Zealand rabbit model with the potential for transgenic and cell migration studies. METHODS: ACL reconstructions were performed in rabbits under general anesthesia. For fresh allograft implantations, two animals were operated in parallel. Each right extensor digitorum longus tendon was harvested and prepared for implantation. After excision of the ACL, tibial and femoral bone tunnels were created to implant each graft in the native ACL position. RESULTS: During a 2-year period, the authors have successfully undertaken this surgery in 61 rabbits and have not noticed any major complications attributed to this surgical technique. In addition, the authors have observed fast recovery in the animals postoperatively. CONCLUSION: The authors recommend this surgical procedure as an excellent model for the study of knee surgery.

Adult hemophagocytic lymphohistiocytosis with severe pulmonary hypertension and a novel perforin gene mutation.

Adult hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly hyperinflammatory syndrome presenting both diagnostic and therapeutic challenges. HLH may be primary, due to an underlying genetic abnormality, and/or secondary to infection, malignancy, or rheumatologic conditions. We describe a case of HLH-associated severe pulmonary hypertension paralleling Epstein-Barr virus (EBV) reactivation in a 52-year-old male in whom a novel perforin missense mutation was found (PRF1 1517C>T). Although intolerant of standard therapy (HLH-2004 protocol), a 6-week course of anti-CD52 (alemtuzumab) was associated with freedom-from-transfusion from weeks 4 to 13. However, 15 weeks after the onset of salvage therapy, he succumbed to polymicrobial sepsis despite treatment with prophylactic anti-infectives, with necropsy revealing disseminated blastomycosis and relapsed HLH. This case illustrates uncertainties in the relationships between pulmonary hypertension, a newly described PRF1 mutation, and possible pre-existing latent infectious risk factors (such as EBV or Blastomyces) in the pathogenesis and therapeutic perils of adult HLH.

Patient-centred assessment of social support, health status and quality of life in patients with acute coronary syndrome.

BACKGROUND: Measurement of health status (HS) and social support are becoming increasingly accepted as tools to guide clinical decision-making and patient-centred practice. PURPOSE: To assess self-reported HS, cardiac-health related quality of life and social support in subjects with a diagnosis of acute coronary syndrome (ACS). DESIGN: The study used a quantitative descriptive design. SAMPLE: 36 subjects with a diagnosis of ACS were selected from patients admitted to medical units at a teaching hospital in Toronto, Ontario. METHODS: One-time, semi-structured interviews were conducted using valid and reliable cardiac-specific HS and social support measures. RESULTS: Analysis indicated that subjects with higher perceived social support and patients with higher income reported greater treatment satisfaction and C-HROL. Subjects with severe angina reported a higher perceived level of social support than those with more moderate physical limitation due to angina. CONCLUSION: Patients' social environment and HS significantly impact their satisfaction with treatment. Patient-centred measures assist in clinical decision-making, patient-centred care planning and patient involvement in their care.

The use of charge-coupled polymeric microparticles and micromagnets for modulating the bioavailability of orally delivered macromolecules.

Protein drugs have low bioavailability after oral administration, which is due in part to fast transit of the drugs or drug delivery vehicles through the gastrointestinal tract. Increasing the time that the drugs spend in the intestine after dosing would allow for greater absorption and increased bioavailability. We developed a formulation strategy that can be used to prolong intestinal retention of drug delivery vehicles without substantial alterations to current polymeric encapsulation strategies. A model drug, insulin, was encapsulated in negatively charged poly(lactic-co-glycolic acid) (PLGA) microparticles, and the microparticles were subsequently mixed with positively charged micromagnets, whose size will prevent them from being absorbed. Stable complexes formed through electrostatic interaction. The complexes were effectively immobilized in vitro in a model of the mouse small intestine by application of an external magnetic field. Mice that were gavaged with radio-labeled complexes and fitted with a magnetic belt retained 32.5% of the (125)I-insulin in the small intestine compared with 5.4% for the control group 6h after administration (p=0.005). Furthermore, mice similarly gavaged with complexes encapsulating insulin (120 Units/kg) exhibited long-term glucose reduction in the groups with magnetic belts. The corresponding bioavailability of insulin was 5.11% compared with 0.87% for the control group (p=0.007).

Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery.

Nanoparticle (NP) size has been shown to significantly affect the biodistribution of targeted and non-targeted NPs in an organ specific manner. Herein we have developed NPs from carboxy-terminated poly(d,L-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) polymer and studied the effects of altering the following formulation parameters on the size of NPs: (1) polymer concentration, (2) drug loading, (3) water miscibility of solvent, and (4) the ratio of water to solvent. We found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient=0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the prostate specific membrane antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in a LNCaP (PSMA+) xenograft mouse model of prostate cancer. The surface functionalization of NPs with the A10 PSMA Apt significantly enhanced delivery of NPs to tumors vs. equivalent NPs lacking the A10 PSMA Apt (a 3.77-fold increase at 24h; NP-Apt 0.83%+/-0.21% vs. NP 0.22%+/-0.07% of injected dose per gram of tissue; mean+/-SD, n=4, p=0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies.

Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo.

Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximately 300 mm3), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.

Magnetically responsive polymeric microparticles for oral delivery of protein drugs.

PURPOSE: Protein drugs cannot be delivered efficiently through oral routes. To address this challenge, we evaluated the effect of prolonged gastrointestinal transit on the bioavailability of insulin carried by magnetically responsive microparticles in the presence of an external magnetic field. METHODS: Magnetite nanocrystals and insulin were coencapsulated into poly(lactide-co-glycolide) (PLGA) microparticles and their effects on hypoglycemia were evaluated in mice in the presence of a circumferentially applied external magnetic field. RESULTS: A single administration of 100 U/kg of insulin-magnetite-PLGA microparticles to fasted mice resulted in a reduction of blood glucose levels of up to 43.8% in the presence of an external magnetic field for 20 h (bioavailability = 2.77 +/- 0.46 and 0.87 +/- 0.29% based on glucose and ELISA assay, respectively), significantly higher than similarly dosed mice without a magnetic field (bioavailability = 0.66 +/- 0.56 and 0.30 +/- 0.06%, based on glucose and ELISA assay, respectively). CONCLUSIONS: A substantially improved hypoglycemic effect was observed in mice that were orally administered with insulin-magnetite-PLGA microparticles in the presence of an external magnetic field, suggesting that magnetic force can be used to improve the efficiency of orally delivered protein therapeutics.