Hemodynamic Optimization by Invasive Ramp Test in Patients Supported With HeartMate 3 Left Ventricular Assist Device.

In patients supported by the HeartMate 3 left ventricular assist device (HM3 LVAD), pump speed adjustments may improve hemodynamics. We investigated the hemodynamic implications of speed adjustments in HM3 recipients undergoing hemodynamic ramp tests. Clinically stable HM3 recipients who underwent routine invasive hemodynamic ramp tests between 2015 and 2022 at our center were included. Filling pressure optimization, defined as central venous pressure (CVP) <12 mm Hg and pulmonary capillary wedge pressure (PCWP) <18 mm Hg, was assessed at baseline and final pump speeds. Patients with optimized pressures were compared to nonoptimized patients. Overall 60 HM3 recipients with a median age of 62 years (56, 71) and time from LVAD implantation of 187 days (124, 476) were included. Optimized filling pressures were found in 35 patients (58%) at baseline speed. Speed was adjusted in 84% of the nonoptimized patients. Consequently, 39 patients (65%) had optimized pressures at final speed. There were no significant differences in hemodynamic findings between baseline and final speeds (p > 0.05 for all). Six and 12 month readmission-free rates were higher in optimized compared with nonoptimized patients (p = 0.03 for both), predominantly due to lower cardiac readmission-free rates (p = 0.052). In stable outpatients supported with HM3 who underwent routine ramp tests, optimized hemodynamics were achieved in only 2 of 3 of the patients. Patients with optimized pressures had lower all-cause readmission rates, primarily driven by fewer cardiac-related hospitalizations.

The utilization of molecular microscope in management of heart transplant recipients in the era of noninvasive monitoring.

INTRODUCTION: Monitoring for graft rejection is a fundamental tenet of post-transplant follow-up. In heart transplantation (HT) in particular, rejection has been traditionally assessed with endomyocardial biopsy (EMB). EMB has potential complications and noted limitations, including interobserver variability in interpretation. Additional tests, such as basic cardiac biomarkers, cardiac imaging, gene expression profiling (GEP) scores, donor-derived cell-free DNA (dd-cfDNA) and the novel molecular microscope diagnostic system (MMDx) have become critical tools in rejection surveillance beyond standard EMB. METHODS: This paper describes an illustrative case followed by a review of MMDx within the context of other noninvasive screening modalities for rejection. CONCLUSIONS: We suggest MMDx be used to assist with early detection of rejection in cases of discordance between EMB and other noninvasive studies.

Protocol endomyocardial biopsy beyond 6 months-It is time to move on.

The optimal duration and frequency of routine surveillance endomyocardial biopsy (EMB) have been questioned in the current era of heart transplantation (HT), where the advances in immunosuppression and donor selection strategies have led to a decline in acute allograft rejection. We investigated the utility of routine EMB beyond 6 months post-HT. A single-center retrospective review was performed on 2963 EMBs from 220 HT recipients over 10 years. Each EMB was categorized into protocol or symptom-triggered biopsy and reviewed for rejection. Heart transplant recipients with ≥2 known risk factors for rejection were designated as an elevated risk group. The majority of rejections occurred within 3 months following HT. The yield of routine protocol EMBs was significantly lower than symptom-triggered EMBs, not only during the first 6 months post-HT (1.6% vs. 33.3%, P < .0001), but more so during the 6-12 months (0.1% vs 83.0%, P < .0001). A similar pattern was observed in heart transplant recipients at both elevated and standard risk for rejection. In conclusion, EMB was found to be a low-yield screening modality for rejection beyond 6 months post-HT.

L-histidine-based pH-sensitive anticancer drug carrier micelle: reconstitution and brief evaluation of its systemic toxicity.

A doxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene glycol)(2K) and poly(l-lactic acid)(3K)-b-PEG(2K)-folate has been developed targeting the early endosomal pH and it have been convincingly proved that intracellular high dose strategy using such micelles is effective in overcoming multidrug resistance (MDR) of cancer cells. Due to the low DOX concentrations in the micelle solution obtained by dialysis and the lack of long-term stability of the micelles, stable and lyophilized micelle formulations were the subject of investigation reported here by using excipients of sucrose, PEG or Pluronic. The reconstituted micelle solutions were examined by particle size, pH sensitivity, and cytotoxicity for MDR cells and the results were compared with the non-lyophilized micelles. Among tested excipients, Pluronic F127 (33 wt%) added to the polymer/drug solution prior to dialysis resulted in a reconstituted product stable for a week and presented equivalent benefits as the fresh micelle formulation. The blank micelles did not present any apparent systemic toxicity in mice up to 2400 mg/kg i.v. injection (800 mg/kg day) for 3 days). The brief toxicity of reconstituted DOX loaded micelles was examined by the maximum tolerated dose (MTD), which was approximately 7.5-fold higher than free DOX and guaranteeing further animal toxicity and efficacy study.

Physicochemical characteristics of pH-sensitive poly(L-histidine)-b-poly(ethylene glycol)/poly(L-lactide)-b-poly(ethylene glycol) mixed micelles.

A novel pH-sensitive polymeric micellar system composed of poly(L-histidine)-b-poly(ethylene glycol) and poly(L-lactide)-b-poly(ethylene glycol) block copolymers was studied by dynamic/static light scattering, spectrofluorimetry and differential scanning calorimetry. The mixed micelles displayed ultra Ph Sensitivity Which Could Be Tuned By Varying The Mixing Ratio Of The Two Polymers. In Particular, Mixed Micelles Composed Of 25 Wt.% Poly(L-lactide)-b-poly(ethylene glycol) exhibited desirable pH dependency which could be used as a drug delivery system that selectively targeted the extracellular pH of acidic solid tumors. Micelles were quite stable from pH 7.4 to 7.0 but underwent a two-stage destabilization as pH decreased further. A significant increase in size and aggregation number was observed when pH dropped to 6.8. Further disruption of the micelle core eventually caused phase separation in the micelle core and dissociation of ionized poly(L-histidine)-b-poly(ethylene glycol) molecules from the micelles as pH decreased to 6.0. Increased electrostatic repulsions which arise from the progressive protonation of imidazole rings overwhelming the hydrophobic interactions among uncharged neutral blocks is considered to be the mechanism for destabilization of the micelle core.

Block polyelectrolyte networks from poly(acrylic acid) and poly(ethylene oxide): sorption and release of cytochrome C.

A new family of block polyelectrolyte networks containing cross-linked poly(acrylic acid) (PAA) and poly(ethylene oxide) (PEO) was synthesized by copolymerization of acrylic acid and bisacrylated PEO (10 kDa). Two materials with different PEO/PAA ratios were compared with a weakly cross-linked PAA homopolymer network. The networks bound a cationic protein, cytochrome C, due to the polyion coupling, leading to the network contraction. After binding the protein the block polyelectrolyte networks were more porous compared to a homopolymer network, facilitating protein absorption within the gel. The protein was released by adding Ca2+ ions or a polycation. Ca2+ ions migrated within the gels and reacted with PAA chains, thus displacing the protein. The polycation transfer into hydrogels, as a result of polyion substitution reactions, was inhibited by the excess of PEO chains in the block polyelectrolyte networks. Overall, these findings advance development of functional polyelectrolyte networks for immobilization and controlled release of proteins.

Block ionomer complexes as prospective nanocontainers for drug delivery.

Nanosized environmentally responsive materials are of special interest for various applications, including drug delivery. Block ionomer complexes (BIC) composed of graft-comb copolymers of Pluronic and poly(acrylic acid) (Pluronic-PAA) and a model cationic surfactant, hexadecyltrimethylammonium bromide (HTAB), were synthesized by mixing the polymer and surfactant in aqueous media. According to TEM, the resulting BIC represented spherical particles of nanoscale size (50 to 100 nm). The stability of the BIC in the aqueous dispersion depended on the lengths of the hydrophilic poly(ethylene oxide) and hydrophobic poly(propylene oxide) chains in Pluronic molecules as well as on the surface charge of the resulting complexes. The latter was controlled by changing the ratio of the Pluronic-PAA and HTAB in the BIC and by changing the pH due to reversible ionization of the PAA chains. The acidification of the media below pH 6.0 resulted in the appearance of a strong positive charge on the BIC, which in the intracellular environment can trigger interaction of such BIC with the cell membranes. An efficient solubilization of a model hydrophobic molecule, Sudan III, and a drug, Etoposide, in such BIC was demonstrated with the loading capacities of about 6 to 15% by weight of the dispersed complex. Overall, these BIC wield a promise as environmentally responsive nanocarriers for pharmaceuticals.

Micellar formulations for drug delivery based on mixtures of hydrophobic and hydrophilic Pluronic block copolymers.

Micelles formed by Pluronic block copolymers (PBC) have been studied in multiple applications as drug delivery systems. Hydrophobic PBC form lamellar aggregates with a higher solubilization capacity than spherical micelles formed by hydrophilic PBC. However, they also have a larger size and low stability. To overcome these limitations, binary mixtures from hydrophobic PBC (L121, L101, L81, and L61) and hydrophilic PBC (F127, P105, F87, P85, and F68) were prepared. In most cases, PBC mixtures were not stable, revealing formation of large aggregates and phase separation within 1-2 day(s). However, stable aqueous dispersions of the particles were obtained upon (1). sonication of the PBC mixtures for 1 or 2 min or (2). heating at 70 degrees C for 30 min. Among all combinations, L121/F127 mixtures (1:1% weight ratio) formed stable dispersions with a small particle size. The solubilizing capacity of this system was examined using a model water-insoluble dye, Sudan (III). Mixed L121/F127 aggregates exhibited approximately 10-fold higher solubilization capacity compared to that of F127 micelles. In conclusion, stable aqueous dispersions of nanoscale size were prepared from mixtures of hydrophobic and hydrophilic PBC by using the external input of energy. The prepared mixed aggregates can efficiently incorporate hydrophobic compounds.