Alleviating iatrogenic effects of paclitaxel via antiinflammatory treatment.

BACKGROUND: Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. METHODS: We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. RESULTS: Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. CONCLUSION: Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.

Hydrophilic Coating Microstructure Mediates Acute Drug Transfer in Drug-Coated Balloon Therapy.

Drug-coated balloon (DCB) therapy is a promising endovascular treatment for obstructive arterial disease. The goal of DCB therapy is restoration of lumen patency in a stenotic vessel, whereby balloon deployment both mechanically compresses the offending lesion and locally delivers an antiproliferative drug, most commonly paclitaxel (PTX) or derivative compounds, to the arterial wall. Favorable long-term outcomes of DCB therapy thus require predictable and adequate PTX delivery, a process facilitated by coating excipients that promotes rapid drug transfer during the inflation period. While a variety of excipients have been considered in DCB design, there is a lack of understanding about the coating-specific biophysical determinants of essential device function, namely, acute drug transfer. We consider two hydrophilic excipients for PTX delivery, urea (UR) and poly(ethylene glycol) (PEG), and examine how compositional and preparational variables in the balloon surface spray-coating process impact resultant coating microstructure and in turn acute PTX transfer to the arterial wall. Specifically, we use scanning electron image analyses to quantify how coating microstructure is altered by excipient solid content and balloon-to-nozzle spray distance during the coating procedure and correlate obtained microstructural descriptors of coating aggregation to the efficiency of acute PTX transfer in a one-dimensional ex vivo model of DCB deployment. Experimental results suggest that despite the qualitatively different coating surface microstructures and apparent PTX transfer mechanisms exhibited with these excipients, the drug delivery efficiency is generally enhanced by coating aggregation on the balloon surface. We illustrate this microstructure-function relation with a finite element-based computational model of DCB deployment, which along with our experimental findings suggests a general design principle to increase drug delivery efficiency across a broad range of DCB designs.

Left ventricle function and post-transcriptional events with exercise training in pigs.

BACKGROUND: Standardized exercise protocols have been shown to improve overall cardiovascular fitness, but direct effects on left ventricular (LV) function, particularly diastolic function and relation to post-transcriptional molecular pathways (microRNAs (miRs)) are poorly understood. This project tested the central hypothesis that adaptive LV remodeling resulting from a large animal exercise training protocol, would be directly associated with specific miRs responsible for regulating pathways relevant to LV myocardial stiffness and geometry. METHODS AND RESULTS: Pigs (n = 9; 25 Kg) underwent a 4 week exercise training protocol (10 degrees elevation, 2.5 mph, 10 min, 5 days/week) whereby LV chamber stiffness (KC) and regional myocardial stiffness (rKm) were measured by Doppler/speckle tracking echocardiography. Age and weight matched non-exercise pigs (n = 6) served as controls. LV KC fell by approximately 50% and rKm by 30% following exercise (both p < 0.05). Using an 84 miR array, 34 (40%) miRs changed with exercise, whereby 8 of the changed miRs (miR-19a, miR-22, miR-30e, miR-99a, miR-142, miR-144, miR-199a, and miR-497) were correlated to the change in KC (r ≥ 0.5 p < 0.05) and mapped to matrix and calcium handling processes. Additionally, miR-22 and miR-30e decreased with exercise and mapped to a localized inflammatory process, the inflammasome (NLRP-3, whereby a 2-fold decrease in NLRP-3 mRNA occurred with exercise (p < 0.05). CONCLUSION: Chronic exercise reduced LV chamber and myocardial stiffness and was correlated to miRs that map to myocardial relaxation processes as well as local inflammatory pathways. These unique findings set the stage for utilization of myocardial miR profiling to identify underlying mechanisms by which exercise causes changes in LV myocardial structure and function.

Novel Payloads to Mitigate Maladaptive Inward Arterial Remodeling in Drug-Coated Balloon Therapy.

Drug-coated balloon therapy is a minimally invasive endovascular approach to treat obstructive arterial disease, with increasing utilization in the peripheral circulation due to improved outcomes as compared to alternative interventional modalities. Broader clinical use of drug-coated balloons is limited by an incomplete understanding of device- and patient-specific determinants of treatment efficacy, including late outcomes that are mediated by postinterventional maladaptive inward arterial remodeling. To address this knowledge gap, we propose a predictive mathematical model of pressure-mediated femoral artery remodeling following drug-coated balloon deployment, with account of drug-based modulation of resident vascular cell phenotype and common patient comorbidities, namely, hypertension and endothelial cell dysfunction. Our results elucidate how postinterventional arterial remodeling outcomes are altered by the delivery of a traditional anti-proliferative drug, as well as by codelivery with an anti-contractile drug. Our findings suggest that codelivery of anti-proliferative and anti-contractile drugs could improve patient outcomes following drug-coated balloon therapy, motivating further consideration of novel payloads in next-generation devices.

Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment.

Background: Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. Objective: Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. Methods: RNAseq analysis, cell and mouse models. Results: RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. Conclusions: Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk.

Acute Mechanical Consequences of Vessel-Specific Coronary Bypass Combinations.

PURPOSE: Premature coronary artery bypass graft (CABG) failure has been linked to geometric, mechanical, and compositional discrepancies between host and graft tissues. Acute hemodynamic disturbances and the introduction of wall stress gradients trigger a myriad of mechanobiological processes at the anastomosis that can be associated with restenosis and graft failure. Although the origins of coronary artery disease dictate the anastomotic target, an opportunity exists for graft-vessel optimization through rationale graft selection. METHODS: Here we explored the four distinct regions of the left (L) and right (R) ITA (1 = proximal, 2 = submuscular, 3 = middle, 4 = distal), and four common target vessels in the coronary circulation including the proximal and distal left anterior descending (PLAD & DLAD), right coronary (RCA), and left circumflex (LCX) arteries. Benchtop biaxial mechanical data was used to acquire constitutive model parameters of these tissues and enable vessel-specific computational models to elucidate the mechanical consequences of 32 unique graft-target combinations. RESULTS: Simulations revealed the maximum principal wall stresses for the PLAD, RCA, and LCX occurred when anastomosed with LITA1, and the maximum flow-induced shear stress occurred with LITA4. The DLAD, on the other hand, reached stress maximums when anastomosed to LITA4. Using a normalized objective function of simulation output variables, we found LITA2 to be the best graft choice for both LADs, RITA3 for the RCA, and LITA3 for the LCX. CONCLUSION: Although mechanical compatibility is just one of many factors determining bypass graft outcomes, our data suggests improvements can be made to the grafting process through vessel-specific regional optimization.

Understudied factors in drug-coated balloon design and evaluation: A biophysical perspective.

Drug-coated balloon (DCB) percutaneous interventional therapy allows for durable reopening of the narrowed lumen via physical tissue expansion and local anti-restenosis drug delivery, providing an alternative to traditional uncoated balloons or a permanent indwelling implant such as a conventional metallic drug-eluting stent. While DCB-based treatment of peripheral arterial disease (PAD) has been incorporated into clinical guidelines, DCB use has been recently curtailed due to reports that showed evidence of increased mortality risk in patients treated with paclitaxel (PTX)-coated balloons. Given the United States Food and Drug Administration's 2019 consequent warning regarding PTX-eluting DCBs and the subsequent marked reduction in clinical DCB use, there is now a critical need to better understand the compositional and mechanical factors underlying DCB efficacy and safety. Most work to date on DCB refinement has focused on designing both the enabling balloon catheter and alternate coatings composed of various drugs and excipients, followed by device evaluation in preclinical and clinical studies. We contend that improvement in DCB performance will require a better understanding of the biophysical factors operative during and following balloon deployment, and moreover that the elaboration and demonstrated control of these factors are needed to address current concerns with DCB use. This article provides a perspective on the biophysical interactions that govern DCB performance and offers new design strategies for the development of next-generation DCB devices.

A Mathematical Model of Maladaptive Inward Eutrophic Remodeling of Muscular Arteries in Hypertension.

We propose a relatively simple two-dimensional mathematical model for maladaptive inward remodeling of resistive arteries in hypertension in terms of vascular solid mechanics. The main premises are: (i) maladaptive inward remodeling manifests as a reduced increase in the arterial mass compared to the case of adaptive remodeling under equivalent hypertensive pressures and (ii) the pressure-induced circumferential stress in the arterial wall is restored to its basal target value as happens in the case of adaptive remodeling. The rationale for these assumptions is the experimental findings that elevated tone in association with sustained hypertensive pressure down-regulate the normal differentiation of vascular smooth muscle cells from contractile to synthetic phenotype and the data for the calculated hoop stress before and after completion of remodeling. Results from illustrative simulations show that as the hypertensive pressure increases, remodeling causes a nonmonotonic variation of arterial mass, a decrease in inner arterial diameter, and an increase in wall thickness. These findings and the model prediction that inward eutrophic remodeling is preceded by inward hypertrophic remodeling are supported by published observations. Limitations and perspectives for refining the mathematical model are discussed.

Self-Assembling Toroidal Cell Constructs for Tissue Engineering Applications.

Developing tissues have intricate, three-dimensional (3D) organizations of cells and extracellular matrix (ECM) that provide the framework necessary to meet morphogenic and necessary demands. Migrating cells, in vivo, are exposed to numerous conflicting signals: chemokines, ECM, growth factors, and physical forces. While most of these have been studied individually in vivo or in vitro, our understanding of how cells integrate these various signals is lacking. We previously developed a novel self-organizing cellularized collagen hydrogel model that is adaptable, tunable, reproducible, and capable of mimicking the multitude of stimuli that cells experience. Our model produced self-assembled toroids of cells that were formed by 24 h. Data we present here show toroids initially form as early as 3 h after seeding. Additionally, toroids formed when cells were seeded on various collagen subtypes and were sensitive to the composition of the hydrogel. Moreover, we found differences in remodeling in toroid gels compared to gels with cells embedded in them using both a collagen binding peptide and rheology. Using scanning electron microscopy, we observed toroids forming a crater-like structure compared to whole gel contractions in mixed in gels. Finally, when multiple cells were mixed prior to seeding, heterogeneous toroids formed with some containing clusters of cells.

Mechanoscopy: A Novel Device and Procedure for in vivo Detection of Chronic Colitis in Mice.

BACKGROUND: Gut stiffening caused by fibrosis plays a critical role in the progression of inflammatory bowel disease (IBD) and colon cancer. Previous studies have characterized the biomechanical response of healthy and pathological gut, with most measurements obtained ex vivo. METHODS: Here, we developed a device and accompanying procedure for in vivo quantification of gut stiffness, termed mechanoscopy. Mechanoscopy includes a flexible balloon catheter, pressure sensor, syringe pump, and control system. The control system activates the balloon catheter and performs automated measurements of the gut stress-strain biomechanical response. RESULTS: A gut stiffness index (GSI) is identified based on the slope of the obtained stress-strain response. Using a colitis mouse model, we demonstrated that GSI positively correlates with the extent of gut fibrosis, the severity of mucosal damage, and the infiltration of immune cells. Furthermore, a critical strain value is suggested, and GSI efficiently detects pathological gut fibrotic stiffening when the strain exceeds this value. CONCLUSIONS: Based on these results, we envision that mechanoscopy and GSI will facilitate the clinical diagnosis of IBD.

Here, we present a novel procedure/device, termed mechanoscopy, which we have demonstrated to accurately detect and differentiate between fibrosis and inflammation in rodent models of colitis. Thus, mechanoscopy offers a translationally relevant approach for ultrasensitive and minimally invasive IBD diagnosis.

Use of Integrated Intraoperative Ocular Coherence Tomography in Pediatric Cataract Surgery: Thinking outside the Box.

The advent of integrated intraoperative optical coherence tomography (i2OCT) has opened the door for safer and more complex surgeries in the retina and cornea. However, to limit its use to just two subspecialties within ophthalmology is an opportunity lost for many other subspecialties. Here, we describe the use of i2OCT in pediatric cataract surgery in circumstances that are not traditionally considered for i2OCT use. The specific circumstances include: evaluation and treatment of a child following cataract extraction with lens implantation who has failed two attempts at YAG capsulotomy; lysis of post-trauma keratolenticular adhesion in an opaque cornea; surgical removal of secondary lens epithelial cell proliferation after pediatric cataract extraction with lens implantation, and identification of posterior capsular openings and defects. In each case the use of i2OCT allowed the procedure to be completed safely and successfully or informed the surgeon, allowing modification of the surgical decision tree.

Evaluation of the Stress-Growth Hypothesis in Saphenous Vein Perfusion Culture.

The great saphenous vein (GSV) has served as a coronary artery bypass graft (CABG) conduit for over 50 years. Despite prevalent use, first-year failure rates remain high compared to arterial autograft options. Amongst other factors, vein graft failure can be attributed to material and mechanical mismatching that lead to apoptosis, inflammation, and intimal-medial hyperplasia. Through the implementation of the continuum mechanical-based theory of "stress-mediated growth and remodeling," we hypothesize that the mechanical properties of porcine GSV grafts can be favorably tuned for CABG applications prior to implantation using a prolonged but gradual transition from venous to arterial loading conditions in an inflammatory and thrombogenic deficient environment. To test this hypothesis, we used a hemodynamic-mimetic perfusion bioreactor to guide remodeling through stepwise incremental changes in pressure and flow over the course of 21-day cultures. Biaxial mechanical testing of vessels pre- and post-remodeling was performed, with results fit to structurally-motivated constitutive models using non-parametric bootstrapping. The theory of "small-on-large" was used to describe appropriate stiffness moduli, while histology and viability assays confirmed microstructural adaptations and vessel viability. Results suggest that stepwise transition from venous-to-arterial conditions results in a partial restoration of circumferential stretch and circumferential, but not axial, stress through vessel dilation and wall thickening in a primarily outward remodeling process. These remodeled tissues also exhibited decreased mechanical isotropy and circumferential, but not axial, stiffening. In contrast, only increases in axial stiffness were observed using culture under venous perfusion conditions and those tissues experienced moderate intimal resorption.

Combining Baerveldt Implant with Trabectome Negates Tube Fenestration: A Coarsened-matched Comparison.

PURPOSE: To assess the efficacy and survival rate of the Trabectome-mediated ab interno trabeculectomy combined with non-fenestrated Baerveldt glaucoma implant compared with the Baerveldt glaucoma implant alone. METHODS: In this retrospective comparative case series, 175 eyes undergoing primary glaucoma surgery (Baerveldt-Trabectome [BT] group: 60 eyes and Baerveldt [B] group: 115 eyes) were included. Participants were identified using the procedural terminology codes. Groups were then matched by Coarsened Exact Matching that resulted in the inclusion of 51 eyes in each group. The primary outcome measure was surgical success defined as 5 mmHg < intraocular pressure (IOP) ≤ 21 mmHg, and IOP reduction ≥ 20% from baseline, and no need to reoperation for glaucoma. Secondary outcome measures were IOP, number of glaucoma medications, and best-corrected visual acuity (BCVA). RESULTS: The cumulative probability of success at one year was 61% in the BT group and 50% in the B group. IOP decreased from 23.5 ± 2.4 mmHg at baseline to 14.1 ± 2.7 mmHg at the final follow-up in the BT group (P = 0.001). The corresponding values for the B group were 23.2 ± 2.0 mmHg and 13.9 ± 1.6 mmHg, respectively (P = 0.001). There was no significant difference between the groups in terms of IOP at the final follow-up (P = 0.56). The number of medications at baseline was 2.3 ± 0.3 in both groups. However, the BT group needed fewer drops at all postoperative time intervals and used 1.1 ± 0.3 versus 2.0 ± 0.4 eye drops (group B) at the final follow-up visit (P = 0.004). Eyes in B with phacoemulsification had a significantly higher IOP on day 1 compared to B (23.2 ± 14.3 versus 17.9 ± 11.4, P = 0.041). During the one-year follow-up, 7 (13.7%) patients in BT group and 18 (35.2%) in B group experienced hypotony (P = 0.04). No dangerous hypotony or hypertension occurred in BT group. The mean BCVA at baseline was 0.64 ± 0.85 logMAR and changed to 0.55 ± 0.75 logMAR in BT and B groups, respectively (P = 0.663). The corresponding numbers for the final follow-up visit was 0.72 ± 1.07 and 0.63 ± 0.97 logMAR, respectively (P = 0.668). CONCLUSION: We observed similar rates of success and IOP reduction using BT and B techniques. BT group needed fewer glaucoma medications. Tube fenestration was unnecessary in BT group resulting in less postoperative ocular hypotony and hypertension. The results of our study indicate that additional trabectome procedure makes Baerveldt glaucoma implant safer, easier to handle, and more predictable in the most vulnerable patients with advanced glaucoma.

Changes in Myocardial Microstructure and Mechanics With Progressive Left Ventricular Pressure Overload.

This study assessed the regional changes in myocardial geometry, microstructure, mechanical behavior, and properties that occur in response to progressive left ventricular pressure overload (LVPO) in a large animal model. Using an index of local biomechanical function at early onset of LVPO allowed for prediction of the magnitude of left ventricular chamber stiffness (Kc) and left atrial area at LVPO late timepoints. Our study found that LV myocardial collagen content alone was insufficient to identify mechanisms for LV myocardial stiffness with progression to heart failure with preserved ejection fraction (HFpEF). Serial assessment of regional biomechanical function might hold value in monitoring the natural history and progression of HFpEF, which would allow evaluation of novel therapeutic approaches.

Surface Modification Using Ultraviolet-Ozone Treatment Enhances Acute Drug Transfer in Drug-Coated Balloon Therapy.

Endovascular deployment of drug-coated balloons (DCB) is an emerging strategy for the revascularization of arterial disease. Randomized clinical trials have demonstrated DCB effectiveness, but a recent meta-analysis reported increased mortality risk in humans with use of DCBs containing the common antiproliferative drug paclitaxel. While many factors could have contributed to adverse outcomes, current DCB designs have poor drug delivery efficiency, risk of systemic toxicity, and limited potential to retain therapeutic drug concentrations within the arterial wall following the procedure. Our study focuses on developing a strategy to enhance acute drug transfer from the balloon to the arterial wall over the short procedural window (∼30-120 s). We employed ultraviolet-ozone plasma (UVO) treatment to increase the hydrophilicity of a prototypical balloon material (Nylon-12) and subsequently applied a urea-paclitaxel coating previously shown to undergo favorable adhesive interactions with the arterial wall under simulated ex-vivo deployment. A series of assays were performed to characterize our experimental DCBs in terms of UVO-induced alterations in balloon surface hydrophobicity, formed coating microstructure, coating stability, and acute drug transfer to the arterial wall. Obtained results suggest that the UVO-based surface modification of angioplasty balloons is a promising design strategy and highlights the critical role of coating microstructure in determining the drug transfer efficiency in DCB therapy.

Laser-induced Damage to Disposable Single-mirror Trabeculoplasty Lens During Selective Laser Trabeculoplasty.

PURPOSE: To demonstrate disposable trabeculoplasty lens damage after routine selective laser trabeculoplasty (SLT) for primary open-angle glaucoma. METHODS: Disposable single-mirror laser lenses were used to perform SLT in 2 patients with primary open-angle glaucoma. Images of the single-use mirrors were taken before and after treatment. RESULTS: One lens showed heavy focal loss of reflectivity of its mirror with SLT settings of 0.8 to 0.9 mJ × 97 shots on a patient with a lightly pigmented angle. Aiming beam splashing or loss was noted after most shots. The second lens showed much less damage with 0.6 mJ × 90 shots in a heavily pigmented angle. CONCLUSION: Although single-use Gonio lenses have gained popularity for their role in infection control and elimination of wear and tear of reusable lenses, our cases show that damage occurs to the silver mirror because of high laser fluence, interfering with proper aiming and possibly diminishing delivered energy and treatment efficacy.

Speckle-Tracking Echocardiography Enables Model-Based Identification of Regional Stiffness Indices in the Left Ventricular Myocardium.

INTRODUCTION: Left ventricular (LV) remodeling is a critical process underlying heart failure (HF) development and progression. While LV global longitudinal strain determined by speckle-tracking echocardiography (STE) provides a promising basis to monitor LV remodeling, reported strain measures are limited by the masking of regional differences and a dependency on hemodynamic load. OBJECTIVES: Our goal is to extend two-dimensional STE to enhance regional mechanical assessment of the LV myocardium-providing clinically accessible and load-independent response variables that directly reflect the LV remodeling process. METHODS: An inverse finite element analysis was employed with a pattern search optimization algorithm to identify regional indices of LV myocardial stiffness based on STE-derived regional LV longitudinal strains and wall geometries. Our framework was applied in two distinct porcine models of early LV remodeling, specifically following myocardial infarction and onset of LV pressure overload. RESULTS: Regional and temporal changes in computed indices of LV myocardial stiffness over diastolic pressures correlate with conventional indices of LV remodeling and show enhanced early sensitivity as compared to LV global longitudinal strain. CONCLUSION: Our findings suggest that STE-integrated computational modeling can be used to track indices of LV myocardial stiffness and, thus, is a potential tool for HF diagnosis and prognosis.