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.

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.

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.

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.

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.

A Two-Dimensional Model of Hypertension-Induced Arterial Remodeling With Account for Stress Interaction Between Elastin and Collagen.

We propose a novel structure-based two-dimensional (2D) mathematical model of hypertension-induced arterial remodeling. The model is built in the framework of the constrained mixture theory and global growth approach, utilizing a recently proposed structure-based constitutive model of arterial tissue that accounts for the individual natural configurations of and stress interaction between elastin and collagen. The basic novel predictive result is that provided remodeling causes a change in the elastin/collagen mass fraction ratio, it leads to a structural reorganization of collagen that manifests as an altered fiber undulation and a change in direction of the helically oriented fibers in the tissue natural state. Results obtained from the illustrative simulations for a porcine renal artery show that when remodeling is complete the collagen reorganization might have significant effects on the initial arterial geometry and mechanical properties of the arterial tissue. The proposed model has potential to describe and advance mechanistic understanding of adaptive arterial remodeling, promote the continual refinement of mathematical models of arterial remodeling, and provide motivation for new avenues of experimental investigation.

Regional and temporal changes in left ventricular strain and stiffness in a porcine model of myocardial infarction.

The aim of the present study was to serially track how myocardial infarction (MI) impacts regional myocardial strain and mechanical properties of the left ventricle (LV) in a large animal model. Post-MI remodeling has distinct regional effects throughout the LV myocardium. Regional quantification of LV biomechanical behavior could help explain changes in global function and thus advance clinical assessment of post-MI remodeling. The present study is based on a porcine MI model to characterize LV biomechanics over 28 days post-MI via speckle-tracking echocardiography (STE). Regional myocardial strain and strain rate were recorded in the circumferential, radial, and longitudinal directions at baseline and at 3, 14, and 28 days post-MI. Regional myocardial wall stress was calculated using standard echocardiographic metrics of geometry and Doppler-derived hemodynamic measurements. Regional diastolic myocardial stiffness was calculated from the resultant stress-strain relations. Peak strain and phasic strain rates were nonuniformly reduced throughout the myocardium post-MI, whereas time to peak strain was increased to a similar degree in the MI region and border zone by 28 days post-MI. Elevations in diastolic myocardial stiffness in the MI region plateaued at 14 days post-MI, after which a significant reduction in MI regional stiffness in the longitudinal direction occurred between 14 and 28 days post-MI. Post-MI biomechanical changes in the LV myocardium were initially limited to the MI region but nonuniformly extended into the neighboring border zone and remote myocardium over 28 days post-MI. STE enabled quantification of regional and temporal differences in myocardial strain and diastolic stiffness, underscoring the potential of this technique for clinical assessment of post-MI remodeling. NEW & NOTEWORTHY For the first time, speckle-tracking echocardiography was used to serially track regional biomechanical behavior and mechanical properties postmyocardial infarction (post-MI). We found that changes initially confined to the MI region extended throughout the myocardium in a nonuniform fashion over 28 days post-MI. Speckle-tracking echocardiography-based evaluation of regional changes in left ventricular biomechanics could advance both clinical assessment of left ventricular remodeling and therapeutic strategies that target aberrant biomechanical behavior post-MI.

Perfusion Tissue Culture Initiates Differential Remodeling of Internal Thoracic Arteries, Radial Arteries, and Saphenous Veins.

Adaptive remodeling processes are essential to the maintenance and viability of coronary artery bypass grafts where clinical outcomes depend strongly on the tissue source. In this investigation, we utilized an ex vivo perfusion bioreactor to culture porcine analogs of common human bypass grafts: the internal thoracic artery (ITA), the radial artery (RA), and the great saphenous vein (GSV), and then evaluated samples acutely (6 h) and chronically (7 days) under in situ or coronary-like perfusion conditions. Although morphologically similar, primary cells harvested from the ITA illustrated lower intimal and medial, but not adventitial, cell proliferation rates than those from the RA or GSV. Basal gene expression levels were similar in all vessels, with only COL3A1, SERPINE1, FN1, and TGFB1 being differentially expressed prior to culture; however, over half of all genes were affected nominally by the culturing process. When exposed to coronary-like conditions, RAs and GSVs experienced pathological remodeling not present in ITAs or when vessels were studied in situ. Many of the remodeling genes perturbed at 6 h were restored after 7 days (COL3A1, FN1, MMP2, and TIMP1) while others (SERPINE1, TGFB1, and VCAM1) were not. The findings elucidate the potential mechanisms of graft failure and highlight strategies to encourage healthy ex vivo pregraft conditioning.

Impact of same-session trabectome surgery on Ahmed glaucoma valve outcomes.

PURPOSE: To evaluate the efficacy and survival rates of same session ab interno trabeculectomy with the trabectome and Ahmed glaucoma valve implant (AT) in comparison to the Ahmed glaucoma valve alone (A). METHOD: A total of 107 eyes undergoing primary glaucoma surgery were enrolled in this retrospective comparative case series, including 48 eyes which underwent AT and 59 eyes which received A alone. Participants were identified using the procedural terminology codes, and their medical records were reviewed. The primary outcome measure was success defined as IOP > 5 mmHg, ≤ 21 mmHg and ≥ 20% reduction of IOP from baseline at two consecutive visits after 3 months, and no need for glaucoma reoperation. Secondary outcome measures were IOP, the number of glaucoma medications, incidence of a hypertensive phase, and best corrected visual acuity (BCVA). RESULTS: The cumulative probability of success at 1 year was 70% in AT, and 65% in A (p = 0.85). IOP decreased significantly from 26.6 ± 10.1 mmHg at baseline to 14.7 ± 3.3 mmHg at the final follow-up in AT (p = 0.001). The corresponding numbers for A were 27.8 ± 10.2 and 16.7 ± 4.9, respectively (p = 0.001). The final IOP was significantly lower in AT (p = 0.022). The number of medications at baseline was comparable in both groups (2.6 ± 1.2 in AT and 2.5 ± 1.3 in A, p = 0.851). Corresponding number at 1 year visit was 1.2 ± 2 in AT and 2.8 ± 1.8 in A (p = 0.001). The incidence of a hypertensive phase was 18.7% in AT and 35.5% in A (p = 0.05). HP resolved in only 30% of eyes. The criteria for HP resolution were fulfilled in 9 eyes (30%). There was no difference in the rate of resolution of the hypertensive phase between AT and A (33.3 and 28.5%, respectively, p = 0.67). CONCLUSION: Ahmed glaucoma valve implant with same session trabectome surgery significantly decreased the rate of the hypertensive phase and postoperative IOP as well as the number of glaucoma medications.

Contractile Smooth Muscle and Active Stress Generation in Porcine Common Carotids.

The mechanical response of intact blood vessels to applied loads can be delineated into passive and active components using an isometric decomposition approach. Whereas the passive response is due predominantly to the extracellular matrix (ECM) proteins and amorphous ground substance, the active response depends on the presence of smooth muscle cells (SMCs) and the contractile machinery activated within those cells. To better understand determinants of active stress generation within the vascular wall, we subjected porcine common carotid arteries (CCAs) to biaxial inflation-extension testing under maximally contracted or passive SMC conditions and semiquantitatively measured two known markers of the contractile SMC phenotype: smoothelin and smooth muscle-myosin heavy chain (SM-MHC). Using isometric decomposition and established constitutive models, an intuitive but novel correlation between the magnitude of active stress generation and the relative abundance of smoothelin and SM-MHC emerged. Our results reiterate the importance of stretch-dependent active stress generation to the total mechanical response. Overall these findings can be used to decouple the mechanical contribution of SMCs from the ECM and is therefore a powerful tool in the analysis of disease states and potential therapies where both constituent are altered.

Longer-term Baerveldt to Trabectome glaucoma surgery comparison using propensity score matching.

PURPOSE: To apply propensity score matching to compare Baerveldt glaucoma drainage implant (BGI) to Trabectome-mediated ab interno trabeculectomy (AIT). Recent data suggests that AIT can produce results similar to BGI which is traditionally reserved for more severe glaucoma. METHODS: BGI and AIT patients with at least 1 year of follow-up were included. The primary outcome measures were intraocular pressure (IOP), number of glaucoma medications, and a Glaucoma Index (GI) score. GI reflected glaucoma severity based on visual field, the number of preoperative medications, and preoperative IOP. Score matching used a genetic algorithm consisting of age, gender, type of glaucoma, concurrent phacoemulsification, baseline number of medications, and baseline IOP. Patients with neovascular glaucoma, with prior glaucoma surgery, or without a close match were excluded. RESULTS: Of 353 patients, 30 AIT patients were matched to 29 BGI patients. Baseline characteristics including, IOP, the number of glaucoma medications, type of glaucoma, the degree of VF loss and GI were not significantly different between AIT and BGI. BGI had a preoperative IOP of 21.6 ± 6.3 mmHg compared to 21.5 ± 7.4 for AIT on 2.8 ± 1.1 medications and 2.5 ± 2.3 respectively. At 30 months, the mean IOP was 15.0 ± 3.9 mmHg for AIT versus 15.0 ± 5.7 mmHg for BGI (p > 0.05), while the number of drops was 1.5 ± 1.3 for AIT (change: p = 0.001) versus 2.4 ± 1.2 for BGI (change: p = 0.17; AIT vs BGI: 0.007). Success, defined as IOP < 21 mmHg, < 20% reduction and no reoperation, was achieved at 1 year in 56% of AIT versus 55% of BGI (p > 0.05) and 50% versus 52% at 2.5 years. CONCLUSIONS: A propensity score matched comparison of AIT and BGI demonstrated a similar IOP reduction through 1 year. AIT required fewer medications.

A simple infrared-augmented digital photography technique for detection of pupillary abnormalities.

BACKGROUND: The purpose of the study was to describe a simple infrared photography technique to aid in the diagnosis and documentation of pupillary abnormalities. METHODS: An unmodified 12-megapixel "point and shoot" digital camera was used to obtain binocular still photos and videos under different light conditions with near-infrared illuminating frames. The near-infrared light of 850 nm allows the capture of clear pupil images in both dim and bright light conditions. It also allows easy visualization of the pupil despite pigmented irides by augmenting the contrast between the iris and the pupil. RESULTS: The photos and videos obtained illustrated a variety of pupillary abnormalities using the aforementioned technique. CONCLUSIONS: This infrared-augmented photography technique supplements medical education, and aids in the more rapid detection, diagnosis, and documentation of a wide spectrum of pupillary abnormalities. Its portability and ease of use with minimal training complements the education of trainees and facilitates the establishment of difficult diagnoses.

Lymphoma of the orbit masquerading as Tolosa-Hunt syndrome.

BACKGROUND: Tolosa-Hunt syndrome is a rare clinical syndrome characterized by painful ophthalmoplegia and ipsilateral cranial neuropathies. It is caused by an inflammatory process of unknown etiology. CASE PRESENTATION: We present a case of a 77-year-old white man with history of Waldenstrom's macroglobulinemia transforming to large B-cell lymphoma who presented to a community physician complaining of 4 months of isolated right retro-orbital pain and later with diplopia, ptosis, 6th nerve and pupil-sparing partial 3rd nerve palsies as well as progressive neurological findings. His clinical course was complicated by debilitating neurological symptoms and multiple hospitalizations leading to a delay in diagnosis caused by incomplete initial workup. CONCLUSION: This case is a reminder that lymphoproliferative disorders often mimic other neurologic disorders and that Tolosa-Hunt is a rare diagnosis that must be considered a diagnosis of exclusion.

Mechanisms of tissue uptake and retention in zotarolimus-coated balloon therapy.

BACKGROUND: Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. METHODS AND RESULTS: Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. CONCLUSIONS: A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue-lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.

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.

A preliminary analysis of the data from an in vitro inflation-extension test can validate the assumption of arterial tissue elasticity.

The objective of this study is to propose a method for preliminary processing of the experimental data from an inflation-extension test on tubular arterial specimens. The method is based on the condition for existence of a strain energy function (SEF) and can be used to verify whether the data from a certain experiment validate the assumption that the tissue can be considered as an elastic solid. As an illustrative example of the proposed method, experimental data for a porcine renal artery are used and the sources of the error in satisfying the condition of elasticity are analyzed. The results lead to the conclusion that the experimental data for a renal artery validate that the artery exhibits an elastic mechanical response and a constitutive formulation based on the existence of the SEF is justified. A modification of the proposed method for the case of an in-plane biaxial stretching test of mechanically isotropic and orthotropic tissues is considered.

Are geometrical and structural variations along the length of the aorta governed by a principle of "optimal mechanical operation"?

It is well-documented that the geometrical dimensions, the longitudinal stretch ratio in situ, certain structural mechanical descriptors such as compliance and pressure-diameter moduli, as well as the mass fractions of structural constituents, vary along the length of the descending aorta. The origins of and possible interrelations among these observed variations remain open questions. The central premise of this study is that having considered the variation of the deformed inner diameter, axial stretch ratio, and area compliance along the aorta to be governed by the systemic requirements for flow distribution and reduction of cardiac preload, the zero-stress state geometry and mass fractions of the basic structural constituents of aortic tissue meet a principle of optimal mechanical operation. The principle manifests as a uniform distribution of the circumferential stress in the aortic wall that ensures effective bearing of the physiological load and a favorable mechanical environment for mechanosensitive vascular smooth muscle cells. A mathematical model is proposed and inverse boundary value problems are solved for the equations that follow from finite elasticity, structure-based constitutive modeling within constrained mixture theory, and stress-induced control of aortic homeostasis, mediated by the synthetic activity of vascular smooth muscle cells. Published experimental data are used to illustrate the predictive power of the proposed model. The results obtained are in agreement with published experimental data and support the proposed principle of optimal mechanical operation for the descending aorta.

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.