Haemodynamic, hormonal and renal actions of osteocrin in normal sheep.

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.

Combined Inhibition of Phosphodiesterase-5 and -9 in Experimental Heart Failure.

BACKGROUND: Intracellular second messenger cyclic guanosine monophosphate (cGMP) mediates bioactivity of the natriuretic peptides and nitric oxide, and is key to circulatory homeostasis and protection against cardiovascular disease. Inhibition of cGMP-degrading phosphodiesterases (PDEs) PDE5 and PDE9 are emerging as pharmacological targets in heart failure (HF). OBJECTIVES: The present study investigated dual enhancement of cGMP in experimental HF by combining inhibition of PDE-5 (P5-I) and PDE-9 (P9-I). METHODS: Eight sheep with pacing-induced HF received on separate days intravenous P5-I (sildenafil), P9-I (PF-04749982), P5-I+P9-I, and vehicle control, in counterbalanced order. RESULTS: Compared with control, separate P5-I and P9-I significantly increased circulating cGMP concentrations in association with reductions in mean arterial pressure (MAP), left atrial pressure (LAP), and pulmonary arterial pressure (PAP), with effects of P5-I on cGMP, MAP, and PAP greater than those of P9-I. Only P5-I decreased pulmonary vascular resistance. Combination P5-I+P9-I further reduced MAP, LAP, and PAP relative to inhibition of either phosphodiesterase alone. P9-I and, especially, P5-I elevated urinary cGMP levels relative to control. However, whereas inhibition of either enzyme increased urine creatinine excretion and clearance, only P9-I induced a significant diuresis and natriuresis. Combined P5-I+P9-I further elevated urine cGMP with concomitant increases in urine volume, sodium and creatinine excretion, and clearance similar to P9-I alone, despite the greater MAP reductions induced by combination treatment. CONCLUSIONS: Combined P5-I+P9-I amalgamated the superior renal effects of P9-I and pulmonary effects of P5-1, while concurrently further reducing cardiac preload and afterload. These findings support combination P5-I+P9-I as a therapeutic strategy in HF.

Bacillus-based probiotic cleansers reduce the formation of dry biofilms on common hospital surfaces.

In the absence of liquid suspension, dry biofilms can form upon hard surfaces within a hospital environment, representing a healthcare-associated infection risk. Probiotic cleansers using generally recognized as safe organisms, such as those of the Bacillus genus, represent a potential strategy for the reduction of dry biofilm bioburden. The mechanisms of action and efficacy of these cleaners are, however, poorly understood. To address this, a preventative dry biofilm assay was developed using steel, melamine, and ceramic surfaces to assess the ability of a commercially available Bacillus spp. based probiotic cleanser to reduce the surface bioburden of Escherichia coli and Staphylococcus aureus. Via this assay, phosphate-buffered saline controls were able to generate dry biofilms within 7 days of incubation, with the application of the probiotic cleanser able to prevent >97.7% of dry biofilm formation across both pathogen analogs and surface types. Further to this, surfaces treated with the probiotic mixture alone also showed a reduction in dry biofilm across both pathogen and surface types. Confocal laser scanning microscopy imaging indicated that the probiotic bacteria were able to germinate and colonize surfaces, likely forming a protective layer upon these hard surfaces.

Interrogating the Role of miR-125b and Its 3'isomiRs in Protection against Hypoxia.

MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5' or 3' addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are few. In this study, we discovered using NGS, four 3'isomiRs of miR-125b, i.e., addition of A (adenosine), along with deletions of A, AG (guanosine) and AGU (uridine) from rat and sheep heart. These findings were validated using RT-qPCR. Comprehensive functional studies were carried out in the H9C2 hypoxia model. After miR-125b, isomiRs of Plus A, Trim A, AG and AGU mimic transfection, the H9C2 cells were subjected to hypoxic challenge. As assessed using cell viability, apoptosis, CCK-8 and LDH release, miR-125b and isomiRs were all protective against hypoxia. However, Plus A and Trim A were more effective than miR-125b, whilst Trim AG and Trim AGU had far weaker effects than miR-125b. Interestingly, both the gene regulation profile and apoptotic gene validation indicated a major overlap among miR-125b, Plus A and Trim A, whilst Trims AG and AGU revealed a different profile compared to miR-125b. Conclusions: miR-125b and its 3' isomiRs are expressed stably in the heart. miR-125b and isomiRs with addition or deletion of A might function concurrently and concordantly under specific physiological and pathophysiological conditions. In-depth understanding of isomiRs' metabolism and function will contribute to better miRNA therapeutic drug design.

Implant-to-implant wireless networking with metamaterial textiles.

Implanted bioelectronic devices can form distributed networks capable of sensing health conditions and delivering therapy throughout the body. Current clinically-used approaches for wireless communication, however, do not support direct networking between implants because of signal losses from absorption and reflection by the body. As a result, existing examples of such networks rely on an external relay device that needs to be periodically recharged and constitutes a single point of failure. Here, we demonstrate direct implant-to-implant wireless networking at the scale of the human body using metamaterial textiles. The textiles facilitate non-radiative propagation of radio-frequency signals along the surface of the body, passively amplifying the received signal strength by more than three orders of magnitude (>30 dB) compared to without the textile. Using a porcine model, we demonstrate closed-loop control of the heart rate by wirelessly networking a loop recorder and a vagus nerve stimulator at more than 40 cm distance. Our work establishes a wireless technology to directly network body-integrated devices for precise and adaptive bioelectronic therapies.

Comparison of SPEED, S-Trap, and In-Solution-Based Sample Preparation Methods for Mass Spectrometry in Kidney Tissue and Plasma.

Mass spectrometry is a powerful technique for investigating renal pathologies and identifying biomarkers, and efficient protein extraction from kidney tissue is essential for bottom-up proteomic analyses. Detergent-based strategies aid cell lysis and protein solubilization but are poorly compatible with downstream protein digestion and liquid chromatography-coupled mass spectrometry, requiring additional purification and buffer-exchange steps. This study compares two well-established detergent-based methods for protein extraction (in-solution sodium deoxycholate (SDC); suspension trapping (S-Trap)) with the recently developed sample preparation by easy extraction and digestion (SPEED) method, which uses strong acid for denaturation. We compared the quantitative performance of each method using label-free mass spectrometry in both sheep kidney cortical tissue and plasma. In kidney tissue, SPEED quantified the most unique proteins (SPEED 1250; S-Trap 1202; SDC 1197). In plasma, S-Trap produced the most unique protein quantifications (S-Trap 150; SDC 148; SPEED 137). Protein quantifications were reproducible across biological replicates in both tissue (R2 = 0.85-0.90) and plasma (SPEED R2 = 0.84; SDC R2 = 0.76, S-Trap R2 = 0.65). Our data suggest SPEED as the optimal method for proteomic preparation in kidney tissue and S-Trap or SPEED as the optimal method for plasma, depending on whether a higher number of protein quantifications or greater reproducibility is desired.

Augmentation of Natriuretic Peptide Bioactivity via Combined Inhibition of Neprilysin and Phosphodiesterase-9 in Heart Failure.

BACKGROUND: The natriuretic peptides (NPs) are potent natriuretic/diuretic and vasodilatory factors, and augmentation of their levels or signaling via inhibition of the enzymes neprilysin (NEP) and phosphodiesterase 9 (PDE9), respectively, has beneficial actions in heart failure (HF). OBJECTIVES: The authors investigated dual enhancement of NP bioactivity by combining PDE9 inhibition and NEP inhibition in HF using an ovine model. METHODS: Eight sheep with pacing-induced HF received on 4 separate days intravenous PDE9 inhibition (PF-04749982), NEP inhibition (SCH-32615), PDE9 inhibition + NEP inhibition (PI+NI), and vehicle control treatment. RESULTS: Compared with the control treatment, NEP inhibition significantly increased plasma NP concentrations with a corresponding rise in second messenger cyclic guanosine monophosphate (cGMP), whereas PDE9 inhibition increased circulating cGMP with a negligible effect on NP levels. Combined PI+NI elevated plasma NPs to an extent comparable to that seen with NEP inhibition alone but further increased cGMP, resulting in a rise in the cGMP-to-NP ratio. All active treatments reduced mean arterial pressure, left atrial pressure, pulmonary arterial pressure, and peripheral resistance, with combined PI+NI further reducing mean arterial pressure and left atrial pressure relative to either inhibitor separately. Active treatments increased urine volume and sodium, potassium and creatinine excretion, and creatinine clearance, in association with rises in urine cGMP levels. PI+NI induced a significantly greater natriuresis and increase in urinary cGMP relative to either inhibitor singly. CONCLUSIONS: The present study demonstrates for the first time that combined PI+NI has additional beneficial hemodynamic and renal effects when compared with either PDE9 inhibition or NEP inhibition alone. The superior efficacy of this 2-pronged augmentation of NP bioactivity supports PI+NI as a potential therapeutic strategy for HF.

Morphological, functional, and biomechanical progression of LV remodelling in a porcine model of HFpEF.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for about half of heart failure cases, but the progression of cardiac biomechanics during pathogenesis is not completely understood. We investigated a published porcine model of HFpEF, generated by progressive constriction of an aortic cuff causing progressive left ventricle (LV) pressure overload, and characterized by hypertrophy, diastolic dysfunction and overt HF with elevated plasma beta natriuretic peptide (BNP). We characterized morphological and functional features and performed image-based finite element modelling over multiple time points, so as to understand how biomechanics evolved with morphological and functional changes during pathogenesis, and to provide data for future growth and remodeling investigations. Results showed that the hypertrophic responses quickly manifested and were effective at preventing an elevation of systolic myocardial stresses, suggesting active compensated remodeling. Consequent to the hypertrophy, diastolic myocardial stresses decreased despite the elevations in diastolic pressures. The left ventricle hypertrophy (LVH) myocardium also exhibited a quick elevation of active tension at the onset of the disease. There was a progressive and significant decrease in myocardial strain, which was more significant in the longitudinal direction. Further, elevated myocardial stiffness and diastolic pressures, which reflected diastolic dysfunction, also manifested, but this was delayed from the onset of the disease. Correlation analysis showed that hypertrophy was closely correlated to systolic pressure, active tension and systolic myocardial stress, suggesting that these factors may play a role in initiating hypertrophy. Myocardial stiffness was weakly correlated to LV pressures and myocardial stresses.

Material property alterations for phenotypes of heart failure with preserved ejection fraction: A numerical study of subject-specific porcine models.

A substantial proportion of heart failure patients have a preserved left ventricular (LV) ejection fraction (HFpEF). This condition carries a high burden of morbidity and mortality and has limited therapeutic options. left ventricular pressure overload leads to an increase in myocardial collagen content, causing left ventricular stiffening that contributes to the development of heart failure patients have a preserved left ventricular ejection fraction. Although several heart failure patients have a preserved left ventricular ejection fraction models have been developed in recent years to aid the investigation of mechanical alterations, none has investigated different phenotypes of the disease and evaluated the alterations in material properties. In this study, two similar healthy swine were subjected to progressive and prolonged pressure overload to induce diastolic heart failure characteristics, providing a preclinical model of heart failure patients have a preserved left ventricular ejection fraction. Cardiac magnetic resonance imaging (cMRI) scans and intracardiac pressures were recorded before and after induction. In both healthy and disease states, a corresponding finite element (FE) cardiac model was developed via mesh morphing of the Living Heart Porcine model. The material properties were derived by calibrating to its passive and active behavior. The change in the passive behavior was predominantly isotropic when comparing the geometries before and after induction. Myocardial thickening allowed for a steady transition in the passive properties while maintaining tissue incompressibility. This study highlights the importance of hypertrophy as an initial compensatory response and might also pave the way for assessing disease severity.

Needle-integrated ultrathin bioimpedance microsensor array for early detection of extravasation.

Extravasation is a common complication during intravenous therapy in which infused fluids leak into the surrounding tissues. Timely intervention can prevent severe adverse consequences, but early detection remains an unmet clinical need because existing sensors are not sensitive to leakage occurring in small volumes (< 200 µL) or at deep venipuncture sites. Here, an ultrathin bioimpedance microsensor array that can be integrated on intravenous needles for early and sensitive detection of extravasation is reported. The array comprises eight microelectrodes fabricated on an ultrathin and flexible polyimide substrate as well as functionalized using poly(3,4-ethylenedioxythiophene) and multi-walled carbon nanotubes. Needle integration places the array proximity to venipuncture site, and functional coating significantly reduces interface impedance, both enable the microsensors with high sensitivity to detect early extravasation. In vitro and in vivo experiments demonstrate the capability of the microsensors to differentiate various intravenous solutions from different tissue layers as well as identify saline extravasation with detection limit as low as 20 µL.

The evolution of alkaliphilic biofilm communities in response to extreme alkaline pH values.

Extremes of pH present a challenge to microbial life and our understanding of survival strategies for microbial consortia, particularly at high pH, remains limited. The utilization of extracellular polymeric substances within complex biofilms allows micro-organisms to obtain a greater level of control over their immediate environment. This manipulation of the immediate environment may confer a survival advantage in adverse conditions to biofilms. Within the present study alkaliphilic biofilms were created at pH 11.0, 12.0, or 13.0 from an existing alkaliphilic community. In each pH system, the biofilm matrix provided pH buffering, with the internal pH being 1.0-1.5 pH units lower than the aqueous environment. Increasing pH resulted in a reduced removal of substrate and standing biomass associated with the biofilm. At the highest pH investigated (pH 13.0), the biofilms matrix contained a greater degree of eDNA and the microbial community was dominated by Dietzia sp. and Anaerobranca sp.

Effects of Hypertrophic and Dilated Cardiac Geometric Remodeling on Ejection Fraction.

Background: Both heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) can present a wide variety of cardiac morphologies consequent to cardiac remodeling. We sought to study if geometric changes to the heart during such remodeling will adversely affect the ejection fraction (EF) parameter's ability to serve as an indicator of heart function, and to identify the mechanism for it. Methods and Results: A numerical model that simulated the conversion of myocardial strain to stroke volume was developed from two porcine animal models of heart failure. Hypertrophic wall thickening was found to elevate EF, while left ventricle (LV) dilation was found to depress EF when myocardial strain was kept constant, causing EF to inaccurately represent the overall strain function. This was caused by EF being calculated using the endocardial boundary rather than the mid-wall layer. Radial displacement of the endocardial boundary resulted in endocardial strain deviating from the overall LV strain, and this deviation varied with LV geometric changes. This suggested that using the epi- or endo-boundaries to calculate functional parameters was not effective, and explained why EF could be adversely affected by geometric changes. Further, when EF was modified by calculating it at the mid-wall layer instead of at the endocardium, this shortcoming was resolved, and the mid-wall EF could differentiate between healthy and HFpEF subjects in our animal models, while the traditional EF could not. Conclusion: We presented the mechanism to explain why EF can no longer effectively indicate cardiac function during cardiac geometric changes relevant to HF remodeling, losing the ability to distinguish between hypertrophic diseased hearts from healthy hearts. Measuring EF at the mid-wall location rather than endocardium can avoid the shortcoming and better represent the cardiac strain function.

A novel coating method to reduce membrane infolding through pre-crimping of covered stents - Computational and experimental evaluation.

A covered stent has been used to treat carotid artery stenosis to reduce the chance of embolization, as it offers improved performance over bare-metal stents. However, membrane infolding of covered stents can affect efficiency and functionality for treating occlusive disease of first-order aortic branches. In order to mitigate the degree of infolding of the stent once it was re-expanded, we proposed a new coating method performed on the pre-crimped stent. A systematic study was carried out to evaluate this new coating technique: a) in vivo animal testing to determine the degree of membrane infolding; b) structural finite element modeling and simulation were used to evaluate the mechanical performance of the covered stent; and c) computational fluid dynamics (CFD) to evaluate hemodynamic behavior of the stents and risk of thrombosis after stent deployment. The degree of infolding was substantially reduced as demonstrated by the in vivo deployment of the pre-crimped stent compared to a conventional dip-coated stent. The structural analysis results demonstrated that the membrane of the covered stent manufactured by conventional dip-coating resulted in a large degree of infolding but this could be minimized by our new pre-crimped coating method. CFD studies showed that the new coating method reduced the risk of thrombosis compared to the conventional coating method. In conclusion, both simulation and in vivo testing demonstrate that our new pre-crimped coating method reduces membrane infolding compared with the conventional dip-coating method and may reduce risk of thrombosis.

Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure.

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)-an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra-mass spectrometry (SWATH-MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2-2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Cardiac mesh morphing method for finite element modeling of heart failure with preserved ejection fraction.

Numerical modeling of heart biomechanics can realistically capture morphological variations in diseases and has been helpful in advancing our understanding of the physiology. Subject-specific models require anatomic representation of medical images, and it is desirable to have a consistently repeatable models for any given morphology. In this study, we propose a novel and easily adaptable cardiac reconstruction algorithm by morphing an existing discretized mesh of an advanced finite element (FE) model, to match anatomies acquired from porcine cardiac magnetic resonance imaging (cMRI) scans. The morphing algorithm involves iterative FE simulations with visco-hyperelastic material properties. The living heart porcine model (LHPM) was chosen as the input baseline FE mesh, in order to preserve detailed anatomical features that cannot be captured in routine scans such as myofiber orientations and conduction pathways. The algorithm was demonstrated for the recreation of porcine hearts of a healthy subject and of a subject induced with heart failure with preserved ejection fraction (HFpEF) conditions, where there were substantial hypertrophy and anatomical alterations. We further used the morphed meshes for FE modeling of cardiac contraction and relaxation, thus demonstrating the applicability of the proposed algorithm in producing viable meshes. The results show that our algorithm can recreate the characteristic anatomical changes of cardiac remodeling, including heart muscle thickening, as well as replicate the reduction in ventricular volume. This algorithm allows for the creation of subject-specific models with the same mesh connectivity, thus enabling spatial comparison and analysis of pathologic progress.

Wirelessly operated bioelectronic sutures for the monitoring of deep surgical wounds.

Monitoring surgical wounds post-operatively is necessary to prevent infection, dehiscence and other complications. However, the monitoring of deep surgical sites is typically limited to indirect observations or to costly radiological investigations that often fail to detect complications before they become severe. Bioelectronic sensors could provide accurate and continuous monitoring from within the body, but the form factors of existing devices are not amenable to integration with sensitive wound tissues and to wireless data transmission. Here we show that multifilament surgical sutures functionalized with a conductive polymer and incorporating pledgets with capacitive sensors operated via radiofrequency identification can be used to monitor physicochemical states of deep surgical sites. We show in live pigs that the sutures can monitor wound integrity, gastric leakage and tissue micromotions, and in rodents that the healing outcomes are equivalent to those of medical-grade sutures. Battery-free wirelessly operated bioelectronic sutures may facilitate post-surgical monitoring in a wide range of interventions.

Acute Decompensated Heart Failure and the Kidney: Physiological, Histological and Transcriptomic Responses to Development and Recovery.

BACKGROUND Acute decompensated heart failure (ADHF) is associated with deterioration in renal function-an important risk factor for poor outcomes. Whether ADHF results in permanent kidney damage/dysfunction is unknown. METHODS AND RESULTS We investigated for the first time the renal responses to the development of, and recovery from, ADHF using an ovine model. ADHF development induced pronounced hemodynamic changes, neurohormonal activation, and decline in renal function, including decreased urine, sodium and urea excretion, and creatinine clearance. Following ADHF recovery (25 days), creatinine clearance reductions persisted. Kidney biopsies taken during ADHF and following recovery showed widespread mesangial cell prominence, early mild acute tubular injury, and medullary/interstitial fibrosis. Renal transcriptomes identified altered expression of 270 genes following ADHF development and 631 genes following recovery. A total of 47 genes remained altered post-recovery. Pathway analysis suggested gene expression changes, driven by a network of inflammatory cytokines centered on IL-1ß (interleukin 1ß), lead to repression of reno-protective eNOS (endothelial nitric oxide synthase) signaling during ADHF development, and following recovery, activation of glomerulosclerosis and reno-protective pathways and repression of proinflammatory/fibrotic pathways. A total of 31 dysregulated genes encoding proteins detectable in urine, serum, and plasma identified potential candidate markers for kidney repair (including CNGA3 [cyclic nucleotide gated channel subunit alpha 3] and OIT3 [oncoprotein induced transcript 3]) or long-term renal impairment in ADHF (including ACTG2 [actin gamma 2, smooth muscle] and ANGPTL4 [angiopoietin like 4]). CONCLUSIONS In an ovine model, we provide the first direct evidence that an episode of ADHF leads to an immediate decline in kidney function that failed to fully resolve after ≈4 weeks and is associated with persistent functional/structural kidney injury. We identified molecular pathways underlying kidney injury and repair in ADHF and highlighted 31 novel candidate biomarkers for acute kidney injury in this setting.

Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model.

The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes underpinned our test of the efficacy of MSC exosomes in a porcine model of myocardial infarction (MI) when administered systemically by the convenient method of intravenous (IV) bolus injection. Results show that 7 days of IV exosomes results in clear reduction (30-40%) of infarct size measured at both 7 and 28 days post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Taken together, these results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.

Large Animal Models of Heart Failure: Reduced vs. Preserved Ejection Fraction.

Heart failure (HF) is the final common end point of multiple metabolic and cardiovascular diseases and imposes a significant health care burden worldwide. Despite significant improvements in clinical management and outcomes, morbidity and mortality remain high and there remains an indisputable need for improved treatment options. The pathophysiology of HF is complex and covers a spectrum of clinical presentations from HF with reduced ejection fraction (HFrEF) (≤40% EF) through to HF with preserved EF (HFpEF), with HFpEF patients demonstrating a reduced ability of the heart to relax despite an EF maintained above 50%. Prior to the last decade, the majority of clinical trials and animal models addressed HFrEF. Despite growing efforts recently to understand underlying mechanisms of HFpEF and find effective therapies for its treatment, clinical trials in patients with HFpEF have failed to demonstrate improvements in mortality. A significant obstacle to therapeutic innovation in HFpEF is the absence of preclinical models including large animal models which, unlike rodents, permit detailed instrumentation and extensive imaging and sampling protocols. Although several large animal models of HFpEF have been reported, none fulfil all the features present in human disease and few demonstrate progression to frank decompensated HF. This review summarizes well-established models of HFrEF in pigs, dogs and sheep and discusses attempts to date to model HFpEF in these species.

Measurement of the Luminal Diameter of Peripheral Arterial Vasculature in Yorkshire×Landrace Swine by Using Ultrasonography and Angiography.

To select animals of appropriate size for preclinical studies of cardiovascular devices, reference knowledge of the cardiovascularanatomy relative to body weight is crucial. We measured the luminal diameters of the arteries (carotid, femoral, and iliac arteries) that are the common access vessels for endovascular and vascular procedures in Yorkshire×Landrace swine. Measurements were performed by using both ultrasound and angiographic methods and were correlated with body weight. Results showed no statistically significant difference between the left and right vessels in the diameters of the carotid,femoral, and iliac arteries. The diameters of the measured arteries showed high correlation with animal weight in pigs thatweighed less than 70 kg.