Search

Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in heart failure patients with reduced and preserved left ventricular ejection fraction (LVEF), but have not yet been investigated in transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to evaluate tolerability, clinical outcomes, and changes in NT-proBNP levels and glomerular filtration rate (GFR) in ATTR-CM patients treated with dapagliflozin., Methods and Results: Patients with stable, tafamidis-treated ATTR-CM were retrospectively evaluated at the initiation of dapagliflozin and 3 months thereafter. Tafamidis-treated ATTR-CM patients without SGLT2i served as a reference cohort. Overall, SLGT2i therapy was initiated in 34 patients. Seventeen patients with stable disease on tafamidis, who were subsequently started on dapagliflozin, were included in the analysis. Patients selected for SGLT2i presented with signs of advanced disease, evidenced by higher Gillmore disease stage (stage ≥2: 53% vs. 27.5%; P = 0.041), baseline median NT-proBNP [median (IQR) 2668 pg/mL (1314-3451) vs. 1424 (810-2059); P = 0.038] and loop diuretic demand (76.5% vs. 45% of patients; P = 0.044), and lower LVEF (46.6 ± 12.9 vs. 53.7 ± 8.7%; P = 0.019) and GFR (51.8 ± 16.5 vs. 68.5 ± 18.6 mL/min; P = 0.037) compared with the reference cohort. At 3-month follow-up, a numerical decrease in NT-proBNP levels was observed in 13/17 (76.5%) patients in the dapagliflozin (-190 pg/mL, IQR: -1,028-71, P = 0.557) and 27/40 (67.5%) of patients in the control cohort (-115 pg/mL, IQR: -357-105, P = 0.551). Other disease parameters remained stable and no adverse events occurred., Conclusions: In tafamidis-treated ATTR-CM patients, initiation of dapagliflozin was well tolerated. The efficacy of SGLT2i therapy in patients with ATTR-CM needs to be studied in randomized controlled trials., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Increased left ventricular afterload resulting from severe aortic stenosis (AS) leads to progressive cardiac remodeling. Left atrial enlargement (LAE) is an early manifestation in a series of maladaptive changes and may affect clinical outcomes after valvular replacement therapy. The aim of this study is to determine the impact of LAE on clinical outcomes in symptomatic patients with severe AS undergoing transcatheter aortic valve implantation (TAVI)., Methods: In a prospective single-center TAVI registry, we analyzed LA dimensions measured by echocardiography before intervention. Patients with atrial fibrillation or concomitant mitral valve disease were excluded. LAE was defined as indexed LA volume >34 ml/m 2 . The primary endpoint was cardiovascular death (CVD) at 1 year., Results: Among 1663 patients undergoing TAVI between August 2007 and December 2016, 768 (46.2%) were eligible for the present analysis and 486 patients had LAE. The prevalence of LAE was higher in males (68.3%) as compared to females (58.8%). Patients with LAE were older (82.3 ± 6.7 years vs. 80.0 ± 6.4 years) and had a higher STS-PROM score (6.1 ± 4.7% vs. 4.7 ± 2.9%). After adjustment, patients with LAE had an increased risk of CVD at 1-year compared to patients with normal LA dimensions (49 [10.4%] vs. 8 [2.9%]; HR adj , 3.52; 95% CI, 1.66-7.44)]. In multivariable analysis, LAE was independently associated with an increased risk of CVD at 1-year (HR adj , 3.52; 95% CI, 1.66-7.44)., Conclusions: LAE secondary to AS was documented in a significant proportion of patients undergoing TAVI and was associated with a more than threefold increased risk of CVD at 1-year., (© 2022 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

We observed a lesion pattern in a series of 4 cases of RANBP2 -mutation-linked acute necrotizing encephalopathy, which appears to be specific for this condition. The setting of synchronous bilateral mammillary, amygdaloid, and lateral geniculate lesions, along with claustro-parahippocampal lesions, can serve as a diagnostic tool in this condition. We add several further details to the MR imaging features of the typical brain lesions encountered in this disease., (© 2021 by American Journal of Neuroradiology.)

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Importance: Left ventricular remodeling following acute myocardial infarction results in progressive myocardial dysfunction and adversely affects prognosis., Objective: To investigate the efficacy of paroxetine-mediated G-protein-coupled receptor kinase 2 inhibition to mitigate adverse left ventricular remodeling in patients presenting with acute myocardial infarction., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial was conducted at Bern University Hospital, Bern, Switzerland. Patients with acute anterior ST-segment elevation myocardial infarction with left ventricular ejection fraction (LVEF) of 45% or less were randomly allocated to 2 study arms between October 26, 2017, and September 21, 2020., Interventions: Patients in the experimental arm received 20 mg of paroxetine daily; patients in the control group received a placebo daily. Both treatments were provided for 12 weeks., Main Outcomes and Measures: The primary end point was the difference in patient-level improvement of LVEF between baseline and 12 weeks as assessed by cardiac magnetic resonance tomography. Secondary end points were changes in left ventricular dimensions and late gadolinium enhancement between baseline and follow-up., Results: Fifty patients (mean [SD] age, 62 [13] years; 41 men [82%]) with acute anterior myocardial infarction were randomly allocated to paroxetine or placebo, of whom 38 patients underwent cardiac magnetic resonance imaging both at baseline and 12 weeks. There was no difference in recovery of LVEF between the experimental group (mean [SD] change, 4.0% [7.0%]) and the control group (mean [SD] change, 6.3% [6.3%]; mean difference, -2.4% [95% CI, -6.8% to 2.1%]; P = .29) or changes in left ventricular end-diastolic volume (mean difference, 13.4 [95% CI, -12.3 to 39.0] mL; P = .30) and end-systolic volume (mean difference, 11.4 [95% CI, -3.6 to 26.4] mL; P = .13). Late gadolinium enhancement as a percentage of the total left ventricular mass decreased to a larger extent in the experimental group (mean [SD], -13.6% [12.9%]) compared with the control group (mean [SD], -4.5% [9.5%]; mean difference, -9.1% [95% CI, -16.6% to -1.6%]; P = .02)., Conclusions and Relevance: In this trial, treatment with paroxetine did not improve LVEF after myocardial infarction compared with placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT03274752.

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.

The relation between discharge location and outcomes after transcatheter aortic valve implantation (TAVI) is largely unknown. Thus, the objective of this study was to investigate the impact of discharge location on clinical outcomes after TAVI. Between August 2007 and December 2018, consecutive patients who underwent transfemoral TAVI at Bern University Hospital were grouped according to discharge location. Clinical adverse events were adjudicated according to VARC-2 end point definitions. Of 1,902 eligible patients, 520 (27.3%) were discharged home, 945 (49.7%) were discharged to a rehabilitation clinic and 437 (23.0%) were transferred to another institution. Compared with patients discharged to a rehabilitation facility or another institution, patients discharged home were younger (80.8 ± 6.5 vs 82.9 ± 5.4 and 82.8 ± 6.4 years), less likely female (37.3% vs 59.7% and 54.2%), and at lower risk according to STS-PROM (4.5 ± 3.0% vs 5.5 ± 3.8% and 6.6 ± 4.4%). At 1 year follow-up, patients discharged home had similar rates of all-cause mortality (HR adj 0.82; 95% CI 0.54 to 1.24), cerebrovascular events (HR adj 1.04; 95% CI 0.52 to 2.08) and bleeding complications (HR adj 0.93; 95% CI 0.61 to 1.41) compared with patients discharged to a rehabilitation facility. Patients discharged home or to rehabilitation were at lower risk for death (HR adj 0.37; 95% CI 0.24 to 0.56 and HR adj 0.44; 95% CI 0.32 to 0.60) and bleeding (HR adj 0.48; 95% CI 0.30 to 0.76 and HR adj 0.66; 95% CI 0.45 to 0.96) during the first year after hospital discharge compared with patients transferred to another institution. In conclusion, discharge location is associated with outcomes after TAVI with patients discharged home or to a rehabilitation facility having better clinical outcomes than patients transferred to another institution. Clinical Trial Registration: https://www.clinicaltrials.gov. NCT01368250., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cancer immunotherapy is a success story of translational medicine that has led to improved survival in patients with different difficult-to-treat types of cancer, such as metastasized melanoma, non-small cell lung cancer or renal cell carcinoma. These novel therapeutic agents exert their antitumor effects by activating the patients' immune system against cancer cells. Immunotherapy can be divided into active agents, such as anti-tumour vaccines or adoptive T-cell transfer, and passive immunotherapies like monoclonal antibodies, checkpoint inhibitors, cytokine therapy, bispecific T-cell engagers. After initial experimental use, broad clinical application revealed a number of important cardiovascular side effects of immunotherapeutics, which limit treatment options and decrease patients' prognosis and quality of life. With the rising rate of new immunotherapeutics at a hand, the number of patients receiving cancer immunotherapy will constantly increase, resulting in improved long-term survival rates. This review aims to summarize available cancer immunotherapies, their mechanism of action, currently known cardiovascular toxicities and their treatment. Further optimization of patient care will depend on the combined efforts by oncologists, cardiologists and cardiac surgeons to identify patients at risk and the implementation of interdisciplinary screening and treatment strategies. It is therefore crucial to familiarize heart specialists with novel cancer therapeutics and their potential adverse effects., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

An increasing number of mechanical assist devices, especially left ventricular assist devices (VADs), are being implanted for prolonged periods and as destination therapy. Some VAD patients require radiotherapy due to concomitant oncologic morbidities, including thoracic malignancies. This raises the potential of VAD malfunction via radiation-induced damage. So far, only case reports and small case series on radiotherapy have been published, most of them on HeartMate II (HMII, Abbott, North Chicago, IL, USA). Significantly, the effects of irradiation on the HeartMate 3 (HM3, Abbott) remain undefined, despite the presence of controller components engineered within the pump itself. We report the first case of a patient with a HM3 who successfully underwent stereotactic hypofractionated radiotherapy due to an early-stage non-small-cell lung cancer. The patient did not suffer from any complications, including toxicity or VAD malfunction. Based on this case report and on published literature, we think that performing radiotherapy after VAD implantation with the aid of a multidisciplinary team could be performed, but more in vitro studies and cases series are needed to reinforce this statement., (© 2019 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Hereby, the supplemental data of the research article "Long-Term Prognostic Value of High-Sensitivity Troponin T added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels before Valve Replacement for Severe Aortic Stenosis" are presented [1]. It offers enhanced input on the predictive value of these biomarkers considering the influence of the presence of concomitant coronary artery disease (CAD) in various severities as well as an additional cox proportional hazard model on cardiovascular mortality. Furthermore, the receiver operating characteristic (ROC) curves are shown as figures. The material described increases therefore the understanding of the predictive value of these already routinely available biomarkers and reduces the risk of potential bias due to possible confounding factors. It also underlines the urge for a multi-factorial approach in diagnostics to detect the optimal point for referral to valve replacement other than just symptomatic status, an observed reduction in left ventricular ejection fraction or the presence of CAD with the necessity for coronary artery bypass grafting (CABG) [2]. The data of the 3595 patients were gathered retrospectively at a consortium of four university hospital centers in Austria and combined with prospectively collected data on cardiovascular and all-cause mortality., (© 2020 The Authors.)

Natriuretic peptide plasma levels help to manage patients with severe aortic stenosis (AS). The role of troponin plasma levels in this patient cohort remains speculative. A consortium of 4 university hospital centers in Austria analyzed retrospectively 3,595 patients admitted for valve replacement because of severe AS since 2007. The aim was to compare the additive preprocedural value of high-sensitivity troponin T (hsTnT) to N-terminal pro brain natriuretic peptide (NT-proBNP) plasma levels in predicting postoperative long-term survival in a large cohort undergoing either surgical (57.8%) or transcatheter (42.2%) aortic valve replacement. During a median follow-up of 2.93 (1.91 to 4.92) years, 919 patients (25.6%) died, in them 556 (15.5%) due to cardiovascular causes. Both normal hsTnT (<14 ng/l) and NT-proBNP (within age- and sex-corrected normal range) plasma levels were found in 481 patients (14.3%, group 1). Normal hsTnT but elevated NT-proBNP plasma levels were found in 748 patients (22.3%, group 2). Elevated hsTnT but normal NT-proBNP plasma levels were found in 258 patients (7.7%, group 3). Both elevated hsTnT and elevated NT-proBNP plasma levels were found in 1,869 patients (55.7%, group 4). Using Log Rank tests for comparison there was a highly significant difference in both cardiovascular mortality (p <0.0001) and all-cause mortality (p <0.0001). All-cause mortality rates after 1, 3, and 5 years were 2.1%, 5.4%, 7.7% in group 1; 4.0%, 7.5%, 11.5% in group 2; 5.8%, 8.9%, 14.0% in group 3; and 12.3%, 22.6%, 28.4% in group 4. In conclusion, hsTnT adds additional impact to NT-proBNP as a routinely available biomarker for risk stratification concerning postoperative survival in patients with severe AS admitted for valve replacement. The present study supports the concept to integrate hsTnT plasma levels in the management of severe AS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pharmacological therapy of heart failure with reduced ejection fraction Abstract. Pharmacological therapy for heart failure has made great progress over the last three decades and evidence-based therapies have significantly improved survival and quality of life. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers are the cornerstone of the heart failure therapy; indicated in virtually every patient with heart failure and reduced ejection fraction. As soon as the left ventricular ejection fraction decreases below 35 % and / or symptoms are still present (NYHA II-IV), a mineralocorticoid receptor antagonist should be added. A rather recent addition to current heart failure therapy with convincing data is the substance combination sacubitril / valsartan. It is indicated for patients with persistent symptomatic heart failure despite optimal medical therapy with ACE inhibitors or ARBs, beta-blockers, and MRAs. Crucial for all mentioned substances is to aim for the maximal tolerated dose. Various additional therapies have no proven survival benefit but are important for symptom control in everyday life. Above all the diuretics, where loop diuretics show a better effect profile compared to thiazide diuretics. Furthermore, achieving an optimal iron status (the limit to start a substitution is significantly higher than in patients without heart failure), decreasing the heart frequency with Ivabradine (if heart rate persists above 70 / min despite fully dosed betablocker) and «lifestyle changes» can add to the success of the medical treatment. The importance of digoxin has been steadily decreasing. The previously advocated therapeutic anticoagulation in patients with severely reduced LVEF is not propagated anymore. Significant arrhythmias (especially atrial fibrillation and ventricular arrhythmias) are common in advanced diseases. In addition to beta-blockers, amiodarone is clearly the antiarrhythmic drug of choice. According to latest data, an early interventional treatment of atrial fibrillation by pulmonary vein ablation may be beneficial and has the potential to reduce mortality in special subgroups of patients. New developments in the field of antidiabetic drugs seem to be promising for reduction of mortality and hospitalization in patients with heart failure.

In this case study, a co-infection with coxsackievirus A5 (family Picornaviridae) and norovirus GII.4 (family Caliciviridae) was detected by RT-PCR in a faecal sample from a six-year-old girl with symptoms of severe acute encephalopathy subsequently diagnosed as the intermittent form of maple syrup urine disease (MSUD). The two co-infecting viruses, which had been detected previously, appeared to have triggered the underlying metabolic disorder. Here, we describe the genotyping of the viruses, as well as the chronological course, laboratory test results, and clinical presentation of this case, which included recurrent vomiting without diarrhoea, metabolic acidosis, unconsciousness, seizure and circulatory collapse, but with a positive final outcome.

We present a fiber-based optical parametric oscillator (FOPO) pumped by a fiber-coupled laser diode. The FOPO consisted of a photonic crystal fiber to convert the pump pulses via four-wave mixing and a dispersive resonator formed by a single-mode fiber. Via dispersion filtering, output pulses with a bandwidth of about 3 nm, a temporal duration of about 8 ps and a pulse energy of up to 22 nJ could be generated. By changing the repetition frequency of the pump laser diode by about ±1  kHz, the wavelength of the output pulses could be tuned between 1130 and 1310 nm within 8 μs, without the need to change the length of the resonator. Therewith, the FOPO should especially be suited for hyperspectral imaging, while its all-electronic control constitutes a promising approach to a turnkey and alignment-free light source.

We present a light source that is well adapted to both narrow- and broadband coherent Raman scattering (CRS) methods. Based on a single oscillator, the light source delivers synchronized broadband pulses via supercontinuum generation and narrowband, frequency-tunable pulses via four-wave mixing in a photonic crystal fiber. Seeding the four-wave mixing with a spectrally filtered part of the supercontinuum yields high-pulse energies up to 8 nJ and the possibility of scanning a bandwidth of 2000  cm(-1) in 25 ms. All pulses are emitted with a repetition frequency of 1 MHz, which ensures efficient generation of CRS signals while avoiding significant damage of the samples. Consequently, the light source combines the performance of individual narrow- and broadband CRS light sources in one setup, thus enabling hyperspectral imaging and rapid single-resonance imaging in parallel.

We present the experimental realization of transverse mode conversion in an optical fiber via an optically induced long-period grating. The transient gratings are generated by femtosecond laser pulses, exploiting the Kerr effect to translate intensity patterns emerging from multimode interference into a spatial refractive index modulation. Since these modulations exist only while the pump beam is present, they can be used for optical switching of transverse modes. As only a localized part of the grating was written at a time and the probe beam was co-propagating with the pump beam the required pulse energies could be reduced to 120 nJ which is about a factor of 600 lower than in previous quasi-continuous-wave experiments. Accompanying numerical simulations allow a better understanding of the involved effects and show excellent agreement to the experimental results.

We present the hyperspectral imaging capabilities of in-line interferometric femtosecond stimulated Raman scattering. The beneficial features of this method, namely, the improved signal-to-background ratio compared to other applicable broadband stimulated Raman scattering methods and the simple experimental implementation, allow for a rather fast acquisition of three-dimensional raster-scanned hyperspectral data-sets, which is shown for PMMA beads and a lipid droplet in water as a demonstration. A subsequent application of a principle component analysis displays the chemical selectivity of the method.

We present in-line interferometric femtosecond stimulated Raman scattering (II-FSRS), a new method to measure the spectral Raman intensity and phase over a broad spectral range, potentially in a single shot. An analytic model is developed, that excellently reproduces the measured spectra. Additionally, the performance of II-FSRS is directly compared in experiments to two established techniques, namely femtosecond stimulated Raman scattering and femtosecond Raman induced Kerr-effect spectroscopy.

Dexamethasone (Dex) is used in a wide range of applications, but may have undesirable systemic side effects. A number of techniques have thus been developed to deliver the substance locally. In this study, dexamethasone was acrylated, pegylated, and tethered to hydrolytically degradable (acrylate based) and nondegradable (vinyl sulfone based) polyethylene glycol hydrogels by nucleophilic addition. Hydrogel swelling, drug elution and drug activity were followed over an extended period in vitro. Nondegradable gels were stable for more than a year, while degradable gels showed increasing swelling ratios due to degradation that resulted in disintegration after ~12 days. Near-linear (zero order) release could be achieved in some cases with the degradable gels, while release from the nondegradable gels approximated first order initial release kinetics. Significantly delayed release was observed in all cases where the Dex was linked to the gels, when compared with controls where the drug was merely physically incorporated. Eluates from the gels containing the tethered drug showed high levels of activity for extended time periods, while the activity of the eluates from gels containing nonbound dexamethasone decreased rapidly within the first few days. Dexamethasone can thus be incorporated using nucleophilic addition chemistry to produce gels that are capable of sustained release of the active drug. The methodology is applicable to a variety of drugs that contain hydroxyl groups., (Copyright © 2012 Wiley Periodicals, Inc.)

We present a purely optical method for background suppression in nonlinear spectroscopy based on linear interferometry. Employing an unbalanced Sagnac interferometer, an unprecedented background reduction of 17  dB over a broad bandwidth of 60  THz (2000  cm(-1)) is achieved and its application to femtosecond stimulated Raman scattering loss spectroscopy is demonstrated. Apart from raising the signal-to-background ratio in the measurement of the Raman intensity spectrum, this interferometric method grants access to the spectral phase of the resonant χ(3) contribution. The spectral phase becomes apparent as a dispersive lineshape and is reproduced numerically with a simple oscillator model.

Biomaterials are increasingly being investigated as a means of reducing stress within the ventricular wall of infarcted hearts and thus attenuating pathological remodelling and loss of function. In this context, we have examined the influence of timing of delivery on the efficacy of a polyethylene glycol hydrogel polymerised with an enzymatically degradable peptide sequence. Delivery of the hydrogel immediately after infarct induction resulted in no observable improvements, but a delay of one week in delivery resulted in significant increases in scar thickness and fractional shortening, as well as reduction in end-systolic diameter against saline controls and immediately injected hydrogel at both 2 and 4 weeks post-infarction (p < 0.05). Hydrogels injected at one week were degraded significantly slower than those injected immediately and this may have played a role in the differing outcomes. The hydrogel assumed markedly different morphologies at the two time points having either a fibrillar or bulky appearance after injection immediately or one week post-infarction respectively. We argue that the different morphologies result from infarction induced changes in the cardiac structure and influence the degradability of the injectates. The results indicate that timing of delivery is important and that very early time points may not be beneficial., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.

External mesh constriction of vein grafts was shown to mitigate intimal hyperplasia by lowering circumferential wall stress and increasing fluid shear stress. As under-constriction leaves vein segments unsupported and thus prone to neointimal proliferation while over-constriction may cause wall folding optimal mesh sizing holds a key to clinical success. Diameter fluctuations and the occurrence of wall folding as a consequence of external constriction with knitted Nitinol meshes were assessed in saphenous vein grafts from 100 consecutive coronary artery bypass (CABG) patients. Subsequently, mesh dimensions were identified that resulted in the lowest number of mesh sizes for all patients either guaranteeing tight continual mesh contact along the entire graft length (stipulation A) or preventing wall folding (stipulation B). A mathematical data classification analysis and a statistical single-stage partitioning approach were independently applied alternatively prioritizing stipulation A or B. Although the risk of folding linearly increased when constriction exceeded 24.6% (Chi squared test p = 0.0004) the actual incidence of folding (8.6% of veins) as well as the degree of lumenal encroachment (6.2 ± 2.1%) were low. Folds were always single, narrow longitudinal formations (height: 23.3 ± 4.0% of inner diameter/base: 16.6 ± 18.1% of luminal circumference). Both analytical methods provided an optimum number of 4 mesh sizes beyond which no further advantage was seen. While the size ranges recommended by both methods assured continual tight mesh contact with the vein the narrower range suggested by the mathematical data classification analysis (3.0-3.7 mm) put 20.6 ± 12.5% of length in 69% of veins at risk of folding as opposed to 21.3 ± 25.9% being at risk in the wider size range (3.0-4.2 mm) suggested by the statistical partitioning approach. Four mesh sizes would provide uninterrupted mesh contact in 98% of vein grafts in CABG procedures with only 26% of their length being at risk of relatively mild wall folding., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Left ventricular remodeling after myocardial infarction is a key component of heart failure and it has long been postulated that it may result from increased wall stress. It has recently been suggested that an injectable, non-degradable polymer may limit pathological remodeling in a manner analogous to that of cardiac support devices. We have tested a non-degradable polyethylene glycol (PEG) gel in a rat infarction model., Methods and Results: After permanent ligation of the left anterior descending artery in male Wistar rats, PEG gel reagents were injected into the infarcted region and polymerized in situ. At 4 weeks, fractional shortening and infarct volume were unchanged relative to a saline injected control, but the infarct-induced left ventricular end-diastolic diameter (LVEDD) increase was substantially reduced (43%, P < .05) and wall thinning was completely prevented. At 13 weeks, the LVEDD were similar for both saline- and PEG-injected hearts. The non-degradable PEG gels did elicit a macrophage-based inflammatory reaction., Conclusions: The injection of non-degradable synthetic gel was effective in ameliorating pathological remodeling in the immediate postinfarction healing phase, but was unable to prevent the dilation that occurred at later stages in the healed heart.

Growth factors are often used in tissue regeneration to stimulate vascularisation of polymeric scaffolds, with vascular endothelial growth factor (VEGF) having been extensively studied for short-term vessel ingrowth. We have therefore evaluated the effect of different concentrations of VEGF on the vascularisation of a porous scaffold in the short-, intermediate- and long-term, by delivering 15, 150 and 1500ng VEGF/day to polyurethane scaffolds by osmotic pumps for up to 6 weeks. An increased vascularisation months after termination of VEGF delivery was only achieved with 150ng/day (46%, p<0.05). This dosage consistently showed elevated levels of vascularisation (144, 125, 160 and 60% above PBS controls at 10, 20, 30 and 42 days, respectively, p<0.05), whilst the vessels induced by the highest dosage, though initially maximally elevated (265 and 270% at 10 and 20 days, p<0.05) tended to regress after 20 days of VEGF delivery. Pericyte coverage was decreased at 20 days for the highest dosage (30%, p<0.05). Lectin perfusion demonstrated that vessels within the scaffold were connected to the host vasculature at all time points and perfusion was substantially raised by VEGF delivery at day 20. These results suggest concentration of VEGF plays a critical role in the nature and persistence of vasculature formed in a tissue regenerative scaffold.