Cardiac stereotactic radiation therapy for refractory ventricular arrhythmias in patients with left ventricular assist devices.

Left ventricular assist device (LVAD) implantation is an established treatment for patients with advanced heart failure refractory to medical therapy. However, the incidence of ventricular arrhythmias (VAs) is high in this population, both in the acute and delayed phases after implantation. About one-third of patients implanted with an LVAD will experience sustained VAs, predisposing these patients to worse outcomes and complicating patient management. The combination of pre-existing myocardial substrate and complex electrical remodeling after LVAD implantation account for the high incidence of VAs observed in this population. LVAD patients presenting VAs refractory to antiarrhythmic therapy and catheter ablation procedures are not rare. In such patients, treatment options are extremely limited. Stereotactic body radiation therapy (SBRT) is a technique that delivers precise and high doses of radiation to highly defined targets, reducing exposure to adjacent normal tissue. Cardiac SBRT has recently emerged as a promising alternative with a growing number of case series reporting the effectiveness of the technique in reducing the VA burden in patients with arrhythmias refractory to conventional therapies. The safety profile of cardiac SBRT also appears favorable, even though the current clinical experience remains limited. The use of cardiac SBRT for the treatment of refractory VAs in patients implanted with an LVAD are even more scarce. This review summarizes the clinical experience of cardiac SBRT in LVAD patients and describes technical considerations related to the implementation of the SBRT procedure in the presence of an LVAD.

Regional anaesthesia via parasternal catheters inserted preoperatively and postoperative delirium after cardiac surgery: A prospective unrandomised clinical trial.

VISUAL ABSTRACT: http://links.lww.com/EJA/A927.

Pyrimidopteridine-catalyzed Photo-mediated Hydroacetoxylation.

Herein we report a photo-mediated formal addition of carboxylic acids to activated alkenes catalyzed by a pyrimidopteridine photoredox catalyst. The decarboxylation of aliphatic carboxylic acids upon single-electron oxidation is countered in the presence of electron-rich alkenes and a hydroacetoxylation is observed. Mechanistic proposals have been made based on CV measurements, competitive Stern-Volmer quenching and EPR experiments. Evidence that tetra-N-substituted pyrimidopteridines function as dual photoredox and hydrogen atom transfer catalyst was supported by spectroscopic means.

Mechanistic Insight into the Mode of Action of Acid ß-Glucosidase Enhancer Ambroxol.

Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid ß-glucosidase (ß-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on ß-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits ß-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant ß-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated ß-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant ß-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional ß-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize ß-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification.

Concomitant Cardiac Surgery and Radiofrequency Ablation of Atrial Fibrillation: A Retrospective Single Center Study.

OBJECTIVES: Concomitant cardiac surgery and radiofrequency atrial fibrillation (AF) ablation is an established procedure recommended in guidelines. However, the results have not been as good as expected. The authors therefore searched for predictive factors of success of the ablation procedure. DESIGN: The authors carried out a retrospective cohort study. SETTING: All the included patients had cardiac surgery in the Dijon University Hospital. PARTICIPANTS: One hundred sixty-three patients with AF underwent a concomitant radiofrequency ablation between January 2009 and December 2016. INTERVENTIONS: A radiofrequency device was used to isolate the pulmonary veins creating a "Box lesion." MEASUREMENTS AND MAIN RESULTS: The primary endpoint of the study was freedom from AF at 12 months with follow-up assessed by an electrocardiogram or a 24-hour recording electrocardiogram Holter. The patient's mean age was 71 ± 9 years with a sex ratio of 1.4. Sixty-six percent of patients had paroxysmal AF and 34% nonparoxysmal AF, which includes persistent and long-standing persistent AF. Sixty-one percent of patients had an AF history for more than 1 year. The mean left atrial diameter was 47 ± 10 mm. No major ablation complications related to the procedure occurred. Overall freedom from AF rate after 1-year follow-up was 60% (n = 98). Six patients (4%) received an additional catheter-based ablation, and 10 patients (6%) had an electrical cardioversion during the follow-up period. The authors identified preoperative paroxysmal AF (odds ratio [OR] 2.54 [1.27-5.14] p = 0.008) and recent history of AF, less than 1 year, (OR 1.99 [1-4.06] p = 0.05) as statistically significant predictors for sinus rhythm maintenance at the 12-month follow-up. At the 12-month follow-up, 64% of patients who had concomitant epicardial treatment were in sinus rhythm and 57% of patients were in sinus rhythm after endocardial treatment. There were no significant differences in rhythm outcome between epicardial and endocardial radiofrequency approach, or between surgical procedures (mitral valve replacement versus coronary artery bypass grafting). The authors could not identify in a univariate analysis a significant left atrium size cutoff upon which ablation was less likely to be successful at 12 months follow-up. CONCLUSIONS: Concomitant cardiac surgery and radiofrequency AF ablation provided freedom from AF for 60% of patients after 1-year follow-up. The authors have shown that paroxysmal AF and recent AF are predictive factors of success. Nevertheless, thorough postoperative care is necessary to improve long-term results, including the use of additional catheter ablation or cardioversion.

Pyrimidopteridine N-Oxide Organic Photoredox Catalysts: Characterization, Application and Non-Covalent Interaction in Solid State.

Herein we report the photo- and electrochemical characterization of pyrimidopteridine N-oxide-based heterocycles. The potential of their application as organic photoredox catalysts is showcased in the photomediated contra-thermodynamic E→Z isomerization of cinnamic acid derivatives and oxidative cyclization of 2-phenyl benzoic acid to benzocoumarin using molecular oxygen as a mild oxidant. Furthermore, unprecedented intermolecular non-covalent n-π-hole interactions in solid state are discussed based on crystallographic and theoretical data.

Extubation of patients undergoing extracorporeal life support. A retrospective study.

INTRODUCTION: The use of extracorporeal life support (ECLS) is increasing worldwide, in particular for the management of refractory cardiac arrest, cardiogenic shock and post cardiopulmonary bypass ventricular failure. Extubation of patients under extracorporeal membrane oxygenation (ECMO) for respiratory failure is a growing practice for adult and pediatric patients, especially for lung transplantation candidates. Because of potential complications and, specifically, accidental arterial decannulation, extubation of patients under ECLS is not standard practice. Our goal was to evaluate the interest in patient extubation under ECLS. MATERIALS AND METHODS: We performed a monocentric, retrospective study of all ECLS cases between January 2014 and January 2016. We excluded patients who died within the first 48 hours of ECLS. RESULTS: We analyzed 57 of the initial 109 patients included in the study. The initial SOFA score was higher in the non-extubated group under ECLS, without significant difference (8.6 ± 2.8 vs 7.2 ± 2.1, p=0.065). Patients who were not extubated had a higher rate of acquired ventilator pneumonia (61.9% vs 26.7%, p=0.03). Moreover, patients who were extubated under ECLS had better 30-day survival rates (73.3% vs 40.5%, p=0.04). In multivariate analyses, the independent factors associated with mortality were age, duration of ECLS and the lack of extubation under ECLS. CONCLUSION: Extubation of patients under ECLS is safe and feasible. Furthermore, in extubated patients, we observed fewer cases of ventilator-associated pneumonia and better 30-day survival rates.

Large Stokes Shift Ionic-Liquid Dye.

We have incorporated the dye N-methyl-6-oxyquinolone [6MQz] in its protonated form as a cation into an ionic liquid (IL) and thus to synthesize an IL dye. The IL dye N-methyl-6-hydroxyquinolinium bis(trifluoromethylsulfonyl) imide [6MQc][NTf2 ] was characterized by NMR, ATR IR spectroscopy and X-ray crystallography. The fluorescence of the IL dye has a large Stokes shift of Δλ=116 nm and a quantum yield of φF =0.56 in acetonitrile. Characteristic solvent dependent shifts can be detected in the emission spectra. In other ILs, acetonitrile and THF we observe a bathochromic shift of up to 28 nm compared to the pure IL dye at 467 nm. For stronger polar solvents the fluorescence signals are strongly red-shifted to 650 nm indicating proton transfer to the solvent molecules in the excited state. This underlines the importance of the IL building block [MQc]+ as photo acid.

Straightforward synthesis of tetraalkynylpyrazines and their photophysical properties.

Tetrafold Sonogashira reactions of tetrachloropyrazine were investigated to provide a one-step synthesis of various tetraalkynylpyrazines. The reaction conditions were thoroughly optimized using modern catalysts and ligands, and products were generally isolated in good to excellent yields. Furthermore, photophysical and electrochemical properties of selected compounds were studied and compared with those of previously reported tetraalkynylpyridines and benzenes. As a matter of fact, tetraalkynylpyrazines proved to show very promising fluorescence properties due to very high quantum yields reaching up to 0.85.

Synthesis of fluorescent 2,3,5,6-tetraalkynylpyridines by site-selective Sonogashira-reactions of 2,3,5,6-tetrachloropyridines.

4-Substituted 2,3,5,6-tetraalkynylpyridines were prepared by tetra-fold Sonogashira reactions of the corresponding 2,3,5,6-tetrachloropyridines. 2,6-Dialkynyl-3,5-dichloropyridines were prepared by site-selective Sonogashira reactions from various 4-unsubstituted and 4-substituted tetrachloropyridines. Subsequent two-fold Sonogashira reactions of the products allowed for the synthesis of various 2,3,5,6-tetraalkynylpyridines containing different alkynyl groups. The products exhibit interesting UV/Vis and fluorescence properties. The position of absorption and emission bands can be tuned by systematic variation of the type of alkynyl substituent and by the type of substituent located at position 4 of the pyridine moiety. The presence of electron withdrawing substituents or of an alkynyl group at position 4 as well as the presence of donor substituted alkynyl groups at positions 2, 3, 5 and 6 resulted in high fluorescence quantum yields of up to 0.6, presumably due to the push-pull substitution pattern of the molecules.

Factors Influencing Unfractionated Heparin Pharmacokinetics and Pharmacodynamics During a Cardiopulmonary Bypass.

BACKGROUND: Unfractionated heparin (UFH) is commonly used during cardiac surgery with a cardiopulmonary bypass to prevent blood clotting. However, empirical administration of UFH leads to variable responses. Pharmacokinetic and pharmacodynamic modeling can be used to optimize UFH dosing and perform real-time individualization. In previous studies, many factors that could influence UFH pharmacokinetics/pharmacodynamics had not been taken into account such as hemodilution or the type of UFH. Few covariates were identified probably owing to a lack of statistical power. This study aims to address these limitations through a meta-analysis of individual data from two studies. METHODS: An individual patient data meta-analysis was conducted using data from two single-center prospective observational studies, where different UFH types were used for anticoagulation. A pharmacodynamic/pharmacodynamic model of UFH was developed using a non-linear mixed-effects approach. Time-varying covariates such as hemodilution and fluid infusions during a cardiopulmonary bypass were considered. RESULTS: Activities of UFH's anti-activated factor/anti-thrombin were best described by a two-compartment model. Unfractionated heparin clearance was influenced by body weight and the specific UFH type. Volume of distribution was influenced by body weight and pre-operative fibrinogen levels. Pharmacodynamic data followed a log-linear model, accounting for the effect of hemodilution and the pre-operative fibrinogen level. Equations were derived from the model to personalize UFH dosing based on the targeted activated clotting time level and patient covariates. CONCLUSIONS: The population model effectively characterized UFH's pharmacokinetics/pharmacodynamics in cardiopulmonary bypass patients. This meta-analysis incorporated new covariates related to UFH's pharmacokinetics/pharmacodynamics, enabling personalized dosing regimens. The proposed model holds potential for individualization using a Bayesian estimation.

Synthesis of fluorinated purine and 1-deazapurine glycosides as potential inhibitors of adenosine deaminase.

The synthesis of 2- and 6-trifluoromethylated purines and 1-deazapurines was performed by formal [3 + 3]-cyclization reactions of 5-aminoimidazoles with a set of trifluoromethyl-substituted 1,3-CCC- and 1,3-CNC-dielectrophiles. The corresponding fluorinated nucleosides were synthesized by glycosylation of 9-unsubstituted purines and 1-deazapurines with peracetylated ß-ribose, ß-glucose, and rhamnose and subsequent deprotection. These scaffolds can be considered as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate dehydrogenase (IMPDH) enzymes.

Comparison of automated fastener device Cor-Knot versus manually-tied knot in minimally-invasive isolated aortic valve replacement surgery.

BACKGROUND: The aim of our prospective study was to evaluate the efficacy and the safety of the Cor-Knot device in isolated aortic valve replacement by right anterior minithoracotomy. METHODS: A single-center, prospective study was conducted between September 2009 and June 2018. Four hundred and forty patients were operated on for aortic valve replacement by right anterior minithoracotomy. Of these patients, 221 underwent isolated AVR surgery with stented prosthesis. Sutures were secured using the Cor-Knot titanium fastener in 63 patients (28.5%) and knots were hand-tied in 158 (71.5%). Statistical analyses were done using a propensity score with 1:1 matching for the automatically tied (AT) and manually tied (MT) patients. RESULTS: The aortic cross-clamping and cardiopulmonary bypass times were significantly decreased in the AT group (74±13.8 minutes vs. 90.4±23.7 minutes, P<0.0001, and 100.8±20.6 minutes vs. 117.6±33.1 minutes, P<0.0001), compared with the MT group. Clinical outcomes were similar in the two groups, whether in the analysis of non-matched or matched groups. There was no difference in 30 day-mortality (1.2% vs. 0%, P=0.37), and the stroke and transient ischemic attack rates were comparable (2.5% vs. 1.6%; P=0.67). There was no significant increase in pacemaker implantation in the AT group (1.3% vs. 0%, P=0.36), and the rate of aortic regurgitation ≥ 2 was lower (3.9% vs. 0%; P=0.11) but not statistically significant. CONCLUSIONS: The automated Cor-Knot fastener is an easy-to-use, time-saving device which does not increase perioperative morbidity and mortality in patients undergoing aortic valve replacement by right anterior minithoracotomy.

Technical points for aortic valve replacement through right anterior minithoracotomy.

After 8 years of practice and over 400 operated patients, we present a technique of minimally invasive aortic valve replacement that can be used by all surgeons on many patients. The access to the aorta is via the 2nd or 3rd right anterior intercostal space. Cardiopulmonary bypass is provided using the femoral artery and vein. The aorta is clamped directly. One shot of Custodiol (EUSA Pharma, Limonest, France) is the most commonly used cardioplegia. Aortic valve replacement is performed in the regular way. To reduce the aortic cross-clamping time, sutureless or rapid-deployment valves, as well as the Cor-Knot (LSI Solutions, Inc., Victor, NY, USA) automatic knotting system, are excellent options. Right anterior minithoracotomy for aortic valve replacement is safe and reproducible.

Extensive Surgical Treatment of Primary Pulmonary Synovial Sarcoma After Recurrent Pneumothorax.

A 26-year-old woman with a history of right-sided recurrent pneumothorax and resection of pulmonary bullae, pleural abrasion, and talc pleurodesis underwent right-sided extensive pleural pneumonectomy for a monophasic primary pleural-pulmonary synovial sarcoma (PPSS). The pathologic diagnosis was predominantly fusiform PPSS with R0 resection. Sixteen months after the operation, she is alive, without signs of new lesions. The extensive tumor resection can achieve a good result for controlling local disease.