Electrocardiographic characteristics in patients with heart failure and normal ejection fraction: A systematic review and meta-analysis.

BACKGROUND: Little is known about ECG abnormalities in patients with heart failure and normal ejection fraction (HeFNEF) and how they relate to different etiologies or outcomes. METHODS AND RESULTS: We searched the literature for peer-reviewed studies describing ECG abnormalities in HeFNEF other than heart rhythm alone. Thirty five studies were identified and 32,006 participants. ECG abnormalities reported in patients with HeFNEF include atrial fibrillation (prevalence 12%-46%), long PR interval (11%-20%), left ventricular hypertrophy (LVH, 10%-30%), pathological Q waves (11%-18%), RBBB (6%-16%), LBBB (0%-8%), and long JTc (3%-4%). Atrial fibrillation is more common in patients with HeFNEF compared to those with heart failure and reduced ejection fraction (HeFREF). In contrast, long PR interval, LVH, Q waves, LBBB, and long JTc are more common in patients with HeFREF. A pooled effect estimate analysis showed that QRS duration ≥120 ms, although uncommon (13%-19%), is associated with worse outcomes in patients with HeFNEF. CONCLUSIONS: There is high variability in the prevalence of ECG abnormalities in patients with HeFNEF. Atrial fibrillation is more common in patients with HeFNEF compared to those with HeFREF. QRS duration ≥120 ms is associated with worse outcomes in patients with HeFNEF. Further studies are needed to address whether ECG abnormalities correlate with different phenotypes in HeFNEF.

Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity.

Antifreeze proteins are produced by extremophile species to control ice formation and growth, and they have potential applications in many fields. There are few examples of synthetic materials which can reproduce their potent ice recrystallization inhibition property. We report that self-assembled enantiomerically pure, amphipathic metallohelicies inhibited ice growth at just 20 µM. Structure-property relationships and calculations support the hypothesis that amphipathicity is the key motif for activity. This opens up a new field of metallo-organic antifreeze protein mimetics and provides insight into the origins of ice-growth inhibition.

Chronic total occlusion in an infarct-related coronary artery and the risk of appropriate ICD therapies.

INTRODUCTION: Risk stratification for ventricular arrhythmias in patients with ischemic cardiomyopathy needs to be improved. Coronary chronic total occlusions in an infarct-related artery (IRA-CTOs) have been associated with an increased arrhythmic risk. This study aimed to evaluate the association between IRA-CTOs and appropriate implantable cardioverter-defibrillator (ICD) therapies. METHODS AND RESULTS: Observational cohort study that included 342 patients with ischemic cardiomyopathy, an ICD implanted for primary or secondary prevention, and a coronary angiography performed shortly before ICD implantation. The ICD was implanted for primary prevention in 163 patients (48%). IRA-CTO was found in 161 patients (47%). During a median follow-up of 33 months, 41% of patients experienced at least one appropriate ICD therapy. Patients with IRA-CTO had higher proportions of appropriate ICD therapies (57% vs. 26%, P < 0.001) and appropriate ICD shocks (40% vs. 17%, P < 0.001). At multivariate Cox regression, IRA-CTO was the only variable that consistently resulted as independent predictor of appropriate ICD therapies and shocks both in the global population of the study (HR 2.3, P < 0.001 and HR 3, P < 0.001, respectively) and when analyzing separately patients with primary or secondary prevention ICD. CONCLUSIONS: IRA-CTO is an independent predictor of appropriate ICD therapies, including appropriate ICD shocks. This association is consistent across all the subgroups analyzed. Patients with IRA-CTO have a very high risk of appropriate ICD therapies. These findings may help improving risk stratification as well as the management of ventricular arrhythmias in patients with ischemic cardiomyopathy.

NMR-based assignment of isoleucine vs. allo-isoleucine stereochemistry.

A simple 1H and 13C NMR spectrometric analysis is demonstrated that permits differentiation of isoleucine and allo-isoleucine residues by inspection of the chemical shift and coupling constants of the signals associated with the proton and carbon at the α-stereocentre. This is applied to the estimation of epimerisation during metal-free N-arylation and peptide coupling reactions.

Axially Chiral Enamides: Substituent Effects, Rotation Barriers, and Implications for their Cyclization Reactions.

The barrier to rotation around the N-alkenyl bond of 38 N-alkenyl-N-alkylacetamide derivatives was measured (ΔG(⧧) rotation varied between <8.0 and 31.0 kcal mol(-1)). The most important factor in controlling the rate of rotation was the level of alkene substitution, followed by the size of the nitrogen substituent and, finally, the size of the acyl substituent. Tertiary enamides with four alkenyl substituents exhibited half-lives for rotation between 5.5 days and 99 years at 298 K, sufficient to isolate enantiomerically enriched atropisomers. The radical cyclizations of a subset of N-alkenyl-N-benzyl-α-haloacetamides exhibiting relatively high barriers to rotation round the N-alkenyl bond (ΔG(⧧) rotation >20 kcal mol(-1)) were studied to determine the regiochemistry of cyclization. Those with high barriers (>27 kcal mol(-1)) did not lead to cyclization, but those with lower values produced highly functionalized γ-lactams via a 5-endo-trig radical-polar crossover process that was terminated by reduction, an unusual cyclopropanation sequence, or trapping with H2O, depending upon the reaction conditions. Because elevated temperatures were necessary for cyclization, this precluded study of the asymmetric transfer in the reaction of individual atropisomers. However, enantiomerically enriched atropsiomeric enamides should be regarded as potential asymmetric building blocks for reactions that can be accomplished at room temperature.

Total synthesis of the azolemycins.

The first total syntheses of newly isolated polyazole natural products azolemycins A-D, along with the synthesis of the tetra-oxazole non-natural analogue, are described.

Stereo- and Chemodivergent NHC-Promoted Functionalisation of Arylalkylketenes with Chloral.

Stereo- and chemodivergent enantioselective reaction pathways are observed upon treatment of alkylarylketenes and trichloroacetaldehyde (chloral) with N-heterocyclic carbenes, giving selectively either ß-lactones (up to 88:12 dr, up to 94 % ee) or α-chloroesters (up to 94 % ee). Either 2-arylsubstitution or an α-branched iPr alkyl substituent within the ketene favours the chlorination pathway, allowing chloral to be used as an electrophilic chlorinating reagent in asymmetric catalysis.

The synthesis and STM/AFM imaging of 'olympicene' benzo[cd]pyrenes.

H-Benzo[cd]pyrene ('Olympicene') is a polyaromatic hydrocarbon and non-Kekulé fragment of graphene. A new synthetic method has been developed for the formation of 6H-benzo[cd]pyrene and related ketones including the first time isolation of the unstable alcohol 6H-benzo[cd]pyren-6-ol. Molecular imaging of the reaction products with scanning tunnelling microscopy (STM) and non-contact atomic force microscopy (NC-AFM) characterised the 6H-benzo[cd]pyrene as well as the previously intangible and significantly less stable 5H-benzo[cd]pyrene, the fully conjugated benzo[cd]pyrenyl radical and the ketones as oxidation products.

Synthesis of 1- and 4-substituted piperazin-2-ones via Jocic-type reactions with N-substituted diamines.

Enantiomerically-enriched trichloromethyl-containing alcohols, obtained by asymmetric reduction, can be transformed regioselectively into 1-substituted piperazinones by modified Jocic reactions with little or no loss of stereochemical integrity. This methodology can be easily used to synthesise important pharmaceutical compounds such as the fluorobenzyl intermediate of a known PGGTase-I inhibitor.

Ring closing metathesis reactions of α-methylene-ß-lactams: application to the synthesis of a simplified phyllostictine analogue with herbicidal activity.

Ring closing metathesis (RCM) reactions of α-methylene-ß-lactams are used to construct strained 11- and 12-membered macrocycles that mimic key structural elements of phyllostictine A. The highest yield and stereoselectivity was achieved making 12-membered macrocycle Z-19 with use of a p-methoxyphenyl group on the lactam nitrogen. Interestingly, substrate concentration had an important influence on the stereochemical course of the reaction. A simplified analogue produced using this approach displays phytotoxic activity against Chlamydomonas reinhardtii suggesting that the α-methylene-ß-lactam subunit is responsible, at least in part, for the herbicidal activity of phyllostictine A.

Oxidation of tertiary amine-derivatized surfaces to control protein adhesion.

Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques.

Iron/tetramethylethylenediamine-catalyzed ambient-temperature coupling of alkyl Grignard reagents and aryl chlorides.

Tetramethylethylenediamine (TMEDA) acts as cheap and readily removed ligand in the iron-catalyzed coupling of alkyl Grignard reagents and activated aryl chlorides. The use of TMEDA allows for low ligand and iron catalyst loading as well as an increased reaction concentration and an ambient reaction temperature on a mole scale.

Electron Paramagnetic Resonance for the Detection of Electrochemically Generated Hydroxyl Radicals: Issues Associated with Electrochemical Oxidation of the Spin Trap.

For the detection of electrochemically produced hydroxyl radicals (HO·) from the oxidation of water on a boron-doped diamond (BDD) electrode, electron paramagnetic resonance spectroscopy (EPR) in combination with spin trap labels is a popular technique. Here, we show that quantification of the concentration of HO· from water oxidation via spin trap electrochemical (EC)-EPR is problematic. This is primarily due to the spin trap oxidizing at potentials less positive than water, resulting in the same spin trap-OH· adduct as formed from the solution reaction of OH· with the spin trap. We illustrate this through consideration of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap for OH·. DMPO oxidation on a BDD electrode in an acidic aqueous solution occurs at a peak current potential of +1.90 V vs SCE; the current for water oxidation starts to rise rapidly at ca. +2.3 V vs SCE. EC-EPR spectra show signatures due to the spin trap adduct (DMPO-OH·) at potentials lower than that predicted thermodynamically (for water/HO·) and in the region for DMPO oxidation. Increasing the potential into the water oxidation region, surprisingly, shows a lower DMPO-OH· concentration than when the potential is in the DMPO oxidation region. This behavior is attributed to further oxidation of DMPO-OH·, production of fouling products on the electrode surface, and bubble formation. Radical scavengers (ethanol) and other spin traps, here N-tert-butyl-α-phenylnitrone, α-(4-pyridyl N-oxide)-N-tert-butylnitrone, and 2-methyl-2-nitrosopropane dimer, also show electrochemical oxidation signals less positive than that of water on a BDD electrode. Such behavior also complicates their use for the intended application.

Atom-transfer cyclization with CuSO4/KBH4: a formal "activators generated by electron transfer" process also applicable to atom-transfer polymerization.

The 4-exo and 5-exo-trig atom-transfer cyclizations of 1, 8a-e, 9, 12, and 13 can be mediated with as little as 0.05 mol % of Cu(TPMA)SO(4)·5H(2)O in the presence of 2.5 mol % of borohydride salts in 10 min at room temperature in air. This formal "activators generated by electron transfer" (AGET) procedure utilizes a cheap and oxidatively stable copper source (CuSO(4)·5H(2)O) and can be carried out in environmentally benign solvents (EtOH). It is possible to alter the product distribution in the 5-endo radical-polar crossover reactions of 10a,b and 11 by tailoring the amount of borohydride. Cyclization onto alkynes 14 and 15 is also possible in only 20 min. Controlled radical polymerization of styrene, with increased rates over conventional atom-transfer radical polymerization (ATRP), can be carried out in a controlled fashion (Mn, PDI) using either CuBr or CuSO(4)·5H(2)O and Bu(4)NBH(4).

Does adenosine response predict clinical recurrence of atrial fibrillation after pulmonary vein isolation?

BACKGROUND: Approximately 30% of patients undergoing pulmonary vein isolation (PVI) for atrial fibrillation (AF) have clinical recurrence of AF, and a great majority of these patients have recovery of vein conduction. Adenosine can be associated with acute recovery of conduction to the pulmonary veins immediately after isolation. However, it is not known whether this is prognostic for permanent recovery of conduction or recurrence of AF. METHODS: Patients with paroxysmal AF underwent PVI, with administration of adenosine after electrical isolation. Those with transient conduction recovery (TCR+) underwent no further ablation and were compared to those without (TCR-) for clinical AF recurrence and conduction recovery at second procedure. RESULTS: Seventy-two consecutive PVI patients were studied (mean age 56.7 ± 9.2, 61 male). Twenty-five (35%) patients had transient recovery of conduction with adenosine. After 1 year, 18 patients (25%) had symptomatic recurrence of AF. In this group of 18 patients, 6 were TCR+ at initial ablation (sensitivity 33%, NPV = 74%). In the remaining group of 54 patients free from AF recurrence, 35 patients (65%) were TCR- at initial ablation (specificity 65%, PPV = 24%). All 18 patients with recurrent AF underwent repeat procedure and had at least 1 pulmonary vein with recurrent conduction. The initial adenosine test correctly predicted 13 out of 36 (36%) veins, with positive predictive value 90% and negative predictive value 15%. CONCLUSIONS: Adenosine testing for TCR does not appear to predict recurrence of clinical AF. TCR- veins remain susceptible to conduction recovery, as determined at the follow-up procedure.

Mechanism of catalytic cyclohydroamination by zirconium salicyloxazoline complexes.

The mechanism of hydroamination/cyclization of primary aminoalkenes by catalysts based on Cp*LZr(NMe(2))(2) (L = κ(2)-salicyloxazoline) is investigated in a range of kinetic, stoichiometric, and structural studies. The rate law is found to be d[substrate]/dt = k[catalyst](1)[substrate](0) for all catalysts and aminoalkenes studied. The overall rate is similar for formation of five- and six-membered rings, and a substantial KIE (k(H)/k(D)) is observed, indicating the involvement of N-H bond-breaking in a rate-determining step (RDS) which is not ring-closure. Remarkably, the reaction proceeds at the same rate in THF as it does in toluene, but added non-cyclizable amine slows the reaction, indicating that while the metal is not acting as a Lewis acid in the RDS, the activated substrate is involved. Also in contrast to other catalysts, increasing steric bulk improves the rate, and the origins of this are investigated by X-ray crystallography. Thermodynamic parameters extracted from eight independent kinetic studies indicate moderate ordering (ΔS(double dagger) = -13 to -23 cal/K·mol) and substantial overall bond disruption (ΔH(double dagger) = 17 to 21 kcal/mol) in the rate-determining transition state. Secondary amines are unreactive, as is a catalyst with a single aminolyzable site, thus excluding an amido mechanism. A catalytic cycle involving rate-determining formation of a reactive imido species is proposed. Stoichiometric steps in the process are shown to be feasible and have appropriate rates by synthetic and in situ NMR spectroscopic studies. The fate of the catalyst in the absence of excess amine (at the end of the catalytic reaction) is conversion to a metallacyclic species arising from CH activation of a peripheral substituent.

Stereocontrolled syntheses of (-)-cubebol and (-)-10-epicubebol involving intramolecular cyclopropanation of alpha-lithiated epoxides.

Formylation of (-)-menthone (11) with LDA and HCO(2)CH(2)CF(3) avoids loss of configurational integrity at the isopropyl group, giving hydroxymethylenementhone 12. Lithium 2,2,6,6-tetramethylpiperidide-induced intramolecular cyclopropanation of derived unsaturated terminal epoxide 17 (and chlorohydrin 16), efficiently generates a substituted tricyclo[4.4.0.0(1,5)]decan-4-ol 18, which is used in a concise synthesis of (-)-cubebol (1). In contrast, isopropyl group inversion during formylation of menthone with NaOMe and HCO(2)Et led, by a similar strategy, to syntheses of 7-epicubebol (33) and (from (+)-menthone) of naturally occurring (-)-10-epicubebol (39), confirming the original structural assignment. Computational studies support the origin of the inversion as being rate-determining formylation of cis-enolate 27 from a mixture of rapidly interconverting enolates. In the synthesis of 7-epicubebol (33), allylic tertiary C-H insertion is observed as a significant competing reaction in the intramolecular cyclopropanation of unsaturated terminal epoxide 22.

The lithiation and acyl transfer reactions of phosphine oxides, sulfides and boranes in the synthesis of cyclopropanes.

Phosphine oxides are lithiated much faster than phosphine sulfides and phosphine boranes. Phosphine sulfides are in turn lithiated much more readily than phosphine boranes. It was possible to trap a phosphine sulfide THF in one case which upon treatment with t-BuOK gave cyclopropane, showing that phosphine sulfides readily undergo both phosphinoyl transfer and cyclopropane ring closure just like their phosphine oxide counterparts. The obtained data show that phosphine oxides are easily lithiated and undergo phosphoryl transfer much more readily and faster than phosphine sulfides and phosphine boranes. The observations suggest that it would be possible to perform reactions involving phosphine oxides in the presence of phosphine boranes or phosphine sulfides, potentially allowing regioselective alkylation of phosphine oxides in the presence of phosphine boranes or phosphine sulfides.

Asymmetric synthesis of trans-disubstituted cyclopropanes using phosphine oxides and phosphine boranes.

The stereocontrolled synthesis of trans-disubstituted cyclopropylketones has been achieved from beta-alkyl, gamma-benzoyl phosphine oxides via a three-step cascade reaction incorporating an acyl transfer, phosphinoyl transfer and cyclisation to form the cyclopropane. Using Evans' chiral oxazolidinone auxiliary and by masking the phosphine oxide moiety as a phosphine borane we have extended the method to the synthesis of enantiomerically-enriched trans-disubstituted cyclopropyl ketones.

Fluoride-free cross coupling using vinyldisiloxanes.

Vinyldisiloxanes equilibrate with the corresponding silanolates under basic conditions and subsequently undergo palladium catalysed cross coupling with aryl/heteroaryl iodides and bromides.