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The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon‐nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)‐discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N‐alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon‐nitrogen bridge, and a reductive N,O‐acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)‐discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen‐bridged discorhabdin and paves the way for future biological evaluation of such compounds. [ABSTRACT FROM AUTHOR]

A simple framework for evaluating experimental kinetic data to provide support for Specific Acid Catalysis (SAC) and General Acid Catalysis (GAC) is described based on the factors affecting their relative efficiency. Observations reveal that increasing the SAC-to-GAC rate constant ratio reduces the effective pH range for GAC.

Background: The role of fiber orientation on a global chamber level in sustaining atrial fibrillation (AF) is unknown. The goal of this study was to correlate the fiber direction derived from Diffusion Tensor Imaging (DTI) with AF inducibility. Methods: Transgenic goats with cardiac-specific overexpression of constitutively active TGF-β1 (n = 14) underwent AF inducibility testing by rapid pacing in the left atrium. We chose a minimum of 10 minutes of sustained AF as a cut-off for AF inducibility. Explanted hearts underwent DTI to determine the fiber direction. Using tractography data, we clustered, visualized, and quantified the fiber helix angles in 8 different regions of the left atrial wall using two reference vectors defined based on anatomical landmarks. Results: Sustained AF was induced in 7 out of 14 goats. The mean helix fiber angles in 7 out of 8 selected regions were statistically different (P-Value < 0.05) in the AF inducible group. The average fractional anisotropy (FA) and the mean diffusivity (MD) were similar in the two groups with FA of 0.32±0.08 and MD of 8.54±1.72 mm2/s in the non-inducible group and FA of 0.31±0.05 (P-value = 0.90) and MD of 8.68±1.60 mm2/s (P-value = 0.88) in the inducible group. Conclusions: DTI based fiber direction shows significant variability across subjects with a significant difference between animals that are AF inducible versus animals that are not inducible. Fiber direction might be contributing to the initiation and sustaining of AF, and its role needs to be investigated further. [ABSTRACT FROM AUTHOR]

Introduction: Esophageal injury is rare but potentially a devastating complication of atrial fibrillation (AF) ablation. The goal here was to provide insight into the short‐term natural history of esophageal thermal injury (ETI) after radiofrequency catheter ablation (RFCA) for AFby esophagogastroduodenoscopy (EGD). Methods: We screened patients who underwent RFCA for AF and EGD based on esophageal late gadolinium enhancement (LGE) in postablation magnetic resonance imaging. Patients with ETI diagnosed with EGD were included. We defined severity of ETI according to Kansas City classification: type 1: erythema; type 2: ulcers (2a: superficial; 2b deep); type 3 perforation (3a: perforation; 3b: perforation with atrioesophageal fistula [AEF]). Repeated EGD was performed within 1−14 days after the last EGD if recommended and possible until any certain healing signs (visible reduction in size without deepening of ETI or complete resolution) were observed. Results: ETI was observed in 62 of 378 patients who underwent EGD after RFCA. Out of these 62 patients with ETI, 21% (13) were type 1, 50% (31) were type 2a and 29% (18) were type 2b at the initial EGD. All esophageal lesions, but one type 2b lesion that developed into an AEF, showed signs of healing in repeated EGD studies within 14 days after the procedure. The one type 2b lesion developing into an AEF showed an increase in size and ulcer deepening in repeat EGD 8 days after the procedure. Conclusion: We found that all ETI which did not progress to AEF presented healing signs within 14 days after the procedure and that worsening ETI might be an early signal for developing esophageal perforation. [ABSTRACT FROM AUTHOR]

Background: Esophageal thermal injury (ETI) is a known and potentially serious complication of catheter ablation for atrial fibrillation. We intended to evaluate the distance between the esophagus and the left atrium posterior wall (LAPW) and its association with esophageal thermal injury. Methods: A retrospective analysis of 73 patients who underwent esophagogastroduodenoscopy (EGD) after LA radiofrequency catheter ablation for symptomatic atrial fibrillation and pre‐ablation magnetic resonance imaging (MRI) was used to identify the minimum distance between the inner lumen of the esophagus and the ablated atrial endocardium (pre‐ablation atrial esophageal distance; pre‐AED) and occurrence of ETI. Parameters of ablation index (AI, Visitag Surpoint) were collected in 30 patients from the CARTO3 system and compared with assess if ablation strategies and AI further impacted risk of ETI. Results: Pre‐AED was significantly larger in patients without ETI than those with ETI (5.23 ± 0.96 mm vs. 4.31 ± 0.75 mm, p <.001). Pre‐AED showed high accuracy for predicting ETI with the best cutoff value of 4.37 mm. AI was statistically comparable between Visitag lesion markers with and without associated esophageal late gadolinium enhancement (LGE) detected by postablation MRI in the low‐power long‐duration ablation group (LPLD, 25‐40 W for 10–30 s, 393.16 [308.62–408.86] vs. 406.58 [364.38–451.22], p =.16) and high‐power short‐duration group (HPSD, 50 W for 5–10 s, 336.14 [299.66–380.11] vs. 330.54 [286.21–384.71], p =.53), respectively. Conclusion: Measuring the distance between the LA and the esophagus in pre‐ablation LGE‐MRI could be helpful in predicting ETI after LAPW ablation. [ABSTRACT FROM AUTHOR]

Background: Recent guidelines recommend a 3‐month blanking period after atrial fibrillation (AF) ablations, which are based on clinical observation. Our goal was to quantify the timeline of the radiofrequency ablation lesion maturation using serial late gadolinium enhancement‐magnetic resonance imaging (LGE‐MRI) and to develop a blanking period estimate based on visible lesion maturation. Methods: Inclusion criteria targeted patients who underwent AF ablation and at least four MRI scans: at baseline before ablation, within 24 hours after (acute), between 24 hours and 90 days after (subacute), and more than 90 days after ablation (chronic). Central nonenhanced (NE) and surrounding hyperenhanced (HE) area volumes were measured and normalized to chronic lesion volume. Results: This study assessed 75 patients with 309 MRIs. The acute lesion was heterogeneous with a HE region surrounding a central NE region in LGE‐MRI; the acute volume of the total (HE + NE) lesion was 2.62 ± 0.46 times larger than that of the chronic lesion. Acute T2‐weighted imaging also showed a relatively large area of edema. Both NE and HE areas gradually receded over time and NE was not observed after 30 days. Larger initial NE volume was associated with a significantly greater chronic scar volume and this total lesion volume receded to equal the chronic lesion size at approximately 72.5 days (95% prediction interval: 57.4‐92.2). Conclusion: On the basis of serial MRI, atrial ablation lesions are often fully mature before the typical 90‐day blanking period, which could support more timely clinical decision making for arrhythmia recurrence. [ABSTRACT FROM AUTHOR]

A simple framework for evaluating experimental kinetic data to provide support for Specific Acid Catalysis (SAC) and General Acid Catalysis (GAC) is described based on the factors affecting their relative efficiency. Observations reveal that increasing the SAC-to-GAC rate constant ratio reduces the effective pH range for GAC.

Background: Atrial fibrillation (AF) is related to numerous electrophysiological changes; however, the extent of structural and electrophysiological remodeling with long‐term AF is not well characterized. Methods: Dogs (n = 6) were implanted with a neurostimulator in the right atrium (AF group). No implantation was done in the Control group (n = 3). Electroanatomical mapping was done prior to and following more than 6 months of AF. Magnetic resonance imaging was also done to assess structural remodeling. Animals were euthanized and tissue samples were acquired for histological analysis. Results: A significant increase was seen in the left atrial (LA) volume among all AF animals (22.25 ± 12.60 cm3 vs 34.00 ± 12.23 cm3, P = .01). Also, mean bipolar amplitude in the LA significantly decreased from 5.96 ± 2.17 mV at baseline to 3.23 ± 1.51 mV (P < .01) after chronic AF. Those significant changes occurred in each anterior, lateral, posterior, septal, and roof regions as well. Additionally, the dominant frequency (DF) in the LA increased from 7.02 ± 0.37 Hz to 10.12 ± 0.28 Hz at chronic AF (P < .01). Moreover, the percentage of fibrosis in chronic AF animals was significantly larger than that of control animals in each location (P < .01). Conclusions: Canine chronic AF is accompanied by a significant decrease in intracardiac bipolar amplitudes. These decreased electrogram amplitude values are still higher than traditional cut‐off values used for diseased myocardial tissue. Despite these "normal" bipolar amplitudes, there is a significant increase in DF and tissue fibrosis. [ABSTRACT FROM AUTHOR]

Introduction: Radiofrequency (RF) and cryoablation are routinely used to treat arrhythmias, but the extent and time course of edema associated with the two different modalities is unknown. Our goal was to follow the lesion maturation and edema formation after RF and cryoablation using serial magnetic resonance imaging (MRI). Methods and Results: Ventricular ablation was performed in a canine model (n = 11) using a cryo or an irrigated RF catheter. T2‐weighted (T2w) edema imaging and late gadolinium enhancement (LGE)‐MRI were done immediately (0 day: acute), 1 to 2 weeks (subacute), and 8 to 12 weeks (chronic) after ablation. After the final MRI, excised hearts underwent pathological evaluation. As a result, 45 ventricular lesions (cryo group: 20; RF group: 25) were evaluated. Acute LGE volume was not significantly different but acute edema volume in cryo group was significantly smaller (1225.0 ± 263.5 vs 1855.2 ± 520.5 mm3; P = 0.01). One week after ablation, edema still existed in both group but was similar in size. Two weeks after ablation there was no edema in either of the groups. In the chronic phase, the lesion volume for cryo and RF in LGE‐MRI (296.7 ± 156.4 vs 281.6 ± 140.8 mm3; P = 0.73); and pathology (243.3 ± 125.9 vs 214.5 ± 148.6 mm3; P = 0.49), as well as depth, was comparable. Conclusions: When comparing cryo and RF lesions of similar chronic size, acute edema is larger for RF lesions. Edema resolves in both cryo and RF lesions in 1 to 2 weeks. [ABSTRACT FROM AUTHOR]

Polarization transfer is demonstrated as a sensitive technique for the measurement of isotopic fractionation of protonated carbons at natural abundance. This method allows kinetic isotope effects (KIEs) to be determined with substantially less material or shorter acquisition time compared with traditional experiments. Computations quantitatively reproduce the KIEs in a Diels-Alder reaction and a catalytic glycosylation. The glycosylation is shown to occur by an effectively concerted mechanism. [ABSTRACT FROM AUTHOR]

We describe a computer algorithm that searches for substitution rules on a set of triangles, the angles of which are all integer multiples of $$\pi /n$$ . We find new substitution rules admitting $$7$$ -fold rotational symmetry at many different inflation factors. [ABSTRACT FROM AUTHOR]

We present a general model for understanding the stereochemical course of intramolecular Michael reactions. We show that the addition of β-ketoester enolates to α,β-unsaturated esters and imides bearing adjacent stereocenters (X, Y = H, Me, OR) leads to high levels of asymmetric induction. Reinforcing and nonreinforcing stereochemical relationships are evaluated from the syn and anti reactant diastereomers. On the basis of synthetic, spectroscopic, and computational studies, we propose that the outcomes of these reactions can be rationalized by a dipole-minimized chair transition-state model. [ABSTRACT FROM AUTHOR]

An unusual intramolecular kinetic isotope effect (KIE) in the reaction of dichloroketene with cis-2-butene does not fit with a simple asynchronous cycloaddition transition state, but it can be predicted from trajectory studies on a bifurcating energy surface. The origin of the KIE is related to a high propensity for transition state recrossing in this system, with heavier masses recrossing less. The KIE can also be predicted by a statistical model that treats the cycloaddition as a stepwise mechanism, the rate-limiting second step being associated with an entropic barrier for formation of the second carbon-carbon bond. The relevance of this stepwise mechanism to other asynchronous but seemingly concerted cycloadditions is suggested by examination of organocatalytic Diels-Alder reactions. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation (AF) is related to numerous electrophysiological changes, however the timeline and extent of these changes are not well characterized. Hypothesis: Using a chronic canine paced AF model, we investigated not only structual remodeling but also electrophysiological remodeling which is changes in electrogram amplitude, dominant frequency (DF). Methods: Eight dogs were implanted with a neurostimulator set to pace at 50 Hz every other second in the high right atrium. Electroanatomical mapping during sinus rhythm was done prior to and following more than 6 months of pacing. Animals were euthanized and tissue samples in several areas (Panel A) were acquired for histological analysis. Results: The maximum number of days of AF duration between studies was 412, with a mean of 183±122 days. About structual remodeling, a significant change was seen in the LA as chamber volume increased fro 22.25±12.60 cm3 to 34.00±12.23 cm3 among all animals (p=0.01).Bipolar amplitude in roof area at baseline was significantly higher than other areas. Here we report a significant decrease in mean bipolar EGM amplitude in the left atrium (LA) from 5.64±0.84 mV at baseline to 3.14±0.89 mV (p<0.01) after AF. Also, the significant bipolar amplitude decrease occurred in each segments but the amount of change was not significantly different among each areas (Panel B). Additionally, the average of dominant frequency increased from 7.02±0.37 Hz to 10.12±0.28 Hz (p<0.001) in the LA. Panel C showed Masson's trichrome stained microscope images of LA tissue samples. The percentage of fibrosis in chronic AF animals was also significaltly larger in each lesions (Panel B). Conclusions: Chronic AF of dog is accompanied by a small but significant decrease in intracardiac bipolar amplitudes. These EGM values were higher than traditional values associated with scarred tissue. However, changes in DF and tissue fibrosis show significant remodeling despite EGM values indicating healthy tissue. [ABSTRACT FROM AUTHOR]

A response by Eugene E. Kwan to a letter to the editor about his article "Factors Affecting the Relative Efficiency of General Acid Catalysis" is presented.