Design and synthesis of versatile ligand precursors based on phosphonium ylides for palladalactam formation and catalytic investigation.

A new series of ligand precursors designed for the synthesis of palladalactams has been developed. These precursors are easily accessible through a one-step reaction involving 2-chloro-N-phenylacetamide and a wide choice of various monophosphines, offering tunable electronic and steric properties within the ligand framework. The stability of both ligand precursors and resulting palladalactams in ambient air enhances their practical applicability. A newly synthesized palladalactam, featuring an electron-donating triethylphosphine moiety on the anionic phosphonium ylide ligand scaffold exhibited promising catalytic activities in the Mizoroki-Heck coupling reaction between aryl chlorides and alkenes. Theoretical calculations further affirmed that the ligand system in the complex is the most electron-donating, forming the strongest Pd-C bond compared to other complexes with alternative phosphine moieties.

Cardiac Resynchronization Therapy for Patients With Mild to Moderately Reduced Ejection Fraction and Left Bundle Branch Block.

BACKGROUND: It is unknown whether cardiac resynchronization therapy (CRT) would improve or halt the progression of heart failure (HF) in patients with mild to moderately reduced ejection fraction (HFmmrEF) and left bundle branch block (LBBB). OBJECTIVE: This study aimed to investigate the outcomes of CRT in patients with HFmmrEF and left ventricular conduction delay. METHODS: A prospective, randomized clinical trial sponsored by the National Heart, Lung, and Blood Institute included 76 patients who met the study inclusion criteria (left ventricular ejection fraction [LVEF] of 36%-50% and LBBB). Patients received CRT-pacemaker and were randomized to CRT-OFF (right ventricular pacing 40 beats/min) or CRT-ON (biventricular pacing 60-150 beats/min). At a 6-month follow-up, pacing programming was changed to the opposite settings. New York Heart Association class, N-terminal pro-brain natriuretic peptide levels, and echocardiographic variables were collected at baseline, 6 months, and 12 months. The primary study end point was the left ventricular end-systolic volume (LVESV) change from baseline, and the primary randomized comparison was the comparison of 6-month to 12-month changes between randomized groups. RESULTS: The mean age of the patients was 68.4 ± 9.8 years (male, 71%). Baseline characteristics were similar between the 2 randomized groups (all P > .05). In patients randomized to CRT-OFF first, then CRT-ON, LVESV was reduced from baseline only after CRT-ON (baseline, 116.1 ± 36.5 mL; CRT-ON, 87.6 ± 26.0 mL; P < .0001). The randomized analysis of LVEF showed a significantly better change from 6 to 12 months in the OFF-ON group (P = .003). LVEF was improved by CRT (baseline, 41.3% ±.7%; CRT-ON, 46.0% ± 8.0%; P = .002). In patients randomized to CRT-ON first, then CRT-OFF, LVESV was reduced after both CRT-ON and CRT-OFF (baseline, 109.8 ± 23.5 mL; CRT-ON, 91.7 ± 30.5 mL [P < .0001]; CRT-OFF, 99.3 ± 28.9 mL [P = .012]). However, the LVESV reduction effect became smaller between CRT-ON and CRT-OFF (P = .027). LVEF improved after both CRT-ON and CRT-OFF (baseline, 42.7% ± 4.3%; CRT-ON, 48.5% ± 8.6% [P < .001]; CRT-OFF, 45.9% ± 7.7% [P = .025]). CONCLUSION: CRT for patients with HFmmrEF significantly improves LVEF and ventricular remodeling after 6 months of CRT. The study provides novel evidence that early CRT benefits patients with HFmmrEF with LBBB.

Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes.

BACKGROUND: Vascular large conductance Ca2+-activated K+ (BK) channel, composed of the α-subunit (BK-α) and the ß1-subunit (BK-ß1), is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbs2 (Sorbin homology [SoHo] and Src homology 3 [SH3] domains-containing protein 2), is ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown. METHODS: The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis. RESULTS: Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and BK-α mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with BK-α subunits, while both the SH3 and SoHo domains of Sorbs2 interact with BK-ß1 subunits. Deletion of the SH3 or SoHo domains abolishes the Sorbs2 effect on the BK-α/BK-ß1 channel current density. Additionally, Sorbs2 is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of Sorbs2 and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that Sorbs2 knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca2+-sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db/db type 2 diabetic mice. CONCLUSIONS: Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of Sorbs2 manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.

Nitron-derivative-based palladium carbene complexes: structural characterization, theoretical calculations, and catalytic applications in the Mizoroki-Heck coupling reaction.

New palladium(0) and palladium(ii) complexes with N-heterocyclic carbene (NHC) ligands derived from nitron and its derivatives were synthesized. The structures of most of these complexes were established by single-crystal X-ray diffraction studies. Among the new complexes, the palladium complex with a monodentate NHC ligand derived from nitron demonstrated the highest efficacy as a catalyst precursor in the Mizoroki-Heck coupling reaction of aryl chlorides with alkenes. Theoretical calculations provide valuable insights into the electronic parameters of both the ligands and the palladium complexes, highlighting the significance of a robust Pd-C bond and the π-accepting property of the NHC ligand in achieving enhanced catalytic activity. Notably, catalyst activation occurred much more rapidly with the preformed palladium(0) complex compared to its palladium(ii) counterpart.

Base-Exchange Enabling the Visualization of SARM1 Activities in Sciatic Nerve-Injured Mice.

Enzymes are important in homeostasis in living organisms. Since abnormal enzyme activities are highly associated with many human diseases, detection of in vivo activities of a specific enzyme is important to study the pathology of the related diseases. In this work, we have designed and synthesized a series of new small-molecule-activatable fluorescent probes for the imaging of Sterile Alpha and TIR Motif-containing 1 (SARM1) activities based on its transglycosidase activities (base-exchange reactions of NAD+). Probe 1a was found to undergo base-exchange reactions with NAD+ in the presence of activated SARM1 but not CD38 nor NADase and formed a highly emissive product AD-1a [about a 100-fold fluorescence enhancement in 20 min with a 150 nm (5665 cm-1) Stokes shift and a 100 nm (3812 cm-1) red shift]. This probe exhibited a higher reactivity and sensitivity than those commonly used for SARM1 imaging. The utilities of 1a have also been demonstrated in live-cell imaging and detection of in vivo activities of SARM1 in a sciatic nerve injury mouse model.

A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1.

Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is an autoinhibitory NAD-consuming enzyme that is activated by the accumulation of nicotinamide mononucleotide (NMN) during axonal injury. Its activation mechanism is not fully understood. Here, we generate a nanobody, Nb-C6, that specifically recognizes NMN-activated SARM1. Nb-C6 stains only the activated SARM1 in cells stimulated with CZ-48, a permeant mimetic of NMN, and partially activates SARM1 in vitro and in cells. Cryo-EM of NMN/SARM1/Nb-C6 complex shows an octameric structure with ARM domains bending significantly inward and swinging out together with TIR domains. Nb-C6 binds to SAM domain of the activated SARM1 and stabilized its ARM domain. Mass spectrometry analyses indicate that the activated SARM1 in solution is highly dynamic and that the neighboring TIRs form transient dimers via the surface close to one BB loop. We show that Nb-C6 is a valuable tool for studies of SARM1 activation.

Direct arylation reaction catalyzed by a PEPPSI-type palladium complex with an amido-functionalized triazole-based mesoionic carbene ligand.

Ligand precursors for amido/amidate-functionalized triazole-based MIC ligands were synthesized. An initial theoretical calculation confirmed that triazole-based MIC ligands were promising ligands in terms of their σ-donating and π-acidic properties. Based on these ligand precursors, three different types of palladium complexes were successfully obtained, namely (1) a PEPPSI-type MIC complex, (2) a complex containing both a bidentate ligand of a MIC and an amidate donor and a mondentate NHC derived from nitron, and (3) a complex featuring a tridentate ligand of a MIC, an amidate, and a phenoxy donor. The structures of all these complexes were established by single-crystal X-ray diffraction studies. Imidazole derivatives are important heterocycles with enormous medicinal value. The catalytic activities of these new palladium complexes in the green direct C-H arylation of imidazoles with aryl halides were investigated and compared to those delivered from palladium complexes with IMes and triazole-based normal NHC ligands. Among the new complexes, the PEPPSI-type palladium complex with the monodentate triazole-based MIC ligand was found to be a very promising precatalyst which was capable of utilizing electron-deficient aryl chlorides as coupling partners in the reaction.

Association of Thoracic Aortic Aneurysm Size With Long-term Patient Outcomes: The KP-TAA Study.

Importance: The risk of adverse events from ascending thoracic aorta aneurysm (TAA) is poorly understood but drives clinical decision-making. Objective: To evaluate the association of TAA size with outcomes in nonsyndromic patients in a large non-referral-based health care delivery system. Design, Setting, and Participants: The Kaiser Permanente Thoracic Aortic Aneurysm (KP-TAA) cohort study was a retrospective cohort study at Kaiser Permanente Northern California, a fully integrated health care delivery system insuring and providing care for more than 4.5 million persons. Nonsyndromic patients from a regional TAA safety net tracking system were included. Imaging data including maximum TAA size were merged with electronic health record (EHR) and comprehensive death data to obtain demographic characteristics, comorbidities, medications, laboratory values, vital signs, and subsequent outcomes. Unadjusted rates were calculated and the association of TAA size with outcomes was evaluated in multivariable competing risk models that categorized TAA size as a baseline and time-updated variable and accounted for potential confounders. Data were analyzed from January 2018 to August 2021. Exposures: TAA size. Main Outcomes and Measures: Aortic dissection (AD), all-cause death, and elective aortic surgery. Results: Of 6372 patients with TAA identified between 2000 and 2016 (mean [SD] age, 68.6 [13.0] years; 2050 female individuals [32.2%] and 4322 male individuals [67.8%]), mean (SD) initial TAA size was 4.4 (0.5) cm (828 individuals [13.0% of cohort] had initial TAA size 5.0 cm or larger and 280 [4.4%] 5.5 cm or larger). Rates of AD were low across a mean (SD) 3.7 (2.5) years of follow-up (44 individuals [0.7% of cohort]; incidence 0.22 events per 100 person-years). Larger initial aortic size was associated with higher risk of AD and all-cause death in multivariable models, with an inflection point in risk at 6.0 cm. Estimated adjusted risks of AD within 5 years were 0.3% (95% CI, 0.3-0.7), 0.6% (95% CI, 0.4-1.3), 1.5% (95% CI, 1.2-3.9), 3.6% (95% CI, 1.8-12.8), and 10.5% (95% CI, 2.7-44.3) in patients with TAA size of 4.0 to 4.4 cm, 4.5 to 4.9 cm, 5.0 to 5.4 cm, 5.5 to 5.9 cm, and 6.0 cm or larger, respectively, in time-updated models. Rates of the composite outcome of AD and all-cause death were higher than for AD alone, but a similar inflection point for increased risk was observed at 6.0 cm. Conclusions and Relevance: In a large sociodemographically diverse cohort of patients with TAA, absolute risk of aortic dissection was low but increased with larger aortic sizes after adjustment for potential confounders and competing risks. Our data support current consensus guidelines recommending prophylactic surgery in nonsyndromic individuals with TAA at a 5.5-cm threshold.

Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis.

Objective: To evaluate and characterize cardiac arrythmias associated with LGI1-IgG (Leucine-rich glioma inactivated 1-IgG) autoimmune encephalitis (AE). Patients and methods: In this retrospective descriptive study, we identified Mayo Clinic patients (May 1, 2008 - December 31, 2020) with LGI1-IgG AE who had electrocardiogram proven bradyarrhythmias during the initial presentation. Inclusion criteria were 1) LGI1-IgG positivity with a consistent clinical syndrome; 2) electrocardiographic evidence of bradyarrhythmia; and 3) sufficient clinical details. We excluded patients who were taking negative ionotropic agents at the time of their bradyarrhythmias. We collected demographic/clinical data including details of bradyarrhythmia (severity, duration, treatments), and neurologic and cardiac outcomes. Results: We found that patients with LGI1-IgG AE had bradyarrhythmia at a frequency of 8% during the initial presentation. The bradyarrhythmia was often asymptomatic (6/11, 55%); however, the episode was severe with one patient requiring a pacemaker. Outcome was also generally favorable with the majority (8/11, 73%) having full resolution without further cardiac intervention. Lastly, we found that mouse and human cardiac tissues express LGI1 (mRNA and protein). Conclusion: LGI1-IgG AE can be rarely associated with bradyarrhythmias. Although the disease course is mostly favorable, some cases may require pacemaker placement to avoid devastating outcomes.

Mediastinal radiation therapy for breast cancer in female patients is an independent risk factor for atrial fibrillation recurrence post-catheter ablation.

BACKGROUND: The aim of this study was to assess the safety, efficacy, and predictors of outcomes for atrial fibrillation (AF) ablation in patients with a history of breast cancer. METHODS: Consecutive patients with a history of breast cancer undergoing AF ablation from January 2010 to December 2021 were propensity matched in a 1:1 ratio to patients without a history of any cancer. The primary outcome was procedural efficacy, defined by clinical AF recurrence and repeat catheter ablation. The secondary outcome was an assessment of safety looking at eight peri-procedural events. RESULTS: Our cohort was comprised of 82 female patients, 41 patients with a history of breast cancer (mean age, 74.6 ± 7.4 years), and 41 patients with no history of cancer (76.7 ± 8.1 years). Both groups had similar echocardiographic, baseline, and arrhythmia characteristics. Breast cancer patients were at an increased risk of AF recurrence post-ablation compared to non-cancer patients (OR 2.68, 95% CI 1.05-6.86, p = 0.04). Multivariate analysis found prior mediastinal radiotherapy (OR 4.79, 95% CI 1.34-17.1) and AF diagnosis to ablation time (OR 1.2, 95% CI 1.03-1.29) were both independent predictors of AF recurrence post-ablation. CONCLUSION: Our study suggests that female patients with a history of breast cancer are at a higher risk of developing AF recurrence after catheter ablation. Multivariate analysis showed that patients with a history of prior mediastinal radiation therapy and AF diagnosis to time to ablation were both independent risk factors.

TRPC6 N338S is a gain-of-function mutant identified in patient with doxorubicin-induced cardiotoxicity.

The canonical transient receptor potential 6 gene, TRPC6, has been implicated as a putative risk gene for chemotherapy-induced congestive heart failure, but knowledge of specific risk variants is lacking. Following our genome-wide association study and subsequent fine-mapping, a rare missense mutant of TRPC6 N338S, was identified in a breast cancer patient who received anthracycline-containing chemotherapy regiments and developed congestive heart failure. However, the function of N338S mutant has not been examined. Using intracellular Ca2+ imaging, patch clamp recording and molecular docking techniques, we assessed the function of N338S mutant heterologously expressed in HEK293 cells and HL-1 cardiac cells. We found that expression of TRPC6 N338S significantly increased intracellular Ca2+ levels ([Ca2+]i) and current densities in response to 50 µM 1-oleoyl 2-acetyl-sn-glycerol (OAG), an activator of TRPC6 channels, compared to those of TRPC6 WT. A 24-h pretreatment with 0.5 µM doxorubicin (DOX) further potentiated the OAG effects on TRPC6 N338S current densities and [Ca2+]i, and these effects were abolished by 1 µM BI-749327, a highly selective TRPC6 inhibitor. Moreover, DOX treatment significantly upregulated the mRNA and protein expressions of TRPC6 N338S, compared to those of TRPC6 WT. Molecular docking and dynamics simulation showed that OAG binds to the pocket constituted by the pore-helix, S5 and S6 domains of TRPC6. However, the N338S mutation strengthened the interaction with OAG, therefore stabilizing the OAG-TRPC6 N338S complex and enhancing OAG binding affinity. Our results indicate that TRPC6 N338S is a gain-of-function mutant that may contribute to DOX-induced cardiotoxicity by increasing Ca2+ influx and [Ca2+]i in cardiomyocytes.

MANP Activation Of The cGMP Inhibits Aldosterone Via PDE2 And CYP11B2 In H295R Cells And In Mice.

BACKGROUND: Aldosterone is a critical pathological driver for cardiac and renal diseases. We recently discovered that mutant atrial natriuretic peptide (MANP), a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP in vivo. MANP and natriuretic peptide (NP)-augmenting therapy sacubitril/valsartan are under investigations for human hypertension treatment. Understanding the elusive mechanism of aldosterone inhibition by NPs remains to be a priority. Conflicting results were reported on the roles of the pGC-A (particulate guanylyl cyclase A receptor) and NP clearance receptor in aldosterone inhibition. Furthermore, the function of PKG (protein kinase G) and PDEs (phosphodiesterases) on aldosterone regulation are not clear. METHODS: In the present study, we investigated the molecular mechanism of aldosterone regulation in a human adrenocortical cell line H295R and in mice. RESULTS: We first provided evidence to show that pGC-A, not NP clearance receptor, mediates aldosterone inhibition. Next, we confirmed that MANP inhibits aldosterone via PDE2 (phosphodiesterase 2) not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer experiments. Further, the inhibitory effect is mediated by a reduction of intracellular Ca2+ levels. We then illustrated that MANP directly reduces aldosterone synthase CYP11B2 (cytochrome p450 family 11 subfamily b member 2) expression via PDE2. Last, in PDE2 knockout mice, consistent with in vitro findings, embryonic adrenal CYP11B2 is markedly increased. CONCLUSIONS: Our results innovatively explore and expand the NP/pGC-A/3',5', cyclic guanosine monophosphate (cGMP)/PDE2 pathway for aldosterone inhibition by MANP in vitro and in vivo. In addition, our data also support the development of MANP as a novel ANP analog drug for aldosterone excess treatment.

Effects of Soy Isoflavones and Green Tea Extract on Simvastatin Pharmacokinetics and Influence of the SLCO1B1 521T > C Polymorphism.

Objectives: Green tea and soy products are extensively consumed by many people and they may influence the activity of drug metabolizing enzymes and drug transporters to result in drug interactions. This study was performed to evaluate the effect of green tea and soy isoflavone extracts on the pharmacokinetics of simvastatin in healthy subjects and to clarify the role of polymorphisms in the SLCO1B1 drug transporter in this effect. Methods: This was an open-label, three-phase randomized crossover pharmacokinetic study. A single dose of simvastatin 20 mg was taken on three occasions (without herbs, with green tea, and with soy isoflavones) by healthy male Chinese subjects. The green tea and soy isoflavone extracts were given at a dose containing EGCG 800 mg once daily or soy isoflavones about 80 mg once daily for 14 days before simvastatin dosing with at least 4-weeks washout period between phases. Results: All the 18 subjects completed the study. Intake of soy isoflavones was associated with reduced systemic exposure to simvastatin acid [geometric mean (% coefficient of variation) AUC0-24h from 16.1 (44.2) h⋅µg/L to 12.1 (54.6) h⋅µg/L, P < 0.05) but not the lactone. Further analysis showed that the interaction between simvastatin and the soy isoflavones only resulted in a significant reduction of AUC in subjects with the SLCO1B1 521TT genotype and not in those with the 521C variant allele. There was no overall effect of the green tea extract on simvastatin pharmacokinetics but the group with the SLCO1B1 521TT genotype showed reduced AUC values for simvastatin acid. Conclusion: This study showed repeated administration of soy isoflavones reduced the systemic bioavailability of simvastatin in healthy volunteers that was dependent on the SLCO1B1 genotype which suggested that soy isoflavones-simvastatin interaction is impacted by genotype-related function of this liver uptake transporter.

The influence of acoustic radiation force beam shape and location on wave spectral content for arterial dispersion ultrasound vibrometry.

Objective. Arterial dispersion ultrasound vibrometry (ADUV) relies on the use of guided waves in arterial geometries for shear wave elastography measurements. Both the generation of waves through the use of acoustic radiation force (ARF) and the techniques employed to infer the speed of the resulting wave motion affect the spectral content and accuracy of the measurement. In particular, the effects of the shape and location of the ARF beam in ADUV have not been widely studied. In this work, we investigated how such variations of the ARF beam affect the induced motion and the measurements in the dispersive modes that are excited.Approach.The study includes an experimental evaluation on an arterial phantom and anin vivovalidation of the observed trends, observing the two walls of the waveguide, simultaneously, when subjected to variations in the ARF beam extension (F/N) and focus location.Main results.Relying on the theory of guided waves in cylindrical shells, the shape of the beam controls the selection and nature of the induced modes, while the location affects the measured dispersion curves (i.e. variation of phase velocity with frequency or wavenumber, multiple modes) across the waveguide walls.Significance.This investigation is important to understand the spectral content variations in ADUV measurements and to maximize inversion accuracy by tuning the ARF beam settings in clinical applications.

Safety and efficacy outcomes of atrial fibrillation ablation in patients with rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease associated with atrial fibrillation (AF) and stroke. Objective: The purpose of this study was to evaluate the safety and efficacy of AF ablation in patients with RA. Methods: All patients with RA undergoing AF ablation at our institution from 2010 to 2021 were propensity matched to patients without RA using 9 baseline characteristics. The primary outcome was procedural efficacy defined by clinical AF recurrence, the need for antiarrhythmic drugs (AADs), and repeat catheter ablation. Secondary outcome was safety. Results: A total of 45 patients with RA (age 66.3 ± 7.7 years) were matched to 45 patients without a history of RA (age 68.0 ± 7.3 years). Both groups had similar procedural and periprocedural characteristics. Before ablation, RA patients had statistically higher C-reactive protein (CRP) levels (P ≤.01) and erythrocyte sedimentation rates (ESRs) (P <.05) compared to non-RA patients. After ablation, RA patients had statistically significant higher rates of AF recurrence (P = .006), were more likely to be taking AADs (P <.05), and more likely to undergo repeat ablations (P <.05). The use of immunosuppression or corticosteroids at the time of ablation did not influence the primary endpoint of AF recurrence, AADs, or repeat ablation. Multivariate regression analysis showed CRP and ESR were independent predictors of AF recurrence. CRP was an independent predictor of repeat ablation. Conclusion: Patients with RA are at higher risk of clinical AF recurrence, and are more likely to be taking AADs and require repeat ablation. Preablation CRP and ESR are independent predictors of AF recurrence, and CRP is an independent predictor of repeat catheter ablation.

Silent cerebral infarcts in patients with atrial fibrillation: Clinical implications of an imaging-adjusted CHA2DS2-VASc score.

BACKGROUND: The CHA2DS2-VASc score does not include silent infarcts on neuroimaging in stroke risk estimation for patients with atrial fibrillation (AF). The inclusion of silent infarcts into CHA2DS2-VASc scoring and its impact on stroke prophylaxis recommendations in patients with AF has not been previously studied. The present study sought to quantify the prevalence of silent infarcts in patients with AF and describe potential changes in management based on magnetic resonance imaging (MRI) findings. METHODS: Participants from the Mayo Clinic Study of Aging with AF and brain MRI were included. Silent infarcts were identified. "Standard" CHA2DS2-VASc scores were calculated for each subject based on clinical history alone and "imaging-adjusted" CHA2DS2-VASc scores based on evidence of cerebral infarction on MRI. Standard and imaging-adjusted scores were compared. RESULTS: One hundred and forty-seven participants (average age 77, 28% female) were identified with AF, MRI, and no clinical history of stroke. Overall, 41 (28%) patients had silent infarcts on MRI, corresponding with a 2-point increase in CHA2DS2-VASc score. Of these participants, only 39% (16/41) with silent infarct were on anticoagulation despite having standard CHA2DS2-VASc scores supportive of anticoagulation. After incorporating silent infarcts, 13% (19/147) would have an indication for periprocedural bridging compared to 0.6% (1/147) at baseline. CONCLUSIONS: Incorporation of silent infarcts into the CHA2DS2-VASc score may change the risk- -benefit ratio of anticoagulation. It may also increase the number of patients who would benefit from periprocedural bridging. Future research should examine whether an anticoagulation strategy based on imaging-adjusted CHA2DS2-VASc scores could result in a greater reduction of stroke and cognitive decline.

Nickel(II) complexes containing tridentate ONCi ligands (i = abnormal N-heterocyclic carbene donors) and their catalytic application in Suzuki-Miyaura coupling reaction.

New nickel complexes with tridentate phenoxy-amidate-aNHC donor groups were synthesized from the reactions between nickel acetate and imidazolium ligand precursors in net pyridine. An unusual degradation pathway was observed, leading to imidazole derivatives occupying the fourth coordination sites in these square planar complexes. A new imidazole-coordinated nickel complex was found to be efficient in catalyzing Suzuki-Miyaura cross-coupling with aryl chlorides under 3 mol% of catalyst loading. The catalytic activities were superior to those of its reported normal NHC counterpart. Instead of the common procedure of using additional phosphine, the addition of IMes·HCl significantly enhances the product yields of the catalytic reaction.

Effect of Green Tea Extract and Soy Isoflavones on the Pharmacokinetics of Rosuvastatin in Healthy Volunteers.

Background and Aim: Green tea and soy products are extensively consumed in daily life. Research has shown that green tea catechins and soy isoflavones may influence the activity of drug metabolizing enzymes and drug transporters. We examined whether regular consumption of green tea extract or soy isoflavones affected the pharmacokinetics of a single dose of rosuvastatin in healthy subjects and whether any interactions were influenced by the polymorphism in the drug transporter ABCG2. Study Design: This was an open-label, three-phase randomized crossover study with single doses of rosuvastatin. Methods: Healthy Chinese male subjects were given a single dose of rosuvastatin 10 mg on 3 occasions: 1. without herbs; 2. with green tea extract; 3. with soy isoflavone extract. The green tea and soy isoflavone extract were given at a dose containing EGCG 800 mg once daily or soy isoflavones-80 mg once daily for 14 days before statin dosing and at the same time as the statin dosing with at least 4-weeks washout period between phases. Results: Twenty healthy male subjects completed the study and the intake of green tea extract significantly reduced the systemic exposure to rosuvastatin by about 20% reducing AUC0-24h from [geometric mean (% coefficient of variation)] 108.7 (28.9) h·µg/L to 74.1 (35.3) h·µg/L and Cmax from 13.1 (32.2) µg/L to 7.9 (38.3) µg/L (P < 0.001 for both), without affecting the elimination half-life. The ABCG2 421C>A polymorphism had a significant effect on rosuvastatin exposure but no impact on the interaction with green tea. Soy isoflavones had no significant effect on rosuvastatin pharmacokinetics. Conclusion: This study showed that repeated administration of green tea extract significantly reduced the systemic exposure of rosuvastatin in healthy volunteers. These effects might be predicted to either reduce or increase the lipid-lowering effect of rosuvastatin depending on the mechanism of the effect.

A real-world experience of atrioventricular synchronous pacing with leadless ventricular pacemakers.

AIMS: The MicraTM transcatheter pacing system (TPS) (Medtronic) is the only leadless pacemaker that promotes atrioventricular (AV) synchrony via accelerometer-based atrial sensing. Data regarding the real-world experience with this novel system are scarce. We sought to characterize patients undergoing MicraTM -AV implants, describe percentage AV synchrony achieved, and analyze the causes for suboptimal AV synchrony. METHODS: In this retrospective cohort study, electronic medical records from 56 consecutive patients undergoing MicraTM -AV implants at the Mayo Clinic sites in Minnesota, Florida, and Arizona with a minimum follow-up of 3 months were reviewed. Demographic data, comorbidities, echocardiographic data, and clinical outcomes were compared among patients with and without atrial synchronous ventricular pacing (AsVP) ≥ 70%. RESULTS: Sixty-five percent of patients achieved AsVP ≥ 70%. Patients with adequate AsVP had smaller body mass indices, a lower proportion of congestive heart failure, and prior cardiac surgery. Echocardiographic parameters and procedural characteristics were similar across the two groups. Active device troubleshooting was associated with higher AsVP. The likely reasons for low AsVP were small A4-wave amplitude, high ventricular pacing burden, and inadequate device reprogramming. Importantly, in patients with low AsVP, subjective clinical worsening was not noted during follow-up. CONCLUSION: With the increasing popularity of leadless pacemakers, it is paramount for device implanting teams to be familiar with common predictors of AV synchrony and troubleshooting with MicraTM -AV devices.

Risk of left atrial appendage thrombus and stroke in patients with atrial fibrillation and mitral regurgitation.

OBJECTIVE: To investigate the association of mitral regurgitation (MR) on thromboembolic risk of patients with non-valvular atrial fibrillation (NVAF) undergoing transoesophageal echocardiography (TEE)-guided cardioversion. METHODS: Data for consecutive patients who underwent TEE-guided cardioversion for NVAF between 2000 and 2012 were analysed. MR severity was assessed by Doppler echocardiography and classified as ≤mild, moderate or severe. Left atrial appendage emptying velocities were averaged for five consecutive cycles. Multivariable regression models were used to identify independent predictors of left atrial appendage thrombus (LAAT) and stroke. RESULTS: 2950 patients (age, 69.3±12.2 years, 67% men) were analysed. 2173 (73.7%) had ≤mild MR; 631 (21.4%), moderate MR; and 146 (4.9%), severe MR. Patients with moderate (age, 72.4±10.7 years) and severe (age, 72.8±12.1 years) MR were older than those with ≤mild MR (age, 68.2±12.5 years). The prevalence of LAAT was 1.5% (n=43). CHA2DS2-VASc scores (≤mild MR, 3.0±1.6; moderate MR, 3.5±1.5; severe MR, 3.9±1.5; p<0.001) and heart failure frequency (≤mild MR, 38.4%; moderate MR, 48.0%; severe MR, 69.2%; p<0.001) were increasingly higher with greater MR severity. Multivariable logistic regression analysis showed no association of moderate MR (OR 0.77, 95% CI 0.38 to 1.56) or severe MR (OR 0.55, 95% CI 0.21 to 1.49) with LAAT. During a mean follow-up of 7.3±5.1 years (median 7.5, IQR, 2.7-10.9), 216 patients had an ischaemic stroke. Adjusted Cox regression analysis showed no significant association of moderate MR (HR 1.22, 95% CI 0.88 to 1.68) or severe MR (HR 0.73, 95% CI 0.31 to 1.46) with stroke. CONCLUSIONS: Among patients with NVAF, the presence or severity of MR was not associated with a decreased risk of LAAT or stroke.