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Importance: Greater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF)., Objective: To explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM)., Design, Setting, and Participants: This was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024., Intervention: SAVM vs sham control procedure., Main Outcomes and Measures: The primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP., Results: A total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, -0.03 mm Hg; 95% CI, -2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, -6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, -9.2% to 18.8%; P = .48)., Conclusions and Relevance: Results show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF., Trial Registration: ClinicalTrials.gov Identifier: NCT04592445.

Background: As the catheter-based device closure of the patent foramen ovale (PFO) is expanding, novel devices aim to address the limitations of first-generation occluders (e.g. bulk, erosion, dislodgment). The second-generation device from Encore Medical (Eagan, MN, USA) features an articulating frame structure which allows the device to better conform to atrial anatomies, has lower disc thickness and metal mass/surface area, and is fully retrievable at any point in the procedure. The aim of the study was to evaluate the feasibility and safety of a novel low-profile, fully retrievable, Encore PFO closure device in the animal model., Methods: Six swine underwent implantation of the novel PFO occluder under fluoroscopic and intra-cardiac echocardiography guidance and survived for 140 days. Interim transthoracic echocardiography (TTE) was conducted on Day 29. Following terminal angiography and TTE at 140 days, the hearts were subjected to gross and histopathologic analysis., Results: All animals were successfully implanted and survived for 140 days. Interim TTE revealed proper device retention with no blood flow across the septum or thrombus in any of the animals. X-ray and pathology results showed preserved implant integrity with no fractures, and complete integration of the devices into the septum with complete re-endothelialization and nearly complete coverage by a mature, relatively thin neoendocardium. No surface fibrin deposition or thrombosis was reported., Conclusions: In the standard porcine model, device retention and biocompatibility remained favorable following structural and functional device modifications exemplified by the second-generation PFO occluder from Encore Medical, including marked reduction of metal mass., Competing Interests: Declaration of competing interest Michael Corcoran is an employee of, and Dr. Nielsen is a consultant to Encore Medical., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The observation of post-transition-state dynamic effects in the context of metal-based transformation is rare. To date, there has been no reported case of a dynamic effect for the widely employed class of palladium-mediated coupling reactions. We performed an experimental and computational study of the trifluoromethylation of Pd (II) F, which is a key step in the Pd (0) /Pd (II) -catalyzed trifluoromethylation of aryl halides or acid fluorides. Our experiments show that the cis / trans speciation of the formed Pd (II) CF 3 is highly solvent- and transmetalation reagent-dependent. We employed GFN2-xTB- and B3LYP-D3-based molecular dynamics trajectory calculations (with and without explicit solvation) along with high-level QM calculations and found that depending on the medium, different transmetalation mechanisms appear to be operative. A statistically representative number of Born-Oppenheimer molecular dynamics (MD) simulations suggest that in benzene, a difluorocarbene is generated in the transmetalation with R 3 SiCF 3 , which subsequently recombines with the Pd via two distinct pathways, leading to either the cis - or trans- Pd (II) CF 3 . Conversely, GFN2-xTB simulations in MeCN suggest that in polar/coordinating solvents an ion-pair mechanism is dominant. A CF 3 anion is initially liberated and then rebinds with the Pd (II) cation to give a cis - or trans- Pd (II) . In both scenarios, a single transmetalation transition state gives rise to both cis - and trans -species directly, owing to bifurcation after the transition state. The potential subsequent cis - to trans isomerization of the Pd (II) CF 3 was also studied and found to be strongly inhibited by free phosphine, which in turn was experimentally identified to be liberated through displacement by a polar/coordinating solvent from the cis -Pd (II) CF 3 complex. The simulations also revealed how the variation of the Pd-coordination sphere results in divergent product selectivities., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Recommendations for pneumococcal vaccination in adults have been updated in the hopes not only of preventing more cases of invasive pneumococcal disease but also of making the recommendations simpler and easier to follow., (Copyright © 2022 The Cleveland Clinic Foundation. All Rights Reserved.)

We report the mild activation of carbamoyl azides to the corresponding nitrenes using a blue light/[Ir]-catalyzed strategy, which enables stereospecific access to N -trifluoromethyl imidazolidinones and benzimidazolones. These novel structural motifs proved to be highly robust, allowing their downstream diversification. On the basis of our combined computational and experimental studies, we propose that an electron rebound with the excited metal catalyst is undergone, involving a reduction-triggered nitrogen loss, followed by oxidation to the corresponding carbamoyl nitrene and subsequent C-H insertion.

In this review we survey recent synergistic applications of a chiral organocatalyst with an achiral metal to perform stereoselective transformations of synthetic utility (since 2016). The transformations are classified by the modes of reactivity deployed, focussing on organocatalytic activation of carbonyl substrates as chiral nucleophiles via the α-position ( e.g. , as enamines) and as chiral electrophiles via the β-position ( e.g. , as iminium ions) combined with complementary activation of their reaction partners by an achiral metal co-catalyst ( e.g. , Pd or Cu-based). Corresponding radical reactions are also presented in which photocatalysis mediated by achiral metal complexes replaces the metal co-catalyst. Certain privileged structures are revealed and opportunities to develop this exciting field are highlighted.

Background: Alcohol septal ablation (ASA) is an accepted treatment for medically refractory hypertrophic obstructive cardiomyopathy (HOCM). The procedural and medium-term outcomes have been reassuring. The iatrogenic targeted septal infarction has raised theoretical concerns about risk of arrhythmia and long-term survival. In this study, we describe the long-term survival in a large cohort of patients from a single referral center and the iterative improvement in procedural technique since its inception., Methods: This cohort includes 580 consecutive patients who underwent 664 ASA procedures between the years 1999 and 2015. Procedural details and outcomes are described. Long-term survival is compared with expected survival of demographically similar controls., Results: Fifty-four percent were women and 85% were Caucasian. At the time of ablation, mean age was 57 ± 15 years, septal thickness was 2.1 ± 0.5 cm, and left ventricular outflow tract (LVOT) gradient was 72 ± 40 mm Hg at rest and 102 ± 58 mm Hg with Valsalva provocation. Mean follow-up was 8.0 ± 4.3 years. LVOT gradient reduction >50% was achieved in 94% of patients with reduction in New York Heart Association functional class scores and increase in exercise treadmill duration. Procedural mortality was 0.9%. Over the 16-year period, survival estimates at 1, 5, 10, and 15 years were 98%, 92%, 84%, and 81%, respectively, which are comparable to demographically similar controls. The standardized mortality ratio was 0.84 (95% confidence interval, 0.66-1.06); P=.09., Conclusions: ASA appears to be a safe and effective treatment for symptomatic HOCM refractory to medical therapy with long-term survival comparable to a demographically similar United States population.

The expansion of chemical space associated with ubiquitous motifs is key to unleash new properties and functions. In this context, alkynamides, prevalent in numerous drugs and materials, represent an untapped resource. We herein report the first synthetic access to N -trifluoromethyl alkynamides. Our strategy relies on a mild and operationally simple Ni-catalyzed coupling of N -CF 3 carbamoyl fluorides with alkynyl silanes. The synthesized N -CF 3 alkynamides proved to be highly robust and readily functioned as a platform to unlock access to valuable derivatives, such as N -CF 3 decorated alkenyl amides, oxindoles, or quinolones, all of which were inaccessible to date.

Background: Alcohol septal ablation (ASA) is a proven method of septal reduction for patients with drug refractory, symptomatic hypertrophic obstructive cardiomyopathy (HOCM). This procedure is associated with a 6.5-11% risk of complete heart block (CHB)., Objective: The aim of this study is to determine factors that predict CHB and to develop a clinical tool for risk stratification of patients., Methods: Patients were enrolled into an ongoing ASA study. A total of 636 patient procedures were included, 527 of whom were used in the development of the prediction tool, and 109 of whom were used for independent validation. Multivariate analysis was performed with odds ratios used to develop the clinical prediction tool. This was then internally and externally validated., Results: Of the 527 in the prediction cohort, 46 developed CHB. The predictors of CHB were age ≥50 years, pre-ASA left bundle branch block (LBBB), transient procedural high-grade block, post-ASA PR prolongation ≥68 ms, and new bifascicular block. An 11-point clinical prediction tool was developed to classify these factors. Internal validation using a receiver operating characteristic curve revealed an area under the curve of 0.88 for the clinical prediction tool. External validation using 109 contemporary patients revealed a 98% negative predictive value, 24% positive predictive value, 75% sensitivity, and 81% specificity in high-risk patients., Conclusion: Among patients undergoing ASA, the risk of CHB can be predicted with easily obtained clinical and electrocardiographic factors. This clinical prediction tool allows identification of high-risk patients who may benefit from additional monitoring and therapy., (© 2021 Wiley Periodicals LLC.)

Downstream intermediates are crucial for the reactivity and selectivity of aminocatalytic reactions. We present an analysis of the stereopreference in aminocatalytic downstream intermediates, which reveals an inconspicuous mechanism of chiral recognition between the catalyst and the rest of the molecule. We delineate a stereoelectronic model to rationalize the mode of chiral transmission. We also exploit it for the resolution of chiral lactols relevant in organic synthesis as well as in the flavor and fragrance industry.

G-Protein-coupled receptors (GPCRs) are ubiquitous within eukaryotes, responsible for a wide array of physiological and pathological processes. Indeed, the fact that they are the most drugged target in the human genome is indicative of their importance. Despite the clear interest in GPCRs, most information regarding their activity has been so far obtained by analyzing the response from a "bulk medium". As such, this Perspective summarizes some of the common methods for this indirect observation. Nonetheless, by inspecting approaches applying super-resolution imaging, we argue that imaging is perfectly situated to obtain more detailed structural and spatial information, assisting in the development of new GPCR-targeted drugs and clinical strategies. The benefits of direct optical visualization of GPCRs are analyzed in the context of potential future directions in the field.

Upon treatment with a combination of HFIP and an organic sulfonic acid, alkenes behave as Brønsted bases and protonate to give carbocations which can be trapped by electron-rich arenes. The reaction constitutes a Friedel-Crafts hydroarylation which proceeds with Markovnikov selectivity and is orthogonal to traditional metal-catalyzed processes. Intermolecular transfer hydrogenation and hydrothiolation under analogous conditions are also demonstrated.

Lymphatic flow is augmented in states of chronic heart failure (cHF). However, the biological mechanism driving increased lymphatic flow capacity (lymphangiogenesis) in cHF is unknown. Recent studies have indicated that vascular endothelial growth factors (VEGF-A, -C, and -D) are involved in lymphangiogenesis. This study examined the association between VEGF-A, -C, and -D levels, invasively measured hemodynamics, and heart failure symptoms. Subjects who underwent clinically indicated right heart catheterization at Medical University of South Carolina between 12/2016 and 7/2018 were eligible for inclusion. These subjects underwent clinical assessment of cHF severity (including 6MWT and KCCQ), hemodynamic assessment with right heart catheterization, laboratory studies including B-type natriuretic peptide, and concomitant measurement of VEGF-A, -C, and -D. Fifty-six patients were included for analysis. Subjects with elevated pulmonary artery wedge pressure (PAWP) had significantly higher VEGF-D levels (263 ± 415 pg/ml vs 65 ± 101 pg/ml; p = 0.02). PAWP was not associated with VEGF-A or VEGF-C levels. When stratified by VEGF-D, subjects with elevated VEGF-D had clinical and hemodynamic characteristics associated with worse HF severity (lower ejection fraction, higher b-type natriuretic peptide, higher PAWP, lower cardiac output), but were not more symptomatic by Kansas City Cardiomyopathy Questionnaire scores and had similar 6-minute walk test distance compared with subjects with lower VEGF-D. Subjects with an elevated VEGF-D were more likely to have a diagnosis of heart failure for >3 years. In conclusion, VEGF-D is associated with elevated PAWP in cHF, and elevated VEGF-D may mitigate cHF symptoms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Visual kinetic analyses extract meaningful mechanistic information from experimental data using the naked-eye comparison of appropriately modified progress reaction profiles. Basic kinetic information is obtained easily and quickly from just a few experiments. Therefore, these methods are valuable tools for all chemists working in process chemistry, synthesis or catalysis with an interest in mechanistic studies. This minireview describes the visual kinetic analyses developed in the last fifteen years and provides answers to the most common queries of new users. Furthermore, a video tutorial is attached detailing the implementation of both VTNA and RPKA.

Herein we report a combined experimental and computational investigation of the acid catalyzed cyclocondensation reaction between styrenyl homoallylic alcohols and salicylaldehyde to form furanochromanes. We disclose a previously unreported isomerisation of the 'unnatural' trans -fused products to the diastereomeric 'natural' cis -fused congeners. Notwithstanding the appeal of assuming this corresponds to endo to exo isomerisation of Diels-Alder (D-A) adducts via concerted retro-cycloaddition/cycloaddition reactions of an in situ generated ortho -quinone methide with the styrenyl alkene, our combined Hammett/DFT study reveals a stepwise Prins-like process via discrete benzylic carbocation intermediates for all but the most electron deficient styrenes. As these reactions fortuitously lie at the intersection of these two mechanistic manifolds, it allows us to propose an experimentally determined indicative ρ + value of ca. -3 as marking this nexus between a stepwise Prins-type pathway and a concerted cycloaddition reaction. This value should prove useful for categorising other reactions formally involving ' ortho -quinomethides', without the need for the extensive computation performed here. Logical optimisation of the reaction based upon the mechanistic insight led to the use of HFIP as an additive which enables exclusive formation of 'natural' cis -fused products with a ∼100-fold reaction rate increase and improved scope.

Importance: In patients with heart failure (HF) and left ventricular ejection fraction (LVEF) equal to or greater than 40%, a transcatheter interatrial shunt device (IASD; Corvia Medical) reduces exercise pulmonary capillary wedge pressure (PCWP) and is safe compared with sham control treatment at 1 month of follow-up. The longer-term safety and patency of the IASD has not yet been demonstrated in the setting of a randomized clinical trial (RCT)., Objective: To evaluate the 1-year safety and clinical outcomes of the IASD compared with a sham control treatment., Design, Setting, and Participants: This phase 2, double-blind, 1-to-1 sham-controlled multicenter RCT of IASD implantation vs a sham procedure (femoral venous access and imaging of the interatrial septum without IASD) was conducted in 22 centers in the United States, Europe, and Australia on patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, LVEF equal to or greater than 40%, exercise PCWP equal to or greater than 25 mm Hg, and PCWP-right atrial pressure gradient equal to or greater than 5 mm Hg., Main Outcomes and Measures: Safety was assessed by major adverse cardiac, cerebrovascular, or renal events (MACCRE). Exploratory outcomes evaluated at 1 year were hospitalizations for HF, NYHA class, quality of life, a 6-minute walk test, and device patency., Results: After 1 year, shunts were patent in all IASD-treated patients; MACCRE did not differ significantly in the IASD arm (2 of 21 [9.5%]) vs the control arm (5 of 22 [22.7%]; P = .41), and no strokes occurred. The yearly rate of hospitalizations for HF was 0.22 in the IASD arm and 0.63 in the control arm (P = .06). Median improvement in NYHA class was 1 class in the IASD arm (IQR, -1 to 0) vs 0 in the control arm (IQR, -1 to 0; P = .08). Quality of life and 6-minute walk test distance were similar in both groups. At 6 months, there was an increase in right ventricular size in the IASD arm (mean [SD], 7.9 [8.0] mL/m2) vs the control arm (-1.8 [9.6] mL/m2; P = .002), consistent with left-to-right shunting through the device; no further increase occurred in the IASD arm at 12 months., Conclusions and Relevance: The REDUCE LAP-HF I phase 2, sham-controlled RCT confirms the longer-term patency of the IASD. Through 1 year of follow-up, IASD treatment appears safe, with no significant differences in MACCRE in patients receiving IASD compared with those who received sham control treatment., Trial Registration: ClinicalTrials.gov identifier: NCT02600234.

Background: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%., Methods: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise., Results: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control ( P =0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group ( P =0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group ( P =1.0)., Conclusions: In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02600234., (© 2017 American Heart Association, Inc.)

Copper complexes of phosphoramidites efficiently catalyzed asymmetric addition of arylboron reagents to acyclic enones. Importantly, rare 1,4-insertion of arylcopper(I) was identified which led directly to O-bound copper enolates. The new mechanism is fundamentally different from classical oxidative addition/reductive elimination of organocopper(I) on enones.

Background: July 2011 saw the implementation of the newest duty hour restrictions, further limiting the working hours of first year residents and necessitating a variety of adaptations on the part of residency programs. The present study sought to characterize the perceived impact of these restrictions on residency program personnel using a multi-specialty and multi-site approach., Methods: We developed and administered a survey to internal medicine and general surgery residency programs at three academic medical centers within an urban region. The survey combined quantitative and qualitative components to gain a broader understanding of the impact of the newest regulations. Quantitative responses were compared between Internal Medicine and General Surgery programs with Student t-tests. Other comparisons were performed using ANOVA or Kruskal-Wallis testing as appropriate. For all comparisons, the threshold for significance was set at 0.01. Two independent reviewers coded all qualitative data and assigned one or more themes based on content. Descriptive statistics were calculated and the diversity of themes identified. No between-group comparisons were conducted with the qualitative data., Results: We found significant differences in the overall perceptions of duty hour restrictions across specialty (internal medicine more positive than general surgery) and across position (first year residents more positive than senior residents and faculty). Notably, individuals who trained at osteopathic medical schools reported significantly more negative views of the duty hour restrictions than those who had trained at allopathic or international medical schools, suggesting an influence of undergraduate medical training. The complementary qualitative data offered insights into the perceived strengths and weaknesses of the duty hour restrictions, as well as actionable suggestions that could help to improve residency program function., Conclusion: This study characterizes responses to the new duty hour restrictions from a variety of perspectives. Our findings show that individual (type of undergraduate medical education, role in graduate medical education) and program-wide (e.g., specialty) factors contribute to participant satisfaction with DHR. This research highlights the value of a mixed methods approach in the study of duty hour restrictions, with our qualitative arm yielding rich data that complemented and expanded upon the insights derived from the quantitative data.

Objectives: We compared the efficacy and safety of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) in young, middle-aged, and elderly patients., Background: Intersociety guidelines suggest based on limited evidence that young patients with medically refractory symptoms of obstructive HCM should undergo surgical myectomy while elderly patients may be more appropriate for ASA., Methods: Data for 360 patients undergoing 389 ASAs were prospectively collected and retrospectively analyzed according to age., Results: Young (<45 years), middle-aged (45-64 years), and elderly (≥65 years) patients comprised 28, 40, and 32% of the study population, respectively. Young patients had thicker left ventricular septal walls at baseline, and elderly patients had more comorbidity and dyspnea. Resting, mean left ventricular outflow tract gradients (LVOTGs) were similar across the age groups at baseline (62, 66, and 68 mm Hg, respectively; P = NS for all comparisons). LVOTGs and dyspnea were significantly and similarly improved in all age groups immediately after ASA and through 12 months of follow-up (P < 0.001 for before and after comparisons; P = NS for intergroup comparisons). Complication rates were similar for young and middle-aged patients but higher for elderly patients (9.1 and 6.3% vs. 20.8%, respectively; P ≤ 0.016 for elderly vs. others). Mortality rates for young and middle-aged patients were lower than for elderly patients, but the differences were not statistically significant., Conclusions: Patients undergoing ASA had significant and similar improvements in LVOTGs and symptoms regardless of age. Procedural complications were increased in elderly patients, who had numerically but not statistically significantly higher mortality rates., (Copyright © 2012 Wiley Periodicals, Inc.)

Atherosclerosis has been shown to develop preferentially at sites of coronary bifurcation, yet culprit lesions resulting in ST-elevation myocardial infarction do not occur more frequently at these sites. We hypothesized that these findings can be explained by similarities in intracoronary lipid and that lipid and lipid core plaque would be found with similar frequency in coronary bifurcation and nonbifurcation segments. One hundred seventy bifurcations were identified, 156 of which had comparative nonbifurcation segments proximal and/or distal to the bifurcation. We compared lipid deposition at bifurcation and nonbifurcation segments in coronary arteries using near-infrared spectroscopy (NIRS), a novel method for the in vivo detection of coronary lipid. Any NIRS signal for the presence of lipid was found with similar frequency in bifurcation and nonbifurcation segments (79% vs 74%, p = NS). Lipid core burden index, a measure of total lipid quantity indexed to segment length, was similar across bifurcation segments as well as their proximal and distal controls (lipid core burden index 66.3 ± 106, 67.1 ± 116, and 66.6 ± 104, p = NS). Lipid core plaque, identified as a high-intensity focal NIRS signal, was found in 21% of bifurcation segments, and 20% of distal nonbifurcation segments (p = NS). In conclusion, coronary bifurcations do not appear to have higher levels of intracoronary lipid or lipid core plaque than their comparative nonbifurcation regions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Fractional flow reserve (FFR), the hyperemic ratio of distal (Pd) to proximal (Pa) coronary pressure, is used to identify the need for coronary revascularization. Changes in left ventricular end-diastolic pressure (LVEDP) might affect measurements of FFR., Methods and Materials: LVEDP was recorded simultaneously with Pd and Pa during conventional FFR measurement as well as during additional infusion of nitroprusside. The relationship between LVEDP, Pa, and FFR was assessed using linear mixed models., Results: Prospectively collected data for 528 cardiac cycles from 20 coronary arteries in 17 patients were analyzed. Baseline median Pa, Pd, FFR, and LVEDP were 73 mmHg, 49 mmHg, 0.69, and 18 mmHg, respectively. FFR<0.80 was present in 14 arteries (70%). With nitroprusside median Pa, Pd, FFR, and LVEDP were 61 mmHg, 42 mmHg, 0.68, and 12 mmHg, respectively. In a multivariable model for the entire population LVEDP was positively associated with FFR such that FFR increased by 0.008 for every 1-mmHg increase in LVEDP (beta=0.008; P<0.001), an association that was greater in obstructed arteries with FFR<0.80 (beta=0.01; P<0.001). Pa did not directly affect FFR in the multivariable model, but an interaction between LVEDP and Pa determined that LVEDP's effect on FFR is greater at lower Pa., Conclusions: LVEDP was positively associated with FFR. The association was greater in obstructive disease (FFR<0.80) and at lower Pa. These findings have implications for the use of FFR to guide revascularization in patients with heart failure., Summary for Annotated Table of Contents: The impact of left ventricular diastolic pressure on measurement of fractional flow reserve (FFR) is not well described. We present a hemodynamic study of the issue, concluding that increasing left ventricular diastolic pressure can increase measurements of FFR, particularly in patients with FFR<0.80 and lower blood pressure., (© 2013.)

This study sought to examine the safety of percutaneous coronary intervention (PCI) before and during de novo establishment of a transradial (TR) program at a teaching hospital. TR access remains underused in the United States, where cardiology fellowship programs continue to produce cardiologists with little TR experience. Establishment of TR programs at teaching hospitals may affect PCI safety. Starting in July 2009 a TR program was established at a teaching hospital. PCI-related data for academic years 2008 to 2009 (Y1) and 2009 to 2010 (Y2) were prospectively collected and retrospectively analyzed. Of 1,366 PCIs performed over 2 years, 0.1% in Y1 and 28.7% in Y2 were performed by TR access. No major complications were identified in 194 consecutive patients undergoing TR PCI, and combined bleeding and vascular complication rates were lower in Y2 versus Y1 (0.7% vs 2.0%, p = 0.05). Patients treated in Y2 versus Y1 and by TR versus transfemoral approach required slightly more fluoroscopy but similar contrast volumes and had similar procedural durations, lengths of stay, and predischarge mortality rates. PCI success rates were 97% in Y1, 97% in Y2, and 98% in TR cases. TR PCIs were performed by 13 cardiology fellows and 9 attending physicians, none of whom routinely performed TR PCI previously. In conclusion, de novo establishment of a TR program improved PCI safety at a teaching hospital. TR programs are likely to improve PCI safety at other teaching hospitals and should be established in all cardiology fellowship training programs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Defibrillation threshold (DFT) testing is performed in part to ensure an adequate safety margin for the termination of spontaneous ventricular arrhythmias. Left ventricular mass is a predictor of high DFTs, so patients with hypertrophic cardiomyopathy (HCM) are often considered to be at risk for increased defibrillation energy requirements. However, there are little prospective data addressing this issue., Objective: To assess DFTs in patients with HCM and evaluate the clinical predictors of elevated DFTs., Methods: Eighty-nine consecutive patients with HCM and 600 control patients with ischemic or nonischemic cardiomyopathy underwent a uniform modified step-down DFT testing protocol. DFT was compared between the control and HCM populations. Predictors of elevated DFT were evaluated in the HCM group., Results: There was no difference in DFT between HCM and control groups (10.4 ± 5.8 J vs 11.2 ± 5.6 J, respectively). Among patients with HCM, clinical parameters such as left ventricular ejection fraction, interventricular septal thickness, left ventricular mass, and QRS duration were not predictive of an elevated DFT. Only 3 patients (3.4%) with HCM had a DFT >20 J., Conclusion: Patients with HCM do not have elevated DFTs as compared to more typical populations undergoing implantable cardioverter-defibrillator implant; high-energy devices or complex lead systems are not needed routinely in this population., (© 2010 Wiley Periodicals, Inc.)

Takotsubo cardiomyopathy (TCM) is usually characterized by left ventricular anteroapical dysfunction in the absence of significant coronary disease commonly precipitated by an emotional or stressful trigger. Hypertrophic cardiomyopathy (HCM) is usually diagnosed on the basis of symptoms, family history, echocardiography, or by the presence of a characteristic murmur. We report a unique case of TCM occurring in a patient with previously undiagnosed HCM with left ventricular outflow tract (LVOT) obstruction who presented with an acute coronary syndrome and ultimately underwent successful alcohol septal ablation. The potential pathophysiologic correlations are discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Friedreich ataxia (FRDA) is typically characterized by slowly progressive ataxia, depressed tendon reflexes, dysarthria, pyramidal signs, and loss of position and vibration sense with onset before 25 years. While several atypical forms of FRDA are recognized, profound vision deficit is rare. We describe here a 41-year-old man with profound vision deficit and episodic complete blindness associated with marked optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia whose diagnostic evaluation revealed compound heterozygosity for two frataxin mutations, a 994 GAA repeat intronic expansion and c.389G > T (p.G130V) missense mutation. This case emphasizes that FRDA should be considered for individuals with significant vision deficit with optic atrophy and sensory neuropathy, even in the absence of ataxia. This case also raises the additional, related concern that prior studies may underestimate the frequency and varieties of variant forms of FRDA.

Objectives: The purpose of this study was to examine the effects of alcohol septal ablation (ASA) on ventricular arrhythmias among patients with obstructive hypertrophic cardiomyopathy (HCM), as measured by appropriate implantable cardioverter-defibrillator (ICD) discharges., Background: Alcohol septal ablation is an effective therapy for patients with symptomatic HCM. However, concern has been raised that ASA may be proarrhythmic secondary to the iatrogenic scar created during the procedure. The impact of ASA on ventricular arrhythmias has not been well described., Methods: This prospective study included 123 consecutive patients with obstructive HCM who underwent ASA and had an ICD implanted for primary prevention of sudden cardiac death (SCD). The ICDs were implanted based on commonly accepted risk factors for SCD in the HCM population. Data from ICD interrogations during routine follow-up were collected., Results: Nine appropriate ICD shocks were recorded over a mean follow-up of 2.9 years in the cohort, which had a mean of 1.5 +/- 0.9 risk factors for SCD. Using Kaplan-Meier survival analysis, the estimated annual event rate was 2.8% over 3-year follow-up. There were no significant differences in the incidence of risk factors between patients who did and did not receive appropriate shocks., Conclusions: The annual rate of appropriate ICD discharges after ASA is low and less than that reported previously for primary prevention of SCD in HCM. This suggests that ASA is not proarrhythmic. Traditional SCD risk factors did not predict ICD shocks in this cohort.

Patients with obstructive hypertrophic cardiomyopathy are presumed to have poor quality of life (QOL) and distress related to their cardiac symptoms and functional limitations. Alcohol septal ablation (ASA) is designed to improve heart function and reduce cardiac symptoms. The purpose of this study was to examine psychosocial factors and QOL in patients with obstructive hypertrophic cardiomyopathy before and 3 months after ASA. Twenty-two adult participants (mean age 57 +/- 14 years, 59% women, 100% Caucasian, 67% married) were recruited during their initial evaluations or scheduled index hospitalizations for ASA. Psychosocial and medical measures were collected before and 3 months after ASA. The results indicated that before ASA, 57% of patients reported clinically relevant levels of depression (Center for Epidemiologic Studies Depression Scale score >16), symptoms of anxiety, and reduced QOL. Repeated-measures analyses of variance revealed that ASA is an effective procedure in reducing disease severity (i.e., peak left ventricular outflow tract gradient, septal thickness, posterior wall thickness) (p = 0.001 to 0.05), depression (p = 0.005), and anxiety (p = 0.029) and improving cardiac-specific QOL (p < 0.001) and generic physical health-related QOL (p = 0.009). Changes in satisfaction with life, optimism, and generic mental health-related QOL were not significant (p = 0.143 to 0.899). In conclusion, significant psychological distress and compromised well-being were present in this sample of pre-ASA patients with obstructive hypertrophic cardiomyopathy. After ASA, significant reductions in psychological distress and improvements in well-being and echocardiographic parameters indicating disease severity were demonstrated. These results suggest that patients perceived broad health benefits from ASA in short-term follow-up.

Purpose: To prospectively evaluate the effect of single- versus two-segment image reconstruction on image quality and diagnostic accuracy at 64-section multidetector computed tomographic (CT) coronary angiography by using conventional coronary angiography as the reference standard., Materials and Methods: The study design was approved by a human research committee; patients gave informed consent. The study was HIPAA compliant. Forty consecutive patients (22 men, 18 women; mean age, 61 years +/- 8 [standard deviation]) underwent both 64-section multidetector CT coronary angiography and conventional angiography. All data sets were reconstructed by using single- and two-segment image reconstruction algorithms, with resulting temporal resolution of 82.5-165 msec. Two experienced observers independently evaluated image quality and signs of coronary artery disease. A five-level grading scheme was used to grade stenosis (0%, <50%, <70%, <99%, 100%) and image quality (1[unacceptable] to 5[excellent]). Interobserver correlation, Spearman correlation coefficients, and diagnostic accuracy were calculated., Results: Six hundred coronary artery segments were visible on conventional angiograms, of which 560 (93.3%) were seen by using single-segment and 561 (93.5%) were seen by using two-segment image reconstruction (P=.35). Mean quality scores were not significantly different (P=.22) for single- (3.1 +/- 0.9) and two-segment (3.2 +/- 0.8) reconstruction. Significantly (P=.03) better image quality was observed for two-segment reconstruction only at heart rates of 80-82 beats per minute, at which temporal resolution was approximately 83 msec. For grading coronary artery stenosis, correlation was 0.64 for single- and 0.66 for two-segment reconstruction (P=.43). Significant stenosis (>50%) was detected on a per-segment basis with 77.1% sensitivity and 98.6% specificity by using single-segment and with 79.2% sensitivity and 99.1% specificity by using two-segment image reconstruction., Conclusion: At heart rates of more than 65 beats per minute, use of two-segment reconstruction improves image quality at multidetector CT coronary angiography but does not significantly affect overall diagnostic accuracy compared with single-segment reconstruction., ((c) RSNA, 2007.)

Purpose: To prospectively evaluate the accuracy of 64-section computed tomographic (CT) coronary angiography for assessing significant stenosis on a global and segmental level, by using conventional coronary artery angiography as the reference standard., Materials and Methods: This study was HIPAA compliant and had local institutional review board approval. Patients gave informed consent. Patients suspected of having coronary artery disease (CAD) underwent both conventional coronary catheter angiography and contrast material-enhanced retrospectively electrocardiographically gated 64-section multi-detector row CT of the coronary arteries. Two experienced observers analyzed all CT scans for signs of CAD (stenosis of 0%, or=50%) stenosis in CAD with an accuracy of 89%. On a per-segment and per-vessel basis, diagnostic accuracy is still impaired, primarily by limited spatial resolution., ((c) RSNA, 2007.)

Treatment of obstructive hypertrophic cardiomyopathy remains challenging. Medical therapy, surgical therapy, and pacemaker therapy have been shown to be beneficial in some patients over the years. Alcohol septal ablation is a catheter-based intervention that causes a controlled infarct in the septum leading to a decrease in the left ventricular outflow tract obstruction. Along with the impressive reductions in left ventricular outflow tract gradient, there is subjective and objective improvement in symptoms. Development of complete heart block requiring a permanent pacemaker after alcohol septal ablation remains a frequent complication, but has decreased in some recent studies. Alcohol septal ablation has been shown to improve diastolic function, decrease mitral regurgitation, decrease left ventricular hypertrophy and mass, as well as cause changes at the cellular and molecular level that improve myocardial function. Comparison of alcohol septal ablation to surgical myectomy has shown favorable results. Long-term follow-up of alcohol septal ablation has shown sustained results out to several years.

Background: Nonsurgical septal reduction therapy (NSRT) has been shown to improve left ventricular outflow tract (LVOT) gradients, decrease septal thickness, and improve symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM). The major complication of this procedure has been the development of complete heart block (CHB) requiring permanent pacemaker implantation, which has been reported in up to 33% of patients in early studies. Since this procedure was first reported, there have been refinements in the technique such as the use of echocardiographic contrast material to localize the site of infarction, slower injection of alcohol, as well as improvement in balloon technology., Hypothesis: We sought to determine the results of NSRT using echocardiographic contrast localization, slow injection of alcohol, and short balloon length. We theorized that the incidence CHB would be lower than earlier reported results using these refined techniques., Methods: We performed 50 NSRT procedures on 46 patients using echocardiographic contrast localization, slow alcohol injection, and currently available balloons. Patients had an echocardiogram before, immediately after NSRT, and at 3 months, and a treadmill test before and at 3 months after NSRT. In the hospital, patients were observed for the development of CHB or other complications, and infarct size was determined by serial creatine kinase (CK) measurements., Results: There was a decrease in the LVOT gradient from 84.2 (+/- 30.8) mmHg at baseline, to 18.5 (+/- 14.8) mmHg immediately after NSRT (p < 0.001). At 3 months, the gradient was not statistically different at 22.7 (+/- 22.2) mmHg 0.27). The septal thickness decreased from 2.21 (+/- 0.66) cm at baseline, to 1.67 (+/- 0.51) cm at 3 months (p < 0.001). New York Heart Association symptom class improved from 3.2 (+/- 0.4) at baseline, to 1.1 (+/- 0.6) at 3 months (p < 0.001). Mean treadmill time in 30 patients was 235 (+/- 142) s at baseline, to 367 (+/- 159) s at 3 months (p < 0.001). Of the 50 procedures, 45 were performed in patients without a previously placed permanent pacemaker or intracardiac cardioverter defibrillator, only 3 (6.7%) of the 45 developed complete heart blocks required permanent pacing. While only three patients in the series had a preexisting left bundle-branch block (LBBB), two of the three patients who required a permanent pacemaker had an LBBB before the prcoedure., Conclusion: Using contrast echocardiographic localization, slow injection of alcohol, and shorter balloon catheters, there continues to be excellent improvement in LVOT gradients, septal thickness, and symptoms, with a reduced incidence of CHB requiring permanent pacemaker implantation. Left bundle-branch block appears to be a strong predictor for the development of CHB after NSRT.

Hypertrophic obstructive cardiomyopathy is a complex and challenging disease. Medical therapy, surgical therapy, and pacing therapy have been used with some success over the years. Nonsurgical septal reduction therapy, also called alcohol septal ablation, has been used recently as a percutaneous catheter-based intervention to improve left ventricular outflow tract obstruction and thereby improve symptoms. The reported results of this procedure have shown impressive reductions in gradient and improvement in symptoms at relatively low risk. The most common complication of the procedure, development of complete heart block requiring a permanent pacemaker, has improved in recent studies with refinements of the procedural technique. Nonsurgical septal reduction therapy has been shown to improve diastolic function, decrease left ventricular hypertrophy and mass, and cause changes at the cellular and molecular level that improve myocardial function. Reported results at 1 year follow-up continue to show benefit, and long-term studies are ongoing.

This retrospective study examined the utilization of coronary stent placement versus PTCA in hemodialysis patients with obstructive coronary disease. Prior studies have demonstrated suboptimal results with PTCA owing primarily to high rates of restenosis. We identified 19 hemodialysis patients who received a percutaneous coronary intervention who were matched with individuals without renal failure undergoing same vessel revascularization. Our study found that 71% of hemodialysis patients receiving PTCA had a recurrent cardiac event defined by subsequent angina, myocardial infarction, or cardiac death. At follow-up, 30% of patients who received stent placement had recurrent cardiac events. Intracoronary stent placement is both safe and feasible and produces more favorable clinical outcomes in the management of coronary disease in hemodialysis patients., (Copyright 2001 Wiley-Liss, Inc.)

The spike timing in rhythmically active interneurons in the mammalian spinal locomotor network varies from cycle to cycle. We tested the contribution from passive membrane properties to this variable firing pattern, by measuring the reliability of spike timing, P, in interneurons in the isolated neonatal rat spinal cord, using intracellular injection of sinusoidal command currents of different frequencies (0.325-31.25 Hz). P is a measure of the precision of spike timing. In general, P was low at low frequencies and amplitudes (P = 0-0.6; 0-1.875 Hz; 0-30 pA), and high at high frequencies and amplitudes (P = 0.8-1; 3.125-31.25 Hz; 30-200 pA). The exact relationship between P and amplitude was difficult to describe because of the well-known low-pass properties of the membrane, which resulted in amplitude attenuation of high-frequency compared with low-frequency command currents. To formalize the analysis we used a leaky integrate and fire (LIF) model with a noise term added. The LIF model was able to reproduce the experimentally observed properties of P as well as the low-pass properties of the membrane. The LIF model enabled us to use the mathematical theory of nonlinear oscillators to analyze the relationship between amplitude, frequency, and P. This was done by systematically calculating the rotational number, N, defined as the number of spikes divided by the number of periods of the command current, for a large number of frequencies and amplitudes. These calculations led to a phase portrait based on the amplitude of the command current versus the frequency-containing areas [Arnold tongues (ATs)] with the same rotational number. The largest ATs in the phase portrait were those where N was a whole integer, and the largest areas in the ATs were seen for middle to high (>3 Hz) frequencies and middle to high amplitudes (50-120 pA). This corresponded to the amplitude- and frequency-evoked increase in P. The model predicted that P would be high when a cell responded with an integer and constant N. This prediction was confirmed by comparing N and P in real experiments. Fitting the result of the LIF model to the experimental data enabled us to estimate the standard deviation of the internal neuronal noise and to use these data to simulate the relationship between N and P in the model. This simulation demonstrated a good correspondence between the theoretical and experimental values. Our data demonstrate that interneurons can respond with a high reliability of spike timing, but only by combining fast and slow oscillations is it possible to obtain a high reliability of firing during rhythmic locomotor movements. Theoretical analysis of the rotation number provided new insights into the mechanism for obtaining reliable spike timing.