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Adaptation, the reduction of neuronal responses by repetitive stimulation, is a ubiquitous feature of auditory cortex (AC). It is not clear what causes adaptation, but short-term synaptic depression (STSD) is a potential candidate for the underlying mechanism. In such a case, adaptation can be directly linked with the way AC produces context-sensitive responses such as mismatch negativity and stimulus-specific adaptation observed on the single-unit level. We examined this hypothesis via a computational model based on AC anatomy, which includes serially connected core, belt, and parabelt areas. The model replicates the event-related field (ERF) of the magnetoencephalogram as well as ERF adaptation. The model dynamics are described by excitatory and inhibitory state variables of cell populations, with the excitatory connections modulated by STSD. We analysed the system dynamics by linearising the firing rates and solving the STSD equation using time-scale separation. This allows for characterisation of AC dynamics as a superposition of damped harmonic oscillators, so-called normal modes. We show that repetition suppression of the N1m is due to a mixture of causes, with stimulus repetition modifying both the amplitudes and the frequencies of the normal modes. In this view, adaptation results from a complete reorganisation of AC dynamics rather than a reduction of activity in discrete sources. Further, both the network structure and the balance between excitation and inhibition contribute significantly to the rate with which AC recovers from adaptation. This lifetime of adaptation is longer in the belt and parabelt than in the core area, despite the time constants of STSD being spatially homogeneous. Finally, we critically evaluate the use of a single exponential function to describe recovery from adaptation., (© 2022. The Author(s).)

Competing Interests: Funding Support and Author Disclosures Dr Toggweiler serves as a consultant for Medtronic, Biosensors, Abbott, Boston Scientific, Medira, AtHeart Medical, Veosource, Teleflex, and Shockwave; has received institutional research grants from Boston Scientific and Fumedica; and holds equity in Hi-D Imaging. Dr Wolfrum serves as proctor for Biosensors. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Objectives: Investigate the impact of concomitant tricuspid regurgitation (TR) on clinical outcomes during long-term follow-up in patients undergoing percutaneous treatment of mitral regurgitation (MR) with the MitraClip system., Background: Patients undergoing mitral repair using the MitraClip frequently present with concomitant TR. It is uncertain how the presence of TR impacts the long-term outcomes of such patients., Methods: We analyzed consecutive patients with MitraClip implantation from the prospective MitraSwiss registry. Endpoints were all-cause mortality, hospitalization for heart failure, and the composite endpoint of the two., Results: We enrolled 177 patients (mean age 76 ± 9 years, 37% female). Acute procedural success was achieved in 149 (84%). Concomitant moderate or severe TR was present in 31% at baseline and 32% before discharge. After a median follow-up of 1103 days (IQR: 555-1766 days), 70 (40%) of patients had died, and 34 (19%) were hospitalized for heart failure. In multivariable analysis, TR at baseline was associated with an increase in all-cause mortality (HR: 2.34, 95% CI: 1.36-4.03, p < 0.01), hospitalization for heart failure (HR: 3.19, 95% CI: 1.37-7.41, p = 0.01), and the composite endpoint (HR: 2.00, 95% CI: 1.19-3.36, p = 0.01)., Conclusion: Despite treatment of MR, TR did not improve in most patients. The presence of relevant TR at baseline was associated with reduced survival and higher rates of hospitalization for heart failure. More research is needed to understand the causal role of TR in such patients and to investigate if simultaneous treatment of concomitant TR may improve prognosis in patients undergoing percutaneous treatment of MR., (© 2022 Wiley Periodicals LLC.)

Muscle bundles in the right atrium are an extremely rare congenital anomaly. We report the case of a patient with 2 atrial septal defects and a large muscle bundle crossing the right atrium. Only 3 comparable cases have previously been published. ( Level of Difficulty: Intermediate. )., Competing Interests: Dr. Wolfrum has served as a proctor for Biosensors. Dr. Kobza has served as a consultant for Medtronic; and has received institutional research grants from Abbott, Boston Scientific, Biotronik, Biosense-Webster, Medtronic, and Sis-Medical. Dr. Kretschmar has received consulting fees from Medtronic, Carag AG, and Abbott. Dr. Toggweiler has served as a proctor and consultant for Abbott, Biosensors, Boston Scientific, and Medtronic; as a consultant for Shockwave, Teleflex, Medira, atHeart, and Veosource; has received institutional research grants from Boston Scientific and Fumedica AG; and has held equity in Hi-D Imaging. Dr. Stämpfli has received consulting and speaker fees from Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, and Takeda. All other authors have reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Limus-eluting stents have become the mainstay for percutaneous coronary intervention (PCI). However, even with the latest generation drug-eluting stent, in-stent restenosis and very late stent thrombosis remain a concern. The Selution SLR™ drug-coated balloon (DCB) is a novel sirolimus-coated balloon that provides a controlled release of the antiproliferative drug. Herein we evaluated its performance in a real-world patient cohort with complex coronary artery lesions., Methods: Patients undergoing PCI using the Selution SLR™ DCB were analyzed from the prospective SIROOP registry. We evaluated procedural success and clinical outcomes, including major adverse cardiovascular event (MACE), cardiac death, target vessel myocardial infarction and target lesion revascularization., Results: From September 2020 to April 2021, we enrolled 78 patients (87 lesions) treated using a "DCB only" strategy. The mean age was 66.7 ± 10.4 years and 28 (36%) presented with an acute coronary syndrome. Almost all lesions were type B2/C 86 (99%) and 49 (63%) had moderate to severe calcifications. Procedural success was 100%. After a median follow-up of 11.2 months (interquartile range: 10.0-12.6), MACE occurred in 5 (6.8%) patients. No acute vessel closure was observed., Conclusions: In complex coronary lesions, a "DCB only" strategy using the Selution SLR™ DCB is not just safe and feasible, but also seems to be associated with a low rate of MACE at 1-year follow-up. Our promising results warrant further evaluation in a dedicated comparative trial.

Background: Optical flow ratio (OFR) is a novel method for fast computation of fractional flow reserve (FFR) from optical coherence tomography (OCT) images., Aims: We aimed to evaluate the accuracy of OFR in predicting post-percutaneous coronary intervention (PCI) FFR and the impact of stent expansion on within-stent OFR pressure drop (in-stent OFR)., Methods: Post-PCI OFR was computed in patients with both OCT and FFR interrogation immediately after PCI. Calculation of post-PCI OFR (called simulated residual OFR) from pre-PCI OCT pullbacks after elimination of the stenotic segment by virtual stenting was performed in a subgroup of patients who had pre-PCI OCT images. Stent underexpansion was quantified by the minimum expansion index (MEI) of the stented segment., Results: A total of 125 paired comparisons between post-PCI OFR and FFR were obtained in 119 patients, among which simulated residual OFR was obtained in 64 vessels. Mean post-PCI FFR was 0.92±0.05. Post-PCI OFR showed good correlation (r=0.74, p<0.001) and agreement (mean difference=-0.01±0.03, p=0.051) with FFR. The accuracy in predicting post-PCI FFR ≤0.90 was 84% for post-PCI OFR. Simulated residual OFR significantly correlated with post-PCI FFR (r=0.42, p<0.001). MEI showed a moderate correlation (r=-0.49, p<0.001) with in-stent OFR., Conclusions: Post-PCI OFR showed good diagnostic concordance with post-PCI FFR. Simulated residual OFR significantly correlated with post-PCI FFR. Stent underexpansion significantly correlated with in-stent pressure drop.

Objectives: We aimed to determine the safety and efficacy of the Allegra transcatheter heart valve (THV) for the treatment of severe aortic valve stenosis in a large patient population treated under real-world conditions., Background: The Allegra is a novel self-expanding THV with supra-annular bovine leaflets. The valve is available in three different sizes (23, 27, and 31 mm), all are delivered through an 18F sheath., Methods: Consecutive patients undergoing TAVR with the Allegra THV were enrolled in a multicenter-registry. Data were collected throughout initial hospital-stay and at 30-day follow-up. Clinical endpoints were defined according to the updated definitions of the Valve-Academic-Research-Consortium., Results: This registry included 255 patients (mean age 83 ± 6 years, 48% women) from four European centers. Median European System for Cardiac Operative Risk Evaluation II score (EuroSCORE II) was 3.3% (IQR 1.9-5.8%). Acute device success was 95.7%. The remaining 11 patients had either moderate paravalvular regurgitation immediately after the procedure (7 patients) or the device could not be optimal positioned requiring implantation of a second THV (4 patients). Major vascular complications and major/life-threatening bleedings occurred in 10 (3.9%) and 12 (4.7%) patients, respectively. At 30 day follow-up, mean effective orifice area was 2.2 ± 0.5 cm 2 , mean gradient was 6.9 ± 3.8 mmHg, 7 (3.3%) patients had more than mild paravalvular leakage, 3 patients (1.2%) had died, 6 patients (2.4%) had a stroke and 30 (12.8%) patients had required implantation of a new permanent pacemaker., Conclusions: Transfemoral implantation of the Allegra THV resulted in favorable clinical and echocardiographic outcomes during hospitalization and short-term follow up., (© 2021 Wiley Periodicals LLC.)

Self-organized coherence-incoherence patterns, called chimera states, have first been reported in systems of Kuramoto oscillators. For coupled excitable units, similar patterns where coherent units are at rest are called bump states. Here, we study bumps in an array of active rotators coupled by nonlocal attraction and global repulsion. We demonstrate how they can emerge in a supercritical scenario from completely coherent Turing patterns: a single incoherent unit appears in a homoclinic bifurcation, undergoing subsequent transitions to quasiperiodic and chaotic behavior, which eventually transforms into extensive chaos with many incoherent units. We present different types of transitions and explain the formation of coherence-incoherence patterns according to the classical paradigm of short-range activation and long-range inhibition.

Objectives: Report MANTA-associated vascular complications after implementation of key insights on failure mechanisms., Background: The MANTA vascular closure device is utilized to close large-bore arterial access sites. We have previously identified and published the mechanisms and predictors of MANTA-associated vascular complications. We identified three distinct mechanisms leading to MANTA-associated vascular complications, predictors were a common femoral artery (CFA) diameter <6 mm and clinically established peripheral artery disease (PAD)., Methods: We compared 100 consecutive patients of the initial cohort (first n = 100) with consecutive patients in which the key insights acquired in the initial cohort were implemented (second n = 100)., Results: The initial cohort (n = 100 patients) had a MANTA-related vascular complication rate of 11% (7% major and 4% minor), and 14% MANTA-related bleeding complications. In a subsequent cohort of n = 100 patients, we applied the abovementioned findings: we did not use the MANTA device if the CFA was <6 mm and in patients with PAD. In addition, femoral puncture was ultrasound guided. This strategy led to a decline in MANTA-related vascular complication rates: 2% (1% major and 1% minor) p = .03, as well as a reduction in MANTA-related bleeding complications to 5% p = .01. To the best of our knowledge, this is the lowest rate of MANTA-related vascular complication reported thus far., Conclusions: Our strategy achieves low MANTA-related vascular and bleeding complication rates. Careful and critical examination of complications can lead to rapid identification of complication mechanism and its predictors. In turn, rapid implementation of these insights can lead to a decline in complication rates., (© 2021 Wiley Periodicals LLC.)

Background: Early studies evaluating the performance of bioresorbable scaffold (BRS) Absorb in in-stent restenosis (ISR) lesions indicated promising short-term to mid-term outcomes., Aims: To evaluate long-term outcomes (up to 5 years) of patients with ISR treated with the Absorb BRS., Methods: We did an observational analysis of long-term outcomes of patients treated for ISR using the Absorb BRS (Abbott Vascular, Santa Clara, California, USA) between 2013 and 2016 at the Heart Centre Luzern. The main outcomes included a device-oriented composite endpoint (DOCE), defined as composite of cardiac death, target vessel (TV) myocardial infarction and TV revascularisation, target lesion revascularisation and scaffold thrombosis (ScT)., Results: Overall, 118 ISR lesions were treated using totally 131 BRS among 89 patients and 31 (35%) presented with an acute coronary syndrome. The median follow-up time was 66.3 (IQR 52.3-77) months. A DOCE had occurred in 17% at 1 year, 27% at 2 years and 40% at 5 years of all patients treated for ISR using Absorb. ScTs were observed in six (8.4%) of the cohort at 5 years., Conclusions: Treatment of ISR using the everolimus-eluting BRS Absorb resulted in high rates of DOCE at 5 years. Interestingly, while event rates were low in the first year, there was a massive increase of DOCE between 1 and 5 years after scaffold implantation. With respect to its complexity, involving also a more unpredictable vascular healing process, current and future BRS should be used very restrictively for the treatment of ISR., Competing Interests: Competing interests: MM, GMC, AA-T, MW, FM, TS, LV, ST and RK report no conflicts of interest. MB has received consulting and speaker fees from Amgen, Astra Zeneca, Bayer and Mundipharma. FC has received consulting and speaker fees from SIS Medical and Abbott Vascular., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes., Methods and Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002)., Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study aimed to investigate the safety and efficacy of ACURATE neo transcatheter aortic valve replacement (TAVR) facilitated by predilatation with the nonocclusive TrueFlow balloon catheter., Background: Now that TAVR is moving forward, physicians have attempted to simplify and streamline the procedure and the so-called minimalist approach has become more popular., Methods: We enrolled 142 patients (mean age: 82 ± 5 years, 61% female) in a prospective registry. Patients at low risk for intraprocedural third-degree atrioventricular block (AVB) underwent TAVR with the TrueFlow balloon without rapid pacing and without insertion of a provisional pacemaker (n = 121). The remaining 21 patients were predilated with rapid pacing using a provisional pacemaker and a standard balloon., Results: Predilatation with the TrueFlow balloon was successful in all 121 patients. Postdilatation was less frequently required after predilatation with the TrueFlow (25% vs. 57%, p = .003). Moreover, median procedural duration with the TrueFlow was significantly shorter (42 [interquartile range, IQR: 34-53] vs. 55 [IQR: 46-61] min, p = .004). In-hospital outcomes were similar. At 30 days, there was no mortality, two (1%) patients had suffered a stroke and only four (3%) had required implantation of a new pacemaker., Conclusion: Among patients with a low risk for intraprocedural third-degree AVB, the TrueFlow nonocclusive balloon catheter facilitates implantation of the ACURATE neo without the necessity of rapid pacing and a provisional pacemaker., (© 2020 Wiley Periodicals, Inc.)

Objectives: Report predictors and the natural course of paravalvular leak (PVL) following implantation of the ACURATE neo transcatheter heart valve (THV)., Background: Understanding the mechanisms of PVL may help to improve patient selection, patient outcomes and the design of next-generation THVs., Methods: A total of 30 patients (mean age 81±5 years, 47% women) undergoing transcatheter aortic valve replacement with the ACURATE neo were enrolled in the PREDICT PVL study. The effective regurgitant orifice area (EROA, in mm 2 ) of PVL was assessed by transthoracic and transoesophageal echocardiography before discharge and at 6 months follow-up., Results: PVL was none/trace in 10 (33%), mild in 18 (60%) and moderate in 2 (7%) patients and occurred in distinct locations with largest EROAs in the area of the left coronary cusp and its adjacent commissures. Independent predictors for EROA were implantation depth (r coefficient -1.9 mm 2 per mm implantation depth, p=0.01), leaflet calcification (6.2 mm 2 per calcification grade, p=0.03) and THV size L (7.6 mm 2 more than size S or M, p=0.01). At 6 months follow-up, EROA decreased by 29% from 13.7±9.7 mm 2 to 9.5±7.9 mm 2 (p<0.01). Patients with smaller EROAs were more likely to be in New York Heart Association class 1 than patients with larger EROAs (p<0.01)., Conclusions: PVL occurred predominantly in the region of the left coronary cusp and decreased by 29% during 6 months of follow-up. Our results underscore the importance of adequate patient selection and optimal implantation depth., Competing Interests: Competing interests: SFS is a consultant for Alnylam, Astra Zeneca and Pfizer. RK has received institutional grants from Abbott, Biosense-Webster, Biotronik, Boston Scientific, Medtronic and SIS Medical. ST is a consultant and proctor for Boston Scientific, Abbott and New Valve Technology, has received institutional research grants from Boston Scientific and Fumedica and is holding equity in Hi-D Imaging., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Coronary microvascular dysfunction (CMD) is a common cause of angina and exercise intolerance in patients without obstructive coronary artery disease. The efficacy of ranolazine, a late sodium channel blocker, in patients with symptomatic obstructive coronary artery disease is well established. To evaluate the efficacy of ranolazine in CMD, we performed a systematic review and meta-analysis of randomized studies., Methods: MEDLINE, EMBASE, Cochrane CENTRAL, and conference abstracts were searched from January 1975 to March 2020. Randomized trials evaluating ranolazine in patients with CMD were screened. Two reviewers independently extracted data and assessed study quality. End points of interest included a change in angina measured by the Seattle Angina Questionnaire (SAQ), coronary flow reserve (CFR), and clinical outcomes. Data were combined using random-effects models., Results: Of 836 citations, 6 randomized studies (318 patients) were included. Median follow-up was 4 weeks. When pooling the 6 trials analyzing ranolazine, we found that patients treated with ranolazine had a higher SAQ value regarding physical functioning (mean difference, 6.42; 95% confidence interval [CI], 2.41; 10.42) quality of life (10.07; 95% CI, 3.4; 16.74), and angina stability (20.14; 95% CI, 10.12; 30.17), as well as improved CFR (0.27; 95% CI, 0.09; 0.45) compared with placebo/control therapy. A high heterogeneity was observed (range I 2 , 30%-84%)., Conclusions: In CMD, ranolazine may be associated with improvements in CFR and some of the SAQ domains, including angina stability, physical functioning, and quality of life. However, it does not seem to beneficially impact angina frequency and treatment satisfaction. It is also unknown if it improves prognosis of afflicted patients., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

We study an excitable active rotator with slowly adapting nonlinear feedback and noise. Depending on the adaptation and the noise level, this system may display noise-induced spiking, noise-perturbed oscillations, or stochastic bursting. We show how the system exhibits transitions between these dynamical regimes, as well as how one can enhance or suppress the coherence resonance or effectively control the features of the stochastic bursting. The setup can be considered a paradigmatic model for a neuron with a slow recovery variable or, more generally, as an excitable system under the influence of a nonlinear control mechanism. We employ a multiple timescale approach that combines the classical adiabatic elimination with averaging of rapid oscillations and stochastic averaging of noise-induced fluctuations by a corresponding stationary Fokker-Planck equation. This allows us to perform a numerical bifurcation analysis of a reduced slow system and to determine the parameter regions associated with different types of dynamics. In particular, we demonstrate the existence of a region of bistability, where the noise-induced switching between a stationary and an oscillatory regime gives rise to stochastic bursting.

Background Previous reports have described a leveling off of mortality from premature coronary artery disease (CAD). In recent years, the prevalence of cardiovascular risk factors has increased in rural communities and young adults. Methods and Results We extracted CAD mortality rates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999 to 2017, focusing on mortality from premature CAD (defined as <65 years of age in women) and urban-rural differences. Variations in mortality rates over time, assessed with Joinpoint regression modeling, are expressed as estimated annual percentage change (95% CI) and stratified by urbanization, sex, age, and race. Age-adjusted mortality rates decreased for women and men. Stratification by urbanization revealed that premature CAD mortality is stagnating among women in rural areas. However, this stagnation conceals a statistically significant increase in CAD mortality rates since 2009 in women aged 55 to 64 years (estimated annual percentage change: +1.4%; 95% CI, +0.3% to +2.5%) and since 1999 in women aged 45 to 54 years (estimated annual percentage change: +0.6%; 95% CI, +0.2% to 1.0%). Since 1999, mortality has been stagnating in the youngest group (aged 35-44 years; estimated annual percentage change: +0.2%; 95% CI, -0.4% to +0.8%). Stratification by race indicated an increase in mortality rates among white rural women. Premature CAD mortality remains consistently higher in the rural versus urban United States, regardless of sex, race, and age group. Conclusions Premature CAD mortality rates have declined over time. However, stratification by sex and urbanization reveals disparities that would otherwise remain concealed: CAD mortality rates have increased among women from rural areas since at least 2009.

Background: Takotsubo syndrome (TTS) occurs predominantly in post-menopausal women but is also found in younger patients., Objectives: This study aimed to investigate age-related differences in TTS., Methods: Patients diagnosed with TTS and enrolled in the International Takotsubo Registry between January 2011 and February 2017 were included in this analysis and were stratified by age (younger: ≤50 years, middle-age: 51 to 74 years, elderly: ≥75 years). Baseline characteristics, hospital course, as well as short- and long-term mortality were compared among groups., Results: Of 2,098 TTS patients, 242 (11.5%) patients were ≤50 years of age, 1,194 (56.9%) were 51 to 74 years of age, and 662 (31.6%) were ≥75 years of age. Younger patients were more often men (12.4% vs. 10.9% vs. 6.3%; p = 0.002) and had an increased prevalence of acute neurological (16.3% vs. 8.4% vs. 8.8%; p = 0.001) or psychiatric disorders (14.1% vs. 10.3% vs. 5.6%; p < 0.001) compared with middle-aged and elderly TTS patients. Furthermore, younger patients had more often cardiogenic shock (15.3% vs. 9.1% vs. 8.1%; p = 0.004) and had a numerically higher in-hospital mortality (6.6% vs. 3.6% vs. 5.1%; p = 0.07). At multivariable analysis, younger (odds ratio: 1.60; 95% confidence interval: 0.86 to 3.01; p = 0.14) and older age (odds ratio: 1.09; 95% confidence interval: 0.66 to 1.80; p = 0.75) were not independently associated with in-hospital mortality using the middle-aged group as a reference. There were no differences in 60-day mortality rates among groups., Conclusions: A substantial proportion of TTS patients are younger than 50 years of age. TTS is associated with severe complications requiring intensive care, particularly in younger patients., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The ACURATE neo transcatheter heart valve has been associated with very low rates of new conduction disorders (CDs). We assessed the clinical relevance of new CDs in patients undergoing transcatheter aortic valve replacement (TAVR) with this valve. Data of consecutive patients without a pre-existing left bundle branch block (LBBB) or a permanent pacemaker (PPM) undergoing TAVR with the ACURATE neo were analyzed from the prospective SwissTAVI registry. Patients with new CDs were compared with patients with an unchanged electrocardiogram (ECG). ACURATE neo was implanted in 203 patients (mean age 82 ± 6 years, 63% women), CDs occurred in 28 patients (22 [11%] developed a LBBB, 6 [3%] required a PPM). New CDs resulted in a longer median duration of hospitalization (7 vs 5 days, interquartile range 4 to 13 vs 3 to 8 days, p = 0.04). At 1-year follow-up, left ventricular ejection fraction was significantly lower in patients with new CDs comparedwith patients with an unchanged ECG (54% ± 13% vs 61% ± 9%, p <0.01). Kaplan-Meier estimates of survival at 1-year were 89% in patients with new CDs and 95% in patients with an unchanged ECG (hazard ratio 2.0, 95% confidence interval 0.7 to 6.2, p = 0.22). After TAVR with the self-expanding ACURATE neo valve, the rate of new CDs, including complete LBBB was low and very few patients required a new PPM. However, new CDs prolonged initial hospitalization and increased the risk for left ventricular-dysfunction at 1-year follow-up. Patients without new CDs had excellent outcomes with a very high survival rate at 1-year follow-up., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Studying nucleic acids often requires labeling. Many labeling approaches require covalent bonds between the nucleic acid and the label, which complicates experimental procedures. Noncovalent labeling avoids the need for highly specific reagents and reaction conditions, and the effort of purifying bioconjugates. Among the least invasive techniques for studying biomacromolecules are NMR and EPR. Here, we report noncovalent labeling of DNA and RNA triplexes with spin labels that are nucleobase derivatives. Spectroscopic signals indicating strong binding were detected in EPR experiments in the cold, and filtration assays showed micromolar dissociation constants for complexes between a guanine-derived label and triplex motifs containing a single-nucleotide gap in the oligopurine strand. The advantages and challenges of noncovalent labeling via this approach that complements techniques relying on covalent links are discussed., (© 2019 The Authors. Published by Wiley-VHCA AG, Zurich, Switzerland.)

Introduction: Stent underexpansion is a predictor of in-stent-restenosis and stent thrombosis. Semi-compliant balloons (SCBs) are generally used for lesion preparation. It remains unknown whether routine predilatation using non-compliant balloons (NCBs) improves stent expansion in ordinary coronary lesions., Methods: The PREdilatation by high-pressure NC balloon catheter for better vessel preparation and Optimal lesion preparation with non-compliant balloons for the implantation of bioresorbable vascular scaffolds studies randomised patients presenting with stable coronary artery disease or non-ST-elevation myocardial infarction requiring stent implantation to lesion preparation using NCBs versus SCBs. Stent expansion index (SEI-minimal luminal area/mean luminal area on optical coherence tomography) and periprocedural complications were compared., Results: We enrolled 104 patients: 53 patients (54 lesions) vs 51 patients (56 lesions) to the NCB and SCB groups, respectively. Predilatation pressure was higher in the NCB group (24±7 atmospheres (atm) vs 14±3 atm, p<0.0001). Postdilatation using NCBs was performed in 41 (76%) lesions vs 46 (82%) lesions pretreated with NCBs versus SCBs (p=0.57). Similar pressures were used for postdilatation with NCB in both groups (23±8 atm vs 23±9 atm, p=0.65). SEI after stent implantation was 0.88±0.13 in the NCB vs 0.85±0.14 in the SCB group (p=0.18). After postdilatation, SEI increased to 0.94±0.13 in the NCB group vs 0.88±0.13 in the SCB group (p=0.02). No relevant complications occurred., Conclusions: In simple coronary lesions, predilatation/postdilatation with NCBs at high pressures appears to result in better scaffold and stent expansion. Using SCBs only for predilatation might lead to inadequate stent expansion and postdilatation with NCBs might only partially correct this. Predilatation and postdilatation using NCBs at high pressure is safe., Trial Registration Number: ClinicalTrials.gov no. NCT03518645., Competing Interests: Competing interests: FC has received speaker fees and research grants from Abbott Vascular and SIS Medical. RK has received institutional grant support from Abbott, Biotronik, Biosense Webster, Boston Scientific, Medtronic and SIS Medical. None of the other authors had any relevant conflicts of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Myocardial recovery after primary percutaneous coronary intervention in acute myocardial infarction is variable and the extent and severity of injury are difficult to predict. We sought to investigate the role of cardiovascular magnetic resonance T1 mapping in the determination of myocardial injury very early after treatment of ST-segment elevation myocardial infarction (STEMI)., Methods: STEMI patients underwent 3 T cardiovascular magnetic resonance (CMR), within 3 h of primary percutaneous intervention (PPCI). T1 mapping determined the extent (area-at-risk as %left ventricle, AAR) and severity (average T1 values of AAR) of acute myocardial injury, and related these to late gadolinium enhancement (LGE), and microvascular obstruction (MVO). The characteristics of myocardial injury within 3 h was compared with changes at 24-h to predict final infarct size., Results: Forty patients were included in this study. Patients with average T1 values of AAR ≥1400 ms within 3 h of PPCI had larger LGE at 24-h (33% ±14 vs. 18% ±10, P = 0.003) and at 6-months (27% ±9 vs. 12% ±9; P < 0.001), higher incidence and larger extent of MVO (85% vs. 40%, P = 0.016) & [4.0 (0.5-9.5)% vs. 0 (0-3.0)%, P = 0.025]. The average T1 value was an independent predictor of acute LGE (β 0.61, 95%CI 0.13 to 1.09; P = 0.015), extent of MVO (β 0.22, 95%CI 0.03 to 0.41, P = 0.028) and final infarct size (β 0.63, 95%CI 0.21 to 1.05; P = 0.005). Receiver-operating-characteristic analysis showed that T1 value of AAR obtained within 3-h, but not at 24-h, predicted large infarct size (LGE > 9.5%) with 100% positive predictive value at the optimal cut-off of 1400 ms (area-under-the-curve, AUC 0.88, P = 0.006)., Conclusion: Hyper-acute T1 values of the AAR (within 3 h post PPCI, but not 24 h) predict a larger extent of MVO and infarct size at both 24 h and 6 months follow-up. Delayed CMR scanning for 24 h could not substitute the significant value of hyper-acute average T1 in determining infarct characteristics.

Nanoscale assemblies of DNA strands are readily designed and can be generated in a wide range of shapes and sizes. Turning them into solids that bind biomolecules reversibly, so that they can act as active material in flow cells, is a challenge. Among the biomolecular ligands, cofactors are of particular interest because they are often the most expensive reagents of biochemical transformations, for which controlled release and recycling are desirable. We have recently described DNA triplex motifs that bind adenine-containing cofactors, such as NAD, FAD and ATP, reversibly with low micromolar affinity. We sought ways to convert the soluble DNA motifs into a macroporous solid for cofactor binding. While assemblies of linear and branched DNA motifs produced hydrogels with undesirable properties, long DNA triplexes treated with protamine gave materials suitable for flow cells. Using exchangeable cells in a flow system, thermally controlled loading and discharge were demonstrated. Employing a flow cell loaded with ATP, bioluminescence was induced through thermal release of the cofactor. The results show that materials generated from functional DNA structures can be successfully employed in macroscopic devices., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

We investigate the appearance of sharp pulses in the mean field of Kuramoto-type globally-coupled phase oscillator systems. In systems with exactly equidistant natural frequencies, self-organized periodic pulsations of the mean field, called mode locking, have been described recently as a new collective dynamics below the synchronization threshold. We show here that mode locking can appear also for frequency combs with modes of finite width, where the natural frequencies are randomly chosen from equidistant frequency intervals. In contrast to that, so-called coherence echoes, which manifest themselves also as pulses in the mean field, have been found in systems with completely disordered natural frequencies as a result of two consecutive stimulations applied to the system. We show that such echo pulses can be explained by a stimulation induced mode locking of a subpopulation representing a frequency comb. Moreover, we find that the presence of a second harmonic in the interaction function, which can lead to the global stability of the mode-locking regime for equidistant natural frequencies, can enhance the echo phenomenon significantly. The nonmonotonic behavior of echo amplitudes can be explained as a result of the linear dispersion within the self-organized mode-locked frequency comb. Finally, we investigate the effect of small periodic stimulations on oscillator systems with disordered natural frequencies and show how the global coupling can support the stimulated pulsation by increasing the width of locking plateaus.

Background: Left ventricular (LV) ejection fraction (EF) during high dobutamine stress (HD) by real-time gated-SPECT myocardial perfusion imaging (MPI) on a cadmium-zinc-telluride (CZT) gamma camera was validated versus cardiac magnetic resonance imaging (CMR)., Methods and Results: After injecting 99mTc-tetrofosmin (320 MBq) in 50 patients (mean age 64 +/- 11 years), EF at rest and post-stress as well as relevant changes in EF at HD (ΔEF ≥ 5%) were assessed. CZT and CMR rest EF values yielded an excellent correlation and agreement (r = 0.96; P < 0.001; Bland-Altman limits of agreement (BA): + 0 to 14.8%). HD EF acquisition was feasible using CZT and correlated better to HD CMR EF than did post-stress CZT EF (r = 0.85 vs 0.76, respectively, all P < 0.001). Agreement in ΔEF detection between HD CMR and immediate post-stress CZT (reflecting standard acquisition using conventional SPECT camera unable to scan during stress) was 45%, while this increased to 85% with real-time HD CZT scan., Conclusion: Real-time ultrafast dobutamine gated-SPECT MPI with a CZT device is feasible and provides accurate measurements of HD LV performance.

Designed DNA nanostructures can be generated in a wide range of sizes and shapes and have the potential to become exciting tools in material sciences, catalysis and medicine. However, DNA nanostructures are thermally labile assemblies of delicate biomacromolecules, and the lability hampers the use in many applications. Disulfide crosslinking is nature's successful approach to stabilize folded proteins against denaturation. It is therefore interesting to ask whether similar approaches can be used to stabilize DNA nanostructures. Here we report the synthesis of two 2'-deoxynucleoside phosphoramidites and two nucleosides linked to controlled pore glass that can be used to prepare oligodeoxynucleotides with protected thiol groups via automated DNA synthesis. Strands with one, two, three or four thiol-bearing nucleotides were prepared. One nicked duplex and three different nanostructures were assembled, the protected thiols were liberated under non-denaturing conditions, and disulfide crosslinking was induced with oxygen. Up to 19 crosslinks were thus placed in folded DNA structures up to 1456 nucleotides in size. The crosslinked structures had increased thermal stability, with UV-melting points 9-50 °C above that of the control structure. Disulfides were converted back to free thiols under reducing conditions. The redox-dependent increase in stability makes crosslinked DNA nanostructures attractive for the construction of responsive materials and biomedical applications.

Localized states are a universal phenomenon observed in spatially distributed dissipative nonlinear systems. Known as dissipative solitons, autosolitons, and spot or pulse solutions, these states play an important role in data transmission using optical pulses, neural signal propagation, and other processes. While this phenomenon was thoroughly studied in spatially extended systems, temporally localized states are gaining attention only recently, driven primarily by applications from fiber or semiconductor lasers. Here we present a theory for temporal dissipative solitons (TDS) in systems with time-delayed feedback. In particular, we derive a system with an advanced argument, which determines the profile of the TDS. We also provide a complete classification of the spectrum of TDS into interface and pseudocontinuous spectrum. We illustrate our theory with two examples: a generic delayed phase oscillator, which is a reduced model for an injected laser with feedback, and the FitzHugh-Nagumo neuron with delayed feedback. Finally, we discuss possible destabilization mechanisms of TDS and show an example where the TDS delocalizes and its pseudocontinuous spectrum develops a modulational instability.

Objectives: This study aimed to compare the value of the index of microcirculatory resistance (IMR) and microvascular obstruction (MVO) measured by cardiac magnetic resonance (CMR) in patients treated for and recovering from ST-segment elevation myocardial infarction., Background: IMR can identify patients with microvascular dysfunction acutely after primary percutaneous coronary intervention (pPCI), and a threshold of >40 has been shown to be associated with an adverse clinical outcome. Similarly, MVO is recognized as an adverse feature in patients with ST-segment elevation myocardial infarction. Even though both IMR and MVO reflect coronary microvascular status, the interaction between these 2 parameters is uncertain., Methods: A total of 110 patients treated with pPCI were included, and IMR was measured immediately at completion of pPCI. Infarct size (IS) as a percentage of left ventricular mass was quantified at 48 h (38.4 ± 12.0 h) and 6 months (194.0 ± 20.0 days) using CMR. MVO was identified and quantified at 48 h by CMR., Results: Overall, a discordance between IMR and MVO was observed in 36.7% of cases, with 31 patients having MVO and IMR ≤40. Compared with patients with MVO and IMR ≤40, patients with both MVO and IMR >40 had an 11.9-fold increased risk of final IS >25% at 6 months (p = 0.001). Patients with MVO and IMR ≤40 had a significantly smaller IS at 6 months (p = 0.001), with significant regression in IS over time (34.4% [interquartile range (IQR): 27.3% to 41.0%] vs. 22.3% [IQR: 16.0% to 30.0%]; p = 0.001)., Conclusions: Discordant prognostic information was obtained from IMR and MVO in nearly one-third of cases; however, IMR can be helpful in grading the degree and severity of MVO., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We study a system of two identical FitzHugh-Nagumo units with a mutual linear coupling in the fast variables. While an attractive coupling always leads to synchronous behavior, a repulsive coupling can give rise to dynamical regimes with alternating spiking order, called leap-frogging. We analyze various types of periodic and chaotic leap-frogging regimes, using numerical path-following methods to investigate their emergence and stability, as well as to obtain the complex bifurcation scenario which organizes their appearance in parameter space. In particular, we show that the stability region of the simplest periodic leap-frog pattern has the shape of a locking cone pointing to the canard transition of the uncoupled system. We also discuss the role of the timescale separation in the coupled FitzHugh-Nagumo system and the relation of the leap-frog solutions to the theory of mixed-mode oscillations in multiple timescale systems.

Aims: We validated a 1-day myocardial perfusion imaging (MPI) protocol using an ultra low-dose(ULD) equal for stress and rest on a cadmium zinc telluride (CZT)., Methods and Results: Fifty-six patients underwent a 1-day MPI protocol using a standard (SD) 99mTc-tetrofosmin dose at stress (320 MBq) and rest (960 MBq) with 5 min acquisition time each (SD). Within 2 weeks MPI was repeated using ULD 99mTc-tetrofosmin equal for stress and rest (160 MBq) with 15 min acquisition time each (ULD). All scans were performed on a CZT camera (DNM 570c, GE Healthcare). Background subtraction was applied on the rest MPI of the ULD using P-mod software. Presence and extent of perfusion defect were analysed. Pearson's correlation was used to compare ejection fraction (EF), end diastolic volume (EDV), and end systolic volume (ESV) between both protocols. SD revealed ischaemia in 23, scar in 3, and an equivocal finding in 1 patient, while normal findings were documented in 29 patients. ULD resulted in the following findings: ischaemia 23, scar 3, and 30 normal scans. Congruence of SD and ULD was 22/23 for ischaemia, 3/3 for scar, and 29/29 in normal patients; one patient with ischaemia in SD was classified as scar in ULD. Overall agreement of ULD with SD was 98%. The mean extent of defect was comparable between SD and ULD for the stress (10% vs. 11%, respectively, P = NS) and rest studies (5% vs. 7%, respectively, P = NS). An excellent correlation between SD and ULD was found for EF (r = 0.93), EDV (r = 0.95), and ESV (r = 0.97)., Conclusion: CZT cameras may enable reliable MPI scanning in patients with known or suspected coronary artery disease using protocols with about a factor 4-decrease in radiation dose exposure compared with traditional protocols.

Aims: Fractional flow reserve (FFR) can be used to detect a suboptimal result after percutaneous coronary intervention (PCI). A lower post-procedure FFR (<0.90) has been shown to be associated with adverse clinical outcomes at follow-up. This pilot study aimed to understand the mechanisms resulting in a suboptimal FFR and whether optical coherence tomography (OCT)-guided optimisation could improve final FFR., Methods and Results: Thirty-five patients undergoing complex PCI were prospectively enrolled. After stenting and post-dilatation, OCT and pressure wire were performed. An FFR threshold <0.90 after PCI was defined as suboptimal and mandated further PCI optimisation. A satisfactory post-PCI FFR (predefined as ≥0.90) was achieved immediately after conventional PCI in 14 patients (40%) and in this group no further treatment was performed. Minor abnormalities (stent malapposition of 200-500 µm) were observed with OCT in three of these patients. Suboptimal functional results after conventional stenting (predefined as an FFR <0.90) were found in 21 patients (60%). In thirteen out of these 21 patients (61.9%), OCT demonstrated a suboptimal stent result. Subsequent OCT-guided optimisation was performed resulting in a higher final FFR (increase from 0.80±0.02 to 0.88±0.01; p=0.008)., Conclusions: Despite a satisfactory angiographic result, a suboptimal functional result is evident in a substantial proportion of patients undergoing complex PCI. Implementation of an OCT-guided PCI optimisation protocol may reveal potentially treatable causes, allowing optimisation of the post-PCI functional result.

The classical notion of excitability refers to an equilibrium state that shows under the influence of perturbations a nonlinear threshold-like behavior. Here, we extend this concept by demonstrating how periodic orbits can exhibit a specific form of excitable behavior where the nonlinear threshold-like response appears only after perturbations applied within a certain part of the periodic orbit, i.e., the excitability happens to be phase-sensitive. As a paradigmatic example of this concept, we employ the classical FitzHugh-Nagumo system. The relaxation oscillations, appearing in the oscillatory regime of this system, turn out to exhibit a phase-sensitive nonlinear threshold-like response to perturbations, which can be explained by the nonlinear behavior in the vicinity of the canard trajectory. Triggering the phase-sensitive excitability of the relaxation oscillations by noise, we find a characteristic non-monotone dependence of the mean spiking rate of the relaxation oscillation on the noise level. We explain this non-monotone dependence as a result of an interplay of two competing effects of the increasing noise: the growing efficiency of the excitation and the degradation of the nonlinear response.

Aims: The Oxford Acute Myocardial Infarction PICSO (OxAMI-PICSO) study aimed to assess the efficacy of index of microcirculatory resistance (IMR)-guided therapy with pressure-controlled intermittent coronary sinus occlusion (PICSO) in anterior ST-elevation myocardial infarction (STEMI)., Methods and Results: Patients with anterior STEMI treated with primary percutaneous coronary intervention (pPCI) were enrolled. Pre-stenting IMR was measured and PICSO treatment delivered if pre-stenting IMR was >40. No PICSO treatment was considered in patients with a pre-stenting IMR ≤40. The control group was derived from a historical cohort of STEMI patients with pre-stenting IMR >40 enrolled in the observational OxAMI study. IMR was measured after completion of pPCI in all patients and within 48 hours in PICSO patients and controls. Cardiac magnetic resonance imaging was performed per protocol for infarct size (IS) assessment within 48 hours after pPCI and at six months. A total of 105 patients were enrolled (25 PICSO, 50 controls with pre-stenting IMR >40, 30 with pre-stenting IMR ≤40). Compared to controls, patients treated with PICSO had a lower IMR at 24-48 hours (24.8 [18.5-35.9] vs. 45.0 [32.0-51.3], p<0.001) and lower IS at six months (26.0% [20.2-30.0] vs. 33.0% [28.0-37.0], p=0.006)., Conclusions: An IMR-guided treatment with PICSO in anterior STEMI is feasible and may be associated with reduced IS and improved microvascular function.

Background: Early risk stratification after primary percutaneous coronary intervention (PPCI) for ST-segment-elevation myocardial infarction is currently challenging. Identification of a low-risk group may improve triage of patients to alternative clinical pathways and support early hospital discharge. Our aim was to assess whether the index of microcirculatory resistance (IMR) at the time of PPCI can identify patients at low risk of early major cardiac complications and to compare its performance against guideline-recommended risk scores., Methods and Results: IMR was measured using a pressure-temperature sensor wire. Cardiac complications were defined as the composite of cardiac death, cardiogenic shock, pulmonary edema, malignant arrhythmias, cardiac rupture, and presence of left ventricular thrombus either before hospital discharge or within 30-day follow-up. In total, 261 patients undergoing PPCI who were eligible for coronary physiology assessment were prospectively enrolled. Twenty-two major cardiac complications were reported. Receiver operating characteristic curve analysis confirmed the utility of IMR in predicting complications and showed significantly better performance than coronary flow reserve, the Primary Angioplasty in Myocardial Infarction II (PAMI-II), and Zwolle score ( P ≤0.006). Low microvascular resistance (IMR ≤40) was measured in 159 patients (61%) of the study population and identified all patients who were free of major cardiac complications (sensitivity: 100%; 95% CI, 80.5-100%)., Conclusions: IMR immediately at the end of PPCI for ST-segment-elevation myocardial infarction reliably predicts early major cardiac complications and performed significantly better than recommended risk scores. These novel data have implications for early risk stratification after PPCI., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

We investigate the dynamics of a Kuramoto-type system of globally coupled phase oscillators with equidistant natural frequencies and a coupling strength below the synchronization threshold. It turns out that in such cases one can observe a stable regime of sharp pulses in the mean field amplitude with a pulsation frequency given by spacing of the natural frequencies. This resembles a process known as mode locking in lasers and relies on the emergence of a phase relation induced by the nonlinear coupling. We discuss the role of the first and second harmonics in the phase-interaction function for the stability of the pulsations and present various bifurcating dynamical regimes such as periodically and chaotically modulated mode locking, transitions to phase turbulence, and intermittency. Moreover, we study the role of the system size and show that in certain cases one can observe type II supertransients, where the system reaches the globally stable mode-locking solution only after an exponentially long transient of phase turbulence.

The field of dynamical systems with time delay is an active research area that connects practically all scientific disciplines including mathematics, physics, engineering, biology, neuroscience, physiology, economics, and many others. This Focus Issue brings together contributions from both experimental and theoretical groups and emphasizes a large variety of applications. In particular, lasers and optoelectronic oscillators subject to time-delayed feedbacks have been explored by several authors for their specific dynamical output, but also because they are ideal test-beds for experimental studies of delay induced phenomena. Topics include the control of cavity solitons, as light spots in spatially extended systems, new devices for chaos communication or random number generation, higher order locking phenomena between delay and laser oscillation period, and systematic bifurcation studies of mode-locked laser systems. Moreover, two original theoretical approaches are explored for the so-called Low Frequency Fluctuations, a particular chaotical regime in laser output which has attracted a lot of interest for more than 30 years. Current hot problems such as the synchronization properties of networks of delay-coupled units, novel stabilization techniques, and the large delay limit of a delay differential equation are also addressed in this special issue. In addition, analytical and numerical tools for bifurcation problems with or without noise and two reviews on concrete questions are proposed. The first review deals with the rich dynamics of simple delay climate models for El Nino Southern Oscillations, and the second review concentrates on neuromorphic photonic circuits where optical elements are used to emulate spiking neurons. Finally, two interesting biological problems are considered in this Focus Issue, namely, multi-strain epidemic models and the interaction of glucose and insulin for more effective treatment.

Aims: The age-thrombus burden-index of microcirculatory resistance (ATI) score is a diagnostic tool able to predict suboptimal myocardial reperfusion before stenting, in patients with ST-elevation myocardial infarction (STEMI). We aimed to validate the ATI score against cardiac magnetic resonance imaging (cMRI)., Methods and Results: The ATI score was calculated prospectively in 80 STEMI patients. cMRI was performed within 48 hours in all patients and in 50 patients at six-month follow-up to assess the extent of infarct size (IS%) and microvascular obstruction (MVO%). The ATI score was calculated using age (>50=1 point), pre-stenting index of microcirculatory resistance (IMR) (>40 and <100=1 point; ≥100=2 points) and angiographic thrombus score (4=1 point; 5=3 points). ATI score was closely related to final IS% (ATI.

We investigate the relation between the dynamics of a single oscillator with delayed self-feedback and a feed-forward ring of such oscillators, where each unit is coupled to its next neighbor in the same way as in the self-feedback case. We show that periodic solutions of the delayed oscillator give rise to families of rotating waves with different wave numbers in the corresponding ring. In particular, if for the single oscillator the periodic solution is resonant to the delay, it can be embedded into a ring with instantaneous couplings. We discover several cases where the stability of a periodic solution for the single unit can be related to the stability of the corresponding rotating wave in the ring. As a specific example, we demonstrate how the complex bifurcation scenario of simultaneously emerging multijittering solutions can be transferred from a single oscillator with delayed pulse feedback to multijittering rotating waves in a sufficiently large ring of oscillators with instantaneous pulse coupling. Finally, we present an experimental realization of this dynamical phenomenon in a system of coupled electronic circuits of FitzHugh-Nagumo type.

Introduction: Cardiovascular disease remains the most common cause of death worldwide. Enormous progress in the technology and applicability of percutaneous techniques to treat obstructive coronary heart disease has been made, and the number of percutaneous coronary interventions (PCI) is increasing. Coronary bifurcations are involved in a substantial number of PCIs and despite recent advances, bifurcation PCI remains a challenge in terms of immediate success and long-term outcome. Angiography has a limited capacity for showing important features of the 3 dimensional coronary vessel anatomy, position of stent struts and exact wire positions and is therefore suboptimal for guiding bifurcation PCI. Intracoronary optical coherence tomography (OCT) provides high resolution and the information gained during PCI is unprecedented compared with angiography guidance and intravascular ultrasound. Areas covered: This review will provide an overview of the use of OCT to guide bifurcation-PCI. Expert commentary: OCT is a promising guide for bifurcation-PCI at each individual step: from planning the strategy (provisional versus two-stent strategy), to guidance during PCI, and finally checking the interventional result. Until dedicated randomized trails are complete, we recommend OCT guidance for interventions in complex coronary bifurcation disease and for imaging when unexpected procedural events occur.

Elevated blood pressure (BP) is frequently diagnosed in very elderly hospitalized patients. Accurate diagnosis of hypertension is challenging in the hospital environment, due to the "white coat effect," and both overtreatment and undertreatment can adversely affect clinical outcome. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has the potential to avoid the "white coat effect" and accurately guide the management of hypertension. However, effects of the hospital environment on ABPM are unknown in the very elderly. We set out to enroll 45 patients, age ≥70 years, with elevated conventional BP during hospitalization in this observational study. It was prespecified by protocol to assess initially the difference between 24-hour BP during hospital-admission and home follow-up. Subsequent analysis should investigate the change in anxiety (Hospital Anxiety and Depression Scale-A [HADS-A]) after discharge, the correlation with change in 24-hour BP after discharge, and the prevalence of orthostatic hypertension. Thirty-one patients were included in the final analysis (age 83.5 ± 4.4 years; 71% female). Twenty-four-hour BP decreased significantly after hospital discharge (systolic from 133.5 ± 15.6 to 126.2 ± 14.4 mm Hg [millimeter of mercury], P = .008; diastolic from 71.0 ± 9.0 to 68.3 ± 8.6 mm Hg, P = .046). Anxiety level (HADS-A) decreased significantly after discharge, from 7.5 (interquartile range [IQR]: 4.0-13.8) to 5.0 (IQR: 4.0-8.0, P = .012). The change in anxiety was a predictor of change in systolic BP after discharge (F[1,20] = 5.9, P = .025). Sixty-one percent of the patients had significant orthostatic hypotension during hospital stay. In conclusion, 24-hour BP in very elderly patients is lower in the home environment than during hospitalization. This phenomenon seems to be directly linked to a lower anxiety-level at home. Reassessing hypertension at home may decrease the need for (intensified) antihypertensive medical therapy in a substantial number of patients. This is particularly important in the very elderly, who have a high prevalence of symptomatic and asymptomatic orthostatic hypotension, making them prone to hazardous effects of antihypertensive therapy.

Objectives: We conducted a meta-analysis of studies comparing deferred stenting strategy versus the conventional approach with immediate stenting in patients with ST elevation myocardial infarction., Background: Deferring stent after mechanical flow restoration has been proposed as a strategy to reduce the risk of "no reflow" in patients with STEMI undergoing primary percutaneous coronary intervention (pPCI). Conflicting evidence is available currently, especially after the recent publication of three randomized clinical trials., Methods: Searches in electronic databases were performed. Comparisons between the two strategies were performed for both hard clinical endpoints (all cause-mortality, cardiovascular mortality, unplanned revascularization, myocardial infarction and readmission for heart failure) and surrogate angiographic endpoints (TIMI flow < 3 and myocardial blush grade (MBG) < 2)., Results: Eight studies (three randomized and five non-randomized) were deemed eligible, accounting for a total of 2101 patients. No difference in terms of hard clinical endpoints was observed between deferred and immediate stenting (OR [95% CI]: 0.79 [0.54-1.15], for all-cause mortality; odds ratio (OR) [95% CI]: 0.79 [0.47-1.31] for cardiovascular mortality; OR [95% CI]: 0.95 [0.64-1.41] for myocardial infarction; OR [95% CI]: 1.37 [0.87-2.16], for unplanned revascularization and OR [95% CI]: 0.50 [0.21-1.17] for readmission for heart failure). Notably, the deferred stenting approach was associated with improved outcome of the surrogate angiographic endpoints (OR [95% CI]: 0.43 [0.18-0.99] of TIMI flow < 3 and OR [95% CI]: 0.25 [0.11-0.57] for MBG < 2., Conclusions: A deferred stenting strategy could be a feasible alternative to the conventional approach with immediate stenting in "selected" STEMI patients undergoing pPCI., (© 2017, Wiley Periodicals, Inc.)

Objectives: The index of microcirculatory resistance (IMR) provides a reproducible assessment of the status of coronary microvasculature in patients with ST-elevation myocardial infarction (STEMI). Frequency-domain optical coherence tomography (FD-OCT) enables detailed assessment of the morphology of coronary plaque.We sought to determine the influence of the initial culprit coronary plaque anatomy within the infarct-related artery on IMR after stenting in STEMI., Patients and Methods: In 25 STEMI patients IMR was measured immediately before and after stent implantation. FD-OCT imaging was performed at the same time points and atherothrombotic volume (ATV) before stenting, prolapsed+floating ATV after stenting and ΔATV was measured using three different strategies., Results: There were no relationships between preprocedural IMR and FD-OCT parameters. Prestenting IMR was related only to pain to wire time (P: 0.02). Irrespective of the method adopted, the final IMR was related to prestenting ATV (ρ: 0.44, P: 0.03 for method I, ρ: 0.48, P: 0.02 for method II and ρ: 0.30, P: 0.06 for method III) and ΔATV (ρ: 0.41, P: 0.04 for method II and ρ: 0.44, P: 0.03 for method III)., Conclusion: IMR measured before stenting is independent of the appearances of the culprit coronary plaque within the infarct-related artery. IMR after stenting, and more importantly, the change in IMR after stenting, reflect the degree of distal embolization during stent implantation.

Aims: Restoration of effective myocardial reperfusion by primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction is difficult to predict. A method to assess the likelihood of a suboptimal response to conventional pharmacomechanical therapies could be beneficial. We aimed to derive and validate a scoring system that can be used acutely at the time of coronary reopening to predict the likelihood of downstream microvascular impairment in patients with STEMI., Methods and Results: A score estimating the risk of post-procedural microvascular injury defined by an index of microcirculatory resistance (IMR) >40 was initially derived in a cohort of 85 STEMI patients (derivation cohort). This score was then tested and validated in three further cohorts of patients (retrospective [30 patients], prospective [42 patients] and external [29 patients]). The ATI score (age [>50=1]; pre-stenting IMR [>40 and <100=1; ≥100=2]; thrombus score [4=1; 5=3]) was highly predictive of a post-stenting IMR >40 in all four cohorts (AUC: 0.87; p<0.001-derivation cohort, 0.84; p=0.002-retrospective cohort, 0.92; p<0.001-prospective cohort and 0.81; p=0.006-external cohort). In the whole population, an ATI score ≥4 presented a 95.1% risk of final IMR >40, while no cases of final IMR >40 occurred in the presence of an ATI score <2., Conclusions: The ATI score appears to be a promising tool capable of identifying patients during PPCI who are at the highest risk of coronary microvascular impairment following revascularisation. This procedural risk stratification has a number of potential research and clinical applications and warrants further investigation.

Synthetic strategies were developed to prepare l-tyrosine-based ionic liquid crystals with structural variations at the carboxylic and phenolic OH groups as well as the amino functionality. Salt metathesis additionally led to counterion variation. The liquid-crystalline properties were investigated by differential scanning calorimetry (DSC), polarizing optical microscopy (POM) and X-ray diffraction (WAXS, SAXS). The symmetrical ILC chlorides bearing the same alkyl chain at both the ester and ether but either an acyclic or cyclic guanidinium group displayed enantiotropic SmA 2 mesophases with phase widths of 31-88 K irrespective of the head group. It was particularly the replacement of chloride in the acyclic guanidinium ILC by hexafluorophosphate that induced a phase change from SmA 2 to Col r . This phase change was attributed to a higher curvature of the interface due to the larger anion, which increased the effective head group cross-sectional area of the amphiphilic ILC. The unsymmetrical acyclic guanidinium chlorides, bearing a constant C 14 ester and variable alkyl chains on the phenolic position, formed enantiotropic SmA 2 phases. The derivative with the largest difference in chain lengths, however, displayed a Col r phase, resulting from discoid aggregates of the cone-shaped guanidinium chloride. The results are discussed in terms of the packing parameters, which indicate that the phase behaviour of the thermotropic tyrosine-based ILCs shows analogies to those of lyotropic liquid crystals., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: FFR is routinely used to guide percutaneous coronary interventions (PCI). Visual assessment of the angiographic result after PCI has limited efficacy. Even when the angiographic result seems satisfactory FFR after a PCI might be useful for identifying patients with a suboptimal interventional result and higher risk for poor clinical outcome who might benefit from additional procedures. The aim of this meta-analysis was to investigate available data of studies that examined clinical outcomes of patients with impaired vs. satisfactory fractional flow reserve (FFR) after percutaneous coronary interventions (PCI)., Methods: This meta-analysis was carried out according to the Cochrane Handbook for Systematic Reviews. The Mantel-Haenszel method using the fixed-effect meta-analysis model was used for combining the results. Studies were identified by searching the literature through mid-January, 2016, using the following search terms: fractional flow reserve, coronary circulation, after, percutaneous coronary intervention, balloon angioplasty, stent implantation, and stenting. Primary endpoint was the rate of major adverse cardiac events (MACE). Secondary endpoints included rates of death, myocardial infarction (MI), repeated revascularisation., Results: Eight relevant studies were found including a total of 1337 patients. Of those, 492 (36.8 %) had an impaired FFR after PCI, and 853 (63.2 %) had a satisfactory FFR after PCI. Odds ratios indicated that a low FFR following PCI was associated with an impaired outcome: major adverse cardiac events (MACE, OR: 4.95, 95 % confidence interval [CI]: 3.39-7.22, p <0.001); death (OR: 3.23, 95 % CI: 1.19-8.76, p = 0.022); myocardial infarction (OR: 13.83, 95 % CI: 4.75-40.24, p <0.0001) and repeated revascularisation (OR: 4.42, 95 % CI: 2.73-7.15, p <0.0001)., Conclusions: Compared to a satisfactory FFR, a persistently low FFR following PCI is associated with a worse clinical outcome. Prospective studies are needed to identify underlying causes, determine an optimal threshold for post-PCI FFR, and clarify whether simple additional procedures can influence the post-PCI FFR and clinical outcome.

We discuss the influence of small phase lags on the synchronization transitions in the Kuramoto model for a large inhomogeneous population of globally coupled phase oscillators. Without a phase lag, all unimodal distributions of the natural frequencies give rise to a classical synchronization scenario, where above the onset of synchrony at the Kuramoto threshold, there is an increasing synchrony for increasing coupling strength. We show that already for arbitrarily small phase lags, there are certain unimodal distributions of natural frequencies such that for increasing coupling strength synchrony may decrease and even complete incoherence may regain stability. Moreover, our example allows a qualitative understanding of the mechanism for such non-universal synchronization transitions.

Background: The optimal antithrombotic therapy in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI) remains a matter of debate. This updated meta-analysis investigated the impact of (1) bivalirudin (with and without prolonged infusion) and (2) prolonged PCI-dose (1.75 mg/hg per hour) bivalirudin infusion compared with conventional antithrombotic therapy on clinical outcomes in patients undergoing primary PCI., Methods and Results: Eligible randomized trials were searched through MEDLINE, EMBASE, Cochrane database, and proceedings of major congresses. Prespecified outcomes were major bleeding (thrombolysis in myocardial infarction major and Bleeding Academic Research Consortium 3-5), acute stent thrombosis, as well as all-cause and cardiac mortality at 30 days. Six randomized trials (n=17 294) were included. Bivalirudin compared with heparin (+/- glycoprotein-IIb/IIIa inhibitor) was associated with reduction in major bleeding (odds ratio [OR]: 0.65, 95% CI: 0.48-0.88, P=0.006, derived from all 6 trials), increase in acute stent thrombosis (OR: 2.75, 95% CI: 1.46-5.18, P=0.002, 5 trials), and lower rate of all-cause mortality (OR: 0.81, 95% CI: 0.67-0.98, P=0.03, 6 trials) as well as cardiac mortality (OR: 0.69, 95% CI: 0.55-0.87, P=0.001, 5 trials). The incidence of acute stent thrombosis did not differ between the prolonged PCI-dose bivalirudin and comparator group (OR: 0.81, 95% CI: 0.27-2.46, P=0.71, 3 trials), whereas the risk of bleeding was reduced despite treatment with high-dose bivalirudin infusion (OR: 0.28, 95% CI: 0.13-0.60, P=0.001, 3 trials)., Conclusions: Bivalirudin (with and without prolonged infusion) compared with conventional antithrombotic therapy in ST-segment-elevation myocardial infarction patients undergoing primary PCI reduces major bleeding and death, but increases the rate of acute stent thrombosis. However, prolonging the bivalirudin infusion at PCI-dose (1.75 mg/kg per hour) for 3 hours eliminates the excess risk of acute stent thrombosis, while maintaining the bleeding benefits., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

We propose a control scheme which can stabilize and fix the position of chimera states in small networks. Chimeras consist of coexisting domains of spatially coherent and incoherent dynamics in systems of nonlocally coupled identical oscillators. Chimera states are generally difficult to observe in small networks due to their short lifetime and erratic drifting of the spatial position of the incoherent domain. The control scheme, like a tweezer, might be useful in experiments, where usually only small networks can be realized.

We study a system of phase oscillators with nonlocal coupling in a ring that supports self-organized patterns of coherence and incoherence, called chimera states. Introducing a global feedback loop, connecting the phase lag to the order parameter, we can observe chimera states also for systems with a small number of oscillators. Numerical simulations show a huge variety of regular and irregular patterns composed of localized phase slipping events of single oscillators. Using methods of classical finite dimensional chaos and bifurcation theory, we can identify the emergence of chaotic chimera states as a result of transitions to chaos via period doubling cascades, torus breakup, and intermittency. We can explain the observed phenomena by a mechanism of self-modulated excitability in a discrete excitable medium.