Publications by authors named "Stavros Stavrakis"

114 Publications

Stochastic and Age-Dependent Proteostasis Decline Underlies Heterogeneity in Heat-Shock Response Dynamics.

Small 2021 Jul 1;17(30):e2102145. Epub 2021 Jul 1.

Institute of Chemical and Bioengineering, ETH Zurich, Zurich, 8093, Switzerland.

Significant non-genetic stochastic factors affect aging, causing lifespan differences among individuals, even those sharing the same genetic and environmental background. In Caenorhabditis elegans, differences in heat-shock response (HSR) are predictive of lifespan. However, factors contributing to the heterogeneity of HSR are still not fully elucidated. Here, the authors characterized HSR dynamics in isogenic C. elegans expressing GFP reporter for hsp-16.2 for identifying the key contributors of HSR heterogeneity. Specifically, microfluidic devices that enable cross-sectional and longitudinal measurements of HSR dynamics in C. elegans at different scales are developed: in populations, within individuals, and in embryos. The authors adapted a mathematical model of HSR to single C. elegans and identified model parameters associated with proteostasis-maintenance of protein homeostasis-more specifically, protein turnover, as the major drivers of heterogeneity in HSR dynamics. It is verified that individuals with enhanced proteostasis fidelity in early adulthood live longer. The model-based comparative analysis of protein turnover in day-1 and day-2 adult C. elegans revealed a stochastic-onset of age-related proteostasis decline that increases the heterogeneity of HSR capacity. Finally, the analysis of C. elegans embryos showed higher HSR and proteostasis capacity than young adults and established transgenerational contribution to HSR heterogeneity that depends on maternal age.
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http://dx.doi.org/10.1002/smll.202102145DOI Listing
July 2021

Atrioventricular junctional ablation: The good, the bad, the better.

Heart Rhythm O2 2020 Oct 25;1(4):311-314. Epub 2020 Jun 25.

Heart Rhythm Institute, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Background: The management of patients with atrial fibrillation and an abnormally fast ventricular response has been through the use of pharmacologic agents. In those cases where rate control cannot be achieved pharmacologically, a standard approach has been atrioventricular (AV) junctional ablation and ventricular pacemaker implantation to achieve a stable ventricular rate. Long-term ventricular pacing has been shown to result in diminished ventricular function that can lead to heart failure.

Objective: To describe an experimental and clinical study demonstrating a modified form of AV junction ablation.

Methods: Ablation of the slow and fast AV nodal input does not produce AV block. Ablation of the connection between the two induces AV block, leaving the AV node and His bundle intact.

Results: Subsequently the escape heart rate is close to normal and responds well to exercise.

Conclusion: In a clinical study with a 42 month follow-up, the modified procedure resulted in significantly reduced pacemaker dependence and mortality compared to the standard AV ablation procedure.
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http://dx.doi.org/10.1016/j.hroo.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183872PMC
October 2020

Low-Level Tragus Stimulation Modulates Atrial Alternans and Fibrillation Burden in Patients With Paroxysmal Atrial Fibrillation.

J Am Heart Assoc 2021 Jun 2;10(12):e020865. Epub 2021 Jun 2.

Cardiovascular Research Center Massachusetts General Hospital Boston MA.

Background Low-level tragus stimulation (LLTS) has been shown to significantly reduce atrial fibrillation (AF) burden in patients with paroxysmal AF. P-wave alternans (PWA) is believed to be generated by the same substrate responsible for AF. Hence, PWA may serve as a marker in guiding LLTS therapy. We investigated the utility of PWA in guiding LLTS therapy in patients with AF. Methods and Results Twenty-eight patients with AF were randomized to either active LLTS or sham (earlobe stimulation). LLTS was delivered through a transcutaneous electrical nerve stimulation device (pulse width 200 μs, frequency 20 Hz, amplitude 10-50 mA), for 1 hour daily over a 6-month period. AF burden over 2-week periods was assessed by noninvasive continuous ECG monitoring at baseline, 3 months, and 6 months. A 5-minute control ECG for PWA analysis was recorded during all 3 follow-up visits. Following the control ECG, an additional 5-minute ECG was recorded during active LLTS in all patients. At baseline, acute LLTS led to a significant rise in PWA burden. However, active patients receiving chronic LLTS demonstrated a significant reduction in both PWA and AF burden after 6 months (<0.05). Active patients who demonstrated an increase in PWA burden with acute LLTS showed a significant drop in AF burden after 6 months of chronic LLTS. Conclusions Chronic, intermittent LLTS resulted in lower PWA and AF burden than did sham control stimulation. Our results support the use of PWA as a potential marker for guiding LLTS treatment of paroxysmal AF.
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http://dx.doi.org/10.1161/JAHA.120.020865DOI Listing
June 2021

Broad-Band Spectrum, High-Sensitivity Absorbance Spectroscopy in Picoliter Volumes.

Anal Chem 2021 06 19;93(21):7673-7681. Epub 2021 May 19.

Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir Prelog Weg 1, 8093 Zürich, Switzerland.

Picoliter-volume droplets within segmented flows can be probed in a rapid and efficient manner using optical detection methods. To date, however, most detection schemes for droplet content analysis have relied on the use of time-integrated fluorescence measurements. Despite its undoubted utility, the implementation of absorbance-based detectors is particularly challenging due to the reduced optical path lengths that are characteristic of microfluidic systems and deleterious scattering at droplet-oil interfaces. Unsurprisingly, efforts to develop sensitive absorbance-based detection schemes for the interrogation of rapidly moving droplets have primarily focused on ensuring adequate analytical sensitivity and, to date, have been exclusively limited to single-wavelength measurements. To address this limitation, and expand the information content associated with absorbance measurements on-chip, we herein describe a detection scheme for the extraction of broad-band absorbance spectra from pL-volume droplets with high sensitivity. The combination of a confocal optical system (that confines incident light to a reduced detection volume) and a postprocessing algorithm (that effectively removes the contribution of the carrier oil from the extracted spectra) engenders significant improvements in signal-to-noise ratios. Our system is initially calibrated by acquiring absorbance spectra from aqueous solutions of fluorescein isothiocyanate. These measurements confirm both excellent linearity over the studied range (from 0 to 100 μM) and a concentration limit of detection of 800 nM. The methodology is then used to monitor the salt-induced aggregation of gold nanoparticles with millisecond time resolution. This approach for small-volume absorbance spectroscopy allows for both high-throughput and high-information content measurements in subnanoliter volumes and will be highly desirable in a wide variety of bioanalytical applications where sensitivity and throughput are priorities.
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http://dx.doi.org/10.1021/acs.analchem.1c00587DOI Listing
June 2021

Neuroscientific therapies for atrial fibrillation.

Cardiovasc Res 2021 Jun;117(7):1732-1745

University of California Los Angeles (UCLA) Cardiac Arrhythmia Center, David Geffen School of Medicine, UCLA, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.
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http://dx.doi.org/10.1093/cvr/cvab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208752PMC
June 2021

Screening for Atrial Fibrillation in American Indian Adults in a Tribal Primary Care Clinic.

J Am Heart Assoc 2021 May 21;10(9):e020069. Epub 2021 Apr 21.

Heart Research Institute Charles Perkins Centre University of Sydney Australia.

Background American Indian adults have a higher risk of atrial fibrillation (AF) compared with other racial groups. We implemented opportunistic screening to detect silent AF in American Indian adults attending a tribal health system using a mobile, single-lead ECG device. Methods and Results American Indian patients aged ≥50 years followed in a tribal primary care clinic with no history of AF underwent a 30-second ECG. A cardiologist overread all tracings to confirm the diagnosis of AF. After AF was confirmed, patients were referred to their primary care physician for initiation of anticoagulation. Patients seen over the same time period, who were not undergoing screening, served as controls. A total of 1019 patients received AF screening (mean age, 61.5±8.9 years, 62% women). Age and sex distribution of those screened was similar to the overall clinic population. New AF was diagnosed in 15 of 1019 (1.5%) patients screened versus 4 of 1267 (0.3%) patients who were not screened (mean difference, 1.2%; 95% CI, 0.3%-2.2%, =0.002). Eight of 15 with new screen-detected AF were aged <65 years. Those with screen-detected AF were slightly older and had a higher CHADS-VASc score than those without AF. Fourteen of 15 patients diagnosed with new AF had a CHADS-VASc score ≥1 and initiated anticoagulation. Conclusions Opportunistic, mobile single-lead ECG screening for AF is feasible in tribal clinics, and detects more AF than usual care, leading to appropriate initiation of anticoagulation. AF develops at a younger age in American Indian adults who would likely benefit from earlier AF screening. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03740477.
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http://dx.doi.org/10.1161/JAHA.120.020069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200768PMC
May 2021

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Front Hum Neurosci 2020 23;14:568051. Epub 2021 Mar 23.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
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http://dx.doi.org/10.3389/fnhum.2020.568051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040977PMC
March 2021

High-throughput multiparametric imaging flow cytometry: toward diffraction-limited sub-cellular detection and monitoring of sub-cellular processes.

Cell Rep 2021 Mar;34(10):108824

Institute for Chemical & Bioengineering, ETH Zürich, Vladimir Prelog Weg 1, 8093 Zürich, Switzerland. Electronic address:

We present a sheathless, microfluidic imaging flow cytometer that incorporates stroboscopic illumination for blur-free fluorescence detection at ultra-high analytical throughput. The imaging platform is capable of multiparametric fluorescence quantification and sub-cellular localization of these structures down to 500 nm with microscopy image quality. We demonstrate the efficacy of the approach through the analysis and localization of P-bodies and stress granules in yeast and human cells using fluorescence and bright-field detection at analytical throughputs in excess of 60,000 and 400,000 cells/s, respectively. Results highlight the utility of our imaging flow cytometer in directly investigating phase-separated compartments within cellular environments and screening rare events at the sub-cellular level for a range of diagnostic applications.
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http://dx.doi.org/10.1016/j.celrep.2021.108824DOI Listing
March 2021

Effect of Obesity on Response to Spironolactone in Patients With Heart Failure With Preserved Ejection Fraction.

Am J Cardiol 2021 05 30;146:36-47. Epub 2021 Jan 30.

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address:

Obesity is common in heart failure with preserved ejection fraction (HFpEF). Whether obesity modifies the response to spironolactone in patients with HFpEF remains unclear. We aimed to investigate the effect of obesity, defined by body mass index (BMI) and waist circumference (WC), on response to spironolactone in patients with HFpEF enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. This was a post-hoc, exploratory analysis of the Americas cohort of Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. BMI≥30 kg/m2 was used to define the obese group and WC≥102 cm in men and ≥88 cm in women were defined as high WC. In separate analyses, BMI and WC were treated as continuous variables. The effect of spironolactone versus placebo on outcomes was calculated by BMI and WC using Cox proportional hazard models. Obese patients were younger and had more co-morbidities. In multivariate analysis, spironolactone use was associated with a significant reduction in the primary end point, compared with placebo in obese [hazard ratio (HR = 0.618, 95% CI 0.460 to 0.831, p = 0.001), but not in nonobese subjects (HR = 0.946, 95% CI 0.623 to 1.437, p = 0.796; p for interaction = 0.056). There was a linear association between continuous BMI and the effect of spironolactone, with the effect becoming significant at 33kg/m. Similar results were obtained for the WC-based analysis. In conclusion, use of spironolactone in obese patients with HFpEF was associated with a decreased risk of the primary end point, cardiovascular death and HF hospitalizations, compared with placebo. Further prospective randomized studies in obese subjects are required.
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http://dx.doi.org/10.1016/j.amjcard.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038969PMC
May 2021

Sex differences in the incidence and mode of death in rats with heart failure with preserved ejection fraction.

Exp Physiol 2021 Mar 19;106(3):673-682. Epub 2021 Jan 19.

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

New Findings: What is the central question of this study? Prior studies failed to address the role of sex in modifying the pathophysiology and response to therapy in heart failure with preserved ejection fraction (HFpEF), potentially introducing bias into translational findings. We aimed to explore sex differences in outcomes and sought to identify the underlying mechanisms in a well-established rat model of HFpEF. What is the main finding and its importance? Male rats with HFpEF exhibited worse survival compared with females and were at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex-specific interventions in HFpEF targeting these abnormalities.

Abstract: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure, and sudden death is the leading cause of mortality. We aimed to explore sex differences in outcomes in rats with HFpEF and sought to identify the underlying mechanisms. Dahl salt-sensitive rats of either sex were randomized into high-salt diet (HS diet; 8% NaCl, n = 46, 50% female) or low-salt diet (LS diet; 0.3% NaCl; n = 24, 50% female) at 7 weeks of age. After 6 and 10 weeks of LS or HS diets, the ECG, heart rate variability, cytokines and echocardiographic parameters were measured. The animals were monitored daily for development of HFpEF and survival. Over 6 weeks of HS diet, rats developed significant hypertension and signs of HFpEF. Compared with female HS diet-fed rats, males exhibited more left ventricular dilatation, a longer QT interval, and worse autonomic tone, as assessed by heart rate variability and elevated inflammatory cytokines. Ten of 23 (46%) male rats died during follow-up, compared with two of 23 (9%) female rats (P = 0.01). There were four sudden deaths in males (with ventricular tachycardia documented in one rat), whereas the females died of heart failure. In conclusion, male rats with HFpEF exhibit worse survival compared with females and are at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex-specific interventions in HFpEF targeting these abnormalities.
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http://dx.doi.org/10.1113/EP089163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920931PMC
March 2021

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

J Card Fail 2021 May 31;27(5):568-576. Epub 2020 Dec 31.

Cardiovascular Section, Department of Internal Medicine; Heart Rhythm Institute.

Background: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation.

Methods And Results: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 μs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement.

Conclusions: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.
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http://dx.doi.org/10.1016/j.cardfail.2020.12.017DOI Listing
May 2021

Laminar Flow-Based Fiber Fabrication and Encoding via Two-Photon Lithography.

ACS Appl Mater Interfaces 2020 Nov 10. Epub 2020 Nov 10.

Institute for Chemical and Bioengineering, ETH Zürich, 8093 Zürich, Switzerland.

In recent years, flow photolithography (FL) has emerged as a powerful synthetic tool for the creation of barcoded microparticles with complex morphologies and chemical compositions which have been shown to be useful in a range of multiplexed bioassay applications. More specifically, FL has been highly successful in producing micron-sized, encoded particles of bespoke shape, size, and color. That said, to date, FL has been restricted to generating barcoded microparticles and has lacked the ability to produce hybrid fibers which are structurally and spectrally encoded. To this end, we herein present a method that combines a continuous flow microfluidic system with two-photon polymerization (2PP) to fabricate microscale-encoded fibers and Janus strips in a high-throughput manner. Specifically, two co-flow liquid streams containing a monomer and initiator are introduced through a Y-shape channel to form a stable interface in the center of a microfluidic channel. The flow containing the (fluorescently labeled) monomer is then patterned by scanning the voxel of the 2PP laser across the interface to selectively polymerize different regions of the forming fiber/particle. Such a process allows for rapid spectral encoding at the single fiber level, with the resulting structurally coded fibers having obvious application in the fields of security identification and anticounterfeiting.
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http://dx.doi.org/10.1021/acsami.0c14917DOI Listing
November 2020

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats.

Sci Rep 2020 10 16;10(1):17576. Epub 2020 Oct 16.

Department of Medicine, Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.
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http://dx.doi.org/10.1038/s41598-020-74257-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567801PMC
October 2020

Analysis of biomolecular condensates and protein phase separation with microfluidic technology.

Biochim Biophys Acta Mol Cell Res 2021 01 13;1868(1):118823. Epub 2020 Aug 13.

Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich 8093, Switzerland. Electronic address:

An increasing body of evidence shows that membraneless organelles are key components in cellular organization. These observations open a variety of outstanding questions about the physico-chemical rules underlying their assembly, disassembly and functions. Some molecular determinants of biomolecular condensates are challenging to probe and understand in complex in vivo systems. Minimalistic in vitro reconstitution approaches can fill this gap, mimicking key biological features, while maintaining sufficient simplicity to enable the analysis of fundamental aspects of biomolecular condensates. In this context, microfluidic technologies are highly attractive tools for the analysis of biomolecular phase transitions. In addition to enabling high-throughput measurements on small sample volumes, microfluidic tools provide for exquisite control of self-assembly in both time and space, leading to accurate quantitative analysis of biomolecular phase transitions. Here, with a specific focus on droplet-based microfluidics, we describe the advantages of microfluidic technology for the analysis of several aspects of phase separation. These include phase diagrams, dynamics of assembly and disassembly, rheological and surface properties, exchange of materials with the surrounding environment and the coupling between compartmentalization and biochemical reactions. We illustrate these concepts with selected examples, ranging from simple solutions of individual proteins to more complex mixtures of proteins and RNA, which represent synthetic models of biological membraneless organelles. Finally, we discuss how this technology may impact the bottom-up fabrication of synthetic artificial cells and for the development of synthetic protein materials in biotechnology.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118823DOI Listing
January 2021

Machine learning versus conventional clinical methods in guiding management of heart failure patients-a systematic review.

Heart Fail Rev 2021 Jan;26(1):23-34

Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Charlestown, Boston, MA, 02129, USA.

Machine learning (ML) algorithms "learn" information directly from data, and their performance improves proportionally with the number of high-quality samples. The aim of our systematic review is to present the state of the art regarding the implementation of ML techniques in the management of heart failure (HF) patients. We manually searched MEDLINE and Cochrane databases as well the reference lists of the relevant review studies and included studies. Our search retrieved 122 relevant studies. These studies mainly refer to (a) the role of ML in the classification of HF patients into distinct categories which may require a different treatment strategy, (b) discrimination of HF patients from the healthy population or other diseases, (c) prediction of HF outcomes, (d) identification of HF patients from electronic records and identification of HF patients with similar characteristics who may benefit form a similar treatment strategy, (e) supporting the extraction of important data from clinical notes, and (f) prediction of outcomes in HF populations with implantable devices (left ventricular assist device, cardiac resynchronization therapy). We concluded that ML techniques may play an important role for the efficient construction of methodologies for diagnosis, management, and prediction of outcomes in HF patients.
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http://dx.doi.org/10.1007/s10741-020-10007-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384870PMC
January 2021

Deformation of leukaemia cell lines in hyperbolic microchannels: investigating the role of shear and extensional components.

Lab Chip 2020 07;20(14):2539-2548

Laboratory of Biological Structure Mechanics (LaBS), Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, piazza Leonardo da Vinci, 32 - 20133 Milan, Italy.

The mechanical properties of cells are of enormous interest in a diverse range of physio and pathological situations of clinical relevance. Unsurprisingly, a variety of microfluidic platforms have been developed in recent years to study the deformability of cells, most commonly employing pure shear or extensional flows, with and without direct contact of the cells with channel walls. Herein, we investigate the effects of shear and extensional flow components on fluid-induced cell deformation by means of three microchannel geometries. In the case of hyperbolic microchannels, cell deformation takes place in a flow with constant extensional rate, under non-zero shear conditions. A sudden expansion at the microchannel terminus allows one to evaluate shape recovery subsequent to deformation. Comparison with other microchannel shapes, that induce either pure shear (straight channel) or pure extensional (cross channel) flows, reveals different deformation modes. Such an analysis is used to confirm the softening and stiffening effects of common treatments, such as cytochalasin D and formalin on cell deformability. In addition to an experimental analysis of leukaemia cell deformability, computational fluid dynamic simulations are used to deconvolve the role of the aforementioned flow components in the cell deformation dynamics. In general terms, the current study can be used as a guide for extracting deformation/recovery dynamics of leukaemia cell lines when exposed to various fluid dynamic conditions.
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http://dx.doi.org/10.1039/d0lc00166jDOI Listing
July 2020

Autonomic Modulation of Cardiac Arrhythmias: Methods to Assess Treatment and Outcomes.

JACC Clin Electrophysiol 2020 05;6(5):467-483

Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Electronic address:

The autonomic nervous system plays a central role in the pathogenesis of multiple cardiac arrhythmias, including atrial fibrillation and ventricular tachycardia. As such, autonomic modulation represents an attractive therapeutic approach in these conditions. Notably, autonomic modulation exploits the plasticity of the neural tissue to induce neural remodeling and thus obtain therapeutic benefit. Different forms of autonomic modulation include vagus nerve stimulation, tragus stimulation, renal denervation, baroreceptor activation therapy, and cardiac sympathetic denervation. This review seeks to highlight these autonomic modulation therapeutic modalities, which have shown promise in early preclinical and clinical trials and represent exciting alternatives to standard arrhythmia treatment. We also present an overview of the various methods used to assess autonomic tone, including heart rate variability, skin sympathetic nerve activity, and alternans, which can be used as surrogate markers and predictors of the treatment effect. Although the use of autonomic modulation to treat cardiac arrhythmias is supported by strong preclinical data and preliminary studies in humans, in light of the disappointing results of a number of recent randomized clinical trials of autonomic modulation therapies in heart failure, the need for optimization of the stimulation parameters and rigorous patient selection based on appropriate biomarkers cannot be overemphasized.
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http://dx.doi.org/10.1016/j.jacep.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370838PMC
May 2020

A Counter Propagating Lens-Mirror System for Ultrahigh Throughput Single Droplet Detection.

Small 2020 05 20;16(20):e1907534. Epub 2020 Apr 20.

Institute for Chemical and Bioengineering, ETH Zürich, Vladimir-Prelog-Weg 1, Zurich, 8093, Switzerland.

Fluorescence-based detection schemes provide for multiparameter analysis in a broad range of applications in the chemical and biological sciences. Toward the realization of fully portable analysis systems, microfluidic devices integrating diverse functional components have been implemented in a range of out-of-lab environments. That said, there still exits an unmet and recognized need for miniaturized, low-cost, and sensitive optical detection systems, which provide not only for efficient molecular excitation, but also enhanced photon collection capabilities. To this end, an optofluidic platform that is adept at enhancing fluorescence light collection from microfluidic channels is presented. The central component of the detection module is a monolithic parabolic mirror located directly above the microfluidic channel, which acts to enhance the number of emitted photons reflected toward the detector. In addition, two-photon polymerization is used to print a microscale-lens below the microfluidic flow channel and directly opposite the mirror, to enhance the delivery of excitation radiation into the channel. Using such an approach, it is demonstrated that fluorescence signals can be enhanced by over two orders of magnitude, with component parallelization enabling the detection of pL-volume droplets at rates up to 40 000 droplets per second.
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http://dx.doi.org/10.1002/smll.201907534DOI Listing
May 2020

Microfluidic Shrinking Droplet Concentrator for Analyte Detection and Phase Separation of Protein Solutions.

Anal Chem 2020 04 6;92(8):5803-5812. Epub 2020 Apr 6.

Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, ETH Zurich, Zurich 8093, Switzerland.

We develop a droplet microfluidic platform to increase the concentration of analytes in solution via reduction of the sample volume under well-defined conditions. This approach improves the detection and quantification of analytes without requiring any information on their structure nor physical chemical properties. Samples are compartmentalized and processed in water-in-oil droplets that are individually stored in cylindrical microwells located on top of a microfluidic channel. The individual droplets shrink over time due to water extraction in the surrounding oil, leading to an increase in the analyte concentration up to 100,000-fold within the droplet. We demonstrate the power of this approach for detection applications by quantifying a broad range of single analytes such as small molecules, proteins, nanoparticles, exosomes, and amyloid fibrils. With this setup, we can measure pM concentrations, corresponding to zeptomole (10 mol) amounts encapsulated in individual droplets. We further show that the droplet concentrator device, or DroMiCo, can quantify unlabeled proteins in nM concentrations and analyze multicomponent mixtures when coupled with a prefractionation step. We illustrate this concept by detecting femtomoles (10 mol) of soluble protein oligomers prefractionated by size exclusion chromatography. Finally, we apply the DroMiCo to the analysis of phase diagrams of macromolecules, including synthetic polymers and proteins. Specifically, we analyze the liquid-liquid phase separation of an model of cellular membraneless compartments, composed of a phase separating protein in the presence of defined concentrations of molecular modulators such as RNA and ATP.
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http://dx.doi.org/10.1021/acs.analchem.9b05329DOI Listing
April 2020

TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A Randomized Clinical Trial.

JACC Clin Electrophysiol 2020 03 29;6(3):282-291. Epub 2020 Jan 29.

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Objectives: This study was a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low level tragus stimulation (LLTS) in patients with paroxysmal AF.

Background: Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus (LLTS) acutely suppresses atrial fibrillation (AF) in humans, but the chronic effect remains unknown.

Methods: LLTS (20 Hz, 1 mA below the discomfort threshold) was delivered using an ear clip attached to the tragus (active arm) (n = 26) or the ear lobe (sham control arm) (n = 27) for 1 h daily over 6 months. AF burden over 2-week periods was assessed by noninvasive continuous electrocardiogram monitoring at baseline, 3 months, and 6 months. Five-minute electrocardiography and serum were obtained at each visit to measure heart rate variability and inflammatory cytokines, respectively.

Results: Baseline characteristics were balanced between the 2 groups. Adherence to the stimulation protocol (≤4 sessions lost per month) was 75% in the active arm and 83% in the control arm (p > 0.05). At 6 months, the median AF burden was 85% lower in the active arm compared with the control arm (ratio of medians: 0.15; 95% confidence interval: 0.03 to 0.65; p = 0.011). Tumor necrosis factor-alpha was significantly decreased by 23% in the active group relative to the control group (ratio of medians: 0.77; 95% confidence interval: 0.63 to 0.94; p = 0.0093). Frequency domain indices of heart rate variability were significantly altered with active versus control stimulation (p < 0.01). No device-related side effects were observed.

Conclusions: Chronic, intermittent LLTS resulted in lower AF burden than did sham control stimulation, supporting its use to treat paroxysmal AF in selected patients. (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation [TREAT-AF]; NCT02548754).
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http://dx.doi.org/10.1016/j.jacep.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100921PMC
March 2020

Cardioneuroablation for vagally mediated bradyarrhythmia: The universal one fits all solution?

Int J Cardiol 2020 04 10;304:45-46. Epub 2020 Jan 10.

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, USA.

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http://dx.doi.org/10.1016/j.ijcard.2020.01.007DOI Listing
April 2020

Scoring systemic lupus erythematosus (SLE) disease activity with simple, rapid outcome measures.

Lupus Sci Med 2019 30;6(1):e000365. Epub 2019 Dec 30.

Department of Rheumatology, Columbia University, New York City, New York, USA.

Objective: Existing methods for grading lupus flares or improvement require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analysed the performance of the SELENA SLEDAI Physician's Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) as measures of improvement or worsening in SLE.

Methods: We evaluated the agreement between prospectively collected measures of lupus disease activity [SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index 2004 (BILAG 2004), Cutaneous Lupus Area and Severity Index (CLASI), SSPGA and LFA-REAL] and response [(SLE Responder Index (SRI)-4 and BILAG-Based Combined Lupus Assessment (BICLA)] in a clinical trial.

Results: Fifty patients (47 females, mean age 45 (±11.6) years) were assessed at 528 consecutive visits (average 10.6 (±4.1) visits/patient). Changes in disease activity compared with baseline were examined in 478 visit pairs. SSPGA and LFA-REAL correlated with each other (r=0.936), and with SLEDAI and BILAG (SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REAL: r=0.778 (SLEDAI), r=0.813 (BILAG); all p<0.0001). Changes (∆) in SSPGA and LFA-REAL compared with screening correlated with each other (r=0.857) and with changes in SLEDAI and BILAG (∆SSPGA: r=0.678 (∆SLEDAI), r=0.624 (∆BILAG); ∆LFA-REAL: r=0.686 (∆SLEDAI) and 0.700 (∆BILAG); all p<0.0001). Changes in SSPGA and LFA-REAL strongly correlated with SRI-4 and BICLA by receiver operating characteristic analysis (p<0.0001 for all). Additionally, LFA-REAL correlated to individual BILAG organ scores (musculoskeletal: r=0.842, mucocutaneous: r=0.826 (p<0.0001 for both)).

Conclusion: SSPGA and LFA-REAL are reliable surrogates of common SLE trial end points and could be used as continuous or dichotomous response measures. Additionally, LFA-REAL can provide individualised scoring at the symptom or organ level.

Trial Registration Number: NCT02270957.
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http://dx.doi.org/10.1136/lupus-2019-000365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937422PMC
December 2019

Droplet-based optofluidic systems for measuring enzyme kinetics.

Anal Bioanal Chem 2020 May 18;412(14):3265-3283. Epub 2019 Dec 18.

Institute for Chemical and Bioengineering, ETH Zürich, Vladimir Prelog Weg 1, 8093, Zürich, Switzerland.

The study of enzyme kinetics is of high significance in understanding metabolic networks in living cells and using enzymes in industrial applications. To gain insight into the catalytic mechanisms of enzymes, it is necessary to screen an enormous number of reaction conditions, a process that is typically laborious, time-consuming, and costly when using conventional measurement techniques. In recent times, droplet-based microfluidic systems have proved themselves to be of great utility in large-scale biological experimentation, since they consume a minimal sample, operate at high analytical throughput, are characterized by efficient mass and heat transfer, and offer high levels of integration and automation. The primary goal of this review is the introduction of novel microfluidic tools and detection methods for use in high-throughput and sensitive analysis of enzyme kinetics. The first part of this review focuses on introducing basic concepts of enzyme kinetics and describing most common microfluidic approaches, with a particular focus on segmented flow. Herein, the key advantages include accurate control over the flow behavior, efficient mass and heat transfer, multiplexing, and high-level integration with detection modalities. The second part describes the current state-of-the-art platforms for high-throughput and sensitive analysis of enzyme kinetics. In addition to our categorization of recent advances in measuring enzyme kinetics, we have endeavored to critically assess the limitations of each of these detection approaches and propose strategies to improve measurements in droplet-based microfluidics. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-019-02294-zDOI Listing
May 2020

Oscillatory Viscoelastic Microfluidics for Efficient Focusing and Separation of Nanoscale Species.

ACS Nano 2020 01 9;14(1):422-433. Epub 2019 Dec 9.

Institute for Chemical and Bioengineering , ETH Zürich , Vladimir Prelog Weg 1 , 8093 Zürich , Switzerland.

The ability to precisely control particle migration within microfluidic systems is essential for focusing, separating, counting, and detecting a wide range of biological species. To date, viscoelastic microfluidic systems have primarily been applied to the focusing, separation, and isolation of micrometer-sized species, with their use in nanoparticle manipulations being underdeveloped and underexplored, due to issues related to nanoparticle diffusivity and a need for extended channel lengths. To overcome such issues, we herein present sheathless oscillatory viscoelastic microfluidics as a method for focusing and separating both micrometer and sub-micrometer species. To highlight the efficacy of our approach, we segment our study into three size regimes, namely, micrometer (where characteristic particle dimensions are above 1 μm), sub-micrometer (where characteristic dimensions are between 1 μm and 100 nm), and nano (where characteristic dimensions are below 100 nm) regimes. Based on the ability to successfully manipulate particles in all these regimes, we demonstrate the successful isolation of p-bodies from biofluids (in the micrometer regime), the focusing of λ-DNA (in the sub-micrometer regime), and the focusing of extracellular vesicles (in the nanoregime). Finally, we characterize the physics underlying viscoelastic microflows using a dimensionless number that relates the lateral velocity (due to elastic effects) to the diffusion constant of the species within the viscoelastic carrier fluid. Based on the ability to precisely manipulate species in all three regimes, we expect that sheathless oscillatory viscoelastic microfluidics may be used to good effect in a range of biological and life science applications.
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http://dx.doi.org/10.1021/acsnano.9b06123DOI Listing
January 2020

New approaches for treating atrial fibrillation: Focus on autonomic modulation.

Trends Cardiovasc Med 2020 10 31;30(7):433-439. Epub 2019 Oct 31.

Department of Cardiology, University of Oklahoma Health Sciences Center, 800 Stanton L. Young Blvd., Suite 5400, Oklahoma, OK, United States; Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma, OK, United States. Electronic address:

Atrial fibrillation (AF) is a rapidly growing clinical problem in routine practice, both for cardiologists as well as general practitioners. Current therapies aimed at the management of AF include anti-arrhythmic drug therapy and catheter ablation. These therapies have a number of limitations and risks, and have disappointing long-term efficacy in maintaining sinus rhythm and improving hard clinical outcomes. Because of this, there is growing interest in pursuing alternative management strategies in patients with AF. This review seeks to highlight emerging AF therapies, with a specific focus on several modalities aimed at modulation of the autonomic nervous system. These therapies have shown promise in early pre-clinical and clinical trials, and represent exciting alternatives to standard AF treatment.
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http://dx.doi.org/10.1016/j.tcm.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190441PMC
October 2020

Simple hematological predictors of AF recurrence in patients undergoing atrial fibrillation ablation.

J Geriatr Cardiol 2019 Sep;16(9):671-675

Department of Cardiology, Electrophysiology Laboratory, Evangelismos General Hospital of Athens, Athens, Greece.

Backgound: Red cell distribution width (RDW) and neutrophil-to-lymphocyte ratio (NLR) are simple hematologic indices that have been used to predict adverse outcomes in different clinical settings. The aim of our study is to determine whether RDW and NLR can predict atrial fibrillation (AF) recurrence in patients undergoing AF ablation.

Methods: Consecutive patients, without known hematological disorders, who underwent AF catheter ablation between January 2014 and April 2017 were enrolled into this study. Blood samples were taken one day before and five hours after the ablation procedure.

Results: A total of 346 patients (224 males (65%), mean age: 59 ± 11 years old) were included. After a mean follow up of 26.2 ± 12.1 months, 80 (23.1%) patients experienced late AF recurrence (defined as any recurrence after the blanking period of three months), while 97 (28%) patients experienced early AF recurrence during the blanking period. Univariate analysis showed that early arrhythmia recurrence, type of AF and NLR after the procedure were significantly associated with late AF recurrence, while early arrhythmia recurrence and NLR remained significant in multivariate analysis. RDW was not associated with late AF recurrence. None of the parameters above predicted early arrhythmia recurrence.

Conclusions: Simple and inexpensive hematological indices such as NLR should be evaluated for their ability to predict AF recurrence in patients undergoing catheter ablation in larger prospective studies.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790958PMC
September 2019

Clinical characteristics and long-term clinical course of patients with Brugada syndrome without previous cardiac arrest: a multiparametric risk stratification approach.

Europace 2019 12;21(12):1911-1918

Second Department of Cardiology, Laboratory of Invasive Cardiac Electrophysiology, "Evangelismos" General Hospital of Athens, Ispilantou 45-47, 10676, Athens, Greece.

Aims: Risk stratification in Brugada syndrome (BrS) still represents an unsettled issue. In this multicentre study, we aimed to evaluate the clinical characteristics and the long-term clinical course of patients with BrS.

Methods And Results: A total of 111 consecutive patients (86 males; aged 45.3 ± 13.3 years) diagnosed with BrS were included and followed-up in a prospective fashion. Thirty-seven patients (33.3%) were symptomatic at enrolment (arrhythmic syncope). An electrophysiological study (EPS) was performed in 59 patients (53.2%), and ventricular arrhythmias were induced in 32 (54.2%). A cardioverter defibrillator was implanted in 34 cases (30.6%). During a mean follow-up period of 4.6 ± 3.5 years, appropriate device therapies occurred in seven patients. Event-free survival analysis (log-rank test) showed that spontaneous type-1 electrocardiogram pattern (P = 0.008), symptoms at presentation (syncope) (P = 0.012), family history of sudden cardiac death (P < 0.001), positive EPS (P = 0.024), fragmented QRS (P = 0.004), and QRS duration in lead V2 > 113 ms (P < 0.001) are predictors of future arrhythmic events. Event rates were 0%, 4%, and 60% among patients with 0-1 risk factor, 2-3 risk factors, and 4-5 risk factors, respectively (P < 0.001). Current multiparametric score models exhibit an excellent negative predictive value and perform well in risk stratification of BrS patients.

Conclusions: Multiparametric models including common risk factors appear to provide better risk stratification of BrS patients than single factors alone.
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http://dx.doi.org/10.1093/europace/euz288DOI Listing
December 2019

High-throughput droplet-based microfluidics for directed evolution of enzymes.

Electrophoresis 2019 11 29;40(21):2860-2872. Epub 2019 Aug 29.

Institute for Chemical and Bioengineering, ETH Zürich, Zürich, Switzerland.

Natural enzymes have evolved over millions of years to allow for their effective operation within specific environments. However, it is significant to note that despite their wide structural and chemical diversity, relatively few natural enzymes have been successfully applied to industrial processes. To address this limitation, directed evolution (DE) (a method that mimics the process of natural selection to evolve proteins toward a user-defined goal) coupled with droplet-based microfluidics allows the detailed analysis of millions of enzyme variants on ultra-short timescales, and thus the design of novel enzymes with bespoke properties. In this review, we aim at presenting the development of DE over the last years and highlighting the most important advancements in droplet-based microfluidics, made in this context towards the high-throughput demands of enzyme optimization. Specifically, an overview of the range of microfluidic unit operations available for the construction of DE platforms is provided, focusing on their suitability and benefits for cell-based assays, as in the case of directed evolution experimentations.
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http://dx.doi.org/10.1002/elps.201900222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899980PMC
November 2019

Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Circ Arrhythm Electrophysiol 2019 09 21;12(9):e007414. Epub 2019 Aug 21.

Cardiovascular Disease Section, University of Oklahoma Health Sciences Center (Z.U.A.A., A.Y., S.S.).

Background: Despite the publication of several randomized clinical trials comparing catheter ablation (CA) with medical therapy (MT) in patients with atrial fibrillation (AF), the superiority of one strategy over another is still questioned by many. In this meta-analysis of randomized controlled trials, we compared the efficacy and safety of CA with MT for AF.

Methods: We systematically searched MEDLINE, EMBASE, and other online sources for randomized controlled trials of AF patients that compared CA with MT. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular hospitalizations and recurrence of atrial arrhythmia. Subgroup analyses stratified by the presence of heart failure with reduced ejection fraction, type of AF, age, and sex were performed. Risk ratios (RRs) with 95% CIs were calculated using a random effects model, and Mantel-Haenszel method was used to pool RR.

Results: Eighteen randomized controlled trials comprising 4464 patients (CA, n=2286; MT, n=2178) were included. CA resulted in a significant reduction in all-cause mortality (RR, 0.69; 95% CI, 0.54-0.88; P=0.003) that was driven by patients with AF and heart failure with reduced ejection fraction (RR, 0.52; 95% CI, 0.35-0.76; P=0.0009). CA resulted in significantly fewer cardiovascular hospitalizations (hazard ratio, 0.56; 95% CI, 0.39-0.81; P=0.002) and fewer recurrences of atrial arrhythmias (RR, 0.42; 95% CI, 0.33-0.53; P<0.00001). Subgroup analyses suggested that younger patients (age, <65 years) and men derived more benefit from CA compared with MT.

Conclusions: CA is associated with all-cause mortality benefit, that is driven by patients with AF and heart failure with reduced ejection fraction. CA reduces cardiovascular hospitalizations and recurrences of atrial arrhythmia for patients with AF. Younger patients and men appear to derive more benefit from CA.
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http://dx.doi.org/10.1161/CIRCEP.119.007414DOI Listing
September 2019
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