Automatic algorithmic driven monitoring of atrioventricular nodal re-entrant tachycardia ablation to improve procedural safety.

Background: During slow pathway modification for atrioventricular nodal reentrant tachycardia, heart block may occur if ablation cannot be stopped in time in response to high risk electrogram features (HREF). Objectives: To develop an automatic algorithm to monitor HREF and terminate ablation earlier than human reaction. Methods: Digital electrogram data from 332 ablation runs from February 2020 to June 2022 were included. They were divided into training and validation sets which contained 126 and 206 ablation runs respectively. HREF in training set was measured. Then a program was developed with cutoff values decided from training set to capture all these HREF. Simulation ablation videos were rendered using validation set electrogram data. The videos were played to three independent electrophysiologists who each determined when to stop ablation. Timing of ablation termination, sensitivity, and specificity were compared between human and program. Results: Reasons for ablation termination in the training set include short AA time, short VV time, AV block and VA block. Cutoffs for the program were set to maximize program sensitivity. Sensitivity and specificity for the program in the validation set were 95.2% and 91.1% respectively, which were comparable to that of human performance at 93.5% and 95.4%. If HREF were recognized by both human and program, ablations were terminated earlier by the program 90.2% of times, by a median of 574 ms (interquartile range 412-807 ms, p < 0.001). Conclusion: Algorithmic-driven monitoring of slow pathway modification can supplement human judgement to improve ablation safety.

Anatomy of the proximal septal vein in patients with focal intramural ventricular arrhythmias.

BACKGROUND: Focal ventricular arrhythmias (VAs) originating from the intramural myocardium of the basal septum are difficult to localize and ablate. Proximal septal veins emptying into the great cardiac vein can reach close to the origin of intramural arrhythmias. OBJECTIVE: To assess characteristics of proximal septal coronary veins in patients with intramural VAs. METHODS AND RESULTS: Among 84 consecutive patients with intramural VAs, 29 patients (age 60 ± 11years, 16 males, ejection fraction 47 ± 13%) underwent preprocedural cardiac computed tomographic angiography (CTA). In 14 of these patients, the intramural site of origin (SOO) was identified with multipolar catheters. The intramural SOO could not be accessed with mapping catheters in the other 15 patients while mapping the coronary venous system. The CTA identified sizable proximal septal veins in all patients in whom the SOO could be accessed with mapping catheters. In the patients in whom the intramural SOO was not identified, the proximal septal veins were often either small (<2 mm at the branching site) or non-existent (n = 9, p = .001). The proximal septal veins in patients in whom the SOO was identified were larger than in the patients in whom the SOO could not be identified (3.0 ± 0.6 mm vs. 2.1 ± 0.9 mm, p = .01). CONCLUSIONS: Preprocedural imaging with CTAs can be beneficial in identifying the anatomy of proximal septal coronary veins that allow adequate mapping of patients with suspected intramural VAs.

Intramural mapping of intramural septal ventricular arrhythmias.

BACKGROUND: Intramural ventricular arrhythmias (VAs) can originate in patients with or without structural heart disease. Electrogram (EGM) recordings from intramural sources of VA have not been described thoroughly. OBJECTIVE: We hypothesized that the presence of scar may be linked to the site of origin (SOO) of focal, intramural VAs. METHODS: In a series of 21 patients (age: 55 ± 11 years, 12 women, mean ejection fraction 43 ± 14%) in whom the SOO of intramural VAs was identified, we analyzed bipolar EGM characteristics at the SOO and compared the findings with the endocardial breakout site. The patients were from a pool of 86 patients with intramural VAs referred for ablation. RESULTS: In 16/21 patients intramural scarring was detected by cardiac magnetic resonance (CMR) imaging In patients in whom the intramural SOO was reached, intramural bipolar EGMs showed a lower voltage and had broader EGMs compared to the endocardial breakout sites (0.97 ± 0.56 vs. 2.28 ± 0.15 mV, p = .001; and 122.3 ± 31.6 vs. 96.5 ± 26.3 ms, p < .01). All intramural sampled sites at the SOO had either low voltage or broad abnormal EGMs. The activation time was significantly earlier at the intramural SOO than at breakout sites (-36.2 ± 11.8 vs. -23.2 ± 9.1 ms, p < .0001). CONCLUSIONS: Sites of origin of intramural VAs with scar by CMR display EGM characteristics of scarring, supporting that scar tissue localizes to the SOO of intramural outflow tract arrhythmias in some patients. Scarring identified by CMR may be helpful in planning ablation procedures in patients with suspected intramural VAs.

Surgical ablation supplemented by ethanol injection for ventricular tachycardia refractory to percutaneous ablation.

BACKGROUND: A combination of endocardial and epicardial approaches has improved the overall success rate of ventricular tachycardia (VT) ablation in patients with cardiomyopathy. However, the origins of some VTs are truly intramural or close to coronary arteries, which makes this combined strategy either prone to failure or too risky. OBJECTIVES: This observational study aimed to explore the feasibility and efficacy of direct epicardial ablation combined with intramural ethanol injection via surgical approach for inaccessible intramural VTs or VTs too close to coronary arteries. METHODS: In four canines ventricular lesions produced by direct epicardial injection of ethanol were assessed. Six consecutive patients with recurrent VT refractory to catheter endocardial and epicardial RF ablation and that remained inducible after surgical epicardial mapping and RF ablation were included. Ethanol was injected by needle at the epicardial RF ablation sites. The primary outcome was freedom of sustained VT determined by device interrogation and periodical 24-h holter recordings subsequently. RESULTS: In an animal study, the lesions were homogenous and increased in size with the volume of ethanol injected. In all six patients, ethanol injection at the target sites in the anterior or lateral left ventricle abolished inducible VT. Over a median follow-up of 22 months (range, 6-65), all patients remained free of sustained VT. One patient died of pulmonary infection one year after the procedure. CONCLUSIONS: A hybrid strategy of surgical ablation combined with intramural ethanol injection is feasible and effective in patients with multiple failed percutaneous ablation attempts.

A multicenter randomized controlled trial of a modified Valsalva maneuver for cardioversion of supraventricular tachycardias.

CLINICAL QUESTION: Valsalva maneuver is a recognized treatment for supraventricular tachycardia, but in clinical setting it has a low chance to achieve successful cardioversion. Studies suggested that the postural modification of valsalva maneuver may improve the rate of cardioversion. We further modified the maneuver and conduct a multicenter randomized controlled trial to test its efficacy. RESEARCH IN CONTEXT: Appelboam A, Reuben A, Mann C, et al. Postural modification of the standard Valsalva maneuver for emergency treatment for supraventricular tachycardias (REVERT): a randomized controlled trial. Lancet 2015; 386 (10005):1747-53 [1]. Allison Michaud, PhD, Eddy Lang. Leg lift Valsalva maneuver for treatment of supraventricular tachycardias. CJEM 2017; 19(3):235-237 [2]. OBJECTIVE: To verify the efficacy of the modified Valsalva maneuver in SVT in Chinese population and simplify the operation process further.

Cell-free Biosystems in the Production of Electricity and Bioenergy.

: Increasing needs of green energy and concerns of climate change are motivating intensive R&D efforts toward the low-cost production of electricity and bioenergy, such as hydrogen, alcohols, and jet fuel, from renewable sugars. Cell-free biosystems for biomanufacturing (CFB2) have been suggested as an emerging platform to replace mainstream microbial fermentation for the cost-effective production of some biocommodities. As compared to whole-cell factories, cell-free biosystems comprised of synthetic enzymatic pathways have numerous advantages, such as high product yield, fast reaction rate, broad reaction condition, easy process control and regulation, tolerance of toxic compound/product, and an unmatched capability of performing unnatural reactions. However, issues pertaining to high costs and low stabilities of enzymes and cofactors as well as compromised optimal conditions for different source enzymes need to be solved before cell-free biosystems are scaled up for biomanufacturing. Here, we review the current status of cell-free technology, update recent advances, and focus on its applications in the production of electricity and bioenergy.

In situ regeneration of NADH via lipoamide dehydrogenase-catalyzed electron transfer reaction evidenced by spectroelectrochemistry.

NAD/NADH is a coenzyme found in all living cells, carrying electrons from one reaction to another. We report on characterizations of in situ regeneration of NADH via lipoamide dehydrogenase (LD)-catalyzed electron transfer reaction to regenerate NADH using UV-vis spectroelectrochemistry. The Michaelis-Menten constant (K(m)) and maximum velocity (V(max)) of NADH regeneration were measured as 0.80±0.15 mM and 1.91±0.09 µM s(-1) in a 1-mm thin-layer spectroelectrochemical cell using gold gauze as the working electrode at the applied potential -0.75 V (vs. Ag/AgCl). The electrocatalytic reduction of the NAD system was further coupled with the enzymatic conversion of pyruvate to lactate by lactate dehydrogenase to examine the coenzymatic activity of the regenerated NADH. Although the reproducible electrocatalytic reduction of NAD into NADH is known to be difficult compared to the electrocatalytic oxidation of NADH, our spectroelectrochemical results indicate that the in situ regeneration of NADH via LD-catalyzed electron transfer reaction is fast and sustainable and can be potentially applied to many NAD/NADH-dependent enzyme systems.

Responsive interface switchable by logically processed physiological signals: toward "smart" actuators for signal amplification and drug delivery.

Biomarkers characteristic of liver injury, alanine transaminase and lactate dehydrogenase, were processed by an enzyme-based system functioning as a logic AND gate. The NAD+ output signal produced by the system upon its activation in the presence of both biomarkers was then biocatalytically converted to a decrease in pH. The acidic pH value biocatalytically produced by the system as a response to the biomarkers triggered the restructuring of a polymer-modified electrode interface. This allowed a soluble redox species to approach the electrode surface, thus switching the electrochemical reaction ON. The redox transformations activated by the biochemical signals resulted in an amplification of signals. This system represents the first example of an integrated sensing-actuating chemical device with the implemented AND Boolean logic for processing natural biomarkers at their physiologically relevant concentrations.

Bacteria-based AND logic gate: a decision-making and self-powered biosensor.

We developed a bacteria-based AND logic gate using a Pseudomonas aeruginosa lasI/rhlI double mutant with two quorum-sensing signaling molecules as the input signals. We showed a distinct electrical output signal, despite the complexity and continuous regulation of metabolic reactions of living cells.

Self-powered biomolecular keypad lock security system based on a biofuel cell.

The enzyme-based keypad lock was integrated with a biofuel cell yielding a self-powered biomolecular information security system. The correct "password" introduced into the keypad lock resulted in the activation of the biofuel cell, while all other "wrong" permutations of the enzyme inputs preserved the "OFF" state of the biofuel cell.

Reversible gating controlled by enzymes at nanostructured interface.

A nanostructured biocatalytic interface reversibly gating electrochemical reactions upon chemical signals processed by immobilized enzymes was architectured. The chemical signals were converted to local interfacial pH changes causing restructuring of the stimuli-responsive polymer and switching ON-OFF the electrochemical reaction.

Reversible "closing" of an electrode interface functionalized with a polymer brush by an electrochemical signal.

The poly(4-vinyl pyridine) (P4VP)-brush-modified indium tin oxide (ITO) electrode was used to switch reversibly the interfacial activity by the electrochemical signal. The application of an external potential (-0.85 V vs Ag|AgCl|KCl, 3M) that electrochemically reduced O(2) resulted in the concomitant consumption of hydrogen ions at the electrode interface, thus yielding a higher pH value and triggering the restructuring of the P4VP brush on the electrode surface. The initial swollen state of the protonated P4VP brush (pH 4.4) was permeable to the anionic [Fe(CN)(6)](4-) redox species, but the electrochemically produced local pH of 9.1 resulted in the deprotonation of the polymer brush. The produced hydrophobic shrunken state of the polymer brush was impermeable to the anionic redox species, thus fully inhibiting its redox process at the electrode surface. The interface's return to the electrochemically active state was achieved by disconnecting the applied potential, followed by stirring the electrolyte solution or by slow diffusional exchange of the electrode-adjacent thin layer with the bulk solution. The developed approach allowed the electrochemically triggered inhibition ("closing") of the electrode interface. The application of this approach to different interfacial systems will allow the use of various switchable electrodes that are useful for biosensors and biofuel cells with externally controlled activity. Further use of this concept was suggested for electrochemically controlled chemical actuators (e.g. operating as electroswitchable drug releasers).

Switchable selectivity for gating ion transport with mixed polyelectrolyte brushes: approaching 'smart' drug delivery systems.

A pH-responsive mixed polyelectrolyte brush from tethered polyacrylic acid (PAA) and poly(2-vinylpyridine) (P2VP) (PAA:P2VP = 69:31 by weight) was prepared and used for selective gating transport of anions and cations across the thin film. An ITO glass electrode was modified with the polymer brush and used to study the switchable permeability of the mixed brush triggered by changes in pH of the aqueous environment in the presence of two soluble redox probes: [Fe(CN)(6)](4-) and [Ru(NH(3))(6)](3+). The responsive behavior of the brush was also investigated using the in situ ellipsometric measurements of the brush swelling, examination of the brush morphology with atomic force microscopy (AFM), and contact angle measurements of the brush samples extracted from aqueous solutions at different pH values. The mixed brush demonstrated a bipolar permselective behavior. At pH<3 the positively charged P2VP chains enabled the electrochemical process for the negatively charged redox probe, [Fe(CN)(6)](4-), while the redox process for the positively charged redox probe was effectively inhibited. On the contrary, at pH>6 a reversible redox process for the positively charged redox probe, [Ru(NH(3))(6)](3+), was observed, while the redox process for the negatively charged redox species, [Fe(CN)(6)](4-), was fully inhibited. Stepwise changing the pH value and recording cyclic voltammograms for the intermediate states of the polymer brush allowed electrochemical observation of the brush transition from the positively charged state, permeable for the negatively charged species, to the negatively charged state, permeable for the positively charged species. The data of ellipsometric, AFM and contact angle measurements are in accord with the electrochemical study. The discovered properties of the brush could be used for the development of 'smart' sensors and drug delivery systems, for example, a smart drug delivery capsule which could release negatively charged molecules of drugs in acidic conditions, while positively charged molecules of drugs will be released in neutral conditions.

Biofuel cell logically controlled by antigen-antibody recognition: towards immune-regulated bioelectronic devices.

A switchable biofuel cell logically controlled by immune signals was developed as a model prototype for future adaptive implantable bioelectronic devices regulated by immune reactions. The cell demonstrated NOR Boolean logic operation in situ controlled by antibody signals.

Switchable electrode controlled by Boolean logic gates using enzymes as input signals.

Application of Boolean logic operations performed by enzymes to control electrochemical systems is presented. Indium-tin oxide (ITO) electrodes with the surface modified with poly-4-vinyl pyridine (P4VP) brush were synthesized and used as switchable electrochemical systems. The switch ON and OFF of the electrode activity were achieved by pH changes generated in situ by biocatalytic reactions in the presence of enzymes used as input signals. Two logic gates operating as AND/OR Boolean functions were designed using invertase and glucose oxidase or esterase and glucose oxidase as input signals, respectively. The electrode surface coated with a shrunk P4VP polymer at neutral pH values was not electrochemically active because of the blocking effect of the polymer film. The positive outputs of the logic operations yielded a pH drop to acidic conditions, resulting in the protonation and swelling of the P4VP polymer allowing penetration of a soluble redox probe to the conducting support, thus switching the electrode activity ON. The electrode interface was reset to the initial OFF state, with the inhibited electrochemical reaction, upon in situ pH increase generated by another enzymatic reaction in the presence of urease. Logically processed biochemical inputs of various enzymes allowed reversible activation-inactivation of the electrochemical reaction.

Enzyme logic gates for the digital analysis of physiological level upon injury.

A biocomputing system composed of a combination of AND/IDENTITY logic gates based on the concerted operation of three enzymes: lactate oxidase, horseradish peroxidase and glucose dehydrogenase was designed to process biochemical information related to pathophysiological conditions originating from various injuries. Three biochemical markers: lactate, norepinephrine and glucose were applied as input signals to activate the enzyme logic system. Physiologically normal concentrations of the markers were selected as logic 0 values of the input signals, while their abnormally increased concentrations, indicative of various injury conditions were defined as logic 1 input. Biochemical processing of different patterns of the biomarkers resulted in the formation of norepiquinone and NADH defined as the output signals. Optical and electrochemical means were used to follow the formation of the output signals for eight different combinations of three input signals. The enzymatically processed biochemical information presented in the form of a logic truth table allowed distinguishing the difference between normal physiological conditions, pathophysiological conditions corresponding to traumatic brain injury and hemorrhagic shock, and abnormal situations (not corresponding to injury). The developed system represents a biocomputing logic system applied for the analysis of biomedical conditions related to various injuries. We anticipate that such biochemical logic gates will facilitate decision-making in connection to an integrated therapeutic feedback-loop system and hence will revolutionize the monitoring and treatment of injured civilians and soldiers.

Biofuel cell controlled by enzyme logic network--approaching physiologically regulated devices.

A "smart" biofuel cell switchable ON and OFF upon application of several chemical signals processed by an enzyme logic network was designed. The biocomputing system performing logic operations on the input signals was composed of four enzymes: alcohol dehydrogenase (ADH), amyloglucosidase (AGS), invertase (INV) and glucose dehydrogenase (GDH). These enzymes were activated by different combinations of chemical input signals: NADH, acetaldehyde, maltose and sucrose. The sequence of biochemical reactions catalyzed by the enzymes models a logic network composed of concatenated AND/OR gates. Upon application of specific "successful" patterns of the chemical input signals, the cascade of biochemical reactions resulted in the formation of gluconic acid, thus producing acidic pH in the solution. This resulted in the activation of a pH-sensitive redox-polymer-modified cathode in the biofuel cell, thus, switching ON the entire cell and dramatically increasing its power output. Application of another chemical signal (urea in the presence of urease) resulted in the return to the initial neutral pH value, when the O(2)-reducing cathode and the entire cell are in the mute state. The reversible activation-inactivation of the biofuel cell was controlled by the enzymatic reactions logically processing a number of chemical input signals applied in different combinations. The studied biofuel cell exemplifies a new kind of bioelectronic device where the bioelectronic function is controlled by a biocomputing system. Such devices will provide a new dimension in bioelectronics and biocomputing benefiting from the integration of both concepts.