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The antibiotic diaminodiphenyl sulfone (DDS) is used in combination with other antibiotics as a first line treatment for leprosy. DDS has been previously reported to extend lifespan in Caenorhabditis elegans through inhibition of pyruvate kinase and decreased mitochondrial function. Here we report an alternative mechanism of action by which DDS promotes longevity in C. elegans by reducing folate production by the microbiome. This results in altered methionine cycle metabolite levels mimicking the effects of metformin and lifespan extension that is dependent on the starvation- and hypoxia-induced flavin containing monoxygenase, FMO-2.

Purpose Descriptions of large series of accessory atrioventricular pathway (AP) ablations in adults and adolescents have been limited to referral centers and published over 20 years ago. We aimed to characterize contemporary accessory AP distribution and features in a large community-based population that influence ablation outcomes. Methods Retrospective analysis of 289 patients (age 14–81) who underwent AP ablation from 2015–2019 was performed. Pathways were categorized into anteroseptal (AS), left freewall (LFW), posteroseptal (PS), and right freewall (RFW) locations. We analyzed patient and pathway features to identify factors associated with prolonged procedure time parameters. Results Initial ablation success rate was 94.7% with long-term success rate of 93.4% and median follow-up of 931 days. APs were in LFW (61.6%), PS (24.6%), RFW (9.6%), and AS (4.3%) locations. Procedure outcome was dependent on pathway location. Acute success was highest for LFW pathways (97.1%) with lowest case times (144 ± 68 minutes) and fluoroscopy times (15 ± 19 minutes). Longest procedure time parameters were seen with AS, left anterolateral, epicardial-coronary sinus, and right anterolateral pathway ablations. A novel ECG algorithm was developed to predicts AP locations and further guide procedure planning. Conclusion In this community-based population, majority of APs are located in the left freewall and posteroseptal region, with only retrograde conduction, and can be ablated using traditional approaches with short time parameters and high success. Using a novel ECG algorithm for pathway localization, we can predict cases with longer procedure times, higher fluoroscopy exposure, and lower acute and long-term success for manifest pathways.

OBJECTIVE To investigate mechanisms by which atrial fibrillation (AF) may terminate during ablation near the pulmonary veins before the veins are isolated (PVI). INTRODUCTION It remains unstudied how AF may terminate during ablation before PVs are isolated, or how patients with PV reconnection can be arrhythmia-free. We studied patients in whom PV antral ablation terminated AF before PVI, using two independent mapping methods. METHODS We studied patients with AF referred for ablation, in whom biatrial contact basket electrograms were studied by both an activation/phase mapping method and by a second validated mapping method reported not to create false rotational activity. RESULTS In 22 patients (age 60.1 ± 10.4, 36% persistent AF), ablation at sites near the PVs terminated AF (77% to sinus rhythm) prior to PVI. AF propagation revealed rotational (n = 20) and focal (n = 2) patterns at sites of termination by mapping method 1 and method 2. Both methods showed organized sites that were spatially concordant (P

Objectives The purpose of this study was to determine the mechanistic overlap between paroxysmal and persistent forms of atrial fibrillation (AF), focusing on AF sources as a classification approach. Background The role of AF substrates is unclear in patients with paroxysmal AF (PAF) that recurs after pulmonary vein isolation (PVI). We hypothesized that patients with recurrent post-ablation (redo) PAF despite PVI have electrical substrates marked by rotors and focal sources and structural substrates that resemble persistent AF more than patients with (de novo) PAF at first ablation. Methods In 175 patients at 11 centers, we compared AF substrates in both atria using 64-pole basket catheters and phase mapping, and indices of anatomical remodeling between patients with de novo or redo PAF and first ablation for persistent AF. Results Sources were seen in all patients. More patients with de novo PAF (78.0%) had sources near pulmonary veins (PVs) than patients with redo PAF (47.4%; p = 0.005) or persistent AF (46.9%; p = 0.001). The total number of sources per patient (p = 0.444), and number of non-PV sources (p = 0.701) were similar between groups, indicating that redo PAF patients had residual non-PV sources after elimination of PV sources by prior PVI. Structurally, left atrial size did not separate de novo from redo PAF (49.5 ± 9.5 mm vs. 49.0 ± 7.1 mm; p = 0.956) but was larger in patients with persistent AF (55.2 ± 8.4 mm; p = 0.001). Conclusions Patients with PAF despite prior PVI show electrical substrates that resemble persistent AF more closely than patients with PAF at first ablation. Notably, these subgroups of PAF are indistinguishable by structural indices. These data motivate studies of trigger versus substrate mechanisms for patients with recurrent PAF after PVI.

Aims Focal Impulse and Rotor Modulation (FIRM) uses 64-electrode basket catheters to identify atrial fibrillation (AF)-sustaining sites for ablation, with promising results in many studies. Accordingly, new basket designs are being tested by several groups. We set out to determine the procedural safety of adding basket mapping and map-guided ablation to conventional pulmonary vein isolation (PVI). Methods and results We collected 30 day procedural safety data in five US centres for consecutive patients undergoing FIRM plus PVI (FIRM-PVI) compared with contemporaneous controls undergoing PVI without FIRM. A total of 625 cases were included in this analysis: 325 FIRM-PVI and 300 PVI-controls. FIRM-PVI patients were more likely than PVI-controls to be male (83% vs. 66%, P

Inspired by the relatively simple morphological blueprint provided by batoid fish such as stingrays and skates, we created a biohybrid system that enables an artificial animal—a tissue-engineered ray—to swim and phototactically follow a light cue. By patterning dissociated rat cardiomyocytes on an elastomeric body enclosing a microfabricated gold skeleton, we replicated fish morphology at 1 10 scale and captured basic fin deflection patterns of batoid fish. Optogenetics allows for phototactic guidance, steering, and turning maneuvers. Optical stimulation induced sequential muscle activation via serpentine-patterned muscle circuits, leading to coordinated undulatory swimming. The speed and direction of the ray was controlled by modulating light frequency and by independently eliciting right and left fins, allowing the biohybrid machine to maneuver through an obstacle course.

Background: The mechanisms by which persistent atrial fibrillation (AF) terminates via localized ablation are not well understood. To address the hypothesis that sites where localized ablation terminates persistent AF have characteristics identifiable with activation mapping during AF, we systematically examined activation patterns acquired only in cases of unequivocal termination by ablation. Methods and Results: We recruited 57 patients with persistent AF undergoing ablation, in whom localized ablation terminated AF to sinus rhythm or organized tachycardia. For each site, we performed an offline analysis of unprocessed unipolar electrograms collected during AF from multipolar basket catheters using the maximum –dV/dt assignment to construct isochronal activation maps for multiple cycles. Additional computational modeling and phase analysis were used to study mechanisms of map variability. At all sites of AF termination, localized repetitive activation patterns were observed. Partial rotational circuits were observed in 26 of 57 (46%) cases, focal patterns in 19 of 57 (33%), and complete rotational activity in 12 of 57 (21%) cases. In computer simulations, incomplete segments of partial rotations coincided with areas of slow conduction characterized by complex, multicomponent electrograms, and variations in assigning activation times at such sites substantially altered mapped mechanisms. Conclusions: Local activation mapping at sites of termination of persistent AF showed repetitive patterns of rotational or focal activity. In computer simulations, complete rotational activation sequence was observed but was sensitive to assignment of activation timing particularly in segments of slow conduction. The observed phenomena of repetitive localized activation and the mechanism by which local ablation terminates putative AF drivers require further investigation.

Introduction Atrial fibrillation (AF) often converts to and from atrial tachycardia (AT), but it is undefined if these rhythms are mechanistically related in such patients. We tested the hypothesis that critical sites for AT may be related to regional AF sources in patients with both rhythms, by mapping their locations and response to ablation on transitions to and from AF. Methods From 219 patients undergoing spatial mapping of AF prior to ablation at 3 centers, we enrolled 26 patients in whom AF converted to AT by ablation (n=19) or spontaneously (n=7; left atrial size 42±6cm, 38% persistent AF). Both atria were mapped in both rhythms by 64-electrode baskets, traditional activation maps and entrainment. Results Each patient had a single mapped AT (17 reentrant, 9 focal) and 3.7±1.7 AF sources. The mapped AT spatially overlapped one AF source in 88% (23/26) of patients, in left (15/23) or right (8/23) atria. AF transitioned to AT by 3 mechanisms: (a) ablation anchoring AF rotor to AT (n=13); (b) residual, unablated AF source producing AT (n=6); (c) spontaneous slowing of AF rotor leaving reentrant AT at this site without any ablation (n=7). Electrogram analysis revealed a lower peak-to-peak voltage at overlapping sites (0.36±0.2mV vs 0.49±0.2mV p=0.03). Conclusions Mechanisms responsible for AT and AF may arise in overlapping atrial regions. This mechanistic inter-relationship may reflect structural and/or functional properties in either atrium. Future work should delineate how acceleration of an organized AT may produce AF, and whether such regions can be targeted a priori to prevent AT recurrence post AF ablation.

Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity., Author summary There are a growing number of studies linking mitochondrial dysfunction to enhanced longevity, especially in the nematode C. elegans. The reasons for these pro-longevity effects have been elusive, but one current model is that adaptive responses to mitochondrial inhibition promote organismal health and stress resistance. Here, we report an intriguing example of mitochondrial stress induced by inhibition of a cytosolic metabolic pathway that extends lifespan in worms. We find that inhibition of the pentose phosphate pathway, which is essential for cytosolic redox homeostasis, affects multiple parameters of mitochondrial function and activates a starvation-like response that promotes longevity through recycling of damaged cellular components and induction of the enzyme flavin-containing monooxygenase 2. These results establish novel links between the pentose phosphate pathway, mitochondrial function, redox homeostasis, and organismal aging.

We thank Dr. Mohanty and colleagues for their letter concerning our study [(1)][1]. Their philosophy that it is unnecessary to map paroxysmal atrial fibrillation (AF) highlights our central point that “paroxysmal” or “persistent” encompasses heterogeneous AF populations who are often

Introduction: Increasing studies find human AF is driven by rotors, but their detection remains challenging. Theoretically, rotor cores display low amplitude and multiphasic signals, but human AF rotors fail to display such signatures. This may reflect rotor precession (obscuring analysis site chosen), poor basket contact or bipoles (that do not register orthogonal wavefronts). We hypothesized that studying unipolar signals at rotor precession areas may reveal hitherto hidden electrogram signatures. Methods: We studied 22 persistent AF patients (60±11 years, CHADS2=1.9), in whom phase mapping of 64 pole basket signals revealed rotors/sources where ablation terminated AF (fig A). Unipolar electrograms over the rotor precession area were measured by 3 blinded observers for spectral dominant frequency (DF), peak-to-peak amplitude and duration. This was compared to a paired source in each patient where ablation did not terminate AF (‘controls’) (fig B). Results: Patients had 3.3±1.7 AF rotor/focal sources. At the index source, AF terminated to sinus rhythm (n=14) or atrial tachycardia by targeted ablation (mean 4.0 mins). Compared to control areas, AF sustaining rotors/sources had lower amplitude (fig C) (0.60±0.30mV vs. 0.87±0.70mV, p=0.02). Conversely, electrogram spectra (90±45Hz vs. 80±46Hz, p=ns), duration (125±45ms vs. 116±47ms, p=ns) and AF cycle length (174±8ms vs. 174±6ms, p=ns) did not differ. Conclusions: Rotors/sources that maintain human persistent AF have lower unipolar amplitude than non-termination sites. This is the first identified electrogram signature for functionally critical human AF rotors, and motivates definition of structure/function correlations at these sites.

Introduction: The mechanisms maintaining human persistent AF are elusive. It is striking how most optical mapping studies in animal and recently human AF show rotors and focal sources, while most classical activation mapping studies of electrograms do not. We tested the hypothesis that sites in human persistent AF showing rotors by phase analysis may, due to precession (‘wobble’) and fibrillatory collision, rarely reveal sources in activation maps. Methods: We studied 25 patients with persistent AF (LA 47 mm, CHADS2=1.9), in whom phase-mapping of electrograms from 64 pole baskets revealed rotors/focal sources where ablation terminated AF. Electrograms (fig A) were annotated (Matlab) using minimum dV/dt (unipoles, fig B) and peak amplitude criteria (bipoles) to create contours (isochrones), that were classified into a) complete, b) partial or c) unresolvable sources. Results: In each case, ablation at phase-identified rotors/sources (4.0±5.7 mins) terminated persistent AF to sinus rhythm (fig C, 64%) or atrial tachycardia. Notably, isochrones detected sources in only 5/25 (20%) of cases (fig D), more easily in unipolar than bipolar signals. Isochrones revealed partial sources in 11 (44%) and were unresolvable in 9 (36%). Source detection in classical maps was obscured by low signal: noise, varying sequence (rotor precession), or electrode noise that phase analysis resolved by analyzing neighboring sites (fig E). The figure summarizes these steps for a case with perfect agreement between activation and phase maps. Conclusions: Rotors and focal sources for human persistent AF detected by phase analysis were mostly undetected in activation maps, due to rotor precession and fibrillatory conduction. These data may inform approaches to revise classical criteria to better map AF.

The response to osmotic stress is a highly conserved process for adapting to changing environmental conditions. Prior studies have shown that hyperosmolarity by addition of sorbitol to the growth medium is sufficient to increase both chronological and replicative lifespan in the budding yeast, Saccharomyces cerevisiae. Here we report a similar phenomenon in the nematode Caenorhabditis elegans. Addition of sorbitol to the nematode growth medium induces an adaptive osmotic response and increases C. elegans lifespan by about 35%. Lifespan extension from 5% sorbitol behaves similarly to dietary restriction in a variety of genetic backgrounds, increasing lifespan additively with mutation of daf-2(e1370) and independently of daf-16(mu86), sir-2.1(ok434), aak-2(ok524), and hif-1(ia04). Dietary restriction by bacterial deprivation or mutation of eat-2(ad1113) fails to further extend lifespan in the presence of 5% sorbitol. Two mutants with constitutive activation of the osmotic response, osm-5(p813) and osm-7(n1515), were found to be long-lived, and lifespan extension from sorbitol required the glycerol biosynthetic enzymes GPDH-1 and GPDH-2. Taken together, these observations demonstrate that exposure to sorbitol at levels sufficient to induce an adaptive osmotic response extends lifespan in worms and define the osmotic stress response pathway as a longevity pathway conserved between yeast and nematodes.

Gene expression profiling was carried out comparing Con A elicited peritoneal macrophages from C57BL/6 and FVB/N wild-type and apolipoprotein (apo)E knockout mice. An EST, W20829 , was expressed at higher levels in C57BL/6 compared with FVB/N mice. W20829 mapped to an atherosclerosis susceptibility locus on chromosome 19 revealed in an intercross between atherosclerosis-susceptible C57BL/6 and atherosclerosis-resistant FVB/N apoE knockout mice. A combination of database search and Northern analysis confirmed that W20829 corresponded to 3′-UTR of a hitherto predicted gene, named HspA12A . Blasting the National Center for Biotechnology Information database revealed a closely related homologue, HspA12B . HspA12A and -B have very close human homologues. TaqMan analysis confirmed the increased HspA12A expression (2.6-fold) in elicited peritoneal macrophages from C57BL/6 compared with FVB/N mice. TaqMan analysis also revealed increased HspA12A and HspA12B expression (87- and 6-fold, respectively) in lesional versus nonlesional portions of the thoracic aorta from C57BL/6 apoE knockout mice on a chow diet. In situ hybridization confirmed that both genes were expressed within lesions but not within nonlesional aortic tissue. Blasting of HspA12A and HspA12B against the National Center for Biotechnology Information database (NR) revealed a hit with the Conserved Domain database for Hsp70 (pfam00012.5, Hsp70). Both genes appear to contain an atypical Hsp70 ATPase domain. The BLAST search also revealed that both genes were more similar to primitive eukaryote and prokaryote than mammalian Hsp70s, making these two genes distant members of the mammalian Hsp70 family. In summary, we describe two genes that code for a subfamily of Hsp70 proteins that may be involved in atherosclerosis susceptibility.