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PubMed2025

Hormetic nutrient stress promotes longevity by orchestrating histone acetylation on key lipid catabolism and antioxidant defense genes.

Exposure to low levels of environmental challenges, known as hormetic stress, such as nutrient deprivation and heat shock, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. In this study, we identified histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. The increase in H3K27ac, mediated by pioneer factor PHA-4/FOXA and cooperating transcription factor NHR-49/HNF4, is crucial for lifespan extension under hermetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch that bridges nutrient status with transcriptomic reprogramming, underpinning the pro-longevity effects of hormetic fasting through orchestrating lipid catabolism and antioxidative defenses.

Journal Article↗
PubMed2025

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Journal Article↗
PubMed1985

Incidence and management of pacemaker-related complications during dual-chamber pacing.

To evaluate the complication rate during AV universal pacing (DDD), 41 consecutive patients with complete heart block were studied and followed up for 2-30 (mean 10.8) months. The Cordis Sequicor Theta was used in 6 patients and the Siemens-Elema 674 in 35. Clinical problems related to the pacemaker treatment occurred in 12 patients (pacemaker tachycardia triggered by retrograde atrial activation in 2, atrial oversensing in 3 and undersensing in 2, ventricular oversensing in 2 and undersensing in 1). Ventricular fibrillation occurred during threshold measurement in one patient. Seven of the problems could be ascribed to the DDD mode. Four of these 7 problems could be solved by reprogramming the pacemaker. A nonprogrammable atrial refractory period in the Cordis Sequicor was found to be a limitation in patients with endless loop tachycardia. In 3 cases reoperation had to be performed. In another 3 cases there were problems with ventricular sensing which in one could be solved by reprogramming. Apart from ventricular fibrillation, which could not be ascribed to the DDD mode, there were no serious problems in the clinical management of the patients.

Adult↗
PubMed1988

Transdifferentiation of ocular tissues in larval Xenopus laevis.

Transdifferentiation phenomena offer a useful opportunity to study experimentally the mechanisms on which cell phenotypic stability depends. The capacities of vertebrate eye tissues to reprogram cell differentiation are well known in avian and mammalian embryos, and in larval and adult newt. From research into the capacity of anuran eye tissues to reprogram differentiation into a new pathway, considerable data have accumulated concerning the transdifferentiative capacities of eye tissues in larval Xenopus laevis. This work reviews the data concerning the transdifferentiative phenomena of eye tissues in that species and, based on these, aims to establish the extent of our knowledge about the mechanism controlling these processes. In larval Xenopus laevis the outer cornea can regenerate a lens by a lens-transdifferentiation process triggered and substained by a factor(s), probably of a protein nature, produced by the neural retina. In a normal eye phenotypic stability of the outer cornea is guaranteed by the presence of the inner cornea and lens, which prevent the spread of retinal factor(s). The stimulus for lens transdifferentiation of the outer cornea can be supplied by other tissues as well, but this capacity is not widely distributed. The iris and retinal pigmented epithelium can transdifferentiate into neural retina if isolated from the surrounding tissues and implanted in the vitreous chamber. As for lens transdifferentiation of the outer cornea, retinal transdifferentiation of the iris can be stimulated by certain nonocular tissues as well.

Animals↗
PubMed1981

Short-term threshold behavior of human ventricular pacing electrode: noninvasive monitoring with a multiprogrammable pacing system.

Twenty-two patients were studied for 8 to 12 weeks following pacemaker implantation. A unipolar multiprogrammable pacing system was used to assess and compensate for early post-implant changes in pulse width threshold (PWT). Changes in PWT were estimated by noninvasive measurements of the lowest pulse width required for 100% capture at constant voltage. All patients showed an early increase in PWT. The magnitude of this change was unpredictable and ranged from 2- to 10-fold. For pacing, we selected an appropriate margin of safety to be a pulse width three times the PWT. During the study period, 4 patients showed critical increases in PWT, requiring reprogramming to an increased pulse width as above, whereas only one patient required lead repositioning. The majority of patients achieved a stable low PWT and were reprogrammed to a reduced pulse width. The programmable pacing system provides a safe accurate technique for monitoring early changes in PWT, defines the need for appropriate alterations in programmable functions, decreases the risk of early pacemaker failure, and offers promise for improved pacemaker longevity in many patients.

Aged↗
PubMed1982

Induction of ventricular tachycardia by pacemaker programming.

The induction of ventricular tachycardia or ventricular fibrillation by competitive pacing, especially in the setting of acute myocardial ischemia, is well known. A case of ventricular tachycardia induced by a multiprogrammable unipolar cathodal ventricular pacemaker is reported. The arrhythmia was caused by reprogramming, which necessitates a short switch to fixed rate pacing in this model (Spectrax 5985 SX). This potential hazard is not well established in patients with unipolar pacemakers. The use of the magnet as one of the preconditions for reprogramming should be avoided in future pacemakers.

Bradycardia↗
PubMed1984

Apparent pacemaker failure due to reversion circuitry within the programming device.

While being evaluated for a recurrent tachyarrhythmia, a patient with a permanent pacemaker underwent reprogramming of the unit from the DVI to the VVI mode for assessment of the underlying rhythm. Subsequent reprogramming of the pacemaker to the DVI or DDD mode was impossible despite multiple attempts and the use of multiple programmers. The problem was considered to be a malfunction of the pacemaker circuitry, and plans were made for the pacemaker to be explanted and a replacement unit implanted. Before the procedure, the pacemaker company was notified of the explantation. We subsequently learned that a special programming sequence had to be carried out because of reversion circuitry present in the pacemaker but not described in the available literature. This report emphasizes the need for familiarity with each of the individual pacemakers being implanted and the need for the manufacturer to be as specific as possible given the complexity of current units.

Equipment Design↗
PubMed1985

Reversion mode activation by myopotential sensing in a ventricular inhibited demand pacemaker.

Pacemaker follow-up in a 72-year-old woman revealed occasional failure to sense and pace, which was confirmed by Holter monitor. Neither reprogramming the pacemaker sensitivity nor repositioning the lead resolved the problem. A recheck of the Holter recordings revealed pacing and sensing failures were concurrent with "baseline artifact," suggestive of myopotentials. Furthermore, the inappropriate pacing spikes occurred at a rate of 90 pulses per minute (ppm). It was theorized that myopotential sensing was alternately inhibiting the pacer and activating the reversion mode, an asynchronous rate of 90 ppm. Reprogramming the unit to a lower sensitivity restored normal pacer function.

Aged↗
PubMed1986

Pacemaker follow-up: its role in the detection and correction of pacemaker system malfunction.

The goal of pacemaker follow-up is not only to detect battery depletion but also to detect all malfunctions of the pacing system and, when possible, to correct such problems using programming. During one year, we discovered 61 such malfunctions in a clinic of 1065 patients (5.7%). These were more frequent in the first year (7.7%) than in the third to fifth years of follow-up (range 3.1-4.8%). The incidence rose again in the sixth and subsequent years (7-7.7%). Despite a significant occurrence of malfunctions (5.2%) among multiprogrammable pacemakers, the necessity for operative intervention for their correction was low (1.2%). Sensing problems were the most common (57%) and the most likely to be corrected by reprogramming (85%); problems involving loss of capture were less likely to be corrected by programming (38.5%). Battery depletion accounted for only 18% of malfunctions, occurring earliest in the forty-third month of follow-up. Pulse generator longevity of those devices reaching end of battery life during the study period was 68.6 +/- 16.7 months (mean + SD). We conclude that specialized pacemaker follow-up continues to be necessary despite improved pulse generator reliability and longevity. Indeed, with reprogramming, it presently plays an even more important role than in the past. Follow-up should be oriented not only to the detection of battery depletion but also toward a comprehensive surveillance of pacemaker system function.

Equipment Failure↗
PubMed1986

Superiority of multiprogrammable to nonprogrammable VVI pacing: a comparative study with special reference to management of pacing system malfunctions.

Analysis of pacing system malfunctions was performed in 374 patients at initial implantation or at pulse generator and lead replacement during a period of 55 months. A total of 150 nonprogrammable pacemakers were implanted in 148 patients, while 236 multiprogrammable pacemakers were implanted in 226 patients. The purpose of the analysis was to investigate the occurrence and management of malfunction unrelated to pacemaker/lead failure or lead dislodgement. The nonprogrammable group was followed for 3-53 months (median, 36). Malfunction occurred in 18 patients (12.0%): muscle stimulation in 14; exit block in three; sensing problem in one. Surgical correction was necessary in 14 of 18 cases. The multiprogrammable group was followed for 3-52 months (median, 12). Malfunction occurred in 30 cases (12.7%): muscle stimulation in 22; threshold increase in seven; sensing problem in one. Only seven of these patients required surgical correction as 23 cases were successfully managed by reprogramming alone. Malfunctions occurred during a period of several days to 36 months (median, 2.3 months). The difference in rate of secondary surgical intervention was significant (p less than 0.01). Measurements during reoperation in the nonprogrammable group showed that at least 40% of late malfunctions would have been correctable by reprogramming alone. Thus, multiprogrammability is of significant value for noninvasive correction of malfunctions unrelated to pacemaker and lead failures, predominantly muscle stimulation and threshold elevation.

Aged↗
PubMed1987

The effects of extracorporeal shock wave lithotripsy on pacemaker function.

Twenty-two pacemaker pulse generators were exposed to shock waves of an extracorporeal shock wave lithotripter to assess the effects of the extremely high pressure transients on pacemaker function. The pulse generator and distal aspect of the lead were positioned 5 cm from the focal point of the lithotripter and 10 cm from each other. Pulse generator function was analyzed during shock wave delivery synchronized with pulse generator output, during shock waves at a rate faster than the escape rate, and after exposure to lithotripsy. During shock waves delivered synchronously with pulse generator output, only one of 22 pulse generators malfunctioned by intermittently reverting to the magnet rate. When subjected to shock waves at a rate greater than the escape rate, 50% of the pulse generators were inhibited by electromechanical interference from the lithotripter. Both bipolar and unipolar devices were affected. However, analysis after exposure to shock waves showed that none of the pacemakers was damaged or spuriously reprogrammed. In conclusion, cardiac pacemakers do not appear to be damaged or reprogrammed by exposure to extracorporeal shock wave lithotripsy. The likelihood of false inhibition appears to be very low if shock waves are delivered synchronously with the QRS.

Equipment Failure↗
PubMed1988

Automatic implantable defibrillator discharge resulting from routine pacemaker programming.

A middle-aged gentleman with an idiopathic dilated cardiomyopathy, drug-refractory sustained ventricular arrhythmia, and high-degree AV block was managed with an automatic implantable cardioverter-defibrillator (AICD) and a Cordis Multicor II VVI pacemaker. During a routine follow-up visit, the pacemaker threshold was determined. Seven seconds after reprogramming the Cordis pacemaker to the "stat" VVI mode, the AICD discharged. The time to discharge after reprogramming the pacemaker equalled the previously determined AICD charge time. No other rhythm disturbance was documented and the rate with double counting of pacemaker stimulus and QRS complex was less than the triggering rate for the AICD. In conclusion, the AICD can be triggered by pacemaker programming signals unrelated to subsequent pacemaker function.

Electric Countershock↗
PubMed1988

Effects of extracorporeal shock wave lithotripsy on cardiac pacemakers and its safety in patients with implanted cardiac pacemakers.

UNLABELLED: Effects of extracorporeal shock wave lithotripsy (ESWL) were studied on 15 pacemakers (standard single chamber n = 5, dual chamber n = 6, rate responsive single chamber [Activitrax] n = 4). In-vitro testing involved suspending the pacemakers in a bath of degassified, deionized water firmly taped to a platform at the point of maximal pressure, i.e., second focal point (F2), where they received pressure shocks (means = 1300) from the HM3 Dornier lithotriptor. The pacemakers, programmed to their most sensitive setting, were continuously pacing at nominal outputs (atrial and ventricular pacing in the DDD mode). All units were assessed by a pacing system analyzer before and after the study, then underwent destructive analysis. During standard single chamber pacing (VVI) the pacing stimulus triggered ESWL. For dual chamber devices, ESWL was triggered by the atrial paced event which induced inhibition of the ventricular output in two pacemaker. This was eliminated by reprogramming to a less sensitive setting. The pacemaker can, hermetic seal and internal circuitry were undamaged in all units. Two rate responsive single chamber pacemakers had their activity sensing piezoelectric elements shattered when placed at F2. Two other units placed 5 cm from F2 were stimulated to their maximum upper programmed pacing rate with ESWL therapy, but were otherwise unaffected. Subsequent to this study, six patients with pacemakers programmed to the VVI (five), DDD (one) modes implanted in the thorax underwent successful ESWL without pacemaker or arrhythmic event. CONCLUSIONS: (A) It is generally safe for patients implanted with standard single chamber devices in a ventricular application to undergo ESWL without modifying the pacing/sensing parameters. (B) Patients implanted with dual chamber devices who pace in the atrium should be reprogrammed to the VVI mode during ESWL. (C) Patients with piezoelectric activity sensing rate responsive single chamber pacemakers should have this feature programmed off during ESWL and, if implanted in the abdomen, probably should not undergo ESWL.

Aged↗
PubMed1988

A new algorithm for a high level of protection against pacemaker-mediated tachycardia.

Pacemaker-mediated tachycardia (PMT) is a well-known complication of DDD pacing. PMT needs a permeable V-A conduction and is usually initiated by a premature ventricular or atrial systole, artifact sensing, or misprogramming (long AV delay [AVD]). Today, protection against PMT is expected from pacemaker multiprogrammability. Unfortunately, this prevention is often ineffective; postventricular atrial refractory period (PVARP) must be prolonged, which limits the upper tracking rate and the patient capacity. The new Chorus ELA Medical DDD pacemaker provides classic protection against PMT (PVARP prolongation after premature V or A complex, magnet application, noise sensing), but also automatically reduces an eventual PMT and adjusts AVD or PVARP for a high level of protection. The process is divided in four steps: (1) a sensing step for 16 cycles, with V-P conduction analysis; (2) confirmation of the presence of the PMT and analysis of V-A conduction time; (3) a termination step, by extending the PVARP after the following ventricular heart beat; and (4) in case of immediate recurrence of the tachycardia, reprogramming of the AVD and eventually of the PVARP. By first reducing AVD, before reprogramming PVARP, the pacemaker preserves point 2:1, providing a higher exercise capacity. This algorithm was successfully tested in three patients who had a permeable V-A conduction, without any adverse effect.

Algorithms↗
PubMed1988

DDD pacemakers maximize hemodynamic benefits and minimize complications for most patients.

A 44-month retrospective analysis was performed on 666 pacemakers implanted at Mt. Sinai Medical Center. Mapping techniques and endocardial waveform analyses were used during lead positioning to ensure the best electrical environment. The optimal pacing lead type was selected based on the clinical situation. Follow-up evaluations were rigorous. Patient population ranged in age from 28 to 103 with a mean of 78 years at time of implant. Seventy percent of the patients received DDD pacemakers with an 81% survival incidence at 44 months. Of the VVI population (30% of the implants), there was a 62% survival incidence. Most problems associated with the pacing systems were related to the atrial channel. Loss of atrial sensing occurred in 7.5% of the population and was corrected noninvasively in 5.8%. Due to chronic loss of atrial sensing, 1.7% of the population remained programmed to DVI/VVI. A total of 7.7% were chronically reprogrammed from DDD to VVI, 5.6% secondary to atrial fibrillation. Reoperations were necessary in 1.2% of the malfunctioning systems that could not be corrected by reprogramming. The following conclusions were reached: (1) maximizing hemodynamic benefits and minimizing pacemaker complications permitted a survival rate equal to or better than that of the general population, and (2) chronic problems related to the atrial lead and malfunctions of the pacing system were minimized by careful patient selection, appropriate pacemaker and lead selection, endocardial waveform analysis, and thorough follow-up.

Adult↗
PubMed1991

Long-term pacing in heart transplant recipients is usually unnecessary.

The indications for and timing of permanent pacing were reviewed in all 17 of 154 adult heart transplant recipients at this center who have had permanent pacemakers implanted. Resting 12-lead ECGs recorded during routine follow-up were examined. A prospective study of pacing requirement was then undertaken. Holter monitoring was performed before and after reprogramming the pacemakers to VVI mode at 50 beats/min. Exercise responses in various pacing modes were then assessed in seven patients with rate responsive pacemakers using a standard Bruce protocol treadmill test. The indication for pacing was sinus node dysfunction in 59% (10/17) and atrioventricular (AV) block in 41% (7/17). The majority of pacemakers were implanted between seven and 21 days after transplantation. There was a progressive reduction in the frequency of pacing on 12-lead ECGs with time after transplantation. There was a progressive reduction in the frequency of pacing on 12-lead ECGs with time after transplantation. Eight of 14 patients with empirically selected programming paced during Holter monitoring. After reprogramming to 50 beats/min VVI mode only three of 14 patients, all with sinus node dysfunction, paced. Rate responsive pacing made no difference to exercise time. The requirement for long-term pacing in cardiac transplant recipients is small (3/154) and is limited to patients with sinus node dysfunction. Rate responsive pacing did not increase exercise tolerance.

Adult↗
PubMed1994

DDI pacing: indications, expectations, and follow-up.

The DDI mode of pacing that permits noncompetitive atrioventricular sequential bradycardia support was chosen in 65 of 480 (14%) patients selected for dual chamber pacing between February 1985 and March 1990. All patients were implanted with Pacesetter 283 or 285 pulse generators and programmed to DDI. The indications for pacing were sick sinus syndrome (n = 52), combined sinus node dysfunction and AV block (n = 13). Forty-two of these patients had a history of paroxysmal atrial arrhythmias. All patients received passive fixation atrial and ventricular leads. Follow-up thereafter was performed predischarge, and at 6 weeks, 3 and 6 months after discharge. The duration of follow-up ranged from 1-61 months (mean 31 months). Fifty-four of 65 (83%) patients chosen for DDI remain programmed in the DDI mode. Three patients were reprogrammed to VVI and eight to DDD. During the course of follow-up, six patients presented with effective VVI pacing with consistent ventriculoatrial conduction that was appropriately sensed by the atrial circuit with atrial output inhibition. A further four patients presented with "functional undersensing" due to ventricular blanking period (VBP) characteristics in these pulse generators and in this mode. Functional undersensing was eliminated in all but one patient by reprogramming the VBP to 13 msec with no subsequent episodes of provoked crosstalk inhibition. Effective VVI pacing was observed in patients with AV block during times of sinus acceleration.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Long-term stability of P wave sensing in single lead VDDR pacing: clinical versus subclinical atrial undersensing.

Optimal function of a single lead P wave synchronous rate adaptive ventricular pacing system (VDDR) requires reliable P wave sensing over time and during daily activities. The stability of P wave sensing and the incidence of sensitivity reprogramming in a single pass lead with a diagonally arranged bipole was assessed in 30 patients with complete atrioventricular block over a follow-up period of 12 +/- 1 months (range 6 months to 3 years). Atrial sensing was assessed during clinic visits, by physical maneuvers (postural changes, breathing, Valsalva maneuver, walking and isometric exercise), maximum treadmill exercise and Holter recordings. P wave amplitude at implantation was 1.21 +/- 0.09 (0.5-3.6) mV, and the atrial sensing threshold remained stable over the entire period of follow-up. Using an atrial sensitivity based on twice the sensing threshold at 1 month, P wave undersensing was found in 2, 4, 3, and 7 patients during clinic visit, physical maneuvers, exercise, and Holter recordings, respectively. Atrial sensitivity reprogramming was performed in three patients based on the correction of undersensing during physical maneuvers. Although eight patients had atrial undersensing on Holter recordings, the number of undersensed P waves was small (total 101 beats or 0.013% +/- 0.001% of total ventricular beats) and no patient was symptomatic. One patient had intermittent atrial undersensing at the highest sensitivity, but the VDDR mode was still functional most of the time. No patient had myopotential interference at the programmed sensitivity. One patient developed chronic atrial fibrillation and was programmed to the VVIR mode. Thus, single lead VDDR pacing is a stable pacing mode in 97% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗