Mucosal Ecological Network of Epithelium and Immune Cells for Gut Homeostasis and Tissue Healing.

The intestinal epithelial barrier includes columnar epithelial, Paneth, goblet, enteroendocrine, and tuft cells as well as other cell populations, all of which contribute properties essential for gastrointestinal homeostasis. The intestinal mucosa is covered by mucin, which contains antimicrobial peptides and secretory IgA and prevents luminal bacteria, fungi, and viruses from stimulating intestinal immune responses. Conversely, the transport of luminal microorganisms-mediated by M, dendritic, and goblet cells-into intestinal tissues facilitates the harmonization of active and quiescent mucosal immune responses. The bacterial population within gut-associated lymphoid tissues creates the intratissue cohabitations for harmonized mucosal immunity. Intermolecular and intercellular communication among epithelial, immune, and mesenchymal cells creates an environment conducive for epithelial regeneration and mucosal healing. This review summarizes the so-called intestinal mucosal ecological network-the complex but vital molecular and cellular interactions of epithelial mesenchymal cells, immune cells, and commensal microbiota that achieve intestinal homeostasis, regeneration, and healing.

GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.

Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.

Submicrometer Particle Impact Dynamics and Chemistry.

Experimental studies of the collision phenomena of submicrometer particles is a developing field. This review examines the range of phenomena that can be observed with new experimental approaches. The primary focus is on single-particle impact studies enabled by charge detection mass spectrometry (CDMS) implemented using the Aerosol Impact Spectrometer (AIS) at the University of California, San Diego. The AIS combines electrospray ionization, aerodynamic lens techniques, CDMS, and an electrostatic linear accelerator to study the dynamics of particle impact over a wide range of incident velocities. The AIS has been used for single-particle impact experiments on positively charged particles of diverse composition, including polystyrene latex spheres, tin particles, and ice grains, over a wide range of impact velocities. Detection schemes based on induced charge measurements and time-of-flight mass spectrometry have enabled measurements of the impact inelasticity through the determination of the coefficient of restitution, measurements of the angular distributions of scattered submicrometer particles, and the chemical composition and dissociation of solute molecules in hypervelocity ice grain impacts.

Divergent roles of estrogen receptor subtypes in regulating estrogen-modulated colonic ion transports and epithelial repair.

Although it was described previously for estrogen (E2) regulation of intestinal epithelial Cl- and HCO3- secretion in sex difference, almost nothing is known about the roles of estrogen receptor (ER) subtypes in regulating E2-modulated epithelial ion transports and epithelial restitution. Here, we aimed to investigate ERα and ERß subtypes in the regulation of E2-modulated colonic epithelial HCO3- and Cl- secretion and epithelial restitution. Through physiological and biochemical studies, in combination of genetic knockdown, we showed that ERα attenuated female colonic Cl- secretion but promoted Ca2+-dependent HCO3- secretion via store-operated calcium entry (SOCE) mechanism in mice. However, ERß attenuated HCO3- secretion by inhibiting Ca2+via the SOCE and inhibiting cAMP via protein kinases. Moreover, ERα but not ERß promoted epithelial cell restitution via SOCE/Ca2+ signaling. ERα also enhanced cyclin D1, proliferating cell nuclear antigen, and ß-catenin expression in normal human colonic epithelial cells. All ERα-mediated biological effects could be attenuated by its selective antagonist and genetic knockdown. Finally, both ERα and ERß were expressed in human colonic epithelial cells and mouse colonic tissues. We therefore conclude that E2 modulates complex colonic epithelial HCO3- and Cl- secretion via ER subtype-dependent mechanisms and that ERα is specifically responsible for colonic epithelial regeneration. This study provides novel insights into the molecular mechanisms of how ERα and ERß subtypes orchestrate functional homeostasis of normal colonic epithelial cells.

The electrical restitution of the non-propagated cardiac ventricular action potential.

Sudden changes in pacing cycle length are frequently associated with repolarization abnormalities initiating cardiac arrhythmias, and physiologists have long been interested in measuring the likelihood of these events before their manifestation. A marker of repolarization stability has been found in the electrical restitution (ER), the response of the ventricular action potential duration to a pre- or post-mature stimulation, graphically represented by the so-called ER curve. According to the restitution hypothesis (ERH), the slope of this curve provides a quantitative discrimination between stable repolarization and proneness to arrhythmias. ER has been studied at the body surface, whole organ, and tissue level, and ERH has soon become a key reference point in theoretical, clinical, and pharmacological studies concerning arrhythmia development, and, despite criticisms, it is still widely adopted. The ionic mechanism of ER and cellular applications of ERH are covered in the present review. The main criticism on ERH concerns its dependence from the way ER is measured. Over the years, in fact, several different experimental protocols have been established to measure ER, which are also described in this article. In reviewing the state-of-the art on cardiac cellular ER, I have introduced a notation specifying protocols and graphical representations, with the aim of unifying a sometime confusing nomenclature, and providing a physiological tool, better defined in its scope and limitations, to meet the growing expectations of clinical and pharmacological research.

Enteric glial cell network function is required for epithelial barrier restitution following intestinal ischemic injury in the early postnatal period.

Ischemic damage to the intestinal epithelial barrier, such as in necrotizing enterocolitis or small intestinal volvulus, is associated with higher mortality rates in younger patients. We have recently reported a powerful pig model to investigate these age-dependent outcomes in which mucosal barrier restitution is strikingly absent in neonates but can be rescued by direct application of homogenized mucosa from older, juvenile pigs by a yet-undefined mechanism. Within the mucosa, a postnatally developing network of enteric glial cells (EGCs) is gaining recognition as a key regulator of the mucosal barrier. Therefore, we hypothesized that the developing EGC network may play an important role in coordinating intestinal barrier repair in neonates. Neonatal and juvenile jejunal mucosa recovering from surgically induced intestinal ischemia was visualized by scanning electron microscopy and the transcriptomic phenotypes were assessed by bulk RNA sequencing. EGC network density and glial activity were examined by Gene Set Enrichment Analysis, three-dimensional (3-D) volume imaging, and Western blot and its function in regulating epithelial restitution was assessed ex vivo in Ussing chamber using the glia-specific inhibitor fluoroacetate (FA), and in vitro by coculture assay. Here we refine and elaborate our translational model, confirming a neonatal phenotype characterized by a complete lack of coordinated reparative signaling in the mucosal microenvironment. Furthermore, we report important evidence that the subepithelial EGC network changes significantly over the early postnatal period and demonstrate that the proximity of a specific functional population of EGC to wounded intestinal epithelium contributes to intestinal barrier restitution following ischemic injury.NEW & NOTEWORTHY This study refines a powerful translational pig model, defining an age-dependent relationship between enteric glia and the intestinal epithelium during intestinal ischemic injury and confirming an important role for enteric glial cell (EGC) activity in driving mucosal barrier restitution. This study suggests that targeting the enteric glial network could lead to novel interventions to improve recovery from intestinal injury in neonatal patients.

Ultraviolet attenuates centromere-mediated meiotic genome stability and alters gametophytic ploidy consistency in flowering plants.

Ultraviolet (UV) radiation influences development and genome stability in organisms; however, its impact on meiosis, a special cell division essential for the delivery of genetic information across generations in eukaryotes, has not yet been elucidated. In this study, by performing cytogenetic studies, we reported that UV radiation does not damage meiotic chromosome integrity but attenuates centromere-mediated chromosome stability and induces unreduced gametes in Arabidopsis thaliana. We showed that functional centromere-specific histone 3 (CENH3) is required for obligate crossover formation and plays a role in the protection of sister chromatid cohesion under UV stress. Moreover, we found that UV specifically alters the orientation and organization of spindles and phragmoplasts at meiosis II, resulting in meiotic restitution and unreduced gametes. We determined that UV-induced meiotic restitution does not rely on the UV Resistance Locus8-mediated UV perception and the Tapetal Development and Function1- and Aborted Microspores-dependent tapetum development, but possibly occurs via altered JASON function and downregulated Parallel Spindle1. This study provides evidence that UV radiation influences meiotic genome stability and gametophytic ploidy consistency in flowering plants.

Behavior and morphology combine to influence energy dissipation in mantis shrimp (Stomatopoda).

Animals deliver and withstand physical impacts in diverse behavioral contexts, from competing rams clashing their antlers together to archerfish impacting prey with jets of water. Though the ability of animals to withstand impact has generally been studied by focusing on morphology, behaviors may also influence impact resistance. Mantis shrimp exchange high-force strikes on each other's coiled, armored telsons (tailplates) during contests over territory. Prior work has shown that telson morphology has high impact resistance. I hypothesized that the behavior of coiling the telson also contributes to impact energy dissipation. By measuring impact dynamics from high-speed videos of strikes exchanged during contests between freely moving animals, I found that approximately 20% more impact energy was dissipated by the telson as compared with findings from a prior study that focused solely on morphology. This increase is likely due to behavior: because the telson is lifted off the substrate, the entire body flexes after contact, dissipating more energy than exoskeletal morphology does on its own. While variation in the degree of telson coil did not affect energy dissipation, proportionally more energy was dissipated from higher velocity strikes and from strikes from more massive appendages. Overall, these findings show that analysis of both behavior and morphology is crucial to understanding impact resistance, and suggest future research on the evolution of structure and function under the selective pressure of biological impacts.

Activation of PKC affects the ventricular restitution properties and arrhythmogenesis through L-type Ca+ current.

OBJECTIVE: To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs). METHODS AND RESULTS: Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli-extra-stimulus (S1-S2) method and dynamic S1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol-12-myristate-13-acetate (PMA) (100 nM) (n = 15) greatly steepened the restitution curves (Smax > 1) (p < .01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of Smax (p < .05) and decreased the thresholds of the VA and APD alternans (p < .01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500 nM) (n = 10), reversibly flattened the APD restitution curves at each site (Smax < 1), decreased the spatial dispersions of Smax, and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca2+ current was significantly increased by addition of PMA compared with control (CTL) group (p < .05). Antagonize this current with verapamil (n = 10) can fully inhibited the PMA induced increasing of Smax and inducibility of VA and alternans. CONCLUSION: PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca2+ influx.

Journey for a cure: Illness narratives of obstetric fistula survivors in North Central Nigeria.

Obstetric fistula is a life transforming event resulting in embodied biographical disruption. Survivors suffer myriad long-term physical and emotional consequences. This paper is an account of a narrative inquiry, conducted with 15 fistula survivors in North-central, Nigeria, who described how their identities had been transformed by their condition. A narrative therapeutic approach, using Frank's 'chaos, restitution and quest' typology, was used to map their recovery narratives. 'Chaos', described by Frank as the opposite of restitution, dominated, with women losing hope of recovery. Women's shift towards 'restitution' began with treatment, but inadequate health-care access often delayed this process. In their quest narratives, women's life and identify changes enabled them to derive meaning from their experience of obstetric fistula within the context of their own lives. The findings highlight socio-structural factors raising the risk of obstetric fistula, which in turn causes biographical disruption and hampers sufferers' treatment and recovery. Rehabilitation should include income-generating skills to bring succour to survivors, particularly those whose incontinence persists after repairs.

Responsiveness of the Reaching Performance Scale for Stroke.

OBJECTIVE: The objective of the study was to estimate the internal and external responsiveness of the Reaching Performance Scale for Stroke (RPSS) in individuals with stroke. DESIGN: Retrospective analysis of data from 4 randomized controlled trials. SETTING: Recruitment locations spanning rehabilitation centers and hospitals in Canada, Italy, Argentina, Peru, and Thailand. PARTICIPANTS: Data from 567 participants (acute to chronic stroke; N=567) were available. INTERVENTIONS: All 4 studies involved training using virtual reality for upper limb rehabilitation. MAIN OUTCOME MEASURES: RPSS and upper extremity Fugl-Meyer Assessment (FMA-UE) scores. Responsiveness was quantified for all data and across different stages of stroke. Internal responsiveness of the RPSS was quantified as effect-sizes calculated using post and preintervention change data. External responsiveness was quantified using orthogonal regressions between FMA-UE and RPSS scores. The area under the Receiver Operating Characteristic curve (AUC) was quantified based on the ability of RPSS scores to detect change above FMA-UE minimal clinically important different values across different stages of stroke. RESULTS: The RPSS had high internal responsiveness overall and across the acute or subacute and chronic stages of stroke. For external responsiveness, orthogonal regression analyses indicated that change in FMA-UE scores had positive moderate correlations with both RPSS Close and Far Target scores for all data and across the acute or subacute and chronic stages of stroke (0.6

Stories of restitution: Family experiences of diagnosis and help-seeking for a child with cerebral palsy.

BACKGROUND: The experience of living with children with CP is dominated by the voice of the mother while others are rarely reported. Incorporation of the voices of other family members is important for a holistic understanding. METHODS: Drawing on the philosophical perspectives of pragmatism, generic qualitative methodology, and Frank's narratives, this article highlights how restitution was constructed by 30 family members. FINDINGS: They constructed restitution by hoping for a cure through either biomedical and/or alternative models of treatment, followed by intransitive and transcendent restitution. DISCUSSION: This appears to be the first time that restitution has been extended to families living with children with chronic illnesses. APPLICATION TO PRACTICE: This would mean that paediatric nursing professionals and other health professionals dealing with family members living with children with CP could attend to their stories in an open and focused manner to honour and validate their stories as well as their experiences.

Assessing the quality of digital patient-therapist communication: the development and validation of a text-based facilitative interpersonal skills task.

OBJECTIVE: Text-based communication is becoming an increasingly salient feature of the psychotherapeutic landscape. Yet little is known about the factors distinguishing high- and low-quality therapeutic conversations taking place over this modality. Prior research on therapist effects has outlined several common factors associated with better clinical outcomes. But these common factors can only be researched in the context of text-based communication if they can be measured. Accordingly, we developed and validated a new behavioral task and coding system: the Facilitative Interpersonal Skills Performance Task for Text (FIS-T) to measure therapists' messaging quality across eight dimensions of facilitative interpersonal skill. METHODS: 1150 survey-takers rated the interpersonal dynamics and response difficulty of the FIS-T Task's text-based stimuli. The FIS-T was then administered to 64 therapists. RESULTS: The FIS-T stimuli displayed similar interpersonal dynamics to those elicited by the original FIS task, demonstrated a similar range of difficulties to those of the video-based stimuli of the original FIS Task, and showed high inter-rater reliability. CONCLUSIONS: The text-based FIS-T Task demonstrates high reliability and convergent validity with the original FIS Task, making it appropriate for use in assessing the common factors in text-based therapy. Future directions in the quality assessment of internet-delivered psychotherapies are discussed.

MEDICAL CONTRACTS WITH CONDITIONS CONTRARY TO PUBLIC POLICY.

OBJECTIVE: The aim: To reveal some features of medical contracts with conditions contrary to public policy. PATIENTS AND METHODS: Materials and methods: The study is based on the statutory acts of countries of European Union. The author also uses acts of international law in the field of medical services, the law and cases court practice of EU. CONCLUSION: Conclusions: The sphere of medical services objectively requires increased control by the state. There are various legal mechanisms for ensuring the rights of the patient and the proper level of medicine. It is important to invalidate the unfair terms of medical contracts, compensation for losses and moral damage. These remedies are obtained through judicial protection and, in some cases, through other jurisdictional means. It is important to implement European standards in national legislation.

miR-195 regulates intestinal epithelial restitution after wounding by altering actin-related protein-2 translation.

Early gut epithelial restitution reseals superficial wounds after acute injury, but the exact mechanism underlying this rapid mucosal repair remains largely unknown. MicroRNA-195 (miR-195) is highly expressed in the gut epithelium and involved in many aspects of mucosal pathobiology. Actin-related proteins (ARPs) are key components essential for stimulation of actin polymerization and regulate cell motility. Here, we reported that miR-195 modulates early intestinal epithelial restitution by altering ARP-2 expression at the translation level. miR-195 directly interacted with the ARP-2 mRNA, and ectopically expressed miR-195 decreased ARP-2 protein without effect on its mRNA content. In contrast, miR-195 silencing by transfection with anti-miR-195 oligo increased ARP-2 expression. Decreased ARP-2 levels by miR-195 overexpression were associated with an inhibition of early epithelial restitution, as indicated by a decrease in cell migration over the wounded area. Elevation of cellular ARP-2 levels by transfection with its transgene restored cell migration after wounding in cells overexpressing miR-195. Polyamines were found to decrease miR-195 abundance and enhanced ARP-2 translation, thus promoting epithelial restitution after wounding. Moreover, increasing the levels of miR-195 disrupted F-actin cytoskeleton organization, which was prevented by ARP2 overexpression. These results indicate that miR-195 inhibits early epithelial restitution by decreasing ARP-2 translation and that miR-195 expression is negatively regulated by cellular polyamines.

STIM1 promotes IPEC-J2 porcine epithelial cell restitution by TRPC1 signaling.

Intestinal epithelial restitution is partly dependent on cell migration, which reseals superficial wounding after injury. Here, we tested the hypothesis that stromal interaction molecule 1(STIM1) regulates porcine intestinal epithelial cell migration by activating transient receptor potential canonical 1 (TRPC1) signaling. Results showed that the knockdown of STIM1 repressed cell migration after wounding, reduced the protein concentration of STIM1 and TRPC1, and decreased the inositol trisphosphate (IP3) content in IPEC-J2 cells (p < 0.05). However, overexpression of STIM1 obtained opposite results (p < 0.05). The inhibition of TRPC1 activity by treatment with SKF96365 in cells overexpressing wild-type and mutant STIM1 attenuated the STIM1 overexpression-induced increase of cell migration, STIM1, TRPC1 and IP3 (p < 0.05). In addition, polyamine depletion caused by α-difluoromethylornithine (DFMO) resulted in the decrease of above-mentioned parameters, and exogenous polyamine could attenuate the negative effects of DFMO on IPEC-J2 cells (p < 0.05). Moreover, the overexpression of STIM1 could rescue cell migration, the protein level of STIM1 and TRPC1, and IP3 content in polyamine-deficient IPEC-J2 cells (p < 0.05). These results indicated that STIM1 could enhance porcine intestinal epithelial cell migration via the TRPC1 signaling pathway. Inhibition of cell migration by polyamine depletion resulted from the reduction of STIM1 activity.

Interpretable machine learning of action potential duration restitution kinetics in single-cell models of atrial cardiomyocytes.

Action potential duration (APD) restitution curve and its maximal slope (Smax) reflect single cell-level dynamic instability for inducing chaotic heart rhythms. However, conventional parameter sensitivity analysis often fails to describe nonlinear relationships between ion channel parameters and electrophysiological phenotypes, such as Smax. We explored the parameter-phenotype mapping in a population of 5000 single-cell atrial cell models through interpretable machine learning (ML) approaches. Parameter sensitivity analyses could explain the linear relationships between parameters and electrophysiological phenotypes, including APD90, resting membrane potential, Vmax, refractory period, and APD/calcium alternans threshold, but not for Smax. However, neural network models had better prediction performance for Smax. To interpret the ML model, we evaluated the parameter importance at the global and local levels by computing the permutation feature importance and the local interpretable model-agnostic explanations (LIME) values, respectively. Increases in ICaL, INCX, and IKr, and decreases in IK1, Ib,Cl, IKur, ISERCA, and Ito are correlated with higher Smax values. The LIME algorithm determined that INaK plays a significant role in determining Smax as well as Ito and IKur. The atrial cardiomyocyte population was hierarchically clustered into three distinct groups based on the LIME values and the single-cell simulation confirmed that perturbations in INaK resulted in different behaviors of APD restitution curves in three clusters. Our combined top-down interpretable ML and bottom-up mechanistic simulation approaches uncovered the role of INaK in heterogeneous behaviors of Smax in the atrial cardiomyocyte population.

RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration.

The airway epithelium's ability to repair itself after injury, known as epithelial restitution, is an essential mechanism enabling the respiratory tract's normal functions. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections worldwide. We sought to determine whether RSV delays the airway epithelium wound repair process both in vitro and in vivo. We found that RSV infection attenuated epithelial cell migration, a step in wound repair, promoted stress fiber formation, and mediated assembly of large focal adhesions. Inhibition of Rho-associated kinase, a master regulator of actin function, reversed these effects. There was increased RhoA and phospho-myosin light chain 2 following RSV infection. In vivo, mice were intraperitoneally inoculated with naphthalene to induce lung injury, followed by RSV infection. RSV infection delayed reepithelialization. There were increased concentrations of phospho-myosin light chain 2 in day 7 naphthalene + RSV animals, which normalized by day 14. This study suggests a key mechanism by which RSV infection delays wound healing.

Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium.

Adaptive cellular responses are often required during wound repair. Following disruption of the intestinal epithelium, wound-associated epithelial (WAE) cells form the initial barrier over the wound. Our goal was to determine the critical factor that promotes WAE cell differentiation. Using an adaptation of our in vitro primary epithelial cell culture system, we found that prostaglandin E2 (PGE2) signaling through one of its receptors, Ptger4, was sufficient to drive a differentiation state morphologically and transcriptionally similar to in vivo WAE cells. WAE cell differentiation was a permanent state and dominant over enterocyte differentiation in plasticity experiments. WAE cell differentiation was triggered by nuclear ß-catenin signaling independent of canonical Wnt signaling. Creation of WAE cells via the PGE2-Ptger4 pathway was required in vivo, as mice with loss of Ptger4 in the intestinal epithelium did not produce WAE cells and exhibited impaired wound repair. Our results demonstrate a mechanism by which WAE cells are formed by PGE2 and suggest a process of adaptive cellular reprogramming of the intestinal epithelium that occurs to ensure proper repair to injury.

Adaptation of ventricular repolarization time following abrupt changes in heart rate: comparisons and reproducibility of repeated atrial and ventricular pacing.

Adequate adaptation of ventricular repolarization (VR) duration to changes in heart rate (HR) is important for cardiac electromechanical function and electrical stability. We studied the QT and QTpeak adaptation in response to abrupt start and stop of atrial and ventricular pacing on two occasions with an interval of at least 1 mo in 25 study subjects with permanent pacemakers. Frank vectorcardiography was used for data collection. Atrial or ventricular pacing was performed for 8 min aiming at a cycle length (CL) of 500 ms. We measured the immediate response (IR), the time constant (τ) of the exponential phase, and T90 End, the time to reach 90% change of QT and QTpeak from baseline to steady state during and after pacing. During atrial pacing, the CL decreased on average 45% from mean (SD) 944 (120) to 518 (46) ms and QT decreased on average 18% from 388 (20) to 318 (17) ms. For QT, T90 End was 103 (24) s and 126 (15) s after start versus stop of atrial pacing; a difference of 24 (27) s (P = 0.006). The response pattern was similar for τ but IR did not differ significantly between pacing start and stop. The response pattern was similar for QTpeak and also for QT and QTpeak following ventricular pacing start and stop. The coefficients of variation for repeated measures were 7%-21% for T90 End and τ. In conclusion, the adaptation of VR duration was significantly more rapid following increasing than decreasing HR and intraindividually a relatively reproducible process.NEW & NOTEWORTHY We studied the duration of ventricular repolarization (VR) adaptation and its hysteresis, following increasing and decreasing heart rate by abrupt start and stop of 8-min atrial or ventricular pacing in study subjects with permanent pacemakers and repeated the protocol with ≥1 mo interval, a novel approach. VR adaptation was significantly longer following decreasing than increasing heart rate corroborating previous observations. Furthermore, VR adaptation was intraindividually a reproducible and, hence, robust phenomenon, a novel finding.