Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway.

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.

Balloon Eustachian Tuboplasty Combined or Not with Myringotomy in Eustachian Tube Dysfunction.

BACKGROUND: Eustachian tube dysfunction (ETD) is a common disorder causing ear pressure, pain, and hearing loss. Balloon Eustachian tuboplasty (BET) is an emerging technique for dilating the Eustachian tube and treating ETD. Whether adding myringotomy improves BET efficacy is controversial. METHODS: This retrospective study included 95 ETD patients undergoing BET alone (n = 44) or BET with myringotomy (BET + M; n = 51) between June 2020 and August 2021 at a single medical center. The primary outcome was the change in ETDQ-7 symptom scores from baseline to 6 months after treatment. Secondary outcomes included audiometry, endoscopy, Valsalva maneuver, and complications. RESULTS: The ETDQ-7 scores improved significantly after treatment in both groups (p < 0.001), without significant between-group differences (p = 0.417). No significant differences occurred in the audiometry, endoscopy, and Valsalva results or in most complications between groups. One BET + M patient had a persistent tympanic membrane perforation. CONCLUSIONS: Both BET alone and BET + M effectively and safely improved the subjective and objective ETD outcomes. However, adding myringotomy did not further improve the outcomes over BET alone, while it incurred risks such as persistent perforation. BET alone may sufficiently treat ETD without requiring myringotomy in this cohort. Further randomized controlled trials should identify optimal candidates for BET alone versus combined approaches.

Early Experience of Patients with left Bundle Branch Block Corrected through Left Bundle Branch Area Pacing Compared with Conventional Right Ventricular Pacing: A Single-Center Retrospective Study.

Background: Left bundle branch area pacing (LBBAP) has the advantages of narrow QRS duration, rapid peak left ventricular (LV) activation, and LV dyssynchrony correction with a low, stable pacing output. Here we report our experience with patients undergoing LBBAP with a left bundle branch block (LBBB) for clinically indicated pacemaker or cardiac resynchronization therapy implantation. We compared the initial follow-up data of these patients and patients undergoing conventional right ventricular pacing (RVP). Methods: This retrospective study was performed between January 2017 and December 2020 and recruited 19 consecutive patients (mean age: 63 years; 8 women, 11 men) who underwent LBBAP (13 LBBAP only and 6 LBBAP + LV pacing), and 14 consecutive patients (mean age: 75 years; 8 women, 6 men) who underwent RVP. Demographic data, QRS durations, and echocardiographic parameters were compared before and after the procedures. Results: LBBAP substantially shortened the QRS duration and improved LV dyssynchrony echocardiographic parameters. However, RVP was not significantly associated with prolonged QRS duration and worse LV dyssynchronization. LBBAP improved cardiac contractility in selected patients. We did not find adverse effects of LBBAP on patients with preserved systolic function, possibly due to the limited number of patients and follow-up time. However, two of the 11 patients with preserved systolic function at baseline who underwent conventional RVP developed heart failure after implantation. Conclusions: In our experience, LBBAP improves LBBB-related ventricular dyssynchrony. However, LBBAP requires greater skill, and doubts remain about lead extraction. LBBAP may be an option for patients with LBBB when performed by an experienced operator, however further studies are needed to verify our findings.

Otoprotective Effects of Fucoidan Reduce Cisplatin-Induced Ototoxicity in Mouse Cochlear UB/OC-2 Cells.

Cisplatin is a widely used standard chemotherapy for various cancers. However, cisplatin treatment is associated with severe ototoxicity. Fucoidan is a complex sulfated polysaccharide mainly derived from brown seaweeds, and it shows multiple bioactivities such as antimicrobial, anti-inflammatory, anticancer, and antioxidant activities. Despite evidence of the antioxidant effects of fucoidan, research on its otoprotective effects remains limited. Therefore, the present study investigated the otoprotective effects of fucoidan in vitro using the mouse cochlear cell line UB/OC-2 to develop new strategies to attenuate cisplatin-induced ototoxicity. We quantified the cell membrane potential and analyzed regulators and cascade proteins in the apoptotic pathway. Mouse cochlear UB/OC-2 cells were pre-treated with fucoidan before cisplatin exposure. The effects on cochlear hair cell viability, mitochondrial function, and apoptosis-related proteins were determined via flow cytometry, Western blot analysis, and fluorescence staining. Fucoidan treatment reduced cisplatin-induced intracellular reactive oxygen species production, stabilized mitochondrial membrane potential, inhibited mitochondrial dysfunction, and successfully protected hair cells from apoptosis. Furthermore, fucoidan exerted antioxidant effects against oxidative stress by regulating the Nrf2 pathway. Therefore, we suggest that fucoidan may represent a potential therapeutic agent for developing a new otoprotective strategy.

Correlations between myocardial injury current and lead performance in His bundle pacing compared with left bundle branch area pacing and right ventricular septum pacing.

BACKGROUND: Conduction system pacing by implanting the lead in the His bundle (HBP) region or in the left bundle branch area (LBBAP) has gained popularity. Myocardial injury current (IC) is useful for predicting adequate lead fixation in right ventricular septal pacing (RVSP). OBJECTIVES AND METHODS: We compared the correlations between IC and lead performance among patients receiving HBP (n = 41), LBBAP (n = 53), and historical RVSP (n = 88). LBBAP was an alternative if optimal HBP was not achieved. A positive IC (STpost-screw-in - STpre-screw-in) was defined as > 0.2 mV or a > 25% ST elevation and prolongation of the ventricular electrograms > 10 ms from baseline. RESULTS: HBP patients with a positive IC (48%, 0.84 ± 0.4 V/0.4 ms) exhibited a similar pacing threshold to their LBBAP counterparts (76%, 0.75 ± 0.3 V/0.4 ms, p = 0.329), but a higher pacing threshold than their RVSP counterparts (67%, 0.50 ± 0.1 V/0.4 ms, p < 0.001) at implantation. The R-wave (5.70 ± 3.4 mV) and impedance (660.91 ± 140.8 Ω) were both lower than those of LBBAP (10.35 ± 6.0 mV, p = 0.002; 822.36 ± 235.8 Ω, p = 0.005) and RVSP (11.24 ± 4.9 mV, p < 0.001; 754.27 ± 126.4 Ω, p = 0.006) patients respectively at implantation. The trend of electrical parameter comparisons remained unchanged during follow-up (3.56 ± 1.4 months). Notably, HBP patients without ICs had a higher pacing threshold (1.24 ± 0.6 V/0.4 ms) compared to their LBBAP (0.73 ± 0.3 V/0.4 ms, p = 0.009) and RVSP (0.53 ± 0.1 V/0.4 ms, p < 0.001) counterparts at implantation and during follow-up. CONCLUSIONS: The detection of positive changes of myocardial ICs during HBP was associated with a better capture threshold equivalent to the LBBAP counterpart both at implantation and during short-term follow-up. Further large-scale studies with longer follow-up are necessary to confirm these findings.

Worsening Rhinosinusitis as a Prognostic Factor for Patients with Nasopharyngeal Carcinoma: A Retrospective Study.

Rhinosinusitis is common in patients with nasopharyngeal carcinoma (NPC). Our study aimed to explore the role of rhinosinusitis severity in NPC prognosis. Medical records and radiologic examinations of 90 patients with NPC at a single medical center from 2009−2016 were retrospectively analyzed. The Lund−Mackay (L−M) score was obtained for each patient before and after 6 months of treatment. Rhinosinusitis diagnosis was based on L−M scores of ≥4. L−M score differences were calculated as pre-treatment rhinosinusitis (PRRS) minus post-treatment rhinosinusitis (PSRS). L−M score difference was sub-grouped into "L−M scores > 0", "L−M scores = 0", and "L−M scores < 0". Clinical staging of our patients based on the American Joint Committee on Cancer 7th edition were: stage I in nine, stage II in seventeen, stage III in twenty-two, and stage IV in forty-two patients; twenty-seven (30%) patients had died. PRRS incidence was 34.4%, and PSRS was 36.7%. Median of L−M scores difference was 0 (−2.2). L−M score difference was an independent prognostic factor for the overall survival of patients with NPC (p < 0.05). Therefore, worsening rhinosinusitis was a prognostic factor for patients with NPC. Clinicians should consider NPC as a warning sign of poor prognosis during routine follow-ups.

Comprehensive Etiologic Analyses in Pediatric Cochlear Implantees and the Clinical Implications.

Cochlear implantation is the treatment of choice for children with profound sensorineural hearing impairment (SNHI), yet the outcomes of cochlear implants (CI) vary significantly across individuals. To investigate the CI outcomes in pediatric patients with SNHI due to various etiologies, we prospectively recruited children who underwent CI surgery at two tertiary referral CI centers from 2010 to 2021. All patients underwent comprehensive history taking, next generation sequencing (NGS)-based genetic examinations, and imaging studies. The CI outcomes were evaluated using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. Of the 160 pediatric cochlear implantees (76 females and 84 males) included in this study, comprehensive etiological work-up helped achieve clinical diagnoses in 83.1% (133/160) of the patients, with genetic factors being the leading cause (61.3%). Imaging studies identified certain findings in 31 additional patients (19.3%). Four patients (2.5%) were identified with congenital cytomegalovirus infection (cCMV), and 27 patients (16.9%) remained with unknown etiologies. Pathogenic variants in the four predominant non-syndromic SNHI genes (i.e., SLC26A4, GJB2, MYO15A, and OTOF) were associated with favorable CI outcomes (Chi-square test, p = 0.023), whereas cochlear nerve deficiency (CND) on imaging studies was associated with unfavorable CI outcomes (Chi-square test, p < 0.001). Our results demonstrated a clear correlation between the etiologies and CI outcomes, underscoring the importance of thorough etiological work-up preoperatively in pediatric CI candidates.

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study.

With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six children with ANSD who underwent cochlear implantation between 2001 and 2021 were included. Comprehensive etiological analyses were conducted, including a history review, next-generation sequencing-based genetic examinations, and imaging studies using high-resolution computed tomography and magnetic resonance imaging. Serial behavioral and speech audiometry were performed before and after surgery, and the outcomes with CI were evaluated using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. By etiology, 18, 1, 1, and 10 patients had OTOF-related, WFS1-related, OPA1-related, and cochlear nerve deficiency (CND)-related ANSD, respectively. Six patients had no definite etiology. The average CI-aided behavioral threshold was 28.3 ± 7.8 dBHL, and those with CND-related ANSD were significantly worse than OTOF-related ANSD. The patients' median CAP and SIR scores were 6 and 4, respectively. Favorable CI outcomes were observed in patients with certain etiologies of ANSD, particularly those with OTOF (CAP/SIR scores 5-7/2-5), WFS1 (CAP/SIR score 6/5), and OPA1 variants (CAP/SIR score 7/5). Patients with CND had suboptimal CI outcomes (CAP/SIR scores 2-6/1-3). Identifying the etiologies in ANSD patients is crucial before surgery and can aid in predicting prognoses.

Cochlear implant mapping strategy to solve difficulty in speech recognition.

BACKGROUND: Cochlear implants (CIs) are viable treatment options in patients with severe to profound hearing loss. Speech recognition difficulties were reported in some CI recipients even with a good-aided hearing threshold. The aim of this study was to report a mapping strategy based on different target-aided hearing thresholds to achieve optimal speech recognition and maximize functional outcomes. The safety and efficacy of the mapping strategy were also inspected in the article. METHODS: This prospective repeated measures study enrolled 20 adult CI recipients with postlingual deafness using the MED-EL CI system. Word and sentence discrimination assessment and administration of a questionnaire pertaining to comfort level were conducted at the end of each session. The electrophysiological features of the CI mapping were recorded. RESULTS: The correlation between audiometry results and word and sentence recognition was not high. CIs performed best at an audiometry threshold between 25 and 35 dB. CONCLUSION: CI performance with the best perception relies on a balance between minimizing the hearing threshold and maximizing the dynamic range while maintaining an appropriate comfort level, which was achieved when the target hearing threshold was set at 25-35 dB in this study.

Comparison Benefit between Hydrogen Peroxide and Adrenaline in Tonsillectomy: A Randomized Controlled Study.

This study aimed to further evaluate the benefit of topical hemostasis agents in tonsillectomy. We compared the clinical effects of topical application between hydrogen peroxide and adrenaline in tonsillectomy. Overall, 60 patients (120 tonsils) were prospectively enrolled for tonsillectomy between February 2018 and December 2020. The patients were randomly assigned to either the hydrogen peroxide or adrenaline group. Then, tonsillectomy was performed using hydrogen peroxide as a hemostatic agent on the assigned side, while adrenaline was applied to the other side. All procedures were performed by a surgeon who was blinded to the randomization. The outcome measurements of operation time, intraoperative blood loss, postoperative pain, and hemorrhage events were analyzed. The intraoperative blood loss was significantly lower in the hydrogen peroxide group than in the adrenaline group (9.99 ± 4.51 mL vs. 13.87 ± 6.32 mL; p = 0.0). The median operation time was also significantly lower in the hydrogen peroxide group (8.02 ± 3.59 min vs. 9.22 ± 3.88 min; p = 0.019). Meanwhile, the visual analogue scale (VAS) scores were significantly higher in the hydrogen peroxide group (4.98 ± 1.94 vs. 4.27 ± 1.97; p = 0.001). The topical application of hydrogen peroxide as a hemostatic agent effectively decreases the operation time and intraoperative blood loss. Thus, hydrogen peroxide can be used as a routine hemostatic agent for bleeding control in tonsillectomy.

Bisdemethoxycurcumin-mediated Attenuation of Apoptosis Prevents Gentamicin-induced Ototoxicity in Mouse Cochlear UB/OC-2 Cells.

BACKGROUND/AIM: Gentamicin has been widely prescribed since the last two decades despite its ototoxicity and nephrotoxicity. Bisdemethoxycurcumin (BDMC) is an affordable and safe curcuminoid with medicinal properties. We aimed to understand the effects of BDMC on the gentamicin-induced hair cell damage in mouse cochlear UB/OC-2 cells, in order to elucidate the therapeutic potential of BDMC against gentamicin-induced ototoxicity. MATERIALS AND METHODS: We quantified the cell membrane potential and examined the regulators and cascade proteins in the intrinsic pathway of hair cell apoptosis. Mouse cochlear UB/OC-2 cells were treated with BDMC before exposure to gentamicin. The effects of BDMC on hair cell viability, mitochondrial function, and apoptosis-related proteins were examined by flow cytometry, western blot, and fluorescent staining. RESULTS: Our results revealed that BDMC reversed gentamicin-mediated cycle arrest at the G2/M phase, stabilizing the mitochondrial membrane potential, decreasing cleaved caspase proteins, and successfully reversing hair cell apoptosis. CONCLUSION: BDMC is a potential agent for reducing gentamicin-induced ototoxicity.

2,3,4',5­Tetrahydroxystilbene­2­O­ß­D­glucoside ameliorates gentamicin­induced ototoxicity by modulating autophagy via Sesn2/AMPK/mTOR signaling.

Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram­negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5­tetrahydroxystilbene­2­O­ß­D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC­2. MTT assay demonstrated that gentamicin reduced UB/OC­2 cell viability and western blotting showed that gentamicin upregulated autophagy­related proteins, such as Beclin, autophagy related 5 and LC3­II. THSG significantly attenuated gentamicin­induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy­related proteins. Reverse­transcription­quantitative (RT­q) PCR and western blotting showed that THSG against gentamicin­induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP­activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin­induced ototoxicity in UB/OC­2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.

Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells.

BACKGROUND: Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. METHODS: Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. RESULTS: Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 µM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. CONCLUSION: In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.

Hearing Features and Cochlear Implantation Outcomes in Patients With Pathogenic MYO15A Variants: a Multicenter Observational Study.

OBJECTIVES: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants. DESIGN: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes. RESULTS: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation. CONCLUSIONS: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.

Residual hearing preservation for cochlear implantation surgery.

Cochlear implantation (CI) has developed for more than four decades. Initially, CI was used for profound bilateral hearing impairment. However, the indications for CI have expanded in recent years to include children with symptomatic partial deafness. Therefore, CI strategies to preserve residual hearing are important for both patients and otologists. The loss of residual low-frequency hearing is thought to be the result of many factors. All surgical methods have the same goal: protect the delicate intracochlear structures and preserve residual low-frequency hearing to improve speech perception abilities. Fully opening the round window membrane, a straight electrode array, slower insertion speed, and the use of corticosteroids result in a higher rate of hearing preservation. Several factors, like the way of surgical approaches, length of arrays and timing of activation, may not affect the residual hearing preservation. Therefore, the classic atraumatic technique, including the very slow and delicate insertion and administration of intraoperative corticosteroids, can improve hearing outcomes.

Hearing Impairment with Monoallelic GJB2 Variants: A GJB2 Cause or Non-GJB2 Cause?

Recessive variants in GJB2 are the most common genetic cause of sensorineural hearing impairment. However, in many patients, only one variant in the GJB2 coding region is identified using conventional sequencing strategy (eg, Sanger sequencing), resulting in nonconfirmative diagnosis. Conceivably, there might be other unidentified pathogenic variants in the noncoding region of GJB2 or other deafness-causing genes in these patients. To address this, a next-generation sequencing-based diagnostic panel targeting the entire GJB2 gene and the coding regions of 158 other known deafness-causing genes was designed and applied to 95 patients with nonsyndromic sensorineural hearing impairment (including 81 Han Taiwanese and 14 Mongolian patients) in whom only a single GJB2 variant had been detected using conventional Sanger sequencing. The panel confirmed the genetic diagnosis in 24 patients (25.3%). Twenty-two of them had causative variants in several deafness-causing genes other than GJB2, including MYO15A, MYO7A, TECTA, POU4F3, KCNQ4, SLC26A4, OTOF, MT-RNR1, MITF, WFS1, and USH2A. The other two patients had causative variants in GJB2, including a Taiwanese patient with a mosaic maternal uniparental disomy c.235delC variant (approximately 69% mosaicism) and a Mongolian patient with compound heterozygous c.35dupG and c.35delG variants, which occurred at the same site. This study demonstrates the utility of next-generation sequencing in clarifying the genetic diagnosis of hearing-impaired patients with nonconfirmative GJB2 genotypes on conventional genetic examinations.

Association of Mean and Variability of HbA1c with Heart Failure in Patients with Type 2 Diabetes.

Heart failure (HF) is a common presentation in patients with type 2 diabetes mellitus (T2DM). Previous studies revealed that the HbA1c level is significantly associated with HF. However, little is known about the association between HbA1c variability and HF. We aimed to evaluate the association of mean and variability of HbA1c with HF in patients with T2DM. Using Diabetes Share Care Program data, patients with T2DM who had mean HbA1c (HbA1c-Mean), and HbA1c variability (tertiles of HbA1c-SD and HbA1c-adjSD) within 12-24 months during 2001-2008 were included. The cutoffs of HbA1c-Mean were set at <7%, 7-7.9%, and ≥8%. Hazard ratios (HRs) for HF during 2008-2018 were estimated using Cox proportional hazard models. A total of 3824 patients were included, of whom 315 patients developed HF during the observation period of 11.72 years. The associated risk of HF increased with tertiles of HbA1c variability and cutoffs of HbA1c-Mean. In mutually adjusted models, HbA1c-Mean showed a consistent dose-response association with HF, while the association of HbA1c variability with HF disappeared. Among patients with HbA1c-Mean <7%, the associated risk of HF in patients with HbA1c variability in tertile 3 was comparable to patients with HbA1c-Mean ≥8%. In conclusion, mean HbA1c was an independent predictor of HF and not explained by HbA1c variability. In addition to absolute HbA1c level, targeting on stability of HbA1c in patients with good glycemic control was also important for the development of HF in patients with T2DM.

Automatic capture management may cause unnecessary battery depletion in selective his-bundle pacing.

A routine change in the automatic capture management algorithm from "adaptive" to "off or monitor" is required to conserve device longevity in a permanent pacemaker with His-bundle pacing.