Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Cav channels.

Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Cav channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Cav1.1 and Cav1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Cav channels.

Long-Term Incidence of Bradycardia and Pacemaker Implantations Among Cross-Country Skiers: A Cohort Study.

BACKGROUND: Bradycardia is more common among well-trained athletes than in the general population, but the association with pacemaker implantations is less known. We investigated associations of endurance training with incidence of bradycardia and pacemaker implantations, including sex differences and long-term outcome, in a cohort of endurance trained individuals. METHODS: All Swedish skiers who completed >1 race in the cross-country skiing event Vasaloppet between 1989 and 2011 (n=209 108) and a sample of 532 290 nonskiers were followed until first event of bradycardia, pacemaker implantation, or death, depending on end point. The Swedish National Patient Register was used to obtain diagnoses. Cox regression was used to investigate associations of number of completed races and finishing time in Vasaloppet with incidence of bradycardia and pacemaker implantations. In addition, Cox regression was used to investigate associations of pacemaker implantations with death in skiers and nonskiers. RESULTS: Male skiers had a higher incidence of bradycardia (adjusted hazard ratio [aHR], 1.19 [95% CI, 1.05-1.34]) and pacemaker implantations (aHR, 1.17 [95% CI, 1.04-1.31]) compared with male nonskiers. Those who completed the most races and had the best performances exhibited the highest incidence. For female skiers in Vasaloppet, the incidence of bradycardia (aHR, 0.98 [95% CI, 0.75-1.30]) and pacemaker implantations (aHR, 0.98 [95% CI, 0.75-1.29]) was not different from that of female nonskiers. The indication for pacemaker differed between skiers and nonskiers, with sick sinus syndrome more common in the former and third-degree atrioventricular block in the latter. Skiers had lower overall mortality rates than nonskiers (aHR, 0.16 [95% CI, 0.15-0.17]). There were no differences in mortality rates by pacemaker status among skiers. CONCLUSIONS: In this study, male endurance skiers had a higher incidence of bradycardia and pacemaker implantations compared with nonskiers, a pattern not seen in women. Among male skiers, those who completed the most races and had the fastest finishing times had the highest incidence of bradycardia and pacemaker implantations. Within each group, mortality rates did not differ in relation to pacemaker status. These findings suggest that bradycardia associated with training leads to a higher risk for pacemaker implantation without a detrimental effect on mortality risk.

Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.

The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 (Mfn2), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.

Leadless pacemakers at 5-year follow-up: the Micra transcatheter pacing system post-approval registry.

BACKGROUND AND AIMS: Prior reports have demonstrated a favourable safety and efficacy profile of the Micra leadless pacemaker over mid-term follow-up; however, long-term outcomes in real-world clinical practice remain unknown. Updated performance of the Micra VR leadless pacemaker through five years from the worldwide post-approval registry (PAR) was assessed. METHODS: All Micra PAR patients undergoing implant attempts were included. Endpoints included system- or procedure-related major complications and system revision rate for any cause through 60 months post-implant. Rates were compared through 36 months post-implant to a reference dataset of 2667 transvenous pacemaker patients using Fine-Gray competing risk models. RESULTS: 1809 patients were enrolled between July 2015 and March 2018 and underwent implant attempts from 179 centres in 23 countries with a median follow-up period of 51.1 months (IQR: 21.6-64.2). The major complication rate at 60 months was 4.5% [95% confidence interval (CI): 3.6%-5.5%] and was 4.1% at 36 months, which was significantly lower than the 8.5% rate observed for transvenous systems (HR: .47, 95% CI: .36-.61; P < .001). The all-cause system revision rate at 60 months was 4.9% (95% CI: 3.9%-6.1%). System revisions among Micra patients were mostly for device upgrades (41.2%) or elevated thresholds (30.6%). There were no Micra removals due to infection noted over the duration of follow-up. At 36 months, the system revision rate was significantly lower with Micra vs. transvenous systems (3.2% vs. 6.6%, P < .001). CONCLUSIONS: Long-term outcomes with the Micra leadless pacemaker continue to demonstrate low rates of major complications and system revisions and an extremely low incidence of infection.

Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant.

Encoded by ANK2, ankyrin-B (AnkB) is a multifunctional adapter protein critical for the expression and targeting of key cardiac ion channels, transporters, cytoskeletal-associated proteins, and signaling molecules. Mice deficient for AnkB expression are neonatal lethal, and mice heterozygous for AnkB expression display cardiac structural and electrical phenotypes. Human ANK2 loss-of-function variants are associated with diverse cardiac manifestations; however, human clinical 'AnkB syndrome' displays incomplete penetrance. To date, animal models for human arrhythmias have generally been knock-out or transgenic overexpression models and thus the direct impact of ANK2 variants on cardiac structure and function in vivo is not clearly defined. Here, we directly tested the relationship of a single human ANK2 disease-associated variant with cardiac phenotypes utilizing a novel in vivo animal model. At baseline, young AnkBp.E1458G+/+ mice lacked significant structural or electrical abnormalities. However, aged AnkBp.E1458G+/+ mice displayed both electrical and structural phenotypes at baseline including bradycardia and aberrant heart rate variability, structural remodeling, and fibrosis. Young and old AnkBp.E1458G+/+ mice displayed ventricular arrhythmias following acute (adrenergic) stress. In addition, young AnkBp.E1458G+/+ mice displayed structural remodeling following chronic (transverse aortic constriction) stress. Finally, AnkBp.E1458G+/+ myocytes harbored alterations in expression and/or localization of key AnkB-associated partners, consistent with the underlying disease mechanism. In summary, our findings illustrate the critical role of AnkB in in vivo cardiac function as well as the impact of single AnkB loss-of-function variants in vivo. However, our findings illustrate the contribution and in fact necessity of secondary factors (aging, adrenergic challenge, pressure-overload) to phenotype penetrance and severity.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Assessment of ventricular electrical heterogeneity in left bundle branch pacing and left ventricular septal pacing by using various electrophysiological methods.

INTRODUCTION: Left bundle branch area pacing (LBBAP) comprises pacing at the left ventricular septum (LVSP) or left bundle branch (LBBP). The aim of the present study was to investigate the differences in ventricular electrical heterogeneity between LVSP, LBBP, right ventricular pacing (RVP) and intrinsic conduction with different dyssynchrony measures using the ECG, vectorcardiograpy, ECG belt, and Ultrahigh frequency (UHF-)ECG. METHODS: Thirty-seven patients with a pacemaker indication for bradycardia or cardiac resynchronization therapy underwent LBBAP implantation. ECG, vectorcardiogram, ECG belt and UHF-ECG signals were recorded during RVP, LVSP and LBBP, and intrinsic activation. QRS duration (QRSd) was measured from the ECG, QRS area was calculated from the vectorcardiogram, LV activation time (LVAT) and standard deviation of activation time (SDAT) from ECG belt and electrical dyssynchrony (e-DYS16) from UHF-ECG. RESULTS: Both LVSP and LBBP significantly reduced ventricular electrical heterogeneity as compared to underlying LBBB and RV pacing in terms of QRS area (p < .001), SDAT (p < .001), LVAT (p < .001) and e-DYS16 (p < .001). QRSd was only reduced as compared to RV pacing(p < .001). QRS area was similar during LBBP and normal intrinsic conduction, e-DYS16 was similar during LVSP and normal intrinsic conduction, whereas SDAT was similar for LVSP, LBBP and normal intrinsic conduction. For all these variables there was no significant difference between LVSP and LBBP. CONCLUSION: Both LVSP and LBBP resulted in a more synchronous LV activation than LBBB and RVP. Especially LBBP resulted in levels of LV synchrony comparable to normal intrinsic conduction.

Left bundle branch area pacing using a lumenless lead: A systematic literature review and meta-analysis.

BACKGROUND: Although left bundle branch area pacing (LBBAP) has been shown to be a feasible option for delivering physiological pacing, data are largely limited to single-center reports. The aim of this analysis was to systematically assess the safety and efficacy of LBBAP with the Model 3830 lead among primarily bradycardia patients. METHODS AND RESULTS: PubMed, Embase, Cochrane Library, and Google Scholar were searched for full-text articles on LBBAP using the SelectSecure Model 3830 lumenless lead. Rates and means were estimated using random- and mixed-effects models. Of 3395 articles, 53 met inclusion criteria, representing 6061 patients undergoing an implant attempt. Average patient age was 68.1 years (95% CI: 66.6, 69.6) and 53.1% were male (95% CI: 50.5%, 55.7%). The average implant success rate among bradycardia-indicated patients was 92.7% (95% CI: 89.5%, 94.9%). The overall estimated procedural adverse event rate was 2.5% (95% CI: 1.1%, 5.4%). The estimated septal perforation rate at implant was 1.6% (95% CI: 1.0%, 2.6%) with no adverse clinical sequelae reported. Pacing thresholds were low at implant (0.67 V [95% CI: 0.64, 0.70]) and remained stable through 12 months (0.76 V [95% CI: 0.72, 0.80]). Among bradycardia-indicated patients, LVEF remained stable from baseline to post-implant (59.5% [95% CI: 57.9%, 61.1%] vs. 60.1% [95% CI: 58.5%, 61.7%]). CONCLUSION: This meta-analysis including 6061 patients implanted with a Model 3830 lead for LBBAP found an average implant success rate of 92.7% and a procedural adverse event rate of 2.5% with stable electrical parameters and LVEF post-implant.

Cardioneuroablation can be an effective strategy to treat glossopharyngeal neuralgia-related sinus bradycardia and pauses.

INTRODUCTION: Cardioneuroablation (CNA) has proven effectiveness in addressing hypervagotonia symptoms, such as neurocardiogenic syncope. METHODS AND RESULTS: In this case, we present the first-time application of CNA in a case of vago-glossopharyngeal neuralgia (VGPN). A 59-year-old female with near-syncope, sinus bradycardia, and sinus pauses triggered by recurrent right-sided neck pain was diagnosed with VGPN. The patient underwent successful treatment with carbamazepine and CNA. Subsequent follow-up revealed the sustained absence of sinus bradycardia or pauses, even upon neck pain resurgence after discontinuing carbamazepine. CONCLUSION: In this patient, CNA successfully prevented pauses associated with VGPN, avoiding permanent pacemaker implantation.

Prognostic benefits of His-Purkinje capture in physiological pacemakers for bradycardia.

INTRODUCTION: Clinical outcomes of long-term ventricular septal pacing (VSP) without His-Purkinje capture remain unknown. This study evaluated the differences in clinical outcomes between conduction system pacing (CSP), VSP, and right ventricular pacing (RVP). METHODS: Consecutive patients with bradycardia indicated for pacing from 2016 to 2022 were prospectively followed for the clinical endpoints of heart failure (HF)-hospitalizations and all-cause mortality at 2 years. VSP was defined as septal pacing due to unsuccessful CSP implant or successful CSP followed by loss of His-Purkinje capture within 90 days. RESULTS: Among 1016 patients (age 73.9 ± 11.2 years, 47% female, 48% atrioventricular block), 612 received RVP, 335 received CSP and 69 received VSP. Paced QRS duration was similar between VSP and RVP, but both significantly longer than CSP (p < .05). HF-hospitalizations occurred in 130 (13%) patients (CSP 7% vs. RVP 16% vs. VSP 13%, p = .001), and all-cause mortality in 143 (14%) patients (CSP 7% vs. RVP 19% vs. VSP 9%, p < .001). The association of pacing modality with clinical events was limited to those with ventricular pacing (Vp) > 20% (pinteraction < .05). Adjusting for clinical risk factors among patients with Vp > 20%, VSP (adjusted hazard ratio [AHR]: 4.74, 95% confidence interval [CI]: 1.57-14.36) and RVP (AHR: 3.08, 95% CI: 1.44-6.60) were associated with increased hazard of HF-hospitalizations, and RVP (2.52, 95% CI: 1.19-5.35) with increased mortality, compared to CSP. Clinical endpoints did not differ between VSP and RVP with Vp > 20%, or amongst groups with Vp < 20%. CONCLUSION: Conduction system capture is associated with improved clinical outcomes. CSP should be preferred over VSP or RVP during pacing for bradycardia.

Breathing patterns and associated cardiovascular changes in intermittently breathing animals: (Partially) correcting a semantic quagmire.

Many animal species do not breathe in a continuous, rhythmic fashion, but rather display a variety of breathing patterns characterized by prolonged periods between breaths (inter-breath intervals), during which the heart continues to beat. Examples of intermittent breathing abound across the animal kingdom, from crustaceans to cetaceans. With respect to human physiology, intermittent breathing-also termed 'periodic' or 'episodic' breathing-is associated with a variety of pathologies. Cardiovascular phenomena associated with intermittent breathing in diving species have been termed 'diving bradycardia', 'submersion bradycardia', 'immersion bradycardia', 'ventilation tachycardia', 'respiratory sinus arrhythmia' and so forth. An examination across the literature of terminology applied to these physiological phenomena indicates, unfortunately, no attempt at standardization. This might be viewed as an esoteric semantic problem except for the fact that many of the terms variously used by different authors carry with them implicit or explicit suggestions of underlying physiological mechanisms and even human-associated pathologies. In this article, we review several phenomena associated with diving and intermittent breathing, indicate the semantic issues arising from the use of each term, and make recommendations for best practice when applying specific terms to particular cardiorespiratory patterns. Ultimately, we emphasize that the biology-not the semantics-is what is important, but also stress that confusion surrounding underlying mechanisms can be avoided by more careful attention to terms describing physiological changes during intermittent breathing and diving.

Heart rate reduction during voluntary deep diving in free-ranging loggerhead sea turtles.

Air-breathing vertebrates exhibit cardiovascular responses to diving including heart rate reduction (diving bradycardia). Field studies on aquatic mammals and birds have shown that the intensity of bradycardia can vary depending on diving behaviour, such as the depth of dives and dive duration. However, in aquatic reptiles, the variation in heart rate during deep dives under natural conditions has not been fully investigated. In this study, we released five loggerhead sea turtles (Caretta caretta) outfitted with recorders into the sea and recorded their electrocardiogram, depth, water temperature and longitudinal acceleration. After 3 days, the recorders automatically detached from the turtles. The heart rate signals were detected from the electrodes placed on the surface of the plastron. The mean (±s.d.) heart rate of 12.8±4.1 beats min-1 during dives was significantly lower than that of 20.9±4.1 beats min-1 during surface periods. Heart rate during dives varied with dive depth, although it remained lower than that at the surface. When the turtle dived deeper than 140 m, despite the relatively high flipper stroke rate (approximately 19 strokes min-1), the heart rate dropped rapidly to approximately 2 beats min-1 temporarily. The minimum instantaneous heart rate during dives was lower at deeper dive depths. Our results indicate that loggerhead sea turtles show variations in the intensity of diving bradycardia depending on their diving behaviour, similar to that shown by marine mammals and birds.

The role of cognition as a factor regulating the diving responses of animals, including humans.

The dive response involves three main components - breath holding, reduced heart rate and increased peripheral vasoconstriction - and is ubiquitous during forced dives in air-breathing vertebrates; however, numerous studies in free-diving animals have shown that the heart rate response to diving varies considerably in a manner that suggests cognitive control. Furthermore, studies on free-diving animals and controlled experiments in trained animals both indicate that the dive response can be conditioned, such that the reduction in heart rate begins before submergence and the extent of the reduction is set early in the dive. In addition, numerous species also experience an increase in heart rate and blood flow during ascent at the end of a dive, a phenomenon commonly called 'ascent tachycardia'. Collectively, these data suggest that although the dive response is under autonomic control, many species can vary its magnitude depending on the length and type of the planned dive - an indication of a role for cognition in the overall physiological responses associated with diving. Here, we provide examples of the conditioned cardiac responses - including anticipatory changes in heart rate - in several diving species and propose potential underlying mechanisms. We also discuss how the anticipatory cardiovascular responses not only improve diving capacity, but also prevent diving-related problems, such as decompression sickness or barotrauma, through a mechanism described by the selective gas exchange hypothesis.

Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Cardioneuroablation for the treatment of reflex syncope and functional bradyarrhythmias: A Scientific Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS).

Cardioneuroablation has emerged as a potential alternative to cardiac pacing in selected cases with vasovagal reflex syncope, extrinsic vagally induced sinus bradycardia-arrest or atrioventricular block. The technique was first introduced decades ago, and its use has risen over the past decade. However, as with any intervention, proper patient selection and technique are a prerequisite for a safe and effective use of cardioneuroablation therapy. This document aims to review and interpret available scientific evidence and provide a summary position on the topic.

Embryonic Exposure to Organophosphate Flame Retardants (OPFRs) Differentially Induces Cardiotoxicity in Rare Minnow (Gobiocypris rarus).

Organophosphorus flame retardants (OPFRs) such as triphenyl phosphate (TPHP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) were reported to impair cardiac function in fish. However, limited information is available regarding their cardiotoxic mechanisms. Using rare minnow (Gobiocypris rarus) as a model, we found that both TPHP and TDCIPP exposures decreased heart rate at 96 h postfertilization (hpf) in embryos. Atropine (an mAChR antagonist) can significantly attenuate the bradycardia caused by TPHP, but only marginally attenuated in TDCIPP treatment, suggesting that TDCIPP-induced bradycardia is independent of mAChR. Unlike TDCIPP, although TPHP-induced bradycardia could be reversed by transferring larvae to a clean medium, the inhibitory effect of AChE activity persisted compared to 96 hpf, indicating the existence of other bradycardia regulatory mechanisms. Transcriptome profiling revealed cardiotoxicity-related pathways in treatments at 24 and 72 hpf in embryos/larvae. Similar transcriptional alterations were also confirmed in the hearts of adult fish. Further studies verified that TPHP and TDCIPP can interfere with Na+/Ca2+ transport and lead to disorders of cardiac excitation-contraction coupling in larvae. Our findings provide useful clues for unveiling the differential cardiotoxic mechanisms of OPFRs and identifying abnormal Na+/Ca2+ transport as one of a select few known factors sufficient to impair fish cardiac function.

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

BRASH syndrome with a complete heart block- a case report.

INTRODUCTION: BRASH syndrome (Bradycardia, Renal failure, Atrioventricular (AV) nodal blocking agent, Shock and Hyperkalemia) is a recently emerging diagnosis that describes the profound bradycardia seen in patients on AV nodal blockers who present with acute kidney injury (AKI) and hyperkalemia. CASE PRESENTATION: We present a case of a 68 years old female patient with past history of hypertension taking atenolol and Enalapril presented to emergency department with the complaint of loss of consciousness of 02 hours duration. She had 03 days history of fatigue, poor oral intake, decreased urine output, appetite loss, vertigo and global headache. Her vital signs were blood pressure of 60/40 mmHg, absent radial pulse and temperature of 36.4 °C. Her systemic examination was remarkable for dry buccal mucosa; apical heart rate was 22 beats per minute. Glasgow Coma Scale was 13/15. Her laboratory tests showed creatinine of 1.83 mg/dL, blood urea nitrogen of 89 mg/dL and potassium elevated to the level of 6.39 mEq/dL. ECG revealed complete heart block with a normal QT interval and T waves and no U waves with ventricular rate of 22 beats per minute. Her previous medications were discontinued and the patient was resuscitated with intravenous (IV) fluids. She was given 03 doses of 1 mg atropine every 5 minutes but there was no increment in heart rate. She was given 50% dextrose with 10 international units of regular insulin, 1 g of calcium gluconate and Intravenous perfusion of norepinephrine and dopamine. Subsequently, after 14 hours of ICU admission the patient had a cardiac arrest with asystole and resuscitation was attempted but she couldn't survive. CONCLUSION: BRASH syndrome is largely an under-recognized life threatening clinical diagnosis. Physicians should have high index of suspicion for BRASH when they encounter patients with bradycardia, hyperkalemia, and renal failure, as timely diagnosis is crucial in the management.

Chronic clinical performance of a novel subxiphoidal pacemaker system: Early feasibility study design.

BACKGROUND: Extravascular and leadless pacemakers are a new class of cardiac devices that may reduce the rate of complications common to traditional cardiac pacemakers with intracardiac leads. These devices also have the potential of expanding access to cardiac pacing therapy by simplifying the complexity and cost of implantation. The objective of this study is to evaluate the implantation, chronic safety, and performance of a novel subxiphoidal pacemaker. METHODS: This study is an open-label, non-randomized, early feasibility study. Ten patients indicated for implantation of a single-chamber ventricular pacemaker will be enrolled and implanted with the investigational device. The pacemaker will be inserted underneath the ribcage and clipped to the xiphoid process, with stimulation electrodes positioned on the cardiac pericardium. Patients will be programmed to chronic pacing; pacing capture threshold, sensing amplitude, and lead impedance will be measured at implant and regularly scheduled follow-up visits. 24-h Holter ECG and cardiac troponin will also be periodically measured. Adverse events will be recorded throughout the study period. CONCLUSION: This study is designed to assess the feasibility, safety, and chronic performance of a novel extravascular pacemaker, and will provide valuable data on whether this device has the potential to be a viable alternative to conventional pacemakers.

Use of a leadless pacemaker in the management of swallow syncope: A case report.

A 41-year-old male presented with syncope whilst eating and was subsequently demonstrated to have recurrent symptomatic sinus pauses whilst swallowing. Following the exclusion of structural heart disease, he was diagnosed with swallow syncope, an uncommon variant of neurocardiogenic syncope. To avoid long-term complications of a transvenous pacemaker, the case was managed with a leadless pacemaker which resulted in complete resolution of symptoms.