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Background: Cardiac implantable electronic devices (CIEDs) are a core component in the management of heart rhythm disorders. The complexity of devices, the information gathered and therapy delivered by CIEDs continues to advance at pace., Objective: The aim of this paper is to provide an update on advances in CIED technology and how this applies to managing patients with CIEDs in general practice., Discussion: In recent years, there have been notable advances in CIED technology. These include widespread magnetic resonance imaging compatibility and automated algorithms to assist in the clinical management of patients. There is the ability for clinicians and pacemaker clinics to monitor devices remotely, avoiding in-clinic visits. Options are now available for leadless pacemakers and subcutaneous defibrillators as an alternative to indwelling leads and associated infection and vascular issues. Techniques have been developed to allow leads to capture the native conduction system, providing physiological cardiac activation (conduction system pacing) for treatment and prevention of heart failure.

Background: Aortic stenosis (AS) remains one of the most commonly encountered valvular pathologies. Medical management does not alter the progression of the disease, making assessment of severity and timing of referral for valve replacement the most important aspects of caring for patients with AS., Objective: To review the contemporary management of AS, including signs and symptoms, echocardiography and decision making in management., Discussion: Severe symptomatic AS is frequently accompanied by dyspnoea, chest pain or syncope and a physical examination might reveal the presence of an ejection systolic murmur. Echocardiography is the first and most useful investigation to stratify risk and determine requirement for valve replacement by assessing valve gradients and left ventricular function. Surgical and transcatheter options now exist for treatment of AS and decision making is usually multidisciplinary and based on individual patient parameters.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na V 1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na V 1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Novel ablation catheters with mini electrode (ME) sensing have become available but their utility is unclear. We investigated whether ablation of the cavotricuspid isthmus (CTI) for atrial flutter (AFL) would be improved using ME signals., Methods: Sixty-one patients (76% male, 63 ± 10 years) with CTI-dependent AFL underwent ablation using a maximum voltage-guided approach, randomized to either standard 8 mm non-irrigated catheter with bipolar signals or IntellaTip MiFi catheter using ME signals alone., Results: Acute bidirectional block was achieved in 97%. Mean follow-up was 16.7 ± 10 months. The median number of ablation lesions was 13 in both groups (range 3-62 vs. 1-43, p  = .85). No significant differences were observed in AFL recurrences (17% vs. 11%, p  = .7), median procedure durations (97 min [interquartile range (IQR), 71-121] vs. 87 min [IQR, 72-107], p  = .55) or fluoroscopy times (31 min [IQR, 21-52] vs. 38 min [IQR, 25-70], p  = .56). Amplitudes of ME signals were on average 160% greater than blinded bipolar signals. In 23.7% of lesions where bipolar signals were difficult to interpret, 13.6% showed a clear ME signal., Conclusions: There was no difference in the effectiveness of CTI ablation guided by ME signals, compared with using bipolar signals from a standard 8 mm ablation catheter. While ME signal amplitudes were larger and sometimes present when the bipolar signal was unclear, this did not improve procedural characteristics or outcomes. The results suggest future research should focus on lesion integrity rather than signal sensing., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Introduction: Septal accessory pathway (AP) ablation can be challenging due to the complex anatomy of the septal region. The decision to access the left atrium (LA) is often made after failure of ablation from the right. We sought to establish whether the difference between ventriculo-atrial (VA) time during right ventricular (RV) apical pacing versus the VA during tachycardia would help establish the successful site for ablation of septal APs., Methods: Intracardiac electrograms of patients with orthodromic reciprocating tachycardia (ORT) using a septal AP with successful catheter ablation were reviewed. The ∆VA was the difference between the VA interval during RV apical pacing and the VA interval during ORT. The difference in the VA interval during right ventricular entrainment and ORT (StimA-VA) was also measured., Results: The median ∆VA time was significantly less in patients with a septal AP ablated on the right side compared with patients with a septal AP ablated on the left side (12 ± 19 vs. 56 ± 10 ms, p < .001). The StimA-VA was significantly different between the two groups (22 ± 14 vs. 53 ± 9 ms, p < .001). The ∆VA and StimA-VA were always ≤ 40 ms in patients with non-decremental septal APs ablated from the right side and always greater than 40 ms in those with septal APs ablated from the left., Conclusion: ΔVA and StimA-VA values identified with RV apical pacing in the setting of ORT involving a septal AP predict when left atrial access will be necessary for successful ablation., (© 2020 Wiley Periodicals LLC.)

Inherited arrhythmia syndromes have traditionally been viewed as monogenic forms of disease whose pathophysiology is driven by a single highly penetrant rare genetic variant. Although an accurate depiction of a proportion of genetic variants, the variable penetrance frequently noted in genotype positive families and the presence of sporadic genotype negative cases have long highlighted a more nuanced truth being operative. Coupled with our more recent recognition that many rare variants implicated in inherited arrhythmia syndromes possess unexpectedly high allele frequencies within the general population, these observations have contributed to the realization that a spectrum of pathogenicity exists among clinically relevant genetic variants. Notably, variable mutation pathogenicity and corresponding variable degrees of penetrance emphasize a limitation of contemporary guidelines, which attempt to dichotomize genetic variants as pathogenic or benign. Recognition of the existence of low and intermediate penetrant variants insufficient to be causative for disease in isolation has served to emphasize the importance of additional genetic, clinical, and environmental factors in the pathogenesis of rare inherited arrhythmia syndromes. Despite being rare, it has also become increasingly evident that common genetic variants play critical roles in both heritable channelopathies and cardiomyopathies and in aggregate may even be the primary drivers in certain instances, such as genotype negative Brugada syndrome. Our growing realization that the genetic substrates of inherited arrhythmia syndromes have intricacies that extend beyond traditionally perceived monogenic paradigms has highlighted a potential value of leveraging more comprehensive genomic risk scores for predicting disease development and arrhythmic risk., (© 2020 Wiley Periodicals, Inc.)

Background: Anticoagulation prior to elective external direct current cardioversion (EDCCV) is mandatory. The inability to monitor compliance with novel oral anticoagulants (NOACs) raises a potential safety issue. We aimed to evaluate whether a structured, nurse-led assessment of compliance prior to EDCCV ensures safety without the need for routine transoesophageal echocardiography (TOE)., Methods: Data was prospectively collected on consecutive patients undergoing EDCCV during 2014-2015. All procedures were supervised by an electrophysiology clinical nurse consultant (EPCNC). Drug compliance was verbally assessed using a standardised questionnaire by the EPCNC. Novel oral anticoagulants compliance was required for a continuous period of 3 weeks prior to EDCCV; otherwise a TOE-guided EDDCV was performed. All patients had follow-up 30 days post-procedure., Results: Three hundred and eleven cardioversions were performed on 256 patients in whom 154 (49.5%) were prescribed a NOAC (rivaroxaban (n=105; 68.2%), dabigatran (n=38; 24.7%), apixaban (n=11; 7.1%)). Median age was 63 years (24-94 yrs), mean CHADS 2 -Vasc score was 2.0±1.5 and 138 (89.6%) were outpatients. One hundred and twenty-nine (83.8%) EDCCV were for atrial fibrillation and 25 (16.2%) for atrial flutter. Sinus rhythm was achieved in 90.3% of cases. Fourteen patients (9%) assessed as non-compliant underwent TOE. 129 (83.8%) EDCCV were performed without prior TOE. No stroke or systemic embolism was identified in any patient treated with either warfarin or a NOAC., Conclusions: A standardised, verbal questionnaire can be administered to detect NOAC non-compliance in patients undergoing EDCCV. With appropriate compliance assessment a nurse-led EDCCV without routine TOE did not significantly compromise safety in this study group., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Introduction: Cardiac resynchronization therapy (CRT) is one of the most important advances in heart failure management in the last twenty years. Approximately one-third of patients appear not to respond to therapy. Although there are a number of possible mechanisms for non-response, an important factor is suboptimal atrioventricular (AV) and interventricular (VV) timing intervals. There remains controversy over whether routinely optimizing intervals is necessary and there is no agreed gold standard methodology. Optimization has classically been performed using echocardiography which has limits related to resource use, time-cost and variable reproducibility. Newer optimization methods using device-based sensors and algorithms show promise in reducing heart-failure hospitalization compared with echocardiography. Areas covered: This review outlines the rationale for optimization, the principles of AV and VV optimization, the standard echocardiographic approach and newer device-based algorithms and the evidence base for their use. Expert commentary: The incremental gains of optimization are likely to be real, but small, compared to the overall improvement gained from cardiac resynchronization itself. At this time routine optimization may not be mandatory but should be performed where there is no response to CRT. Device-based optimization algorithms appear to be practical and in some cases, deliver superior clinical outcomes compared to echocardiography.

Background: Cardiac sarcoidosis (CS) is an uncommon and under-recognised disease which most frequently presents with atrioventricular (AV) block and may also present with ventricular arrhythmias and left ventricular (LV) systolic dysfunction. Because of its protean clinical manifestations, confirming a diagnosis of CS is often challenging., Methods: We report two cases where patients presented with atrioventricular (AV) block without evidence of underlying myocardial disease, underwent chronic dual-chamber pacing, and presented several years later with severe LV systolic dysfunction., Results: Both patients were referred for assessment of pacing-induced cardiomyopathy with a view to upgrading their device to cardiac resynchronisation therapy (CRT). Subsequent investigation revealed features consistent with CS and appropriate immunosuppressive therapy resulted in improvement in LV function avoiding the requirement for CRT., Conclusion: We present a review of the diagnosis of cardiac sarcoidosis, the importance of imaging modalities and current treatment recommendations., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Chronic right ventricular (RV) apical pacing may lead to the development of heart failure in some patients. Although pacing of the RV septum has been proposed as an alternative, positioning a lead in the true septum has proven challenging. In addition to fluoroscopy at implant, it has been suggested that 12-lead surface electrocardiogram (ECG) can be used to determine septal lead position; however, studies show this may be inaccurate. We present a case where a change in the ECG QRS axis late after pacemaker insertion with an active fixation lead highlights the difficulties of ECG localization of pacing leads., (© 2017 Wiley Periodicals, Inc.)

Background: Controversy exists regarding the optimal lead position for chronic right ventricular (RV) pacing. Placing a lead at the RV septum relies upon fluoroscopy assisted by a surface 12-lead electrocardiogram (ECG). We compared the postimplant lead position determined by ECG-gated multidetector contrast-enhanced computed tomography (MDCT) with the position derived from the surface 12-lead ECG., Methods: Eighteen patients with permanent RV leads were prospectively enrolled. Leads were placed in the RV septum (RVS) in 10 and the RV apex (RVA) in eight using fluoroscopy with anteroposterior and left anterior oblique 30° views. All patients underwent MDCT imaging and paced ECG analysis. ECG criteria were: QRS duration; QRS axis; positive or negative net QRS amplitude in leads I, aVL, V1, and V6; presence of notching in the inferior leads; and transition point in precordial leads at or after V4., Results: Of the 10 leads implanted in the RVS, computed tomography (CT) imaging revealed seven to be at the anterior RV wall, two at the anteroseptal junction, and one in the true septum. For the eight RVA leads, four were anterior, two septal, and two anteroseptal. All leads implanted in the RVS met at least one ECG criteria (median 3, range 1-6). However, no criteria were specific for septal position as judged by MDCT. Mean QRS duration was 160 ± 24 ms in the RVS group compared with 168 ± 14 ms for RVA pacing (P = 0.38)., Conclusions: We conclude that the surface ECG is not sufficiently accurate to determine RV septal lead tip position compared to cardiac CT., (© 2017 Wiley Periodicals, Inc.)

Bipolar disorder is a serious psychiatric condition that has been treated for over 50 years with lithium. Lithium is a well established glycogen synthase kinase-3 (GSK-3) inhibitor, suggesting that manipulating GSK-3 may have therapeutic value in treating bipolar disorder. GSK-3 is regulated by a wide variety of mechanisms including phosphorylation, binding with protein complexes, phosphorylation state of its substrates, cellular localization and autoregulation, thus providing a wide number of potential therapeutic mechanisms. Mounting evidence suggests that GSK-3 regulation can be used to manage bipolar disorder symptoms. Although GSK-3 mutations have not been detected amongst the general bipolar population, they have been correlated with females with bipolar II and most of the drugs used for successful bipolar disorder treatment regulate GSK-3. These drugs produce a weak anti-depressant-like and a strong anti-mania-like effect in a wide range of animal models tested, mirroring their utility in treating bipolar disorder symptoms. Taken together, the evidence suggests that targeting GSK-3 may be a means to control the symptoms of bipolar disorder.

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3beta activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including beta-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.

In this study, patients with panic disorder (PD) who suffered nocturnal panic (NP) attacks were compared with PD patients who never experienced NP attacks and healthy controls. Three tasks were chosen to evaluate attention to cardiac cues, reactivity to induction of respiratory cues, and reactivity to relaxation cues. Relative to healthy controls, PD groups reported more fear of all three tasks and showed more physiological arousal in response to the hyperventilation task. The only task on which the two PD groups differed was the relaxation task, where nocturnal panickers were significantly more distressed. These findings are consistent with the notion that nocturnal panickers are fearful of states involving a diminution of conscious awareness or vigilance.

We examined the relationship between metabolic stress, brain adenosine regulation, and the learned helplessness effect in four experiments in rats. Glucoprivation and metabolic inhibition were induced by treating previously restrained (nonshocked) rats with 2-deoxy-D-glucose (2DG) shortly before escape testing. Experiment 1 demonstrated that 2-deoxy-D-glucose impairs escape performance in a dose-dependent manner. Experiment 2 showed that 2-deoxy-D-glucose and shock induced escape deficits are completely reversed by peripheral administration of the adenosine receptor antagonist caffeine. This result indicates that both inescapable shock and 2-deoxy-D-glucose result in compensatory adenosine regulation which, in turn, mediates the behavioral impairment. Experiment 3 determined that 8-[p-sulfophenyl]-theophylline, a peripheral adenosine receptor antagonist, fails to reverse the escape deficit resulting from metabolic stress, whereas centrally acting theophylline does. Experiment 4 showed that the behavioral impairments from both 2-deoxy-D-glucose and inescapable shock are reversed by intracranial ventricular (icv) caffeine treatment. The results of Experiments 3 and 4 indicate that the enhanced adenosine regulation and the ensuing performance deficit resulting from 2-deoxy-D-glucose treatment occurred in the central nervous system. These data are discussed in terms of the metabolic demands of neuronal over-activation during escape testing in inescapably shocked rats and the loss of normal behavioral function due to compensatory adenosine regulation in the brain.

Objective: To measure the association between gynecologic conditions and quality of life in women before hysterectomy., Methods: We retrospectively identified 482 women who had hysterectomies for nononcologic and nonemergency indications in one of nine capitated medical groups in Southern California between 1993 and 1995. Their symptoms and quality of life before hysterectomy were assessed by medical record review and telephone interview. Women were placed into four symptom-based groups (pain, bleeding, pelvic discomfort, and asymptomatic groups) and compared across six quality-of-life scales., Results: Women with primary pain conditions reported the highest average role impairment compared with women with primary bleeding, pelvic discomfort, or asymptomatic conditions (8.6 days/month versus 5.0, 2.5, and 1.9 days/month, respectively; P < .05). On the five 0 to 100-point quality-of-life scales, women with primary pain conditions, compared with women with bleeding, pelvic discomfort, or asymptomatic conditions, had the highest mean levels of sexual impairment (71.5 versus 54.1, 29.6, and 17.9, respectively; P < .05) and mood impairment (55.2 versus 45.2, 34.6, and 38.1, respectively; P < .05), the poorest perception of general health (74.4 versus 60.7, 44.1, and 49.4, respectively; P < .05), and the greatest increase in severity of symptoms before hysterectomy (77.2 versus 68.7, 61.5, and 57.1, respectively; P < .05)., Conclusion: Women's primary symptoms before hysterectomy are associated differentially with varying levels of impairment. Standardized measurement of quality of life among women with gynecologic complaints that lead to hysterectomy might help in the development of treatment guidelines and in the assessment of appropriateness and outcomes of care for those women.

The current investigation assessed the relative treatment benefits of persistence with one specific stimulus vs exposure to multiple versions of a stimulus. The study was a 2 (type of stimulus) x 3 (assessment occasion) design, in which two spider-fearful groups (N = 28) were compared across three different occasions: pre-treatment, post-treatment, and follow-up. Exposure trials were conducted with the same tarantula for participants in the control group, whereas experimental participants were exposed to four novel tarantulas. As predicted, the control group demonstrated significantly more habituation than the experimental group across exposure trials, yet showed a clear return of fear in response to a control spider at a 3-week follow-up assessment whereas the experimental group showed no increase in fear. These findings offer support for the beneficial effects of varying the stimulus during exposure, and challenge the reliance on indices of fear activation and habituation as accurate signals of the permanence of fear reduction.

The current investigation assessed the relative benefits of a massed vs an expanding-spaced exposure schedule. The study was a 2 (distribution of sessions) x 3 (assessment occasion) design, in which two spider-fearful groups (N = 31) were compared across three different occasions: pre-training, post-training, and follow-up. Four exposure trials were conducted within the same day for participants in the massed exposure (ME) group, whereas sessions were distributed over the course of 1 week (inter-trial intervals doubled between sessions) for the expanding-spaced exposure (ESE) group. As predicted, although the ME group demonstrated significantly more habituation than the ESE group across exposure trials, they also showed a clear return of fear (ROF) in response to the training spider at a 1-month follow-up assessment, whereas the ESE group showed no increase in fear. Additionally, the ME group showed ROF in response to novel spiders post-training and at the 1-month follow-up, whereas ESE participants did not. These findings offer support for the beneficial effects of an expanding-spaced schedule and challenge the reliance on indices of fear activation and habituation as accurate signals of the permanence of fear reduction.