ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy.

Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex- and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.

Biventricular Function is Impaired in Right Ventricular Septal Pacing-A Prospective Study Using Myocardial Strain Imaging.

BACKGROUND: Left ventricular (LV) dysfunction is known to occur after right ventricular (RV) pacing; the effect on RV function is less well studied. The aim of this study was to assess the impact of RV mid-septal pacing upon RV function using the novel parameters of speckle-tracking derived RV global longitudinal strain (RV GLS) and RV free wall strain (RV FWS), as well as the conventional parameters RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), and tricuspid annular systolic velocity (RV S'). METHODS: Thirty-two (32) consecutive patients with normal baseline LV and RV function requiring permanent pacemaker insertion (for high-grade AV block or sinus node dysfunction) were prospectively recruited. Echocardiography was performed prior to implantation, at 1 day, 1 month and 1 year after implantation, with 29 patients completing follow-up. RESULTS: After 1 year, three patients (10%) with otherwise normal RV parameters developed abnormal RV strain patterns. Compared to 1 day after implantation, at 1 year significant reductions were observed in mean RV GLS (-24.8 to -21.8%) RV S' (15.1 to 12.2 cm/s), TAPSE (24.2 to 21.9 mm), RV GLS (-24.8 to -21.8%), left ventricular ejection fraction (LVEF) (66.0 to 57.9%), LV GLS (-19.9 to 17.0), all p<0.01. There was a non-significant reduction for RV FWS (-29.0 to -26.7%, p=0.06) and there was no change in RV FAC (49.1 to 46.9%, p=0.24). CONCLUSION: We report abnormalities of RV strain developing 1 year after pacemaker insertion. Measurement of myocardial strain is emerging as an additional method to detect patients at risk of RV dysfunction in those who have undergone pacemaker implantation.

Using and improving the PHISICC paper-based tools in the health facility laboratories: Examples of Human Centered Design taking systems thinking into practice, in Côte d'Ivoire and Nigeria.

Background: Health workers in low- and middle-income countries are increasingly demanded to collect more and more data to report them to higher levels of the health information system (HIS), in detriment of useful data for clinical and public health decision-making, potentially compromising the quality of their health care provison. In order to support health workers' decision-making, we engaged with partners in Côte d'Ivoire, Mozambique and Nigeria in a research project to conceive, design, produce, implement and test paper-based health information tools: the PHISICC tools. Our aim was to understand the use of PHISICC tools by health workers and to improve them based on their feedback. Methods: The design Health Facility Laboratories (HF Labs) in Côte d'Ivoire and in Nigeria were set up after months of use of PHISICC tools. Activities were structured in three phases or 'sprints' of co-creative research. We used a transdisciplinary approach, including anthropology and Human Centered Design (HCD), observations, shadowing, structured interviews and co-creation. Results: Health workers appreciated the standardization of the tools across different health care areas, with a common visual language that optimized use. Several design issues were raised, in terms of formats and contents. They strongly appreciated how the PHISICC registers guided their clinical decision-making and how it facilitated tallying and counting for monthly reporting. However, adherence to new procedures was not universal. The co-creation sessions resulted in modifications to the PHISICC tools of out-patient care and postnatal care. Discussion: Although health systems and systemic thinking allowed the teams to embrace complexity, it was the HCD approach that actually produced a shift in researchers' mind-set: from HIS as data management tools to HIS as quality of care instruments. HCD allowed navigating the complexity of health systems interventions due to its capacity to operate change: it not only allowed us to understand how the PHISICC tools were used but also how to further improve them. In the absence of (or even with) an analytical health systems framework, HCD approaches can work in real-life situations for the ideation, testing and implementation of interventions to improve health systems and health status outcomes.

Efficacy and Safety of an Extravascular Implantable Cardioverter-Defibrillator.

BACKGROUND: The extravascular implantable cardioverter-defibrillator (ICD) has a single lead implanted substernally to enable pause-prevention pacing, antitachycardia pacing, and defibrillation energy similar to that of transvenous ICDs. The safety and efficacy of extravascular ICDs are not yet known. METHODS: We conducted a prospective, single-group, nonrandomized, premarket global clinical study involving patients with a class I or IIa indication for an ICD, all of whom received an extravascular ICD system. The primary efficacy end point was successful defibrillation at implantation. The efficacy objective would be met if the lower boundary of the one-sided 97.5% confidence interval for the percentage of patients with successful defibrillation was greater than 88%. The primary safety end point was freedom from major system- or procedure-related complications at 6 months. The safety objective would be met if the lower boundary of the one-sided 97.5% confidence interval for the percentage of patients free from such complications was greater than 79%. RESULTS: A total of 356 patients were enrolled, 316 of whom had an implantation attempt. Among the 302 patients in whom ventricular arrhythmia could be induced and who completed the defibrillation testing protocol, the percentage of patients with successful defibrillation was 98.7% (lower boundary of the one-sided 97.5% confidence interval [CI], 96.6%; P<0.001 for the comparison with the performance goal of 88%); 299 of 316 patients (94.6%) were discharged with a working ICD system. The Kaplan-Meier estimate of the percentage of patients free from major system- or procedure-related complications at 6 months was 92.6% (lower boundary of the one-sided 97.5% CI, 89.0%; P<0.001 for the comparison with the performance goal of 79%). No major intraprocedural complications were reported. At 6 months, 25 major complications were observed, in 23 of 316 patients (7.3%). The success rate of antitachycardia pacing, as assessed with generalized estimating equations, was 50.8% (95% CI, 23.3 to 77.8). A total of 29 patients received 118 inappropriate shocks for 81 arrhythmic episodes. Eight systems were explanted without extravascular ICD replacement over the 10.6-month mean follow-up period. CONCLUSIONS: In this prospective global study, we found that extravascular ICDs were implanted safely and were able to detect and terminate induced ventricular arrhythmias at the time of implantation. (Funded by Medtronic; ClinicalTrials.gov number, NCT04060680.).

The development of the extravascular defibrillator with substernal lead placement: A new Frontier for device-based treatment of sudden cardiac arrest.

INTRODUCTION: The extravascular implantable cardioverter-defibrillato (EV ICD) system with substernal lead placement is a novel nontransvenous alternative to current commercially available ICD systems. The EV ICD provides defibrillation and pacing therapies without the potential long-term complications of endovascular lead placement but requires a new procedure for implantation with a safety profile under evaluation. METHODS: This paper summarizes the development of the EV ICD, including the preclinical and clinical evaluations that have contributed to the system and procedural refinements to date. RESULTS: Extensive preclinical research evaluations and four human clinical studies with >140 combined acute and chronic implants have enabled the development and refinement of the EV ICD system, currently in worldwide pivotal study. CONCLUSION: The EV ICD may represent a clinically valuable solution in protecting patients from sudden cardiac death while avoiding the long-term consequences of transvenous hardware. The EV ICD offers advantages over transvenous and subcutaneous systems by avoiding placement in the heart and vasculature; relative to subcutaneous systems, EV ICD requires less energy for defibrillation, enabling a smaller device, and provides pacing features such as antitachycardia and asystole pacing in a single system.

The extravascular implantable cardioverter-defibrillator: characterization of anatomical parameters impacting substernal implantation and defibrillation efficacy.

AIMS: The aim of this study is to provide a thorough, quantified assessment of the substernal space as the site of extravascular implantable cardioverter-defibrillator (ICD) lead placement using computed tomography (CT) scans and summarizing adverse events and defibrillation efficacy across anatomical findings. Subcutaneous ICDs are an alternative to transvenous defibrillators but have limitations related to ICD lead distance from the heart. An alternative extravascular system with substernal lead placement has the potential to provide defibrillation at lower energy and pacing therapies from a single device. METHODS AND RESULTS: A multi-centre, non-randomized, retrospective analysis of 45 patient CT scans quantitatively and qualitatively assessing bony, cardiac, vascular, and other organ structures from two human clinical studies with substernal lead placement. Univariate logistic regression was used to evaluate 15 anatomical parameters for impact on defibrillation outcome and adjusted for multiple comparisons. Adverse events were summarized. Substernal implantation was attempted or completed in 45 patients. Defibrillation testing was successful in 37 of 41 subjects (90%) using ≥10 J safety margin. There were two intra-procedural adverse events in one patient, including reaction to anaesthesia and an episode of transient atrial fibrillation during ventricular fibrillation induction. Anatomical factors associated with defibrillation failure included large rib cage width, myocardium extending very posteriorly, and a low heart position in the chest (P-values <0.05), though not significant adjusting for multiple comparisons. CONCLUSION: Retrospective analysis demonstrates the ability to implant within the substernal space with low intra-procedural adverse events and high defibrillation efficacy despite a wide range of anatomical variability.

Researching, co-creating and testing innovations in paper-based health information systems (PHISICC) to support health workers' decision-making: protocol of a multi-country, transdisciplinary, mixed-methods research programme in three sub-Saharan countries.

BACKGROUND: Health information systems are crucial to provide data for decision-making and demand for data is constantly growing. However, the link between data and decisions is not always rational or linear and the management of data ends up overloading frontline health workers, which may compromise quality of healthcare delivery. Despite limited evidence, there is an increasing push for the digitalization of health information systems, which poses enormous challenges, particularly in remote, rural settings in low- and middle-income countries. Paper-based tools will continue to be used in combination with digital solutions and this calls for efforts to make them more responsive to local needs. Paper-based Health Information Systems in Comprehensive Care (PHISICC) is a transdisciplinary, multi-country research initiative to create and test innovative paper-based health information systems in three sub-Saharan African countries. METHODS/DESIGN: The PHISICC initiative is being carried out in remote, rural settings in Côte d'Ivoire, Mozambique and Nigeria through partnership with ministries of health and research institutions. We began with research syntheses to acquire the most up-to-date knowledge on health information systems. These were coupled with fieldwork in the three countries to understand the current design, patterns and contexts of use, and healthcare worker perspectives. Frontline health workers, with designers and researchers, used co-creation methods to produce the new PHISICC tools. This suite of tools is being tested in the three countries in three cluster-randomized controlled trials. Throughout the project, we have engaged with a wide range of stakeholders and have maintained the highest scientific standards to ensure that results are relevant to the realities in the three countries. DISCUSSION: We have deployed a comprehensive research approach to ensure the robustness and future policy uptake of findings. Besides the innovative PHISICC paper-based tools, our process is in itself innovative. Rather than emphasizing the technical dimensions of data management, we focused instead on frontline health workers' data use and decision-making. By tackling the whole scope of primary healthcare areas rather than a subset of them, we have developed an entirely new design and visual language for a suite of tools across healthcare areas. The initiative is being tested in remote, rural areas where the most vulnerable live.

Ventricular activation patterns during intrinsic conduction and right ventricular pacing in cardiac resynchronization therapy patients.

BACKGROUND: Cardiac resynchronization therapy (CRT) involves stimulation of both right ventricle (RV) and left ventricle (LV). LV pacing from the sites of delayed electrical activation improves CRT response. The RV-LV conduction is typically measured in intrinsic rhythm. The differences in RV-LV conduction patterns and timing between intrinsic rhythm and during paced RV activation, these differences are not fully understood. METHODS: Enrolled patients were implanted with a de novo CRT device and quadripolar LV lead, with lead implant locations at the implanting physician's discretion. QRS duration and conduction delay between the RV lead and each of the four LV electrodes (D1, M2, M3, and P4) were measured during intrinsic conduction and RV pacing. RESULTS: Conduction measurements were collected from 275 patients across 14 international centers (68 ± 13 years of age, 73% male, 45% ischemic, 158 ± 22 ms QRS duration). Mean RV-LV conduction time was shorter during intrinsic conduction versus RV pacing by 59.6 ms (106.5 ± 36.5 versus 166.1 ± 32.1 ms, p < 0.001). The intra-LV activation delay between the latest and earliest activating LV electrode was also shorter during intrinsic conduction versus RV pacing by 6.6 ms (20.6 ± 13.1 vs. 27.2 ± 21.2 ms, p < 0.001). Intrinsic conduction and RV pacing resulted in a different activation order in 72.7% of patients, and the same LV activation order in 27.3%. CONCLUSIONS: Differences in RV-LV conduction time, intra-LV conduction time, and activation pattern were observed between intrinsic conduction and RV pacing. These findings highlight the importance of evaluating intrinsic versus paced ventricular activation to guide LV pacing site selection in CRT patients.

Sex differences in Cardiac electronic device implantation: Outcomes from an Australian multi-centre clinical quality registry.

BACKGROUND: There is uncertainty regarding whether outcomes after Cardiac Implantable Electronic Devices (CIED) differ between women and men. There are no prospectively collected data regarding Australian CIED outcomes. This study aimed to determine whether the characteristics and outcomes of Australian patients undergoing CIED implantation differ by sex. METHODS: We prospectively followed 5,360 patients undergoing CIED implantation between 2015 and 2019 in a large multi-centre Australian registry. Patient characteristics, procedural data, medications and clinical outcomes to 1 year were analysed. RESULTS: The mean age was 76.2 + 11.2 years, and 2022 (37.7%) were female. Women were older than men at device implantation (77.0 ±â€¯11.6 years vs. 75.5 ±â€¯10.9 years, p < 0.001). Most implants were de novo (79.7%). Pacing was more commonly for sick sinus syndrome in women than men (54.4% vs. 47.2%, p < 0.001) and less often for A-V block (28.3% vs. 35.1%, p < 0.001). Adverse events at 30 days were low compared to international cohorts, for mortality (0.06%) and major complications (0.6%). There were no significant sex differences (women vs. men) for death (HR 1.33, 95% CI 0.58-3.13, p = 0.49) or major complications (HR 1.41, 95% 95% CI 0.65-3.03, p = 0.39). At 1-year, there was no difference in major complications or risk-adjusted all-cause mortality (HR 1.05, 95% CI 0.70-1.29, p = 0.77) between women and men. CONCLUSIONS: Clinical practice and 30-day outcomes after CIED implantation in Australia are consistent with international reports. There were no differences in procedural complication rates or clinical outcomes at 1-year between women and men, regardless of age or CIED system implanted.

The extravascular implantable cardioverter-defibrillator: The pivotal study plan.

BACKGROUND: Transvenous implantable cardioverter defibrillators (TV ICD) provide life-saving therapy for millions of patients worldwide. However, they are susceptible to several potential short- and long- term complications including cardiac perforation and pneumothorax, lead dislodgement, venous obstruction, and infection. The extravascular ICD system's novel design and substernal implant approach avoids the risks associated with TV ICDs while still providing pacing features and similar generator size to TV ICDs. STUDY DESIGN: The EV ICD pivotal study is a prospective, multicenter, single-arm, nonrandomized, premarket clinical study designed to examine the safety and acute efficacy of the system. This study will enroll up to 400 patients with a Class I or IIa indication for implantation of an ICD. Implanted subjects will be followed up to approximately 3.5 years, depending on when the patient is enrolled. OBJECTIVE: The clinical trial is designed to demonstrate safety and effectiveness of the EV ICD system in human use. The safety endpoint is freedom from major complications, while the efficacy endpoint is defibrillation success. Both endpoints will be assessed against prespecified criteria. Additionally, this study will evaluate antitachycardia pacing performance, electrical performance, extracardiac pacing sensation, asystole pacing, appropriate and inappropriate shocks, as well as a summary of adverse events. CONCLUSION: The EV ICD pivotal study is designed to provide clear evidence addressing the safety and efficacy performance of the EV ICD System.

Design and Preliminary Results of Sensing and Detection for an Extravascular Implantable Cardioverter-Defibrillator.

OBJECTIVES: This study reports the sensing and arrhythmia detection performance of a novel extravascular (EV) implantable cardioverter-defibrillator (ICD) in a first-in-human pilot study. BACKGROUND: The EV ICD lead is implanted in the substernal space, resulting in novel sensing and detection challenges. It uses a programmable sensing profile with new or modified discrimination of oversensing and of ventricular tachycardia (VT) from supraventricular tachycardia (SVT). METHODS: Electrograms were post-processed from induced ventricular fibrillation (VF) at implant to determine virtual detection times for each programmable sensitivity and the least-sensitive safe sensitivity setting. In ambulatory patients, programmed sensitivity provided at least a twofold safety margin for detecting induced VF. Noise discrimination was stress tested, and the effects of source, posture, and lead maturation were determined on electrogram amplitude. Telemetry Holter monitors were used to quantify undersensing and oversensing. RESULTS: In 20 patients at implant, the least-sensitive safe sensitivity for VF detection ranged from 0.1 to 0.6 mV. Seventeen patients were followed up for a total of 16.6 patient-years. Electrogram amplitudes were stable over time, but there were significant differences among postures and sensing vectors. For the primary sensing vector, the weighted oversensing and undersensing rates were 1.03% and 0.40% respectively, on a beat-to-beat basis. Oversensing did not cause inappropriate therapy in patients with in situ leads. Oversensing discriminators withheld VF detection in 4 of 5 spontaneous, sustained oversensed episodes. SVT-VT discriminators correctly classified 93% of 128 sustained SVTs in monitor zones. CONCLUSIONS: In the EV ICD pilot study, oversensing did not cause inappropriate therapy during ambulatory follow-up of stable leads.

Gut microbiome contributions to altered metabolism in a pig model of undernutrition.

The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, we developed a feature-selection algorithm to identify representative characteristics distinguishing DR fecal microbiomes from those of full-fed (FF) pigs as both groups consumed a common sequence of diets during their growth cycle. Gnotobiotic mice were then colonized with DR and FF microbiomes and subjected to controlled feeding with a pig diet. DR microbiomes have reduced representation of genes that degrade dominant components of late growth-phase diets, exhibit reduced production of butyrate, a key host-accessible energy source, and are causally linked to reduced hepatic fatty acid metabolism (ß-oxidation) and the selection of alternative energy substrates. The approach described could aid in the development of guidelines for microbiome stewardship in diverse species, including farm animals, in order to support their healthy growth.

Electrical synchronization achieved by multipoint pacing combined with dynamic atrioventricular delay.

PURPOSE: Multipoint pacing (MPP) improves left ventricular (LV) electrical synchrony in cardiac resynchronization therapy (CRT). SyncAV automatically adjusts atrioventricular delay (AVD) according to intrinsic AV intervals and may further improve synchrony. Their combination has not been assessed. The objective was to evaluate the improvement in electrical synchrony achieved by SyncAV combined with MPP in an international, multicenter study. METHODS: Patients with LBBB undergoing CRT implant with a quadripolar lead (Abbott Quartet™) were prospectively enrolled. QRS duration (QRSd) was measured by blinded observers from 12-lead ECG during: intrinsic conduction, BiV pacing (conventional biventricular pacing, nominal static AVD), MPP (2 LV cathodes maximally spaced, nominal static AVD), BiV + SyncAV, and MPP + SyncAV. All SyncAV offsets were individualized for each patient to yield the narrowest QRSd during BiV pacing. QRSd changes were compared by ANOVA and post hoc Tukey-Kramer tests. RESULTS: One hundred and three patients were enrolled (65.7 ± 12.1 years, 67% male, 37% ischemic, EF 26.4 ± 6.5%, PR 190.3 ± 39.1 ms). Relative to intrinsic conduction (QRSd of 165 ± 16 ms), BiV reduced QRSd by 11.9% to 145 ± 18 ms (P < 0.001 vs intrinsic), and MPP reduced QRSd by 13.3% to 142 ± 19 ms (P < 0.001 vs intrinsic). However, enabling SyncAV with a patient-optimized offset nearly doubled this QRSd reduction. BiV + SyncAV reduced QRSd by 22.0% to 128 ± 13 ms (P < 0.001 vs BiV), while MPP + SyncAV reduced QRSd further by 25.6% to 122 ± 14 ms (P < 0.05 vs BiV + SyncAV). CONCLUSION: SyncAV can significantly improve acute electrical synchrony beyond conventional CRT, with further improvement achieved by superimposing MPP.

Systematic quantification of histologic ventricular fibrosis in isolated mitral valve prolapse and sudden cardiac death.

BACKGROUND: Cardiac fibrosis in mitral valve prolapse (MVP) is implicated in the development of sudden cardiac death (SCD); however, the pattern remains poorly characterized. OBJECTIVE: The purpose of this study was to systematically quantify left and right ventricular fibrosis in individuals with isolated MVP and SCD (iMVP-SCD), whereby other potential causes of death are excluded, compared to a control cohort. METHODS: Individuals with iMVP-SCD were identified from the Victorian Institute of Forensic Medicine, Australia, and matched for age, sex, and body mass index to control cases with noncardiac death. Cardiac tissue sections were analyzed to determine collagen deposition in the left ventricular free wall (anterior, lateral, and posterior portions), interventricular septum, and right ventricle. Within the iMVP-SCD cases, the endocardial-to-epicardial distribution of fibrosis within the left ventricle was specifically characterized. RESULTS: Seventeen cases with iMVP-SCD were matched 1:1 with 17 controls, yielding 149 samples and 1788 histologic regions. The iMVP-SCD group had increased left ventricular (anterior, lateral, and posterior; all P <.001) and interventricular septum fibrosis (P <.001), but similar amounts of right ventricular fibrosis (P = .62) compared to controls. In iMVP-SCD, left ventricular fibrosis was significantly higher in the lateral and posterior walls compared to the anterior wall and interventricular septum (all P <.001). Within the lateral and posterior walls, iMVP-SCD cases had a significant endocardial-to-epicardial gradient of cardiac fibrosis (P <.01) similar to other known conditions that cause cardiac remodeling. CONCLUSION: Our study indicates that nonuniform left ventricular remodeling with both localized and generalized left ventricular fibrosis is important in the pathogenesis of SCD in individuals with MVP.

First-in-Human Chronic Implant Experience of the Substernal Extravascular Implantable Cardioverter-Defibrillator.

OBJECTIVES: The aim of this study was to evaluate the safety and performance of an extravascular (EV) implantable cardioverter-defibrillator (ICD). BACKGROUND: Limitations of existing transvenous and subcutaneous ICD systems include lead reliability and morbidity issues associated with ICD lead implantation in the vasculature or lack of pacing therapies (e.g., antitachycardia pacing) in subcutaneous systems. The EV defibrillator uses a novel substernal lead placement to address these limitations. METHODS: This was a prospective, nonrandomized, chronic pilot study conducted at 4 centers in Australia and New Zealand. Participants were 21 patients referred for ICD implantation. Patients received EV ICD systems. Data collection included major systemic and procedural adverse events, defibrillation testing at implantation, and sensing and pacing thresholds. RESULTS: Among 20 patients who underwent successful implantation, the median defibrillation threshold was 15 J, and 90% passed defibrillation testing with a ≥10-J safety margin. Mean R-wave amplitude was 3.4 ± 2.0 mV, mean ventricular fibrillation amplitude was 2.8 ± 1.7 mV, and pacing was successful in 95% at ≤10 V. There were no intraprocedural complications. Two patients have undergone elective chronic system removal since hospital discharge. In the 15 patients presently implanted, the systems are stable in long-term follow-up. CONCLUSIONS: This first-in-human evaluation of an EV ICD demonstrated the feasibility of substernal lead placement, defibrillation, and pacing with a chronically implanted system. There were no acute major complications, and pacing, defibrillation, and sensing performance at implantation were successful in most patients. (Extravascular ICD Pilot Study [EV ICD]; NCT03608670).

Sudden Cardiac Death in the Young: Incidence, Trends, and Risk Factors in a Nationwide Study.

BACKGROUND: Sudden cardiac death (SCD) in the young is devastating. Contemporary incidence remains unclear with few recent nationwide studies and limited data addressing risk factors for causes. We aimed to determine incidence, trends, causes, and risk factors for SCD in the young. METHODS AND RESULTS: The National Coronial Information System registry was reviewed for SCD in people aged 1 to 35 years from 2000 to 2016 in Australia. Subjects were identified by the International Classification of Diseases, Tenth Revision code relating to circulatory system diseases (I00-I99) from coronial reports. Baseline demographics, circumstances, and cause of SCD were obtained from coronial and police reports, alongside autopsy and toxicology analyses where available. During the study period, 2006 cases were identified (median age, 28±7 years; men, 75%; mean body mass index, 29±8 kg/m2). Annual incidence ranged from 0.91 to 1.48 per 100 000 age-specific person-years, which was the lowest in 2013 to 2015 compared with previous 3-year intervals on Poisson regression model (P=0.001). SCD incidence was higher in nonmetropolitan versus metropolitan areas (0.99 versus 0.53 per 100 000 person-years; P<0.001). The most common cause of SCD was coronary artery disease (40%), followed by sudden arrhythmic death syndrome (14%). Incidence of coronary artery disease-related SCD decreased from 2001-2003 to 2013-2015 (P<0.001). Proportion of SCD related to sudden arrhythmic death syndrome increased during the study period (P=0.02) although overall incidence was stable (P=0.22). Residential remoteness was associated with coronary artery disease-related SCD (odds ratio, 1.44 [95% CI, 1.24-1.67]; P<0.001). For every 1-unit increase, body mass index was associated with increased likelihood of SCD from cardiomegaly (odds ratio, 1.08 [95% CI, 1.05-1.11]; P<0.001) and dilated cardiomyopathy (odds ratio, 1.04 [95% CI, 1.01-1.06]; P=0.005). CONCLUSIONS: Incidence of SCD in the young and specifically coronary artery disease-related SCD has declined in recent years. Proportion of SCD related to sudden arrhythmic death syndrome increased over the study period. Geographic remoteness and obesity are risk factors for specific causes of SCD in the young.

Characteristic Histopathological Findings and Cardiac Arrest Rhythm in Isolated Mitral Valve Prolapse and Sudden Cardiac Death.

Background The association between mitral valve prolapse (MVP) and sudden death remains controversial. We aimed to describe histopathological changes in individuals with autopsy-determined isolated MVP (iMVP) and sudden death and document cardiac arrest rhythm. Methods and Results The Australian National Coronial Information System database was used to identify cases of iMVP between 2000 and 2018. Histopathological changes in iMVP and sudden death were compared with 2 control cohorts matched for age, sex, height, and weight (1 group with noncardiac death and 1 group with cardiac death). Data linkage with ambulance services provided cardiac arrest rhythm for iMVP cases. From 77 221 cardiovascular deaths in the National Coronial Information System database, there were 376 cases with MVP. Individual case review yielded 71 cases of iMVP. Mean age was 49±18 years, and 51% were women. Individuals with iMVP had higher cardiac mass (447 g versus 355 g; P<0.001) compared with noncardiac death, but similar cardiac mass (447 g versus 438 g; P=0.64) compared with cardiac death. Individuals with iMVP had larger mitral valve annulus compared with noncardiac death (121 versus 108 mm; P<0.001) and cardiac death (121 versus 110 mm; P=0.002), and more left ventricular fibrosis (79% versus 38%; P<0.001) compared with noncardiac death controls. In those with iMVP and witnessed cardiac arrest, 94% had ventricular fibrillation. Conclusions Individuals with iMVP and sudden death have increased cardiac mass, mitral annulus size, and left ventricular fibrosis compared with a matched cohort, with cardiac arrest caused by ventricular fibrillation. The histopathological changes in iMVP may provide the substrate necessary for development of malignant ventricular arrhythmias.

Real-world behavior of CRT pacing using the AdaptivCRT algorithm on patient outcomes: Effect on mortality and atrial fibrillation incidence.

BACKGROUND: The AdaptivCRT (aCRT) algorithm continuously adjusts cardiac resynchronization therapy (CRT) according to intrinsic atrioventricular conduction, providing synchronized left ventricular pacing in patients with normal PR interval and adaptive BiV pacing in patients with prolonged PR interval. Previous analyses demonstrated an association between aCRT and clinical benefit. We evaluated the incidence of patient mortality and atrial fibrillation (AF) with aCRT compared with standard CRT in a real-world population. METHODS AND RESULTS: Patients enrolled in the Medtronic Personalized CRT Registry and implanted with a CRT from 2013-2018 were divided into aCRT ON or standard CRT groups based upon device-stored data. A Frailty survival model was used to evaluate the potential survival benefit of aCRT, accounting for patient heterogeneity and center variability. Daily AF burden and first device-detected AF episodes of various durations were recorded by the device during follow-up. A total of 1814 CRT patients with no reported long-standing AF history at implant were included. Mean follow-up time was 26.1 ± 16.5 months and 1162 patients (64.1%) had aCRT ON. Patient survival probability at 36 months was 88.3% for aCRT ON and 83.7% for standard CRT (covariate-adjusted hazard ratio [HR] = 0.71, 95% CI: 0.53-0.96, P = .028). Mean AF burden during follow-up was consistently lower in aCRT ON patients compared with standard CRT. At 36 months, the probability of AF was lower in patients with aCRT ON, regardless of which AF definition threshold was applied (6 minutes-30 days, all P < .001). CONCLUSION: Use of the AdaptivCRT algorithm was associated with improved patient survival and lower incidence of AF in a real-world, prospective, nonrandomized registry.

Applying indirect open-circuit calorimetry to study energy expenditure in gnotobiotic mice harboring different human gut microbial communities.

Given the increasing use of gnotobiotic mouse models for deciphering the effects of human microbial communities on host biology, there is a need to develop new methods for characterizing these animals while maintaining their isolation from environmental microbes. We describe a method for performing open-circuit indirect calorimetry on gnotobiotic mice colonized with gut microbial consortia obtained from different human donors. In this illustrative case, cultured collections of gut bacterial strains were obtained from obese and lean co-twins. The approach allows microbial contributions to host energy homeostasis to be characterized.