Telomere dynamics during aging in polygenic left ventricular hypertrophy.

Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk.

Trends in use of intraosseous and intravenous access in out-of-hospital cardiac arrest across English ambulance services: A registry-based, cohort study.

INTRODUCTION: The optimum route for drug administration in cardiac arrest is unclear. Recent data suggest that use of the intraosseous route may be increasing. This study aimed to explore changes over time in use of the intraosseous and intravenous drug routes in out-of-hospital cardiac arrest in England. METHODS: We extracted data from the UK Out-of-Hospital Cardiac Arrest Outcomes registry. We included adult out-of-hospital cardiac arrest patients between 2015-2020 who were treated by an English Emergency Medical Service that submitted vascular access route data to the registry. The primary outcome was any use of the intraosseous route during cardiac arrest. We used logistic regression models to describe the association between time (calendar month) and intraosseous use. RESULTS: We identified 75,343 adults in cardiac arrest treated by seven Emergency Medical Service systems between January 2015 and December 2020. The median age was 72 years, 64% were male and 23% presented in a shockable rhythm. Over the study period, the percentage of patients receiving intraosseous access increased from 22.8% in 2015 to 42.5% in 2020. For each study-month, the odds of receiving any intraosseous access increased by 1.019 (95% confidence interval 1.019 to 1.020, p < 0.001). This observed effect was consistent across sensitivity analyses. We observed a corresponding decrease in use of intravenous access. CONCLUSION: In England, the use of intraosseous access in out-of-hospital cardiac arrest has progressively increased over time. There is an urgent need for randomised controlled trials to evaluate the clinical effectiveness of the different vascular access routes in cardiac arrest.

Three-year trends in out-of-hospital cardiac arrest across the world: Second report from the International Liaison Committee on Resuscitation (ILCOR).

BACKGROUND: The International Liaison Committee on Resuscitation (ILCOR) Research and Registries Working Group previously reported data on systems of care and outcomes of out-of-hospital cardiac arrest (OHCA) in 2015 from 16 national and regional registries. To describe the temporal trends with updated data on OHCA, we report the characteristics of OHCA from 2015 through 2017. METHODS: We invited national and regional population-based OHCA registries for voluntary participation and included emergency medical services (EMS)-treated OHCA. We collected descriptive summary data of core elements of the latest Utstein style recommendation during 2016 and 2017 at each registry. For registries that participated in the previous 2015 report, we also extracted the 2015 data. RESULTS: Eleven national registries in North America, Europe, Asia, and Oceania, and 4 regional registries in Europe were included in this report. Across registries, the estimated annual incidence of EMS-treated OHCA was 30.0-97.1 individuals per 100,000 population in 2015, 36.4-97.3 in 2016, and 40.8-100.2 in 2017. The provision of bystander cardiopulmonary resuscitation (CPR) varied from 37.2% to 79.0% in 2015, from 2.9% to 78.4% in 2016, and from 4.1% to 80.3% in 2017. Survival to hospital discharge or 30-day survival for EMS-treated OHCA ranged from 5.2% to 15.7% in 2015, from 6.2% to 15.8% in 2016, and from 4.6% to 16.4% in 2017. CONCLUSION: We observed an upward temporal trend in provision of bystander CPR in most registries. Although some registries showed favourable temporal trends in survival, less than half of registries in our study demonstrated such a trend.

Location of out-of-hospital cardiac arrests and automated external defibrillators in relation to schools in an English ambulance service region.

Introduction: This study sought to identify the availability of automated external defibrillators (AEDs) in schools in the region served by West Midlands Ambulance Service University NHS Trust (WMAS), United Kingdom, and the number of out-of-hospital cardiac arrests (OHCA) that occurred at or near to schools. A secondary aim was to explore the cost effectiveness of school-based defibrillators. Methods: This observational study used data from the national registry for OHCA (University of Warwick) to identify cases occurring at or near schools between January 2014 and December 2016 in WMAS region (n = 11,399). A school survey (n = 2,453) was carried out in September 2017 to determine the presence of AEDs and their registration status with WMAS. Geographical Information System mapping software identified OHCAs occurring within a 300-metre radius of a school. An economic analysis calculated the cost effectiveness of school-based AEDs. Results: A total of 39 (0.34%) of all OHCAs occurred in schools, although 4,250 (37.3%) of OHCAs in the region were estimated to have occurred within 300 metres of a school. Of 323 school survey responses, 184 (57%) had an AED present, of which 24 (13.0%) were available 24 h/day. Economic modelling of a school-based AED programme showed additional quality-adjusted life years (QALY) of 0.26 over the lifetime of cardiac arrest survivors compared with no AED programme. The incremental cost-effectiveness ratio (ICER) was £8,916 per QALY gained. Conclusion: Cardiac arrests in schools are rare. Registering AEDs with local Emergency Medical Services and improving their accessibility within their local community would increase their utility.

Risk prediction models for out-of-hospital cardiac arrest outcomes in England.

AIMS: The out-of-hospital cardiac arrest (OHCA) outcomes project is a national research registry. One of its aims is to explore sources of variation in OHCA survival outcomes. This study reports the development and validation of risk prediction models for return of spontaneous circulation (ROSC) at hospital handover and survival to hospital discharge. METHODS AND RESULTS: The study included OHCA patients who were treated during 2014 and 2015 by emergency medical services (EMS) from seven English National Health Service ambulance services. The 2014 data were used to identify important variables and to develop the risk prediction models, which were validated using the 2015 data. Model prediction was measured by area under the curve (AUC), Hosmer-Lemeshow test, Cox calibration regression, and Brier score. All analyses were conducted using mixed-effects logistic regression models. Important factors included age, gender, witness/bystander cardiopulmonary resuscitation (CPR) combined, aetiology, and initial rhythm. Interaction effects between witness/bystander CPR with gender, aetiology and initial rhythm and between aetiology and initial rhythm were significant in both models. The survival model achieved better discrimination and overall accuracy compared with the ROSC model (AUC = 0.86 vs. 0.67, Brier score = 0.072 vs. 0.194, respectively). Calibration tests showed over- and under-estimation for the ROSC and survival models, respectively. A sensitivity analysis individually assessing Index of Multiple Deprivation scores and location in the final models substantially improved overall accuracy with inconsistent impact on discrimination. CONCLUSION: Our risk prediction models identified and quantified important pre-EMS intervention factors determining survival outcomes in England. The survival model had excellent discrimination.

Out-of-hospital cardiac arrest across the World: First report from the International Liaison Committee on Resuscitation (ILCOR).

BACKGROUND: Since development of the Utstein style recommendations for the uniform reporting of cardiac arrest, increasing numbers of national and regional out-of-hospital cardiac arrest (OHCA) registries have been established worldwide. The International Liaison Committee on Resuscitation (ILCOR) created the Research and Registries Working Group and aimed to systematically report data collected from these registries. METHODS: We conducted two surveys of voluntarily participating national and regional registries. The first survey aimed to identify which core elements of the current Utstein style for OHCA were collected by each registry. The second survey collected descriptive summary data from each registry. We chose the data collected for the second survey based on the availability of core elements identified by the first survey. RESULTS: Seven national and four regional registries were included in the first survey and nine national and seven regional registries in the second survey. The estimated annual incidence of emergency medical services (EMS)-treated OHCA was 30.0-97.1 individuals per 100,000 population. The combined data showed the median age varied from 64 to 79 years and more than half were male in all 16 registries. The provision of bystander cardiopulmonary resuscitation (CPR) and bystander automated external defibrillator (AED) use was 19.1-79.0% in all registries and 2.0-37.4% among 11 registries, respectively. Survival to hospital discharge or 30-day survival after EMS-treated OHCA was 3.1-20.4% across all registries. Favorable neurological outcome at hospital discharge or 30 days after EMS-treated OHCA was 2.8-18.2%. Survival to hospital discharge or 30-day survival after bystander-witnessed shockable OHCA ranged from 11.7% to 47.4% and favorable neurological outcome from 9.9% to 33.3%. CONCLUSION: This report from ILCOR describes data on systems of care and outcomes following OHCA from nine national and seven regional registries across the world. We found variation in reported survival outcomes and other core elements of the current Utstein style recommendations for OHCA across nations and regions.

Survival after out-of-hospital cardiac arrest in Europe - Results of the EuReCa TWO study.

BACKGROUND: The epidemiology and outcome after out-of-hospital cardiac arrest (OHCA) varies across Europe. Following on from EuReCa ONE, the aim of this study was to further explore the incidence of and outcomes from OHCA in Europe and to improve understanding of the role of the bystander. METHODS: This prospective, multicentre study involved the collection of registry-based data over a three-month period (1st October 2017 to 31st December 2017). The core study dataset complied with the Utstein-style. Primary outcomes were return of spontaneous circulation (ROSC) and survival to hospital admission. Secondary outcome was survival to hospital discharge. RESULTS: All 28 countries provided data, covering a total population of 178,879,118. A total of 37,054 OHCA were confirmed, with CPR being started in 25,171 cases. The bystander cardiopulmonary resuscitation (CPR) rate ranged from 13% to 82% between countries (average: 58%). In one third of cases (33%) ROSC was achieved and 8% of patients were discharged from hospital alive. Survival to hospital discharge was higher in patients when a bystander performed CPR with ventilations, compared to compression-only CPR (14% vs. 8% respectively). CONCLUSION: In addition to increasing our understanding of the role of bystander CPR within Europe, EuReCa TWO has confirmed large variation in OHCA incidence, characteristics and outcome, and highlighted the extent to which OHCA is a public health burden across Europe. Unexplained variation remains and the EuReCa network has a continuing role to play in improving the quality management of resuscitation.

Characteristics of neighbourhoods with high incidence of out-of-hospital cardiac arrest and low bystander cardiopulmonary resuscitation rates in England.

Aims: The aim of the project was to identify the neighbourhood characteristics of areas in England where out-of-hospital cardiac arrest (OHCA) incidence was high and bystander cardiopulmonary resuscitation (BCPR) was low using registry data. Methods and results: Analysis was based on 67 219 cardiac arrest events between 1 April 2013 and 31 December 2015. Arrest locations were geocoded to give latitude/longitude. Postcode district was chosen as the proxy for neighbourhood. High-risk neighbourhoods, where OHCA incidence based on residential population was >127.6/100 000, or based on workday population was >130/100 000, and BCPR in bystander witnessed arrest was <60% were observed to have: a greater mean residential population density, a lower workday population density, a lower rural-urban index, a higher proportion of people in routine occupations and lower proportion in managerial occupations, a greater proportion of population from ethnic minorities, a greater proportion of people not born in UK, and greater level of deprivation. High-risk areas were observed in the North-East, Yorkshire, South-East, and Birmingham. Conclusion: The study identified neighbourhood characteristics of high-risk areas that experience a high incidence of OHCA and low bystander resuscitation rate that could be targeted for programmes of training in cardiopulmonary resuscitation and automated external defibrillator use.

Attitudes to Cardiopulmonary Resuscitation and Defibrillator Use: A Survey of UK Adults in 2017.

Background Bystander cardiopulmonary resuscitation ( CPR ) and public access defibrillator ( PAD ) use can save the lives of people who experience out-of-hospital cardiac arrest. Little is known about the proportions of UK adults trained, their characteristics and willingness to act if witnessing an out-of-hospital cardiac arrest, or the public's knowledge regarding where the nearest PAD is located. Methods and Results An online survey was administered by YouGov to a nonprobabilistic purposive sample of UK adults, achieving 2084 participants, from a panel that was matched to be representative of the population. We used descriptive statistics and multivariate logistic regression modeling for analysis. Almost 52% were women, 61% were aged <55 years, and 19% had witnessed an out-of-hospital cardiac arrest. Proportions ever trained were 57% in chest-compression-only CPR, 59% in CPR , and 19.4% in PAD use. Most with training in any resuscitation technique had trained at work (54.7%). Compared with people not trained, those trained in PAD use said they were more likely to use one (odds ratio: 2.61), and those trained in CPR or chest-compression-only CPR were more likely to perform it (odds ratio: 5.39). Characteristics associated with being trained in any resuscitation technique included youth, female sex, higher social grade, and full-time employment. Conclusions In the United Kingdom, training makes a difference in people's willingness to act in the event of a cardiac arrest. Although there is considerable opportunity to increase the proportion of the general population trained in CPR , consideration should be also given to encouraging training in PAD use and targeting training for those who are older or from lower social grades.

Data quality and 30-day survival for out-of-hospital cardiac arrest in the UK out-of-hospital cardiac arrest registry: a data linkage study.

OBJECTIVES: The Out-of-Hospital Cardiac Arrest Outcomes (OHCAO) project aims to understand the epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) across the UK. This data linkage study is a subproject of OHCAO. The aim was to establish the feasibility of linking OHCAO data to National Health Service (NHS) patient demographic data and Office for National Statistics (ONS) date of death data held on the NHS Personal Demographics Service (PDS) database to improve OHCAO demographic data quality and enable analysis of 30-day survival from OHCA. DESIGN AND SETTING: Data were collected from 1 January 2014 to 31 December 2014 as part of a prospective, observational study of OHCA attended by 10 English NHS Ambulance Services. 28 729 OHCA cases had resuscitation attempted by Emergency Medical Services and were included in the study. Data linkage was carried out using a data linkage service provided by NHS Digital, a national provider of health-related data. To assess data linkage feasibility a random sample of 3120 cases was selected. The sample was securely transferred to NHS Digital to be matched using OHCAO patient demographic data to return previously missing demographic data and provide ONS date of death data. RESULTS: A total of 2513 (80.5%) OHCAO cases were matched to patients in the NHS PDS database. Using the linkage process, missing demographic data were retrieved for 1636 (72.7%) out of 2249 OHCAO cases that had previously incomplete demographic data. Returned ONS date of death data allowed analysis of 30-day survival status. The results showed a 30-day survival rate of 9.3%, reducing unknown survival status from 46.1% to 8.5%. CONCLUSIONS: In this sample, data linkage between the OHCAO registry and NHS PDS database was shown to be feasible, improving demographic data quality and allowing analysis of 30-day survival status.

Epidemiology and outcomes from out-of-hospital cardiac arrests in England.

INTRODUCTION: This study reports the epidemiology and outcomes from out-of-hospital cardiac arrest (OHCA) in England during 2014. METHODS: Prospective observational study from the national OHCA registry. The incidence, demographic and outcomes of patients who were treated for an OHCA between 1st January 2014 and 31st December 2014 in 10 English ambulance service (EMS) regions, serving a population of almost 54 million, are reported in accordance with Utstein recommendations. RESULTS: 28,729 OHCA cases of EMS treated cardiac arrests were reported (53 per 100,000 of resident population). The mean age was 68.6 (SD=19.6) years and 41.3% were female. Most (83%) occurred in a place of residence, 52.7% were witnessed by either the EMS or a bystander. In non-EMS witnessed cases, 55.2% received bystander CPR whilst public access defibrillation was used rarely (2.3%). Cardiac aetiology was the leading cause of cardiac arrest (60.9%). The initial rhythm was asystole in 42.4% of all cases and was shockable (VF or pVT) in 20.6%. Return of spontaneous circulation at hospital transfer was evident in 25.8% (n=6302) and survival to hospital discharge was 7.9%. CONCLUSION: Cardiac arrest is an important cause of death in England. With less than one in ten patients surviving, there is scope to improve outcomes. Survival rates were highest amongst those who received bystander CPR and public access defibrillation.

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.

Tripartite motif-containing 55 identified as functional candidate for spontaneous cardiac hypertrophy in the rat locus cardiac mass 22.

BACKGROUND: Left ventricular (LV) hypertrophy is a risk factor for cardiovascular death, but the genetic factors determining LV size and predisposition to hypertrophy are not well understood. We have previously linked the quantitative trait locus cardiac mass 22 (Cm22) on chromosome 2 with cardiac hypertrophy independent of blood pressure in the spontaneously hypertensive rat. From an original cross of spontaneously hypertensive rat with F344 rats, we derived a normotensive polygenic model of spontaneous cardiac hypertrophy, the hypertrophic heart rat (HHR) and its control strain, the normal heart rat (NHR). METHODS AND RESULTS: To identify the genes and molecular mechanisms underlying spontaneous LV hypertrophy we sequenced the HHR genome with special focus on quantitative trait locus Cm22. For correlative analyses of function, we measured global RNA transcripts in LV of neonatal HHR and NHR and 198 neonatal rats of an HHR × NHR F2 crossbred population. Only one gene within locus Cm22 was differentially expressed in the parental generation: tripartite motif-containing 55 (Trim55), with mRNA downregulation in HHR (P < 0.05) and reduced protein expression. Trim55 mRNA levels were negatively correlated with LV mass in the F2 cross (r = -0.16, P = 0.025). In exon nine of Trim55 in HHR, we found one missense mutation that functionally alters protein structure. This mutation was strongly associated with Trim55 mRNA expression in F2 rats (F = 10.35, P < 0.0001). Similarly, in humans, we found reduced Trim55 expression in hearts of subjects with idiopathic dilated cardiomyopathy. CONCLUSION: Our study suggests that the Trim55 gene, located in Cm22, is a novel candidate gene for polygenic LV hypertrophy independent of blood pressure.