Five-year follow-up of intracoronary autologous cell therapy in acute myocardial infarction: the REGENERATE-AMI trial

Aims: The long-term outcomes of the intracoronary delivery of autologous bone marrow-derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE-AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo. Methods and results: A 5 year follow-up of major adverse cardiac events (defined as the composite of all-cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC-treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non-cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group. Conclusion: This 5 year follow-up analysis of the REGENERATE-AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index

The impact of the COVID-19 pandemic on the delivery of primary percutaneous coronary intervention in STEMI

Objectives: The clinical environment has been forced to adapt to meet the unprecedented challenges posed by the COVID-19 pandemic. Intensive care facilities were expanded in anticipation of the pandemic where the consequences include severe delays in elective procedures. Emergent procedures such as Percutaneous Coronary Intervention (PCI) in acute myocardial infarction (AMI) in which delays in timely delivery have well established adverse prognostic effects must also be explored in the context of changes in procedure and public behaviour associated with the COVID-19 pandemic. The aim for this single centre retrospective cohort study is to determine if door-to-balloon (D2B) times in PCI for ST Elevation Myocardial Infarction (STEMI) during the United Kingdom’s first wave of the COVID-19 pandemic differed from pre-COVID-19 populations. Methods: Data was extracted from our single centre PCI database for all patients that underwent pPCI for STEMI. The reference (Pre-COVID-19) cohort was collected over the period 01-03-2019 to 31-05-2019 and the exposure group (COVID-19) over the period 01-03-2020 to 31-05-2020. Baseline patient characteristics for both populations were extracted. The primary outcome measurement was D2B times. Secondary outcome measurements included: time of symptom onset to call for help, transfer time to first hospital, transfer time from non-PCI to PCI centre, time from call-to-help to PCI centre, time to table and onset of symptoms to balloon time. Categorical and continuous variables were assessed with Chi squared and Mann-Whitney U analysis respectively. Procedural times were calculated and compared in the context of heterogeneity findings. Results: 4 baseline patient characteristics were unbalanced between populations with statistical significance (P<0.05). The pre-covid-19 cohort was more likely to have suffered out of hospital cardiac arrest (OHCA) and had left circumflex disease, whereas the 1st wave cohort were more likely to have been investigated with left ventriculography and be of Afro-Caribbean origin. No statistically significant difference in in-hospital procedural times was found with D2B, C2B, O2B times comparable between groups. Pre-hospital delays were the greatest contributors in missed target times: the 1st wave group had significantly longer delayed time of symptom onset to call for help (Control: 31 mins; IQR [82.5] vs 1st wave: 60 mins; IQR [90.0], P=0.001) and time taken from call for help to arrival at the PCI hospital (control: 72 mins; IQR [23] vs 1st wave: 80 mins; IQR [66.5], P=0.042). Conclusion: Enhanced infection prevention and control procedures considering the COVID-19 pandemic did not impede the delivery of pPCI in our single centre cohort. The public health impact of the pandemic has been demonstrated with times being significantly impacted by patient related delays. The recovery of public engagement in emergency medical services must become the focus for public health initiatives as we emerge from the height of COVID-19 disease burden in the UK.Publisher PDFPeer reviewe

Cardiovascular magnetic resonance imaging of myocardial oedema following acute myocardial infarction: Is whole heart coverage necessary?

© 2016 Hamshere et al. Background: AAR measurement is useful when assessing the efficacy of reperfusion therapy and novel cardioprotective agents after myocardial infarction. Multi-slice (Typically 10-12) T2-STIR has been used widely for its measurement, typically with a short axis stack (SAX) covering the entire left ventricle, which can result in long acquisition times and multiple breath holds. This study sought to compare 3-slice T2-short-tau inversion recovery (T2- STIR) technique against conventional multi-slice T2-STIR technique for the assessment of area at risk (AAR). Methods: CMR imaging was performed on 167 patients after successful primary percutaneous coronary intervention. 82 patients underwent a novel 3-slice SAX protocol and 85 patients underwent standard 10-slice SAX protocol. AAR was obtained by manual endocardial and epicardial contour mapping followed by a semi- automated selection of normal myocardium; the volume was expressed as mass (%) by two independent observers. Results: 85 patients underwent both 10-slice and 3-slice imaging assessment showing a significant and strong correlation (intraclass correlation coefficient = 0.92;p < 0.0001) and a low Bland-Altman limit (mean difference -0.03 ± 3.21 %, 95 % limit of agreement,- 6.3 to 6.3) between the 2 analysis techniques. A further 82 patients underwent 3-slice imaging alone, both the 3-slice and the 10-slice techniques showed statistically significant correlations with angiographic risk scores (3-slice to BARI r = 0.36, 3-slice to APPROACH r = 0.42, 10-slice to BARI r = 0.27, 10-slice to APPROACH r = 0.46). There was low inter-observer variability demonstrated in the 3-slice technique, which was comparable to the 10-slice method (z = 1.035, p = 0.15). Acquisition and analysis times were quicker in the 3-slice compared to the 10-slice method (3-slice median time: 100 seconds (IQR: 65-171 s) vs (10-slice time: 355 seconds (IQR: 275-603 s); p < 0.0001. Conclusions: AAR measured using 3-slice T2-STIR technique correlates well with standard 10-slice techniques, with no significant bias demonstrated in assessing the AAR. The 3-slice technique requires less time to perform and analyse and is therefore advantageous for both patients and clinicians

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe