A randomised double-blind control study of early intracoronary autologous bone marrow cell infusion in acute myocardial infarction (REGENERATEAMI)

This article has been accepted for publication in European Heart Journal Published by Oxford University Press.UK Stem Cells Foundation, the Heart Cells Foundation, and Barts and the London Charity. Funding to pay the Open Access publication charges for this article was provided by the Barts Cardiovascular Biomedical Research Unit (CVBRU)

Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs

Background Genome-wide linkage studies for Alzheimer's disease have implicated several chromosomal regions as potential loci for susceptibility genes. Methods In the present study, we have combined a selection of affected relative pairs (ARPs) from the UK and the USA included in a previous linkage study by Myers et al. (Am J Med Genet, 2002), with ARPs from Sweden and Washington University. In this total sample collection of 397 ARPs, we have analyzed linkage to chromosomes 1, 9, 10, 12, 19 and 21, implicated in the previous scan. Results The analysis revealed that linkage to chromosome 19q13 close to the APOE locus increased considerably as compared to the earlier scan. However, linkage to chromosome 10q21, which provided the strongest linkage in the previous scan could not be detected. Conclusion The present investigation provides yet further evidence that 19q13 is the only chromosomal region consistently linked to Alzheimer's disease

COVID-19 and changes in activity and treatment of ST elevation MI from a UK cardiac centre.

Background: The international healthcare response to COVID-19 has been driven by epidemiological data related to case numbers and case fatality rate. Second order effects have been less well studied. This study aimed to characterise the changes in emergency activity of a high-volume cardiac catheterisation centre and to cautiously model any excess indirect morbidity and mortality. Method: Retrospective cohort study of patients admitted with acute coronary syndrome fulfilling criteria for the heart attack centre (HAC) pathway at St. Bartholomew's hospital, UK. Electronic data were collected for the study period March 16th - May 16th 2020 inclusive and stored on a dedicated research server. Standard governance procedures were observed in line with the British Cardiovascular Intervention Society audit. Results: There was a 28% fall in the number of primary percutaneous coronary interventions (PCIs) for ST elevation myocardial infarction (STEMI) during the study period (111 vs. 154) and 36% fewer activations of the HAC pathway (312 vs. 485), compared to the same time period averaged across three preceding years. In the context of 'missing STEMIs', the excess harm attributable to COVID-19 could result in an absolute increase of 1.3% in mortality, 1.9% in nonfatal MI and 4.5% in recurrent ischemia. Conclusions: The emergency activity of a high-volume PCI centre was significantly reduced for STEMI during the peak of the first wave of COVID-19. Our data can be used as an exemplar to help future modelling within cardiovascular workstreams to refine aggregate estimates of the impact of COVID-19 and inform targeted policy action

A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial

Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1–7 days post-acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary autologous BMC on LV function when delivered within 24 h of successful reperfusion therapy. Methods and results A multi-centre phase II randomized, double-blind, and placebo-controlled trial. One hundred patients with anterior AMI and significant regional wall motion abnormality were randomized to receive either intracoronary infusion of BMC or placebo (1:1) within 24 h of successful primary percutaneous intervention (PPCI). The primary endpoint was the change in left ventricular ejection fraction (LVEF) between baseline and 1 year as determined by advanced cardiac imaging. At 1 year, although LVEF increased compared with baseline in both groups, the between-group difference favouring BMC was small (2.2%; 95% confidence interval, CI: −0.5 to 5.0; P = 0.10). However, there was a significantly greater myocardial salvage index in the BMC-treated group compared with placebo (0.1%; 95% CI: 0.0–0.20; P = 0.048). Major adverse events were rare in both treatment groups. Conclusion The early infusion of intracoronary BMC following PPCI for patients with AMI and regional wall motion abnormality leads to a small non-significant improvement in LVEF when compared with placebo; however, it may play an important role in infarct remodelling and myocardial salvage.UK Stem Cells Foundation, the Heart Cells Foundation, and Barts and the London Charity. Funding to pay the Open Access publication charges for this article was provided by the Barts Cardiovascular Biomedical Research Unit (CVBRU)

Randomised trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy - the regenerate-dcm randomized phase II

The REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopathy (DCM) and significant cardiac dysfunction. Methods and results Sixty patients with DCM and left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy were randomized equally into four groups: peripheral placebo (saline), peripheral G-CSF, peripheral G-CSF and IC serum, and peripheral G-CSF and IC BMC. All patients, except the peripheral placebo group, received 5 days of G-CSF. In the IC groups, this was followed by bone marrow harvest and IC infusion of cells or serum on Day 6. The primary endpoint was LVEF change from baseline to 3 months, determined by advanced cardiac imaging. At 3 months, peripheral G-CSF combined with IC BMC therapy was associated with a 5.37% point increase in LVEF (38.30%+12.97 from 32.93%+16.46 P ¼ 0.0138), which was maintained to 1 year. This was associated with a decrease in NYHA classification, reduced NT-pro BNP, and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups. Conclusion This is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.The trial was supported by unrestricted grants from the Heart Cells Foundation and Barts and the London Charity. Chugai Pharmaceutical donated supplies of G-CSF and pharmaceutical costs. Funding to pay the Open Access publication charges for this article was provided by the Barts Cardiovascular Biomedical Research Unit (CVBRU)

Reintroduction of elective cardiac interventions in the era of COVID-19: the Barts experience.

BACKGROUND: The response to COVID-19 has required cancellation of all but the most urgent procedures; there is therefore a need for the reintroduction of a safe elective pathway. METHODS: This was a study of a pilot pathway performed at Barts Heart Centre for the admission of patients requiring elective coronary and structural procedures during the COVID-19 pandemic (April-June 2020). All patients on coronary and structural waiting lists were screened for procedural indications, urgency and adverse features for COVID-19 prognosis and discussed at dedicated multidisciplinary teams. Dedicated admission pathways involving preadmission isolation, additional consent, COVID-19 PCR testing and dedicated clean areas were used. RESULTS: 143 patients (101 coronary and 42 structural) underwent procedures (coronary angiography, percutaneous coronary intervention, transcatheter aortic valve intervention and MitralClip) during the study period. The average age was 68.2; 74% were male; and over 93% had one or more moderate COVID-19 risk factors. All patients were COVID-19 PCR negative on admission with (8.1%) COVID-19 antibody positive (swab negative). All procedures were performed successfully with low rates of procedural complications (9.8%). At 2-week follow-up, no patients had symptoms or confirmed COVID-19 infection with significant improvements in quality if life and symptoms. CONCLUSION: We demonstrated that patients undergoing coronary and structural procedures can be safely admitted during the COVID-19 pandemic, with no patients contracting COVID-19 during their admission. Reassuringly, patients reflective of typical practice, that is, those at moderate or higher risk, were treated successfully. This pilot provides important information applicable to other settings, specialties and areas to reintroduce services safely

Combined analysis of the safety of intra-coronary drug delivery during primary percutaneous coronary intervention for acute myocardial infarction: A study of three clinical trials.

Background: The local injection of novel cardioprotective study drugs prior to percutaneous coronary intervention could cause embolisation of thrombus, resulting in increased reperfusion injury and subsequent infarct size. The aim of this study was to assess the safety of the delivery of an intracoronary therapy delivered during primary percutaneous coronary intervention for acute myocardial infarction prior to the re-establishment of thrombolysis in myocardial infarction III flow. Methods: One hundred sixty-seven patients with acute myocardial infarction successfully reperfused through primary percutaneous coronary intervention and undergoing Cardiac MRI within the first week after reperfusion were studied. Patients either underwent the delivery of an intracoronary agent (IMP or placebo) prior to balloon dilatation (n = 80) or standard primary percutaneous coronary intervention procedure (n = 117). Results: Baseline characteristics were similar between the two groups. There were a similar number of successful procedures (IC IMP 75 (93.8%) vs. No IMP 114, (97.4%), p = 0.374), rates of no-reflow (IC IMP 1 (1.3%) vs. No IMP 2 (1.7%), p = 0.99) and levels of ST segment resolution (88.5% IC IMP vs. No IC IMP 87.0%, p = 0.669) between the two groups. Similar levels of microvascular obstruction were seen between the two groups with a trend to reduced infarct size, and improved ejection fractions in the IMP group. Lower MACE rates were seen in the IMP group. Conclusion: The local intracoronary infusion of potential cardioprotective agents prior to the restoration of TIMI flow in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction appears to be safe and does not increase microvascular damage. This route should be considered when testing novel cardioprotective agents.The author would like to thank National Institute for Health Research, UK and Heart Cells Foundation for the financial suppo

High loading of polygenic risk for ADHD in children with comorbid aggression

Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results: Polygenic risk for ADD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by,the aggression items. Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity

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