THE THERAPEUTIC USE OF ADULT AUTOLOGOUS BONE MARROW DERIVED CELLS IN ISCHAEMIC CARDIOMYOPATHY

The effect of combined cytokine and cell therapy in ischaemic cardiomyopathy is unclear. Meta-analyses suggest improved cardiac function with cell therapy. The optimal cell delivery route remains unclear. The mechanism of effect on cardiac function with cell therapy remains to be elucidated. This thesis aims to address these unanswered questions. Chapter 1 introduces cell therapy in ischaemic cardiomyopathy. Chapter 2 details the methods. This thesis can be divided into three projects. The first project investigates whether granulocyte-colony stimulating factor (G-CSF) alone or in combination with intracoronary (IC) or intramyocardial (IM) injection of autologous bone marrow-derived cells (BMC) improves cardiac function as well as functional and biochemical parameters in patients with ischaemic cardiomyopathy. Chapter 3 details the results of the study which suggests an improvement in cardiac function, patient functional characteristics and biochemical parameters in patients who received IM BMC therapy along with G-CSF. The second and third projects assess the mechanisms by which improvements in cardiac function and/or symptoms may have occurred. The second study looked at the association between various pro- and anti-inflammatory cytokines as well as pro-angiogenic cytokines with G-CSF/cell therapy. Chapter 4 details the results of the cytokine sub-study. Important signals were observed including a reduction in certain pro-inflammatory cytokines (e.g. MCP-1, IL-8 and IL-1b) and an increase in the pro-angiogenic cytokine VEGF in the group with a significant improvement in cardiac function at 1 year i.e. the IM BMC group. The third project (chapter 5) looked at myocardial scar, diastolic function and cell characteristics in relation to G-CSF/cell therapy and cardiac function. The results highlighted important correlations including a significant association between colony-forming unit granulocyte-macrophage counts and improvement in cardiac function in the IM BMC group. Lastly, in chapter 6, I discuss the findings and the implications of the research in everyday practice

An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial

This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute of Health Research. This work was funded by unrestricted grants from the Heart Cells Foundation, Barts, and the London Charity and Chugai Pharmaceuticals

Emergent Percutaneous Rotational Atherectomy to Bailout Surgical Transapical Aortic Valve Implantation: A Successful Case of Heart Team Turnaround.

Transcatheter aortic valve implantation (TAVI) is an established treatment for severe aortic stenosis (AS) in patients with elevated surgical risk. Concomitant coronary artery disease affects 55-70% of patients with severe AS. Percutaneous coronary intervention in patients with TAVI can be challenging. We report a case of acute coronary obstruction immediately following transapical TAVI deployment requiring emergent rotational atherectomy

Impact of COVID-19 pandemic on patients with ST-segment elevation myocardial infarction: Insights from a British cardiac center

The current study aimed to examine the impact of COVID-19 pandemic on patient-related delay with ST-segment elevation myocardial infarction (STEMI) at a tertiary center in the United Kingdom. The study demonstrated a significant delay in symptom-to-first medical contact and a higher cardiac troponin-I level on admission in patients with STEMI during the COVID-19 pandemic versus the pre-COVID era

Meta-analysis comparing direct oral anticoagulants to vitamin K antagonists for the management of left ventricular thrombus

Introduction: To compare vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) treatment in patients with left ventricular (LV) thrombus. The primary outcome was stroke or systemic embolism (SSE). Secondary outcomes were thrombus resolution, bleeding, and death.  Areas covered: Five observational studies were included (total n = 700; VKAs n = 480; DOACs n = 220). There was a trend toward less SSE with VKAs compared to DOACs (5.2% vs. 9%; odds ratio [OR] = 0.54, 95% confidence interval [CI] = 0.29–1.01, p = 0.05). No significant difference between VKAs and DOACs in rates of thrombus resolution (61.6% vs. 56.8%; OR = 1.00, 95% CI = 0.58–1.73, p = 0.99), bleeding (8.2% vs. 4.4%; OR = 1.62, 95% CI = 0.69–3.77, p = 0.27), or death (12.7% vs. 11.8%; OR = 1.09, 95% CI = 0.59–2.0, p = 0.79) was noted. In non-primary percutaneous coronary intervention setting, VKAs were associated with less SSE in prespecified analysis (5.2% vs.10.6%; OR = 0.48, 95% CI = 0.25–0.93, p = 0.03).  Expert opinion: The current meta-analysis suggests a trend toward higher SSE with the use of DOACs compared to VKAs. Our recommendation is for VKAs to retain the preferred management of LV thrombus with cautious off-label use of DOACs

Clinical feasibility study to detect angiogenesis following bone marrow stem cell transplantation in chronic ischaemic heart failure

Background: Bone marrow stem cell (BMSC) therapy for cardiovascular disease has shown considerable preclinical and clinical promise, but there remains a need for mechanistic studies to help bridge the transition from bench to bedside. We have designed a substudy to our REGENERATE-IHD trial (ClinicalTrial.gov Identifier: NCT00747708) to assess the feasibility of a novel imaging technique to detect angiogenesis following BMSC therapy. Methods and Results: Nine patients who had been randomized to receive intracoronary injection of G-CSF-mobilized BMSCs or control (serum) were included in this substudy. Patients underwent SPECT imaging using a novel radiolabelled peptide (99mTc-NC100692), which has a high affinity for the αvβ3 integrin, an angiogenesis-related integrin. This was repeated 4 days after intracoronary injection of BMSCs/control to assess for neoangiogenesis. The imaging study was well tolerated with no adverse effects. Myocardial tracer uptake was detectable at baseline in all nine patients, with no myocardial uptake seen in two control patients used for comparison. Baseline uptake appeared to correlate with baseline ejection fraction but changes with therapy did not reach statistical significance. Conclusion: SPECT imaging with a 99mTc-NC100692 is feasible in patients with heart failure, with baseline activity suggesting persistent angiogenesis in patients with remote myocardial infarction

Pre-operative use of aspirin in patients undergoing coronary artery bypass grafting: a systematic review and updated meta-analysis

Background: Aspirin therapy improves saphenous vein graft (SVG) patency in patients undergoing coronary artery bypass graft (CABG), however, its use in the pre-operative period remains controversial. Therefore, we conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) to update the evidence about risk and benefits of pre-operative aspirin therapy in patients undergoing CABG.Methods: Electronic databases (Medline, Embase, PubMed, Cochrane Library, and Scopus) were searched to identify RCTs evaluating the effect of aspirin versus placebo/control before CABG. Two investigators independently and in duplicate screened citations and extracted data and rated the risk of bias. The strength of evidence was appraised using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Meta-analysis was performed using a random-effects model. The main outcomes of interest were 30-day mortality, peri-operative myocardial infarction (MI), chest tube drainage and SVG occlusion.Results: A total of 13 RCTs involving 4,377 participants (2,266/2,111 pre-operative aspirin/control) met the inclusion criteria. Pre-operative aspirin reduced the risk of SVG occlusion [risk ratio (RR): 0.69, 95% confidence interval (CI): 0.49-0.97, P=0.03, I-2=16%], but no differences in mortality (RR: 1.41, 95% Cl: 0.73-2.74, I-2=0%) and MI (RR: 0.84, 95% CI: 0.69-1.03, I-2=0%) were found. However, pre-operative aspirin increased chest tube drainage (MD: 100.40 mL, 95% CI: 24.32-176.47 mL, P=0.01, I-2=84%) and surgical re-exploration (RR: 1.52, 95% CI: 1.02-2.27, P=0.04, I-2=8%), with no significant difference in RBC transfusion (RR: 1.06, 95% CI: 0.90-1.25, I-2=35%).Conclusions: Based on trials where the rated body of evidence was of low to very-low quality, pre-operative aspirin improves SVG patency but increases chest tube drainage and need for surgical re-exploration

Erratum to pre-operative use of aspirin in patients undergoing coronary artery bypass grafting: a systematic review and updated meta-analysis

[This corrects the article DOI: 10.21037/jtd.2018.05.187.]