Safety and Efficacy of Bone Marrow Derived Progenitor Cells in Patients with Chronic Ischaemic Heart Failure

MD (res)Bone marrow stem/progenitor cell (BMSC) therapy for cardiac repair in humans is yet to fulfil the exciting potential demonstrated in preclinical experiments. This thesis presents three clinical studies addressing some of the unresolved issues regarding the ideal delivery method, the effect of patient-related factors on progenitor cell concentration/function and the possible biological mechanism(s) of action. The first study describes the intramyocardial arm of the REGENERATE-IHD trial- a randomised controlled trial assessing the efficacy of mobilised BMSCs in patients with ischaemic heart failure. In summary, 30 patients were randomised 1:1 to receive injection of BMSCs suspended in autologous serum or serum alone (control group). All patients received a 5-day course of G-CSF prior to bone marrow harvest and intramyocardial injection. At 1-year, there was a significant increase in ejection fraction, the primary end-point, in patients treated with BMSCs. There were also significant improvements in the secondary end-points of NT-proBNP and symptoms. In the second study, progenitor cell concentration and function were assessed in patients with ischaemic heart failure (IHD), dilated cardiomyopathy (DCM) and acute myocardial infarction (AMI). Findings include ageing having an inverse association with circulating CD34+ cell concentration as well as blunting the effects of G-CSF on BMSC mobilisation. DCM patients had 2 3 significantly higher baseline circulating progenitor cell concentrations compared to IHD/AMI. The final study presents preliminary data regarding a novel imaging technique to detect angiogenesis which is recognised as a potential therapeutic effect of BMSCs. Nine patients with heart failure underwent nuclear imaging using a radio-tracer peptide with a high affinity for v 3, an angiogenesis-related integrin, before and after intracoronary infusion of BMSCs/serum. Preliminary results showed detectable baseline uptake of the radio-tracer suggesting a novel finding of persistent angiogenesis following remote myocardial infarction and also hint at a tantalising possibility that BMSC infusion may lead to therapeutic angiogenesis.Heart Cells Foundation, Barts & The London Charity, Chugai Pharma UK and Cordis Corporation

Effects of five preoperative cardiovascular drugs on mortality after coronary artery bypass surgery: a retrospective analysis of an observational study of 16?192 patients

BACKGROUND: Statins reduce risk from coronary artery bypass graft (CABG) surgery, but the influence of angiotensin-converting enzyme inhibitors, alpha-2 adrenergic agonists, calcium channel blockers and beta-blockers is less clear.OBJECTIVES: We investigated the association of each of these drugs with perioperative risk, accounting for different confounders, and evaluated the class, dose-response and long-term protective effect of statins.DESIGN: A retrospective analysis of observational data.SETTING: United Kingdom.PATIENTS: Sixteen thousand one hundred and ninety-two patients who underwent CABG surgery during the period 01 January 2004 to 31 December 2013 and contributed data to Primary Care Clinical Practice Research Datalink.EXPOSURE VARIABLES: Cardiovascular drugs.OUTCOME MEASURE: Perioperative mortality within 30 days of surgery.STATISTICAL ANALYSIS: Five multivariable logistic regression models and a further Cox regression model were used to account for preexisting cardiovascular and other comorbidities along with lifestyle factors such as BMI, smoking and alcohol use.RESULTS: Exposure to statins was most prevalent (85.1% of patients), followed by beta-blockers (72.8%), angiotensin-converting enzyme inhibitors (60.5%), calcium channel blockers (42.8%) and alpha-2 adrenergic agonists (1.2%). The mortality rate was 0.8% in patients not prescribed statins and 0.4% in those on statins. Statins were associated with a statistically significant reduced perioperative mortality in all five logistic regression models with adjusted odds ratios (OR) (95% confidence interval, 95% CI) ranging from 0.26 (0.13 to 0.54) to 0.35 (0.18 to 0.67). Cox regression for perioperative mortality [adjusted hazard ratio (95% CI) 0.40 (0.20 to 0.80)] and 6-month mortality [adjusted hazard ratio (95% CI) 0.63 (0.42 to 0.92)] produced similar results. Of the statin doses tested, only simvastatin 40?mg exerted protective effects. The other cardiovascular drugs lacked consistent effects across models.CONCLUSION: Statins appear consistently protective against perioperative mortality from CABG surgery in multiple models, an effect not shared by the other cardiovascular drugs. Further data are needed on whether statins exert class and dose-response effects

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

Fractional Flow Reserve versus Angiography–Guided Management of Coronary Artery Disease: A Meta–Analysis of Contemporary Randomised Controlled Trials

Background and Aims: Randomised controlled trials (RCTs) comparing outcomes after fractional flow reserve (FFR)-guided versus angiography-guided management for obstructive coronary artery disease (CAD) have produced conflicting results. We investigated the efficacy and safety of an FFR-guided versus angiography-guided management strategy among patients with obstructive CAD. Methods: A systematic electronic search of the major databases was performed from inception to September 2022. We included studies of patients presenting with angina or myocardial infarction (MI), managed with medications, percutaneous coronary intervention, or bypass graft surgery. A meta-analysis was performed by pooling the risk ratio (RR) using a random-effects model. The endpoints of interest were all-cause mortality, MI and unplanned revascularisation. Results: Eight RCTs, with outcome data from 5077 patients, were included. The weighted mean follow up was 22 months. When FFR-guided management was compared to angiography-guided management, there was no difference in all-cause mortality [3.5% vs. 3.7%, RR: 0.99 (95% confidence interval (CI) 0.62–1.60), p = 0.98, heterogeneity (I2) 43%], MI [5.3% vs. 5.9%, RR: 0.93 (95%CI 0.66–1.32), p = 0.69, I2 42%], or unplanned revascularisation [7.4% vs. 7.9%, RR: 0.92 (95%CI 0.76–1.11), p = 0.37, I2 0%]. However, the number patients undergoing planned revascularisation by either stent or surgery was significantly lower with an FFR-guided strategy [weighted mean difference: 14 (95% CI 3 to 25)%, p =< 0.001]. Conclusion: In patients with obstructive CAD, an FFR-guided management strategy did not impact on all-cause mortality, MI and unplanned revascularisation, when compared to an angiography-guided management strategy, but led to up to a quarter less patients needing revascularisation

Preoperative chronic beta-blocker prescription in elderly patients as a risk factor for postoperative mortality stratified by preoperative blood pressure: a cohort study

Background:: Recent data suggest that beta blockers are associated with increased perioperative risk in hypertensive patients. We investigated whether beta blockers were associated with an increased risk in elderly patients with raised preoperative arterial blood pressure. Methods: We conducted a propensity-score-matched cohort study of primary care data from the UK Clinical Practice Research Datalink (2004–13), including 84 633 patients aged 65 yr or over. Conditional logistic regression models, including factors that were significantly associated with the outcome, were constructed for 30-day mortality after elective noncardiac surgery. The effects of beta blockers (primary outcome), renin–angiotensin system (RAS)inhibitors, calcium-channel blockers, thiazides, loop diuretics, and statins were investigated at systolic and diastolic arterial pressure thresholds. Results: Beta blockers were associated with increased odds of postoperative 30-day mortality in patients with systolic hypertension (defined as systolic BP &gt;140 mm Hg; adjusted odds ratio [aOR]: 1.92; 95% confidence interval [CI]: 1.05–3.51). After excluding patients for whom prior data suggest benefit from perioperative beta blockade (patients with prior myocardial infarction or heart failure), rather than adjusting for them, the point estimate shifted slightly (aOR: 2.06; 95% CI: 1.09–3.89). Compared with no use, statins (aOR: 0.35; 95% CI: 0.17–0.75)and thiazides (aOR: 0.28; 95% CI: 0.10–0.78)were associated with lower mortality in patients with systolic hypertension. Conclusions: These data suggest that the safety of perioperative beta blockers may be influenced by preoperative blood pressure thresholds. A randomised controlled trial of beta-blocker withdrawal, in select populations, is required to identify a causal relationship.</p

Outcomes following PCI in CABG candidates during the COVID‐19 pandemic: The prospective multicentre UK‐ReVasc registry

Objectives: To describe outcomes following percutaneous coronary intervention (PCI) in patients who would usually have undergone coronary artery bypass grafting (CABG). Background: In the United Kingdom, cardiac surgery for coronary artery disease (CAD) was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with “surgical disease” instead underwent PCI. Methods: Between 1 March 2020 and 31 July 2020, 215 patients with recognized “surgical” CAD who underwent PCI were enrolled in the prospective UK-ReVasc Registry (ReVR). 30-day major cardiovascular event outcomes were collected. Findings in ReVR patients were directly compared to reference PCI and isolated CABG pre-COVID-19 data from British Cardiovascular Intervention Society (BCIS) and National Cardiac Audit Programme (NCAP) databases. Results: ReVR patients had higher incidence of diabetes (34.4% vs 26.4%, P =.008), multi-vessel disease with left main stem disease (51.4% vs 3.0%, P &lt;.001) and left anterior descending artery involvement (94.8% vs 67.2%, P &lt;.001) compared to BCIS data. SYNTAX Score in ReVR was high (mean 28.0). Increased use of transradial access (93.3% vs 88.6%, P =.03), intracoronary imaging (43.6% vs 14.4%, P &lt;.001) and calcium modification (23.6% vs 3.5%, P &lt;.001) was observed. No difference in in-hospital mortality was demonstrated compared to PCI and CABG data (ReVR 1.4% vs BCIS 0.7%, P =.19; vs NCAP 1.0%, P =.48). Inpatient stay was half compared to CABG (3.0 vs 6.0 days). Low-event rates in ReVR were maintained to 30-day follow-up. Conclusions: PCI undertaken using contemporary techniques produces excellent short-term results in patients who would be otherwise CABG candidates. Longer-term follow-up is essential to determine whether these outcomes are maintained over time.</p

Complex percutaneous coronary intervention in patients unable to undergo coronary artery bypass grafting during the COVID-19 pandemic: insights from the UK-ReVasc Registry.

Cardiac surgery for coronary artery disease was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with disease ordinarily treated with coronary artery bypass grafting (CABG) instead underwent percutaneous coronary intervention (PCI). We sought to describe 12-month outcomes following PCI in patients who would typically have undergone CABG. Between March 1 and July 31, 2020, patients who received revascularization with PCI when CABG would have been the primary choice of revascularization were enrolled in the prospective, multicenter UK-ReVasc Registry. We evaluated the following major adverse cardiovascular events at 12 months: all-cause mortality, myocardial infarction, repeat revascularization, stroke, major bleeding, and stent thrombosis. A total of 215 patients were enrolled across 45 PCI centers in the United Kingdom. Twelve-month follow up data were obtained for 97% of the cases. There were 9 deaths (4.3%), 5 myocardial infarctions (2.4%), 12 repeat revascularizations (5.7%), 1 stroke (0.5%), 3 major bleeds (1.4%), and no cases of stent thrombosis. No difference in the primary endpoint was observed between patients who received complete vs incomplete revascularization (residual SYNTAX score £ 8 vs &gt; 8) (P = .22). In patients with patterns of coronary disease in whom CABG would have been the primary therapeutic choice outside of the pandemic, PCI was associated with acceptable outcomes at 12 months of follow-up. Contemporary randomized trials that compare PCI to CABG in such patient cohorts may be warranted