Proteomics Identifies Thymidine Phosphorylase As a Key Regulator of the Angiogenic Potential of Colony-Forming Units and Endothelial Progenitor Cell Cultures

Endothelial progenitor cell (EPC) cultures and colony-forming units (CFUs) have been extensively studied for their therapeutic and diagnostic potential. Recent data suggest a role for EPCs in the release of proangiogenic factors. To identify factors secreted by EPCs, conditioned medium from EPC cultures and CFUs was analyzed using a matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometer combined with offline peptide separation by nanoflow liquid chromatography. Results were verified by RT-PCR and multiplex cytokine assays and complemented by a cellular proteomic analysis of cultured EPCs and CFUs using difference in-gel electrophoresis. This extensive proteomic analysis revealed the presence of the proangiogenic factor thymidine phosphorylase (TP). Functional experiments demonstrated that inhibition of TP by 5-bromo-6-amino-uracil or gene silencing resulted in a significant increase in basal and oxidative stress-induced apoptosis, whereas supplementation with 2-deoxy-D-ribose-1-phosphate (dRP), the enzymatic product of TP, abrogated this effect. Moreover, dRP produced in EPC cultures stimulated endothelial cell migration in a paracrine manner, as demonstrated by gene-silencing experiments in transmigration and wound repair assays. RGD peptides and inhibitory antibodies to integrin alphavbeta3 attenuated the effect of conditioned medium from EPC cultures on endothelial migration. Finally, the effect of TP on angiogenesis was investigated by implantation of Matrigel plugs in mice. In these in vivo experiments, dRP strongly promoted neovascularization. Our data support the concept that EPCs exert their proangiogenic activity in a paracrine manner and demonstrate a key role of TP activity in their survival and proangiogenic potential

Impact of inter-hospital transfer for primary percutaneous coronary intervention on survival (10 108 STEMI patients from the London Heart Attack Group)

Background Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy in patients with ST-segment elevation myocardial infarction (STEMI). We evaluated whether direct transfer to a cardiac centre performing primary percutaneous coronary intervention (PPCI) leads to improved survival compared with transfer via a non-PPCI performing hospital in STEMI patients in a regional network. Methods This was an observational cohort study of 10 108 patients with STEMI treated with PPCI between 2004 and 2011 at eight tertiary cardiac centres across London, UK. Patient ’s details were recorded at the time of the procedure into the British Cardiac Intervention Society (BCIS) database. Outcome was assessed by all-cause mortality. Anonymous datasets from the eight centres were merged for analysis. The primary end-point was all-cause mortality at a median follow-up of 3.0 years (IQR range 1.2 – 4.6 years). Results 6492 patients (64.2%) were transferred directly to a PCI performing centre (direct) and 3616, (35.8%) were transferred via a non-PCI performing centre (indirect). There were higher rates of previous MI and previous CABG in the indirect group, with higher rates of poor LV function in the direct group (table 1). Median time to reperfusion (symptom to balloon) in transferred patients was 58 min longer compared to patients admitted directly (p0.0001) at presentation compared to those transferred directly. Kaplan-Meier analysis demonstrated no significant difference in mortality rates between patients with and without transfer (12.3% direct vs 14.3% indirect, p=0.060). Age-adjusted Cox analysis revealed inter-hospital transfer for PPCI was associated with all cause mortality (HR 0.89 (95% CI 0.79 to 0.99)), however this was not maintained after multivariate adjustment (HR 0.84 (95% CI 0.62 to 1.14)). Conclusions In this large registry survival appear comparable in patients with STEMI admitted directly versus transferred for primary PCI. This is despite longer symptom to balloon times. This unexpected finding may reflect the earlier initiation of medical therapy (eg, anti-platelets and GpIIb/IIIa receptor inhibitors) and earlier pharmacological reperfusion, reflected by lower IRA TIMI 0 rates at angiography in the patients transferred from a non-PCI hospital. https://heart.bmj.com/content/heartjnl/99/suppl_2/A22.2.full.pdf This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ http://dx.doi.org/10.1136/heartjnl-2013-304019.3

Mechanical thrombectomy use is associated with decreased mortality in patients treated with primary percutaneous coronary intervention (9935 patients from the London Heart Attack Group)

Introduction During Primary Percutaneous Coronary Intervention (PPCI) post ST-Segment Myocardial Infarction (STEMI), distal embolisation of thrombus may lead to failure to re-establish normal flow in the infarct-related artery. Manual thrombus aspiration has been shown to improve coronary perfusion as assessed by time to ST-segment resolution and myocardial blush grade. Evidence supporting the benefit of thrombus aspiration on clinical outcomes, however, is limited and inconsistent. We aimed to assess the impact of manual thrombectomy on mortality in patients presenting with STEMI across all PPCI centres in London over a 5 year period from 2007 until 2012. Methods This was an observational cohort study of 9935 consecutive patients with STEMI treated with PPCI between 2007 and 2012 at eight tertiary cardiac centres across London, UK. Patient's details were recorded at the time of the procedure into the British Cardiac Intervention Society (BCIS) database. Outcome was assessed by all-cause mortality. Anonymous datasets from the eight centres were merged for analysis. The primary end-point was all-cause mortality at a median follow-up of 2.0 years (IQR range 1.1 –3.1 years). Results Of the 9935 consecutive STEMI patients presenting for PPCI, 2859 had mechanical thrombectomy. Patients who had manual thrombectomy were significantly younger (average age 60.6 vs 62.9) and were less likely to have had a previous myocardial infarction (11.9% of thrombectomy patients vs 14.7% of nonthrombectomy patients). Patients receiving manual thromectomy were found to be significantly more likely to have had PPCI via a radial approach (33.1% in thrombectomy patients vs 19.9% in nonthromectomy patients). Procedural success (defined as TIMI 3 flow at the end of procedure) was found to be significantly more likely in patients receiving manual thrombectomy (89.5% vs 86.7%) (table 1). Patients with thrombectomy use had similar unadjusted all-cause mortality rates to those without thrombectomy use (12.7% vs 16.5%, p=NS) during the 5-year follow-up period (figure 1). After multivariable adjustment thrombectomy use was associated with significantly decreased mortality rates (HR: 0.82, 95% CI 0.68 to 0.9, p=0.04). Conclusion Mechanical thrombectomy use appears to be associated with improved outcome, in the form of decreased mortality, in this large observational trial. https://heart.bmj.com/content/heartjnl/99/suppl_2/A32.2.full.pdf This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ http://dx.doi.org/10.1136/heartjnl-2013-304019.4

Coronary artery bypass graft patients treated with primary percutaneous coronary intervention have high long-term adverse event rates (10 920 STEMI patients from the London Heart Attack Group)

Background Limited information exists regarding procedural success and clinical outcomes of ST-segment elevation myocardial infarction (STEMI) in patients with previous CABG undergoing primary PCI. We sought to compare outcomes in STEMI patients undergoing primary percutaneous coronary intervention (PCI) with or without previous coronary artery bypass grafts (CABG). Methods This was an observational cohort study of 10,920 patients with STEMI who were treated with PPCI between 2004 and 2011 at eight tertiary cardiac centres across London, UK. Patient’s details were recorded at the time of the procedure into the British Cardiac Intervention Society (BCIS) database. Outcome was assessed by all-cause mortality. Anonymous datasets from the eight centres were merged for analysis. The primary end-point was all-cause mortality at a mean follow-up of 3.0 years. Results 347 (3.2%) patients had previous CABG. Patients with previous CABG were older and had more associated comorbidities than patients who have never had CABG. In patients with previous CABG, the infarct related artery (IRA) was split evenly between a bypass graft and a native vessel. Procedural success (defined as TIMI 3 flow at the end of procedure) was less likely in patients with previous CABG than in patients who had never undergone CABG (80.7 vs 88.2% respectively, p<0.001). Patients with previous CABG had higher all-cause mortality (30.1% vs 16.7%, p<=0.0001) during the follow-up period (figure 1). After multivariate adjustment this difference persisted (HR: 1.3, 95% CI 1.11 to 1.63, p=0.02). When stratifying prior CABG patients by the type of IRA (figure 2); long term MACE were significant more likely in patients who had bypass graft PCI than in patients that had native vessel PCI, 35.7% versus 20.4% (p=0.03). Conclusions Previous CABG patients with STEMI treated with primary PCI have higher long-term adverse events. The long-term outcome is also worse if the IRA is a bypass graft rather than a native coronary artery. https://heart.bmj.com/content/heartjnl/99/suppl_2/A30.full.pdf This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ http://dx.doi.org/10.1136/heartjnl-2013-304019.4

Outcome of 1051 octogenarians after primary percutaneous coronary intervention for ST elevation myocardial infarction: observational cohort from the London Heart Attack Group

Introduction The use of primary percutaneous coronary intervention (PCI) in octogenarians to treat ST elevation myocardial infarction (STEMI) is less than in other age groups. This is due in part to underrepresentation in clinical trials and perceived increased risk. We present long-term survival of a large cohort of elderly patients following primary PCI in London. Methods This was an observational study of 10 249 consecutive patients undergoing primary PCI for STEMI at eight London heart attack centres between January 2005 and November 2011. Patient’s details were recorded at the time of procedure into the British Cardiac Intervention Society (BCIS) database. Outcome was assessed by all-cause mortality. Anonymous datasets from the eight centres were merged for analysis. The primary end-point was all-cause mortality at a median follow-up of 3.0 years (IQR range 1.2–4.6 years). Results A total of 1051 octogenarians (10.3% of the study population) with an average age of 84.2 years (IQR 80–101) were treated with primary PCI during the study period. Over time, the annual proportion of octogenarians gradually increased from 9.1% in 2005 to 10.5% in 2010. Unsurprisingly, when compared to patients under 80, octogenarian STEMI patients included a higher proportion of women, and had a higher prevalence of hypertension, hypercholesterolaemia, multi-vessel disease, previous infarction and previous CABG (table 1). They additionally were less likely to undergo radial access, receive GPIIb/IIIa inhibitors or a drug-eluting stent. When compared with younger patients, primary PCI in octogenarians was less likely to achieve TIMI flow grade 3. However between 2005 and 2011 the rates of post-procedural TIMI flow grade 3 increased significantly from 80.5% in 2005 to 90% in 2011 (p for trend 0.05). The cumulative incidence of all-cause mortality during follow-up was significantly higher in the octogenarian group compared to the younger subgroup (51.6% vs 12.8%, p<0.0001) (figure 1). As expected, the hazard of death during follow-up increased with age (unadjusted HR 1.069 per year increase (95% CI 1.064 to 1.074), p<0.0001), which persisted after adjustment for other predictors of mortality (HR of 1.059 (95% CI 1.048 to 1.071), p<0.0001). Table 1 Under 80 Over 80 p Value Gender (female) 1800 (19.6%) 474 (45.4%) <0.0001 Hypertension 3692 (42.3%) 501 (51.3%) 0.02 Hypercholesterolaemia 3708 (42.5%) 548 (56.1%) <0.0001 Previous MI 1442 (16.9%) 182 (18.7%) 0.150 Previous CABG 264 (3.0%) 46 (4.6%) 0.010 Multi vessel disease 3821 (41.8%) 562 (54.0%) <0.0001 GPIIb/IIIa 6515 (74.4%) 530 (53.8%) <0.0001 DES use 4058 (45.9%) 311 (30.9%) <0.0001 Access (radial) 2115 (23.4%) 194 (18.8%) 0.001 Procedural success 6932 (88.3%) 736 (84.7%) 0.003 Figure 1 Heart May 2013 Vol 99 Suppl S2 A27 BCS Abstracts 2013 (NHS). Protected by copyright. on January 7, 2020 at Manchester University NHS Foundation Trust http://heart.bmj.com/ Heart: first published as 10.1136/heartjnl-2013-304019.37 on 24 May 2013. Downloaded from Conclusions Octogenarians constitute an important subgroup of STEMI patients. Data from London ’s experience would suggest that primary PCI rates are increasing in this group and that despite the high long term mortality, acute/year one rates survival rates are very encouraging. https://heart.bmj.com/content/heartjnl/99/suppl_2/A27.full.pdf This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ http://dx.doi.org/10.1136/heartjnl-2013-304019.3

Angiography Alone Versus Angiography Plus Optical Coherence Tomography to Guide Percutaneous Coronary Intervention: Outcomes From the Pan-London PCI Cohort.

OBJECTIVES: This study aimed to determine the effect on long-term survival of using optical coherence tomography (OCT) during percutaneous coronary intervention (PCI). BACKGROUND: Angiographic guidance for PCI has substantial limitations. The superior spatial resolution of OCT could translate into meaningful clinical benefits, although limited data exist to date about their effect on clinical endpoints. METHODS: This was a cohort study based on the Pan-London (United Kingdom) PCI registry, which includes 123,764 patients who underwent PCI in National Health Service hospitals in London between 2005 and 2015. Patients undergoing primary PCI or pressure wire use were excluded leaving 87,166 patients in the study. The primary endpoint was all-cause mortality at a median of 4.8 years. RESULTS: OCT was used in 1,149 (1.3%) patients, intravascular ultrasound (IVUS) was used in 10,971 (12.6%) patients, and angiography alone in the remaining 75,046 patients. Overall OCT rates increased over time (p < 0.0001), with variation in rates between centers (p = 0.002). The mean stent length was shortest in the angiography-guided group, longer in the IVUS-guided group, and longest in the OCT-guided group. OCT-guided procedures were associated with greater procedural success rates and reduced in-hospital MACE rates. A significant difference in mortality was observed between patients who underwent OCT-guided PCI (7.7%) compared with patients who underwent either IVUS-guided (12.2%) or angiography-guided (15.7%; p < 0.0001) PCI, with differences seen for both elective (p < 0.0001) and acute coronary syndrome subgroups (p = 0.0024). Overall this difference persisted after multivariate Cox analysis (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.26 to 0.81; p = 0.001) and propensity matching (hazard ratio: 0.39; 95% CI: 0.21 to 0.77; p = 0.0008; OCT vs. angiography-alone cohort), with no difference in matched OCT and IVUS cohorts (HR: 0.88; 95% CI: 0.61 to 1.38; p = 0.43). CONCLUSIONS: In this large observational study, OCT-guided PCI was associated with improved procedural outcomes, in-hospital events, and long-term survival compared with standard angiography-guided PCI

Complete Versus Culprit-Only Lesion Intervention in Patients With Acute Coronary Syndromes.

BACKGROUND: A large proportion of patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI) present with multivessel disease (MVD). There is uncertainty in the role of complete coronary revascularization in this group of patients. OBJECTIVES: The aim of this study was to investigate the outcomes of complete revascularization compared with culprit vessel-only intervention in a large contemporary cohort of patients undergoing percutaneous coronary intervention (PCI) for NSTEMI. METHODS: The authors undertook an observational cohort study of 37,491 NSTEMI patients treated between 2005 and 2015 at the 8 heart attack centers in London. Clinical details were recorded at the time of the procedure into local databases using the British Cardiac Intervention Society (BCIS) PCI dataset. A total of 21,857 patients (58.3%) presented with NSTEMI and MVD. Primary outcome was all-cause mortality at a median follow-up of 4.1 years (interquartile range: 2.2 to 5.8 years). RESULTS: A total of 11,737 (53.7%) patients underwent single-stage complete revascularization during PCI for NSTEMI, rates that significantly increased during the study period (p = 0.006). Those patients undergoing complete revascularization were older and more likely to be male, diabetic, have renal disease and a history of previous myocardial infarction/revascularization compared with the culprit-only revascularization group. Although crude, in-hospital major adverse cardiac event rates were similar (5.2% vs. 4.8%; p = 0.462) between the 2 groups. Kaplan-Meier analysis demonstrated significant differences in mortality rates between the 2 groups (22.5% complete revascularization vs. 25.9% culprit vessel intervention; p = 0.0005) during the follow-up period. After multivariate Cox analysis (hazard ratio: 0.90; 95% confidence interval: 0.85 to 0.97) and the use of propensity matching (hazard ratio: 0.89; 95% confidence interval: 0.76 to 0.98) complete revascularization was associated with reduced mortality. CONCLUSIONS: In NSTEMI patients with MVD, despite higher initial (in-hospital) mortality rates, single-stage complete coronary revascularization appears to be superior to culprit-only vessel PCI in terms of long-term mortality rates. This supports the need for further randomized study to confirm these findings.Dr. Dalby has received research grants from Abbott Vascular, Daiichi-Sankyo/Lily, and Sanofi; and has been a consultant for AstraZeneca, Eli Lilly, Medtronic, Edwards Lifesciences, and Boston Scientific. Dr. Smith has received speakers fees/honoraria from Boston Scientific, Abbott Vascular, Vascular Perspectives, and Biosensors Internationa