Daniel I. Bromage

Culprit Vessel Versus Multivessel Intervention at the Time of Primary Percutaneous Coronary Intervention in Patients With ST-Segment–Elevation Myocardial Infarction and Multivessel Disease: Real-World Analysis of 3984 Patients in London

Background—It is estimated that up to two thirds of patients presenting with ST-segment–elevation myocardial infarction have multivessel disease. The optimal strategy for treating nonculprit disease is currently under debate. This study provides a real-world analysis comparing a strategy of culprit-vessel intervention (CVI) versus multivessel intervention at the time of primary percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction. Methods and Results—We compared CVI versus multivessel intervention in 3984 patients with multivessel disease undergoing primary percutaneous coronary intervention between 2004 and 2011 at all 8 tertiary cardiac centers in London. Multivariable-adjusted models were built to determine independent predictors for in-hospital major adverse cardiovascular events (MACEs) and all-cause mortality at 1 year. To reduce confounding and bias, propensity score methods were used. CVI was associated with reduced in-hospital MACE (4.6% versus 7.2%; P=0.010) and mortality at 1 year (7.4% versus 10.1%; P=0.031). CVI was an independent predictor for reduced in-hospital MACE (odds ratio, 0.49; 95% confidence interval [CI], 0.32–0.75; P<0.001) and survival at 1 year (hazard ratio, 0.65; 95% CI, 0.47–0.91; P=0.011) in the complete cohort; and in 2821 patients in propensity-matched cohort (in-hospital MACE: odds ratio, 0.49; 95% CI, 0.32–0.76; P=0.002; and 1-year survival: hazard ratio, 0.64; 95% CI, 0.45–0.90; P=0.010). Inverse probability treatment weighted analyses also confirmed CVI as an independent predictor for reduced in-hospital MACE (odds ratio, 0.38; 95% CI, 0.15–0.96; P=0.040) and survival at 1 year (hazard ratio, 0.44; 95% CI, 0.21–0.93; P=0.033). Conclusions—In this observational analysis of patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, CVI was associated with increased survival at 1 year. Acknowledging the limitations with observational analyses, our findings support current recommended practice guidelines.

Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis

Aims The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

Prognostic impact of anaemia on patients with ST-elevation myocardial infarction treated by primary PCI.

AimThe aim of this study was to investigate the effects of baseline anaemia on the outcome in patients treated by primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction. MethodsThis study was a retrospective cohort study of 2418 patients with ST-elevation myocardial infarction treated by PPCI between January 2004 and August 2010 at a single centre. We investigated the outcome in patients with anaemia compared with that in patients with a normal haemoglobin (Hb) level. Anaemia was defined according to the WHO definition as an Hb level less than 12 g/dl for female individuals and less than 13 g/dl for male individuals. We also calculated hazard ratios using a stratified model according to the Hb level. ResultsA total of 471 (19%) patients were anaemic at presentation. The anaemic cohort was older (72.2 vs. 62.4 years, P<0.0001) and had a higher incidence of diabetes (28 vs. 16%, P<0.0001), hypertension (57 vs. 43%, P=0.01), hypercholesterolaemia (48 vs. 40%, P=0.007), previous PCI (15 vs. 9%, P<0.0001), previous myocardial infarction (23 vs. 12%, P=0.002), and cardiogenic shock (12 vs. 5%, P<0.0001). Over a mean follow-up period of 3 years there was significantly higher all-cause mortality in the anaemic group compared with the normal Hb group (20.4 vs. 13.5%, P<0.0001). However, after adjustment for all variables using multivariate analysis, anaemia (on the basis of the WHO definitions) was found not to be an independent predictor of mortality or major adverse cardiac events over the follow-up period. Further, when we used a model stratified by g/dl, we found that there was an increased risk for adverse outcomes among men with low Hb levels. There appeared to be a threshold value of Hb (13 g/dl) associated with increased risk. Although a similar trend was observed among women, no significant difference was observed. ConclusionPatients with anaemia undergoing PPCI are at a higher risk of an adverse outcome. Anaemia is a simple and powerful marker of poor prognosis. Although anaemia (based on the WHO definitions) does not appear to be an independent predictor of all-cause mortality or major adverse cardiac events after PPCI on multivariate analysis, there appears to be a threshold value of Hb among men, below which there is an associated increased risk for PPCI.

Out-of-hours primary percutaneous coronary intervention for ST-elevation myocardial infarction is not associated with excess mortality: a study of 3347 patients treated in an integrated cardiac network

Objectives Timely delivery of primary percutaneous coronary intervention (PPCI) is the treatment of choice for ST-segment elevation myocardial infarction (STEMI). Optimum delivery of PPCI requires an integrated network of hospitals, following a multidisciplinary, consultant-led, protocol-driven approach. We investigated whether such a strategy was effective in providing equally effective in-hospital and long-term outcomes for STEMI patients treated by PPCI within normal working hours compared with those treated out-of-hours (OOHs). Design Observational study. Setting Large PPCI centre in London. Participants 3347 STEMI patients were treated with PPCI between 2004 and 2012. The follow-up median was 3.3 years (IQR: 1.2–4.6 years). Primary and secondary outcome measures The primary endpoint was long-term major adverse cardiac events (MACE) with all-cause mortality a secondary endpoint. Results Of the 3347 STEMI patients, 1299 patients (38.8%) underwent PPCI during a weekday between 08:00 and 18:00 (routine-hours group) and 2048 (61.2%) underwent PPCI on a weekday between 18:00 and 08:00 or a weekend (OOHs group). There were no differences in baseline characteristics between the two groups with comparable door-to-balloon times (in-hours (IHs) 67.8 min vs OOHs 69.6 min, p=0.709), call-to-balloon times (IHs 116.63 vs OOHs 127.15 min, p=0.60) and procedural success. In hospital mortality rates were comparable between the two groups (IHs 3.6% vs OOHs 3.2%) with timing of presentation not predictive of outcome (HR 1.25 (95% CI 0.74 to 2.11). Over the follow-up period there were no significant differences in rates of mortality (IHs 7.4% vs OFHs 7.2%, p=0.442) or MACE (IHs 15.4% vs OFHs 14.1%, p=0.192) between the two groups. After adjustment for confounding variables using multivariate analysis, timing of presentation was not an independent predictor of mortality (HR 1.04 95% CI 0.78 to 1.39). Conclusions This large registry study demonstrates that the delivery of PPCI with a multidisciplinary, consultant-led, protocol-driven approach provides safe and effective treatment for patients regardless of the time of presentation.

Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models

Background Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility. Methods and findings In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced. Conclusions The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.

Outcome of 1051 Octogenarian Patients With ST‐Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention: Observational Cohort From the London Heart Attack Group

Background ST‐segment elevation myocardial infarction is increasingly common in octogenarians, and optimal management in this cohort is uncertain. This study aimed to describe the outcomes of octogenarians with ST‐segment elevation myocardial infarction treated by primary percutaneous coronary intervention. Methods and Results We analyzed 10 249 consecutive patients with ST‐segment elevation myocardial infarction treated with primary percutaneous coronary intervention between 2005 and 2011 at 8 tertiary cardiac centers across London, United Kingdom. The primary end point was all‐cause mortality at a median follow‐up of 3 years. In total, 1051 patients (10.3%) were octogenarians, with an average age of 84.2 years, and the proportion increased over the study period (P=0.04). In‐hospital mortality (7.7% vs 2.4%, P<0.0001) and long‐term mortality (51.6% vs 12.8%, P<0.0001) were increased in octogenarians compared with patients aged <80 years, and age was an independent predictor of mortality in a fully adjusted model (hazard ratio 1.07, 95% CI 1.07–1.09, P<0.0001). Time‐stratified analysis revealed an increasingly elderly and more complex cohort over time. Nonetheless, long‐term mortality rates among octogenarians remained static over time, and this may be attributable to improved percutaneous coronary intervention techniques, including significantly higher rates of radial access and lower bleeding complications. Variables associated with bleeding complications were similar between octogenarian and younger cohorts. Conclusions In this large registry, octogenarians undergoing primary percutaneous coronary intervention had a higher rate of complications and mortality compared with a younger population. Over time, octogenarians undergoing primary percutaneous coronary intervention increased in number, age, and complexity. Nevertheless, in‐hospital outcomes were reasonable, and long‐term mortality rates were static.

Radial primary percutaneous coronary intervention is independently associated with decreased long-term mortality in high-risk ST-elevation myocardial infarction patients.

AIM To compare long-term clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PPCI) using radial and femoral arterial access. METHODS AND RESULTS The present study was an observational cohort study of patients with STEMI treated consecutively with PPCI between 2004 and 2011 at a single centre. The primary end point was all-cause mortality at a median follow-up of 3 years.Among 2727 patients, 1600 (58.7%) underwent PPCI via the femoral route. The femoral group was older (64.7 vs. 61.7 years; P < 0.0001), and had higher rates of diabetes (18.6% vs. 16.0%; P < 0.0001), previous PCI (11.2 vs. 7.8%; P = 0.004), previous myocardial infarction (15.3 vs. 8.3%; P < 0.0001) and cardiogenic shock (9.8 vs. 1.3%; P < 0.0001). Bleeding complications were more frequent in the femoral group (4.7 vs. 1.2%; P < 0.0001). The 5-year death rate was significantly higher in the femoral group than in the radial group (10.4 vs. 3.0%; P < 0.0001). After adjustment for confounding variables, bleeding complications [heart rate 2.07 (95% confidence interval 1.05-4.08)] and femoral access [heart rate 1.60 (95% confidence interval 1.02-2.53)] were independent predictors of all-cause mortality. After stratification using the propensity score, excess long-term mortality in patients treated via the femoral approach was predominantly in patients with a high baseline risk of death. CONCLUSION Patients undergoing PPCI via the femoral route are at a higher risk of adverse short-term and long-term outcomes than patients undergoing PPCI via the radial route. Patients with a high baseline risk may benefit most from radial access, and future outcome studies should focus on the most at-risk patients.

Therapeutic strategies utilizing SDF-1α in ischaemic cardiomyopathy

Abstract Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

A novel recombinant antibody specific to full-length stromal derived factor-1 for potential application in biomarker studies

Background Stromal derived factor-1α (SDF-1α/CXCL12) is a chemokine that is up-regulated in diseases characterised by tissue hypoxia, including myocardial infarction, ischaemic cardiomyopathy and remote ischaemic conditioning (RIC), a technique of cyclical, non-injurious ischaemia applied remote from the heart that protects the heat from lethal ischaemia-reperfusion injury. Accordingly, there is considerable interest in SDF-1α as a potential biomarker of such conditions. However, SDF-1α is rapidly degraded and inactivated by dipeptidyl peptidase 4 and other peptidases, and the kinetics of intact SDF-1α remain unknown. Methods & results To facilitate investigation of full-length SDF-1α we established an ELISA using a novel recombinant human antibody we developed called HCI.SDF1. HCI.SDF1 is specific to the N-terminal sequence of all isoforms of SDF-1 and has a comparable KD to commercially available antibodies. Together with a detection antibody specific to the α-isoform, HCI.SDF1 was used to specifically quantify full-length SDF-1α in blood for the first time. Using RIC applied to the hind limb of Sprague-Dawley rats or the arms of healthy human volunteers, we demonstrate an increase in SDF-1α using a commercially available antibody, as previously reported, but an unexpected decrease in full-length SDF-1α after RIC in both species. Conclusions We report for the first time the development of a novel recombinant antibody specific to full-length SDF-1. Applied to RIC, we demonstrate a significant decrease in SDF-1α that is at odds with the literature and suggests a need to investigate the kinetics of full-length SDF-1α in conditions characterised by tissue hypoxia.

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.