Simon Wilson

Inhaled Nanoparticles Accumulate at Sites of Vascular Disease

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.

Cardiovascular Outcomes Following Rotational Atherectomy: A UK Multicentre Experience.

To identify factors associated with outcomes following rotational atherectomy (RA).

Antegrade Dissection and Reentry as Part of the Hybrid Chronic Total Occlusion Revascularization Strategy A Subanalysis of the RECHARGE Registry (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom)

Background— Development of the CrossBoss and Stingray devices for antegrade dissection and reentry (ADR) of chronic total occlusions has improved historically suboptimal outcomes. However, the outcomes, safety, and failure modes of the technique have to be studied in a larger patient cohort. This preplanned substudy of the RECHARGE registry (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom) aims to evaluate the value and use of ADR and determine its future position in contemporary chronic total occlusion intervention. Methods and Results— Patients were selected if an ADR strategy was applied. Outcomes, safety, and failure modes of the technique were assessed. The ADR technique was used in 23% (n=292/1253) of the RECHARGE registry and was mainly applied for complex lesions (Japanese chronic total occlusion score=2.7±1.1). ADR was the primary strategy in 30% (n=88/292), of which 67% were successful. Bail-out ADR strategies were successful in 63% (n=133/210). The Controlled ADR (ie, combined CrossBoss-Stingray) subtype was applied most frequently (32%; n=93/292) and successfully (81%; n=75/93). Overall per-lesion success rate was 78% (n=229/292), after use of additional bail-out strategies. The inability to reach the distal target zone (n=48/100) or to reenter (n=43/100) most commonly led to failure. ADR-associated major events occurred in 3.4% (n=10/292). Conclusions— Although mostly applied as a bail-out strategy for complex lesions, the frequency, outcomes, and low complication rate of the ADR technique and its subtypes confirm the benefit and value of the technique in hybrid chronic total occlusion percutaneous coronary intervention, especially when antegrade wiring or retrograde approaches are not feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02075372.

Cardiovascular Outcomes Following Rotational Atherectomy

To identify factors associated with outcomes following rotational atherectomy (RA).

PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation

Objective— BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. Approach and Results— Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 &mgr;M)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (&mgr;m2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%–38.7%; P<0.001) at 2 hours and by 21.4% (9.3%–32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%–47.3%; P<0.001) at 2 hours and 23.3% (5.1%–38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. Conclusions— BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439190.

Duration of dual antiplatelet therapy in acute coronary syndrome

Despite a large volume of evidence supporting the use of dual antiplatelet therapy in patients with acute coronary syndrome, there remains major uncertainty regarding the optimal duration of therapy. Clinical trials have varied markedly in the duration of therapy, both across and within trials. Recent systematic reviews and meta-analyses suggest that shorter durations of dual antiplatelet therapy are superior because the avoidance of atherothrombotic events is counterbalanced by the greater risks of excess major bleeding with apparent increases in all-cause mortality with longer durations. These findings did not show significant heterogeneity according to whether patients had stable or unstable coronary heart disease. Moreover, the potential hazards and benefits may differ when applied to the general broad population of patients encountered in everyday clinical practice who have markedly higher bleeding and atherothrombotic event rates. Clinicians lack definitive information regarding the duration of therapy in patients with acute coronary syndrome and risk scores do not appear to be sufficiently robust to address these concerns. We believe that there is a pressing need to undertake a broad inclusive safety trial of shorter durations of therapy in real world populations of patients with acute coronary syndrome. The clinical evidence would further inform future research into strategies for personalised medicine.

Thrombin Exosite 1 Inhibition with JNJ-64179375 Inhibits Thrombus Formation in a Human Translational Model of Thrombosis

Abstract Aims JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis. Methods and results Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 μg/mL), bivalirudin (6 μg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively. JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 μg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both). Conclusion Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications.

A Novel Utility of Facilitated Antegrade Dissection Re-Entry Technique to Recanalize Chronic Total Occlusions

Percutaneous coronary intervention for chronic total occlusions (CTO) in patients with coronary artery bypass graft remains a challenge [(1–3)][1]. The use of the graft as a retrograde conduit to recanalize native vessel occlusions is well-described in the presence of a degenerated, severely

111 Improved Clinical Outcomes with Multi-Vessel Compared to Culprit only Percutaneous Coronary Intervention in Patients Presenting with Acute ST Elevation Myocardial Infarction

Introduction In patients with acute ST elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) improves survival. Multi-vessel coronary disease is identified in up to two thirds of patients and is associated with poorer outcomes. Historically, registry data and guidelines favoured culprit only PCI in STEMI, although recent data suggest that more complete revascularisation may improve outcomes. To examine this issue locally, we studied clinical outcomes in consecutive patients presenting with STEMI and multivessel disease in SE Scotland stratified according to revascularisation strategy (culprit versus multivessel angioplasty). Methods We retrospectively examined clinical outcomes according to revascularisation strategy (culprit versus multi-vessel) in all patients with multivessel disease (defined as >70% lumen stenosis in at least one non-infarct artery that was suitable for revascularisation) undergoing PCI for STEMI in SE Scotland, October 2013 – August 2014. Patients with significant left main stenosis, cardiogenic shock or previous bypass surgery were excluded. Survival analysis for MACE (death, recurrent myocardial infarction (MI), stroke) was performed using the log-rank test before and after stratification by combined syntax score of the non-culprit vessels. Results One hundred and nineteen patients with multivessel disease at index PCI for STEMI were included in the analysis (mean age 63.8 years (SD 12.8), male 81.5%, diabetes 13.4%, hypertension 35.3%, previous MI 18.5%, previous stroke 5.8%). Eighty-five (71%) patients underwent culprit only PCI and 34 (29%) underwent multivessel PCI. There were no differences in baseline variables between the two groups. Mean duration of follow up was 153.7 days (SD 137.4). MACE occurred in 14 patients from the culprit only PCI group (6 MI, 3 stroke and 6 deaths) while no events occurred in the multivessel PCI group (Figure 1). High syntax score (defined as >median) of the non-infarct vessels predicted increased MACE in the non-culprit PCI group (Figure 2). Abstract 111 Figure 1 K-M Curves for MACE survival by PCI strategy Abstract 111 Figure 2 K-M Curves for MACE survival in culprit only PCI by Syntax group Conclusions In this single centre, retrospective analysis, multivessel PCI was associated with significantly improved clinical outcomes when compared to culprit only PCI in patients presenting with STEMI and multivessel disease. Our findings provide support for the results of recently published clinical trials.