Scott Harding

Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers.

Background—Smoking is a potent cardiovascular risk factor and is associated with proinflammatory and prothrombotic responses. The CD40/CD40 ligand (CD40L) dyad and platelet-monocyte aggregation mediate a range of proinflammatory and prothrombotic processes thought to be important in atherothrombosis. We investigated whether expression of the CD40/CD40L dyad and platelet-monocyte aggregation are altered in cigarette smokers. Methods and Results—C-reactive protein (CRP), soluble (s) CD40L, and surface expression of CD40L on platelets and T cells and of CD40 on monocytes and platelet-monocyte aggregates were compared in 25 cigarette smokers and 25 age-and gender-matched nonsmokers. Cigarette smokers had increased serum CRP (2.47±2.60 versus 0.94±0.96 mg/L, P =0.008) and appeared to have elevated plasma sCD40L (0.8±1.09 versus 0.37±0.21 ng/mL, P =0.07) concentrations. Smokers also had increased surface expression of CD40 on monocytes (45.9±7.7% versus 39.9±6.5%, P =0.006), of CD40L on platelets (2.9±1.0% versus 2.3±0.6%, P =0.03), and of platelet-monocyte aggregates (26.6±10.9% versus 19.7±8.6%, P =0.02). Plasma cotinine concentrations correlated with monocyte CD40 expression, platelet CD40L expression, and platelet-monocyte aggregates. Conclusions—Cigarette smokers have upregulation of the CD40/CD40L dyad and platelet-monocyte aggregation that may account for the atherothrombotic consequences of this major cardiovascular risk factor.

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study

Objective The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. Design and setting and patients A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10u2005mg) or saline placebo. Main outcome measures Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24u2005h after study intervention. Results Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254±15 vs 0.12±0.02 pg/ml; p<0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4±0.6 vs 8.8±0.6×109 cells/l; p=0.03) and plasma interleukin-6 concentrations (5.8±2.0 vs 10.6±4.0u2005pg/ml; p=0.012) at 24u2005h but increased platelet–monocyte aggregation (30±5 vs 20±3%; p=0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p>0.1 for all). Conclusions Following acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction

Objective The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. Design and setting and patients A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10u2005mg) or saline placebo. Main outcome measures Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24u2005h after study intervention. Results Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254±15 vs 0.12±0.02 pg/ml; p<0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4±0.6 vs 8.8±0.6×109 cells/l; p=0.03) and plasma interleukin-6 concentrations (5.8±2.0 vs 10.6±4.0u2005pg/ml; p=0.012) at 24u2005h but increased platelet–monocyte aggregation (30±5 vs 20±3%; p=0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p>0.1 for all). Conclusions Following acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.

Ligand discovery and virtual screening using the program LIDAEUS

This paper discusses advances in docking and scoring approaches with examples from the high‐throughput virtual screening program LIDAEUS. We describe the discovery of small molecule inhibitors for the immunophilin CypA, the cyclin‐dependent kinase CDK2 and the cyclapolin series of potent Polo‐like kinase inhibitors. These results are discussed in the context of advances in massively parallel computing and in the development of annotated databases.

Functional interplay between platelet activation and endothelial dysfunction in patients with coronary heart disease

Platelet–monocyte binding and surface P-selectin expression are sensitive markers of platelet activation. Endothelium-derived factors are known to inhibit platelet activation and may confer important anti-atherothrombotic effects. We assessed the relationship between platelet activation and endothelium-dependent vasomotion in patients with coronary heart disease (CHD). Twenty male patients with stable CHD were compared with 20 healthy men. Platelet–monocyte binding and platelet surface expression of P-selectin were assessed using two-colour flow cytometry on whole blood. Forearm blood flow was assessed in patients using venous occlusion plethysmography during intra-arterial infusions of substance P, acetylcholine and sodium nitroprusside. Platelet activation was higher in patients than healthy men (platelet–monocyte binding, 27u2009±u20093 vs. 20u2009±u20091%; Pu2009<u20090.05). In patients with CHD, there was an inverse correlation between maximal substance P induced vasodilatation and both platelet–monocyte binding (Pu2009=u20090.003) and P-selectin expression (Pu2009=u20090.02). A similar correlation was observed between platelet–monocyte binding and the vasomotor response to acetylcholine (Pu2009=u20090.08) but not with sodium nitroprusside. In patients with stable coronary heart disease, there is a strong inverse relationship between markers of platelet activation and endothelium-dependent vasomotor function. This may explain the pathophysiological mechanism linking endothelial vasomotor dysfunction and the risk of acute atherothrombotic events.

Antiplatelet treatment in unstable angina: aspirin, clopidogrel, glycoprotein IIb/IIIa antagonist, or all three?

Evidence on the role of antiplatelet agents in patients with non-ST elevation acute coronary syndrome is reviewed, and a strategy for their use in unstable angina is presented

Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin

Objectives: To determine the in vitro effects of unfractionated heparin, fractionated heparin and direct thrombin inhibition on platelet–monocyte aggregation, and to establish the in vivo effects of unfractionated heparin and direct thrombin inhibition on platelet–monocyte aggregates in patients scheduled for percutaneous coronary intervention (PCI). Design: Platelet–monocyte aggregates were assessed in whole blood from 18 healthy volunteers after the addition of unfractionated heparin (1 U/ml), enoxaparin (0.8 U/ml) or lepirudin (5.6 µg/ml), and in 28 patients scheduled for elective PCI before and after administration of 100 U/kg of unfractionated heparin or 0.75 mg/kg bivalirudin. The influence of P-selectin-mediated platelet–monocyte aggregation was assessed with specific blocking antibodies. Results: Addition of unfractionated heparin in vitro was associated with a higher level of platelet–monocyte aggregates than in controls (20.1 (1.9)% v 16.2 (1.6)%, respectively, p < 0.001). However, platelet–monocyte aggregation was not affected by enoxaparin or lepirudin (16.9 (2.0)% and 17.0 (2.2)%, respectively, NS). Intravenous unfractionated heparin in vivo also resulted in an increase in platelet–monocyte aggregates (absolute Δ 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Δ −1.5 (2.4)%, NS). The addition of P-selectin blockade abolished any increase in platelet–monocyte aggregates associated with heparin. Conclusions: In vitro and in vivo unfractionated heparin is associated with increased platelet–monocyte aggregation through a P-selectin-dependent mechanism. These findings provide a potential explanation for the superior cardiovascular outcomes associated with fractionated heparins and direct thrombin inhibitors.

The role of vasodilators in the prevention and treatment of no‐reflow following percutaneous coronary intervention

The routine use of vasodilators in patients with acute coronary syndromes or other groups undergoing percutaneous coronary intervention (PCI) cannot be recommended at present. However, in the event of no-reflow occurring following PCI, intracoronary adenosine or verapamil should be administered

Coronary stent thrombosis in the perioperative period

Is potentially life threatening, but simple steps can minimise the risk

Response to the Letter Regarding Article, “Previous Coronary Stent Implantation and Cardiac Events in Patients Undergoing Noncardiac Surgery”

To the Editor:nnDr Lozano and colleagues highlight 2 important points that were not directly examined in our study. First, premature discontinuation of antiplatelet therapy in patients with coronary stents undergoing noncardiac surgery should be avoided. Aspirin and clopidogrel are irreversible inhibitors of platelet activation, yet with the exception of neurosurgery, dual antiplatelet therapy appears to increase surgical bleeding rates by no more than ≈50% without affecting morbidity or mortality.1 Careful consideration, therefore, should be given …