Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery.

When patients with coronary stents undergo non-cardiac surgery, bridging therapy with low-molecular-weight heparin (LMWH) is not infrequent in clinical practice. However, the efficacy and safety of this approach is poorly understood. This was a retrospective analysis of patients with coronary stent(s) on any antiplatelet therapy undergoing non-cardiac surgery between March 2003 and February 2012. The primary efficacy endpoint was the 30-day incidence of major adverse cardiac or cerebrovascular events (MACCE), defined as the composite of cardiac death, myocardial infarction, acute coronary syndrome leading to hospitalisation, or stroke. The primary safety endpoint was the 30-day composite of Bleeding Academic Research Consortium (BARC) bleedings ≥ 2. Among 515 patients qualifying for the analysis, LMWH bridging was used in 251 (49 %). At 30 days, MACCE occurred more frequently in patients who received LMWH (7.2 % vs 1.1 %, p=0.001), driven by a higher rate of myocardial infarction (4.8 % vs 0 %, p< 0.001). This finding was consistent across several instances of statistical adjustment and after the propensity matching of 179 pairs. Patients bridged with LMWH also experienced a significantly higher risk of BARC bleedings ≥ 2 (21.9 % vs 11.7 %, p=0.002) compared to those who were not, which remained significant across different methods of statistical adjustment and propensity matching. In conclusion, LMWH bridging in patients with coronary stents undergoing surgery is a common and possibly harmful practice, resulting in worse ischaemic outcomes at 30 days, and a significant risk of bleeding.

The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease.

CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

Transferring from clopidogrel loading dose to prasugrel loading dose in acute coronary syndrome patients. High on-treatment platelet reactivity analysis of the TRIPLET trial.

High on-treatment platelet reactivity (HPR) has been identified as an independent risk factor for ischaemic events. The randomised, double-blind, TRIPLET trial included a pre-defined comparison of HPR in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) following a placebo/600-mg clopidogrel loading dose (LD) immediately before a subsequent prasugrel 60-mg or 30-mg LD. Platelet reactivity was assessed using the VerifyNow® P2Y12 assay (P2Y12 Reaction Units, PRU) within 24 hours (h) following the placebo/clopidogrel LD (immediately prior to prasugrel LD), and at 2, 6, 24, 72 h following prasugrel LDs. The impact of CYP2C19 predicted metaboliser phenotype (extensive metabolisers [EM] and reduced metabolisers [RM]) on HPR status was also assessed. HPR (PRU ≥240) following the clopidogrel LD (prior to the prasugrel LD) was 58.5% in the combined clopidogrel LD groups. No significant difference was noted when stratified by time between the clopidogrel and prasugrel LDs (≤6 hs vs>6 h). At 6 h following the 2nd loading dose in the combined prasugrel LD groups, HPR was 7.1%, with 0% HPR by 72 h. There was no significant effect of CYP2C19 genotype on pharmacodynamic (PD) response following either prasugrel LD treatments at any time point, regardless of whether it was preceded by a clopidogrel 600-mg LD. In conclusion, in this study, patients with ACS intended for PCI showed a high prevalence of HPR after clopidogrel 600-mg LD regardless of metaboliser status. When prasugrel LD was added, HPR decreased substantially by 6 h, and was not seen by 72 h.

Detecting a thienopyridine effect by platelet reactivity assessment and its implications for risk stratification.

BACKGROUND: On-treatment platelet reactivity (OTR) is a predictor of clinical outcomes in patients receiving thienopyridine therapy. OBJECTIVE: To assess whether point-of-care platelet reactivity testing can discriminate between patients who have and have not received a thienopyridine. PATIENTS/METHODS: This was an analysis of a randomized, multicenter, pharmacodynamic trial. Subjects with coronary artery disease treated with aspirin were randomly assigned to clopidogrel 75 mg daily or prasugrel 10 mg daily for 7 days. Platelet reactivity assessment with the VerifyNow P2Y12 test was performed before study drug admistration and 24 h after the final dose. Optimal cut-offs for a detectable drug effect were identified by the use of receiver operating characteristic curve analysis. RESULTS: A total of 54 subjects were enrolled and completed the study. The c-statistic for the identification of a thienopyridine effect was highly significant (0.93, P < 0.001), including for the clopidogrel and prasugrel groups considered separately (P < 0.001 for both). The optimal cut-off was < 213 P2Y12 reaction units (PRU), which provided a sensitivity of 80% and a specificity of 98%. This cut-off provided a sensitivity of 58% and a specificity of 100% for a clopidogrel effect, and a sensitivity of 100% and specificity of 96% for a prasugrel effect. CONCLUSIONS: OTR of < 213 PRU is highly specific for exposure to either clopidogrel or prasugrel. This may be useful in the management of thienoypridine-treated patients who require surgery. Furthermore, this diagnostic cut-off is similar to levels of OTR that have been associated with ischemic events in thienopyridine-treated patients, supporting the contention that a lack of drug effect is the mechanistic basis for the prognostic relationship between OTR and clinical outcomes.

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation.

The activation of thromboxane prostanoid (TP) receptor on platelets, monocytes/macrophages, endothelial cells, and vascular smooth muscle cells (SMC) plays important roles in regulating platelet activation and vascular tone and in the pathogenesis of thrombosis and vascular inflammation. Oxidative stress and vascular inflammation increase the formation of TP receptor agonists, which promote initiation and progression of atherogenesis and thrombosis. Furthermore, TP receptor activation promotes angiogenesis and vessel wall constriction. Besides thromboxane A2 and its endoperoxide precursors, prostaglandin G2 and H2, isoprostanes, and 20-hydroxyeicosatetraenoic acid also activate TP receptor as autocrine or paracrine ligands. These additional TP activators play a role in pathological conditions such as diabetes, obesity, and hypertension, and their biosynthesis is not inhibited by aspirin, at variance with that of thromboxane A2. The understanding of TP receptor function increased our current knowledge of the pathogenesis of atherosclerosis and thrombosis, highlighting the great impact that this receptor has in cardiovascular disorders.

Antiplatelet therapy: new pharmacological agents and changing paradigms.

Recurrent atherothrombotic events in patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI) are essentially platelet-driven processes, underscoring the need for effective pharmacological platelet inhibition. Dual antiplatelet therapy with aspirin and clopidogrel has been, for over a decade, the mainstay of antiplatelet management in ACS/PCI. However, atherothrombotic events continue to occur in a relevant proportion of subjects despite the benefit of this combination, which has led to the clinical development of newer and more potent antiplatelet drugs. Two of these, prasugrel and ticagrelor, have been recently approved for clinical use. The scope of this manuscript is to provide an up-to-date overview on new antiplatelet drugs in the setting of ACS and PCI, including the most recent advances on newly approved agents as well as on emerging compounds in clinical development.

Safety and efficacy of protease-activated receptor-1 antagonists in patients with coronary artery disease: a meta-analysis of randomized clinical trials.

BACKGROUND: Thrombin receptor antagonists blocking protease-activated receptor-1 (PAR-1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. OBJECTIVES: We investigated the safety and efficacy of PAR-1 antagonists in patients with coronary artery disease (CAD). PATIENTS/METHODS: Randomized, placebo-controlled trials of the PAR-1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. RESULTS: A total of 41 647 patients from eight trials were included. PAR-1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39-1.57, P < 0.001), major (OR 1.46, 95% CI 1.28-1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40-2.00, P < 0.001) bleeding than placebo in the fixed-effects model. PAR-1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81-0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78-0.92, P < 0.001). Conversely, PAR-1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90-1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84-1.10, P = 0.59). CONCLUSIONS: PAR-1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.

New perspectives in antiplatelet therapy.

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin αIIbß3, and the purinergic P2Y(12) receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications. The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y(12) receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.

Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies.

Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

Platelet monitoring for PCI: which test is the one to choose?

Despite the clinical benefit associated with the combined use of aspirin and clopidogrel in patients with acute coronary syndrome or those undergoing percutaneous coronary intervention, a considerable interindividual variability in response to these drugs have been consistently reported. There is a growing interest on applying platelet functional tests with the goal of identifying patients at increased risk of recurrent ischaemic events and potentially tailoring antiplatelet treatment regimens. This manuscript will review the state of the art on the most commonly available platelet functional tests, describing their advantages and disadvantages and exploring their applicability in clinical practice.

Stent thrombosis in the era of drug eluting stents.

Despite a marked reduction in restenosis and the need for repeat revascularization procedures with the use of drug-eluting stents (DES), the risk for stent thrombosis remains of serious concern. Although the safety profiles of DES dose not seem to differ from those of bare metal stent (BMS) in the acute and subacute phases following coronary intervention, recent data suggest a potential increase of thrombotic events late after DES deployment. The main factors associated with late stent thrombosis remain elusive. Delayed re-endothelialization, hypersensitivity reaction, technical and mechanical factors and hypercoagulability have all been proposed as contributing factors. It is unlikely that any of these variables alone can cause stent thrombosis, as the incidence of each factor is much higher than the currently known rates of DES thrombosis. Further, temporal appearances of the thrombotic events represent a challenge to our understanding of re-endothelialization, as one would expect that endothelial coverage would be higher in the later phases after treatment. New expanded definitions of stent thrombosis, which also include events secondary to repeat revascularization, have been proposed to provide a better comparative endpoint between BMS and DES. Such clinical attempt to characterize stent thrombosis is valuable, but does not provide much insight into the pathophysiology and intrinsic thrombotic risk of each device. A true progress in this field will only be possible after we improve our understanding of the patho-physiology of very late stent thromboses, which may differ from events occurring earlier after treatment. The incidence of stent thrombosis remains rare, but its potential catastrophic consequences should remind clinicians and scientists to make every effort to develop strategies and technologies for its prevention. The topic of stent thrombosis in the era of DES will be reviewed in this article.

Percutaneous coronary intervention of bifurcation coronary disease.

Bifurcation coronary artery disease is a frequent problem faced by interventional cardiologists and it affects approximately 15-20% of patients undergoing percutaneous coronary intervention (PCI). The application of drug-eluting stents (DES) technology to prevent restenosis after PCI represents one of the success stories in cardiology, but DES have not resolved the bifurcation PCI challenge. Bifurcation PCI remains associated with higher procedural failure and worse outcomes compared with PCI of non-bifurcated lesions even in DES era. A dependable strategy for PCI of bifurcation lesions has yet to be established, which is likely due to the paucity of studies evaluating the anatomical intricacies of the bifurcation as well as the lack of large scale randomized therapeutic trials. Further, bifurcation has many anatomical variants and it is unlike that one technique will fit all. Currently, we are left with the option of a tailor-made strategy for each patient and bifurcation anatomy and make the most of the limited evidence available to support our therapeutic decisions. In this review, we attempted to describe the current understanding of bifurcation anatomy and corresponding PCI strategies.

Usefulness of cardiac magnetic resonance imaging for coronary artery disease detection.

Cardiac magnetic resonance imaging (cMRI) is a promising non-invasive technique to assess the presence of coronary artery disease (CAD), which is free of ionizing radiation and iodine contrast. cMRI can detect CAD by angiographic methods or indirectly by perfusion stress techniques. While coronary angiography by cMRI remains limited to research protocols, stress perfusion cMRI is currently being applied worldwide in the clinical setting. Studies have shown good correlation between adenosine-induced stress myocardial perfusion cMRI and single-photon-emission computed tomography or positron emission tomography to detect CAD. Quantitative methods to analyze cMRI perfusion data have been developed in an attempt to provide a more objective imaging interpretation. Standardization of such quantitative methods, with minimal operator dependency, would be useful for clinical and research applications. Myocardial perfusion reserve (MPR), calculated using Fermi deconvolution technique, has been compared with well established anatomical and physiological CAD detection techniques. MPR appears to be the most accurate quantitative index to detect anatomical and hemodynamically significant CAD. Beyond physiological assessment of CAD, cMRI provides information regarding regional and global left ventricular function and morphology, myocardial infarction size, transmurality and viability. Such comprehensive information would require the performance of multiple tests if other modalities were used. This article describes current applications of cMRI for evaluation of patients with CAD.

Findings of intravascular ultrasound during acute stent thrombosis.

OBJECTIVE: To evaluate the potential role of intravascular ultrasound (IVUS) in evaluating patients experiencing an episode of acute stent thrombosis. DESIGN AND SETTING: Prospective observational study in a cardiac catheterisation laboratory in a university teaching hospital. PATIENTS AND INTERVENTIONS: IVUS was used to examine 12 patients undergoing coronary interventions for stent thrombosis to gain further mechanistic insights and to guide treatment. IVUS studies were obtained before and after intervention with a motorised pullback device. MAIN OUTCOME MEASURES: Qualitative and volumetric IVUS analyses. RESULTS: Angiographically, 10 patients had occluded vessels and two patients had intraluminal filling defects within the stent. IVUS showed an occlusive thrombus in all patients. Thrombus volume was 90 (77) mm3, which was 51 (21)% of total stent volume. There was evidence of severe stent underexpansion in most patients and no patient fulfilled standard criteria for optimal stent implantation. Stent malapposition was detected in four patients, edge dissections were seen in two patients, and significant inflow-outflow disease was present in 11 patients. During interventions IVUS findings led to the use of higher pressures or larger balloons than those used during initial stenting in 10 patients. In addition, four patients required additional stenting, whereas a thrombectomy device alone was selected for one patient. After the procedure final minimum stent area (7.1 (2.1) v 5.3 (2) mm2, p < 0.005) and stent expansion (83.2 (17) v 62.1 (15)%, p < 0.005) improved compared with pre-interventional values. However, residual lining thrombus was still visualised in eight patients (25 (19) mm3, accounting for a 17% of final stent volume). CONCLUSIONS: IVUS provides an attractive technique to characterise fully the pattern of stent thrombosis, to identify readily the underlying mechanical predisposing factors, and to guide repeated coronary interventions.

Saphenous vein graft disease.

Saphenous vein graft (SVG) disease has been an obstinate problem facing the cardiologist since the early days of coronary artery bypass grafting (CABG) surgery. SVG disease follows temporally distinct phases of thrombosis, intimal hyperplasia and progressive atherosclerosis leading to recurrent ischemia which can be treated with repeat operation or percutaneous revascularization. However, repeat operation is associated with high mortality and morbidity. Also, percutaneous treatment of SVG disease is complicated by a high rate of procedural and long term complications due to the interrelated phenomena of distal embolization, slow flow or no reflow, periprocedure myocardial infarction, and subsequent restenosis. Long-term patency is poor in this patient population regardless of the treatment modality. Many pharmaceutical and device based approaches have been tested to avert these complications, but few, such as the use of distal protection devices, have shown benefit. The novel drug-eluting stents show promise in reducing the occurrence of restenosis and solving one of the problems associated with the percutaneous treatment of SVG disease. The pathogenesis and therapeutic options for SVG disease is reviewed in this article.

Enhanced response of blood monocytes to in vitro lipopolysaccharide-challenge in patients with recurrent unstable angina.

BACKGROUND: C-reactive protein (CRP) plasma levels have been associated with short- and long-term occurrence of coronary events. We investigated whether circulating inflammatory cell responsiveness to low-grade stimuli could contribute to the reported association between CRP and coronary events. METHODS AND RESULTS: We studied 32 patients with unstable angina who were followed for 24 months and were free of symptoms for 6 months (group 1): 19 patients had persistently high CRP levels (>0.3 mg/dL) (group 1A); 13 patients had normal CRP levels (group 1B). During the follow-up, 12 (63%) group 1A but no group 1B patients developed an infarction or recurrence of unstable angina (P<0.001). Eighteen patients with chronic stable angina (group 2) and 18 healthy subjects (group 3) were studied as controls. Interleukin (IL)-6 production (median, range) by peripheral blood mononuclear cells after 4 hours of in vitro stimulation with 1 ng/mL lipopolysaccharide (LPS) was significantly higher in group 1A (4526 pg/mL, 3042 to 10 583 pg/mL) than in group 1B (1752 pg/mL, 75 to 3981 pg/mL), group 2 (707 pg/mL, 41 to 3275 pg/mL), and group 3 (488 pg/mL, 92 to 3503 pg/mL) (all P<0.001). No significant differences were observed among the other groups. IL-6 production after LPS-challenge was correlated with baseline CRP levels (r=0.42, P=0.005). CONCLUSIONS: Mononuclear cells of patients with recurrent phases of instability exhibit an enhanced production of IL-6 in response to low-dose of LPS, correlated with baseline CRP levels, 6 months after the last acute event. This persisting enhanced acute-phase responsiveness may help explain the association between CRP and acute coronary events.

Current role of lung scintigraphy in pulmonary embolism.

The pivotal role of lung scintigraphy in the diagnosis of pulmonary embolism (PE) has been questioned in recent years due to the introduction of spiral computed tomography. However, the scintigraphic results used for comparisons are often those of the authoritative PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) study, carried out in the 1980s. Pulmonary scintigraphy has progressed from those years both in the methodological and interpretative fields, although perhaps too slowly. Results better than those of PIOPED's have been presented by study groups who used: 1) perfusion-only approach, 2) SPET imaging; 3) new interpretative criteria; 4) different prediction rules to integrate clinical and scintigraphic probabilities of PE. These advances are still insufficiently recognised by the nuclear medicine community, possibly due to a sort of PIOPED-based "cultural globalisation". This paper reviews the actual advantages and limitations of nuclear medicine techniques, the diagnostic role of scintigraphy within the diagnostic algorithms proposed by international working groups and scientific societies and the results obtained from SPET imaging in the diagnosis of PE.

Inflammation and acute coronary syndromes.

The presence of inflammatory infiltrates in unstable coronary plaques suggests that inflammatory processes may contribute to the pathogenesis of these syndromes. In patients with unstable angina, coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent, T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion; moreover, the rupture-related inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption. These observations are confirmed by clinical studies demonstrating activated circulating neutrophils, lymphocytes and monocytes, and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL) 1 and 6, and of acute phase reactants in patients with unstable angina and myocardial infarction. In particular elevated levels of C-reactive protein are associated with an increased risk of in-hospital and 1 to 2 years new coronary events in patients with unstable angina, but are also associated with an increased long-term risk of death and myocardial infarction in apparently normal subjects. Thus, accumulating evidence suggests that inflammation may cause local endothelial activation and, possibly, plaque fissure, leading to unstable angina and infarction. Although no information is yet available on the causes of inflammation and on its localization, these novel lines of research may open the way to a different approach to the patient with acute coronary syndromes.

In vitro hyperreactivity to lipopolysaccharide in patients with history of unstable angina is not associated with seropositivity for Cytomegalovirus, Helicobacter pylori and Chlamydia pneumoniae.

BACKGROUND: Inflammation and possibly chronic infections are associated with acute coronary syndromes; however, the mechanisms responsible for this association are not yet fully elucidated. The aim of this study was to assess whether the hyperreactivity of the inflammatory system, that we have shown in unstable patients with persistently elevated C-reactive protein and with recurrence of symptoms, was associated with chronic infection. METHODS: In 20 unstable angina patients seropositivity and antibody levels vs Cytomegalovirus, Helicobacter pylori and Chlamydia pneumoniae were measured and correlated with the interleukin-6 production in vivo in 1 ml of whole blood stimulated with 0.1 microgram lipopolysaccharide for 4 hours. RESULTS: No positive correlation was found between antibody titer and interleukin-6 levels. No correlation was also found between seropositivity to Cytomegalovirus, Helicobacter pylori or Chlamydia pneumoniae and interleukin-6 levels. CONCLUSIONS: Our study suggests that seropositivity for infective agents, including Chlamydia pneumoniae, does not affect the monocyte response to lipopolysaccharide and thus cannot account for the enhanced interleukin-6 production observed in unstable angina patients with raised levels of C-reactive protein and worse prognosis, and suggests the predominant role of the individual response to different stimuli.