Mode of delivery and peripartum outcome in women with heart disease according to the ESC guidelines: an Italian multicenter study.

INTRODUCTION: The European Society of Cardiology (ESC) guidelines (GL) provide indications on the mode of delivery in women with heart disease. However available data suggests that the rate of Cesarean Delivery (CD) is high and widely variable among such patients. In this study, we aimed to investigate the degree of adherence to the ESC recommendations among women delivering in four tertiary maternity services in Italy and how this affects the maternal and neonatal outcomes. MATERIAL AND METHODS: Retrospective multicenter cohort study including pregnant women with heart disease who gave birth between January 2014 and July 2020. Composite adverse maternal outcome (CAM) was defined by the occurrence of one or more of the following: major postpartum hemorrhage, thrombo-embolic or ischemic event, de novo arrhythmia, heart failure, endocarditis, aortic dissection, need for re-surgery, sepsis, maternal death. Composite Adverse Neonatal outcome (CAN) was defined as cord arterial pH <7.00, APGAR <7 at 5 min, admission to the intensive care unit, and neonatal death. We compared the incidence of CAM and CAN between the cases with planned delivery in accordance (group "ESC consistent") or in disagreement (group "ESC not consistent") with the ESC GL. RESULTS: Overall, 175 women and 181 liveborn were included. A higher frequency of CAN was found when delivery was not planned accordingly to the ESC guidelines [("ESC consistent" 9/124 (7.2%) vs "ESC not consistent" 13/57 (22.8%) p = 0.002 OR 3.74 (CI 95% 1.49-9.74) , while the occurrence of CAM was comparable between the two groups. At logistic regression analysis, the gestational age at delivery was the only parameter independently associated with the occurrence of CAN (p = 0.006). CONCLUSION: Among pregnant women with heart disease, deviating from the ESC guidelines scheduling cesarean delivery does not seem to improve maternal outcomes and it is associated with worse perinatal outcomes, mainly due to lower gestational age at birth.

EU-CaRE study: Could exercise-based cardiac telerehabilitation also be cost-effective in elderly?

BACKGROUND: The role of cardiac rehabilitation (CR) is well established in the secondary prevention of ischemic heart disease. Unfortunately, the participation rates across Europe remain low, especially in elderly. The EU-CaRE RCT investigated the effectiveness of a home-based mobile CR programme in elderly patients that were not willing to participate in centre-based CR. The initial study concluded that a 6-month home-based mobile CR programme was safe and beneficial in improving VO2peak when compared with no CR. OBJECTIVE: To assess whether a 6-month guided mobile CR programme is a cost-effective therapy for elderly patients who decline participation in CR. METHODS: Patients were enrolled in a multicentre randomised clinical trial from November 11, 2015, to January 3, 2018, and follow-up was completed on January 17, 2019, in a secondary care system with 6 cardiac institutions across 5 European countries. A total of 179 patients who declined participation in centre-based CR and met the inclusion criteria consented to participate in the European Study on Effectiveness and Sustainability of Current Cardiac Rehabilitation Programs in the Elderly trial. The data of patients (n = 17) that were lost in follow-up were excluded from this analysis. The intervention (n = 79) consisted of 6 months of mobile CR programme with telemonitoring, and coaching based on motivational interviewing to stimulate patients to reach exercise goals. Control patients did not receive any form of CR throughout the study period. The costs considered for the cost-effectiveness analysis of the RCT are direct costs 1) of the mobile CR programme, and 2) of the care utilisation recorded during the observation time from randomisation to the end of the study. Costs and outcomes (utilities) were compared by calculation of the incremental cost-effectiveness ratio. RESULTS: The healthcare utilisation costs (P = 0.802) were not significantly different between the two groups. However, the total costs were significantly higher in the intervention group (P = 0.040). The incremental cost-effectiveness ratio for the primary endpoint VO2peak at 6 months was €1085 per 1-unit [ml/kg/min] improvement in change VO2peak and at 12 months it was €1103 per 1 unit [ml/kg/min] improvement in change VO2peak. Big differences in the incremental cost-effectiveness ratios for the primary endpoint VO2peak at 6 months and 12 months were present between the adherent participants and the non-adherent participants. CONCLUSION: From a health-economic point of view the home-based mobile CR programme is an effective and cost-effective alternative for elderly cardiac patients who are not willing to participate in a regular rehabilitation programme to improve cardiorespiratory fitness. The change of QoL between the mobile CR was similar for both groups. Adherence to the mobile CR programme plays a significant role in the cost-effectiveness of the intervention. Future research should focus on the determinants of adherence, on increasing the adherence of patients and the implementation of comprehensive home-based mobile CR programmes in standard care.

Genetic predisposition to atorvastatin-induced myopathy: a case report.

WHAT IS KNOWN AND OBJECTIVE: The major clinical complication of statins is a variety of muscle complaints ranging from myalgia to rhabdomyolysis. There is growing evidence that carriers of genetic polymorphisms in the enzymes and transporters implicated in statin disposition, particularly the SLCO1B1 gene, are at increased risk of myotoxicity. Our objective is to report on two cases of statin-induced myopathy occurring in a family with two patients who are carriers of the loss of function SLCO1B1 genetic variant and to briefly review the related literature. CASE SUMMARY: Patient 1, a 48-year-old man with history of coronary artery disease, experienced rapidly evolving muscle pain and weakness of the extremities during treatment with atorvastatin 40 mg. Patient 2, a 65-year-old man, father of patient 1, had symptoms similar to those of his son after 2 weeks' treatment with the same statin. Atorvastatin was stopped in both cases, and symptoms resolved. On the basis of family relationship between the two patients, it was possible to hypothesize a genetic basis for the myopathy. Genotyping showed the patients to be carriers of the rs4363657 polymorphism of SLCO1B1 gene. WHAT IS NEW AND CONCLUSION: The two cases reported here and the brief literature review emphasize the impact of genetic factors on the risk of myopathy with statins. Although genotyping all patients before initiating therapy is not recommended at present, pharmacogenetic testing may be useful for new patients who have a family history of statin-induced myopathy.

Prognostic value of CT coronary angiography: focus on obstructive vs. nonobstructive disease and on the presence of left main disease.

PURPOSE: The authors investigated the prognostic value of computed tomography coronary angiography (CTCA) for major adverse cardiac events (MACE) in patients with suspected or known coronary artery disease (CAD), with particular focus on left main (LM) disease and obstructive vs. nonobstructive disease. MATERIALS AND METHODS: A total of 727 consecutive patients (485 men, age 62 ± 11 years) with suspected (514; 70.1%) or known (213; 29.9%) CAD underwent CTCA. Patients were followed up for the occurrence of MACE (i.e. cardiac death, nonfatal myocardial infarction, unstable angina, percutaneous/surgical revascularisation). RESULTS: A total of 117 MACE [five cardiac deaths, 11 acute myocardial infarctions (AMI), five unstable angina, 86 percutaneous coronary interventions, ten coronary artery bypass grafts] occurred during a mean follow-up of 20 months. Severity and extension of CAD was associated with a progressively worse prognosis. The event rate was 0% among patients with normal coronary arteries at CTCA. The presence of LM disease was not associated with a worse prognosis either in patients with no history of CAD or in those with a history of CAD. At multivariate analysis, presence of obstructive CAD and diabetes were the only independent predictors of MACE. CONCLUSIONS: Evaluation of atherosclerotic burden by CTCA provides an independent prognostic value for prediction of MACE. Patients with normal CTCA findings have an excellent prognosis at follow-up.

The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease.

AIMS: Gain-of-function variants of genes encoding coagulation factor V (F5 G1691A) and prothrombin (F2 G20210A) cause hypercoagulability and are established risk factors for venous thrombosis. A meta-analysis of 66,155 cases and 91,307 controls found that either polymorphism is associated with a moderately increased risk of coronary artery disease (CAD). Because genetic factors play a particularly important role when acute myocardial infarction (AMI) occurs in the young, we chose to replicate these results by investigating, in the frame of a case-control study, a large cohort of Italian patients who had AMI before the age of 45years. METHODS AND RESULTS: In 1880 patients with AMI (1680 men and 210 women) and an equal number of controls, the minor A allele of F5 G1691A (2.6% frequency in cases and 1.7% in controls) was associated with an increased risk of AMI, the association remaining significant after adjustment for traditional risk factors (OR, 1.66; 95% CI, 1.15-2.38; P=0.006). The positive association with AMI for the minor A allele of F2 G20210A (2.5% frequency in cases and 1.9% in controls) did not reach statistical significance (OR, 1.32; 95% CI, 0.96-1.80; P=0.159). CONCLUSIONS: In a large cohort of young AMI patients the gain-of-function variant F5 G1691A was associated with an increased risk of AMI. The findings on the variant F2 G20210A confirmed the previously reported results, but the association was statistically not significant. These data suggest that a number of young patients with AMI carry gene variants associated with a procoagulant phenotype.

Stress-ECG vs. CT coronary angiography for the diagnosis of coronary artery disease: a "real-world" experience.

PURPOSE: This study aimed to evaluate the diagnostic accuracy of stress electrocardiogram (ECG) and computed tomography coronary angiography (CTCA) for the detection of significant coronary artery stenosis (> or =50%) in the real world using conventional CA as the reference standard. MATERIALS AND METHODS: A total of 236 consecutive patients (159 men, 77 women; mean age 62.8+/-10.2 years) at moderate risk and with suspected coronary artery disease (CAD) were enrolled in the study and underwent stress ECG, CTCA and CA. The CTCA scan was performed after i.v. administration of a 100-ml bolus of iodinated contrast material. The stress ECG and CTCA reports were used to evaluate diagnostic accuracy compared with CA in the detection of significant stenosis > or =50%. RESULTS: We excluded 16 patients from the analysis because of the nondiagnostic quality of stress ECG and/or CTCA. The prevalence of disease demonstrated at CA was 62% (n=220), 51% in the population with comparable stress ECG and CTCA (n=147) and 84% in the population with equivocal stress ECG (n=73). Stress ECG was classified as equivocal in 73 cases (33.2%), positive in 69 (31.4%) and negative in 78 (35.5%). In the per-patient analysis, the diagnostic accuracy of stress ECG was sensitivity 47%, specificity 53%, positive predictive value (PPV) 51% and negative predictive value (NPV) 49%. On stress ECG, 40 (27.2%) patients were misclassified as negative, and 34 (23.1%) patients with nonsignificant stenosis were overestimated as positive. The diagnostic accuracy of CTCA was sensitivity 96%, specificity 65%, PPV 74% and NPV 94%. CTCA incorrectly classified three (2%) as negative and 25 (17%) as positive. The difference in diagnostic accuracy between stress ECG and CTCA was significant (p<0.01). CONCLUSIONS: CTCA in the real world has significantly higher diagnostic accuracy compared with stress ECG and could be used as a first-line study in patients at moderate risk.

64-slice computed tomography coronary angiography: diagnostic accuracy in the real world.

PURPOSE: This study was done to evaluate the diagnostic accuracy of 64-slice computed tomography coronary angiography (CTCA) for the detection of significant coronary artery stenosis in the real clinical world. MATERIALS AND METHOD: From the CTCA database of our institution, we enrolled 145 patients (92 men, 52 women, mean age 63.4 +/- 10.2 years) with suspected coronary artery disease. All patients presented with atypical or typical chest pain and underwent CTCA and conventional coronary angiography (CA). For the CTCA scan (Sensation 64, Siemens, Germany), we administered an IV bolus of 100 ml of iodinated contrast material (Iomeprol 400 mgI/ml, Bracco, Italy). The CTCA and CA reports used to evaluate diagnostic accuracy adopted > or =50% and > or =70%, respectively, as thresholds for significant stenosis. RESULT: Eleven patients were excluded from the analysis because of the nondiagnostic quality of CTCA. The prevalence of disease demonstrated at CA was 63% (84/134). Sensitivity, specificity and positive and negative predictive values for CTCA on a per-segment, per-vessel, and per-patient basis were 75.6%, 85.1%, 97.6%; 86.9%, 81.8%, 58.0%; 48.2%, 68.1%, 79.6%; and 95.7%, 92.3%, 93.5%, respectively. Only two out of 134 eligible patients were false negative. Heart rate did not significantly influence diagnostic accuracy, whereas the absence or minimal presence of coronary calcification improved diagnostic accuracy. The positive and negative likelihood ratios at the per-patient level were 2.32 and 0.041, respectively. CONCLUSION: CTCA in the real clinical world shows a diagnostic performance lower than reported in previous validation studies. The excellent negative predictive value and negative likelihood ratio make CTCA a noninvasive gold standard for exclusion of significant coronary artery disease.

Long-term mortality in patients unsuitable for surgical revascularization undergoing elective left main coronary artery angioplasty.

AIM: Elective percutaneous coronary intervention (PCI) of left main coronary artery disease remains an important challenge in interventional cardiology. Nonetheless, this procedure is useful for patients with significant left main stenosis who are candidates for revascularization but unsuitable for coronary artery bypass graft. In this study the Authors sought to evaluate the safety and long-term mortality of PCI of left main coronary artery disease. Secondary endpoints were to analyse long-term mortality in various categories (patients<75 years vs patients<75 years, males vs females, drug eluting stents [DES] vs bare metal stents [BMS]). METHODS: Between January 2003 and December 2006, 131 patients who consecutively under-went PCI on left main stem were reviewed. The mean follow-up time was 14.0+/-10.8 months. Survival curves were plotted with the Kaplan-Meier method and compared with the Log-rank test. RESULTS: The Kaplan-Meier curves did not show statistically significant differences in terms of all-cause mortality at follow-up between protected and unprotected left main coronary disease (12% vs 14% respectively, P=0.67). In the protected left main group, there was a significantly higher use of DES compared with unprotected left main group (59% vs 43%, P=0.02). CONCLUSION: The data show that PCI for left main coronary disease is feasible, safe and with an acceptable long-term mortality rate in patients at high-surgical risk unsuitable for surgical revascularization.

Multislice computed tomography coronary angiography: clinical applications.

Cardiac and coronary computed tomography (CT) is becoming increasingly common in clinical practice. Even if there is no well-established evidence, this diagnostic modality is so strong and effective and, in skilled hand, it can be readily used in clinical practice. After learning its potential and the technical limits, this tool could be used for risk stratification as well as for revascularization evaluation. In this review, we will describe the results of present literature, clinical applications at present considered suitable to CT technology (i.e. 64-slice and dual-source scanners) and future applications and innovations.

Diagnostic accuracy of 64-slice CT in the assessment of coronary stents.

PURPOSE: The purpose of this study was to assess the diagnostic accuracy of 64-slice computed tomography (64-CT) coronary angiography in the detection of coronary in-stent restenosis. MATERIALS AND METHODS: Ninety-five patients (72 men and 23 women, mean age 58+/-8 years) with previous percutaneous coronary intervention with stenting and suspected restenosis underwent 64-CT (Sensation 64, Siemens). The mean time between stent deployment and 64-CT was 6.1+/-4.2 months. The scan parameters were: slices 32 x 2, individual detector width 0.6 mm, rotation time 0.33 s, feed 3.84 mm/rotation, 120 kV, 900 mAs. After the intravenous administration of iodinated contrast material (Iomeprol 400 mgI/ml, Iomeron, Bracco) and a bolus chaser (40 ml of saline), the scan was completed in <12 s. All coronary segments with a stent were assessed on 64-CT by two observers in consensus and judged as: patent, with intimal hyperplasia (lumen reduction of <50%), with in-stent restenosis (> or =50%), or with in-stent occlusion (100%). The consensus reading was compared with conventional coronary angiography. RESULTS: Four patients were excluded because of insufficient image quality. In the remaining 91, we assessed 102 stents (31 RCA; 10 LM; 54 LAD; 7 CX). In 14 (13.7%) stents, in-stent restenosis (n=8) or in-stent occlusion (n=6) was found. Intimal hyperplasia was detected in 11 (10.8%) stents. The sensitivity and negative predictive value of 64-CT for in-stent occlusion were 100% and 100%, respectively, whereas for all stenoses, >50% they were 92.9% and 98.7%, respectively. CONCLUSIONS: We found that 64-CT has a high diagnostic accuracy for the detection of in-stent restenosis in a selected patient population.

MRI evaluation of myocardial viability.

Cardiac magnetic resonance imaging (MRI) has become an accurate noninvasive imaging procedure for the study of postischaemic residual cardiac function, thanks to the evolution of MRI machines, postprocessing software and, above all, sequences. After infarction, and in chronic myocardial ischaemia, the degree of contractile dysfunction is one of the main determinants of longterm survival. The identification and quantification of viable dysfunctional myocardium and the possibility of improving its contractility after revascularisation improves patient prognosis and quality of life. In current clinical practice, myocardial viability is evaluated with stress echocardiography and nuclear methods. Thanks to its intrinsic characteristics and to the delayed-enhancement technique (DE-MRI), MRI has recently emerged as the only noninvasive modality able to provide a three-dimensional (3D) evaluation of cardiac viability with a multiparametric approach.

Imaging of post-traumatic cardiac rhabdomyolysis with normal coronary arteries.

Numerous cases of acute myocardial infarction (AMI) have been reported in the literature following closed chest injuries, due to post-traumatic dissection or thrombosis of a coronary artery. In the follow-up of AMI, wall thickness during diastole and systole provides important information on heart viability. Multidetector computed tomography (MDCT) is currently the only noninvasive instrumental investigation which provides an appreciable assessment of the coronary arteries, as well as heart wall thickness measurements. We describe and discuss the clinical and imaging findings, especially of MDCT, in a case of post-traumatic regional myocardial necrosis with normal coronary arteries.

Direct thrombin inhibitors for the treatment of acute coronary syndromes and during percutaneous coronary interventions.

As acute coronary syndromes are principally sustained by plaque complication and subsequent thrombus formation, anticoagulant therapy plays a central role in avoiding ischemic events; its main targets are thrombin activity and generation. Despite its limitations, such as its scarce ability to activate bound thrombin and its unpredictable pharmacological response, heparin is the most widely used drug for this purpose. Direct thrombin inhibitors are biologically superior to heparin principally because they inhibit clot-bound and circulating thrombin without interacting with other plasma proteins. Their clinical role in acute coronary syndromes and during coronary intervention has been tested in several trials. This article overviews the principal trials involving active-site direct thrombin inhibitors in acute coronary syndrome and during coronary intervention and compares their efficacy and safety with unfractionated heparin. It also describes ongoing trials and analyzes further clinical developments such as their use in addition to the glycoprotein IIb/IIIa inhibitors and the potential advantage possible with new agents orally administered.

Phenotype commitment in vascular smooth muscle cells derived from coronary atherosclerotic plaques: differential gene expression of endothelial nitric oxide synthase.

Unstable angina and myocardial infarction are the clinical manifestations of the abrupt thrombotic occlusion of an epicardial coronary artery as a result of spontaneous atherosclerotic plaque rupture or fissuring, and the exposure of highly thrombogenic material to blood. It has been demonstrated that the proliferation of vascular smooth muscle cells (VSMCs) and impaired bioavailabilty of nitric oxide (NO) are among the most important mechanisms involved in the progression of atherosclerosis. It has also been suggested that a NO imbalance in coronary arteries may be involved in myocardial ischemia as a result of vasomotor dysfunction triggering plaque rupture and the thrombotic response. We used 5' nuclease assays (TaqMan PCRs) to study gene expression in coronary plaques collected by means of therapeutic directional coronary atherectomy from 15 patients with stable angina (SA) and 15 with acute coronary syndromes (ACS) without ST elevation. Total RNA was extracted from the 30 plaques and the cDNA was amplified in order to determine endothelial nitric oxide synthase (eNOS) gene expression. Analysis of the results showed that the expression of eNOS was significantly higher (p<0.001) in the plaques from the ACS patients. Furthermore, isolated VSMCs from ACS and SA plaques confirmed the above pattern even after 25 plating passages. In situ RT-PCR was also carried out to co-localize the eNOS messengers and the VSMC phenotype. The eNOS gene was more expressed in ACS plaques and VSMCs cultured from them, thus indicating that: a) the expression of the most important differentiation markers is retained under in vitro conditions; and b) NO may play a pivotal role in coronary artery disease. Our findings suggest a new cell system model for studying the pathophysiology of unstable angina and myocardial infarction.

Multicolor fluorescence technique to detect apoptotic cells in advanced coronary atherosclerotic plaques.

Apoptosis occurring in atherosclerotic lesions has been suggested to be involved in the evolution and the structural stability of the plaques. It is still a matter of debate whether apoptosis mainly involves vascular smooth muscle cells (vSMCs) in the fibrous tissue or inflammatory (namely foam) cells, thus preferentially affecting the cell-poor lipid core of the atherosclerotic plaques. The aim of the present investigation was to detect the presence of apoptotic cells and to estimate their percentage in a series of atherosclerotic plaques obtained either by autopsy or during surgical atherectomy. Apoptotic cells were identified on paraffin-embedded sections on the basis of cell nuclear morphology after DNA staining and/or by cytochemical reactions (TUNEL assay, immunodetection of the proteolytic poly (ADP-ribose) polymerase-1 [PARP-1] fragment); biochemical procedures (identifying DNA fragmentation or PARP-1 proteolysis) were also used. Indirect immunofluorescence techniques were performed to label specific antigens for either vSMCs or macrophages (i.e., the cells which are most likely prone to apoptosis in atherosclerotic lesions): the proper selection of fluorochrome labeling allowed the simultaneous detection of the cell phenotype and the apoptotic characteristics, by multicolor fluorescence techniques. Apoptotic cells proved to be less than 5% of the whole cell population, in atherosclerotic plaque sections: this is, in fact, a too low cell fraction to be detected by widely used biochemical methods, such as agarose gel electrophoresis of low-molecular-weight DNA or Western-blot analysis of PARP-1 degradation. Most apoptotic cells were of macrophage origin, and clustered in the tunica media, near or within the lipid-rich core; only a few TUNEL-positive cells were labeled for antigens specific for vSMCs. These results confirm that, among the cell populations in atherosclerotic plaques, macrophage foam-cells are preferentially involved in apoptosis. Their death may decrease the cell number in the lipid core and generate a possibly defective apoptotic clearance: the resulting release of matrix-degrading enzymes could contribute to weakening the fibrous cap and promote the plaque rupture with the risk of acute ischemic events, while increasing the thrombogenic pultaceous pool of the plaque core.

Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial.

BACKGROUND: Intracranial haemorrhage is an important limitation to pharmacologic reperfusion therapy for acute myocardial infarction. The combination of a glycoprotein IIb/IIIa inhibitor, half-dose plasminogen activator and reduced-dose heparin has been evaluated as an alternative to standard fibrinolytic therapy in this setting. METHODS AND RESULTS: We evaluated the relation between univariate and multivariate predictors of intracranial haemorrhage and the effect of treatment with either reteplase alone (10 U bolus twice, 30 min apart) with standard-dose heparin (5000 U bolus followed by an infusion of 1000 Uh(-1)for patients > or =80 kg and 800 Uh(-1)for those <80 kg) or combination therapy with abciximab (0.25mg/kg bolus and 0.125 microg/kg/min for 12h) and half-dose reteplase (two boluses of 5U 30 min apart) with reduced-dose heparin (60 Ukg(-1)bolus, maximum 5000 U, followed by an infusion of 7 Ukg(-1)h(-1)) in the 16 588 patients randomized in the GUSTO V trial. Overall, the incidence of intracranial haemorrhage was similar in the two groups (0.6% vs 0.6%; OR 1.05, 95% CI 0.71, 1.56). The median (25th-75th) time from drug administration to intracranial haemorrhage was 5.5 (3.4-11) hours with combination therapy and 9.2 (5.9-22) hours with reteplase (P=0.048). Among the multivariable predictors of intracranial haemorrhage, only age showed a significant interaction with treatment effect (age per treatment interaction chi-square 4.60, P=0.032) with a lower risk of combination therapy for younger patients and a higher risk for the elderly. CONCLUSIONS: Although no additional risk of intracranial haemorrhage has been observed with combination therapy in the whole population, a significant age pertreatment interaction exists, with a lower risk with combination therapy in younger patients, and a higher risk in the elderly.

Identification of differentially expressed genes in coronary atherosclerotic plaques from patients with stable or unstable angina by cDNA array analysis.

The composition of atherosclerotic plaques is a crucial factor in determining rupture, thrombosis and clinical events. In this study, we analyzed gene expression in coronary plaques from patients with stable or unstable angina using gene arrays. Total RNA was extracted from eight plaques collected by therapeutic directional coronary atherectomy. cDNA probes, generated by amplification, were hybridized to nylon arrays containing 482 genes. Here we report the results for the inflammation, adhesion and hemostasis subsets. Many genes not previously associated with atherosclerosis, such as the lymphocyte adhesion molecule MadCAM, were expressed in the plaques. anova analysis showed higher tissue factor (TF) expression in unstable angina samples. Five genes were expressed at lower levels in unstable angina samples: anticoagulant protein S, cyclooxygenase (COX)-1, interleukin (IL)-7 and chemokines monocyte chemotactic protein (MCP)-1 and -2. Gene arrays provide a new approach to study plaque composition and identify candidate markers of plaque instability.

Effect of hirudin vs heparin on haemostatic activity in patients with acute coronary syndromes; the GUSTO-IIb haemostasis substudy.

AIMS: We compared the effects of hirudin and heparin on thrombin generation and activity among 350 patients with acute coronary syndromes enrolled in the GUSTO-IIb trial. METHODS AND RESULTS: We obtained blood at baseline; at 4, 8, and 24h into infusion; at drug termination; and 6 and 24h after termination. We assayed for thrombin activity (fibrinopeptide A, activated protein C, thrombin-antithrombin complex), thrombin generation (prothrombin fragment 1.2), and platelet activation (platelet factor 4). Median baseline fibrinopeptide A and platelet factor 4 levels were elevated. Thrombin formation tended to increase with hirudin and decrease with heparin; by 8h into infusion, thrombin formation was significantly less for heparin (P<0.01). Most patients showed reduced thrombin activity and platelet activation during infusion of either agent. Hirudin-assigned patients had significantly lower fibrinopeptide A levels during infusion. Six h post-termination, both groups had increased thrombin activity. Thrombin formation was increased in heparin patients (P<0.0001), significantly more than with hirudin (P=0.005). Higher values of haemostasis markers tended to be associated with poorer 30-day outcomes. CONCLUSION: Although hirudin did not prevent generation of new thrombin, it appeared to inhibit thrombin activity more than did heparin and produced slower increases in thrombin formation after discontinuation. The reelevation of thrombotic markers after stopping intravenous antithrombin therapy and the tendency toward increased thrombotic events with post-treatment increases in marker levels suggest an ongoing, clinically significant prothrombotic state. These results raise the possibility of improving on current antithrombotics by preventing thrombin generation and thrombin activity and by sustained suppression of the prothrombotic state.

[New strategies in the treatment of acute myocardial infarction]. / Nuove strategie di trattamento dell'infarto miocardico acuto.

A number of experimental and clinical studies have recently underlined the importance, in acute myocardial infarction, of platelet adhesion and aggregation after plaque rupture. During clot resolution, platelet-rich thrombi are relatively resistant to fibrinolytic agents, mainly due to the release of plasminogen inhibitor-1 by platelets which are activated as a result of the increase in thrombin generation induced by plasminogen activator therapy despite heparin administration. Platelet glycoprotein (GP) IIb/IIIa integrin receptor blockers prevent platelet aggregation by blocking the final pathway of platelet activation. Thus, they also prevent the formation of an intraluminal white thrombus without affecting adhesion. Animal and human studies have shown that the potent inhibition of platelet GP IIb/IIIa receptors can lead to modest reperfusion rates even without exogenous fibrinolytic therapy. This suggests that combining the "dethrombotic" effects of a GP IIb/IIIa antagonist with lower fibrynolytic doses may result in a synergistic effect. Preclinical studies including patients with myocardial infarction have shown that such combined treatment increases the incidence, speed and durability of reperfusion. It has also been proved to be useful in improving the microcirculatory coronary flow and in facilitating subsequent percutaneous coronary interventions. In the phase III GUSTO V trial, abciximab combined with 5 + 5 U of reteplase and low-dose weight-adjusted heparin led to a 30-day mortality rate that was similar to that obtained with full-dose reteplase (10 + 10 U) and standard heparin therapy, without causing a significant increase in the incidence of intracranial hemorrhage. The results of this trial offer a rationale for alternative reperfusion therapy, although further analyses, including a 1-year follow-up, are needed to define the patient groups that are most likely to benefit from such a new regimen.