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Purpose To study the effects of a perindopril-based regimen on cardiovascular (CV) outcomes in patients with vascular disease in relation to background statin therapy. Methods A pooled analysis of the randomized ADVANCE, EUROPA, and PROGRESS trials was performed to evaluate CV outcomes in 29,463 patients with vascular disease treated with perindopril-based regimens versus placebo. The primary endpoint was a composite of CV mortality, nonfatal myocardial infarction, and stroke. Multivariable Cox regression analyses were performed to assess the effects of a perindopril-based regimen versus placebo in relation to statin use. Results At randomization, 39.5% of the overall combined study population used statins. After a mean follow-up of 4.0 years (SD 1.0), the cumulative event-free survival was highest in the statin/perindopril group and lowest in the no statin/placebo group (91.2% vs. 85.6%, respectively, log-rank p Conclusion Our data suggest that the treatment benefits of a perindopril-based regimen in patients with vascular disease are independent of statin use.

The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology

In patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure response to ACE inhibitors are observed and as such heterogeneity in clinical treatment effect would be likely as well. Assessing the consistency of treatment benefit is essential for the rational and cost-effective prescription of ACE inhibitors. Information on heterogeneities in treatment effect between subgroups of patients could be used to develop an evidence-based guidance for the installation of ACE-inhibitor therapy. Obviously, therapy should only be applied in those patients who most likely will benefit. Attempts to develop such treatment guidance by using clinical characteristics have been unsuccessful. No heterogeneity in risk reduction by ACE inhibitors has been observed in relation to relevant clinical characteristics. A new approach to such ‘guided-therapy’ could be to integrate more patient-specific characteristics such as the patients’ genetic information. If proven feasible, pharmacogenetic profiling could optimise patients’ benefit of treatment and reduce unnecessary treatment of patients. Cardiovascular pharmacogenetic research of ACE inhibitors in coronary artery disease patients is in a formative stage and studies are limited. The PERGENE study is a large pharmacogenetic substudy of the EUROPA trial, aimed to assess the achievability of pharmacogenetic profiling. We provide an overview of the main results of the PERGENE study in terms of the genetic determinants of treatment benefit and blood pressure response. The main results of the PERGENE study show a pharmacogenetic profile related to the treatment benefit of perindopril identifying responders and non-responders to treatment.

OBJECTIVE: To evaluate a 30-day and long-term outcome of patients with acute myocardial infarction (AMI) treated with intra-aortic balloon pump (IABP) counterpulsation and to identify predictors of a 30-day and long-term all-cause mortality. METHODS: Retrospective cohort study of 437 consecutive AMI patients treated with IABP between January 1990 and June 2004. A Cox proportional hazards model was used to identify predictors of a 30-day and long-term all-cause mortality. RESULTS: Mean age of the study population was 61 ± 11 years, 80% of the patients were male, and 68% had cardiogenic shock. Survival until IABP removal after successful haemodynamic stabilisation was 78% (n = 341). Cumulative 30-day survival was 68%. Median follow-up was 2.9 years (range, 6 months to 15 years). In patients who survived until IABP removal, cumulative 1-, 5-, and 10-year survival was 75%, 61%, and 39%, respectively. Independent predictors of higher long-term mortality were prior cerebrovascular accident (hazard ratio (HR), 1.8; 95% confidence interval (CI), 1.0-3.4), need for antiarrhythmic drugs (HR, 2.3; 95% CI, 1.5-3.3), and need for renal replacement therapy (HR, 2.3; 95% CI, 1.2-4.3). Independent predictors of lower long-term mortality were primary percutaneous coronary intervention (PCI; HR, 0.6; 95% CI, 0.4-1.0), failed thrombolysis with rescue PCI (HR, 0.5; 95% CI, 0.3-0.9), and coronary artery bypass grafting (HR, 0.3; 95% CI, 0.1-0.5). CONCLUSIONS: Despite high in-hospital mortality in patients with AMI treated with IABP, a favourable number of patients survived in the long-term. These results underscore the value of aggressive haemodynamic support of patients throughout the acute phase of AMI.

Objective To evaluate the predictive value of seven biomarkers, which individually have been shown to be independent predictors, for use in a combined multimarker model for long-term cardiovascular outcome after non-ST-segment elevation acute coronary syndrome (NSTEACS). Design and Setting Levels of high-sensitivity C-reactive protein (hsCRP), myeloperoxidase, pregnancy-associated plasma protein A, placental growth factor (PlGF), soluble CD40 ligand (sCD40L), interleukin 10 (IL-10) and troponin-T (TnT) were determined in patients enrolled in the CAPTURE trial. Cox proportional hazard regression analyses were applied to evaluate the relation between biomarkers and the occurrence of all-cause mortality or non-fatal myocardial infarction (MI). Patients 1090 patients with NSTEACS. Main outcome measure All-cause mortality and non-fatal MI during a median follow-up of 4 years. Results The composite endpoint was reached by 15.3% of patients. Admission levels of TnT >0.01 mg/l (adjusted HR 1.8), IL-10 350 mg/l (1.5) and PlGF >27 ng/l (1.9) remained significant predictors for the incidence of all-cause mortality or non-fatal MI after multivariable adjustment for other biomarkers and clinical characteristics, whereas hsCRP, pregnancy-associated plasma protein A and sCD40L were only associated with the endpoint in univariate analysis. A multimarker model consisting of TnT, IL-10, myeloperoxidase and PlGF predicted 4-year event rates that varied between 6.0% (all markers normal) and 35.8% (three or more biomarkers abnormal). Conclusion In patients with NSTEACS, biomarkers characterising distinct aspects of the underlying atherosclerotic process and myocardial damage of the initial cardiac event can assist in predicting long-term adverse cardiac outcomes. The use of combinations of selected biomarkers adds incremental predictive value to further risk stratification in an otherwise seemingly homogeneous NSTEACS population.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage. METHODS: The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at -40 degrees C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (promoter) and existing relevant literature. The main outcome measure of PERGENE is the effect of genetic factors on the treatment benefit with ACE-inhibitors. The size of this pharmacogenetic substudy allows detection with a statistical power of 98% to detect a difference in hazard ratios (treatment effect) of 20% between genotypes with minor allele frequency of 0.20 (two-sided alpha 0.05). CONCLUSION: The PERGENE study is a large cardiovascular pharmacogenetic study aimed to assess the feasibility of pharmacogenetic profiling of the treatment effect of ACE-inhibitor use with the perspective to individualize treatment in patients with stable coronary artery disease

Drug-eluting stents (DES) were introduced into clinical practice in 2002 in order to reduce restenosis that occurred in 15–25% of patients receiving bare-metal stents (BMS).1–3 Subsequent trials with different types of DES confirmed their efficacy in this regard.4 However, late stent thrombosis was reported as early as 2004, typically in patients discontinuing dual anti-platelet therapy.5 At the European and World Congress of Cardiology in Barcelona 2006, alarming data were presented on a worse long-term prognosis following DES implantation compared with BMS.6,7 As a result both randomized controlled trials and registry data were scrutinized to validate these concerns, bearing in mind the differential values of both types of studies.8,9 Furthermore, the worldwide discussion on the long-term safety and efficacy of DES triggered the European Society of Cardiology together with the European Association for Percutaneous Cardiovascular Interventions to organize a forum on DES. On 27 and 28 September 2007, key opinion leaders in (interventional) cardiology and representatives from industry and regulatory bodies gathered in the European Heart House with the intention to review: (i) the most recent data on the long-term efficacy (reduction of restenosis, re-intervention) and safety (late stent thrombosis, myocardial infarction, mortality) of DES and its effects on outcome (survival, event-free survival), (ii) specific indications for DES; (iii) health economical analyses currently performed with DES; (iv) the DES registration process in Europe; (v) current and possible future trial designs. The overall goal was to provide general recommendations to the medical community for the use, clinical development, and future assessment of DES. In several randomized controlled trials comparing sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) and BMS, increased rates of death or myocardial infarction were observed at follow-up, beyond the first year,6–8,10 while no excess …

Objectives: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease [EUROPA] demonstrates reduction in cardiovascular mortality and myocardial infarction for a possible vascular and antiatherosclerotic effect of angiotensin-converting enzyme (ACE) inhibition with perindopril. Our objective was to study the effect of perindopril on endothelial function and to verify its link to risk and occurrence of cardiovascular events. Methods: Blood from 1200 EUROPA patients was withdrawn at baseline and after 1 year of treatment with either perindopril or placebo to measure von Willebrand factor and from 45 healthy subjects and 87 EUROPA patients to study endothelial function at the cellular level by cultivating in vitro human umbilical vein endothelial cells. In this setting, we determined protein expression/activity of endothelial nitric oxide synthase and the rate of apoptosis. Plasma levels of angiotensin II, bradykinin, tumor necrosis factor α, and nitrite/nitrate were also measured. Results: The occurrence of cardiovascular events was related to von Willebrand factor at baseline ( P =0.013) that also significantly decreased after 1 year's treatment ( P

Patients who develop a reinfarction are at increased risk for subsequent reinfarctions and death. However, follow-up studies in these patients are rare.The purpose of this study was to examine the risk of mortality after a first myocardial reinfarction and to determine the independent contribution of nonfatal reinfarction to the risk of subsequent mortality.The prognostic value of nonfatal reinfarction was assessed in a large series (n=3097) of patients with a first myocardial infarction who participated in the ASPECT trial, comparing coumarin or matching placebo.A second myocardial infarction was documented in 299 patients (82% Q-wave infarctions), 45 (15%) of which were fatal. Of the 254 nonfatal reinfarctions, 31 patients (12%) died during subsequent follow-up. After adjustment for baseline characteristics, the relative risks of nonfatal reinfarction for subsequent cardiac mortality at one month were: 2.90 (1.49-5.64), at one year: 2.50 (1.47-4.23) and at three years: 2.71 (1.77-4.17). Rates of death or a second reinfarction in patients who did not undergo a revascularisation procedure after a first reinfarction were almost three times higher than in patients who did have PTCA or bypass surgery after a reinfarction (38% versus 14%; p0.0001).This study population with three-year follow-up confirms that nonfatal reinfarction carries a strong and independent risk for recurrent reinfarction and subsequent mortality. Thus, prevention of reinfarction by intensive treatment might contribute in reduction of mortality.

Guidelines for the management of patients with cardiovascular disease are designed to assist cardiologists and other physicians in their practice. Surveys are conducted to assess whether guidelines are followed in practice. The results of surveys on acute coronary syndromes, coronary revascularisation, secondary prevention, valvular heart disease and heart failure are presented. Comparing surveys conducted between 1995 and 2002, a gradual improvement in use of secondary preventive therapy is observed. Nevertheless, important deviations from established guidelines are noted, with a significant variation among different hospitals in the Netherlands and in other European countries. Measures for further improvement of clinical practice include more rapid treatment of patients with evolving myocardial infarction, more frequent use of clopidogrel and glycoprotein IIb/IIIa receptor blockers in patients with acute coronary syndromes, more frequent use of β-blockers in patients with heart failure and more intense measures to encourage patients to stop smoking. Targets for the proportion of patients who might receive specific therapies are presented.

Angiotensin-converting-enzyme (ACE) inhibitors reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD). Three large trials have assessed the effect of ACE inhibitors in stable patients without these conditions but with atherosclerosis. We undertook a systematic review of the Heart Outcomes Prevention Evaluation (HOPE), the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA), and the Prevention of Events with ACE inhibition (PEACE) studies to determine the consistency with which ACE inhibitors reduce total mortality and fatal and non-fatal cardiovascular events.We computed cardiovascular outcomes and total mortality in the 29,805 patients of these three trials, randomly assigned an ACE inhibitor or placebo and followed up for a mean of about 4.5 years. The results were also analysed within the context of five large trials of ACE inhibitors in patients with heart failure or LVSD.When the findings of the HOPE, EUROPA, and PEACE trials were combined, ACE inhibitors significantly reduced all-cause mortality (7.8 vs 8.9%, p=0.0004), cardiovascular mortality (4.3 vs 5.2%, p=0.0002), non-fatal myocardial infarction (5.3 vs 6.4%, p=0.0001), all stroke (2.2 vs 2.8%, p=0.0004), heart failure (2.1 vs 2.7%, p=0.0007), coronary-artery bypass surgery (6.0 vs 6.9%, p=0.0036) but not percutaneous coronary intervention (7.4 vs 7.6%, p=0.481). The composite outcomes of cardiovascular mortality, non-fatal myocardial infarction, or stroke occurred in 1599 (10.7%) of the patients allocated ACE inhibitor and in 1910 (12.8%) of those allocated placebo (odds ratio, 0.82; 95% CIs 0.76-0.88; p0.0001). Except for stroke and revascularisation, these results were similar to those of the five trials in patients with heart failure or LVSD.ACE inhibitors reduce serious vascular events in patients with atherosclerosis without known evidence of LVSD or heart failure. Results showing these benefits in intermediate-risk patients complement existing evidence of similar benefit in higher-risk patients with LVSD or heart failure. Therefore, use of ACE inhibitors should be considered in all patients with atherosclerosis.

Background/Aims:A large proportion of patients with a ST-elevation acute coronary syndrome do not receive reperfusion therapy. In order to contribute to a better understanding of the clinical decision making process, we analyzed which factors are associated with the application of reperfusion therapy. Methods: From the Euro Heart Survey of Acute Coronary Syndromes I, 4,260 patients with ST-elevation acute coronary syndrome were selected for the current analysis, of which 1,539 (36%) patients received fibrinolysis and 904 (21%) primary percutaneous coronary intervention (PCI). The analysis contained 32 variables on demographics, medical history, admission parameters and reperfusion therapy. Results: A short pre-hospital delay, arrival in a hospital with PCI facilities, severe ST-elevation, and participation in a clinical trial were the strongest predictors for receiving reperfusion therapy. Primary PCI was more likely to be performed than fibrinolysis in patients with a long pre-hospital delay, arriving in a hospital with PCI facilities, not participating in a clinical trial, and with at least one previous PCI. Conclusion:Hospital facilities and culture, pre-hospital delay and infarction size play a major role in management decisions regarding reperfusion therapy in ST-elevation acute coronary syndrome. This analysis indicates which factors require special attention when implementing and reviewing the reperfusion guidelines.

Background Great concern exists about the ability of the anatomic right ventricle to sustain the systemic circulation in patients with transposition of the great arteries who have undergone a Mustard procedure. A prospective study was made to examine long-term survival, clinical outcome, and right ventricular function 25 years after surgery. Methods Ninety-one consecutive patients underwent the Mustard procedure between 1973 and 1980. After 14 years and again after 25 years (range 22–29 years), patients were studied with ECG, echocardiography, exercise testing, and Holter monitoring. Results The cumulative survival and event-free survival were 77% and 36%, respectively, after 25 years. Reoperation was necessary in 46%. No major loss of sinus rhythm was found. While all patients had good right ventricular function 14 years after repair, 61% of patients showed moderate-to-severe dysfunction after 25 years, when studied by echocardiography. Furthermore, the QRS complex widened and exercise capacity decreased. Conclusion The anatomic right ventricle appears to be unable to sustain the systemic circulation at long-term follow-up and the clinical condition of patients late after Mustard repair is declining. We can expect more deaths or need for heart transplantation in the next decade.

Background Immediate, as well as early, revascularisation is of benefit in patients with acute coronary syndromes (ACS) presenting with ST elevation. However, trials comparing invasive versus medical treatment in patients with an acute coronary syndrome without ST elevation do not consistently show improvement in survival after revascularisation. Accordingly, additional data are warranted. Methods The effect of revascularisation within 30 days on one-year survival in the GUSTO IV ACS trial was investigated. A total of 7800 patients were included with an acute coronary syndrome without ST elevation, documented by either elevated cardiac troponin or transient or persistent ST-segment depression. In this trial, comparing abciximab versus placebo as initial medical therapy, coronary angiography within 60 h after randomisation was discouraged. In 30-day survivors, those who underwent revascularisation were compared with 30-day survivors without revascularisation. Adjustments were made for patient characteristics, and for a propensity score that was adjusted for covariates associated with the likelihood of early revascularisation. Findings Of the 7496 patients who survived at least 30 days, 2265 (30%) underwent coronary revascularisation within 30 days: 789 patients CABG, 1450 PCI and 26 both CABG and PCI. Procedure-related mortality was low at 1.8%. Patients with revascularisation had a lower one-year mortality compared to medically treated patients (2.3% vs. 5.6%, p

Background Long-term survival and clinical outcome after surgical closure of a VSD is poorly documented. Such data are important for the future perspectives, medical care, employability, and insurability of these patients. Methods 176 consecutive patients underwent surgical closure of an isolated VSD between 1968 and 1980 in our hospital. A systematic follow-up study was performed in 1990 and again in 2001. Findings Late survival was poorer than in the general population. Pulmonary hypertension and right ventricular hypertrophy were present in the 4 patients who died suddenly, late after operation. During follow-up no new pulmonary hypertension became manifest. Re-operations were necessary in 6%. Some patients (4%) developed sinus node disease late after repair, requiring pacemaker implantation. At last follow-up (91 survivors) 92% of the patients were in NYHA class I. Pulmonary hypertension was found in 4%, and aorta insufficiency in 16%. Patients experienced difficulties when applying for insurance. Conclusion Among patients with surgically repaired VSDs, late results were good, although some late sudden deaths occurred in the patients with pulmonary hypertension. Furthermore, some patients developed sinus node disease late after repair, requiring pacemaker implantation. Employability is good, but pregnancy and insurance matters need further attention.

Objective: To investigate the incidence of clinical problems related to a bicuspid valve (aortic stenosis and regurgitation) and the incidence of ascending aorta and aortic arch pathology in combination with coarctation repair. Patients: 124 adult patients after surgical correction of aortic coarctation were studied. The incidence of aortic valve, ascending aorta, and aortic arch pathology was determined using echocardiography and magnetic resonance imaging. The median age at coarctation repair was 9 years and at last follow up 28 years. Results: Three patients died from aorta pathology. Aortic valve disease was found in 63% of the patients, requiring an intervention in 22%, at a median of 13 years after coarctation repair. Ascending aorta dilatation was observed in 28% and aortic arch abnormalities in 23%, among whom kinking of the aortic arch was found in 12%. Antihypertensive medication was used in 24%. In the patients with hypertension the age at operation and age at follow up were significantly higher (p = 0.0001 and p < 0.0001, respectively). Conclusion: In addition to the well known problems of hypertension and recoarctation, aortic valve and aortic arch pathology are commonly encountered in patients with previous coarctation repair. Aortic abnormalities may predispose to dilatation and dissection, thus necessitating careful lifelong attention in all patients with coarctation.

Aims Thrombolytic therapy restores coronary patency in patients with acute myocardial infarction, although normal perfusion (TIMI 3 flow) is not achieved in all patients. In an attempt to improve TIMI 3 flow, a combination of full-dose streptokinase, aspirin and escalating dosages of a platelet glycoprotein IIb/IIIa receptor blocker, eptifibatide, vs placebo were tested. Methods and Results A bolus of 180μg.kg−1of eptifibatide was administered in each group, followed by a 72h continuous infusion of 0·75 (44 patients), 1·33 (n=45) and 2·00μg.kg−1.min−1(n=30); 62 patients received placebo. Normal perfusion (TIMI 3 flow) at 90min was observed in 31% of placebo patients compared to 46, 42 and 45% in the ascending eptifibatide groups (44% for combined eptifibatide groups, P =0·07). Patency (TIMI 2 and 3 flow combined) increased from 61% (placebo) to 78% for the combined eptifibatide groups ( P =0·02). Reocclusion was infrequent. No differences were observed in TIMI flow grades among eptifibatide groups. Major and minor bleeding was increased and occurred mainly at the arterial puncture site. Conclusion A combination of full dose streptokinase with different eptifibatide regimens enhanced coronary perfusion, but bleeding risk was excessive. Additional trials are needed with different dosage regimens to determine the optimal combination of fibrinolytic agents and platelet glycoprotein IIb/IIIa receptor blockers.

Management of acute coronary syndromes : acute coronary syndromes without persistent ST segment elevation; recommendations of the Task Force of the European Society of Cardiology.

Aims Oral glycoprotein IIb/IIIa inhibitors might enhance the early benefit of an intravenous agent and prevent subsequent cardiac events in patients with acute coronary syndromes. We assessed the safety and preliminary efficacy of 1 month treatment with three dose levels of the oral GP IIb/IIIa blocker lefradafiban in patients with unstable angina or myocardial infarction without persistent ST elevation. Methods The Fibrinogen Receptor Occupancy STudy (FROST) was designed as a dose-escalation trial with 20, 30 and 45mg lefradafiban t.i.d. or placebo. Five hundred and thirty-one patients were randomized in a 3:1 ratio to lefradafiban or placebo in a double-blind manner. Efficacy was assessed by the incidence of death, myocardial infarction, coronary revascularization and recurrent angina. Safety was evaluated by the occurrence of bleeding classified according to the TIMI criteria and by measuring clinical laboratory parameters. Results There was a trend towards a reduction in cardiac events with lefradafiban 30mg when compared with placebo and lefradafiban 20mg. The benefit was particularly apparent in patients with a positive (≥0·1ng.ml−1) troponin I test at baseline and less so in those with a negative test result. In patients receiving lefradafiban, the cardiac event rate decreased with increasing minimal levels of fibrinogen receptor occupancy. There was a dose-dependent increase in the incidence of bleeding: the composite of major or minor bleeding occurred in 1% of placebo patients, 5% of patients receiving lefradafiban 20mg and in 7% of patients receiving 30mg, with an excessive risk (15%) in the 45mg group which resulted in early discontinuation of this dose level. Gingival and arterial or venous puncture site bleedings were most common and accounted for more than 60% of all haemorrhagic events. There was an increased incidence of neutropenia (neutrophils

Aims To risk stratify and shorten hospital stay in patients with spontaneous (resting) chest pain and a non-diagnostic electrocardiogram (ECG). Methods and Results The study comprised 102 patients (mean age 58±12 years, 67 men) with spontaneous chest pain and a non-diagnostic ECG. Forty-three patients had suspected coronary artery disease and 59 had known (but of unknown actual significance) coronary artery disease. All patients underwent serial creatine kinase enzyme measurements, continuous ECG monitoring for at least 12h and early dobutamine–atropine stress echocardiography in patients with negative creatine kinase enzymes and normal findings at ECG monitoring. Dobutamine–atropine stress echocardiography was considered positive in patients with new or worsening wall thickening abnormalities. Patients with negative dobutamine–atropine stress echocardiography were discharged after the test. In-hospital and 6 month follow-up events noted were cardiac death, non-fatal myocardial infarction, unstable angina, and coronary artery bypass surgery or angioplasty. Thirteen patients had evidence of evolving myocardial infarction by elevated creatine kinase enzymes, or unstable angina by ECG monitoring. In the remaining 89 patients, dobutamine–atropine stress echocardiography was performed after a median observation period of 31h (range 12–68h). During dobutamine–atropine stress echocardiography no serious complications (death, non-fatal myocardial infarction, sustained ventricular tachycardia or ventricular fibrillation) occurred. Dobutamine–atropine stress echocardiography results were of poor quality in three, non-diagnostic in six, negative in 44 and positive in 36 patients. In the 80 patients with diagnostic dobutamine–atropine stress echocardiography, variables associated with in-hospital events (n=7) were history of exertional angina ( P

This document was developed by a consensus conference initiated by Kristian Thygesen, MD, and Joseph S. Alpert, MD, after formal approval by Lars Rydén, MD, President of the European Society of Cardiology (ESC), and Arthur Garson, MD, President of the American College of Cardiology (ACC). All of the participants were selected for their expertise in the field they represented, with approximately one-half of the participants selected from each organization. Participants were instructed to review the scientific evidence in their area of expertise and to attend the consensus conference with prepared remarks. The first draft of the document was prepared during the consensus conference itself. Sources of funding appear in Appendix A. The recommendations made in this document represent the attitudes and opinions of the participants at the time of the conference, and these recommendations were revised subsequently. The conclusions reached will undoubtedly need to be revised as new scientific evidence becomes available. This document has been reviewed by members of the ESC Committee for Scientific and Clinical Initiatives and by members of the Board of the ESC who approved the document on April 15, 2000.*

In a prospective trial, the diagnostic performance of the second version of the troponin T rapid assay (Trop T; cutoff 0.2 microg/L) was compared with the quantitative cardiac-specific troponin T assay (cTnT ELISA; cutoff 0.1 microg/L) and other established cardiac markers such as CK, CK-MB activity, CK-MB mass and myoglobin. Additionally, a 30-day follow-up was performed to determine the suitability of the Trop T assay and the reference markers for short-term risk stratification. Two-hundred-and-eighty-six consecutive patients with chest pain and suspected acute myocardial infarction (AMI) were enrolled in two CCU departments. Serial blood specimens were taken at admission and at 3, 6, 12, 24, 48, 72 and 96 h after admission. According to the biochemical criterion CK-MB mass, the patients were classified as having AMI in 154 patients (54%), unstable angina (UAP) in 72 patients (27%) and no evidence for acute cardiac ischemia in 55 patients (19%). Analytical method comparison of Trop T with cTnT ELISA (cutoff 0.1 microg/L) showed a good agreement, Trop T yielded only 4% false-negative and 3% false-positive results. The diagnostic performance of Trop T for the detection of AMI was only slightly inferior compared to cTnT ELISA. Beyond 12 h after admission, Trop T and cTnT ELISA maintained a sensitivity close to 100%, whereas the sensitivity of the other cardiac markers decreased sharply. The diagnostic sensitivity of Trop T for the detection of minor myocardial damage in UAP patients was the same as for cTnT ELISA. Death within 30 days' follow-up occurred only in AMI patients with a positive Trop T test result within the first 6 h after admission. The admission Trop T and cTnT ELISA were the only significant biochemical predictors of major cardiac events. In conclusion, these data show that Trop T has similar diagnostic sensitivity as cTnT ELISA and is a useful tool to confirm acute or subacute myocardial infarction. Trop T is an excellent marker in detecting minor myocardial damage in UAP patients and is suitable for short-term risk stratification.

Background —Stroke occurs concurrently with myocardial infarction (MI) in ≈30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States. Methods and Results —Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non–bypass surgery–related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44% ($29 242 versus $20 301, P P P P =0.002). Conclusions —In this first large prospective economic study of stroke in AMI patients, we found that strokes were associated with a 60% ($15 092) increase in cumulative 1-year medical costs. Baseline hospitalization costs were 44% higher because of longer mean lengths of stay. Stroke type was a key determinant of baseline cost. Follow-up costs were more than quadrupled for stroke survivors because of the need for institutional care. Disability level was the main determinant of institutional care and thus of follow-up costs.

Although it is well known that smoking is strongly associated with coronary heart disease, many patients continue or resume smoking after being diag- nosed with coronary heart disease and even after an important event such as a myocardial infarction, angio- plasty or coronary bypass surgery. The evidence that smoking causes cardiovascular disease and new events in patients with coronary heart disease, among other serious disorders such as lung cancer and emphysema, justifies the promotion of smoking cessation. All rec- ommendations on the prevention of coronary heart dis- ease emphasize the importance of smoking cessation in the reduction of the risk of coronary death and non-fatal coronary events[3,4]. The recent EUROASPIRE study on the status of secondary prevention of coronary heart disease in nine European countries has shown, however, that success in smoking cessation among coronary heart disease patients is far from satisfactory[5]. In this era of evidence-based medicine, information from systematic reviews of published studies should guide physicians and other health professionals advising patients in smoking cessation. With this in mind, we have carried out a systematic review of published observational studies on the impact of smoking cessation on the prognosis and on smoking intervention trials in patients with coronary heart disease.

Aims To investigate whether the benefit of thrombolytic therapy was sustained beyond the first decade. We report the 10–14 year outcome of 533 patients who were randomized to treatment with intracoronary streptokinase or to conventional therapy during the years 1980–1985. Methods and Results Details of survival and cardiac events were obtained from the civil registry, from medical records or from the patient’s physician. At follow-up, 158 patients (59%) of the 269 patients allocated to thrombolytic treatment and only 129 patients (49%) of the 264 conventionally treated patients were alive. The cumulative 1-, 5- and 10-year survival rates were 91%, 81% and 69% in patients treated with streptokinase and 84%, 71% and 59% in the control group, respectively ( P =0·02). Reinfarction during 10-years of follow-up was more frequent after thrombolytic therapy, particularly during the first year. Coronary bypass surgery and coronary angioplasty were more frequently performed after thrombolytic therapy. At 10 years approximately 30% of the patients were free from subsequent cardiac events.Independent determinants of mortality were elderly age, indicators of impaired residual left ventricular function, multivessel disease and an inability to perform an exercise test at the time of hospital discharge. Conclusion Improved survival after thrombolytic therapy is maintained beyond the first decade. Age, left ventricular function, multivessel disease and an inability to perform an exercise test were independent predictors for long-term mortality, as they are predictors for early mortality.

Background —Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence. Methods and Results —We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter. Conclusions —Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed.

Background—Treatment policy of acute rejection after heart transplantation has been changed after adopting the ISHLT endomyocardial biopsy grading system in 1991. Objective—To determine the effect of this policy change on clinical outcome after transplantation. Methods—The outcome of 147 patients who had a transplant before (early group, median follow up 96 months) and 114 patients who had a transplant after (late group, median follow up 41 months) the introduction of the ISHLT biopsy grading system was studied retrospectively. Initially "moderate rejection" according to Billingham's conventional criteria was treated. From January 1991 grade 3A and higher was considered to require intensification of immunosuppression. Results—There were some differences between the two groups: recipients (50 v 44 years) as well as donors (28 v 24 years) were older in the "late group" and more patients of this group received early anti-T cell prophylaxis (92% v 56%). Despite more extensive use of early prophylaxis more rejection episodes were diagnosed (2.4 v 1.4) and considerably more courses of rejection treatment were instituted in the late compared with the early group (3.2 v 1.5). There were no deaths because of rejection in the late group, however, more infections occurred within the first year (mean 1.8 v 1.4) and more non-skin malignancies within the first 41 months were diagnosed (8 of 57 v 6 of 147, 95% CIs of difference includes 0). The incidence of graft vascular disease in the late group has been comparable to the early group until now. Conclusion—The interpretation of the ISHLT grading system resulted in lowering of the threshold for the diagnosis of rejection thereby increasing the number of rejections and subsequently the immunosuppressive load and its complications. Keywords: transplantation; biopsy grading system; rejection

At the European Congresses of Cardiology inAmsterdam (1995) and Birmingham (1996), and atrecent American meetings, large audiences weredrawn to presentations and discussions about directpercutaneous transluminal coronary angioplasty andstenting for acute myocardial infarction. Apparentlythis topic appeals to many cardiologists, and theprocedure is being performed in many hospitalsworldwide. In Rotterdam, we receive an increasingnumber of telephone calls from cardiologists inhospitals without facilities for coronary intervention,who wish to transfer their patients for either directpercutaneous transluminal coronary angioplasty orrescue percutaneous transluminal coronary angio-plasty. This pressure for percutaneous transluminalcoronary angioplasty in patients with evolving myo-cardial infarction is, in our opinion, not appropriate!First, because data supporting the superiority ofdirect percutaneous transluminal coronary angio-plasty over thrombolysis is limited and secondbecause the attention should be focused more onother procedures which may have a greater impact onsurvival in patients with myocardial infarction, inparticular very early pre-hospital therapy.

The selection of ECG leads used for ST monitoring may influence detection and quantitation of ischaemia.We compared on-line continuous 48-h 12-lead against 3-lead ST monitoring in 130 unstable angina patients (Mortara. ELI-100). Onset and offset of ST episodes were defined by the lead with the firstor = 100 microV ST change relative to baseline and the lead with the latest return to baseline ST level, respectively. ST episodes were calculated for 12 leads and 3 leads (V2, V5, III) separately.ST episodes were detected in 88 patients (77%) by 12-lead and in 71 patients (62%) by 3-lead ST monitoring (P0.02). The median number (25.75%) of episodes/patient was 1 (0.3) for 3-lead and 2 (1.6) for 12-lead (P0.0001). The total duration of ischaemia detected during 12-lead far exceeded 3-lead monitoring: 12.3 (1, 58.2) and 1.7 (0, 23.3) min respectively (P0.0001). The probability of recurrent ischaemia declined most during the first 24 h of monitoring. After a period without ST changes of 1, 12, 24 and 36 h, the probabilities of recurrent ischaemia were 63, 31, 14 and 9%, respectively.Continuous 12-lead ST monitoring increases detection rate and duration of ST episodes compared to 3-lead ST monitoring. The use of continuous 12-lead ECG monitoring devices on emergency wards and coronary care units is recommended.

Previous studies of management of unstable angina have revealed substantial differences in management between different hospitals, especially with respect to the use of coronary angiography. Physicians in a hospital with angiography facilities were more inclined to perform angiography than were physicians in hospitals without these facilities, even when differences in patient populations were taken into account. The authors compared the management strategies of 18 cardiologists, working in hospitals with and without angiography facilities, using a series of paper-case summaries, in order to assess the contribution of individual variability between physicians to practice differences. Physicians who worked in a hospital with in-house angiography facilities were more inclined to request angiography in similar case summaries, but the inter-individual variation exceeded the between-hospital variation. The variation in individual policies with respect to the decision to initiate coronary angiography could be associated with differences in weighting clinical information. These results confirm that practice variations may have many causes: variability in patients' characteristics, variations in how physicians react to these, differences in the availability of services, and variability in thresholds for action. Key words: unstable angina; coronary angiography; policy analysis; practice variation. (Med Decis Making 1997;17:292-297)

textabstractOBJECTIVES: Examination of the difference in management strategies with respect to coronary angiography in patients with unstable angina pectoris, and the consequences of this difference on prognosis. DESIGN: Prospective registration of consecutive patients admitted to two different hospitals. SETTING: University and a large community hospital in Rotterdam, the Netherlands. SUBJECTS: Patients under 80 years, without recent (< 4 weeks) infarction or recent (< 6 months) coronary revascularization procedure, admitted for chest pain suspected to indicate unstable angina pectoris. MAIN OUTCOME MEASURES: Decision to initiate coronary angiography or to continue on medical treatment. At 6 months the occurrence of death and myocardial infarction was measured. RESULTS: Clinical variables associated with the decision to initiate angiography were young age, male gender, progression of angina, multiple pain episodes and use of beta-blocker or calcium antagonists before admission, abnormal ST-T segment on baseline ECG, recurrent pain in hospital, and ECG changes during pain. These associations did not differ between hospitals. Nevertheless, angiography was performed more often in the presence of angiography facilities (university hospital), independent of the variable case-mix. Survival and infarct-free survival were similar in both hospitals, 96% and 90% respectively. CONCLUSION: The difference in angiography rate for unstable angina can be explained in part by differences in patient population and hospital facilities, but no difference was observed in physicians' assessment of patient characteristics. The observed practice variation did not affect prognosis.

BACKGROUND: The recent international GUSTO trial of 41,021 patients with acute myocardial infarction demonstrated improved 90-min infarct related artery patency as well as reduced mortality in patients treated with an accelerated regimen of tissue plasminogen activator, compared to patients treated with streptokinase. A regimen combining tissue plasminogen activator and streptokinase yielded intermediate results. The present study investigated the effects of treatment on infarct size and enzyme release kinetics in a subgroup of these patients. METHODS: A total of 553 patients from 15 hospitals were enrolled in the study. Four thrombolytic strategies were compared: streptokinase with subcutaneous heparin, streptokinase with intravenous (i.v.) heparin, tissue plasminogen activator with i.v. heparin, and streptokinase plus tissue plasminogen activator with i.v. heparin. The activity of alpha-hydroxybutyrate dehydrogenase (HBDH) in plasma was centrally analysed and infarct size was defined as cumulative HBDH release per litre of plasma within 72 h of the first symptoms (Q(72)). Patency of the infarct-related vessel was determined by angiography in 159 patients, 90 min after treatment. RESULTS: Infarct size was 3.72 g-eq.1(-1) in patients with adequate coronary perfusion (TIMI-3) at the 90 min angiogram and larger in patients with TIMI-2 (4.35 g-eq.1(-1) or TIMI 0-1 (5.07 g-eq.1(-1) flow (P = 0.024). In this subset of the GUSTO angiographic study, early coronary patency rates (TIMI 2 + 3) were similar in the two streptokinase groups (53 and 46%). Higher, but similar, patency rates were observed in the tissue plasminogen activator and combination therapy groups (87 and 90%). Median infarct size for the four treatment groups, expressed in gram-equivalents (g-eq) of myocardium, was 4.4, 4.5, 3.9 and 3.9 g-eq per litre of plasma (P = 0.04 for streptokinase vs tissue plasminogen activator). Six hours after the first symptoms, respectively 5.3, 6.6, 14.0 and 13.6% of total HBDH release was complete (P < 0.0001 for streptokinase vs tissue plasminogen activator). CONCLUSIONS: Rapid and complete coronary reperfusion salvages myocardial tissue, resulting in limitation of infarct size and accelerated release of proteins from the myocardium. Treatment with tissue plasminogen activator, resulting in earlier reperfusion was more effective in reducing infarct size than the streptokinase regimens, which contributes to the differences in survival between treatment groups in the GUSTO trial.

Objective To improve pre-hospital triage of patients with suspected acute cardiac disease Design Prospective study Subjects Patients with symptoms suggestive of acute cardiac pathology, who were seen by a general practitioner, for whom acute admission into hospital was requested, and in whom a pre-hospital electrocardiogram was recorded by the ambulance service Methods The study consisted of two phases. In the first phase, a decision rule was developed based on clinical characteristics and electrocardiographic findings in 1005 patients with suspected acute cardiac pathology. In the second phase, the decision rule was prospectively validated. Symptoms were recorded by a standardized questionnaire by the general practitioner and a computerized electrocardiogram was made by the ambulance nurses at the patient's home. Three electrocardiographic outcomes were available: ‘normal electrocardiogram’, ‘possible myocardial infarction’ or ‘extensive myocardial infarction’. By use of the predictive model, the general practitioner could decide if hospitalization was necessary or not. Main outcome measurements Identification of patients at low (stable angina, atypical chest pain, other pathology) and high (myocardial infarction, unstable angina) probability of acute cardiac pathology. Results Among 977 patients with a complete pre-hospital evaluation in the validation phase of the study, the decision rule recommended ‘no hospitalization’ in 227 patients (23%). The general practitioner followed this advice in 44% of these patients. Although seven of them developed a non-Q wave myocardial infarction, no complications occurred in patients not admitted. In addition, the general practitioner did not hospitalize 19 (2%) of 750 patients for whom the decision rule recommended admission. Prehospital triage by the general practitioner resulted in a 12% (118 of 977 patients) reduction of the number of patients admitted to the Coronary Care Units. Conclusions Pre-hospital triage by the general practitioner was facilitated using a standardized questionnaire and pre-hospital electrocardiography, and resulted in a reduction in the number of patients admitted to the Coronary Care Unit, and proved to be safe.

Objective To assess the practical application, safety and long-term outcome of pre-hospital thrombolytic intervention with either alteplase or streptokinase in patients with extensive myocardial infarction. Design Prospective study. Subjects Patients with chest pain of more than 30 min duration, presenting within 6 h of symptom onset and with electrocardiographic evidence of extensive evolving myocardial infarction. Methods Eligibility of patients was established by the general practitioner or the ambulance nurse using a standardized questionnaire with (contra-) indications for thrombolytic therapy. Computerized ECG was recorded by ambulance nurses. In the presence of extensive ST segment elevation (sum ST deviation of at least 1.0 m V), eligible patients received either 100 mg alteplase (n=246) or 50 mg alteplase in the ambulance followed by 0.75 × 106 IE streptokinase in hospital (n=90), or 1.5 × 106 IE streptokinase intravenously (n=193). Main outcome measurements Death and life-threatening complications (ventricular fibrillation, cardiac arrest) and side effects (hypotension, allergic reactions) during transportation to hospital and in the first 24 h following hospitalization, and survival up to 5 years follow-up. Results From 1988–1993, 529 patients received thrombolytic treatment initiated pre-hospital. The time gained by pre-hospital administration of thrombolysis amounted to 50 min. The rate of complications during transportation and during the first 24 h after hospitalization was low. Hospital mortality was 2% and 1-year mortality 3%. Cumulative survival at 5 years was 92%. This was superior to the 84% 5-year survival observed in a matched group of 239 patients with similar baseline characteristics treated with alteplase in hospital. Conclusions Pre-hospital administration of either alteplase or streptokinase is feasible and safe and results in significant time gain. The long-term prognosis is excellent in spite of extensive evolving myocardial infarction upon admission.

Objective: To evaluate previously developed algorithms for the improvement of pre-hospital triage of patients with suspected acute cardiac disease. Design: Prospective study. Subjects: Patients with symptoms of possible cardiac origin, who were seen by a general practitioner and subsequently referred to hospital in the municipality of Rotterdam. Methods: Prior to hospital admission, patients with suspected acute coronary disease recorded their symptoms by standardized questionnaire and a computerized ECG was made. All patients were hospitalized and a final diagnosis was established. Algorithms, proposed by other investigators to distinguish patients with, from those without, acute cardiac disease were tested. Main outcome: Identification of patients whose likelihood for acute cardiac pathology was low (stable angina, atypical chest pain, oilier pathology) or high (myocardial infarction, unstable angina). Results: A total of 1005 patients were studied. Forty-two percent had myocardial infarction or unstable angina pectoris. Evaluation of previously developed algoritlims showed that their diagnostic accuracy was poor in the pre-hospital setting. In a separate multivariate analysis, six cliaracteristics from the clinical history and an electrocardiogram appeared to be independently and significantly associated with acute cardiac pathology. The presence of an abnormal ECG proved to be the most important predictor. Conclusions: The hospital-based algorithms were unsuitable as a predictor for pre-hospital acute cardiac pathology. A new practical hospital admission model was developed, based on six clinical predictors, including analysis of an electrocardiogram Following appropriate validation, this out-of hospital protocol may lead to better triage decisions by the general practitioner.

BACKGROUND Patients with unstable angina despite intensive medical therapy, ie, refractory angina, are at high risk for developing thrombotic complications: myocardial infarction or coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA). Chimeric 7E3 (c7E3) Fab is an antibody fragment that blocks the platelet glycoprotein (GP) IIb/IIIa receptor and potently inhibits platelet aggregation. METHODS AND RESULTS To evaluate whether potent platelet inhibition could reduce these complications, 60 patients with dynamic ST-T changes and recurrent pain despite intensive medical therapy were randomized to c7E3 Fab or placebo. After initial angiography had demonstrated a culprit lesion suitable for PTCA, placebo or c7E3 Fab was administered as 0.25 mg/kg bolus injection followed by 10 micrograms/min for 18 to 24 hours until 1 hour after completion of second angiography and PTCA. During study drug infusion, ischemia occurred in 9 c7E3 Fab and 16 placebo patients (P = .06). During hospital stay, 12 major events occurred in 7 placebo patients (23%), including 1 death, 4 infarcts, and 7 urgent interventions. In the c7E3 Fab group, only 1 event (an infarct) occurred (3%, P = .03). Angiography showed improved TIMI flow in 4 placebo and 6 c7E3 Fab patients and worsening of flow in 3 placebo patients but in none of the c7E3 Fab patients. Quantitative analysis showed significant improvement of the lesion in the patients treated with c7E3 Fab, which was not observed in the placebo group, although the difference between the two treatment groups was not significant. Measurement of platelet function and bleeding time demonstrated > 90% blockade of GPIIb/IIIa receptors, > 90% reduction of ex vivo platelet aggregation to ADP, and a significantly prolonged bleeding time during c7E3 Fab infusion, without excess bleeding. CONCLUSIONS Combined therapy with c7E3 Fab, heparin, and aspirin appears safe. These pilot study results support the concept that effective blockade of the platelet GPIIb/IIIa receptors can reduce myocardial infarction and facilitate PTCA in patients with refractory unstable angina.

Serum C-reactive protein rises in acute myocardial infarction, correlating positively with infarct size if thrombolytic treatment is not given. This correlation disappears if thrombolytic treatment is given, although the serum C-reactive protein concentration is still associated with the clinical outcome of the patient. We studied the effect of early coronary recanalization induced by thrombolytic treatment alone or combined with coronary angioplasty on the infarct related rise in serum C-reactive protein concentration. The C-reactive protein response caused by the myocardial infarct was lower in patients with an open infarct-related coronary artery than in patients with a closed infarct-related coronary artery, or in control patients who did not receive thrombolytic therapy. In control patients we found the expected strong positive correlation between infarct size and serum C-reactive protein (r = 0.58; P < 0.001, n = 48), which was similar to that in patients with a closed infarct-related coronary artery (r = 0.62; P < 0.001, n = 17). In patients with an open infarct-related coronary artery the correlation between infarct size and serum C-reactive protein was much weaker (r = 30; P < 0.01, n = 91). Consequently infarct size explained approximately 35% of the variation in serum C-reactive protein values in the control patients and 36% in the patients with a closed infarct-related coronary artery, but only 9% of the variation in the patients with an open infarct-related artery. Ejection fraction correlated negatively with serum C-reactive protein in both control and recanalized patients. The association was again much stronger in the control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective —Assessment of changes in left ventricular diastolic function and wall thickness after heart transplantation to verify whether these changes predicted acute rejection assessed by endomyocardial biopsy. Design —Follow up according to a predefined protocol of consecutive patients from the first week after transplantation. Setting —Heart transplantation unit of the Thoraxcentre, University Hospital Rotterdam Dijkzigt, The Netherlands. Patients —All 32 patients undergoing orthotopic heart transplantation from 1 January 1989 to 31 March 1990 were examined. Two were excluded from the analysis. Patients were treated with cyclosporin and low dose steroids. Main outcome measures —Data obtained by digitised M mode echocardiography were compared with the results of endomyocardial biopsy (Billingham classification). Mean values for left ventricular wall thickness, internal dimension, and their standardised rates of change and fractional shortening were determined from 4–6 consecutive expiratory beats. Mean values and individual trends during follow up were also investigated for each ultrasound variable. The results of these average values were compared with values in a group of 10 healthy volunteers. Results —Median follow-up was 177 days (range 10–399). Two hundred and sixty three consecutive M mode studies were examined in relation to concurrent biopsy results. No significant differences were observed between the ultrasound variables at the time of moderate acute rejection (Billingham class 2, n = 37) and other biopsy classes (n = 226). Nor did changes in individual patients predict (moderate) acute rejection episodes. Twenty six of the 30 patients had an abnormal (slow) left ventricular relaxation pattern throughout follow up. Conclusions —Digitised left ventricular M mode echocardiography did not predict the presence of acute rejection. In most patients there was a persistent slow left ventricular relaxation pattern.

The improvement in survival in patients undergoing thrombolytic therapy in myocardial infarction is determined by the delay between coronary occlusion and reperfusion. The REPerfusion in Acute Infarction Rotterdam (REPAIR) study was designed to examine the feasibility and safety of prehospital thrombolysis with alteplase (rt-PA, 'Actilyse'). A small portable ECG computer system is used to confirm the presence of a large myocardial infarction (at least 1.0 mV ST-deviation) 'on the spot'. Between 22 June 1988 and 1 January 1991, 226 patients were treated by the ambulance service after the evaluation of 9052 patients complaining of chest pain. Therapy could be initiated within an average of 100 +/- 56 min (SD) after the onset of symptoms, and within 22 +/- 9 min after ambulance arrival. Three patients were defibrillated during transportation. Six patients (3%) died after arrival in the hospital. The time gained by prehospital treatment was 47 min (95% confidence limits 44-51 min) in comparison with 220 patients who did not meet the criteria for prehospital thrombolysis, but received thrombolytic therapy as soon as possible after hospital admission. The developed procedure allows rapid and safe initiation of thrombolytic therapy in selected patients, even in the absence of a physician. The observed low mortality supports the concept that prehospital thrombolytic therapy is indeed beneficial to the patient.

OBJECTIVE--To investigate the prognostic value of frequently occurring slight variations in the ST segment for cardiovascular mortality in healthy subjects. DESIGN--Follow up study of mortality in relation to variations in ST segment level in a cohort over the 28 years from 1953 to 1981. A case-cohort sampling design was applied to limit the number of electrocardiograms that had to be coded by hand. SETTING--General health examination carried out in 1953 of civil servants in Amsterdam and assessment of subsequent mortality. SUBJECTS--Apparently healthy civil servants aged 40 to 65 years: 1583 men and 1508 women. MAIN OUTCOME MEASURES--Relative risk of variations in ST segment level for mortality from all causes, cardiovascular disease, and coronary heart disease. RESULTS--In men the multivariate relative risks of 15 year mortality from cardiovascular disease and coronary heart disease of slight ST elevation at 80 ms past the J point (compared with isoelectric ST segment) were 0.5 (95% confidence interval 0.3 to 0.9) and 0.4 (0.2 to 0.8), respectively. As expected, ST segment depression (greater than 0.25 mm) was associated with increased risk: 1.9 (1.1 to 3.0) and 2.2 (1.2 to 3.9), respectively. In women associations were weaker. The full 28 year period showed a similar pattern of somewhat weaker associations for men; among women, however, no predictive value was apparent. CONCLUSION--These results are empirical evidence for the intuitive opinion among doctors that a curved, upward sloping ST segment, resulting in slight ST elevation at 80 ms, indicates low risk compared with the isoelectric flat, stretched ST segment.

Plaque vulnerability is an important determinant in the prognosis of CAD. However the mechanism of transition from stable to vulnerable plaque (VP) remains unclear. Heme oxygenase 1 (HO-1) and its metabolites of heme degradation have been implicated in the cytoprotective defense response against oxidative injury. Here, we sought to assess the role of HO-1 in the development of VP in carotid artery disease in human and in a mouse model of VP. Atherectomy biopsies of 109 patients with clinical significant CAD were collected and stratified according to plaque morphology. HO-1 protein expression was determined by ELISA and was correlated with plaque parameters and pro-inflammatory biomarkers.To evaluate the function of HO-1 in VP, HO-1 was induced by CoPPIX injections in a murine model for VP in APOE −/− mice. HO-1 expression correlated closely to characteristics of atheromatous plaque vulnerability (p< 0.005) as indicated by intimal macrophage and lipid accumulation, and inverse correlations coincided with VSMCs and collagen. HO-1 expression levels correlated with proinflammatory biomarker titers including intraplaque MMP9 and IL-8 and IL6. HO-1 was mainly expressed in atheromatous infiltrating macrophages. In line with these observations, HO-1 expression was significantly increased in the VP vs. the stable lesions in our murine VP model. Systemic CoPPIX injections in the murine model resulted in an effective five-fold increase at HO-1 protein level. HO-1 induction did not affect the intima/media ratio, nor the percentage of intimal collagen or macrophages in the intima. However, systemic HO-1 induction significantly increased the percentage of intraplaque VSMCs by two-fold, while decreasing the percentage of lipids by two-fold. HO-1 protein expression closely correlated with histomorphological atherosclerotic plaque vulnerability and with expression levels of MMPs and pro-inflammatory cytokines in CAD patients. HO-1 induction in the murine VP model stabilized plaque morphology by reducing lipid accumulation and increasing VSMCs contect in these lesions. These data indicate that HO-1 expression in VP vs. stable plaques is enhanced as a compensatory atheroprotective response.

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD.

The aim of the clinical practice guideline 'Cardiovascular risk management' is an integral approach to all relevant risk factors for cardiovascular disease (CVD) caused by atherothrombosis. Patients with CVD, diabetes mellitus type 2 (DM2), elevated blood pressure or cholesterol, men of 50 years or older who smoke and women of 55 years or older who smoke are eligible for assessment of relevant risk factors for CVD. All high-risk patients should receive lifestyle counselling. In patients with CVD the use of acetylsalicylic acid and often, depending on the specific disease, a beta-blocker or an angiotensin converting enzyme (ACE) inhibitor are recommended. The use of a statin is recommended if the LDL-cholesterol concentration isor = 2.5 mmol/l. In patients with DM2, the use of statins is recommended if LDL-cholesterol isor = 2.5 mmol/l and use of a blood pressure lowering drug with a systolic blood pressureor = 140 mmHg, as well as glucose lowering drugs. In patients without CVD and DM2, the need for drug treatment will be determined by estimation of the absolute 10-year mortality risk of CVD. Treatment is recommended if this risk exceeds 10%. The treatment and follow-up plan will be determined individually, depending on the risk profile, morbidity, comorbidity and patient's preferences.

A large proportion of patients with a ST-elevation acute coronary syndrome do not receive reperfusion therapy. In order to contribute to a better understanding of the clinical decision making process, we analyzed which factors are associated with the application of reperfusion therapy.From the Euro Heart Survey of Acute Coronary Syndromes I, 4,260 patients with ST-elevation acute coronary syndrome were selected for the current analysis, of which 1,539 (36%) patients received fibrinolysis and 904 (21%) primary percutaneous coronary intervention (PCI). The analysis contained 32 variables on demographics, medical history, admission parameters and reperfusion therapy.A short pre-hospital delay, arrival in a hospital with PCI facilities, severe ST-elevation, and participation in a clinical trial were the strongest predictors for receiving reperfusion therapy. Primary PCI was more likely to be performed than fibrinolysis in patients with a long pre-hospital delay, arriving in a hospital with PCI facilities, not participating in a clinical trial, and with at least one previous PCI.Hospital facilities and culture, pre-hospital delay and infarction size play a major role in management decisions regarding reperfusion therapy in ST-elevation acute coronary syndrome. This analysis indicates which factors require special attention when implementing and reviewing the reperfusion guidelines.