Showing papers in "European Heart Journal in 2009"

Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)

Abstract: Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk/benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. Unpublished clinical trial results are not taken into account. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk/benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise …

Guidelines for the diagnosis and management of syncope (version 2009): the Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC)

Abstract: Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk/benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been previously discussed. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC Web Site (http://www.escardio.org/guidelines). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk/benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House Headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified …

Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009)

Abstract: Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome, as well as the risk/benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk/ benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to …

Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications.

Abstract: Atrial fibrillation (AF), the most commonly encountered clinical arrhythmia, often complicates acute myocardial infarction (AMI) with an incidence between 6 and 21%. Predictors of the arrhythmia in the setting of AMI include advanced age, heart failure symptoms, and depressed left ventricular function. The bulk of evidence demonstrates that AF in patients hospitalized for AMI has serious adverse prognostic implications regarding in-hospital, but also long-term mortality. This seems to apply for all patient populations studied without significant differences related to the treatment of AMI (i.e. no reperfusion therapy vs. thrombolysis vs. percutaneous coronary intervention). Mortality is particularly high in patients who have congestive heart failure and/or a reduced left ventricular ejection fraction. Finally, there are persuasive data indicating that AF complicating AMI not only increases the risk for ischaemic stroke during hospitalization but also during follow-up. This seems to apply also for transient AF which has reversed back to sinus rhythm at the time of discharge. These observations emphasize the need for prospective studies evaluating optimal therapeutic approaches for patients with AMI complicated by AF.

Percutaneous left ventricular assist devices vs. intra-aortic balloon pump counterpulsation for treatment of cardiogenic shock: a meta-analysis of controlled trials

Abstract: Aims Studies have compared safety and efficacy of percutaneous left ventricular assist devices (LVADs) with intra-aortic balloon pump (IABP) counterpulsation in patients with cardiogenic shock. We performed a meta-analysis of controlled trials to evaluate potential benefits of percutaneous LVAD on haemodynamics and 30-day survival. Methods and results Two independent investigators searched Medline, Embase, and Cochrane Central Register of Controlled Trials for all controlled trials using percutaneous LVAD in patients with cardiogenic shock, where after data were extracted using standardized forms. Weighted mean differences (MDs) were calculated for cardiac index (CI), mean arterial pressure (MAP), and pulmonary capillary wedge pressure (PCWP). Relative risks (RRs) were calculated for 30-day mortality, leg ischaemia, bleeding, and sepsis. In main analysis, trials were combined using inverse-variance random effects approach. Two trials evaluated the TandemHeart and a recent trial used the Impella device. After device implantation, percutaneous LVAD patients had higher CI (MD 0.35 L/min/m2, 95% CI 0.09–0.61), higher MAP (MD 12.8 mmHg, 95% CI 3.6–22.0), and lower PCWP (MD −5.3 mm Hg, 95% CI −9.4 to −1.2) compared with IABP patients. Similar 30-day mortality (RR 1.06, 95% CI 0.68–1.66) was observed using percutaneous LVAD compared with IABP. No significant difference was observed in incidence of leg ischaemia (RR 2.59, 95% CI 0.75–8.97) in percutaneous LVAD patients compared with IABP patients. Bleeding (RR 2.35, 95% CI 1.40–3.93) was significantly more observed in TandemHeart patients compared with patients treated with IABP. Conclusion Although percutaneous LVAD provides superior haemodynamic support in patients with cardiogenic shock compared with IABP, the use of these more powerful devices did not improve early survival. These results do not yet support percutaneous LVAD as first-choice approach in the mechanical management of cardiogenic shock.

Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study

Abstract: Aims To evaluate the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy. Methods and results This randomized, double-blind, placebo-controlled study included 85 patients with myocarditis and chronic (>6 months) heart failure unresponsive to conventional therapy, with no evidence of myocardial viral genomes. Patients received either prednisone 1 mg kg–1 day–1 for 4 weeks followed by 0.33 mg kg–1 day–1 for 5 months and azathioprine 2 mg kg–1 day–1 for 6 months (43 patients, Group 1) or placebo (42 patients, Group 2) in addition to conventional therapy for heart failure. Primary outcome was the 6 month improvement in left-ventricular function. Group 1 showed a significant improvement of left-ventricular ejection fraction and a significant decrease in left-ventricular dimensions and volumes compared with baseline. None of Group 2 patients showed improvement of ejection fraction, that significantly worsened compared with baseline. No major adverse reaction was registered as a result of immunosuppression. Conclusion These data confirm the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy. Lack of response in 12% of cases suggests the presence of not screened viruses or mechanisms of damage and inflammation not susceptible to immunosuppression.

Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial.

Abstract: Aims Comparison of intracoronary infusion of bone marrow (BM)-derived unselected mononuclear cells (UNSEL) and selected CD34+CXCR4+ cells (SEL) in patients with acute myocardial infarction (AMI) and reduced <40% left ventricular ejection fraction (LVEF). Methods and results Two hundred patients were randomized to intracoronary infusion of UNSEL ( n = 80) or SEL ( n = 80) BM cells or to the control (CTRL) group without BM cell treatment. Primary endpoint: change of LVEF and volumes measured by magnetic resonance imaging before and 6 months after the procedure. After 6 months, LVEF increased by 3% ( P = 0.01) in patients treated with UNSEL, 3% in patients receiving SEL ( P = 0.04) and remained unchanged in CTRL group ( P = 0.73). There were no significant differences in absolute changes of LVEF between the groups. Absolute changes of left ventricular end-systolic volume and left ventricular end-diastolic volume were not significantly different in all groups. Significant increase of LVEF was observed only in patients treated with BM cells who had baseline LVEF < median (37%). Baseline LVEF < median and time from the onset of symptoms to primary percutaneous coronary intervention ≥ median were predictors of LVEF improvement in patients receiving BM cells. There were no differences in major cardiovascular event (death, re-infarction, stroke, target vessel revascularization) between groups. Conclusion In patients with AMI and impaired LVEF, treatment with BM cells does not lead to a significant improvement of LVEF or volumes. There was however a trend in favour of cell therapy in patients with most severely impaired LVEF and longer delay between the symptoms and revascularization.

Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial

Abstract: Aims We assessed whether a single intracoronary infusion of autologous bone marrow cells (BMCs) can have a sustained impact on left ventricular ejection fraction (LVEF) in patients after ST-elevation myocardial infarction (STEMI). In the BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial, 60 patients with STEMI and successful percutaneous coronary intervention were randomized to a control and a cell therapy group. As previously reported, BMC transfer led to an improvement of LVEF by 6.0% at 6 months ( P = 0.003) and 2.8% at 18 months ( P = 0.27). Methods and results Left ventricular ejection fraction and clinical status were re-assessed in all surviving patients after 61 ± 11 months. Major adverse cardiac events occurred with similar frequency in both groups. When compared with baseline, LVEF assessed by magnetic resonance imaging at 61 months decreased by 3.3 ± 9.5% in the control group and by 2.5 ± 11.9% in the BMC group ( P = 0.30). Patients with an infarct transmurality > median appeared to benefit from BMC transfer throughout the 61-month study period ( P = 0.040). Conclusion A single intracoronary application of BMCs does not promote a sustained improvement of LVEF in STEMI patients with relatively preserved systolic function. It is conceivable that a subgroup of patients with more transmural infarcts may derive a sustained benefit from BMC therapy. However, this needs to be tested prospectively in a randomized trial.

Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial

Abstract: Aims To evaluate the associations of myocardial infarction (MI) and major bleeding with 1-year mortality. Both MI and major bleeding predict 1-year mortality in patients presenting with acute coronary syndrome (ACS). However, the risk of each of these events on the magnitude and timing of mortality has not been well studied. Methods and Results A multivariable Cox regression model was developed relating 13 independent baseline predictors to 1-year mortality for 13 819 patients with moderate and high-risk ACS enrolled in the Acute Catheterization and Urgent Intervention Triage strategy trial. After adjustment for baseline predictors, Cox models with major bleeding and recurrent MI as time-updated covariates estimated the effect of these events on mortality hazard over time. Within 30 days of randomization, 705 patients (5.1%) had an MI, 645 (4.7%) had a major bleed; 524 (3.8%) died within a year. The occurrence of an MI was associated with a hazard ratio of 3.1 compared with patients not yet having an MI, after adjustment for baseline predictors. However, MI within 30 days markedly increased the mortality risk for the first 2 days after the event (adjusted hazard ratio of 17.6), but this risk declined rapidly post-infarct (hazard ratio of 1.4 beyond 1 month after the MI event). In contrast, major bleeding had a prolonged association with mortality risk (hazard ratio of 3.5) which remained fairly steady over time throughout 1 year. Conclusion After accounting for baseline predictors of mortality, major bleeds and MI have similar overall strength of association with mortality in the first year after ACS. MI is correlated with a dramatic increase in short-term risk, whereas major bleeding correlates with a more prolonged mortality risk.

P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use.

Abstract: Currently, clopidogrel is recommended for treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention. However, the delayed onset of the effect and the occurrence of poor platelet inhibition responders with clopidogrel as well as non-compliance to dual antiplatelet treatment are associated with a raised risk of stent thrombosis. The molecular target of the active metabolite of clopidogrel and several emerging antiplatelet treatments is the P2Y(12) receptor, which is the main platelet receptor responsible for ADP-induced platelet aggregation. Active metabolites of the thienopyridine prodrugs (ticlopidine, clopidogrel, and prasugrel) covalently bind to the P2Y(12) receptor and are irreversible, indirect platelet inhibitors. The newer, direct-acting P2Y(12) inhibitors (cangrelor and ticagrelor) change the conformation of the P2Y(12) receptor, resulting in reversible, concentration dependent inhibition of the receptor. An understanding of the similarities and differences in the properties and mechanisms of action of these new inhibitors compared with clopidogrel is needed in order to optimize the development and use of these agents in clinical practice. The objectives of this systematic review are to summarize the pharmacokinetics, pharmacodynamics, and pharmacogenetics of the different P2Y(12) inhibitors and to discuss the clinical implications for treatment of patients.

Long-term follow-up of persistent atrial fibrillation ablation using termination as a procedural endpoint

Abstract: Aims Catheter ablation of long-lasting persistent atrial fibrillation (AF) has been performed with varying results using a combination of different techniques. Whether arrhythmia termination during ablation is associated with an improved clinical outcome is controversial. Methods and results In this prospective study, 153 consecutive patients (56 ± 10 years) underwent catheter ablation of persistent AF (25 ± 33 months) using a stepwise approach with the desired procedural endpoint being AF termination. Repeat ablation was performed for patients with recurrent AF or atrial tachycardia (AT) after a 1 month blanking period. A minimum follow-up of 12 months with repeated Holter monitoring was performed. Atrial fibrillation was terminated in 130 patients (85%). There was a lower incidence of AF in those patients in whom AF was terminated during the index procedure compared with those who had not (5 vs. 39% P < 0.0001, mean follow-up 32 ± 11 months). Seventy-nine patients underwent repeat procedures: 64/130 in the termination group (6 AF, 58 AT) and 15 in the non-termination group (9 AF, 7 AT). After repeat ablation, sinus rhythm was maintained in 95% in whom AF was terminated compared with 52% in those in whom AF could not be terminated. Conclusion Procedural termination of long-lasting AF by catheter ablation alone is associated with an improved outcome.

Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial

Abstract: Aims To evaluate the anti-anginal and anti-ischaemic efficacy of the selective I f current inhibitor ivabradine in patients with chronic stable angina pectoris receiving beta-blocker therapy. Methods and results In this double-blinded trial, 889 patients with stable angina receiving atenolol 50 mg/day were randomized to receive ivabradine 5 mg b.i.d. for 2 months, increased to 7.5 mg b.i.d. for a further 2 months, or placebo. Patients underwent treadmill exercise tests at the trough of drug activity using the standard Bruce protocol for randomization and at 2 and 4 months. Total exercise duration at 4 months increased by 24.3 ± 65.3 s in the ivabradine group, compared with 7.7 ± 63.8 s with placebo ( P < 0.001). Ivabradine was superior to placebo for all exercise test criteria at 4 months ( P < 0.001 for all) and 2 months ( P -values between <0.001 and 0.018). Ivabradine in combination with atenolol was well tolerated. Only 1.1% of patients withdrew owing to sinus bradycardia in the ivabradine group. Conclusion The combination of ivabradine 7.5 mg b.i.d. and atenolol at the commonly used dosage in clinical practice in patients with chronic stable angina pectoris produced additional efficacy with no untoward effect on safety or tolerability.

Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry.

Abstract: Aims To determine 3-year event rates in outpatients with vascular disease enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry Methods and results REACH enrolled 67 888 outpatients with atherothrombosis [established coronary artery disease (CAD), cerebrovascular disease, or peripheral arterial disease (PAD)], or with at least three atherothrombotic risk factors, from 44 countries Among the 55 499 patients at baseline with symptomatic disease, 39 675 were eligible for 3-year follow-up, and 32 247 had data available (81% retention rate) Among the symptomatic patients at 3 years, 92% were taking an antithrombotic agent, 91% an antihypertensive, and 76% were on lipid-lowering therapy For myocardial infarction (MI)/stroke/vascular death, 1- and 3-year event rates for all patients were 42 and 110%, respectively Event rates (MI/stroke/vascular death) were significantly higher for patients with symptomatic disease vs those with risk factors only at 1 year (47 vs 23%, P < 0001) and at 3 years (120 vs 60%, P < 0001) One and 3-year rates of MI/stroke/vascular death/rehospitalization were 144 and 284%, respectively, for patients with symptomatic disease Rehospitalization for a vascular event other than MI/stroke/vascular death was common at 3 years (190% overall; 336% for PAD; 230% for CAD) For patients with symptomatic vascular disease in one vascular bed vs multiple vascular beds, 3-year event rates for MI/stroke/vascular death/rehospitalization were 255 vs 405% ( P < 0001) Conclusion Despite contemporary therapy, outpatients with symptomatic atherothrombotic vascular disease experience high rates of recurrent vascular events and rehospitalizations

Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials

Abstract: Aims Thrombectomy in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is associated to better myocardial reperfusion. However, no single trial was adequately powered to asses the impact of thrombectomy on long-term clinical outcome and to identify patients at higher benefit. Thus, we sought to assess these issues in a collaborative individual patient-data pooled analysis of randomized studies (study acronym: ATTEMPT, number of registration: NCT00766740). Methods and results Individual data of 2686 patients enrolled in 11 trials entered the pooled analysis. Primary endpoint of the study was all-cause mortality. Major adverse cardiac events (MACE) were considered as the occurrence of all-cause death and/or target lesion/vessel revascularization and/or myocardial infarction (MI). Subgroups analysis was planned according to type of thrombectomy device (manual or non-manual), diabetic status, IIb/IIIa-inhibitor therapy, ischaemic time, infarct-related artery, pre-PCI TIMI flow. Clinical follow-up was available in 2674 (99.6%) patients at a median of 365 days. Kaplan–Meier analysis showed that allocation to thrombectomy was associated with significantly lower all-cause mortality ( P = 0.049). Thrombectomy was also associated with significantly reduced MACE ( P = 0.011) and death + MI rate during the follow-up ( P = 0.015). Subgroups analysis showed that thrombectomy is associated to improved survival in patients treated with IIb/IIIa-inhibitors ( P = 0.045) and that the survival benefit is confined to patients treated in manual thrombectomy trials ( P = 0.011). Conclusion The present large pooled analysis of randomized trials suggests that thrombectomy (in particular manual thrombectomy) significantly improves the clinical outcome in patients with STEMI undergoing mechanical reperfusion and that its effect may be additional to that of IIb/IIIa-inhibitors.

Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure

Abstract: Aims Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin-2) is a glycoprotein with bacteriostatic properties. Growing evidence suggests that NGAL may also be involved in cell survival, inflammation, and matrix degradation. We therefore aimed to investigate the role of NGAL in heart failure (HF). Methods and results Our main findings were (i) patients with acute post-myocardial infarction (MI) HF ( n = 236) and chronic HF ( n = 150) had elevated serum levels of NGAL (determined by enzyme immunoassay), significantly correlated with clinical and neurohormonal deterioration, (ii) in patients with HF following acute MI, elevated NGAL levels of at baseline were associated with adverse outcomes (median of 27 months follow-up), (iii) in a rat model of post-MI HF, NGAL/lipocalin-2 gene expression was increased in the non-ischaemic part of the left ventricle primarily located to cardiomyocytes, (iv) strong NGAL immunostaining was found in cardiomyocytes within the failing myocardium both in experimental and clinical HF, (v) interleukin-1β and agonists for toll-like receptors 2 and 4, representing components of the innate immune system, were potent inducers of NGAL/lipocalin-2 in isolated neonatal cardiomyocytes. Conclusion Our demonstration of enhanced systemic and myocardial NGAL expression in clinical and experimental HF further support a role for innate immune responses in the pathogenesis of HF.

Impact of myocardial haemorrhage on left ventricular function and remodelling in patients with reperfused acute myocardial infarction

Abstract: Aims Myocardial haemorrhage is a common complication following reperfusion of ST-segment-elevation acute myocardial infarction (MI). Although its presence is clearly related to infarct size, at present it is unknown whether post-reperfusion haemorrhage affects left ventricular (LV) remodelling. Magnetic resonance imaging (MRI) can be used to identify MI, myocardial haemorrhage, and microvascular obstruction (MVO), as well as measure LV volumes, function, and mass. Methods and results Ninety-eight patients (14 females, 84 males, mean age: 57.7 years) with MI reperfused with percutaneous coronary intervention (PCI) were studied within the first week (1W) and at 4 months (4M) after the event. T2-weighted MRI was used to differentiate between haemorrhagic (i.e. hypointense core) and non-haemorrhagic infarcts (i.e. hyperintense core). Microvascular obstruction and infarct size were determined on contrast-enhanced MRI, whereas cine MRI was used to quantify LV volumes, mass, and function. Twenty-four patients (25%) presented with a haemorrhagic MI. In the acute phase, the presence of myocardial haemorrhage was related to larger infarct size and infarct transmurality, lower LV ejection fraction, and lower systolic wall thickening in the infarcted myocardium (all P -values <0.001). At 4M, a significant improvement in LV ejection fraction in patients with non-haemorrhagic MI was seen (baseline: 49.3 ± 7.9% vs. 4M: 52.9 ± 8.1%; P < 0.01). Left ventricular ejection fraction did, however, not improve in patients with haemorrhagic MI (baseline: 42.8 ± 6.5% vs. 4M: 41.9 ± 8.5%; P = 0.68). Multivariate analysis showed myocardial haemorrhage to be an independent predictor of adverse LV remodelling at 4M (defined as an increase in LV end-systolic volume). This pattern was independent of the initial infarct size. Conclusion Myocardial haemorrhage, the presence of which can easily be detected with T2-weighted MRI, is a frequent complication after successful myocardial reperfusion and an independent predictor of adverse LV remodelling regardless of the initial infarct size.

Strain analysis in patients with severe aortic stenosis and preserved left ventricular ejection fraction undergoing surgical valve replacement

Abstract: Aims To evaluate myocardial multidirectional strain and strain rate (S-and-SR) in severe aortic stenosis (AS) patients with preserved left ventricular (LV) ejection fraction (EF), using two-dimensional speckle-tracking strain imaging (2D-STI). The long-term effect of aortic valve replacement (AVR) on S-and-SR was also evaluated. Methods and results Changes in LV radial, circumferential, and longitudinal S-and-SR were evaluated in 73 severe AS patients (65 ± 13 years; aortic valve area 0.8 ± 0.2 cm2) with preserved LVEF (61 ± 11%), before and 17 months after AVR. Strain and strain rate data were compared with data from 40 controls (20 healthy individuals and 20 patients with LV hypertrophy) matched by age, gender, body surface area, and LVEF. Compared with controls, severe AS patients had significantly decreased values of LV S-and-SR in the radial (33.1 ± 14.8%, P = 0.2; 1.7 ± 0.5 s−1, P = 0.003), circumferential (−15.2 ± 5.0%, P = 0.001; −0.9 ± 0.3 s−1, P < 0.0001), and longitudinal (−14.6 ± 4.1%, P < 0.0001; −0.8 ± 0.2 s−1, P < 0.0001) directions. At 17 months after AVR, LV S-and-SR significantly improved in all the three directions, whereas LVEF remained unchanged (60 ± 12%, P = 0.7). Conclusion In severe AS patients, impaired LV S-and-SR existed although LVEF was preserved. After AVR, a significant S-and-SR improvement in all the three directions was observed. These subtle changes in LV contractility can be detected by 2D-STI.

Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial.

Abstract: Aims To examine the extent of platelet inhibition by prasugrel vs . clopidogrel in a TRITON-TIMI 38 substudy. Methods and results TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) ( n = 125 patients) and, in a subset ( n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1–2 h post-PCI (≥1 h after loading dose) ( P 50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1–2 h ( P < 0.001) and 30 days ( P = 0.03). Conclusions The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.

Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease

Abstract: Aims The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmaco ...

Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis

Abstract: Background Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered to be a risk factor for atherosclerosis. However, the mechanisms relating ADMA with vascular function have been evaluated in vitro and in animal models, but its effect in human vasculature is unclear. Aims We examined the impact of serum ADMA on endothelial nitric oxide (NO) bioavailability and vascular superoxide radical (O2-) production in patients with advanced atherosclerosis. Methods and results Paired samples of saphenous veins (SVs) and internal mammary arteries (IMAs) were collected from 201 patients undergoing coronary bypass surgery, and serum ADMA was measured pre-operatively. The vasomotor responses of SV segments to acetylcholine (ACh) and bradykinin (Bk) were evaluated ex vivo . Vascular O2- was measured in paired SV and IMA by lucigenin-enhanced chemiluminescence. The l-NAME-inhibitable as well as the NADPH-stimulated vascular O2- generation was also determined by chemiluminescence. High serum ADMA levels were associated with decreased vasorelaxation of SV to ACh ( P < 0.05) and Bk ( P < 0.05). Similarly, high serum ADMA was associated with higher total O2- production in both SVs and IMAs ( P < 0.05) and greater l-NAME-inhibitable vascular O2- ( P < 0.05). However, serum ADMA was not associated with NADPH-stimulated vascular O2-. In multivariable linear regression, serum ADMA was independently associated with vascular O2- in both SVs [ β (SE): 0.987 (0.412), P = 0.019] and IMAs [ β (SE): 1.905 (0.541), P = 0.001]. Asymmetrical dimethylarginine was also independently associated with maximum vasorelaxation in response to both ACh [ β (SE): 14.252 (3.976), P = 0.001] and Bk [ β (SE): 9.564 (3.762), P = 0.013]. Conclusion This is the first study that demonstrates an association between ADMA and important measures of vascular function, such as vascular O2- production and NO bioavailability directly in human vessels. Although serum ADMA has no effect on NADPH-stimulated superoxide in intact vessels, it is associated with greater eNOS uncoupling in the human vascular endothelium of patients with coronary artery disease.

Modelling the decreasing coronary heart disease mortality in Sweden between 1986 and 2002.

Abstract: Aims Coronary heart disease (CHD) mortality rates have been falling in Sweden since the 1980s. We used the previously validated IMPACT CHD model to examine how much of the mortality decrease in Sweden between 1986 and 2002 could be attributed to medical and surgical treatments, and how much to changes in cardiovascular risk factors. Methods and results The IMPACT mortality model was used to combine and analyse data on uptake and effectiveness of cardiological treatments and risk factor trends in Sweden. The main data sources were official statistics, national quality of care registers, published trials and meta-analyses, and national population surveys. Between 1986 and 2002, CHD mortality rates in Sweden decreased by 53.4% in men and 52.0% in women aged 25–84 years. This resulted in 13 180 fewer deaths in 2002. Approximately 36% of this decrease was attributed to treatments in individuals and 55% to population risk factor reductions. Adverse trends were seen for diabetes and overweight. Conclusion More than half of the substantial CHD mortality decrease in Sweden between 1986 and 2002 was attributable to reductions in major risk factors, mainly a large decrease in total serum cholesterol. These findings emphasize the value of a comprehensive strategy that promotes primary prevention and evidence-based medical treatments, especially secondary prevention.

Quantification of left ventricular volumes using three-dimensional echocardiographic speckle tracking: comparison with MRI

Abstract: Aims Although the utility of two-dimensional (2D) speckle tracking echocardiography (STE) to quantify left ventricular (LV) volume has been demonstrated, this methodology is limited by foreshortened views, geometric modelling, and the assumption that speckles can be tracked from frame to frame, despite their out of plane motion. To circumvent these limitations, a three-dimensional (3D) speckle tracking algorithm was recently developed. Our goal was to evaluate the accuracy of the new 3D-STE side by side with 2D-STE using cardiac magnetic resonance (CMR) as a reference. Methods and results Apical two- and four-chamber views (A2C and A4C) and real-time 3D datasets (Toshiba Artida 4D System) obtained in 43 patients with a wide range of LV size and function were analysed to measure LV end-systolic and end-diastolic volumes (ESV and EDV) using 2D and 3D-STE techniques. Short-axis CMR images (Siemens 1.5T scanner) acquired on the same day were analysed to obtain ESV and EDV reference values using the method of disks approximation. Reproducibility of both STE techniques was assessed using repeated measurements. While 2D-STE correlated well with CMR ( r : 0.72–0.88), it underestimated LV volumes with relatively large biases (10–30 mL) and wide limits of agreement (SD: 36–51 mL), with A2C-derived measurements being worse than A4C values. The 3D-STE measurements showed higher correlation with CMR (0.87–0.92), and importantly smaller biases (1–16 mL) and narrower limits of agreement (SD: 28–37 mL). In addition, 3D-STE showed lower inter- and intra-observer variability (11–14% and 12–13%), than 2D-STE (16–17% and 12–16%, respectively). Conclusion This is the first study to validate the new 3D-STE technique for LV volume measurements and demonstrate its superior accuracy and reproducibility over previously used 2D-STE technique.

Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy

Abstract: Aims The ability of mesenchymal stem cells (MSCs) to heal the chronically injured heart remains controversial. Here we tested the hypothesis that autologous MSCs can be safely injected into a chronic myocardial infarct scar, reduce its size, and improve ventricular function. Methods and results Female adult Gottingen swine ( n = 15) underwent left anterior descending coronary artery balloon occlusion to create reproducible ischaemia–reperfusion infarctions. Bone-marrow-derived MSCs were isolated and expanded from each animal. Twelve weeks post-myocardial infarction (MI), animals were randomized to receive surgical injection of either phosphate buffered saline (placebo, n = 6), 20 million (low dose, n = 3), or 200 million (high dose, n = 6) autologous MSCs in the infarct and border zone. Injections were administered to the beating heart via left anterior thoracotomy. Serial cardiac magnetic resonance imaging was performed to evaluate infarct size, myocardial blood flow (MBF), and left ventricular (LV) function. There was no difference in mortality, post-injection arrhythmias, cardiac enzyme release, or systemic inflammatory markers between groups. Whereas MI size remained constant in placebo and exhibited a trend towards reduction in low dose, high-dose MSC therapy reduced infarct size from 18.2 ± 0.9 to 14.4 ± 1.0% ( P = 0.02) of LV mass. In addition, both low and high-dose treatments increased regional contractility and MBF in both infarct and border zones. Ectopic tissue formation was not observed with MSCs. Conclusion Together these data demonstrate that autologous MSCs can be safely delivered in an adult heart failure model, producing substantial structural and functional reverse remodelling. These findings demonstrate the safety and efficacy of autologous MSC therapy and support clinical trials of MSC therapy in patients with chronic ischaemic cardiomyopathy.

Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials.

Abstract: Aims Several randomized trials and a previous meta-analysis have shown significant benefits from Gp IIb-IIIa inhibitors, especially abciximab. Recent randomized trials (BRAVE-3 and HORIZON trials) have shown no benefits from adjunctive Gp IIb-IIIa inhibitors on the top of clopidogrel administration. However, the relatively low mortality may have hampered the conclusion of these recent trials. Thus, the aim of the current study was to perform an update meta-analysis of randomized trials on adjunctive Gp IIb-IIIa inhibitors in primary angioplasty, and to evaluate by meta-regression analysis, whether the results may be related to risk profile. Methods and results We obtained results from all randomized trials evaluating the benefits of adjunctive Gp IIb-IIIa inhibitors among STEMI patients undergoing primary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to September 2008. The following key words were used: randomized trial, myocardial infarction, reperfusion, primary angioplasty, Gp IIb-IIIa inhibitors, abciximab, tirofiban, and eptifibatide. Clinical endpoint was mortality at 30 days. Major bleeding complications were assessed as safety endpoint. No language restriction was applied. A total of 16 randomized trials were finally included in the meta-analysis, involving 10 085 patients (5094 or 50.5% in the Gp IIb-IIIa inhibitors group and 4991 or 49.5% in the control group. Gp IIb-IIIa inhibitors did not reduce 30 day mortality (2.8 vs. 2.9%, P = 0.75) or re-infarction (1.5 vs. 1.9%, P = 0.22), but were associated with higher risk of major bleeding complications (4.1 vs. 2.7%, P = 0.0004). However, we observed a significant relationship between patient's risk profile and benefits from adjunctive Gp IIb-IIIa inhibitors in terms of death ( P = 0.008) but not re-infarction ( P = 0.25). Conclusion This meta-analysis shows a significant relationship between benefits in mortality from Gp IIb-IIIa inhibitors and patient's risk profile. Thus, Gp IIb-IIIa inhibitors should be strongly considered among high-risk patients.

The European cardiac resynchronization therapy survey

Abstract: Aims The European cardiac resynchronization therapy (CRT) survey is a joint initiative taken by the Heart Failure Association and the European Heart Rhythm Association of the European Society of Cardiology. The primary aim of this survey is to describe current European practice associated with CRT implantations. Methods and results A total of 140 centres from 13 European countries contributed data from consecutive patients successfully implanted with a CRT device with or without an ICD between November 2008 and June 2009. The total number of patients enrolled was 2438. The median age of the patients was 70 years (IQR 62–76) and 31% were ≥75 years. It was found that 78% were in NYHA functional class III or IV and 22% in I or II. The mean ejection fraction was 27% ± 8 and the mean QRS duration 157 ms ± 32. The QRS duration was <120 ms in 9%. Atrial fibrillation was reported in 23%. It was found that 26% of patients had a previously implanted permanent pacemaker or ICD; 76% of procedures were performed by an electrophysiologist; 82% had an elective admission for implantation and the median duration of hospitalization was 3 days (IQR 2–7); and 73% received a CRT-D device which was more often implanted in men, younger patients, and with ischaemic aetiology. The mean QRS duration was reduced to 133 ms ± 27 ( P < 0.0001) at discharge. Peri-procedural complication rates were comparable to the rates reported in randomized trials. Conclusion This CRT survey provides important information describing current European practice with regard to patient demographics, selection criteria, procedural routines, and status at discharge. These data should be useful for benchmarking individual patient management and national practice against wider experience.

Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period

Abstract: Aims To assess the incidence, timing, and relation of drug-eluting stent (DES) thrombosis to discontinuation of clopidogrel therapy. Methods and results This prospective observational cohort study included 6816 consecutive patients that underwent successful DES implantation. Primary endpoint was definite stent thrombosis (ST). During 4 years of follow-up, definite ST was observed in 73 patients, corresponding to a cumulative incidence of 1.2%. Cumulative incidence of ST at 30 days was 0.5 and 0.8% at 1 year, respectively. Discontinuation of clopidogrel therapy was significantly associated with ST only in the first 6 months after the procedure ( P < 0.001). During that period, the median time interval from clopidogrel discontinuation to ST was 9 days [interquartile range (IQR) 5.5–22.5] while thereafter it was 104.3 days (IQR 7.4–294.8). Conclusion The 4 year incidence of ST after DES implantation is low. A relevant number of ST occur early after discontinuation of clopidogrel therapy. The dependence of ST on discontinuation of clopidogrel therapy seems to be mostly confined to the first 6 months after DES implantation. However, specifically designed randomized studies are required to establish the optimal length of clopidogrel therapy after DES implantation.

Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up.

Abstract: Aims The CAPTIM (Comparison of primary Angioplasty and Pre-hospital fibrinolysis In acute Myocardial infarction) study found no evidence that a strategy of primary angioplasty was superior in terms of 30-day outcomes to a strategy of pre-hospital fibrinolysis with transfer to an interventional facility in patients managed early at the acute phase of an acute myocardial infarction. The present analysis was designed to compare both strategies at 5 years. Methods and results The CAPTIM study included 840 patients managed in a pre-hospital setting within 6 h of an acute ST-segment elevation myocardial infarction. Patients were randomized to either a primary angioplasty ( n = 421) or a pre-hospital fibrinolysis (rt-PA) with immediate transfer to a centre with interventional facilities ( n = 419). Long-term follow-up was obtained in blinded fashion from 795 patients (94.6%). Using an intent-to-treat analysis, all-cause mortality at 5 years was 9.7% in the pre-hospital fibrinolysis group when compared with 12.6% in the primary angioplasty group [HR 0.75 (95% CI, 0.50–1.14); P = 0.18]. For patients included within 2 h, 5 year mortality was 5.8% in the pre-hospital fibrinolysis group when compared with 11.1% in the primary angioplasty group [HR 0.50 (95% CI, 0.25–0.97); P = 0.04], whereas it was, respectively, 14.5 and 14.4% in patients included after 2 h [HR 1.02, (95% CI 0.59–1.75), P = 0.92]. Conclusion The 5-year follow-up is consistent with the 30-day outcomes of the trial, showing similar mortality for primary percutaneous coronary intervention and a policy of pre-hospital lysis followed by transfer to an interventional center. In addition, for patients treated within 2 h of symptom onset, 5-year mortality was lower with pre-hospital lysis.

Toward understanding response to cardiac resynchronization therapy: left ventricular dyssynchrony is only one of multiple mechanisms

Abstract: AIM: To date, most published echocardiographic methods have assessed left ventricular (LV) dyssynchrony (DYS) alone as a predictor for response to cardiac resynchronization therapy (CRT). We hypothesized that the response is instead dictated by multiple correctable factors. METHODS AND RESULTS: A total of 161 patients (66 +/- 10 years, EF 24 +/- 6%, QRS > 120 ms) were investigated pre- and post-CRT (median of 6 months). Reduction in NYHA Class >/=1 or LV reverse remodelling (end-systolic volume reduction >/= 10%) defined response. Four different pathological mechanisms were identified. Group1: LVDYS characterized by a pre-ejection septal flash (SF) (87 patients, 54%). Elimination of SF (77 of 87 patients) resulted in reverse remodelling in 100%. Group 2: short-AV delay (21 patients, 13%) resolution (19 of 21 patients) resulted in reverse remodelling in 16 of 19. Group 3: long-AV delay (16 patients, 10%) resolution (14 of 16 patients) resulted in NYHA Class reduction >/=1 in 11 with reverse remodelling in five patients. Group 4: exaggerated LV-RV interaction (15 patients, 9%) reduced post-CRT. All responded clinically with fall in pulmonary artery pressure (P = 0.003) but did not volume respond. Group 5: patients with none of the above correctable mechanisms (22 patients, 14%). None responded to CRT. CONCLUSION: CRT response is dictated by correction of multiple independent mechanisms of which LVDYS is only one. Long-axis DYS measurements alone failed to detect 40% of responders.

Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study.

Abstract: Aims Growth-differentiation factor-15 (GDF-15) is emerging as an independent prognostic biomarker in patients with cardiovascular (CV) disease. Little is known about the pathophysiological basis for the close association of GDF-15 to future CV events. We hypothesized that GDF-15 is related to underlying CV pathologies. Methods and results To relate the levels of GDF-15 to indices of CV dysfunction and disease in elderly individuals, serum levels of GDF-15 were measured in 1004 subjects aged 70 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Carotid intima-media thickness and plaque burden, and left ventricular (LV) geometry and function were assessed by ultrasound. Endothelial function was evaluated in forearm resistance vessels and in the brachial artery by venous occlusion plethysmography and ultrasound imaging, respectively. Elevated levels of GDF-15 were related to several CV risk factors (male gender, current smoking, body mass index, waist circumference, diabetes, fasting glucose, triglycerides, and low HDL cholesterol). After adjustment for CV risk factors, increased levels of GDF-15 were associated with reduced endothelium-dependent vasodilation in resistance vessels, plaque burden, LV mass and concentric LV hypertrophy, reduced LV ejection fraction, and clinical manifestations of coronary artery disease and heart failure. Conclusion GDF-15 carries information on CV dysfunction and disease that is not captured by traditional CV risk factors in elderly individuals.

Randomized, Non-Inferiority Trial of Three Limus Agent-Eluting Stents With Different Polymer Coatings: The Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial

Abstract: Aims Although biodegradable polymer drug-eluting stent (DES) platforms have potential to enhance long-term clinical outcomes, data concerning their efficacy are limited to date. We previously demonstrated angiographic antirestenotic efficacy with a microporous, biodegradable polymer DES. In the current study, we hypothesized that at 12 months, its clinical safety and efficacy would be non-inferior to that of permanent polymer DES. Methods and results This prospective, randomized, open-label, active-controlled trial was conducted at two tertiary referral cardiology centres in Munich, Germany. Patients presenting with stable coronary disease or acute coronary syndromes undergoing DES implantation in de novo native-vessel coronary lesions were randomly assigned to treatment with biodegradable polymer DES (rapamycin-eluting; n = 1299) or permanent polymer DES ( n = 1304: rapamycin-eluting, Cypher, n = 652; or everolimus-eluting, Xience, n = 652) and underwent clinical follow-up to 1 year. The primary endpoint was a composite of cardiac death, myocardial infarction (MI) related to the target vessel, or revascularization related to the target lesion (TLR). Biodegradable polymer DES was non-inferior to permanent polymer DES concerning the primary endpoint [13.8 vs. 14.4%, respectively, P non-inferiority 0.005; relative risk = 0.96 (95% confidence interval, 0.78–1.17), P superiority = 0.66]. Biodegradable polymer DES in comparison with permanent polymer DES showed similar rates of cardiac death or MI related to the target vessel (6.3 vs. 6.2%, P = 0.94), TLR (8.8 vs. 9.4%, P = 0.58), and stent thrombosis (definite/probable: 1.0 vs. 1.5%, P = 0.29). Subgroup analysis of the biodegradable polymer DES vs. individual Cypher and Xience stent arms revealed no signal of performance difference. Conclusion A biodegradable polymer rapamycin-eluting stent is non-inferior to permanent polymer-based DES in terms of clinical efficacy over 1 year. These results provide a framework for testing the potential clinical advantage of biodegradable polymer DES over the medium to long term. The trial was registered at ClinicalTrials.gov (identifier: NCT00598676).