Ketil Lunde

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient Data

RATIONALE The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.

Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease

2D-STE (two-dimensional speckle tracking echocardiography) is a novel echocardiographic modality that enables angle-independent assessment of myocardial deformation indices. In the present study, we tested whether peak systolic epsilon(parallel) (longitudinal strain) values measured by 2D-STE could identify areas of MI (myocardial infarction) as determined by CE MRI (contrast-enhanced magnetic resonance imaging). Conventional echocardiographic apical long-axis recordings were performed in 38 patients, 9 months after a first MI. Peak systolic epsilon(parallel) measured by 2D-STE in 16 left ventricle segments was compared with segmental infarct mass and transmurality assessed by CE MRI. Segmental values were averaged to global and territorial values for assessment of global function and myocardial function in the coronary distribution areas. CE MRI identified transmural infarction in 27 patients, and a mean infarct size of 36+/-25 g. Peak systolic epsilon( parallel) correlated with the infarct mass at the global level (r=0.84, P<0.001). A strain value of -15% identified infarction with 83% sensitivity and 93% specificity at the global level and 76% and 95% at the territorial level, and a strain value of -13% identified transmural infarction with 80% sensitivity and 83% specificity at the segmental level. Global infarct mass correlates with the wall motion score index (r=0.70, P<0.001), and left ventricular ejection fraction measured by MRI or echocardiography (r=-0.71 and -0.58, both P<0.001). In chronic infarction, peak systolic epsilon(parallel) measured by 2D-STE correlates with the infarct mass assessed by CE MRI at a global level, and separates infarcted from non-infarcted tissue. Global strain is an excellent predictor of myocardial infarct size in chronic ischaemic heart disease.

Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study

Objective: To investigate long-term safety and efficacy after intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) in acute myocardial infarction (AMI). Design: Randomised, controlled trial. Setting: Two university hospitals in Oslo, Norway. Patients: Patients from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) study were re-assessed 3 years after inclusion. Interventions: 100 patients with anterior wall ST-elevation myocardial infarction treated with acute percutaneous coronary intervention (PCI) were randomised to receive intracoronary injection of mBMCs (n = 50) or not (n = 50). Main outcome measures: Change in left ventricular (LV) ejection fraction (primary). Change in exercise capacity (peak VO2) and quality of life (secondary). Infarct size (additional aim), and safety. Results: The rates of adverse clinical events in the groups were low and equal. There were no significant differences between groups in change of global LV systolic function by echocardiography or magnetic resonance imaging (MRI) during the follow-up. On exercise testing, the mBMC-treated patients had larger improvement in exercise time from 2–3 weeks to 3 years (1.5 minutes vs 0.6 minutes, p = 0.05), but the change in peak oxygen consumption did not differ (3.0 ml/kg/min vs 3.1 ml/kg/min, p = 0.75). Conclusion: The results indicate that intracoronary mBMC treatment in AMI is safe in the long term. A small improvement in exercise time in the mBMC group was found, but no other effects of treatment could be identified 3 years after cell therapy.

Autologous stem cell transplantation in acute myocardial infarction: The ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects

Objectives Intracoronary transplantation of different cell populations has been used in acute myocardial infarction (AMI) with promising results. The primary objective of the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) study is to test whether intracoronary transplantation of autologous mononuclear bone marrow cells (mBMC) improves left ventricular ejection fraction (LVEF) after anterior wall AMI. Design The ASTAMI study is a randomized, controlled, prospective study. One hundred patients with acute anterior wall ST-elevation myocardial infarction (STEMI) treated with acute percutaneous coronary intervention (PCI) are randomized in a 1:1 way to either intracoronary transplantation of autologous mBMC 5–8 d after PCI or to control. Left ventricular function, exercise capacity, biochemical status, functional class, quality of life and complications are validated at baseline and during a 12-month follow-up. Results By August 2004, out of 1004 patients with STEMI, 49 patients have been included in the study. Twenty-four patients have been randomized to intracoronary mBMC transplantation. Twenty patients had chest pain and 16 patients had ischemic ECG changes during the mBMC transplantation procedure. One patient had ventricular fibrillation 24 h after transplantation. Conclusions Intracoronary transplantation of autologous mBMC in the acute phase after AMI is feasible and seems safe in the short term.

Noninvasive Separation of Large, Medium, and Small Myocardial Infarcts in Survivors of Reperfused ST-Elevation Myocardial Infarction A Comprehensive Tissue Doppler and Speckle-Tracking Echocardiography Study

Background—The objective of the study was to evaluate the ability of established and new parameters of global systolic left ventricle function to estimate myocardial infarct size. Increasing infarct extent is associated with impaired prognosis in chronic ischemic heart disease. Systolic myocardial deformation is a complex 3D process that is mainly influenced by the amount and transmural distribution of viable myocardium. Speckle-tracking echocardiography (2D-STE) enables deformation assessment along the 3 main cardiac axes independent of insonation angle. Methods and Results—Global longitudinal, circumferential, and radial strain and left ventricle twist by 2D-STE, global longitudinal strain rate and strain by tissue Doppler imaging, and left ventricle ejection fraction and wall motion score index were assessed in 40 patients 8.5±5.4 months after a first myocardial infarct and compared with global myocardial infarct mass assessed by contrast-enhanced MRI. Longitudinal and circumferential strain by 2D-STE and longitudinal strain and strain rate by tissue Doppler imaging significantly separated medium-sized infarcts from small or large infarcts at the global level (P<0.05). All deformation indices correlated significantly with global infarct mass (P<0.01). Circumferential and longitudinal strains by 2D-STE demonstrated the best ability to identify medium-sized global myocardial infarcts. Conclusions—Circumferential and longitudinal strains by 2D-STE correlate with myocardial infarct mass and significantly differentiate among large, medium, and small myocardial infarcts.

Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis

AIMS The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. METHODS AND RESULTS We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m², 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m², 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥ 55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥ 40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes. CONCLUSION Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.

Fractional Flow Reserve–Guided Multivessel Angioplasty in Myocardial Infarction

BACKGROUND In patients with ST‐segment elevation myocardial infarction (STEMI), the use of percutaneous coronary intervention (PCI) to restore blood flow in an infarct‐related coronary artery improves outcomes. The use of PCI in non‐infarct‐related coronary arteries remains controversial. METHODS We randomly assigned 885 patients with STEMI and multivessel disease who had undergone primary PCI of an infarct‐related coronary artery in a 1:2 ratio to undergo complete revascularization of non‐infarct‐related coronary arteries guided by fractional flow reserve (FFR) (295 patients) or to undergo no revascularization of non‐infarct‐related coronary arteries (590 patients). The FFR procedure was performed in both groups, but in the latter group, both the patients and their cardiologist were unaware of the findings on FFR. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, revascularization, and cerebrovascular events at 12 months. Clinically indicated elective revascularizations performed within 45 days after primary PCI were not counted as events in the group receiving PCI for an infarct‐related coronary artery only. RESULTS The primary outcome occurred in 23 patients in the complete‐revascularization group and in 121 patients in the infarct‐artery‐only group that did not receive complete revascularization, a finding that translates to 8 and 21 events per 100 patients, respectively (hazard ratio, 0.35; 95% confidence interval [CI], 0.22 to 0.55; P<0.001). Death occurred in 4 patients in the complete‐revascularization group and in 10 patients in the infarct‐artery‐only group (1.4% vs. 1.7%) (hazard ratio, 0.80; 95% CI, 0.25 to 2.56), myocardial infarction in 7 and 28 patients, respectively (2.4% vs. 4.7%) (hazard ratio, 0.50; 95% CI, 0.22 to 1.13), revascularization in 18 and 103 patients (6.1% vs. 17.5%) (hazard ratio, 0.32; 95% CI, 0.20 to 0.54), and cerebrovascular events in 0 and 4 patients (0 vs. 0.7%). An FFR‐related serious adverse event occurred in 2 patients (both in the group receiving infarct‐related treatment only). CONCLUSIONS In patients with STEMI and multivessel disease who underwent primary PCI of an infarct‐related artery, the addition of FFR‐guided complete revascularization of non‐infarct‐related arteries in the acute setting resulted in a risk of a composite cardiovascular outcome that was lower than the risk among those who were treated for the infarct‐related artery only. This finding was mainly supported by a reduction in subsequent revascularizations. (Funded by Maasstad Cardiovascular Research and others; Compare‐Acute ClinicalTrials.gov number, NCT01399736.)

Anterior myocardial infarction with acute percutaneous coronary intervention and intracoronary injection of autologous mononuclear bone marrow cells: safety, clinical outcome, and serial changes in left ventricular function during 12-months' follow-up.

To the Editor: Intracoronary injection of bone marrow cells (BMC) has been introduced for improvement of left ventricular (LV) function after acute myocardial infarction (AMI). In the randomized ASTAMI (Autologous Stem cell Transplantation in Acute Myocardial Infarction) study, BMC treatment did not

Frequency of Left Ventricular Thrombus in Patients With Anterior Wall Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention and Dual Antiplatelet Therapy

The aim of the present study was to investigate the prevalence of left ventricular (LV) thrombus formation and important determinants in patients with acute ST elevation myocardial infarction localized to the anterior wall treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy. One hundred selected patients with ST elevation myocardial infarctions revascularized with PCI in the left anterior descending coronary artery were included. The patients participated in the Autologous Stem Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial. All were treated with aspirin 75 mg/day and clopidogrel 75 mg/day and underwent serial echocardiography and magnetic resonance imaging during the first 3 months after PCI. After 4 to 5 days, the ejection fraction and infarct size in percentage of the left anterior descending coronary artery area were assessed using single photon-emission computed tomography in addition to the ejection fraction by echocardiography. LV thrombi were detected in 15 patients during the first 3 months, 2/3 of them within the first week. No differences in baseline characteristics between the groups with and without LV thrombi were shown. However, in the thrombus group, significantly higher peak creatine kinase levels (6,128 vs 2,197 U/L, p <0.01), larger infarct sizes (82.5% vs 63.8%, p <0.01), and lower ejection fractions on single photon-emission computed tomography (35.5% vs 40.0%, p = 0.03) and on echocardiography (43.0% vs 46.0%, p = 0.03) were found compared to patients without LV thrombi. In conclusion, LV thrombus formation is a frequent finding in patients with anterior wall ST elevation myocardial infarction treated acutely with PCI and dual-antiplatelet therapy and should be assessed by echocardiography within the first week.

Apical Rotation by Speckle Tracking Echocardiography: A Simplified Bedside Index of Left Ventricular Twist

OBJECTIVE The study objective was to determine whether left ventricular (LV) apical rotation by speckle tracking echocardiography (STE) may serve as a clinically feasible index of LV twist. LV twist has been proposed as a sensitive marker of LV function, but clinical implementation has not been feasible because of the complexity and limitations of present methodologies. METHODS The relationship between apical rotation and LV twist was investigated in anesthetized dogs (n = 9) and a clinical study that included healthy controls (n = 18) and patients (n = 27) with previous myocardial infarction. Rotation by STE was compared with twist measured by magnetic resonance imaging and sonomicrometry in humans and dogs, respectively. RESULTS In dogs, apical rotation by STE correlated well with LV twist over a wide range of loading conditions and inotropic states, and during myocardial ischemia (R = 0.94, P < .01). Similarly, in humans there was a strong correlation between apical rotation and twist (R = 0.88, P < .01) but only a weak correlation between basal rotation and twist (R = 0.53, P < .01). Apical rotation accounted for 72% +/- 14% and 73% +/- 15% of the twisting deformation by magnetic resonance imaging in controls and patients, respectively. In dogs, apical rotation and twist decreased during myocardial ischemia (P < .05). In patients, LV twist and apical rotation were reduced (P < .05) only when LV ejection fraction was less than 50%. CONCLUSION Apical rotation represents the dominant contribution to LV twist, and apical rotation by STE reflects LV twist over a wide range of hemodynamic conditions. These findings suggest that apical rotation by STE may serve as a simple and feasible clinical index of LV twist.