Svein Solheim

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.

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.

Reduced levels of TNFα in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks

BACKGROUND cellular adhesion molecules (CAMs) expressed on the endothelial surface play a key role in the inflammatory process of atherosclerosis, and increased expression of CAMs has been shown in hypercholesterolemic individuals. The expression of CAMs is mediated by several cytokines including tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6). The aim of the present study was to assess the influence of pravastatin 40 mg per day on selected soluble CAMs; intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), E-selectin, P-selectin and some circulating markers of inflammation; C-reactive protein (CRP) and the cytokines TNF alpha and IL-6. 40 non-diabetic men, age below 70 years, with serum total cholesterol 6--10 mmol/l combined with HDL-cholesterol < or =1.2 mmol/l were included. The study was randomized, double blinded, placebo controlled, cross over designed with 8 weeks intervention periods. Fasting blood samples were drawn after 8 and 16 weeks. RESULTS (MEDIAN VALUES) significant reduction of total cholesterol was achieved after treatment with pravastatin (7.8 on placebo vs. 5.7 mmol/l on pravastatin). TNF alpha was significantly reduced after treatment with pravastatin (1.33 on placebo vs. 1.10 pg/ml on pravastatin, P=0.032), whereas no differences in the levels of the measured sCAMs, CRP and IL-6 were found. Subgroup analysis among smokers versus non-smokers showed a significant reduction in the level of TNF alpha only among the smokers. CONCLUSION hypercholesterolemic individuals treated with pravastatin 40 mg per day for 8 weeks showed a statistically significant reduction in the levels of TNF alpha as compared with placebo.

Increased circulating mitochondrial DNA after myocardial infarction

DBP (R=0.022; p=0.01), LVM index (R=0.124 pb0.001) and body surface area (R=0.068; pb0.001) associated with AoRD in a model adjusted for age, gender, diabetes mellitus, hypertension, brachial supine SBP and triglycerides. This report provided novel knowledge that either in subjects with low cardiovascular risk (sample A) or in individuals with cardiovascular risk factors (sample B), leg BP, but not brachial BP, was independently related to AoRD. Moreover, the present results showed that changes in body posture influenced this relationship. These findings might have clinical implications. First, they could provide a novel indication for lower limbBPmeasurementas a predictor of AoRD,whichmightexpand its use in clinical practice. Currently, leg BP evaluation is not routinely performed, except when there is suspicion of aortic constriction or peripheral artery insufficiency [9,10]. Second, they suggest that evaluation of leg BP in orthostatic posture might be useful, at least in subjects with cardiovascular risk factors. To our knowledge, there are no reference values for leg BP measured in standing position and no previous study evaluated the relationship between orthostatic leg BP and vascular phenotypes. Conversely, current guidelines recommend assessmentof legBPonly inhorizontal position [9]. Therefore our results may shed novel light in a neglected BP measurement. In conclusion, our study demonstrated that leg BP was associated with AoRD in individuals with or without cardiovascular risk factors, and further showed that changes in body posture played a role in this relationship. Despite the underlying mechanisms, these findings suggest that leg BP evaluation might be an alternative approach in order to predict AoRD. However, further studies in other populations are necessary to confirm this assumption.

Influence of aspirin on inflammatory markers in patients after acute myocardial infarction

The aim of this study was to assess the influence of aspirin on selected inflammatory markers in patients recovering from acute myocardial infarction (AMI). Patients participating in the Warfarin Aspirin Re-Infarction Study-II were randomized to either aspirin 160 mg/day or aspirin 75 mg/day + warfarin, or warfarin alone after AMI. After AMI, aspirin 160 mg/day was associated with significantly lower levels of high-sensitivity C-reactive protein and tumor necrosis factor-alpha than warfarin alone over 4 years. However, the same levels were not predictors for clinical end points.

Regional myocardial function after intracoronary bone marrow cell injection in reperfused anterior wall infarction - a cardiovascular magnetic resonance tagging study

BackgroundTrials have brought diverse results of bone marrow stem cell treatment in necrotic myocardium. This substudy from the Autologous Stem Cell Transplantation in Acute Myocardial Infarction trial (ASTAMI) explored global and regional myocardial function after intracoronary injection of autologous mononuclear bone marrow cells (mBMC) in acute anterior wall myocardial infarction treated with percutaneous coronary intervention.MethodsCardiovascular magnetic resonance (CMR) tagging was performed 2-3 weeks and 6 months after revascularization in 15 patients treated with intracoronary stem cell injection (mBMC group) and in 13 controls without sham injection. Global and regional left ventricular (LV) strain and LV twist were correlated to cine CMR and late gadolinium enhancement (LGE).ResultsIn the control group myocardial function as measured by strain improved for the global LV (6 months: -13.1 ± 2.4 versus 2-3 weeks: -11.9 ± 3.4%, p = 0.014) and for the infarct zone (-11.8 ± 3.0 versus -9.3 ± 4.1%, p = 0.001), and significantly more than in the mBMC group (inter-group p = 0.027 for global strain, respectively p = 0.009 for infarct zone strain). LV infarct mass decreased (35.7 ± 20.4 versus 45.7 ± 29.5 g, p = 0.024), also significantly more pronounced than the mBMC group (inter-group p = 0.034). LV twist was initially low and remained unchanged irrespective of therapy.ConclusionsLGE and strain findings quite similarly demonstrate subtle differences between the mBMC and control groups. Intracoronary injection of autologous mBMC did not strengthen regional or global myocardial function in this substudy.Trial registrationClinicalTrials.gov: NCT00199823

Age and stress related phenotypical changes in bone marrow CD34+ cells

Objective. Phenotypical changes in the human bone marrow (BM) due to age and stress have not so far been properly addressed in the literature. In the present study, we compared CD34+ BM cells between older and young volunteers. The influence of stress on CD34+ cell phenotype in older patients was investigated in an age‐matched group with acute myocardial infarction (AMI). Cytokines thought to influence BM CD34+ cell homeostasis were also analysed. Material and methods. BM mononuclear cells of 10 older volunteers and of 7 young volunteers (18–25 years), as well as 22 AMI patients, were analysed by flow cytometry for the following markers: CD34, CD38, CD117 (c‐kit) and CD133. Blood samples were analysed for CRP, IL‐6, MCP‐1, IL‐8, MMP‐9, TIMP‐1 and TNFα by ELISA methods. Results. Significantly higher numbers of CD34+ CD38− cells (both absolute and relative) were observed in older volunteers than in young volunteers and AMI patients. Higher numbers of immature progenitors, namely CD34+CD38− cells and CD34+CD38−CD117+CD133+ cells, were observed among older volunteers compared to the other groups. However, the relative number of CD34+ cells lacking CD38 expression or expressing CD133 was higher in the old volunteers and AMI patients. None of the circulating factors investigated correlated with any of the cell population yields. Conclusion. In this study, we found that the absolute and relative numbers of BM CD34+CD38− progenitor cells increase with age. The increment is attenuated in patients with AMI.

Inflammatory responses after percutaneous coronary intervention in patients with acute myocardial infarction or stable angina pectoris

Objective. To investigate the profile of circulating inflammatory markers after percutaneous coronary intervention (PCI) in patients with AMI or stable angina pectoris (AP). Material and methods. Twenty patients with AMI and 10 with stable AP were treated with PCI of a central coronary artery. Blood samples were drawn immediately before PCI, in the AP group and after 3 and 12 h, days 1, 3, 5, 7 and 14 in both groups. Results. Interleukin 6 increased in both groups to time‐point 12 h and day 1 (peak), being significantly higher in the AMI group compared to the AP group at 3 and 12 h, and also at days 1 and 3. A similar profile was demonstrated for CRP with significantly higher levels in the AMI group at days 1, 3 and 5 compared to the AP group. A slightly different pattern was shown for Interleukin 10 (IL‐10) with significantly higher levels in the AMI group at 3 and 12 h, days 1 and 14 compared to the AP group. Conclusion. AMI patients treated with PCI experienced a marked short‐term increase in pro‐inflammatory mediators as well as IL‐10 compared to patients with stable angina pectoris treated with PCI.