Suzana A. Silva

Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure

Background—This study evaluated the hypothesis that transendocardial injections of autologous mononuclear bone marrow cells in patients with end-stage ischemic heart disease could safely promote neovascularization and improve perfusion and myocardial contractility. Methods and Results—Twenty-one patients were enrolled in this prospective, nonrandomized, open-label study (first 14 patients, treatment; last 7 patients, control). Baseline evaluations included complete clinical and laboratory evaluations, exercise stress (ramp treadmill), 2D Doppler echocardiogram, single-photon emission computed tomography perfusion scan, and 24-hour Holter monitoring. Bone marrow mononuclear cells were harvested, isolated, washed, and resuspended in saline for injection by NOGA catheter (15 injections of 0.2 cc). Electromechanical mapping was used to identify viable myocardium (unipolar voltage ≥6.9 mV) for treatment. Treated and control patients underwent 2-month noninvasive follow-up, and treated patients alone underwent a 4-month invasive follow-up according to standard protocols and with the same procedures used as at baseline. Patient population demographics and exercise test variables did not differ significantly between the treatment and control groups; only serum creatinine and brain natriuretic peptide levels varied in laboratory evaluations at follow-up, being relatively higher in control patients. At 2 months, there was a significant reduction in total reversible defect and improvement in global left ventricular function within the treatment group and between the treatment and control groups (P =0.02) on quantitative single-photon emission computed tomography analysis. At 4 months, there was improvement in ejection fraction from a baseline of 20% to 29% (P =0.003) and a reduction in end-systolic volume (P =0.03) in the treated patients. Electromechanical mapping revealed significant mechanical improvement of the injected segments (P <0.0005) at 4 months after treatment. Conclusions—Thus, the present study demonstrates the relative safety of intramyocardial injections of bone marrow–derived stem cells in humans with severe heart failure and the potential for improving myocardial blood flow with associated enhancement of regional and global left ventricular function.

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions. Design Systematic review and meta-regression analysis of randomised controlled trials. Data sources Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field. Study selection In teams of two, reviewers independently determined eligibility of randomised trials that tested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months. Data extraction and synthesis Using standardised, pre-piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated. Results The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk of cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high density lipoprotein cholesterol explained almost no variability (<1%) in any of the outcomes. The change in the quotient of low density lipoprotein cholesterol and high density lipoprotein cholesterol did not explain more of the variability in any of the outcomes than did the change in low density lipoprotein cholesterol alone. For a 10 mg/dl (0.26 mmol/l) reduction in low density lipoprotein cholesterol, the relative risk reduction was 7.2% (95% confidence interval 3.1% to 11%; P=0.001) for coronary heart disease deaths, 7.1% (4.5% to 9.8%; P<0.001) for coronary heart disease events, and 4.4% (1.6% to 7.2%; P=0.002) for total deaths, when adjusted for change in high density lipoprotein cholesterol and drug class. Conclusions Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths. The results support reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions.

Improved Exercise Capacity and Ischemia 6 and 12 Months After Transendocardial Injection of Autologous Bone Marrow Mononuclear Cells for Ischemic Cardiomyopathy

Background—We recently reported the safety and feasibility of autologous bone marrow mononuclear cell (ABMMNC) injection into areas of ischemic myocardium in patients with end-stage ischemic cardiomyopathy. The present study evaluated the safety and efficacy of this therapy at 6- and 12-month follow-up. Methods and Results—Twenty patients with 6- and 12-month follow-up (11 treated subjects; 9 controls) were enrolled in this prospective, nonrandomized, open-label study. Complete clinical and laboratory evaluations as well as exercise stress (ramp treadmill), 2-dimensional Doppler echocardiography, single-photon emission computed tomography (SPECT) perfusion scanning, and 24-hour Holter monitoring were performed at baseline and follow-up. Transendocardial delivery of ABMMNCs was performed with the aid of electromechanical mapping to identify viable myocardium. Each patient received 15 ABMMNC injections of 0.2 mL each. At 6 and 12 months, total reversible defect, as measured by SPECT perfusion scanning, was significantly reduced in the treatment group as compared with the control group. At 12 months, exercise capacity was significantly improved in the treatment group. This improvement correlated well with monocyte, B-cell, hematopoietic progenitor cell, and early hemapoietic progenitor cell phenotypes. Conclusions—The 6- and 12-month follow-up data in this study suggest that transendocardial injection of ABMMNCs in patients with end-stage ischemic heart disease may produce a durable therapeutic effect and improve myocardial perfusion and exercise capacity.

Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: postmortem anatomicopathologic and immunohistochemical findings.

Background—Cell-based therapies for treatment of ischemic heart disease are currently under investigation. We previously reported the results of a phase I trial of transendocardial injection of autologous bone marrow mononuclear (ABMM) cells in patients with end-stage ischemic heart disease. The current report focuses on postmortem cardiac findings from one of the treated patients, who died 11 months after cell therapy. Methods and Results—Anatomicopathologic, morphometric, and immunocytochemical findings from the anterolateral ventricular wall (with cell therapy) were compared with findings from the interventricular septum (normal perfusion and no cell therapy) and from the inferoposterior ventricular wall (extensive scar tissue and no cell therapy). No signs of adverse events were found in the cell-injected areas. Capillary density was significantly higher (P<0.001) in the anterolateral wall than in the previously infarcted tissue in the posterior wall. The prominent vasculature of the anterolateral wall was associated with hyperplasia of pericytes, mural cells, and adventitia. Some of these cells had acquired cytoskeletal elements and contractile proteins (troponin, sarcomeric &agr;-actinin, actinin), as well as the morphology of cardiomyocytes, and appeared to have migrated toward adjacent bundles of cardiomyocytes. Conclusions—Eleven months after treatment, morphological and immunocytochemical analysis of the sites of ABMM cell injection showed no abnormal cell growth or tissue lesions and suggested that an active process of angiogenesis was present in both the fibrotic cicatricial tissue and the adjacent cardiac muscle. Some of the pericytes had acquired the morphology of cardiomyocytes, suggesting long-term sequential regeneration of the cardiac vascular tree and muscle.

Autologous bone-marrow mononuclear cell transplantation after acute myocardial infarction: comparison of two delivery techniques.

The objective of this study was to investigate safety and feasibility of autologous bone marrow mononuclear cells (BMMNC) transplantation in ST elevation myocardial infarction (STEMI), comparing anterograde intracoronary artery (ICA) delivery with retrograde intracoronary vein (ICV) approach. An open labeled, randomized controlled trial of 30 patients admitted with STEMI was used. Patients were enrolled if they 1) were successfully reperfused within 24 h from symptoms onset and 2) had infarct size larger than 10% of the left ventricle (LV). One hundred million BMMNC were injected in the infarct-related artery (intra-arterial group) or vein (intravenous group), 1% of which was labeled with Tc99m-hexamethylpropylenamineoxime. Cell distribution was evaluated 4 and 24 h after injection. Baseline MRI was performed in order to evaluate microbstruction pattern. Baseline radionuclide ventriculography was performed before cell transfer and after 3 and 6 months. All the treated patients were submitted to repeat coronary angiography after 3 months. Thirty patients (57 ± 11 years, 70% males) were randomly assigned to ICA (n = 14), ICV (n = 10), or control (n = 6) groups. No serious adverse events related to the procedure were observed. Early and late retention of radiolabeled cells was higher in the ICA than in the ICV group, independently of microcirculation obstruction. An increase of EF was observed in the ICA group (p = 0.02) compared to baseline. Injection procedures through anterograde and retrograde approaches seem to be feasible and safe. BMMNC retention by damaged heart tissue was apparently higher when the anterograde approach was used. Further studies are required to confirm these initial data.

Segurança do transplante autólogo, intra-arterial, de células mononucleares da medula óssea na fase aguda do acidente vascular cerebral isquêmico

Stroke is the third cause of death and the leading cause of disability in adult subjects. Although stroke mortality has been declining in some countries, stroke morbidity has been increasing due to the aging of population and patients improved survival.1 Treatment with recombinant tissue plasminogen activator (rtPA) is successful provided it is administered within 3 hours of symptoms onset,2 but its use is limited to about 5% of the patients with acute ischemic stroke. Furthermore, no neuroprotective agent has yet been proven effective in human clinical trials. The development of other therapeutic strategies is, therefore, warranted. The use of stem cells in animal models has led to functional improvement following stroke.3 Recent publications have shown that bone marrow mononuclear cells (BM-MNC) therapy through intracoronary injection is a safe procedure in patients with acute or chronic ischemic heart disease.4,5 Based on these preliminary data, there has been growing interest in the study of BM-MNC transplantation for acute ischemic stroke. We report the first case of intra-arterial autologous BM-MNC transplantation for acute ischemic stroke.

Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study

BackgroundCardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials.Method/DesignWe have designed clinical trials to test for the efficacy of autologous bone marrow derived mononuclear cell therapies in four different cardiopathies: acute and chronic ischemic heart disease, and Chagasic and dilated cardiomyopathy. All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled and receive optimized therapy for their specific condition. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). For each trial there are specific inclusion and exclusion criteria and the method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction (determined by Simpsons rule) six and twelve months after intervention in relation to the basal ejection fraction. The main hypothesis of this study is that the patients who receive the autologous bone-marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute left ventricular ejection fraction in comparison with the control group.DiscussionMany phase I clinical trials using cell therapy for cardiac diseases have already been performed. The few randomized studies have yielded conflicting results, rendering necessary larger well controlled trials to test for efficacy of cell therapies in cardiopathies.The trials registration numbers at the NIH registry are the following: Chagasic cardiomyopathy (NCT00349271), dilated cardiomyopathy (NCT00333827), acute myocardial infarction (NCT00350766) and Chronic Ischemic Heart Disease (NCT00362388).

Multicentre, randomized, double-blind trial of intracoronary autologous mononuclear bone marrow cell injection in non-ischaemic dilated cardiomyopathy (the dilated cardiomyopathy arm of the MiHeart study).

AIMS Pre-clinical and few clinical studies suggest that transplantation of autologous bone marrow mononuclear cells (BMNC) improves heart function in dilated cardiomyopathies. Our objective was to determine if intracoronary injection of autologous BMNC improves the left ventricular ejection fraction (LVEF) of patients with non-ischaemic dilated cardiomyopathy (NIDCM). METHODS AND RESULTS This study was a multicentre, randomized, double-blind, placebo controlled trial with a follow-up of 12 months. Patients with NIDCM and LVEF <35% were recruited at heart failure ambulatories in specialized hospitals around Brazil. One hundred and sixty subjects were randomized to intracoronary injection of BMNC or placebo (1:1). The primary endpoint was the difference in change of LVEF between BMNC and placebo groups as determined by echocardiography. One hundred and fifteen patients completed the study. Left ventricular ejection fraction decreased from 24.0% (21.6-26.3) to 19.9% (15.4-24.4) in the BMNC group and from 24.3% (22.1-26.5) to 22.1% (17.4-26.8) in the placebo group. There were no significant differences in changes between cell and placebo groups for left ventricular systolic and diastolic volumes and ejection fraction. Mortality rate was 20.37% in placebo and 21.31% in BMNC. CONCLUSION Intracoronary injection of autologous BMNC does not improve left ventricular function in patients with NIDCM. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00333827.

Systolic function of patients with myocardial infarction undergoing autologous bone marrow transplantation

BACKGROUND Several studies have been published on the effect of bone-marrow stem cells on the left ventricle when acting on post- acute myocardial infarction remodeling. However, the results have been controversial. OBJECTIVE To carry out an echocardiographic analysis of the systolic function of patients with acute myocardial infarction after autologous mononuclear bone marrow cell transplantation (AMBMCT) as performed via the intracoronary and intravenous routes. METHODS This is an open-label, prospective, randomized study. INCLUSION CRITERIA patients admitted for ST-elevation acute myocardial infarction (MI) who had undergone mechanical or chemical reperfusion within 24 hours of the onset of symptoms and whose echocardiogram showed decreased segmental wall motion and fixed perfusion defect related to the culprit artery. Autologous bone marrow was aspirated from the posterior iliac crest under sedation and analgesia of the patients randomly assigned for the treatment group. After laboratory manipulation, intracoronary or intravenous injection of 100 x 106 mononuclear cells was performed. Echocardiography (Vivid 7) was used to assess ventricular function before and three and six months after cell infusion. RESULTS A total of 30 patients were included, 14 in the arterial group (AG), 10 in the venous group (VG), and six in the control group (CG). No statistical difference was found between the groups for the echocardiographic parameters studied. CONCLUSION Autologous mononuclear bone marrow cell transplantation did not improve the echocardiographic parameters of systolic function.FUNDAMENTO: Diversos estudos foram publicados sobre a acao de celulas tronco da medula ossea no ventriculo esquerdo, ao atuarem no remodelamento pos-infarto agudo do miocardio. Os resultados, no entanto, tem se mostrado controversos. OBJETIVO: Avaliar atraves do ecocardiograma a funcao sistolica de pacientes com infarto agudo do miocardio apos o Transplante Autologo de Celulas Mononucleares da Medula Ossea (TACMMO) atraves de duas vias injecao: intracoronariana e intravenosa. METODOS: Estudo aberto, prospectivo, randomizado. Foram incluidos pacientes admitidos por infarto agudo do miocardio (IAM) com supradesnivelamento do segmento ST e submetidos a reperfusao mecânica ou quimica, dentro de 24 horas apos o inicio dos sintomas, que apresentavam ao ecocardiograma reducao da contratilidade segmentar e defeito fixo da perfusao relacionada a arteria culpada pelo IAM. A medula ossea autologa foi aspirada da crista iliaca posterior sob sedacao e analgesia, nos pacientes randomizados para o grupo tratado. Apos manipulacao laboratorial, 100 milhoes de celulas mononucleares foram injetadas por via intracoronariana ou intravenosa. Utilizamos o ecocardiograma (Vivid 7) para avaliar a funcao ventricular antes e apos tres e seis meses da infusao de celulas. RESULTADOS: Foram incluidos trinta pacientes, 14 no grupo arterial (GA), dez no grupo venoso (GV) e seis no grupo controle (GC). Nao houve diferenca estatistica dos parâmetros ecocardiograficos estudados entre os grupos. CONCLUSAO: O transplante autologo de celulas mononucleares da medula ossea nao demonstrou melhora dos parâmetros ecocardiograficos da funcao sistolica.

Where is the wisdom? II – Evidence‐based medicine and the epistemological crisis in clinical medicine. Exposition and commentary on Djulbegovic, B., Guyatt, G. H. & Ashcroft, R. E. (2009) Cancer Control, 16, 158–168

Evidence-based medicine (EBM) burst on the scene in 1992 [1] as a challenging, innovative and ultimately enigmatic newcomer to the stage of clinical medicine. Its challenge to blind obeisance to authority and its systematic approach to the problems posed by the rapidly expanding terrain of medical knowledge ranked high on the list of EBM’s compelling features. A critical historical review, and companion piece to this exposition and commentary [2], concluded that EBM contributed tools and resources of unprecedented importance to the practice of clinical medicine in the Age of Information, but fell short of its initially bold claims to define a comprehensive and revolutionary practice model, despite several published attempts to elaborate it. Challenges to EBM on epistemological and philosophical grounds have constituted a prominent aspect of criticisms of EBM since the 1992 proclamation. However, with few exceptions [3], responses to criticisms from the EBM camp have been confined to methodological issues pertaining to clinical research designs and to general goals and objectives [4]. Djulbegovic et al.’s [5] recent contribution constitutes the first attempt from within EBM to respond systematically to the published epistemological and philosophical challenges and, for this reason alone, deserves attention. However, our commentary is motivated not only by the historical importance of their submission. Rather we perceive clinical medicine to be in the midst of an epistemological crisis and the issues to which Djulbegovic et al. appear to be responding to be centrally related to this crisis. The stated objective of EBM has been to close the gap between research and clinical practice [6]. However, such an endeavour begs the question of what constitutes the nature of that gap, that is, the proper role of research in determining or informing clinical action. As pointed out by Tonelli [6], this in turn constitutes an epistemological question insofar as it implies, following Djulbegovic, a ‘propose(d) specific relationship between theory, evidence, and knowledge’. It defines the need for a more rigorous delineation and understanding of the scientific foundations of clinical practice. As stated by Tonelli, EBM represents a school of medical epistemology [6]. Epistemology deals with the theory of knowledge and is concerned not just with the nature but also with the limitations of knowledge. Hence, to discuss EBM within an epistemological framework we must address not only its accomplishments but also its main limitations. Epistemology deals with questions such as ‘What is knowledge?’, ‘How do we know what we know?’, ‘How is knowledge acquired?’ and ‘How does knowledge lead to wise and just action?’Among these, the latter, corresponding to the realm of ‘practical wisdom’ or ‘phronesis’ in classical Aristotelian terms, appears most salient to the issue at hand. Thus, the need to address these matters in the framework of relevant concepts of science and scientific knowledge defines the need for a ‘clinical epistemology.’ [7] We find the paper by Djulbegovic to be a convenient and timely pretext for clarifying these issues in some depth.