Hans Fernando Rocha Dohmann

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.

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.

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.

Injeção intracoronariana de células tronco após infarto do miocárdio: subestudo da microcirculação

BACKGROUND The injection of stem cells in the context of acute myocardial infarction (AMI) has been tested almost exclusively by anterograde intra-arterial coronary (IAC) delivery. The retrograde intravenous coronary (IVC) delivery may be an additional route. OBJECTIVE To compare the cell distribution and retention pattern in the anterograde and retrograde routes. To investigate the role of microvascular obstruction by magnetic resonance imaging in cell retention by cardiac tissue after the injection of bone marrow mononuclear cells (BMMC) in AMI. METHODS This was a prospective, open label, randomized study. Patients with AMI who presented: (1) successful chemical or mechanical reperfusion within 24 hours of symptom onset and (2) infarction involving more than 10% of the left ventricle (LV) at the myocardial scintigraphy were included in the study. One hundred million BMMC were injected into the infarction-related artery through IAC route, or vein through the IVC route. One percent of the injected cells were labeled with 99mTc-hexamethyl-propylene-amine-oxime (99mTc-HMPAO). Cell distribution was evaluated at 4 and 24 hours after the myocardial scintigraphy injection. Cardiac magnetic resonance imaging was performed before cell injection. RESULTS Thirty patients were randomized into three groups. There were no serious adverse events related to the procedure. The early and late retention of labeled cells was higher in the IAC group than in IVC group, regardless of the presence of microcirculation obstruction. CONCLUSION The injection using the retrograde approach was feasible and safe. Cell retention by cardiac tissue was higher using the anterograde approach. More studies are needed to confirm these findings.

Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction – MiHeart/AMI study

BackgroundMyocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls.MethodsA sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 × 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum).ImplicationsMany phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required.Trial RegisterThis trial is registered at the NIH registry under the number NCT00350766.

Gastrointestinal bleeding diagnosed by red blood cell scintigraphy in a patient with aortic stenosis: a case of Heyde syndrome.

The authors report a case of small bowel bleeding diagnosed by Tc-99m-labeled red blood cell (RBC) scintigraphy during the postoperative period after aortic valve replacement. There is a relationship between aortic valve stenosis and gastrointestinal bleeding in elderly patients, called Heyde syndrome. The described patient had chronic anemia that worsened after surgery. RBC scintigraphy localized the source of bleeding from jejunal angiodysplasia confirmed by mesenteric angiography. This case illustrates the diagnostic information provided by RBC scintigraphy in this syndrome.

Função sistólica de pacientes com infarto miocárdico submetidos a transplante autólogo da medula óssea

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.

Prevalência de isquemia induzida por estresse mental

BACKGROUND The myocardial radionuclide imaging with mental distress seems to induce ischemia through a particular physiopathology when compared to radionuclide imaging with physical or pharmacological distress. OBJECTIVE To assess the prevalence of induced myocardial ischemia by mental distress in patients with thoracic pain and radionuclide imaging with normal conventional distress, with 99mTc-Sestamibi. METHODS Twenty-two patients were admitted with thoracic pain at emergency or were referred to the nuclear medicine service of our institution, where myocardial radionuclide imaging of distress or rest without ischemic alterations was carried out. The patients were, then, invited to go through an additional phase with mental distress induced by color conflict (Strop Color Test) with the objective of detecting myocardial ischemia. Two cardiologists and nuclear physicians performed the blind analysis of perfusional data and consequent quantification through Summed Difference Score (SDS), punctuating the segments that were altered after mental distress and comparing it to the rest period image. The presence of myocardial ischemia was considered if SDS > or = 3. RESULTS The prevalence of mental distress-induced myocardial ischemia was 40% (9 positive patients). Among the 22 studied patients, there were no statistical differences with regard to the number of risk factors, mental distress-induced hemodynamic alterations, usage of medications, presented symptoms, presence or absence of coronary disease and variations of ejection fraction and final systolic volume of Gated SPECT. CONCLUSION In a selected sample of patients with thoracic pain and normal myocardial radionuclide imaging, the research of myocardial ischemia induced by mental distress through radionuclide imaging may be positive in up to 40% of cases.