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This review discusses a novel experimental approach for the regeneration of original tissue structure by recruitment of endogenous stem-cells to injured sites following administration of α-gal nanoparticles, which harness the natural anti-Gal antibody. Anti-Gal is produced in large amounts in all humans, and it binds the multiple α-gal epitopes (Galα1-3Galß1-4GlcNAc-R) presented on α-gal nanoparticles. In situ binding of anti-Gal to α-gal nanoparticles activates the complement system and generates complement cleavage chemotactic-peptides that rapidly recruit macrophages. Macrophages reaching anti-Gal coated α-gal nanoparticles bind them via Fc/Fc receptor interaction and polarize into M2 pro-reparative macrophages. These macrophages secrete various cytokines that orchestrate regeneration of the injured tissue, including VEGF inducing neo-vascularization and cytokines directing homing of stem-cells to injury sites. Homing of stem-cells is also directed by interaction of complement cleavage peptides with their corresponding receptors on the stem-cells. Application of α-gal nanoparticles to skin wounds of anti-Gal producing mice results in decrease in healing time by half. Furthermore, α-gal nanoparticles treated wounds restore the normal structure of the injured skin without fibrosis or scar formation. Similarly, in a mouse model of occlusion/reperfusion myocardial-infarction, near complete regeneration after intramyocardial injection of α-gal nanoparticles was demonstrated, whereas hearts injected with saline display ~20% fibrosis and scar formation of the left ventricular wall. It is suggested that recruitment of stem-cells following anti-Gal/α-gal nanoparticles interaction in injured tissues may result in induction of localized regeneration facilitated by conducive microenvironments generated by pro-reparative macrophage secretions and "cues" provided by the extracellular matrix in the injury site.
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Cicatriz , Nanopartículas , Animais , Ativação do Complemento , Citocinas , Epitopos , Humanos , Macrófagos , Camundongos , Nanopartículas/química , Receptores Fc , Células-Tronco , Fator A de Crescimento do Endotélio Vascular , CicatrizaçãoRESUMO
RATIONALE: Despite direct immediate intervention and therapy, ST-segment-elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. OBJECTIVE: To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. METHODS AND RESULTS: Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months (P<0.001). In secondary analyses, when adjusted for time of ischemia, a consistently favorable cell dose-dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. CONCLUSIONS: This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01495364.
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Antígenos CD34/administração & dosagem , Transplante de Medula Óssea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/terapia , Idoso , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Infusões Intra-Arteriais/métodos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Transplante Autólogo/métodos , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologiaRESUMO
Aims: Autologous CD34+ (auto-CD34+) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34+ cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34+ cells. Methods and results: Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34+ cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34+ compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 105 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion: Treatment with auto-CD34+ cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.
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Angina Pectoris/terapia , Tolerância ao Exercício , Mortalidade , Transplante de Células-Tronco/métodos , Idoso , Angina Pectoris/fisiopatologia , Antígenos CD34/metabolismo , Feminino , Humanos , Injeções Intramusculares , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Miocárdio , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante AutólogoRESUMO
BACKGROUND: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. METHODS: In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. FINDINGS: Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). INTERPRETATION: To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. FUNDING: Vericel Corporation.
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Cardiomiopatia Dilatada/complicações , Terapia Baseada em Transplante de Células e Tecidos/métodos , Insuficiência Cardíaca/terapia , Isquemia Miocárdica/complicações , Adulto , Idoso , Cardiomiopatia Dilatada/etiologia , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
Dual antiplatelet therapy (DAPT) following an acute coronary syndrome or after placement of a coronary artery stent is superior to aspirin alone for prevention of atherothrombotic events but carries an increased bleeding risk. DAPT should be continued for at least 12 months based on current guidelines. Recent randomized trials demonstrate reduced ischemic events including myocardial infarction (MI), stroke, and death with continued DAPT for up to 30 months or longer, particularly in the post-MI population. However, this clinical benefit is accompanied by an increased risk of bleeding. Additional trials show mixed safety and efficacy with duration of DAPT of less than 12 months. The current data emphasizes the need to individualize DAPT duration at the patient level to balance the clinical benefits of a reduced risk of cardiovascular ischemic events with the greater risk of clinically significant bleeding. Patients at an increased risk of ischemic events and a lower risk of bleeding should be strongly considered for prolonged DAPT beyond the 1 year currently recommended in the practice guidelines.
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Doença da Artéria Coronariana/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Quimioterapia Combinada , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação Plaquetária/efeitos adversos , Risco , Acidente Vascular Cerebral/prevenção & controleRESUMO
RATIONALE: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. OBJECTIVE: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. METHODS AND RESULTS: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. CONCLUSIONS: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.
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Quimiocina CXCL12/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Plasmídeos , Idoso , Quimiocina CXCL12/metabolismo , Estudos de Coortes , Relação Dose-Resposta a Droga , Ecocardiografia , Tolerância ao Exercício , Feminino , Seguimentos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Tomografia por Emissão de Pósitrons , Qualidade de Vida , Resultado do TratamentoRESUMO
The healing of skin wounds, myocardial, and spinal cord injuries in salamander, newt, and axolotl amphibians, and in mouse neonates, results in scar-free regeneration, whereas injuries in adult mice heal by fibrosis and scar formation. Although both types of healing are mediated by macrophages, regeneration in these amphibians and in mouse neonates also involves innate activation of the complement system. These differences suggest that localized complement activation in adult mouse injuries might induce regeneration instead of the default fibrosis and scar formation. Localized complement activation is feasible by antigen/antibody interaction between biodegradable nanoparticles presenting α-gal epitopes (α-gal nanoparticles) and the natural anti-Gal antibody which is abundant in humans. Administration of α-gal nanoparticles into injuries of anti-Gal-producing adult mice results in localized complement activation which induces rapid and extensive macrophage recruitment. These macrophages bind anti-Gal-coated α-gal nanoparticles and polarize into M2 pro-regenerative macrophages that orchestrate accelerated scar-free regeneration of skin wounds and regeneration of myocardium injured by myocardial infarction (MI). Furthermore, injection of α-gal nanoparticles into spinal cord injuries of anti-Gal-producing adult mice induces recruitment of M2 macrophages, that mediate extensive angiogenesis and axonal sprouting, which reconnects between proximal and distal severed axons. Thus, α-gal nanoparticle treatment in adult mice mimics physiologic regeneration in amphibians. These studies further suggest that α-gal nanoparticles may be of significance in the treatment of human injuries.
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Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.
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Angina Estável/cirurgia , Antígenos CD34/imunologia , Transplante de Células-Tronco/métodos , Células-Tronco/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Estável/diagnóstico , Angina Estável/imunologia , Método Duplo-Cego , Eletrocardiografia , Teste de Esforço , Feminino , Seguimentos , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Miocárdio , Estudos Prospectivos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Assess accuracy of Helix injections via fluoroscopic-mapping and evaluate delivery safety. BACKGROUND: Percutaneous intramyocardial-delivery of agents must be safe and accurate; retention is also important. A delivery system (Helical Infusion/Morph Guide-Catheter, Biocardia Inc) has been developed to improve maneuverability and stability of catheter-needle-myocardium intersection. METHODS: Accuracy and safety: 12 swine underwent LV and coronary angiography via 8F sheath. Targeted delivery was assigned into LAD, LCX, or RCA. System was advanced into LV and 6 targeted intramyocardial dye injections (5 mm apart) delivered using fluoroscopy. After euthanization, hearts underwent gross and histologic evaluation. Retention was assessed by iron-oxide and fluorochrome labeled CD34+ cells. Cells were injected into 6 swine using same techniques. Delivery system was advanced into LV, and injections delivered using fluoroscopy. Euthanization was performed at 2 hr and hearts formalin fixed. MRI was performed on 6 treated hearts and 4 untreated controls. Blinded analysis performed by 2 radiologists. Two treated hearts underwent immunohistological analysis. RESULTS: Accuracy and safety evaluation: 71/72 injections (98.6%) were within prespecified zone; 7/72 (9.7%) less than 5 mm apart. No adverse events occurred. MRI-presence of iron-oxide labeled CD34+ cells were correctly identified in 95% (19/20) of imaged injections. Anti-CD34+ antibody staining and fluorescence microscopy confirmed CD34+ cells in myocardium. Histology confirmed cell viability at fixation. CONCLUSIONS: Helix system was accurate and safe. Retention of CD34+ cells was confirmed by MRI and immunohistology. Further preclinical studies are needed to characterize retention over time and quantify efficiency. Studies are needed to confirm accuracy, safety, and retention in humans.
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Antígenos CD34/metabolismo , Catéteres , Transplante de Células-Tronco Hematopoéticas/instrumentação , Células-Tronco Hematopoéticas/metabolismo , Miocárdio/metabolismo , Agulhas , Animais , Biomarcadores/metabolismo , Sobrevivência Celular , Angiografia Coronária , Desenho de Equipamento , Fluoroscopia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imuno-Histoquímica , Injeções Intramusculares , Imageamento por Ressonância Magnética , Microscopia de Fluorescência , Modelos Animais , Radiografia Intervencionista/métodos , Suínos , Fatores de TempoRESUMO
Background: Neonatal mice, but not older mice, can regenerate their hearts after myocardial-infarction (MI), a process mediated by pro-reparative macrophages. α-Gal nanoparticles applied to skin wounds in adult-mice bind the anti-Gal antibody, activate the complement cascade and generate complement chemotactic peptides that recruit pro-reparative macrophages which are further activated by these nanoparticles. The recruited macrophages decrease wound healing time by ~50%, restore the normal skin structure and prevent fibrosis and scar formation in mice. Objectives: The objective of this study is to determine if α-gal nanoparticles injected into the reperfused myocardium after MI in adult-mice can induce myocardial repair that restores normal structure, similar to that observed in skin injuries. Methods and Results: MI was induced by occluding the mid-portion of the left anterior descending (LAD) coronary artery for 30 min. Immediately following reperfusion, each mouse received two 10 µl injections of 100 µg α-gal nanoparticles in saline into the LAD territory (n = 20), or saline for controls (n = 10). Myocardial infarct size was measured by planimetry following Trichrome staining and macrophage recruitment by hematoxylin-eosin staining. Left ventricular (LV) function was measured by echocardiography. Control mice displayed peak macrophage infiltration at 4-days, whereas treated mice had a delayed peak macrophage infiltration at 7-days. At 28-days, control mice demonstrated large transmural infarcts with extensive scar formation and poor contractile function. In contrast, mice treated with α-gal nanoparticles demonstrated after 28-days a marked reduction in infarct size (~10-fold smaller), restoration of normal myocardium structure and contractile function. Conclusions: Intramyocardial injection of α-gal nanoparticles post-MI in anti-Gal producing adult-mice results in near complete repair of the infarcted territory, with restoration of normal LV structure and contractile function. The mechanism responsible for this benefit likely involves alteration of the usual inflammatory response post-MI, as previously observed with regeneration of injured hearts in adult zebrafish, salamanders and neonatal mice.
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This study evaluated the safety and feasibility of transendocardial injections of VentriGel, a cardiac extracellular matrix hydrogel, in early and late post-myocardial infarction (MI) patients with left ventricular (LV) dysfunction. VentriGel was delivered in 15 patients with moderate LV dysfunction (25% ≤ LV ejection fraction ≤ 45%) who were between 60 days to 3 years post-MI and were revascularized by percutaneous coronary intervention. The primary endpoints were incidence of adverse events and abnormal clinical laboratory results. This first-in-man study established the safety and feasibility of delivering VentriGel in post-MI patients, thus warranting further evaluation in larger, randomized clinical trials.
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Endocardial mapping of the left ventricle (LV) using the NOGA® XP Cardiac Navigation System can identify chronically ischemic and viable myocardium in patients with coronary artery disease by generating electromechanical maps. These maps are very useful when targeting myocardial tissue for injection of stem cells. We present the case of a woman who developed a perforation at the site of an LV aneurysm during NOGA mapping prior to the transendocardial injection of stem cells, as part of a multicenter clinical trial. The presence of an LV aneurysm is currently not a contraindication (or caution) to the use the NOGA mapping catheter. As the field of stem cell therapy evolves and the use of this technique increases, operators must be aware that the presence of an LV aneurysm may increase the risk of perforation during a NOGA mapping procedure.
Assuntos
Mapeamento Potencial de Superfície Corporal/efeitos adversos , Cateterismo Cardíaco/efeitos adversos , Aneurisma Cardíaco/etiologia , Traumatismos Cardíacos/complicações , Ventrículos do Coração/lesões , Isquemia Miocárdica/diagnóstico , Idoso , Mapeamento Potencial de Superfície Corporal/instrumentação , Cateterismo Cardíaco/métodos , Diagnóstico Diferencial , Ecocardiografia , Feminino , Aneurisma Cardíaco/diagnóstico , Traumatismos Cardíacos/diagnóstico , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento Tridimensional , Ventriculografia com RadionuclídeosAssuntos
Angioplastia Coronária com Balão , Infarto do Miocárdio , Fenômeno de não Refluxo , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Angiografia Coronária , Humanos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/terapia , Fenômeno de não Refluxo/diagnóstico por imagem , Fenômeno de não Refluxo/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
The benefits of stem cell therapy for patients with chronic symptomatic systolic heart failure due to ischemic and nonischemic cardiomyopathy (ICM and NICM, respectively) are unclear. We performed a systematic review of major published and ongoing trials of stem cell therapy for systolic heart failure and compared measured clinical outcomes for both types of cardiomyopathy. The majority of the 29 published studies demonstrated clinical benefits of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). Left ventricular ejection fraction (LVEF) was improved in the majority of trials after therapy. Cell delivery combined with coronary artery bypass grafting was associated with the greatest improvement in LVEF. Left ventricular end-systolic volume (or diameter), New York Heart Association functional classification, quality of life, and exercise capacity were also improved in most studies after cell therapy. Most ICM trials demonstrated a significant improvement in perfusion defects, infarct size, and myocardial viability. Several larger clinical trials that are in progress employ alternative delivery modes, cell types, and longer follow-up periods. Stem cells are a promising therapeutic modality for patients with heart failure due to ICM or NICM. More data are required from larger blinded trials to determine which combination of cell type and delivery mode will yield the most benefit with avoidance of harm in these patient populations.
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Insuficiência Cardíaca Sistólica/terapia , Transplante de Células-Tronco , Cardiomiopatias/fisiopatologia , Cardiomiopatias/terapia , Terapia Baseada em Transplante de Células e Tecidos , Ensaios Clínicos como Assunto , Insuficiência Cardíaca Sistólica/patologia , Humanos , Células-Tronco/citologia , Células-Tronco/metabolismo , Função Ventricular EsquerdaRESUMO
OBJECTIVES: This study was conducted to evaluate the differences in the procedural variables between transradial and transfemoral access for coronary angiography, with cardiology fellows as the primary operators. METHODS: This was a retrospective study of 163 radial and 180 femoral access diagnostic cardiac catheterization procedures, and involved cardiology fellowship trainees as primary operators. RESULTS: The radial approach was associated with significantly higher fluoroscopy time (8.0 ± 6.97 min vs 4.25 ± 3.01 min; P<.001), dose area product (10775 ± 6724 µGy/m² vs 7952 ± 4236 µGy/m²; P<.001), procedure time (38.31 ± 12.25 min vs 27 ± 17.56 min; P<.001), procedure start to vascular access time (8.24 ± 6.31 min vs 5.31 ± 4.59 min; P<.001), and vascular access to procedure end time (30 ± 15.34 min vs 21.2 ± 9.57 min; P<.001). These differences persisted after adjusting for patients with bypass grafts and additional imaging (P<.001). The contrast amount was not significantly different between the two groups (P=.12). Procedure start to vascular access time improved significantly with fellowship training year in both the radial (9.57 ± 6.96 min vs 8.23 ± 6.08 min vs 5.57 ± 4.82 min) and femoral groups (6.17 ± 5.07 min vs 5.47 ± 4.75 min vs 4.01 ± 3.31 min). Fluoroscopy time showed significant difference in only the femoral access group (P=.01). Dose area product did not improve with training in either access group. CONCLUSION: Radial procedures were associated with higher radiation dose and longer procedure time. Despite decrease in total procedural time for radial cases with the level of training, total radiation dose did not decrease.
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Cateterismo Cardíaco/métodos , Cardiologia/educação , Angiografia Coronária/métodos , Educação Médica Continuada/métodos , Artéria Femoral , Humanos , Artéria Radial , Estudos RetrospectivosRESUMO
Ixmyelocel-T is an investigational patient-specific, expanded, multicellular therapy produced from a patient's own bone marrow. It is produced by selectively expanding two key types of bone marrow mononuclear cells (BM-MNCs), CD90+ mesenchymal stem cells (MSCs), and CD45+CD14+ autofluorescent, alternatively activated macrophages. Earlier clinical trials suggested that intramyocardial ixmyelocel-T might improve clinical, functional, symptomatic, and quality of life outcomes in patients with ischemic dilated cardiomyopathy (IDCM). This ongoing randomized, double-blinded, placebo-controlled phase 2b trial (ixCELL-DCM) was designed to assess the efficacy, safety, and tolerability of catheter-based transendocardial injection of ixmyelocel-T in patients with heart failure due to IDCM. Patients (N = 114) with New York Heart Association class III or IV symptomatic heart failure due to IDCM, who have left ventricular ejection fraction ≤35% and an automatic implantable cardioverter defibrillator, but are ineligible for revascularization procedures, were randomly assigned (1:1 ratio) to ixmyelocel-T or placebo (vehicle control). The primary efficacy endpoint is a composite of the total number of deaths, cardiovascular hospitalizations, or unplanned clinic visits to treat acutely decompensated heart failure during the 12 months following treatment administration. Secondary endpoints include the win ratio analysis for hierarchical occurrences of clinical events in the primary endpoint, total numbers of clinical events, left ventricular structure and function, and quality-of-life assessments. ixCELL-DCM is one of the largest cell therapy trials in heart failure patients to date and the first double-blinded, placebo-controlled study of ixmyelocel-T administered via transendocardial catheter-based injections in patients with heart failure secondary to IDCM.
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Cardiomiopatia Dilatada/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Insuficiência Cardíaca/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais , Pessoa de Meia-Idade , Qualidade de Vida , Transplante Autólogo , Resultado do Tratamento , Função Ventricular Esquerda/fisiologiaRESUMO
An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34+ stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI (N = 167), patients treated with autologous CD34+ stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 105 CD34/kg body weight), and high dose (5 × 105 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III-IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency (p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time (p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34+ cells had significant reduction in angina frequency (p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose (p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively (p = 0.08). Autologous CD34+ cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.
Assuntos
Angina Pectoris/terapia , Antígenos CD34/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco/metabolismo , Transplante Autólogo/métodos , Método Duplo-Cego , Teste de Esforço , Humanos , Miocárdio/patologia , Células-Tronco/fisiologia , Resultado do TratamentoRESUMO
OBJECTIVES: This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. BACKGROUND: IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. METHODS: RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. RESULTS: The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)]). CONCLUSIONS: Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910).
Assuntos
Angina Pectoris/cirurgia , Antígenos CD34/metabolismo , Células Progenitoras Endoteliais/transplante , Transplante de Células-Tronco/métodos , Idoso , Angina Pectoris/diagnóstico , Angina Pectoris/metabolismo , Angina Pectoris/fisiopatologia , Biomarcadores/metabolismo , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Células Progenitoras Endoteliais/metabolismo , Tolerância ao Exercício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Fisiológica , Recuperação de Função Fisiológica , Fatores de Risco , Transplante de Células-Tronco/efeitos adversos , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVES: We sought to relate left ventricular ejection fraction (EF), end-systolic volume index (ESVI) and infarct size (IS), as measured in a single randomized trial, to six-month mortality after myocardial infarction (MI) treated with thrombolysis. BACKGROUND: These three prognostic indicators have never been compared in the same study group. METHODS: Radionuclide angiographic and single-photon emission computed tomographic sestamibi measurements of IS were performed in 1,194 and 1,181 patients, respectively, of the 2,948 patients enrolled in the Collaborative Organization for RheothRx Evaluation (CORE) trial. Ejection fraction, ESVI and IS, as measured by central laboratories in these radionuclide substudies, were tested for their association with six-month mortality. RESULTS: Ejection fraction (n = 1,137; p < 0.0001), ESVI (n = 945; p = 0.055) and IS (n = 1,164; p = 0.03) were all associated with six-month mortality. Each of these measurements was significantly correlated with the other two, regardless of MI location. In an "overlap" group of 753 patients (25.5% of the population; 13 deaths) in whom all three measurements were available, EF (p = 0.001) was a stronger predictor than ESVI (p = 0.005) or IS (p = 0.01). Neither of the other two measurements added independent prognostic information. The highest risk subgroup (EF < 30%) had an 11% six-month mortality, but comprised only 95 patients (8.3%). CONCLUSIONS: Ejection fraction, ESVI and IS measurements performed one to two weeks after MI can each predict six-month mortality. Ejection fraction was superior to the other two measurements. However, this study had limited power to detect independent significance of ESVI or IS.