Dataset Information

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

ABSTRACT:

Background

The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide.

Trial design

The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized, phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on single-photon emission computed tomography assessment.

Results

After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow-derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures.

Conclusions

The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.

SUBMITTER: Willerson JT

PROVIDER: S-EPMC2921924 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

Willerson James T JT Perin Emerson C EC Ellis Stephen G SG Pepine Carl J CJ Henry Timothy D TD Zhao David X M DX Lai Dejian D Penn Marc S MS Byrne Barry J BJ Silva Guilherme G Gee Adrian A Traverse Jay H JH Hatzopoulos Antonis K AK Forder John R JR Martin Daniel D Kronenberg Marvin M Taylor Doris A DA Cogle Christopher R CR Baraniuk Sarah S Westbrook Lynette L Sayre Shelly L SL Vojvodic Rachel W RW Gordon David J DJ Skarlatos Sonia I SI Moyé Lemuel A LA Simari Robert D RD

American heart journal 20100801 2

<h4>Background</h4>The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide.<h4>Trial design</h4>The Cardiovascular Cell Therapy Research Network (CCTRN) ...[more]

PMID: 20691824

Similar Datasets

Project description:Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina.A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011.Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group).Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory.Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement.Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT.clinicaltrials.gov Identifier: NCT00824005.

Project description:Inducing axial vascularisation of tissue engineering constructs is a well-established method to support tissue growth in large 3-dimensional tissues. Progenitor cell chemotaxis towards axially vascularized tissues has not been well characterized. In a prospective randomized controlled study including 32 male syngeneic Lewis rats we investigated the capability of the axially vascularized constructs to attract systemically injected bone marrow mononuclear cells (BMMNCs). The underlying mechanism for cell homing was investigated focusing on the role of hypoxia and the SDF1-CXCR4-7 axis. Sixteen animals were used as donors for BMMNCs. The other animals were subjected to implantation of a tissue engineering construct in the subcutaneous groin region. These constructs were axially vascularized either via an arteriovenous loop (AVL, n = 6) or via uninterrupted flow-through vessels (non-AVL, n = 10). BMMNCs were labelled with quantum dots (Qdot® 655) and injected 12 days after surgery either via intra-arterial or intravenous routes. 2 days after cell injection, the animals were sacrificed and examined using fluorescence microscopy. The Qdot® 655 signals were detected exclusively in the liver, spleen, AVL constructs and to a minimal extent in the non-AVL constructs. A significant difference could be detected between the number of labelled cells in the AVL and non-AVL constructs with more cells detected in the AVL constructs specially in central zones (p <0.0001). The immunohistological analysis showed a significant increase in the absolute expression of HIF-1 in the AVL group in comparison to the non-AVL group. The PCR analysis confirmed a 1.4-fold increase in HIF-1 expression in AVL constructs. Although PCR analysis showed an enhanced expression of CXCR4 and CXCR7 in AVL constructs, no significant differences in SDF1 expression were detected via immunohistological or PCR analysis. At the examined time point, the AVL constructs can attract BMMNCs in a mechanism probably related to the hypoxia associated with a robust tissue formation.

Project description:The devastating effect of traumatic brain injury is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure due to cerebral edema. The treatment effect of cell-based therapies in the acute post-traumatic brain injury period has not been clinically studied although preclinical data demonstrate that bone marrow-derived mononuclear cell infusion down-regulates the inflammatory response. Our study evaluates whether pediatric traumatic brain injury patients receiving IV autologous bone marrow-derived mononuclear cells within 48 hours of injury experienced a reduction in therapeutic intensity directed toward managing elevated intracranial pressure relative to matched controls.The study was a retrospective cohort design comparing pediatric patients in a phase I clinical trial treated with IV autologous bone marrow-derived mononuclear cells (n = 10) to a control group of age- and severity-matched children (n = 19).The study setting was at Children's Memorial Hermann Hospital, an American College of Surgeons Level 1 Pediatric Trauma Center and teaching hospital for the University of Texas Health Science Center at Houston from 2000 to 2008.Study patients were 5-14 years with postresuscitation Glasgow Coma Scale scores of 5-8.The treatment group received 6 million autologous bone marrow-derived mononuclear cells/kg body weight IV within 48 hours of injury. The control group was treated in an identical fashion, per standard of care, guided by our traumatic brain injury management protocol, derived from American Association of Neurological Surgeons guidelines.The primary measure was the Pediatric Intensity Level of Therapy scale used to quantify treatment of elevated intracranial pressure. Secondary measures included the Pediatric Logistic Organ Dysfunction score and days of intracranial pressure monitoring as a surrogate for length of neurointensive care. A repeated-measure mixed model with marginal linear predictions identified a significant reduction in the Pediatric Intensity Level of Therapy score beginning at 24 hours posttreatment through week 1 (p < 0.05). This divergence was also reflected in the Pediatric Logistic Organ Dysfunction score following the first week. The duration of intracranial pressure monitoring was 8.2 ± 1.3 days in the treated group and 15.6 ± 3.5 days (p = 0.03) in the time-matched control group.IV autologous bone marrow-derived mononuclear cell therapy is associated with lower treatment intensity required to manage intracranial pressure, associated severity of organ injury, and duration of neurointensive care following severe traumatic brain injury. This may corroborate preclinical data that autologous bone marrow-derived mononuclear cell therapy attenuates the effects of inflammation in the early post-traumatic brain injury period.

Project description:ObjectiveWe tested the hypothesis that direct intramyocardial injection of bone marrow mononuclear cells in patients with non-ischemic dilated cardiomyopathy can improve left ventricular function and physical capacity.MethodsThirty non-ischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% were randomized at a 1:2 ratio into two groups, control and treated. The bone marrow mononuclear cells group received 1.06±108 bone marrow mononuclear cells through mini-thoracotomy. There was no intervention in the control group. Assessment was carried out through clinical evaluations as well as a 6-min walk test, nuclear magnectic resonance imaging and echocardiogram.ResultsThe bone marrow mononuclear cells group showed a trend toward left ventricular ejection fraction improvement, with magnectic resonance imaging - at 3 months, showing an increase from 27.80±6.86% to 30.13±9.06% (P=0.08) and returning to baseline at 9 months (28.78%, P=0.77). Magnectic resonance imaging showed no changes in left ventricular ejection fraction during follow-up of the control group (28.00±4.32%, 27.42±7.41%, and 29.57±4.50%). Echocardiogram showed left ventricular ejection fraction improved in the bone marrow mononuclear cells group at 3 months, 25.09±3.98 to 30.94±9.16 (P=0.01), and one year, 30.07±7.25% (P=0.001). The control group showed no change (26.1±4.4 vs 26.5±4.7 and 30.2±7.39%, P=0.25 and 0.10, respectively). Bone marrow mononuclear cells group showed improvement in New York Heart Association functional class, from 3.40±0.50 to 2.41±0.79 (P=0.002); patients in the control group showed no change (3.37±0.51 to 2.71±0.95; P=0.17). Six-minute walk test improved in the bone marrow mononuclear cells group (348.00±93.51m at baseline to 370.41±91.56m at 12 months, P=0.66) and there was a non-significant decline in the control group (361.25±90.78m to 330.00±123.42m after 12 months, P=0.66). Group comparisons were non-significant.ConclusionThe trend of intragroup functional and subjective improvement was not confirmed when compared to the control group. Direct intramyocardial application of bone marrow mononuclear cells in non-ischemic dilated cardiomyopathy was not associated with significant changes in left ventricular function. Differences observed within the bone marrow mononuclear cells group could be due to placebo effect or low statistical power.

Dataset Information

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

Background

Trial design

Results

Conclusions

Publications

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

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