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1.  Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients with Acute Myocardial Infarction Based on Individual Patient Data 
Circulation research  2015;116(8):1346-1360.
The ACCRUE (Meta-Analysis of Cell-based CaRdiac stUdiEs) is the first prospectively declared collaborative multinational database including individual data of patients (IPD) with ischemic heart disease treated with cell therapy.
We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI) including IPDs from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252).
Methods and Results
The primary endpoint was freedom from combined major adverse cardiac and cerebrovascular events (MACCE; including all-cause death, re-AMI, stroke, and target vessel revascularization). The secondary endpoint was freedom from hard clinical endpoints (death, re-AMI, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy endpoints included changes in end-diastolic volume (ΔEDV), end-systolic volume (ΔESV), and ejection fraction (ΔEF), analyzed with random-effects meta-analyses and analysis of covariance. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on MACCE (14.0% vs. 16.3%, hazard ratio 0.86, 95%CI: 0.63;1.18) or death (1.4% vs 2.1%) or death/re-AMI/stroke (2.9% vs 4.7%) was identified in comparison to controls. No change in ΔEF (mean difference: 0.96%, 95%CI: −0.2;2.1), ΔEDV, or ΔESV was observed compared to controls. These results were not influenced by anterior AMI location, reduced baseline EF, or the use of MRI for assessing left ventricular parameters.
This meta-analysis of IPD from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function.
PMCID: PMC4509791  PMID: 25700037
Stem cell; acute myocardial infarction; meta-analysis; heart failure; outcome
2.  Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury 
Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR = 1.27, 95% CI: (1.00, 1.61), P = 0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.
Graphical abstract
PMCID: PMC4721249  PMID: 26218563
Metals; Autism spectrum disorder; Environment; Distance; Pollution
3.  A Detailed Analysis of Bone Marrow from Patients with Ischemic Heart Disease and Left Ventricular Dysfunction: BM CD34, CD11b and Clonogenic Capacity as Biomarkers for Clinical Outcomes 
Circulation research  2014;115(10):867-874.
Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche following acute myocardial infarction (AMI).
To study the BM composition in patients with IHD and severe left ventricular dysfunction (LVD).
Methods & Results
BM from 280 patients with IHD and LVD were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% vs. 2.3-2.7% in other cohorts; p< 0.05). BM-derived endothelial colonies were significantly decreased (p< 0.05). Increased BM CD11b+ cells associated with worse left ventricular ejection fraction (LVEF) after AMI (p< 0.05). While increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% vs. +2.3%, p=0.03, for AMI patients; and +6.6% vs. -0.02%, p=0.021 for chronic IHD patients), decreased BM CD34+ percentage in chronic IHD patients correlated with decrement in LVEF after cell therapy (-2.9% vs. +0.7%, p=0.0355).
In this study we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir seven days after AMI, a negative correlation between CD11b percentage and post-infarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and/or reversal of co-morbid BM impairment.
PMCID: PMC4358751  PMID: 25136078
Myocardial infarction; blood cells; angiogenesis; bone marrow; stem and progenitor cells
4.  Bone Marrow-Derived Cell Therapy After Myocardial Infarction 
JAMA  2013;309(14):1459.
PMCID: PMC4580329  PMID: 23571574
7.  Implementation of Cardiovascular Cell Therapy Network Trials Challenges, Innovation, and Lessons Learned: Experiences of the CCTRN 
The Cardiovascular Cell Therapy Network (CCTRN) was developed by the National Heart, Lung, and Blood Institute to design and conduct clinical trials to advance the field of cardiovascular (CV) cell-based therapy. The CCTRN successfully completed three clinical trials involving approximately 300 subjects across five centers and six satellites. Although the concept of a network within clinical trials research is not new, the knowledge gained in the implementation of such large-scale trials, particularly in novel therapeutic areas such as cell therapy is not often detailed in the literature. The purpose of this communication is to summarize key factors in achieving Network goals and share the knowledge gained to promote success in future CV disease cell therapy trials and networks.
PMCID: PMC4117343  PMID: 24147517
stem cell therapy; network; cardiovascular disease; acute myocardial infarction; heart failure; TIME; LateTIME; FOCUS; Cardiovascular Cell Therapy Network
8.  A Critical Analysis of Clinical Outcomes Reported in Stem Cell Trials for Acute Myocardial Infarction: Some Thoughts for Design of Future Trials 
The purpose of stem cell therapy for myocardial infarction (MI) is to improve clinical outcomes, and detailed information on clinical outcomes is critical to appropriate planning of phase III trials. We examined data from select phase II trials using autologous bone marrow-derived stem cells (BMCs) in patients with acute MI. We extracted available definitions and outcome data, and generated standardized estimates of events to permit summary comparisons. Nine trials (1040 patients) with results for 6 months to 5 years were evaluated. Adverse outcomes varied widely, and there was a general lack of details in the definitions of these outcomes. Heart failure related hospitalizations occurred in only 16 (1.5%) and death in only 43 (4.1%) of all patients. Ischemia-related outcomes outnumbered heart failure outcomes more than 10-fold. Uniform criteria need to be developed to better define clinical outcomes of interest. Furthermore, a refocus from heart failure to ischemia-related outcomes seems appropriate.
PMCID: PMC3800160  PMID: 23793731
stem cells; acute myocardial infarction; clinical outcomes; secondary outcomes; phase II trials
9.  Phase II Clinical Research Design in Cardiology 
Circulation  2013;127(15):1630-1635.
PMCID: PMC3967793  PMID: 23588961
clinical trials; phase II; research design; stem cell; therapy
10.  Factors affecting the Turnaround Time for Manufacturing, Testing and Release of Cellular Therapy Products prepared at Multiple Sites in support of Multicenter Cardiovascular Regenerative Medicine Protocols – a Cardiovascular Cell Therapy Research Network (CCTRN) Study 
Transfusion  2012;52(10):2225-2233.
Cellular therapy studies are often conducted at multiple clinical sites in order to accrue larger patient numbers. In many cases this necessitates use of localized Good Manufacturing Practices (GMP) facilities to supply the cells. To assure consistent quality, oversight by a quality assurance group is advisable. In this study we report the findings of such a group established as part of the Cardiovascular Cell Therapy Research Network (CCTRN) studies involving use of autologous bone marrow mononuclear cells (ABMMC) to treat myocardial infarction and heart failure.
Factors affecting cell manufacturing time were studied in 269 patients enrolled on 3 CCTRN protocols using Sepax-separated ABMMC. The cells were prepared at 5 GMP cell processing facilities and delivered to local treatment sites or more distant satellite Centers.
Although the Sepax procedure takes only 90 minutes, the total time for processing was approximately seven hours. Contributing to this were incoming testing and device preparation, release testing, patient randomization and product delivery. The average out-of body-time (OBT), which was to be <12 hours, averaged 9 hours. A detailed analysis of practices at each Center revealed a variety of factors that contributed to this OBT.
We conclude that rapid cell enrichment procedures may give a false impression of the time actually required to prepare a cellular therapy product for release and administration. Institutional procedures also differ and can contribute to delays; however, in aggregate it is possible to achieve an overall manufacturing and testing time that is similar at multiple facilities.
PMCID: PMC3355200  PMID: 22320233
Cellular therapy; Regenerative medicine; Cardiovascular cell therapy; Turnaround time
11.  Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial Infarction: The TIME Randomized Trial 
While the delivery of cell therapy following ST segment myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular (LV) function has not been analyzed in a trial that randomly designated the time of delivery.
To determine 1) the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery following STEMI on recovery of global and regional LV function and 2) if timing of BMC delivery (3 versus 7 days following reperfusion) influences this effect.
Design, Setting, and Patients
Between July 17, 2008 and November 15, 2011, 120 patients were enrolled in a randomized, 2×2 factorial, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of patients with LV dysfunction (LV Ejection Fraction (LVEF) ≤45%) following successful primary percutaneous coronary intervention (PCI) of anterior STEMI.
Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1 BMC:placebo) within 12 hours of aspiration and processing administered at Day 3 or Day 7 (randomized 1:1) post-PCI.
Main Outcome Measures
Co-primary endpoints were: 1) Change in global (LVEF) and regional (wall motion) LV function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and 2) Change in LV function as affected by timing of treatment on Day 3 versus Day 7. Secondary endpoints included major adverse cardiovascular events as well as changes in LV volumes and infarct size.
Patient mean age was 56.9±10.9 years with 87.5% male. At 6 months, LVEF increased similarly in both BMC (45.2±10.6 to 48.3±13.3 %) and placebo groups (44.5±10.8 to 47.8±13.6 %). No detectable treatment effect on regional LV function was observed in either infarct or border zones. Differences between therapy groups in the change in global LV function over time when treated at Day 3 (−0.9±2.9%, 95% CI 6.6 to 4.9%, p=0.763) or Day 7 (1.1±2.9%, 95% CI −4.7 to 6.9, p=0.702) were not significant, nor were they different from each other. Also, timing of treatment had no detectable effect on recovery of regional LV function. Major adverse events were rare with no difference between groups.
Patients with STEMI, who underwent successful primary PCI and administration of intra-coronary BMCs at either 3 or 7 days following the event, had recovery of global and regional LV function similar to placebo
Trial Registration Number, NCT00684021
PMCID: PMC3652242  PMID: 23129008
12.  Cell tracking and the development of cell-based therapies: a view from the Cardiovascular Cell Therapy Research Network 
JACC. Cardiovascular imaging  2012;5(5):559-565.
Cell-based therapies are being developed for myocardial infarction (MI) and its consequences (e.g. heart failure) as well as refractory angina and critical limb ischemia. The promising results obtained in pre-clinical studies led to the translation of this strategy to clinical studies. To date, the initial results have been mixed: some studies showed benefit, while in others no benefit was observed. There is a growing consensus among the scientific community that a better understanding of the fate of transplanted cells (e.g., cell homing and viability over time) will be critical for the long term success of these strategies and that future studies should include an assessment of cell homing, engraftment and fate as an integral part of the trial design. In this review, different imaging methods and technologies will be discussed within the framework of the physiological answers that the imaging strategies can provide, with special focus on the inherent regulatory issues.
PMCID: PMC3632261  PMID: 22595165
13.  Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Ischemic Heart Failure: The FOCUS-CCTRN Trial 
Previous studies utilizing autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. The FOCUS protocol was designed to assess efficacy of a larger cell dose in an adequately well-powered phase II study.
To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular (LV) end systolic volume, or enhances maximal oxygen consumption in patients with coronary artery disease (CAD), LV dysfunction, and limiting heart failure and/or angina.
Design, Setting, and Patients
This is a 100 million cell, first-in-man randomized, double-blind, placebo-controlled trial was performed by the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) in symptomatic patients (NYHA II-III and/or CCS II-IV) receiving maximal medical therapy, with a left ventricular ejection fraction (LVEF)≤45%, perfusion defect by single-photon emission tomography (SPECT), and CAD not amenable to revascularization.
All patients underwent bone marrow aspiration, isolation of BMCs using a standardized automated system performed locally, and transendocardial injection of 100 million BMCs or placebo (2:1 BMC: placebo).
Main Outcome Measures
Three co-primary endpoints assessed at 6 months were changes in (a) LV end systolic volume (LVESV) by echocardiography, (b) maximal oxygen consumption (MVO2), and (c) reversibility on SPECT. Secondary measures included other SPECT measures, magnetic resonance imaging (MRI), echocardiography, clinical improvement, and major adverse cardiac events (MACE). Phenotypic and functional analyses of the cell product were performed by the CCTRN Biorepository lab.
Of 153 consented patients, a total of 92 (82 men; average age, 63 years) were randomized (n= 61 BMC, 31 placebo) at 5 sites between April 29, 2009 and April 18, 2011. Changes in LVESV index, (−0.9 ± 11.3 mL/m2; P = 0.733; 95% CI, −6.1 to 4.3), MVO2 (1.0 ± 2.9; P = 0.169; 95% CI, −0.42 to 2.34), percent reversible defect change, (−1.2 ± 23.3; P = 0.835; 95% CI, −12.50 to 10.12), and incidence of MACEwere not statistically significant. However, in an exploratory analysis the change in LVEF across the entire cohort by therapy group was significant (2.7 ± 5.2%; P = 0.030; 95% CI, 0.27 to 5.07).
This is the largest cell therapy trial of autologous BMCs in patients with ischemic LV dysfunction. In patients with chronic ischemic heart disease, transendocardial injection of BMCs compared to placebo did not improve LVESV, MVO2, or reversibility on SPECT.
PMCID: PMC3600947  PMID: 22447880
Chronic CAD; Ischemic Heart Failure; Chronic Angina; bone marrow mononuclear cells; cardiac performance
14.  Effect of Intracoronary Delivery of Autolologous Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction on Left-Ventricular Function: The LateTIME Randomized Trial 
Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, since a substantial number of patients may not present for early cell delivery, we investigated the efficacy of autologous BMC delivery 2–3 weeks post-MI.
To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2–3 weeks following first MI.
Design, Setting, and Patients
LateTIME is a randomized, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute - sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of 87 patients with significant LV dysfunction (LVEF ≤ 45%) following successful primary percutaneous coronary intervention (PCI).
Intracoronary infusion of 150 × 106 autologous BMCs (total nucleated cells) or placebo (2:1 BMC:placebo) was performed within 12 hours of bone marrow aspiration after local automated cell processing.
Main Outcome Measures
The primary endpoints were changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone from baseline to 6 months as measured by cardiac MRI at a core lab blinded to treatment assignment Secondary endpoints included changes in LV volumes and infarct size.
87 patients were randomized between July 2008 and February 2011: mean age = 57 ± 11 yrs, 83% male. Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible and safe. The change from baseline to six months in the BMC group, when compared to the placebo group, for LVEF (48.7 to 49.2% vs. 45.3 to 48.8%; Difference = −3.0, 95% CI −7.0 to 0.9), wall motion in the infarct zone (6.2 to 6.5 vs. 4.9 to 5.9 mm; Difference = −0.7, 95% CI −2.8 to 1.3), and wall motion in the border zone (16.0 to 16.6 mm vs. 16.1 to 19.3 mm; Difference = −2.6; 95% CI −6.0 to 0.8) were not statistically significant. There was no significant change in LV volumes and infarct volumes decreased by a similar amount in both groups at 6 months compared to baseline.
Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs compared to intracoronary placebo infusion, 2–3 weeks after PCI did not improve global or regional function at 6 months.
PMCID: PMC3600981  PMID: 22084195
Acute myocardial infarction; bone marrow mononuclear cells; LVEF; cardiac MRI
15.  Multicenter Cell Processing for Cardiovascular Regenerative Medicine Applications - The Cardiovascular Cell Therapy Research Network (CCTRN) Experience 
Cytotherapy  2010;12(5):684-691.
Background Aims
Multi-center cellular therapy clinical trials require the establishment and implementation of standardized cell processing protocols and associated quality control mechanisms. The aims here were to develop such an infrastructure in support of the Cardiovascular Cell Therapy Research Network (CCTRN) and to report on the results of processing for the first 60 patients.
Standardized cell preparations, consisting of autologous bone marrow mononuclear cells, prepared using the Sepax device were manufactured at each of the five processing facilities that supported the clinical treatment centers. Processing staff underwent centralized training that included proficiency evaluation. Quality was subsequently monitored by a central quality control program that included product evaluation by the CCTRN biorepositories.
Data from the first 60 procedures demonstrate that uniform products, that met all release criteria, could be manufactured at all five sites within 7 hours of receipt of the bone marrow. Uniformity was facilitated by use of the automated systems (the Sepax for processing and the Endosafe device for endotoxin testing), standardized procedures and centralized quality control.
Complex multicenter cell therapy and regenerative medicine protocols can, where necessary, successfully utilize local processing facilities once an effective infrastructure is in place to provide training, and quality control.
PMCID: PMC3600982  PMID: 20524773
cell therapy; regenerative medicine; multicenter trials; cardiac cell therapy; quality control; Sepax
16.  Developing Mechanistic Insights into Cardiovascular Cell Therapy: Cardiovascular Cell Therapy Research Network (CCTRN) Biorepository Core Laboratory Rationale 
American heart journal  2011;162(6):973-980.
Moderate improvements in cardiac performance have been reported in some clinical settings after delivery of bone marrow mononuclear cells to patients with cardiovascular disease (CVD). However, mechanistic insights into how these cells impact outcomes are lacking. To address this, the NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) established a Biorepository Core for extensive phenotyping and cell function studies, and storing bone marrow and peripheral blood for 10 years. Analyzing cell populations and cell function in the context of clinical parameters and clinical outcomes, after cell or placebo treatment, empower the development of novel diagnostic and prognostics. Developing such biomarkers that define the safety and efficacy of cell therapy is a major Biorepository aim.
PMCID: PMC3236502  PMID: 22137069
17.  Cell Therapy and Satellite Centers: The Cardiovascular Cell Therapy Research Network Experience 
Contemporary clinical trials  2011;32(6):841-847.
Due to the changing population in patients with myocardial infarction, recruiting patients in clinical trials continues to challenge clinical investigators. The Cardiovascular Cell Therapy Research Network (CCTRN) chose to expand the reach and power of its recruitment effort by incorporating both referral and treatment satellite centers. Eight treatment satellites were successfully identified and they screened patients over a two year period. The result of this effort was an increase in recruitment, with these treatment satellites contributing 30 percent of the patients to two of the three Network studies. The hurdles these satellite treatment centers faced and how they surmounted them provide instruction to clinical research groups eager to expand to satellite systems and to health care practitioners who are interested in taking part in multicenter clinical trials.
PMCID: PMC3202446  PMID: 21767663
satellite centers; management; referral; recruitment
18.  Oversight and Management of a Cell Therapy Clinical Trial Network: Experience and Lessons Learned 
Contemporary clinical trials  2011;32(5):614-619.
The Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was established to develop, coordinate, and conduct multiple collaborative protocols testing the effects of cell therapy on cardiovascular diseases. The Network was born into a difficult political and ethical climate created by the recent removal of a dozen drugs from the US formulary and the temporary halting of 27 gene therapy trials due to safety concerns. This article describes the Network's challenges as it initiated three protocols in a polarized cultural atmosphere at a time when oversight bodies were positioning themselves for the tightest vigilance of promising new therapies. Effective strategies involving ongoing education, open communication, and relationship building with the oversight community are discussed.
PMCID: PMC3157886  PMID: 21616173
cell therapy; clinical trial network; institutional review boards; data safety and monitoring boards
19.  Combining Censored and Uncensored Data in a U-Statistic: Design and Sample Size Implications for Cell Therapy Research 
The assumptions that anchor large clinical trials are rooted in smaller, Phase II studies. In addition to specifying the target population, intervention delivery, and patient follow-up duration, physician-scientists who design these Phase II studies must select the appropriate response variables (endpoints). However, endpoint measures can be problematic. If the endpoint assesses the change in a continuous measure over time, then the occurrence of an intervening significant clinical event (SCE), such as death, can preclude the follow-up measurement. Finally, the ideal continuous endpoint measurement may be contraindicated in a fraction of the study patients, a change that requires a less precise substitution in this subset of participants.
A score function that is based on the U-statistic can address these issues of 1) intercurrent SCE's and 2) response variable ascertainments that use different measurements of different precision. The scoring statistic is easy to apply, clinically relevant, and provides flexibility for the investigators' prospective design decisions. Sample size and power formulations for this statistic are provided as functions of clinical event rates and effect size estimates that are easy for investigators to identify and discuss. Examples are provided from current cardiovascular cell therapy research.
PMCID: PMC3154087  PMID: 21841940
U-statistic; clinical trials; score function; stem cells
20.  Rationale and Design for the Intramyocardial Injection of Autologous Bone Marrow Mononuclear Cells for Patients with Chronic Ischemic Heart Disease and Left Ventricular Dysfunction Trial (FOCUS) 
American heart journal  2010;160(2):215-223.
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 SPECT assessment.
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.
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.
PMCID: PMC2921924  PMID: 20691824
21.  Kids Identifying and Defeating Stroke (KIDS): Development and Implementation of a Multi-Ethnic Health Education Intervention to Increase Stroke Awareness Among Middle School Students and Their Parents 
Health promotion practice  2008;11(1):95-103.
The KIDS (Kids Identifying and Defeating Stroke) Program is a three-year prospective, randomized, controlled, multiethnic school-based intervention study. Program goals include increasing knowledge of stroke signs and treatment and intention to immediately call 911 among Mexican American (MA) and non-Hispanic white (NHW) middle school students and their parents. This article describes the design, implementation and interim evaluation of this theory-based intervention. Intervention students received a culturally appropriate stroke education program divided into four 50-minute classes each year during the 6th, 7th, and 8th grades. Each class session also included a homework assignment that involved the students’ parents or other adult partners. Interim-test results indicate that this educational intervention was successful in improving students’ stroke symptom and treatment knowledge and intent to call 911 upon witnessing a stroke compared with controls (p<0.001). We conclude that this school-based educational intervention to reduce delay time to hospital arrival for stroke shows early promise.
PMCID: PMC2799540  PMID: 18332150
stroke; health disparities; Mexican Americans; social cognitive theory; school-based program
22.  Development of a Network to Test Strategies in Cardiovascular Cell Delivery: The NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) 
The emerging sciences of stem cell biology and cellular plasticity have led to the development of cell-based therapies for advanced human disease. Pre-clinical studies which defined the potential of bone marrow-derived mononuclear cells to repair damaged and dysfunctional myocardium led to the rapid advancement of these strategies to the clinic. Such rapid advancement has led to controversy regarding the appropriate conduct of such studies. In the United States, the National Heart, Lung, and Blood Institute established the Cardiovascular Cell Therapy Research Network (CCTRN) to facilitate the early translation of clinical trials of cell therapy for left ventricular dysfunction. The premise upon which the CCTRN was established was that multiple clinical trial sites would interact effectively with a Data Coordinating Center to perform early phase 1 and 2 clinical trials within a highly coordinated network structure. In order to develop this network, the unmet needs of the community needed to be defined, the clinical trials identified, and the structure to perform the studies needed to be established. This manuscript highlights the challenges in the development of the CCTRN and the approaches faced to define a network to perform clinical trials in human cell therapy of cardiovascular disease.
PMCID: PMC2863075  PMID: 20445812
Network; Cell Therapy; Biorepository; Management; Multicenter
23.  A study to assess the effects of a broad-spectrum immune modulatory therapy on mortality and morbidity in patients with chronic heart failure: The ACCLAIM trial rationale and design 
Evidence has accumulated regarding the importance of inflammatory mediators in the development and progression of heart failure (HF). Although targeted anticytokine treatment strategies, specifically antitumour necrosis factor-alpha, have yielded disappointing results, this may simply reflect the redundancy of the cytokine cascade and the fact that antitumour necrosis factor-alpha therapies do not stimulate increased activity of the anti-inflammatory arm of the immune system.
Ex vivo exposure of autologous blood to controlled oxidative stress and subsequent intramuscular administration is a device-based procedure shown in experimental studies to have a broad-spectrum effect on a number of immune mediators. These studies have demonstrated that this approach downregulates inflammatory cytokines, whereas several anti-inflammatory cytokines are increased. In a feasibility study of 73 patients with moderate to severe HF, active therapy (versus placebo) had a significant benefit on both mortality and hospitalization, and was not associated with adverse hemodynamic or metabolic effects.
The Advanced Chronic heart failure CLinical Assessment of Immune Modulation therapy (ACCLAIM) trial is a multicentre, randomized, double-blind, placebo-controlled clinical trial of New York Heart Association functional class II to IV chronic HF patients with left ventricular ejection fraction of 30% or less. Enrolling approximately 2400 subjects at 177 sites, the primary end point of the study was the cumulative incidence (time to first event) of the combined end point of total mortality or hospitalization for cardiovascular causes. The study was completed in late 2005, when 701 primary end point events had occurred and all patients had been treated for six months.
If the ACCLAIM trial confirms earlier results, this approach represents a novel nonpharmacological treatment for HF that targets a pathogenic mechanism contributing to progression of this syndrome not addressed by current therapies.
PMCID: PMC2649187  PMID: 17440642
Heart failure; Immune modulation; Ventricular dysfunction
24.  Excess Stroke in Mexican Americans Compared with Non-Hispanic Whites: The Brain Attack Surveillance in Corpus Christi Project 
American journal of epidemiology  2004;160(4):376-383.
Mexican Americans are the largest subgroup of Hispanics, the largest minority population in the United States. Stroke is the leading cause of disability and third leading cause of death. The authors compared stroke incidence among Mexican Americans and non-Hispanic Whites in a population-based study. Stroke cases were ascertained in Nueces County, Texas, utilizing concomitant active and passive surveillance. Cases were validated on the basis of source documentation by board-certified neurologists masked to subjects’ ethnicity. From January 2000 to December 2002, 2,350 cerebrovascular events occurred. Of the completed strokes, 53% were in Mexican Americans. The crude cumulative incidence was 168/10,000 in Mexican Americans and 136/ 10,000 in non-Hispanic Whites. Mexican Americans had a higher cumulative incidence for ischemic stroke (ages 45–59 years: risk ratio = 2.04, 95% confidence interval: 1.55, 2.69; ages 60–74 years: risk ratio = 1.58, 95% confidence interval: 1.31, 1.91; ages ≥75 years: risk ratio = 1.12, 95% confidence interval: 0.94, 1.32). Intracerebral hemorrhage was more common in Mexican Americans (age-adjusted risk ratio = 1.63, 95% confidence interval: 1.24, 2.16). The subarachnoid hemorrhage age-adjusted risk ratio was 1.57 (95% confidence interval: 0.86, 2.89). Mexican Americans experience a substantially greater ischemic stroke and intracerebral hemorrhage incidence compared with non-Hispanic Whites. As the Mexican-American population grows and ages, measures to target this population for stroke prevention are critical.
PMCID: PMC1524675  PMID: 15286023
cerebral hemorrhage; cerebrovascular accident; ethnic groups; Hispanic Americans; ischemic attack; transient; Mexican Americans; population surveillance; subarachnoid hemorrhage; BASIC, Brain Attack Surveillance in Corpus Christi

Results 1-25 (26)