Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.

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.

Metabolically active human brown adipose tissue derived stem cells.

Brown adipose tissue (BAT) plays a key role in the evolutionarily conserved mechanisms underlying energy homeostasis in mammals. It is characterized by fat vacuoles 5-10 µm in diameter and expression of uncoupling protein one, central to the regulation of thermogenesis. In the human newborn, BAT depots are typically grouped around the vasculature and solid organs. These depots maintain body temperature during cold exposure by warming the blood before its distribution to the periphery. They also ensure an optimal temperature for biochemical reactions within solid organs. BAT had been thought to involute throughout childhood and adolescence. Recent studies, however, have confirmed the presence of active BAT in adult humans with depots residing in cervical, supraclavicular, mediastinal, paravertebral, and suprarenal regions. While human pluripotent stem cells have been differentiated into functional brown adipocytes in vitro and brown adipocyte progenitor cells have been identified in murine skeletal muscle and white adipose tissue, multipotent metabolically active BAT-derived stem cells from a single depot have not been identified in adult humans to date. Here, we demonstrate a clonogenic population of metabolically active BAT stem cells residing in adult humans that can: (a) be expanded in vitro; (b) exhibit multilineage differentiation potential; and (c) functionally differentiate into metabolically active brown adipocytes. Our study defines a new target stem cell population that can be activated to restore energy homeostasis in vivo for the treatment of obesity and related metabolic disorders.

An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure.

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.

Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study.

RATIONALE: MultiStem is an allogeneic bone marrow-derived adherent adult stem cell product that has shown efficacy in preclinical models of acute myocardial infarction (AMI). In this phase I clinical trial in patients with first ST-elevation-myocardial infarction (STEMI), we combine first-in-man delivery of MultiStem with a first-in-coronary adventitial delivery system to determine the effects of this system on left ventricular function at 4 months after AMI. OBJECTIVE: Test the effects of adventitial delivery of Multistem in the peri-infarct period in patients with first STEMI. METHODS AND RESULTS: This study was a phase I, open-label, dose-escalating registry control group study. Nineteen patients received MultiStem (20 million, n=6; 50 million, n=7; or 100 million, n=6) and 6 subjects were assigned to the registry control group. Two to 5 days after AMI, we delivered MultiStem to the adventitia of the infarct-related vessel in patients with first-time STEMI. All patients underwent primary percutaneous coronary intervention with resulting Thrombolysis In Myocardial Infarction grade 3 flow and with ejection fraction (EF) ≤45% as determined by echocardiogram or left ventriculogram within 12 hours of primary percutaneous coronary intervention. The cell product (20 million, 50 million, or 100 million) was well tolerated, and no serious adverse events were deemed related to MultiStem. There was no increase in creatine kinase-MB or troponin associated with the adventitial delivery of MultiStem. In patients with EF determined to be ≤45% by a core laboratory within 24 hours before the MultiStem injection, we observed a 0.9 (n=4), 3.9 (n=4), 13.5 (n=5), and 10.9 (n=2) percent absolute increases in EF in the registry, 20 million, 50 million, and 100 million dose groups, respectively. The increases in EF in the 50 million and 100 million groups were accompanied by 25.4 and 8.4 mL increases in left ventricular stroke volume. CONCLUSIONS: In this study, the delivery of MultiStem to the myocardium in patients with recent STEMI was well tolerated and safe. In patients who exhibited significant myocardial damage, the delivery of ≥50 million MultiStem resulted in improved EF and stroke volume 4 months later. These findings support further development of MultiStem in patients with AMI and they validate the potential of a system for delivery of adult stem cells at any time after primary percutaneous coronary intervention.

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

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.

Allogeneic stem cell transplantation for ischemic myocardial dysfunction.

PURPOSE OF REVIEW: Stem cell therapy for the treatment of cardiovascular disease is rapidly moving from bench to bedside. In the settings of acute and chronic myocardial injury, approaches to treatment have explored various cell populations, delivery methods, and times of administration. RECENT FINDINGS: Although initial studies in patients were performed with unfractionated bone marrow cells, further investigations in animal models of myocardial disease have elucidated mechanisms of benefit and opened doors to treatment strategies with stem cells of varied derivation. SUMMARY: Allogeneic stem cell populations have demonstrated therapeutic promise in ischemic heart disease, without a requirement for immunosuppressive drugs, and offer the potential to create large-scale, cryopreserved banks of cells for 'off the shelf' utility.

A double-blind, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction.

BACKGROUND: We sought to determine the safety and preliminary efficacy of transcatheter intramyocardial administration of myoblasts in patients with heart failure (HF). METHODS: MARVEL is a randomized placebo-controlled trial of image-guided, catheter-based intramyocardial injection of placebo or myoblasts (400 or 800 million) in patients with class II to IV HF and ejection fraction <35%. Primary end points were frequency of serious adverse events (safety) and changes in 6-minute walk test and Minnesota Living With HF score (efficacy). Of 330 patients intended for enrollment, 23 were randomized (MARVEL-1) before stopping the study for financial reasons. RESULTS: At 6 months, similar numbers of events occurred in each group: 8 (placebo), 7 (low dose), and 8 (high dose), without deaths. Ventricular tachycardia responsive to amiodarone was more frequent in myoblast-treated patients: 1 (placebo), 3 (low dose), and 4 (high dose). A trend toward improvement in functional capacity was noted in myoblast-treated groups (Δ6-minute walk test of -3.6 vs +95.6 vs +85.5 m [placebo vs low dose vs high dose; P = .50]) without significant changes in Minnesota Living With HF scores. CONCLUSIONS: In HF patients with chronic postinfarction cardiomyopathy, transcatheter administration of myoblasts in doses of 400 to 800 million cells is feasible and may lead to important clinical benefits. Ventricular tachycardia may be provoked by myoblast injection but appears to be a transient and treatable problem. A large-scale outcome trial of myoblast administration in HF patients with postinfarction cardiomyopathy is feasible and warranted.

Dual catheter technique for the treatment of severe coronary artery perforations.

OBJECTIVES: To evaluate the outcome of patients with coronary perforations who were treated with the dual catheter approach. BACKGROUND: Coronary artery perforation is a grave complication of percutaneous coronary intervention (PCI) with high mortality and morbidity. Treating a coronary artery perforation with two catheters through dual access enables a rapid delivery of covered stent or coils to the vessel, without losing control of the perforation site. METHODS: We retrospectively reviewed all patients who had a severe coronary perforation during a PCI in our center, and compared outcomes of patients treated with the dual versus the traditional single guiding catheter approach. RESULTS: Between April 2004 and October 2008, 13,466 PCI's were performed in Columbia University - New York Presbyterian Medical Center. There were 33 documented cases of coronary perforations during that period of time (0.245%), among these, 26 were angiographically severe (Ellis type 2 or 3 perforations). Eleven patients were treated acutely with a dual catheter technique whereas the other fifteen patients were treated using a single guiding catheter. In the dual catheter group one patient expired after emergent CABG (9.1%), and four patients underwent emergent paricardiocentesis (36.4%). In patients treated with single catheter, there were three deaths (20%), two surgical explorations (13.3%), eight emergent pericardiocenthesis (53.3%), and one event of severe anoxic brain damage (6.7%). CONCLUSION: The dual catheter technique is a relatively safe and reproducible approach to treat a PCI induced severe coronary artery perforation, and may improve outcome compared to historical series.

Cardiopoietic stem cell therapy in ischaemic heart failure: long-term clinical outcomes.

AIMS: This study aims to explore long-term clinical outcomes of cardiopoiesis-guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial. METHODS AND RESULTS: CHART-1 is a multinational, randomized, and double-blind trial conducted in 39 centres in heart failure patients (n = 315) on standard-of-care therapy. The 'active' group received cardiopoietic stem cells delivered intramyocardially using a retention-enhanced catheter. The 'control' group underwent patient-level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann-Whitney estimator 0.52, 95% confidence interval (CI) 0.45-0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow-up, patients with left ventricular end-diastolic volume of 200-370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16-0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09-0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. CONCLUSIONS: Longitudinal follow-up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long-term clinical follow-up thus offers guidance for future targeted trials.

Percutaneous cell delivery into the heart using hydrogels polymerizing in situ.

Heart disease is the leading cause of death in the US. Following an acute myocardial infarction, a fibrous, noncontractile scar develops, and results in congestive heart failure in more than 500,000 patients in the US each year. Muscle regeneration and the induction of new vascular growth to treat ischemic disorders of the heart can have significant therapeutic implications. Early studies in patients with chronic ischemic systolic left ventricular dysfunction (SLVD) using skeletal myoblasts or bone marrow-derived cells report improvement in left ventricular ejection function (LVEF) and clinical status, without notable safety issues. Nonetheless, the efficacy of cell transfer for cardiovascular disease is not established, in part due to a lack of control over cell retention, survival, and function following delivery. We studied the use of biocompatible hydrogels polymerizable in situ as a cell delivery vehicle, to improve cell retention, survival, and function following delivery into the ischemic myocardium. The study was conducted using human bone marrow-derived mesenchymal stem cells and fibrin glue, but the methods are applicable to any human stem cells (adult or embryonic) and a wide range of hydrogels. We first evaluated the utility of several commercially available percutaneous catheters for delivery of viscous cell/hydrogel suspensions. Next we characterized the polymerization kinetics of fibrin glue solutions to define the ranges of concentrations compatible with catheter delivery. We then demonstrate the in vivo effectiveness of this preparation and its ability to increase cell retention and survival in a nude rat model of myocardial infarction.

Myoblast transfer in ischemic heart failure: effects on rhythm stability.

Skeletal myoblast (SM) implantation promotes recovery of myocardial function after ischemic injury. Clinical observations suggest an association of SM implantation and ventricular arrhythmias. Support for this link has been sought in animal studies, but none employing models of congestive heart failure. In a canine model of postinfarction congestive heart failure (CHF) we compared the frequency of rhythm disturbances using ambulatory electrocardiography monitoring following skeletal myoblast or saline (SAL) implantation. In 19 mongrel dogs ischemic injury and CHF were induced by intracoronary microsphere infusions. Direct intramyocardial injection of autologous skeletal myoblasts (ASM) (2.7-8.3 x 10(8) cells) or SAL controls was administered to 11 and 8 dogs, respectively. Serial echocardiography and 24-h ambulatory electrocardiography were recorded at baseline (after CHF induction) and at 4 weeks and at 8-10 weeks after injection. Comparisons between groups of left ventricular ejection fraction (LVEF) and the frequency of ventricular arrhythmias, supraventricular arrhythmias, and measures of heart rate variability (HRV) were made at each of the three time points. LVEF increased from 41 +/- 6% to 47 +/- 2% (p < 0.03) in the ASM group, and did not change (42 +/- 6% to 40 +/- 2%, p = ns) in SAL. After injection, no differences were seen in the number of dogs demonstrating ventricular tachycardia (n = 3 vs. n = 2, p = ns) or frequent PVCs (n = 3 vs. n = 3, p = ns) in the ASM versus SAL groups, respectively. Significant changes were observed in a time-domain measure of HRV, standard deviation of normal-to-normal RR interval (in ms: 4 weeks 174 +/- 95 vs. 242 +/- 19; 8 weeks 174 +/- 78 vs. 276 +/- 78, ASM vs. SAL), but not in other time domain parameters. In this canine model of ischemic CHF, ASM implantation did not result in a significant increase in ventricular arrhythmias compared to controls animals. The potential for ASM implantation to affect time-domain parameters of HRV merits further study.

Myocyte replacement therapy: skeletal myoblasts.

Skeletal myoblasts function as precursors to adult skeletal myocytes. More so than other muscle progenitors, their capacity for de novo self-renewal and their positive functional effects in the cardiac environment have been demonstrated, even though they do not attain a cardiomyocyte phenotype. Autologous skeletal myoblasts are easily procured by established methods and can be administered into diseased myocardium safely and without technical difficulty, features that at this time set them apart from any other myogenic cell. Clinical studies in patients with chronic myocardial disease have consistently reported modest improvements in ventricular function and clinical status. Data from the Myogenesis Heart efficiency and Regeneration Trial (MYOHEART) trial are currently being evaluated. Larger, randomized, placebo-controlled studies in patients with congestive heart failure due to postinfarction systolic left ventricular dysfunction are under way, such as Myoblast Autologous Grafting in Ischemic Cardiomayopathy (MAGIC) and Multicenter Study of the Safety and Cardiovascular Effects Of Myoblasts in Congestive Heart Failure (MARVEL). The future role of skeletal myoblasts in the clinical setting will be determined by the results of randomized trials as well as by the investigation of subsequent generations of myoblasts, engineered for enhanced efficacy.

Burning questions in heart failure management: why do surgeons and interventional cardiologists talk of regenerative cell therapy?

That cardiac regeneration is remotely feasible elicits thoughts of curing one of the most debilitating of human diseases. The term stem cell brings to the surface many hopes, and concerns, among physicians and the public alike, both of which have come to expect frequent advances in medical therapeutics. The evolution of public opinion toward embryonic stem cell research is clear and positive, and, unfortunately, overshadows, even confuses, that of adult stem cells, despite their use in essentially all clinical studies of cardiovascular disease to date. Strange, perhaps, that the voices of cardiovascular specialists are not to be heard.

Independent academic Data Monitoring Committees for clinical trials in cardiovascular and cardiometabolic diseases.

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Influence of sex on in-hospital outcomes and long-term survival after contemporary percutaneous coronary intervention.

BACKGROUND: Early studies suggested that morbidity and mortality after percutaneous coronary intervention (PCI) were greater for women than men. However, in recent reports, sex-related differences in short-term outcome have decreased as outcomes among women have improved. OBJECTIVE: The aim of the study was to evaluate the effect of sex on long-term mortality among a large cohort of patients undergoing PCI in the contemporary era. METHODS: Three hospitals in New York City contributed prospectively defined data elements on 4284 consecutive patients undergoing PCI in 1998 to 1999. All-cause mortality at a mean follow-up of 3 years was the primary end point. RESULTS: Of the 4284 patients, 1331 (31%) were women. Women were significantly older than men (mean age 67 vs 62 years, P < .001) and less often white (72% vs 80%, P < .001). Hypertension (78% vs 66%, P < .001) and diabetes (36% vs 22%, P < .001) were more prevalent in women. Prior cardiac surgery (14% vs 19%, P = .001) and previous myocardial infarction (MI) (33% vs 36%, P = .08) were less common among women. Presentation with unstable angina was more frequent in women (45% vs 41%, P = .034), whereas presentation with acute MI did not differ by sex. Congestive heart failure developed more commonly among women (7.1% vs 4.1%, P < .001). The extent of coronary disease (1-, 2-, or 3-vessel disease) did not differ between women and men. Mean ejection fraction was 52% in women and 50% in men (P < .001). Stents were placed in 77% of both groups. Procedural success was 97% for both women and men. Inhospital adverse outcomes including death, post-PCI MI, emergency bypass surgery, abrupt closure, and stent thrombosis were uncommon and not different between groups. Mortality at 3 years was 10% for women and 8.9% for men (P = .197). However, using Cox proportional hazards analysis to adjust for comorbidities and possible confounders, female sex was associated with a significant independent reduction in the hazard of long-term mortality (hazard ratio 0.78, 95% CI 0.620-0.969, P = .02). CONCLUSIONS: Despite more high-risk characteristics, female sex conferred a long-term survival advantage after PCI.

Catheter-based delivery of cells to the heart.

Clinical trials have begun to assess the feasibility, safety, and efficacy of administering progenitor cells to the heart in order to repair or perhaps reverse the effects of myocardial ischemia and injury. In contrast to surgical-based injections, which are often coupled with coronary bypass surgery, catheter-based injections are less invasive and make it possible to evaluate cell products used as sole interventions. The two methods that have been tested in humans are injecting cells directly into the ventricular wall with catheter systems dedicated to that purpose and infusing cells into coronary arteries with standard balloon angioplasty catheters. The catheters described in this article have been shown in both animal and clinical studies to be effective in cell delivery and to be safe. They are well-designed and user-friendly devices, but require further investigation to identify means for optimizing cell retention and to address other limitations. Randomized, placebo-controlled trials utilizing catheters for cell implantation are under way, and others are soon to follow. The results of these studies will help to shape the direction of future investigations, both clinical and basic. The spectrum of cardiac diseases, the variety of catheters for cell delivery, and the wide array of progenitor cell types open up this young field to creative discoveries.

Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial design.

AIMS: Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy. METHODS: Patients (n = 240) with chronic HF secondary to ischaemic heart disease, reduced LVEF (<35%), and at high risk for recurrent HF-related events, despite optimal medical therapy, will be randomized 1:1 to receive 600 × 10(6) bone marrow-derived and lineage-directed autologous cardiopoietic stem cells administered via a retention-enhanced intramyocardial injection catheter or a sham procedure. The primary efficacy endpoint is a hierarchical composite of mortality, worsening HF, Minnesota Living with Heart Failure Questionnaire score, 6 min walk test, LV end-systolic volume, and LVEF at 9 months. The secondary efficacy endpoint is the time to cardiovascular death or worsening HF at 12 months. Safety endpoints include mortality, readmissions, aborted sudden deaths, and serious adverse events at 12 and 24 months. CONCLUSION: The CHART-1 clinical trial is powered to examine the therapeutic impact of lineage-directed stem cells as a strategy to achieve cardiac regeneration in HF populations. On completion, CHART-1 will offer a definitive evaluation of the efficacy and safety of cardiopoietic stem cells in the treatment of chronic ischaemic HF. TRIAL REGISTRATION: NCT01768702.

Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction.

OBJECTIVES: The purpose of this study was to evaluate the safety and feasibility of endovascular cooling during primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: In experimental models of AMI, mild systemic hypothermia has been shown to reduce metabolic demand and limit infarct size. METHODS: In a multi-center study, 42 patients with AMI (<6 h from symptom onset) were randomized to primary PCI with or without endovascular cooling (target core temperature 33 degrees C). Cooling was maintained for 3 h after reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to reduce the shivering threshold. The primary end point was major adverse cardiac events at 30 days. Infarct size at 30 days was measured using (99m)Tc-sestamibi SPECT imaging. RESULTS: Endovascular cooling was performed successfully in 20 patients (95%). All achieved a core temperature below 34 degrees C (mean target temperature 33.2 +/- 0.9 degrees C). The mean temperature at reperfusion was 34.7 +/- 0.9 degrees C. Cooling was well tolerated, with no hemodynamic instability or increase in arrhythmia. Nine patients experienced mild episodic shivering. Major adverse cardiac events occurred in 0% vs. 10% (p = NS) of treated versus control patients. The median infarct size was non-significantly smaller in patients who received cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). CONCLUSIONS: Endovascular cooling can be performed safely as an adjunct to primary PCI for AMI. Further clinical trials are required to determine whether induction of mild systemic hypothermia with endovascular cooling will limit infarct size in patients undergoing reperfusion therapy.