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AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Background Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marr...

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

We know that endocardial mapping reports left ventricular electrical activity (voltage) and that these data can predict outcomes in patients undergoing traditional revascularization. Because the mapping data from experimental models have also been linked with myocardial viability, we hypothesized an association between increased unipolar voltage in patients undergoing intramyocardial injections and their subsequent improvement in left ventricular performance. For this exploratory analysis, we evaluated 86 patients with left ventricular dysfunction, heart-failure symptoms, possible angina, and no revascularization options, who were undergoing endocardial mapping. Fifty-seven patients received bone marrow mononuclear cell (BMC) injections and 29 patients received cell-free injections of a placebo. The average mapping site voltage was 9.7 ± 2 mV, and sites with voltage of ≥6.9 mV were engaged by needle and injected (with BMC or placebo). For all patients, at 6 months, left ventricular ejection fraction (LVEF) improved, and after covariate adjustment this improvement was best predicted by injection-site voltage. For every 2-mV increase in baseline voltage, we detected a 1.3 increase in absolute LVEF units for all patients (P=0.038). Multiple linear regression analyses confirmed that voltage and the CD34+ count present in bone marrow (but not treatment assignment) were associated with improved LVEF (P=0.03 and P=0.014, respectively). In an exploratory analysis, higher endocardial voltage and bone marrow CD34+ levels were associated with improved left ventricular function among ischemic cardiomyopathy patients. Intramyocardial needle injections, possibly through stimulation of angiogenesis, might serve as a future therapy in patients with reduced left ventricular function and warrants investigation.

Representing the first link between pathology and a biomarker signal, biomarkers pose unique challenges in assessing their precision, accuracy and predictive values. Quality control is a key first step in assessing the utility of biomarkers. The notion of surrogacy is a continuing challenge. Established relationship building tools such as logistic regression and Cox regression have been particularly useful in understanding the strength of the biomarker-clinical endpoint relationship. Integrated discriminant improvement translates slope comparison to the incremental value of one predictive model over another. Net reclassification improvement (NCI) is an assessment of whether a new model changes the reclassification of patients from one model to a new model, demonstrating how many patients are shifted into different clinical risk categories (low, moderate, high) by using a different model. Relationships between biomarkers are readily assessed by commonly used relationship building models in biostatistics. Bayes analyses and machine learning offer real promise in this field. Finally, measure theory and big data concepts offer a firm foundation for future examination of the relationships biomarkers and both disease and clinical sequela.

Rationale: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit + cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. Objective: CONCERT-HF (Combination of Mesenchymal and c-kit + Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). Methods and Results: Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States. Conclusions: CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02501811.

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Objectives SENECA ( S t E m cell i N j EC tion in c A ncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). Background AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. Methods The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). Conclusions This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.

Rationale: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment–elevation myocardial infarction affects recovery of left ventricular (LV) function. Objective: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. Methods and Results: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment–elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%). Conclusions: In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment–elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00684021.

The Cardiovascular Cell Therapy Research Network was established by the National Institutes of Health/National Heart, Lung, and Blood Institute in 2007 to support the conduct of early phase clinical trials of cell-based therapy for cardiovascular disease. With an original focus on acute and chronic LV dysfunction, the CCTRN completed three trials of autologous bone marrow-derived cells following acute myocardial infarction and in the setting of congestive heart failure. In 2012, the CCTRN was renewed for an additional 7-year period and increased from five to seven clinical centers with the expanded charter to study a broader range of cardiovascular disease. The impact and progress of the CCTRN is reviewed.

Objective: Results from several randomized, controlled cell therapy trials suggest that the use of autologous bone marrow mononuclear cells (BMMNCs) results in only modest benefits in patients with ST-segment elevation myocardial infarction (STEMI). However, the patients in these trials had varying combinations of underlying cardiovascular risk factors (CVRFs) and comorbidities. The autologous BMMNC product administered to each patient was unique. Based on our previous findings, the purpose of this study was to identify potential associations between specific CVRFs and BMMNC subsets in patients with STEMI. Methods: This study evaluated a cohort of patients with STEMI who were enrolled in either the CCTRN TIME or LateTIME trials and underwent BMMNC or placebo treatment (N=139). Flow cytometric analysis targeting phenotypic markers (eg, CD45, CD14, CD11b, CD3, CD19, CD31, and CD34) was used to assess the frequency of BMMNC subsets at baseline. The GRACE ACS Risk Score 2.0 - 3 year death (GRS) was used to stratify patients according to cardiovascular risk (low: GRS 30%). Multivariable models were then applied to assess relationships between BMMNC subsets and CVRFs, including age, smoking, hypertension, hyperlipidemia, and sex. Results: Patients were grouped as low GRS (n=69, 49.6%), moderate GRS (n=49, 35.3%), and high GRS (n=21, 15.1%). Patients with a high GRS had significantly lower frequencies of CD45+CD31+ cells than those with a low GRS (35.6% vs 40.3%, respectively, P=0.041). In multivariable analyses, age was inversely associated with the frequencies of CD34+ (P=0.011) and CD45+CD31+ (P=0.001) cells, and smoking was associated with a decrease in CD45+CD31+ cells (P=0.022). In addition, higher frequencies of CD11b+ cells were associated with hypertension (P=0.010) and hyperlipidemia (P=0.029). In contrast, the CD11b+ cell frequency was less in females (P=0.005). Conclusions: This study identified associations between specific CVRFs and BMMNC subsets. These associations may contribute to the heterogeneity of the cell product received. Thus, differences in patients’ comorbidities should be considered when designing future autologous cell therapy trials.

Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation–myocardial infarction. Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, −21.0±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31 + BMCs ( P =0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays ( P =0.033 and P =0.032, respectively). Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation–myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation–myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00684021.

Background. Despite the fact that coronary artery disease is the leading cause of death among women, previous studies have suggested that physicians are less likely to pursue an aggressive approach to coronary artery disease in women than in men. To define this issue further, we compared the care previously received by men and women who were enrolled in a large postinfarction intervention trial. Methods. We assessed the nature and severity of anginal symptoms and the use of antianginal and anti-ischemic interventions before enrollment in the 1842 men and 389 women with left ventricular ejection fractions ≤40 percent after an acute myocardial infarction who were randomized in the Survival and Ventricular Enlargement trial. Results. Before their index infarction, women were as likely as men to have had angina and to have been treated with antianginal drugs. However, despite reports by women of symptoms consistent with greater functional disability from angina, fewer women had undergone cardiac catheterizati...

Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow–derived ALDH br cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging–based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH br cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points.