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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...

Cell therapy trials for heart failure (HF) have shown modest improvement; however, the mechanisms underlying improvement in some patients but not others are not well understood. Although immune cells are important in the course of HF, our understanding of the immune processes in HF is limited. The objective of this study was to evaluate associations between temporal changes in peripheral blood (PB) cell subpopulations and improved outcome in patients with chronic ischemic cardiomyopathy after bone marrow-derived mononuclear cell therapy or placebo in the FOCUS-CCTRN trial. Peripheral blood was collected at days 0, 1, 30, 90, and 180 from consented participants. We used flow cytometry to compare PB populations in patients with the best (cohort 1) or worst functional outcome (cohort 2) in three primary endpoints: left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption (VO2 max). A linear mixed model was used to assess changes over time in 32 cell populations. The difference between each time point and baseline was calculated as linear contrast. Compared with cohort 2, patients who improved (cohort 1) had a higher frequency of CD45+CD19+ B cells at days 0, 1, 90, and 180. CD11B+ cells increased over baseline at day 1 in both cohorts and remained higher in cohort 2 until day 30. CD45+CD133+ progenitor cells decreased over baseline at day 30 in cohort 1. We identified specific cell subpopulations associated with improved cardiac function in patients with chronic LV dysfunction. These findings may improve patient selection and prediction of outcomes in cell therapy trials.

Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell–based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF with reduced ejection fraction studies, the joint frailty model is utilized to reflect characteristics of the high-risk patient population with important unmet therapeutic needs. In some cases, use of the joint frailty model may substantially reduce sample size requirements. In addition, using an end point that is acceptable to the Food and Drug Administration and the European Medicines Agency, such as recurrent nonfatal HF-related major adverse cardiac events, enables generation of clinically relevant pharmacoeconomic data while providing comprehensive views of the patient’s overall cardiovascular disease burden. The major goal of this review is to provide lessons learned from the ongoing DREAM-HF trial that relate to biologic plausibility and flexible clinical trial design and are potentially applicable to other development programs of innovative therapies for patients with advanced cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02032004.

Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav–short hairpin RNA (shRNA) or a control AAV9 viral vector carrying green fluorescent protein (GFP) directly into border zone cardiomyocytes via catheter-mediated subendocardial injection. Three months after injection, pig hearts treated with a high dose of AAV9-Sav-shRNA exhibited a 14.3% improvement in ejection fraction (a measure of left ventricular systolic function), evidence of cardiomyocyte division, and reduced scar sizes compared to pigs receiving AAV9-GFP. AAV9-Sav-shRNA–treated pig hearts also displayed increased capillary density and reduced cardiomyocyte ploidy. AAV9-Sav-shRNA gene therapy was well tolerated and did not induce mortality. In addition, liver and lung pathology revealed no tumor formation. Local delivery of AAV9-Sav-shRNA gene therapy to border zone cardiomyocytes in pig hearts after myocardial infarction resulted in tissue renewal and improved function and may have utility in treating heart failure.

In this study, we created a reproducible myocardial infarction (MI) model in pigs characterized by a low mortality rate and significant changes in left ventricular function. After administering an arrhythmia prevention regimen, we created a 90-min balloon-induced percutaneous MI in 42 pigs below the first diagonal branch (D1) of the left anterior descending artery. Echocardiograms were performed before and 14 days after MI induction. Pigs with a > 30% decrease in left ventricular ejection fraction (LVEF) underwent electrophysiological mapping by the NOGA system. Our mortality rate was 4.8%. The incidence of ventricular fibrillation (VF) was 28.6%; all VF events were successfully resuscitated. At day 14, echocardiography and NOGA mapping confirmed transmural scar. LVEF decreased 41% from baseline. Radial and circumferential strain significantly decreased in the LAD distal to D1, and the LV showed dyssynchrony. An anti-arrhythmia regimen decreased mortality significantly, and our model induced dramatic functional changes. The basic procedures of the model included an arrhythmia prevention protocol and myocardial infarction creation, which effectively decreased mortality and provided a robust change in left ventricular (LV) function after 14 days.

The concept that cell‐based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.

Highlights • Sudden cardiac death (SCD), especially in young athletes, should be avoided. • Current pre-sports screening is based on history/physical exam (insufficient). • ECG is an excellent test for electrically induced SCD but requires expert review. • Screening MRI is the best tool for identifying myocardiopathies/coronary anomalies. • Results of a preliminary population-based study confirm the value of screening MRI., Preventing sudden cardiac death (SCD) in athletes is a primary duty of sports cardiologists. Current recommendations for detecting high-risk cardiovascular conditions (hr-CVCs) are history and physical examination (H&P)-based. We discuss the effectiveness of H&P-based screening versus more-modern and accurate methods. In this position paper, we review current authoritative statements and suggest a novel alternative: screening MRI (s-MRI), supported by evidence from a preliminary population-based study (completed in 2018), and a prospective, controlled study in military recruits (in development). We present: 1. Literature-Based Comparisons (for diagnosing hr-CVCs): Two recent studies using traditional methods to identify hr-CVCs in >3,000 young athletes are compared with our s-MRI-based study of 5,169 adolescents. 2. Critical Review of Previous Results: The reported incidence of SCD in athletes is presently based on retrospective, observational, and incomplete studies. H&P’s screening value seems minimal for structural heart disease, versus echocardiography (which improves diagnosis for high-risk cardiomyopathies) and s-MRI (which also identifies high-risk coronary artery anomalies). Electrocardiography is valuable in screening for potentially high-risk electrophysiological anomalies. 3. Proposed Project: We propose a prospective, controlled study (2 comparable large cohorts: one historical, one prospective) to compare: (1) diagnostic accuracy and resulting mortality-prevention performance of traditional screening methods versus questionnaire/electrocardiography/s-MRI, during 2-month periods of intense, structured exercise (in military recruits, in advanced state of preparation); (2) global costs and cost/efficiency between these two methods. This study should contribute significantly toward a comprehensive understanding of the incidence and causes of exercise-related mortality (including establishing a definition of hr-CVCs) while aiming to reduce mortality.

Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term ‘stem cell therapy’ is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

Introduction: Although preclinical studies of cell delivery in models of ischemic heart failure (HF) suggest a beneficial interaction between mesenchymal stromal cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) resulting in additive therapeutic effects, no clinical trial has examined a combination of different cell types in ischemic HF. Furthermore, comparative studies of different cell products in humans are rare. CONCERT-HF (NCT02501811) is an NHLBI-sponsored, randomized, double-blind, placebo-controlled, Phase II trial of the Cardiovascular Cell Therapy Research Network (CCTRN) investigating feasibility, safety, and efficacy of MSCs and CPCs, alone and in combination, in patients with chronic ischemic HF. Objectives: To address the following questions: Is combined treatment with MSCs and CPCs feasible and safe in patients with ischemic HF? Do MSCs and CPCs, given alone or in combination, alleviate LV dysfunction, reduce scar size, improve quality of life, and/or augment functional capacity? Is either cell type more effective than the other? Is the combination of MSCs and CPCs more efficacious than MSCs alone or CPCs alone? Methods: Patients were randomized (1:1:1:1) to receive i) the combination of autologous bone marrow-derived MSCs and autologous CPCs, ii) MSCs alone, iii) CPCs alone, or iv) placebo. Target doses were 150 x 10 6 MSCs and 5 x 10 6 CPCs. All patients underwent bone marrow aspiration and right heart catheterization. Endomyocardial biopsy was performed only in the MSC + CPC and CPC alone groups; a “sham biopsy” was performed in the MSC alone and placebo groups. All patients underwent study product injection using the NOGA ® XP Mapping System and were followed for 12 months. Results: A total of 125 patients (116 M, 9 F), 62.5 ± 8.9 years old, were enrolled at 7 CCTRN centers between Nov 2016 and Oct 2018. Baseline LVEF (cardiac MRI) was 28.6 ± 6.1% with a mean scar size of 31.8 ± 10.9 g and NYHA class II (80%) or class III (15.2%). Conclusions: CONCERT-HF is the first cell therapy trial to assess a combination of different cell types and to directly compare two different cell products in patients with HF. All patients will complete follow-up by the end of June and final primary (12-month) safety and outcomes data will be available in August 2020.

Introduction: The evidence supporting the impact of electroanatomic guidance in defining the targets for transendocardial cell injections in chronic heart failure (CHF) remains inconclusive. Hypothesis: We evaluated a correlation between electroanatomic properties of the myocardium at the cell injection sites and clinical response to CD34 + cell therapy in CHF patients. Methods: We enrolled 131 consecutive patients with CHF and LVEF+ cell therapy at a single study site. All patients received bone-marrow stimulation with filgrastim for 5 days; CD34 + cells were collected by apheresis and injected transendocardialy (80x10 6 cells per patient). Target injection sites were defined by electroanatomical mapping as myocardial areas with unipolar voltage >8.3mV and local linear shortening Results: Of 131 patients 69 (53%) displayed a favorable clinical response (Group A) and 62 (47%) patients failed to respond to cell therapy (Group B). At baseline, the groups did not differ in gender (male: 89% in Group A vs. 84% in Group B, P=0.45), age (53±12 years vs. 55±11 years, P=0.25), CHF etiology (ischemic: 22% vs. 32%, P=0.17), LVEF (29±6% vs. 32±7%, P=0.06), or LVEDD (6.3±1.2 cm vs. 6.7±1.0 cm, P=0.10). Patients in Group A had lower baseline creatinine (81±20 μmol/L vs. 92±24 μmol/L in Group B, P=0.005), and lower levels of NT-proBNP (931±1078 pg/mL vs. 2716±2716, P=0.001). The number of cell injections in Groups A and B was comparable (17.3±2.6 injections vs. 17.6±3.5 injections, P=0.60). When analyzing the electroanatomical properties at cell injection sites, we found significantly higher unipolar voltage in Group A (11.2±3.7 mV vs. 9.5±2.6 mV in Group B, P=0.005). However, we found no differences in injection site local linear shortening between the groups (2.7±3.9% in Group A vs. 3.4±3.4 in group B, P=0.56). Conclusions: In CHF patients, higher unipolar voltage at the cell injection sites appears to correlate with better clinical response to transendocardial CD34 + cell therapy. Thus, cell injections guided by measurements of myocardial viability may offer an advantage over blind cell injection strategies in this patient population.

Heart failure (HF), a devastating disease and a leading cause of death worldwide, is an unmet clinical need. The Hippo pathway, an inhibitory kinase cascade, represses adult cardiomyocyte (CM) proliferation post-myocardial infarction (MI) in rodent models. Here, we investigated an Adeno Associated Virus 9 (AAV9) gene therapy that knocks down the Hippo pathway gene, Sav, in a pig model of MI after ischemic reperfusion (I/R), to closely model the human condition. Two weeks post-MI, when pigs had established left ventricular (LV) systolic dysfunction, we delivered an AAV9- Sav -shRNA or control virus by subendocardial injections to border zone (BZ) CMs. Three months post viralinjections, AAV9- Sav -shRNA injected pigs had improved LV systolic function, evidence of CM division, and reduced scar size. In addition, AAV9- Sav- shRNA treated hearts had more capillaries and reduced CM ploidy. AAV9- Sav -shRNA therapy was well tolerated without any mortality and pathologic examination of liver and lungs failed to uncover evidence for tumor formation revealing that AAV9- Sav -shRNA gene therapy is safe within the timeframe of this study. Our findings indicate that gene therapy, knocking down the Hippo pathway post-MI, in a pig model improves heart function and may have utility for humans.

Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac Safety Research Consortium sponsored a session during the Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine in September 2017. This session convened leaders in cardiovascular regenerative medicine, including participants from academia, the pharmaceutical industry, the US Food and Drug Administration, and the Cardiac Safety Research Consortium, with particular focus on treatments closest to regulatory approval. A goal of the session was to identify barriers to regulatory approval and potential pathways to overcome them. Barriers identified include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical end points required for regulatory decisions. Strategies to overcome these barriers include precompetitive development of a cell therapy registry network to enable dual-purposing of clinical data as part of pragmatic clinical trial design, development of standardized terminology for product activity and end points to facilitate this registry, use of innovative statistical methods and quality of life or functional end points to supplement outcomes such as death or heart failure hospitalization and reduce sample size, involvement of patients in determining the research agenda, and use of the Food and Drug Administration’s new Regenerative Medicine Advanced Therapy designation to facilitate early discussion with regulatory authorities when planning development pathways.

Background Cancer patients with recently placed drug-eluting stents (DESs) often require premature dual antiplatelet therapy (DAPT) discontinuation for cancer-related procedures. Optical coherence tomography (OCT) can identify risk factors for stent thrombosis such as stent malapposition, incomplete strut coverage and in-stent restenosis and may help guide discontinuation of DAPT. Methods We conducted a single-center prospective study in cancer patients with recently placed (1-12 months) DES who required premature DAPT discontinuation. Patients were evaluated with diagnostic coronary angiogram and OCT. Individuals with appropriate stent strut coverage, expansion, apposition, and absence of in-stent restenosis or intraluminal masses were considered low risk and transiently discontinued DAPT to allow optimal cancer therapy. Patients who did not meet all these criteria were considered high risk and underwent further endovascular treatment when appropriate and bridging with low-molecular weight heparin. The incidence of adverse cardiovascular events was assessed after the procedure and at 12 months. Results A total of 40 patients were included. Twenty-seven patients (68%) were considered low risk by OCT criteria and DAPT was transiently discontinued. Thirteen patients (32%) were considered high risk with one or more OCT findings: uncovered stent struts (4 patients, 10%); stent underexpansion (3 patients, 8%); malapposition (8 patients, 20%); in-stent restenosis (2 patients, 5%). The high-risk patients with uncovered stent struts and malapposition underwent additional stent dilatation. There were no cardiovascular events in the low-risk group. One myocardial infarction occurred in the high-risk group. Fourteen non-cardiac deaths were registered before 12 months due to cancer progression or cancer therapy. Conclusion OCT imaging allows identification of low-risk cancer patients with DES placed who may safely discontinue DAPT and proceed with cancer-related surgery or procedures.

Objective To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. Background Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. Methods The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II–IV) or heart failure (NYHA Class II–III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. Results Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. −9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (−21.6 + 13.9 vs. −5.5 + 23.8, P = 0.038). Conclusions A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in “no option” CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.

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.

Background Anthracycline-induced cardiomyopathy (AIC) can be irreversible with a poor prognosis, and disproportionately affects women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure treatment. Allo-MSCs are known to favorably affect fibrosis, apoptosis, and inflammation, which are key features of AIC. Methods This phase I study evaluated 37 adult cancer survivors (68% female) with left ventricular dysfunction secondary to chronic AIC. The study included a six-subject open-label, lead-in phase followed by 31 subjects randomized 1:1 to receive 1 × 108 allo-MSCs or vehicle via 20 transendocardial injections. Subjects were followed for 1 year to assess safety and feasibility (Fisher's test). Secondary efficacy measures included cardiac function/structure measured by magnetic resonance imaging (MRI), functional capacity, quality of life (MLHFQ), and biomarkers. These were assessed by ANCOVA adjusting for baseline values. Results Ninety-seven percent of subjects underwent successful study product injections, all allo-MSC-assigned subjects received the target dose. Follow-up visits were well attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-MRI compatible devices, MRI endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes including major adverse cardiac events, other significant adverse events, and days alive and out of the hospital. Ten of the 13 efficacy measures numerically favored the allo-MSC group including a lower MLHFQ score (p = .048). Conclusion In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible and MRI was successfully performed in the majority of patients with devices. This study provides crucial information for designing Phase II trials aimed at assessing efficacy of cell therapy in patients with AIC.

Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac Safety Research Consortium sponsored a session during the Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine in September 2017. This session convened leaders in cardiovascular regenerative medicine, including participants from academia, the pharmaceutical industry, the US Food and Drug Administration, and the Cardiac Safety Research Consortium, with particular focus on treatments closest to regulatory approval. A goal of the session was to identify barriers to regulatory approval and potential pathways to overcome them. Barriers identified include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical end points required for regulatory decisions. Strategies to overcome these barriers include precompetitive development of a cell therapy registry network to enable dual-purposing of clinical data as part of pragmatic clinical trial design, development of standardized terminology for product activity and end points to facilitate this registry, use of innovative statistical methods and quality of life or functional end points to supplement outcomes such as death or heart failure hospitalization and reduce sample size, involvement of patients in determining the research agenda, and use of the Food and Drug Administration's new Regenerative Medicine Advanced Therapy designation to facilitate early discussion with regulatory authorities when planning development pathways.

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.

Rationale: Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). Objective: To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. Methods and Results: We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan–Meier statistics >3 years ( P =0.025 for 150 million MPC group versus control). Conclusions: Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.

Background Optical coherence tomography (OCT) is a new intracoronary imaging modality that has excellent resolution and image quality and has been used to image neointimal coverage after stent implantation. OCT has been compared to histologic, intravascular ultrasound, and scanning electron microscopy (SEM) studies. However, OCT has not been compared with SEM for imaging stent coverage over side branches. Objective The aim of this study was to compare OCT with SEM in imaging neointimal coverage over stent struts bridging coronary side-branch ostia. Methods: Using a balloon-overstretch in-stent restenosis model, we deployed 38 everolimus-eluting stents across coronary bifurcations in nine pigs. We performed OCT immediately after stenting and 4 weeks later; SEM was performed after euthanizing the pigs. OCT images of each stent were compared to the corresponding SEM image. Results We analyzed OCT frames (n = 111) for strut-level neointimal coverage and compared them to corresponding SEM images. The concordance correlation coefficient was 0.809 (95%CI; 0.734–0.864) and 0.951 (95%CI; 0.930–0.966) for covered and uncovered struts, respectively. Conclusions In a non-atherosclerotic pig model, we showed strong agreement between OCT and SEM in imaging coverage of stent struts bridging side-branch ostia. © 2014 Wiley Periodicals, Inc.

A gentle, rapid method has been developed to introduce a polyacrylic acid (PAA) polymer coating on the surface of gadonanotubes (GNTs) which significantly increases their dispersibility in water without the need of a surfactant. As a result, the polymer, with its many carboxylic acid groups, coats the surface of the GNTs to form a new GNT-polymer hybrid material (PAA-GNT) which can be highly dispersed in water (ca. 20 mg·mL−1) at physiological pH. When dispersed in water, the new PAA-GNT material is a powerful MRI contrast agent with an extremely short water proton spin-lattice relaxation time (T1) which results in a T1-weighted relaxivity of 150 mM−1·s−1 per Gd3+ ion at 1.5 T. Furthermore, the PAA-GNTs have been used to safely label porcine bone-marrow-derived mesenchymal stem cells for magnetic resonance imaging. The labeled cells display excellent image contrast in phantom imaging experiments, and transmission electron microscopy images of the labeled cells reveal the presence of highly dispersed PAA-GNTs within the cytoplasm with 1014 Gd3+ ions per cell.

There is an ever increasing interest in developing new stem cell therapies. However, imaging and tracking stem cells in vivo after transplantation remains a serious challenge. In this work, we report new, functionalized and high-performance Gd(3+)-ion-containing ultra-short carbon nanotube (US-tube) MRI contrast agent (CA) materials which are highly-water-dispersible (ca. 35 mg ml(-1)) without the need of a surfactant. The new materials have extremely high T1-weighted relaxivities of 90 (mM s)(-1) per Gd(3+) ion at 1.5 T at room temperature and have been used to safely label porcine bone-marrow-derived mesenchymal stem cells for MR imaging. The labeled cells display excellent image contrast in phantom imaging experiments, and TEM images of the labeled cells, in general, reveal small clusters of the CA material located within the cytoplasm with 10(9) Gd(3+) ions per cell.

Clinical heart failure prevention and contemporary therapy often involve breaking the vicious cycle of global haemodynamic consequences of myocardial decay. The lack of effective regenerative therapies results in a primary focus on preventing further deterioration of cardiac performance. The cellular transplantation hypothesis has been evaluated in many different preclinical models and a handful of important clinical trials. The primary expectation that cellular transplants will be embedded into failing myocardium and fuse with existing functioning cells appears unlikely. A multitude of cellular formulas, access routes and clinical surrogate endpoints for evaluation add to the complexity of cellular therapies. Several recent large clinical trials have provided insights into both the regenerative potential and clinical improvement from non-regenerative mechanisms. Initiating endogenous repair seems to be another meaningful alternative to recover structural integrity in myocardial injury. This option may be achieved using a transcoronary sinus catheter intervention, implying the understanding of basic principles in biology. With intermittent reduction of outflow in cardiac veins (PICSO), vascular cells appear to be activated and restart a programme similar to pathways in the developing heart. Structural regeneration may be possible without requiring exogenous agents, or a combination of both approaches may become clinical reality in the next decade.

Thrombus formation after stent deployment has been linked to the use of heparin and of antithrombotic agents, such as bivalirudin, during percutaneous coronary intervention. Fluoroscopy has been used to identify stent thrombosis, typically after patients become symptomatic. We describe our use of optical coherence tomography to diagnose and evaluate intraprocedural stent thrombosis in a 68-year-old man who was given bivalirudin just before a percutaneous coronary procedure. This imaging method enabled immediate therapeutic intervention.

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.

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P =0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P =0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P =0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01774097.

Background & Aim Cardiomyopathy and cardiovascular toxicities can occur up to 20 years after anthracycline exposure with an incidence of 20%. Anthracycline cardiotoxicity (AC) is mediated by reactive oxygen species. Despite guideline directed medical therapy (GDMT) 52% of AC patients develop progressive heart failure. Mesenchymal stem cells (MSCs) have been shown to improve left ventricular structure/function by reducing fibrosis and inducing neoangiogenesis in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy. MSCs home to sites of injury and secrete VEGF in response to hypoxia, encouraging angiogenesis and increased oxygenated blood flow. MSCs create an immunosuppressive microenvironment which mitigates inflammatory response and decreases formation of scar tissue. In the AMI setting others have reported a dose related reduction in both end-systolic and end-diastolic volumes, demonstrating reverse cardiac remodeling. Methods, Results & Conclusion Methods MSCs have not been used in the AC setting. We conducted a phase 2 trial to evaluate safety and efficacy of MSCs in the AC setting. Eligibility required that patients be adults receiving maximal GDMT for heart failure and have a LVEF Conclusion Our results are consistent with prior reports in the AMI setting that the time from injury/exposure to treatment with stem cells is important. We postulate that the first patient, with exposure to anthracycline two decades prior and longstanding heart failure had scar tissue and fibrosis that was not reversible. The last two patients had more recent anthracycline exposure and both had a sustained significant improvement in EF following intravenous treatment with MSCs. No adverse events were noted. Accrual to the trial continues.

Transendocardial injections of cell-based products are being studied as a therapeutic delivery modality for patients with chronic heart failure (HF) and are generally considered to be safe. Our aim is to determine the acute effects of intramyocardial injections on left ventricular (LV) function as

This editorial refers to ‘Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial)’[†][1], by A.B. Mathiasen et al. , on page 1744. Cell therapy continues to hold promise as a future therapeutic modality for patients with heart failure. The first cells to be utilised in clinical trials in cardiovascular disease were autologous bone marrow-derived mononuclear cells (ABMMNCs).1–3 This was likely due to the fact that these cells are readily accessible and can be easily processed and given back to patients as an autologous fresh product in a short amount of time. In the absence of clinical experience, this was a good starting point. Over the next decade, important additional data were obtained with the use of ABMMNCs,4–6 and the initial positive results were tempered by negative results. Nonetheless, after much scrutiny, there seems to be a therapeutic signal, … [1]: #fn-2

Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b+ cells (P = 0.045 and P = 0.016, respectively). In addition, we found that females had lower frequencies of CD11b+ (P = 0.018) and CD45+CD14+ (P = 0.028) cells than males, age was inversely associated with the frequency of CD45+CD31+ cells (P = 0.001), smoking was associated with a decreased frequency of CD45+CD31+ cells (P = 0.013), glucose level was positively associated with the frequency of CD45+CD3+ cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45+CD3+ cells (P = 0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients’ CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.

Background Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies. Methods The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow–derived ALDH br stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI). Results The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization. Conclusions Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.

To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients.Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions.The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II-IV) or heart failure (NYHA Class II-III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo.Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V0A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in "no option" CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.