Paracrine-mediated rejuvenation of aged mesenchymal stem cells is associated with downregulation of the autophagy-lysosomal pathway.

Age-related differences in stem-cell potency contribute to variable outcomes in clinical stem cell trials. To help understand the effect of age on stem cell potency, bone marrow-derived mesenchymal stem cells (MSCs) were isolated from young (6 weeks) and old (18-24 months) mice. HUVEC tubule formation (TF) induced by the old and young MSCs and ELISA of conditioned media were compared to one another, and to old MSCs after 7 d in indirect co-culture with young MSCs. Old MSCs induced less TF than did young (1.56 ± 0.11 vs 2.38 ± 0.17, p = 0.0003) and released lower amounts of VEGF (p = 0.009) and IGF1 (p = 0.037). After 7 d in co-culture with young MSCs, TF by the old MSCs significantly improved (to 2.09 ± 0.18 from 1.56 ± 0.11; p = 0.013), and was no longer different compared to TF from young MSCs (2.09 ± 0.18 vs 2.38 ± 0.17; p = 0.27). RNA seq of old MSCs, young MSCs, and old MSCs following co-culture with young MSCs revealed that the age-related differences were broadly modified by co-culture, with the most significant changes associated with lysosomal pathways. These results indicate that the age-associated decreased paracrine-mediated effects of old MSCs are improved following indirect co-culture with young MSC. The observed effect is associated with broad transcriptional modification, suggesting potential targets to both assess and improve the therapeutic potency of stem cells from older patients.

Dare to dream? Cell-based therapies for heart failure after DREAM-HF: Review and roadmap for future clinical study.

Clinical trials of cell-based therapies for heart failure have resulted in significant strides forward in our understanding of the potential the failing heart has for regeneration and repair. Yet, two decades on, the need for novel cell-based therapies for heart failure has never been greater. The DREAM-HF trial, which was presented as a late-breaking trial at the American Heart Association Scientific Sessions 2021 did not meet the primary heart failure outcome, but did show a large, clinically significant reduction in major adverse cardiovascular events (MACE) in patients receiving cells, an effect that was most pronounced in patients with evidence of maladaptive inflammation. These results represent an important step forward in our understanding of how cell-based therapies can exert beneficial effects in patients with heart failure and should serve as a guide for future clinical efforts. In light of the results of DREAM-HF, this review serves to provide an understanding of the current state of cell-based therapies for heart failure, as well as to highlight major knowledge gaps and suggest guiding principles for clinical trials of cell therapy going forward. Using the knowledge gained from DREAM-HF along with the trials that preceded it, the potential for breakthrough cell-based therapies for heart failure in the coming decade is immense.

Biomaterials-based Approaches for Cardiac Regeneration.

The limited ability of cardiomyocytes to proliferate is a major cause of mortality and morbidity in cardiovascular diseases. There exist therapies for cardiac regeneration that are cell-based as well as that involve bioactive molecules. However, delivery remains one of the major challenges impeding such therapies from having clinical impact. Recent advancements in biomaterials-based approaches for cardiac regeneration have shown promise in clinical trials and animal studies in improving cardiac function, promoting angiogenesis, and reducing adverse immune response. This review will focus on current clinical studies of three contemporary biomaterials-based approaches for cardiac regeneration (extracellular vesicles, injectable hydrogels, and cardiac patches), remaining challenges and shortcomings to be overcome, and future directions for the use of biomaterials to promote cardiac regeneration.

Anomalous Origin of the Right Coronary Artery Causing Myocardial Ischemia: A Case for a Multimodality Imaging Approach.

A 46-year-old man was admitted with non-ST elevation myocardial infarction and newly diagnosed acutely decompensated heart failure. Echocardiogram demonstrated left ventricular ejection fraction of 30% with basal inferior and inferolateral akinesis. Coronary angiography showed mild diffuse coronary artery disease and an anomalous right coronary artery arising from the left coronary cusp. Further imaging was consistent with ischemia in the right coronary distribution. Etiology of ischemia was thought to be the anomalous right coronary artery, and surgical unroofing of the right coronary ostium was performed. Here, we report a multimodality imaging approach, including cardiac magnetic resonance, cardiac computed tomographic angiography, and single-photon emission computed tomography, to support the diagnosis and management of a patient with anomalous right coronary artery arising from the left coronary cusp.

Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort.

AIM: Heart failure following myocardial infarction (MI) is a potentially lethal problem with a staggering incidence. The CardiAMP Heart Failure trial represents the first attempt to personalize marrow-derived cell-based therapy to individuals with cell characteristics associated with beneficial responses in prior trials. Before the initiation of the randomized pivotal trial, an open-label "roll-in cohort" was completed to ensure the feasibility of the protocol's procedures. METHODS: Patients with chronic post-MI heart failure (NYHA class II-III) receiving stable, guideline-directed medical therapy with a left ventricular ejection fraction between 20 and 40% were eligible. Two weeks prior to treatment, a ~ 5 mL bone marrow aspiration was performed to examine "cell potency". On treatment day, a 60 mL bone marrow aspiration, bone marrow mononuclear cell (BM MNC) enrichment and transendocardial injection of 200 million BM MNC's was performed in a single, point of care encounter. Patients were then followed to assess clinical outcomes. RESULTS: The cell potency small volume bone marrow aspirate, the 60 mL bone marrow aspirate, and transendocardial injections were well tolerated in 10 patients enrolled. There were no serious adverse events related to bone marrow aspiration or cell delivery. Improvement in 6-min walk distance was observed at 6 months (+47.8 m, P = 0.01) and trended to improvement at 12 months (+46.4, P = 0.06). Similarly, trends to improved NYHA heart failure functional class, quality of life, left ventricular ejection fraction and recruitment of previously akinetic left ventricular wall segments were observed. CONCLUSION: All CardiAMP HF protocol procedures were feasible and well tolerated. Favorable functional, echo and quality of life trends suggest this approach may offer promise for patients with post MI heart failure. The randomized CardiAMP Heart Failure pivotal trial is underway to confirm the efficacy of this approach. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02438306.

Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction.

Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.

The CardiAMP Heart Failure trial: A randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: Trial rationale and study design.

BACKGROUND: Heart failure following myocardial infarction is a common, disabling, and deadly condition. Direct injection of autologous bone marrow mononuclear cells into the myocardium may result in improved functional recovery, relieve symptoms, and improve other cardiovascular outcomes. METHODS: CardiAMP-HF is a randomized, double-blind, sham-controlled, pivotal trial designed to investigate the safety and efficacy of autologous bone marrow mononuclear cells treatment for patients with medically refractory and symptomatic ischemic cardiomyopathy. The primary end point is change in 6-minute walk distance adjusted for major adverse cardiovascular events at 12 months following treatment. Particularly novel aspects of this trial include a cell potency assay to screen subjects who have bone marrow cell characteristics that suggest a favorable response to treatment, a point-of-care treatment method, a high target dose of 200 million cells, and an efficient transcatheter intramyocardial delivery method that is associated with high cell retention. CONCLUSIONS: This novel approach may lead to a new treatment for those with ischemic heart disease suffering from medically refractory heart failure.

Usefulness of a Noninvasive Device to Identify Elevated Left Ventricular Filling Pressure Using Finger Photoplethysmography During a Valsalva Maneuver.

The high rate of re-hospitalization for heart failure might be reduced by improving noninvasive techniques for identifying elevated left ventricular (LV) filling pressure. We previously showed that changes in a finger photoplethysmography (PPG) waveform during the Valsalva maneuver (VM) reflect invasively measured LV end-diastolic pressure (LVEDP). We have since developed a hand-held device that analyzes PPG while guiding the expiratory effort of a VM. Here we assessed the sensitivity and specificity of this device for identifying elevated LVEDP in patients. We tested 82 participants (28 women), aged 40 to 85 years, before a clinically indicated left heart catheterization. Each performed a VM between 18 and 25 mm Hg for 10 seconds into a pressure transducer. PPG was recorded continuously before and during the VM. LVEDP was measured during the catheterization. An equation for calculating LVEDP was derived using (1) ratio of signal amplitudes: minimum during VM to average at baseline, (2) ratio of peak-to-peak time intervals: minimum during VM to average at baseline, and (3) mean blood pressure. Calculated and measured LVEDP were compared. The range of measured LVEDP was 4 to 35 mm Hg. Calculated LVEDP correlated with measured LVEDP (p <0.0001, r = 0.56). A calculated LVEDP >20 mm Hg had a 70% sensitivity and 86% specificity for identifying measured LVEDP >20 mm Hg (area under receiver-operating characteristic curve 0.83). In conclusion, a hand-held device for assessing LV filling pressure had high specificity and good sensitivity for identifying LVEDP >20 mm Hg, a clinically meaningful threshold in heart failure.

Patients without ST elevation after return of spontaneous circulation may benefit from emergent percutaneous intervention: A systematic review and meta-analysis.

INTRODUCTION: The American Heart Association recommends that post-arrest patients with evidence of ST elevation myocardial infarction (STEMI) on electrocardiogram (ECG) be emergently taken to the catheterization lab for percutaneous coronary intervention (PCI). However, recommendations regarding the utility of emergent PCI for patients without ST elevation are less specific. This review examined the literature on the utility of PCI in post-arrest patients without ST elevation compared to patients with STEMI. METHODS: A systematic review of the English language literature was performed for all years to March 1, 2015 to examine the hypothesis that a percentage of post-cardiac arrest patients without ST elevation will benefit from emergent PCI as defined by evidence of an acute culprit coronary lesion. RESULTS: Out of 1067 articles reviewed, 11 articles were identified that allowed for analysis of data to examine our study hypothesis. These studies show that patients presenting post cardiac arrest with STEMI are thirteen times more likely to be emergently taken to the catheterization lab than patients without STEMI; OR 13.8 (95% CI 4.9-39.0). Most importantly, the cumulative data show that when taken to the catheterization lab as much as 32.2% of patients without ST elevation had an acute culprit lesion requiring intervention, compared to 71.9% of patients with STEMI; OR 0.15 (95% CI 0.06-0.34). CONCLUSION: The results of this systematic review demonstrate that nearly one third of patients who have been successfully resuscitated from cardiopulmonary arrest without ST elevation on ECG have an acute lesion that would benefit from emergent percutaneous coronary intervention.

Stem cell impregnated nanofiber stent sleeve for on-stent production and intravascular delivery of paracrine factors.

Stem cell therapies for atherosclerotic diseases are promising, but benefits remain modest with present cell delivery devices in part due to cell washout and immune attack. Many stem cell effects are believed mediated by paracrine factors (PFs) secreted by the stem cells which potentiate tissue repair via activation and enhancement of intrinsic host repair mechanisms We therefore sought to create an "intravascular paracrine factor factory" by harnessing stem cells on a stent using a nanofiber (NF) stent sleeve, and thus providing a sheltered milieu for cells to continuously produce PFs on-stent. The NF sleeve acts as a substrate on which stem cells grow, and as a semi-permeable barrier that protects cells from washout and host immune response while allowing free outward passage of PFs. NF stent sleeves were created by covering stents with electrospun poly-lactic-co-glycolic acid nanofibers and were then uniformly coated with mesenchymal stem cells (MSCs). NF sleeves blocked cell passage but did not hamper MSC attachment or proliferation, and did not alter MSC morphology or surface markers. NF sleeve MSCs continued to secrete PFs that were biologically active and successfully induced tubulogenesis in human endothelial cells. NF stent sleeves seeded with allogeneic MSCs implanted in pigs remained patent at 7 days without thrombotic occlusion or immune rejection. Our results demonstrate the feasibility of creating an intravascular PF factory using a stem cell impregnated NF stent sleeve, and pave the way for animal studies to assess the efficacy of local PF production to treat ischemic artery disease.

Fused X-ray and MR imaging guidance of intrapericardial delivery of microencapsulated human mesenchymal stem cells in immunocompetent swine.

PURPOSE: To assess intrapericardial delivery of microencapsulated, xenogeneic human mesenchymal stem cells (hMSCs) by using x-ray fused with magnetic resonance (MR) imaging (x-ray/MR imaging) guidance as a potential treatment for ischemic cardiovascular disease in an immunocompetent swine model. MATERIALS AND METHODS: All animal experiments were approved by the institutional animal care and use committee. Stem cell microencapsulation was performed by using a modified alginate-poly-l-lysine-alginate encapsulation method to include 10% (wt/vol) barium sulfate to create barium-alginate microcapsules (BaCaps) that contained hMSCs. With x-ray/MR imaging guidance, eight female pigs (approximately 25 kg) were randomized to receive either BaCaps with hMSCs, empty BaCaps, naked hMSCs, or saline by using a percutaneous subxiphoid approach and were compared with animals that received empty BaCaps (n = 1) or BaCaps with hMSCs (n = 2) by using standard fluoroscopic delivery only. MR images and C-arm computed tomographic (CT) images were acquired before injection and 1 week after delivery. Animals were sacrificed immediately or at 1 week for histopathologic validation. Cardiac function between baseline and 1 week after delivery was evaluated by using a paired Student t test. RESULTS: hMSCs remained highly viable (94.8% ± 6) 2 days after encapsulation in vitro. With x-ray/MR imaging, successful intrapericardial access and delivery were achieved in all animals. BaCaps were visible fluoroscopically and at C-arm CT immediately and 1 week after delivery. Whereas BaCaps were free floating immediately after delivery, they consolidated into a pseudoepicardial tissue patch at 1 week, with hMSCs remaining highly viable within BaCaps; naked hMSCs were poorly retained. Follow-up imaging 1 week after x-ray/MR imaging-guided intrapericardial delivery showed no evidence of pericardial adhesion and/or effusion or adverse effect on cardiac function. In contradistinction, BaCaps delivery with x-ray fluoroscopy without x-ray/MR imaging (n = 3) resulted in pericardial adhesions and poor hMSC viability after 1 week. CONCLUSION: Intrapericardial delivery of BaCaps with hMSCs leads to high cell retention and survival. With x-ray/MR imaging guidance, intrapericardial delivery can be performed safely in the absence of preexisting pericardial effusion to provide a novel route for cardiac cellular regenerative therapy.

Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial.

RATIONALE: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. OBJECTIVE: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. METHODS AND RESULTS: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (-43.7 ± 4.4%; n=95; P<0.01) and noninjected segments (-25.1 ± 7.8%; n=148; P<0.001; between-group comparison P<0.05). Conversely, segmental ejection fraction (a measure of contractile performance) improved in injected scar segments (19.9 ± 3.3-26.3 ± 3.5%; P=0.003) but not in noninjected scar segments (21.3 ± 2.6-23.5 ± 3.2%; P=0.20; between-group comparison P<0.05). Furthermore, segmental ejection fraction in injected scar segments improved to a greater degree in patients with baseline segmental ejection fraction <20% (12.1 ± 1.2-19.9 ± 2.7%; n=18; P=0.003), versus <20% (31.7 ± 3.4-35.5 ± 3.3%; n=12; P=0.33, between-group comparison P<0.0001). CONCLUSIONS: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction).

OBJECTIVES: This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. BACKGROUND: Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown. METHODS: Autologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients. RESULTS: In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI. CONCLUSIONS: Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360).

Comparison of allogeneic vs autologous bone marrow­derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

CONTEXT: Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. OBJECTIVE: To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. DESIGN, SETTING, AND PATIENTS: A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. INTERVENTION: Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. MAIN OUTCOME MEASURES: Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. RESULTS: Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. CONCLUSIONS: In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01087996.

Finger photoplethysmography during the Valsalva maneuver reflects left ventricular filling pressure.

It is often challenging to assess cardiac filling pressure clinically. An improved system for detecting or ruling out elevated cardiac filling pressure may help reduce hospitalizations for heart failure. The blood pressure response to the Valsalva maneuver reflects left heart filling pressure, but its underuse clinically may be due in part to lack of continuous blood pressure recording along with lack of standardization of expiratory effort. In this study, we tested whether Valsalva-induced changes in the pulse amplitude of finger photoplethysmography (PPG), a technology already widely available in medical settings, correlate with invasively measured left ventricular end-diastolic pressure (LVEDP). We tested 33 subjects before clinically scheduled cardiac catheterizations. A finger photoplethysmography waveform was recorded during a Valsalva effort of 20 mmHg expiratory pressure sustained for 10 s, an effort most patients can achieve. Pulse amplitude ratio (PAR) was calculated as the PPG waveform amplitude just before release of expiratory effort divided by the waveform amplitude at baseline. PAR was well correlated with LVEDP (r = 0.68; P < 0.0001). For identifying LVEDP > 15 mmHG, PAR > 0.4 was 85% sensitive [95% confidence interval (95CI): 54-97%] and 80% specific (95CI: 56-93%). In conclusion, finger PPG, a technology already ubiquitous in medical centers, may be useful for assessing clinically meaningful categories of left heart filling pressure, using simple analysis of the waveform after a Valsalva maneuver effort that most patients can achieve.

Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.

BACKGROUND: Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. METHODS: In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360. FINDINGS: Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. INTERPRETATION: We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. FUNDING: US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.

Subacute stent thrombosis owing to complete clopidogrel resistance successfully managed with prasugrel.

This report describes a case of an acute anterior myocardial infarction secondary to subacute stent thrombosis of a drug-eluting stent within the proximal segment of the left anterior descending artery (LAD) 5 days after percutaneous transluminal coronary angioplasty and stenting (PCI). The patient was initially managed with conventional dual-antiplatelet therapy (aspirin and clopidogrel) and was subsequently found to have complete absence of adenosine diphosphate (ADP) receptor P2Y12 receptor inhibition. Following additional PCI of the LAD and substitution of clopidogrel for the thienopyridine prasugrel, therapeutic platelet inhibition was achieved without recurrence of stent thrombosis.