Transendocardial Injection Research Articles

A meta-analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease.

The electrophysiologic impact of cell-based therapy on the injured myocardium remains highly controversial. We aimed to perform a meta-analysis of studies comparing arrhythmia burden following transendocardial stem cell therapy vs placebo in patients with chronic ischemic heart disease (CIHD). PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. No restriction of stem cell type was specified. The outcomes included sustained supraventricular or ventricular arrhythmias (VAs), sudden cardiac death (SCD), and resuscitated sudden cardiac arrest (SCA). Effect sizes were reported as odds ratio (OR) and 95% CI. Poisson regression was used to account for zero-events data. Twelve randomized trials that included 736 patients (384 in the cell therapy group and 352 in the placebo group) were analyzed. Six different cell types were used. Follow-up ranged from 6 to 12 months. There was a significant decrease in risk of SCD in the cell therapy group, (FE OR, 0.19 [0.04, 0.93]; P = .04). In subgroup analysis, there was a significantly lower risk of SCD or resuscitated SCA in the cell therapy group limited to studies that did not use skeletal myoblasts, (FE OR, 0.23 [0.06, 0.83]; P = .03). There was no significant difference in the incidence of sustained VA between groups (FE OR, 0.91 [0.47, 1.77]; P = .8), even after stratifying by cell type. There was no difference in supraventricular arrhythmias between groups. Nonskeletal myoblast transendocardial cell therapy was associated with a significantly lower risk of SCD or resuscitated SCA compared to control, with no proarrhythmic effects.

First-in-Man Study of a Cardiac Extracellular Matrix Hydrogel in Early and Late Myocardial Infarction Patients

This study evaluated the safety and feasibility of transendocardial injections of VentriGel, a cardiac extracellular matrix hydrogel, in early and late post-myocardial infarction (MI) patients with left ventricular (LV) dysfunction. VentriGel was delivered in 15 patients with moderate LV dysfunction (25%≤ LV ejection fraction≤ 45%) who were between 60days to 3 years post-MI and were revascularized by percutaneous coronary intervention. The primary endpoints were incidence of adverse events and abnormal clinical laboratory results. This first-in-man study established the safety and feasibility of delivering VentriGel in post-MI patients, thus warranting furtherevaluation in larger, randomized clinical trials.

Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair.

Although rare cardiomyogenesis is reported in the adult mammalian heart, whether this results from differentiation or proliferation of cardiomyogenic cells remains controversial. The tumor suppressor genes RB1 (retinoblastoma) and CDKN2a (cyclin-dependent kinase inhibitor 2a) are critical cell-cycle regulators, but their roles in human cardiomyogenesis remains unclear. We hypothesized that developmental activation of RB1 and CDKN2a cooperatively cause permanent cell-cycle withdrawal of human cardiac precursors (CPCs) driving terminal differentiation into mature cardiomyocytes, and that dual inactivation of these tumor suppressor genes promotes myocyte cell-cycle reentry. Directed differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes revealed that RB1 and CDKN2a are upregulated at the onset of cardiac precursor specification, simultaneously with GATA4 (GATA-binding protein 4) homeobox genes PBX1 (pre-B-cell leukemia transcription factor 1) and MEIS1 (myeloid ecotropic viral integration site 1 homolog), and remain so until terminal cardiomyocyte differentiation. In both GATA4+ hPSC cardiac precursors and postmitotic hPSC-cardiomyocytes, RB1 is hyperphosphorylated and inactivated. Transient, stage-specific, depletion of RB1 during hPSC differentiation enhances cardiomyogenesis at the cardiac precursors stage, but not in terminally differentiated hPSC-cardiomyocytes, by transiently upregulating GATA4 expression through a cell-cycle regulatory pathway involving CDKN2a. Importantly, cytokinesis in postmitotic hPSC-cardiomyocytes can be induced with transient, dual RB1, and CDKN2a silencing. The relevance of this pathway in vivo was suggested by findings in a porcine model of cardiac cell therapy post-MI, whereby dual RB1 and CDKN2a inactivation in adult GATA4+ cells correlates with the degree of scar size reduction and endogenous cardiomyocyte mitosis, particularly in response to combined transendocardial injection of adult human hMSCs (bone marrow-derived mesenchymal stromal cells) and cKit+ cardiac cells. Together these findings reveal an important and coordinated role for RB1 and CDKN2a in regulating cell-cycle progression and differentiation during human cardiomyogenesis. Moreover, transient, dual inactivation of RB1 and CDKN2a in endogenous adult GATA4+ cells and cardiomyocytes mediates, at least in part, the beneficial effects of cell-based therapy in a post-MI large mammalian model, a finding with potential clinical implications.

INJECTION INDUCED MYOCARDIAL STUNNING: ACUTE DETERIORATION OF LEFT VENTRICULAR EJECTION FRACTION FOLLOWING TRANSENDOCARDIAL INJECTIONS

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

Abstract 16707: Human Embryonic Stem Cell-Derived Cardiomyocytes Are Safe and Improve Infarct Size and Cardiac Function in a Porcine Model of Myocardial Infarction

Introduction: Stem cell therapy is an emerging means of stimulating cardiac repair after myocardial infarction (MI). Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are a novel therapeutic option, with the potential for cell derived remuscularization. This study assessed the safety and efficacy of these cells, is the first to test these cells in a porcine model of MI, and used electrophysiologic (EPS) testing to evaluate potential arrhythmogenicity. Methods: Yucatan swine underwent a left anterior descending coronary artery ischemia/reperfusion protocol to form an MI. Four weeks later, either placebo (n=3) or 3 x 10 8 hESC-CMs were delivered via transendocardial stem cell injection (TESI) (n=4). All animals received immunosuppression for 2 weeks following TESI. Three uninfarcted animals received cells. Cardiac function and LV chamber volumes were measured using pressure volume catheterization and cardiac MRI at 4, 8 and 12 weeks post-TESI. Inducibility of ventricular tachycardia (VT) was tested at 4 and 12 weeks post-TESI by programmed ventricular stimulation via a catheter in the RV apex. Histology of heart tissue and organs was evaluated. Results: Twelve weeks post-TESI, scar size (scar mass as a % of total LV mass) was reduced in the cell treated group by -2.33±0.03% (p=0.034), a 12.69±1.87% reduction from pre-TESI. Scar size remained constant in the placebo group. The rise in end diastolic volume at 12 weeks in the placebo group (15.6±7.35 mL; p=0.032) was attenuated in the cell treated group (10.39±6.36mL; p=0.17). By 12 weeks post-TESI, Ees (slope of ESPVR) increased by 0.51±0.15 mmHg/mL (p=0.045) and in the cell treated group but was unchanged in placebo (-0.09±0.85 mmHg/mL; p= 0.92). Following TESI, only 1 animal from each group had inducible VT. No animals had spontaneous VT as measured by an implantable loop recorder. Cardiac function and structure of uninfarcted animals did not change over the study, and none of these animals had inducible VT. Histology did not reveal ectopic tissue formation or signs of rejection. Conclusion: TESI of hESC in a porcine MI model is safe, does not increase the risk of either spontaneous or inducible arrhythmias compared to placebo, reduces scar size and remodeling and improves cardiac contractility as measured by Ees. Translation to clinical studies is warranted.

Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial.

The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina. Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS II-IV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (≥ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment. The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period. Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia.

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

BackgroundIschemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done.Methods and ResultsWe conducted a subanalysis of 3 single‐center, randomized, and blinded clinical trials: (1) TAC‐HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON‐DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1‐year cardiac structure and function and quality‐of‐life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within‐group, P=0.002) compared to ICM (1.5%; within‐group, P=0.14; between‐group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (−0.2 mL; P=0.73; between‐group, P=0.02). End‐diastolic volume improved only in ICM (10.6 mL; P=0.04) and end‐systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (−0.04; P=0.0002). End‐diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (−4.1 g; P=0.34; between‐group, P=0.007). The 6‐minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between‐group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between‐group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (−19.5; P=0.002) and ICM (−6.4; P=0.03; δ between‐group difference P=0.042) patients.ConclusionsMesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: TAC‐HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON‐DCM: NCT01392625.

Cell-Based Therapy in Cardiac Regeneration: An Overview.

Although pioneering preclinical research on the use of cell therapy for cardiac regeneration was conducted in the last quarter of the 20th century,1,2 a preponderance of advances have occurred in the 21st century, making this a relatively young field. In the first important clinical trial of cardiac cell therapy, begun in 2001, Menasche et al3 implanted autologous skeletal myoblasts into postinfarct scar at the time of coronary artery bypass surgery. Although the transplanted cells remained viable and exhibited contraction, they formed the nidus for serious ventricular tachyarrhythmias, which led to premature discontinuation of the trial. Despite this outcome, the trial energized the field, accelerating both preclinical and clinical research, albeit not with skeletal myoblasts. The extensive progress in cardiac regeneration is reviewed in this Compendium, and as occurs frequently in science, important observations have led to more questions and challenges (Table). View this table: Table. Important Challenges to Cell Therapy for Cardiac Regeneration Many cell types have been evaluated as candidates for cardiac regeneration. Among the earliest clinical trials, Zeiher’s group infused autologous bone marrow-derived progenitor cells into the coronary arteries of patients with acute,4 as well as healed myocardial infarction (MI)5 and reported improvements in left ventricular (LV) function. However, these results have not been fully confirmed by later studies, as pointed out in the review in the Compendium by Banarjee, Bolli, and Hare.6 Pittenger et al7 were among the first to direct attention to bone marrow-derived (stromal) mesenchymal stem cells (MSCs), emphasizing that these cells proliferated extensively in culture and suggesting that they could be attractive candidates for transplantation. In 2004, Chen et al8 reported that intracoronary infusion of autologous bone marrow-derived MSCs improved cardiac function. Zimmet and Hare pointed out that MSCs lack histocompatibility type II markers and elude rejection by …

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial

ObjectivesSENECA (StEm cell iNjECtion in cAncer 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). BackgroundAIC 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. MethodsThe 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). ConclusionsThis 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.

In this Issue

HomeCirculation ResearchVol. 121, No. 11In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published10 Nov 2017https://doi.org/10.1161/RES.0000000000000186Circulation Research. 2017;121:1205P2Y2R Prompts Cardiac Progenitor Cell Activation (p 1224)Khalafalla et al rejuvenate cardiac progenitor cells via nucleotide receptor signaling.Download figureDownload PowerPointThe use of autologous cardiac progenitor cells (CPCs) for repairing failing hearts has shown promising results in animal models, but trials in patients with heart failure have provided modest, if any, clinical benefits. One reason for the limited efficacy of CPCs may be that CPCs from patients carry genetic predispositions for heart failure, or have reduced regenerative capacity because of patient’s age or other characteristics. Boosting the potency of autologous CPCs may, therefore, improve their clinical performance. Regeneration in a variety of tissues has been shown to be promoted by the nucleotide receptor P2Y2R, which is activated by extracellular UTP. Now, Khalafalla and colleagues have discovered that P2Y2R is more abundantly expressed in healthy, fast-growing human CPCs than in slow-growing, more senescent cells. Furthermore, UTP treatment of human CPCs increased their regenerative potency (proliferation and migration rates) as did overexpression of P2Y2R. Knockdown of the receptor had the opposite effect. The team went on to show that CPC activation via UTP and P2Y2R was dependent on the downstream signaling factor YAP (Yes-associated protein). Together, these results indicate that rejuvenating CPCs by activating the UTP–P2Y2R–YAP pathway may improve outcomes of CPC therapy.CBSCs Preserve Structure and Function After MI (p 1263)Sharp et al bring cortical bone stem cell therapy one step closer to the clinic.Download figureDownload PowerPointA variety of cell types have been tested in animals and patients for their potential to promote the regeneration of injured and failing hearts. Mesenchymal stem cells (MSCs) and cardiac-derived progenitor cells (CDCs), for example, are among the most commonly tested cells, but while these cells have given encouraging results in animals, clinical benefits in patients remain uncertain. Stem cells derived from the cortical region—the dense outer layer— of bone (CBSCs) have recently been shown to be more effective than CDCs at improving heart function and reducing scar size after myocardial infarction in mice. Now, Sharp and colleagues have tested these cells in a larger animal model, more comparable to human patients. After undergoing induced myocardial infarctions, a group of pigs was given transendocardial injections of allogenic CBSCs, while another group was given control injections. After 3 months, the hearts of the CBSC-treated pigs exhibited smaller infarct scars, less ventricular dilation, and better preservation of function than control pigs. Although the study did not compare CBSCs to other types of stem cells, the results warrant further investigations of CBSCs as a potential cell therapy option.Cell Dosing in Ischemic Cardiomyopathy (p 1279)Stem cell dose is critical to cell therapy outcomes, say Florea et al.Download figureDownload PowerPointMany preclinical studies and clinical trials of cell therapies for heart disease have focused on identifying the best cell type to use, but few have focused on determining the optimal dose. Even the studies that have investigated cell dosage have given complicated and seemingly contradictory results. Given the importance of resolving questions of dosage, Florea and colleagues tested the safety and efficacy of 2 different doses of human allogenic mesenchymal stem cells (hMSCs) in 30 patients with chronic ischemic left ventricle dysfunction following myocardial infarction. Fifteen of the patients were given transendocardial injections of 20-million hMSCs, while the other 15 were dosed with 100-million cells. All patients were then followed for 12 months during which time none experienced serious adverse events. While the size of the infarct scars and the presence of systemic inflammation was shown to decrease similarly in both treatment groups, only patients in the 100-million cell group experienced improvements in left ventricle function. The results show that cell dosage is an important determinant of the clinical outcome of cell therapies and highlight the need for further trials aimed at evaluating optimal dosage. Previous Back to top Next FiguresReferencesRelatedDetails November 10, 2017Vol 121, Issue 11 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000186 Originally publishedNovember 10, 2017 PDF download Advertisement

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

BackgroundThe combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). ObjectivesThis study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. MethodsGöttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. ResultsBoth ACCT and allo-MSCs reduced scar size by −11.1 ± 4.8% (p = 0.012) and −9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. ConclusionsACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

Ischemic vs. Non-Ischemic Dilated Cardiomyopathy: a Comparative Study in Stem Cell Therapy Efficacy

Background: Ischemic (ICM) versus dilated cardiomyopathy (DCM) have different pathogenesis and outcomes with standard medical therapy. Mesenchymal stem cell (MSC) therapy has produced improvements in both diseases. However, whether the efficacy of MSCs between ICM and DCM subjects is comparable, remains undetermined. Hypothesis: Subjects with DCM respond better than those with ICM. Methods: We analysed the effects of transendocardial MSC injections in patients with ICM vs. DCM from three single-institution, randomized, double-blinded, clinical trials: TAC-HFT, POSEIDON and POSEIDON-DCM. Cardiac structure, function and subject quality of life data were compared between ICM and DCM groups at baseline and one year follow-up. Results: Ejection fraction improved in DCM 7% (2.9, 11.0, p=0.002) vs. ICM 1.5% (-0.2, 3.2, p=0.08) subjects with a significant difference between groups (p=0.005). Similarly, stroke-volume increased in DCM 10.59mL (0.2, 21, p=0.046) vs. ICM -0.16mL (-4.6, 4.3, p=0.94) subjects with a significant difference between groups (p=0.02). End-diastolic volume improved only in ICM subjects, -10.68mL (-21, -0.1, p=0.047), and end-systolic volume improved only in DCM subjects, -17.8mL (-54.5, 17.0, p=0.049). Sphericity index only decreased in ICM, -0.04 (-0.06, -0.02, p=0.0002), subjects. End-diastolic mass increased in ICM, 3.57g (-3.1, 28, p=0.004), vs. DCM subjects, -4.1g (-15, 7, p=0.45), with a significant difference between groups (p=0.007). Six-minute walk test improved in DCM, 34m (18, 53, p=0.009), and ICM, 30m (-16, 89, p=0.0007), subjects with a difference between groups (p=0.03) favoring ICM subjects. NYHA class improved in both DCM (p=0.005) and ICM (p=0.02) subjects (between group p=0.20). Similarly, the Minnesota Heart Failure Questionnaire improved in DCM, -19 (-31, -7.1, p=0.003), and ICM, -9.3 (-16, -2.7, p=0.007), subjects (between group difference p=0.12). Conclusion: MSC therapy exerts distinct effects in ICM vs DCM. It improves functionality in DCM, cardiac remodelling in ICM, and enhances quality of life parameters in both disease processes.

Paracrine-Mediated Systemic Anti-Inflammatory Activity of Intravenously Administered Mesenchymal Stem Cells: A Transformative Strategy for Cardiac Stem Cell Therapeutics.

Stem cell therapy as a treatment option for acute myocardial infarction or heart failure caused by ischemic or nonischemic cardiomyopathy has focused on direct cardiac delivery of stem cells to facilitate cardiac engraftment. Once engrafted, it was believed that these cells would either transdifferentiate into new functioning myocytes or stimulate the expansion of resident myocardial stem cells. However, a sea change in thinking about cell therapy in cardiovascular disease has occurred as mounting evidence indicates that (1) inflammation is a major mechanism contributing to the progressive myocardial dysfunction seen in patients post-acute myocardial infarction and in patients with cardiomyopathy, and (2) systemic paracrine-mediated anti-inflammatory effects of stem cells can drive beneficial cardiac effects in these diseases. These concepts lead to a potentially transformative strategy that intravenous delivery of stem cells, through systemic anti-inflammatory mechanisms, improves myocardial function and thereby obviates the need for invasive methods of stem cell delivery. Until recently, the prevailing view of the mechanism responsible for any potential benefit of stem cells in patients with acute myocardial infarction (AMI) or with heart failure (HF) caused by ischemic or nonischemic cardiomyopathy (ICM/NICM) was that benefit derived from local effects—once engrafted in damaged myocardium, the stem cells either transdifferentiate into functional myocardium, stimulate resident myocardial stem cells to expand, and repopulate the heart with functioning myocytes or secrete substances leading to myocardial healing. This mechanistic perspective implied that the greater the number of engrafted cells in the myocardium, the greater the cardiac benefit. Because few intravenously administered stem cells engraft in injured myocardium, invasive strategies providing direct delivery of stem cells to the heart were uniformly adopted. This necessarily involved either catheter-based delivery (intracoronary or transendocardial injection) or surgical delivery (direct intramyocardial injection). A transformative concept relating to stem cell treatment of patients with AMI or ICM/NICM has recently …

Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction.

Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early-stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients. To determine whether post-MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model. Female Göttingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia-reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n=9; 2×107 cells total) or placebo (vehicle; n=9) through NOGA-guided transendocardial injections. 5-ethynyl-2'deoxyuridine (EdU)-a thymidine analog-containing minipumps were inserted at the time of MI induction. At 72 hours (n=8), initial injury and cell retention were assessed. At 3 months post-MI, cardiac structure and function were evaluated by serial echocardiography and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72 hours post-MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC-treated hearts had significantly reduced scar size, smaller myocytes, and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular volumes and ejection fraction were significantly more preserved in CBSC-treated hearts, and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU+ cardiac myocytes was increased in CBSC- versus vehicle- treated animals. CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves left ventricular functional reserve. These effects reduce those processes that can lead to heart failure with reduced ejection fraction.

Abstract 35: Transendocardial Mesenchymal Stem Cell Injection Demonstrates Reverse Remodeling Effects of Global LV Volumes and Enhanced Lateral Papillary Muscle Shortening

Rationale: Secondary mitral regurgitation (MR) carries a poor prognosis despite improvements in surgical and transcatheter interventions. Mesenchymal stem cell (MSC) therapy for heart disease reduces infarct size and left ventricle (LV) dilatation, reverses remodeling, and improves regional contractility and functional capacity. However, it is unknown if the benefits of MSC therapy on LV structure and function apply to lateral papillary muscle shortening, an important predictor of secondary MR severity. Hypothesis: Test the hypothesis that administration of MSCs promotes interpapillary muscle distance (IPMD) shortening. Methods/Results: This retrospective analysis draws on results from autologous or allogeneic MSC injection therapies in a Göttingen swine model of chronic ischemic cardiomyopathy (ICM). MRI was used to measure end-diastolic volume (EDV), end-systolic volume (ESV), diastolic/systolic IPMD, and IPMD shortening. NOGA mapping and angiographic tracings of left ventriculography allowed for assessment of the effect of injection localized to papillary muscles (defined as injection within cardiac segments 4, 6, 10 and 12 in the 16-segment model). Three months after stem cell injection, EDV increased in both placebo- (12.2±3.6 mL; p=0.002) and MSC- (10.2±2.6 mL; p=0.03) treated swine. ESV increased only in placebo- (7.1±2.2 mL; p=0.003) but not MSC- treated swine. Systolic IPMD was maintained with MSC therapy (1.20±0.74 mm; p=0.33) but increased in placebo (1.83±0.60 mm; p=0.01). Systolic IPMD was preserved whether MSC injection was localized to papillary muscle (0.53±0.49 mm; p=0.44) or not (0.22±0.40 mm; p=0.24). Notably, IPMD shortening was significantly greater in MSC- (8.1±5.6%; p=0.02) but not placebo-injected (4.7±5.0%; p=0.69) swine. There were no between group differences in IPMD shortening (p=0.08). Conclusion: This study is the first to show that transendocardial MSC injections significantly enhanced IPMD shortening and lateral interpapillary muscle contraction in a model of chronic ICM. This effect was independent of injection site.

Left ventricular perforation in a patient with a left ventricular aneurysm during NOGA® catheter mapping

Endocardial mapping of the left ventricle (LV) using the NOGA® XP Cardiac Navigation System can identify chronically ischemic and viable myocardium in patients with coronary artery disease by generating electromechanical maps. These maps are very useful when targeting myocardial tissue for injection of stem cells. We present the case of a woman who developed a perforation at the site of an LV aneurysm during NOGA mapping prior to the transendocardial injection of stem cells, as part of a multicenter clinical trial. The presence of an LV aneurysm is currently not a contraindication (or caution) to the use the NOGA mapping catheter. As the field of stem cell therapy evolves and the use of this technique increases, operators must be aware that the presence of an LV aneurysm may increase the risk of perforation during a NOGA mapping procedure.

Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials.

Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery. We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF). We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, -15.9 to -3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement. MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies.

Route TESI

Imagine driving to Santa Monica, CA, from Chicago, IL. How can one determine the most efficient route to get to the destination? Is it the shortest distance? The most highways? The least construction routes? The most scenic routes? All the parameters need to be taken into account when evaluating the trajectory toward the destination. Article, see p 1139 In this issue of Circulation Research , Kanelidis et al1 investigated the impact of cell delivery route for mesenchymal stem cells (MSC) to reach their destination, that is, the heart. Using a meta-analysis approach, they first confirmed that MSC therapy is indeed effective in improving left ventricular ejection fraction and reducing infarct size after myocardial infarction (MI) in rodents, swine, and human studies. Next, to determine which route is the most efficient (in this case, for achieving therapeutic effect), Kanelidis et al1 conducted a meta-analysis focusing on the impact of the delivery route on the therapeutic outcomes in swine and human studies. They found that transendocardial stem cell injection (TESI) was the most efficient in improving left ventricular ejection fraction and reducing the infarct size after acute MI in pigs and humans and chronic MI in pigs. The study has several important implications. First, it provides strong evidence that cardiac MSC therapy can improve cardiac function and can also reduce the infarct size after an MI throughout the various species examined, including humans. Meanwhile, it is very interesting to find that the more advanced the species …

Effects of Transendocardial Stem Cell Injection on Ventricular Proarrhythmia in Patients with Ischemic Cardiomyopathy: Results from the POSEIDON and TAC-HFT Trials

Transendocardial stem cell injection in patients with ischemic cardiomyopathy (ICM) improves left ventricular function and structure but has ill‐defined effects on ventricular arrhythmias. We hypothesized that mesenchymal stem cell (MSC) implantation is not proarrhythmic. Post hoc analyses were performed on ambulatory ECGs collected from the POSEIDON and TAC‐HFT trials. Eighty‐eight subjects (mean age 61 ± 10 years) with ICM (mean EF 32.2% ± 9.8%) received treatment with MSC (n = 48), Placebo (n = 21), or bone marrow mononuclear cells (BMC) (n = 19). Heart rate variability (HRV) and ventricular ectopy (VE) were evaluated over 12 months. VE did not change in any group following MSC implantation. However, in patients with ≥ 1 VE run (defined as ≥ 3 consecutive premature ventricular complexes in 24 hours) at baseline, there was a decrease in VE runs at 12 months in the MSC group (p = .01), but not in the placebo group (p = .07; intergroup comparison: p = .18). In a subset of the MSC group, HRV measures of standard deviation of normal intervals was 75 ± 30 msec at baseline and increased to 87 ± 32 msec (p =.02) at 12 months, and root mean square of intervals between successive complexes was 36 ± 30 msec and increased to 58.2 ± 50 msec (p = .01) at 12 months. In patients receiving MSCs, there was no evidence for ventricular proarrhythmia, manifested by sustained or nonsustained ventricular ectopy or worsened HRV. Signals of improvement in ventricular arrhythmias and HRV in the MSC group suggest a need for further studies of the antiarrhythmic potential of MSCs. Stem Cells Translational Medicine 2017;6:1366–1372

In This Issue

HomeCirculation ResearchVol. 120, No. 4In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published17 Feb 2017https://doi.org/10.1161/RES.0000000000000137Circulation Research. 2017;120:593miR-210 Enhances Atherosclerotic Plaque Stability (p 633)Download figureDownload PowerPointMicroRNA-210 stabilizes vulnerable atherosclerotic plaques, report Eken et al.Disruption or destabilization of atherosclerotic plaques often results in the formation of an occlusive thrombus, which leads to tissue ischemia and the onset of clinical symptoms of myocardial ischemia or stroke. Hence, identification and treatment of unstable plaques is likely to be highly beneficial to patients with advanced atherosclerotic disease. Because microRNAs (miRs) offer great potential as therapeutic agents, Eken and colleagues searched for differences in the abundance of miRs in patients with stable and unstable carotid plaques. In a comparison of ≈750 miRs expressed in atherosclerotic plaques, the team found that 8 miRs were differentially regulated between patients whose atherosclerosis was asymptomatic versus symptomatic (indicative of plaque instability). Of these, miR-210, present in the stable fibrous cap of atherosclerotic lesions, was the most significantly downregulated in unstable plaques. Furthermore, miR210 was also downregulated in animal models of atherosclerotic lesions, the team showed. And overexpression of this miR, using miR-210 mimics, increased plaque stability in such animals. Boosting miR-210 levels in vulnerable plaques might, therefore, be a means to prevent life-threatening plaque ruptures, say the authors.Intramyocardial CD133+ Cells in Refractory Angina (p 670)Download figureDownload PowerPointA trial of bone marrow stem cells for refractory angina yields inconclusive results, according to Wojakowski et al.Despite considerable progress in the treatment of coronary artery disease, there remain many patients for whom current therapies do not help. New approaches for such refractory angina patients are thus greatly needed. One potential treatment under study is transendocardial delivery of bone marrow stem cells. Indeed, recent studies have shown that such treatment reduces symptoms and improves quality of life in refractive angina patients. However, bone marrow contains a mixed population of cells, so it is possible that certain subpopulations of these cells are more effective than others in alleviating angina symptoms. CD133-positive bone marrow stem cells, for example, are known to have angiogenic potential, which might improve myocardial perfusion in patients. To test this idea, Wojakowski and colleagues administered transendocardial injections of CD133+ cells to patients with refractory angina. They observed no difference in myocardial perfusion or left ventricle ejection fraction between the test and control patients, but they suggest that with so few patients enrolled, the study might have lacked statistical power. Nevertheless, because the procedure was deemed safe, the authors suggest that a larger scale multicenter study is warranted.Pediatric CPC-Derived Exosome Therapy (p 701)Download figureDownload PowerPointDonor age and oxygen levels effect exosomes’ reparative potential, say Agarwal and colleagues.Stem and progenitor cells are being investigated for their potential to treat coronary artery disease (CAD). It is believed that these cells promote tissue repair via their paracrine effects on myocardial tissue or other noncardiac sites. Cardiac progenitor cells (CPCs), for example, release exosomes—small membrane-bound vesicles containing bioactive components—that have been shown in animal models to improve ventricular remodeling and promote healing after myocardial infarction. Evidence suggests that the effectiveness of stem cell therapies depends on oxygen levels and the age of the donor. To examine whether these factors also influence exosome therapies, Agarwal and colleagues isolated CPC exosomes from newborn babies, infants, and children undergoing heart surgery, and compared their reparative potential with and without hypoxic preconditioning. The team showed that, in rats suffering ischemia–reperfusion injuries, exosomes from newborns were the most effective at improving heart function. They also found that even though the potency of the exosomes diminished with increasing donor age, it could be restored by hypoxic preconditioning. The team went on to show that differences in the microRNA content of the exosomes were predictive of their effectiveness. Hence, it seems likely that microRNA analysis of exosomes from other cell types might reveal additional sources of exosome with high therapeutic potential. Previous Back to top Next FiguresReferencesRelatedDetails February 17, 2017Vol 120, Issue 4 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000137 Originally publishedFebruary 17, 2017 PDF download Advertisement