Transendocardial Injection Research Articles

The Application of Mesenchymal Stem Cells in Different Cardiovascular Disorders: Ways of Administration, and the Effectors.

The heart is an organ with a low ability to renew and repair itself. MSCs have cell surface markers such as CD45-, CD34-, CD31-, CD4+, CD11a+, CD11b+, CD15+, CD18+, CD25+, CD49d+, CD50+, CD105+, CD73+, CD90+, CD9+, CD10+, CD106+, CD109+, CD127+, CD120a+, CD120b+, CD124+, CD126+, CD140a+, CD140b+, adherent properties and the ability to differentiate into cells such as adipocytes, osteoblasts and chondrocytes. Autogenic, allogeneic, normal, pretreated and genetically modified MSCs and secretomes are used in preclinical and clinical studies. MSCs and their secretomes (the total released molecules) generally have cardioprotective effects. Studies on cardiovascular diseases using MSCs and their secretomes include myocardial infraction/ischemia, fibrosis, hypertrophy, dilated cardiomyopathy and atherosclerosis. Stem cells or their secretomes used for this purpose are administered to the heart via intracoronary (Antegrade intracoronary and retrograde coronary venous injection), intramyocardial (Transendocardial and epicardial injection) and intravenous routes. The protective effects of MSCs and their secretomes on the heart are generally attributed to their differentiation into cardiomyocytes and endothelial cells, their immunomodulatory properties, paracrine effects, increasing blood vessel density, cardiac remodeling, and ejection fraction and decreasing apoptosis, the size of the wound, end-diastolic volume, end-systolic volume, ventricular myo-mass, fibrosis, matrix metalloproteins, and oxidative stress. The present review aims to assist researchers and physicians in selecting the appropriate cell type, secretomes, and technique to increase the chance of success in designing therapeutic strategies against cardiovascular diseases.

Establishing delivery route-dependent safety and efficacy of living biodrug mesenchymal stem cells in heart failure patients.

Mesenchymal stem cells (MSCs) as living biopharmaceuticals with unique properties, i.e., stemness, viability, phenotypes, paracrine activity, etc., need to be administered such that they reach the target site, maintaining these properties unchanged and are retained at the injury site to participate in the repair process. Route of delivery (RoD) remains one of the critical determinants of safety and efficacy. This study elucidates the safety and effectiveness of different RoDs of MSC treatment in heart failure (HF) based on phase II randomized clinical trials (RCTs). We hypothesize that the RoD modulates the safety and efficacy of MSC-based therapy and determines the outcome of the intervention. To investigate the effect of RoD of MSCs on safety and efficacy in HF patients. RCTs were retrieved from six databases. Safety endpoints included mortality and serious adverse events (SAEs), while efficacy outcomes encompassed changes in left ventricular ejection fraction (LVEF), 6-minute walk distance (6MWD), and pro-B-type natriuretic peptide (pro-BNP). Subgroup analyses on RoD were performed for all study endpoints. Twelve RCTs were included. Overall, MSC therapy demonstrated a significant decrease in mortality [relative risk (RR): 0.55, 95% confidence interval (95%CI): 0.33-0.92, P = 0.02] compared to control, while SAE outcomes showed no significant difference (RR: 0.84, 95%CI: 0.66-1.05, P = 0.11). RoD subgroup analysis revealed a significant difference in SAE among the transendocardial (TESI) injection subgroup (RR = 0.71, 95%CI: 0.54-0.95, P = 0.04). The pooled weighted mean difference (WMD) demonstrated an overall significant improvement of LVEF by 2.44% (WMD: 2.44%, 95%CI: 0.80-4.29, P value ≤ 0.001), with only intracoronary (IC) subgroup showing significant improvement (WMD: 7.26%, 95%CI: 5.61-8.92, P ≤ 0.001). Furthermore, the IC delivery route significantly improved 6MWD by 115 m (WMD = 114.99 m, 95%CI: 91.48-138.50), respectively. In biochemical efficacy outcomes, only the IC subgroup showed a significant reduction in pro-BNP by -860.64 pg/mL (WMD: -860.64 pg/Ml, 95%CI: -944.02 to -777.26, P = 0.001). Our study concluded that all delivery methods of MSC-based therapy are safe. Despite the overall benefits in efficacy, the TESI and IC routes provided better outcomes than other methods. Larger-scale trials are warranted before implementing MSC-based therapy in routine clinical practice.

Abstract 17540: Functional Mitral Regurgitation is Associated With Decreased Papillary Muscle Viability Patients With Non-Ischemic Dilated Cardiomyopathy

Background: The underlying mechanisms of functional mitral regurgitation (FMR) in non-ischemic cardiomyopathy (NICM) are incompletely understood. Aims: We investigated the correlation between papillary muscle viability and FMR in NICM. Methods: We enrolled 66 patients with NICM (LVEF<40%, NHYA III) undergoing CD34 + cell transplantation. At baseline, patients underwent electroanatomical mapping; papillary muscle viability was quantified by local unipolar voltage (UV) measurement, and decreased viability was defined as UV<8.3 mV. All patients received granulocyte-colony stimulating factor; CD34 + cells were collected by apheresis and delivered by transendocardial injections. Echocardiography was performed at baseline and 6 months after cell therapy; severity of FMR was graded by multi-parametric approach. FMR improvement was defined as a reduction in FMR by ≥1 grade when compared to baseline. Results: At baseline, papillary muscle viability was decreased in 24 (36%) and preserved in 42 (64%) of patients. Moderate to severe (2-3+) FMR was more common in patients with decreased papillary muscle viability (6/24; 25%) than in patients with preserved viability (2/42; 5%, P=0.015). Transendocardial cell injections were performed in the papillary muscle area in 26 patients (Group A) and in other areas of the left ventricle in 40 patients (Group B). The groups did not differ in age (56±11 years in Group A vs. 54±10 years in Group B, P=0.32), sex (male: 96% vs. 85%, P=0.21), creatinine (0.98±0.27 mg/dL vs. 0.96±0.28 mg/dL, P=0.92), bilirubin (0.89±0.37 mg/dL vs. 0.92±0.35 mg/dL, P=0.45), LVEF (34±9% vs. 31±7%, P=0.12), NT-proBNP levels (1196±994 pg/mL vs. 1077±1176 pg/mL, P=0.68), the degree of FMR (1.28±0.78 vs. 1.02±0.38, P=0.20), or papillary muscle viability (9.9±3.0 mV vs. 10.3±3.2 mV, P=0.62). At 6 months after cell injection, FMR improved in 77% of patients in Group A vs. 13% in Group B (P=0.001). On multivariate analysis, cell injection in the papillary muscle area was an independent correlate of FMR improvement (P=0.01). Conclusions: FMR in patients with NICM is associated with decreased papillary muscle viability. Transendocardial injection of CD34 + cells in the papillary muscle area may improve FMR in this patient population.

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model.

Myocardial infarction is one of the leading causes of death and disability worldwide, and there is an urgent need for novel cardioprotective or regenerative strategies. An essential component of drug development is determining how a novel therapeutic is to be administered. Physiologically relevant large animal models are of critical importance in assessing the feasibility and efficacy of various therapeutic delivery strategies. Due to their similarities to humans in cardiovascular physiology, coronary vascular anatomy, and heart weight to body weight ratio, swine is one of the preferred species in the preclinical evaluation of new therapies for myocardial infarction. The present protocol describes three methods of administering cardioactive therapeutic agents in a porcine model. After percutaneously induced myocardial infarction, female landrace swine received treatment with novel agents through either: (1) thoracotomy and transepicardial injection, (2) catheter-based transendocardial injection, or (3) intravenous infusion via jugular vein osmotic minipump. The procedures employed for each technique are reproducible, resulting in reliable cardioactive drug delivery. These models can be easily adapted to suit individual study designs, and each of these delivery techniques can be used to investigate a variety of possible interventions. Therefore, these methods are a useful tool for translational scientists pursuing novel biological approaches in cardiac repair following myocardial infarction.

Acute Effect of Selective Chemical Inactivation of Sympathetic or Parasympathetic Atrial Ganglionated Plexus Structures on Atrial Fibrillation Inducibility in Pigs.

We studied the role of both parts of the autonomic intracardiac nervous system in the pathogenesis of atrial fibrillation (AF). In 12 pigs weighing 39±3 kg, AF was induced by burst stimulation. Chemical inactivation of intrinsic cardiac neurons within the right atria was performed by transendocardial injections of liposomal neuromodulators into the dorsal part of the right atrial wall. Sympathetic and parasympathetic terminals were inactivated with 6-hydroxydopamine (6-OHDA, n=6) and ethylcholine aziridinium ion (AF64A, n=6), respectively. Neuromodulators were encapsulated in liposomes (LS) with diameters of 310±50 nm for OHDA and 290±50 nm for AF64A. LS-6-OHDA and LS-AF64A were injected into the ganglionated plexuses after measuring the baseline effective refractory period and assessing myocardial resistance to AF. These measurements were repeated 90 min after the injections. The optimal doses were 0.2 mg/kg for LS-6-OHDA and 0.4 mg/kg for LS-AF64A (in 4 ml of suspension). Immediately after injections of liposomal neuromodulators, almost all pigs showed an increase in HR, and a short-term BP elevation was observed in the LS-AF64A group. At the end of the experiment, similar decrease in the effective refractory period and similar increase in the resistance to AF were observed in all animals. Thus, selective chemical inactivation of cholinergic and adrenergic terminals of the intracardiac nervous system with liposomal neuromodulators increased the resistance to AF in an acute experiment. However, the short observation period does not allow making a definite conclusion about the role of the autonomic nervous system in the pathogenesis of AF, which requires verification of the obtained data in a chronic experiment.

Abstract P1009: Size And Distribution Of Human Cardiac Tissue Grafts Following Transendocardial Delivery Of Committed Cardiac Progenitors In A Swine Ischemic Heart Failure Model

Introduction: iPSC-derived committed cardiac progenitor cells (CCP) have exciting potential to remuscularize infarcted myocardium; however, little is known about CCP engraftment and differentiation following injection. We hypothesized that transendocardial injection (TEI) of CCPs with an injectable cardiac fibroblast derived extracellular matrix (ECM) retention agent would result in cardiac tissue grafts in an immunosuppressed porcine ischemic heart failure (HF) model. Methods: Coronary artery balloon-occlusion myocardial infarction was induced in Yucatan mini-swine. After 1 month, 300M CCPs with and without 50 mg ECM particles were delivered in 15 intramyocardial injections to the border zone and infarct zone using a steerable Myostar injection catheter with NOGA XP mapping. Immunosuppressed swine were sacrificed up to 2 months following treatment. Hearts were systematically sectioned and stained for human nuclear antigen (Ku80) and cardiac troponin I/T to define the area and distribution of human grafts and cardiomyocyte content. Results: Clusters of human grafts composed of predominantly troponin positive cardiomyocytes were observed in the infarct, at the infarct border, and in adjacent healthy tissue. Overall, 21/25 (84%) of treated pigs had human cardiac tissue grafts. In the current analysis, grafts were identified in 11/12 (91.6%) and 10/13 (76.9%) of pigs in the CCP+ECM and CCP, respectively (see Figure). The observed mean graft area was 62,930 ± 40,332 μm 2 and 185,200 ± 329,080 μm 2 per pig in the CCP+ECM and CCP only groups, respectively (p=0.23). Conclusion: In an immunosuppressed swine ischemic HF model, TEI of CCPs ± ECM yields persistent human cardiac tissue grafts composed of predominantly of cardiomyocytes in both infarcted and non-infarcted regions of the myocardium up to 2 months following treatment.

Trans-endocardial delivery of progenitor cells to compromised myocardium using the "needle technique"and risk of myocardial injury.

Recent analysis from CHART-1 study indicated that the therapeutic effects of trans-endocardial cardiopoetic cell transplantation in chronic ischemic heart failure (iCHF) may be lost with an increasing number of injections perfomed to deliver therapeutic cells. To evaluate global and regional contractility and diastolic function of the left ventricle of patients with iCHF who received trans-endomyocardial cardiopoietic stem cells (CSCs) delivery or sham procedures. The study included patients (mean age: 60.8 ±7.1 years) with iCHF (left ventricular ejection fraction (LVEF) < 35%) and a history of hospitalization for worsening heart failure within 12 months despite optimal medical therapy. The patients underwent transmyocardial CSCs transplantation using perforated needle technique or a sham procedure. The wall motion score index (WMSI), LVEF, transmitral E-velocity, E-wave deceleration time, E/A-ratio, and E/e'-mean value were measured with two-dimensional echocardiography on days 1 and 30. A total of 170 segments were analyzed, including 48 targeted segments where 92 injections of 0.5 ml of CSCs were performed. In the transendocardial injections cohort, a decrease in regional contractility was observed in 30.6% (26/85) and 18.9% (16/85) of the segments on days 1 and 30, respectively. This was accompanied by an increase in WMSI by 0.32 ±0.06 and 0.19 ±0.18 (day 1, p = 0.02, day 30, p = 0.03) and a reduction in LVEF (-3.15 ±1.23%, p = 0.065). Transendocardial injections performed to deliver therapeutic cells were associated with myocardial injury. This adverse effect remained, albeit at a lesser degree, at 30-days. Mechanical injury with trans-endocardial delivery of progenitor cells using the "needle technique" may counterbalance, at least in part, any cell-related benefit(s).

Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials

BackgroundTrials investigating the role of mesenchymal stem cells (MSCs) in increasing ejection fraction (LVEF) after acute myocardial infarction (AMI) have raised some controversies. This study was conducted to find whether transplantation of MSCs after AMI can help improve myocardial performance indices or clinical outcomes.MethodsRandomized trials which evaluated transplantation of MSCs after AMI were enrolled. The primary outcome was LVEF change. We also assessed the role of cell origin, cell number, transplantation time interval after AMI, and route of cell delivery on the primary outcome.ResultsThirteen trials including 956 patients (468 and 488 in the intervention and control arms) were enrolled. After excluding the biased data, LVEF was significantly increased compared to the baseline among those who received MSC (WMD = 3.78%, 95% CI: 2.14 to 5.42, p < 0.001, I2 = 90.2%) with more pronounced effect if the transplantation occurred within the first week after AMI (MD = 5.74%, 95%CI: 4.297 to 7.183; I2 = 79.2% p < 0.001). The efficacy of trans-endocardial injection was similar to that of intracoronary infusion (4% [95%CI: 2.741 to 5.259, p < 0.001] vs. 3.565% [95%CI: 1.912 to 5.218, p < 0.001], respectively). MSC doses of lower and higher than 107 cells did not improve LVEF differently (5.24% [95%CI: 2.06 to 8.82, p = 0.001] vs. 3.19% [95%CI: 0.17 to 6.12, p = 0.04], respectively).ConclusionTransplantation of MSCs after AMI significantly increases LVEF, showing a higher efficacy if done in the first week. Further clinical studies should be conducted to investigate long-term clinical outcomes such as heart failure and cardiovascular mortality.

Abstract 12803: Human IPSC-Derived Committed Cardiac Progenitor Cells Engraft and Differentiate Following Transendocardial Injections in a Swine Ischemic Heart Failure Model

Introduction: A hallmark of human myocardium is the inability to regenerate functional myocardium following myocardial infarction (MI) which can result in heart failure. In an effort to remuscularize infarcted myocardium, we tested a novel human iPSC-derived committed cardiac progenitor (CCP) cell population. Whether CCPs survive and differentiate to form grafts following transcatheter delivery in a clinically representative large animal model is unknown. Hypothesis: We hypothesized that transendocardial injection (TEI) of CCPs, combined with a cardiac fibroblast-derived matrix (CFM) particles as a cell retention agent leads to functional cardiac tissue grafts. Methods: Large MI following coronary artery balloon-occlusion reperfusion was induced in mini-swine that received a 4-drug immunosuppression regimen. 28 days later, TEI targeting the peri-infarct region was performed using combinations of 200 million CCPs with or without 50 mg CFM particles and Flexbumin control. 14 injections/pig were performed, and animals were followed for 4-8 weeks. Histopathology, continuous ECG recording and cardiac MRI were performed. Results: Human cell grafts were identified using Ku80+ human cell specific antibody in the initial n=11 evaluable CCP treated swine after 1 month (see representative image, Ku80+ human cells=green). The CCPs largely differentiate into TnI positive cardiomyocytes (red) in grafts observed at one month. Immunolabeling for a panel of cardiomyocyte markers confirmed the presence of human cardiomyocytes. Of n=29 initial pigs, no treatment-related safety issues were identified, such as post TEI pericardial effusion, ventricular tachyarrhythmias or tumors. Conclusions: TEI of CCPs, with and without CFM, resulted in grafts of human cardiomyocytes in the myocardium of immunosuppressed pigs, after 1 month post MI. Ongoing cardiac MRI analyses will determine the impact of CCP therapy on cardiac structure and function.

Effect of intravenous cell therapy in rats with old myocardial infarction.

Mounting evidence shows that cell therapy provides therapeutic benefits in experimental and clinical settings of chronic heart failure. However, direct cardiac delivery of cells via transendocardial injection is logistically complex, expensive, entails risks, and is not amenable to multiple dosing. Intravenous administration would be a more convenient and clinically applicable route for cell therapy. Thus, we determined whether intravenous infusion of three widely used cell types improves left ventricular (LV) function and structure and compared their efficacy. Rats with a 30-day-old myocardial infarction (MI) received intravenous infusion of vehicle (PBS) or 1 of 3 types of cells: bone marrow mesenchymal stromal cells (MSCs), cardiac mesenchymal cells (CMCs), and c-kit-positive cardiac cells (CPCs), at a dose of 12 × 106 cells. Rats were followed for 35days after treatment to determine LV functional status by serial echocardiography and hemodynamic studies. Blood samples were collected for Hemavet analysis to determine inflammatory cell profile. LV ejection fraction (EF) dropped ≥ 20 points in all hearts at 30 days after MI and deteriorated further at 35-day follow-up in the vehicle-treated group. In contrast, deterioration of EF was halted in rats that received MSCs and attenuated in those that received CMCs or CPCs. None of the 3 types of cells significantly altered scar size, myocardial content of collagen or CD45-positive cells, or Hemavet profile. This study demonstrates that a single intravenous administration of 3 types of cells in rats with chronic ischemic cardiomyopathy is effective in attenuating the progressive deterioration in LV function. The extent of LV functional improvement was greatest with CPCs, intermediate with CMCs, and least with MSCs.

Doppler-Guided Acoustically Active Injection Catheter: Transendocardial Delivery Assessed by an Efficacy Testing Animal Model.

Percutaneous transendocardial injections of therapeutic agents into the myocardium may not always be effective. We used an animal model for assessing the efficacy of the injections using linoleic acid as a testing agent. Efficacious delivery into the myocardium of a beating heart was indicated by rapidly developed local myocardial necrosis and wall motion abnormalities using echocardiography. We employed this experimental model to test our innovative technology, an acoustically active injection catheter. The Doppler ultrasound-guided acoustically active injection catheter effectively delivers the substance to the myocardium but needs further technical improvements to minimize an unwanted systemic distribution of the agent.

AUTOLOGICAL CELL THERAPY AND ITS ROLE IN THE TREATMENT OF REFRACTORY ANGINA

The first clinical studies dedicated to the use of autological mesenchymal stem сells(MSCs) for the treatment of angina by means of their intravenous and transendocardialinjection is carried out in State Institution «Institute of Urgent and Recovery Surgerynamed after V.K. Gusak of National Academy of Medical Science of Ukraine» since 2007.The effectiveness of autological mesenchymal stem cells (MSCs) was researched in 60patients, and it was established that injection of 50 million of cells per a person withrefractory angina is an effective and a safe method of treatment. The results of clinicalresearch have shown that the delivery of MSCs to the lesion provides restoring ofmyocardial function and influences on the left ventricular remodeling.Objective – to substantiate the effectiveness of autological MSCs in the treatment ofrefractory angina.Material and methods. The results of examination, treatment and observation of 60patients with refractory angina (52 men and 8 women aged from 46 to 70 years) since2007 to 2012 are performed in the article.Results. We obtained the following data while studying of the dynamics of left ventricularend diastolic volume (LVEDV), which is a prognostic factor of the course of heart failure(HF). The decrease of LVEDV from 248.5 ± 22.3 to 194.3 ± 26.4 ml was observed inthe group of patients 3 months later after endocardial injection. This rate was stable 6months later after an injection, but lower than the initial one (p value &gt; 0.05). A similartrend was observed in the group of intravenous injection . LVEDV decreased from 244.1± 24.3 to 193.4 ± 18.9 ml within 3 months and remained stable up to 6 months but lowerto the rate that was observed before the treatment with a trend to increasing to the initiallevel. Ultrasound studying of the left ventricular ejection fraction (LVEF) in patients of transendocardial injection of cell transplant showed an increasing of LVEF from 41.3 ±3.2 to 49.3 ± 4.6% 3 months later after the procedure and it was stable up to 6 months ofthe posttransplant period. LVEF is also increased in the group of intravenous transplantadmission (from 33.8 ± 3.6 to 42.8 ± 4.8%) after procedure, with its gradually decreasingin terms of 3 months, LVEF approaches the starting values up to 6 months after celltransplantation.Conclusions. The received clinical data have shown that MSCs facilitate the restoringof mechanical myocardial function and influence left ventricular remodeling aftertheir admission to the lesion zone. This effect has been confirmed according to cardiacechocardiography, treadmill-test, electromechanical mapping of the LV. The positiveeffect was remaining for 6 months. The received data allows to recommend the clinicaluse of biotechnology in ischemic heart disease treatment.

Abstract 15258: Higer Unipolar Voltage at Cell Injection Sites Correlates With Better Outcomes After Transendocardial Cd34 + Cell Transplantation in Patients With Chronic Heart Failure

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&lt;40% undergoing CD34 + 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 &gt;8.3mV and local linear shortening &lt;6%. Favorable clinical response was defined as an increase in LVEF≥5% between baseline and 6 months follow-up. 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.

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

AimHeart 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. MethodsPatients 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. ResultsThe 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. ConclusionAll 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 registrationhttps://clinicaltrials.gov/ct2/show/NCT02438306

Larger End-Diastolic Volume Associates With Response to Cell Therapy in Patients With Nonischemic Dilated Cardiomyopathy

ObjectiveTo investigate the association of left ventricular end-diastolic volume (LVEDV) and the response to cell therapy in patients with nonischemic dilated cardiomyopathy (NICM). Patients and MethodsFive-year registry data from 133 consecutive patients with NICM who underwent CD34+ cell treatment were analyzed. All patients received granulocyte-colony stimulating factor; CD34+ cells were collected by apheresis and delivered by transendocardial injections. Patients with baseline LVEDV less than 200 mL (group A; n=72) and patients with LVEDV 200 to 370 mL (group B; n=54) were included. Patients with LVEDV greater than 370 mL were excluded (n=7). Favorable ejection fraction response was pre-defined by improvement in left ventricular ejection fraction (LVEF) greater than or equal to 5% at 1 y post-cell therapy. ResultsAt baseline, groups A and B were comparable with regards to age (52±11 y in group A vs 53±10 y in group B; P=.95), sex (male: 79% vs 83%, respectively; P=.55), creatinine (1.07±0.28 mg/dL vs 1.03±0.21 mg/dL, respectively; P=.21), or N-terminal probrain natriuretic peptide (1454±1658 pg/mL vs 1589±1338 pg/mL, respectively; P=.80). Baseline LVEF was higher in group A (32.8±8.7%) than in group B (30.2±8.7%; P=.03). During follow-up, there were four deaths in group A (5.6%), and 2 in group B (3.7%, P=.63). At 1-year post-cell therapy, LVEDV decreased significantly in group B (-56±30 mL; P=.003), but not in group A (+12±97 mL; P=.13). On multivariate analysis, baseline LVEDV was an independent correlate of favorable response in LVEF to therapy (P=.02). ConclusionLarger LVEDV was associated with more pronounced increase in LVEF after transendocardial CD34+ cell therapy in NICM patients, informing target individuals with the highest likelihood of regenerative response. Trial Registrationclinicaltrials.gov identifier: NCT02445534

A Phase I Study of Allogeneic Mesenchymal Stem Cell Therapy in Patients with Heart Failure Secondary to Anthracycline-induced Cardiomyopathy: The Cctrn Stem Cell Injection in Cancer Survivors (Seneca) Trial

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.

Clinical Safety Profile of Transendocardial Catheter Injection Systems: A Plea for Uniform Reporting

ObjectivesThe aim of this study was to characterize the clinical safety profile of transendocardial injection catheters (TIC) reported in the published literature. BackgroundTransendocardial delivery is a minimally invasive approach to deliver potential therapeutic agents directly into the myocardium. The rate of adverse events across TIC is uncertain. MethodsA systematic search was performed for trial publications using TIC. Procedure-associated adverse event data were abstracted, pooled and compared across catheters for active treatment and placebo injected patients. The transendocardial injection associated serious adverse events (TEI-SAE) was defined as the composite of death, myocardial infarction, stroke or transient ischemic attack within 30 days and cardiac perforation causing death or requiring evacuation, serious intraprocedural arrhythmias and serious coronary artery or peripheral vascular complications. ResultsThe search identified 4 TIC systems: a helical needle (HN), an electro-anatomically tracked straight needle (EAM-SN), a straight needle without tracking elements (SN), and a curved needle (CN). Of 1799 patients who underwent transendocardial injections, the combined TEI-SAE was 3.4% across all catheters, and 1.1%, 3.3%, 7.1%, and 8.3% for HN, EAM-SN, SN and CN, respectively. However, TIC procedure duration and post procedural cardiac biomarker levels were reported in only 24% and 36% of published trials, respectively. ConclusionsTransendocardial injection is associated with varied TEI-SAE but the data are very limited. The HN catheter appeared to be associated with lower TEI-SAE, versus other catheters. Procedure duration and post procedure cardiac biomarker levels were under-reported. Clearly, standardized, procedure-related event reporting for trials involving transcatheter delivery would improve our understanding of complications across different systems.

The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials

BackgroundDespite limited human data, there is a growing interest in the use of stem cell therapy (SCT) for erectile dysfunction (ED). AimTo determine the effect of transendocardial stem cell injection on erectile function on men with cardiomyopathy and ED. MethodsWe used International Index of Erectile Function (IIEF) scores collected from men enrolled in 3 separate randomized controlled trials: Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy (POSEIDON), Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy (TAC-HFT), and Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (TRIDENT). These trials recruited patients with ischemic cardiomyopathy and ejection fraction less than 50%. Inclusion and exclusion criteria were identical in all 3 trials. The primary intervention in these trials included transendocardial stem cell injection of stem cells or placebo via cardiac catheterization. The follow-up period was 1 year. IIEF data were collected at baseline and at multiple time points in each trial. OutcomesWe investigated erectile function over time based on cell dose, cell source (autologous vs allogenic), cell type (mesenchymal stem cells vs bone marrow mononuclear cells), and comparing men who received SCT with those who received placebo. ResultsA total of 36 men were identified with complete IIEF data. 8 men received placebo injection, and 28 received SCT. The median age was 66.5 years. Comorbidities were similar among all men. Analysis was performed on men with ED, defined by an IIEF-EF score of 24 or less. In the placebo and all-comer SCT group, the median IIEF-EF score was 5 [1–8] and 5 [1–15] at baseline and was 3.5 [3–5.8] and 7 [1–18] at 12 months (P > .05). When analyzed by cell dose, the IIEF-EF score in men who received 200 million cells increased significantly over 12 months (14 [4–23] to 20 [15–24.5], P = .014.) Similarly, an autologous cell source resulted in a similar increase from baseline to 12 months (14 [3.8–23.3] to 20 [12–22], P = .030). Clinical ImplicationsErectile function may improve after systemic delivery of SCT in men with ischemic cardiomyopathy and at least mild ED. Strengths & LimitationsThis post hoc analysis is the first to investigate the effect of SCT on erectile function using randomized, placebo-controlled data. Weaknesses include that ED was not a primary end point, and men were not originally recruited based on erectile function. ConclusionFuture trials on systemic delivery of SCT for ED should focus on high cell dose and autologous cell source, as these seem to provide the best response in men with at least mild ED.Ory J, Saltzman RG, Blachman-Braun R, et al. The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials. J Sex Med 2020;17:695–701.

310 Does Improvement in Endothelial Function affect Erectile Function following Stem Cell Therapy in Men with Cardiomyopathy?

Endothelial dysfunction is an important component in the pathogenesis of cardiovascular disease and erectile dysfunction (ED). Interest in cell-based therapy (CBT) for cardiovascular disease and ED is growing. Early trials have shown CBT to improve cardiac function in men with ischemic cardiomyopathy, with concurrent improvement in endothelial function. Whether or not the improvement in endothelial function from CBT may benefit ED has yet to be explored. To determine if a change in endothelial function affects erectile function in men who received transendocardial injection of stem cells. We performed a post hoc sub-analysis of the TRIDENT trial to examine the relationship between endothelial function and erectile function. The TRIDENT study recruited 30 participants with ischemic cardiomyopathy and reduced ejection fraction (<50%) to receive allogenic bone-marrow derived mesenchymal stem cells (MSC) via transendocardial injection (TESI). Participants were randomized to receive MSCs in doses of 20 or 100 million cells and were followed for 1 year. International Index of Erectile Function (IIEF) questionnaires were administered at baseline and at 3, 6 and 12 months. Endothelial function was assessed at baseline and 3 months post-therapy and consisted of two measures: brachial artery percent Flow Mediated Vasodilation (FMD) and quantification of Endothelial Progenitor Cell-Colony Forming Units (EPC-CFUs). Patients with FMD less than 7% were considered to have endothelial dysfunction (normal = >10%), and higher counts of circulating EPCs indicate a greater capacity for endothelial self-regeneration.

009 Effect of Transendocardial Stem Cell Injection on Erectile Function in Men with Cardiomyopathy: Results from the TRIDENT and TAC-HFT Trials.

009 Effect of Transendocardial Stem Cell Injection on Erectile Function in Men with Cardiomyopathy: Results from the TRIDENT and TAC-HFT Trials.