Epicardial Injections of Allogenic Human Induced Pluripotent Stem Cells-derived Cardiomyocytes for Severe Chronic Ischemic Heart Failure: The HEAL-CHF Trial

Epicardial Injections of Allogenic Human Induced Pluripotent Stem Cells-derived Cardiomyocytes for Severe Chronic Ischemic Heart Failure: The HEAL-CHF Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Epicardial Injections of Allogenic Human Induced Pluripotent Stem Cells-derived Cardiomyocytes for Severe Chronic Ischemic Heart Failure: The HEAL-CHF Trial Jiaxian Wang, He Zhang, Jiahao Fan, Yun-Xing Xue, Xiyu Zhu, Qian Wang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7414031/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Heart failure continues to impose a significant global health burden, with a continuous search for therapies capable of promoting a true myocardial regeneration. The HEAL-CHF trial evaluated the safety and efficacy of intramyocardial injections of allogeneic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in advanced heart failure (LVEF≤45%) patients with concomittent coronary artery bypass grafting (CABG). The primary safety endpoints, defined as the incidence of sustained ventricular arrhythmias at 1-6-month follow-up and tumorigenicity at 12-month follow-up, were not observed. Efficacy analyses suggested benefits of cell transplantation compared with CABG alone, primarily evidenced by significant improvements in 6-minute walk distance (6MWD), stroke volume (SV), myocardial perfusion recovery and myocardial contractility. This first randomized and controlled clinical trial of human iPSC-based cardiac regenerative therapy demonstrates the safety and therapeutic potential of hiPSC-CMs and provides a strong incentive for moving to trials adequately powered to yield robust efficacy data. (ClinicalTrials.gov registration: NCT03763136.) Health sciences/Diseases/Cardiovascular diseases/Heart failure Biological sciences/Stem cells/Pluripotent stem cells/Induced pluripotent stem cells Biological sciences/Stem cells/Regeneration Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Heart failure (HF) remains a leading cause of death and disability worldwide, affecting more than 56 million people 1,2 . This chronic condition imposes a substantial burden on healthcare systems, driven by its high morbidity, frequent hospitalizations, and increased mortality rates 2–4 . Despite significant advances in pharmacological and device-based interventions, these strategies, while effective for relieving symptoms and slowing disease progression, still fail to address one of the major root causes of the disease, i.e., the loss of a substantial number of cardiomyocytes 5 . Over the past years, it has become increasingly recognized that compensation for this loss aimed at achieving a true myocardial regeneration, as opposed to repair, best required to deliver cardiac-committed cells. Such cells can now be produced in large amounts through the targeted differentiation of pluripotent stem cells (PSC). Within this framework induced pluripotent stem cells (iPSC), reprogrammed from somatic cells, have taken precedence over embryonic stem cells (ESC) because of an easier procurement and the lack of ethical issues. Even though iPSC-derived cardiomyocytes (iPSC-CMs) still display some features of immaturity, preclinical studies in rodent and nonhuman primate models of myocardial infarction (MI)-induced heart failure have shown that they had the capacity to engraft, electrically integrate, and improve cardiac function 6 thus suggesting their potential as a transformative therapeutic option. In our previous landmark first-in-human study, two individuals in China became the first subjects worldwide to receive intramyocardial injections of allogeneic hiPSC-CMs 7,8 in conjunction with coronary artery bypass grafting (CABG). While the observed improvements in exercise capacity, left ventricular (LV) function and quality of life were interpreted with caution because of the confounding effect of the associated myocardial revascularization, the major information drawn from this early experience was the lack of cell-related safety issues over a now 4-year follow-up, thereby providing a strong incentive to consolidate these data by a larger-size randomized trial. In the present study, the HEAL-CHF trial was thus specifically designed to evaluate the safety and efficacy of transepicardial intramyocardial injections of allogeneic hiPSC-CMs in patients with severe chronic ischemic heart failure undergoing CABG. Conducted at Nanjing Drum Tower Hospital, this randomized, open-label, controlled study is the first and largest clinical trial to date to report outcome data using a PSC-based regenerative treatment of heart failure. The positivity of these outcomes should help HEAL-CHF to bridge the translational gap between preclinical advancements and real-world clinical applications and thus contribute to further integrate iPSC-CMs among the treatment options for severe heart failure. Methods Trial oversight The HEAL-CHF study is an investigator-initiated, single-center, randomized, open-label, controlled trial conducted at Nanjing Drum Tower Hospital, affiliated with Nanjing University. The trial was designed to assess the safety and efficacy of intramyocardial injections of hiPSC-CMs in patients with severe chronic ischemic heart failure who had otherwise an indication for CABG. The study was initiated in August 2021, with the first participant enrolled October, 15, 2021 and final enrolment was completed on May, 5, 2023. The trial was registered at clinicalTrials.gov (NCT03763136), and the protocol was approved by the Institutional Ethics Committee of Nanjing Drum Tower Hospital, affiliated with Nanjing University (No. SC202000102), and by the National Health Commission of the People's Republic of China (MR-32-21-014649). The study was conducted in accordance with the tenets of the Declaration of Helsinki. The authors take responsibility for the accuracy and completeness of the data and analyses. Screening and eligibility A comprehensive inventory of inclusion and exclusion criteria is provided in Table S1 . Briefly, patients between 35 and 75 years of age with symptoms (New York Heart Association [NYHA] class III or IV despite guideline-directed medical therapy), severe ischemic heart failure (LV ejection fraction ≤45%), and indication for CABG surgery were eligible for enrolment. Patients with any other significant cardiovascular disease or a history of malignancy within the previous five years were excluded from the study. All eligible patients provided a written inform consent. Randomization and blinding The trial employed a open-label design. Only the outcome assessors were blinded to group allocation. Prior to trial initiation, a statistician generated 20 random numbers using the SAS PLAN procedure, and participants were randomized in a 1:1 ratio into two groups, labeled as numbers 1 to 20. Each randomization result was sealed in an opaque envelope of identical specifications, with the corresponding number printed on the envelope. This approach ensured that during the participant screening process and before randomization, the research team was blinded to the group allocation, thereby maintaining the integrity of the randomization process. Study Design Following a screening period, 20 patients were randomly assigned (1:1) to receive either (i) CABG only (Control group, n=10), or (ii) CABG combined with transplantation of hiPSC-CMs (Cell therapy group, n=10). The pre-specified sample size of 20 was based on an empirical estimate to evaluate the initial safety and tolerability of hiPSC-CMs. For patients in the Cell therapy group, 2×10 8 hiPSC-CMs were injected intramyocardially, once the coronary anastomoses had been completed, at 10 discrete sites surrounding the area of myocardial infarction, using a 30 gauge needle. The sites were determined by the surgeon based on preoperative imaging and intraoperative inspection and were documented. Post-operative evaluations, including cardiac imaging, laboratory tests, and functional assessments, were performed 1, 6, and 12 months after the procedure. A detailed study protocol is available in the Supplementary Information. Immunosuppressive protocol Patients in the Cell therapy group were administered the following immunosuppressive regimen: intravenous immunoglobulin (2.5 g, IV) on preoperative day 1, intraoperative day (IOD), and postoperative day (POD) 3, combined with methylprednisolone (500 mg, IV) on preoperative day 1; rituximab (20 mg, IV) on IOD and POD4 to target CD20 + B-cell depletion; oral tacrolimus started preoperative day 3 and dose-adjusted to maintain trough levels within the target range of 3-5 ng/mL, as monitored by blood drug concentration until POD28, concurrently with mycophenolate mofetil (1 g, orally on preoperative day 1, increasing to 1.5 g/day until POD28) and prednisone (20 mg/day started IOD until POD28). The Control group did not receive any immunosuppressive medications. Outcome measures The primary outcomes, focused on safety, were the incidence of sustained ventricular tachycardia (VT), assessed at 1 and 6 month post-procedure using 24-hour holter electrocardiogram monitoring, and the occurrence of newly formed tumors, evaluated from the baseline to 12 months post-intervention using 18 F-Fluorodeoxyglucose (FDG) positron emission tomography-computed tomography scan (PET-CT). The secondary safety end points included serious adverse events (all-cause death, non-fatal myocardial infarction, stroke, any surgical complication) during the perioperative period, alloimmune responses (based on assays of donor-specific antibodies), perioperative electrocardiographic (EKG) changes and cardiac failure biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP]). The secondary efficacy outcomes encompassed a range of assessments, including NYHA functional classification, quality of life (assessed by the Minnesota Living with Heart Failure Questionnaire [MLHFQ] score), exercise tolerance (assessed by the 6-minute walk test), LV function and structure (assessed by echocardiography and cardiac magnetic resonance imaging [MRI]), myocardial perfusion (assessed by 99m Tc single-photon emission with computed tomography [SPECT-CT]), myocardial metabolism (using 18 F-FDG PET-CT) and incidence of major adverse cardiac events (defined as all-cause death, non-fatal myocardial infarction, and rehospitalization for heart failure). G eneration and preparation of h iPSC -CMs hiPSCs were derived from peripheral blood mononuclear cells that had been transduced with the transcription factors Oct3/4, Sox2, c-Myc, and Klf4. The differentiation of hiPSC-CMs from hiPSCs was conducted in accordance with previously established protocols 9,10 . All reprogramming and manufacturing processes were meticulously executed in the GMP-grade laboratories of HELP Therapeutics. The hiPSC-CMs were subjected to rigorous quality control tests. Cryopreserved hiPSC-CMs were transported and stored in a liquid nitrogen tank at the Nanjing Drug Tower Hospital Stem Cell Center. Prior to transplantation, cryopreserved cardiomyocytes were thawed in a 37°C water bath and then resuspended in a 5% albumin solution. Electrocardiographic monitoring Continuous ambulatory EKG monitoring was performed using a lightweight ambulatory EKG recorder (Light-1800 series, GE Healthcare, Chicago, USA) with recording durations of 24, 48, or 72 h, depending on clinical requirements. Measurements from e chocardiography , MRI, SPECT -CT , and PET - CT Two-dimensional speckle-tracking echocardiography was performed in all enrolled patients according to a standardized protocol 11 . All examinations were performed by a single senior cardiologist, blinded to group allocation, using a Vivid E95 ultrasound system (GE Healthcare). Patients were positioned in the left lateral decubitus position with quiet respiration, and image acquisition was ECG-gated. Cardiac MRI examinations were performed using two identical 3.0T MRI scanners (Achieva and Ingenia, Philips Medical Systems, Best, Netherlands), equipped with a 32-element phased array body coil 12 . Late gadolinium enhancement (LGE) imaging was performed 10-15 min after intravenous administration of 0.2 mmol/kg MRI contrast agent (Magnevist, Bayer Healthcare, Berlin, Germany) using phase-sensitive inversion recovery T1-weighted gradient-echo pulse sequences. The infarcted myocardium was defined on LGE images as a region with mean signal intensity at least five standard deviations higher than that of a reference region of interest (ROI) drawn in the remote myocardium. Post-processing and quantitative analysis of CMR images were performed using a dedicated software (CVI42, version 5.13.1, Circle Cardiovascular Imaging Inc., Calgary, Canada). SPECT-CT imaging was acquired using a dual-detector gamma camera (GE Healthcare) 13 . Image acquisition started 60-90 min post-intravenous administration of 740-925 MBq 99m Tc-sestamibi under resting conditions to assess myocardial perfusion. Summed rest score (SRS) was calculated by summing scores of the 17 segments. Myocardial metabolism imaging was conducted using a high-resolution full-ring PET scanner (Vereos, Philips Healthcare) 14 . Patients were first administered a glucose load and subsequently received intravenous injections of regular short-acting insulin, with the dosage adjusted according to their serum glucose levels. This was followed by the intravenous injection of 4.44 MBq/kg of 18 F-FDG. After acquisition, gated and non-gated SPECT-CT and PET-CT data sets were exported to a nuclear cardiology processing platform (Xeleris 4DR, GE Healthcare) for synchronized analysis. The gated SPECT-CT and PET-CT images were analyzed using identical functional parameters with the ECTB software (version 4.0, Emory University Hospital, Atlanta, USA). Statistical analysis Continuous data were presented as the mean ± SD, and discrete data were presented as number (%). For participants with incomplete follow-up, the Last Observation Carried Forward method was applied to impute missing endpoint data. Specifically, in the Control group, one patient lost to follow up after the 6-month visit had his 12-month outcomes imputed based on the last available 6-month measurements. Data distribution was evaluated with the Shapiro-Wilk normality test. Normally and non-normally distributed data were compared with two-tailed Student's t -tests and the Wilcoxon rank-sum test, respectively. Statistical analyses were performed with SPSS software (version 22.0), and a P value of <0.05 was considered statistically significant. Results Patient population From October 2021 to May 2023, a total of 625 patients diagnosed with advanced heart failure were screened at Nanjing Drum Tower Hospital. Of these, 55 met the enrollment criteria (Table S1) and 20 of them were finally included in the trial ( Fig 1 ). The baseline characteristics of the two groups were well balanced, as illustrated in Table 1 . All patients underwent CABG surgery with half of them receiving additional trans-epicardial injections of 2x10 8 hiPSC-CMs after completion of the CABG anastomoses. Patients in the Control group did not receive sham injections. Table 1 ： Baseline characteristics of randomized patients Control group (n=10) Cell therapy group (n=10) P value (2-tailed) Demographics Sex Male 9 (90%) 9 (90%) Female 1 (10%) 1 (10%) Age, years 53.70±8.46 54.00±11.52 .948 Physical findings Body-mass index, kg/m 2 24.64±4.95 23.95±2.64 .703 Resting Heart rate, beats/min 76.70±10.03 78.60±7.38 .635 Systolic Blood Pressure, mmHg 116.80±10.01 117.20±12.81 .939 Diastolic Blood Pressure, mmHg 74.80±9.09 71.60±7.28 .396 Risk Factors Smoking (current or former) 7 (70%) 7 (70%) 1.000 Drinking (current or former) 2 (20%) 3 (30%) 1.000 Hypertension 5 (50%) 3 (30%) .650 Diabetes 4 (40%) 5 (50%) 1.000 Obesity 2 (20%) 0 (0%) .474 Hyperlipidemia 2 (20%) 2 (20%) 1.000 Cardiovascular prognostic parameters Left ventricular ejection fraction (MRI) 28.08±9.02 27.57±4.10 .871 Left ventricular ejection fraction (ECHO) 36.16±3.86 37.80±4.78 .410 NYHA functional class 3.10±0.316 3.10±0.316 1.000 6MWD 326.0±72.37 321.1±60.30 .876 MLHFQ 44.4±23.56 47.6±22.42 .759 SYNTAX score 23.40±3.36 22.50±3.06 .539 Myocardial infarction 7 (70%) 6 (60%) 1.000 Arrhythmia 2 (20%) 2 (20%) 1.000 Stent implantation 4 (40%) 3 (30%) 1.000 PTCA 2 (20%) 0 (0%) .474 PCI 2 (20%) 1 (10%) 1.000 Data presented as mean±SD or n (%). MRI: magnetic resonance imaging; ECHO: Echocardiography; NYHA: New York Heart Association; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; PTCA: Percutaneous Transluminal Coronary Angioplasty; PCI: Percutaneous Coronary Intervention; 6MWD: 6-mintue walking test distance; MLHFQ: Minnesota Living with Heart Failure Questionnaire. Primary Safety Outcomes Similar with our previous findings in 2 patients followed up to 4 years 8 , no cases of de novo tumor formation were identified at the 12-month follow-up time point in the Cell therapy group, as assessed by 18 F-FDG PET-CT ( Fig. S1 ). Accelerated idiopathic ventricular rhythm (AIVR) occurred in all patients following hiPSC-CMs transplantation ( Table S2 ) and featured a distinct temporal pattern ( Fig. S2 ), with a typical emergence at Day 5-7 post-transplantation. However, clinically significant VT (>140 bpm) requiring a prolongation of hospitalization developed in only 2/10 cell-treated patients peaking at 2 - 3 weeks post-procedure. Both patients fully recovered to sinus rhythm after cardioversion therapy, and no further VT was observed. Amiodarone and ivabradine, which were previously reported effective in mitigating post-operative rhythm management in non-human primates injected with PSC-derived cardiomyocytes 15 were used in the current trial. However, ivabradine was only used in 3 patients and then ceased because of its failure to manage VT frequency. During the subsequent 1-6-month post-operative observation window defined per protocol for the primary endpoint assessment, neither group exhibited any sustained VT. Seven serious adverse events (SAEs) were documented in four patients ( Table S3 ). In the Control group, one patient died suddenly at home 8 months post-procedure and no autopsy was performed. In the Cell therapy group, 3 patients experienced 6 SAEs, none of which were fatal. They included the 2 previously mentioned VT deemed likely cell-related, 1 early post-operative (2 days) ventricular fibrillation, 1 episode of cardiac dysfunction and 2 significant liver and renal function impairments defined by AST, ALT>1000U/L and creatinine >200nmol/L; these complications occurred on POD 18 and 20, respectively, were related to the immunosuppressants side effects and resolved following drug adjustments. The non serious adverse events and immune indicators across both groups are summarized in Table S4-S5 , respectively. Efficacy Outcomes The baseline NYHA functional class, MLHFQ scores and 6-minute walk distance (6MWD) were not significantly different between two groups, as shown in Table 1 . Clinical Symptoms (NYHA) At 6 months of follow-up, seven patients in both groups were in NYHA Class II, and two patients were in NYHA Class III. At 12 months of follow-up, 9/10 patients in the Cell therapy group achieved NYHA class II versus 6/10 controls ( Fig. 2A ). One control patient died from a cardiovascular event 8 months post-procedure and failed to complete follow-up. Quality of Life (MLHFQ) At 6 months of follow-up, both groups reported an improved status though not significant different between groups (Absolute MLHFQ: Controls: 16.89 ± 15.89 points vs. hiPSC-CMs: 28.56 ± 27.57 points, P =0.288). At the 12-month follow-up point, reductions were maintained in both groups without between-group differences (Absolute MLHFQ: Controls: 7.75 ± 6.41 points vs. hiPSC-CMs: 19.22 ± 25.08 points, P =0.229) . Functional Capacity (6-minute walk test) At 6 months of follow-up, the Cell therapy group showed a significantly greater improvement in 6MWD relative to baseline, compared to the Control group (Absolute 6MWD: Controls: 412.2 ± 66.05 m vs. hiPSC-CMs: 459.4 ± 45.63 m ; P = 0.070; Δ 6MWD: Controls: 80.56 ± 55.53 m vs . hiPSC-CMs: 138.8 ± 35.83 m, P =0.023) ( Fig. 2B-C ). This trend was maintained at 12 months of follow-up (Absolute 6MWD: Controls. 431.6 ± 72.67 vs . hiPSC-CMs: 489.4 ± 25.56; P = 0.064; Δ 6MWD: Controls: 97.25 ± 51.48 m vs. hiPSC-CMs: 168.8 ± 49.98 m, P =0.014) ( Fig. 2B & 2D ). Left Ventricular Function Baseline LVEF, as assessed by echocardiography, was similar between the two groups (Controls: 36.16 ± 3.86% vs. hiPSC-CMs: 37.80 ± 4.78%; P = 0.410). At 12 months of follow-up, LVEF had improved in all patients but without significant differences between two groups (Absolute LVEF: Controls 41.50 ± 3.88% vs . hiPSC-CMs: 42.56 ± 5.68%; P = 0.665; ΔLVEF: Control: 4.80 ± 3.65% vs. hiPSC-CMs: 4.67 ± 3.54%; P = 0.940) ( Fig. 3A ). On MRI, the evolution of the scar size featured divergent patterns with a reduction in the Cell therapy group contrasting with an increase in Controls. However, the difference did not reach statistical significance at the 12-month follow-up time point (Controls: 13.02 ± 71.57% vs . hiPSC-CMs: -4.71 ± 51.75%; P = 0.564) ( Fig. 3B ). Stroke volume (SV) was initially lower in patients of the Cell therapy group compared with Controls (33.79 ± 13.42 mL vs. 41.07 ± 7.07 mL, respectively, P =0.165). It then increased in the Cell therapy group while it decreased in Controls, yielding 12-month follow-up values of 40.73 ± 16.62 mL and 34.13 ± 8.09 mL, respectively, which resulted in a significant difference when end-study SV data were compared with their respective baseline values (Controls: -8.41 ± 7.92 mL vs. hiPSC-CMs: 9.03 ± 20.15 mL; P =0.036) ( Fig. 3C-D ). The other cardiac functional parameters, either assessed by echocardiography or MRI showed similar results between the two groups and are listed in Table S6 and S7 , respectively. Myocardial perfusion and contractility Baseline myocardial perfusion, as assessed by 99m Tc single photon emission computed tomography/computed tomography ( 99 mTc SPECT-CT) ( Fig. 4A ), was significantly better in the Control group than in the Cell therapy group, as reflected by lower SRS values (Controls: 36.30 ± 5.17 vs . hiPSC-CMs: 44.44 ± 7.15, P = 0.010). At the 12-month follow-up study point, myocardial perfusion had significantly improved after cell therapy compared with Controls (Absolute SRS value: Controls: 34.50 ± 9.49 vs. hiPSC-CMs: 33.89 ± 9.77; ΔSRS: Control -1.50 ± 7.73 vs. hiPSC-CMs: -10.56 ± 4.67, P =0.010). ( Fig. 4B-C ). Since cells were transplanted along the left anterior descending coronary (LAD) artery region, further analysis of the apical myocardial segments showed a similar trend. At 12 months of follow-up, the Cell therapy group achieved a significant reduction in apical regional SRS, whereas the Control group showed an increase, and the difference between the two groups was statistically significant (Control: 0.38 ± 2.33 points vs. hiPSC-CMs: -2.00 ± 2.12 points, P =0.044) ( Fig. S3 ). Myocardial contractile function was quantified by MRI-measured cell-targeted LAD territory Wall Thickening (WT). At 12 months of follow-up, WT had significantly higher improvement in Cell therapy groups, yielding an increase from baseline of -33.1 ± 117.2% and 96.9 ± 129.0% in Controls and cell-treated patients, respectively. ( P =0.047) ( Fig. 4D-F ). Discussion Several clinical trials are currently investigating the use of PSC-based cardiomyocyte transplantation in different formats including cell suspensions, spheroids or epicardial patches 16 . The HEAL-CHF trial, however, is the first randomized controlled trial whose completion yet allows to report safety and efficacy data in 20 patients with ischemic advanced heart failure who received direct transepicardial intramyocardial injections of 2x10 8 allogeneic iPSC-CM during concomitant CABG. With regard to safety, the outcomes of this trial shed light on the three major concerns raised by the clinical translation of PSC-based therapy. The first pertains to tumorigenicity which could result from the persistence, in the transplant, of residual still undifferentiated cells endowed with a potential of uncontrolled proliferation. However, the 1-year results of the HEAL-HF trial, along with those of a previous report in which the follow-up extended to 4 years 8 , provide reassuring data as none of the patients developed a tumour. Further reassurance is provided by another trial which entailed the transplantation of ESC-derived cardiovascular progenitor cells and also failed to document any cell-related tumour with a maximum follow-up of 10 years 17 . More generally, a recent survey of PSC-based trials spanning a variety of diseases and totaling at least 1,200 patients similarly confirmed the safety of the procedure 16 which reflects an improvement in cell differentiation and sorting procedures 18 along with the identification of lineage-specific phenotypic markers and the concurrent development of sensitive assays for detecting them 19 . The second concern is the occurrence of ventricular arrhythmias. Indeed, in keeping with data reported in large animal models of PSC-derived cardiomyocyte transplantation 20–23 , our results show the consistent occurrence of accelerated AIVR and VT which were recorded from D-7 to Day-28 post-operatively in the cell therapy group; however, only two of these VT episodes were considered clinically relevant. While their origin may be multifactorial, the prevailing hypothesis is that these events are caused by the generation of impulses from ectopic pacing rather than reentry; these impulses would originate from a fraction of early-differentiated phenotypically nodal-like cells present in the initial transplant and endowed with an automaticity potential 24,25 . This view is primarily supported by the finding that the time frame of the arrhythmic events, which peaked around one week after the procedure (for this reason, the very early postoperative timing of the only episode of ventricular fibrillation in our series is rather attributed to a complication of surgery) and wane over the next few weeks, grossly mirrors the maturation of these pulse-generating cells 26 . In our experience, and in contrast with data collected in porcine hearts 27 , conventional anti-arrhythmic drugs failed to suppress the arrhythmia burden. In particular, the failure of ivabradine, a HCN channel inhibitor, was possibly due to the fact that the drug suppresses the natural sino-atrial nodal firing which otherwise helps in preventing VT. Whatsoever, the prevention of cell-triggered ventricular arrhythmias is an important concern which might be partly addressed by the optimization of iPSC differentiation procedures so as to maximize the maturation of their cardiomyocyte progeny before implantation 28 . An alternate solution is the epicardial delivery of a tissue-engineered patch which can still contribute to improve mechanical function despite the lack of electro-mechanical connections of the embedded cells with the host cardiomyocytes 29,30 . Of note, because this study was primarily designed to understand the potential safety issues raised by trans-epicardial iPS-CM injections and to explore their effects on rhythmic events, no implantable cardioverter-defibrillator (ICD) was implanted. However, since current guidelines provide the strongest recommendation (Class I) for ICD in patients with LVEF ≤35% (NYHA class II-III) 31 , one can anticipate that, in clinical practice, most of the patients eligible for cell therapy would qualify for an ICD implantation, which yet represents a reassuring safety net. The third concern is the rejection of the graft linked to the allogeneic origin of the cells whose major practical advantages (off-the-shelf availability, reduction of production costs) are offset by the induction of an immune response 32 currently managed by immunosuppressive drugs. While, in the absence of a consensus, we had initially considered a lifelong immunosuppressive regimen, our hospital's IRB downscaled this duration to 1 month on the basis of a risk analysis. Of note, an even rather vigorous immunosuppressive treatment may not consistently prevent the occurrence of DSA, as shown by our data, a concern compounded by the fact that this alloimmune response remained clinically silent. Actually, beyond the choice of the drugs and their dosing which vary from one protocol to the other 16 , a key issue is the duration of the treatment. This, in turn, raises the fundamental question of the expected mechanism of action of the transplanted cells. If one adheres to the initial objective of a remuscularization of the myocardium, then the immunosuppressive treatment should remain uninterrupted. However, in these patients who often have renal and hepatic co-morbidities, a lifelong immunosuppression is fraught with several side effects, indeed recorded in the present trial, explaining why most of the protocols entail its only transient implementation and/or tapering of dosing. However, such an immunosuppression-free strategy implies a paradigm shift in that absence 33 or withdrawal of immunosuppression 29 will cause rejection of the graft and thus exclusive reliance on the paracrine effect exerted by the cells as long as they remain alive; the cell-released biomolecules may then contribute to cardiac repair through mechanisms like reduction of fibrosis or enhancement of angiogenesis, rather than direct force generation, and the once activated pathways could then remain self-sustained, accounting for the persistence of the functional benefits despite the disappearance of the cells, as reported in cardiac 34 and non-cardiac preclinical models 35 . Of note, even though this paracrine mechanism of action is predominant, the use of cardiac-committed cells still looks important as the content of their lineage-specific cargo seems best appropriate for salvage of cardiac tissue through activation of diverse healing pathways 36,37 . Regardless of the mechanism of action of the transplanted cells, it is likely important to leverage their cardio-reparative properties by extending their duration of engraftment, hence the importance of the strategies currently developed to eliminate immunosuppression or at least reduce its dosing. These strategies primarily include the use of Major Histocompatibility Complex haplotyped cell lines 38 gene-edited cell lines made “hypoimmunogenic” 39 or combined differentiation, from the same PSC line, of both cardiomyocytes and antigen-presenting cells, with the latter first made tolerogenic and subsequently delivered to induce an immune unresponsiveness specific for the sequentially transplanted cardiomyocytes 40 . In addition to safety data, this study also provides some encouraging hints of efficacy, primarily manifest as an improvement in the functional status, exercise capacity and myocardial perfusion and contractility. A particularly interesting finding was that quantitative analysis of the SRS showed its decrease in the cell therapy group, while it remained unchanged in control patients and even worsened in some of them. This outcome measure has been reported as one of the best independent predictors of major adverse cardiac events, including mortality, in patients with suspected or known coronary artery disease 41–44 , independent of hemodynamic changes, myocardial contractility, and medical treatment. As all patients in this trial underwent a comparable myocardial revascularization, this result is unlikely to have been biased by the concomitant CABG and could rather reflect a cell-induced increase in cardiac angiogenesis, consistent with the paracrine effects of the grafted cells. However, these positive outcomes failed to translate in a significant difference in LVEF between the two groups. This might also be due to the concurrent surgical revascularization which already yielded increases in LVEF in the order of magnitude of what has been reported in previous studies featuring a similar design, i.e., CABG alone vs. CABG + cells 45,46 but may then have let little space, in particular in view of the small sample sizes, for documenting a potential incremental benefit attributable to the cells. In the future, comparison of stand-alone iPSC-CM delivery with either sham procedures or standard of care would be helpful for unraveling a cardio-reparative effect specifically induced by the cellular graft. L imitations We acknowledge some limitations of this study, including the limited number of patients in each group, the lack of placebo injections in the Control group and a possibly sub-optimal immunosuppression regimen. We also acknowledge that the greater improvements in stroke volume ,SRS and myocardial contractility following cell therapy may have been skewed by the fact that, despite randomization, baseline values for these two metrics were more impaired in this group, with an attendant risk of regression to the mean. However, both the randomized design, the first of its type with iPSC-CM transplantation, as well as the extension of follow-up to one year yet tend to validate the conclusions pertaining to safety and, to a lesser extent, efficacy. Conclusions and Perspectives HEAL-CHF study provides valuable real-world data that should be beneficial for advancing the field of cardiac regenerative therapy. The key finding is that in these patients with severe heart failure, those who received cell therapy in addition to CABG experienced greater improvements in exercise capacity, a now recognized valid metric by the FDA, and myocardial perfusion and that, importantly, these benefits were not achieved at the cost of an increased risk, as evidenced by the absence of tumour and of life-threatening arrhythmias. Nevertheless, we recognize that our experimental design was less than perfect and needs to be further refined in future clinical trials. These areas of improvement should include (1) the selection of the optimal cell dosage and immunosuppression regimen, which is particularly challenging because the limitations of animal models preclude a fully reliable translatability of non-clinical data to the clinical setting, (2) the investigation of less invasive routes of cell delivery compatible with repeated dosing to maximise the benefits of hiPSC-CMs therapy, and (3) the fine-tuning of patient selection, possibly with the aid of artificial intelligence 47 , to focus on those expected to be responders identified by baseline characteristics like the presence of inflammation 48 or their genotypic profile 49 . In this burgeoning landscape, the HEAL-CHF trial already represents a clear step forward for utilizing regenerative medicine approaches to treat human cardiac diseases. Declarations DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. FUNDING STATEMENT This work was supported by the National Key Research and Development Program of China (2022YFA1105100) and the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai. This work was also supported by grants from HELP Therapeutics Co., Ltd. COMPETING INTERESTS J.W. is a scientific founder and equity holder in HELP Therapeutics Co., Ltd. P.M. is a Medical Consultant for HELP Therapeutics Co., Ltd. Q.W., Y.X., J.F. and C.L. are current employees of HELP Therapeutics Co., Ltd. All other authors declare no competing interests. ETHICS APPROVAL STATEMENT The study was registered at ClinicalTrials.gov (NCT03763136), and the protocol was approved by the Institutional Ethics Committee of Nanjing Drum Tower Hospital, affiliated with Nanjing University (No. SC202000102), and by the National Health Commission of the People's Republic of China (MR-32-21-014649). AUTHOR CONTRIBUTIONS D.W., J.W. and P.M. contributed to the conceptualization and designed the clinical trial, and D.W. served as the Principal Investigator, who performed surgical interventions. H.Z., Y.X. and X.Z. performed patients’ recruitment, follow-ups and data analysis. Q.W., C.L., J.F. and Y.X. were responsible for hiPSC-CMs manufacturing, quality control and logistics. All authors reviewed and approved the submission of the paper. References Khan MS, Shahid I, Bennis A, Rakisheva A, Metra M, Butler J. Global epidemiology of heart failure. Nat Rev Cardiol. 2024 Oct;21(10):717–34. 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Stüdemann T, Schwarzová B, Schneidewind T, Geertz B, von Bibra C, Nehring M, et al. Impulse initiation in engrafted pluripotent stem cell-derived cardiomyocytes can stimulate the recipient heart. Stem Cell Rep. 2024 Aug 13;19(8):1053–60. Ichimura H, Kadota S, Kashihara T, Yamada M, Ito K, Kobayashi H, et al. Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo. Sci Rep. 2020 Jul 17;10(1):11883. Nakamura K, Neidig LE, Yang X, Weber GJ, El-Nachef D, Tsuchida H, et al. Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes. Stem Cell Rep. 2021 Oct 12;16(10):2473–87. Thomas D, Cunningham NJ, Shenoy S, Wu JC. Human-induced pluripotent stem cells in cardiovascular research: current approaches in cardiac differentiation, maturation strategies, and scalable production. Cardiovasc Res. 2022 Jan 7;118(1):20–36. Jebran AF, Seidler T, Tiburcy M, Daskalaki M, Kutschka I, Fujita B, et al. Engineered heart muscle allografts for heart repair in primates and humans. Nature. 2025 Mar;639(8054):503–11. Gerbin KA, Yang X, Murry CE, Coulombe KLK. Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts. PloS One. 2015;10(7):e0131446. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2018 Sep 25;138(13):e272–391. Deuse T, Hu X, Gravina A, Wang D, Tediashvili G, De C, et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat Biotechnol. 2019 Mar;37(3):252–8. Lin Y, Sato N, Hong S, Nakamura K, Ferrante EA, Yu ZX, et al. Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques. Cell Stem Cell. 2024 Jul 5;31(7):974-988.e5. Zhu K, Wu Q, Ni C, Zhang P, Zhong Z, Wu Y, et al. Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman Primates. Circ Res. 2018 Mar 30;122(7):958–69. Li Y, Li D, Raisman G. Functional Repair of Rat Corticospinal Tract Lesions Does Not Require Permanent Survival of an Immunoincompatible Transplant. Cell Transplant. 2016;25(2):293–9. González-King H, Rodrigues PG, Albery T, Tangruksa B, Gurrapu R, Silva AM, et al. Head-to-head comparison of relevant cell sources of small extracellular vesicles for cardiac repair: Superiority of embryonic stem cells. J Extracell Vesicles. 2024 May;13(5):e12445. Tachibana A, Santoso MR, Mahmoudi M, Shukla P, Wang L, Bennett M, et al. Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium. Circ Res. 2017 Sep 1;121(6):e22–36. Kawamura T, Miyagawa S, Fukushima S, Maeda A, Kashiyama N, Kawamura A, et al. Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates. Stem Cell Rep. 2016 Mar 8;6(3):312–20. Shasteen 2 min read | Hayley. BioSpace. 2022 [cited 2025 Jul 1]. CRISPR and ViaCyte Dose First Patient in Historic Type 1 Diabetes Trial. Available from: https://www.biospace.com/crispr-and-viacyte-announce-phase-i-clinical-trial-for-type-1-diabetes Cai S, Hou J, Fujino M, Zhang Q, Ichimaru N, Takahara S, et al. iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells. Stem Cell Rep. 2017 May 9;8(5):1174–89. Schinkel AFL, Boiten HJ, Van Der Sijde JN, Ruitinga PR, Sijbrands EJG, Valkema R, et al. Prediction of 9-year cardiovascular outcomes by myocardial perfusion imaging in patients with normal exercise electrocardiographic testing. Eur Heart J - Cardiovasc Imaging. 2012 Nov 1;13(11):900–4. Uebleis C, Becker A, Griesshammer I, Cumming P, Becker C, Schmidt M, et al. Stable Coronary Artery Disease: Prognostic Value of Myocardial Perfusion SPECT in Relation to Coronary Calcium Scoring—Long-term Follow-up. Radiology. 2009 Sep;252(3):682–90. Gimelli A, Rossi G, Landi P, Marzullo P, Iervasi G, L’Abbate A, et al. Stress/Rest Myocardial Perfusion Abnormalities by Gated SPECT: Still the Best Predictor of Cardiac Events in Stable Ischemic Heart Disease. J Nucl Med. 2009 Apr;50(4):546–53. Adelstein EC, Tanaka H, Soman P, Miske G, Haberman SC, Saba SF, et al. Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy. Eur Heart J. 2011 Jan 1;32(1):93–103. Ulus AT, Mungan C, Kurtoglu M, Celikkan FT, Akyol M, Sucu M, et al. Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial). Int J Stem Cells. 2020 Nov 30;13(3):364–76. Pätilä T, Lehtinen M, Vento A, Schildt J, Sinisalo J, Laine M, et al. Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2014 Jun;33(6):567–74. Cunningham JW, Abraham WT, Bhatt AS, Dunn J, Felker GM, Jain SS, et al. Artificial Intelligence in Cardiovascular Clinical Trials. J Am Coll Cardiol. 2024 Nov 12;84(20):2051–62. Perin EC, Borow KM, Henry TD, Jenkins M, Rutman O, Hayes J, et al. Mesenchymal precursor cells reduce mortality and major morbidity in ischaemic heart failure with inflammation: DREAM-HF. Eur J Heart Fail. 2024 Nov 26; Rieger AC, Myerburg RJ, Florea V, Tompkins BA, Natsumeda M, Premer C, et al. Genetic determinants of responsiveness to mesenchymal stem cell injections in non-ischemic dilated cardiomyopathy. EBioMedicine. 2019 Oct;48:377–85. Additional Declarations Yes there is potential Competing Interest. J.W. is a scientific founder and equity holder in HELP Therapeutics Co., Ltd. P.M. is a Medical Consultant for HELP Therapeutics Co., Ltd. Q.W., Y.X., J.F. and C.L. are current employees of HELP Therapeutics Co., Ltd. All other authors declare no competing interests. Supplementary Files CONSORT2025checklist.docx CONSORT 2025 Checklist hiPSCCMpatientSuppl20250817.pdf Supplement materials StudyProtocolv6.1Final.pdf Clinical Trial Protocol Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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(\u003cstrong\u003eD\u003c/strong\u003e) 12-month absolute change in SV, as measured by MRI. Differences between the groups (two-tailed Student's \u003cem\u003et\u003c/em\u003e-test (A-D) are numerically annotated on the corresponding panels.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7414031/v1/a9ff13ec2d458853c18f3059.png"},{"id":91962640,"identity":"c1a794fa-0ff1-4bc0-850b-f15f44b86633","added_by":"auto","created_at":"2025-09-23 07:56:41","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":298906,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging and quantitative analysis of myocardial perfusion and contractility. 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The cell-targeted LAD territory was defined as mid anterior (7), mid anteroseptal (8), apical anterior (13), apical septal (14), apical inferior (15), apical lateral (16) segments according to the 17-segment myocardial model. Differences between groups (two-tailed Student's \u003cem\u003et\u003c/em\u003e-test) are numerically annotated in the corresponding panels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7414031/v1/a2b16c20151a58dceb594feb.png"},{"id":91963386,"identity":"efb05da5-903c-486b-b8c2-348d5255de80","added_by":"auto","created_at":"2025-09-23 08:04:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1513815,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7414031/v1/0d79d5cc-b2af-4203-b7c6-8cb1a07831de.pdf"},{"id":91960794,"identity":"bcefbf0c-1541-4f66-af26-bc87e2f05c7a","added_by":"auto","created_at":"2025-09-23 07:48:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31163,"visible":true,"origin":"","legend":"CONSORT 2025 Checklist","description":"","filename":"CONSORT2025checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7414031/v1/21e479f02124b824df04bfaf.docx"},{"id":91960799,"identity":"f8c5ec19-3293-4864-99bf-7cf7c2db8a41","added_by":"auto","created_at":"2025-09-23 07:48:41","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":542803,"visible":true,"origin":"","legend":"Supplement materials","description":"","filename":"hiPSCCMpatientSuppl20250817.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7414031/v1/f38948f79f350c30ecc56eaa.pdf"},{"id":91960800,"identity":"6c150f4a-6003-40d9-a314-735ce4409c47","added_by":"auto","created_at":"2025-09-23 07:48:41","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":918016,"visible":true,"origin":"","legend":"Clinical Trial Protocol","description":"","filename":"StudyProtocolv6.1Final.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7414031/v1/3a3767ba3dbfe100266b42b0.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nJ.W. is a scientific founder and equity holder in HELP Therapeutics Co., Ltd. P.M. is a Medical Consultant for HELP Therapeutics Co., Ltd. Q.W., Y.X., J.F. and C.L. are current employees of HELP Therapeutics Co., Ltd. All other authors declare no competing interests.","formattedTitle":"Epicardial Injections of Allogenic Human Induced Pluripotent Stem Cells-derived Cardiomyocytes for Severe Chronic Ischemic Heart Failure: The HEAL-CHF Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHeart failure (HF) remains a leading cause of death and disability worldwide, affecting more than 56 million people\u003csup\u003e1,2\u003c/sup\u003e. This chronic condition imposes a substantial burden on healthcare systems, driven by its high morbidity, frequent hospitalizations, and increased mortality rates\u003csup\u003e2\u0026ndash;4\u003c/sup\u003e. Despite significant advances in pharmacological and device-based interventions, these strategies, while effective for relieving symptoms and slowing disease progression, still fail to address one of the major root causes of the disease, i.e., the loss of a substantial number of cardiomyocytes\u003csup\u003e5\u003c/sup\u003e. Over the past years, it has become increasingly recognized that compensation for this loss aimed at achieving a true myocardial regeneration, as opposed to repair, best required to deliver cardiac-committed cells.\u003c/p\u003e\n\u003cp\u003eSuch cells can now be produced in large amounts through the targeted differentiation of pluripotent stem cells (PSC). Within this framework induced pluripotent stem cells (iPSC), reprogrammed from somatic cells, have taken precedence over embryonic stem cells (ESC) because of an easier procurement and the lack of ethical issues. Even though iPSC-derived cardiomyocytes (iPSC-CMs) still display some features of immaturity, preclinical studies in rodent and nonhuman primate models of myocardial infarction (MI)-induced heart failure have shown that they had the capacity to engraft, electrically integrate, and improve cardiac function\u003csup\u003e6\u003c/sup\u003e thus suggesting their potential as a transformative therapeutic option.\u003c/p\u003e\n\u003cp\u003eIn our previous landmark first-in-human study, two individuals in China became the first subjects worldwide to receive intramyocardial injections of allogeneic hiPSC-CMs\u003csup\u003e7,8\u003c/sup\u003e in conjunction with coronary artery bypass grafting (CABG). While the observed improvements in exercise capacity, left ventricular (LV) function and quality of life were interpreted with caution because of the confounding effect of the associated myocardial revascularization, the major information drawn from this early experience was the lack of cell-related safety issues over a now 4-year follow-up, thereby providing a strong incentive to consolidate these data by a larger-size randomized trial.\u003c/p\u003e\n\u003cp\u003eIn the present study, the HEAL-CHF trial was thus specifically designed to evaluate the safety and efficacy of transepicardial intramyocardial injections of allogeneic hiPSC-CMs in patients with severe chronic ischemic heart failure undergoing CABG. Conducted at Nanjing Drum Tower Hospital, this randomized, open-label, controlled study is the first and largest clinical trial to date to report outcome data using a PSC-based regenerative treatment of heart failure. The positivity of these outcomes should help HEAL-CHF to bridge the translational gap between preclinical advancements and real-world clinical applications and thus contribute to further integrate iPSC-CMs among the treatment options for severe heart failure.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003e\u003cstrong\u003eTrial oversight\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe HEAL-CHF study is an investigator-initiated, single-center, randomized, open-label, controlled trial conducted at Nanjing Drum Tower Hospital, affiliated with Nanjing University. The trial was designed to assess the safety and efficacy of intramyocardial injections of hiPSC-CMs in patients with severe chronic ischemic heart failure who had otherwise an indication for CABG. The study was initiated in August 2021, with the first participant enrolled October, 15, 2021 and final enrolment was completed on May, 5, 2023. The trial was registered at clinicalTrials.gov (NCT03763136), and the protocol was approved by the Institutional Ethics Committee of Nanjing Drum Tower Hospital, affiliated with Nanjing University (No. SC202000102), and by the National Health Commission of the People\u0026apos;s Republic of China (MR-32-21-014649). The study was conducted in accordance with the tenets of the Declaration of Helsinki. The authors take responsibility for the accuracy and completeness of the data and analyses.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eScreening and eligibility\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eA comprehensive inventory of inclusion and exclusion criteria is provided in \u003cstrong\u003eTable S1\u003c/strong\u003e. Briefly, patients between 35 and 75 years of age with symptoms (New York Heart Association [NYHA] class III or IV despite guideline-directed medical therapy), severe ischemic heart failure (LV ejection fraction \u0026le;45%), and indication for CABG surgery were eligible for enrolment. Patients with any other significant cardiovascular disease or a history of malignancy within the previous five years were excluded from the study. All eligible patients provided a written inform consent.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and blinding\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe trial employed a open-label design. Only the outcome assessors were blinded to group allocation. Prior to trial initiation, a statistician generated 20 random numbers using the SAS PLAN procedure, and participants were randomized in a 1:1 ratio into two groups, labeled as numbers 1 to 20. Each randomization result was sealed in an opaque envelope of identical specifications, with the corresponding number printed on the envelope. This approach ensured that during the participant screening process and before randomization, the research team was blinded to the group allocation, thereby maintaining the integrity of the randomization process.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eFollowing a screening period, 20 patients were randomly assigned (1:1) to receive either (i) CABG only (Control group, n=10), or (ii) CABG combined with transplantation of hiPSC-CMs (Cell therapy group, n=10).\u0026nbsp;The pre-specified\u0026nbsp;sample size of 20 was based on an empirical estimate to evaluate the initial safety and tolerability of hiPSC-CMs.\u0026nbsp;For patients in the\u0026nbsp;Cell therapy\u0026nbsp;group, 2\u0026times;10\u003csup\u003e8\u0026nbsp;\u003c/sup\u003ehiPSC-CMs were injected intramyocardially, once the coronary anastomoses had been completed, at 10 discrete sites surrounding the area of myocardial infarction, using a 30 gauge needle. The sites were determined by the surgeon based on preoperative imaging and intraoperative inspection and were documented. Post-operative evaluations, including cardiac imaging, laboratory tests, and functional assessments, were performed 1, 6, and 12 months after the procedure. A detailed study protocol is available in the Supplementary Information.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eImmunosuppressive\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eprotocol\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003ePatients in the\u0026nbsp;Cell therapy group\u0026nbsp;were administered\u0026nbsp;the following\u0026nbsp;immunosuppressive\u0026nbsp;regimen:\u0026nbsp;intravenous immunoglobulin (2.5\u0026nbsp;g,\u0026nbsp;IV) on preoperative day 1, intraoperative day (IOD), and postoperative day (POD)\u0026nbsp;3, combined with methylprednisolone\u0026nbsp;(500\u0026nbsp;mg,\u0026nbsp;IV)\u0026nbsp;on preoperative day 1; rituximab (20\u0026nbsp;mg,\u0026nbsp;IV) on IOD and POD4 to target CD20\u003csup\u003e+\u003c/sup\u003e B-cell depletion; oral tacrolimus started preoperative day 3 and dose-adjusted to maintain trough levels within the target range of 3-5 ng/mL, as monitored by blood drug concentration until POD28, concurrently with mycophenolate mofetil (1 g, orally on preoperative day 1, increasing to 1.5 g/day until POD28) and prednisone (20 mg/day started IOD until POD28). The Control group did not receive any immunosuppressive medications.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe primary outcomes, focused on safety, were the incidence of sustained ventricular tachycardia (VT), assessed at 1 and 6 month post-procedure using 24-hour holter electrocardiogram monitoring, and the occurrence of newly formed tumors, evaluated from the baseline to 12 months post-intervention using \u003csup\u003e18\u003c/sup\u003eF-Fluorodeoxyglucose (FDG) positron emission \u0026nbsp;tomography-computed tomography scan (PET-CT). The secondary safety end points included serious adverse events (all-cause death, non-fatal myocardial infarction, stroke, any surgical complication) during the perioperative period, alloimmune responses (based on assays of donor-specific antibodies), perioperative electrocardiographic (EKG) changes and cardiac failure biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP]). The secondary efficacy outcomes encompassed a range of assessments, including NYHA functional classification, quality of life (assessed by the Minnesota Living with Heart Failure Questionnaire [MLHFQ] score), exercise tolerance (assessed by the 6-minute walk test), LV function and structure (assessed by echocardiography and cardiac magnetic resonance imaging [MRI]), myocardial perfusion (assessed by \u003csup\u003e99m\u003c/sup\u003eTc single-photon emission with computed tomography\u0026nbsp;[SPECT-CT]), myocardial metabolism (using\u003csup\u003e18\u003c/sup\u003eF-FDG PET-CT) and incidence of major adverse cardiac events (defined as all-cause death, non-fatal myocardial infarction, and rehospitalization for heart failure).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eG\u003c/strong\u003e\u003cstrong\u003eeneration and preparation\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eh\u003c/strong\u003e\u003cstrong\u003eiPSC\u003c/strong\u003e\u003cstrong\u003e-CMs\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003ehiPSCs were derived from peripheral blood mononuclear cells that had been transduced with the transcription factors Oct3/4, Sox2, c-Myc, and Klf4.\u0026nbsp;The differentiation of hiPSC-CMs from hiPSCs was conducted in accordance with previously established protocols\u003csup\u003e9,10\u003c/sup\u003e. All reprogramming and manufacturing processes were meticulously executed in the GMP-grade laboratories of HELP Therapeutics. The hiPSC-CMs were subjected to rigorous quality control tests. Cryopreserved hiPSC-CMs were transported and stored in a liquid nitrogen tank at the Nanjing Drug Tower Hospital Stem Cell Center. Prior to transplantation, cryopreserved cardiomyocytes were thawed in a 37\u0026deg;C water bath and then resuspended in a 5% albumin solution.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eElectrocardiographic monitoring\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eContinuous ambulatory EKG monitoring was performed using a lightweight ambulatory EKG recorder (Light-1800 series, GE Healthcare, Chicago, USA) with recording durations of 24, 48, or 72 h, depending on clinical requirements.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eMeasurements from e\u003c/strong\u003e\u003cstrong\u003echocardiography\u003c/strong\u003e\u003cstrong\u003e, MRI,\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSPECT\u003c/strong\u003e\u003cstrong\u003e-CT\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eand PET\u003c/strong\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003cstrong\u003eCT\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eTwo-dimensional speckle-tracking echocardiography was performed in all enrolled patients according to a standardized protocol \u003csup\u003e11\u003c/sup\u003e. All examinations were performed by a single senior cardiologist, blinded to group allocation, using a Vivid E95 ultrasound system (GE Healthcare). Patients were positioned in the left lateral decubitus position with quiet respiration, and image acquisition was ECG-gated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCardiac MRI examinations were performed using two identical 3.0T MRI scanners (Achieva and Ingenia, Philips Medical Systems, Best, Netherlands), equipped with a 32-element phased array body coil \u003csup\u003e12\u003c/sup\u003e. Late gadolinium enhancement (LGE) imaging was performed 10-15 min after intravenous administration of 0.2 mmol/kg MRI contrast agent (Magnevist, Bayer Healthcare, Berlin, Germany) using phase-sensitive inversion recovery T1-weighted gradient-echo pulse sequences. The infarcted myocardium was defined on LGE images as a region with mean signal intensity at least five standard deviations higher than that of a reference region of interest (ROI) drawn in the remote myocardium. Post-processing and quantitative analysis of CMR images were performed using a dedicated software (CVI42, version 5.13.1, Circle Cardiovascular Imaging Inc., Calgary, Canada).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSPECT-CT imaging was acquired using a dual-detector gamma camera (GE Healthcare)\u003csup\u003e13\u003c/sup\u003e. Image acquisition started 60-90 min post-intravenous administration of 740-925 MBq \u003csup\u003e99m\u003c/sup\u003eTc-sestamibi under resting conditions\u0026nbsp;to assess myocardial perfusion. Summed rest score (SRS) was calculated by summing scores of the 17 segments. Myocardial metabolism imaging was conducted using a high-resolution full-ring PET scanner (Vereos,\u0026nbsp;Philips Healthcare)\u003csup\u003e14\u003c/sup\u003e. Patients were first administered a glucose load and subsequently received intravenous injections of regular short-acting insulin, with the dosage adjusted according to their serum glucose levels. This was followed by the intravenous injection of 4.44 MBq/kg of \u003csup\u003e18\u003c/sup\u003eF-FDG. After acquisition, gated and non-gated SPECT-CT and PET-CT data sets were exported to a nuclear cardiology processing platform (Xeleris 4DR, GE Healthcare) for synchronized analysis. The gated SPECT-CT and PET-CT images were analyzed using identical functional parameters with the ECTB software (version 4.0, Emory University Hospital, Atlanta, USA).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eContinuous data were presented as the mean \u0026plusmn; SD, and discrete data were presented as number (%). For participants with incomplete follow-up, the Last Observation Carried Forward method was applied to impute missing endpoint data. Specifically, in the Control group, one patient lost to follow up after the 6-month visit had his 12-month outcomes imputed based on the last available 6-month measurements. Data distribution was evaluated with the Shapiro-Wilk normality test. Normally and non-normally distributed data were compared with two-tailed Student\u0026apos;s \u003cem\u003et\u003c/em\u003e-tests and the Wilcoxon rank-sum test, respectively. Statistical analyses were performed with SPSS software (version 22.0), and a \u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue of \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom October 2021 to May 2023, a total of 625 patients diagnosed with advanced heart failure were screened at Nanjing Drum Tower Hospital. Of these, 55 met the enrollment criteria \u003cstrong\u003e(Table S1)\u003c/strong\u003e and 20 of them were finally included in the trial (\u003cstrong\u003eFig 1\u003c/strong\u003e). The baseline characteristics of the two groups were well balanced, as illustrated in \u003cstrong\u003eTable 1\u003c/strong\u003e. All patients underwent CABG surgery with half of them receiving additional trans-epicardial injections of 2x10\u003csup\u003e8\u003c/sup\u003e hiPSC-CMs after completion of the CABG anastomoses. Patients in the Control group did not receive sham injections.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003cstrong\u003eBaseline characteristics of randomized patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"104%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003cp\u003e(n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003eCell therapy group\u003c/p\u003e\n \u003cp\u003e(n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003cp\u003e(2-tailed)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e9 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e9 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e53.70\u0026plusmn;8.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e54.00\u0026plusmn;11.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.948\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003ePhysical findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eBody-mass index, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e24.64\u0026plusmn;4.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e23.95\u0026plusmn;2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.703\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eResting Heart rate, beats/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e76.70\u0026plusmn;10.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e78.60\u0026plusmn;7.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.635\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eSystolic Blood Pressure, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e116.80\u0026plusmn;10.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e117.20\u0026plusmn;12.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.939\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eDiastolic Blood Pressure, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e74.80\u0026plusmn;9.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e71.60\u0026plusmn;7.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.396\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eRisk Factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Smoking (current or former)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e7 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e7 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Drinking (current or former)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.650\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e4 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Obesity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.474\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hyperlipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eCardiovascular prognostic parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Left ventricular ejection fraction (MRI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e28.08\u0026plusmn;9.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e27.57\u0026plusmn;4.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.871\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eLeft ventricular ejection fraction (ECHO)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e36.16\u0026plusmn;3.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e37.80\u0026plusmn;4.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.410\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; NYHA functional class\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e3.10\u0026plusmn;0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e3.10\u0026plusmn;0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; 6MWD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e326.0\u0026plusmn;72.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e321.1\u0026plusmn;60.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.876\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; MLHFQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e44.4\u0026plusmn;23.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e47.6\u0026plusmn;22.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.759\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; SYNTAX score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e23.40\u0026plusmn;3.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e22.50\u0026plusmn;3.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.539\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Myocardial infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e7 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e6 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Arrhythmia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; Stent implantation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e4 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; PTCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e.474\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp; PCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData presented as mean\u0026plusmn;SD or n (%). MRI: magnetic resonance imaging; ECHO: Echocardiography; NYHA: New York Heart Association; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; PTCA: Percutaneous Transluminal Coronary Angioplasty; PCI: Percutaneous Coronary Intervention; 6MWD: 6-mintue walking test distance; MLHFQ: Minnesota Living with Heart Failure Questionnaire.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Safety Outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSimilar with our previous findings in 2 patients followed up to 4 years\u0026nbsp;\u003csup\u003e8\u003c/sup\u003e, no cases of \u003cem\u003ede novo\u003c/em\u003e tumor formation were identified at the 12-month follow-up time point in the Cell therapy group, as assessed by \u003csup\u003e18\u003c/sup\u003eF-FDG PET-CT (\u003cstrong\u003eFig. S1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccelerated idiopathic ventricular rhythm (AIVR) occurred in all patients following hiPSC-CMs transplantation (\u003cstrong\u003eTable S2\u003c/strong\u003e) and featured a distinct temporal pattern (\u003cstrong\u003eFig. S2\u003c/strong\u003e), with a typical emergence at Day 5-7 post-transplantation. However, clinically significant VT (\u0026gt;140 bpm) requiring a prolongation of hospitalization developed in only 2/10 cell-treated patients peaking at 2 - 3 weeks post-procedure. Both patients fully recovered to sinus rhythm after cardioversion therapy, and no further VT was observed. Amiodarone and ivabradine, which were previously reported effective in mitigating post-operative rhythm management in non-human primates injected with PSC-derived cardiomyocytes\u003csup\u003e15\u003c/sup\u003e were used in the current trial. However, ivabradine was only used in 3 patients and then ceased because of its failure to manage VT frequency. During the subsequent 1-6-month post-operative observation window defined \u003cem\u003eper protocol\u003c/em\u003e for the primary endpoint assessment, neither group exhibited any sustained VT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeven serious adverse events (SAEs) were documented in four patients (\u003cstrong\u003eTable S3\u003c/strong\u003e). In the Control group, one patient died suddenly at home 8 months post-procedure and no autopsy was performed. In the Cell therapy group, 3 patients experienced 6 SAEs, none of which were fatal. They included the 2 previously mentioned VT deemed likely cell-related, 1 early post-operative (2 days) ventricular fibrillation, 1 episode of cardiac dysfunction and 2 significant liver and renal function impairments defined by AST, ALT\u0026gt;1000U/L and creatinine \u0026gt;200nmol/L; these complications occurred on POD 18 and 20, respectively, were related to the immunosuppressants side effects and resolved following drug adjustments. The non serious adverse events and immune indicators across both groups are summarized in \u003cstrong\u003eTable S4-S5\u003c/strong\u003e, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy Outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline NYHA functional class, MLHFQ scores and 6-minute walk distance (6MWD) were not significantly different between two groups, as shown in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Symptoms (NYHA)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 6 months of follow-up, seven patients in both groups were in NYHA Class II, and two patients were in NYHA Class III. At 12 months of follow-up, 9/10 patients in the Cell therapy group achieved NYHA class II versus 6/10 controls (\u003cstrong\u003eFig. 2A\u003c/strong\u003e). One control patient died from a cardiovascular event 8 months post-procedure and failed to complete follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality of Life (MLHFQ)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 6 months of follow-up, both groups reported an improved status though not significant different between groups (Absolute MLHFQ: Controls: 16.89 \u0026plusmn; 15.89 points \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 28.56 \u0026plusmn; 27.57 points, \u003cem\u003eP\u003c/em\u003e=0.288). At the 12-month follow-up point, reductions were maintained in both groups without between-group differences (Absolute MLHFQ: Controls: 7.75 \u0026plusmn; 6.41 points \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 19.22 \u0026plusmn; 25.08 points, \u003cem\u003eP\u003c/em\u003e=0.229) .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunctional Capacity (6-minute walk test)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 6 months of follow-up, the Cell therapy group showed a significantly greater improvement in 6MWD relative to baseline, compared to the Control group (Absolute 6MWD: Controls: 412.2 \u0026plusmn; 66.05 m \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 459.4 \u0026plusmn; 45.63 m ; \u003cem\u003eP\u003c/em\u003e = 0.070; \u0026Delta; 6MWD: Controls: 80.56 \u0026plusmn; 55.53 m \u003cem\u003evs\u003c/em\u003e. hiPSC-CMs: 138.8 \u0026plusmn; 35.83 m, \u003cem\u003eP\u003c/em\u003e=0.023) (\u003cstrong\u003eFig. 2B-C\u003c/strong\u003e). This trend was maintained at 12 months of follow-up (Absolute 6MWD: Controls. 431.6 \u0026plusmn; 72.67\u003cem\u003e\u0026nbsp;vs\u003c/em\u003e. hiPSC-CMs: 489.4 \u0026plusmn; 25.56; \u003cem\u003eP\u003c/em\u003e = 0.064; \u0026Delta; 6MWD: Controls: 97.25 \u0026plusmn; 51.48 m \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 168.8 \u0026plusmn; 49.98 m, \u003cem\u003eP\u003c/em\u003e=0.014) (\u003cstrong\u003eFig. 2B \u0026amp; 2D\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLeft Ventricular Function\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline LVEF, as assessed by echocardiography, was similar between the two groups (Controls: 36.16 \u0026plusmn; 3.86% \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 37.80 \u0026plusmn; 4.78%; \u003cem\u003eP\u003c/em\u003e = 0.410). At 12 months of follow-up, LVEF had improved in all patients but without significant differences between two groups (Absolute LVEF: Controls 41.50 \u0026plusmn; 3.88% \u003cem\u003evs\u003c/em\u003e. hiPSC-CMs: 42.56 \u0026plusmn; 5.68%;\u003cem\u003e\u0026nbsp;P\u003c/em\u003e = 0.665; \u0026Delta;LVEF: Control: 4.80 \u0026plusmn; 3.65% \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 4.67 \u0026plusmn; 3.54%; \u003cem\u003eP\u003c/em\u003e = 0.940) (\u003cstrong\u003eFig. 3A\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn MRI, the evolution of the scar size featured divergent patterns with a reduction in the Cell therapy group contrasting with an increase in Controls. However, the difference did not reach statistical significance at the 12-month follow-up time point (Controls: 13.02 \u0026plusmn; 71.57%\u003cem\u003e\u0026nbsp;vs\u003c/em\u003e. hiPSC-CMs: -4.71 \u0026plusmn; 51.75%; \u003cem\u003eP\u003c/em\u003e= 0.564) (\u003cstrong\u003eFig. 3B\u003c/strong\u003e). Stroke volume (SV) was initially lower in patients of the Cell therapy group compared with Controls (33.79 \u0026plusmn; 13.42 mL \u003cem\u003evs.\u003c/em\u003e 41.07 \u0026plusmn; 7.07 mL, respectively, \u003cem\u003eP\u003c/em\u003e=0.165). It then increased in the Cell therapy group while it decreased in Controls, yielding 12-month follow-up values of 40.73 \u0026plusmn; 16.62 mL and 34.13 \u0026plusmn; 8.09 mL, respectively, which resulted in a significant difference when end-study SV data were compared with their respective baseline values (Controls: -8.41 \u0026plusmn; 7.92 mL \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 9.03 \u0026plusmn; 20.15 mL; \u003cem\u003eP\u003c/em\u003e=0.036) (\u003cstrong\u003eFig. 3C-D\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe other cardiac functional parameters, either assessed by echocardiography or MRI showed similar results between the two groups and are listed in \u003cstrong\u003eTable S6\u003c/strong\u003e and \u003cstrong\u003eS7\u003c/strong\u003e, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMyocardial perfusion and contractility\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline myocardial perfusion, as assessed by \u003csup\u003e99m\u003c/sup\u003eTc single photon emission computed tomography/computed tomography\u0026nbsp;(\u003csup\u003e99\u003c/sup\u003emTc SPECT-CT) (\u003cstrong\u003eFig. 4A\u003c/strong\u003e), was significantly better in the Control group than in the Cell therapy group, as reflected by lower SRS values (Controls: 36.30 \u0026plusmn; 5.17 \u003cem\u003evs\u003c/em\u003e. hiPSC-CMs: 44.44 \u0026plusmn; 7.15, \u003cem\u003eP\u003c/em\u003e= 0.010). At the 12-month follow-up study point, myocardial perfusion had significantly improved after cell therapy compared with Controls (Absolute SRS value: Controls: 34.50 \u0026plusmn; 9.49 \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: 33.89 \u0026plusmn; 9.77; \u0026Delta;SRS: Control -1.50 \u0026plusmn; 7.73 \u0026nbsp; \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: -10.56 \u0026plusmn; 4.67, \u003cem\u003eP\u003c/em\u003e=0.010). (\u003cstrong\u003eFig. 4B-C\u003c/strong\u003e). Since cells were transplanted along the left anterior descending coronary (LAD) artery region, further analysis of the apical myocardial segments showed a similar trend. At 12 months of follow-up, the Cell therapy group achieved a significant reduction in apical regional SRS, whereas the Control group showed an increase, and the difference between the two groups was statistically significant (Control: 0.38 \u0026plusmn; 2.33 points \u003cem\u003evs.\u003c/em\u003e hiPSC-CMs: -2.00 \u0026plusmn; 2.12 points, \u003cem\u003eP\u003c/em\u003e=0.044) (\u003cstrong\u003eFig. S3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMyocardial contractile function was quantified by MRI-measured cell-targeted LAD territory Wall Thickening (WT). At 12 months of follow-up, WT had significantly higher improvement in Cell therapy groups, yielding an increase from baseline of -33.1 \u0026plusmn; 117.2% and 96.9 \u0026plusmn; 129.0% in Controls and cell-treated patients, respectively. (\u003cem\u003eP\u003c/em\u003e=0.047) (\u003cstrong\u003eFig. 4D-F\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSeveral clinical trials are currently investigating the use of PSC-based cardiomyocyte transplantation in different formats including cell suspensions, spheroids or epicardial patches\u0026nbsp;\u003csup\u003e16\u003c/sup\u003e. The HEAL-CHF trial, however, is the first randomized controlled trial whose completion yet allows to report safety and efficacy data in 20 patients with ischemic advanced heart failure who received direct transepicardial intramyocardial injections of 2x10\u003csup\u003e8\u003c/sup\u003e allogeneic iPSC-CM during concomitant CABG.\u003c/p\u003e\n\u003cp\u003eWith regard to safety, the outcomes of this trial shed light on the three major concerns raised by the clinical translation of PSC-based therapy.\u003c/p\u003e\n\u003cp\u003eThe first pertains to tumorigenicity which could result from the persistence, in the transplant, of residual still undifferentiated cells endowed with a potential of uncontrolled proliferation. However, the 1-year results of the HEAL-HF trial, along with those of a previous report in which the follow-up extended to 4 years\u003csup\u003e8\u003c/sup\u003e, provide reassuring data as none of the patients developed a tumour. Further reassurance is provided by another trial which entailed the transplantation of ESC-derived cardiovascular progenitor cells and also failed to document any cell-related tumour with a maximum follow-up of 10 years \u003csup\u003e17\u003c/sup\u003e. More generally, a recent survey of PSC-based trials spanning a variety of diseases and totaling at least 1,200 patients similarly confirmed the safety of the procedure\u003csup\u003e16\u003c/sup\u003e which reflects an improvement in cell differentiation and sorting procedures\u003csup\u003e18\u003c/sup\u003e along with the identification of lineage-specific phenotypic markers and the concurrent development of sensitive assays for detecting them\u003csup\u003e19\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe second concern is the occurrence of ventricular arrhythmias. Indeed, in keeping with data reported in large animal models of PSC-derived cardiomyocyte transplantation\u003csup\u003e20\u0026ndash;23\u003c/sup\u003e,\u0026nbsp;our results show the consistent occurrence of accelerated AIVR and VT which were recorded from D-7 to Day-28 post-operatively in the cell therapy group; however, only two of these VT episodes were considered clinically relevant. While their origin may be multifactorial, the prevailing hypothesis is that these events are caused by the generation of impulses from ectopic pacing rather than reentry; these impulses would originate from a fraction of early-differentiated phenotypically nodal-like cells present in the initial transplant and endowed with an automaticity potential\u003csup\u003e24,25\u003c/sup\u003e. This view is primarily supported by the finding that the time frame of the arrhythmic events, which peaked around one week after the procedure (for this reason, the very early postoperative timing of the only episode of ventricular fibrillation in our series is rather attributed to a complication of surgery) and wane over the next few weeks, grossly mirrors the maturation of these pulse-generating cells\u003csup\u003e26\u003c/sup\u003e. In our experience, and in contrast with data collected in porcine hearts\u003csup\u003e27\u003c/sup\u003e, conventional anti-arrhythmic drugs failed to suppress the arrhythmia burden. In particular, the failure of ivabradine, a HCN channel inhibitor, was possibly due to the fact that the drug suppresses the natural sino-atrial nodal firing which otherwise helps in preventing VT. Whatsoever, the prevention of cell-triggered ventricular arrhythmias is an important concern which might be partly addressed by the optimization of iPSC differentiation procedures so as to maximize the maturation of their cardiomyocyte progeny before implantation\u003csup\u003e28\u003c/sup\u003e. An alternate solution is the epicardial delivery of a tissue-engineered patch which can still contribute to improve mechanical function despite the lack of electro-mechanical connections of the embedded cells with the host cardiomyocytes\u003csup\u003e29,30\u003c/sup\u003e. Of note, because this study was primarily designed to understand the potential safety issues raised by trans-epicardial iPS-CM injections and to explore their effects on rhythmic events, no implantable cardioverter-defibrillator (ICD) was implanted. However, since current guidelines provide the strongest recommendation (Class I) for ICD in patients with LVEF \u0026le;35% (NYHA class II-III)\u003csup\u003e31\u003c/sup\u003e, one can anticipate that, in clinical practice, most of the patients eligible for cell therapy would qualify for an ICD implantation, which yet represents a reassuring safety net.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe third concern is the rejection of the graft linked to the allogeneic origin of the cells whose major practical advantages (off-the-shelf availability, reduction of production costs) are offset by the induction of an immune response\u003csup\u003e32\u003c/sup\u003e currently managed by immunosuppressive drugs. While, in the absence of a consensus, we had initially considered a lifelong immunosuppressive regimen, our hospital\u0026apos;s IRB downscaled this duration to 1 month on the basis of a risk analysis. Of note, an even rather vigorous immunosuppressive treatment may not consistently prevent the occurrence of DSA, as shown by our data, a concern compounded by the fact that this alloimmune response remained clinically silent. Actually, beyond the choice of the drugs and their dosing which vary from one protocol to the other\u003csup\u003e16\u003c/sup\u003e, a key issue is the duration of the treatment. This, in turn, raises the fundamental question of the expected mechanism of action of the transplanted cells. If one adheres to the initial objective of a remuscularization of the myocardium, then the immunosuppressive treatment should remain uninterrupted. However, in these patients who often have renal and hepatic co-morbidities, a lifelong immunosuppression is fraught with several side effects, indeed recorded in the present trial, explaining why most of the protocols entail its only transient implementation and/or tapering of dosing. However, such an immunosuppression-free strategy implies a paradigm shift in that absence\u003csup\u003e33\u003c/sup\u003e or withdrawal of immunosuppression\u003csup\u003e29\u003c/sup\u003e will cause rejection of the graft and thus exclusive reliance on the paracrine effect exerted by the cells as long as they remain alive; the cell-released biomolecules may then contribute to cardiac repair through mechanisms like reduction of fibrosis or enhancement of angiogenesis, rather than direct force generation, and the once activated pathways could then remain self-sustained, accounting for the persistence of the functional benefits despite the disappearance of the cells, as reported in cardiac\u003csup\u003e34\u003c/sup\u003e and non-cardiac preclinical models\u003csup\u003e35\u003c/sup\u003e. Of note, even though this paracrine mechanism of action is predominant, the use of cardiac-committed cells still looks important as the content of their lineage-specific cargo seems best appropriate for salvage of cardiac tissue through activation of diverse healing pathways\u003csup\u003e36,37\u003c/sup\u003e. Regardless of the mechanism of action of the transplanted cells, it is likely important to leverage their cardio-reparative properties by extending their duration of engraftment, hence the importance of the strategies currently developed to eliminate immunosuppression or at least reduce its dosing. These strategies primarily include the use of Major Histocompatibility Complex haplotyped cell lines\u003csup\u003e38\u003c/sup\u003e gene-edited cell lines made \u0026ldquo;hypoimmunogenic\u0026rdquo;\u003csup\u003e39\u003c/sup\u003e or combined differentiation, from the same PSC line, of both cardiomyocytes and antigen-presenting cells, with the latter first made tolerogenic and subsequently delivered to induce an immune unresponsiveness specific for the sequentially transplanted cardiomyocytes\u003csup\u003e40\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition to safety data, this study also provides some encouraging hints of efficacy, primarily manifest as an improvement in the functional status, exercise capacity and myocardial perfusion and contractility. A particularly interesting finding was that quantitative analysis of the SRS showed its decrease in the cell therapy group, while it remained unchanged in control patients and even worsened in some of them. This outcome measure has been reported as one of the best independent predictors of major adverse cardiac events, including mortality, in patients with suspected or known coronary artery disease\u003csup\u003e41\u0026ndash;44\u003c/sup\u003e, independent of hemodynamic changes, myocardial contractility, and medical treatment. \u0026nbsp;As all patients in this trial underwent a comparable myocardial revascularization, this result is unlikely to have been biased by the concomitant CABG and could rather reflect a cell-induced increase in cardiac angiogenesis, consistent with the paracrine effects of the grafted cells. However, these positive outcomes failed to translate in a significant difference in LVEF between the two groups. This might also be due to the concurrent surgical revascularization which already yielded increases in LVEF in the order of magnitude of what has been reported in previous studies featuring a similar design, i.e., CABG alone vs. CABG + cells\u003csup\u003e45,46\u003c/sup\u003e but may then have let little space, in particular in view of the small sample sizes, for documenting a potential incremental benefit attributable to the cells. In the future, comparison of stand-alone iPSC-CM delivery with either sham procedures or standard of care would be helpful for unraveling a cardio-reparative effect specifically induced by the cellular graft.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eL\u003c/strong\u003e\u003cstrong\u003eimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge some limitations of this study, including the limited number of patients in each group, the lack of placebo injections in the Control group and a possibly sub-optimal immunosuppression regimen. We also acknowledge that the greater improvements in stroke volume ,SRS and myocardial contractility following cell therapy may have been skewed by the fact that, despite randomization, baseline values for these two metrics were more impaired in this group, with an attendant risk of regression to the mean. However, both the randomized design, the first of its type with iPSC-CM transplantation, as well as the extension of follow-up to one year yet tend to validate the conclusions pertaining to safety and, to a lesser extent, efficacy. \u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions and Perspectives","content":"\u003cp\u003eHEAL-CHF study provides valuable real-world data that should be beneficial for advancing the field of cardiac regenerative therapy. The key finding is that in these patients with severe heart failure, those who received cell therapy in addition to CABG experienced greater improvements in exercise capacity, a now recognized valid metric by the FDA, and myocardial perfusion and that, importantly, these benefits were not achieved at the cost of an increased risk, as evidenced by the absence of tumour and of life-threatening arrhythmias. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNevertheless, we recognize that our experimental design was less than perfect and needs to be further refined in future clinical trials. These areas of improvement should include (1) the selection of the optimal cell dosage and immunosuppression regimen, which is particularly challenging because the limitations of animal models preclude a fully reliable translatability of non-clinical data to the clinical setting, (2) the investigation of less invasive routes of cell delivery compatible with repeated dosing to maximise the benefits of hiPSC-CMs therapy, and (3) the fine-tuning of patient selection, possibly with the aid of artificial intelligence\u003csup\u003e47\u003c/sup\u003e, to focus on those expected to be responders identified by \u0026nbsp;baseline characteristics like the presence of inflammation\u003csup\u003e48\u003c/sup\u003e or their genotypic profile\u003csup\u003e49\u003c/sup\u003e. In this burgeoning landscape, the HEAL-CHF trial already represents a clear step forward for utilizing regenerative medicine approaches to treat human cardiac diseases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Key Research and Development Program of China (2022YFA1105100) and the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai. This work was also supported by grants from HELP Therapeutics Co., Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.W. is a scientific founder and equity holder in HELP Therapeutics Co., Ltd. P.M. is a Medical Consultant for HELP Therapeutics Co., Ltd. Q.W., Y.X., J.F. and C.L. are current employees of HELP Therapeutics Co., Ltd. All other authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was registered at ClinicalTrials.gov (NCT03763136), and the protocol was approved by the Institutional Ethics Committee of Nanjing Drum Tower Hospital, affiliated with Nanjing University (No. SC202000102), and by the National Health Commission of the People\u0026apos;s Republic of China (MR-32-21-014649).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD.W., J.W. and P.M. contributed to the conceptualization and designed the clinical trial, and D.W. served as the Principal Investigator, who performed surgical interventions. H.Z., Y.X. and X.Z. performed patients\u0026rsquo; recruitment, follow-ups and data analysis. Q.W., C.L., J.F. and Y.X. were responsible for hiPSC-CMs manufacturing, quality control and logistics. All authors reviewed and approved the submission of the paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKhan MS, Shahid I, Bennis A, Rakisheva A, Metra M, Butler J. Global epidemiology of heart failure. Nat Rev Cardiol. 2024 Oct;21(10):717\u0026ndash;34.\u003c/li\u003e\n \u003cli\u003eBozkurt B, Ahmad T, Alexander K, Baker WL, Bosak K, Breathett K, et al. HF STATS 2024: Heart Failure Epidemiology and Outcomes Statistics An Updated 2024 Report from the Heart Failure Society of America. J Card Fail. 2025 Jan;31(1):66\u0026ndash;116.\u003c/li\u003e\n \u003cli\u003eDunlay SM, Roger VL, Killian JM, Weston SA, Schulte PJ, Subramaniam AV, et al. Advanced Heart Failure Epidemiology and Outcomes: A Population-Based Study. JACC Heart Fail. 2021 Oct;9(10):722\u0026ndash;32.\u003c/li\u003e\n \u003cli\u003eCrespo-Leiro MG, Barge-Caballero E. Advanced Heart Failure: Definition, Epidemiology, and Clinical Course. Heart Fail Clin. 2021 Oct;17(4):533\u0026ndash;45.\u003c/li\u003e\n \u003cli\u003eZhang JJ, Pogwizd SM, Fukuda K, Zimmermann WH, Fan C, Hare JM, et al. Trials and tribulations of cell therapy for heart failure: an update on ongoing trials. Nat Rev Cardiol [Internet]. 2024 Nov 15 [cited 2024 Nov 18]; Available from: https://www.nature.com/articles/s41569-024-01098-8\u003c/li\u003e\n \u003cli\u003eKishino Y, Tohyama S, Morita Y, Soma Y, Tani H, Okada M, et al. Cardiac Regenerative Therapy Using Human Pluripotent Stem Cells for Heart Failure: A State-of-the-Art Review. J Card Fail. 2023 Apr;29(4):503\u0026ndash;13.\u003c/li\u003e\n \u003cli\u003eDeerinck T. \u0026lsquo;REPROGRAMMED\u0026rsquo; STEM CELLS FOR HEART DISEASE TESTED IN CHINA.\u003c/li\u003e\n \u003cli\u003eZhang H, Wang Q, Zhu X, Xue Y, Wang J, Wang D. Reviving Hearts, Restoring Lives. JACC Basic Transl Sci. 2025 Mar;10(3):253\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eGuan X, Xu W, Zhang H, Wang Q, Yu J, Zhang R, et al. 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Int J Stem Cells. 2020 Nov 30;13(3):364\u0026ndash;76.\u003c/li\u003e\n \u003cli\u003eP\u0026auml;til\u0026auml; T, Lehtinen M, Vento A, Schildt J, Sinisalo J, Laine M, et al. Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2014 Jun;33(6):567\u0026ndash;74.\u003c/li\u003e\n \u003cli\u003eCunningham JW, Abraham WT, Bhatt AS, Dunn J, Felker GM, Jain SS, et al. Artificial Intelligence in Cardiovascular Clinical Trials. J Am Coll Cardiol. 2024 Nov 12;84(20):2051\u0026ndash;62.\u003c/li\u003e\n \u003cli\u003ePerin EC, Borow KM, Henry TD, Jenkins M, Rutman O, Hayes J, et al. Mesenchymal precursor cells reduce mortality and major morbidity in ischaemic heart failure with inflammation: DREAM-HF. Eur J Heart Fail. 2024 Nov 26;\u003c/li\u003e\n \u003cli\u003eRieger AC, Myerburg RJ, Florea V, Tompkins BA, Natsumeda M, Premer C, et al. Genetic determinants of responsiveness to mesenchymal stem cell injections in non-ischemic dilated cardiomyopathy. EBioMedicine. 2019 Oct;48:377\u0026ndash;85.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7414031/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7414031/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Heart failure continues to impose a significant global health burden, with a continuous search for therapies capable of promoting a true myocardial regeneration. The HEAL-CHF trial evaluated the safety and efficacy of intramyocardial injections of allogeneic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in advanced heart failure (LVEF≤45%) patients with concomittent coronary artery bypass grafting (CABG). The primary safety endpoints, defined as the incidence of sustained ventricular arrhythmias at 1-6-month follow-up and tumorigenicity at 12-month follow-up, were not observed. Efficacy analyses suggested benefits of cell transplantation compared with CABG alone, primarily evidenced by significant improvements in 6-minute walk distance (6MWD), stroke volume (SV), myocardial perfusion recovery and myocardial contractility. This first randomized and controlled clinical trial of human iPSC-based cardiac regenerative therapy demonstrates the safety and therapeutic potential of hiPSC-CMs and provides a strong incentive for moving to trials adequately powered to yield robust efficacy data. 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