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After more than ten years of human research in the field of cardiac regenerative medicine, application of stem cells in different phases of ischemic heart disease has come to age. Randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease, and several efficacy phase III trials with clinical endpoints are on their way. Nevertheless, a complete knowledge on the mechanisms of action of stem cells still remains elusive. Of the three main mechanisms by which stem cells could exert their benefit, paracrine signaling from the administered cells and stimulation of endogenous repair are nowadays the most plausible ones. However, in this review we will define and discuss the concept of stem cell potency and differentiation, will examine the evidence available, and will depict future directions of research. [ABSTRACT FROM AUTHOR]

Left ventricular electromechanical mapping (LVEM) is a method for mapping the left ventricular cavity in 3 dimensions by use of a catheter that samples points on the endocardial surface. These points provide data on unipolar voltage and linear local shortening, which can then be used to evaluate myocardial ischemia and viability. The new QwikStar multielectrode catheter, which acquires data from multiple points simultaneously, potentially improves map quality and decreases mapping time in comparison with the single-point NogaStar catheter. Our study sought to validate the QwikStar catheter's LVEM capabilities in a porcine model of chronic ischemia. Eight pigs underwent ameroid placement over the proximal left circumflex artery, to induce chronic ischemia. In 60 days, LVEM was performed on each animal with the Noga-Star and QwikStar catheters. Unipolar voltage and linear local shortening results were displayed in 9-segment polar maps. The unipolar voltage data from both maps were then correlated by means of linear regression. There were no adverse events during LVEM. Mapping time was similar for both groups (QwikStar, 44.6 ± 25.62 min; NogaStar, 65.75 ± 25.33 min; P=0.13). Results of mean unipolar voltage maps acquired with the 2 catheters showed a moderate correlation (r =0.59, P <0.001). Selecting segments with more than 6 point samples increased the Pearson coefficient to 0.69 (P <0.001). Our findings show that the QwikStar catheter enables the reproducible performance of LVEM by sampling fewer points, which shortens procedure time, decreases manipulation of the left ventricular cavity, and might increase procedural safety. [ABSTRACT FROM AUTHOR]

Background: Despite tremendous therapeutic advancements, a significant proportion of coronary artery disease patients suffer from refractory angina pectoris, that is, quality-of-life-compromising angina that is non-manageable with established pharmacological and interventional treatment options. Adenoviral vascular endothelial growth factor-D ΔNΔC (AdVEGF-D)-encoding gene therapy (GT) holds promise for the treatment of refractory angina., Methods: ReGenHeart is an investigator-initiated, multicentre, randomised, placebo-controlled and double-blinded phase 2 clinical trial that aims to study the safety and efficacy of intramyocardially administered angiogenic AdVEGF-D GT for refractory angina. Patients will be randomised in a 2:1 ratio and blocks of six to receive either AdVEGF-D or placebo. Primary endpoints are improvements in functional capacity assessed with the 6 min walking test and angina symptoms with Canadian Cardiovascular Society class after 6 month follow-up. Secondary endpoints are improvements in myocardial perfusion assessed with either positron emission tomography or single-photon emission CT after 6 month follow-up and functional capacity and angina symptoms after 12 months. In addition, changes in the quality of life, the use of angina medication and the incidence of major adverse cardiac and cerebrovascular events will be evaluated., Conclusions: The phase 2 ReGenHeart trial will provide knowledge of the safety and efficacy of AdVEGF-D GT to ameliorate symptoms in refractory angina patients, extending and further testing positive results from the preceding phase 1/2a trial., Competing Interests: Competing interests: JEKH received consultancy fees from Novo Nordisk and speaker fees from the BMS-Pfizer alliance. JK received consultancy fees from GE Healthcare and Synektik and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer-Ingelheim, Pfizer, Siemens Healthineers and Merck, outside of the submitted work. AS received consultancy fees from Amgen, Astra Zeneca, Boehringer Ingelheim and Pfizer, and speaker fees from Abbott, Astra Zeneca and Bayer. Other authors declare that they have no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stem cell therapy is one of the most promising therapeutic innovations to help restore cardiac structure and function after ischemic insults to the heart. However, phase I and II clinical trials with autologous "first-generation stem cells" have yielded inconsistent results in ischemic cardiomyopathy patients and have not produced the definitive evidence for their broad clinical application. Recently, new cell types such as cardiac stem cells (CSC) and new allogeneic sources have attracted the attention of researchers given their inherent biological, clinical and logistic advantages. Preclinical evidence and emerging clinical data show that exogenous CSC produce a range of protein-based factors that have a powerful cardioprotective effect in the ischemic myocardium, immunoregulatory properties that promote angiogenesis and reduce scar formation, and are able to activate endogenous CSC which multiply and differentiate into cardiomyocytes and microvasculature. Furthermore, allogeneic CSC can be produced in large quantities beforehand and can be administered "off-the-shelf" early during the acute phase of myocardial ischemia. The distinctive immunological behavior of allogeneic CSC and their interaction with the host immune system is supposed to produce immunomodulatory beneficial effects in the short-term, preventing long-term side-effects after their rejection. Preclinical studies have shown highly promising results with allogeneic CSC, and clinical trials are already ongoing. Finally, unraveling questions about the biology and physiology of CSC, the characterization of their secretome, the conduction of larger clinical trials with autologous CSC, the definitive evidence on the safety and efficacy of allogeneic CSC in humans and the possibility of repeated administrations or combinations with other cell types and soluble factors will pave the road for further developments with CSC, that will undoubtedly determine the future of cardiovascular regenerative medicine in human beings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction and Objectives: The exponential increase in coronary interventions plus the generalization of the radial approach represent the ideal scenario for starting outpatient angioplasty programs with the aim of reducing the costs while maintaining safety. This article reports data from a multicenter Spanish registry on fully ambulatory transradial angioplasty in selected patients for the first time., Methods: Prospective registry of elective outpatient transradial-ulnar angioplasty in patients with stable coronary disease. Patients were discharged the same day and were followed up at 24hours and 30 days. Safety and feasibility were analyzed., Results: Of the 723 patients included (76% male; age, 66.6±10.5 years), 533 (73.7%) were finally discharged after 4 to 12hours of surveillance. Among the remaining 190 (26.7%) patients, the most common reason for hospitalization was clinical instability after the procedure (60.5%). Independent predictors of admission were a history of peripheral artery disease, a higher baseline creatinine level, ad hoc performance of the procedure, and multivessel disease. At 24hours, there was 1 major adverse event in 1 patient (0.19%), who required hospitalization for major bleeding not related to vascular access. At 30 days, there were 3 major adverse events (0.56%): 1 subacute stent thrombosis, 1 revascularization of a vessel other than the treated vessel, and 1 minor stroke. Eight patients (1.5%) required admission at 30 days., Conclusions: The application of an outpatient transradial-ulnar angioplasty program with discharge after 4 to 12 hours' surveillance is safe and feasible in well-selected patients., (Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort., Methods and Results: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death., Conclusion: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The objective of this article is to present an in vitro model of atrial cardiac tissue that could serve to study the mechanisms of remodeling related to atrial fibrillation (AF). We analyze the modification on gene expression and modifications on rotor dynamics following tissue remodeling. Atrial murine cells (HL-1 myocytes) were maintained in culture after the spontaneous initiation of AF and analyzed at two time points: 3.1 ± 1.3 and 9.7 ± 0.5 days after AF initiation. The degree of electrophysiological remodeling (i.e., relative gene expression of key ion channels) and structural inhomogeneity was compared between early and late cell culture times both in nonfibrillating and fibrillating cell cultures. In addition, the electrophysiological characteristics of in vitro fibrillation [e.g., density of phase singularities (PS/cm(2)), dominant frequency, and rotor meandering] analyzed by means of optical mapping were compared with the degree of electrophysiological remodeling. Fibrillating cell cultures showed a differential ion channel gene expression associated with atrial tissue remodeling (i.e., decreased SCN5A, CACN1C, KCND3, and GJA1 and increased KCNJ2) not present in nonfibrillating cell cultures. Also, fibrillatory complexity was increased in late- vs. early stage cultures (1.12 ± 0.14 vs. 0.43 ± 0.19 PS/cm(2), P < 0.01), which was associated with changes in the electrical reentrant patterns (i.e., decrease in rotor tip meandering and increase in wavefront curvature). HL-1 cells can reproduce AF features such as electrophysiological remodeling and an increased complexity of the electrophysiological behavior associated with the fibrillation time that resembles those occurring in patients with chronic AF., (Copyright © 2015 the American Physiological Society.)

The best definitive treatment option for end-stage heart failure currently is transplantation, which is limited by donor availability and immunorejection. Generating an autologous bioartificial heart could overcome these limitations. Here, we have decellularized a human heart, preserving its 3-dimensional architecture and vascularity, and recellularized the decellularized extracellular matrix (dECM). We decellularized 39 human hearts with sodium-dodecyl-sulfate for 4-8 days. Cell removal and architectural integrity were determined anatomically, functionally, and histologically. To assess cytocompatibility, we cultured human cardiac-progenitor cells (hCPC), bone-marrow mesenchymal cells (hMSCs), human endothelial cells (HUVECs), and H9c1 and HL-1 cardiomyocytes in vitro on dECM ventricles up to 21 days. Cell survival, gene expression, organization and/or electrical coupling were analyzed and compared to conventional 2-dimensional cultures. Decellularization removed cells but preserved the 3-dimensional cardiac macro and microstructure and the native vascular network in a perfusable state. Cell survival was observed on dECM for 21 days. hCPCs and hMSCs expressed cardiocyte genes but did not adopt cardiocyte morphology or organization; HUVECs formed a lining of endocardium and vasculature; differentiated cardiomyocytes organized into nascent muscle bundles and displayed mature calcium dynamics and electrical coupling in recellularized dECM. In summary, decellularization of human hearts provides a biocompatible scaffold that retains 3-dimensional architecture and vascularity and that can be recellularized with parenchymal and vascular cells. dECM promotes cardiocyte gene expression in stem cells and organizes existing cardiomyocytes into nascent muscle showing electrical coupling. These findings represent a first step toward manufacturing human heart grafts or matrix components for treating cardiovascular disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Over the last years, stem cell therapy has emerged as an inspiring alternative to restore cardiac function after myocardial infarction. A large body of evidence has been obtained in this field but there is no conclusive data on the efficacy of these treatments. Preclinical studies and early reports in humans have been encouraging and have fostered a rapid clinical translation, but positive results have not been uniformly observed and when present, they have been modest. Several types of stem cells, manufacturing methods and delivery routes have been tested in different clinical settings but direct comparison between them is challenging and hinders further research. Despite enormous achievements, major barriers have been found and many fundamental issues remain to be resolved. A better knowledge of the molecular mechanisms implicated in cardiac development and myocardial regeneration is critically needed to overcome some of these hurdles. Genetic and pharmacological priming together with the discovery of new sources of cells have led to a "second generation" of cell products that holds an encouraging promise in cardiovascular regenerative medicine. In this report, we review recent advances in this field focusing on the new types of stem cells that are currently being tested in human beings and on the novel strategies employed to boost cell performance in order to improve cardiac function and outcomes after myocardial infarction.