Phases I–III Clinical Trials Using Adult Stem Cells

First 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. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field

Functional Multipotency of Stem Cells: What Do We Need from Them in the Heart?

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

Role of atrial tissue remodeling on rotor dynamics an in vitro study

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/cm2), 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.This work was supported in part by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882, PI13-00903, and TEC2013-50391-EXP), and the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain).Climent, A.; Guillem Sánchez, MS.; Fuentes, L.; Lee, P.; Bollensdorff, C.; Fernandez-Santos, M.; Suarez-Sancho, S.... (2015). Role of atrial tissue remodeling on rotor dynamics an in vitro study. AJP - Heart and Circulatory Physiology. 309(11):H1964-H1973. doi:10.1152/ajpheart.00055.2015SH1964H197330911Allessie, M. (2002). 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Comparison of Radiofrequency Catheter Ablation of Drivers and Circumferential Pulmonary Vein Isolation in Atrial Fibrillation. Journal of the American College of Cardiology, 64(23), 2455-2467. doi:10.1016/j.jacc.2014.09.053Bikou, O., Thomas, D., Trappe, K., Lugenbiel, P., Kelemen, K., Koch, M., … Bauer, A. (2011). Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovascular Research, 92(2), 218-225. doi:10.1093/cvr/cvr209Bollmann, A., Sonne, K., Esperer, H.-D., Toepffer, I., & Klein, H. U. (2002). Patients with Persistent Atrial Fibrillation Taking Oral Verapamil Exhibit a Lower Atrial Frequency on the ECG. Annals of Noninvasive Electrocardiology, 7(2), 92-97. doi:10.1111/j.1542-474x.2002.tb00148.xBRUNDEL, B. (2004). Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation. Cardiovascular Research, 62(3), 521-528. doi:10.1016/j.cardiores.2004.02.007Calkins, H., Kuck, K. 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Circulation: Arrhythmia and Electrophysiology, 5(6), 1160-1167. doi:10.1161/circep.111.969519Haïssaguerre, M., Jaïs, P., Shah, D. C., Takahashi, A., Hocini, M., Quiniou, G., … Clémenty, J. (1998). Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins. New England Journal of Medicine, 339(10), 659-666. doi:10.1056/nejm199809033391003Haralick, R. M., Shanmugam, K., & Dinstein, I. (1973). Textural Features for Image Classification. IEEE Transactions on Systems, Man, and Cybernetics, SMC-3(6), 610-621. doi:10.1109/tsmc.1973.4309314Jalife, J. (2010). Deja vu in the theories of atrial fibrillation dynamics. Cardiovascular Research, 89(4), 766-775. doi:10.1093/cvr/cvq364Koivumäki, J. T., Seemann, G., Maleckar, M. M., & Tavi, P. (2014). In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation. PLoS Computational Biology, 10(5), e1003620. doi:10.1371/journal.pcbi.1003620Lee, P., Klos, M., Bollensdorff, C., Hou, L., Ewart, P., Kamp, T. J., … Herron, T. J. (2012). Simultaneous Voltage and Calcium Mapping of Genetically Purified Human Induced Pluripotent Stem Cell–Derived Cardiac Myocyte Monolayers. Circulation Research, 110(12), 1556-1563. doi:10.1161/circresaha.111.262535Lieu, D. K., Fu, J.-D., Chiamvimonvat, N., Tung, K. C., McNerney, G. P., Huser, T., … Li, R. A. (2013). Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes. Circulation: Arrhythmia and Electrophysiology, 6(1), 191-201. doi:10.1161/circep.111.973420Liu, X., Shi, H., Tan, H., Wang, X., Zhou, L., & Gu, J. (2009). Decreased Connexin 43 and Increased Fibrosis in Atrial Regions Susceptible to Complex Fractionated Atrial Electrograms. Cardiology, 114(1), 22-29. doi:10.1159/000210398Mansour, M., Mandapati, R., Berenfeld, O., Chen, J., Samie, F. H., & Jalife, J. (2001). Left-to-Right Gradient of Atrial Frequencies During Acute Atrial Fibrillation in the Isolated Sheep Heart. Circulation, 103(21), 2631-2636. doi:10.1161/01.cir.103.21.2631Martins, R. P., Kaur, K., Hwang, E., Ramirez, R. J., Willis, B. C., Filgueiras-Rama, D., … Jalife, J. (2014). Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation. Circulation, 129(14), 1472-1482. doi:10.1161/circulationaha.113.004742McDowell, K. S., Vadakkumpadan, F., Blake, R., Blauer, J., Plank, G., MacLeod, R. S., & Trayanova, N. A. (2013). Mechanistic Inquiry into the Role of Tissue Remodeling in Fibrotic Lesions in Human Atrial Fibrillation. Biophysical Journal, 104(12), 2764-2773. doi:10.1016/j.bpj.2013.05.025Narayan, S. M., Krummen, D. E., Shivkumar, K., Clopton, P., Rappel, W.-J., & Miller, J. M. (2012). Treatment of Atrial Fibrillation by the Ablation of Localized Sources. 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Propuesta de regulación de los ingresos involuntarios

A propósito de la declaración de incostitucionalidad del Artículo 763-1 de la Ley de Enjuiciamiento Civil en virtud de sentencia del Tribunal Constitucional Nº 132/2010 de 2 de diciembre

Relatos de vida con nombre propio: proceso de escucha activa para transformar realidades desde el derecho

Memoria ID2022-031. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2022-2023

El Tratamiento Ambulatorio Involuntario. Historia de una obstinación

Sin resumen

Propuesta de regulación de los ingresos involuntarios

A propósito de la declaración de incostitucionalidad del Artículo 763-1 de la Ley de Enjuiciamiento Civil en virtud de sentencia del Tribunal Constitucional Nº 132/2010 de 2 de diciembre