Evaluación del efecto de la hipoxia hipobárica crónica natural y la hipoxia aguda inducida en el proceso de regeneración cardíaca en el pez cebra (Danio rerio). Establecimiento de modelo con interés biomédico.

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1PLANTEAMIENTO DEL PROBLEMA La insuficiencia cardíaca es uno de los principales problemas de salud a nivel mundial. Cerca de 64,3 millones de pacientes en todo el mundo padecen este síndrome (1). Dentro de este contexto para América Latina se presenta una incidencia de 199 por 100.000 habitantes cada año, así como una prevalencia de 1% de la población afectada (2). En Colombia se estima que cerca de 1 millón de pacientes ha sido diagnosticado con insuficiencia cardíaca (3). Esta situación, aunque multifactorial, tiene como principal causa el evento isquémico agudo, que lleva a daño progresivo y a la pérdida de la función y eyección ventricular. Los pacientes afectados tienen un pronóstico de sobrevivencia de solamente el 57% en los siguientes cinco años posteriores al diagnóstico (1). Esto sucede, a pesar de los avances médicos. Uno de los principales obstáculos para la recuperación es la imposibilidad para regenerar significativamente las zonas lesionadas, entendiendo este proceso como el restablecimiento de la estructura y la función de los tejidos cardíacos perdidos (4). Esta pobre regeneración es una característica común en los mamíferos (3,5). La recuperación y rehabilitación cardíaca presupone un mayor reto para poblaciones humanas que habitan ambientes de altura moderada (1500 msnm – 2500 msnm) o gran altitud (2500 msnm – 3500 msnm), en condiciones de hipoxia hipobárica natural. En estos ambientes existe menor presión barométrica y una menor disponibilidad de oxígeno, lo que lleva a una mayor demanda cardiorrespiratoria y a un mayor trabajo cardíaco, especialmente en individuos expuestos de forma aguda. Todo esto puede dificultar el cuidado de pacientes con insuficiencia cardíacaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.14336/AD.2014.0500274","ISSN":"21525250","abstract":"Beside genetic and life-style characteristics environmental factors may profoundly influence mortality and life expectancy. The high altitude climate comprises a set of conditions bearing the potential of modifying morbidity and mortality of approximately 400 million people who are permanently residing at elevations above 1500 meters. However, epidemiological data on the effects of high altitude living on mortality from major diseases are inconsistent probably due to differences in ethnicity, behavioral factors and the complex interactions with environmental conditions. The available data indicate that residency at higher altitudes are associated with lower mortality from cardiovascular diseases, stroke and certain types of cancer. In contrast mortality from COPD and probably also from lower respiratory tract infections is rather elevated. It may be argued that moderate altitudes are more protective than high or even very high altitudes. Whereas living at higher elevations may frequently protect from development of diseases, it could adversely affect mortality when diseases progress. Corroborating and expanding these findings would be helpful for optimization of medical care and disease management in the aging residents of higher altitudes.","author":[{"dropping-particle":"","family":"Burtscher","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Aging and Disease","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"page":"274-280","title":"Effects of Living at Higher Altitudes on Mortality: A Narrative Review","type":"article-journal","volume":"5"},"uris":["http://www.mendeley.com/documents/?uuid=5ccb8341-028f-45eb-b41c-2ef6c1fe2836"]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.ahj.2009.10.028","ISSN":"00028703","abstract":"Our aging population combined with the ease of travel and the interest in high altitude recreation pursuits exposes more patients to the acute physiologic effects of high altitude and lower oxygen availability. Acute exposure to high altitude is associated with significant alterations to the cardiovascular system. These may be important in patients with underlying cardiovascular disease who are not able to compensate to such physiologic changes. Exacerbating factors pertinent to patients with cardiovascular disease include acute hypoxia, increased myocardial work, increased epinephrine release, and increased pulmonary artery pressures. This review summarizes the physiology and clinical evidence regarding acute altitude exposure on the cardiopulmonary system with practical recommendations to address the question: \"Is it safe for me to ski in the Rockies or climb Mt. Kilimanjaro?\". © 2010 Mosby, Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Higgins","given":"John P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuttle","given":"Troy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Higgins","given":"Johanna A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Heart Journal","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2010"]]},"page":"25-32","publisher":"Mosby, Inc.","title":"Altitude and the heart: Is going high safe for your cardiac patient?","type":"article-journal","volume":"159"},"uris":["http://www.mendeley.com/documents/?uuid=20660ebe-e00a-49a3-b90c-94a48fb59446"]},{"id":"ITEM-3","itemData":{"DOI":"10.1152/physrev.1991.71.4.1135","ISSN":"0031-9333","PMID":"1924550","abstract":"review, 541 references","author":[{"dropping-particle":"","family":"Monge","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"León-Velarde","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological reviews","id":"ITEM-3","issue":"4","issued":{"date-parts":[["1991"]]},"page":"1135-72","title":"Physiological adaptation to high altitude: oxygen transport in mammals and birds.","type":"article-journal","volume":"71"},"uris":["http://www.mendeley.com/documents/?uuid=a3992d1b-c52c-444d-a2c2-0d61ee8d66b9"]}],"mendeley":{"formattedCitation":"(6–8)","plainTextFormattedCitation":"(6–8)","previouslyFormattedCitation":"(6–8)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(6–8). Sin embargo, y de forma paradójica, se ha descrito un posible efecto cardioprotector en habitantes permanentes de altitudes moderadas y gran altitud ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.108.819250","ISSN":"00097322","abstract":"BACKGROUND: Studies assessing the effect of altitude on cardiovascular disease have provided conflicting results. Most studies were limited because of the heterogeneity of the population, their ecological design, or both. In addition, effects of place of birth were rarely considered. Here, we examine mortality from coronary heart disease and stroke in relation to the altitude of the place of residence in 1990 and at birth. METHODS AND RESULTS: Mortality data from 1990 to 2000, sociodemographic information, and places of birth and residence in 1990 (men and women between 40 and 84 years of age living at altitudes of 259 to 1960 m) were obtained from the Swiss National Cohort, a longitudinal, census-based record linkage study. The 1.64 million German Swiss residents born in Switzerland provided 14.5 million person-years. Relative risks were calculated with multivariable Poisson regression. Mortality from coronary heart disease (-22% per 1000 m) and stroke (-12% per 1000 m) significantly decreased with increasing altitude. Being born at altitudes higher or lower than the place of residence was associated with lower or higher risk. CONCLUSIONS: The protective effect of living at higher altitude on coronary heart disease and stroke mortality was consistent and became stronger after adjustment for potential confounders. Being born at high altitude had an additional and independent beneficial effect on coronary heart disease mortality. The effect is unlikely to be due to classic cardiovascular disease risk factors and rather could be explained by factors related to climate.","author":[{"dropping-particle":"","family":"Faeh","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gutzwiller","given":"Felix","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bopp","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2009"]]},"page":"495-501","title":"Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland","type":"article-journal","volume":"120"},"uris":["http://www.mendeley.com/documents/?uuid=ca96eaaa-fa01-4f75-b3c0-319674fe9d0b"]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.resp.2007.03.005","ISSN":"15699048","abstract":"This review deals with the capability of the heart to adapt to chronic hypoxia in animals exposed to either natural or simulated high altitude. From the broad spectrum of related issues, we focused on the development and reversibility of both beneficial and adverse adaptive myocardial changes. Particular attention was paid to cardioprotective effects of adaptation to chronic high-altitude hypoxia and their molecular mechanisms. Moreover, interspecies and age differences in the cardiac sensitivity to hypoxia-induced effects in various experimental models were emphasized. © 2007 Elsevier B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Ostadal","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolar","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Respiratory Physiology and Neurobiology","id":"ITEM-2","issue":"2-3","issued":{"date-parts":[["2007"]]},"page":"224-236","title":"Cardiac adaptation to chronic high-altitude hypoxia: Beneficial and adverse effects","type":"article-journal","volume":"158"},"uris":["http://www.mendeley.com/documents/?uuid=99c10c62-b022-451f-b97d-d30b97c2d5f0"]},{"id":"ITEM-3","itemData":{"DOI":"10.1136/jech.2010.112938","ISSN":"0143005X","abstract":"BACKGROUND: There is a substantial variation in life expectancy across US counties, primarily owing to differentials in chronic diseases. The authors' aim was to examine the association of life expectancy and mortality from selected diseases with altitude.\\n\\nMETHODS: The authors used data from the National Elevation Dataset, National Center for Heath Statistics and US Census. The authors analysed the crude association of mean county altitude with life expectancy and mortality from ischaemic heart disease (IHD), stroke, chronic obstructive pulmonary disease (COPD) and cancers, and adjusted the associations for socio-demographic factors, migration, average annual solar radiation and cumulative exposure to smoking in multivariable regressions.\\n\\nRESULTS: Counties above 1500 m had longer life expectancies than those within 100 m of sea level by 1.2-3.6 years for men and 0.5-2.5 years for women. The association between altitude and life expectancy became non-significant for women and non-significant or negative for men in multivariate analysis. After adjustment, altitude had a beneficial association with IHD mortality and harmful association with COPD, with a dose-response relationship. IHD mortality above 1000 m was 4-14 per 10,000 people lower than within 100 m of sea level; COPD mortality was higher by 3-4 per 10,000. The adjusted associations for stroke and cancers were not statistically significant.\\n\\nCONCLUSIONS: Living at higher altitude may have a protective effect on IHD and a harmful effect on COPD. At least in part due to these two opposing effects, living at higher altitude appears to have no net effect on life expectancy.","author":[{"dropping-particle":"","family":"Ezzati","given":"Majid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horwitz","given":"Mara E M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Deborah S K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedman","given":"Ari B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roach","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clark","given":"Timothy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Christopher J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honigman","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Epidemiology and Community Health","id":"ITEM-3","issue":"7","issued":{"date-parts":[["2012"]]},"title":"Altitude, life expectancy and mortality from ischaemic heart disease, stroke, COPD and cancers: National population-based analysis of US counties","type":"article-journal","volume":"66"},"uris":["http://www.mendeley.com/documents/?uuid=c41fb5f7-fd39-433a-9486-fcd253ad714f"]}],"mendeley":{"formattedCitation":"(9–11)","plainTextFormattedCitation":"(9–11)","previouslyFormattedCitation":"(9–11)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(9–11). En estas poblaciones se reporta un menor número de enfermedades coronarias agudas, infartos y aterosclerosis con respecto a poblaciones habitantes de bajas altitudes. Existen explicaciones potenciales para estos hallazgos, como una mejor neovascularización y mayor proliferación celular, evidenciados en murinos y en humanos (12–14). También se contempla un posible efecto protector contra el estrés oxidativo y sus consecuencias, que pueden detonarse aún más con la re-oxigenación o la reperfusión. Esto se ha evidenciado en modelos animales generalmente cuando se evalúan condiciones de hipoxia aguda inducida en laboratorio (15,16). Sin embargo, aún no hay claridad sobre los efectos de la hipoxia hipobárica natural y crónica (desde el nacimiento) en el proceso de regeneración cardíaca. Por otro lado, el sistema nervioso autónomo juega un papel esencial para la adaptación cardiovascular y el mantenimiento del gasto cardíaco, especialmente en condiciones de desarrollo temprano y bajo situaciones estresantes. Estos ajustes autónomos se muestran mediante cambios en la frecuencia cardíaca y su variabilidad (R-R), que son evaluables por medio de electrocardiografía. De forma interesante, la hipoxia parece tener un impacto significativo en estos ajustes autónomos. En modelos animales expuestos a hipoxia en el desarrollo temprano, se observan aumentos temporales en el tono simpático. Lo anterior parece estar relacionado con una mayor actividad del Factor de Crecimiento Endotelial Vascular (VEGF) y, por tanto, una mayor angiogénesis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0006-8993(02)02903-7","ISSN":"00068993","abstract":"This study was conducted on unanesthetized rainbow trout equipped with two ECG electrodes and with an intracerebroventricular (i.c.v.) micro-guide. The ECG signal was recorded during three experimental sessions of 30 min and the heart rate variability (HRV) spectral analysis was performed during stabilized periods of recording. The first recording session was conducted during the control period and the mean heart rate (HR) of the trout was 44±2 bpm. The total power spectral density (PSD) of the R-R interval signal of the ECG was 21233±4400 ms2/Hz. A major high frequency (HF) spectral band centered at 0.16 Hz and a minor low frequency (LF) spectral band centered at 0.04 Hz were the two main components of the PSD. An i.c.v. injection of 0.5 μl of vehicle during the second session had no significant statistical effect, either on the mean HR (43±2 bpm), the total PSD (24693±6394 ms2/Hz) or on the center frequency and power of the two main spectral bands. Conversely, an i.c.v. injection of ANGII (1.5, 6.25 and 50 pmol) during the third recording session induced a significant increase in the mean HR (+3%, +15%, +30%, respectively) but the effect of the peptide was more obvious on the total PSD which was profoundly decreased (-27%, -65%, -76%, respectively). The two main spectral bands of the PSD were totally blunted after the injection of 50 pmol of ANGII. In another group of control trout, intraperitoneal (i.p.) injection of atropine abolished the PSD of the R-R interval signal of the ECG demonstrating that the parasympathetic system is the main contributor of HRV in trout. Our results have thus demonstrated for the first time, at least in a non-mammalian species, that i.c.v. injection of native ANGII profoundly reduces HRV. We hypothesize that ANGII in the brain of the trout alters the pattern of the electrical activity along preganglionic cardiac vagal motoneurons. © 2002 Elsevier Science B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Mével","given":"Jean Claude","non-dropping-particle":"Le","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mimassi","given":"Nagi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lancien","given":"Frédéric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mabin","given":"Dominique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boucher","given":"Jean Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanc","given":"Jean Jacques","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Brain Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2002"]]},"page":"34-40","title":"Heart rate variability, a target for the effects of angiotensin II in the brain of the trout Oncorhynchus mykiss","type":"article-journal","volume":"947"},"uris":["http://www.mendeley.com/documents/?uuid=53353f95-8050-43ad-b249-baff6c78fb7d"]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(17). Sumado a esto, se reporta un tono simpático más alto en ratas expuestas de forma aguda a hipoxia con respecto a grupos expuestos de forma prolongada a esta condición ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2165/00007256-200333120-00003","ISSN":"01121642","abstract":"This review examines the influence on heart rate variability (HRV) indices in athletes from training status, different types of exercise training, sex and ageing, presented from both cross-sectional and longitudinal studies. The predictability of HRV in over-training, athletic condition and athletic performance is also included. Finally, some recommendations concerning the application of HRV methods in athletes are made. The cardiovascular system is mostly controlled by autonomic regulation through the activity of sympathetic and parasympathetic pathways of the autonomic nervous system. Analysis of HRV permits insight in this control mechanism. It can easily be determined from ECG recordings, resulting in time series (RR-intervals) that are usually analysed in time and frequency domains. As a first approach, it can be assumed that power in different frequency bands corresponds to activity of sympathetic (0.04-0.15Hz) and parasympathetic (0.15-0.4Hz) nerves. However, other mechanisms (and feedback loops) are also at work, especially in the low frequency band. During dynamic exercise, it is generally assumed that heart rate increases due to both a parasympathetic withdrawal and an augmented sympathetic activity. However, because some authors disagree with the former statement and the fact that during exercise there is also a technical problem related to the non-stationary signals, a critical look at interpretation of results is needed. It is strongly suggested that, when presenting reports on HRV studies related to exercise physiology in general or concerned with athletes, a detailed description should be provided on analysis methods, as well as concerning population, and training schedule, intensity and duration. Most studies concern relatively small numbers of study participants, diminishing the power of statistics. Therefore, multicentre studies would be preferable. In order to further develop this fascinating research field, we advocate prospective, randomised, controlled, long-term studies using validated measurement methods. Finally, there is a strong need for basic research on the nature of the control and regulating mechanism exerted by the autonomic nervous system on cardiovascular function in athletes, preferably with a multidisciplinary approach between cardiologists, exercise physiologists, pulmonary physiologists, coaches and biomedical engineers.","author":[{"dropping-particle":"","family":"Aubert","given":"André E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seps","given":"Bert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beckers","given":"Frank","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Sports Medicine","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2003"]]},"page":"889-919","title":"Heart Rate Variability in Athletes","type":"article-journal","volume":"33"},"uris":["http://www.mendeley.com/documents/?uuid=c9d0defd-76b7-43f7-b215-3d67f74ad838"]}],"mendeley":{"formattedCitation":"(18)","plainTextFormattedCitation":"(18)","previouslyFormattedCitation":"(18)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(18). Este hallazgo está asociado con reportes de poblaciones humanas adaptadas ancestralmente a gran altura en las que predomina la actividad parasimpática y con esto, una mayor variabilidad en la frecuencia cardíaca ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0006-8993(02)02903-7","ISSN":"00068993","abstract":"This study was conducted on unanesthetized rainbow trout equipped with two ECG electrodes and with an intracerebroventricular (i.c.v.) micro-guide. The ECG signal was recorded during three experimental sessions of 30 min and the heart rate variability (HRV) spectral analysis was performed during stabilized periods of recording. The first recording session was conducted during the control period and the mean heart rate (HR) of the trout was 44±2 bpm. The total power spectral density (PSD) of the R-R interval signal of the ECG was 21233±4400 ms2/Hz. A major high frequency (HF) spectral band centered at 0.16 Hz and a minor low frequency (LF) spectral band centered at 0.04 Hz were the two main components of the PSD. An i.c.v. injection of 0.5 μl of vehicle during the second session had no significant statistical effect, either on the mean HR (43±2 bpm), the total PSD (24693±6394 ms2/Hz) or on the center frequency and power of the two main spectral bands. Conversely, an i.c.v. injection of ANGII (1.5, 6.25 and 50 pmol) during the third recording session induced a significant increase in the mean HR (+3%, +15%, +30%, respectively) but the effect of the peptide was more obvious on the total PSD which was profoundly decreased (-27%, -65%, -76%, respectively). The two main spectral bands of the PSD were totally blunted after the injection of 50 pmol of ANGII. In another group of control trout, intraperitoneal (i.p.) injection of atropine abolished the PSD of the R-R interval signal of the ECG demonstrating that the parasympathetic system is the main contributor of HRV in trout. Our results have thus demonstrated for the first time, at least in a non-mammalian species, that i.c.v. injection of native ANGII profoundly reduces HRV. We hypothesize that ANGII in the brain of the trout alters the pattern of the electrical activity along preganglionic cardiac vagal motoneurons. © 2002 Elsevier Science B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Mével","given":"Jean Claude","non-dropping-particle":"Le","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mimassi","given":"Nagi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lancien","given":"Frédéric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mabin","given":"Dominique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boucher","given":"Jean Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanc","given":"Jean Jacques","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Brain Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2002"]]},"page":"34-40","title":"Heart rate variability, a target for the effects of angiotensin II in the brain of the trout Oncorhynchus mykiss","type":"article-journal","volume":"947"},"uris":["http://www.mendeley.com/documents/?uuid=53353f95-8050-43ad-b249-baff6c78fb7d"]},{"id":"ITEM-2","itemData":{"DOI":"10.2165/00007256-200333120-00003","ISSN":"01121642","abstract":"This review examines the influence on heart rate variability (HRV) indices in athletes from training status, different types of exercise training, sex and ageing, presented from both cross-sectional and longitudinal studies. The predictability of HRV in over-training, athletic condition and athletic performance is also included. Finally, some recommendations concerning the application of HRV methods in athletes are made. The cardiovascular system is mostly controlled by autonomic regulation through the activity of sympathetic and parasympathetic pathways of the autonomic nervous system. Analysis of HRV permits insight in this control mechanism. It can easily be determined from ECG recordings, resulting in time series (RR-intervals) that are usually analysed in time and frequency domains. As a first approach, it can be assumed that power in different frequency bands corresponds to activity of sympathetic (0.04-0.15Hz) and parasympathetic (0.15-0.4Hz) nerves. However, other mechanisms (and feedback loops) are also at work, especially in the low frequency band. During dynamic exercise, it is generally assumed that heart rate increases due to both a parasympathetic withdrawal and an augmented sympathetic activity. However, because some authors disagree with the former statement and the fact that during exercise there is also a technical problem related to the non-stationary signals, a critical look at interpretation of results is needed. It is strongly suggested that, when presenting reports on HRV studies related to exercise physiology in general or concerned with athletes, a detailed description should be provided on analysis methods, as well as concerning population, and training schedule, intensity and duration. Most studies concern relatively small numbers of study participants, diminishing the power of statistics. Therefore, multicentre studies would be preferable. In order to further develop this fascinating research field, we advocate prospective, randomised, controlled, long-term studies using validated measurement methods. Finally, there is a strong need for basic research on the nature of the control and regulating mechanism exerted by the autonomic nervous system on cardiovascular function in athletes, preferably with a multidisciplinary approach between cardiologists, exercise physiologists, pulmonary physiologists, coaches and biomedical engineers.","author":[{"dropping-particle":"","family":"Aubert","given":"André E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seps","given":"Bert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beckers","given":"Frank","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Sports Medicine","id":"ITEM-2","issue":"12","issued":{"date-parts":[["2003"]]},"page":"889-919","title":"Heart Rate Variability in Athletes","type":"article-journal","volume":"33"},"uris":["http://www.mendeley.com/documents/?uuid=c9d0defd-76b7-43f7-b215-3d67f74ad838"]}],"mendeley":{"formattedCitation":"(17,18)","plainTextFormattedCitation":"(17,18)","previouslyFormattedCitation":"(17,18)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(17,18). Estos ajustes autónomos, significativos para la adaptación cardiovascular aún no han sido explorados en un modelo animal bajo hipoxia hipobárica crónica y en contextos de regeneración cardíaca. Debido a que globalmente, un número cercano a cuatrocientos millones de personas habitan permanentemente en altitudes mayores a 1500 msnm ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.14336/AD.2014.0500274","ISSN":"21525250","abstract":"Beside genetic and life-style characteristics environmental factors may profoundly influence mortality and life expectancy. The high altitude climate comprises a set of conditions bearing the potential of modifying morbidity and mortality of approximately 400 million people who are permanently residing at elevations above 1500 meters. However, epidemiological data on the effects of high altitude living on mortality from major diseases are inconsistent probably due to differences in ethnicity, behavioral factors and the complex interactions with environmental conditions. The available data indicate that residency at higher altitudes are associated with lower mortality from cardiovascular diseases, stroke and certain types of cancer. In contrast mortality from COPD and probably also from lower respiratory tract infections is rather elevated. It may be argued that moderate altitudes are more protective than high or even very high altitudes. Whereas living at higher elevations may frequently protect from development of diseases, it could adversely affect mortality when diseases progress. Corroborating and expanding these findings would be helpful for optimization of medical care and disease management in the aging residents of higher altitudes.","author":[{"dropping-particle":"","family":"Burtscher","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Aging and Disease","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"page":"274-280","title":"Effects of Living at Higher Altitudes on Mortality: A Narrative Review","type":"article-journal","volume":"5"},"uris":["http://www.mendeley.com/documents/?uuid=5ccb8341-028f-45eb-b41c-2ef6c1fe2836"]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"(6)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(6), se ha hecho prioritario entender los efectos que la hipoxia hipobárica crónica puede tener sobre el proceso de regeneración cardíaca, después de una lesión ventricular masiva. Este conocimiento puede contribuir significativamente en el campo biológico y biomédico traslacional. Lo anterior ha motivado investigaciones previas que buscaban evaluar el papel de la hipoxia en la regeneración cardíaca, usando tanto modelos celulares como animales con niveles variables de regeneración. Uno de estos es el pez cebra (Danio rerio), un organismo modelo para investigación biomédica y de regeneración tisular. Esto último, debido a sus semejanzas con los humanos en estructura y función cardiovascular; pero además, por la gran capacidad de restauración de estos tejidos tras una lesión (19,20). Aunque los trabajos que intentan explicar este efecto son escasos, sus resultados sugieren que la hipoxia aguda inducida farmacológicamente en pez cebra (Danio rerio) favorece la desdiferenciación y proliferación de cardiomiocitos, mejorando el proceso de regeneración ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107888","ISBN":"1524-4539 (Electronic) 0009-7322 (Linking)","ISSN":"00097322","PMID":"23151342","abstract":"BACKGROUND: Hypoxia plays an important role in many biological/pathological processes. In particular, hypoxia is associated with cardiac ischemia. which, although initially inducing a protective response, will ultimately lead to the death of cardiomyocytes and loss of tissue, severely affecting cardiac functionality. Although myocardial damage/loss remains an insurmountable problem for adult mammals, the same is not true for adult zebrafish, which are able to completely regenerate their heart after extensive injury. Myocardial regeneration in zebrafish involves the dedifferentiation and proliferation of cardiomyocytes to replace the damaged/missing tissue; at present, however, little is known about what factors regulate this process.\\n\\nMETHODS AND RESULTS: We surmised that ventricular amputation would lead to hypoxia induction in the myocardium of zebrafish and that this may play a role in regulating the regeneration of the missing cardiac tissue. Using a combination of O(2) perturbation, conditional transgenics, in vitro cell culture, and microarray analysis, we found that hypoxia induces cardiomyocytes to dedifferentiate and proliferate during heart regeneration in zebrafish and have identified a number of genes that could play a role in this process.\\n\\nCONCLUSION: These results indicate that hypoxia plays a positive role during heart regeneration, which should be taken into account in future strategies aimed at inducing heart regeneration in humans.","author":[{"dropping-particle":"","family":"Jopling","given":"Chris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suñé","given":"Guillermo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faucherre","given":"Adèle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabregat","given":"Carme","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Izpisua Belmonte","given":"Juan Carlos","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"25","issued":{"date-parts":[["2012"]]},"page":"3017-3027","title":"Hypoxia induces myocardial regeneration in zebrafish","type":"article-journal","volume":"126"},"uris":["http://www.mendeley.com/documents/?uuid=c36210f2-0302-4d86-a035-e9e2462626c3"]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0053748","ISSN":"19326203","abstract":"Aims: the adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it. Methods and Results: adult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2-6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9±2.6% of myocardial cell nuclei were TUNEL+ and 15.0±2.5% were AO+. At the 30-day (d) time point myocardial cell death was back to baseline (n = 3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18-24 h after H/R, it achieved its peak 3-7d later, and was back to baseline at 30d. 7d after H/R 17.4±2.3% of all cardiomyocytes were pHH3+ and 7.4±0.6% were PCNA+ (n = 3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3±2.0% in normoxia to 16.4±1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n = 12 at each time point). Conclusions: zebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models. © 2013 Parente et al.","author":[{"dropping-particle":"","family":"Parente","given":"Valeria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balasso","given":"Serena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pompilio","given":"Giulio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verduci","given":"Lorena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Colombo","given":"Gualtiero I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milano","given":"Giuseppina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guerrini","given":"Uliano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Squadroni","given":"Lidia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cotelli","given":"Franco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pozzoli","given":"Ombretta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capogrossi","given":"Maurizio C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2013"]]},"title":"Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart","type":"article-journal","volume":"8"},"uris":["http://www.mendeley.com/documents/?uuid=fcc89409-08ce-4879-af8a-4d6694011a18"]}],"mendeley":{"formattedCitation":"(21,22)","plainTextFormattedCitation":"(21,22)","previouslyFormattedCitation":"(21,22)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(21,22). Sin embargo, no hay información sobre la influencia de la hipoxia hipobárica crónica y natural en el proceso de regeneración cardíaca en el pez cebra u otros modelos animales. Tampoco se han comparado sus efectos frente a la exposición aguda a condiciones de hipoxia. Todo lo anterior evidencia un potencial efecto cardioprotector de la hipoxia, que puede estar directamente asociado con la capacidad regenerativa y la recuperación funcional del corazón después de una lesión. No obstante, las evidencias existentes, mayoritariamente reportadas en modelo murino, solo se han realizado en condiciones de hipoxia agudas e inducidas en laboratorio. Estos datos pueden distar significativamente de contextos naturales y crónicos de hipoxia, que son los que naturalmente se presentan para muchas poblaciones animales y humanas. Conocer los efectos de la hipoxia crónica en el proceso de regeneración cardíaca del pez cebra (Danio rerio) y contrastarlos con los contextos de hipoxia aguda inducida y normoxia, puede tener un gran impacto en el campo de la regeneración, desde la investigación básica y traslacional. 1.2 JUSTIFICACIÓN Los pacientes con insuficiencia cardíaca pierden cardiomiocitos y se compromete de forma profunda la estructura y función del corazón ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Douglas L. Mann; Murali Chakinala","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"chapter-number":"Insuficien","container-title":"Harrison. Principios de Medicina Interna","edition":"20","editor":[{"dropping-particle":"","family":"J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo","given":"Joseph Loscalzo","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2018"]]},"publisher":"McGrawHill","publisher-place":"Mexico D.F.","title":"No Title","type":"chapter"},"uris":["http://www.mendeley.com/documents/?uuid=56f6135b-27a6-4b2e-9c3f-645d6d492fa0"]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/s41232-017-0046-5","abstract":"Inflammatory and fibrotic responses to myocardial damage are essential for cardiac repair; however, these responses often result in extensive fibrotic remodeling with impaired systolic function. Recent reports have suggested that such acute phase responses provide a favorable environment for endogenous cardiac regeneration, which is mainly driven by the division of pre-existing cardiomyocytes (CMs). Existing CMs in mammals can re-acquire proliferative activity after substantial cardiac damage, and elements other than CMs in the physiological and/or pathological environment, such as hypoxia, angiogenesis, and the polarity of infiltrating macrophages, have been reported to regulate replication. Cardiac fibroblasts comprise the largest cell population in terms of cell number in the myocardium, and they play crucial roles in the proliferation and protection of CMs. The in vivo direct reprogramming of functional CMs has been investigated in cardiac regeneration. Currently, growth factors, transcription factors, microRNAs, and small molecules promoting the regeneration and protection of these CMs have also been actively researched. Here, we summarize and discuss current studies on the relationship between cardiac inflammation and fibrosis, and cardiac regeneration and protection, which would be useful for the development of therapeutic strategies to treat and prevent advanced heart failure.","author":[{"dropping-particle":"","family":"Hara","given":"Hironori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takeda","given":"Norifumi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Komuro","given":"Issei","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Inflammation and Regeneration","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2017"]]},"page":"1-10","publisher":"Inflammation and Regeneration","title":"Pathophysiology and therapeutic potential of cardiac fibrosis","type":"article-journal","volume":"37"},"uris":["http://www.mendeley.com/documents/?uuid=97803057-e692-4efc-bb56-8b3cb3bb70c9"]}],"mendeley":{"formattedCitation":"(5,23)","plainTextFormattedCitation":"(5,23)","previouslyFormattedCitation":"(5,23)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(5,23). Aunque se ha documentado el reemplazo anual de un pequeño porcentaje de cardiomiocitos en humanos, esta tasa de recambio no logra corregir la pérdida masiva en situación de lesión ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1126/science.1164680","ISSN":"0036-8075","author":[{"dropping-particle":"","family":"Bergmann","given":"Olaf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhardwaj","given":"Ratan D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bernard","given":"Samuel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zdunek","given":"Sofia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barnabé-Heider","given":"Fanie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walsh","given":"Stuart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zupicich","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alkass","given":"Kanar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buchholz","given":"Bruce A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Druid","given":"Henrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jovinge","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisén","given":"Jonas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Science","id":"ITEM-1","issue":"5923","issued":{"date-parts":[["2009","4","3"]]},"page":"98-102","title":"Evidence for Cardiomyocyte Renewal in Humans","type":"article-journal","volume":"324"},"uris":["http://www.mendeley.com/documents/?uuid=b4c31e81-d08b-4398-a7a1-a5dfc1a3511f"]},{"id":"ITEM-2","itemData":{"DOI":"10.1126/science.1164680.Evidence","abstract":"WHO does not recommend travel restrictions in relation to MERS-CoV, but rather recommends raising awareness among travellers to and from affected countries. EU residents travelling to Middle Eastern countries need to be made aware that MERS-CoV is currently circulating in the region, and that transmission in hospital settings is still one of the main sources of infection. EU travellers should also be reminded that the risk of infection can be reduced by taking simple infection prevention measures. Should someone infected with MERS-CoV enter Europe, they are likely to present themselves to a healthcare facility. The risk of nosocomial spread highlights the need for awareness among healthcare workers, stringent infection control precautions, early detection through functioning testing algorithms and preparedness planning. The risk of widespread transmission of MERS-CoV in the community after sporadic importation into the EU/EEA remains low. Previously issued advice for travellers, including pilgrims, and healthcare workers remains valid. Source and date of request ECDC internal decision, 8 October 2015. RAPID RISK ASSESSMENT Severe respiratory disease associated with Middle East respiratory syndrome coronavirus (MERS-CoV) 21st update, 21 October 2015 RAPID RISK ASSESSMENT Middle East respiratory syndrome coronavirus (MERS-CoV), 21 October 2015 2 Public health issue This update of ECDC's risk assessment on MERS-CoV has been triggered by an increase in MERS cases acquired through nosocomial transmission in Amman, Jordan. In this update, we assess whether this event changes the risk of international spread or increases the risk to EU residents staying in or travelling to Jordan.","author":[{"dropping-particle":"al","family":"Olaf Bergmann","given":"Ratan D. Bhardwaj Samuel Bernard et","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issue":"October","issued":{"date-parts":[["2015"]]},"page":"1-16","title":"Evidence for cardiomyocyte renewal in humans","type":"article-journal","volume":"324"},"uris":["http://www.mendeley.com/documents/?uuid=0bc83fab-4295-45d2-8c00-5e9e18ad5245"]}],"mendeley":{"formattedCitation":"(24,25)","plainTextFormattedCitation":"(24,25)","previouslyFormattedCitation":"(24,25)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(24,25). Por esto uno de los principales factores que obstaculiza la recuperación de los pacientes, es la incapacidad de restablecer los tejidos perdidos o afectados ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1146/annurev-bioeng-071812-152344","ISSN":"1523-9829","abstract":"Heart disease is the leading cause of morbidity and mortality worldwide, and regenerative therapies that replace damaged myocardium could benefit millions of patients annually. The many cell types in the heart, including cardiomyocytes, endothelial cells, vascular smooth muscle cells, pericytes, and cardiac fibroblasts, communicate via intercellular signaling and modulate each other's function. Although much progress has been made in generating cells of the cardiovascular lineage from human pluripotent stem cells, a major challenge now is creating the tissue architecture to integrate a microvascular circulation and afferent arterioles into such an engineered tissue. Recent advances in cardiac and vascular tissue engineering will move us closer to the goal of generating functionally mature tissue. Using the biology of the myocardium as the foundation for designing engineered tissue and addressing the challenges to implantation and integration, we can bridge the gap from bench to bedside for a clinically tractable engineered cardiac tissue.","author":[{"dropping-particle":"","family":"Coulombe","given":"Kareen L.K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bajpai","given":"Vivek K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreadis","given":"Stelios T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murry","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annual Review of Biomedical Engineering","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"1-28","title":"Heart Regeneration with Engineered Myocardial Tissue","type":"article-journal","volume":"16"},"uris":["http://www.mendeley.com/documents/?uuid=0b755bf5-b7da-41aa-bf9c-c97ae7b308f8"]},{"id":"ITEM-2","itemData":{"author":[{"dropping-particle":"","family":"Gilbert, Scoot F; Barresi","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""}],"chapter-number":"22","container-title":"Developmental Biology","edition":"11","editor":[{"dropping-particle":"","family":"Gilbert, Scoot F; Barresi","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["2016"]]},"page":"693-721","publisher":"Sinauer Associates, Inc.","publisher-place":"Sunderland, Massachusetts","title":"Regeneration","type":"chapter"},"uris":["http://www.mendeley.com/documents/?uuid=4cd9b587-a910-41f9-a3bd-87d71b3b06c4"]}],"mendeley":{"formattedCitation":"(4,26)","plainTextFormattedCitation":"(4,26)","previouslyFormattedCitation":"(4,26)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(4,26). Situación que ha motivado la investigación en el campo de la regeneración desde distintas aproximaciones, empleando células madre, biomateriales y modelos animales ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1146/annurev-bioeng-071812-152344","ISSN":"1523-9829","abstract":"Heart disease is the leading cause of morbidity and mortality worldwide, and regenerative therapies that replace damaged myocardium could benefit millions of patients annually. The many cell types in the heart, including cardiomyocytes, endothelial cells, vascular smooth muscle cells, pericytes, and cardiac fibroblasts, communicate via intercellular signaling and modulate each other's function. Although much progress has been made in generating cells of the cardiovascular lineage from human pluripotent stem cells, a major challenge now is creating the tissue architecture to integrate a microvascular circulation and afferent arterioles into such an engineered tissue. Recent advances in cardiac and vascular tissue engineering will move us closer to the goal of generating functionally mature tissue. Using the biology of the myocardium as the foundation for designing engineered tissue and addressing the challenges to implantation and integration, we can bridge the gap from bench to bedside for a clinically tractable engineered cardiac tissue.","author":[{"dropping-particle":"","family":"Coulombe","given":"Kareen L.K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bajpai","given":"Vivek K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreadis","given":"Stelios T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murry","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annual Review of Biomedical Engineering","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"1-28","title":"Heart Regeneration with Engineered Myocardial Tissue","type":"article-journal","volume":"16"},"uris":["http://www.mendeley.com/documents/?uuid=0b755bf5-b7da-41aa-bf9c-c97ae7b308f8"]},{"id":"ITEM-2","itemData":{"DOI":"10.1155/2018/1909346","ISSN":"1687-966X","abstract":"During the past decades, stem cell-based therapy has acquired a promising role in regenerative medicine. The application of novel cell therapeutics for the treatment of cardiovascular diseases could potentially achieve the ambitious aim of effective cardiac regeneration. Despite the highly positive results from preclinical studies, data from phase I/II clinical trials are inconsistent and the improvement of cardiac remodeling and heart performance was found to be quite limited. The major issues which cardiac stem cell therapy is facing include inefficient cell delivery to the site of injury, accompanied by low cell retention and weak effectiveness of remaining stem cells in tissue regeneration. According to preclinical and clinical studies, various stem cells (adult stem cells, embryonic stem cells, and induced pluripotent stem cells) represent the most promising cell types so far. Beside the selection of the appropriate cell type, researchers have developed several strategies to produce “second-generation” stem cell products with improved regenerative capacity. Genetic and nongenetic modifications, chemical and physical preconditioning, and the application of biomaterials were found to significantly enhance the regenerative capacity of transplanted stem cells. In this review, we will give an overview of the recent developments in stem cell engineering with the goal to facilitate stem cell delivery and to promote their cardiac regenerative activity.","author":[{"dropping-particle":"","family":"Lemcke","given":"Heiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Voronina","given":"Natalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinhoff","given":"Gustav","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"David","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stem Cells International","id":"ITEM-2","issued":{"date-parts":[["2018"]]},"page":"1-22","publisher":"Hindawi","title":"Recent Progress in Stem Cell Modification for Cardiac Regeneration","type":"article-journal","volume":"2018"},"uris":["http://www.mendeley.com/documents/?uuid=8e0fa880-496d-47ad-92cc-f3b802bfa625"]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.stemcr.2016.10.009","ISSN":"22136711","abstract":"We hypothesized that the neonatal rat heart would bring transplanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to maturity as it grows to adult size. In neonatal rat heart, engrafted hiPSC derivatives developed partially matured myofibrils after 3 months, with increasing cell size and sarcomere length. There was no difference between grafts from hiPSC-CMs or hiPSC-derived cardiac progenitors (hiPSC-CPs) at 3 months, nor was maturation influenced by infarction. Interestingly, the infarcted adult heart induced greater human cardiomyocyte hypertrophy and induction of cardiac troponin I expression than the neonatal heart. Although human cardiomyocytes at all time points were significantly smaller than the host rat cardiomyocytes, transplanted neonatal rat cardiomyocytes reached adult size and structure by 3 months. Thus, the adult rat heart induces faster maturation than the neonatal heart, and human cardiomyocytes mature more slowly than rat cardiomyocytes. The slower maturation of human cardiomyocytes could be related to environmental mismatch or cell-autonomous factors.","author":[{"dropping-particle":"","family":"Kadota","given":"Shin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pabon","given":"Lil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reinecke","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murry","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Stem Cell Reports","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2017"]]},"page":"278-289","publisher":"ElsevierCompany.","title":"In Vivo Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Neonatal and Adult Rat Hearts","type":"article-journal","volume":"8"},"uris":["http://www.mendeley.com/documents/?uuid=3a43654b-1c68-42fa-9c27-9e2a3d5f8652"]},{"id":"ITEM-4","itemData":{"author":[{"dropping-particle":"","family":"Gilbert, Scoot F; Barresi","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""}],"chapter-number":"22","container-title":"Developmental Biology","edition":"11","editor":[{"dropping-particle":"","family":"Gilbert, Scoot F; Barresi","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-4","issued":{"date-parts":[["2016"]]},"page":"693-721","publisher":"Sinauer Associates, Inc.","publisher-place":"Sunderland, Massachusetts","title":"Regeneration","type":"chapter"},"uris":["http://www.mendeley.com/documents/?uuid=4cd9b587-a910-41f9-a3bd-87d71b3b06c4"]},{"id":"ITEM-5","itemData":{"DOI":"10.3389/fcvm.2019.00107","ISSN":"2297055X","abstract":"Myocardial infarction (MI) in humans is a common cause of cardiac injury and results in irreversible loss of myocardial cells and formation of fibrotic scar tissue. This fibrotic tissue preserves the integrity of the ventricular wall but undermines pump function, leading to congestive heart failure. Unfortunately, the mammalian heart is unable to replace cardiomyocytes, so the life expectancy for patients after an episode of MI is lower than for most common types of cancers. Whereas, humans cannot efficiently regenerate their heart after injury, the teleost zebrafish have the capability to repair a “broken” heart. The zebrafish is probably one of the most important models for developmental and regenerative biology of the heart. In the last decades, the zebrafish has become increasingly important for scientific research: it has many characteristics that make it a smart model for studying human disease. Moreover, adult zebrafish efficiently regenerate their hearts following different forms of injury. Due to these characteristics, and to the availability of genetic approaches, and biosensor zebrafish lines, it has been established useful for studying molecular mechanisms of heart regeneration. Regeneration of cardiomyocytes in zebrafish is not based on stem cells or transdifferentiation of other cells but on the proliferation of preexisting cardiomyocytes. For this reason, future studies into the zebrafish cardiac regenerative mechanisms could identify specific molecules able to regulate the proliferation of preexisting cardiomyocytes; these factors may be studied in order to understand regulation of myocardial plasticity in cardiac repair processes after injury and, in particular, after MI in humans.","author":[{"dropping-particle":"","family":"Beffagna","given":"Giorgia","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Cardiovascular Medicine","id":"ITEM-5","issue":"August","issued":{"date-parts":[["2019"]]},"page":"1-8","title":"Zebrafish as a Smart Model to Understand Regeneration After Heart Injury: How Fish Could Help Humans","type":"article-journal","volume":"6"},"uris":["http://www.mendeley.com/documents/?uuid=7bb8d3c9-b626-4138-9b98-36c19a2c674e"]}],"mendeley":{"formattedCitation":"(4,26–29)","plainTextFormattedCitation":"(4,26–29)","previouslyFormattedCitation":"(4,26–29)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(4,26–29). Con estos últimos, se busca comprender la esencia del fenómeno regenerativo y así aportar información sobre procesos celulares, moléculas y vías de señalización, entre otros factores implicados en el restablecimiento tisular (29,30). Los resultados de la investigaciones básicas en este campo han contribuido sustancialmente en el desarrollo de aproximaciones preclínicas con potencial aplicación traslacional (29,30). Es así como, empleando modelo animal se ha explorado la influencia de distintos factores dentro del proceso de regeneración cardíaca ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1242/dmm.040691","ISSN":"17548411","PMID":"31562250","abstract":"Heart failure is a major cause of death worldwide owing to the inability of the adult human heart to regenerate after a heart attack. However, many vertebrate species are capable of complete cardiac regeneration following injury. In this Review, we discuss the various model organisms of cardiac regeneration, and outline what they have taught us thus far about the cellular and molecular responses essential for optimal cardiac repair. We compare across different species, highlighting evolutionarily conserved mechanisms of regeneration and demonstrating the importance of developmental gene expression programmes, plasticity of the heart and the pathophysiological environment for the regenerative response. Additionally, we discuss how the findings from these studies have led to improvements in cardiac repair in preclinical models such as adult mice and pigs, and discuss the potential to translate these findings into therapeutic approaches for human patients following myocardial infarction.","author":[{"dropping-particle":"","family":"Price","given":"Eleanor L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vieira","given":"Joaquim M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Riley","given":"Paul R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"DMM Disease Models and Mechanisms","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2019"]]},"title":"Model organisms at the heart of regeneration","type":"article-journal","volume":"12"},"uris":["http://www.mendeley.com/documents/?uuid=e4a7d7cc-20b7-412c-be7f-539bf926cee0"]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/reg2.83","abstract":"Cardiovascular disease is the leading cause of death worldwide. Compared to other organs such as the liver, the adult human heart lacks the capacity to regenerate on a macroscopic scale after injury. As a result, myocardial infarctions are responsible for approximately half of all car-diovascular related deaths. In contrast, the zebrafish heart regenerates efficiently upon injury through robust myocardial proliferation. Therefore, deciphering the mechanisms that underlie the zebrafish heart's endogenous regenerative capacity represents an exciting avenue to identify novel therapeutic strategies for inducing regeneration of the human heart. This review provides a historical overview of adult zebrafish heart regeneration. We summarize 15 years of research, with a special focus on recent developments from this fascinating field. We discuss experimental findings that address fundamental questions of regeneration research. What is the origin of regenerated muscle? How is regeneration controlled from a genetic and molecular perspective? How do different cell types interact to achieve organ regeneration? Understanding natural models of heart regeneration will bring us closer to answering the ultimate question: how can we stimulate myocardial regeneration in humans? K E Y W O R D S cardiomyocyte proliferation, heart regeneration, myocardial infarction, zebrafish","author":[{"dropping-particle":"","family":"González-Rosa","given":"Juan Manuel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burns","given":"Caroline E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burns","given":"C. Geoffrey","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Regeneration","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2017"]]},"page":"105-123","title":"Zebrafish heart regeneration: 15 years of discoveries","type":"article-journal","volume":"4"},"uris":["http://www.mendeley.com/documents/?uuid=d0584b1f-64ec-4972-af64-0f165269f999"]}],"mendeley":{"formattedCitation":"(30,31)","plainTextFormattedCitation":"(30,31)","previouslyFormattedCitation":"(30,31)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(30,31). Uno de estos es la hipoxia, que en investigaciones iniciales en modelo murino ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/japplphysiol.00328.2017","ISSN":"8750-7587","abstract":"Eccentric muscle actions are associated with ultrastructural changes. The severity and types of change depend on the nature of the stimulation protocol, and on the method for assessing such changes, and can be regarded as a continuum from mild changes to pathological-like changes. Most studies describing more severe changes have been performed on animals and only a few in humans, some using electrical stimuli. Hence, a debate has emerged on whether voluntary actions are associated with the pathological-like end of the continuum. The aim of this study was to determine whether severe muscle damage, i.e., extensive ultrastructural changes, is confined to animal studies and studies on humans using electrical stimuli. Second, because there is no generally approved method to quantify the degree of muscle damage, we compared two published methods, analyzing the Z disks or sarcomeres, as well as novel analyses of pathological-like changes. A group of untrained subjects performed 70 voluntary maximal eccentric muscle actions using the elbow flexors. On the basis of large reductions in maximal force-generating capacity (on average, -62 +/- 3% immediately after exercise, and -35 +/- 6% 9 days later), five subjects were selected for further analysis. Biopsies were taken from m. biceps brachii in both the exercised and nonexercised arm. In exercised muscle, more disrupted (13 +/- 4 vs. 3 +/- 3%) and destroyed (15 +/- 6 vs. 0%) Z disks were found compared with nonexercised muscle. A significant proportion of exercised myofibers had focal (85 +/- 5 vs. 11 +/- 7%), moderate (65 +/- 7 vs. 11 +/- 6%), and extreme (38 +/- 9 vs. 0%) myofibrillar disruptions. Hypercontracted myofibrils, autophagic vacuoles, granular areas, central nuclei, and necrotic fiber segments were found to various degrees. The present study demonstrates that the more severe end of the continuum of ultrastructural changes occurs in humans after voluntary exercise when maximal eccentric muscle actions are involved.","author":[{"dropping-particle":"","family":"Kimura","given":"Wataru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Yuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadek","given":"Hesham A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Applied Physiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2017"]]},"page":"1676-1681","title":"Hypoxia-induced myocardial regeneration","type":"article-journal","volume":"123"},"uris":["http://www.mendeley.com/documents/?uuid=06e59df3-15d1-4180-9cc6-0cc8854f6094"]},{"id":"ITEM-2","itemData":{"DOI":"10.1038/nature20173","ISSN":"14764687","abstract":"The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the devastating impact of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium(1), and the adult heart is capable of modest self-renewal(2,3). In both these scenarios, cardiomyocyte renewal occurs through proliferation of pre-existing cardiomyocytes, and is regulated by aerobic respiration-mediated oxidative DNA damage(4,5). Therefore, we reasoned that systemic hypoxemia inhibits aerobic respiration and alleviates oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that gradual exposure to severe systemic hypoxemia, where inspired oxygen is gradually decreased by 1% and maintained at 7% for two weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species (ROS) production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Intriguingly, we found that exposure to hypoxemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Finally, genetic fate mapping confirmed that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.","author":[{"dropping-particle":"","family":"Nakada","given":"Yuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Canseco","given":"Diana C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thet","given":"Suwannee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdisalaam","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asaithamby","given":"Aroumougame","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santos","given":"Celio X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"Ajay M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faber","given":"James E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinter","given":"Michael T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szweda","given":"Luke I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xing","given":"Chao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Zeping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deberardinis","given":"Ralph J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schiattarella","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hill","given":"Joseph A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oz","given":"Orhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lu","given":"Zhigang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Cheng Cheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kimura","given":"Wataru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadek","given":"Hesham A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature","id":"ITEM-2","issue":"7636","issued":{"date-parts":[["2017"]]},"page":"222-227","publisher":"Nature Publishing Group","title":"Hypoxia induces heart regeneration in adult mice","type":"article-journal","volume":"541"},"uris":["http://www.mendeley.com/documents/?uuid=90421b66-a360-444d-8226-4cfd93dfd2a6"]}],"mendeley":{"formattedCitation":"(15,16)","plainTextFormattedCitation":"(15,16)","previouslyFormattedCitation":"(15,16)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(15,16) y en pez cebra (Danio rerio) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107888","ISSN":"00097322","PMID":"23151342","abstract":"BACKGROUND-: Hypoxia plays an important role in many biological/ pathological processes. In particular, hypoxia is associated with cardiac ischemia. which, although initially inducing a protective response, will ultimately lead to the death of cardiomyocytes and loss of tissue, severely affecting cardiac functionality. Although myocardial damage/loss remains an insurmountable problem for adult mammals, the same is not true for adult zebrafish, which are able to completely regenerate their heart after extensive injury. Myocardial regeneration in zebrafish involves the dedifferentiation and proliferation of cardiomyocytes to replace the damaged/missing tissue; at present, however, little is known about what factors regulate this process. METHODS AND RESULTS-: We surmised that ventricular amputation would lead to hypoxia induction in the myocardium of zebrafish and that this may play a role in regulating the regeneration of the missing cardiac tissue. Using a combination of O2 perturbation, conditional transgenics, in vitro cell culture, and microarray analysis, we found that hypoxia induces cardiomyocytes to dedifferentiate and proliferate during heart regeneration in zebrafish and have identified a number of genes that could play a role in this process. CONCLUSION-: These results indicate that hypoxia plays a positive role during heart regeneration, which should be taken into account in future strategies aimed at inducing heart regeneration in humans. © 2012 American Heart Association, Inc.","author":[{"dropping-particle":"","family":"Jopling","given":"Chris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suñé","given":"Guillermo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faucherre","given":"Adèle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabregat","given":"Carme","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Izpisua Belmonte","given":"Juan Carlos","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-1","issue":"25","issued":{"date-parts":[["2012"]]},"page":"3017-3027","title":"Hypoxia induces myocardial regeneration in zebrafish","type":"article-journal","volume":"126"},"uris":["http://www.mendeley.com/documents/?uuid=a776bf95-e05c-4d52-8bf0-57c091ab9780"]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0053748","ISSN":"19326203","abstract":"Aims: the adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it. Methods and Results: adult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2-6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9±2.6% of myocardial cell nuclei were TUNEL+ and 15.0±2.5% were AO+. At the 30-day (d) time point myocardial cell death was back to baseline (n = 3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18-24 h after H/R, it achieved its peak 3-7d later, and was back to baseline at 30d. 7d after H/R 17.4±2.3% of all cardiomyocytes were pHH3+ and 7.4±0.6% were PCNA+ (n = 3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3±2.0% in normoxia to 16.4±1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n = 12 at each time point). Conclusions: zebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models. © 2013 Parente et al.","author":[{"dropping-particle":"","family":"Parente","given":"Valeria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balasso","given":"Serena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pompilio","given":"Giulio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verduci","given":"Lorena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Colombo","given":"Gualtiero I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milano","given":"Giuseppina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guerrini","given":"Uliano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Squadroni","given":"Lidia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cotelli","given":"Franco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pozzoli","given":"Ombretta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capogrossi","given":"Maurizio C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2013"]]},"title":"Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart","type":"article-journal","volume":"8"},"uris":["http://www.mendeley.com/documents/?uuid=fcc89409-08ce-4879-af8a-4d6694011a18"]}],"mendeley":{"formattedCitation":"(22,32)","plainTextFormattedCitation":"(22,32)","previouslyFormattedCitation":"(22,32)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(22,32) ha mostrado un posible rol favorecedor en el restablecimiento tisular. Esto al incrementar la proliferación de cardiomiocitos y los procesos de angiogénesis, así como, facilitando la recuperación del parénquima y la estructura cardíaca tras lesión. Sin embargo, en estas primeras aproximaciones experimentales las condiciones de hipoxia han sido agudas e inducidas artificialmente en laboratorio ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nature20173","ISSN":"14764687","abstract":"The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the devastating impact of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium(1), and the adult heart is capable of modest self-renewal(2,3). In both these scenarios, cardiomyocyte renewal occurs through proliferation of pre-existing cardiomyocytes, and is regulated by aerobic respiration-mediated oxidative DNA damage(4,5). Therefore, we reasoned that systemic hypoxemia inhibits aerobic respiration and alleviates oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that gradual exposure to severe systemic hypoxemia, where inspired oxygen is gradually decreased by 1% and maintained at 7% for two weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species (ROS) production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Intriguingly, we found that exposure to hypoxemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Finally, genetic fate mapping confirmed that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.","author":[{"dropping-particle":"","family":"Nakada","given":"Yuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Canseco","given":"Diana C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thet","given":"Suwannee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdisalaam","given":"Salim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asaithamby","given":"Aroumougame","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santos","given":"Celio X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"Ajay M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faber","given":"James E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinter","given":"Michael T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szweda","given":"Luke I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xing","given":"Chao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Zeping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deberardinis","given":"Ralph J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schiattarella","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hill","given":"Joseph A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oz","given":"Orhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lu","given":"Zhigang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Cheng Cheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kimura","given":"Wataru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadek","given":"Hesham A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature","id":"ITEM-1","issue":"7636","issued":{"date-parts":[["2017"]]},"page":"222-227","publisher":"Nature Publishing Group","title":"Hypoxia induces heart regeneration in adult mice","type":"article-journal","volume":"541"},"uris":["http://www.mendeley.com/documents/?uuid=90421b66-a360-444d-8226-4cfd93dfd2a6"]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/japplphysiol.00328.2017","ISSN":"8750-7587","abstract":"Eccentric muscle actions are associated with ultrastructural changes. The severity and types of change depend on the nature of the stimulation protocol, and on the method for assessing such changes, and can be regarded as a continuum from mild changes to pathological-like changes. Most studies describing more severe changes have been performed on animals and only a few in humans, some using electrical stimuli. Hence, a debate has emerged on whether voluntary actions are associated with the pathological-like end of the continuum. The aim of this study was to determine whether severe muscle damage, i.e., extensive ultrastructural changes, is confined to animal studies and studies on humans using electrical stimuli. Second, because there is no generally approved method to quantify the degree of muscle damage, we compared two published methods, analyzing the Z disks or sarcomeres, as well as novel analyses of pathological-like changes. A group of untrained subjects performed 70 voluntary maximal eccentric muscle actions using the elbow flexors. On the basis of large reductions in maximal force-generating capacity (on average, -62 +/- 3% immediately after exercise, and -35 +/- 6% 9 days later), five subjects were selected for further analysis. Biopsies were taken from m. biceps brachii in both the exercised and nonexercised arm. In exercised muscle, more disrupted (13 +/- 4 vs. 3 +/- 3%) and destroyed (15 +/- 6 vs. 0%) Z disks were found compared with nonexercised muscle. A significant proportion of exercised myofibers had focal (85 +/- 5 vs. 11 +/- 7%), moderate (65 +/- 7 vs. 11 +/- 6%), and extreme (38 +/- 9 vs. 0%) myofibrillar disruptions. Hypercontracted myofibrils, autophagic vacuoles, granular areas, central nuclei, and necrotic fiber segments were found to various degrees. The present study demonstrates that the more severe end of the continuum of ultrastructural changes occurs in humans after voluntary exercise when maximal eccentric muscle actions are involved.","author":[{"dropping-particle":"","family":"Kimura","given":"Wataru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Yuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadek","given":"Hesham A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Applied Physiology","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2017"]]},"page":"1676-1681","title":"Hypoxia-induced myocardial regeneration","type":"article-journal","volume":"123"},"uris":["http://www.mendeley.com/documents/?uuid=06e59df3-15d1-4180-9cc6-0cc8854f6094"]},{"id":"ITEM-3","itemData":{"DOI":"10.1161/CIRCULATIONAHA.112.107888","ISBN":"1524-4539 (Electronic) 0009-7322 (Linking)","ISSN":"00097322","PMID":"23151342","abstract":"BACKGROUND: Hypoxia plays an important role in many biological/pathological processes. In particular, hypoxia is associated with cardiac ischemia. which, although initially inducing a protective response, will ultimately lead to the death of cardiomyocytes and loss of tissue, severely affecting cardiac functionality. Although myocardial damage/loss remains an insurmountable problem for adult mammals, the same is not true for adult zebrafish, which are able to completely regenerate their heart after extensive injury. Myocardial regeneration in zebrafish involves the dedifferentiation and proliferation of cardiomyocytes to replace the damaged/missing tissue; at present, however, little is known about what factors regulate this process.\\n\\nMETHODS AND RESULTS: We surmised that ventricular amputation would lead to hypoxia induction in the myocardium of zebrafish and that this may play a role in regulating the regeneration of the missing cardiac tissue. Using a combination of O(2) perturbation, conditional transgenics, in vitro cell culture, and microarray analysis, we found that hypoxia induces cardiomyocytes to dedifferentiate and proliferate during heart regeneration in zebrafish and have identified a number of genes that could play a role in this process.\\n\\nCONCLUSION: These results indicate that hypoxia plays a positive role during heart regeneration, which should be taken into account in future strategies aimed at inducing heart regeneration in humans.","author":[{"dropping-particle":"","family":"Jopling","given":"Chris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suñé","given":"Guillermo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faucherre","given":"Adèle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabregat","given":"Carme","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Izpisua Belmonte","given":"Juan Carlos","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-3","issue":"25","issued":{"date-parts":[["2012"]]},"page":"3017-3027","title":"Hypoxia induces myocardial regeneration in zebrafish","type":"article-journal","volume":"126"},"uris":["http://www.mendeley.com/documents/?uuid=c36210f2-0302-4d86-a035-e9e2462626c3"]}],"mendeley":{"formattedCitation":"(15,16,21)","plainTextFormattedCitation":"(15,16,21)","previouslyFormattedCitation":"(15,16,21)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(15,16,21). Condiciones experimentales que distan significativamente de las características naturales de hipoxia hipobárica a las que muchas poblaciones animales y humanas están expuestas de forma crónica ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"9972623270, 9789972623271","author":[{"dropping-particle":"","family":"Carlos Monge Cassinelli","given":"F León Velarde","non-dropping-particle":"","parse-names":false,"suffix":""}],"editor":[{"dropping-particle":"","family":"Instituto Francés de Estudios Andinos","given":"IFEA","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2003"]]},"number-of-pages":"435","title":"El Reto Fisiológico de Vivir en Los Andes","type":"book"},"uris":["http://www.mendeley.com/documents/?uuid=7e4d1f23-78e2-48b7-8f03-eb42c9e7f0db"]},{"id":"ITEM-2","itemData":{"DOI":"10.1073/pnas.0701985104","ISSN":"0027-8424","author":[{"dropping-particle":"","family":"Beall","given":"C. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-2","issue":"Supplement 1","issued":{"date-parts":[["2007","5","15"]]},"page":"8655-8660","title":"Two routes to functional adaptation: Tibetan and Andean high-altitude natives","type":"article-journal","volume":"104"},"uris":["http://www.mendeley.com/documents/?uuid=bc5b8342-7504-4edd-98d1-a39779ec0996"]}],"mendeley":{"formattedCitation":"(33,34)","plainTextFormattedCitation":"(33,34)","previouslyFormattedCitation":"(33,34)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(33,34). Estos contextos naturales pueden potencialmente generar un impactos importantes y aun no conocidos en el proceso de regeneración. Para poder explorar este efecto ambiental en el contexto de regeneración cardíaca es muy útil el empleo de organismos con alta capacidad regenerativa como el pez cebra (Danio rerio). Esta especie presenta restablecimiento completo de su estructura y función cardíaca después de sufrir lesión ventricular ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/reg2.83","abstract":"Cardiovascular disease is the leading cause of death worldwide. Compared to other organs such as the liver, the adult human heart lacks the capacity to regenerate on a macroscopic scale after injury. As a result, myocardial infarctions are responsible for approximately half of all car-diovascular related deaths. In contrast, the zebrafish heart regenerates efficiently upon injury through robust myocardial proliferation. Therefore, deciphering the mechanisms that underlie the zebrafish heart's endogenous regenerative capacity represents an exciting avenue to identify novel therapeutic strategies for inducing regeneration of the human heart. This review provides a historical overview of adult zebrafish heart regeneration. We summarize 15 years of research, with a special focus on recent developments from this fascinating field. We discuss experimental findings that address fundamental questions of regeneration research. What is the origin of regenerated muscle? How is regeneration controlled from a genetic and molecular perspective? How do different cell types interact to achieve organ regeneration? Understanding natural models of heart regeneration will bring us closer to answering the ultimate question: how can we stimulate myocardial regeneration in humans? K E Y W O R D S cardiomyocyte proliferation, heart regeneration, myocardial infarction, zebrafish","author":[{"dropping-particle":"","family":"González-Rosa","given":"Juan Manuel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burns","given":"Caroline E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burns","given":"C. Geoffrey","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Regeneration","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2017"]]},"page":"105-123","title":"Zebrafish heart regeneration: 15 years of discoveries","type":"article-journal","volume":"4"},"uris":["http://www.mendeley.com/documents/?uuid=d0584b1f-64ec-4972-af64-0f165269f999"]}],"mendeley":{"formattedCitation":"(31)","plainTextFormattedCitation":"(31)","previouslyFormattedCitation":"(31)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(31). Este teleósteo, es un organismo con grandes similitudes en el desarrollo, estructura y función cardiaca. Además, comparte un 70% de genes ortólogos con los humanos ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fcvm.2019.00107","ISSN":"2297055X","abstract":"Myocardial infarction (MI) in humans is a common cause of cardiac injury and results in irreversible loss of myocardial cells and formation of fibrotic scar tissue. This fibrotic tissue preserves the integrity of the ventricular wall but undermines pump function, leading to congestive heart failure. Unfortunately, the mammalian heart is unable to replace cardiomyocytes, so the life expectancy for patients after an episode of MI is lower than for most common types of cancers. Whereas, humans cannot efficiently regenerate their heart after injury, the teleost zebrafish have the capability to repair a “broken” heart. The zebrafish is probably one of the most important models for developmental and regenerative biology of the heart. In the last decades, the zebrafish has become increasingly important for scientific research: it has many characteristics that make it a smart model for studying human disease. Moreover, adult zebrafish efficiently regenerate their hearts following different forms of injury. Due to these characteristics, and to the availability of genetic approaches, and biosensor zebrafish lines, it has been established useful for studying molecular mechanisms of heart regeneration. Regeneration of cardiomyocytes in zebrafish is not based on stem cells or transdifferentiation of other cells but on the proliferation of preexisting cardiomyocytes. For this reason, future studies into the zebrafish cardiac regenerative mechanisms could identify specific molecules able to regulate the proliferation of preexisting cardiomyocytes; these factors may be studied in order to understand regulation of myocardial plasticity in cardiac repair processes after injury and, in particular, after MI in humans.","author":[{"dropping-particle":"","family":"Beffagna","given":"Giorgia","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Cardiovascular Medicine","id":"ITEM-1","issue":"August","issued":{"date-parts":[["2019"]]},"page":"1-8","title":"Zebrafish as a Smart Model to Understand Regeneration After Heart Injury: How Fish Could Help Humans","type":"article-journal","volume":"6"},"uris":["http://www.mendeley.com/documents/?uuid=7bb8d3c9-b626-4138-9b98-36c19a2c674e"]}],"mendeley":{"formattedCitation":"(29)","plainTextFormattedCitation":"(29)","previouslyFormattedCitation":"(29)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(29). Todo esto lo hace un modelo ideal para entender los mecanismos celulares, moleculares y funcionales implicados en la regeneración bajo ambientes naturalmente hipóxicos. Ahondar en esta pregunta es prioritario y potencialmente útil. Este estudio será la primera aproximación para entender el efecto global de la hipoxia hipobárica crónica (2638 msnm) en el proceso de regeneración cardíaca del pez cebra (Danio rerio). Logrando contrastar este resultado con aquellos bajo hipoxia aguda inducida farmacológicamente y la hipobaria con suplementación de oxígeno. Todo esto servirá para generar un panorama inicial sobre el impacto de esta condición ambiental a nivel tisular, en la evolución histopatológica y en la proliferación de cardiomiocitos. Adicionalmente, este trabajo permitirá evaluar por primera vez el restablecimiento de la función eléctrica del corazón e indirectamente los cambios en la respuesta autónoma por medio del comportamiento en la VFC para las variables de altura y lesión evaluadas. En este contexto, el conocimiento derivado de este proyecto puede aportar información valiosa que aclare el papel cardioprotector, estimulador o agravante de la hipoxia hipobárica en la regeneración cardíaca del pez cebra (Danio rerio). Lo que contribuye, no solo al área de la regeneración y la fisiología ambiental, sino que, además generará datos valiosos que se utilicen en el campo biomédica y la investigación traslacional. Donde este conocimiento apoye el desarrollo futuro de posibles terapias y abordajes diseñados para las poblaciones humanas habitantes permanentes en moderada y gran altitud. Una condición propia de nuestro territorio nacional y de la Región Andina. 1.3 PREGUNTA DE INVESTIGACIÓN ¿Cuál es el efecto de la hipoxia tisular en la regeneración cardíaca de peces cebra (Danio rerio) expuestos de forma crónica o aguda a diferentes condiciones de oxigenación y presión barométrica? El detalle de las referencias citadas puede consultarse en numeral 13 del texto completo de la propuesta, en el ANEXO No. 1.
StatusFinished
Effective start/end date10/11/2109/05/23

Project Status

  • Not defined

Project funding

  • Internal
  • Pontificia Universidad Javeriana

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