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Sample records for human heart cells

  1. Dynamics of Cell Generation and Turnover in the Human Heart.

    PubMed

    Bergmann, Olaf; Zdunek, Sofia; Felker, Anastasia; Salehpour, Mehran; Alkass, Kanar; Bernard, Samuel; Sjostrom, Staffan L; Szewczykowska, Mirosława; Jackowska, Teresa; Dos Remedios, Cris; Malm, Torsten; Andrä, Michaela; Jashari, Ramadan; Nyengaard, Jens R; Possnert, Göran; Jovinge, Stefan; Druid, Henrik; Frisén, Jonas

    2015-06-18

    The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived (14)C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart. PMID:26073943

  2. Programming and reprogramming a human heart cell

    PubMed Central

    Sahara, Makoto; Santoro, Federica; Chien, Kenneth R

    2015-01-01

    The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the “programming” and “reprogramming” of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart. PMID:25712211

  3. Telocytes and putative stem cells in ageing human heart

    PubMed Central

    Popescu, Laurentiu M; Curici, Antoanela; Wang, Enshi; Zhang, Hao; Hu, Shengshou; Gherghiceanu, Mihaela

    2015-01-01

    Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit http://www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days–1 year), children (6–17 years) and adults (34–60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm2) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52–62%; vascular smooth muscle cells and pericytes 22–28%, Schwann cells with nerve endings 6–7%, fibroblasts 3–10%, macrophages 1–8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults). PMID:25545142

  4. Myocardial commitment from human pluripotent stem cells: Rapid production of human heart grafts.

    PubMed

    Garreta, Elena; de Oñate, Lorena; Fernández-Santos, M Eugenia; Oria, Roger; Tarantino, Carolina; Climent, Andreu M; Marco, Andrés; Samitier, Mireia; Martínez, Elena; Valls-Margarit, Maria; Matesanz, Rafael; Taylor, Doris A; Fernández-Avilés, Francisco; Izpisua Belmonte, Juan Carlos; Montserrat, Nuria

    2016-08-01

    Genome editing on human pluripotent stem cells (hPSCs) together with the development of protocols for organ decellularization opens the door to the generation of autologous bioartificial hearts. Here we sought to generate for the first time a fluorescent reporter human embryonic stem cell (hESC) line by means of Transcription activator-like effector nucleases (TALENs) to efficiently produce cardiomyocyte-like cells (CLCs) from hPSCs and repopulate decellularized human heart ventricles for heart engineering. In our hands, targeting myosin heavy chain locus (MYH6) with mCherry fluorescent reporter by TALEN technology in hESCs did not alter major pluripotent-related features, and allowed for the definition of a robust protocol for CLCs production also from human induced pluripotent stem cells (hiPSCs) in 14 days. hPSCs-derived CLCs (hPSCs-CLCs) were next used to recellularize acellular cardiac scaffolds. Electrophysiological responses encountered when hPSCs-CLCs were cultured on ventricular decellularized extracellular matrix (vdECM) correlated with significant increases in the levels of expression of different ion channels determinant for calcium homeostasis and heart contractile function. Overall, the approach described here allows for the rapid generation of human cardiac grafts from hPSCs, in a total of 24 days, providing a suitable platform for cardiac engineering and disease modeling in the human setting. PMID:27179434

  5. Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types.

    PubMed

    Loh, Kyle M; Chen, Angela; Koh, Pang Wei; Deng, Tianda Z; Sinha, Rahul; Tsai, Jonathan M; Barkal, Amira A; Shen, Kimberle Y; Jain, Rajan; Morganti, Rachel M; Shyh-Chang, Ng; Fernhoff, Nathaniel B; George, Benson M; Wernig, Gerlinde; Salomon, Rachel E A; Chen, Zhenghao; Vogel, Hannes; Epstein, Jonathan A; Kundaje, Anshul; Talbot, William S; Beachy, Philip A; Ang, Lay Teng; Weissman, Irving L

    2016-07-14

    Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT. PMID:27419872

  6. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.

    PubMed

    Shiba, Yuji; Fernandes, Sarah; Zhu, Wei-Zhong; Filice, Dominic; Muskheli, Veronica; Kim, Jonathan; Palpant, Nathan J; Gantz, Jay; Moyes, Kara White; Reinecke, Hans; Van Biber, Benjamin; Dardas, Todd; Mignone, John L; Izawa, Atsushi; Hanna, Ramy; Viswanathan, Mohan; Gold, Joseph D; Kotlikoff, Michael I; Sarvazyan, Narine; Kay, Matthew W; Murry, Charles E; Laflamme, Michael A

    2012-09-13

    Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair. PMID:22864415

  7. "The state of the heart": Recent advances in engineering human cardiac tissue from pluripotent stem cells.

    PubMed

    Sirabella, Dario; Cimetta, Elisa; Vunjak-Novakovic, Gordana

    2015-08-01

    The pressing need for effective cell therapy for the heart has led to the investigation of suitable cell sources for tissue replacement. In recent years, human pluripotent stem cell research expanded tremendously, in particular since the derivation of human-induced pluripotent stem cells. In parallel, bioengineering technologies have led to novel approaches for in vitro cell culture. The combination of these two fields holds potential for in vitro generation of high-fidelity heart tissue, both for basic research and for therapeutic applications. However, this new multidisciplinary science is still at an early stage. Many questions need to be answered and improvements need to be made before clinical applications become a reality. Here we discuss the current status of human stem cell differentiation into cardiomyocytes and the combined use of bioengineering approaches for cardiac tissue formation and maturation in developmental studies, disease modeling, drug testing, and regenerative medicine. PMID:26069271

  8. Can stem cells really regenerate the human heart? Use your noggin, dickkopf! Lessons from developmental biology.

    PubMed

    Sommer, Paula

    2013-06-01

    The human heart is the first organ to develop and its development is fairly well characterised. In theory, the heart has the capacity to regenerate, as its cardiomyocytes may be capable of cell division and the adult heart contains a cardiac stem cell niche, presumably capable of differentiating into cardiomyocytes and other cardiac-associated cell types. However, as with most other organs, these mechanisms are not activated upon serious injury. Several experimental options to induce regeneration of the damaged heart tissue are available: activate the endogenous cardiomyocytes to divide, coax the endogenous population of stem cells to divide and differentiate, or add exogenous cell-based therapy to replace the lost cardiac tissue. This review is a summary of the recent research into all these avenues, discussing the reasons for the limited successes of clinical trials using stem cells after cardiac injury and explaining new advances in basic science. It concludes with a reiteration that chances of successful regeneration would be improved by understanding and implementing the basics of heart development and stem cell biology. PMID:24217168

  9. Tracking Fusion of Human Mesenchymal Stem Cells After Transplantation to the Heart

    PubMed Central

    Freeman, Brian T.; Kouris, Nicholas A.

    2015-01-01

    Evidence suggests that transplanted mesenchymal stem cells (MSCs) can aid recovery of damaged myocardium caused by myocardial infarction. One possible mechanism for MSC-mediated recovery is reprogramming after cell fusion between transplanted MSCs and recipient cardiac cells. We used a Cre/LoxP-based luciferase reporter system coupled to biophotonic imaging to detect fusion of transplanted human pluripotent stem cell-derived MSCs to cells of organs of living mice. Human MSCs, with transient expression of a viral fusogen, were delivered to the murine heart via a collagen patch. At 2 days and 1 week later, living mice were probed for bioluminescence indicative of cell fusion. Cell fusion was detected at the site of delivery (heart) and in distal tissues (i.e., stomach, small intestine, liver). Fusion was confirmed at the cellular scale via fluorescence in situ hybridization for human-specific and mouse-specific centromeres. Human cells in organs distal to the heart were typically located near the vasculature, suggesting MSCs and perhaps MSC fusion products have the ability to migrate via the circulatory system to distal organs and engraft with local cells. The present study reveals previously unknown migratory patterns of delivered human MSCs and associated fusion products in the healthy murine heart. The study also sets the stage for follow-on studies to determine the functional effects of cell fusion in a model of myocardial damage or disease. Significance Mesenchymal stem cells (MSCs) are transplanted to the heart, cartilage, and other tissues to recover lost function or at least limit overactive immune responses. Analysis of tissues after MSC transplantation shows evidence of fusion between MSCs and the cells of the recipient. To date, the biologic implications of cell fusion remain unclear. A newly developed in vivo tracking system was used to identify MSC fusion products in living mice. The migratory patterns of fusion products were determined both in the

  10. Alloproliferation of purified CD4+ T cells to adult human heart endothelial cells, and study of second-signal requirements.

    PubMed Central

    McDouall, R M; Page, C S; Hafizi, S; Yacoub, M H; Rose, M L

    1996-01-01

    Human endothelial cells have been shown to be capable of causing direct allostimulation of T cells. However, the majority of immunological studies of human endothelial cells have been performed on cells of fetal origin. Here we use endothelial cells isolated from the adult human heart, both large vessel (coronary artery, pulmonary artery and aorta) and also microvascular. We have examined the ability of all these endothelial cells to cause direct allostimulation of T cells, and show that purified CD4+ T cells can proliferate in response to adult human heart endothelial cells, the response being dependent on pretreatment of the endothelial cells with interferon-gamma (IFN-gamma) and inhibited by anti-HLA-DR monoclonal antibody. The proliferative responses of CD8+ T cells to adult but not fetal endothelial cells was inconsistent and weak. Proliferative responses were not blocked by CTLA4-Ig, which inhibits T-cell responses to "classical' antigen-presenting cells (APC), but > 50% inhibition was achieved with monoclonal antibody to lymphocyte function-associated antigen-3 (LFA-3). These results show that adult human cardiovascular endothelial cells are capable of causing allostimulation of resting CD4+ T cells, using a different second signal to classical APC. In view of these findings endothelial cells should be considered as APC following solid organ transplantation. PMID:8943718

  11. Immunochemistry of the Streptococcus mutans BHT cell membrane: detection of determinants cross-reactive with human heart tissue.

    PubMed Central

    Ayakawa, G Y; Siegel, J L; Crowley, P J; Bleiweis, A S

    1985-01-01

    Cell membranes of Streptococcus mutans BHT serotype b were prepared after glass bead disruption or mutanolysin digestion of whole cells. Immunoblot analyses of BHT membrane extracts revealed major polypeptides of 42,000, 46,000, 62,000, and 82,000 daltons, as well as several minor bands, to be reactive with rabbit anti-human heart immunoglobulins. Heart cross-reactive antigens have been reported in the cell walls and culture fluids of several S. mutans serotypes. This represents the first report of cell membrane-localized heart cross-reactive antigens in this oral pathogen. Positive enzyme-linked immunosorbent assay and immunoblot reactions were also obtained with heart tissue antigen and anti-BHT sera, indicating mutual cross-reactivity. The major cross-reactive component detected by immunoblotting of human heart extracts was a 69,000-dalton polypeptide. Images PMID:3886543

  12. Monophasic and Biphasic Electrical Stimulation Induces a Precardiac Differentiation in Progenitor Cells Isolated from Human Heart

    PubMed Central

    Pietronave, Stefano; Zamperone, Andrea; Oltolina, Francesca; Colangelo, Donato; Follenzi, Antonia; Novelli, Eugenio; Diena, Marco; Pavesi, Andrea; Consolo, Filippo; Fiore, Gianfranco Beniamino; Soncini, Monica

    2014-01-01

    Electrical stimulation (ES) of cells has been shown to induce a variety of responses, such as cytoskeleton rearrangements, migration, proliferation, and differentiation. In this study, we have investigated whether monophasic and biphasic pulsed ES could exert any effect on the proliferation and differentiation of human cardiac progenitor cells (hCPCs) isolated from human heart fragments. Cells were cultured under continuous exposure to monophasic or biphasic ES with fixed cycles for 1 or 3 days. Results indicate that neither stimulation protocol affected cell viability, while the cell shape became more elongated and reoriented more perpendicular to the electric field direction. Moreover, the biphasic ES clearly induced the upregulation of early cardiac transcription factors, MEF2D, GATA-4, and Nkx2.5, as well as the de novo expression of the late cardiac sarcomeric proteins, troponin T, cardiac alpha actinin, and SERCA 2a. Both treatments increased the expression of connexin 43 and its relocation to the cell membrane, but biphasic ES was faster and more effective. Finally, when hCPCs were exposed to both monophasic and biphasic ES, they expressed de novo the mRNA of the voltage-dependent calcium channel Cav 3.1(α1G) subunit, which is peculiar of the developing heart. Taken together, these results show that ES alone is able to set the conditions for early differentiation of adult hCPCs toward a cardiac phenotype. PMID:24328510

  13. Fetal heart extract facilitates the differentiation of human umbilical cord blood-derived mesenchymal stem cells into heart muscle precursor cells.

    PubMed

    Pham, Truc Le-Buu; Nguyen, Tam Thanh; Van Bui, Anh; Nguyen, My Thu; Van Pham, Phuc

    2016-08-01

    Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are a promising stem cell source with the potential to modulate the immune system as well as the capacity to differentiate into osteoblasts, chondrocytes, and adipocytes. In previous publications, UCB-MSCs have been successfully differentiated into cardiomyocytes. This study aimed to improve the efficacy of differentiation of UCB-MSCs into cardiomyocytes by combining 5-azacytidine (Aza) with mouse fetal heart extract (HE) in the induction medium. UCB-MSCs were isolated from umbilical cord blood according to a published protocol. Murine fetal hearts were used to produce fetal HE using a rapid freeze-thaw procedure. MSCs at the 3rd to 5th passage were differentiated into cardiomyocytes in two kinds of induction medium: complete culture medium plus Aza (Aza group) and complete culture medium plus Aza and fetal HE (Aza + HE group). The results showed that the cells in both kinds of induction medium exhibited the phenotype of cardiomyocytes. At the transcriptional level, the cells expressed a number of cardiac muscle-specific genes such as Nkx2.5, Gata 4, Mef2c, HCN2, hBNP, α-Ca, cTnT, Desmin, and β-MHC on day 27 in the Aza group and on day 18 in the Aza + HE group. At the translational level, sarcomic α-actin was expressed on day 27 in the Aza group and day 18 in the Aza + HE group. Although they expressed specific genes and proteins of cardiac muscle cells, the induced cells in both groups did not contract and beat spontaneously. These properties are similar to properties of heart muscle precursor cells in vivo. These results demonstrated that the fetal HE facilitates the differentiation process of human UCB-MSCs into heart muscle precursor cells. PMID:25377264

  14. Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21.

    PubMed

    Bosman, Alexis; Letourneau, Audrey; Sartiani, Laura; Del Lungo, Martina; Ronzoni, Flavio; Kuziakiv, Rostyslav; Tohonen, Virpi; Zucchelli, Marco; Santoni, Federico; Guipponi, Michel; Dumevska, Biljana; Hovatta, Outi; Antonarakis, Stylianos E; Jaconi, Marisa E

    2015-05-01

    Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in DS, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1(+) progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by downregulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21 cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21 cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX, and L-type Ca(2+) channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. Stem Cells 2015;33:1434-1446. PMID:25645121

  15. Human placenta-derived adherent cells improve cardiac performance in mice with chronic heart failure.

    PubMed

    Chen, Hong-Jung; Chen, Chien-Hsi; Chang, Ming-Yao; Tsai, Da-Ching; Baum, Ellen Z; Hariri, Robert; Herzberg, Uri; Hsieh, Patrick C H

    2015-03-01

    Human placenta-derived adherent cells (PDACs) are a culture-expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory, anti-inflammatory, angiogenic, and neuroprotective properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. We tested the therapeutic effects of PDA-001 in mice with chronic heart failure (CHF). Three weeks after transaortic constriction surgery to induce CHF, the mice underwent direct intramyocardial (IM) or i.v. injection of PDA-001 at a high (0.5 × 10(6) cells per mouse), medium (0.5 × 10(5) cells per mouse), or low (0.5 × 10(4) cells per mouse) dose. The mice were sacrificed 4 weeks after treatment. Echocardiography and ventricular catheterization showed that IM injection of PDA-001 significantly improved left ventricular systolic and diastolic function compared with injection of vehicle or i.v. injection of PDA-001. IM injection of PDA-001 also decreased cardiac fibrosis, shown by trichrome staining in the vicinity of the injection sites. Low-dose treatment showed the best improvement in cardiac performance compared with the medium- and high-dose groups. In another independent study to determine the mechanism of action with bromodeoxyuridine labeling, the proliferation rates of endothelial cells and cardiomyocytes were significantly increased by low or medium IM dose PDA-001. However, no surviving PDA-001 cells were detected in the heart 1 month after injection. In vivo real-time imaging consistently revealed that the PDA-001 cells were detectable only within 2 days after IM injection of luciferase-expressing PDA-001. Together, these results have demonstrated the cardiac therapeutic potential of PDA-001, likely through a paracrine effect. PMID:25673767

  16. Functional Effects of Delivering Human Mesenchymal Stem Cell-Seeded Biological Sutures to an Infarcted Heart

    PubMed Central

    Hansen, Katrina J.; Favreau, John T.; Guyette, Jacques P.; Tao, Ze-Wei; Coffin, Spencer T.; Cunha-Gavidia, Anny; D'Amore, Brian; Perreault, Luke R.; Fitzpatrick, John P.; DeMartino, Angelica; Gaudette, Glenn R.

    2016-01-01

    Abstract Stem cell therapy has the potential to improve cardiac function after myocardial infarction (MI); however, existing methods to deliver cells to the myocardium, including intramyocardial injection, suffer from low engraftment rates. In this study, we used a rat model of acute MI to assess the effects of human mesenchymal stem cell (hMSC)-seeded fibrin biological sutures on cardiac function at 1 week after implant. Biological sutures were seeded with quantum dot (Qdot)-loaded hMSCs for 24 h before implantation. At 1 week postinfarct, the heart was imaged to assess mechanical function in the infarct region. Regional parameters assessed were regional stroke work (RSW) and systolic area of contraction (SAC) and global parameters derived from the pressure waveform. MI (n = 6) significantly decreased RSW (0.026 ± 0.011) and SAC (0.022 ± 0.015) when compared with sham operation (RSW: 0.141 ± 0.009; SAC: 0.166 ± 0.005, n = 6) (p < 0.05). The delivery of unseeded biological sutures to the infarcted hearts did not change regional mechanical function compared with the infarcted hearts (RSW: 0.032 ± 0.004, SAC: 0.037 ± 0.008, n = 6). The delivery of hMSC-seeded sutures exerted a trend toward increase of regional mechanical function compared with the infarcted heart (RSW: 0.057 ± 0.011; SAC: 0.051 ± 0.014, n = 6). Global function showed no significant differences between any group (p > 0.05); however, there was a trend toward improved function with the addition of either unseeded or seeded biological suture. Histology demonstrated that Qdot-loaded hMSCs remained present in the infarcted myocardium after 1 week. Analysis of serial sections of Masson's trichrome staining revealed that the greatest infarct size was in the infarct group (7.0% ± 2.2%), where unseeded (3.8% ± 0.6%) and hMSC-seeded (3.7% ± 0.8%) suture groups maintained similar infarct sizes. Furthermore, the remaining suture area

  17. Functional Effects of Delivering Human Mesenchymal Stem Cell-Seeded Biological Sutures to an Infarcted Heart.

    PubMed

    Hansen, Katrina J; Favreau, John T; Guyette, Jacques P; Tao, Ze-Wei; Coffin, Spencer T; Cunha-Gavidia, Anny; D'Amore, Brian; Perreault, Luke R; Fitzpatrick, John P; DeMartino, Angelica; Gaudette, Glenn R

    2016-01-01

    Stem cell therapy has the potential to improve cardiac function after myocardial infarction (MI); however, existing methods to deliver cells to the myocardium, including intramyocardial injection, suffer from low engraftment rates. In this study, we used a rat model of acute MI to assess the effects of human mesenchymal stem cell (hMSC)-seeded fibrin biological sutures on cardiac function at 1 week after implant. Biological sutures were seeded with quantum dot (Qdot)-loaded hMSCs for 24 h before implantation. At 1 week postinfarct, the heart was imaged to assess mechanical function in the infarct region. Regional parameters assessed were regional stroke work (RSW) and systolic area of contraction (SAC) and global parameters derived from the pressure waveform. MI (n = 6) significantly decreased RSW (0.026 ± 0.011) and SAC (0.022 ± 0.015) when compared with sham operation (RSW: 0.141 ± 0.009; SAC: 0.166 ± 0.005, n = 6) (p < 0.05). The delivery of unseeded biological sutures to the infarcted hearts did not change regional mechanical function compared with the infarcted hearts (RSW: 0.032 ± 0.004, SAC: 0.037 ± 0.008, n = 6). The delivery of hMSC-seeded sutures exerted a trend toward increase of regional mechanical function compared with the infarcted heart (RSW: 0.057 ± 0.011; SAC: 0.051 ± 0.014, n = 6). Global function showed no significant differences between any group (p > 0.05); however, there was a trend toward improved function with the addition of either unseeded or seeded biological suture. Histology demonstrated that Qdot-loaded hMSCs remained present in the infarcted myocardium after 1 week. Analysis of serial sections of Masson's trichrome staining revealed that the greatest infarct size was in the infarct group (7.0% ± 2.2%), where unseeded (3.8% ± 0.6%) and hMSC-seeded (3.7% ± 0.8%) suture groups maintained similar infarct sizes. Furthermore, the remaining suture area was

  18. Stromal Cells in Dense Collagen Promote Cardiomyocyte and Microvascular Patterning in Engineered Human Heart Tissue.

    PubMed

    Roberts, Meredith A; Tran, Dominic; Coulombe, Kareen L K; Razumova, Maria; Regnier, Michael; Murry, Charles E; Zheng, Ying

    2016-04-01

    Cardiac tissue engineering is a strategy to replace damaged contractile tissue and model cardiac diseases to discover therapies. Current cardiac and vascular engineering approaches independently create aligned contractile tissue or perfusable vasculature, but a combined vascularized cardiac tissue remains to be achieved. Here, we sought to incorporate a patterned microvasculature into engineered heart tissue, which balances the competing demands from cardiomyocytes to contract the matrix versus the vascular lumens that need structural support. Low-density collagen hydrogels (1.25 mg/mL) permit human embryonic stem cell-derived cardiomyocytes (hESC-CMs) to form a dense contractile tissue but cannot support a patterned microvasculature. Conversely, high collagen concentrations (density ≥6 mg/mL) support a patterned microvasculature, but the hESC-CMs lack cell-cell contact, limiting their electrical communication, structural maturation, and tissue-level contractile function. When cocultured with matrix remodeling stromal cells, however, hESC-CMs structurally mature and form anisotropic constructs in high-density collagen. Remodeling requires the stromal cells to be in proximity with hESC-CMs. In addition, cocultured cardiac constructs in dense collagen generate measurable active contractions (on the order of 0.1 mN/mm(2)) and can be paced up to 2 Hz. Patterned microvascular networks in these high-density cocultured cardiac constructs remain patent through 2 weeks of culture, and hESC-CMs show electrical synchronization. The ability to maintain microstructural control within engineered heart tissue enables generation of more complex features, such as cellular alignment and a vasculature. Successful incorporation of these features paves the way for the use of large scale engineered tissues for myocardial regeneration and cardiac disease modeling. PMID:26955856

  19. Relationship between deoxyribonucleic acid content and nucleoli in human heart muscle cells and estimation of cell number during cardiac growth and hyperfunction.

    PubMed

    Adler, C P

    1975-01-01

    In the myocardium of 30 human hearts of all age groups quantitative deoxyribonucleic acid (DNA) measurements were performed and the results of the measurements were correlated with the pure myocardium weight. By means of the diphenylamine reaction the total amount of DNA (DNA concentration and DNA amount) in the myocardium was estimated. By means of Feulgen cytophotometry the DNA amount exclusively in the heart muscle cell nuclei was measured. With the use of myocardial tissue spread on slides, the nuclear areas of the heart muscle nuclei were planimetrically measured. After preparation with DNase and staining with gallocyanine chromalumn the nucleoli in heart muscle nuclei were specifically presented and their number per nucleus as well as their area values were demonstrated. From the biochemical and cytophotometric results of the myocardial DNA content it was possible to estimate the absolute cell number of the hearts, keeping the pure myocardium weight in consideration. The investigations led to the following results. In growing childrens' hearts the DNA concentration decreases to a constant level of 0.3-0.4 mg/g. The amount of DNA rises with increasing heart weight. During the growth of the heart of a child between the ages of 8 and 12 the DNA amount doubles in the heart muscle nuclei, and most of the muscle nuclei of an adult have a tetraploid DNA content. In pathological heart hypertrophy a further polyploidization of the heart muscle nuclei occurs. The areas of the nuclei increases with growing polyploidization. The nuclear areas form the same grouping as the ploidy classes. With growing nuclear areas, the total areas of the nucleoli and their number per nucleus also increase. Right after birth an increase in the number of connective tissue and heart muscle cells follows. A normal heart contains about 2 x 10(9) muscle cells. In hypertrophic hearts the number of muscle cells can double. PMID:129834

  20. A fetal human heart cardiac-inducing RNA (CIR) promotes the differentiation of stem cells into cardiomyocytes.

    PubMed

    Kochegarov, Andrei; Moses-Arms, Ashley; Lemanski, Larry F

    2015-08-01

    A specific human fetal heart RNA has been discovered, which has the ability to induce myocardial cell formation from mouse embryonic and human-induced pluripotent stem cells in culture. In this study, commercially obtained RNA from human fetal heart was cloned, sequenced, and synthesized using standard laboratory approaches. Molecular analyses of the specific fetal cardiac-inducing RNA (CIR), revealed that it is a fragment of N-sulfoglucosaminesulfohydrolase and the caspase recruitment domain family member 14 precursor. Stem cells transfected with CIRs often form into spindle-shaped cells characteristic of cardiomyocytes,and express the cardiac-specific contractile protein marker, troponin-T, in addition to tropomyosin and α-actinin as detected by immunohistochemical staining. Expression of these contractile proteins showed organization into sarcomeric myofibrils characteristic of striated cardiac muscle cells. Computer analyses of the RNA secondary structures of the active CIR show significant similarities to a RNA from salamander or myofibril-inducing RNA (MIR), which also promotes non-muscle cells to differentiate into cardiac muscle. Thus, these two RNAs, salamander MIR and the newly discovered human-cloned CIR reported here, appear to have evolutionarily conserved secondary structures suggesting that both play major roles in vertebrate heart development and, particularly, in the differentiation of cardiomyocytes from non-muscle cells during development. PMID:25761723

  1. Data from acellular human heart matrix.

    PubMed

    Sánchez, Pedro L; Fernández-Santos, M Eugenia; Espinosa, M Angeles; González-Nicolas, M Angeles; Acebes, Judith R; Costanza, Salvatore; Moscoso, Isabel; Rodríguez, Hugo; García, Julio; Romero, Jesús; Kren, Stefan M; Bermejo, Javier; Yotti, Raquel; Del Villar, Candelas Pérez; Sanz-Ruiz, Ricardo; Elizaga, Jaime; Taylor, Doris A; Fernández-Avilés, Francisco

    2016-09-01

    Perfusion decellularization of cadaveric hearts removes cells and generates a cell-free extracellular matrix scaffold containing acellular vascular conduits, which are theoretically sufficient to perfuse and support tissue-engineered heart constructs. This article contains additional data of our experience decellularizing and testing structural integrity and composition of a large series of human hearts, "Acellular human heart matrix: a critical step toward whole heat grafts" (Sanchez et al., 2015) [1]. Here we provide the information about the heart decellularization technique, the valve competence evaluation of the decellularized scaffolds, the integrity evaluation of epicardial and myocardial coronary circulation, the pressure volume measurements, the primers used to assess cardiac muscle gene expression and, the characteristics of donors, donor hearts, scaffolds and perfusion decellularization process. PMID:27331090

  2. Human Cardiosphere-Derived Cells From Advanced Heart Failure Patients Exhibit Augmented Functional Potency in Myocardial Repair

    PubMed Central

    Shen, Deliang; Sun, Baiming; Blusztajn, Agnieszka; Xie, Yucai; Ibrahim, Ahmed; Aminzadeh, Mohammad Amin; Liu, Weixin; Li, Tao-Sheng; De Robertis, Michele A.; Marbán, Linda; Czer, Lawrence S. C.; Trento, Alfredo; Marbán, Eduardo

    2014-01-01

    Objectives This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts. Background Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency. Methods In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation. Results Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor 1 (SDF-1), which may contribute to the cells’ augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs. Conclusions CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1–mediated mechanisms. PMID:24511463

  3. S-Nitrosylation Proteome Profile of Peripheral Blood Mononuclear Cells in Human Heart Failure

    PubMed Central

    Spratt, Heidi M.; Gupta, Shivali; Petersen, John R.; Kuyumcu-Martinez, Muge N.

    2016-01-01

    Nitric oxide (NO) protects the heart against ischemic injury; however, NO- and superoxide-dependent S-nitrosylation (S-NO) of cysteines can affect function of target proteins and play a role in disease outcome. We employed 2D-GE with thiol-labeling FL-maleimide dye and MALDI-TOF MS/MS to capture the quantitative changes in abundance and S-NO proteome of HF patients (versus healthy controls, n = 30/group). We identified 93 differentially abundant (59-increased/34-decreased) and 111 S-NO-modified (63-increased/48-decreased) protein spots, respectively, in HF subjects (versus controls, fold-change | ≥1.5|, p ≤ 0.05). Ingenuity pathway analysis of proteome datasets suggested that the pathways involved in phagocytes' migration, free radical production, and cell death were activated and fatty acid metabolism was decreased in HF subjects. Multivariate adaptive regression splines modeling of datasets identified a panel of proteins that will provide >90% prediction success in classifying HF subjects. Proteomic profiling identified ATP-synthase, thrombospondin-1 (THBS1), and vinculin (VCL) as top differentially abundant and S-NO-modified proteins, and these proteins were verified by Western blotting and ELISA in different set of HF subjects. We conclude that differential abundance and S-NO modification of proteins serve as a mechanism in regulating cell viability and free radical production, and THBS1 and VCL evaluation will potentially be useful in the prediction of heart failure.

  4. Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells.

    PubMed

    Pannella, Micaela; Caliceti, Cristiana; Fortini, Francesca; Aquila, Giorgio; Vieceli Dalla Sega, Francesco; Pannuti, Antonio; Fortini, Cinzia; Morelli, Marco Bruno; Fucili, Alessandro; Francolini, Gloria; Voltan, Rebecca; Secchiero, Paola; Dinelli, Giovanni; Leoncini, Emanuela; Ferracin, Manuela; Hrelia, Silvana; Miele, Lucio; Rizzo, Paola

    2016-12-01

    It is unknown whether components present in heart failure (HF) patients' serum provide an angiogenic stimulus. We sought to determine whether serum from HF patients affects angiogenesis and its major modulator, the Notch pathway, in human umbilical vein endothelial cells (HUVECs). In cells treated with serum from healthy subjects or from patients at different HF stage we determined: (1) Sprouting angiogenesis, by measuring cells network (closed tubes) in collagen gel. (2) Protein levels of Notch receptors 1, 2, 4, and ligands Jagged1, Delta-like4. We found a higher number of closed tubes in HUVECs treated with advanced HF patients serum in comparison with cells treated with serum from mild HF patients or controls. Furthermore, as indicated by the reduction of the active form of Notch4 (N4IC) and of Jagged1, advanced HF patients serum inhibited Notch signalling in HUVECs in comparison with mild HF patients' serum and controls. The circulating levels of NT-proBNP (N-terminal of the pro-hormone brain natriuretic peptide), a marker for the detection and evalutation of HF, were positively correlated with the number of closed tubes (r = 0.485) and negatively with Notch4IC and Jagged1 levels in sera-treated cells (r = -0.526 and r = -0.604, respectively). In conclusion, we found that sera from advanced HF patients promote sprouting angiogenesis and dysregulate Notch signaling in HUVECs. Our study provides in vitro evidence of an angiogenic stimulus arising during HF progression and suggests a role for the Notch pathway in it. J. Cell. Physiol. 231: 2700-2710, 2016. © 2016 Wiley Periodicals, Inc. PMID:26987674

  5. Stem Cell Treatment of the Heart

    PubMed Central

    Angelini, Paolo; Markwald, Roger R.

    2005-01-01

    Stem cells are multipotent, undifferentiated cells capable of multiplication and differentiation. Preliminary experimental evidence suggests that stem cells derived from embryonic or adult tissues (especially bone marrow) may develop into myocardial cells. Some experts believe that this phenomenon occurs naturally in human beings, specifically during recovery from a myocardial infarction. Recently, stem cells have been used with the therapeutic intention of regenerating damaged tissues. Cardiac experiments, mainly with adult homologous stem cells, have proved that this therapy is safe and may improve myocardial vascularization and pump function. We review current fundamental concepts regarding the normal development of embryonic stem cells into myocardial tissue and the heart as a whole. We describe the multiple conditions that naturally enable a stem cell to become a myocardial cell and a group of stem cells to become a heart. We also discuss the challenge of translating basic cellular and molecular mechanisms into effective, clinically relevant treatment options. PMID:16429891

  6. Human Cardiac Mesenchymal Stromal Cells with CD105+CD34- Phenotype Enhance the Function of Post-Infarction Heart in Mice

    PubMed Central

    Wiśniewska, Ewa; Jarosz-Biej, Magdalena; Smolarczyk, Ryszard; Cichoń, Tomasz; Głowala-Kosińska, Magdalena; Śliwka, Joanna; Garbacz, Marcin; Szczypior, Mateusz; Jaźwiec, Tomasz; Langrzyk, Agnieszka; Zembala, Michał; Szala, Stanisław

    2016-01-01

    Aims The aim of the present study was to isolate mesenchymal stromal cells (MSC) with CD105+CD34- phenotype from human hearts, and to investigate their therapeutic potential in a mouse model of hindlimb ischemia and myocardial infarction (MI). The study aimed also to investigate the feasibility of xenogeneic MSCs implantation. Methods and Results MSC isolated from human hearts were multipotent cells. Separation of MSC with CD105+CD34- phenotype limited the heterogeneity of the originally isolated cell population. MSC secreted a number of anti-inflammatory and proangiogenic cytokines (mainly IL-6, IL-8, and GRO). Human MSC were transplanted into C57Bl/6NCrl mice. Using the mouse model of hindlimb ischemia it was shown that human MSC treated mice demonstrated a higher capillary density 14 days after injury. It was also presented that MSC administrated into the ischemic muscle facilitated fast wound healing (functional recovery by ischemic limb). MSC transplanted into an infarcted myocardium reduced the post-infarction scar, fibrosis, and increased the number of blood vessels both in the border area, and within the post-infarction scar. The improvement of left ventricular ejection fraction was also observed. Conclusion In two murine models (hindlimb ischemia and MI) we did not observe the xenotransplant rejection. Indeed, we have shown that human cardiac mesenchymal stromal cells with CD105+CD34- phenotype exhibit therapeutic potential. It seems that M2 macrophages are essential for healing and repair of the post-infarcted heart. PMID:27415778

  7. The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation in Hearts with Post-Infarct LV Remodeling

    PubMed Central

    Chen, Yong; Ye, Lei; Zhong, Jia; Li, Xin; Yan, Chen; Chandler, Margaret P.; Calvin, Steve; Xiao, Feng; Negia, Mesfin; Low, Walter C.; Zhang, Jianyi; Yu, Xin

    2015-01-01

    Cellular therapy for myocardial repair has been one of the most intensely investigated interventional strategies for acute myocardium infarction. Although the therapeutic potential of stem cells has been demonstrated in various studies, the underlying mechanisms for such improvement are poorly understood. In the present study, we investigated the long-term effects of stem cell therapy on both myocardial fiber organization and regional contractile function using a rat model of post-infarct remodeling. Human non-hematopoietic umbilical cord blood stem cells (nh-UCBSCs) were administered via tail vein to rats 2 days after infarct surgery. Animals were maintained without immunosuppressive therapy. In vivo and ex vivo MR imaging was performed on infarct hearts ten months after cell transplantation. Compared to the age-matched rats exposed to the identical surgery, both global and regional cardiac function of the nh-UCBSC-treated hearts, such as ejection fraction, ventricular strain and torsion, were significantly improved. More importantly, the treated hearts exhibited preserved fiber orientation and water diffusivities that were similar to those in sham-operated control hearts. These data provide the first evidence that nh-UCBSC treatment may prevent/delay untoward structural remodeling in post-infarct hearts, which supports the improved LV function observed in vivo in the absence of immunosuppression, suggesting a beneficial paracrine effect that occurred with the cellular therapy. PMID:24332083

  8. Contrast media are incomplete secretagogues acting on human basophils and mast cells isolated from heart and lung, but not skin tissue.

    PubMed

    Genovese, A; Stellato, C; Patella, V; Lamparter-Schummert, B; de Crescenzo, G; Adt, M; Marone, G

    1996-01-01

    To investigate the mechanisms of anaphylactoid reactions to radiocontrast media, in vitro mediator release induced by three iodinated contrast agents was examined using peripheral blood basophils and mast cells purified from human lung parenchyma, heart, and skin tissues. Three iodinated contrast agents, sodium and meglumine salts of ioxaglic acid, sodium and meglumine salts of ioxithalamic acid, and ioversol, were incubated with basophils purified from peripheral blood and human mast cells isolated and purified from different anatomical sites. Release of preformed (histamine and tryptase) and de novo synthesized mediators (prostaglandin D2 and leukotriene C4) into the supernatans was determined at various contrast medium concentrations after incubation for 60 min. Ioxaglate (0.2-0.3 M), ioxithalamate (0.3-0.5 M), and to a lesser extent ioversol (0.3-0.5 M) induced histamine release from basophils in a concentration-dependent manner. All three induced the release of preformed mediators (histamine and tryptase) from human lung, but not from skin mast cells. They also induced histamine and tryptase release from human heart mast cells. However, they did not induce the de novo synthesis of leukotriene C1 or prostaglandin D2 from human basophils or any type of mast cell examined. Cross-linking of IgE by anti-IgE induced the release of leukotriene C4 or prostaglandin D2 from human basophils or mast cells. Mannitol, an osmotic stimulus, induced the release of histamine from human basophils, but to a lesser extent from mast cells. These results show that different contrast media can differ in their ability to release mediators from enriched preparations of human basophils and mast cells. The three contrast agents examined act on basophils and mast cells as incomplete secretagogues, causing the release of preformed mediators, but not these novo synthesis of chemical mediators. It may be useful to measure plasma tryptase levels to detect adverse reactions caused by iodinated

  9. Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: modulation by single components of ischaemia.

    PubMed

    Krüger, C; Haunstetter, A; Gerber, S; Serf, C; Kaufmann, A; Kübler, W; Haass, M

    1995-08-01

    The influence of single components of myocardial ischaemia, such as anoxia, substrate withdrawal, hyperkalemia and extracellular acidosis, on nicotine-induced norepinephrine (NE) release was investigated in the isolated perfused guinea-pig heart, in incubated human atrial tissue and in cultured bovine adrenal chromaffin cells (BCC). In normoxia, nicotine (1-1000 mumol/l) evoked a concentration-dependent release of NE (determined by high pressure liquid chromatography and electrochemical detection) from guinea-pig heart and human atrium. In contrast to selective anoxia (Po2 < 5 mmHg) or glucose withdrawal, respectively, anoxia in combination with glucose withdrawal (5-40 min) markedly potentiated nicotine-induced NE release both in guinea-pig heart and human atrium. The sensitization of cardiac sympathetic nerve endings to nicotine was characterized by a lower threshold concentration and an approximate two-fold increase of maximum NE release, peaking after 10 min of anoxia and glucose withdrawal. Cyanide intoxication (1 mmol/l) combined with glucose withdrawal resulted in a similar increase of nicotine-induced sympathetic transmitter release both in guinea-pig heart and human atrium. In contrast, the nicotine-induced (10 mumol/l) NE overflow was only slightly potentiated by 10 min of global ischaemia in guinea-pig heart. Both hyperkalemia ([K+] 16 mmol/l) and acidosis (pH 6.8-6.0) distinctly attenuated the stimulatory effect of nicotine in guinea-pig heart and human atrium under normoxic conditions. Consistent with an exocytotic release mechanism, NE release was dependent on the presence of extracellular calcium under all conditions tested. Furthermore, NE overflow from guinea-pig heart was accompanied by a release of the exocytosis marker neuropeptide Y (NPY; determined by radioimmunoassay). In BCC, nicotine (1-10 mumol/l) evoked a release of NE and NPY and a transient rise of [Ca2+]i (determined with fura-2) during normoxia which were both dependent on the

  10. Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure

    PubMed Central

    Sundararaman, S; Miller, T J; Pastore, J M; Kiedrowski, M; Aras, R; Penn, M S

    2011-01-01

    We previously demonstrated that transient stromal cell-derived factor-1 alpha (SDF-1) improved cardiac function when delivered via cell therapy in ischemic cardiomyopathy at a time remote from acute myocardial infarction (MI) rats. We hypothesized that non-viral gene transfer of naked plasmid DNA-expressing hSDF-1 could similarly improve cardiac function. To optimize plasmid delivery, we tested SDF-1 and luciferase plasmids driven by the cytomegalovirus (CMV) promoter with (pCMVe) or without (pCMV) translational enhancers or α myosin heavy chain (pMHC) promoter in a rodent model of heart failure. In vivo expression of pCMVe was 10-fold greater than pCMV and pMHC expression and continued over 30 days. We directly injected rat hearts with SDF-1 plasmid 1 month after MI and assessed heart function. At 4 weeks after plasmid injection, we observed a 35.97 and 32.65% decline in fractional shortening (FS) in control (saline) animals and pMHC-hSDF1 animals, respectively, which was sustained to 8 weeks. In contrast, we observed a significant 24.97% increase in animals injected with the pCMVe-hSDF1 vector. Immunohistochemistry of cardiac tissue revealed a significant increase in vessel density in the hSDF-1-treated animals compared with control animals. Increasing SDF-1 expression promoted angiogenesis and improved cardiac function in rats with ischemic heart failure along with evidence of scar remodeling with a trend toward decreased myocardial fibrosis. These data demonstrate that stand-alone non-viral hSDF-1 gene transfer is a strategy for improving cardiac function in ischemic cardiomyopathy. PMID:21472007

  11. The winding road to regenerating the human heart

    PubMed Central

    Gerbin, Kaytlyn A.; Murry, Charles E.

    2015-01-01

    Regenerating the human heart is a challenge that has engaged researchers and clinicians around the globe for nearly a century. From the repair of the first septal defect in 1953, followed by the first successful heart transplant in 1967, and later to the first infusion of bone-marrow derived cells to the human myocardium in 2002, significant progress has been made in heart repair. Yet, chronic heart failure remains a leading pathological burden worldwide. Why has regenerating the human heart been such a challenge, and how close are we to achieving clinically relevant regeneration? Exciting progress has been made to establish cell transplantation techniques in recent years, and new pre-clinical studies in large animal models have shed light on the promises and challenges that lie ahead. In this review, we will discuss the history of cell therapy approaches and provide an overview of clinical trials using cell transplantation for heart regeneration. Focusing on the delivery of human stem cell-derived cardiomyocytes, current experimental strategies in the field will be discussed as well as their clinical translation potential. Although the human heart has not been regenerated yet, decades of experimental progress have guided us onto a promising pathway. Summary Exciting progress has been made in recent years to establish clinical cell transplantation techniques, and new pre-clinical studies in large animal models have shed light on the promises and challenges that lie ahead. Although the human heart has not been regenerated yet, decades of experimental progress in pre-clinical and clinical trials have guided us onto a promising pathway. PMID:25795463

  12. Cell migration during heart regeneration in zebrafish.

    PubMed

    Tahara, Naoyuki; Brush, Michael; Kawakami, Yasuhiko

    2016-07-01

    Zebrafish possess the remarkable ability to regenerate injured hearts as adults, which contrasts the very limited ability in mammals. Although very limited, mammalian hearts do in fact have measurable levels of cardiomyocyte regeneration. Therefore, elucidating mechanisms of zebrafish heart regeneration would provide information of naturally occurring regeneration to potentially apply to mammalian studies, in addition to addressing this biologically interesting phenomenon in itself. Studies over the past 13 years have identified processes and mechanisms of heart regeneration in zebrafish. After heart injury, pre-existing cardiomyocytes dedifferentiate, enter the cell cycle, and repair the injured myocardium. This process requires interaction with epicardial cells, endocardial cells, and vascular endothelial cells. Epicardial cells envelope the heart, while endocardial cells make up the inner lining of the heart. They provide paracrine signals to cardiomyocytes to regenerate the injured myocardium, which is vascularized during heart regeneration. In addition, accumulating results suggest that local migration of these major cardiac cell types have roles in heart regeneration. In this review, we summarize the characteristics of various heart injury methods used in the research community and regeneration of the major cardiac cell types. Then, we discuss local migration of these cardiac cell types and immune cells during heart regeneration. Developmental Dynamics 245:774-787, 2016. © 2016 Wiley Periodicals, Inc. PMID:27085002

  13. Isolation and expansion of adult cardiac stem/progenitor cells in the form of cardiospheres from human cardiac biopsies and murine hearts.

    PubMed

    Chimenti, Isotta; Gaetani, Roberto; Barile, Lucio; Forte, Elvira; Ionta, Vittoria; Angelini, Francesco; Frati, Giacomo; Messina, Elisa; Giacomello, Alessandro

    2012-01-01

    The successful isolation and ex vivo expansion of resident cardiac stem/progenitor cells from human heart biopsies has allowed us to study their biological characteristics and their applications in therapeutic approaches for the repair of ischemic/infarcted heart, the preparation of tissue-engineered cardiac grafts and, possibly, the design of cellular kits for drug screening applications. From the first publication of the original method in 2004, several adjustments and slight changes have been introduced to optimize and adjust the procedure to the evolving experimental and translational needs. Moreover, due to the wide applicability of such a method (which is based on the exploitation of intrinsic functional properties of cells with regenerative properties that are present in most tissues), the key steps of this procedure have been used to derive several kinds of tissue-specific adult stem cells for preclinical or clinical purposes.In order to define the original procedure, complete with the up-to-date modifications introduced through the years, an exhaustive description of the current protocol is performed in this chapter, with particular attention in highlighting critical steps and troubleshoots. The procedure described here consists of modular steps, that could be employed to derive cells from any kind of tissue biopsy, and needs to be considered the gold standard of all the so-called "explant methods" or "cardiosphere methods," and it represents a milestone in the clinical translation of autologous cell therapy. PMID:22610568

  14. Morphology and biomechanics of human heart

    NASA Astrophysics Data System (ADS)

    Chelnokova, Natalia O.; Golyadkina, Anastasiya A.; Kirillova, Irina V.; Polienko, Asel V.; Ivanov, Dmitry V.

    2016-03-01

    Object of study: A study of the biomechanical characteristics of the human heart ventricles was performed. 80 hearts were extracted during autopsy of 80 corpses of adults (40 women and 40 men) aged 31-70 years. The samples were investigated in compliance with the recommendations of the ethics committee. Methods: Tension and compression tests were performed with help of the uniaxial testing machine Instron 5944. Cardiometry was also performed. Results: In this work, techniques for human heart ventricle wall biomechanical properties estimation were developed. Regularities of age and gender variability in deformative and strength properties of the right and left ventricle walls were found. These properties were characterized by a smooth growth of myocardial tissue stiffness and resistivity at a relatively low strain against reduction in their strength and elasticity from 31-40 to 61-70 years. It was found that tissue of the left ventricle at 61-70 years had a lower stretchability and strength compared with tissues of the right ventricle and septum. These data expands understanding of the morphological organization of the heart ventricles, which is very important for the development of personalized medicine. Taking into account individual, age and gender differences of the heart ventricle tissue biomechanical characteristics allows to rationally choosing the type of patching materials during reconstructive operations on heart.

  15. Stem cells for heart valve regeneration.

    PubMed

    Weber, Benedikt; Emmert, Maximilian Y; Hoerstrup, Simon P

    2012-01-01

    Heart valve tissue engineering holds the potential to overcome limitations of currently used heart valve prostheses. It involves the isolation and expansion of autologous patient cells, the subsequent seeding of these cells onto an appropriate scaffold material, the in vitro incubation and the in vivo implantation of the derived tissue-engineered construct into the patient from whom the cells were taken. While vascular-derived cells require harvest of intact donor tissue and show limited expansion capacities, the use of stem or progenitor cells may overcome these limitations and expand the versatility of the concept of heart valve tissue engineering. Possible sources include cells isolated from blood, bone marrow, adipose tissue, amniotic fluid, chorionic villi, umbilical cord and induced pluripotent stem cells. Here we review different stem cell sources with particular regard to cellular phenotypes and their suitability for application in heart valve tissue engineering. PMID:22802212

  16. Cardiac Cell Lineages that Form the Heart

    PubMed Central

    Meilhac, Sigolène M.; Lescroart, Fabienne; Blanpain, Cédric; Buckingham, Margaret E.

    2014-01-01

    Myocardial cells ensure the contractility of the heart, which also depends on other mesodermal cell types for its function. Embryological experiments had identified the sources of cardiac precursor cells. With the advent of genetic engineering, novel tools have been used to reconstruct the lineage tree of cardiac cells that contribute to different parts of the heart, map the development of cardiac regions, and characterize their genetic signature. Such knowledge is of fundamental importance for our understanding of cardiogenesis and also for the diagnosis and treatment of heart malformations. PMID:25183852

  17. Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction.

    PubMed

    Wang, Qingjie; Yang, Hui; Bai, Aobing; Jiang, Wei; Li, Xiuya; Wang, Xinhong; Mao, Yishen; Lu, Chao; Qian, Ruizhe; Guo, Feng; Ding, Tianling; Chen, Haiyan; Chen, Sifeng; Zhang, Jianyi; Liu, Chen; Sun, Ning

    2016-10-01

    With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells-derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future. PMID:27509303

  18. Combination stem cell therapy for heart failure

    PubMed Central

    2010-01-01

    Patients with congestive heart failure (CHF) that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a) increasing stem cell migration to the heart; b) augmenting stem cell activity; and c) combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells. PMID:20398245

  19. Cardiac progenitor cells for heart repair

    PubMed Central

    Le, TYL; Chong, JJH

    2016-01-01

    Stem cell therapy is being investigated as an innovative and promising strategy to restore cardiac function in patients with heart failure. Several stem cell populations, including adult (multipotent) stem cells from developed organs and tissues, have been tested for cardiac repair with encouraging clinical and pre-clinical results. The heart has been traditionally considered a post-mitotic organ, however, this view has recently changed with the identification of stem/progenitor cells residing within the adult heart. Given their cardiac developmental origins, these endogenous cardiac progenitor cells (CPCs) may represent better candidates for cardiac cell therapy compared with stem cells from other organs such as the bone marrow and adipose tissue. This brief review will outline current research into CPC populations and their cardiac repair/regenerative potential. PMID:27551540

  20. Xenotransplantation of Human Cardiomyocyte Progenitor Cells Does Not Improve Cardiac Function in a Porcine Model of Chronic Ischemic Heart Failure. Results from a Randomized, Blinded, Placebo Controlled Trial

    PubMed Central

    Jansen of Lorkeers, Sanne J.; Gho, Johannes M. I. H.; Koudstaal, Stefan; van Hout, Gerardus P. J.; Zwetsloot, Peter Paul M.; van Oorschot, Joep W. M.; van Eeuwijk, Esther C. M.; Leiner, Tim; Hoefer, Imo E.; Goumans, Marie-José; Doevendans, Pieter A.; Sluijter, Joost P. G.; Chamuleau, Steven A. J.

    2015-01-01

    Background Recently cardiomyocyte progenitor cells (CMPCs) were successfully isolated from fetal and adult human hearts. Direct intramyocardial injection of human CMPCs (hCMPCs) in experimental mouse models of acute myocardial infarction significantly improved cardiac function compared to controls. Aim Here, our aim was to investigate whether xenotransplantation via intracoronary infusion of fetal hCMPCs in a pig model of chronic myocardial infarction is safe and efficacious, in view of translation purposes. Methods & Results We performed a randomized, blinded, placebo controlled trial. Four weeks after ischemia/reperfusion injury by 90 minutes of percutaneous left anterior descending artery occlusion, pigs (n = 16, 68.5 ± 5.4 kg) received intracoronary infusion of 10 million fetal hCMPCs or placebo. All animals were immunosuppressed by cyclosporin (CsA). Four weeks after infusion, endpoint analysis by MRI displayed no difference in left ventricular ejection fraction, left ventricular end diastolic and left ventricular end systolic volumes between both groups. Serial pressure volume (PV-)loop and echocardiography showed no differences in functional parameters between groups at any timepoint. Infarct size at follow-up, measured by late gadolinium enhancement MRI showed no difference between groups. Intracoronary pressure and flow measurements showed no signs of coronary obstruction 30 minutes after cell infusion. No premature death occurred in cell treated animals. Conclusion Xenotransplantation via intracoronary infusion of hCMPCs is feasible and safe, but not associated with improved left ventricular performance and infarct size compared to placebo in a porcine model of chronic myocardial infarction. PMID:26678993

  1. Endogenous cardiac stem cells for the treatment of heart failure

    PubMed Central

    Fuentes, Tania; Kearns-Jonker, Mary

    2013-01-01

    Stem cell-based therapies hold promise for regenerating the myocardium after injury. Recent data obtained from phase I clinical trials using endogenous cardiovascular progenitors isolated directly from the heart suggest that cell-based treatment for heart patients using stem cells that reside in the heart provides significant functional benefit and an improvement in patient outcome. Methods to achieve improved engraftment and regeneration may extend this therapeutic benefit. Endogenous cardiovascular progenitors have been tested extensively in small animals to identify cells that improve cardiac function after myocardial infarction. However, the relative lack of large animal models impedes translation into clinical practice. This review will exclusively focus on the latest research pertaining to humans and large animals, including both endogenous and induced sources of cardiovascular progenitors. PMID:24426784

  2. Influence of heart failure on nucleolar organization and protein expression in human hearts

    SciTech Connect

    Rosello-Lleti, Esther; Rivera, Miguel; Cortes, Raquel; Azorin, Inmaculada; Sirera, Rafael; Martinez-Dolz, Luis; Hove, Leif; Cinca, Juan; Lago, Francisca; Gonzalez-Juanatey, Jose R.; Salvador, Antonio; Portoles, Manuel

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Heart failure alters nucleolar morphology and organization. Black-Right-Pointing-Pointer Nucleolin expression is significant increased in ischemic and dilated cardiomyopathy. Black-Right-Pointing-Pointer Ventricular function of heart failure patients was related with nucleolin levels. -- Abstract: We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n = 38) and DCM (n = 27) patients, undergoing heart transplantation and control donors (n = 6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p < 0.05) and DCM (141%, p < 0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p < 0.05) and DCM (1.70-fold, p < 0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p < 0.0001), and it was increased in pathological hearts (p < 0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p < 0.05 and 131%, p < 0.001) and DCM (56%, p < 0.01 and 69%, p < 0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p < 0.001), perinucleolar chromatin (p < 0.01) and dense fibrillar components (p < 0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p < 0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein.

  3. Bioartificial Heart: A Human-Sized Porcine Model – The Way Ahead

    PubMed Central

    Weymann, Alexander; Patil, Nikhil Prakash; Sabashnikov, Anton; Jungebluth, Philipp; Korkmaz, Sevil; Li, Shiliang; Veres, Gabor; Soos, Pal; Ishtok, Roland; Chaimow, Nicole; Pätzold, Ines; Czerny, Natalie; Schies, Carsten; Schmack, Bastian; Popov, Aron-Frederik; Simon, André Rüdiger; Karck, Matthias; Szabo, Gabor

    2014-01-01

    Background A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Native hearts decellularized with preserved architecture and vasculature may provide an acellular tissue platform for organ regeneration. We sought to develop a tissue-engineered whole-heart neoscaffold in human-sized porcine hearts. Methods We decellularized porcine hearts (n = 10) by coronary perfusion with ionic detergents in a modified Langendorff circuit. We confirmed decellularization by histology, transmission electron microscopy and fluorescence microscopy, quantified residual DNA by spectrophotometry, and evaluated biomechanical stability with ex-vivo left-ventricular pressure/volume studies, all compared to controls. We then mounted the decellularized porcine hearts in a bioreactor and reseeded them with murine neonatal cardiac cells and human umbilical cord derived endothelial cells (HUVEC) under simulated physiological conditions. Results Decellularized hearts lacked intracellular components but retained specific collagen fibers, proteoglycan, elastin and mechanical integrity; quantitative DNA analysis demonstrated a significant reduction of DNA compared to controls (82.6±3.2 ng DNA/mg tissue vs. 473.2±13.4 ng DNA/mg tissue, p<0.05). Recellularized porcine whole-heart neoscaffolds demonstrated re-endothelialization of coronary vasculature and measurable intrinsic myocardial electrical activity at 10 days, with perfused organ culture maintained for up to 3 weeks. Conclusions Human-sized decellularized porcine hearts provide a promising tissue-engineering platform that may lead to future clinical strategies in the treatment of heart failure. PMID:25365554

  4. Human cytomegalovirus-specific T-cell immune reconstitution in preemptively treated heart transplant recipients identifies subjects at critical risk for infection.

    PubMed

    Abate, Davide; Fiscon, Marta; Saldan, Alda; Cofano, Simona; Mengoli, Carlo; Sgarabotto, Dino; d'Agostino, Chiara; Barzon, Luisa; Cusinato, Riccardo; Toscano, Giuseppe; Feltrin, Giuseppe; Gambino, Antonio; Gerosa, Gino; Palù, Giorgio

    2012-06-01

    Human cytomegalovirus (CMV) infection represents a major threat for heart transplant recipients (HTXs). CMV-specific T cells effectively control virus infection, and thus, assessment of antiviral immune recovery may have clinical utility in identifying HTXs at risk of infection. In this study, 10 CMV-seropositive (R(+)) pretransplant patients and 48 preemptively treated R(+) HTXs were examined before and after 100 days posttransplant. Preemptive treatment is supposed to favor the immune recovery. CMV DNAemia and gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay were employed to assess the viremia and immune reconstitution. HTXs could be categorized into three groups characterized by high (>100), medium (50 to 100), and low (<50) spot levels. Early-identified high responders efficiently controlled the infection and also maintained high immunity levels after 100 days after transplant. No episodes of grade ≥2R rejection occurred in the high responders. Midresponders were identified as a group with heterogeneous trends of immune reconstitution. Low responders were 41% and 21% of HTXs before and after 100 days posttransplant, respectively. Low responders were associated with a higher incidence of infection. The effect of viremia on immune recovery was investigated: a statistically significant inverse correlation between magnitude of viremia and immune recovery emerged; in particular, each 10-fold increase in viremia (>4 log(10) DNAemia/ml) was associated with a 36% decrease of the ELISPOT assay spot levels. All episodes of high viremia (>4 log(10) DNAemia/ml) occurred from 1 to 60 days after transplant. Thus, the concomitant evaluation of viremia and CMV immune reconstitution has clinical utility in identifying HTXs at risk of infection and may represent a helpful guide in making therapeutic choices. PMID:22461674

  5. Echocardiographic image of an active human heart

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Echocardiographic images provide quick, safe images of the heart as it beats. While a state-of-the art echocardiograph unit is part of the Human Research Facility on International Space Station, quick transmission of images and data to Earth is a challenge. NASA is developing techniques to improve the echocardiography available to diagnose sick astronauts as well as study the long-term effects of space travel on their health. Echocardiography uses ultrasound, generated in a sensor head placed against the patient's chest, to produce images of the structure of the heart walls and valves. However, ultrasonic imaging creates an enormous volume of data, up to 220 million bits per second. This can challenge ISS communications as well as Earth-based providers. Compressing data for rapid transmission back to Earth can degrade the quality of the images. Researchers at the Cleveland Clinic Foundation are working with NASA to develop compression techniques that meet imaging standards now used on the Internet and by the medical community, and that ensure that physicians receive quality diagnostic images.

  6. Influence of heart failure on nucleolar organization and protein expression in human hearts.

    PubMed

    Roselló-Lletí, Esther; Rivera, Miguel; Cortés, Raquel; Azorín, Inmaculada; Sirera, Rafael; Martínez-Dolz, Luis; Hove, Leif; Cinca, Juan; Lago, Francisca; González-Juanatey, José R; Salvador, Antonio; Portolés, Manuel

    2012-02-10

    We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n=38) and DCM (n=27) patients, undergoing heart transplantation and control donors (n=6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p<0.05) and DCM (141%, p<0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p<0.05) and DCM (1.70-fold, p<0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p<0.0001), and it was increased in pathological hearts (p<0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p<0.05 and 131%, p<0.001) and DCM (56%, p<0.01 and 69%, p<0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p<0.001), perinucleolar chromatin (p<0.01) and dense fibrillar components (p<0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p<0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein. PMID:22244875

  7. Stem Cell Therapy Shows Promise Against Heart Failure

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_158122.html Stem Cell Therapy Shows Promise Against Heart Failure A second ... 4, 2016 MONDAY, April 4, 2016 (HealthDay News) -- Stem cell therapy shows promise for people battling heart failure, ...

  8. Critical Scale Invariance in a Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Sakata, Seiichiro; Hayano, Junichiro; Yamamoto, Yoshiharu

    2004-10-01

    We demonstrate the robust scale-invariance in the probability density function (PDF) of detrended healthy human heart rate increments, which is preserved not only in a quiescent condition, but also in a dynamic state where the mean level of the heart rate is dramatically changing. This scale-independent and fractal structure is markedly different from the scale-dependent PDF evolution observed in a turbulentlike, cascade heart rate model. These results strongly support the view that a healthy human heart rate is controlled to converge continually to a critical state.

  9. Human Engineered Heart Tissue: Analysis of Contractile Force.

    PubMed

    Mannhardt, Ingra; Breckwoldt, Kaja; Letuffe-Brenière, David; Schaaf, Sebastian; Schulz, Herbert; Neuber, Christiane; Benzin, Anika; Werner, Tessa; Eder, Alexandra; Schulze, Thomas; Klampe, Birgit; Christ, Torsten; Hirt, Marc N; Huebner, Norbert; Moretti, Alessandra; Eschenhagen, Thomas; Hansen, Arne

    2016-07-12

    Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane- and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling. PMID:27211213

  10. [Changes of heart function after different cell type stem cell transplantation in chronic heart failure].

    PubMed

    Fan, Zhongcai; Chen, Mao; Deng, Juelin; Liu, Xiaojing; Zhang, Li; Rao, Li; Yang, Qing; Huang, Dejia

    2006-12-01

    To investigate the feasibility of introcoronary cell infusion into nonischemic heart failure (HF) heart and whether different types of stem cell transplantation would affect heart function to a similar degree. Japanese white ears rabbits were used as HF models by intravenous injection adriamycin. Autologous bone marrow mononuclear cells(BMCs), bone marrow stromal cells (MSCs), skeletal myoblasts (SMs) or culture medium were infused into coronary arteries respectively by occluding the root of ascending aorta. The mortality during and 4 weeks after the procedure the mortality was 7.1% and 16.7% respectively. After 4 weeks, the ejection fraction (EF) in BMCs group had significant improvement (P < 0.05, n=8). No significant difference was seen in MSCs (n =8), SMs (n=6) and sham groups (n=8) compared with pretransplantation (P > 0.05). In sham group,the left ventricular endostolic diameter (LVED) had significant enlargement (P < 0.05), No significant difference was seen in MBCs, MSCs and SMs groups compared with pretransplantation (P > 0.05). Immunofluorescence revealed de novo expression of cardiac troponin I in BMCs and MSCs groups, cardiac troponin I was not detected in SMs group. In conclusions, intracoronary cell transplantation could provide effective cell delivery into dilated cardiomyopathy hearts and could be a useful strategy for treating CHF, BMCs cell transplantation may be the first choice in all the above cell types. PMID:17228727

  11. Evolutionary anticipation of the human heart.

    PubMed Central

    Victor, S.; Nayak, V. M.

    2000-01-01

    We have studied the comparative anatomy of hearts from fish, frog, turtle, snake, crocodile, birds (duck, chicken, quail), mammals (elephant, dolphin, sheep, goat, ox, baboon, wallaby, mouse, rabbit, possum, echidna) and man. The findings were analysed with respect to the mechanism of evolution of the heart. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:11041025

  12. Stem Cell Therapy for Ischemic Heart Disease

    PubMed Central

    Jameel, Mohammad Nurulqadr

    2010-01-01

    Abstract Stem cell transplantation has emerged as a novel treatment option for ischemic heart disease. Different cell types have been utilized and the recent development of induced pluripotent stem cells has generated tremendous excitement in the regenerative field. Bone marrow-derived multipotent progenitor cell transplantation in preclinical large animal models of postinfarction left ventricular remodeling has demonstrated long-term functional and bioenergetic improvement. These beneficial effects are observed despite no significant engraftment of bone marrow cells in the myocardium and even lower differentiation of these cells into cardiomyocytes. It is thought to be related to the paracrine effect of these stem cells, which secrete factors that lead to long-term gene expression changes in the host myocardium, thereby promoting neovascularization, inhibiting apoptosis, and stimulating resident cardiac progenitor cells. Future studies are warranted to examine the changes in the recipient myocardium after stem cell transplantation and to investigate the signaling pathways involved in these effects. Antioxid. Redox Signal. 13, 1879–1897. PMID:20687781

  13. High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue

    SciTech Connect

    Magnusson, Lisa U.; Lundqvist, Annika; Asp, Julia; Synnergren, Jane; Johansson, Cecilia Thalen; Palmqvist, Lars; Jeppsson, Anders; Hulten, Lillemor Mattsson

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We found a 17-fold upregulation of ALOX15 in the ischemic heart. Black-Right-Pointing-Pointer Incubation of human muscle cells in hypoxia showed a 22-fold upregulation of ALOX15. Black-Right-Pointing-Pointer We observed increased levels of proinflammatory markers in ischemic heart tissue. Black-Right-Pointing-Pointer Suggesting a link between ischemia and inflammation in ischemic heart biopsies. -- Abstract: A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1{alpha} (HIF-1{alpha}) regulates adaptive responses to low concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1{alpha} mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield

  14. Phase Transition in a Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Togo, Fumiharu; Yamamoto, Yoshiharu

    2005-07-01

    A healthy human heart rate displays complex fluctuations which share characteristics of physical systems in a critical state. We demonstrate that the human heart rate in healthy individuals undergoes a dramatic breakdown of criticality characteristics, reminiscent of continuous second order phase transitions. By studying the germane determinants, we show that the hallmark of criticality—highly correlated fluctuations—is observed only during usual daily activity, and a breakdown of these characteristics occurs in prolonged, strenuous exercise and sleep. This finding is the first reported discovery of the dynamical phase transition phenomenon in a biological control system and will be a key to understanding the heart rate control system in health and disease.

  15. Cardiac myosin-Th17 responses promote heart failure in human myocarditis

    PubMed Central

    Myers, Jennifer M.; Cooper, Leslie T.; Kem, David C.; Stavrakis, Stavros; Kosanke, Stanley D.; Shevach, Ethan M.; Fairweather, DeLisa; Stoner, Julie A.; Cox, Carol J.; Cunningham, Madeleine W.

    2016-01-01

    In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF–secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17–producing T cells and IL-17–promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option. PMID:27366791

  16. Mitochondrial dynamics and cell death in heart failure.

    PubMed

    Marín-García, José; Akhmedov, Alexander T

    2016-03-01

    The highly regulated processes of mitochondrial fusion (joining), fission (division) and trafficking, collectively called mitochondrial dynamics, determine cell-type specific morphology, intracellular distribution and activity of these critical organelles. Mitochondria are critical for cardiac function, while their structural and functional abnormalities contribute to several common cardiovascular diseases, including heart failure (HF). The tightly balanced mitochondrial fusion and fission determine number, morphology and activity of these multifunctional organelles. Although the intracellular architecture of mature cardiomyocytes greatly restricts mitochondrial dynamics, this process occurs in the adult human heart. Fusion and fission modulate multiple mitochondrial functions, ranging from energy and reactive oxygen species production to Ca(2+) homeostasis and cell death, allowing the heart to respond properly to body demands. Tightly controlled balance between fusion and fission is of utmost importance in the high energy-demanding cardiomyocytes. A shift toward fission leads to mitochondrial fragmentation, while a shift toward fusion results in the formation of enlarged mitochondria and in the fusion of damaged mitochondria with healthy organelles. Mfn1, Mfn2 and OPA1 constitute the core machinery promoting mitochondrial fusion, whereas Drp1, Fis1, Mff and MiD49/51 are the core components of fission machinery. Growing evidence suggests that fusion/fission factors in adult cardiomyocytes play essential noncanonical roles in cardiac development, Ca(2+) signaling, mitochondrial quality control and cell death. Impairment of this complex circuit causes cardiomyocyte dysfunction and death contributing to heart injury culminating in HF. Pharmacological targeting of components of this intricate network may be a novel therapeutic modality for HF treatment. PMID:26872674

  17. How Live Performance Moves the Human Heart.

    PubMed

    Shoda, Haruka; Adachi, Mayumi; Umeda, Tomohiro

    2016-01-01

    We investigated how the audience member's physiological reactions differ as a function of listening context (i.e., live versus recorded music contexts). Thirty-seven audience members were assigned to one of seven pianists' performances and listened to his/her live performances of six pieces (fast and slow pieces by Bach, Schumann, and Debussy). Approximately 10 weeks after the live performance, each of the audience members returned to the same room and listened to the recorded performances of the same pianists' via speakers. We recorded the audience members' electrocardiograms in listening to the performances in both conditions, and analyzed their heart rates and the spectral features of the heart-rate variability (i.e., HF/TF, LF/HF). Results showed that the audience's heart rate was higher for the faster than the slower piece only in the live condition. As compared with the recorded condition, the audience's sympathovagal balance (LF/HF) was less while their vagal nervous system (HF/TF) was activated more in the live condition, which appears to suggest that sharing the ongoing musical moments with the pianist reduces the audience's physiological stress. The results are discussed in terms of the audience's superior attention and temporal entrainment to live performance. PMID:27104377

  18. How Live Performance Moves the Human Heart

    PubMed Central

    Shoda, Haruka; Adachi, Mayumi; Umeda, Tomohiro

    2016-01-01

    We investigated how the audience member’s physiological reactions differ as a function of listening context (i.e., live versus recorded music contexts). Thirty-seven audience members were assigned to one of seven pianists’ performances and listened to his/her live performances of six pieces (fast and slow pieces by Bach, Schumann, and Debussy). Approximately 10 weeks after the live performance, each of the audience members returned to the same room and listened to the recorded performances of the same pianists’ via speakers. We recorded the audience members’ electrocardiograms in listening to the performances in both conditions, and analyzed their heart rates and the spectral features of the heart-rate variability (i.e., HF/TF, LF/HF). Results showed that the audience’s heart rate was higher for the faster than the slower piece only in the live condition. As compared with the recorded condition, the audience’s sympathovagal balance (LF/HF) was less while their vagal nervous system (HF/TF) was activated more in the live condition, which appears to suggest that sharing the ongoing musical moments with the pianist reduces the audience’s physiological stress. The results are discussed in terms of the audience’s superior attention and temporal entrainment to live performance. PMID:27104377

  19. The Living Heart Project: A robust and integrative simulator for human heart function.

    PubMed

    Baillargeon, Brian; Rebelo, Nuno; Fox, David D; Taylor, Robert L; Kuhl, Ellen

    2014-11-01

    The heart is not only our most vital, but also our most complex organ: Precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. While numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. Here we present a proof-of-concept simulator for a four-chamber human heart model created from computer topography and magnetic resonance images. We illustrate the governing equations of excitation-contraction coupling and discretize them using a single, unified finite element environment. To illustrate the basic features of our model, we visualize the electrical potential and the mechanical deformation across the human heart throughout its cardiac cycle. To compare our simulation against common metrics of cardiac function, we extract the pressure-volume relationship and show that it agrees well with clinical observations. Our prototype model allows us to explore and understand the key features, physics, and technologies to create an integrative, predictive model of the living human heart. Ultimately, our simulator will open opportunities to probe landscapes of clinical parameters, and guide device design and treatment planning in cardiac diseases such as stenosis, regurgitation, or prolapse of the aortic, pulmonary, tricuspid, or mitral valve. PMID:25267880

  20. Heart regeneration.

    PubMed

    Breckwoldt, Kaja; Weinberger, Florian; Eschenhagen, Thomas

    2016-07-01

    Regenerating an injured heart holds great promise for millions of patients suffering from heart diseases. Since the human heart has very limited regenerative capacity, this is a challenging task. Numerous strategies aiming to improve heart function have been developed. In this review we focus on approaches intending to replace damaged heart muscle by new cardiomyocytes. Different strategies for the production of cardiomyocytes from human embryonic stem cells or human induced pluripotent stem cells, by direct reprogramming and induction of cardiomyocyte proliferation are discussed regarding their therapeutic potential and respective advantages and disadvantages. Furthermore, different methods for the transplantation of pluripotent stem cell-derived cardiomyocytes are described and their clinical perspectives are discussed. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID:26597703

  1. Right ventricular long noncoding RNA expression in human heart failure

    PubMed Central

    Guo, Yan; Su, Yan Ru; Clark, Travis; Brittain, Evan; Absi, Tarek; Maltais, Simon; Hemnes, Anna

    2015-01-01

    Abstract The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible functional roles using a variety of online tools. In HF hearts, RNA-Seq identified 84,793 total messenger RNA coding and noncoding different transcripts, including 13,019 protein-coding genes, 2,085 total lncRNA genes, and 1,064 pseudogenes. By Ensembl noncoding RNA categories, there were 48 lncRNAs, 27 pseudogenes, and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs in HF hearts. Compared with donor hearts, HF hearts exhibited differential expression of 7.7% of protein-coding genes, 3.7% of lncRNAs (including pseudogenes), and 2.5% of pseudogenes. There were not consistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent genes, implying differential regulation of expression. Exploratory in silico functional analyses using online tools suggested a variety of possible lncRNA regulatory roles. By providing a comprehensive profile of right ventricular polyadenylated messenger RNA transcriptome in HF, RNA-Seq provides an inventory of differentially expressed lncRNAs, including antisense transcripts and pseudogenes, for future mechanistic study. PMID:25992278

  2. Transplantation of Human Pericyte Progenitor Cells Improves the Repair of Infarcted Heart Through Activation of an Angiogenic Program Involving Micro-RNA-132

    PubMed Central

    Katare, Rajesh; Riu, Federica; Mitchell, Kathryn; Gubernator, Miriam; Campagnolo, Paola; Cui, Yuxin; Fortunato, Orazio; Avolio, Elisa; Cesselli, Daniela; Beltrami, Antonio Paolo; Angelini, Gianni; Emanueli, Costanza; Madeddu, Paolo

    2013-01-01

    Rationale Pericytes are key regulators of vascular maturation, but their value for cardiac repair remains unknown. Objective We investigated the therapeutic activity and mechanistic targets of saphenous vein-derived pericyte progenitor cells (SVPs) in a mouse myocardial infarction (MI) model. Methods and Results SVPs have a low immunogenic profile and are resistant to hypoxia/starvation (H/S). Transplantation of SVPs into the peri-infarct zone of immunodeficient CD1/Foxn-1nu/nu or immunocompetent CD1 mice attenuated left ventricular dilatation and improved ejection fraction compared to vehicle. Moreover, SVPs reduced myocardial scar, cardiomyocyte apoptosis and interstitial fibrosis, improved myocardial blood flow and neovascularization, and attenuated vascular permeability. SVPs secrete vascular endothelial growth factor A, angiopoietin-1, and chemokines and induce an endogenous angiocrine response by the host, through recruitment of vascular endothelial growth factor B expressing monocytes. The association of donor- and recipient-derived stimuli activates the proangiogenic and prosurvival Akt/eNOS/Bcl-2 signaling pathway. Moreover, microRNA-132 (miR-132) was constitutively expressed and secreted by SVPs and remarkably upregulated, together with its transcriptional activator cyclic AMP response element-binding protein, on stimulation by H/S or vascular endothelial growth factor B. We next investigated if SVP-secreted miR-132 acts as a paracrine activator of cardiac healing. In vitro studies showed that SVP conditioned medium stimulates endothelial tube formation and reduces myofibroblast differentiation, through inhibition of Ras-GTPase activating protein and methyl-CpG-binding protein 2, which are validated miR-132 targets. Furthermore, miR-132 inhibition by antimiR-132 decreased SVP capacity to improve contractility, reparative angiogenesis, and interstitial fibrosis in infarcted hearts. Conclusion SVP transplantation produces long-term improvement of cardiac

  3. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo

    SciTech Connect

    Herrmann, Julia E.; Heale, Jason; Bieraugel, Mike; Ramos, Meg; Fisher, Robyn L.; Vickers, Alison E.M.

    2014-01-15

    Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices. - Highlights: • Human response to isoproterenol induced cardiac injury evaluated in heart slices. • Isoproterenol altered apoptosis, energy, inflammation and remodeling pathways. • Human model verified by comparison to rat heart slices and rat heart in vivo. • Human and rat respond to isoproterenol

  4. Neonatal Heart-Enriched miR-708 Promotes Differentiation of Cardiac Progenitor Cells in Rats

    PubMed Central

    Deng, Shengqiong; Zhao, Qian; Zhou, Xianjin; Zhang, Lin; Bao, Luer; Zhen, Lixiao; Zhang, Yuzhen; Fan, Huimin; Liu, Zhongmin; Yu, Zuoren

    2016-01-01

    Cardiovascular disease is becoming the leading cause of death throughout the world. However, adult hearts have limited potential for regeneration after pathological injury, partly due to the quiescent status of stem/progenitor cells. Reactivation of cardiac stem/progenitor cells to create more myocyte progeny is one of the key steps in the regeneration of a damaged heart. In this study, miR-708 was identified to be enriched in the neonatal cardiomyocytes of rats, but this has not yet been proven in adult humans. A lower level of miR-708 in c-kit(+) stem/progenitor cells was detected compared to non-progenitors. Overexpression of miR-708 induced cardiomyocyte differentiation of cardiac stem/progenitor cells. This finding strengthened the potential of applying miRNAs in the regeneration of injured hearts, and this indicates that miR-708 could be a novel candidate for treatment of heart diseases. PMID:27338347

  5. Cardiac regenerative potential of cardiosphere-derived cells from adult dog hearts

    PubMed Central

    Hensley, Michael Taylor; de Andrade, James; Keene, Bruce; Meurs, Kathryn; Tang, Junnan; Wang, Zegen; Caranasos, Thomas G; Piedrahita, Jorge; Li, Tao-Sheng; Cheng, Ke

    2015-01-01

    The regenerative potential of cardiosphere-derived cells (CDCs) for ischaemic heart disease has been demonstrated in mice, rats, pigs and a recently completed clinical trial. The regenerative potential of CDCs from dog hearts has yet to be tested. Here, we show that canine CDCs can be produced from adult dog hearts. These cells display similar phenotypes in comparison to previously studied CDCs derived from rodents and human beings. Canine CDCs can differentiate into cardiomyocytes, smooth muscle cells and endothelial cells in vitro. In addition, conditioned media from canine CDCs promote angiogenesis but inhibit cardiomyocyte death. In a doxorubicin-induced mouse model of dilated cardiomyopathy (DCM), intravenous infusion of canine CDCs improves cardiac function and decreases cardiac fibrosis. Histology revealed that injected canine CDCs engraft in the mouse heart and increase capillary density. Out study demonstrates the regenerative potential of canine CDCs in a mouse model of DCM. PMID:25854418

  6. Neonatal Heart-Enriched miR-708 Promotes Differentiation of Cardiac Progenitor Cells in Rats.

    PubMed

    Deng, Shengqiong; Zhao, Qian; Zhou, Xianjin; Zhang, Lin; Bao, Luer; Zhen, Lixiao; Zhang, Yuzhen; Fan, Huimin; Liu, Zhongmin; Yu, Zuoren

    2016-01-01

    Cardiovascular disease is becoming the leading cause of death throughout the world. However, adult hearts have limited potential for regeneration after pathological injury, partly due to the quiescent status of stem/progenitor cells. Reactivation of cardiac stem/progenitor cells to create more myocyte progeny is one of the key steps in the regeneration of a damaged heart. In this study, miR-708 was identified to be enriched in the neonatal cardiomyocytes of rats, but this has not yet been proven in adult humans. A lower level of miR-708 in c-kit(+) stem/progenitor cells was detected compared to non-progenitors. Overexpression of miR-708 induced cardiomyocyte differentiation of cardiac stem/progenitor cells. This finding strengthened the potential of applying miRNAs in the regeneration of injured hearts, and this indicates that miR-708 could be a novel candidate for treatment of heart diseases. PMID:27338347

  7. Current Status and Perspectives in Stem Cell Therapy for Heart

    PubMed Central

    Lin, Fen-Chiung; Chen, Wen-Pin; Chu, Pao-Hsien; Shyu, Kou-Gi; Wen, Ming-Shien

    2014-01-01

    For most patients, the prognosis of heart failure remains poor despite therapeutic advancement in recent decades. The option of cardiac transplantation is high risk and limited by a shortage of donors. Traditionally, the heart had been considered a terminally differentiated organ incapable of regeneration. However, numerous preclinical and clinical studies have been performed since the first report of cell therapy in heart failure using skeletal myoblasts in 2001. These investigations looked at the promising potential and use of several kinds of stem cells, which could some day dramatically alter the understanding of the regenerative capacity of the heart. To date, although there is no existing cardiac cell therapy that has been conclusively reported to be effective, stem cell-related cardiomyocyte regeneration strategies have become significant areas of research in modern cardiovascular medicine. In this review, we outline a variety of common cell sources, surface biomarkers of stem cells, and provide information related to cardiac cell therapy clinical trials. PMID:27122815

  8. Human myocardial Na,K-ATPase concentration in heart failure.

    PubMed

    Bundgaard, H; Kjeldsen, K

    1996-01-01

    The Na,K-ATPase is of major importance for active ion transport across the sarcolemma and thus for electrical as well as contractile function of the myocardium. Furthermore, it is receptor for digitalis glycosides. In human studies of the regulatory aspects of myocardial Na,K-ATPase concentration a major problem has been to obtain tissue samples. Methodological accomplishments in quantification of myocardial Na,K-ATPase using vanadate facilitated 3H-ouabain binding to intact samples have, however, made it possible to obtain reliable measurements on human myocardial necropsies obtained at autopsy as well as on biopsies of a wet weight of only 1-2 mg obtained during heart catheterisation. However, access to the ultimately, normal, vital myocardial tissue has come from the heart transplantation programs, through which myocardial samples from cardiovascular healthy organ donors have become available. In the present paper we evaluate the various values reported for normal human myocardial Na,K-ATPase concentration, its regulation in heart disease and the association with digitalization. Normal myocardial Na,K-ATPase concentration level is found to be 700 pmol/g wet weight. No major variations were found between or within the walls of the heart ventricles. During the first few years of life a marked decrease in myocardial Na,K-ATPase concentration is followed by a stable level obtained in early adulthood and normally maintained throughout life. In patients with enlarged cardiac x-ray silhouette a significant positive, linear correlation between left ventricular ejection fraction (EF) and Na,K-ATPase concentration was established. A maximum reduction in Na,K-ATPase concentration of 89% was obtained when EF was reduced to 20%. Generally, heart failure associated with heart dilatation, myocardial hypertrophy as well as ischaemic heart disease is associated with reductions in myocardial Na,K-ATPase concentration of around 25%. During digoxin treatment of heart failure

  9. FISH CONSUMPTION, METHYLMERCURY, AND HUMAN HEART DISEASE.

    SciTech Connect

    LIPFERT, F.W.; SULLIVAN, T.M.

    2005-09-21

    Environmental mercury continues to be of concern to public health advocates, both in the U.S. and abroad, and new research continues to be published. A recent analysis of potential health benefits of reduced mercury emissions has opened a new area of public health concern: adverse effects on the cardiovascular system, which could account for the bulk of the potential economic benefits. The authors were careful to include caveats about the uncertainties of such impacts, but they cited only a fraction of the applicable health effects literature. That literature includes studies of the potentially harmful ingredient (methylmercury, MeHg) in fish, as well as of a beneficial ingredient, omega-3 fatty acids or ''fish oils''. The U.S. Food and Drug Administration (FDA) recently certified that some of these fat compounds that are primarily found in fish ''may be beneficial in reducing coronary heart disease''. This paper briefly summarizes and categorizes the extensive literature on both adverse and beneficial links between fish consumption and cardiovascular health, which are typically based on studies of selected groups of individuals (cohorts). Such studies tend to comprise the ''gold standard'' of epidemiology, but cohorts tend to exhibit a great deal of variability, in part because of the limited numbers of individuals involved and in part because of interactions with other dietary and lifestyle considerations. Note that eating fish will involve exposure to both the beneficial effects of fatty acids and the potentially harmful effects of contaminants like Hg or PCBs, all of which depend on the type of fish but tend to be correlated within a population. As a group, the cohort studies show that eating fish tends to reduce mortality, especially due to heart disease, for consumption rates up to about twice weekly, above which the benefits tend to level off. A Finnish cohort study showed increased mortality risks in the highest fish-consuming group ({approx}3 times

  10. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed Central

    Lovering, Ruth C

    2014-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’.  ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach. PMID:24627794

  11. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed

    Khodiyar, Varsha K; Howe, Doug; Talmud, Philippa J; Breckenridge, Ross; Lovering, Ruth C

    2013-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer's vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer's vesicle determine asymmetry in the developing heart, the direction of 'heart jogging' and the direction of 'heart looping'.  'Heart jogging' is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward 'jog'. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish 'heart jogging orthologs' are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach. PMID:24627794

  12. Direct observation of homoclinic orbits in human heart rate variability

    NASA Astrophysics Data System (ADS)

    Żebrowski, J. J.; Baranowski, R.

    2003-05-01

    Homoclinic trajectories of the interbeat intervals between contractions of ventricles of the human heart are identified. The interbeat intervals are extracted from 24-h Holter ECG recordings. Three such recordings are discussed in detail. Mappings of the measured consecutive interbeat intervals are constructed. In the second and in some cases in the fourth iterate of the map of interbeat intervals homoclinic trajectories associated with a hyperbolic saddle are found. The homoclinic trajectories are often persistent for many interbeat intervals, sometimes spanning many thousands of heartbeats. Several features typical for homoclinic trajectories found in other systems were identified, including a signature of the gluing bifurcation. The homoclinic trajectories are present both in recordings of heart rate variability obtained from patients with an increased number of arrhythmias and in cases in which the sinus rhythm is dominant. The results presented are a strong indication of the importance of deterministic nonlinear instabilities in human heart rate variability.

  13. Basic axes of human heart in correlation with heart mass and right ventricular wall thickness.

    PubMed

    Skwarek, M; Grzybiak, M; Kosiński, A; Hreczecha, J

    2006-11-01

    A comparison of the data published in anatomy textbooks and anthropological tables does not reveal any change in basic heart dimensions during the period since the beginning of the 20th century to nowadays. However, normal values of many other parameters have changed up to 30% over the same period. These changes may be caused by the acceleration phenomenon or the extension of average lifespan. The progress of laboratory medicine methodology permitted the introduction of new biochemical tests in myocardial infarct diagnosis, such as myoglobin and troponins T and I measurement, as well as better understanding of cardiac metabolism. Parameters describing the direction and intensity of metabolic changes are substrate extraction and metabolic equilibrium. The expression describing metabolic equilibrium contains heart mass value. Therefore, as studying heart mass in vivo is not possible, it may be important to study it in vitro. The study was performed on a group of 107 formalin-fixed human hearts. The organs came from adults of both sexes: 30 women and 77 men, aged 18 to 90 years. None of the hearts carried signs of macroscopic developmental abnormalities or pathologic changes. PMID:17171620

  14. Mechanical Unloading Promotes Myocardial Energy Recovery in Human Heart Failure

    PubMed Central

    Gupte, Anisha A.; Hamilton, Dale J.; Cordero-Reyes, Andrea M.; Youker, Keith A.; Yin, Zheng; Estep, Jerry D.; Stevens, Robert D.; Wenner, Brett; Ilkayeva, Olga; Loebe, Matthias; Peterson, Leif E.; Lyon, Christopher J.; Wong, Stephen T.C.; Newgard, Christopher B.; Torre-Amione, Guillermo; Taegtmeyer, Heinrich; Hsueh, Willa A.

    2015-01-01

    Background Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results We compared metabolomic, gene transcript, and protein data from six paired failing human left ventricular (LV) tissue samples obtained during left ventricular assist device (LVAD) insertion (heart failure (HF) samples) and at heart transplant (post-LVAD samples). Non-failing left ventricular (NFLV) wall samples procured from explanted hearts of patients with right HF served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in HF tissue: 2.6 fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor gamma co-activator1α (PGC1A, 1.3 fold) and estrogen-related receptor α (ERRA, 1.2 fold) and γ (ERRG, 2.2 fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with LVAD improved all of these metabolic and transcriptional defects. Conclusions These observations underscore an important pathophysiologic role for severely defective metabolism in HF, while the reversibility of these defects by LVAD suggests metabolic resilience of the human heart. PMID:24825877

  15. Heart research advances using database search engines, Human Protein Atlas and the Sydney Heart Bank.

    PubMed

    Li, Amy; Estigoy, Colleen; Raftery, Mark; Cameron, Darryl; Odeberg, Jacob; Pontén, Fredrik; Lal, Sean; Dos Remedios, Cristobal G

    2013-10-01

    This Methodological Review is intended as a guide for research students who may have just discovered a human "novel" cardiac protein, but it may also help hard-pressed reviewers of journal submissions on a "novel" protein reported in an animal model of human heart failure. Whether you are an expert or not, you may know little or nothing about this particular protein of interest. In this review we provide a strategic guide on how to proceed. We ask: How do you discover what has been published (even in an abstract or research report) about this protein? Everyone knows how to undertake literature searches using PubMed and Medline but these are usually encyclopaedic, often producing long lists of papers, most of which are either irrelevant or only vaguely relevant to your query. Relatively few will be aware of more advanced search engines such as Google Scholar and even fewer will know about Quertle. Next, we provide a strategy for discovering if your "novel" protein is expressed in the normal, healthy human heart, and if it is, we show you how to investigate its subcellular location. This can usually be achieved by visiting the website "Human Protein Atlas" without doing a single experiment. Finally, we provide a pathway to discovering if your protein of interest changes its expression level with heart failure/disease or with ageing. PMID:23856366

  16. Building A New Treatment For Heart Failure-Transplantation of Induced Pluripotent Stem Cell-derived Cells into the Heart

    PubMed Central

    Miyagawa, Shigeru; Fukushima, Satsuki; Imanishi, Yukiko; Kawamura, Takuji; Mochizuki-Oda, Noriko; Masuda, Shigeo; Sawa, Yoshiki

    2016-01-01

    Advanced cardiac failure is a progressive intractable disease and is the main cause of mortality and morbidity worldwide. Since this pathology is represented by a definite decrease in cardiomyocyte number, supplementation of functional cardiomyocytes into the heart would hypothetically be an ideal therapeutic option. Recently, unlimited in vitro production of human functional cardiomyocytes was established by using induced pluripotent stem cell (iPSC) technology, which avoids the use of human embryos. A number of basic studies including ours have shown that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) into the damaged heart leads to recovery of cardiac function, thereby establishing “proof-of-concept” of this iPSC-transplantation therapy. However, considering clinical application of this therapy, its feasibility, safety, and therapeutic efficacy need to be further investigated in the pre-clinical stage. This review summarizes up-to-date important topics related to safety and efficacy of iPSC-CMs transplantation therapy for cardiac disease and discusses the prospects for this treatment in clinical studies.

  17. Guided Tissue Regeneration in Heart Valve Replacement: From Preclinical Research to First-in-Human Trials

    PubMed Central

    Iop, L.; Gerosa, G.

    2015-01-01

    Heart valve tissue-guided regeneration aims to offer a functional and viable alternative to current prosthetic replacements. Not requiring previous cell seeding and conditioning in bioreactors, such exceptional tissue engineering approach is a very fascinating translational regenerative strategy. After in vivo implantation, decellularized heart valve scaffolds drive their same repopulation by recipient's cells for a prospective autologous-like tissue reconstruction, remodeling, and adaptation to the somatic growth of the patient. With such a viability, tissue-guided regenerated conduits can be delivered as off-the-shelf biodevices and possess all the potentialities for a long-lasting resolution of the dramatic inconvenience of heart valve diseases, both in children and in the elderly. A review on preclinical and clinical investigations of this therapeutic concept is provided with evaluation of the issues still to be well deliberated for an effective and safe in-human application. PMID:26495295

  18. Geometry of the capillary net in human hearts.

    PubMed

    Rakusan, K; Cicutti, N; Spatenka, J; Samánek, M

    1997-01-01

    The geometry of the coronary capillary bed in human hearts was studied using samples obtained during cardiac surgery of children operated for tetralogy of Fallot and samples from fresh normal hearts used for valve harvesting. The results revealed a similar coronary capillary density and heterogeneity of capillary spacing in samples from both groups. A double-staining method was used to distinguish between capillary segments close to the feeding arteriole (proximal capillaries) and segments distant from the arteriole (distal capillaries). In both groups of hearts, capillary segment length was consistently shorter on the venular than the arteriolar portion of the capillary. Similarly, capillary domain areas were also smaller and the resulting capillary supply unit was smaller along venular portions compared to arteriolar regions of the capillary bed. This distinctive geometry would provide advantageous geometric conditions for tissue oxygen supply. PMID:9176723

  19. Stem cells in the management of heart failure: what have we learned from clinical trials?

    PubMed

    Vogel, Rebecca; Hussein, Emad A; Mousa, Shaker A

    2015-01-01

    Research shows that various types of stem cells (SCs) have the ability to rebuild damaged heart tissue. The TIME and Late TIME human trials shed light on the optimum timing of SC therapy administration after myocardial damage. The FOCUS study failed to show a substantial positive effect of bone marrow-derived mononuclear cells in patients suffering from ischemic heart failure; however, some completed human trials do show promise, with improvement in cardiac function. Recent clinical trials have identified a subset of marrow cells that was able to stimulate endogenous adult cardiac SCs where cardiac SCs administration showed promise in the SCIPIO trial. This review addresses some of the lessons learned from clinical trials with SC therapy in ischemic heart failure. PMID:25434419

  20. General anesthesia suppresses normal heart rate variability in humans

    NASA Astrophysics Data System (ADS)

    Matchett, Gerald; Wood, Philip

    2014-06-01

    The human heart normally exhibits robust beat-to-beat heart rate variability (HRV). The loss of this variability is associated with pathology, including disease states such as congestive heart failure (CHF). The effect of general anesthesia on intrinsic HRV is unknown. In this prospective, observational study we enrolled 100 human subjects having elective major surgical procedures under general anesthesia. We recorded continuous heart rate data via continuous electrocardiogram before, during, and after anesthesia, and we assessed HRV of the R-R intervals. We assessed HRV using several common metrics including Detrended Fluctuation Analysis (DFA), Multifractal Analysis, and Multiscale Entropy Analysis. Each of these analyses was done in each of the four clinical phases for each study subject over the course of 24 h: Before anesthesia, during anesthesia, early recovery, and late recovery. On average, we observed a loss of variability on the aforementioned metrics that appeared to correspond to the state of general anesthesia. Following the conclusion of anesthesia, most study subjects appeared to regain their normal HRV, although this did not occur immediately. The resumption of normal HRV was especially delayed on DFA. Qualitatively, the reduction in HRV under anesthesia appears similar to the reduction in HRV observed in CHF. These observations will need to be validated in future studies, and the broader clinical implications of these observations, if any, are unknown.

  1. Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes

    PubMed Central

    Funakoshi, Shunsuke; Miki, Kenji; Takaki, Tadashi; Okubo, Chikako; Hatani, Takeshi; Chonabayashi, Kazuhisa; Nishikawa, Misato; Takei, Ikue; Oishi, Akiko; Narita, Megumi; Hoshijima, Masahiko; Kimura, Takeshi; Yamanaka, Shinya; Yoshida, Yoshinori

    2016-01-01

    Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. Although transplantation of induced pluripotent stem cell (iPSC)-derived CMs have been reported in several animal models, the treatment effect was limited, probably due to poor optimization of the injected cells. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-iPSCs, day4 mesodermal cells, and day8, day20, and day30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day20 CMs was significantly higher compared to other cells. Transplantation of day20 CMs into the infarcted hearts of immunodeficient mice showed good engraftment, and echocardiography showed significant functional improvement by cell therapy. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. They also demonstrate this model can be used to track the fate of transplanted cells over a long time. PMID:26743035

  2. Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model.

    PubMed

    Weber, Benedikt; Dijkman, Petra E; Scherman, Jacques; Sanders, Bart; Emmert, Maximilian Y; Grünenfelder, Jürg; Verbeek, Renier; Bracher, Mona; Black, Melanie; Franz, Thomas; Kortsmit, Jeroen; Modregger, Peter; Peter, Silvia; Stampanoni, Marco; Robert, Jérôme; Kehl, Debora; van Doeselaar, Marina; Schweiger, Martin; Brokopp, Chad E; Wälchli, Thomas; Falk, Volkmar; Zilla, Peter; Driessen-Mol, Anita; Baaijens, Frank P T; Hoerstrup, Simon P

    2013-10-01

    Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs. PMID:23810254

  3. Virtual histology of the human heart using optical coherence tomography

    PubMed Central

    Ambrosi, Christina M.; Moazami, Nader; Rollins, Andrew M.; Efimov, Igor R.

    2009-01-01

    Optical coherence tomography (OCT) allows for the visualization of micron-scale structures within nontransparent biological tissues. For the first time, we demonstrate the use of OCT in identifying components of the cardiac conduction system and other structures in the explanted human heart. Reconstructions of cardiac structures up to 2 mm below the tissue surface were achieved and validated with Masson Trichrome histology in atrial, ventricular, sinoatrial nodal, and atrioventricular nodal preparations. The high spatial resolution of OCT provides visualization of cardiac fibers within the myocardium, as well as elements of the cardiac conduction system; however, a limiting factor remains its depth penetration, demonstrated to be ∼2 mm in cardiac tissues. Despite its currently limited imaging depth, the use of OCT to identify the structural determinants of both normal and abnormal function in the intact human heart is critical in its development as a potential aid to intracardiac arrhythmia diagnosis and therapy. PMID:19895104

  4. Virtual histology of the human heart using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Ambrosi, Christina M.; Moazami, Nader; Rollins, Andrew M.; Efimov, Igor R.

    2009-09-01

    Optical coherence tomography (OCT) allows for the visualization of micron-scale structures within nontransparent biological tissues. For the first time, we demonstrate the use of OCT in identifying components of the cardiac conduction system and other structures in the explanted human heart. Reconstructions of cardiac structures up to 2 mm below the tissue surface were achieved and validated with Masson Trichrome histology in atrial, ventricular, sinoatrial nodal, and atrioventricular nodal preparations. The high spatial resolution of OCT provides visualization of cardiac fibers within the myocardium, as well as elements of the cardiac conduction system; however, a limiting factor remains its depth penetration, demonstrated to be ~2 mm in cardiac tissues. Despite its currently limited imaging depth, the use of OCT to identify the structural determinants of both normal and abnormal function in the intact human heart is critical in its development as a potential aid to intracardiac arrhythmia diagnosis and therapy.

  5. Dysfunction of the β2-spectrin-based pathway in human heart failure.

    PubMed

    Smith, Sakima A; Hughes, Langston D; Kline, Crystal F; Kempton, Amber N; Dorn, Lisa E; Curran, Jerry; Makara, Michael; Webb, Tyler R; Wright, Patrick; Voigt, Niels; Binkley, Philip F; Janssen, Paul M L; Kilic, Ahmet; Carnes, Cynthia A; Dobrev, Dobromir; Rasband, Matthew N; Hund, Thomas J; Mohler, Peter J

    2016-06-01

    β2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β2-spectrin for vertebrate function is illustrated by dysfunction of β2-spectrin-based pathways in disease. Recently, defects in β2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, β2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced β2-spectrin protein levels. Mechanistically, we identify that β2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of β2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis. PMID:27106045

  6. Invasion of Aortic and Heart Endothelial Cells by Porphyromonas gingivalis

    PubMed Central

    Deshpande, Rajashri G.; Khan, Mahfuz B.; Attardo Genco, Caroline

    1998-01-01

    Invasion of host cells is believed to be an important strategy utilized by a number of pathogens, which affords them protection from the host immune system. The connective tissues of the periodontium are extremely well vascularized, which allows invading microorganisms, such as the periodontal pathogen Porphyromonas gingivalis, to readily enter the bloodstream. However, the ability of P. gingivalis to actively invade endothelial cells has not been previously examined. In this study, we demonstrate that P. gingivalis can invade bovine and human endothelial cells as assessed by an antibiotic protection assay and by transmission and scanning electron microscopy. P. gingivalis A7436 was demonstrated to adhere to and to invade fetal bovine heart endothelial cells (FBHEC), bovine aortic endothelial cells (BAEC), and human umbilical vein endothelial cells (HUVEC). Invasion efficiencies of 0.1, 0.2, and 0.3% were obtained with BAEC, HUVEC, and FBHEC, respectively. Invasion of FBHEC and BAEC by P. gingivalis A7436 assessed by electron microscopy revealed the formation of microvillus-like extensions around adherent bacteria followed by the engulfment of the pathogen within vacuoles. Invasion of BAEC by P. gingivalis A7436 was inhibited by cytochalasin D, nocodazole, staurosporine, protease inhibitors, and sodium azide, indicating that cytoskeletal rearrangements, protein phosphorylation, energy metabolism, and P. gingivalis proteases are essential for invasion. In contrast, addition of rifampin, nalidixic acid, and chloramphenicol had little effect on invasion, indicating that bacterial RNA, DNA, and de novo protein synthesis are not required for P. gingivalis invasion of endothelial cells. Likewise de novo protein synthesis by endothelial cells was not required for invasion by P. gingivalis. P. gingivalis 381 was demonstrated to adhere to and to invade BAEC (0.11 and 0.1% efficiency, respectively). However, adherence and invasion of the corresponding fimA mutant DPG3, which

  7. In situ expression of cytokines in human heart allografts.

    PubMed Central

    Van Hoffen, E.; Van Wichen, D.; Stuij, I.; De Jonge, N.; Klöpping, C.; Lahpor, J.; Van Den Tweel, J.; Gmelig-Meyling, F.; De Weger, R.

    1996-01-01

    Although allograft rejection, the major complication of human organ transplantation, has been extensively studied, little is known about the exact cellular localization of the cytokine expression inside the graft during rejection. Therefore, we used in situ hybridization and immunohistochemistry to study local cytokine mRNA and protein expression in human heart allografts, in relation to the phenotypical characteristics of the cellular infiltrate. Clear expression of mRNA for interleukin (IL)-6, IL-8, IL-9, and IL-10 and weak expression for IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha was detected in biopsies exhibiting high rejection grades (grade 3A/B). Also at lower grades of rejection, mRNA for IL-6 and IL-9 was present. Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies. Using immunohistochemistry, IL-2, IL-3, and IL-10 protein was detected in biopsies with high rejection grades, whereas few cells expressed IL-6, IL-8, and IFN-gamma. In biopsies with lower grades of rejection, a weaker expression of these cytokines was observed. IL-4 was hardly detected in any of the biopsies. The level of IL-12 expression was equal in all biopsies. Although mRNA expression of several cytokines was expressed at a low level compared with the protein level of those cytokines, there was a good correlation between localization of cytokine mRNA and protein. Expression of IL-2, IL-4, IL-5, TNF-alpha, and IFN-gamma was mainly detected in lymphocytes. IL-3, IL-6, IL-10, and IL-12 were not detected or not only detected in lymphocytes but also in other stromal elements (eg, macrophages). Macrophage production of IL-3 and IL-12 was confirmed by immunofluorescent double labeling with CD68. We conclude that cardiac allograft rejection is not simply regulated by T helper cell cytokine production, but other intragraft elements contribute considerably to this process. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8952534

  8. High Contrast Ultrafast Imaging of the Human Heart

    PubMed Central

    Papadacci, Clement; Pernot, Mathieu; Couade, Mathieu; Fink, Mathias; Tanter, Mickael

    2014-01-01

    Non-invasive ultrafast imaging for human cardiac applications is a big challenge to image intrinsic waves such as electromechanical waves or remotely induced shear waves in elastography imaging techniques. In this paper we propose to perform ultrafast imaging of the heart with adapted sector size by using diverging waves emitted from a classical transthoracic cardiac phased array probe. As in ultrafast imaging with plane wave coherent compounding, diverging waves can be summed coherently to obtain high-quality images of the entire heart at high frame rate in a full field-of-view. To image shear waves propagation at high SNR, the field-of-view can be adapted by changing the angular aperture of the transmitted wave. Backscattered echoes from successive circular wave acquisitions are coherently summed at every location in the image to improve the image quality while maintaining very high frame rates. The transmitted diverging waves, angular apertures and subapertures size are tested in simulation and ultrafast coherent compounding is implemented on a commercial scanner. The improvement of the imaging quality is quantified in phantom and in vivo on human heart. Imaging shear wave propagation at 2500 frame/s using 5 diverging waves provides a strong increase of the Signal to noise ratio of the tissue velocity estimates while maintaining a high frame rate. Finally, ultrafast imaging with a 1 to 5 diverging waves is used to image the human heart at a frame rate of 900 frames/s over an entire cardiac cycle. Thanks to spatial coherent compounding, a strong improvement of imaging quality is obtained with a small number of transmitted diverging waves and a high frame rate, which allows imaging the propagation of electromechanical and shear waves with good image quality. PMID:24474135

  9. Endothelial cells derived from human embryonic stem cells

    NASA Astrophysics Data System (ADS)

    Levenberg, Shulamit; Golub, Justin S.; Amit, Michal; Itskovitz-Eldor, Joseph; Langer, Robert

    2002-04-01

    Human embryonic stem cells have the potential to differentiate into various cell types and, thus, may be useful as a source of cells for transplantation or tissue engineering. We describe here the differentiation steps of human embryonic stem cells into endothelial cells forming vascular-like structures. The human embryonic-derived endothelial cells were isolated by using platelet endothelial cell-adhesion molecule-1 (PECAM1) antibodies, their behavior was characterized in vitro and in vivo, and their potential in tissue engineering was examined. We show that the isolated embryonic PECAM1+ cells, grown in culture, display characteristics similar to vessel endothelium. The cells express endothelial cell markers in a pattern similar to human umbilical vein endothelial cells, their junctions are correctly organized, and they have high metabolism of acetylated low-density lipoprotein. In addition, the cells are able to differentiate and form tube-like structures when cultured on matrigel. In vivo, when transplanted into SCID mice, the cells appeared to form microvessels containing mouse blood cells. With further studies, these cells could provide a source of human endothelial cells that could be beneficial for potential applications such as engineering new blood vessels, endothelial cell transplantation into the heart for myocardial regeneration, and induction of angiogenesis for treatment of regional ischemia.

  10. Mesp1 Marked Cardiac Progenitor Cells Repair Infarcted Mouse Hearts

    PubMed Central

    Liu, Yu; Chen, Li; Diaz, Andrea Diaz; Benham, Ashley; Xu, Xueping; Wijaya, Cori S.; Fa’ak, Faisal; Luo, Weijia; Soibam, Benjamin; Azares, Alon; Yu, Wei; Lyu, Qiongying; Stewart, M. David; Gunaratne, Preethi; Cooney, Austin; McConnell, Bradley K.; Schwartz, Robert J.

    2016-01-01

    Mesp1 directs multipotential cardiovascular cell fates, even though it’s transiently induced prior to the appearance of the cardiac progenitor program. Tracing Mesp1-expressing cells and their progeny allows isolation and characterization of the earliest cardiovascular progenitor cells. Studying the biology of Mesp1-CPCs in cell culture and ischemic disease models is an important initial step toward using them for heart disease treatment. Because of Mesp1’s transitory nature, Mesp1-CPC lineages were traced by following EYFP expression in murine Mesp1Cre/+; Rosa26EYFP/+ ES cells. We captured EYFP+ cells that strongly expressed cardiac mesoderm markers and cardiac transcription factors, but not pluripotent or nascent mesoderm markers. BMP2/4 treatment led to the expansion of EYFP+ cells, while Wnt3a and Activin were marginally effective. BMP2/4 exposure readily led EYFP+ cells to endothelial and smooth muscle cells, but inhibition of the canonical Wnt signaling was required to enter the cardiomyocyte fate. Injected mouse pre-contractile Mesp1-EYFP+ CPCs improved the survivability of injured mice and restored the functional performance of infarcted hearts for at least 3 months. Mesp1-EYFP+ cells are bona fide CPCs and they integrated well in infarcted hearts and emerged de novo into terminally differentiated cardiac myocytes, smooth muscle and vascular endothelial cells. PMID:27538477

  11. Stem cell niches in the adult mouse heart

    PubMed Central

    Urbanek, Konrad; Cesselli, Daniela; Rota, Marcello; Nascimbene, Angelo; De Angelis, Antonella; Hosoda, Toru; Bearzi, Claudia; Boni, Alessandro; Bolli, Roberto; Kajstura, Jan; Anversa, Piero; Leri, Annarosa

    2006-01-01

    Cardiac stem cells (CSCs) have been identified in the adult heart, but the microenvironment that protects the slow-cycling, undifferentiated, and self-renewing CSCs remains to be determined. We report that the myocardium possesses interstitial structures with the architectural organization of stem cell niches that harbor long-term BrdU-retaining cells. The recognition of long-term label-retaining cells provides functional evidence of resident CSCs in the myocardium, indicating that the heart is an organ regulated by a stem cell compartment. Cardiac niches contain CSCs and lineage-committed cells, which are connected to supporting cells represented by myocytes and fibroblasts. Connexins and cadherins form gap and adherens junctions at the interface of CSCs–lineage-committed cells and supporting cells. The undifferentiated state of CSCs is coupled with the expression of α4-integrin, which colocalizes with the α2-chain of laminin and fibronectin. CSCs divide symmetrically and asymmetrically, but asymmetric division predominates, and the replicating CSC gives rise to one daughter CSC and one daughter committed cell. By this mechanism of growth kinetics, the pool of primitive CSCs is preserved, and a myocyte progeny is generated together with endothelial and smooth muscle cells. Thus, CSCs regulate myocyte turnover that is heterogeneous across the heart, faster at the apex and atria, and slower at the base–midregion of the ventricle. PMID:16754876

  12. Mesp1 Marked Cardiac Progenitor Cells Repair Infarcted Mouse Hearts.

    PubMed

    Liu, Yu; Chen, Li; Diaz, Andrea Diaz; Benham, Ashley; Xu, Xueping; Wijaya, Cori S; Fa'ak, Faisal; Luo, Weijia; Soibam, Benjamin; Azares, Alon; Yu, Wei; Lyu, Qiongying; Stewart, M David; Gunaratne, Preethi; Cooney, Austin; McConnell, Bradley K; Schwartz, Robert J

    2016-01-01

    Mesp1 directs multipotential cardiovascular cell fates, even though it's transiently induced prior to the appearance of the cardiac progenitor program. Tracing Mesp1-expressing cells and their progeny allows isolation and characterization of the earliest cardiovascular progenitor cells. Studying the biology of Mesp1-CPCs in cell culture and ischemic disease models is an important initial step toward using them for heart disease treatment. Because of Mesp1's transitory nature, Mesp1-CPC lineages were traced by following EYFP expression in murine Mesp1(Cre/+); Rosa26(EYFP/+) ES cells. We captured EYFP+ cells that strongly expressed cardiac mesoderm markers and cardiac transcription factors, but not pluripotent or nascent mesoderm markers. BMP2/4 treatment led to the expansion of EYFP+ cells, while Wnt3a and Activin were marginally effective. BMP2/4 exposure readily led EYFP+ cells to endothelial and smooth muscle cells, but inhibition of the canonical Wnt signaling was required to enter the cardiomyocyte fate. Injected mouse pre-contractile Mesp1-EYFP+ CPCs improved the survivability of injured mice and restored the functional performance of infarcted hearts for at least 3 months. Mesp1-EYFP+ cells are bona fide CPCs and they integrated well in infarcted hearts and emerged de novo into terminally differentiated cardiac myocytes, smooth muscle and vascular endothelial cells. PMID:27538477

  13. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure

    NASA Astrophysics Data System (ADS)

    Urbanek, Konrad; Torella, Daniele; Sheikh, Farooq; de Angelis, Antonella; Nurzynska, Daria; Silvestri, Furio; Beltrami, C. Alberto; Bussani, Rossana; Beltrami, Antonio P.; Quaini, Federico; Bolli, Roberto; Leri, Annarosa; Kajstura, Jan; Anversa, Piero

    2005-06-01

    In this study, we tested whether the human heart possesses a cardiac stem cell (CSC) pool that promotes regeneration after infarction. For this purpose, CSC growth and senescence were measured in 20 hearts with acute infarcts, 20 hearts with end-stage postinfarction cardiomyopathy, and 12 control hearts. CSC number increased markedly in acute and, to a lesser extent, in chronic infarcts. CSC growth correlated with the increase in telomerase-competent dividing CSCs from 1.5% in controls to 28% in acute infarcts and 14% in chronic infarcts. The CSC mitotic index increased 29-fold in acute and 14-fold in chronic infarcts. CSCs committed to the myocyte, smooth muscle, and endothelial cell lineages increased 85-fold in acute infarcts and 25-fold in chronic infarcts. However, p16INK4a-p53-positive senescent CSCs also increased and were 10%, 18%, and 40% in controls, acute infarcts, and chronic infarcts, respectively. Old CSCs had short telomeres and apoptosis involved 0.3%, 3.8%, and 9.6% of CSCs in controls, acute infarcts, and chronic infarcts, respectively. These variables reduced the number of functionally competent CSCs from 26,000/cm3 of viable myocardium in acute to 7,000/cm3 in chronic infarcts, respectively. In seven acute infarcts, foci of spontaneous myocardial regeneration that did not involve cell fusion were identified. In conclusion, the human heart possesses a CSC compartment, and CSC activation occurs in response to ischemic injury. The loss of functionally competent CSCs in chronic ischemic cardiomyopathy may underlie the progressive functional deterioration and the onset of terminal failure. cardiac progenitor cells | human heart | myocardial infarction

  14. Human Engineered Heart Tissue as a Versatile Tool in Basic Research and Preclinical Toxicology

    PubMed Central

    Schaaf, Sebastian; Shibamiya, Aya; Mewe, Marco; Eder, Alexandra; Stöhr, Andrea; Hirt, Marc N.; Rau, Thomas; Zimmermann, Wolfram-Hubertus; Conradi, Lenard

    2011-01-01

    Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30–40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5–10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research. PMID:22028871

  15. Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology.

    PubMed

    Schaaf, Sebastian; Shibamiya, Aya; Mewe, Marco; Eder, Alexandra; Stöhr, Andrea; Hirt, Marc N; Rau, Thomas; Zimmermann, Wolfram-Hubertus; Conradi, Lenard; Eschenhagen, Thomas; Hansen, Arne

    2011-01-01

    Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30-40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5-10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research. PMID:22028871

  16. Characterisation of the human embryonic and foetal epicardium during heart development

    PubMed Central

    Risebro, Catherine A.; Vieira, Joaquim Miguel; Klotz, Linda; Riley, Paul R.

    2015-01-01

    The epicardium is essential for mammalian heart development. At present, our understanding of the timing and morphogenetic events leading to the formation of the human epicardium has essentially been extrapolated from model organisms. Here, we studied primary tissue samples to characterise human epicardium development. We reveal that the epicardium begins to envelop the myocardial surface at Carnegie stage (CS) 11 and this process is completed by CS15, earlier than previously inferred from avian studies. Contrary to prevailing dogma, the formed human epicardium is not a simple squamous epithelium and we reveal evidence of more complex structure, including novel spatial differences aligned to the developing chambers. Specifically, the ventricular, but not atrial, epicardium exhibited areas of expanded epithelium, preferential cell alignment and spindle-like morphology. Likewise, we reveal distinct properties ex vivo, such that ventricular cells spontaneously differentiate and lose epicardial identity, whereas atrial-derived cells remained ‘epithelial-like’. These data provide insight into the developing human epicardium that may contribute to our understanding of congenital heart disease and have implications for the development of strategies for endogenous cell-based cardiac repair. PMID:26395486

  17. Vascular Potential of Human Pluripotent Stem Cells

    PubMed Central

    Iacobas, Ionela; Vats, Archana; Hirschi, Karen K.

    2010-01-01

    Cardiovascular disease is the number one cause of death and disability in the US. Understanding the biological activity of stem and progenitor cells, and their ability to contribute to the repair, regeneration and remodeling of the heart and blood vessels affected by pathologic processes is an essential part of the paradigm in enabling us to achieve a reduction in related deaths. Both human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are promising sources of cells for clinical cardiovascular therapies. Additional in vitro studies are needed, however, to understand their relative phenotypes and molecular regulation toward cardiovascular cell fates. Further studies in translational animal models are also needed to gain insights into the potential and function of both human ES- and iPS-derived cardiovascular cells, and enable translation from experimental and pre-clinical studies to human trials. PMID:20453170

  18. VEGF improves survival of mesenchymal stem cells in infarcted hearts

    SciTech Connect

    Pons, Jennifer; Huang Yu; Arakawa-Hoyt, Janice; Washko, Daniel; Takagawa, Junya; Ye, Jianqin; Grossman, William; Su Hua

    2008-11-14

    Bone marrow-derived mesenchymal stem cells (MSC) are a promising source for cell-based treatment of myocardial infarction (MI), but existing strategies are restricted by low cell survival and engraftment. We examined whether vascular endothelial growth factor (VEGF) improve MSC viability in infracted hearts. We found long-term culture increased MSC-cellular stress: expressing more cell cycle inhibitors, p16{sup INK}, p21 and p19{sup ARF}. VEGF treatment reduced cellular stress, increased pro-survival factors, phosphorylated-Akt and Bcl-xL expression and cell proliferation. Co-injection of MSCs with VEGF to MI hearts increased cell engraftment and resulted in better improvement of cardiac function than that injected with MSCs or VEGF alone. In conclusion, VEGF protects MSCs from culture-induce cellular stress and improves their viability in ischemic myocardium, which results in improvements of their therapeutic effect for the treatment of MI.

  19. Cyclic GMP-mediated inhibition of L-type Ca2+ channel activity by human natriuretic peptide in rabbit heart cells.

    PubMed Central

    Tohse, N; Nakaya, H; Takeda, Y; Kanno, M

    1995-01-01

    1. Effects of atrial natriuretic peptide (ANP) on the L-type Ca2+ channels were examined in rabbit isolated ventricular cells by use of whole-cell and cell-attached configurations of the patch clamp methods. ANP produced a concentration-dependent decrease (10-100 nM) in amplitude of a basal Ca2+ channel current. 2. The inactive ANP (methionine-oxidized ANP, 30 nM) failed to decrease the current. 3. 8-Bromo-cyclic GMP (300 microM), a potent activator of cyclic GMP-dependent protein kinase (PKG), produced the same effects on the basal Ca2+ channel current as those produced by ANP. The cyclic GMP-induced inhibition of the Ca2+ channel current was still evoked in the presence of 1-isobutyl-3-methyl-xanthine, an inhibitor of phosphodiesterase. ANP failed to produce inhibition of the Ca2+ channel current in the presence of 8-bromo-cyclic GMP. 4. In the single channel recording, ANP and 8-bromo-cyclic GMP also inhibited the activities of the L-type Ca2+ channels. Both agents decreased the open probability (NPo) without affecting the unit amplitude. 5. The present results suggest that ANP inhibits the cardiac L-type Ca2+ channel activity through the intracellular production of cyclic GMP and then activation of PKG. PMID:7540093

  20. PDE4 in the human heart – major player or little helper?

    PubMed Central

    Eschenhagen, Thomas

    2013-01-01

    PDEs restrict the positive inotropic effects of β-adrenoceptor stimulation by degrading cAMP. Hence, PDE inhibitors sensitize the heart to catecholamines and are therefore used as positive inotropes. On the downside, this is accompanied by exaggerated energy expenditure, cell death and arrhythmias. For many years, PDE3 was considered to be the major isoform responsible for the control of cardiac force and rhythm. However, recent work in gene-targeted mice and rodent cells has indicated that PDE4 is also involved. Furthermore, selective PDE4 inhibitors augment catecholamine-stimulated cAMP levels and induce arrhythmias in human atrial preparations, which suggests that PDE4 has a more prominent role in the human heart than anticipated, and that PDE4 inhibitors such as roflumilast may carry an arrhythmogenic risk. In this issue of the journal, a team of researchers from three laboratories report on the effect of PDE3 and PDE4 inhibitors on ventricular trabeculae from explanted human hearts. The key result is that the PDE4 inhibitor rolipram does not affect the positive inotropic effects of β1- or β2-adrenoceptor stimulation. Given that the ventricle rather than the atria is the critical region in terms of arrhythmogenic consequences, this is an important and reassuring finding. Linked Article This article is a commentary on the research paper by Molenaar et al., pp. 528–538 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12167 PMID:23489196

  1. Arrhythmogenic and metabolic remodelling of failing human heart.

    PubMed

    Gloschat, C R; Koppel, A C; Aras, K K; Brennan, J A; Holzem, K M; Efimov, I R

    2016-07-15

    Heart failure (HF) is a major cause of morbidity and mortality worldwide. The global burden of HF continues to rise, with prevalence rates estimated at 1-2% and incidence approaching 5-10 per 1000 persons annually. The complex pathophysiology of HF impacts virtually all aspects of normal cardiac function - from structure and mechanics to metabolism and electrophysiology - leading to impaired mechanical contraction and sudden cardiac death. Pharmacotherapy and device therapy are the primary methods of treating HF, but neither is able to stop or reverse disease progression. Thus, there is an acute need to translate basic research into improved HF therapy. Animal model investigations are a critical component of HF research. However, the translation from cellular and animal models to the bedside is hampered by significant differences between species and among physiological scales. Our studies over the last 8 years show that hypotheses generated in animal models need to be validated in human in vitro models. Importantly, however, human heart investigations can establish translational platforms for safety and efficacy studies before embarking on costly and risky clinical trials. This review summarizes recent developments in human HF investigations of electrophysiology remodelling, metabolic remodelling, and β-adrenergic remodelling and discusses promising new technologies for HF research. PMID:27019074

  2. Snake heart: a case of atavism in a human being.

    PubMed

    Walia, Ishmeet; Arora, Harvinder S; Barker, Esmond A; Delgado, Reynolds M; Frazier, O H

    2010-01-01

    Atavism is the rare reappearance, in a modern organism, of a trait from a distant evolutionary ancestor. We describe an apparent case of atavism involving a 59-year-old man with chest pain whose coronary circulation and myocardial architecture resembled those of the reptilian heart. The chest pain was attributed to a coronary steal phenomenon. The patient was discharged from the hospital on a heightened regimen of β-blockers, and his symptoms improved significantly. To our knowledge, this is only the 2nd reported clinical case of a human coronary circulation similar to that of reptiles. PMID:21224948

  3. THERP and HEART integrated methodology for human error assessment

    NASA Astrophysics Data System (ADS)

    Castiglia, Francesco; Giardina, Mariarosa; Tomarchio, Elio

    2015-11-01

    THERP and HEART integrated methodology is proposed to investigate accident scenarios that involve operator errors during high-dose-rate (HDR) treatments. The new approach has been modified on the basis of fuzzy set concept with the aim of prioritizing an exhaustive list of erroneous tasks that can lead to patient radiological overexposures. The results allow for the identification of human errors that are necessary to achieve a better understanding of health hazards in the radiotherapy treatment process, so that it can be properly monitored and appropriately managed.

  4. Rapid manufacturing techniques for the tissue engineering of human heart valves.

    PubMed

    Lueders, Cora; Jastram, Ben; Hetzer, Roland; Schwandt, Hartmut

    2014-10-01

    Three-dimensional (3D) printing technologies have reached a level of quality that justifies considering rapid manufacturing for medical applications. Herein, we introduce a new approach using 3D printing to simplify and improve the fabrication of human heart valve scaffolds by tissue engineering (TE). Custom-made human heart valve scaffolds are to be fabricated on a selective laser-sintering 3D printer for subsequent seeding with vascular cells from human umbilical cords. The scaffolds will be produced from resorbable polymers that must feature a number of specific properties: the structure, i.e. particle granularity and shape, and thermic properties must be feasible for the printing process. They must be suitable for the cell-seeding process and at the same time should be resorbable. They must be applicable for implementation in the human body and flexible enough to support the full functionality of the valve. The research focuses mainly on the search for a suitable scaffold material that allows the implementation of both the printing process to produce the scaffolds and the cell-seeding process, while meeting all of the above requirements. Computer tomographic data from patients were transformed into a 3D data model suitable for the 3D printer. Our current activities involve various aspects of the printing process, material research and the implementation of the cell-seeding process. Different resorbable polymeric materials have been examined and used to fabricate heart valve scaffolds by rapid manufacturing. Human vascular cells attached to the scaffold surface should migrate additionally into the inner structure of the polymeric samples. The ultimate intention of our approach is to establish a heart valve fabrication process based on 3D rapid manufacturing and TE. Based on the computer tomographic data of a patient, a custom-made scaffold for a valve will be produced on a 3D printer and populated preferably by autologous cells. The long-term goal is to support

  5. The fibrosis-cell death axis in heart failure.

    PubMed

    Piek, A; de Boer, R A; Silljé, H H W

    2016-03-01

    Cardiac stress can induce morphological, structural and functional changes of the heart, referred to as cardiac remodeling. Myocardial infarction or sustained overload as a result of pathological causes such as hypertension or valve insufficiency may result in progressive remodeling and finally lead to heart failure (HF). Whereas pathological and physiological (exercise, pregnancy) overload both stimulate cardiomyocyte growth (hypertrophy), only pathological remodeling is characterized by increased deposition of extracellular matrix proteins, termed fibrosis, and loss of cardiomyocytes by necrosis, apoptosis and/or phagocytosis. HF is strongly associated with age, and cardiomyocyte loss and fibrosis are typical signs of the aging heart. Fibrosis results in stiffening of the heart, conductivity problems and reduced oxygen diffusion, and is associated with diminished ventricular function and arrhythmias. As a consequence, the workload of cardiomyocytes in the fibrotic heart is further augmented, whereas the physiological environment is becoming less favorable. This causes additional cardiomyocyte death and replacement of lost cardiomyocytes by fibrotic material, generating a vicious cycle of further decline of cardiac function. Breaking this fibrosis-cell death axis could halt further pathological and age-related cardiac regression and potentially reverse remodeling. In this review, we will describe the interaction between cardiac fibrosis, cardiomyocyte hypertrophy and cell death, and discuss potential strategies for tackling progressive cardiac remodeling and HF. PMID:26883434

  6. Normal and abnormal consequences of apoptosis in the human heart: from postnatal morphogenesis to paroxysmal arrhythmias.

    PubMed Central

    James, T. N.

    1994-01-01

    Apoptosis and necrosis are two distinctly different forms of cell death and both occur in the human heart. In contrast to necrosis, apoptosis is not associated with inflammation and there are two reasons for this. The apoptotic cell does not swell or rupture prior to its being engulfed by either a macrophage or even a neighboring like cell. And the phagocytosis occurs with unusual rapidity. Apoptosis, also thought of as cell suicide, is a tidy way of removing cells no longer useful, in essence a form of selective deletion. These features make apoptosis a valuable component of morphogenesis, mediation of hormonal and immunological responses, and the homeostatic balance between hypertrophy and atrophy or involution. In the human heart apoptosis has been found in the sinus node of patients with the long QT syndrome. It most likely participates in the important postnatal morphogenesis of the sinus node, AV (atrioventricular) node and His bundle. Apoptosis may also participate in the genesis and pathophysiology of cardiomyopathy, paroxysmal arrhythmias or conduction disturbances (some of which may be responsible for sudden death), focal fibromuscular dysplasia of small coronary arteries, hereditary medial degeneration of the tunica media of coronary arteries, and arrhythmogenic right ventricular dysplasia. The possible role of apoptosis in numerous other changes in the human heart merit future investigation, among them being the pathogenesis of atherosclerosis and mechanisms of ageing in the myocardium. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 PMID:7974966

  7. Potential benefits of cell therapy in coronary heart disease.

    PubMed

    Grimaldi, Vincenzo; Mancini, Francesco Paolo; Casamassimi, Amelia; Al-Omran, Mohammed; Zullo, Alberto; Infante, Teresa; Napoli, Claudio

    2013-11-01

    Cardiovascular disease is the leading cause of morbidity and mortality in the world. In recent years, there has been an increasing interest both in basic and clinical research regarding the field of cell therapy for coronary heart disease (CHD). Several preclinical models of CHD have suggested that regenerative properties of stem and progenitor cells might help restoring myocardial functions in the event of cardiac diseases. Here, we summarize different types of stem/progenitor cells that have been tested in experimental and clinical settings of cardiac regeneration, from embryonic stem cells to induced pluripotent stem cells. Then, we provide a comprehensive description of the most common cell delivery strategies with their major pros and cons and underline the potential of tissue engineering and injectable matrices to address the crucial issue of restoring the three-dimensional structure of the injured myocardial region. Due to the encouraging results from preclinical models, the number of clinical trials with cell therapy is continuously increasing and includes patients with CHD and congestive heart failure. Most of the already published trials have demonstrated safety and feasibility of cell therapies in these clinical conditions. Several studies have also suggested that cell therapy results in improved clinical outcomes. Numerous ongoing clinical trials utilizing this therapy for CHD will address fundamental issues concerning cell source and population utilized, as well as the use of imaging techniques to assess cell homing and survival, all factors that affect the efficacy of different cell therapy strategies. PMID:23834957

  8. Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts

    PubMed Central

    Gerbin, Kaytlyn A.; Yang, Xiulan; Murry, Charles E.; Coulombe, Kareen L. K.

    2015-01-01

    Cardiac tissue engineering is a promising approach to provide large-scale tissues for transplantation to regenerate the heart after ischemic injury, however, integration with the host myocardium will be required to achieve electromechanical benefits. To test the ability of engineered heart tissues to electrically integrate with the host, 10 million human embryonic stem cell (hESC)-derived cardiomyocytes were used to form either scaffold-free tissue patches implanted on the epicardium or micro-tissue particles (~1000 cells/particle) delivered by intramyocardial injection into the left ventricular wall of the ischemia/reperfusion injured athymic rat heart. Results were compared to intramyocardial injection of 10 million dispersed hESC-cardiomyocytes. Graft size was not significantly different between treatment groups and correlated inversely with infarct size. After implantation on the epicardial surface, hESC-cardiac tissue patches were electromechanically active, but they beat slowly and were not electrically coupled to the host at 4 weeks based on ex vivo fluorescent imaging of their graft-autonomous GCaMP3 calcium reporter. Histologically, scar tissue physically separated the patch graft and host myocardium. In contrast, following intramyocardial injection of micro-tissue particles and suspended cardiomyocytes, 100% of the grafts detected by fluorescent GCaMP3 imaging were electrically coupled to the host heart at spontaneous rate and could follow host pacing up to a maximum of 300–390 beats per minute (5–6.5 Hz). Gap junctions between intramyocardial graft and host tissue were identified histologically. The extensive coupling and rapid response rate of the human myocardial grafts after intramyocardial delivery suggest electrophysiological adaptation of hESC-derived cardiomyocytes to the rat heart’s pacemaking activity. These data support the use of the rat model for studying electromechanical integration of human cardiomyocytes, and they identify lack of

  9. Hierarchical Structure of Heart Rate Variability in Humans

    NASA Astrophysics Data System (ADS)

    Gao, X. Z.; Ching, E. S. C.; Lin, D. C.

    2004-03-01

    We show a hierarchical structure (HS) of the She-Leveque form in the beat-to-beat RR intervals of heart rate variability (HRV) in humans. This structure, first found as an empirical law in turbulent fluid flows, implies further details in the HRV multifractal scaling. We tested HS using daytime RRi data from healthy subjects and heart diseased patients with congestive heart failure and found a universal law C(b) where b characterizes the multifractality of HRV and C is related to a co-dimension parameter of the most violent events in the fluctuation. The potential of diagnosis is discussed based on the characteristics of this finding. To model the HRV phenomenology, we propose a local-feedback-global-cascade (LFGC) model based on the She-Waymire (SW) cascade solution to the HS in fluid turbulence. This model extends from the previous work in that it integrates additive law multiplicatively into the cascade structure. It is an attempt to relate to the cardiovascular physiology which consists of numerous feedback controls that function primarily on the principle of additive law. In particular, the model is based on the same philosophy as the SW cascade that its multifractal dynamics consists of a singular and a modulating component. In the LFGC model, we introduce local feedback to model the dynamics of the modulating effect. The novelty of our model is to incorporate the cascade structure in the scheduling for the feedback control. This model also represents an alternative solution to the HS. We will present the simulation results by the LFGC model and discuss its implication in physiology terms.

  10. Organophosphate inhibition of human heart muscle cholinesterase isoenzymes.

    PubMed

    Chemnitius, J M; Sadowski, R; Winkel, H; Zech, R

    1999-05-14

    The rate of acetylcholine hydrolysis of mammalian heart muscle influences cardiac responses to vagal innervation. We characterized cholinesterases of human left ventricular heart muscle with respect to both substrate specificity and irreversible inhibition kinetics with the organophosphorus inhibitor N,N'-di-isopropylphosphorodiamidic fluoride (mipafox). Specimens were obtained postmortem from three men and four women (61 +/- 5 years) with no history of cardiovascular disease. Myocardial choline ester hydrolyzing activity was determined with acetylthiocholine (ASCh; 1.25 mM), acetyl-beta-methylthiocholine (AbetaMSCh; 2.0 mM), and butyrylthiocholine (BSCh; 30 mM). After irreversible and covalent inhibition (60 min; 25 degrees C) with a wide range of mipafox concentrations (50 nM-5 mM), residual choline ester hydrolyzing activities were fitted to a sum of up to five exponentials using weighted least-squares non-linear curve fitting. In each ease, quality of curve fitting reached its optimum on the basis of a four component model. Final classification of heart muscle cholinesterases was achieved according to substrate hydrolysis patterns (nmol/min per g wet weight) and to second-order organophosphate inhibition rate constants k2 (1/mol per min); one choline ester hydrolyzing enzyme was identified as acetylcholinesterase (AChE; k2/mipafox = 6.1 (+/- 0.8) x 10(2)), and one as butyrylcholinesterase (BChE; k2/mipafox = 5.3 (+/- 1.1) x 10(3)). An enzyme exhibiting both ChE-like substrate specificity and relative resistance to mipafox inhibition (k2/mipafox = 5.2 (+/- 1.0) x 10(-1)) was classified as atypical cholinesterase. PMID:10421452

  11. Human heart rate variability relation is unchanged during motion sickness

    NASA Technical Reports Server (NTRS)

    Mullen, T. J.; Berger, R. D.; Oman, C. M.; Cohen, R. J.

    1998-01-01

    In a study of 18 human subjects, we applied a new technique, estimation of the transfer function between instantaneous lung volume (ILV) and instantaneous heart rate (HR), to assess autonomic activity during motion sickness. Two control recordings of ILV and electrocardiogram (ECG) were made prior to the development of motion sickness. During the first, subjects were seated motionless, and during the second they were seated rotating sinusoidally about an earth vertical axis. Subjects then wore prism goggles that reverse the left-right visual field and performed manual tasks until they developed moderate motion sickness. Finally, ILV and ECG were recorded while subjects maintained a relatively constant level of sickness by intermittent eye closure during rotation with the goggles. Based on analyses of ILV to HR transfer functions from the three conditions, we were unable to demonstrate a change in autonomic control of heart rate due to rotation alone or due to motion sickness. These findings do not support the notion that moderate motion sickness is manifested as a generalized autonomic response.

  12. Statistical Properties of the Interbeat Interval Cascade in Human Hearts

    NASA Astrophysics Data System (ADS)

    Ghasemi, Fatemeh; Peinke, J.; Reza Rahimi Tabar, M.; Sahimi, Muhammad

    Statistical properties of interbeat intervals cascade in human hearts are evaluated by considering the joint probability distribution P (Δx2, τ2 Δx1, τ1) for two interbeat increments Δx1 and Δx2 of different time scales τ1 and τ2. We present evidence that the conditional probability distribution P (Δx2, τ2 | Δx1, τ1) may be described by a Chapman-Kolmogorov equation. The corresponding Kramers-Moyal (KM) coefficients are evaluated. The analysis indicates that while the first and second KM coefficients take on well-defined and significant values, the higher-order coefficients in the KM expansion are small. As a result, the joint probability distributions of the increments in the interbeat intervals are described by a Fokker-Planck equation, with the first two KM coefficients acting as the drift and diffusion coefficients. The method provides a novel technique for distinguishing two classes of subjects, namely, healthy ones and those with congestive heart failure, in terms of the drift and diffusion coefficients which behave differently for two classes of the subjects.

  13. Human Embryonic Stem Cells and Cardiac Repair

    PubMed Central

    Zhu, Wei-Zhong; Hauch, Kip; Xu, Chunhui; Laflamme, Michael A.

    2008-01-01

    The muscle lost after a myocardial infarction is replaced with non-contractile scar tissue, often initiating heart failure. Whole-organ cardiac transplantation is the only currently available clinical means of replacing the lost muscle, but this option is limited by the inadequate supply of donor hearts. Thus, cell-based cardiac repair has attracted considerable interest as an alternative means of ameliorating cardiac injury. Because of their tremendous capacity for expansion and unquestioned cardiac potential, pluripotent human embryonic stem cells (hESCs) represent an attractive candidate cell source for obtaining cardiomyocytes and other useful mesenchymal cell types for such therapies. hESC-derived cardiomyocytes (hESC-CMs) exhibit a committed cardiac phenotype and robust proliferative capacity, and recent testing in rodent infarct models indicates that they can partially remuscularize injured hearts and improve contractile function. Although the latter successes give good reason for optimism, considerable challenges remain to the successful application of hESCs to cardiac repair, including the need for preparations of high cardiac purity, improved methods of delivery, and approaches to overcome immune rejection and other causes of graft cell death. This review will describe the phenotype of hESC-CMs and preclinical experience with these cells and will consider strategies to overcoming the aforementioned challenges. PMID:18657407

  14. Mesenchymal stem cell therapy for heart disease.

    PubMed

    Gnecchi, Massimiliano; Danieli, Patrizia; Cervio, Elisabetta

    2012-08-19

    Mesenchymal stem cells (MSC) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Initially described in the bone marrow, MSC are also present in other organs and tissues. From a therapeutic perspective, because of their easy preparation and immunologic privilege, MSC are emerging as an extremely promising therapeutic agent for tissue regeneration and repair. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSC to engraft and differentiate into cardiomyocytes and vascular cells. Most importantly, engrafted MSC secrete a wide array of soluble factors that mediate beneficial paracrine effects and may greatly contribute to cardiac repair. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. In this review we will focus on the current understanding of MSC biology and MSC mechanism of action in cardiac repair. PMID:22521741

  15. Intracellular Renin Disrupts Chemical Communication between Heart Cells. Pathophysiological Implications

    PubMed Central

    De Mello, Walmor C.

    2015-01-01

    Highlights Intracellular renin disrupts chemical communication in the heartAngiotensinogen enhances the effect of reninIntracellular enalaprilat reduces significantly the effect of reninIntracellular renin increases the inward calcium currentHarmful versus beneficial effect during myocardial infarction The influence of intracellular renin on the process of chemical communication between cardiac cells was investigated in cell pairs isolated from the left ventricle of adult Wistar Kyoto rats. The enzyme together with Lucifer yellow CH was dialyzed into one cell of the pair using the whole cell clamp technique. The diffusion of the dye in the dialyzed and in non-dialyzed cell was followed by measuring the intensity of fluorescence in both cells as a function of time. The results indicated that; (1) under normal conditions, Lucifer Yellow flows from cell to cell through gap junctions; (2) the intracellular dialysis of renin (100 nM) disrupts chemical communication – an effect enhanced by simultaneous administration of angiotensinogen (100 nM); (3) enalaprilat (10−9 M) administered to the cytosol together with renin reduced drastically the uncoupling action of the enzyme; (4) aliskiren (10−8 M) inhibited the effect of renin on chemical communication; (5) the possible role of intracellular renin independently of angiotensin II (Ang II) was evaluated including the increase of the inward calcium current elicited by the enzyme and the possible role of oxidative stress on the disruption of cell communication; (6) the possible harmful versus the beneficial effect of intracellular renin during myocardial infarction was discussed; (7) the present results indicate that intracellular renin due to internalization or in situ synthesis causes a severe impairment of chemical communication in the heart resulting in derangement of metabolic cooperation with serious consequences for heart function. PMID:25657639

  16. Nanoparticles-Assisted Stem Cell Therapy for Ischemic Heart Disease

    PubMed Central

    Zhu, Kai; Li, Jun; Wang, Yulin; Lai, Hao; Wang, Chunsheng

    2016-01-01

    Stem cell therapy has attracted increasing attention as a promising treatment strategy for cardiac repair in ischemic heart disease. Nanoparticles (NPs), with their superior physical and chemical properties, have been widely utilized to assist stem cell therapy. With the help of NPs, stem cells can be genetically engineered for enhanced paracrine profile. To further understand the fate and behaviors of stem cells in ischemic myocardium, imaging NPs can label stem cells and be tracked in vivo under multiple modalities. Besides that, NPs can also be used to enhance stem cell retention in myocardium. These facts have raised efforts on the development of more intelligent and multifunctional NPs for cellular application. Herein, an overview of the applications of NPs-assisted stem cell therapy is given. Key issues and future prospects are also critically addressed. PMID:26839552

  17. The establishment of regular beating in populations of pacemaker heart cells. A study with tissue-cultured rat heart cells.

    PubMed

    Jongsma, H J; Tsjernina, L; de Bruijne, J

    1983-02-01

    Single isolated neonatal rat heart cells beat slowly (mean beating interval duration in the range of seconds) and irregularly (coefficient of variation greater than 40%). It is shown that slowness and irregularity of beating are intrinsic properties of the cells and are not caused by dissociation damage or lack of conditioning factors in the culture medium. When cell contacts are established either by letting the cultures grow for given amounts of time or by plating cells at increasing densities both interval duration and irregularity decrease. The beating regularity of small groups of interconnected cells (3 to 35 cells) and larger groups (200 to 15000 cells) is comparable. There is no clear cut proportionality between number of interconnected cells and beating regularity. Confluent monolayers beat fast (mean interval duration ranging between 200 and 400 ms and regular (coefficient of variation less than 5%). The hypothesis is discussed that this clock-like behavior of monolayers of heart cells is caused by the interaction of several pacemaker centers which are by themselves less regular and beat more slowly. PMID:6854658

  18. A Simple Dissection Method for the Conduction System of the Human Heart

    ERIC Educational Resources Information Center

    Yanagawa, Nariaki; Nakajima, Yuji

    2009-01-01

    A simple dissection guide for the conduction system of the human heart is shown. The atrioventricular (AV) node, AV bundle, and right bundle branch were identified in a formaldehyde-fixed human heart. The sinu-atrial (SA) node could not be found, but the region in which SA node was contained was identified using the SA nodal artery. Gross…

  19. A fast method to measure the 3D surface of the human heart

    NASA Astrophysics Data System (ADS)

    Cao, Yiping; Su, Xianyu; Xiang, Liqun; Chen, Wenjing; Zhang, Qican

    2003-12-01

    Three-dimensional (3-D) automatic measurement of an object is widely used in many fields. In Biology and Medicine society, it can be applicable for surgery, orthopedics, viscera disease analysis and diagnosis etc. Here a new fast method to measure the 3D surface of human heart is proposed which can provide doctors a lot of information, such as the size of heart profile, the sizes of the left or right heart ventricle, and the curvature center and radius of heart ventricle, to fully analyze and diagnose pathobiology of human heart. The new fast method is optically and noncontacted and based upon the Phase Measurement Profilometry (PMP), which has higher measuring precision. A human heart specimen experiment has verified our method.

  20. Morphological Study of Chordae Tendinae in Human Cadaveric Hearts

    PubMed Central

    Gunnal, S. A.; Wabale, R. N.; Farooqui, M. S.

    2015-01-01

    Objectives: The chordae tendinae (CT) are strong, fibrous connections between the valve leaflets and the papillary muscles. Dysfunction of the papillary muscles and chordae is frequent. Mitral valve replacement with preservation of CT and papillary muscles may preserve postoperative left ventricular function better than conventional mitral valve replacement in patients with chronic mitral regurgitation. Methods: The study was carried out on 116 human cadaveric hearts. The heart was opened through the atrioventricular valve to view the constituents of the complex. Origin, attachments, insertions, distribution, branching pattern and gross structure of CT were observed and studied in detail. Results: In the present study more than 21 terminologies of CT were defined by classifying it into six different types. Classification is done according to the origin, attachments, insertion, distribution, branching pattern and gross structure. Terminologies defined are as follows. Apical pillar chordae, Basal pillar chordae, True chordae, False chordae, Interpillar chordae, Pillar wall chordae, Cusp chordae, Cleft chordae, Commissural chordae, First order chordae, Second order chordae, Free zone chordae, Marginal chordae, Rough zone chordae, Straight chordae, Branched-fan shaped chordae, Spiral chordae, Irregular-web chordae, Tendinous chordae, Muscular chordae, Membranous chordae. Basal pillar chordae are found in 9.48%. Mean number of chordae taking origin from apical half of a single papillary muscle or single head of papillary muscle was 9.09 with the range of 3-18. Mean number of the marginal chordae attached to a single cusp was 22.63 ranging from 11 to 35. Strut chordae showed interesting insertion with broad aponeurosis in 38.79% and large muscular flaps in 13.79%. Chordae muscularis were found in 14% and membranous chordae were found in 6%. Conclusions: This knowledge may prove useful for cardiologists and cardiac surgeons. PMID:25838872

  1. Heart disease is common in humans and chimpanzees, but is caused by different pathological processes.

    PubMed

    Varki, Nissi; Anderson, Dan; Herndon, James G; Pham, Tho; Gregg, Christopher J; Cheriyan, Monica; Murphy, James; Strobert, Elizabeth; Fritz, Jo; Else, James G; Varki, Ajit

    2009-02-01

    Heart disease is common in both humans and chimpanzees, manifesting typically as sudden cardiac arrest or progressive heart failure. Surprisingly, although chimpanzees are our closest evolutionary relatives, the major cause of heart disease is different in the two species. Histopathology data of affected chimpanzee hearts from two primate centers, and analysis of literature indicate that sudden death in chimpanzees (and in gorillas and orangutans) is commonly associated with diffuse interstitial myocardial fibrosis of unknown cause. In contrast, most human heart disease results from coronary artery atherosclerosis, which occludes myocardial blood supply, causing ischemic damage. The typical myocardial infarction of humans due to coronary artery thrombosis is rare in these apes, despite their human-like coronary-risk-prone blood lipid profiles. Instead, chimpanzee 'heart attacks' are likely due to arrythmias triggered by myocardial fibrosis. Why do humans not often suffer from the fibrotic heart disease so common in our closest evolutionary cousins? Conversely, why do chimpanzees not have the kind of heart disease so common in humans? The answers could be of value to medical care, as well as to understanding human evolution. A preliminary attempt is made to explore possibilities at the histological level, with a focus on glycosylation changes. PMID:25567850

  2. Parthenogenetic stem cells for tissue-engineered heart repair

    PubMed Central

    Didié, Michael; Christalla, Peter; Rubart, Michael; Muppala, Vijayakumar; Döker, Stephan; Unsöld, Bernhard; El-Armouche, Ali; Rau, Thomas; Eschenhagen, Thomas; Schwoerer, Alexander P.; Ehmke, Heimo; Schumacher, Udo; Fuchs, Sigrid; Lange, Claudia; Becker, Alexander; Tao, Wen; Scherschel, John A.; Soonpaa, Mark H.; Yang, Tao; Lin, Qiong; Zenke, Martin; Han, Dong-Wook; Schöler, Hans R.; Rudolph, Cornelia; Steinemann, Doris; Schlegelberger, Brigitte; Kattman, Steve; Witty, Alec; Keller, Gordon; Field, Loren J.; Zimmermann, Wolfram-Hubertus

    2013-01-01

    Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair. PMID:23434590

  3. Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart.

    PubMed

    Lemieux, Hélène; Semsroth, Severin; Antretter, Herwig; Höfer, Daniel; Gnaiger, Erich

    2011-12-01

    Heart failure is a consequence of progressive deterioration of cardiac performance. Little is known about the role of impaired oxidative phosphorylation in the progression of the disease, since previous studies of mitochondrial injuries are restricted to end-stage chronic heart failure. The present study aimed at evaluating the involvement of mitochondrial dysfunction in the development of human heart failure. We measured the control of oxidative phosphorylation with high-resolution respirometry in permeabilized myocardial fibres from donor hearts (controls), and patients with no or mild heart failure but presenting with heart disease, or chronic heart failure due to dilated or ischemic cardiomyopathy. The capacity of the phosphorylation system exerted a strong limitation on oxidative phosphorylation in the human heart, estimated at 121 pmol O(2)s(-1)mg(-1) in the healthy left ventricle. In heart disease, a specific defect of the phosphorylation system, Complex I-linked respiration, and mass-specific fatty acid oxidation were identified. These early defects were also significant in chronic heart failure, where the capacities of the oxidative phosphorylation and electron transfer systems per cardiac tissue mass were decreased with all tested substrate combinations, suggesting a decline of mitochondrial density. Oxidative phosphorylation and electron transfer system capacities were higher in ventricles compared to atria, but the impaired mitochondrial quality was identical in the four cardiac chambers of chronic heart failure patients. Coupling was preserved in heart disease and chronic heart failure, in contrast to the mitochondrial dysfunction observed after prolonged cold storage of cardiac tissue. Mitochondrial defects in the phosphorylation system, Complex I respiration and mass-specific fatty acid oxidation occurred early in the development of heart failure. Targeting these mitochondrial injuries with metabolic therapy may offer a promising approach to delay

  4. Protection against hyperacute xenograft rejection of transgenic rat hearts expressing human decay accelerating factor (DAF) transplanted into primates.

    PubMed Central

    Charreau, B.; Ménoret, S.; Tesson, L.; Azimzadeh, A.; Audet, M.; Wolf, P.; Marquet, R.; Verbakel, C.; Ijzermans, J.; Cowan, P.; Pearse, M.; d'Apice, A.; Soulillou, J. P.; Anegon, I.

    1999-01-01

    BACKGROUND: Production of transgenic pigs for multiple transgenes is part of a potential strategy to prevent immunological events involved in xenograft rejection. Use of a genetically engineerable rodent as a donor in primates could allow testing in vivo of the effects of different transgenes on controlling xenograft rejection. As a first step in the development of a donor containing multiple transgenes, transgenic rats for human decay-accelerating factor (DAF) were used as heart donors to test their resistance against complement (C)-mediated rejection by non-human primates. MATERIALS AND METHODS: Transgenic rats were generated by using a construct containing the human DAF cDNA under the transcriptional control of the endothelial cell (EC)-specific human ICAM-2 promoter. DAF expression was evaluated by immunohistology and by FACS analysis of purified ECs. Resistance of transgenic hearts against C-mediated damage was evaluated by ex vivo perfusion with human serum and by transplantation into cynomolgus monkeys. RESULTS: Immunohistological analysis of DAF expression in several organs from two transgenic lines showed uniform expression on the endothelium of all blood vessels. ECs purified from transgenic hearts showed 50% DAF expression compared to human ECs and >70% reduction of C-dependent cell lysis compared to control rat ECs. Hemizygous transgenic hearts perfused with human serum showed normal function for >60 min vs. 11. 2 +/- 1.7 min in controls. Hemi- or homozygous transgenic hearts transplanted into cynomolgus monkeys showed longer survival (15.2 +/- 7 min and >4.5 hr, respectively) than controls (5.5 +/- 1.4 min). In contrast to hyperacutely rejected control hearts, rejected homozygous DAF hearts showed signs of acute vascular rejection (AVR) characterized by edema, hemorrhage, and an intense PMN infiltration. CONCLUSIONS: We demonstrate that endothelial-specific DAF expression increased heart transplant survival in a rat-to-primate model of

  5. Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts

    PubMed Central

    Rath, Arianna; Liu, Jie; Silverman, Earl D.; Liu, Xiaoru; Siragam, Vinayakumar; Ackerley, Cameron; Su, Brenda Bin; Yan, Jane Yuqing; Capecchi, Marco; Biavati, Luca; Accorroni, Alice; Yuen, William; Quattrone, Filippo; Lung, Kalvin; Jaeggi, Edgar T.; Backx, Peter H.; Deber, Charles M.; Hamilton, Robert M.

    2013-01-01

    Background Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB. Methodology/Principal Findings We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells. Conclusions/Significance Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets. PMID:24039792

  6. Modelling sarcomeric cardiomyopathies in the dish: from human heart samples to iPSC cardiomyocytes

    PubMed Central

    Eschenhagen, Thomas; Mummery, Christine; Knollmann, Bjorn C.

    2015-01-01

    One of the obstacles to a better understanding of the pathogenesis of human cardiomyopathies has been poor availability of heart-tissue samples at early stages of disease development. This has possibly changed by the advent of patient-derived induced pluripotent stem cell (hiPSC) from which cardiomyocytes can be derived in vitro. The main promise of hiPSC technology is that by capturing the effects of thousands of individual gene variants, the phenotype of differentiated derivatives of these cells will provide more information on a particular disease than simple genotyping. This article summarizes what is known about the ‘human cardiomyopathy or heart failure phenotype in vitro’, which constitutes the reference for modelling sarcomeric cardiomyopathies in hiPSC-derived cardiomyocytes. The current techniques for hiPSC generation and cardiac myocyte differentiation are briefly reviewed and the few published reports of hiPSC models of sarcomeric cardiomyopathies described. A discussion of promises and challenges of hiPSC-modelling of sarcomeric cardiomyopathies and individualized approaches is followed by a number of questions that, in the view of the authors, need to be answered before the true potential of this technology can be evaluated. PMID:25618410

  7. Calcium Activation Profile In Electrically Stimulated Intact Rat Heart Cells

    NASA Astrophysics Data System (ADS)

    Geerts, Hugo; Nuydens, Rony; Ver Donck, Luc; Nuyens, Roger; De Brabander, Marc; Borgers, Marcel

    1988-06-01

    Recent advances in fluorescent probe technology and image processing equipment have made available the measurement of calcium in living systems on a real-time basis. We present the use of the calcium indicator Fura-2 in intact normally stimulated rat heart cells for the spatial and dynamic measurement of the calcium excitation profile. After electric stimulation (1 Hz), the activation proceeds from the center of the myocyte toward the periphery. Within two frame times (80 ms), the whole cell is activated. The activation is slightly faster in the center of the cell than in the periphery. The mean recovery time is 200-400 ms. There is no difference along the cell's long axis. The effect of a beta-agonist and of a calcium antagonist is described.

  8. Cell-cell interaction in blood flow in patients with coronary heart disease (in vitro study)

    NASA Astrophysics Data System (ADS)

    Malinova, Lidia I.; Simonenko, Georgy V.; Denisova, Tatyana P.; Tuchin, Valery V.

    2007-02-01

    Blood cell-cell and cell-vessel wall interactions are one of the key patterns in blood and vascular pathophysiology. We have chosen the method of reconstruction of pulsative blood flow in vitro in the experimental set. Blood flow structure was studied by PC integrated video camera with following slide by slide analysis. Studied flow was of constant volumetric blood flow velocity (1 ml/h). Diameter of tube in use was comparable with coronary arteries diameter. Glucose solution and unfractured heparin were used as the nonspecial irritants of studied flow. Erythrocytes space structure in flow differs in all groups of patients in our study (men with stable angina pectoris (SAP), myocardial infarction (MI) and practically healthy men (PHM). Intensity of erythrocytes aggregate formation was maximal in patients with SAP, but time of their "construction/deconstruction" at glucose injection was minimal. Phenomena of primary clotting formation in patients with SAP of high function class was reconstructed under experimental conditions. Heparin injection (10 000 ED) increased linear blood flow velocity both in patients with SAP, MI and PHP but modulated the cell profile in the flow. Received data correspond with results of animal model studies and noninvasive blood flow studies in human. Results of our study reveal differences in blood flow structure in patients with coronary heart disease and PHP under irritating conditions as the possible framework of metabolic model of coronary blood flow destabilization.

  9. Time-lapse imaging of human heart motion with switched array UWB radar.

    PubMed

    Brovoll, Sverre; Berger, Tor; Paichard, Yoann; Aardal, Øyvind; Lande, Tor Sverre; Hamran, Svein-Erik

    2014-10-01

    Radar systems for detection of human heartbeats have mostly been single-channel systems with limited spatial resolution. In this paper, a radar system for ultra-wideband (UWB) imaging of the human heart is presented. To make the radar waves penetrate the human tissue the antenna is placed very close to the body. The antenna is an array with eight elements, and an antenna switch system connects the radar to the individual elements in sequence to form an image. Successive images are used to build up time-lapse movies of the beating heart. Measurements on a human test subject are presented and the heart motion is estimated at different locations inside the body. The movies show rhythmic motion consistent with the beating heart, and the location and shape of the reflections correspond well with the expected response form the heart wall. The spatial dependent heart motion is compared to ECG recordings, and it is confirmed that heartbeat modulations are seen in the radar data. This work shows that radar imaging of the human heart may provide valuable information on the mechanical movement of the heart. PMID:25350945

  10. Characteristic parameters of electromagnetic signals from a human heart system

    NASA Astrophysics Data System (ADS)

    Liu, Xin-Yuan; Pei, Liu-Qing; Wang, Yin; Zhang, Su-Ming; Gao, Hong-Lei; Dai, Yuan-Dong

    2011-04-01

    The electromagnetic field of a human heart system is a bioelectromagnetic field. Electrocardiography (ECG) and magnetocardiography (MCG) are both carriers of electromagnetic information about the cardiac system, and they are nonstationary signals. In this study, ECG and MCG data from healthy subjects are acquired; the MCG data are captured using a high-Tc radio frequency superconducting quantum interference device (HTc rf SQUIDs) and the QRS complexes in these data are analysed by the evolutionary spectrum analysis method. The results show that the quality factor Q and the central frequency fz of the QRS complex evolutionary spectrum are the characteristic parameters (CHPs) of ECG and MCG in the time—frequency domain. The confidence intervals of the mean values of the CHPs are estimated by the Student t distribution method in mathematical statistics. We believe that there are threshold ranges of the mean values of Q and fz for healthy subjects. We have postulated the following criterion: if the mean values of CHPs are in the proper ranges, the cardiac system is in a normal condition and it possesses the capability of homeostasis. In contrast, if the mean values of the CHPs do not lie in the proper ranges, the homeostasis of the cardiac system is lacking and some cardiac disease may follow. The results and procedure of MCG CHPs in the study afford a technological route for the application of HTc rf SQUIDs in cardiology.

  11. Developing a novel comprehensive framework for the investigation of cellular and whole heart electrophysiology in the in situ human heart: historical perspectives, current progress and future prospects.

    PubMed

    Taggart, Peter; Orini, Michele; Hanson, Ben; Hayward, Martin; Clayton, Richard; Dobrzynski, Halina; Yanni, Joseph; Boyett, Mark; Lambiase, Pier D

    2014-08-01

    Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial "M" cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a "mother" rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related

  12. Human heart conjugate cooling simulation: Unsteady thermo-fluid-stress analysis

    PubMed Central

    Abdoli, Abas; Dulikravich, George S.; Bajaj, Chandrajit; Stowe, David F.; Jahania, M. Salik

    2015-01-01

    The main objective of this work was to demonstrate computationally that realistic human hearts can be cooled much faster by performing conjugate heat transfer consisting of pumping a cold liquid through the cardiac chambers and major veins while keeping the heart submerged in cold gelatin filling a cooling container. The human heart geometry used for simulations was obtained from three-dimensional, high resolution MRI scans. Two fluid flow domains for the right (pulmonic) and left (systemic) heart circulations, and two solid domains for the heart tissue and gelatin solution were defined for multi-domain numerical simulation. Detailed unsteady temperature fields within the heart tissue were calculated during the conjugate cooling process. A linear thermoelasticity analysis was performed to assess the stresses applied on the heart due to the coolant fluid shear and normal forces and to examine the thermal stress caused by temperature variation inside the heart. It was demonstrated that a conjugate cooling effort with coolant temperature at +4°C is capable of reducing the average heart temperature from +37°C to +8°C in 25 minutes for cases in which the coolant was steadily pumped only through major heart inlet veins and cavities. PMID:25045006

  13. Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease

    PubMed Central

    Werner, Petra; Paluru, Prasuna; Simpson, Anisha M.; Latney, Brande; Iyer, Radhika; Brodeur, Garrett M.; Goldmuntz, Elizabeth

    2014-01-01

    Congenital heart defects (CHDs) are the most common major birth defects and the leading cause of death from congenital malformations. The etiology remains largely unknown, though genetic variants clearly contribute. In a previous study, we identified a large copy number variant (CNV) that deleted 46 genes in a patient with a malalignment type ventricular septal defect (VSD). The CNV included the gene NTRK3 encoding neurotrophic tyrosine kinase receptor C (TrkC), which is essential for normal cardiogenesis in animal models. To evaluate the role of NTRK3 in human CHDs, we studied 467 patients with related heart defects for NTRK3 mutations. We identified four missense mutations in four patients with VSDs that were not found in ethnically matched controls and were predicted to be functionally deleterious. Functional analysis using neuroblastoma cell lines expressing mutant TrkC demonstrated that one of the mutations (c.278C>T, p.T93M) significantly reduced autophosphorylation of TrkC in response to ligand binding, subsequently decreasing phosphorylation of downstream target proteins. In addition compared to WT, three of the four cell lines expressing mutant TrkC showed altered cell growth in low-serum conditions without supplemental NT-3. These findings suggest a novel pathophysiological mechanism involving NTRK3 in the development of VSDs. PMID:25196463

  14. A phenotypic in vitro model for the main determinants of human whole heart function.

    PubMed

    Stancescu, Maria; Molnar, Peter; McAleer, Christopher W; McLamb, William; Long, Christopher J; Oleaga, Carlota; Prot, Jean-Matthieu; Hickman, James J

    2015-08-01

    This article details the construction and testing of a phenotypic assay system that models in vivo cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model features a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for cardiac side effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems. PMID:25978005

  15. A phenotypic in vitro model for the main determinants of human whole heart function

    PubMed Central

    Stancescu, Maria; Molnar, Peter; McAleer, Christopher W.; McLamb, William; Long, Christopher J.; Oleaga, Carlota; Prot, Jean-Matthieu; Hickman, James J.

    2015-01-01

    This article details the construction and testing of a phenotypic assay system that models in vivo cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model featured a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for cardiac side effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems. PMID:25978005

  16. Heart Regeneration with Embryonic Cardiac Progenitor Cells and Cardiac Tissue Engineering

    PubMed Central

    Tian, Shuo; Liu, Qihai; Gnatovskiy, Leonid; Ma, Peter X.; Wang, Zhong

    2015-01-01

    Myocardial infarction (MI) is the leading cause of death worldwide. Recent advances in stem cell research hold great potential for heart tissue regeneration through stem cell-based therapy. While multiple cell types have been transplanted into MI heart in preclinical studies or clinical trials, reduction of scar tissue and restoration of cardiac function have been modest. Several challenges hamper the development and application of stem cell-based therapy for heart regeneration. Application of cardiac progenitor cells (CPCs) and cardiac tissue engineering for cell therapy has shown great promise to repair damaged heart tissue. This review presents an overview of the current applications of embryonic CPCs and the development of cardiac tissue engineering in regeneration of functional cardiac tissue and reduction of side effects for heart regeneration. We aim to highlight the benefits of the cell therapy by application of CPCs and cardiac tissue engineering during heart regeneration. PMID:26744736

  17. Wavelet analysis of nonequilibrium ionic currents in human heart sodium channel (hH1a).

    PubMed

    Hosein-Sooklal, A; Kargol, A

    2002-08-01

    Nonequilibrium response spectroscopy (NRS), the technique of using rapidly fluctuating voltage pulses in the study of ion channels, is applied here. NRS is known to drive an ensemble of ion channels far from equilibrium where, it has been argued, new details of ion channel kinetics can be studied under nonequilibrium conditions. In this paper, a single-pulse NRS technique with custom-designed waveforms built from wavelets is used. The pulses are designed to produce different responses from two competing models of a human heart isoform of the sodium channel (hH1a). Experimental data using this new type of pulses are obtained through whole-cell recordings from mammalian cells (HEK 293). Wavelet analysis of the model response and the experimental data is introduced to show how these NRS pulses can aid in distinguishing the better of the two models and thus introduces another important application of this new technique. PMID:12181611

  18. Cell electrospinning cardiac patches for tissue engineering the heart.

    PubMed

    Ehler, Elisabeth; Jayasinghe, Suwan N

    2014-09-21

    Cell electrospinning has tremendous applicability to a wide range of uses within both the laboratory and clinic. This has directly resulted from the technology's unique ability to immobilize multiple cell types with a wide range of molecules simultaneously within a fiber during the scaffold generation process. The technology has been shown to generate many cell laden complex architectures from true three-dimensional sheets to those multi-core vessels. Although those studies have demonstrated the versatility of this platform biotechnology, we show here for the first time the ability to immobilize primary cardiac myocytes within these fibers in our quest to develop this technology for creating three-dimensional cardiac patches which could be used for repairing, replacing and rejuvenating damaged, diseased and/or ageing cardiac tissues. These advances are unrivalled by any other technology currently available in the regenerative medicine toolbox, and have many interesting ramifications for repairing a damaged heart. PMID:25058315

  19. Heart Anatomy

    MedlinePlus

    ... Incredible Machine Bonus poster (PDF) The Human Heart Anatomy Blood The Conduction System The Coronary Arteries The ... of the Leg Vasculature of the Torso Heart anatomy illustrations and animations for grades K-6. Heart ...

  20. Multipotent (adult) and pluripotent stem cells for heart regeneration: what are the pros and cons?

    PubMed

    Liao, Song-Yan; Tse, Hung-Fat

    2013-01-01

    Heart failure after myocardial infarction is the leading cause of mortality and morbidity worldwide. Existing medical and interventional therapies can only reduce the loss of cardiomyocytes during myocardial infarction but are unable to replenish the permanent loss of cardiomyocytes after the insult, which contributes to progressive pathological left ventricular remodeling and progressive heart failure. As a result, cell-based therapies using multipotent (adult) stem cells and pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells) have been explored as potential therapeutic approaches to restore cardiac function in heart failure. Nevertheless, the optimal cell type with the best therapeutic efficacy and safety for heart regeneration is still unknown. In this review, the potential pros and cons of different types of multipotent (adult) stem cells and pluripotent stem cells that have been investigated in preclinical and clinical studies are reviewed, and the future perspective of stem cell-based therapy for heart regeneration is discussed. PMID:24476362

  1. Human gene copy number spectra analysis in congenital heart malformations.

    PubMed

    Tomita-Mitchell, Aoy; Mahnke, Donna K; Struble, Craig A; Tuffnell, Maureen E; Stamm, Karl D; Hidestrand, Mats; Harris, Susan E; Goetsch, Mary A; Simpson, Pippa M; Bick, David P; Broeckel, Ulrich; Pelech, Andrew N; Tweddell, James S; Mitchell, Michael E

    2012-05-01

    The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency "spectra" to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways. PMID:22318994

  2. Human gene copy number spectra analysis in congenital heart malformations

    PubMed Central

    Mahnke, Donna K.; Struble, Craig A.; Tuffnell, Maureen E.; Stamm, Karl D.; Hidestrand, Mats; Harris, Susan E.; Goetsch, Mary A.; Simpson, Pippa M.; Bick, David P.; Broeckel, Ulrich; Pelech, Andrew N.; Tweddell, James S.; Mitchell, Michael E.

    2012-01-01

    The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways. PMID:22318994

  3. The human subject: an integrative animal model for 21st century heart failure research

    PubMed Central

    Chandrasekera, P Charukeshi; Pippin, John J

    2015-01-01

    Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21st century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research. PMID:26550463

  4. Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure

    PubMed Central

    Trenor, Beatriz; Cardona, Karen; Gomez, Juan F.; Rajamani, Sridharan; Ferrero, Jose M.; Belardinelli, Luiz; Saiz, Javier

    2012-01-01

    Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na+ current (INaL) is relevant and is currently under investigation. In this study we examined the role of INaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of INaL. A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for INaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca2+ transient. A mechanistic investigation of intracellular Na+ accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na+/K+ pump, the Na+/Ca2+ exchanger and INaL. The results of the simulations also showed that in failing myocytes, the enhancement of INaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the INaL prolong APD and alter Ca2+ transient facilitating the development of early afterdepolarizations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca2+]i homeostasis of failing myocytes. PMID:22427860

  5. Embryonic stem cell transplantation: promise and progress in the treatment of heart disease.

    PubMed

    Zhang, Feixiong; Pasumarthi, Kishore B S

    2008-01-01

    neither practical nor ethical to test the potential of fetal cardiomyocytes in clinical trials, embryonic stem (ES) cells serve as a novel source for generation of unlimited quantities of cardiomyocytes for myocardial repair. The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising. However, multiple hurdles need to be crossed before the potential benefits of ES cells can be translated to the clinic. In this review, we summarize the current knowledge of cardiomyocyte derivation and enrichment from ES-cell cultures and provide a brief survey of factors increasing cardiomyogenic induction in both mouse and human ES cultures. Subsequently, we summarize the current state of research using mouse and human ES cells for the treatment of heart disease in various experimental models. Furthermore, we discuss the challenges that need to be overcome prior to the successful clinical utilization of ES-derived cardiomyocytes for the treatment of end-stage heart disease. While we are optimistic that the researchers in this field will sail across the hurdles, we also suggest that a more cautious approach to the validation of ES cardiomyocytes in experimental models would certainly prevent future disappointments, as seen with skeletal myoblast studies. PMID:18998754

  6. ATP flux through creatine kinase in the normal, stressed, and failing human heart.

    PubMed

    Weiss, Robert G; Gerstenblith, Gary; Bottomley, Paul A

    2005-01-18

    The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is "energy starved" has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 +/- 0.6 vs. 3.2 +/- 0.9 micromol/g of wet weight per sec, P <0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and/or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness. PMID:15647364

  7. ATP flux through creatine kinase in the normal, stressed, and failing human heart

    PubMed Central

    Weiss, Robert G.; Gerstenblith, Gary; Bottomley, Paul A.

    2005-01-01

    The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is “energy starved” has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 ± 0.6 vs. 3.2 ± 0.9 μmol/g of wet weight per sec, P < 0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and/or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness. PMID:15647364

  8. Stem cell therapy for heart failure: Ensuring regenerative proficiency.

    PubMed

    Terzic, Andre; Behfar, Atta

    2016-07-01

    Patient-derived stem cells enable promising regenerative strategies, but display heterogenous cardiac reparative proficiency, leading to unpredictable therapeutic outcomes impeding practice adoption. Means to establish and certify the regenerative potency of emerging biotherapies are thus warranted. In this era of clinomics, deconvolution of variant cytoreparative performance in clinical trials offers an unprecedented opportunity to map pathways that segregate regenerative from non-regenerative states informing the evolution of cardio-regenerative quality systems. A maiden example of this approach is cardiopoiesis-mediated lineage specification developed to ensure regenerative performance. Successfully tested in pre-clinical and early clinical studies, the safety and efficacy of the cardiopoietic stem cell phenotype is undergoing validation in pivotal trials for chronic ischemic cardiomyopathy offering the prospect of a next-generation regenerative solution for heart failure. PMID:27020904

  9. Heart attack

    MedlinePlus

    ... infarction; Non-ST-elevation myocardial infarction; NSTEMI; CAD-heart attack; Coronary artery disease-heart attack ... made up of cholesterol and other cells. A heart attack may occur when: A tear in the ...

  10. Visualization of Fiber Structurein the Left and Right Ventricleof a Human Heart

    SciTech Connect

    Rohmer, Damien; Sitek, Arkadiusz; Gullberg, Grant T.

    2006-07-12

    The human heart is composed of a helical network of musclefibers. Anisotropic least squares filtering followed by fiber trackingtechniques were applied to Diffusion Tensor Magnetic Resonance Imaging(DTMRI) data of the excised human heart. The fiber configuration wasvisualized by using thin tubes to increase 3-dimensional visualperception of the complex structure. All visualizations were performedusing the high-quality ray-tracing software POV-Ray. The fibers are shownwithin the left and right ventricles. Both ventricles exhibit similarfiber architecture and some bundles of fibers are shown linking right andleft ventricles on the posterior region of the heart.

  11. Minimal changes in heart rate of incubating American Oystercatchers (Haematopus palliatus) in response to human activity

    USGS Publications Warehouse

    Borneman, Tracy E.; Rose, Eli T.; Simons, Theodore R.

    2014-01-01

    An organism's heart rate is commonly used as an indicator of physiological stress due to environmental stimuli. We used heart rate to monitor the physiological response of American Oystercatchers (Haematopus palliatus) to human activity in their nesting environment. We placed artificial eggs with embedded microphones in 42 oystercatcher nests to record the heart rate of incubating oystercatchers continuously for up to 27 days. We used continuous video and audio recordings collected simultaneously at the nests to relate physiological response of birds (heart rate) to various types of human activity. We observed military and civilian aircraft, off-road vehicles, and pedestrians around nests. With the exception of high-speed, low-altitude military overflights, we found little evidence that oystercatcher heart rates were influenced by most types of human activity. The low-altitude flights were the only human activity to significantly increase average heart rates of incubating oystercatchers (12% above baseline). Although statistically significant, we do not consider the increase in heart rate during high-speed, low-altitude military overflights to be of biological significance. This noninvasive technique may be appropriate for other studies of stress in nesting birds.

  12. Stem cells for the treatment of heart failure.

    PubMed

    Menasché, P; Vanneaux, V

    2016-01-01

    Stem cell-based therapy is currently tested in several trials of chronic heart failure. The main question is to determine how its implementation could be extended to standard clinical practice. To answer this question, it is helpful to capitalize on the three main lessons drawn from the accumulated experience, both in the laboratory and in the clinics. Regarding the cell type, the best outcomes seem to be achieved by cells the phenotype of which closely matches that of the target tissue. This argues in favor of the use of cardiac-committed cells among which the pluripotent stem cell-derived cardiac progeny is particularly attractive. Regarding the mechanism of action, there has been a major paradigm shift whereby cells are no longer expected to structurally integrate within the recipient myocardium but rather to release biomolecules that foster endogenous repair processes. This implies to focus on early cell retention, rather than on sustained cell survival, so that the cells reside in the target tissue long enough and in sufficient amounts to deliver the factors underpinning their action. Biomaterials are here critical adjuncts to optimize this residency time. Furthermore, the paracrine hypothesis gives more flexibility for using allogeneic cells in that targeting an only transient engraftment requires to delay, and no longer to avoid, rejection, which, in turn, should simplify immunomodulation regimens. Regarding manufacturing, a broad dissemination of cardiac cell therapy requires the development of automated systems allowing to yield highly reproducible cell products. This further emphasizes the interest of allogeneic cells because of their suitability for industrially-relevant and cost-effective scale-up and quality control procedures. At the end, definite confirmation that the effects of cells can be recapitulated by the factors they secrete could lead to acellular therapies whereby factors alone (possibly clustered in extracellular vesicles) would be

  13. Endothelial cells regulate neural crest and second heart field morphogenesis

    PubMed Central

    Milgrom-Hoffman, Michal; Michailovici, Inbal; Ferrara, Napoleone; Zelzer, Elazar; Tzahor, Eldad

    2014-01-01

    ABSTRACT Cardiac and craniofacial developmental programs are intricately linked during early embryogenesis, which is also reflected by a high frequency of birth defects affecting both regions. The molecular nature of the crosstalk between mesoderm and neural crest progenitors and the involvement of endothelial cells within the cardio–craniofacial field are largely unclear. Here we show in the mouse that genetic ablation of vascular endothelial growth factor receptor 2 (Flk1) in the mesoderm results in early embryonic lethality, severe deformation of the cardio–craniofacial field, lack of endothelial cells and a poorly formed vascular system. We provide evidence that endothelial cells are required for migration and survival of cranial neural crest cells and consequently for the deployment of second heart field progenitors into the cardiac outflow tract. Insights into the molecular mechanisms reveal marked reduction in Transforming growth factor beta 1 (Tgfb1) along with changes in the extracellular matrix (ECM) composition. Our collective findings in both mouse and avian models suggest that endothelial cells coordinate cardio–craniofacial morphogenesis, in part via a conserved signaling circuit regulating ECM remodeling by Tgfb1. PMID:24996922

  14. Total lymphatic irradiation and bone marrow in human heart transplantation

    SciTech Connect

    Kahn, D.R.; Hong, R.; Greenberg, A.J.; Gilbert, E.F.; Dacumos, G.C.; Dufek, J.H.

    1984-08-01

    Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and donor bone marrow can produce specific tolerance to donor antigens and allow easy control of rejection, but infection is still a major problem. We describe a new technique of administering TLI with early reduction of prednisone that may help this problem.

  15. Application of Laser Doppler Vibrometery for human heart auscultation.

    PubMed

    Koegelenberg, S; Scheffer, C; Blanckenberg, M M; Doubell, A F

    2014-01-01

    In this study the potential of a Laser Doppler Vibrometer (LDV) was tested as a non-contact sensor for the classification of heart sounds. Of the twenty participants recorded using the LDV, five presented with Aortic Stenosis (AS), three were healthy and twelve presented with other pathologies. The recorded heart sounds were denoised and segmented using a combination of the Electrocardiogram (ECG) data and the complexity of the signal. Frequency domain features were extracted from the segmented heart sound cycles and used to train a K-nearest neighbor classifier. Due to the small number of participants, the classifier could not be trained to differentiate between normal and abnormal participants, but could successfully distinguish between participants who presented with AS and those who did not. A sensitivity of 80 % and a specificity of 100 % were achieved a test dataset. PMID:25570986

  16. Stem cell implantation in ischemic mouse heart: a high-resolution magnetic resonance imaging investigation.

    PubMed

    Küstermann, Ekkehard; Roell, Wilhelm; Breitbach, Martin; Wecker, Stefan; Wiedermann, Dirk; Buehrle, Christian; Welz, Armin; Hescheler, Juergen; Fleischmann, Bernd K; Hoehn, Mathias

    2005-10-01

    Advances in the biology of stem cells have evoked great interest in cell replacement therapies for the regeneration of heart tissue after myocardial infarction. However, results from human trials are controversial, since the destination of the injected cells, their engraftment and their long-term fate have remained unclear. Here we investigate whether transplanted cells can be identified in the intact and lesioned murine myocardium employing high-resolution MRI. Cardiac progenitor cells, expressing the enhanced green fluorescent protein (EGFP), were labeled with ultra-small paramagnetic iron-oxide (USPIO) nanoparticles and transplanted into the intact or injured myocardium of mice. Their precise location was determined with high-resolution MRI and compared with histological tissue sections, stained with Prussian blue for iron content. These experiments showed that iron nanoparticle-loaded cells could be identified at high resolution in the mouse heart. However, ischemic myocardium (after cryoinjury or left coronary artery ligation) was characterized by a signal attenuation similar to that induced by USPIO-labeled cells in T2*-weighted MR images, making detection of labeled stem cells in this area by T2*-sensitive contrast rather difficult. In animals with myocardial injury only, the signal attenuated areas were of the same size in proton density- and T2*-weighted MR images. In injured animals also receiving labeled cells the lesioned area appeared larger in T2*--than in proton density-weighted MR images. This sequence-dependent lesion size change is due to the increased signal loss caused by the iron oxide nanoparticles, most sensitively detectable in the T2*-sensitive images. Thus, using the novel combination of these two parameter weightings, USPIO-labeled cells can be detected at high resolution in ischemic myocardium. PMID:15948224

  17. Resident c-kit(+) cells in the heart are not cardiac stem cells.

    PubMed

    Sultana, Nishat; Zhang, Lu; Yan, Jianyun; Chen, Jiqiu; Cai, Weibin; Razzaque, Shegufta; Jeong, Dongtak; Sheng, Wei; Bu, Lei; Xu, Mingjiang; Huang, Guo-Ying; Hajjar, Roger J; Zhou, Bin; Moon, Anne; Cai, Chen-Leng

    2015-01-01

    Identifying a bona fide population of cardiac stem cells (CSCs) is a critical step for developing cell-based therapies for heart failure patients. Previously, cardiac c-kit(+) cells were reported to be CSCs with a potential to become myocardial, endothelial and smooth muscle cells in vitro and after cardiac injury. Here we provide further insights into the nature of cardiac c-kit(+) cells. By targeting the c-kit locus with multiple reporter genes in mice, we find that c-kit expression rarely co-localizes with the expression of the cardiac progenitor and myogenic marker Nkx2.5, or that of the myocardial marker, cardiac troponin T (cTnT). Instead, c-kit predominantly labels a cardiac endothelial cell population in developing and adult hearts. After acute cardiac injury, c-kit(+) cells retain their endothelial identity and do not become myogenic progenitors or cardiomyocytes. Thus, our work strongly suggests that c-kit(+) cells in the murine heart are endothelial cells and not CSCs. PMID:26515110

  18. Resident c-kit+ cells in the heart are not cardiac stem cells

    PubMed Central

    Sultana, Nishat; Zhang, Lu; Yan, Jianyun; Chen, Jiqiu; Cai, Weibin; Razzaque, Shegufta; Jeong, Dongtak; Sheng, Wei; Bu, Lei; Xu, Mingjiang; Huang, Guo-Ying; Hajjar, Roger J.; Zhou, Bin; Moon, Anne; Cai, Chen-Leng

    2015-01-01

    Identifying a bona fide population of cardiac stem cells (CSCs) is a critical step for developing cell-based therapies for heart failure patients. Previously, cardiac c-kit+ cells were reported to be CSCs with a potential to become myocardial, endothelial and smooth muscle cells in vitro and after cardiac injury. Here we provide further insights into the nature of cardiac c-kit+ cells. By targeting the c-kit locus with multiple reporter genes in mice, we find that c-kit expression rarely co-localizes with the expression of the cardiac progenitor and myogenic marker Nkx2.5, or that of the myocardial marker, cardiac troponin T (cTnT). Instead, c-kit predominantly labels a cardiac endothelial cell population in developing and adult hearts. After acute cardiac injury, c-kit+ cells retain their endothelial identity and do not become myogenic progenitors or cardiomyocytes. Thus, our work strongly suggests that c-kit+ cells in the murine heart are endothelial cells and not CSCs. PMID:26515110

  19. Bioengineering and Stem Cell Technology in the Treatment of Congenital Heart Disease

    PubMed Central

    Bosman, Alexis; Edel, Michael J.; Blue, Gillian; Dilley, Rodney J.; Harvey, Richard P.; Winlaw, David S.

    2015-01-01

    Congenital heart disease places a significant burden on the individual, family and community despite significant advances in our understanding of aetiology and treatment. Early research in ischaemic heart disease has paved the way for stem cell technology and bioengineering, which promises to improve both structural and functional aspects of disease. Stem cell therapy has demonstrated significant improvements in cardiac function in adults with ischaemic heart disease. This finding, together with promising case studies in the paediatric setting, demonstrates the potential for this treatment in congenital heart disease. Furthermore, induced pluripotent stems cell technology, provides a unique opportunity to address aetiological, as well as therapeutic, aspects of disease. PMID:26239354

  20. Heart Rate and Heart Rate Variability in Dairy Cows with Different Temperament and Behavioural Reactivity to Humans

    PubMed Central

    Tőzsér, János; Szenci, Ottó; Póti, Péter; Pajor, Ferenc

    2015-01-01

    From the 1990s, extensive research was started on the physiological aspects of individual traits in animals. Previous research has established two extreme (proactive and reactive) coping styles in several animal species, but the means of reactivity with the autonomic nervous system (ANS) activity has not yet been investigated in cattle. The aim of this study was the characterization of cardiac autonomic activity under different conditions in cows with different individual characteristics. For this purpose, we investigated heart rate and ANS-related heart rate variability (HRV) parameters of dairy cows (N = 282) on smaller- and larger-scale farms grouped by (1) temperament and (2) behavioural reactivity to humans (BRH). Animals with high BRH scores were defined as impulsive, while animals with low BRH scores were defined as reserved. Cardiac parameters were calculated for undisturbed lying (baseline) and for milking bouts, the latter with the presence of an unfamiliar person (stressful situation). Sympathetic tone was higher, while vagal activity was lower in temperamental cows than in calm animals during rest both on smaller- and larger-scale farms. During milking, HRV parameters were indicative of a higher sympathetic and a lower vagal activity of temperamental cows as compared to calm ones in farms of both sizes. Basal heart rate did not differ between BRH groups either on smaller- or larger-scale farms. Differences between basal ANS activity of impulsive and reserved cows reflected a higher resting vagal and lower sympathetic activity of reserved animals compared to impulsive ones both on smaller- and larger-scale farms. There was no difference either in heart rate or in HRV parameters between groups during milking neither in smaller- nor in larger-scale farms. These two groupings allowed to draw possible parallels between personality and cardiac autonomic activity during both rest and milking in dairy cows. Heart rate and HRV seem to be useful for

  1. Stem Cells and Progenitor Cells for Tissue-Engineered Solutions to Congenital Heart Defects

    PubMed Central

    Gao, Yang; Jacot, Jeffrey G

    2015-01-01

    Synthetic patches and fixed grafts currently used in the repair of congenital heart defects are nonliving, noncontractile, and not electrically responsive, leading to increased risk of complication, reoperation, and sudden cardiac death. Studies suggest that tissue-engineered patches made from living, functional cells could grow with the patient, facilitate healing, and help recover cardiac function. In this paper, we review the research into possible sources of cardiomyocytes and other cardiac cells, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, adipose-derived stem cells, umbilical cord blood cells, amniotic fluid-derived stem cells, and cardiac progenitor cells. Each cell source has advantages, but also has technical hurdles to overcome, including heterogeneity, functional maturity, immunogenicity, and pathogenicity. Additionally, biomaterials used as patch materials will need to attract and support desired cells and induce minimal immune responses. PMID:26379417

  2. Encounters with the Human Heart: An Interview with John Stone.

    ERIC Educational Resources Information Center

    Flynn, Dale Bachman

    1995-01-01

    Interviews Dale Bachman Flynn, professor of cardiology and dean of admissions and student affairs at Emory University School of Medicine, about his "In the Country of Hearts," a collection of stories about his medical practice. Discusses Flynn's personal life; his life-long practice of writing; and his interest in the intersections among medicine,…

  3. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts.

    PubMed Central

    Gulizia, J. M.; Kandolf, R.; Kendall, T. J.; Thieszen, S. L.; Wilson, J. E.; Radio, S. J.; Costanzo, M. R.; Winters, G. L.; Miller, L. L.; McManus, B. M.

    1995-01-01

    In heart transplantation, long-term engraftment success is severely limited by the rapid development of obliterative disease of the coronary arteries. Data from various groups have been suggestive of a pathogenetic role of herpesviruses, particularly human cytomegalovirus, in accelerated allograft coronary artery disease; however, results are not yet conclusive. This study examines the hypothesis that human cytomegalovirus infection of allograft tissues is related pathogenetically and directly to accelerated coronary artery disease. Using in situ DNA hybridization and polymerase chain reaction, we examined particular coronary artery segments from 41 human heart allografts (ranging from 4 days to greater than 4 years after transplantation; mean, 457 days) and 22 donor age- and gender-comparable, coronary site-matched trauma victims for presence of human cytomegalovirus DNA. Human cytomegalovirus genome was detected in 8 of 41 (19.5%) allografts and in 1 of 22 (4.5%) control hearts. This difference in positivity was not statistically significant (P = 0.10). In the human cytomegalovirus-positive hearts, viral genome was localized to perivascular myocardium or coronary artery media or adventitia. Human cytomegalovirus genome was not detected in arterial intima of any allograft or control heart, although human cytomegalovirus genome was readily identified within intima of small pulmonary arteries from lung tissue with human cytomegalovirus pneumonitis. By statistical analyses, the presence of human cytomegalovirus genome was not associated with the nature or digitized extent of transplant arteriopathy, evidence of rejection, allograft recipient or donor serological data suggestive of human cytomegalovirus infection, duration of allograft implantation, or causes of death or retransplantation. Thus, our data indicate a low frequency of detectable human cytomegalovirus genome in accelerated coronary artery disease and do not support a direct role for human cytomegalovirus

  4. Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.

    PubMed Central

    Zisman, L S; Abraham, W T; Meixell, G E; Vamvakias, B N; Quaife, R A; Lowes, B D; Roden, R L; Peacock, S J; Groves, B M; Raynolds, M V

    1995-01-01

    It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE. Images PMID:7657820

  5. A nondenatured, noncrosslinked collagen matrix to deliver stem cells to the heart

    PubMed Central

    Kouris, Nicholas A; Squirrell, Jayne M; Jung, Jangwook P; Pehlke, Carolyn A; Hacker, Timothy; Eliceiri, Kevin W; Ogle, Brenda M

    2011-01-01

    Aims Stem cell transplantation holds promise as a therapeutic approach for the repair of damaged myocardial tissue. One challenge of this approach is efficient delivery and long-term retention of the stem cells. Although several synthetic and natural biomaterials have been developed for this purpose, the ideal formulation has yet to be identified. Materials & methods Here we investigate the utility of a nondenatured, noncrosslinked, commercially available natural biomaterial (TissueMend® [TEI Biosciences, Boston, MA, USA]) for delivery of human mesenchymal stem cells (MSCs) to the murine heart. Results We found that MSCs attached, proliferated and migrated within and out of the TissueMend matrix in vitro. Human MSCs delivered to damaged murine myocardium via the matrix (2.3 × 104 ± 0.8 × 104 CD73+ cells/matrix) were maintained in vivo for 3 weeks and underwent at least three population doublings during that period (21.9 × 104 ± 14.4 × 104 CD73+ cells/matrix). In addition, collagen within the TissueMend matrix could be remodeled by MSCs in vivo, resulting in a significant decrease in the coefficient of alignment of fibers (0.12 ± 0.12) compared with the matrix alone (0.28 ± 0.07), and the MSCs were capable of migrating out of the matrix and into the host tissue. Conclusion Thus, TissueMend matrix offers a commercially available, biocompatible and malleable vehicle for the delivery and retention of stem cells to the heart. PMID:21916593

  6. Age-Dependent Changes in Geometry, Tissue Composition and Mechanical Properties of Fetal to Adult Cryopreserved Human Heart Valves

    PubMed Central

    van Geemen, Daphne; Soares, Ana L. F.; Oomen, Pim J. A.; Driessen-Mol, Anita; Janssen-van den Broek, Marloes W. J. T.; van den Bogaerdt, Antoon J.; Bogers, Ad J. J. C.; Goumans, Marie-José T. H.; Baaijens, Frank P. T.; Bouten, Carlijn V. C.

    2016-01-01

    There is limited information about age-specific structural and functional properties of human heart valves, while this information is key to the development and evaluation of living valve replacements for pediatric and adolescent patients. Here, we present an extended data set of structure-function properties of cryopreserved human pulmonary and aortic heart valves, providing age-specific information for living valve replacements. Tissue composition, morphology, mechanical properties, and maturation of leaflets from 16 pairs of structurally unaffected aortic and pulmonary valves of human donors (fetal-53 years) were analyzed. Interestingly, no major differences were observed between the aortic and pulmonary valves. Valve annulus and leaflet dimensions increase throughout life. The typical three-layered leaflet structure is present before birth, but becomes more distinct with age. After birth, cell numbers decrease rapidly, while remaining cells obtain a quiescent phenotype and reside in the ventricularis and spongiosa. With age and maturation–but more pronounced in aortic valves–the matrix shows an increasing amount of collagen and collagen cross-links and a reduction in glycosaminoglycans. These matrix changes correlate with increasing leaflet stiffness with age. Our data provide a new and comprehensive overview of the changes of structure-function properties of fetal to adult human semilunar heart valves that can be used to evaluate and optimize future therapies, such as tissue engineering of heart valves. Changing hemodynamic conditions with age can explain initial changes in matrix composition and consequent mechanical properties, but cannot explain the ongoing changes in valve dimensions and matrix composition at older age. PMID:26867221

  7. Stem cells for the treatment of heart failure.

    PubMed

    Kearns-Jonker, Mary; Dai, Wangde; Kloner, Robert A

    2010-08-01

    An increasing number of clinical trials are enrolling patients in studies designed to examine the safety and efficacy of autologous stem cells for cardiac repair. Recent reports suggest that most patients receiving autologous cell-based therapies after myocardial infarction, or as a treatment for ischemic cardiomyopathy, benefit from a modest increase in global left ventricular function. Despite a significant amount of variability in efficacy reported among different treatment centers, most studies demonstrate an improvement in the ejection fraction that ranges between 2 and 7% after stem cell treatment. The validation of long-term clinical benefit will first require well-controlled studies in appropriate preclinical animal models to develop procedures that enhance cell retention, integration and viability. This review highlights new developments that will benefit long-term cardiomyocyte survival and function of human cardiovascular progenitors as a prelude to achieving clinically significant outcomes in stem cell therapies for cardiac repair. PMID:20677094

  8. Identification of cardiac-related circulating microRNA profile in human chronic heart failure

    PubMed Central

    Li, Huaping; Fan, Jiahui; Yin, Zhongwei; Wang, Feng; Chen, Chen; Wang, Dao Wen

    2016-01-01

    Background During chronic heart failure, levels of circulating miRNAs endued with characteristics of diseased cells could be identified as biomarkers. In this study, we sought to identify cardiac-related circulating miRNAs as biomarkers of failing heart. Methods Total RNA of plasma and heart samples was extracted from 10 normal controls and 14 patients with chronic heart failure. Microarray was applied for miRNA profiles. Validation and organ/tissue distribution analysis was performed by qRT-PCR. In addition, bioinformatics analysis was performed to understand the critical roles of these cardiac-related circulating miRNAs in heart failure. Results Results showed that levels of more than half of the miRNAs dysregulated in heart failed to show any differences in plasma. Meanwhile, more than 90% of the miRNAs dysregulated in plasma remained stable in heart. Four cardiac fibroblast-derived miRNAs (miR-660-3p, miR-665, miR-1285-3p and miR-4491) were found significantly upregulated in heart and plasma during heart failure. These 4 miRNAs strongly discriminated patients from controls, and 3 of them showed significant correlations with LVEF. Conclusions This study provides global profiles of miRNAs changes in plasma and failing heart, and using a circulation-tissue miRNA profiling comparison model, we successfully identify 3 cardiac-related circulating miRNAs as potential biomarkers for diagnosis of heart failure. PMID:26683101

  9. Ca2+ cycling in heart cells from ground squirrels: adaptive strategies for intracellular Ca2+ homeostasis.

    PubMed

    Li, Xiao-Chen; Wei, Ling; Zhang, Guang-Qin; Bai, Zai-Ling; Hu, Ying-Ying; Zhou, Peng; Bai, Shu-Hua; Chai, Zhen; Lakatta, Edward G; Hao, Xue-Mei; Wang, Shi-Qiang

    2011-01-01

    Heart tissues from hibernating mammals, such as ground squirrels, are able to endure hypothermia, hypoxia and other extreme insulting factors that are fatal for human and nonhibernating mammals. This study was designed to understand adaptive mechanisms involved in intracellular Ca(2+) homeostasis in cardiomyocytes from the mammalian hibernator, ground squirrel, compared to rat. Electrophysiological and confocal imaging experiments showed that the voltage-dependence of L-type Ca(2+) current (I(Ca)) was shifted to higher potentials in ventricular myocytes from ground squirrels vs. rats. The elevated threshold of I(Ca) did not compromise the Ca(2+)-induced Ca(2+) release, because a higher depolarization rate and a longer duration of action potential compensated the voltage shift of I(Ca). Both the caffeine-sensitive and caffeine-resistant components of cytosolic Ca(2+) removal were more rapid in ground squirrels. Ca(2+) sparks in ground squirrels exhibited larger amplitude/size and much lower frequency than in rats. Due to the high I(Ca) threshold, low SR Ca(2+) leak and rapid cytosolic Ca(2+) clearance, heart cells from ground squirrels exhibited better capability in maintaining intracellular Ca(2+) homeostasis than those from rats and other nonhibernating mammals. These findings not only reveal adaptive mechanisms of hibernation, but also provide novel strategies against Ca(2+) overload-related heart diseases. PMID:21935466

  10. Electron microscopic stereology of capillary endothelial cells and cardiomyocytes in artificially arrested canine hearts.

    PubMed

    Schmiedl, A.; Schnabel, P. A.; Marten, K.; Kausch Blecken Von Schmeling, H.; Richter, J.

    1999-12-01

    In open heart surgery and transplantation, sufficient structural preservation of the myocardium immediately following cardioplegic arrest is a precondition for overcoming ischemia and for resumption of postischemic function. Therefore, we compared the protective effect of three clinically applied cardioplegic solutions with fibrillating and beating hearts using structural criteria. Left ventricular samples were taken from (1) beating, or (2) fibrillating or arrested hearts following coronary perfu-sion with (3) St. Thomas' Hospital solution, (4) histidine tryptophane ketoglutalate (HTK) (Custodiol), or (5) University of Wisconsin (UW) solution and fixed by immersion. Ultrastructural differences in the swelling of capillary endothelial cells and myocytes were quantitatively evaluated using stereological methods. Endothelial cells were somewhat more swollen after St. Thomas perfusion than those in beating and fibrillating hearts. HTK-arrested hearts showed significantly lower values for cellular edema than beating hearts. UW perfusion resulted in the (significantly) lowest degree of endothelial cell edema. Edematous changes in myocytes were significantly greater in St. Thomas-arrested hearts than in UW- or HTK-arrested hearts. Cardiomyocyte edema in beating and fibrillating hearts was comparable to that in St. Thomas-perfused hearts. Thus, the stereol-ogical analysis revealed significant differences between cardioplegic solutions in structural preservation of myocardial ultrastructure. PMID:11810439

  11. Carbon Nanotubes and Human Cells?

    ERIC Educational Resources Information Center

    King, G. Angela

    2005-01-01

    Single-walled carbon nanotubes that were chemically altered to be water soluble are shown to enter fibroblasts, T cells, and HL60 cells. Nanoparticles adversely affect immortalized HaCaT human keratinocyte cultures, indicating that they may enter cells.

  12. Regenerative Medicine for the Heart: Perspectives on Stem-Cell Therapy

    PubMed Central

    Cho, Gun-Sik; Fernandez, Laviel

    2014-01-01

    Abstract Significance: Despite decades of progress in cardiovascular biology and medicine, heart disease remains the leading cause of death, and there is no cure for the failing heart. Since heart failure is mostly caused by loss or dysfunction of cardiomyocytes (CMs), replacing dead or damaged CMs with new CMs might be an ideal way to reverse the disease. However, the adult heart is composed mainly of terminally differentiated CMs that have no significant self-regeneration capacity. Recent Advances: Stem cells have tremendous regenerative potential and, thus, current cardiac regenerative research has focused on developing stem cell sources to repair damaged myocardium. Critical Issues: In this review, we examine the potential sources of cells that could be used for heart therapies, including embryonic stem cells and induced pluripotent stem cells, as well as alternative methods for activating the endogenous regenerative mechanisms of the heart via transdifferentiation and cell reprogramming. We also discuss the current state of knowledge of cell purification, delivery, and retention. Future Directions: Efforts are underway to improve the current stem cell strategies and methodologies, which will accelerate the development of innovative stem-cell therapies for heart regeneration. Antioxid. Redox Signal. 21, 2018–2031. PMID:25133793

  13. Formation of sulphidopeptide-leukotrienes by cell-cell interaction causes coronary vasoconstriction in isolated, cell-perfused heart of rabbit.

    PubMed Central

    Sala, A.; Rossoni, G.; Buccellati, C.; Berti, F.; Folco, G.; Maclouf, J.

    1993-01-01

    1. We have studied the transcellular biosynthesis of bioactive leukotrienes (LTs), generated upon blood cell-vascular wall interactions and their functional consequences, in the spontaneously beating, cell-perfused, heart of the rabbit. Rabbit isolated hearts were perfused under recirculating conditions (50 ml) with 5 x 10(6) cells of unpurified (buffy coat) or purified human neutrophils (PMNL), and challenged with 0.5 microM A23187 for 30 min. Coronary perfusion pressure (CPP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and left ventricular pressure (LVP) were monitored continuously. Leukotriene formation was measured by specific enzyme-immunoassay and confirmed by reversed phase h.p.l.c. and u.v. spectral analysis. 2. Basal CPP values averaged 44 +/- 1.4 mmHg; A23187 triggered a marked increase in CPP both in the presence of buffy coat cells (+100% above basal) and PMNL (+270% above basal); the latter change in CPP was accompanied by a rise in LVEDP (+138% above basal). 3. The increase in CPP was preceded by a statistically significant rise in iLTC4-D4 concentration in the circulating buffer. Pretreatment with two structurally unrelated LTD4 receptor antagonists, LY171883 and SKF104353 (10 microM), fully prevented the increase in CPP and LVEDP. A similar protection was also observed when the rabbit heart was perfused with PMNL that had been pretreated with MK886 (1 microM), a potent inhibitor of leukotriene biosynthesis. 4. The increased coronary tone was accompanied by a marked release of lactate dehydrogenase (LDH), a marker of ischaemic damage; pretreatment of the heart with the LTD4 receptor antagonists as well as of the PMNL with MK886 resulted in a complete suppression of LDH activity release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8298810

  14. Dynamic Heterogeneity of the Heart Valve Interstitial Cell Population in Mitral Valve Health and Disease

    PubMed Central

    Sauls, Kimberly; Koenig, Sara N.; Anstine, Lindsey J.; Garg, Vidu; Norris, Russell A.; Lincoln, Joy

    2015-01-01

    The heart valve interstitial cell (VIC) population is dynamic and thought to mediate lay down and maintenance of the tri-laminar extracellular matrix (ECM) structure within the developing and mature valve throughout life. Disturbances in the contribution and distribution of valve ECM components are detrimental to biomechanical function and associated with disease. This pathological process is associated with activation of resident VICs that in the absence of disease reside as quiescent cells. While these paradigms have been long standing, characterization of this abundant and ever-changing valve cell population is incomplete. Here we examine the expression pattern of Smooth muscle α-actin, Periostin, Twist1 and Vimentin in cultured VICs, heart valves from healthy embryonic, postnatal and adult mice, as well as mature valves from human patients and established mouse models of disease. We show that the VIC population is highly heterogeneous and phenotypes are dependent on age, species, location, and disease state. Furthermore, we identify phenotypic diversity across common models of mitral valve disease. These studies significantly contribute to characterizing the VIC population in health and disease and provide insights into the cellular dynamics that maintain valve structure in healthy adults and mediate pathologic remodeling in disease states. PMID:26527432

  15. An elastomeric patch derived from poly(glycerol sebacate) for delivery of embryonic stem cells to the heart.

    PubMed

    Chen, Qi-Zhi; Ishii, Hikaru; Thouas, George A; Lyon, Alexander R; Wright, Jamie S; Blaker, Jonny J; Chrzanowski, Wojciech; Boccaccini, Aldo R; Ali, Nadire N; Knowles, Jonathan C; Harding, Siân E

    2010-05-01

    We hypothesize that a combinatorial approach of ventricle constraint and stem cell therapy would offer a greater benefit for the treatment of heart failure than either strategy alone. A heart patch would serve two therapeutic purposes: biomechanical support and cell delivery. In this study, we describe a hybrid heart patch engineered from a synthetic elastomer, poly(glycerol sebacate) (PGS), supplemented with cardiomyocytes differentiated from human embryonic stem cells (hESCs). In line with two therapeutically relevant considerations, i.e. biocompatibility and cell delivery efficiency, the PGS was (a) pre-conditioned in culture medium for 6 days, and (b) prepared without gelatin coatings to facilitate detachment and delivery of cardiomyocytes following patch implantation. Following pre-conditioning under physiological conditions, the PGS patch material without gelatin coating was found to satisfactorily support cardiomyocyte viability and attachment, with active cell beating for periods of longer than 3 months until interrupted. Dynamic culture studies revealed that cells detached more efficiently from the uncoated surface of PGS than from gelatin-coated PGS. No significant differences were detected between the beating rates of human embryonic stem cell-derived cardiomyocytes on tissue culture plate and the pre-conditioned and gelatin-uncoated PGS. PGS patches sutured over the left ventricle of rats in vivo remained intact over a 2 week period without any deleterious effects on ventricular function. We conclude that PGS is a suitable biomaterial for stem cell-based regeneration strategies to restore cardiomyocyte function, and the hybrid heart patch engineered under optimal conditions would be a promising support device for the cardiac repair. PMID:20153041

  16. Representing variability and transmural differences in a model of human heart failure.

    PubMed

    Elshrif, Mohamed M; Shi, Pengcheng; Cherry, Elizabeth M

    2015-07-01

    During heart failure (HF) at the cellular level, the electrophysiological properties of single myocytes get remodeled, which can trigger the occurrence of ventricular arrhythmias that could be manifested in many forms such as early afterdepolarizations (EADs) and alternans (ALTs). In this paper, based on experimentally observed human HF data, specific ionic and exchanger current strengths are modified from a recently developed human ventricular cell model: the O'Hara-Virág-Varró-Rudy (OVVR) model. A new transmural HF-OVVR model is developed that incorporates HF changes and variability of the observed remodeling. This new heterogeneous HF-OVVR model is able to replicate many of the failing action potential (AP) properties and the dynamics of both [Ca(2+)]i and [Na(+)]i in accordance with experimental data. Moreover, it is able to generate EADs for different cell types and exhibits ALTs at modest pacing rate for transmural cell types. We have assessed the HF-OVVR model through the examination of the AP duration and the major ionic currents' rate dependence in single myocytes. The evaluation of the model comes from utilizing the steady-state (S-S) and S1-S2 restitution curves and from probing the accommodation of the HF-OVVR model to an abrupt change in cycle length. In addition, we have investigated the effect of chosen currents on the AP properties, such as blocking the slow sodium current to shorten the AP duration and suppress the EADs, and have found good agreement with experimental observations. This study should help elucidate arrhythmogenic mechanisms at the cellular level and predict unseen properties under HF conditions. In addition, this AP cell model might be useful for modeling and simulating HF at the tissue and organ levels. PMID:26068919

  17. A Novel Class of Human Cardiac Stem Cells

    PubMed Central

    Moccetti, Tiziano; Leri, Annarosa; Goichberg, Polina; Rota, Marcello; Anversa, Piero

    2015-01-01

    Following the recognition that hematopoietic stem cells improve the outcome of myocardial infarction in animal models, bone marrow mononuclear cells, CD34-positive cells and mesenchymal stromal cells have been introduced clinically. The intracoronary or intramyocardial injection of these cell classes has been shown to be safe and to produce a modest but significant enhancement in systolic function. However, the identification of resident cardiac stem cells in the human heart (hCSCs) has created great expectation concerning the potential implementation of this category of autologous cells for the management of the human disease. Although phase 1 clinical trials have been conducted with encouraging results, the search for the most powerful hCSC for myocardial regeneration is in its infancy. This manuscript discusses the efforts performed in our laboratory to characterize the critical biological variables that define the growth reserve of hCSCs. Based on the theory of the immortal DNA template, we propose that stem cells retaining the old DNA represent one of the most powerful cells for myocardial regeneration. Similarly, the expression of insulin-like growth factor-1 receptors in hCSCs recognizes a cell phenotype with superior replicating reserve. However, the impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the “mother” DNA underscores the clinical relevance of this hCSC class for the treatment of human heart failure. PMID:25807105

  18. Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart.

    PubMed

    Roche, Ellen T; Hastings, Conn L; Lewin, Sarah A; Shvartsman, Dmitry E; Brudno, Yevgeny; Vasilyev, Nikolay V; O'Brien, Fergal J; Walsh, Conor J; Duffy, Garry P; Mooney, David J

    2014-08-01

    Cell delivery to the infarcted heart has emerged as a promising therapy, but is limited by very low acute retention and engraftment of cells. The objective of this study was to compare a panel of biomaterials to evaluate if acute retention can be improved with a biomaterial carrier. Cells were quantified post-implantation in a rat myocardial infarct model in five groups (n = 7-8); saline injection (current clinical standard), two injectable hydrogels (alginate, chitosan/β-glycerophosphate (chitosan/ß-GP)) and two epicardial patches (alginate, collagen). Human mesenchymal stem cells (hMSCs) were delivered to the infarct border zone with each biomaterial. At 24 h, retained cells were quantified by fluorescence. All biomaterials produced superior fluorescence to saline control, with approximately 8- and 14-fold increases with alginate and chitosan/β-GP injectables, and 47 and 59-fold increases achieved with collagen and alginate patches, respectively. Immunohistochemical analysis qualitatively confirmed these findings. All four biomaterials retained 50-60% of cells that were present immediately following transplantation, compared to 10% for the saline control. In conclusion, all four biomaterials were demonstrated to more efficiently deliver and retain cells when compared to a saline control. Biomaterial-based delivery approaches show promise for future development of efficient in vivo delivery techniques. PMID:24862441

  19. Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart

    PubMed Central

    Lewin, Sarah A.; Shvartsman, Dmitry; Brudno, Yevgeny; Vasilyev, Nikolay V.; O'Brien, Fergal J.; Walsh, Conor J.; Duffy, Garry P.; Mooney, David J.

    2014-01-01

    Cell delivery to the infarcted heart has emerged as a promising therapy, but is limited by very low acute retention and engraftment of cells. The objective of the study was to compare a panel of biomaterials to evaluate if acute retention can be improved with a biomaterial carrier. Cells were quantified post-implantation in a rat myocardial infarct model in five groups (n=7–8); saline injection (current clinical standard), two injectable hydrogels (alginate, chitosan/β-glycerophosphate) and two epicardial patches (alginate, collagen). Human mesenchymal stem cells (hMSCs) were delivered to the infarct border zone with each biomaterial. At 24 hours, retained cells were quantified by fluorescence. All biomaterials had superior fluorescence to saline control, with 8 and 14-fold increases with alginate and chitosan/β-GP injectables, and 47 and 59-fold increases achieved with collagen and alginate patches, respectively. Immunohistochemical analysis qualitatively confirmed these findings. All four biomaterials retained 50–60% of cells that were present immediately following transplantation, compared to 10% for the saline control. In conclusion, all four injectable hydrogels and epicardial patches were demonstrated to more efficiently deliver and retain cells when compared to a saline control. Biomaterial-based delivery approaches show promise for future development of efficient in vivo delivery techniques. PMID:24862441

  20. Prolactin mediates effects of chronic psychological stress on induction of fibrofatty cells in the heart.

    PubMed

    Song, Jiangping; Wang, Mangyuan; Chen, Xiao; Liu, Li; Chen, Liang; Song, Zhizhao; Teng, Xiao; Xing, Yong; Chen, Kai; Zhao, Kun; Hou, Jianfeng; Yang, Pingchang

    2016-01-01

    Cardiocyte apoptosis plays an important role in the pathogenesis of heart diseases. The mechanism is unclear. It is reported that prolactin (PRL) is involved in cardiac disorders. This study aims to investigate the role of PRL in mediating the psychological stress-induced fibrofatty cell differentiation in the heart. In this study, BALB/c mice were treated with a 30-day restraint stress. The heart tissue was processed by paraffin embedding and hematoxylin and eosin. The expression of Sca1 in NIH3T3 cells was assessed by cell culture, flow cytometry and Western blotting. The results showed that chronic stress induced fibrofatty cells in the mouse heart and high serum PRL levels. The induction of fibrofatty cell was mimicked by administration with recombinant PRL. The stress also induced the expression of Sca1 in the mouse heart. Exposure of NIH3T3 cells (a fibroblast cell line) to PRL in the culture enhanced the expression of stem cell antigen-1 (Sca1), phosphorylation of signal transducer and activator of transcription 3 (STAT3) and expression of adipocyte-related protein molecules, including adiponectin, fatty acid binding protein (aP2), peroxisome proliferator activated receptor-g (PPARg) and CCAAT/enhancer binding protein (C/EBP)α, in the cells. We conclude that psychological stress-derived PRL induces fibroblasts to differentiate into fibrofatty cells in the heart. PMID:27158356

  1. Prolactin mediates effects of chronic psychological stress on induction of fibrofatty cells in the heart

    PubMed Central

    Song, Jiangping; Wang, Mangyuan; Chen, Xiao; Liu, Li; Chen, Liang; Song, Zhizhao; Teng, Xiao; Xing, Yong; Chen, Kai; Zhao, Kun; Hou, Jianfeng; Yang, Pingchang

    2016-01-01

    Cardiocyte apoptosis plays an important role in the pathogenesis of heart diseases. The mechanism is unclear. It is reported that prolactin (PRL) is involved in cardiac disorders. This study aims to investigate the role of PRL in mediating the psychological stress-induced fibrofatty cell differentiation in the heart. In this study, BALB/c mice were treated with a 30-day restraint stress. The heart tissue was processed by paraffin embedding and hematoxylin and eosin. The expression of Sca1 in NIH3T3 cells was assessed by cell culture, flow cytometry and Western blotting. The results showed that chronic stress induced fibrofatty cells in the mouse heart and high serum PRL levels. The induction of fibrofatty cell was mimicked by administration with recombinant PRL. The stress also induced the expression of Sca1 in the mouse heart. Exposure of NIH3T3 cells (a fibroblast cell line) to PRL in the culture enhanced the expression of stem cell antigen-1 (Sca1), phosphorylation of signal transducer and activator of transcription 3 (STAT3) and expression of adipocyte-related protein molecules, including adiponectin, fatty acid binding protein (aP2), peroxisome proliferator activated receptor-g (PPARg) and CCAAT/enhancer binding protein (C/EBP)α, in the cells. We conclude that psychological stress-derived PRL induces fibroblasts to differentiate into fibrofatty cells in the heart. PMID:27158356

  2. Cardiomyogenic potential of c-kit+ expressing cells derived from neonatal and adult mouse hearts

    PubMed Central

    Zaruba, Marc-Michael; Soonpaa, Mark; Reuter, Sean; Field, Loren J.

    2010-01-01

    Summary Background c-kit is a receptor tyrosine kinase family member expressed in hematopoietic stem cells. c-kit is also transiently expressed in cardiomyocyte precursors during development, and in a rare cell population in the normal adult heart. Here, the cardiomyogenic potential of c-kit+ cells isolated from normal neonatal, normal adult and infarcted adult mouse hearts was evaluated. Methods and Results Magnetic activated cell sorting (MACS) was used to prepare c-kit+ cells from the hearts of ACT-EGFP/MHC-nLAC double transgenic mice. These animals exhibit widespread enhanced green fluorescent protein (EGFP) expression and cardiomyocyte-restricted nuclear β-galactosidase activity, thus permitting simultaneous tracking of cell survival and differentiation. A subset of the c-kit+ cells from double transgenic neonatal hearts acquired a cardiomyogenic phenotype when co-cultured with fetal cardiomyocytes (2.4% of all EGFP+ cells screened), but not when cultured alone or when co-cultured with mouse fibroblasts (0.03% and 0.05% of the EGFP+ cells screened, respectively). In contrast, c-kit+ cells from normal adult double transgenic hearts failed to undergo cardiomyogenic differentiation when co-cultured with non-transgenic fetal cardiomyocytes (>18,000 EGFP+ cells screened) or when transplanted into normal or infarcted adult mouse hearts (14 EGFP+ grafts examined). A single c-kit+ cell from an infarcted double transgenic adult heart was observed to acquire a cardiomyogenic phenotype in co-culture (>37,000 EGFP+ cells screened). Conclusions These data suggest that the ability of cardiac-resident c-kit+ cells to acquire a cardiomyogenic phenotype is subject to temporal limitations, or alternatively that the cardiomyogenic population is lost. Elucidation of the underlying molecular basis may permit robust cardiomyogenic induction in adult-derived cardiac c-kit+ cells. PMID:20421520

  3. Regional pulmonary perfusion following human heart-lung transplantation

    SciTech Connect

    Lisbona, R.; Hakim, T.S.; Dean, G.W.; Langleben, D.; Guerraty, A.; Levy, R.D. )

    1989-08-01

    Ventilation and perfusion scans were obtained in six subjects who had undergone heart-lung transplantation with consequent denervation of the cardiopulmonary axis. Two of the subjects had developed obliterative bronchiolitis, which is believed to be a form of chronic rejection. Their pulmonary function tests demonstrated airflow obstruction and their scintigraphic studies were abnormal. In the remaining four subjects without obstructive airways disease, ventilation and planar perfusion scans were normal. Single photon emission computed tomography imaging of pulmonary perfusion in these patients revealed a layered distribution of blood flow indistinguishable from that of normal individuals. It is concluded that neurogenic mechanisms have little influence on the pattern of local pulmonary blood flow at rest.

  4. Heart rate variability in exercising humans: effect of water immersion.

    PubMed

    Perini, R; Milesi, S; Biancardi, L; Pendergast, D R; Veicsteinas, A

    1998-03-01

    Power spectrum analysis of heart-rate variability was made in seven men [mean age 22 (SEM 1) years] in head-out water immersion (W) and in air (A, control) at rest and during steady-state cycling to maximal intensity (maximum oxygen uptake, VO2max). At rest W resulted in a trebled increase in the total power (P < 0.05), coupled with minimal changes in the power (as a percentage of the total) of the high frequency peak (HF, centred at 0.26 Hz; 18% vs 28%) and of the low frequency peak (LF, 0.1 Hz; 24% vs 32%). A third peak at about 0.03 Hz (very low frequency, VLF) represented the remaining power both in W and A. These changes as a whole indicated that immersion caused a vagal dominance in cardiac autonomic interaction, due to the central pooling of blood and/or the pressure of water on the trunk. Exercise caused a decrease in the total power in W and A. The LF% did not change up to about 50% V02max, thereafter decreasing towards nil in both conditions. The HF% decreased in similar ways in W and A to about half at 55%-60% VO2max and then increased to reach 1.5 times the resting values at VO2max. The central frequency of HF increased linearly with oxygen uptake, showing a tendency to be higher in W than in A at medium to high intensities. The VLF% remained unchanged. The lack of differences in the LF peak between W and A during exercise would suggest that blood distribution had no effect on the readjustments in control mechanisms of arterial pressure. On the other hand, the findings of similar HF powers and the very similar values for ventilation in W and A confirmed the direct effect of the respiratory activity in heart rate modulation during exercise. PMID:9562361

  5. Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism

    SciTech Connect

    De Siena, Rocco; Balducci, Luigi; Blasi, Antonella; Montanaro, Manuela Gessica; Saldarelli, Marilisa; Saponaro, Vittorio; Martino, Carmela; Logrieco, Gaetano; Soleti, Antonio; Fiobellot, Simona; Madeddu, Paolo; Rossi, Giacomo; Ribatti, Domenico; Crovace, Antonio; Cristini, Silvia; Invernici, Gloria; Parati, Eugenio Agostino; Alessandri, Giulio

    2010-07-01

    Cell-based therapy could be a valid option to treat myocardial infarct (MI). Adipose-derived stromal cells (ADStCs) have demonstrated tissue regenerative potential including cardiomyogenesis. Omentum is an extremely rich source of visceral fat and its accumulation seems to correlate with cardiovascular diseases. We investigated the capacity of human fat Omentum-derived StCs (FOStCs) to affect heart function upon acute infarct in pigs induced by permanent ligation of the anterior interventricular artery (IVA). We demonstrated for the first time that the local injection of 50 x 10{sup 6} of FOStCs ameliorates the functional parameters of post-infarct heart. Most importantly, histology of FOStCs treated hearts demonstrated a substantial improvement of cardiomyogenesis. In culture, FOStCs produced an impressive number and amount of angiogenic factors and cytokines. Moreover, the conditioned medium of FOStCs (FOStCs-CM) stimulates in vitro cardiac endothelial cells (ECs) proliferation and vascular morphogenesis and inhibits monocytes, EC activation and cardiomyocyte apoptosis. Since FOStCs in vivo did not trans-differentiate into cardiomyocyte-like cells, we conclude that FOStCs efficacy was presumably mediated by a potent paracrine mechanism involving molecules that concomitantly improved angiogenesis, reduced inflammation and prevented cardiomyocytes death. Our results highlight for the first time the important role that human FOStCs may have in cardiac regeneration.

  6. Metabolic aspects of programmed cell survival and cell death in the heart.

    PubMed

    Depre, C; Taegtmeyer, H

    2000-02-01

    Normal cardiac function requires a tight interaction between metabolism, contractile function and gene expression. The main perturbation challenging this equilibrium in vivo is ischemia, which alters energy flux through the control of key enzymes. The review highlights metabolic imprints and energetic aspects of programmed cell survival, programmed cell death, and of necrosis. When sustained and severe, ischemia leads to a total collapse of energy transfer, to the accumulation of metabolic endproducts, and to the development of myocardial necrosis. When moderate, ischemia results in a coordinated cellular response including enhanced anaerobic glucose metabolism, a modification of cardiac gene expression, and the development of specific mechanisms for programmed cell survival (preconditioning, stunning, hibernation). Repetitive stress results in a decrease of contractile function, a downregulation of gene expression and an impairment of energy transfer, which eventually cause the heart to fail. When the failing heart becomes energy-depleted, the programs of cell survival are no longer operational and programmed cell death ensues. To define the point of departure from programmed cell survival to cell death remains a major challenge. PMID:10728375

  7. Amitosis in human adrenal cells.

    PubMed

    Magalhães, M C; Pignatelli, D; Magalhães, M M

    1991-04-01

    Adrenal pieces obtained from 3 female and 2 male patients showed morphological figures of amitosis in adrenal zona reticularis cells. Such aspects were observed in both normal and hyperactive adrenals. Nuclei appeared constricted, heavily stained, with coarse chromatin, sometimes scattered among cytoplasmic organelles, but never marginating in crescentic caps. Cleavage of the cells originated two halves with a nucleolus in each pole. Binucleated cells were also seen in zona reticularis. The meaning of amitosis in human adrenal is discussed. PMID:1802124

  8. Stem cell therapy and tissue engineering for correction of congenital heart disease

    PubMed Central

    Avolio, Elisa; Caputo, Massimo; Madeddu, Paolo

    2015-01-01

    This review article reports on the new field of stem cell therapy and tissue engineering and its potential on the management of congenital heart disease. To date, stem cell therapy has mainly focused on treatment of ischemic heart disease and heart failure, with initial indication of safety and mild-to-moderate efficacy. Preclinical studies and initial clinical trials suggest that the approach could be uniquely suited for the correction of congenital defects of the heart. The basic concept is to create living material made by cellularized grafts that, once implanted into the heart, grows and remodels in parallel with the recipient organ. This would make a substantial improvement in current clinical management, which often requires repeated surgical corrections for failure of implanted grafts. Different types of stem cells have been considered and the identification of specific cardiac stem cells within the heterogeneous population of mesenchymal and stromal cells offers opportunities for de novo cardiomyogenesis. In addition, endothelial cells and vascular progenitors, including cells with pericyte characteristics, may be necessary to generate efficiently perfused grafts. The implementation of current surgical grafts by stem cell engineering could address the unmet clinical needs of patients with congenital heart defects. PMID:26176009

  9. Comparison of Standard and Heart-pacer Type 3rd Electrodes in Design Variable Cells

    NASA Technical Reports Server (NTRS)

    Morrow, G. W.

    1984-01-01

    Nine packs of sealed aerospace nickel cadmium cells were put on life test in February 1979. Each 5 cell pack contained one cell with a standard sensor signal electrode and one cell with a new heart pacer sensor signal electrode. Testing was discontinued in May 1983 and the signal electrode performance data was studied. It was found that the heart pacer electrode generally provided a greater voltage swing over a cycle; that both types of electrodes lost significant sensitivity during life, and that both types of electrodes show great signal variation from cell to cell.

  10. Sleep Stage Dependence of Invariance Characteristics in Fluctuations of Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Togo, Fumiharu; Kiyono, Ken; Struzik, Zbigniew R.; Yamamoto, Yoshiharu

    2005-08-01

    The outstanding feature of healthy human heart rate is the robust scale invariance in the non-Gaussian probability density function (PDF), which is preserved not only in a quiescent condition, but also in a dynamic state during waking hours [K. Kiyono et al. Phys. Rev. Lett. 93 (2004)]. Together with 1/f like scaling, this characteristic is a strong indication of far-from-equilibrium, critical-like dynamics of heart rate regulation. Our results suggest that healthy human heart rate departs from a critical state-like operation during sleeping hours, at a rate which is heterogeneous with respect to sleep stages annotated according to traditional techniques. We study specific contributions of sleep stages to the relative departure from criticality through the analysis of sleep stage dependence of the root mean square of multiscale local energy and the multiscale PDF. There is a possibility that the involvement of cortical activity may be important for a critical state-like operation.

  11. cap alpha. -skeletal and. cap alpha. -cardiac actin genes are coexpressed in adult human skeletal muscle and heart

    SciTech Connect

    Gunning, P.; Ponte, P.; Blau, H.; Kedes, L.

    1983-11-01

    The authors determined the actin isotypes encoded by 30 actin cDNA clones previously isolated from an adult human muscle cDNA library. Using 3' untranslated region probes, derived from ..cap alpha.. skeletal, ..beta..- and ..gamma..-actin cDNAs and from an ..cap alpha..-cardiac actin genomic clone, they showed that 28 of the cDNAs correspond to ..cap alpha..-skeletal actin transcripts. Unexpectedly, however, the remaining two cDNA clones proved to derive from ..cap alpha..-cardiac actin mRNA. Sequence analysis confirmed that the two skeletal muscle ..cap alpha..-cardiac actin cDNAs are derived from transcripts of the cloned ..cap alpha..-cardiac actin gene. Comparison of total actin mRNA levels in adult skeletal muscle and adult heart revealed that the steady-state levels in skeletal muscle are about twofold greater, per microgram of total cellular RNA, than those in heart. Thus, in skeletal muscle and in heart, both of the sarcomeric actin mRNA isotypes are quite abundant transcripts. They conclude that ..cap alpha..-skeletal and ..cap alpha..-cardiac actin genes are coexpressed as an actin pair in human adult striated muscles. Since the smooth-muscle actins (aortic and stomach) and the cytoplasmic actins (..beta.. and ..gamma..) are known to be coexpressed in smooth muscle and nonmuscle cells, respectively, they postulate that coexpression of actin pairs may be a common feature of mammalian actin gene expression in all tissues.

  12. Patterning human stem cells and endothelial cells with laser printing for cardiac regeneration.

    PubMed

    Gaebel, Ralf; Ma, Nan; Liu, Jun; Guan, Jianjun; Koch, Lothar; Klopsch, Christian; Gruene, Martin; Toelk, Anita; Wang, Weiwei; Mark, Peter; Wang, Feng; Chichkov, Boris; Li, Wenzhong; Steinhoff, Gustav

    2011-12-01

    Recent study showed that mesenchymal stem cells (MSC) could inhibit apoptosis of endothelial cells in hypoxic condition, increase their survival, and stimulate the angiogenesis process. In this project we applied Laser-Induced-Forward-Transfer (LIFT) cell printing technique and prepared a cardiac patch seeded with human umbilical vein endothelial cells (HUVEC) and human MSC (hMSC) in a defined pattern for cardiac regeneration. We seeded HUVEC and hMSC in a defined pattern on a Polyester urethane urea (PEUU) cardiac patch. On control patches an equal amount of cells was randomly seeded without LIFT. Patches were cultivated in vitro or transplanted in vivo to the infarcted zone of rat hearts after LAD-ligation. Cardiac performance was measured by left ventricular catheterization 8 weeks post infarction. Thereafter hearts were perfused with fluorescein tomato lectin for the assessment of functional blood vessels and stored for histology analyses. We demonstrated that LIFT-derived cell seeding pattern definitely modified growth characteristics of co-cultured HUVEC and hMSC leading to increased vessel formation and found significant functional improvement of infarcted hearts following transplantation of a LIFT-tissue engineered cardiac patch. Further, we could show enhanced capillary density and integration of human cells into the functionally connected vessels of murine vascular system. LIFT-based Tissue Engineering of cardiac patches for the treatment of myocardial infarction might improve wound healing and functional preservation. PMID:21911255

  13. Heart rate responses provide an objective evaluation of human disturbance stimuli in breeding birds.

    PubMed

    Ellenberg, Ursula; Mattern, Thomas; Seddon, Philip J

    2013-01-01

    Intuition is a poor guide for evaluating the effects of human disturbance on wildlife. Using the endangered Yellow-eyed penguin, Megadyptes antipodes, as an example, we show that heart rate responses provide an objective tool to evaluate human disturbance stimuli and encourage the wider use of this simple and low-impact approach. Yellow-eyed penguins are a flagship species for New Zealand's wildlife tourism; however, unregulated visitor access has recently been associated with reduced breeding success and lower first year survival. We measured heart rate responses of Yellow-eyed penguins via artificial eggs to evaluate a range of human stimuli regularly occurring at their breeding sites. We found the duration of a stimulus to be the most important factor, with elevated heart rate being sustained while a person remained within sight. Human activity was the next important component; a simulated wildlife photographer, crawling slowly around during his stay, elicited a significantly higher heart rate response than an entirely motionless human spending the same time at the same distance. Stimuli we subjectively might perceive as low impact, such as the careful approach of a 'wildlife photographer', resulted in a stronger response than a routine nest-check that involved lifting a bird up to view nest contents. A single, slow-moving human spending 20 min within 2 m from the nest may provoke a response comparable to that of 10 min handling a bird for logger deployment. To reduce cumulative impact of disturbance, any human presence in the proximity of Yellow-eyed penguins needs to be kept at a minimum. Our results highlight the need for objective quantification of the effects of human disturbance in order to provide a sound basis for guidelines to manage human activity around breeding birds. PMID:27293597

  14. Heart rate responses provide an objective evaluation of human disturbance stimuli in breeding birds

    PubMed Central

    Ellenberg, Ursula; Mattern, Thomas; Seddon, Philip J.

    2013-01-01

    Intuition is a poor guide for evaluating the effects of human disturbance on wildlife. Using the endangered Yellow-eyed penguin, Megadyptes antipodes, as an example, we show that heart rate responses provide an objective tool to evaluate human disturbance stimuli and encourage the wider use of this simple and low-impact approach. Yellow-eyed penguins are a flagship species for New Zealand's wildlife tourism; however, unregulated visitor access has recently been associated with reduced breeding success and lower first year survival. We measured heart rate responses of Yellow-eyed penguins via artificial eggs to evaluate a range of human stimuli regularly occurring at their breeding sites. We found the duration of a stimulus to be the most important factor, with elevated heart rate being sustained while a person remained within sight. Human activity was the next important component; a simulated wildlife photographer, crawling slowly around during his stay, elicited a significantly higher heart rate response than an entirely motionless human spending the same time at the same distance. Stimuli we subjectively might perceive as low impact, such as the careful approach of a ‘wildlife photographer’, resulted in a stronger response than a routine nest-check that involved lifting a bird up to view nest contents. A single, slow-moving human spending 20 min within 2 m from the nest may provoke a response comparable to that of 10 min handling a bird for logger deployment. To reduce cumulative impact of disturbance, any human presence in the proximity of Yellow-eyed penguins needs to be kept at a minimum. Our results highlight the need for objective quantification of the effects of human disturbance in order to provide a sound basis for guidelines to manage human activity around breeding birds. PMID:27293597

  15. Increased Heart Rate Variability but Normal Resting Metabolic Rate in Hypocretin/Orexin-Deficient Human Narcolepsy

    PubMed Central

    Fronczek, Rolf; Overeem, Sebastiaan; Reijntjes, Robert; Lammers, Gert Jan; van Dijk, J. Gert; Pijl, Hanno

    2008-01-01

    Study Objectives: We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects. Methods: Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were determined in the fasted resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index. Results: Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p = 0.01; systolic blood pressure: p = 0.02; diastolic: p < 0.01). The low to high frequency ratio of heart rate power did not differ between groups (p = 0.48), nor did resting metabolic rate (controls: 1767 ± 226 kcal/24 h; patients: 1766 ± 227 kcal/24h; p = 0.99). Conclusions: Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability—suggesting reduced sympathetic tone—is involved in this regard remains to be elucidated. Citation: Fronczek R; Overeem S; Reijntjes R; Lammers GJ; van Dijk JG; Pijl H. Increased heart rate variability but normal resting metabolic rate in hypocretin/orexin-deficient human narcolepsy. J Clin Sleep Med 2008;4(3):248–254. PMID:18595438

  16. Heart Attacks, Strokes, and Peripheral Artery Disease in Patients With Giant-Cell Arteritis

    MedlinePlus

    Annals of Internal Medicine Summaries for Patients Heart Attacks, Strokes, and Peripheral Artery Disease in Patients With Giant-Cell Arteritis The full report is titled “Risk for Cardiovascular Disease Early and Late ...

  17. mga genosensor for early detection of human rheumatic heart disease.

    PubMed

    Singh, Swati; Kaushal, Ankur; Khare, Shashi; Kumar, Ashok

    2014-05-01

    The 5' amino-labeled DNA probe complementary to mga gene of Streptococcus pyogenes was immobilized on carboxylated multiwall carbon nanotubes electrode and hybridized with 0.1-100 ng/6 μl single-stranded genomic DNA (ssG-DNA) of S. pyogenes from throat swab of suspected rheumatic heart disease (RHD) patients. Electrochemical response was measured by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance (EI). The sensitivity of the sensor was 106.03 (μA/cm(2))/ng and limit of detection (LOD) was found 0.014 ng/6 μl with regression coefficient (R(2)) of 0.921 using DPV. The genosensor was characterized by FTIR and SEM, and electrode was found stable for 6 months on storage at 4 °C with 5-6 % loss in initial DPV current. mga genosensor is the first report on RHD sensor which can save life of several suspected patients by early diagnosis in 30 min. PMID:24639090

  18. Modeling heart disease in a dish: From somatic cells to disease-relevant cardiomyocytes

    PubMed Central

    Zanella, Fabian; Lyon, Robert C.; Sheikh, Farah

    2016-01-01

    A scientific milestone that has tremendously impacted the cardiac research field has been the discovery and establishment of human-induced pluripotent stem cells (hiPSC). Key to this discovery has been uncovering a viable path in generating human patient and disease-specific cardiac cells to dynamically model and study human cardiac diseases in an in vitro setting. Recent studies have demonstrated that hiPSC-derived cardiomyocytes can be used to model and recapitulate various known disease features in hearts of patient donors harboring genetic-based cardiac diseases. Experimental drugs have also been tested in this setting and shown to alleviate disease phenotypes in hiPSC-derived cardiomyocytes, further paving the way for therapeutic interventions for cardiac disease. Here, we review state-of-the-art methods to generate high-quality hiPSC and differentiate them towards cardiomyocytes as well as the full range of genetic-based cardiac diseases, which have been modeled using hiPSC. We also provide future perspectives on exploiting the potential of hiPSC to compliment existing studies and gain new insights into the mechanisms underlying cardiac disease. PMID:24054750

  19. A “PET” area of interest: myocardial metabolism in human systolic heart failure

    PubMed Central

    Kadkhodayan, Ana; Coggan, Andrew R.; Peterson, Linda R.

    2013-01-01

    Myocardial substrate metabolism provides the energy needed for cardiac contraction and relaxation. The normal adult heart uses predominantly fatty acids (FAs) as its primary fuel source. However, the heart can switch and use glucose (and to a lesser extent, ketones, lactate, as well as endogenous triglycerides and glycogen), depending on the metabolic milieu and superimposed conditions. FAs are not a wholly better fuel than glucose, but they do provide more energy per mole than glucose. Conversely, glucose is the more oxygen-efficient fuel. Studies in animal models of heart failure (HF) fairly consistently demonstrate a shift away from myocardial fatty acid metabolism and towards glucose metabolism. Studies in humans are less consistent. Some show the same metabolic switch away from FA metabolism but not all. This may be due to differences in the etiology of HF, sex-related differences, or other mitigating factors. For example, obesity, insulin resistance, and diabetes are all related to an increased risk of HF and may complicate or contribute to its development. However, these conditions are associated with increased FA metabolism. This review will discuss aspects of human heart metabolism in systolic dysfunction as measured by the noninvasive, quantitative method – positron emission tomography. Continued research in this area is vital if we are to ameliorate HF by manipulating heart metabolism with the aim of increasing energy production and/or efficiency. PMID:23180281

  20. Visualization of human heart conduction system by means of fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    Venius, Jonas; Bagdonas, Saulius; Žurauskas, Edvardas; Rotomskis, Ricardas

    2011-10-01

    The conduction system of the heart is a specific muscular tissue, where a heartbeat signal originates and initiates the depolarization of the ventricles. The muscular origin makes it complicated to distinguish the conduction system from the surrounding tissues. A surgical intervention can lead to the accidental harm of the conduction system, which may eventually result in a dangerous obstruction of the heart functionality. Therefore, there is an immense necessity for developing a helpful method to visualize the conduction system during the operation time. The specimens for the spectroscopic studies were taken from nine diverse human hearts. The localization of distinct types of the tissue was preliminary marked by the pathologist and approved histologically after the spectral measurements. Variations in intensity, as well as in shape, were detected in autofluorescence spectra of different heart tissues. The most distinct differences were observed between the heart conduction system and the surrounding tissues under 330 and 380 nm excitation. The spectral region around 460 nm appeared to be the most suitable for an unambiguous differentiation of the human conduction system avoiding the absorption peak of blood. The visualization method, based on the intensity ratios calculated for two excitation wavelengths, was also demonstrated.

  1. An embryonic heart cell line is susceptible to dengue virus infection.

    PubMed

    Angel-Ambrocio, Antonio H; Soto-Acosta, Rubén; Tammineni, Eshwar R; Carrillo, Elba D; Bautista-Carbajal, Patricia; Hernández, Ascención; Sánchez, Jorge A; del Angel, Rosa M

    2015-02-16

    Dengue virus (DENV) is the causative agent of dengue fever. In recent years, patients with more severe form of the disease with acute heart failure or progression to cardiogenic shock and death have been reported. However, the pathogenesis of myocardial lesions and susceptibility of cardiomyocytes to DENV infection have not been evaluated. Under this perspective, the susceptibility of the myoblast cell line H9c2, obtained from embryonic rat heart, to DENV infection was analyzed. Our findings indicate that H9c2 cells are susceptible to the infection with the four DENV serotypes. Moreover, virus translation/replication and viral production in this cell line is as efficient as in other susceptible cell lines, supporting the idea that DENV may target heart cells as evidenced by infection of H9c2 cells. This cell line may thus represent an excellent model for the study and characterization of cardiac physiopathology in DENV infection. PMID:25598317

  2. Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

    PubMed Central

    Mao, Rong; Wang, Xiaowen; Spitznagel, Edward L; Frelin, Laurence P; Ting, Jason C; Ding, Huashi; Kim, Jung-whan; Ruczinski, Ingo; Downey, Thomas J; Pevsner, Jonathan

    2005-01-01

    Background Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported. Results We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21. Conclusions In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes. PMID:16420667

  3. Assessment of DNA synthesis in Islet-1{sup +} cells in the adult murine heart

    SciTech Connect

    Weinberger, Florian Mehrkens, Dennis Starbatty, Jutta Nicol, Philipp Eschenhagen, Thomas

    2015-01-02

    Highlights: • Islet-1 was expressed in the adult heart. • Islet-1-positive cells did not proliferate in the adult heart. • Sinoatrial node cells did not proliferate in the adult heart. - Abstract: Rationale: Islet-1 positive (Islet-1{sup +}) cardiac progenitor cells give rise to the right ventricle, atria and outflow tract during murine cardiac development. In the adult heart Islet-1 expression is limited to parasympathetic neurons, few cardiomyocytes, smooth muscle cells, within the proximal aorta and pulmonary artery and sinoatrial node cells. Its role in these cells is unknown. Here we tested the hypothesis that Islet-1{sup +} cells retain proliferative activity and may therefore play a role in regenerating specialized regions in the heart. Methods and results: DNA synthesis was analyzed by the incorporation of tritiated thymidine ({sup 3}H-thymidine) in Isl-1-nLacZ mice, a transgenic model with an insertion of a nuclear beta-galactosidase in the Islet-1 locus. Mice received daily injections of {sup 3}H-thymidine for 5 days. DNA synthesis was visualized throughout the heart by dipping autoradiography of cryosections. Colocalization of an nLacZ-signal and silver grains would indicate DNA synthesis in Islet-1{sup +} cells. Whereas Islet{sup −} non-myocyte nuclei were regularly marked by accumulation of silver grains, colocalization with nLacZ-signals was not detected in >25,000 cells analyzed. Conclusions: Islet-1{sup +} cells are quiescent in the adult heart, suggesting that, under normal conditions, even pacemaking cells do not proliferate at higher rates than normal cardiac myocytes.

  4. SIV replication in human cells

    PubMed Central

    Sakuma, Ryuta; Takeuchi, Hiroaki

    2012-01-01

    Current human immunodeficiency virus type 1 pandemic is believed to originate from cross-species transmission of simian immunodeficiency virus (SIV) into human population. Such cross-species transmission, however, is not efficient in general, because viral replication is modulated by host cell factors, with the species-specificity of these factors affecting viral tropism. An understanding of those host cell factors that affect viral replication contributes to elucidation of the mechanism for determination of viral tropism. This review will focus an anti-viral effect of ApoB mRNA editing catalytic subunit, tripartite motif protein 5 alpha, and cyclophilins on SIV replication and provide insight into the mechanism of species-specific barriers against viral infection in human cells. It will then present our current understanding of the mechanism that may explain zoonotic transmission of retroviruses. PMID:22679440

  5. Common multifractality in the heart rate variability and brain activity of healthy humans

    NASA Astrophysics Data System (ADS)

    Lin, D. C.; Sharif, A.

    2010-06-01

    The influence from the central nervous system on the human multifractal heart rate variability (HRV) is examined under the autonomic nervous system perturbation induced by the head-up-tilt body maneuver. We conducted the multifractal factorization analysis to factor out the common multifractal factor in the joint fluctuation of the beat-to-beat heart rate and electroencephalography data. Evidence of a central link in the multifractal HRV was found, where the transition towards increased (decreased) HRV multifractal complexity is associated with a stronger (weaker) multifractal correlation between the central and autonomic nervous systems.

  6. Anti-wrinkle effects of a tuna heart H2O fraction on Hs27 human fibroblasts

    PubMed Central

    KIM, YOUNG-MIN; JUNG, HEE-JIN; CHOI, JAE-SUE; NAM, TAEK-JEONG

    2016-01-01

    With the increase in life expectancy, there is also growing interest in anti-aging treatments and technologies. The development of anti-aging functional drugs for the skin, and foods from natural sources, may offer solutions to this global matter. Aging involves structural, functional and biochemical changes that occur throughout cells and bodily tissues; the amount of hormones secreted from of all human organs, including the skin, decreases over time. Matrix metalloproteinase (MMP) genes (MMP-1 and -8) play an important role in the aging of skin fibroblasts. For example, an increased MMP expression causes accelerated aging and the degradation of skin elasticity-related genes. In the present study, we examined the anti-wrinkle effects of tuna heart extract which are mediated through the inhibition of MMPs in skin cells. Generally, tuna contains high concentrations of selenium and antioxidants, which serve to remove free radicals, and is known to delay skin and body aging. In addition, unsaturated fatty acids in tuna help to maintain the natural glossy look of skin, and increase skin elasticity, providing moisture for dry skin. A recent study confirmed the various bio-effects of boiled tuna extract and muscle. However, bioactivity studies using tuna heart are limited. Thus, in the present study, we obtained extracts and fractions of tuna heart, and examined their effects on Hs27 human fibroblast proliferation using an MTS assay. In addition, we measured procollagen type 1 levels and elastase activity, and performed β-galactosidase staining. We then measured the expression levels of phosphatidylinositol 3-kinase/Akt and MMP-related genes by western blot analysis and RT-PCR. Our results revealed that tuna heart extract decreased MMP expression by upregulating tissue inhibitors of metallopro-teinase-1 (TIMP-1) and decreasing elastase activity, thus exerting anti-aging and anti-wrinkle effects by increasing collagen synthesis and promoting skin fibroblast proliferation

  7. Anti-wrinkle effects of a tuna heart H2O fraction on Hs27 human fibroblasts.

    PubMed

    Kim, Young-Min; Jung, Hee-Jin; Choi, Jae-Sue; Nam, Taek-Jeong

    2016-01-01

    With the increase in life expectancy, there is also growing interest in anti-aging treatments and technologies. The development of anti-aging functional drugs for the skin, and foods from natural sources, may offer solutions to this global matter. Aging involves structural, functional and biochemical changes that occur throughout cells and bodily tissues; the amount of hormones secreted from of all human organs, including the skin, decreases over time. Matrix metalloproteinase (MMP) genes (MMP-1 and -8) play an important role in the aging of skin fibroblasts. For example, an increased MMP expression causes accelerated aging and the degradation of skin elasticity-related genes. In the present study, we examined the anti-wrinkle effects of tuna heart extract which are mediated through the inhibition of MMPs in skin cells. Generally, tuna contains high concentrations of selenium and antioxidants, which serve to remove free radicals, and is known to delay skin and body aging. In addition, unsaturated fatty acids in tuna help to maintain the natural glossy look of skin, and increase skin elasticity, providing moisture for dry skin. A recent study confirmed the various bio-effects of boiled tuna extract and muscle. However, bioactivity studies using tuna heart are limited. Thus, in the present study, we obtained extracts and fractions of tuna heart, and examined their effects on Hs27 human fibroblast proliferation using an MTS assay. In addition, we measured procollagen type 1 levels and elastase activity, and performed β-galactosidase staining. We then measured the expression levels of phosphatidylinositol 3-kinase/Akt and MMP-related genes by western blot analysis and RT-PCR. Our results revealed that tuna heart extract decreased MMP expression by upregulating tissue inhibitors of metalloproteinase-1 (TIMP-1) and decreasing elastase activity, thus exerting anti-aging and anti-wrinkle effects by increasing collagen synthesis and promoting skin fibroblast

  8. [Ca2+]i in human heart failure: a review and discussion of current areas of controversy.

    PubMed Central

    Liao, R.; Helm, P. A.; Hajjar, R. J.; Saha, C.; Gwathmey, J. K.

    1994-01-01

    Multiple abnormalities have been reported in the setting of human heart failure. It is unclear whether detected changes reflect adaptive alterations in myocardium subjected to increased and sustained hemodynamic overload or are pathogenic to the disease process. As a result of the observation that the primary defect in heart failure is decreased pump function, investigators have concentrated their efforts on determining systolic [Ca2+]i as a logical corollary and a causative mechanism for contractile dysfunction. A simple cause and effect relationship has therefore been proposed with regard to contractile dysfunction and [Ca2+]i. Yet some investigators have found no difference in peak systolic [Ca2+]i between failing and non-failing human myocardium, whereas others have found peak [Ca2+]i to be significantly reduced in failing hearts. Resting calcium concentrations have been reported either to be elevated in failing human myocardium or not different from non-failing human myocardium. Investigators should now appreciate that the force-calcium relationship is not a simple relationship. One must take into account the prolonged time course and slowed mobilization of [Ca2+]i as opposed to simply peak [Ca2+]i. When put in perspective of mechanisms and determinants of the Ca(2+)-force relationship, we begin to realize that failing human myocardium has the "potential" to generate normal levels of force. Only when stressed by [Ca2+]i overload and/or frequency perturbation does myocardium from patients with end-stage heart disease demonstrate contractile failure. Although [Ca2+]i availability and mobilization are likely to play a role in the systolic as well as diastolic dysfunction reported in human heart failure, it is likely that other mechanisms are involved as well (e.g., myocardial energetics). Myocardial energetics is directly related to [Ca2+]i and mobilization in failing human myocardium, because metabolites, e.g., ADP, inhibit pumps, such as sarcoplasmic reticulum

  9. The Physiological Effect of Human Grooming on the Heart Rate and the Heart Rate Variability of Laboratory Non-Human Primates: A Pilot Study in Male Rhesus Monkeys

    PubMed Central

    Grandi, Laura Clara; Ishida, Hiroaki

    2015-01-01

    Grooming is a widespread, essential, and complex behavior with social and affiliative valence in the non-human primate world. Its impact at the autonomous nervous system level has been studied during allogrooming among monkeys living in a semi-naturalistic environment. For the first time, we investigated the effect of human grooming to monkey in a typical experimental situation inside laboratory. We analyzed the autonomic response of male monkeys groomed by a familiar human (experimenter), in terms of the heart rate (HR) and heart rate variability (HRV) at different body parts. We considered the HRV in both the time (SDNN, RMSSD, and RMSSD/SDNN) and the frequency domain (HF, LF, and LF/HF). For this purpose, we recorded the electrocardiogram of two male rhesus monkeys seated in a primate chair while the experimenter groomed their mouth, chest, or arm. We demonstrated that (1) the grooming carried out by a familiar human determined a decrement of the HR and an increment of the HRV; (2) there was a difference in relation to the groomed body part. In particular, during grooming the mouth the HRV was higher than during grooming the arm and the chest. Taken together, the results represent the first evidence that grooming carried out by a familiar human on experimental monkeys has the comparable positive physiological effect of allogrooming between conspecifics. Moreover, since the results underlined the positive modulation of both HR and HRV, the present study could be a starting point to improve the well-being of non-human primates in experimental condition by means of grooming by a familiar person. PMID:26664977

  10. Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes.

    PubMed Central

    Gulizia, J. M.; Cunningham, M. W.; McManus, B. M.

    1991-01-01

    Association of group A streptococci with acute rheumatic fever and valvular heart disease is well established; however the basis of valve injury remains unclear. In this study, anti-streptococcal monoclonal antibodies (MAbs) cross-reactive with myocardium were reacted with sections from 22 rheumatic valves, nine normal, five endocarditic, one 'floppy,' and one Marfan valve. In immunohistochemical studies, MAb reactivity was observed with cardiac myocytes, smooth muscle cells, cell surface and cytoplasm of endothelial cells lining valves, and valvular interstitial cells. Endothelial basement membrane and elastin fibrils reacted with the MAbs, whereas collagen was unreactive. Similar reactivity was seen with sera from acute rheumatic fever patients. The anti-streptococcal MAbs reacted with intravalvular myosin and vimentin in Western blots, and purified elastin competitively inhibited the binding of the anti-streptococcal MAbs to whole group A streptococci. The data show that human heart valves have numerous sites of immunoreactivity with anti-streptococcal MAbs and acute rheumatic fever sera of potential importance in the pathogenesis of rheumatic valvular injury. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 PMID:1704188

  11. Human Induced Pluripotent Stem Cell Models of Inherited Cardiovascular Diseases.

    PubMed

    Jiang, Wenjian; Lan, Feng; Zhang, Hongjia

    2014-10-16

    Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery. PMID:25322695

  12. Decellularized GGTA1-KO pig heart valves do not bind preformed human xenoantibodies.

    PubMed

    Ramm, Robert; Niemann, Heiner; Petersen, Björn; Haverich, Axel; Hilfiker, Andres

    2016-07-01

    Pre-clinical and clinical data have unequivocally demonstrated the usefulness of decellularized heart valve (HV) matrices implanted for HV replacement therapy. However, human donor valves applicable for decellularization are in short supply, which prompts the search for suitable alternatives, such as porcine grafts. Since decellularization might be insufficient to remove all xenoantigens, we analysed the interaction of human preformed antibodies with decellularized porcine HV in vitro to assess potential immune reactions upon implantation. Detergent-decellularized pulmonary HV from German Landrace wild-type (wt) or α1,3-galactosyltransferase knockout (GGTA1-KO) pigs were investigated by inhibition ELISA and GSL I-B4 staining to localize and quantify matrix-bound αGal epitopes, which represent the most prominent xenoantigen. Additionally, preformed human xenoantibodies were affinity purified by perfusing porcine kidneys. Binding of purified human antibodies to decellularized HV was investigated by inhibition ELISA. Furthermore, binding of human plasma proteins to decellularized matrices was determined by western blot. Decellularized human pulmonary artery served as controls. Decellularization of wt HV led to a reduction of αGal epitopes by 70 %. Residual epitopes were associated with the subendothelial extracellular matrix. As expected, no αGal epitopes were found on decellularized GGTA1-KO matrix. The strongest binding of preformed human anti-pig antibodies was found on wt matrices, whereas GGTA1-KO matrices bound similar or even fewer xenoantibodies than human controls. These results demonstrate the suitability of GGTA1-KO pigs as donors for decellularized heart valves for human patients. Besides the presence of αGal antibodies on decellularized heart valves, no further preformed xenoantibodies against porcine matrix were detected in tested human sera. PMID:27154491

  13. Computerised 3-D anatomical modelling using plastinates: an example utilising the human heart.

    PubMed

    Tunali, S; Kawamoto, K; Farrell, M L; Labrash, S; Tamura, K; Lozanoff, S

    2011-08-01

    Computerised modelling methods have become highly useful for generating electronic representations of anatomical structures. These methods rely on crosssectional tissue slices in databases such as the Visible Human Male and Female, the Visible Korean Human, and the Visible Chinese Human. However, these databases are time consuming to generate and require labour-intensive manual digitisation while the number of specimens is very limited. Plastinated anatomical material could provide a possible alternative to data collection, requiring less time to prepare and enabling the use of virtually any anatomical or pathological structure routinely obtained in a gross anatomy laboratory. The purpose of this study was to establish an approach utilising plastinated anatomical material, specifically human hearts, for the purpose computerised 3-D modelling. Human hearts were collected following gross anatomical dissection and subjected to routine plastination procedures including dehydration (-25(o)C), defatting, forced impregnation, and curing at room temperature. A graphics pipeline was established comprising data collection with a hand-held scanner, 3-D modelling, model polishing, file conversion, and final rendering. Representative models were viewed and qualitatively assessed for accuracy and detail. The results showed that the heart model provided detailed surface information necessary for gross anatomical instructional purposes. Rendering tools facilitated optional model manipulation for further structural clarification if selected by the user. The use of plastinated material for generating 3-D computerised models has distinct advantages compared to cross-sectional tissue images. PMID:21866531

  14. Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal.

    PubMed

    Kreipke, R E; Birren, S J

    2015-12-01

    Sympathetic drive to the heart is a key modulator of cardiac function and interactions between heart tissue and innervating sympathetic fibres are established early in development. Significant innervation takes place during postnatal heart development, a period when cardiomyocytes undergo a rapid transition from proliferative to hypertrophic growth. The question of whether these innervating sympathetic fibres play a role in regulating the modes of cardiomyocyte growth was investigated using 6-hydroxydopamine (6-OHDA) to abolish early sympathetic innervation of the heart. Postnatal chemical sympathectomy resulted in rats with smaller hearts, indicating that heart growth is regulated by innervating sympathetic fibres during the postnatal period. In vitro experiments showed that sympathetic interactions resulted in delays in markers of cardiomyocyte maturation, suggesting that changes in the timing of the transition from hyperplastic to hypertrophic growth of cardiomyocytes could underlie changes in heart size in the sympathectomized animals. There was also an increase in the expression of Meis1, which has been linked to cardiomyocyte cell cycle withdrawal, suggesting that sympathetic signalling suppresses cell cycle withdrawal. This signalling involves β-adrenergic activation, which was necessary for sympathetic regulation of cardiomyocyte proliferation and hypertrophy. The effect of β-adrenergic signalling on cardiomyocyte hypertrophy underwent a developmental transition. While young postnatal cardiomyocytes responded to isoproterenol (isoprenaline) with a decrease in cell size, mature cardiomyocytes showed an increase in cell size in response to the drug. Together, these results suggest that early sympathetic effects on proliferation modulate a key transition between proliferative and hypertrophic growth of the heart and contribute to the sympathetic regulation of adult heart size. PMID:26420487

  15. Stretchable, multiplexed pH sensors with demonstrations on rabbit and human hearts undergoing ischemia.

    PubMed

    Chung, Hyun-Joong; Sulkin, Matthew S; Kim, Jong-Seon; Goudeseune, Camille; Chao, Hsin-Yun; Song, Joseph W; Yang, Sang Yoon; Hsu, Yung-Yu; Ghaffari, Roozbeh; Efimov, Igor R; Rogers, John A

    2014-01-01

    Stable pH is an established biomarker of health, relevant to all tissues of the body, including the heart. Clinical monitoring of pH in a practical manner, with high spatiotemporal resolution, is particularly difficult in organs such as the heart due to its soft mechanics, curvilinear geometry, heterogeneous surfaces, and continuous, complex rhythmic motion. The results presented here illustrate that advanced strategies in materials assembly and electrochemical growth can yield interconnected arrays of miniaturized IrOx pH sensors encapsulated in thin, low-modulus elastomers to yield conformal monitoring systems capable of noninvasive measurements on the surface of the beating heart. A thirty channel custom data acquisition system enables spatiotemporal pH mapping with a single potentiostat. In vitro testing reveals super-Nernstian sensitivity with excellent uniformity (69.9 ± 2.2 mV/pH), linear response to temperature (-1.6 mV °C(-1) ), and minimal influence of extracellular ions (<3.5 mV). Device examples include sensor arrays on balloon catheters and on skin-like stretchable membranes. Real-time measurement of pH on the surfaces of explanted rabbit hearts and a donated human heart during protocols of ischemia-reperfusion illustrate some of the capabilities. Envisioned applications range from devices for biological research, to surgical tools and long-term implants. PMID:23868871

  16. Assessment of three techniques for delivering stem cells to the heart using PET and MR imaging

    PubMed Central

    2013-01-01

    Background Stem cell therapy has a promising potential for the curing of various degenerative diseases, including congestive heart failure (CHF). In this study, we determined the efficacy of different delivery methods for stem cell administration to the heart for the treatment of CHF. Both positron emission tomography (PET) and magnetic resonance imaging (MRI) were utilized to assess the distribution of delivered stem cells. Methods Adipose-derived stem cells of male rats were labeled with super-paramagnetic iron oxide (SPIO) and 18 F-fluorodeoxyglucose (FDG). The left anterior descending coronary artery (LAD) of the female rats was occluded to induce acute ischemic myocardial injury. Immediately after the LAD occlusion, the double-labeled stem cells were injected into the ischemic myocardium (n = 5), left ventricle (n = 5), or tail vein (n = 4). In another group of animals (n = 3), the stem cells were injected directly into the infarct rim 1 week after the LAD occlusion. Whole-body PET images and MR images were acquired to determine biodistribution of the stem cells. After the imaging, the animals were euthanized and retention of the stem cells in the vital organs was determined by measuring the cDNA specific to the Y chromosome. Results PET images showed that retention of the stem cells in the ischemic myocardium was dependent on the cell delivery method. The tail vein injection resulted in the least cell retention in the heart (1.2% ± 0.6% of total injected cells). Left ventricle injection led to 3.5% ± 0.9% cell retention and direct myocardial injection resulted in the highest rate of cell retention (14% ± 4%) in the heart. In the animals treated 1 week after the LAD occlusion, rate of cell retention in the heart was only 4.5% ±1.1%, suggesting that tissue injury has a negative impact on cell homing. In addition, there was a good agreement between the results obtained through PET-MR imaging and histochemical measurements. Conclusion PET

  17. On endocytosis of foreign ferritin and occurrence of phagolysosomes in fish heart endothelial cells.

    PubMed

    Leknes, Ingvar Leiv

    2016-04-01

    In the present study the ultrastructure and function of the endothelial cells enveloping the muscle trabeculae in heart in two teleosts, platyfish and firemouth cichlid, are described and discussed. These cells displayed a structure making them able to take up large amounts of foreign ferritin particles from the blood stream. The ferritin particles were assembled into huge phagolysosomes. Large amounts of Prussian blue were precipitated throughout these lysosomes when treated with acid ferrohexacyanide solution. The occurrence of Prussian blue precipitations in the control heart endothelial cells after Schmorl's solution, suggests that these cells normally contain undigestible material, a finding which strengthens the view that this tissue is involved in blood clearance in the present species. In conclusion, these heart endothelial cells seem able to perform a very efficient blood clearance of scavenger and foreign macromolecules and particles in the present species. PMID:26852295

  18. Efficient Differentiation of Human Induced Pluripotent Stem Cells Generates Cardiac Cells That Provide Protection Following Myocardial Infarction in the Rat

    PubMed Central

    Carr, Carolyn; Yang, Cheng Tao; Stuckey, Daniel J.; Clarke, Kieran; Watt, Suzanne M.

    2012-01-01

    Induced pluripotent stem (iPS) cells are being used increasingly to complement their embryonic counterparts to understand and develop the therapeutic potential of pluripotent cells. Our objectives were to identify an efficient cardiac differentiation protocol for human iPS cells as monolayers, and demonstrate that the resulting cardiac progenitors could provide a therapeutic benefit in a rodent model of myocardial infarction. Herein, we describe a 14-day protocol for efficient cardiac differentiation of human iPS cells as a monolayer, which routinely yielded a mixed population in which over 50% were cardiomyocytes, endothelium, or smooth muscle cells. When differentiating, cardiac progenitors from day 6 of this protocol were injected into the peri-infarct region of the rat heart; after coronary artery ligation and reperfusion, we were able to show that human iPS cell-derived cardiac progenitor cells engrafted, differentiated into cardiomyocytes and smooth muscle, and persisted for at least 10 weeks postinfarct. Hearts injected with iPS-derived cells showed a nonsignificant trend toward protection from decline in function after myocardial infarction, as assessed by magnetic resonance imaging at 10 weeks, such that the ejection fraction at 10 weeks in iPS treated hearts was 62%±4%, compared to that of control infarcted hearts at 45%±9% (P<0.2). In conclusion, we demonstrated efficient cardiac differentiation of human iPS cells that gave rise to progenitors that were retained within the infarcted rat heart, and reduced remodeling of the heart after ischemic damage. PMID:22182484

  19. Human Adrenocortical Carcinoma Cell Lines

    PubMed Central

    Wang, Tao; Rainey, William E.

    2011-01-01

    Summary The human adrenal cortex secretes mineralocorticoids, glucocorticoids and adrenal androgens. These steroids are produced from unique cell types located within the three distinct zones of the adrenal cortex. Disruption of adrenal steroid production results in a variety of diseases that can lead to hypertension, metabolic syndrome, infertility and androgen excess. The adrenal cortex is also a common site for the development of adenomas, and rarely the site for the development of carcinomas. The adenomas can lead to diseases associated with adrenal steroid excess, while the carcinomas are particularly aggressive and have a poor prognosis. In vitro cell culture models provide an important tool to examine molecular and cellular mechanisms controlling both the normal and pathologic function of the adrenal cortex. Herein we discuss the human adrenocortical cell lines and their use as model systems for adrenal studies. PMID:21924324

  20. Bone Marrow-Derived Cells Contribute to Fibrosis in the Chronically Failing Heart

    PubMed Central

    Chu, Po-Yin; Mariani, Justin; Finch, Samara; McMullen, Julie R.; Sadoshima, Junichi; Marshall, Tanneale; Kaye, David M.

    2010-01-01

    Cardiac fibrosis contributes significantly to the phenotype of the chronically failing heart. It is not clear whether in this setting the fibrosis is contributed by native cardiac fibroblasts or alternatively by recruitment of cells arising from the bone marrow. We aimed to determine the contribution of bone marrow-derived cells to cardiac fibrosis in the failing heart and to investigate potentially contributing cytokines. Bone marrow-derived fibrocyte recruitment to the failing heart was studied in a transgenic (Mst1 mice) model of dilated cardiomyopathy. In conjunction, we examined the role of stromal-derived factor-1 (SDF-1), a key chemoattractant, by assessing myocardial expression and secretion by cardiomyocytes and in clinical samples. Bone marrow-derived cells were recruited in significantly greater numbers in Mst1 versus control mice (P < 0.001), contributing 17 ± 4% of the total fibroblast load in heart failure. Patients with heart failure had higher plasma levels of SDF-1 than healthy control subjects (P < 0.01). We found that cardiomyocytes constitutively secrete SDF-1, which is significantly up-regulated by angiotensin II. SDF-1 was shown to increases cardiac fibroblast migration by 59% (P < 0.05). Taken together, our data suggest that recruitment of bone marrow-derived cells under the influence of factors, including SDF-1, may play an important role in the pathogenesis of cardiac fibrosis in heart failure. PMID:20150435

  1. Generation of an expandable intermediate mesoderm restricted progenitor cell line from human pluripotent stem cells.

    PubMed

    Kumar, Nathan; Richter, Jenna; Cutts, Josh; Bush, Kevin T; Trujillo, Cleber; Nigam, Sanjay K; Gaasterland, Terry; Brafman, David; Willert, Karl

    2015-01-01

    The field of tissue engineering entered a new era with the development of human pluripotent stem cells (hPSCs), which are capable of unlimited expansion whilst retaining the potential to differentiate into all mature cell populations. However, these cells harbor significant risks, including tumor formation upon transplantation. One way to mitigate this risk is to develop expandable progenitor cell populations with restricted differentiation potential. Here, we used a cellular microarray technology to identify a defined and optimized culture condition that supports the derivation and propagation of a cell population with mesodermal properties. This cell population, referred to as intermediate mesodermal progenitor (IMP) cells, is capable of unlimited expansion, lacks tumor formation potential, and, upon appropriate stimulation, readily acquires properties of a sub-population of kidney cells. Interestingly, IMP cells fail to differentiate into other mesodermally-derived tissues, including blood and heart, suggesting that these cells are restricted to an intermediate mesodermal fate. PMID:26554899

  2. [Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease].

    PubMed

    Stegmann, T J; Hoppert, T; Schneider, A; Gemeinhardt, S; Köcher, M; Ibing, R; Strupp, G

    2000-09-01

    Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction either by reducing myocardial oxygen demand, preventing further disease progression, restoring coronary blood flow pharmacologically or mechanically, or bypassing the stenotic lesions and obstructed coronary artery segments. Gene therapy, especially using angiogenic growth factors, has emerged recently as a potential new treatment for cardiovascular disease. Following extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease and peripheral vascular lesions have been performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) appear to be particularly effective in initiating neovascularization (neoangiogenesis) in hypoxic or ischemic tissues. The first clinical study on patients with coronary heart disease treated by local intramyocardial injection of FGF-1 showed a 3-fold increase of capillary density mediated by the growth factor. Also, angiogenic growth factor injection intramyocardially as sole therapy for end-stage coronary disease showed an improvement of myocardial perfusion in the target areas as well as a reduction of symptoms and an increase in working capacity. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this new approach may evolve into a fourth principle of treatment of atherosclerotic cardiovascular disease. PMID:11076317

  3. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus–Seropositive Patients

    PubMed Central

    Kittleson, Michelle M.; Dilibero, Deanna; Hardy, W. David; Kobashigawa, Jon A.; Esmailian, Fardad

    2016-01-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus—accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation. PMID:27047290

  4. MicroRNA-214 Is Upregulated in Heart Failure Patients and Suppresses XBP1-Mediated Endothelial Cells Angiogenesis

    PubMed Central

    DUAN, QUANLU; YANG, LEI; GONG, WEI; CHAUGAI, SANDIP; WANG, FENG; CHEN, CHEN; WANG, PEIHUA; ZOU, MING-HUI; WANG, DAO WEN

    2016-01-01

    More and more miRNAs have been shown to regulate gene expression in the heart and dysregulation of their expression has been linked to cardiovascular diseases including the miR-199a/214 cluster. However, the signature of circulating miR-214 expression and its possible roles during the development of heart failure has been less well studied. In this study, we elucidated the biological and clinical significance of miR-214 dysregulation in heart failure. Firstly, circulating miR-214 was measured by quantitative PCR, and we found that miR-214 was upregulated in the serum of chronic heart failure patients, as well as in hypertrophic and failing hearts of humans and mice. Adeno-associated virus serotype 9 (AAV9)-mediated miR-214 silencing attenuates isoproterenol (ISO) infusion-induced cardiac dysfunction and impairment of cardiac angiogenesis in mice. Mechanistically, miR-214 overexpression reduces angiogenesis of HUVECs by targeting XBP1, an important transcription factor of unfolded protein response, and XBP1 silencing decreases HUVECs proliferation and angiogenesis similar to miR-214 overexpression. Furthermore, ectopic expression of XBP1 enhances endothelial cells proliferation and tube formation, and reverses anti-angiogenic effect of miR-214 over expression. All these findings suggest that miR-214 is an important regulator of angiogenesis in heart in vitro and in vivo, likely via regulating the expression of XBP1, and demonstrate that miR-214 plays an essential role in the control/inhibition of cardiac angiogenesis. PMID:25656649

  5. Simulated Microgravity Exerts an Age-Dependent Effect on the Differentiation of Cardiovascular Progenitors Isolated from the Human Heart.

    PubMed

    Fuentes, Tania I; Appleby, Nancy; Raya, Michael; Bailey, Leonard; Hasaniya, Nahidh; Stodieck, Louis; Kearns-Jonker, Mary

    2015-01-01

    Microgravity has a profound effect on cardiovascular function, however, little is known about the impact of microgravity on progenitors that reside within the heart. We investigated the effect of simulated microgravity exposure on progenitors isolated from the neonatal and adult human heart by quantifying changes in functional parameters, gene expression and protein levels after 6-7 days of 2D clinorotation. Utilization of neonatal and adult cardiovascular progenitors in ground-based studies has provided novel insight into how microgravity may affect cells differently depending on age. Simulated microgravity exposure did not impact AKT or ERK phosphorylation levels and did not influence cell migration, but elevated transcripts for paracrine factors were identified in neonatal and adult cardiovascular progenitors. Age-dependent responses surfaced when comparing the impact of microgravity on differentiation. Endothelial cell tube formation was unchanged or increased in progenitors from adults whereas neonatal cardiovascular progenitors showed a decline in tube formation (p<0.05). Von Willebrand Factor, an endothelial differentiation marker, and MLC2v and Troponin T, markers for cardiomyogenic differentiation, were elevated in expression in adult progenitors after simulated microgravity. DNA repair genes and telomerase reverse transcriptase which are highly expressed in early stem cells were increased in expression in neonatal but not adult cardiac progenitors after growth under simulated microgravity conditions. Neonatal cardiac progenitors demonstrated higher levels of MESP1, OCT4, and brachyury, markers for early stem cells. MicroRNA profiling was used to further investigate the impact of simulated microgravity on cardiovascular progenitors. Fifteen microRNAs were significantly altered in expression, including microRNAs-99a and 100 (which play a critical role in cell dedifferentiation). These microRNAs were unchanged in adult cardiac progenitors. The effect of

  6. Cardiac repair and regeneration: the Rubik's cube of cell therapy for heart disease.

    PubMed

    Boudoulas, Konstantinos D; Hatzopoulos, Antonis K

    2009-01-01

    Acute ischemic injury and chronic cardiomyopathies damage healthy heart tissue. Dead cells are gradually replaced by a fibrotic scar, which disrupts the normal electromechanical continuum of the ventricular muscle and compromises its pumping capacity. Recent studies in animal models of ischemic cardiomyopathy suggest that transplantation of various stem cell preparations can improve heart recovery after injury. The first clinical trials in patients produced some encouraging results, showing modest benefits. Most of the positive effects are probably because of a favorable paracrine influence of stem cells on the disease microenvironment. Stem cell therapy attenuates inflammation, reduces apoptosis of surrounding cells, induces angiogenesis, and lessens the extent of fibrosis. However, little new heart tissue is formed. The current challenge is to find ways to improve the engraftment, long-term survival and appropriate differentiation of transplanted stem cells within the cardiovascular tissue. Hence, there has been a surge of interest in pluripotent stem cells with robust cardiogenic potential, as well as in the inherent repair and regenerative mechanisms of the heart. Recent discoveries on the biology of adult stem cells could have relevance for cardiac regeneration. Here, we discuss current developments in the field of cardiac repair and regeneration, and present our ideas about the future of stem cell therapy. PMID:19553696

  7. Proteomics in human disease: cancer, heart and infectious diseases.

    PubMed

    Jungblut, P R; Zimny-Arndt, U; Zeindl-Eberhart, E; Stulik, J; Koupilova, K; Pleissner, K P; Otto, A; Müller, E C; Sokolowska-Köhler, W; Grabher, G; Stöffler, G

    1999-07-01

    In recent years, genomics has increased the understanding of many diseases. Proteomics is a rapidly growing research area that encompasses both genetic and environmental factors. The protein composition represents the functional status of a biological compartment. The five approaches presented here resulted in the detection of disease-associated proteins. Calgranulin B was upregulated in colorectal cancer, and hepatoma-derived aldose reductase-like protein was reexpressed in a rat model during hepatocarcinogenesis. In these two investigations, attention was focused on one protein, obviously differing in amount, directly after two-dimensional electrophoresis (2-DE). Additional methods, such as enzyme activity measurements and immunohistochemistry, confirmed the disease association of the two candidates resulting from 2-DE subtractive analysis. The following three investigations take advantage of the holistic potential of the 2-DE approach. The comparison of 2-DE patterns from dilated cardiomyopathy patients with those of controls revealed 25 statistically significant intensity differences, from which 12 were identified by amino acid analysis, Edman degradation or matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). A human myocardial 2-DE database was constructed, containing 3300 protein spots and 150 identified protein species. The number of identified proteins was limited by the capacity of our group, rather than by the principle of feasibility. Another field where proteomics proves to be a valuable tool in identifying proteins of importance for diagnosis is proteome analysis of pathogenic microorganisms such as Borrelia burgdorferi (Lyme disease) and Toxoplasma gondii (toxoplasmosis). Sera from patients with early or late symptoms of Lyme borreliosis contained antibodies of various classes against about 80 antigens each, containing the already described antigens OspA, B and C, flagellin, p83/100, and p39. Similarly, antibody reactivity to

  8. Cultured Human Renal Cortical Cells

    NASA Technical Reports Server (NTRS)

    1998-01-01

    During the STS-90 shuttle flight in April 1998, cultured renal cortical cells revealed new information about genes. Timothy Hammond, an investigator in NASA's microgravity biotechnology program was interested in culturing kidney tissue to study the expression of proteins useful in the treatment of kidney diseases. Protein expression is linked to the level of differentiation of the kidney cells, and Hammond had difficulty maintaining differentiated cells in vitro. Intrigued by the improvement in cell differentiation that he observed in rat renal cells cultured in NASA's rotating wall vessel (a bioreactor that simulates some aspects of microgravity) and during an experiment performed on the Russian Space Station Mir, Hammond decided to sleuth out which genes were responsible for controlling differentiation of kidney cells. To do this, he compared the gene activity of human renal cells in a variety of gravitational environments, including the microgravity of the space shuttle and the high-gravity environment of a centrifuge. Hammond found that 1,632 genes out of 10,000 analyzed changed their activity level in microgravity, more than in any of the other environments. These results have important implications for kidney research as well as for understanding the basic mechanism for controlling cell differentiation.

  9. 2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure

    PubMed Central

    Moussavi-Harami, Farid; Razumova, Maria V.; Racca, Alice W.; Cheng, Yuanhua; Stempien-Otero, April; Regnier, Michael

    2014-01-01

    We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca2+ concentrations with dATP compared to ATP. This resulted in an increase in the Ca2+ sensitivity of force (pCa50) by 0.06 pCa units. The rate of force redevelopment (kTR) in demembranated wall muscle was also increased, as was the rate of contractile activation (kACT) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development was increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models shows the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure. PMID:25498214

  10. Cardiosphere-derived cell sheet primed with hypoxia improves left ventricular function of chronically infarcted heart.

    PubMed

    Hosoyama, Tohru; Samura, Makoto; Kudo, Tomoaki; Nishimoto, Arata; Ueno, Koji; Murata, Tomoaki; Ohama, Takashi; Sato, Koichi; Mikamo, Akihito; Yoshimura, Koichi; Li, Tao-Sheng; Hamano, Kimikazu

    2015-01-01

    Cardiosphere-derived cells (CDCs) isolated from postnatal heart tissue are a convenient and efficientresource for the treatment of myocardial infarction. However, poor retention of CDCs in infarcted hearts often causes less than ideal therapeutic outcomes. Cell sheet technology has been developed as a means of permitting longer retention of graft cells, and this therapeutic strategy has opened new avenues of cell-based therapy for severe ischemic diseases. However, there is still scope for improvement before this treatment can be routinely applied in clinical settings. In this study, we investigated whether hypoxic preconditioning enhances the therapeutic efficacy of CDC monolayer sheets. To induce hypoxia priming, CDC monolayer sheets were placed in an incubator adjusted to 2% oxygen for 24 hours, and then preconditioned mouse CDC sheets were implanted into the infarcted heart of old myocardial infarction mouse models. Hypoxic preconditioning of CDC sheets remarkably increased the expression of vascular endothelial growth factor through the PI3-kinase/Akt signaling pathway. Implantation of preconditioned CDC sheets improved left ventricular function inchronically infarcted hearts and reduced fibrosis. The therapeutic efficacy of preconditioned CDC sheets was higher than the CDC sheets that were cultured under normaxia condition. These results suggest that hypoxic preconditioning augments the therapeutic angiogenic and anti-fibrotic activity of CDC sheets. A combination of cell sheets and hypoxic preconditioning offers an attractive therapeutic protocol for CDC transplantation into chronically infarcted hearts. PMID:26885271

  11. Cardiosphere-derived cell sheet primed with hypoxia improves left ventricular function of chronically infarcted heart

    PubMed Central

    Hosoyama, Tohru; Samura, Makoto; Kudo, Tomoaki; Nishimoto, Arata; Ueno, Koji; Murata, Tomoaki; Ohama, Takashi; Sato, Koichi; Mikamo, Akihito; Yoshimura, Koichi; Li, Tao-Sheng; Hamano, Kimikazu

    2015-01-01

    Cardiosphere-derived cells (CDCs) isolated from postnatal heart tissue are a convenient and efficientresource for the treatment of myocardial infarction. However, poor retention of CDCs in infarcted hearts often causes less than ideal therapeutic outcomes. Cell sheet technology has been developed as a means of permitting longer retention of graft cells, and this therapeutic strategy has opened new avenues of cell-based therapy for severe ischemic diseases. However, there is still scope for improvement before this treatment can be routinely applied in clinical settings. In this study, we investigated whether hypoxic preconditioning enhances the therapeutic efficacy of CDC monolayer sheets. To induce hypoxia priming, CDC monolayer sheets were placed in an incubator adjusted to 2% oxygen for 24 hours, and then preconditioned mouse CDC sheets were implanted into the infarcted heart of old myocardial infarction mouse models. Hypoxic preconditioning of CDC sheets remarkably increased the expression of vascular endothelial growth factor through the PI3-kinase/Akt signaling pathway. Implantation of preconditioned CDC sheets improved left ventricular function inchronically infarcted hearts and reduced fibrosis. The therapeutic efficacy of preconditioned CDC sheets was higher than the CDC sheets that were cultured under normaxia condition. These results suggest that hypoxic preconditioning augments the therapeutic angiogenic and anti-fibrotic activity of CDC sheets. A combination of cell sheets and hypoxic preconditioning offers an attractive therapeutic protocol for CDC transplantation into chronically infarcted hearts. PMID:26885271

  12. Human stem cell ethics: beyond the embryo.

    PubMed

    Sugarman, Jeremy

    2008-06-01

    Human embryonic stem cell research has elicited powerful debates about the morality of destroying human embryos. However, there are important ethical issues related to stem cell research that are unrelated to embryo destruction. These include particular issues involving different types of cells used, the procurement of such cells, in vivo use of stem cells, intellectual property, and conflicts of interest. PMID:18522846

  13. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure.

    PubMed

    Madonna, Rosalinda; Van Laake, Linda W; Davidson, Sean M; Engel, Felix B; Hausenloy, Derek J; Lecour, Sandrine; Leor, Jonathan; Perrino, Cinzia; Schulz, Rainer; Ytrehus, Kirsti; Landmesser, Ulf; Mummery, Christine L; Janssens, Stefan; Willerson, James; Eschenhagen, Thomas; Ferdinandy, Péter; Sluijter, Joost P G

    2016-06-14

    Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair. PMID:27055812

  14. Heart of glass anchors Rasip1 at endothelial cell-cell junctions to support vascular integrity

    PubMed Central

    de Kreuk, Bart-Jan; Gingras, Alexandre R; Knight, James DR; Liu, Jian J; Gingras, Anne-Claude; Ginsberg, Mark H

    2016-01-01

    Heart of Glass (HEG1), a transmembrane receptor, and Rasip1, an endothelial-specific Rap1-binding protein, are both essential for cardiovascular development. Here we performed a proteomic screen for novel HEG1 interactors and report that HEG1 binds directly to Rasip1. Rasip1 localizes to forming endothelial cell (EC) cell-cell junctions and silencing HEG1 prevents this localization. Conversely, mitochondria-targeted HEG1 relocalizes Rasip1 to mitochondria in cells. The Rasip1-binding site in HEG1 contains a 9 residue sequence, deletion of which abrogates HEG1’s ability to recruit Rasip1. HEG1 binds to a central region of Rasip1 and deletion of this domain eliminates Rasip1’s ability to bind HEG1, to translocate to EC junctions, to inhibit ROCK activity, and to maintain EC junctional integrity. These studies establish that the binding of HEG1 to Rasip1 mediates Rap1-dependent recruitment of Rasip1 to and stabilization of EC cell-cell junctions. DOI: http://dx.doi.org/10.7554/eLife.11394.001 PMID:26780829

  15. Organization of ventricular fibrillation in the human heart: experiments and models.

    PubMed

    ten Tusscher, K H W J; Mourad, A; Nash, M P; Clayton, R H; Bradley, C P; Paterson, D J; Hren, R; Hayward, M; Panfilov, A V; Taggart, P

    2009-05-01

    Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co-ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three-dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 +/- 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 +/- 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human-based clinical and computational studies complement animal research. PMID:19168541

  16. Muscarinic cholinergic receptor in the human heart evidenced under physiological conditions by positron emission tomography.

    PubMed Central

    Syrota, A; Comar, D; Paillotin, G; Davy, J M; Aumont, M C; Stulzaft, O; Maziere, B

    1985-01-01

    The muscarinic receptor was studied in vivo in the human heart by a noninvasive method, positron emission tomography (PET). The study showed that the binding sites of 11C-labeled methiodide quinuclidinyl benzilate [( 11C]-MQNB), a muscarinic antagonist, were mainly distributed in the ventricular septum (98 pmol/cm3 of heart) and in the left ventricular wall (89 pmol/cm3), while the atria were not visualized. A few minutes after a bolus intravenous injection, the concentration of [11C]MQNB in blood fell to a negligible level (less than 100th of the concentration measured in the ventricular septum). When injected at high specific radioactivity, the concentration of [11C]MQNB in the septum rapidly increased and then remained constant with time. This result was explained by rebinding of the ligand to receptors. It was the major difference observed between the kinetics of binding of [11C]MQNB to receptor sites after intravenous injection in vivo and that of [3H]MQNB to heart homogenates in vitro. The MQNB concentrations in the ventricular septum of different individuals were found to be highest when the heart rate at the time of injection was slow. This result suggests that the antagonist binding site is related to a low-affinity conformational state of the receptor under predominant vagal stimulation. Thus, positron emission tomography might be the ideal method to study the physiologically active form of the muscarinic acetylcholine receptor in man. Images PMID:3871527

  17. Embryonic Stem Cell Patents and Human Dignity

    PubMed Central

    Resnik, David B.

    2009-01-01

    This article examines the assertion that human embryonic stem cells patents are immoral because they violate human dignity. After analyzing the concept of human dignity and its role in bioethics debates, this article argues that patents on human embryos or totipotent embryonic stem cells violate human dignity, but that patents on pluripotent or multipotent stem cells do not. Since patents on pluripotent or multipotent stem cells may still threaten human dignity by encouraging people to treat embryos as property, patent agencies should carefully monitor and control these patents to ensure that patents are not inadvertently awarded on embryos or totipotent stem cells. PMID:17922198

  18. Acute phase lipocalin Ex-FABP is involved in heart development and cell survival.

    PubMed

    Gentili, C; Tutolo, G; Zerega, B; Di Marco, E; Cancedda, R; Cancedda, F Descalzi

    2005-03-01

    Ex-FABP is an extracellular fatty acid binding protein, expressed during chicken embryo development in cartilage, muscle fibers, and blood granulocytes. Transfection of chondrocytes and myoblasts with anti-sense Ex-FABP cDNA results in inhibition of cell proliferation and apoptosis induction. Ex-FABP expression is dramatically enhanced by inflammatory stimuli and in pathological conditions. In this paper, by in situ whole mount and immunohistochemistry analysis we show that, at early developmental stage, Ex-FABP is diffuse in all tissues of chick embryos. Particularly high level of transcript and protein are expressed in the heart. During acute phase response (APR) induced by endotoxin LPS injection, a marked increase of Ex-FABP mRNA was observed in embryos, highest Ex-FABP expression being in heart and liver. To investigate in vivo the biological role of Ex-FABP, we have directly microinjected chicken embryos with antibody against Ex-FABP. Almost 70% of chicken embryos died and the target tissue was the heart. We detected in heart of the treated embryos a significant increase of apoptotic cells and high level of fatty acids. We propose that the accumulation of fatty acid, specific ligand of Ex-FABP, in the cell microenvironment is responsible of heart cell death, and we suggest that Ex-FABP may act as a survival protein by playing a role as scavenger for fatty acids. PMID:15455366

  19. Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

    PubMed Central

    Ribeiro, Inês; Kawakami, Yasuhiko; Büscher, Dirk; Raya, Ángel; Rodríguez-León, Joaquín; Morita, Masanobu; Rodríguez Esteban, Concepción; Izpisúa Belmonte, Juan Carlos

    2007-01-01

    Background The heart forms from a linear tube that is subject to complex remodeling during embryonic development. Hallmarks of this remodeling are the looping of the heart tube and the regionalization into chamber and non-chamber myocardium. Cardiomyocytes in the future chamber myocardium acquire different cellular and physiological characteristics through activation of a chamber-specific genetic program, which is in part mediated by T-box genes. Methodology/Principal Finding We characterize two new zebrafish T-box transcription factors, tbx3b and tbx2a, and analyze their role during the development of the atrioventricular canal. Loss- and gain-of-function analyses demonstrate that tbx3b and tbx2a are necessary to repress the chamber-genetic program in the non-chamber myocardium. We also show that tbx3b and tbx2a are required to control cell proliferation in the atrioventricular canal and that misregulation of cell proliferation in the heart tube influences looping. Furthermore, we characterize the heart phenotype of a novel Tbx3 mutation in mice and show that both the control of cell proliferation and the repression of chamber-specific genetic program in the non-chamber myocardium are conserved roles of Tbx3 in this species. Conclusions/Significance Taken together, our results uncover an evolutionarily conserved role of Tbx2/3 transcription factors during remodeling of the heart myocardium and highlight the importance of controlling cell proliferation as a driving force of morphogenesis. PMID:17460765

  20. Interleukin-1{beta} regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells

    SciTech Connect

    Zitta, Karina; Brandt, Berenice; Wuensch, Annegret; Meybohm, Patrick; Bein, Berthold; Steinfath, Markus; Scholz, Jens; Albrecht, Martin

    2010-09-03

    Research highlights: {yields} Levels of IL-1{beta} are increased in the pig myocardium after infarction. {yields} Cultured pig heart cells possess IL-1 receptors. {yields} IL-1{beta} increases cell proliferation of pig heart cells in-vitro. {yields} IL-1{beta} increases MMP-2 and MMP-9 activity in pig heart cells in-vitro. {yields} IL-1{beta} may be important for tissue remodelling events after myocardial infarction. -- Abstract: After myocardial infarction, elevated levels of interleukins (ILs) are found within the myocardial tissue and IL-1{beta} is considered to play a major role in tissue remodelling events throughout the body. In the study presented, we have established a cell culture model of primary pig heart cells to evaluate the effects of different concentrations of IL-1{beta} on cell proliferation as well as expression and activity of enzymes typically involved in tissue remodelling. Primary pig heart cell cultures were derived from three different animals and stimulated with recombinant pig IL-1{beta}. RNA expression was detected by RT-PCR, protein levels were evaluated by Western blotting, activity of matrix metalloproteinases (MMPs) was quantified by gelatine zymography and cell proliferation was measured using colorimetric MTS assays. Pig heart cells express receptors for IL-1 and application of IL-1{beta} resulted in a dose-dependent increase of cell proliferation (P < 0.05 vs. control; 100 ng/ml; 24 h). Gene expression of caspase-3 was increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h), and pro-caspase-3 but not active caspase was detected in lysates of pig heart cells by Western blotting. MMP-2 gene expression as well as enzymatic activities of MMP-2 and MMP-9 were increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h for gene expression, 48 and 72 h for enzymatic activities of MMP-2 and MMP-9, respectively). Our in vitro data suggest that IL-1{beta} plays a major role in the events of tissue remodelling in the heart. Combined

  1. The Evolution of the Stem Cell Theory for Heart Failure.

    PubMed

    Silvestre, Jean-Sébastien; Menasché, Philippe

    2015-12-01

    Various stem cell-based approaches for cardiac repair have achieved encouraging results in animal experiments, often leading to their rapid proceeding to clinical testing. However, freewheeling evolutionary developments of the stem cell theory might lead to dystopian scenarios where heterogeneous sources of therapeutic cells could promote mixed clinical outcomes in un-stratified patient populations. This review focuses on the lessons that should be learnt from the first generation of stem cell-based strategies and emphasizes the absolute requirement to better understand the basic mechanisms of stem cell biology and cardiogenesis. We will also discuss about the unexpected "big bang" in the stem cell theory, "blasting" the therapeutic cells to their unchallenged ability to release paracrine factors such as extracellular membrane vesicles. Paradoxically, the natural evolution of the stem cell theory for cardiac regeneration may end with the development of cell-free strategies with multiple cellular targets including cardiomyocytes but also other infiltrating or resident cardiac cells. PMID:26844266

  2. Time Course of Cell Sheet Adhesion to Porcine Heart Tissue after Transplantation

    PubMed Central

    Chang, Dehua; Shimizu, Tatsuya; Haraguchi, Yuji; Gao, Shuai; Sakaguchi, Katsuhisa; Umezu, Mitsuo; Yamato, Masayuki; Liu, Zhongmin; Okano, Teruo

    2015-01-01

    Multilayered cell sheets have been produced from bone marrow-derived mesenchymal stem cells (MSCs) for investigating their adhesion properties onto native porcine heart tissue. Once MSCs reached confluence after a 7-day culture on a temperature-responsive culture dish, a MSCs monolayer spontaneously detached itself from the dish, when the culture temperature was reduced from 37 to 20°C. The basal extracellular matrix (ECM) proteins of the single cell sheet are preserved, because this technique requires no proteolytic enzymes for harvesting cell sheet, which become a basic building block for assembling a multilayer cell sheet. The thickness of multilayered cell sheets made from three MSC sheets was found to be approximately 60 μm. For investigating the adhesion properties of the basal and apical sides, the multilayered cell sheets were transplanted onto the surface of the heart’s left ventricle. Multilayered cell sheets were histological investigated at 15, 30, 45 and 60 minutes after transplantation by hematoxylin eosin (HE) and azan dyes to determine required time for the adhesion of the multilayered sheets following cell-sheet transplantation. The results showed that only the basal side of multilayered cell sheets significantly enhanced the sheets adhesion onto the surface of heart 30 minutes after transplantation. This study concluded that (1) cell sheets had to be transplanted with its basal side onto the surface of heart tissue and (2) at least 30 minutes were necessary for obtaining the histological adhesion of the sheets to the heart tissue. This study provided clinical evidence and parameters for the successful application of MSC sheets to the myocardium and allowed cell sheet technology to be adapted clinical cell-therapy for myocardial diseases. PMID:26444683

  3. Sca-1+ cells from fetal heart with high aldehyde dehydrogenase activity exhibit enhanced gene expression for self-renewal, proliferation, and survival.

    PubMed

    Dey, Devaveena; Pan, Guodong; Varma, Nadimpalli Ravi S; Palaniyandi, Suresh Selvaraj

    2015-01-01

    Stem/progenitor cells from multiple tissues have been isolated based on enhanced activity of cytosolic aldehyde dehydrogenase (ALDH) enzyme. ALDH activity has emerged as a reliable marker for stem/progenitor cells, such that ALDH(bright/high) cells from multiple tissues have been shown to possess enhanced stemness properties (self-renewal and multipotency). So far though, not much is known about ALDH activity in specific fetal organs. In this study, we sought to analyze the presence and activity of the ALDH enzyme in the stem cell antigen-1-positive (Sca-1+) cells of fetal human heart. Biochemical assays showed that a subpopulation of Sca-1+ cells (15%) possess significantly high ALDH1 activity. This subpopulation showed increased expression of self-renewal markers compared to the ALDH(low) fraction. The ALDH(high) fraction also exhibited significant increase in proliferation and pro-survival gene expression. In addition, only the ALDH(high) and not the ALDH(low) fraction could give rise to all the cell types of the original population, demonstrating multipotency. ALDH(high) cells showed increased resistance against aldehyde challenge compared to ALDH(low) cells. These results indicate that ALDH(high) subpopulation of the cultured human fetal cells has enhanced self-renewal, multipotency, high proliferation, and survival, indicating that this might represent a primitive stem cell population within the fetal human heart. PMID:25861413

  4. Combined use of autogenic therapy and biofeedback in training effective control of heart rate by humans

    NASA Technical Reports Server (NTRS)

    Cowings, P. S.

    1977-01-01

    Experiments were performed on 24 men and women (aged 20-27 yr) in three equal groups who were taught to control their own heart rates by autogenic training and biofeedback under dark and sound-isolated conditions. Group I was parasympathetic dominant, group II was sympathetic dominant, and group III consisted of parasympathetic-dominant subjects and controls who received only biofeedback of their own heart rates. The results corroborate three hypotheses: (1) subjects with para-sympathetic-dominant autonomic profiles perform in a way that is both qualitatively and quantitatively different from subjects with sympathetic-dominant autonomic profiles; (2) tests of interindividual variability yield data relevant to individual performance in visceral learning tasks; and (3) the combined use of autogenic training, biofeedback, and verbal feedback is suitable for conditioning large stable autonomic responses in humans.

  5. Sizing up models of heart failure: Proteomics from flies to humans

    PubMed Central

    Kooij, Viola; Venkatraman, Vidya; Tra, John; Kirk, Jonathan A; Rowell, Janelle; Blice-Baum, Anna; Cammarato, Anthony; Van Eyk, Jennifer E

    2014-01-01

    Cardiovascular disease is the leading cause of death in the western world. Heart failure is a heterogeneous and complex syndrome, arising from various etiologies, which result in cellular phenotypes that vary from patient to patient. The ability to utilize genetic manipulation and biochemical experimentation in animal models has made them indispensable in the study of this chronic condition. Similarly, proteomics has been helpful for elucidating complicated cellular and molecular phenotypes and has the potential to identify circulating biomarkers and drug targets for therapeutic intervention. In this review, the use of human samples and animal model systems (pig, dog, rat, mouse, zebrafish, and fruit fly) in cardiac research is discussed. Additionally, the protein sequence homology between these species and the extent of conservation at the level of the phospho-proteome in major kinase signaling cascades involved in heart failure are investigated. PMID:24723306

  6. Heart rate variability of human in hypoxic oxygen-argon environment

    NASA Astrophysics Data System (ADS)

    Khayrullina, Rezeda; Smoleevskiy, Alexandr; Bubeev, Yuri

    Human adaptive capacity, reliability and stability in extreme environments depend primarily on the individual resistance to stresses, includes both innate and acquired components. We have conducted studies in six healthy subjects - men aged between 24 to 42 years who psychophysiological indicators acterizing the severity of stress reactions studied directly during an emergency situation, before and after it. The subjects were in a hypoxic oxygen-argon atmosphere 10 days. Cardiovascular system is one of the first to respond to stressful reaction. The method of heart rate variability (HRV) allows us to estimate balance of sympathetic and parasympathetic parts of vegetative nervous system. In the course of the baseline study it was found that resting heart rate (HR) in the examined individuals is within normal limits. During the experiment in all subjects there was a trend towards more frequent heartbeat. Each subject at one stage or another stay in a hypoxic oxygen-argon environment heart rate go beyond the group norm, but the extent and duration of these abnormalities were significantly different. Marked increase in middle heart rate during of subjects experiment, fluctuating within a wide range (from 2.3% to 29.1%). Marked increase in middle heart rate during of subjects experiment, fluctuating within a wide range (from 2.3% to 29.1%). This suggests that the ability to adapt to living in the investigated gas environment have marked individual differences. SDNN (mean square deviation of all R-R intervals) is the integral indicator of the total effect of the sinus node to the sympathetic and parasympathetic parts of vegetative nervous system, as well as indicating the higher functional reserves of the cardiovascular systems. Increase in heart rate in the majority of subject was accompanied by an increase in individual SDNN. This suggests that the parasympathetic system is able to balance the increase in activity of the sympathetic system, and functional reserves are

  7. Sodium MRI of the human heart at 7.0 T: preliminary results.

    PubMed

    Graessl, Andreas; Ruehle, Anjuli; Waiczies, Helmar; Resetar, Ana; Hoffmann, Stefan H; Rieger, Jan; Wetterling, Friedrich; Winter, Lukas; Nagel, Armin M; Niendorf, Thoralf

    2015-08-01

    The objective of this work was to examine the feasibility of three-dimensional (3D) and whole heart coverage (23)Na cardiac MRI at 7.0 T including single-cardiac-phase and cinematic (cine) regimes. A four-channel transceiver RF coil array tailored for (23)Na MRI of the heart at 7.0 T (f = 78.5 MHz) is proposed. An integrated bow-tie antenna building block is used for (1)H MR to support shimming, localization and planning in a clinical workflow. Signal absorption rate simulations and assessment of RF power deposition were performed to meet the RF safety requirements. (23) Na cardiac MR was conducted in an in vivo feasibility study. 3D gradient echo (GRE) imaging in conjunction with Cartesian phase encoding (total acquisition time T(AQ)  = 6 min 16 s) and whole heart coverage imaging employing a density-adapted 3D radial acquisition technique (T(AQ)  = 18 min 20 s) were used. For 3D GRE-based (23)Na MRI, acquisition of standard views of the heart using a nominal in-plane resolution of (5.0 × 5.0) mm(2) and a slice thickness of 15 mm were feasible. For whole heart coverage 3D density-adapted radial (23)Na acquisitions a nominal isotropic spatial resolution of 6 mm was accomplished. This improvement versus 3D conventional GRE acquisitions reduced partial volume effects along the slice direction and enabled retrospective image reconstruction of standard or arbitrary views of the heart. Sodium cine imaging capabilities were achieved with the proposed RF coil configuration in conjunction with 3D radial acquisitions and cardiac gating. Cardiac-gated reconstruction provided an enhancement in blood-myocardium contrast of 20% versus the same data reconstructed without cardiac gating. The proposed transceiver array enables (23)Na MR of the human heart at 7.0 T within clinical acceptable scan times. This capability is in positive alignment with the needs of explorations that are designed to examine the potential of (23)Na MRI for the assessment of cardiovascular and

  8. Bone Marrow Mesenchymal Stem Cell Transplantation Retards the Natural Senescence of Rat Hearts

    PubMed Central

    Zhang, Mingyu; Liu, Di; Li, Shuang; Chang, Lingling; Zhang, Yu; Liu, Ruixue; Sun, Fei; Duan, Wenqi; Du, Weijie; Wu, Yanping; Zhao, Tianyang; Xu, Chaoqian

    2015-01-01

    Bone marrow mesenchymal stem cells (BMSCs) have been shown to offer a wide variety of cellular functions including the protective effects on damaged hearts. Here we investigated the antiaging properties of BMSCs and the underlying mechanism in a cellular model of cardiomyocyte senescence and a rat model of aging hearts. Neonatal rat ventricular cells (NRVCs) and BMSCs were cocultured in the same dish with a semipermeable membrane to separate the two populations. Monocultured NRVCs displayed the senescence-associated phenotypes, characterized by an increase in the number of β-galactosidase-positive cells and decreases in the degradation and disappearance of cellular organelles in a time-dependent manner. The levels of reactive oxygen species and malondialdehyde were elevated, whereas the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase were decreased, along with upregulation of p53, p21Cip1/Waf1, and p16INK4a in the aging cardiomyocytes. These deleterious alterations were abrogated in aging NRVCs cocultured with BMSCs. Qualitatively, the same senescent phenotypes were consistently observed in aging rat hearts. Notably, BMSC transplantation significantly prevented these detrimental alterations and improved the impaired cardiac function in the aging rats. In summary, BMSCs possess strong antisenescence action on the aging NRVCs and hearts and can improve cardiac function after transplantation in aging rats. The present study, therefore, provides an alternative approach for the treatment of heart failure in the elderly population. PMID:25855590

  9. Vascular potential of human pluripotent stem cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cardiovascular disease is the number one cause of death and disability in the US. Understanding the biological activity of stem and progenitor cells, and their ability to contribute to the repair, regeneration and remodeling of the heart and blood vessels affected by pathological processes is an ess...

  10. Immunopathology of experimental Chagas' disease: binding of T cells to Trypanosoma cruzi-infected heart tissue.

    PubMed Central

    Mortatti, R C; Maia, L C; de Oliveira, A V; Munk, M E

    1990-01-01

    The immunopathology of Chagas' disease was studied in the experimental model of chronic infection in C57BL/10JT or mice. Sublethal infection with Trypanosoma cruzi, Y strain, induced specific antibodies and a delayed hypersensitivity response to parasite antigens. Mice developed chronic chagasic myocarditis but not skeletal muscle myositis. Binding of T cells to infected heart tissue was investigated during short-term cocultivation of lymphocytes with heart cryostat sections. T cells from infected mice and from normal controls bound equally to myocardium and liver sections from both infected and normal mice. A search in depth was attempted with cells heavily tagged with 99mTc. Labeled T cells from chagasic mice bound to both normal and infected myocardium slices. 99mTc-labeled T cells from controls gave the same binding values. Glass-adherent spleen cells behaved identically to T cells. Prior treatment of the tissue with serum from chronically infected mice did not increase the number of binding cells. Peritoneal macrophages tagged with 99mTc-sulfur colloid also bound to infected myocardium slices. The binding of macrophages was not changed by pretreatment of infected tissue with anti-T, cruzi antibodies. In short, this work did not detect any population of T cells or macrophages which could bind specifically to infected heart tissue to initiate an autoreactive process. Images PMID:2228230