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Sample records for adaptive cardiac binding

  1. Matricellular Proteins in Cardiac Adaptation and Disease

    PubMed Central

    Frangogiannis, Nikolaos G.

    2015-01-01

    The term “matricellular proteins” describes a family of structurally unrelated extracellular macromolecules that, unlike structural matrix proteins, do not play a primary role in tissue architecture, but are induced following injury and modulate cell:cell and cell:matrix interactions. When released to the matrix, matricellular proteins associate with growth factors, cytokines and other bioactive effectors and bind to cell surface receptors transducing signaling cascades. Matricellular proteins are upregulated in the injured and remodeling heart and play an important role in regulation of inflammatory, reparative, fibrotic and angiogenic pathways. Thrombospondins (TSP)-1, -2 and -4, tenascin-C and –X, secreted protein acidic and rich in cysteine (SPARC), osteopontin, periostin and members of the CCN family (including CCN1 and CCN2/Connective Tissue Growth Factor) are involved in a variety of cardiac pathophysiologic conditions, including myocardial infarction, cardiac hypertrophy and fibrosis, aging-associated myocardial remodeling, myocarditis, diabetic cardiomyopathy and valvular disease. This review manuscript discusses the properties and characteristics of the matricellular proteins and presents our current knowledge on their role in cardiac adaptation and disease. Understanding the role of matricellular proteins in myocardial pathophysiology and identification of the functional domains responsible for their actions may lead to design of peptides with therapeutic potential for patients with heart disease. PMID:22535894

  2. Cardiac fluid dynamics anticipates heart adaptation.

    PubMed

    Pedrizzetti, Gianni; Martiniello, Alfonso R; Bianchi, Valter; D'Onofrio, Antonio; Caso, Pio; Tonti, Giovanni

    2015-01-21

    Hemodynamic forces represent an epigenetic factor during heart development and are supposed to influence the pathology of the grown heart. Cardiac blood motion is characterized by a vortical dynamics, and it is common belief that the cardiac vortex has a role in disease progressions or regression. Here we provide a preliminary demonstration about the relevance of maladaptive intra-cardiac vortex dynamics in the geometrical adaptation of the dysfunctional heart. We employed an in vivo model of patients who present a stable normal heart function in virtue of the cardiac resynchronization therapy (CRT, bi-ventricular pace-maker) and who are expected to develop left ventricle remodeling if pace-maker was switched off. Intra-ventricular fluid dynamics is analyzed by echocardiography (Echo-PIV). Under normal conditions, the flow presents a longitudinal alignment of the intraventricular hemodynamic forces. When pacing is temporarily switched off, flow forces develop a misalignment hammering onto lateral walls, despite no other electro-mechanical change is noticed. Hemodynamic forces result to be the first event that evokes a physiological activity anticipating cardiac changes and could help in the prediction of longer term heart adaptations. PMID:25529139

  3. Cardiac adaptation to endurance exercise in rats.

    PubMed

    Fenning, Andrew; Harrison, Glenn; Dwyer, Dan; Rose'Meyer, Roselyn; Brown, Lindsay

    2003-09-01

    Endurance exercise is widely assumed to improve cardiac function in humans. This project has determined cardiac function following endurance exercise for 6 (n = 30) or 12 (n = 25) weeks in male Wistar rats (8 weeks old). The exercise protocol was 30 min/day at 0.8 km/h for 5 days/week with an endurance test on the 6th day by running at 1.2 km/h until exhaustion. Exercise endurance increased by 318% after 6 weeks and 609% after 12 weeks. Heart weight/kg body weight increased by 10.2% after 6 weeks and 24.1% after 12 weeks. Echocardiography after 12 weeks showed increases in left ventricular internal diameter in diastole (6.39 +/- 0.32 to 7.90 +/- 0.17 mm), systolic volume (49 +/- 7 to 83 +/- 11 miccrol) and cardiac output (75 +/- 3 to 107 +/- 8 ml/min) but not left wall thickness in diastole (1.74 +/- 0.07 to 1.80 +/- 0.06 mm). Isolated Langendorff hearts from trained rats displayed decreased left ventricular myocardial stiffness (22 +/- 1.1 to 19.1 +/- 0.3) and reduced purine efflux during pacing-induced workload increases. 31P-NMR spectroscopy in isolated hearts from trained rats showed decreased PCr and PCr/ATP ratios with increased creatine, AMP and ADP concentrations. Thus, this endurance exercise protocol resulted in physiological hypertrophy while maintaining or improving cardiac function. PMID:14575304

  4. Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis.

    PubMed

    Jiang, Jianming; Burgon, Patrick G; Wakimoto, Hiroko; Onoue, Kenji; Gorham, Joshua M; O'Meara, Caitlin C; Fomovsky, Gregory; McConnell, Bradley K; Lee, Richard T; Seidman, J G; Seidman, Christine E

    2015-07-21

    Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc(t/t) myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc(t/t) myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc(t/t) mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia. PMID:26153423

  5. Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

    PubMed Central

    Jiang, Jianming; Burgon, Patrick G.; Wakimoto, Hiroko; Onoue, Kenji; Gorham, Joshua M.; O’Meara, Caitlin C.; Fomovsky, Gregory; McConnell, Bradley K.; Lee, Richard T.; Seidman, J. G.; Seidman, Christine E.

    2015-01-01

    Homozygous cardiac myosin binding protein C-deficient (Mybpct/t) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpct/t myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpct/t myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpct/t mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3+/− individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3−/− mice is primarily myocyte hyperplasia. PMID:26153423

  6. Adaptive phase-coded reconstruction for cardiac CT

    NASA Astrophysics Data System (ADS)

    Hsieh, Jiang; Mayo, John; Acharya, Kishor; Pan, Tin-Su

    2000-04-01

    Cardiac imaging with conventional computed tomography (CT) has gained significant attention in recent years. New hardware development enables a CT scanner to rotate at a faster speed so that less cardiac motion is present in acquired projection data. Many new tomographic reconstruction techniques have also been developed to reduce the artifacts induced by the cardiac motion. Most of the algorithms make use of the projection data collected over several cardiac cycles to formulate a single projection data set. Because the data set is formed with samples collected roughly in the same phase of a cardiac cycle, the temporal resolution of the newly formed data set is significantly improved compared with projections collected continuously. In this paper, we present an adaptive phase- coded reconstruction scheme (APR) for cardiac CT. Unlike the previously proposed schemes where the projection sector size is identical, APR determines each sector size based on the tomographic reconstruction algorithm. The newly proposed scheme ensures that the temporal resolution of each sector is substantially equal. In addition, the scan speed is selected based on the measured EKG signal of the patient.

  7. Cardiac adaptations of bullfrog tadpoles in response to chytrid infection.

    PubMed

    Salla, Raquel Fernanda; Gamero, Fernando Urban; Ribeiro, Larissa Rodrigues; Rizzi, Gisele Miglioranza; Medico, Samuel Espinosa Dal; Rissoli, Rafael Zanelli; Vieira, Conrado Augusto; Silva-Zacarin, Elaine Cristina Mathias; Leite, Domingos Silva; Abdalla, Fábio Camargo; Toledo, Luis Felipe; Costa, Monica Jones

    2015-08-01

    The chytrid fungus Batrachochytrium dendrobatidis (Bd) can result in heart failure in Bd-susceptible species. Since Bd infection generally does not cause mortality in North American bullfrogs, the aim of this work was to verify whether this species presents any cardiac adaptation that could improve the tolerance to the fungus. Thus, we analyzed tadpoles' activity level, relative ventricular mass, ventricle morphology, in loco heart frequency, and in vitro cardiac function. The results indicate that infected animals present an increase in both ventricular relative mass and in myofibrils' incidence, which accompanied the increase in myocytes' diameter. Such morphological alterations enabled an increase in the in vitro twitch force that, in vivo, would result in elevation of the cardiac stroke volume. This response requires much less energy expenditure than an elevation in heart frequency, but still enables the heart to pump a higher volume of blood per minute (i.e., an increase in cardiac output). As a consequence, the energy saved in the regulation of the cardiac function of Bd-infected tadpoles can be employed in other homeostatic adjustments to avoid the lethal effect of the fungus. Whether other species present this ability, and to what extent, remains uncertain, but such possible interspecific variability might explain different mortality rates among different species of Bd-infected amphibians. PMID:26055358

  8. Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation.

    PubMed

    Chung, Eunhee; Yeung, Fan; Leinwand, Leslie A

    2012-05-01

    Although the signaling pathways underlying exercise-induced cardiac adaptation have been extensively studied, little is known about the molecular mechanisms that result in the response of the heart to pregnancy. The objective of this study was to define the morphological, functional, and gene expression patterns that define the hearts of pregnant mice, and to identify the signaling pathways that mediate this response. Mice were divided into three groups: nonpregnant diestrus control, midpregnancy, and late pregnancy. Both time points of pregnancy were associated with significant cardiac hypertrophy. The prosurvival signaling cascades of Akt and ERK1/2 were activated in the hearts of pregnant mice, while the stress kinase, p38, was decreased. Given the activation of Akt in pregnancy and its known role in cardiac hypertrophy, the hypertrophic response to pregnancy was tested in mice expressing a cardiac-specific activated (myristoylated) form of Akt (myrAkt) or a cardiac-specific constitutively active (antipathologic hypertrophic) form of its downstream target, glycogen synthase kinase 3β (caGSK3β). The pregnancy-induced hypertrophic responses of hearts from these mice were significantly attenuated. Finally, we tested whether pregnancy-associated sex hormones could induce hypertrophy and alter signaling pathways in isolated neonatal rat ventricular myocytes (NRVMs). In fact, progesterone, but not estradiol treatment increased NRVM cell size via phosphorylation of ERK1/2. Inhibition of MEK1 effectively blocked progesterone-induced cellular hypertrophy. Taken together, our study demonstrates that pregnancy-induced cardiac hypertrophy is mediated by activation of Akt and ERK1/2 pathways. PMID:22345431

  9. Metabolic adaptation to chronic hypoxia in cardiac mitochondria.

    PubMed

    Heather, Lisa C; Cole, Mark A; Tan, Jun-Jie; Ambrose, Lucy J A; Pope, Simon; Abd-Jamil, Amira H; Carter, Emma E; Dodd, Michael S; Yeoh, Kar Kheng; Schofield, Christopher J; Clarke, Kieran

    2012-05-01

    Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions. PMID:22538979

  10. Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy

    PubMed Central

    Abel, E. Dale; Doenst, Torsten

    2011-01-01

    Cardiac hypertrophy is a stereotypic response of the heart to increased workload. The nature of the workload increase may vary depending on the stimulus (repetitive, chronic, pressure, or volume overload). If the heart fully adapts to the new loading condition, the hypertrophic response is considered physiological. If the hypertrophic response is associated with the ultimate development of contractile dysfunction and heart failure, the response is considered pathological. Although divergent signalling mechanisms may lead to these distinct patterns of hypertrophy, there is some overlap. Given the close relationship between workload and energy demand, any form of cardiac hypertrophy will impact the energy generation by mitochondria, which are the key organelles for cellular ATP production. Significant changes in the expression of nuclear and mitochondrially encoded transcripts that impact mitochondrial function as well as altered mitochondrial proteome composition and mitochondrial energetics have been described in various forms of cardiac hypertrophy. Here, we review mitochondrial alterations in pathological and physiological hypertrophy. We suggest that mitochondrial adaptations to pathological and physiological hypertrophy are distinct, and we shall review potential mechanisms that might account for these differences. PMID:21257612

  11. Staying young at heart: autophagy and adaptation to cardiac aging.

    PubMed

    Leon, Leonardo J; Gustafsson, Åsa B

    2016-06-01

    Aging is a predominant risk factor for developing cardiovascular disease. Therefore, the cellular processes that contribute to aging are attractive targets for therapeutic interventions that can delay or prevent the development of age-related diseases. Our understanding of the underlying mechanisms that contribute to the decline in cell and tissue functions with age has greatly advanced over the past decade. Classical hallmarks of aging cells include increased levels of reactive oxygen species, DNA damage, accumulation of dysfunctional organelles, oxidized proteins and lipids. These all contribute to a progressive decline in the normal physiological function of the cell and to the onset of age-related conditions. A major cause of the aging process is progressive loss of cellular quality control. Autophagy is an important quality control pathway and is necessary to maintain cardiac homeostasis and to adapt to stress. A reduction in autophagy has been observed in a number of aging models and there is compelling evidence that enhanced autophagy delays aging and extends life span. Enhancing autophagy counteracts age-associated accumulation of protein aggregates and damaged organelles in cells. In this review, we discuss the functional role of autophagy in maintaining homeostasis in the heart, and how a decline is associated with accelerated cardiac aging. We also evaluate therapeutic approaches being researched in an effort to maintain a healthy young heart. PMID:26549356

  12. Multiple cardiac arrhythmia recognition using adaptive wavelet network.

    PubMed

    Lin, Chia-Hung; Chen, Pei-Jarn; Chen, Yung-Fu; Lee, You-Yun; Chen, Tainsong

    2005-01-01

    This paper proposes a method for electrocardiogram (ECG) heartbeat pattern recognition using adaptive wavelet network (AWN). The ECG beat recognition can be divided into a sequence of stages, starting from feature extraction and conversion of QRS complexes, and then identifying cardiac arrhythmias based on the detected features. The discrimination method of ECG beats is a two-subnetwork architecture, consisting of a wavelet layer and a probabilistic neural network (PNN). Morlet wavelets are used to extract the features from each heartbeat, and then PNN is used to analyze the meaningful features and perform discrimination tasks. The AWN is suitable for application in a dynamic environment, with add-in and delete-off features using automatic target adjustment and parameter tuning. The experimental results obtained by testing the data of the MIT-BIH arrhythmia database demonstrate the efficiency of the proposed method. PMID:17281539

  13. Cardiac function adaptations in hibernating grizzly bears (Ursus arctos horribilis).

    PubMed

    Nelson, O Lynne; Robbins, Charles T

    2010-03-01

    Research on the cardiovascular physiology of hibernating mammals may provide insight into evolutionary adaptations; however, anesthesia used to handle wild animals may affect the cardiovascular parameters of interest. To overcome these potential biases, we investigated the functional cardiac phenotype of the hibernating grizzly bear (Ursus arctos horribilis) during the active, transitional and hibernating phases over a 4 year period in conscious rather than anesthetized bears. The bears were captive born and serially studied from the age of 5 months to 4 years. Heart rate was significantly different from active (82.6 +/- 7.7 beats/min) to hibernating states (17.8 +/- 2.8 beats/min). There was no difference from the active to the hibernating state in diastolic and stroke volume parameters or in left atrial area. Left ventricular volume:mass was significantly increased during hibernation indicating decreased ventricular mass. Ejection fraction of the left ventricle was not different between active and hibernating states. In contrast, total left atrial emptying fraction was significantly reduced during hibernation (17.8 +/- 2.8%) as compared to the active state (40.8 +/- 1.9%). Reduced atrial chamber function was also supported by reduced atrial contraction blood flow velocities and atrial contraction ejection fraction during hibernation; 7.1 +/- 2.8% as compared to 20.7 +/- 3% during the active state. Changes in the diastolic cardiac filling cycle, especially atrial chamber contribution to ventricular filling, appear to be the most prominent macroscopic functional change during hibernation. Thus, we propose that these changes in atrial chamber function constitute a major adaptation during hibernation which allows the myocardium to conserve energy, avoid chamber dilation and remain healthy during a period of extremely low heart rates. These findings will aid in rational approaches to identifying underlying molecular mechanisms. PMID:19940994

  14. Cardiac MyBP-C regulates the rate and force of contraction in mammalian myocardium Cardiac Myosin Binding Protein C

    PubMed Central

    Moss, Richard L.; Fitzsimons, Daniel P.; Ralphe, J. Carter

    2014-01-01

    Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated protein that appears to contribute to the regulation of cardiac contraction through interactions with either myosin or actin or both. Several studies over the past several years have suggested that the interactions of cMyBP-C with its binding partners vary with its phosphorylation state, binding predominantly to myosin when dephosphorylated and to actin when it is phosphorylated by PKA or other kinases. Here, we summarize evidence suggesting that phosphorylation of cMyBP-C is a key regulator of the kinetics and amplitude of cardiac contraction during β-adrenergic stimulation and increased stimulus frequency. We propose a model for these effects via a phosphorylation-dependent regulation of the kinetics and extent of cooperative recruitment of cross-bridges to the thin filament – phosphorylation of cMyBP-C accelerates cross-bridge binding to actin, thereby accelerating recruitment and increasing the amplitude of the cardiac twitch. In contrast, enhanced lusitropy as a result of phosphorylation appears to be due to a direct effect of phosphorylation to accelerate cross-bridge detachment rate. Depression or elimination of one or both of these processes in a disease such as end-stage heart failure appears to contribute to the systolic and diastolic dysfunction that characterizes the disease. PMID:25552695

  15. Temperature and pressure adaptation of the binding site of acetylcholinesterase.

    PubMed

    Hochachka, P W

    1974-12-01

    1. Studies with a carbon substrate analogue, 3,3-dimethylbutyl acetate, indicate that the hydrophobic contribution to binding at the anionic site of acetylcholinesterase is strongly disrupted at low temperatures and high pressures. 2. Animals living in different physical environments circumvent this problem by adjusting the enthalpic and entropic contributions to binding. 3. An extreme example of this adaptational strategy is supplied by brain acetylcholinesterase extracted from an abyssal fish living at 2 degrees C and up to several hundred atmospheres of pressure. This acetylcholinesterase appears to have a smaller hydrophobic binding region in the anionic site, playing a measurably decreased role in ligand binding. PMID:4462739

  16. Molecular Modulation of Actomyosin Function by Cardiac Myosin-Binding Protein C

    PubMed Central

    Previs, Michael J.; Michalek, Arthur J.; Warshaw, David M.

    2014-01-01

    Cardiac myosin-binding protein C is a key regulator of cardiac contractility and is capable of both activating the thin filament to initiate actomyosin motion generation and governing maximal sliding velocities. While MyBP-C’s C-terminus localizes the molecule within the sarcomere the N-terminus appears to confer regulatory function by binding to the myosin motor domain and/or actin. Literature pertaining to how MyBP-C binding to the myosin motor domain and or actin leads to MyBP-C’s dual modulatory roles that can impact actomyosin interactions are discussed. PMID:24407948

  17. Neuropsychological, Academic, and Adaptive Functioning in Children Who Survive In-Hospital Cardiac Arrest and Resuscitation.

    ERIC Educational Resources Information Center

    Morris, Robin D.; And Others

    1993-01-01

    This study of 25 children, ages 2-15, who survived a cardiac arrest while hospitalized, found that a majority of subjects exhibited low-average to deficient levels of performance on neuropsychologic, achievement, and adaptive behavior measures. Duration of cardiac arrest and a medical risk score were significantly correlated with decreased…

  18. Evaluation of an adaptive filtering algorithm for CT cardiac imaging with EKG modulated tube current

    NASA Astrophysics Data System (ADS)

    Li, Jianying; Hsieh, Jiang; Mohr, Kelly; Okerlund, Darin

    2005-04-01

    We have developed an adaptive filtering algorithm for cardiac CT scans with EKG-modulated tube current to optimize resolution and noise for different cardiac phases and to provide safety net for cases where end-systole phase is used for coronary imaging. This algorithm has been evaluated using patient cardiac CT scans where lower tube currents are used for the systolic phases. In this paper, we present the evaluation results. The results demonstrated that with the use of the proposed algorithm, we could improve image quality for all cardiac phases, while providing greater noise and streak artifact reduction for systole phases where lower CT dose were used.

  19. Differential and Conditional Activation of PKC-Isoforms Dictates Cardiac Adaptation during Physiological to Pathological Hypertrophy

    PubMed Central

    Naskar, Shaon; Datta, Kaberi; Mitra, Arkadeep; Pathak, Kanchan; Datta, Ritwik; Bansal, Trisha; Sarkar, Sagartirtha

    2014-01-01

    A cardiac hypertrophy is defined as an increase in heart mass which may either be beneficial (physiological hypertrophy) or detrimental (pathological hypertrophy). This study was undertaken to establish the role of different protein kinase-C (PKC) isoforms in the regulation of cardiac adaptation during two types of cardiac hypertrophy. Phosphorylation of specific PKC-isoforms and expression of their downstream proteins were studied during physiological and pathological hypertrophy in 24 week male Balb/c mice (Mus musculus) models, by reverse transcriptase-PCR, western blot analysis and M-mode echocardiography for cardiac function analysis. PKC-δ was significantly induced during pathological hypertrophy while PKC-α was exclusively activated during physiological hypertrophy in our study. PKC-δ activation during pathological hypertrophy resulted in cardiomyocyte apoptosis leading to compromised cardiac function and on the other hand, activation of PKC-α during physiological hypertrophy promoted cardiomyocyte growth but down regulated cellular apoptotic load resulting in improved cardiac function. Reversal in PKC-isoform with induced activation of PKC-δ and simultaneous inhibition of phospho-PKC-α resulted in an efficient myocardium to deteriorate considerably resulting in compromised cardiac function during physiological hypertrophy via augmentation of apoptotic and fibrotic load. This is the first report where PKC-α and -δ have been shown to play crucial role in cardiac adaptation during physiological and pathological hypertrophy respectively thereby rendering compromised cardiac function to an otherwise efficient heart by conditional reversal of their activation. PMID:25116170

  20. Scl binds to primed enhancers in mesoderm to regulate hematopoietic and cardiac fate divergence.

    PubMed

    Org, Tõnis; Duan, Dan; Ferrari, Roberto; Montel-Hagen, Amelie; Van Handel, Ben; Kerényi, Marc A; Sasidharan, Rajkumar; Rubbi, Liudmilla; Fujiwara, Yuko; Pellegrini, Matteo; Orkin, Stuart H; Kurdistani, Siavash K; Mikkola, Hanna Ka

    2015-03-12

    Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated. PMID:25564442

  1. The Binding of Learning to Action in Motor Adaptation

    PubMed Central

    Gonzalez Castro, Luis Nicolas; Monsen, Craig Bryant; Smith, Maurice A.

    2011-01-01

    In motor tasks, errors between planned and actual movements generally result in adaptive changes which reduce the occurrence of similar errors in the future. It has commonly been assumed that the motor adaptation arising from an error occurring on a particular movement is specifically associated with the motion that was planned. Here we show that this is not the case. Instead, we demonstrate the binding of the adaptation arising from an error on a particular trial to the motion experienced on that same trial. The formation of this association means that future movements planned to resemble the motion experienced on a given trial benefit maximally from the adaptation arising from it. This reflects the idea that actual rather than planned motions are assigned ‘credit’ for motor errors because, in a computational sense, the maximal adaptive response would be associated with the condition credited with the error. We studied this process by examining the patterns of generalization associated with motor adaptation to novel dynamic environments during reaching arm movements in humans. We found that these patterns consistently matched those predicted by adaptation associated with the actual rather than the planned motion, with maximal generalization observed where actual motions were clustered. We followed up these findings by showing that a novel training procedure designed to leverage this newfound understanding of the binding of learning to action, can improve adaptation rates by greater than 50%. Our results provide a mechanistic framework for understanding the effects of partial assistance and error augmentation during neurologic rehabilitation, and they suggest ways to optimize their use. PMID:21731476

  2. FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease.

    PubMed

    Zissimopoulos, Spyros; Thomas, N Lowri; Jamaluddin, Wan W; Lai, F Anthony

    2009-04-15

    In the present paper we show that distinct human RyR2 (ryanodine receptor type 2) inherited mutations expressed in mammalian cells exhibit either unaltered or increased FKBP12.6 (12.6 kDa FK506-binding protein) binding compared with the wild-type. Oxidizing conditions result in decreased FKBP12.6 binding, but to the same extent as for the wild-type. Our findings suggest that FKBP12.6 regulation of RyR2 is unlikely to be the primary defect in inherited arrhythmogenic cardiac disease. PMID:19226252

  3. 17ß-Estradiol Regulates mTORC2 Sensitivity to Rapamycin in Adaptive Cardiac Remodeling

    PubMed Central

    Kusch, Angelika; Schmidt, Maria; Gürgen, Dennis; Postpieszala, Daniel; Catar, Rusan; Hegner, Björn; Davidson, Merci M.; Mahmoodzadeh, Shokoufeh; Dragun, Duska

    2015-01-01

    Adaptive cardiac remodeling is characterized by enhanced signaling of mTORC2 downstream kinase Akt. In females, 17ß-estradiol (E2), as well as Akt contribute essentially to sex-related premenopausal cardioprotection. Pharmacologic mTOR targeting with rapamycin is increasingly used for various clinical indications, yet burdened with clinical heterogeneity in therapy responses. The drug inhibits mTORC1 and less-so mTORC2. In male rodents, rapamycin decreases maladaptive cardiac hypertrophy whereas it leads to detrimental dilative cardiomyopathy in females. We hypothesized that mTOR inhibition could interfere with 17β-estradiol (E2)-mediated sexual dimorphism and adaptive cell growth and tested responses in murine female hearts and cultured female cardiomyocytes. Under physiological in vivo conditions, rapamycin compromised mTORC2 function only in female, but not in male murine hearts. In cultured female cardiomyocytes, rapamycin impaired simultaneously IGF-1 induced activation of both mTOR signaling branches, mTORC1 and mTORC2 only in presence of E2. Use of specific estrogen receptor (ER)α- and ERβ-agonists indicated involvement of both estrogen receptors (ER) in rapamycin effects on mTORC1 and mTORC2. Classical feedback mechanisms common in tumour cells with upregulation of PI3K signaling were not involved. E2 effect on Akt-pS473 downregulation by rapamycin was independent of ERK as shown by sequential mTOR and MEK-inhibition. Furthermore, regulatory mTORC2 complex defining component rictor phosphorylation at Ser1235, known to interfere with Akt-substrate binding to mTORC2, was not altered. Functionally, rapamycin significantly reduced trophic effect of E2 on cell size. In addition, cardiomyocytes with reduced Akt-pS473 under rapamycin treatment displayed decreased SERCA2A mRNA and protein expression suggesting negative functional consequences on cardiomyocyte contractility. Rictor silencing confirmed regulation of SERCA2A expression by mTORC2 in E2-cultured

  4. Cardiac fiber tracking using adaptive particle filtering based on tensor rotation invariant in MRI

    NASA Astrophysics Data System (ADS)

    Kong, Fanhui; Liu, Wanyu; Magnin, Isabelle E.; Zhu, Yuemin

    2016-03-01

    Diffusion magnetic resonance imaging (dMRI) is a non-invasive method currently available for cardiac fiber tracking. However, accurate and efficient cardiac fiber tracking is still a challenge. This paper presents a probabilistic cardiac fiber tracking method based on particle filtering. In this framework, an adaptive sampling technique is presented to describe the posterior distribution of fiber orientations by adjusting the number and status of particles according to the fractional anisotropy of diffusion. An observation model is then proposed to update the weight of particles by rotating diffusion tensor from the primary eigenvector to a given fiber orientation while keeping the shape of the tensor invariant. The results on human cardiac dMRI show that the proposed method is robust to noise and outperforms conventional streamline and particle filtering techniques.

  5. Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay.

    PubMed

    Saber, Walid; Begin, Kelly J; Warshaw, David M; VanBuren, Peter

    2008-06-01

    The modulatory role of whole cardiac myosin binding protein-C (cMyBP-C) on myosin force and motion generation was assessed in an in vitro motility assay. The presence of cMyBP-C at an approximate molar ratio of cMyBP-C to whole myosin of 1:2, resulted in a 25% reduction in thin filament velocity (P<0.002) with no effect on relative isometric force under maximally activated conditions (pCa 5). Cardiac MyBP-C was capable of inhibiting actin filament velocity in a concentration-dependent manner using either whole myosin, HMM or S1, indicating that the cMyBP-C does not have to bind to myosin LMM or S2 subdomains to exert its effect. The reduction in velocity by cMyBP-C was independent of changes in ionic strength or excess inorganic phosphate. Co-sedimentation experiments demonstrated S1 binding to actin is reduced as a function of cMyBP-C concentration in the presence of ATP. In contrast, S1 avidly bound to actin in the absence of ATP and limited cMyBP-C binding, indicating that cMyBP-C and S1 compete for actin binding in an ATP-dependent fashion. However, based on the relationship between thin filament velocity and filament length, the cMyBP-C induced reduction in velocity was independent of the number of cross-bridges interacting with the thin filament. In conclusion, the effects of cMyBP-C on velocity and force at both maximal and submaximal activation demonstrate that cMyBP-C does not solely act as a tether between the myosin S2 and LMM subdomains but likely affects both the kinetics and recruitment of myosin cross-bridges through its direct interaction with actin and/or myosin head. PMID:18482734

  6. Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function.

    PubMed

    Tong, Carl W; Stelzer, Julian E; Greaser, Marion L; Powers, Patricia A; Moss, Richard L

    2008-10-24

    Normal cardiac function requires dynamic modulation of contraction. beta1-adrenergic-induced protein kinase (PK)A phosphorylation of cardiac myosin binding protein (cMyBP)-C may regulate crossbridge kinetics to modulate contraction. We tested this idea with mechanical measurements and echocardiography in a mouse model lacking 3 PKA sites on cMyBP-C, ie, cMyBP-C(t3SA). We developed the model by transgenic expression of mutant cMyBP-C with Ser-to-Ala mutations on the cMyBP-C knockout background. Western blots, immunofluorescence, and in vitro phosphorylation combined to show that non-PKA-phosphorylatable cMyBP-C expressed at 74% compared to normal wild-type (WT) and was correctly positioned in the sarcomeres. Similar expression of WT cMyBP-C at 72% served as control, ie, cMyBP-C(tWT). Skinned myocardium responded to stretch with an immediate increase in force, followed by a transient relaxation of force and finally a delayed development of force, ie, stretch activation. The rate constants of relaxation, k(rel) (s-1), and delayed force development, k(df) (s-1), in the stretch activation response are indicators of crossbridge cycling kinetics. cMyBP-C(t3SA) myocardium had baseline k(rel) and k(df) similar to WT myocardium, but, unlike WT, k(rel) and k(df) were not accelerated by PKA treatment. Reduced dobutamine augmentation of systolic function in cMyBP-C(t3SA) hearts during echocardiography corroborated the stretch activation findings. Furthermore, cMyBP-C(t3SA) hearts exhibited basal echocardiographic findings of systolic dysfunction, diastolic dysfunction, and hypertrophy. Conversely, cMyBP-C(tWT) hearts performed similar to WT. Thus, PKA phosphorylation of cMyBP-C accelerates crossbridge kinetics and loss of this regulation leads to cardiac dysfunction. PMID:18802026

  7. Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

    PubMed Central

    Winkelmann, Eliane Roseli; Dallazen, Fernanda; Bronzatti, Angela Beerbaum Steinke; Lorenzoni, Juliara Cristina Werner; Windmöller, Pollyana

    2015-01-01

    Objective To analyze a cardiac rehabilitation adapted protocol in physical therapy during the postoperative hospital phase of cardiac surgery in a service of high complexity, in aspects regarded to complications and mortality prevalence and hospitalization days. Methods This is an observational cross-sectional, retrospective and analytical study performed by investigating 99 patients who underwent cardiac surgery for coronary artery bypass graft, heart valve replacement or a combination of both. Step program adapted for rehabilitation after cardiac surgery was analyzed under the command of the physiotherapy professional team. Results In average, a patient stays for two days in the Intensive Care Unit and three to four days in the hospital room, totalizing six days of hospitalization. Fatalities occurred in a higher percentage during hospitalization (5.1%) and up to two years period (8.6%) when compared to 30 days after hospital discharge (1.1%). Among the postoperative complications, the hemodynamic (63.4%) and respiratory (42.6%) were the most prevalent. 36-42% of complications occurred between the immediate postoperative period and the second postoperative day. The hospital discharge started from the fifth postoperative day. We can observe that in each following day, the patients are evolving in achieving the Steps, where Step 3 was the most used during the rehabilitation phase I. Conclusion This evolution program by steps can to guide the physical rehabilitation at the hospital in patients after cardiac surgery. PMID:25859866

  8. Acute response and chronic stimulus for cardiac structural and functional adaptation in a professional boxer.

    PubMed

    Oxborough, David; George, Keith; Utomi, Victor; Lord, Rachel; Morton, James; Jones, Nigel; Somauroo, John

    2014-06-01

    The individual response to acute and chronic changes in cardiac structure and function to intense exercise training is not fully understood and therefore evidence in this setting may help to improve the timing and interpretation of pre-participation cardiac screening. The following case report highlights an acute increase in right ventricular (RV) size and a reduction in left ventricular (LV) basal radial function with concomitant increase at the mid-level in response to a week's increase in training volume in a professional boxer. These adaptations settle by the second week; however, chronic physiological adaptation occurs over a 12-week period. Electrocardiographic findings demonstrate an acute lateral T-wave inversion at 1 week, which revert to baseline for the duration of training. It appears that a change in training intensity and volume generates an acute response within the RV that acts as a stimulus for chronic adaptation in this professional boxer. PMID:25988031

  9. Adaptive Service Binding with Lightweight Semantic Web Services

    NASA Astrophysics Data System (ADS)

    Pedrinaci, Carlos; Lambert, Dave; Maleshkova, Maria; Liu, Dong; Domingue, John; Krummenacher, Reto

    Adaptive service selection is acknowledged to provide a certain number of advantages to optimise the service provisioning process or to cater for advanced service brokering. Semantic Web Services, that is services that have been enriched with semantic annotations have often been used for providing adaptive service selection by deferring the binding of services until runtime. Thus far, however, research on Semantic Web Services has mainly been dominated by rich conceptual frameworks such as WSMO and OWL-S which require a significant effort towards the annotation of services and rely on complex reasoning for which there are no efficient solutions that can scale to the Web yet. In this chapter, inline with current trends on the Semantic Web that sacrifice expressivity in favour of performance, we present a novel approach to providing adaptive service selection that relies on simple conceptual models for services and less expressive formalisms for which there currently exist mature and performant implementations. In particular, we present a set of conceptual models defined in RDF(S) that support both Web services and Web APIs and we show how simple templates abstracting user requirements can be automatically transformed into SPARQL to enable service selection in a scalable manner.

  10. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing

    PubMed Central

    Maatz, Henrike; Jens, Marvin; Liss, Martin; Schafer, Sebastian; Heinig, Matthias; Kirchner, Marieluise; Adami, Eleonora; Rintisch, Carola; Dauksaite, Vita; Radke, Michael H.; Selbach, Matthias; Barton, Paul J.R.; Cook, Stuart A.; Rajewsky, Nikolaus; Gotthardt, Michael; Landthaler, Markus; Hubner, Norbert

    2014-01-01

    Mutations in the gene encoding the RNA-binding protein RBM20 have been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure, presumably through altering cardiac RNA splicing. Here, we combined transcriptome-wide crosslinking immunoprecipitation (CLIP-seq), RNA-seq, and quantitative proteomics in cell culture and rat and human hearts to examine how RBM20 regulates alternative splicing in the heart. Our analyses revealed the presence of a distinct RBM20 RNA-recognition element that is predominantly found within intronic binding sites and linked to repression of exon splicing with RBM20 binding near 3′ and 5′ splice sites. Proteomic analysis determined that RBM20 interacts with both U1 and U2 small nuclear ribonucleic particles (snRNPs) and suggested that RBM20-dependent splicing repression occurs through spliceosome stalling at complex A. Direct RBM20 targets included several genes previously shown to be involved in DCM as well as genes not typically associated with this disease. In failing human hearts, reduced expression of RBM20 affected alternative splicing of several direct targets, indicating that differences in RBM20 expression may affect cardiac function. Together, these findings identify RBM20-regulated targets and provide insight into the pathogenesis of human heart failure. PMID:24960161

  11. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing.

    PubMed

    Maatz, Henrike; Jens, Marvin; Liss, Martin; Schafer, Sebastian; Heinig, Matthias; Kirchner, Marieluise; Adami, Eleonora; Rintisch, Carola; Dauksaite, Vita; Radke, Michael H; Selbach, Matthias; Barton, Paul J R; Cook, Stuart A; Rajewsky, Nikolaus; Gotthardt, Michael; Landthaler, Markus; Hubner, Norbert

    2014-08-01

    Mutations in the gene encoding the RNA-binding protein RBM20 have been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure, presumably through altering cardiac RNA splicing. Here, we combined transcriptome-wide crosslinking immunoprecipitation (CLIP-seq), RNA-seq, and quantitative proteomics in cell culture and rat and human hearts to examine how RBM20 regulates alternative splicing in the heart. Our analyses revealed the presence of a distinct RBM20 RNA-recognition element that is predominantly found within intronic binding sites and linked to repression of exon splicing with RBM20 binding near 3' and 5' splice sites. Proteomic analysis determined that RBM20 interacts with both U1 and U2 small nuclear ribonucleic particles (snRNPs) and suggested that RBM20-dependent splicing repression occurs through spliceosome stalling at complex A. Direct RBM20 targets included several genes previously shown to be involved in DCM as well as genes not typically associated with this disease. In failing human hearts, reduced expression of RBM20 affected alternative splicing of several direct targets, indicating that differences in RBM20 expression may affect cardiac function. Together, these findings identify RBM20-regulated targets and provide insight into the pathogenesis of human heart failure. PMID:24960161

  12. Cardiac hypertrophy, arrhythmogenicity and the new myocardial phenotype. II. The cellular adaptational process.

    PubMed

    Swynghedauw, B; Chevalier, B; Charlemagne, D; Mansier, P; Carré, F

    1997-07-01

    Ventricular fibrosis is not the only structural determinant of arrhythmias in left ventricular hypertrophy. In an experimental model of compensatory cardiac hypertrophy (CCH) the degree of cardiac hypertrophy is also independently linked to ventricular arrhythmias. Cardiac hypertrophy reflects the level of adaptation, and matches the adaptational modifications of the myocardial phenotype. We suggest that these modifications have detrimental aspects. The increased action potential (AP) and QT duration and the prolonged calcium transient both favour spontaneous calcium oscillations, and both are potentially arrhythmogenic and linked to phenotypic changes in membrane proteins. To date, only two ionic currents have been studied in detail: Ito is depressed (likely the main determinant in AP durations), and If, the pacemaker current, is induced in the overloaded ventricular myocytes. In rat CCH, the two components of the sarcoplasmic reticulum, namely Ca(2+)-ATPase and ryanodine receptors, are down-regulated in parallel. Nevertheless, while the inward calcium current is unchanged, the functionally linked duo composed of the Na+/Ca2+ exchanged and (Na+, K+)-ATPase, is less active. Such an imbalance may explain the prolonged calcium transient. The changes in heart rate variability provide information about the state of the autonomic nervous system and has prognostic value even in CCH. Transgenic studies have demonstrated that the myocardial adrenergic and muscarinic receptor content is also a determining factor. During CCH, several phenotypic membrane changes participate in the slowing of contraction velocity and are thus adaptational. They also have a detrimental counterpart and, together with fibrosis, favour arrhythmias. PMID:9302342

  13. Ouabain binding sites and (Na/sup +/,K/sup +/)-ATPase activity in rat cardiac hypertrophy: expression of the neonatal forms

    SciTech Connect

    Not Available

    1986-01-05

    The adaptation of the myocardium to mechanical overload which results in cardiac hypertrophy involved several membrane functions. The digitalis receptor in sarcolemma vesicles from hypertrophied rat hearts is characterized by binding of (/sup 3/H)ouabain and ouabain-induced inhibition of (Na/sup +/,K/sup +/)-ATPase. The results show the existence of two families of ouabain binding sites with apparent dissociation constants (K/sub d/) of 1.8-3.2 x 10/sup -8/ M and 1-8 x 10/sup -6/ M, respectively, which are similar to those found in normal hearts. The presence of the high affinity receptor in hypertrophied rat heart is correlated to a detectable inhibition of the (Na/sup +/,K/sup +/)-ATPase (IC/sub 50/ = 1-3 x 10/sup -8/ M). However, the high and low affinity sites in hypertrophied hearts bind and release ouabain at 4-5-fold slower rates than the corresponding sites in normal hearts. These properties are similar to that observed in newborn rat cardiac preparations. Taken together with the expression of myosin isoforms, the data show that the physiological adaptation of the heart also involves the resurgence of the neonatal forms of the digitalis receptor.

  14. Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review

    PubMed Central

    Sheng, Juan-Juan; Jin, Jian-Ping

    2014-01-01

    Troponin plays a central role in regulating the contraction and relaxation of vertebrate striated muscles. This review focuses on the isoform gene regulation, alternative RNA splicing, and posttranslational modifications of troponin subunits in cardiac development and adaptation. Transcriptional and posttranscriptional regulations such as phosphorylation and proteolysis modifications, and structure-function relationships of troponin subunit proteins are summarized. The physiological and pathophysiological significances are discussed for impacts on cardiac muscle contractility, heart function, and adaptations in health and diseases. PMID:24817852

  15. Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure

    PubMed Central

    Mayer, Sandra C.; Gilsbach, Ralf; Preissl, Sebastian; Monroy Ordonez, Elsa Beatriz; Schnick, Tilman; Beetz, Nadine; Lother, Achim; Rommel, Carolin; Ihle, Hannah; Bugger, Heiko; Rühle, Frank; Schrepper, Andrea; Schwarzer, Michael; Heilmann, Claudia; Bönisch, Ulrike; Gupta, Shashi Kumar; Wilpert, Jochen; Kretz, Oliver; von Elverfeldt, Dominik; Orth, Joachim; Aktories, Klaus; Beyersdorf, Friedhelm; Bode, Christoph; Stiller, Brigitte; Krüger, Markus; Thum, Thomas; Doenst, Torsten; Stoll, Monika

    2015-01-01

    Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. Objective: The aim of this study was to identify the mechanism of regulation of the methyl-CpG–binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. Methods and Results: MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α1- and β1-adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. Conclusions: These data connect adrenergic activation with a microRNA—MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure. PMID:26195221

  16. New cardiac MRI gating method using event-synchronous adaptive digital filter.

    PubMed

    Park, Hodong; Park, Youngcheol; Cho, Sungpil; Jang, Bongryoel; Lee, Kyoungjoung

    2009-11-01

    When imaging the heart using MRI, an artefact-free electrocardiograph (ECG) signal is not only important for monitoring the patient's heart activity but also essential for cardiac gating to reduce noise in MR images induced by moving organs. The fundamental problem in conventional ECG is the distortion induced by electromagnetic interference. Here, we propose an adaptive algorithm for the suppression of MR gradient artefacts (MRGAs) in ECG leads of a cardiac MRI gating system. We have modeled MRGAs by assuming a source of strong pulses used for dephasing the MR signal. The modeled MRGAs are rectangular pulse-like signals. We used an event-synchronous adaptive digital filter whose reference signal is synchronous to the gradient peaks of MRI. The event detection processor for the event-synchronous adaptive digital filter was implemented using the phase space method-a sort of topology mapping method-and least-squares acceleration filter. For evaluating the efficiency of the proposed method, the filter was tested using simulation and actual data. The proposed method requires a simple experimental setup that does not require extra hardware connections to obtain the reference signals of adaptive digital filter. The proposed algorithm was more effective than the multichannel approach. PMID:19644754

  17. Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury.

    PubMed

    Baker, James O; Tyther, Raymond; Liebetrau, Christoph; Clark, James; Howarth, Robert; Patterson, Tiffany; Möllmann, Helge; Nef, Holger; Sicard, Pierre; Kailey, Balrik; Devaraj, Renuka; Redwood, Simon R; Kunst, Gudrun; Weber, Ekkehard; Marber, Michael S

    2015-05-01

    Cardiac troponins are released and cleared slowly after myocardial injury, complicating the diagnosis of early, and recurrent, acute myocardial infarction. Cardiac myosin-binding protein C (cMyC) is a similarly cardiac-restricted protein that may have different release/clearance kinetics. Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release. In rodents, we demonstrate rapid release of cMyC using in vitro and in vivo models of acute myocardial infarction. In patients, with ST elevation myocardial infarction (STEMI, n = 20), undergoing therapeutic ablation of septal hypertrophy (TASH, n = 20) or having coronary artery bypass surgery (CABG, n = 20), serum was collected prospectively and frequently. cMyC appears in the serum as full-length and fragmented protein. Compared to cTnT measured using a contemporary high-sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 ± 3.1 vs 11.8 ± 3.4 h, P < 0.007; TASH, 9.7 ± 1.4 vs 21.6 ± 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 ± 1.9 vs 4.0 ± 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001). Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT. We speculate that these characteristics could enable earlier diagnosis of myocardial infarction and reinfarction in suspected non-STEMI, a population not included in this early translational study. PMID:25837837

  18. The contribution of cardiac myosin binding protein-c Ser282 phosphorylation to the rate of force generation and in vivo cardiac contractility

    PubMed Central

    Gresham, Kenneth S; Mamidi, Ranganath; Stelzer, Julian E

    2014-01-01

    Cardiac myosin binding protein-C phosphorylation plays an important role in modulating cardiac muscle function and accelerating contraction. It has been proposed that Ser282 phosphorylation may serve as a critical molecular switch that regulates the phosphorylation of neighbouring Ser273 and Ser302 residues, and thereby govern myofilament contractile acceleration in response to protein kinase A (PKA). Therefore, to determine the regulatory roles of Ser282 we generated a transgenic (TG) mouse model expressing cardiac myosin binding protein-C with a non-phosphorylatable Ser282 (i.e. serine to alanine substitution, TGS282A). Myofibrils isolated from TGS282A hearts displayed robust PKA-mediated phosphorylation of Ser273 and Ser302, and the increase in phosphorylation was identical to TG wild-type (TGWT) controls. No signs of pathological cardiac hypertrophy were detected in TGS282A hearts by either histological examination of cardiac sections or echocardiography. Baseline fractional shortening, ejection fraction, isovolumic relaxation time, rate of pressure development and rate of relaxation (τ) were unaltered in TGS282A mice. However, the increase in cardiac contractility as well as the acceleration of pressure development observed in response to β-adrenergic stimulation was attenuated in TGS282A mice. In agreement with our in vivo data, in vitro force measurements revealed that PKA-mediated acceleration of cross-bridge kinetics in TGS282A myocardium was significantly attenuated compared to TGWT myocardium. Taken together, our data suggest that while Ser282 phosphorylation does not regulate the phosphorylation of neighbouring Ser residues and basal cardiac function, full acceleration of cross-bridge kinetics and left ventricular pressure development cannot be achieved in its absence. PMID:24951619

  19. Cellular localization and adaptive changes of the cardiac delta opioid receptor system in an experimental model of heart failure in rats.

    PubMed

    Treskatsch, Sascha; Feldheiser, Aarne; Shaqura, Mohammed; Dehe, Lukas; Habazettl, Helmut; Röpke, Torsten K; Shakibaei, Mehdi; Schäfer, Michael; Spies, Claudia D; Mousa, Shaaban A

    2016-02-01

    The role of the cardiac opioid system in congestive heart failure (CHF) is not fully understood. Therefore, this project investigated the cellular localization of delta opioid receptors (DOR) in left ventricle (LV) myocardium and adaptive changes in DOR and its endogenous ligand, the precursor peptide proenkephalin (PENK), during CHF. Following IRB approval, DOR localization was determined by radioligand binding using [H(3)]Naltrindole and by double immunofluorescence confocal analysis in the LV of male Wistar rats. Additionally, 28 days following an infrarenal aortocaval fistula (ACF) the extent of CHF and adaptions in left ventricular DOR and PENK expression were examined by hemodynamic measurements, RT-PCR, and Western blot. DOR specific membrane binding sites were identified in LV myocardium. DOR were colocalized with L-type Ca(2+)-channels (Cav1.2) as well as with intracellular ryanodine receptors (RyR) of the sarcoplasmatic reticulum. Following ACF severe congestive heart failure developed in all rats and was accompanied by up-regulation of DOR and PENK on mRNA as well as receptor proteins representing consecutive adaptations. These findings might suggest that the cardiac delta opioid system possesses the ability to play a regulatory role in the cardiomyocyte calcium homeostasis, especially in response to heart failure. PMID:25552382

  20. A Space-Time Adaptive Method for Simulating Complex Cardiac Dynamics

    NASA Astrophysics Data System (ADS)

    Cherry, E. M.; Greenside, H. S.; Henriquez, C. S.

    2000-03-01

    A new space-time adaptive mesh refinement algorithm (AMRA) is presented and analyzed which, by automatically adding and deleting local patches of higher-resolution Cartesian meshes, can simulate quantitatively accurate models of cardiac electrical dynamics efficiently in large domains. We find in two space dimensions that the AMRA is able to achieve a factor of 5 speedup and a factor of 5 reduction in memory while achieving the same accuracy compared to a code based on a uniform space-time mesh at the highest resolution of the AMRA method. We summarize applications of the code to the Luo-Rudy 1 cardiac model in large two- and three-dimensional domains and discuss the implications of our results for understanding the initiation of arrhythmias.

  1. Primary Cardiac Angiosarcoma Treated With Positron Emission Tomography/Magnetic Resonance Imaging-Guided Adaptive Radiotherapy.

    PubMed

    Elsayad, Khaled; Lehrich, Philipp; Yppaerilae-Wolters, Heidi; Dieckmann, Chantal; Kriz, Jan; Haverkamp, Uwe; Eich, Hans Theodor

    2016-06-01

    Radiotherapy (RT) for inoperable patients with primary cardiac sarcomas or residual tumor is often limited by the sensitivity of the heart and lung to radiation injury. We describe a novel treatment modality with adaptive radiotherapy (ART) using tumor volume tracking in a 37-year-old woman who presented with unresectable primary cardiac angiosarcoma. The patient was treated using positron emission tomography/magnetic resonance imaging-guided ART with 55.8 Gy concomitant with paclitaxel chemotherapy. In conclusion, the treatment was well tolerated, and a significant tumor volume reduction of ∼ 57% was achieved during radiotherapy, suggesting the effectiveness and tolerability of ART in combination with paclitaxel-based chemotherapy. PMID:26514752

  2. Titin isoform switching is a major cardiac adaptive response in hibernating grizzly bears.

    PubMed

    Nelson, O Lynne; Robbins, Charles T; Wu, Yiming; Granzier, Henk

    2008-07-01

    The hibernation phenomenon captures biological as well as clinical interests to understand how organs adapt. Here we studied how hibernating grizzly bears (Ursus arctos horribilis) tolerate extremely low heart rates without developing cardiac chamber dilation. We evaluated cardiac filling function in unanesthetized grizzly bears by echocardiography during the active and hibernating period. Because both collagen and titin are involved in altering diastolic function, we investigated both in the myocardium of active and hibernating grizzly bears. Heart rates were reduced from 84 beats/min in active bears to 19 beats/min in hibernating bears. Diastolic volume, stroke volume, and left ventricular ejection fraction were not different. However, left ventricular muscle mass was significantly lower (300 +/- 12 compared with 402 +/- 14 g; P = 0.003) in the hibernating bears, and as a result the diastolic volume-to-left ventricular muscle mass ratio was significantly greater. Early ventricular filling deceleration times (106.4 +/- 14 compared with 143.2 +/- 20 ms; P = 0.002) were shorter during hibernation, suggesting increased ventricular stiffness. Restrictive pulmonary venous flow patterns supported this conclusion. Collagen type I and III comparisons did not reveal differences between the two groups of bears. In contrast, the expression of titin was altered by a significant upregulation of the stiffer N2B isoform at the expense of the more compliant N2BA isoform. The mean ratio of N2BA to N2B titin was 0.73 +/- 0.07 in the active bears and decreased to 0.42 +/- 0.03 (P = 0.006) in the hibernating bears. The upregulation of stiff N2B cardiac titin is a likely explanation for the increased ventricular stiffness that was revealed by echocardiography, and we propose that it plays a role in preventing chamber dilation in hibernating grizzly bears. Thus our work identified changes in the alternative splicing of cardiac titin as a major adaptive response in hibernating grizzly

  3. Radiotracers for Cardiac Sympathetic Innervation: Transport Kinetics and Binding Affinities for the Human Norepinephrine Transporter

    PubMed Central

    Raffel, David M.; Chen, Wei; Jung, Yong-Woon; Jang, Keun Sam; Gu, Guie; Cozzi, Nicholas V.

    2013-01-01

    Introduction Most radiotracers for imaging of cardiac sympathetic innervation are substrates of the norepinephrine transporter (NET). The goal of this study was to characterize the NET transport kinetics and binding affinities of several sympathetic nerve radiotracers, including [11C]-(−)-meta-hydroxyephedrine, [11C]-(−)-epinephrine, and a series of [11C]-labeled phenethylguanidines under development in our laboratory. For comparison, the NET transport kinetics and binding affinities of some [3H]-labeled biogenic amines were also determined. Methods Transport kinetics studies were performed using rat C6 glioma cells stably transfected with the human norepinephrine transporter (C6-hNET cells). For each radiolabeled NET substrate, saturation transport assays with C6-hNET cells measured the Michaelis-Menten transport constants Km and Vmax for NET transport. Competitive inhibition binding assays with homogenized C6-hNET cells and [3H]mazindol provided estimates of binding affinities (KI) for NET. Results Km, Vmax and KI values were determined for each NET substrate with a high degree of reproducibility. Interestingly, C6-hNET transport rates for ‘tracer concentrations’ of substrate, given by the ratio Vmax/Km, were found to be highly correlated with neuronal transport rates measured previously in isolated rat hearts (r2 = 0.96). This suggests that the transport constants Km and Vmax measured using the C6-hNET cells accurately reflect in vivo transport kinetics. Conclusion The results of these studies show how structural changes in NET substrates influence NET binding and transport constants, providing valuable insights that can be used in the design of new tracers with more optimal kinetics for quantifying regional sympathetic nerve density. PMID:23306137

  4. Extracellular allosteric Na(+) binding to the Na(+),K(+)-ATPase in cardiac myocytes.

    PubMed

    Garcia, Alvaro; Fry, Natasha A S; Karimi, Keyvan; Liu, Chia-chi; Apell, Hans-Jürgen; Rasmussen, Helge H; Clarke, Ronald J

    2013-12-17

    Whole-cell patch-clamp measurements of the current, Ip, produced by the Na(+),K(+)-ATPase across the plasma membrane of rabbit cardiac myocytes show an increase in Ip over the extracellular Na(+) concentration range 0-50 mM. This is not predicted by the classical Albers-Post scheme of the Na(+),K(+)-ATPase mechanism, where extracellular Na(+) should act as a competitive inhibitor of extracellular K(+) binding, which is necessary for the stimulation of enzyme dephosphorylation and the pumping of K(+) ions into the cytoplasm. The increase in Ip is consistent with Na(+) binding to an extracellular allosteric site, independent of the ion transport sites, and an increase in turnover via an acceleration of the rate-determining release of K(+) to the cytoplasm, E2(K(+))2 → E1 + 2K(+). At normal physiological concentrations of extracellular Na(+) of 140 mM, it is to be expected that binding of Na(+) to the allosteric site would be nearly saturated. Its purpose would seem to be simply to optimize the enzyme's ion pumping rate under its normal physiological conditions. Based on published crystal structures, a possible location of the allosteric site is within a cleft between the α- and β-subunits of the enzyme. PMID:24359741

  5. Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling

    PubMed Central

    Previs, Michael J.; Prosser, Benjamin L.; Mun, Ji Young; Previs, Samantha Beck; Gulick, James; Lee, Kyounghwan; Robbins, Jeffrey; Craig, Roger; Lederer, W. J.; Warshaw, David M.

    2015-01-01

    The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies. PMID:25839057

  6. Plasma Fatty Acid Binding Protein 4 and Risk of Sudden Cardiac Death in Older Adults

    PubMed Central

    Djoussé, Luc; Maziarz, Marlena; Biggs, Mary L.; Ix, Joachim H.; Zieman, Susan J.; Kizer, Jorge R.; Lemaitre, Rozenn N.; Mozaffarian, Dariush; Tracy, Russell P.; Mukamal, Kenneth J.; Siscovick, David S.; Sotoodehnia, Nona

    2013-01-01

    Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95–1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07–1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62–1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted. PMID:24455402

  7. Echo motion imaging with adaptive clutter filter for assessment of cardiac blood flow

    NASA Astrophysics Data System (ADS)

    Takahashi, Hiroki; Hasegawa, Hideyuki; Kanai, Hiroshi

    2015-07-01

    Visualization of the vortex blood flow in the cardiac chamber is a potential diagnostic tool for the evaluation of cardiac function. In the present study, a method for automatic selection of the desirable cutoff frequency of a moving target indicator filter, namely, a clutter filter, was proposed in order to visualize complex blood flows by the ultrahigh-frame-rate imaging of echoes from blood particles while suppressing clutter echoes. In this method, the cutoff frequency was adaptively changed as a function of the velocity of the heart wall (clutter source) in each frame. The feasibility of the proposed method was examined through the measurement of a healthy volunteer using parallel receive beamforming with a single transmission of a non-steered diverging beam. Using the moving target indicator filter as above with the cutoff frequency determined by the proposed method, the vortex-like blood flow in the cardiac chamber was visualized as movements of echoes from blood particles at a very high frame rate of 6024 Hz while suppressing clutter echoes.

  8. Mechanical Unfolding of Cardiac Myosin Binding Protein-C by Atomic Force Microscopy

    PubMed Central

    Karsai, Árpád; Kellermayer, Miklós S.Z.; Harris, Samantha P.

    2011-01-01

    Cardiac myosin-binding protein-C (cMyBP-C) is a thick-filament-associated protein that performs regulatory and structural roles within cardiac sarcomeres. It is a member of the immunoglobulin (Ig) superfamily of proteins consisting of eight Ig- and three fibronectin (FNIII)-like domains, along with a unique regulatory sequence referred to as the M-domain, whose structure is unknown. Domains near the C-terminus of cMyBP-C bind tightly to myosin and mediate the association of cMyBP-C with thick (myosin-containing) filaments, whereas N-terminal domains, including the regulatory M-domain, bind reversibly to myosin S2 and/or actin. The ability of MyBP-C to bind to both myosin and actin raises the possibility that cMyBP-C cross-links myosin molecules within the thick filament and/or cross-links myosin and thin (actin-containing) filaments together. In either scenario, cMyBP-C could be under mechanical strain. However, the physical properties of cMyBP-C and its behavior under load are completely unknown. Here, we investigated the mechanical properties of recombinant baculovirus-expressed cMyBP-C using atomic force microscopy to assess the stability of individual cMyBP-C molecules in response to stretch. Force-extension curves showed the presence of long extensible segment(s) that became stretched before the unfolding of individual Ig and FNIII domains, which were evident as sawtooth peaks in force spectra. The forces required to unfold the Ig/FNIII domains at a stretch rate of 500 nm/s increased monotonically from ∼30 to ∼150 pN, suggesting a mechanical hierarchy among the different Ig/FNIII domains. Additional experiments using smaller recombinant proteins showed that the regulatory M-domain lacks significant secondary or tertiary structure and is likely an intrinsically disordered region of cMyBP-C. Together, these data indicate that cMyBP-C exhibits complex mechanical behavior under load and contains multiple domains with distinct mechanical properties. PMID

  9. Cardiac resynchronization therapy pacemaker: critical appraisal of the adaptive CRT-P device

    PubMed Central

    Daoud, Georges E; Houmsse, Mahmoud

    2016-01-01

    Cardiac resynchronization therapy (CRT) is an effective and well-established therapy for patients suffering with heart failure, left ventricular (LV) systolic dysfunction (ejection fraction ≤35%), and electrical dyssynchrony, demonstrated by a surface QRS duration of ≥120 ms. Patients undergoing treatment with CRT have shown significant improvement in functional class, quality of life, LV ejection fraction, exercise capacity, hemodynamics, and reverse remodeling of LV, and ultimately, morbidity and mortality. However, 30%–40% of patients who receive a CRT device may not show improvement, and they are termed as non responders. The nonresponders have a poor prognosis; several methods have been developed to try to enhance response to CRT. Echocardiography-guided optimization of CRT has not resulted in significant clinical benefit, since it is done at rest with the patient in supine position. An ideal optimization strategy would provide continuous monitoring and adjustment of device pacing to provide maximal cardiac resynchronization, under a multitude of physiologic states. Intrinsic activation of the right ventricle (RV) with paced activation of the RV, even in the setting of biventricular (BiV) pacing, may result in an adverse effect on cardiac performance. With this physiology, the use of LV-only pacing may be preferred and may enhance CRT. Adaptive CRT is a novel device-based algorithm that was designed to achieve patient-specific adjustment in CRT so as to provide appropriate BiV pacing or LV-only pacing. This article will review the goals of CRT optimization, and implementation and outcomes associated with adaptive CRT. PMID:26848278

  10. Piceatannol attenuates cardiac hypertrophy in an animal model through regulation of the expression and binding of the transcription factor GATA binding factor 6.

    PubMed

    Kee, Hae Jin; Park, Sangha; Kang, Wanseok; Lim, Kyung Seob; Kim, Jung Ha; Ahn, Youngkeun; Jeong, Myung Ho

    2014-05-01

    Piceatannol is found in grapes, passion fruit, and Japanese knotweed. Piceatannol pretreatment suppresses cardiac hypertrophy induced by isoproterenol as assessed by heart weight/body weight ratio, cross-sectional area, and expression of hypertrophic markers. The anti-hypertrophic effect of piceatannol in rat neonatal cardiomyocytes is the same as that in vivo. Piceatannol inhibits lentiviral-GATA6-induced cardiomyocyte hypertrophy. Furthermore, piceatannol reduces the interaction between GATA4 and GATA6 as well as the DNA-binding activity of endogenous GATA6 in the ANP promoter. Our results suggest that piceatannol may be a novel therapeutic agent for the prevention of cardiac hypertrophy. PMID:24662306

  11. Thermodynamics and kinetics of adaptive binding in the malachite green RNA aptamer.

    PubMed

    Da Costa, Jason B; Andreiev, Aurelia I; Dieckmann, Thorsten

    2013-09-24

    Adaptive binding, the ability of molecules to fold themselves around the structure of a ligand and thereby incorporating it into their three-dimensional fold, is a key feature of most RNA aptamers. The malachite green aptamer (MGA) has been shown to bind several closely related triphenyl dyes with planar and nonplanar structures in this manner. Competitive binding studies using isothermal titration calorimetry and stopped flow kinetics have been conducted with the aim of understanding the adaptive nature of RNA-ligand interaction. The results of these studies reveal that binding of one ligand can reduce the ability of the aptamer pocket to adapt to another ligand, even if this second ligand has a significantly higher affinity to the free aptamer. A similar effect is observed in the presence of Mg(2+) ions which stabilize the binding pocket in a more ligand bound-like conformation. PMID:23984874

  12. Phosphorylation Modulates the Mechanical Stability of the Cardiac Myosin-Binding Protein C Motif

    PubMed Central

    Michalek, Arthur J.; Howarth, Jack W.; Gulick, James; Previs, Michael J.; Robbins, Jeffrey; Rosevear, Paul R.; Warshaw, David M.

    2013-01-01

    Cardiac myosin-binding protein C (cMyBP-C) is a thick-filament-associated protein that modulates cardiac contractility through interactions of its N-terminal immunoglobulin (Ig)-like C0-C2 domains with actin and/or myosin. These interactions are modified by the phosphorylation of at least four serines located within the motif linker between domains C1 and C2. We investigated whether motif phosphorylation alters its mechanical properties by characterizing force-extension relations using atomic force spectroscopy of expressed mouse N-terminal cMyBP-C fragments (i.e., C0-C3). Protein kinase A phosphorylation or serine replacement with aspartic acids did not affect persistence length (0.43 ± 0.04 nm), individual Ig-like domain unfolding forces (118 ± 3 pN), or Ig extension due to unfolding (30 ± 0.38 nm). However, phosphorylation did significantly decrease the C0-C3 mean contour length by 24 ± 2 nm. These results suggest that upon phosphorylation, the motif, which is freely extensible in the nonphosphorylated state, adopts a more stable and/or different structure. Circular dichroism and dynamic light scattering data for shorter expressed C1-C2 fragments with all four serines replaced by aspartic acids confirmed that the motif did adopt a more stable structure that was not apparent in the nonphosphorylated motif. These biophysical data provide both a mechanical and structural basis for cMyBP-C regulation by motif phosphorylation. PMID:23442866

  13. Exploration of the psychological impact and adaptation to cardiac events in South Asians in the UK: a qualitative study

    PubMed Central

    Bhattacharyya, Mimi; Stevenson, Fiona; Walters, Kate

    2016-01-01

    Objective There is little research on how different ethnic groups adapt after an acute cardiac event. This qualitative study explores between-ethnicity and within-ethnicity variation in adaptation, and the psychological impact of an acute cardiac event among UK South Asian and white British people. Setting We purposively sampled people by ethnic group from general practices in London who had a new myocardial infarction, angina or acute arrhythmia in the preceding 18 months. Participants We conducted 28 semistructured interviews for exploring the psychological symptoms, experiences and adaptations following a cardiac event among South Asians (Indian and Bangladeshi) in comparison to white British people. Data were analysed using a thematic ‘framework’ approach. Results Findings showed heterogeneity in experiences of the cardiac event and its subsequent psychological and physical impact. Adaptation to the event related predominantly to life circumstances, personal attitudes and employment status. Anxiety and low mood symptoms were common sequelae, especially in the Bangladeshi group. Indian men tended to normalise symptoms and the cardiac event, and reported less negative mood symptoms than other groups. Fear of physical exertion, particularly heavy lifting, persisted across the groups. Some people across all ethnic groups indicated the need for more psychological therapy postcardiac event. Socioeconomic circumstances, age and prior work status appeared to be more important in relation to adaptation after a cardiac event than ethnic status. Conclusions Heterogeneity in views and experiences related to the socioeconomic background, age and work status of the participants along with some cultural influences. Rehabilitation programmes should be flexibly tailored for individuals in particular and where relevant, specific support should be provided for returning to work. PMID:27401355

  14. Adaptive volume rendering of cardiac 3D ultrasound images: utilizing blood pool statistics

    NASA Astrophysics Data System (ADS)

    Åsen, Jon Petter; Steen, Erik; Kiss, Gabriel; Thorstensen, Anders; Rabben, Stein Inge

    2012-03-01

    In this paper we introduce and investigate an adaptive direct volume rendering (DVR) method for real-time visualization of cardiac 3D ultrasound. DVR is commonly used in cardiac ultrasound to visualize interfaces between tissue and blood. However, this is particularly challenging with ultrasound images due to variability of the signal within tissue as well as variability of noise signal within the blood pool. Standard DVR involves a global mapping of sample values to opacity by an opacity transfer function (OTF). While a global OTF may represent the interface correctly in one part of the image, it may result in tissue dropouts, or even artificial interfaces within the blood pool in other parts of the image. In order to increase correctness of the rendered image, the presented method utilizes blood pool statistics to do regional adjustments of the OTF. The regional adaptive OTF was compared with a global OTF in a dataset of apical recordings from 18 subjects. For each recording, three renderings from standard views (apical 4-chamber (A4C), inverted A4C (IA4C) and mitral valve (MV)) were generated for both methods, and each rendering was tuned to the best visual appearance by a physician echocardiographer. For each rendering we measured the mean absolute error (MAE) between the rendering depth buffer and a validated left ventricular segmentation. The difference d in MAE between the global and regional method was calculated and t-test results are reported with significant improvements for the regional adaptive method (dA4C = 1.5 +/- 0.3 mm, dIA4C = 2.5 +/- 0.4 mm, dMV = 1.7 +/- 0.2 mm, d.f. = 17, all p < 0.001). This improvement by the regional adaptive method was confirmed through qualitative visual assessment by an experienced physician echocardiographer who concluded that the regional adaptive method produced rendered images with fewer tissue dropouts and less spurious structures inside the blood pool in the vast majority of the renderings. The algorithm has been

  15. Potential benefit of the CT adaptive statistical iterative reconstruction method for pediatric cardiac diagnosis

    NASA Astrophysics Data System (ADS)

    Miéville, Frédéric A.; Ayestaran, Paul; Argaud, Christophe; Rizzo, Elena; Ou, Phalla; Brunelle, Francis; Gudinchet, François; Bochud, François; Verdun, Francis R.

    2010-04-01

    Adaptive Statistical Iterative Reconstruction (ASIR) is a new imaging reconstruction technique recently introduced by General Electric (GE). This technique, when combined with a conventional filtered back-projection (FBP) approach, is able to improve the image noise reduction. To quantify the benefits provided on the image quality and the dose reduction by the ASIR method with respect to the pure FBP one, the standard deviation (SD), the modulation transfer function (MTF), the noise power spectrum (NPS), the image uniformity and the noise homogeneity were examined. Measurements were performed on a control quality phantom when varying the CT dose index (CTDIvol) and the reconstruction kernels. A 64-MDCT was employed and raw data were reconstructed with different percentages of ASIR on a CT console dedicated for ASIR reconstruction. Three radiologists also assessed a cardiac pediatric exam reconstructed with different ASIR percentages using the visual grading analysis (VGA) method. For the standard, soft and bone reconstruction kernels, the SD is reduced when the ASIR percentage increases up to 100% with a higher benefit for low CTDIvol. MTF medium frequencies were slightly enhanced and modifications of the NPS shape curve were observed. However for the pediatric cardiac CT exam, VGA scores indicate an upper limit of the ASIR benefit. 40% of ASIR was observed as the best trade-off between noise reduction and clinical realism of organ images. Using phantom results, 40% of ASIR corresponded to an estimated dose reduction of 30% under pediatric cardiac protocol conditions. In spite of this discrepancy between phantom and clinical results, the ASIR method is as an important option when considering the reduction of radiation dose, especially for pediatric patients.

  16. Cardiac vagal control and children’s adaptive functioning: A meta-analysis

    PubMed Central

    Graziano, Paulo; Derefinko, Karen

    2014-01-01

    Polyvagal theory has influenced research on the role of cardiac vagal control, indexed by respiratory sinus arrhythmia withdrawal (RSA-W) during challenging states, in children’s self-regulation. However, it remains unclear how well RSA-W predicts adaptive functioning (AF) outcomes and whether certain caveats of measuring RSA (e.g., respiration) significantly impact these associations. A meta-analysis of 44 studies (n = 4,996 children) revealed small effect sizes such that greater levels of RSA-W were related to fewer externalizing, internalizing, and cognitive/academic problems. In contrast, RSA-W was differentially related to children’s social problems according to sample type (community vs. clinical/at-risk). The relations between RSA-W and children’s AF outcomes were stronger among studies that co-varied baseline RSA and in Caucasian children (no effect was found for respiration). Children from clinical/at-risk samples displayed lower levels of baseline RSA and RSA-W compared to children from community samples. Theoretical/practical implications for the study of cardiac vagal control are discussed. PMID:23648264

  17. Controlled Release of Collagen-Binding SDF-1α Improves Cardiac Function after Myocardial Infarction by Recruiting Endogenous Stem Cells

    PubMed Central

    Sun, Jie; Zhao, Yannan; Li, Qingguo; Chen, Bing; Hou, Xianglin; Xiao, Zhifeng; Dai, Jianwu

    2016-01-01

    Stromal cell-derived factor-1α (SDF-1α) is a well-characterized chemokine that mobilizes stem cells homing to the ischemic heart, which is beneficial for cardiac regeneration. However, clinically administered native SDF-1α diffuses quickly, thus decreasing its local concentration, and results in side effects. Thus, a controlled release system for SDF-1α is required to produce an effective local concentration in the ischemic heart. In this study, we developed a recombinant chemokine, consisting of SDF-1α and a collagen-binding domain, which retains both the SDF-1α and collagen-binding activity (CBD-SDF-1α). In an in vitro assay, CBD-SDF-1α could specifically bind to a collagen gel and achieve sustained release. An intramyocardial injection of CBD-SDF-1α after acute myocardial infarction demonstrated that the protein was largely tethered in the ischemic area and that controlled release had been achieved. Furthermore, CBD-SDF-1α enhanced the recruitment of c-kit positive (c-kit+) stem cells, increased capillary density and improved cardiac function, whereas NAT-SDF-1α had no such beneficial effects. Our findings demonstrate that CBD-SDF-1α can specifically bind to collagen and achieve controlled release both in vitro and in vivo. Local delivery of this protein could mobilize endogenous stem cells homing to the ischemic heart and improve cardiac function after myocardial infarction. PMID:27226084

  18. Cardiac hypertrophy and failure--a disease of adaptation. Modifications in membrane proteins provide a molecular basis for arrhythmogenicity.

    PubMed

    Moalic, J M; Charlemagne, D; Mansier, P; Chevalier, B; Swynghedauw, B

    1993-05-01

    Cardiac hypertrophy is the physiological adaptation of the heart to chronic mechanical overload. Cardiac failure indicates the limits of the process. Cardiac hypertrophy is only one example of biological adaptation and results from the induction of several changes in gene expression, mostly of the fetal type, including those coding for the myosin heavy chain or the alpha-subunit of the Na+,K(+)-ATPase. From a thermodynamic point of view, the decrease in Vmax allows the heart to produce a normal tension at a lower cost. This process results from changes both in the sarcomere and in the expression of certain membrane proteins. The decrease in calcium transient is determined by several changes in membrane proteins that result in a rather fragile equilibrium in terms of calcium homeostasis. Any abnormal input in calcium will have exaggerated detrimental consequences on a hypertrophied myocyte and may cause automaticity and arrhythmias or an exaggerated response to anoxia in terms of compliance. PMID:8485830

  19. Peri-operative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery

    PubMed Central

    Schaub, Jennifer A.; Garg, Amit X.; Coca, Steven G.; Testani, Jeffrey M.; Shlipak, Michael G.; Eikelboom, John; Kavsak, Peter; McArthur, Eric; Shortt, Colleen; Whitlock, Richard; Parikh, Chirag R.

    2015-01-01

    Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery. PMID:25830762

  20. Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas' disease.

    PubMed

    Hernandez, Ciria C; Nascimento, Jose H; Chaves, Elen A; Costa, Patricia C; Masuda, Masako O; Kurtenbach, Eleonora; Campos DE Carvalho, Antonio C; Gimenez, Luis E

    2008-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M(2)-muscarinic acetylcholine receptors (M(2)AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M(2)AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M(2)AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [(3)H]-N-methyl scopolamine ([(3)H]-NMS) in allosterism binding assays. A peptide corresponding to the M(2)AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [(3)H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [(3)H]-NMS dissociation right shifted from an IC(50) of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 x 10(- 8), 1.33 x 10(- 7), and 2.0 x 10(- 7) mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M(2)AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  1. Autoantibodies Enhance Agonist Action and Binding to Cardiac Muscarinic Receptors in Chronic Chagas’ Disease

    PubMed Central

    Hernández, Ciria C.; Nascimento, José H.; Chaves, Elen A.; Costa, Patrícia C.; Masuda, Masako O.; Kurtenbach, Eleonora; Campos de Carvalho, Antônio C.; Giménez, Luis E.

    2009-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M2-muscarinic acetylcholine receptors (M2AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M2AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M2AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [3H]-N-methyl scopolamine ([3H]-NMS) in allosterism binding assays. A peptide corresponding to the M2AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [3H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [3H]-NMS dissociation right shifted from an IC50 of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 × 10−8, 1.33 × 10−7, and 2.0 × 10−7 mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M2AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  2. An adaptive gating approach for x-ray dose reduction during cardiac interventional procedures

    SciTech Connect

    Abdel-Malek, A.; Yassa, F.; Bloomer, J. )

    1994-03-01

    The increasing number of cardiac interventional procedures has resulted in a tremendous increase in the absorbed x-ray dose by radiologists as well as patients. A new method is presented for x-ray dose reduction which utilizes adaptive tube pulse-rate scheduling in pulsed fluoroscopic systems. In the proposed system, pulse-rate scheduling depends on the heart muscle activity phase determined through continuous guided segmentation of the patient's electrocardiogram (ECG). Displaying images generated at the proposed adaptive nonuniform rate is visually unacceptable; therefore, a frame-filling approach is devised to ensure a 30 frame/sec display rate. The authors adopted two approaches for the frame-filling portion of the system depending on the imaging mode used in the procedure. During cine-mode imaging (high x-ray dose), collected image frame-to-frame pixel motion is estimated using a pel-recursive algorithm followed by motion-based pixel interpolation to estimate the frames necessary to increase the rate to 30 frames/sec. The other frame-filling approach is adopted during fluoro-mode imaging (low x-ray dose), characterized by low signal-to-noise ratio images. This approach consists of simply holding the last collected frame for as many frames as necessary to maintain the real-time display rate.

  3. Ancestral Protein Reconstruction Yields Insights into Adaptive Evolution of Binding Specificity in Solute-Binding Proteins.

    PubMed

    Clifton, Ben E; Jackson, Colin J

    2016-02-18

    The promiscuous functions of proteins are an important reservoir of functional novelty in protein evolution, but the molecular basis for binding promiscuity remains elusive. We used ancestral protein reconstruction to experimentally characterize evolutionary intermediates in the functional expansion of the polar amino acid-binding protein family, which has evolved to bind a variety of amino acids with high affinity and specificity. High-resolution crystal structures of an ancestral arginine-binding protein in complex with l-arginine and l-glutamine show that the promiscuous binding of l-glutamine is enabled by multi-scale conformational plasticity, water-mediated interactions, and selection of an alternative conformational substate productive for l-glutamine binding. Evolution of specialized glutamine-binding proteins from this ancestral protein was achieved by displacement of water molecules from the protein-ligand interface, reducing the entropic penalty associated with the promiscuous interaction. These results provide a structural and thermodynamic basis for the co-option of a promiscuous interaction in the evolution of binding specificity. PMID:26853627

  4. The expression of CG9940 affects the adaptation of cardiac function, mobility, and lifespan to exercise in aging Drosophila.

    PubMed

    Wen, Deng-Tai; Zheng, Lan; Ni, Liu; Wang, Hui; Feng, Yue; Zhang, Min

    2016-10-01

    The CG9940 gene, which encodes the NAD(+) synthase protein in Drosophila, is conserved in human, zebra fish, and mosquito. NAD(+) synthase is a homodimer, which catalyzes the final step in de novo nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, an amide transfer from either ammonia or glutamine to nicotinic acid adenine dinucleotide (NaAD). Both the CG9940 and exercise are closely relative to NAD(+) level, and NAD(+) plays important roles not only in energy metabolism and mitochondrial functions but also in aging. In our study, the expression of CG9940 was changed by UAS/GAL4 system in Drosophila. Flies were trained by a training device. Cardiac function was analyzed by M-mode traces, climbing index was measured through negative geotaxis assay, and lifespan was measured via lifespan assays. The important new findings from our present study included the following: (1) the expression of the CG9940 could affect cardiac function, mobility, and lifespan in Drosophila. Over-expression of the CG9940 gene had positive effects on Drosophila, such as enhanced aging cardiac output, reduced heart failure, delayed age-related mobility decline, and prolonged lifespan, but lower-expression of the CG9940 had negative effects on them. (2) Different expressions of the CG9940 resulted in different influences on the adaptation of cardiac function, mobility, and lifespan to exercise in aging Drosophila. Both normal-expression and over-expression of the CG9940 resulted in positive influences on the adaptation of cardiac functions, mobility, and lifespan to exercise in aging Drosophila such as exercise slowed age-related decline of cardiac function, mobility and extent of lifespan in these flies, while lower-expression of the CG9940 led to negative impacts on the adaptation of mobility and lifespan to exercise in Drosophila. PMID:27448710

  5. The tropomyosin binding region of cardiac troponin T modulates crossbridge recruitment dynamics in rat cardiac muscle fibers.

    PubMed

    Gollapudi, Sampath K; Gallon, Clare E; Chandra, Murali

    2013-05-13

    The cardiac muscle comprises dynamically interacting components that use allosteric/cooperative mechanisms to yield unique heart-specific properties. An essential protein in this allosteric/cooperative mechanism is cardiac muscle troponin T (cTnT), the central region (CR) and the T2 region of which differ significantly from those of fast skeletal muscle troponin T (fsTnT). To understand the biological significance of such sequence heterogeneity, we replaced the T1 or T2 domain of rat cTnT (RcT1 or RcT2) with its counterpart from rat fsTnT (RfsT1or RfsT2) to generate RfsT1-RcT2 and RcT1-RfsT2 recombinant proteins. In addition to contractile function measurements, dynamic features of RfsT1-RcT2- and RcT1-RfsT2-reconstituted rat cardiac muscle fibers were captured by fitting the recruitment-distortion model to the force response of small-amplitude (0.5%) muscle length changes. RfsT1-RcT2 fibers showed a 40% decrease in tension and a 44% decrease in ATPase activity, but RcT1-RfsT2 fibers were unaffected. The magnitude of length-mediated increase in crossbridge (XB) recruitment (E0) decreased by ~33% and the speed of XB recruitment (b) increased by ~100% in RfsT1-RcT2 fibers. Our data suggest the following: (1) the CR of cTnT modulates XB recruitment dynamics; (2) the N-terminal end region of cTnT has a synergistic effect on the ability of the CR to modulate XB recruitment dynamics; (3) the T2 region is important for tuning the Ca(2+) regulation of cardiac thin filaments. The combined effects of CR-tropomyosin interactions and the modulating effect of the N-terminal end of cTnT on CR-tropomyosin interactions may lead to the emergence of a unique property that tunes contractile dynamics to heart rates. PMID:23357173

  6. The Cardiac Stress Response Factor Ms1 Can Bind to DNA and Has a Function in the Nucleus.

    PubMed

    Zaleska, Mariola; Fogl, Claudia; Kho, Ay Lin; Ababou, Abdessamad; Ehler, Elisabeth; Pfuhl, Mark

    2015-01-01

    Ms1 (also known as STARS and ABRA) has been shown to act as an early stress response gene in processes as different as hypertrophy in skeletal and cardiac muscle and growth of collateral blood vessels. It is important for cardiac development in zebrafish and is upregulated in mouse models for cardiac hypertrophy as well as in human failing hearts. Ms1 possesses actin binding sites at its C-terminus and is usually found in the cell bound to actin filaments in the cytosol or in sarcomeres. We determined the NMR structure of the only folded domain of Ms1 comprising the second actin binding site called actin binding domain 2 (ABD2, residues 294-375), and found that it is similar to the winged helix-turn-helix fold adopted mainly by DNA binding domains of transcriptional factors. In vitro experiments show specific binding of this domain, in combination with a newly discovered AT-hook motif located N-terminally, to the sequence (A/C/G)AAA(C/A). NMR and fluorescence titration experiments confirm that this motif is indeed bound specifically by the recognition helix. In neonatal rat cardiomyocytes endogenous Ms1 is found in the nucleus in a spotted pattern, reminiscent of PML bodies. In adult rat cardiomyocytes Ms1 is exclusively found in the sarcomere. A nuclear localisation site in the N-terminus of the protein is required for nuclear localisation. This suggests that Ms1 has the potential to act directly in the nucleus through specific interaction with DNA in development and potentially as a response to stress in adult tissues. PMID:26656831

  7. The Cardiac Stress Response Factor Ms1 Can Bind to DNA and Has a Function in the Nucleus

    PubMed Central

    Kho, Ay Lin; Ababou, Abdessamad; Ehler, Elisabeth; Pfuhl, Mark

    2015-01-01

    Ms1 (also known as STARS and ABRA) has been shown to act as an early stress response gene in processes as different as hypertrophy in skeletal and cardiac muscle and growth of collateral blood vessels. It is important for cardiac development in zebrafish and is upregulated in mouse models for cardiac hypertrophy as well as in human failing hearts. Ms1 possesses actin binding sites at its C-terminus and is usually found in the cell bound to actin filaments in the cytosol or in sarcomeres. We determined the NMR structure of the only folded domain of Ms1 comprising the second actin binding site called actin binding domain 2 (ABD2, residues 294–375), and found that it is similar to the winged helix-turn-helix fold adopted mainly by DNA binding domains of transcriptional factors. In vitro experiments show specific binding of this domain, in combination with a newly discovered AT-hook motif located N-terminally, to the sequence (A/C/G)AAA(C/A). NMR and fluorescence titration experiments confirm that this motif is indeed bound specifically by the recognition helix. In neonatal rat cardiomyocytes endogenous Ms1 is found in the nucleus in a spotted pattern, reminiscent of PML bodies. In adult rat cardiomyocytes Ms1 is exclusively found in the sarcomere. A nuclear localisation site in the N-terminus of the protein is required for nuclear localisation. This suggests that Ms1 has the potential to act directly in the nucleus through specific interaction with DNA in development and potentially as a response to stress in adult tissues. PMID:26656831

  8. Patient Perspectives on the Hula Empowering Lifestyle Adaptation Study: Benefits of Dancing Hula for Cardiac Rehabilitation

    PubMed Central

    Maskarinec, Gregory G.; Look, Mele; Tolentino, Kalehua; Trask-Batti, Mililani; Seto, Todd; de Silva, Mapuana; Kaholokula, Joseph Keawe‘aimoku

    2014-01-01

    Background The Hula Empowering Lifestyle Adaption Study, funded by the National Institute on Minority Health and Health Disparities, was a 5-year research trial evaluating the impact of the traditional Native Hawaiian dance form, hula, as an exercise modality for cardiac rehabilitation, compared with usual care, on individuals recently hospitalized for a cardiac event or who had recently undergone coronary artery bypass surgery. Method and results Seeking to learn what physical, mental, spiritual, and social effects the intervention may have had for participants, we interviewed 20 of a total of 35 patients who were enrolled in the dance arm of the study. Classical thematic triangulation analysis was used. Participants recognized that hula’s coordination of body, mind, and spirit as a group activity deepened their appreciation of and connections to Hawaiian culture. This was true for those who were Native Hawaiian, connecting to their own cultural heritage, as well as for non–Native Hawaiians, who found that it improved their appreciation of the surrounding cultural traditions of the host culture where they now live. Conclusions Not only was hula a safe activity that improved functional capacity, participants also regarded its significant sociocultural aspects—even for participants who are not Native Hawaiian —as enhancing its value and meaningfulness. Learning the words of well-known Hawaiian songs provided additional long-term cues that encouraged “ownership” of the therapy and acted as practical reminders of the importance of exercise and lifestyle moderation while also offering new spiritual connections to the surrounding social environment. PMID:24677383

  9. Cross-Species Mechanical Fingerprinting of Cardiac Myosin Binding Protein-C

    PubMed Central

    Karsai, Árpád; Kellermayer, Miklós S.Z.; Harris, Samantha P.

    2013-01-01

    Cardiac myosin binding protein-C (cMyBP-C) is a member of the immunoglobulin (Ig) superfamily of proteins and consists of 8 Ig- and 3 fibronectin III (FNIII)-like domains along with a unique regulatory sequence referred to as the MyBP-C motif or M-domain. We previously used atomic force microscopy to investigate the mechanical properties of murine cMyBP-C expressed using a baculovirus/insect cell expression system. Here, we investigate whether the mechanical properties of cMyBP-C are conserved across species by using atomic force microscopy to manipulate recombinant human cMyBP-C and native cMyBP-C purified from bovine heart. Force versus extension data obtained in velocity-clamp experiments showed that the mechanical response of the human recombinant protein was remarkably similar to that of the bovine native cMyBP-C. Ig/Fn-like domain unfolding events occurred in a hierarchical fashion across a threefold range of forces starting at relatively low forces of ∼50 pN and ending with the unfolding of the highest stability domains at ∼180 pN. Force-extension traces were also frequently marked by the appearance of anomalous force drops suggestive of additional mechanical complexity such as structural coupling among domains. Both recombinant and native cMyBP-C exhibited a prominent segment ∼100 nm-long that could be stretched by forces <50 pN before the unfolding of Ig- and FN-like domains. Combined with our previous observations of mouse cMyBP-C, these results establish that although the response of cMyBP-C to mechanical load displays a complex pattern, it is highly conserved across species. PMID:23746519

  10. Effects of Chemically Induced Ovarian Failure on Voluntary Wheel-Running Exercise and Cardiac Adaptation in Mice

    PubMed Central

    Perez, Jessica N; Chen, Hao; Regan, Jessica A; Emert, Ashlie; Constantopoulos, Eleni; Lynn, Melissa; Konhilas, John P

    2013-01-01

    The role of exercise in decreasing the risk of cardiovascular disease in postmenopausal women has not been studied sufficiently. Accordingly, we investigated the effect of voluntary wheel-running and forced treadmill exercise on cardiac adaptation in mice treated with 4-vinylcyclohexine diepoxide (VCD), which selectively accelerates the loss of primary and primordial follicles and results in a state that closely mimics human menopause. Two-month-old female C57BL/6 mice injected with VCD (160 mg/kg) for 20 consecutive days underwent ovarian failure by 60 to 90 d after injection. Responses to voluntary wheel running and treadmill exercise did not differ between VCD- and vehicle-treated 7-mo-old C57BL/6 or outbred B6C3F1 mice. Moreover, adaptive cardiac hypertrophy, hypertrophic marker expression, and skeletal muscle characteristics after voluntary cage-wheel exercise did not differ between VCD- and vehicle-treated mice. Because 5′ AMP-activated protein kinase (AMPK) is a key component for the maintenance of cardiac energy balance during exercise, we determined the effect of exercise and VCD-induced ovarian failure on the AMPK signaling axis in the heart. According to Western blotting, VCD treatment followed by voluntary cage-wheel exercise differently affected the upstream AMPK regulatory components AMPKα1 and AMPKα2. In addition, net downstream AMPK signaling was reduced after VCD treatment and exercise. Our data suggest that VCD did not affect exercise-induced cardiac hypertrophy but did alter cellular cardiac adaptation in a mouse model of menopause. PMID:23759526

  11. Substrate adaptabilities of Thermotogae mannan binding proteins as a function of their evolutionary histories.

    PubMed

    Boucher, Nathalie; Noll, Kenneth M

    2016-09-01

    The Thermotogae possess a large number of ATP-binding cassette (ABC) transporters, including two mannan binding proteins, ManD and CelE (previously called ManE). We show that a gene encoding an ancestor of these was acquired by the Thermotogae from the archaea followed by gene duplication. To address the functional evolution of these proteins as a consequence of their evolutionary histories, we measured the binding affinities of ManD and CelE orthologs from representative Thermotogae. Both proteins bind cellobiose, cellotriose, cellotetraose, β-1,4-mannotriose, and β-1,4-mannotetraose. The CelE orthologs additionally bind β-1,4-mannobiose, laminaribiose, laminaritriose and sophorose while the ManD orthologs additionally only weakly bind β-1,4-mannobiose. The CelE orthologs have higher unfolding temperatures than the ManD orthologs. An examination of codon sites under positive selection revealed that many of these encode residues located near or in the binding site, suggesting that the proteins experienced selective pressures in regions that might have changed their functions. The gene arrangement, phylogeny, binding properties, and putative regulatory networks suggest that the ancestral mannan binding protein was a CelE ortholog which gave rise to the ManD orthologs. This study provides a window on how one class of proteins adapted to new functions and temperatures to fit the physiologies of their new hosts. PMID:27457081

  12. Phosphorylation of Cardiac Myosin Binding Protein-C is a Critical Mediator of Diastolic Function

    PubMed Central

    Rosas, Paola C.; Liu, Yang; Abdalla, Mohamed I.; Thomas, Candice M.; Kidwell, David T.; Dusio, Giuseppina F.; Mukhopadhyay, Dhriti; Kumar, Rajesh; Baker, Kenneth M.; Mitchell, Brett M.; Powers, Patricia A.; Fitzsimons, Daniel P.; Patel, Bindiya G.; Warren, Chad M.; Solaro, R. John; Moss, Richard L.; Tong, Carl W.

    2015-01-01

    Background Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of all cases of heart failure and currently has no effective treatment. Diastolic dysfunction underlies HFpEF; therefore, elucidation of the mechanisms that mediate relaxation can provide new potential targets for treatment. Cardiac myosin binding protein-C (cMyBP-C) is a thick filament protein that modulates cross-bridge cycling rates via alterations in its phosphorylation status. Thus, we hypothesize that phosphorylated cMyBP-C accelerates rate of cross-bridge detachment, thereby enhancing relaxation to mediate diastolic function. Methods and Results We compared mouse models expressing phosphorylation deficient cMyBP-C(S273A/S282A/S302A)-cMyBP-C(t3SA), phosphomimetic cMyBP-C(S273D/S282D/S302D)-cMyBP-C(t3SD), and WT-control cMyBP-C(tWT) to elucidate the functional effects of cMyBP-C phosphorylation. Decreased voluntary running distances, increased lung/body weight ratios, and increased brain natriuretic peptide (BNP) levels in cMyBP-C(t3SA) mice demonstrate that phosphorylation deficiency is associated with signs of heart failure. Echocardiography (ejection fraction, myocardial relaxation velocity) and pressure/volume measurements (−dP/dtmin, pressure decay time constant Tau-Glantz, passive filling stiffness) show that cMyBP-C phosphorylation enhances myocardial relaxation in cMyBP-C(t3SD) mice while deficient cMyBP-C phosphorylation causes diastolic dysfunction with preserved ejection fraction in cMyBP-C(t3SA) mice. Simultaneous force and [Ca2+]i measurements on intact papillary muscles show that enhancement of relaxation in cMyBP-C(t3SD) mice and impairment of relaxation in cMyBP-C(t3SA) mice are not due to altered [Ca2+]i handling, implicating that altered cross-bridge detachment rates mediate these changes in relaxation rates. Conclusions cMyBP-C phosphorylation enhances relaxation while deficient phosphorylation causes diastolic dysfunction and phenotypes

  13. Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation.

    PubMed

    Mamidi, Ranganath; Gresham, Kenneth S; Verma, Sujeet; Stelzer, Julian E

    2016-01-01

    Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is an important regulator of contractile function, however, its contributions to length-dependent changes in cross-bridge (XB) kinetics is unknown. Therefore, we performed mechanical experiments to quantify contractile function in detergent-skinned ventricular preparations isolated from wild-type (WT) hearts, and hearts expressing non-phosphorylatable cMyBP-C [Ser to Ala substitutions at residues Ser273, Ser282, and Ser302 (i.e., 3SA)], at sarcomere length (SL) 1.9 μm or 2.1μm, prior and following protein kinase A (PKA) treatment. Steady-state force generation measurements revealed a blunting in the length-dependent increase in myofilament Ca(2+)-sensitivity of force generation (pCa50) following an increase in SL in 3SA skinned myocardium compared to WT skinned myocardium. Dynamic XB behavior was assessed at submaximal Ca(2+)-activations by imposing an acute rapid stretch of 2% of initial muscle length, and measuring both the magnitudes and rates of resultant phases of force decay due to strain-induced XB detachment and delayed force rise due to recruitment of additional XBs with increased SL (i.e., stretch activation). The magnitude (P2) and rate of XB detachment (k rel) following stretch was significantly reduced in 3SA skinned myocardium compared to WT skinned myocardium at short and long SL, and prior to and following PKA treatment. Furthermore, the length-dependent acceleration of k rel due to decreased SL that was observed in WT skinned myocardium was abolished in 3SA skinned myocardium. PKA treatment accelerated the rate of XB recruitment (k df) following stretch at both SL's in WT but not in 3SA skinned myocardium. The amplitude of the enhancement in force generation above initial pre-stretch steady-state levels (P3) was not different between WT and 3SA skinned myocardium at any condition measured. However, the magnitude of the entire delayed force phase which can dip below initial pre

  14. Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

    PubMed Central

    Mamidi, Ranganath; Gresham, Kenneth S.; Verma, Sujeet; Stelzer, Julian E.

    2016-01-01

    Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is an important regulator of contractile function, however, its contributions to length-dependent changes in cross-bridge (XB) kinetics is unknown. Therefore, we performed mechanical experiments to quantify contractile function in detergent-skinned ventricular preparations isolated from wild-type (WT) hearts, and hearts expressing non-phosphorylatable cMyBP-C [Ser to Ala substitutions at residues Ser273, Ser282, and Ser302 (i.e., 3SA)], at sarcomere length (SL) 1.9 μm or 2.1μm, prior and following protein kinase A (PKA) treatment. Steady-state force generation measurements revealed a blunting in the length-dependent increase in myofilament Ca2+-sensitivity of force generation (pCa50) following an increase in SL in 3SA skinned myocardium compared to WT skinned myocardium. Dynamic XB behavior was assessed at submaximal Ca2+-activations by imposing an acute rapid stretch of 2% of initial muscle length, and measuring both the magnitudes and rates of resultant phases of force decay due to strain-induced XB detachment and delayed force rise due to recruitment of additional XBs with increased SL (i.e., stretch activation). The magnitude (P2) and rate of XB detachment (krel) following stretch was significantly reduced in 3SA skinned myocardium compared to WT skinned myocardium at short and long SL, and prior to and following PKA treatment. Furthermore, the length-dependent acceleration of krel due to decreased SL that was observed in WT skinned myocardium was abolished in 3SA skinned myocardium. PKA treatment accelerated the rate of XB recruitment (kdf) following stretch at both SL's in WT but not in 3SA skinned myocardium. The amplitude of the enhancement in force generation above initial pre-stretch steady-state levels (P3) was not different between WT and 3SA skinned myocardium at any condition measured. However, the magnitude of the entire delayed force phase which can dip below initial pre-stretch steady

  15. Cardiac ryanodine receptor: Selectivity for alkaline earth metal cations points to the EF-hand nature of luminal binding sites.

    PubMed

    Gaburjakova, Jana; Gaburjakova, Marta

    2016-06-01

    A growing body of evidence suggests that the regulation of cardiac ryanodine receptor (RYR2) by luminal Ca(2+) is mediated by luminal binding sites located on the RYR2 channel itself and/or its auxiliary protein, calsequestrin. The localization and structure of RYR2-resident binding sites are not known because of the lack of a high-resolution structure of RYR2 luminal regions. To obtain the first structural insight, we probed the RYR2 luminal face stripped of calsequestrin by alkaline earth metal divalents (M(2+): Mg(2+), Ca(2+), Sr(2+) or Ba(2+)). We show that the RYR2 response to caffeine at the single-channel level is significantly modified by the nature of luminal M(2+). Moreover, we performed competition experiments by varying the concentration of luminal M(2+) (Mg(2+), Sr(2+) or Ba(2+)) from 8mM to 53mM and investigated its ability to compete with 1mM luminal Ca(2+). We demonstrate that all tested M(2+) bind to exactly the same RYR2 luminal binding sites. Their affinities decrease in the order: Ca(2+)>Sr(2+)>Mg(2+)~Ba(2+), showing a strong correlation with the M(2+) affinity of the EF-hand motif. This indicates that the RYR2 luminal binding regions and the EF-hand motif likely share some structural similarities because the structure ties directly to the function. PMID:26849106

  16. Binding of Transcription Factors Adapts to Resolve Information-Energy Tradeoff

    NASA Astrophysics Data System (ADS)

    Savir, Yonatan; Kagan, Jacob; Tlusty, Tsvi

    2016-03-01

    We examine the binding of transcription factors to DNA in terms of an information transfer problem. The input of the noisy channel is the biophysical signal of a factor bound to a DNA site, and the output is a distribution of probable DNA sequences at this site. This task involves an inherent tradeoff between the information gain and the energetics of the binding interaction—high binding energies provide higher information gain but hinder the dynamics of the system as factors are bound too tightly. We show that adaptation of the binding interaction towards increasing information transfer under a general energy constraint implies that the information gain per specific binding energy at each base-pair is maximized. We analyze hundreds of prokaryote and eukaryote transcription factors from various organisms to evaluate the discrimination energies. We find that, in accordance with our theoretical argument, binding energies nearly maximize the information gain per energy. This work suggests the adaptation of information gain as a generic design principle of molecular recognition systems.

  17. Mannose-binding lectin (MBL) insufficiency protects against the development of systemic inflammatory response after pediatric cardiac surgery.

    PubMed

    Pągowska-Klimek, Izabela; Świerzko, Anna S; Michalski, Mateusz; Moll, Maciej; Szala-Poździej, Agnieszka; Sokołowska, Anna; Krajewski, Wojciech R; Cedzyński, Maciej

    2016-02-01

    We investigated MBL2 and MASP2 genotypes, serum MBL (mannose-binding lectin) levels and activities of its complexes with associated serine proteases (MASP-1, MASP -2), in relation to complications following cardiac surgery in 195 children. The incidence of SIRS was lower in patients carrying MBL2 A/O and O/O genotypes (p=0.024). Children with MBL levels <500ng/ml had a lower risk of SIRS (p=0.014) and fever (p=0.044). Median MBL concentration was higher in patients who developed SIRS (p=0.048) but lower in those with post-operative infections (p=0.046). MBL-MASP-2 activities <100mU/ml protected from SIRS (p=0.007), low cardiac output syndrome (p=0.03) and multiorgan failure (p=0.012). In contrast, MBL2 YA/YA genotypes were associated with SIRS (p=0.018), low cardiac output syndrome (p=0.018), fever (p=0.018) and high inotropic score (VIS>30) (p=0.021). Thus, low MBL concentrations and associated genotypes may protect patients from systemic inflammation while high MBL serum levels and corresponding genotypes are risk factors of postoperative complications. PMID:26382056

  18. The hearts of competitive athletes: an up-to-date overview of exercise-induced cardiac adaptations.

    PubMed

    Dores, Hélder; Freitas, António; Malhotra, Aneil; Mendes, Miguel; Sharma, Sanjay

    2015-01-01

    Intense and regular physical exercise is responsible for various cardiac changes (electrical, structural and functional) that represent physiological adaptation to exercise training. This remodeling, commonly referred to as 'athlete's heart', can overlap with several pathological entities, in which sudden cardiac death may be the first clinical presentation. Although pre-competitive screening can identify athletes with life-threatening cardiovascular abnormalities, there are no widely used standardized pre-participation programs and those currently implemented are controversial. Data from personal and family history, features of physical examination and changes in the 12-lead electrocardiogram can raise the suspicion of cardiac disease and lead to early detection of entities such as hypertrophic cardiomyopathy. However, interpreting the electrocardiogram is often challenging, because some changes are considered physiological in athletes. Thus, clinical decision-making in such cases can prove difficult: missing a condition associated with an increased risk of life-threatening events, or conversely, mislabeling an athlete with a disease that leads to unnecessary disqualification, are both situations to avoid. This paper provides an up-to-date review of the physiological cardiac effects of exercise training and highlights key points that should be taken into consideration in the assessment of young competitive athletes. PMID:25575633

  19. GTPase Activating Protein (Sh3 Domain) Binding Protein 1 Regulates the Processing of MicroRNA-1 during Cardiac Hypertrophy

    PubMed Central

    He, Minzhen; Yang, Zhi; Abdellatif, Maha; Sayed, Danish

    2015-01-01

    Background MicroRNAs (miR) are small, posttranscriptional regulators, expressed as part of a longer primary transcript, following which they undergo nuclear and cytoplasmic processing by Drosha and Dicer, respectively, to form the functional mature ~20mer that gets incorporated into the silencing complex. Others and we have shown that mature miR-1 levels decrease with pressure-induced cardiac hypertrophy, however, there is little or no change in the primary transcript encompassing miR-1 stem-loop, suggesting critical regulatory step in microRNA processing. The objective of this study was to investigate the underlying mechanisms regulating miR-1 expression in cardiomyocytes. Results Here we report that GTPase–activating protein (SH3 domain) binding protein 1 (G3bp1), an endoribonuclease regulates miR-1 processing in cardiomyocytes. G3bp1 is upregulated during cardiac hypertrophy and restricts miR-1 processing by binding to its consensus sequence in the pre-miR-1-2 stem-loop. In accordance, exogenous G3bp1 is sufficient to reduce miR-1 levels, along with derepression of miR-1 targets; General transcription factor IIB (Gtf2b), cyclin dependent factor 9 (Cdk9) and eukaryotic initiation factor 4E (Eif4e). While Cdk9 and Gtf2b are essential for transcription, Eif4e is required for translation. Thus, downregulation of miR-1 is necessary for increase in these molecules. Similar to miR-1 knockdown, G3bp1 overexpression is not sufficient for development of cardiac hypertrophy. Conversely, knockdown of G3bp1 in hypertrophying cardiomyocytes inhibited downregulation of miR-1 and upregulation of its targets along with restricted hypertrophy, suggesting that G3bp1 is necessary for development of cardiac hypertrophy. These results indicate that G3bp1-mediated inhibition of miR-1 processing with growth stimulation results in decrease in mature miR-1 and, thereby, an increase of its targets, which play fundamental roles in the development of hypertrophy. Conclusion G3bp1

  20. Cardiac Myosin-binding Protein C and Troponin-I Phosphorylation Independently Modulate Myofilament Length-dependent Activation.

    PubMed

    Kumar, Mohit; Govindan, Suresh; Zhang, Mengjie; Khairallah, Ramzi J; Martin, Jody L; Sadayappan, Sakthivel; de Tombe, Pieter P

    2015-12-01

    β-Adrenergic stimulation in heart leads to increased contractility and lusitropy via activation of protein kinase A (PKA). In the cardiac sarcomere, both cardiac myosin binding protein C (cMyBP-C) and troponin-I (cTnI) are prominent myofilament targets of PKA. Treatment of permeabilized myocardium with PKA induces enhanced myofilament length-dependent activation (LDA), the cellular basis of the Frank-Starling cardiac regulatory mechanism. It is not known, however, which of these targets mediates the altered LDA and to what extent. Here, we employed two genetic mouse models in which the three PKA sites in cMyBP-C were replaced with either phospho-mimic (DDD) or phospho-null (AAA) residues. AAA- or DDD-permeabilized myocytes (n = 12-17) were exchanged (~93%) for recombinant cTnI in which the two PKA sites were mutated to either phospho-mimic (DD) or phospho-null (AA) residues. Force-[Ca(2+)] relationships were determined at two sarcomere lengths (SL = 1.9 μm and SL = 2.3 μm). Data were fit to a modified Hill equation for each individual cell preparation at each SL. LDA was indexed as ΔEC50, the difference in [Ca(2+)] required to achieve 50% force activation at the two SLs. We found that PKA-mediated phosphorylation of cMyBP-C and cTnI each independently contribute to enhance myofilament length-dependent activation properties of the cardiac sarcomere, with relative contributions of ~67 and ~33% for cMyBP-C for cTnI, respectively. We conclude that β-adrenergic stimulation enhances the Frank-Starling regulatory mechanism predominantly via cMyBP-C PKA-mediated phosphorylation. We speculate that this molecular mechanism enhances cross-bridge formation at long SL while accelerating cross-bridge detachment and relaxation at short SLs. PMID:26453301

  1. Identification of Cardiac Myosin-binding Protein C as a Candidate Biomarker of Myocardial Infarction by Proteomics Analysis*

    PubMed Central

    Jacquet, Sebastien; Yin, Xiaoke; Sicard, Pierre; Clark, James; Kanaganayagam, Gajen S.; Mayr, Manuel; Marber, Michael S.

    2009-01-01

    Acute myocardial infarction (AMI) is a common cause of death for which effective treatments are available provided that diagnosis is rapid. The current diagnostic gold standards are circulating cardiac troponins I and T. However, their slow release delays diagnosis, and their persistence limits their utility in the identification of reinfarction. The aim was to identify candidate biomarkers of AMI. Isolated mouse hearts were perfused with oxygenated protein-free buffer, and coronary effluent was collected after ischemia or during matched normoxic perfusion. Effluents were analyzed using proteomics approaches based on one- or two-dimensional initial separation. Of the 459 proteins identified after ischemia with one-dimensional separation, 320 were not detected in the control coronary effluent. Among these were all classic existing biomarkers of AMI. We also identified the cardiac isoform of myosin-binding protein C in its full-length form and as a 40-kDa degradation product. This protein was not detected in the other murine organs examined, increased markedly with even trivial myocardial infarction, and could be detected in the plasma after myocardial infarction in vivo, a profile compatible with a biomarker of AMI. Two-dimensional fluorescence DIGE of ischemic and control coronary effluents identified more than 200 asymmetric spots verified by swapping dyes. Once again existing biomarkers of injury were confirmed as well as posttranslational modifications of antioxidant proteins such as peroxiredoxins. Perfusing hearts with protein-free buffers provides a platform of graded ischemic injury that allows detailed analysis of protein release and identification of candidate cardiac biomarkers like myosin-binding protein C. PMID:19721077

  2. Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics.

    PubMed

    Colson, Brett A; Thompson, Andrew R; Espinoza-Fonseca, L Michel; Thomas, David D

    2016-03-22

    We have used the site-directed spectroscopies of time-resolved fluorescence resonance energy transfer (TR-FRET) and double electron-electron resonance (DEER), combined with complementary molecular dynamics (MD) simulations, to resolve the structure and dynamics of cardiac myosin-binding protein C (cMyBP-C), focusing on the N-terminal region. The results have implications for the role of this protein in myocardial contraction, with particular relevance to β-adrenergic signaling, heart failure, and hypertrophic cardiomyopathy. N-terminal cMyBP-C domains C0-C2 (C0C2) contain binding regions for potential interactions with both thick and thin filaments. Phosphorylation by PKA in the MyBP-C motif regulates these binding interactions. Our spectroscopic assays detect distances between pairs of site-directed probes on cMyBP-C. We engineered intramolecular pairs of labeling sites within cMyBP-C to measure, with high resolution, the distance and disorder in the protein's flexible regions using TR-FRET and DEER. Phosphorylation reduced the level of molecular disorder and the distribution of C0C2 intramolecular distances became more compact, with probes flanking either the motif between C1 and C2 or the Pro/Ala-rich linker (PAL) between C0 and C1. Further insight was obtained from microsecond MD simulations, which revealed a large structural change in the disordered motif region in which phosphorylation unmasks the surface of a series of residues on a stable α-helix within the motif with high potential as a protein-protein interaction site. These experimental and computational findings elucidate structural transitions in the flexible and dynamic portions of cMyBP-C, providing previously unidentified molecular insight into the modulatory role of this protein in cardiac muscle contractility. PMID:26908877

  3. The development and application of a high-sensitivity immunoassay for cardiac myosin–binding protein C

    PubMed Central

    Marjot, Jack; Liebetrau, Christoph; Goodson, Robert J.; Kaier, Thomas; Weber, Ekkehard; Heseltine, Peter; Marber, Michael S.

    2016-01-01

    Cardiac troponins (cTns) are released and cleared slowly after myocardial injury. Cardiac myosin–binding protein C (cMyC) is a similar cardiac-restricted protein that has more rapid release and clearance kinetics. Direct comparisons are hampered by the lack of an assay for cMyC that matches the sensitivity of the contemporary assays for cTnI and cTnT. Using a novel pair of monoclonal antibodies, we generated a sensitive assay for MyC on the Erenna platform (Singulex) and compared serum concentrations with those of cTnI (Abbott) and cTnT (Roche) in stable ambulatory cardiac patients without evidence of acute cardiac injury or significant coronary artery stenoses. The assay for cMyC had a lower limit of detection of 0.4 ng/L, a lower limit of quantification (LLoQ) of 1.2 ng/L (LLoQ at 20% coefficient of variation [CV]) and reasonable recovery (107.1 ± 3.7%; mean ± standard deviation), dilutional linearity (101.0 ± 7.7%), and intraseries precision (CV, 11 ± 3%) and interseries precision (CV, 13 ± 3%). In 360 stable patients, cMyC was quantifiable in 359 patients and compared with cTnT and cTnI measured using contemporary high-sensitivity assays. cMyC concentration (median, 12.2 ng/L; interquartile range [IQR], 7.9–21.2 ng/L) was linearly correlated with those for cTnT (median, <3.0 ng/L; IQR, <3.0–4.9 ng/L; R = 0.56, P < 0.01) and cTnI (median, 2.10 ng/L; IQR, 1.3–4.2 ng/L; R = 0.77, P < 0.01) and showed similar dependencies on age, renal function, and left ventricular function. We have developed a high-sensitivity assay for cMyC. Concentrations of cMyC in clinically stable patients are highly correlated with those of cTnT and cTnI. This high correlation may enable ratiometric comparisons between biomarkers to distinguish clinical instability. PMID:26713894

  4. Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C

    PubMed Central

    2011-01-01

    Background Cardiac contractility is regulated by dynamic phosphorylation of sarcomeric proteins by kinases such as cAMP-activated protein kinase A (PKA). Efficient phosphorylation requires that PKA be anchored close to its targets by A-kinase anchoring proteins (AKAPs). Cardiac Myosin Binding Protein-C (cMyBPC) and cardiac troponin I (cTNI) are hypertrophic cardiomyopathy (HCM)-causing sarcomeric proteins which regulate contractility in response to PKA phosphorylation. Results During a yeast 2-hybrid (Y2H) library screen using a trisphosphorylation mimic of the C1-C2 region of cMyBPC, we identified isoform 4 of myomegalin (MMGL) as an interactor of this N-terminal cMyBPC region. As MMGL has previously been shown to interact with phosphodiesterase 4D, we speculated that it may be a PKA-anchoring protein (AKAP). To investigate this possibility, we assessed the ability of MMGL isoform 4 to interact with PKA regulatory subunits R1A and R2A using Y2H-based direct protein-protein interaction assays. Additionally, to further elucidate the function of MMGL, we used it as bait to screen a cardiac cDNA library. Other PKA targets, viz. CARP, COMMD4, ENO1, ENO3 and cTNI were identified as putative interactors, with cTNI being the most frequent interactor. We further assessed and confirmed these interactions by fluorescent 3D-co-localization in differentiated H9C2 cells as well as by in vivo co-immunoprecipitation. We also showed that quantitatively more interaction occurs between MMGL and cTNI under β-adrenergic stress. Moreover, siRNA-mediated knockdown of MMGL leads to reduction of cMyBPC levels under conditions of adrenergic stress, indicating that MMGL-assisted phosphorylation is requisite for protection of cMyBPC against proteolytic cleavage. Conclusions This study ascribes a novel function to MMGL isoform 4: it meets all criteria for classification as an AKAP, and we show that is involved in the phosphorylation of cMyBPC as well as cTNI, hence MMGL is an important

  5. EFIA/YB-1 is a component of cardiac HF-1A binding activity and positively regulates transcription of the myosin light-chain 2v gene.

    PubMed Central

    Zou, Y; Chien, K R

    1995-01-01

    Transient assays in cultured ventricular muscle cells and studies in transgenic mice have identified two adjacent regulatory elements (HF-1a and HF-1b/MEF-2) as required to maintain ventricular chamber-specific expression of the myosin light-chain 2v (MLC-2v) gene. A rat neonatal heart cDNA library was screened with an HF-1a binding site, resulting in the isolation of EFIA, the rat homolog of human YB-1. Purified recombinant EFIA/YB-1 protein binds to the HF-1a site in a sequence-specific manner and contacts a subset of the HF-1a contact points made by the cardiac nuclear factor(s). The HF-1a sequence contains AGTGG, which is highly homologous to the inverted CCAAT core of the EFIA/YB-1 binding sites and is found to be essential for binding of the recombinant EFIA/YB-1. Antiserum against Xenopus YB-3 (100% identical in the DNA binding domain and 89% identical in overall amino acid sequence to rat EFIA) can specifically abolish a component of the endogenous HF-1a complex in the rat cardiac myocyte nuclear extracts. In cotransfection assays, EFIA/YB-1 increased 250-bp MLC-2v promoter activity by 3.4-fold specifically in the cardiac cell context and in an HF-1a site-dependent manner. EFIA/YB-1 complexes with an unknown protein in cardiac myocyte nuclear extracts to form the endogenous HF-1a binding activity. Immunocoprecipitation revealed that EFIA/YB-1 has a major associated protein of approximately 30 kDa (p30) in cardiac muscle cells. This study suggests that EFIA/YB-1, together with the partner p30, binds to the HF-1a site and, in conjunction with HF-1b/MEF-2, mediates ventricular chamber-specific expression of the MLC-2v gene. PMID:7760795

  6. Candida glabrata binds to glycosylated and lectinic receptors on the coronary endothelial luminal membrane and inhibits flow sense and cardiac responses to agonists.

    PubMed

    Torres-Tirado, David; Knabb, Maureen; Castaño, Irene; Patrón-Soberano, Araceli; De Las Peñas, Alejandro; Rubio, Rafael

    2016-01-01

    Candida glabrata (CG) is an opportunistic fungal pathogen that initiates infection by binding to host cells via specific lectin-like adhesin proteins. We have previously shown the importance of lectin-oligosaccharide binding in cardiac responses to flow and agonists. Because of the lectinic-oligosaccharide nature of CG binding, we tested the ability of CG to alter the agonist- and flow-induced changes in cardiac function in isolated perfused guinea pig hearts. Both transmission and scanning electron microscopy showed strong attachment of CG to the coronary endothelium, even after extensive washing. CG shifted the coronary flow vs. auricular-ventricular (AV) delay relationship upward, indicating that greater flow was required to achieve the same AV delay. This effect was completely reversed with mannose, partially reversed with galactose and N-acetylgalactosamine, but hyaluronan had no effect. Western blot analysis was used to determine binding of CG to isolated coronary endothelial luminal membrane (CELM) receptors, and the results indicate that flow-sensitive CELM receptors, ANG II type I, α-adrenergic 1A receptor, endothelin-2, and VCAM-1 bind to CG. In addition, CG inhibited agonist-induced effects of bradykinin, angiotensin, and phenylephrine on AV delay, coronary perfusion pressure, and left ventricular pressure. Mannose reversed the inhibitory effects of CG on the agonist responses. These results suggest that CG directly binds to flow-sensitive CELM receptors via lectinic-oligosaccharide interactions with mannose and disrupts the lectin-oligosaccharide binding necessary for flow-induced cardiac responses. PMID:26491100

  7. Does p49/STRAP, a SRF-binding protein (SRFBP1), modulate cardiac mitochondrial function in aging?

    PubMed

    Zhang, Xiaomin; Williams, Emmanuel D; Azhar, Gohar; Rogers, Steven C; Wei, Jeanne Y

    2016-09-01

    p49/STRAP (SRFBP1) is a transcriptional regulator that has been implicated in cardiac aging. p49/STRAP has a SRF binding domain and a BUD22 domain (which modulates cellular growth rate and cell size). We have observed that p49/STRAP alters the intracellular NAD/NADH ratio and induces protein deacetylation. Here we report that p49/STRAP overexpression caused the deacetylation of histone H4 on lysine 16 (H4K16) and suppressed the expression of PGC-1α as well as mitofusin-1 and mitofusin-2 at both the mRNA and protein levels. P49/STRAP also reduced mitochondrial size, mitochondrial membrane potential and the mitochondrial oxygen consumption rate. We noted that P49/STRAP expression was increased in the old versus young adult mouse hearts and also increased with advancing population doubling levels in cultured human umbilical vein endothelial cells (HUVECs). It is therefore very plausible that increased expression of p49/STRAP in late life may alter the status of histone acetylation and impact mitochondrial dynamics and thereby reduce mitochondrial function and cardiac performance during mammalian senescence. PMID:27337995

  8. Hrd1 and ER-Associated Protein Degradation, ERAD, Are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes

    PubMed Central

    Doroudgar, Shirin; Völkers, Mirko; Thuerauf, Donna J; Khan, Mohsin; Mohsin, Sadia; Respress, Jonathan L; Wang, Wei; Gude, Natalie; Müller, Oliver J; Wehrens, Xander HT; Sussman, Mark A; Glembotski, Christopher C

    2015-01-01

    Rationale Hrd1 is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER protein quality control by ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER stress. Neither Hrd1 nor ERAD have been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function. Objective The objectives of this study were to elucidate roles for Hrd1 in ER stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, in vivo. Methods and Results The effects of siRNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus (AAV)-mediated Hrd1 knockdown and overexpression were examined in the hearts of mice subjected to pressure-overload induced pathological cardiac hypertrophy, which challenges protein-folding capacity. In cardiac myocytes, the ER stressors, thapsigargin (TG) and tunicamycin (TM) increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, TG and TM dramatically decreased ERAD, while increasing maladaptive ER stress proteins and cell death. In vivo, Hrd1 knockdown exacerbated cardiac dysfunction, and increased apoptosis and cardiac hypertrophy, while Hrd1 overexpression preserved cardiac function, and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure-overload. Conclusions Hrd1 and ERAD are essential components of the adaptive ER stress response in cardiac myocytes. Hrd1 contributes to preserving heart structure and function in a mouse model of pathological cardiac hypertrophy. PMID:26137860

  9. A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation

    PubMed Central

    Sikkel, Markus B.; Caorsi, Valentina; Vydyanath, Anupama; Torre, Iratxe; Copeland, O'Neal; Lyon, Alexander R.; Marston, Steven B.; Luther, Pradeep K.; Macleod, Kenneth T.; West, Timothy G.; Ferenczi, Michael A.

    2016-01-01

    Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic “compensation” and congestive “decompensation.” Nothing is known about the ability of uninfarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drives progression of compensation. We hypothesized that enhanced cross-bridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared with noninfarcted controls. Isometric force during submaximal activations was raised >2.4-fold, while power was 2-fold greater. Electron and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae. PMID:27233767

  10. A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation.

    PubMed

    Toepfer, Christopher N; Sikkel, Markus B; Caorsi, Valentina; Vydyanath, Anupama; Torre, Iratxe; Copeland, O'Neal; Lyon, Alexander R; Marston, Steven B; Luther, Pradeep K; Macleod, Kenneth T; West, Timothy G; Ferenczi, Michael A

    2016-08-01

    Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic "compensation" and congestive "decompensation." Nothing is known about the ability of uninfarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drives progression of compensation. We hypothesized that enhanced cross-bridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared with noninfarcted controls. Isometric force during submaximal activations was raised >2.4-fold, while power was 2-fold greater. Electron and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae. PMID:27233767

  11. A Method to Study the Impact of Chemically-induced Ovarian Failure on Exercise Capacity and Cardiac Adaptation in Mice

    PubMed Central

    Chen, Hao; Perez, Jessica N.; Constantopoulos, Eleni; McKee, Laurel; Regan, Jessica; Hoyer, Patricia B.; Brooks, Heddwen L.; Konhilas, John

    2014-01-01

    The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exercise, as a preventative measure for CVD risk in post-menopausal women has not been adequately studied. Accordingly, we investigated the impact of voluntary cage-wheel exercise and forced treadmill exercise on cardiac adaptation in menopausal mice. The most commonly used inducible model for mimicking menopause in women is the ovariectomized (OVX) rodent. However, the OVX model has a few dissimilarities from menopause in humans. In this study, we administered 4-vinylcyclohexene diepoxide (VCD) to female mice, which accelerates ovarian failure as an alternative menopause model to study the impact of exercise in menopausal mice. VCD selectively accelerates the loss of primary and primordial follicles resulting in an endocrine state that closely mimics the natural progression from pre- to peri- to post-menopause in humans. To determine the impact of exercise on exercise capacity and cardiac adaptation in VCD-treated female mice, two methods were used. First, we exposed a group of VCD-treated and untreated mice to a voluntary cage wheel. Second, we used forced treadmill exercise to determine exercise capacity in a separate group VCD-treated and untreated mice measured as a tolerance to exercise intensity and endurance. PMID:24747886

  12. A method to study the impact of chemically-induced ovarian failure on exercise capacity and cardiac adaptation in mice.

    PubMed

    Chen, Hao; Perez, Jessica N; Constantopoulos, Eleni; McKee, Laurel; Regan, Jessica; Hoyer, Patricia B; Brooks, Heddwen L; Konhilas, John

    2014-01-01

    The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exercise, as a preventative measure for CVD risk in post-menopausal women has not been adequately studied. Accordingly, we investigated the impact of voluntary cage-wheel exercise and forced treadmill exercise on cardiac adaptation in menopausal mice. The most commonly used inducible model for mimicking menopause in women is the ovariectomized (OVX) rodent. However, the OVX model has a few dissimilarities from menopause in humans. In this study, we administered 4-vinylcyclohexene diepoxide (VCD) to female mice, which accelerates ovarian failure as an alternative menopause model to study the impact of exercise in menopausal mice. VCD selectively accelerates the loss of primary and primordial follicles resulting in an endocrine state that closely mimics the natural progression from pre- to peri- to post-menopause in humans. To determine the impact of exercise on exercise capacity and cardiac adaptation in VCD-treated female mice, two methods were used. First, we exposed a group of VCD-treated and untreated mice to a voluntary cage wheel. Second, we used forced treadmill exercise to determine exercise capacity in a separate group VCD-treated and untreated mice measured as a tolerance to exercise intensity and endurance. PMID:24747886

  13. Cardiac myosin isoforms exhibit differential rates of MgADP release and MgATP binding detected by myocardial viscoelasticity.

    PubMed

    Wang, Yuan; Tanner, Bertrand C W; Lombardo, Andrew T; Tremble, Sarah M; Maughan, David W; Vanburen, Peter; Lewinter, Martin M; Robbins, Jeffrey; Palmer, Bradley M

    2013-01-01

    We measured myosin crossbridge detachment rate and the rates of MgADP release and MgATP binding in mouse and rat myocardial strips bearing one of the two cardiac myosin heavy chain (MyHC) isoforms. Mice and rats were fed an iodine-deficient, propylthiouracil diet resulting in ~100% expression of β-MyHC in the ventricles. Ventricles of control animals expressed ~100% α-MyHC. Chemically-skinned myocardial strips prepared from papillary muscle were subjected to sinusoidal length perturbation analysis at maximum calcium activation pCa 4.8 and 17°C. Frequency characteristics of myocardial viscoelasticity were used to calculate crossbridge detachment rate over 0.01 to 5mM [MgATP]. The rate of MgADP release, equivalent to the asymptotic value of crossbridge detachment rate at high MgATP, was highest in mouse α-MyHC (111.4±6.2s(-1)) followed by rat α-MyHC (65.0±7.3s(-1)), mouse β-MyHC (24.3±1.8s(-1)) and rat β-MyHC (15.5±0.8s(-1)). The rate of MgATP binding was highest in mouse α-MyHC (325±32 mM(-1) s(-1)) then mouse β-MyHC (152±23 mM(-1) s(-1)), rat α-MyHC (108±10 mM(-1) s(-1)) and rat β-MyHC (55±6 mM(-1) s(-1)). Because the events of MgADP release and MgATP binding occur in a post power-stroke state of the myosin crossbridge, we infer that MgATP release and MgATP binding must be regulated by isoform- and species-specific structural differences located outside the nucleotide binding pocket, which is identical in sequence for these four myosins. We postulate that differences in the stiffness profile of the entire myosin molecule, including the thick filament and the myosin-actin interface, are primarily responsible for determining the strain on the nucleotide binding pocket and the subsequent differences in the rates of nucleotide release and binding observed among the four myosins examined here. PMID:23123290

  14. Bnip3 Binds and Activates p300: Possible Role in Cardiac Transcription and Myocyte Morphology.

    PubMed

    Thompson, John W; Wei, Jianqin; Appau, Kweku; Wang, Huilan; Yu, Hong; Spiga, Maria G; Graham, Regina M; Webster, Keith A

    2015-01-01

    Bnip3 is a hypoxia-regulated member of the Bcl-2 family of proteins that is implicated in apoptosis, programmed necrosis, autophagy and mitophagy. Mitochondria are thought to be the primary targets of Bnip3 although its activities may extend to the ER, cytoplasm, and nucleus. Bnip3 is induced in the heart by ischemia and pressure-overload, and may contribute to cardiomyopathy and heart failure. Only mitochondrial-dependent programmed death actions have been described for Bnip3 in the heart. Here we describe a novel activity of Bnip3 in cultured cardiac myocytes and transgenic mice overexpressing Bnip3 in the heart (Bnip3-TG). In cultured myocytes Bnip3 bound and activated the acetyltransferase p300, increased acetylation of histones and the transcription factor GATA4, and conferred p300 and GATA4-sensitive cellular morphological changes. In intact Bnip3-TG hearts Bnip3 also bound p300 and GATA4 and conferred enhanced GATA4 acetylation. Bnip3-TG mice underwent age-dependent ventricular dilation and heart failure that was partially prevented by p300 inhibition with curcumin. The results suggest that Bnip3 regulates cardiac gene expression and perhaps myocyte morphology by activating nuclear p300 acetyltransferase activity and hyperacetylating histones and p300-selective transcription factors. PMID:26317696

  15. Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing*

    PubMed Central

    Song, Daisheng; Li, Lin-sheng; Arsenault, Patrick R.; Tan, Qiulin; Bigham, Abigail W.; Heaton-Johnson, Katherine J.; Master, Stephen R.; Lee, Frank S.

    2014-01-01

    The Tibetan population has adapted to the chronic hypoxia of high altitude. Tibetans bear a genetic signature in the prolyl hydroxylase domain protein 2 (PHD2/EGLN1) gene, which encodes for the central oxygen sensor of the hypoxia-inducible factor (HIF) pathway. Recent studies have focused attention on two nonsynonymous coding region substitutions, D4E and C127S, both of which are markedly enriched in the Tibetan population. These amino acids reside in a region of PHD2 that harbors a zinc finger, which we have previously discovered binds to a Pro-Xaa-Leu-Glu (PXLE) motif in the HSP90 cochaperone p23, thereby recruiting PHD2 to the HSP90 pathway to facilitate HIF-α hydroxylation. We herein report that the Tibetan PHD2 haplotype (D4E/C127S) strikingly diminishes the interaction of PHD2 with p23, resulting in impaired PHD2 down-regulation of the HIF pathway. The defective binding to p23 depends on both the D4E and C127S substitutions. We also identify a PXLE motif in HSP90 itself that can mediate binding to PHD2 but find that this interaction is maintained with the D4E/C127S PHD2 haplotype. We propose that the Tibetan PHD2 variant is a loss of function (hypomorphic) allele, leading to augmented HIF activation to facilitate adaptation to high altitude. PMID:24711448

  16. Cardiac Myosin Binding Protein C Phosphorylation Affects Cross-Bridge Cycle's Elementary Steps in a Site-Specific Manner

    PubMed Central

    Wang, Li; Sadayappan, Sakthivel; Kawai, Masakata

    2014-01-01

    Based on our recent finding that cardiac myosin binding protein C (cMyBP-C) phosphorylation affects muscle contractility in a site-specific manner, we further studied the force per cross-bridge and the kinetic constants of the elementary steps in the six-state cross-bridge model in cMyBP-C mutated transgenic mice for better understanding of the influence of cMyBP-C phosphorylation on contractile functions. Papillary muscle fibres were dissected from cMyBP-C mutated mice of ADA (Ala273-Asp282-Ala302), DAD (Asp273-Ala282-Asp302), SAS (Ser273-Ala282-Ser302), and t/t (cMyBP-C null) genotypes, and the results were compared to transgenic mice expressing wide-type (WT) cMyBP-C. Sinusoidal analyses were performed with serial concentrations of ATP, phosphate (Pi), and ADP. Both t/t and DAD mutants significantly reduced active tension, force per cross-bridge, apparent rate constant (2πc), and the rate constant of cross-bridge detachment. In contrast to the weakened ATP binding and enhanced Pi and ADP release steps in t/t mice, DAD mice showed a decreased ADP release without affecting the ATP binding and the Pi release. ADA showed decreased ADP release, and slightly increased ATP binding and cross-bridge detachment steps, whereas SAS diminished the ATP binding step and accelerated the ADP release step. t/t has the broadest effects with changes in most elementary steps of the cross-bridge cycle, DAD mimics t/t to a large extent, and ADA and SAS predominantly affect the nucleotide binding steps. We conclude that the reduced tension production in DAD and t/t is the result of reduced force per cross-bridge, instead of the less number of strongly attached cross-bridges. We further conclude that cMyBP-C is an allosteric activator of myosin to increase cross-bridge force, and its phosphorylation status modulates the force, which is regulated by variety of protein kinases. PMID:25420047

  17. Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage.

    PubMed

    Suzuki, Takehiro; Yamaguchi, Hiroaki; Kikusato, Motoi; Hashizume, Osamu; Nagatoishi, Satoru; Matsuo, Akihiro; Sato, Takeya; Kudo, Tai; Matsuhashi, Tetsuro; Murayama, Kazutaka; Ohba, Yuki; Watanabe, Shun; Kanno, Shin-Ichiro; Minaki, Daichi; Saigusa, Daisuke; Shinbo, Hiroko; Mori, Nobuyoshi; Yuri, Akinori; Yokoro, Miyuki; Mishima, Eikan; Shima, Hisato; Akiyama, Yasutoshi; Takeuchi, Yoichi; Kikuchi, Koichi; Toyohara, Takafumi; Suzuki, Chitose; Ichimura, Takaharu; Anzai, Jun-Ichi; Kohzuki, Masahiro; Mano, Nariyasu; Kure, Shigeo; Yanagisawa, Teruyuki; Tomioka, Yoshihisa; Toyomizu, Masaaki; Tsumoto, Kohei; Nakada, Kazuto; Bonventre, Joseph V; Ito, Sadayoshi; Osaka, Hitoshi; Hayashi, Ken-Ichi; Abe, Takaaki

    2016-07-01

    Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction. PMID:26609120

  18. Isolation and characterization of a Streptococcus pyogenes protein that binds to basal laminae of human cardiac muscle.

    PubMed Central

    Winters, B D; Ramasubbu, N; Stinson, M W

    1993-01-01

    A 9-kDa glycosaminoglycan-binding protein (GAG-BP) was isolated from Streptococcus pyogenes and purified to homogeneity by affinity chromatography on heparin-agarose. The protein selectively bound to the basal laminae of human cardiac muscle and had an apparent dissociation constant of 2.5 x 10(-7) M. Chemical analyses indicated that the GAG-BP was rich in alanine, lysine, and arginine (pI 9.5) and devoid of tyrosine, methionine, histidine, and half-cystine. There were no detectable carbohydrate or phosphate substituents. The amino acid sequence of the N terminus of GAG-BP showed homology with those of histone-like DNA-binding proteins of several other bacteria. Circular dichroism spectroscopy indicated that the protein was made up of 50% beta-sheet and 50% beta-turn and random coil in aqueous solution; however, when the protein complexed with heparin, it adopted a more ordered structure containing 25% alpha-helix, 50% beta-sheet, and 25% beta-turn and random coil. The GAG-BP cross-reacted serologically with a component of similar size in extracts of other group A streptococci and was present in the culture medium during late logarithmic growth. Images PMID:8335359

  19. Conformational selection and adaptation to ligand binding in T4 lysozyme cavity mutants.

    PubMed

    López, Carlos J; Yang, Zhongyu; Altenbach, Christian; Hubbell, Wayne L

    2013-11-12

    The studies presented here explore the relationship between protein packing and molecular flexibility using ligand-binding cavity mutants of T4 lysozyme. Although previously reported crystal structures of the mutants investigated show single conformations that are similar to the WT protein, site-directed spin labeling in solution reveals additional conformational substates in equilibrium exchange with a WT-like population. Remarkably, binding of ligands, including the general anesthetic halothane shifts the population to the WT-like state, consistent with a conformational selection model of ligand binding, but structural adaptation to the ligand is also apparent in one mutant. Distance mapping with double electron-electron resonance spectroscopy and the absence of ligand binding suggest that the new substates induced by the cavity-creating mutations represent alternate packing modes in which the protein fills or partially fills the cavity with side chains, including the spin label in one case; external ligands compete with the side chains for the cavity space, stabilizing the WT conformation. The results have implications for mechanisms of anesthesia, the response of proteins to hydrostatic pressure, and protein engineering. PMID:24167295

  20. Ginseng Gintonin Activates the Human Cardiac Delayed Rectifier K+ Channel: Involvement of Ca2+/Calmodulin Binding Sites

    PubMed Central

    Choi, Sun-Hye; Lee, Byung-Hwan; Kim, Hyeon-Joong; Jung, Seok-Won; Kim, Hyun-Sook; Shin, Ho-Chul; Lee, Jun-Hee; Kim, Hyoung-Chun; Rhim, Hyewhon; Hwang, Sung-Hee; Ha, Tal soo; Kim, Hyun-Ji; Cho, Hana; Nah, Seung-Yeol

    2014-01-01

    Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits [Ca2+]i transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier K+ (IKs) channel is a cardiac K+ channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating IKs channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human IKs channel activity by expressing human IKs channels in Xenopus oocytes. We found that gintonin enhances IKs channel currents in concentration- and voltage-dependent manners. The EC50 for the IKs channel was 0.05 ± 0.01 μg/ml. Gintonin-mediated activation of the IKs channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an IP3 receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the IKs channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 [Ca2+]i/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on IKs channel. However, gintonin had no effect on hERG K+ channel activity. These results show that gintonin-mediated enhancement of IKs channel currents is achieved through binding of the [Ca2+]i/CaM complex to the C terminus of KCNQ1 subunit. PMID:25234465

  1. Stereoselective binding in cardiac tissue of the enatiomers of benzetimide, and antimuscarinic drug.

    PubMed Central

    Gray, J A; Lüllmann, H; Mitchelson, F; Reil, G H

    1976-01-01

    1 Benzetimide, possessing two stable enantiomers, dexetimide and levetimide, has been investigated in guinea-pig atria with respect to its atropine-like action and its tissue distribution. 2 The antagonistic potency of dexetimide was found to be over 6000 times higher than that of levetimide, the pA2 values being 9.82 and 6.0 respectively. 3 The tissue accumulation was investigated for both isomers in the concentration range from 1.5 X 10(-9) M to 10(-6) M yielding tissue to medium ratios (T/M) of between approximately 50 and 10. The highest values were found for the lowest concentrations. At any concentration investigated, dexetimide exhibited a higher uptake than the levoisomer. 4 The rate of uptake and washout of dexetimide was extremely slow, that of levetimide being considerably faster at equimolar concentrations. The same pattern held true for the onset and decline of the antagonistic action. 5 The high accumulation was found to be almost entirely due to unspecific binding. Even in the case of dexetimide the relative size of the receptor compartment could not be determined. The unspecific binding sites displayed a certain stereoselectivity but to a much lesser extent than the specific receptor binding sites. PMID:1260229

  2. Gene 33/Mig-6, a Transcriptionally Inducible Adapter Protein That Binds GTP-Cdc42 and Activates SAPK/JNK*

    PubMed Central

    Makkinje, Anthony; Quinn, Deborah A.; Chen, Ang; Cadilla, Carmen L.; Force, Thomas; Bonventre, Joseph V.; Kyriakis, John M.

    2013-01-01

    Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical consequences, including hypertrophy and acute respiratory distress syndrome. Pathologic hypertrophy contributes to decreased organ function and, ultimately, organ failure; and cardiac and diabetic renal hypertrophy are major causes of morbidity and morality in the developed world. Likewise, acute respiratory distress syndrome is a serious potential side effect of mechanical pulmonary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extra-cellular stimuli. The physiologic function of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sharply in response to a set of commonly occurring chronic stress stimuli: mechanical strain, vasoactive peptides, and diabetic nephropathy. Induction of gene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases. This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress. The structure of Gene 33 indicates an adapter protein capable of binding monomeric GTPases of the Rho subfamily. Consistent with this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs. These results imply a reciprocal, positive feedback relationship between Gene 33 expression and SAPK activation. Expression of Gene 33 at sufficient levels may enable a compensatory reprogramming of cellular function in response to chronic stress, which may have pathophysiological consequences. PMID:10749885

  3. Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or β1-Adrenergic Stimulation

    PubMed Central

    Tong, Carl W.; Wu, Xin; Liu, Yang; Rosas, Paola C.; Sadayappan, Sakthivel; Hudmon, Andy; Muthuchamy, Mariappan; Powers, Patricia A.; Valdivia, Héctor H.; Moss, Richard L.

    2015-01-01

    Background Mammalian hearts exhibit positive inotropic responses to β-adrenergic stimulation as a consequence of protein kinase A (PKA)-mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) by PKA accelerates the kinetics of force development in permeabilized heart muscle, but its role in vivo is unknown. Such understanding is important, since adrenergic responsiveness of the heart and the Bowditch effect are both depressed in heart failure. Methods and Results The roles of cMyBP-C phosphorylation were studied using mice in which either WT or nonphosphorylatable forms of cMyBP-C [ser273ala, ser282ala, ser302ala: cMyBP-C(t3SA)] were expressed at similar levels on a cMyBP-C null background. Force and [Ca2+]in measurements in isolated papillary muscles showed that the increased force and twitch kinetics due to increased pacing or β1-adrenergic stimulation were nearly absent in cMyBP-C(t3SA) myocardium, even though [Ca2+]intransients under each condition were similar to WT. Biochemical measurements confirmed that PKA phosphorylated ser273, ser282 and ser302 in WT cMyBP-C. In contrast, CaMKIIδ, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all. Conclusions Phosphorylation of cMyBP-C increases the force and kinetics of twitches in living cardiac muscle. Further, cMyBP-C is a principal mediator of increased contractility observed with β-adrenergic stimulation or increased pacing, due to PKA and CaMKIIδ phosphorylations of cMyB-C. PMID:25740838

  4. The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency.

    PubMed

    van Dijk, Sabine J; Bezold Kooiker, Kristina; Mazzalupo, Stacy; Yang, Yuanzhang; Kostyukova, Alla S; Mustacich, Debbie J; Hoye, Elaine R; Stern, Joshua A; Kittleson, Mark D; Harris, Samantha P

    2016-07-01

    Mutations in MYBPC3, the gene encoding cardiac myosin binding protein C (cMyBP-C), are a major cause of hypertrophic cardiomyopathy (HCM). While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Here we investigated effects of a single proline for alanine substitution at amino acid 31 (A31P) in the C0 domain of cMyBP-C, which was identified as a natural cause of HCM in cats. Results using recombinant proteins showed that the mutation disrupted C0 structure, altered sensitivity to trypsin digestion, and reduced recognition by an antibody that preferentially recognizes N-terminal domains of cMyBP-C. Western blots detecting A31P cMyBP-C in myocardium of cats heterozygous for the mutation showed a reduced amount of A31P mutant protein relative to wild-type cMyBP-C, but the total amount of cMyBP-C was not different in myocardium from cats with or without the A31P mutation indicating altered rates of synthesis/degradation of A31P cMyBP-C. Also, the mutant A31P cMyBP-C was properly localized in cardiac sarcomeres. These results indicate that reduced protein expression (haploinsufficiency) cannot account for effects of the A31P cMyBP-C mutation and instead suggest that the A31P mutation causes HCM through a poison polypeptide mechanism that disrupts cMyBP-C or myocyte function. PMID:26777460

  5. Length-dependent changes in contractile dynamics are blunted due to cardiac myosin binding protein-C ablation

    PubMed Central

    Mamidi, Ranganath; Gresham, Kenneth S.; Stelzer, Julian E.

    2014-01-01

    Enhanced cardiac contractile function with increased sarcomere length (SL) is, in part, mediated by a decrease in the radial distance between myosin heads and actin. The radial disposition of myosin heads relative to actin is modulated by cardiac myosin binding protein-C (cMyBP-C), suggesting that cMyBP-C contributes to the length-dependent activation (LDA) in the myocardium. However, the precise roles of cMyBP-C in modulating cardiac LDA are unclear. To determine the impact of cMyBP-C on LDA, we measured isometric force, myofilament Ca2+-sensitivity (pCa50) and length-dependent changes in kinetic parameters of cross-bridge (XB) relaxation (krel), and recruitment (kdf) due to rapid stretch, as well as the rate of force redevelopment (ktr) in response to a large slack-restretch maneuver in skinned ventricular multicellular preparations isolated from the hearts of wild-type (WT) and cMyBP-C knockout (KO) mice, at SL's 1.9 μm or 2.1 μm. Our results show that maximal force was not significantly different between KO and WT preparations but length-dependent increase in pCa50 was attenuated in the KO preparations. pCa50 was not significantly different between WT and KO preparations at long SL (5.82 ± 0.02 in WT vs. 5.87 ± 0.02 in KO), whereas pCa50 was significantly different between WT and KO preparations at short SL (5.71 ± 0.02 in WT vs. 5.80 ± 0.01 in KO; p < 0.05). The ktr, measured at half-maximal Ca2+-activation, was significantly accelerated at short SL in WT preparations (8.74 ± 0.56 s−1 at 1.9 μm vs. 5.71 ± 0.40 s−1 at 2.1 μm, p < 0.05). Furthermore, krel and kdf were accelerated by 32% and 50%, respectively at short SL in WT preparations. In contrast, ktr was not altered by changes in SL in KO preparations (8.03 ± 0.54 s−1 at 1.9 μm vs. 8.90 ± 0.37 s−1 at 2.1 μm). Similarly, KO preparations did not exhibit length-dependent changes in krel and kdf. Collectively, our data implicate cMyBP-C as an important regulator of LDA via its impact on

  6. Alpha-1-Adrenergic Receptors in Heart Failure: The Adaptive Arm of the Cardiac Response to Chronic Catecholamine Stimulation

    PubMed Central

    Jensen, Brian C.; O'Connell, Timothy D.; Simpson, Paul C.

    2013-01-01

    Alpha-1-adrenergic receptors are G-protein coupled receptors (GPCRs) activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the non-failing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and b□eta-AR dysfunction. Decades of evidence from gain- and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs, to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure. PMID:24145181

  7. Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation.

    PubMed

    Jensen, Brian C; OʼConnell, Timothy D; Simpson, Paul C

    2014-04-01

    Alpha-1-adrenergic receptors (ARs) are G protein-coupled receptors activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the nonfailing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and beta-AR dysfunction. Decades of evidence from gain and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure. PMID:24145181

  8. Subfamily-specific adaptations in the structures of two penicillin-binding proteins from Mycobacterium tuberculosis

    DOE PAGESBeta

    Prigozhin, Daniil M.; Krieger, Inna V.; Huizar, John P.; Mavrici, Daniela; Waldo, Geoffrey S.; Hung, Li -Wei; Sacchettini, James C.; Terwilliger, Thomas C.; Alber, Tom; Mayer, Claudine

    2014-12-31

    Beta-lactam antibiotics target penicillin-binding proteins including several enzyme classes essential for bacterial cell-wall homeostasis. To better understand the functional and inhibitor-binding specificities of penicillin-binding proteins from the pathogen, Mycobacterium tuberculosis, we carried out structural and phylogenetic analysis of two predicted D,D-carboxypeptidases, Rv2911 and Rv3330. Optimization of Rv2911 for crystallization using directed evolution and the GFP folding reporter method yielded a soluble quadruple mutant. Structures of optimized Rv2911 bound to phenylmethylsulfonyl fluoride and Rv3330 bound to meropenem show that, in contrast to the nonspecific inhibitor, meropenem forms an extended interaction with the enzyme along a conserved surface. Phylogenetic analysis shows thatmore » Rv2911 and Rv3330 belong to different clades that emerged in Actinobacteria and are not represented in model organisms such as Escherichia coli and Bacillus subtilis. Clade-specific adaptations allow these enzymes to fulfill distinct physiological roles despite strict conservation of core catalytic residues. The characteristic differences include potential protein-protein interaction surfaces and specificity-determining residues surrounding the catalytic site. Overall, these structural insights lay the groundwork to develop improved beta-lactam therapeutics for tuberculosis.« less

  9. Subfamily-Specific Adaptations in the Structures of Two Penicillin-Binding Proteins from Mycobacterium tuberculosis

    PubMed Central

    Prigozhin, Daniil M.; Krieger, Inna V.; Huizar, John P.; Mavrici, Daniela; Waldo, Geoffrey S.; Hung, Li-Wei; Sacchettini, James C.; Terwilliger, Thomas C.; Alber, Tom

    2014-01-01

    Beta-lactam antibiotics target penicillin-binding proteins including several enzyme classes essential for bacterial cell-wall homeostasis. To better understand the functional and inhibitor-binding specificities of penicillin-binding proteins from the pathogen, Mycobacterium tuberculosis, we carried out structural and phylogenetic analysis of two predicted D,D-carboxypeptidases, Rv2911 and Rv3330. Optimization of Rv2911 for crystallization using directed evolution and the GFP folding reporter method yielded a soluble quadruple mutant. Structures of optimized Rv2911 bound to phenylmethylsulfonyl fluoride and Rv3330 bound to meropenem show that, in contrast to the nonspecific inhibitor, meropenem forms an extended interaction with the enzyme along a conserved surface. Phylogenetic analysis shows that Rv2911 and Rv3330 belong to different clades that emerged in Actinobacteria and are not represented in model organisms such as Escherichia coli and Bacillus subtilis. Clade-specific adaptations allow these enzymes to fulfill distinct physiological roles despite strict conservation of core catalytic residues. The characteristic differences include potential protein-protein interaction surfaces and specificity-determining residues surrounding the catalytic site. Overall, these structural insights lay the groundwork to develop improved beta-lactam therapeutics for tuberculosis. PMID:25551456

  10. Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

    PubMed Central

    Spengler, Ryan M.; Zhang, Xiaoming; Cheng, Congsheng; McLendon, Jared M.; Skeie, Jessica M.; Johnson, Frances L.; Davidson, Beverly L.; Boudreau, Ryan L.

    2016-01-01

    MicroRNAs (miRs) have emerged as key biological effectors in human health and disease. These small noncoding RNAs are incorporated into Argonaute (Ago) proteins, where they direct post-transcriptional gene silencing via base-pairing with target transcripts. Although miRs have become intriguing biological entities and attractive therapeutic targets, the translational impacts of miR research remain limited by a paucity of empirical miR targeting data, particularly in human primary tissues. Here, to improve our understanding of the diverse roles miRs play in cardiovascular function and disease, we applied high-throughput methods to globally profile miR:target interactions in human heart tissues. We deciphered Ago2:RNA interactions using crosslinking immunoprecipitation coupled with high-throughput sequencing (HITS-CLIP) to generate the first transcriptome-wide map of miR targeting events in human myocardium, detecting 4000 cardiac Ago2 binding sites across >2200 target transcripts. Our initial exploration of this interactome revealed an abundance of miR target sites in gene coding regions, including several sites pointing to new miR-29 functions in regulating cardiomyocyte calcium, growth and metabolism. Also, we uncovered several clinically-relevant interactions involving common genetic variants that alter miR targeting events in cardiomyopathy-associated genes. Overall, these data provide a critical resource for bolstering translational miR research in heart, and likely beyond. PMID:27418678

  11. Role of Innate and Adaptive Immunity in Cardiac Injury and Repair

    PubMed Central

    Epelman, Slava; Liu, Peter P.; Mann, Douglas L.

    2015-01-01

    Despite significant advances, cardiovascular disease is the leading cause of world-wide mortality, highlighting an important yet unmet clinical need. Understanding the pathophysiological basis underlying cardiovascular tissue injury and repair in therefore of prime importance. Following cardiac tissue injury, the immune system plays an important and complex role throughout the acute inflammatory response and regenerative response. This review will summarize the role of the immune system in cardiovascular disease, and focus on the idea that the immune system evolved to promote tissue homeostasis following tissue injury and/or infection, and that the inherent cost of this evolutionary development is unwanted inflammatory mediated damage. While inflammation induced tissue damage is of little evolutionary consequence in organisms that have limited life spans, as will be discussed below, inflammation plays a major role in the development of cardiovascular disease worldwide in humans. PMID:25614321

  12. A fiber optic sensor system for control of rate-adaptive cardiac pacemakers and implantable defibrillators.

    PubMed

    Müller, Stefan; Hexamer, Martin; Werner, Jürgen

    2006-12-01

    Commercially available cardiac pacemakers and implantable cardioverters/defibrillators (ICDs) predominantly use an intracardiac-derived electrocardiogram (ECG) for the detection of arrhythmias. To achieve automatic control of the heart frequency in accordance with cardiovascular strain and improved detection of life-threatening arrhythmias, it is desirable to monitor the heart by an input signal correlated with the hemodynamic state. One possible approach to derive such a signal is to measure the inotropy (mechanical contraction strength of the heart muscle). For this purpose, an optoelectronic measurement system has been designed. The fundamental function of the system has been shown in earlier investigations using an isolated beating pig heart. In this paper the design of two algorithms for use in pacemakers and ICDs based on a fiber optic sensor signal is presented. PMID:17155869

  13. Reduction of cardiac and pulmonary complication probabilities after breathing adapted radiotherapy for breast cancer

    SciTech Connect

    Korreman, Stine S. . E-mail: stine.k@rh.dk; Pedersen, Anders N.; Aarup, Lasse Rye; Nottrup, Trine J.; Specht, Lena; Nystroem, Hakan

    2006-08-01

    Purpose: Substantial reductions of cardio-pulmonary radiation doses can be achieved using voluntary deep inspiration breath-hold (DIBH) or free breathing inspiration gating (IG) in radiotherapy after conserving surgery for breast cancer. The purpose of this study is to evaluate the radiobiological implications of such dosimetric benefits. Methods and Materials: Patients from previously reported studies were pooled for a total of 33 patients. All patients underwent DIBH and free breathing (FB) scans, and 17 patients underwent an additional IG scan. Tangential conformal treatment plans covering the remaining breast, internal mammary, and periclavicular nodes were optimized for each scan, prescription dose 48 Gy. Normal tissue complication probabilities were calculated using the relative seriality model for the heart, and the model proposed by Burman et al. for the lung. Results: Previous computed tomography studies showed that both voluntary DIBH and IG provided reduction of the lung V{sub 5} (relative volume receiving more than 50% of prescription dose) on the order of 30-40%, and a 80-90% reduction of the heart V{sub 5} for left-sided cancers. Corresponding pneumonitis probability of 28.1% (range, 0.7-95.6%) for FB could be reduced to 2.6% (range, 0.1-40.1%) for IG, and 4.3% (range, 0.1-59%) for DIBH. The cardiac mortality probability could be reduced from 4.8% (range, 0.1-23.4%) in FB to 0.5% (range, 0.1-2.6%) for IG and 0.1% (range, 0-3.0%) for DIBH. Conclusions: Remarkable potential is shown for simple voluntary DIBH and free breathing IG to reduce the risk of both cardiac mortality and pneumonitis for the common technique of adjuvant tangential breast irradiation.

  14. The Δ14 Mutation of Human Cardiac Troponin T Enhances ATPase Activity and Alters the Cooperative Binding of S1-ADP to Regulated Actin†

    PubMed Central

    Gafurov, Boris; Fredricksen, Scott; Cai, Anmei; Brenner, Bernhard; Chase, P. Bryant; Chalovich, Joseph M.

    2005-01-01

    The complex of tropomyosin and troponin binds to actin and inhibits activation of myosin ATPase activity and force production of striated muscles at low free Ca2+ concentrations. Ca2+ stimulates ATP activity, and at subsaturating actin concentrations, the binding of NEM-modified S1 to actin–tropomyosin–troponin increases the rate of ATP hydrolysis even further. We show here that the Δ14 mutation of troponin T, associated with familial hypertrophic cardiomyopathy, results in an increase in ATPase rate like that seen with wild-type troponin in the presence of NEM-S1. The enhanced ATPase activity was not due to a decreased incorporation of mutant troponin T with troponin I and troponin C to form an active troponin complex. The activating effect was more prominent with a hybrid troponin (skeletal TnI, TnC, and cardiac TnT) than with all cardiac troponin. Thus it appears that changes in the troponin–troponin contacts that result from mutations or from forming hybrids stabilize a more active state of regulated actin. An analysis of the effect of the Δ14 mutation on the equilibrium binding of S1-ADP to actin was consistent with stabilization of an active state of actin. This change in activation may be important in the development of cardiac disease. PMID:15568820

  15. Species-dependent adaptation of the cardiac Na+/K+ pump kinetics to the intracellular Na+ concentration

    PubMed Central

    Lewalle, Alexandre; Niederer, Steven A; Smith, Nicolas P

    2014-01-01

    The Na+/K+ ATPase (NKA) plays a critical role in maintaining ionic homeostasis and dynamic function in cardiac myocytes, within both the in vivo cell and in silico models. Physiological conditions differ significantly between mammalian species. However, most existing formulations of NKA used to simulate cardiac function in computational models are derived from a broad range of experimental sources spanning many animal species. The resultant inability of these models to discern species-specific features is a significant obstacle to achieving a detailed quantitative and comparative understanding of physiological behaviour in different biological contexts. Here we present a framework for characterising the steady-state NKA current using a biophysical mechanistic model specifically designed to provide a mechanistic explanation of the NKA flux supported by self-consistent species-specific data. We thus compared NKA kinetics specific to guinea- pig and rat ventricular myocytes. We observe that the apparent binding affinity for sodium in the rat is significantly lower, whereas the overall pump cycle rate is doubled, in comparison to the guinea pig. This sensitivity of NKA to its regulatory substrates compensates for the differences in Na+ concentrations between the cell types. NKA is thereby maintained within its dynamic range over a wide range of pacing frequencies in these two species, despite significant disparities in sodium concentration. Hence, by replacing a conventional generic NKA model with our rat-specific NKA formula into a whole-cell simulation, we have, for the first time, been able to accurately reproduce the action potential duration and the steady-state sodium concentration as functions of pacing frequency. PMID:25362154

  16. Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise.

    PubMed

    Motta-Santos, Daisy; Dos Santos, Robson Augusto Souza; Oliveira, Marilene; Qadri, Fatimunnisa; Poglitsch, Marko; Mosienko, Valentina; Kappes Becker, Lenice; Campagnole-Santos, Maria Jose; M Penninger, Joseph; Alenina, Natalia; Bader, Michael

    2016-07-01

    The renin-angiotensin system (RAS) is related to physiological adaptations induced by exercise. Angiotensin-converting enzyme (ACE) 2 is a major regulator of the RAS in tissues, as it metabolizes angiotensin (Ang) II to Ang-(1-7). The aim of this study was to determine the effects of ACE2 deficiency on physical performance and physiological adaptations induced by voluntary running. Physical performance, body composition and plasma angiotensin levels, as well as tissue morphology and gene expression of RAS components in the left ventricle (LV) and skeletal muscle (gastrocnemius), were evaluated in ACE2-deficient (ACE2(-/y)) and wild-type (ACE2(+/y)) mice after 6 weeks of voluntary wheel running. ACE2(-/y) mice run less than ACE2(+/y) mice (19±4.7 vs. 26±12.6 revolutions per day × 100, P<0.01). The ACE2(+/y) group presented a lower fat mass (15±1.1%) and higher muscle mass (76.6±1.6%) after 6 weeks of voluntary running compared with the sedentary control group (fat mass: 18.3±2.1%; muscle mass: 72.7±2.2). However, no change in body composition was observed in ACE2(-/y) mice after exercise. Heart and skeletal muscle hypertrophy was observed only in trained ACE2(+/y) mice. Besides a small decrease in Ang I in ACE2(-/y) mice, plasma levels of angiotensin peptides remained unchanged by exercise or ACE2 deficiency. In the LV of trained animals, AT2 gene expression was higher in ACE2(+/y) compared with ACE2(-/y) mice. ACE2 deficiency leads to an increase in AT1 gene expression in skeletal muscle. ACE expression in soleus was increased in all exercised groups. ACE2 deficiency affects physical performance and impairs cardiac and skeletal muscle adaptations to exercise. PMID:27053009

  17. Two saturable recognition sites for (-) (125I)iodo-N6-(4-hydroxyphenyl-isopropyl)-adenosine binding on purified cardiac sarcolemma

    SciTech Connect

    Hausleithner, V.; Freissmuth, M.; Schuetz, W.

    1986-01-01

    Analysis of (-) (125)iodo-N6-(4-hydroxyphenylisopropyl)-adenosine (( /sup 125/I)HPIA) binding to purified sarcolemmal preparations of guinea pig and bovine hearts revealed two classes of binding sites when unlabeled iodo-HPIA (100 mumol/l) was used as non-specific binding marker. In the presence of 1 mmol/l theophylline, however, only the high affinity component was detected. Adenosine receptor agonists caused biphasic displacement of (/sup 125/I)HPIA binding, with a high affinity potency rank order typical of interaction with A1-adenosine receptors. Biphasic competition curves were also observed with 8-phenyltheophylline and isobutylmethylxanthine, whereas the theophylline curve was monophasic up to 1 mmol/l. In brain membranes, specific binding of (/sup 125/I)HPIA as well as of (/sup 3/H)PIA was further reduced when unlabeled iodo-HPIA replaces theophylline as the non-specific binding marker. These results suggest the presence of two (/sup 125/I)HPIA binding sites on cardiac sarcolemma and brain membranes, but receptor function can only be ascribed to the high affinity sites. The low affinity site probably represents an artefact, which is often observed when non-specific binding is defined with the unlabeled counterpart or a structurally related ligand of the radioligand used.

  18. Elevation of urinary liver-type fatty acid binding protein after cardiac catheterization related to cardiovascular events

    PubMed Central

    Kamijo-Ikemori, Atsuko; Hashimoto, Nobuyuki; Sugaya, Takeshi; Matsui, Katsuomi; Hisamichi, Mikako; Shibagaki, Yugo; Miyake, Fumihiko; Kimura, Kenjiro

    2015-01-01

    Purpose Contrast medium (CM) induces tubular hypoxia via endothelial damage due to direct cytotoxicity or viscosity. Urinary liver-type fatty acid binding protein (L-FABP) increases along with tubular hypoxia and may be a detector of systemic circulation injury. The aim of this study was to evaluate the clinical usefulness of detecting increases in urinary L-FABP levels due to administration of CM, as a prognostic biomarker for cardiovascular disease in patients without occurrence of CM-induced nephropathy undergoing cardiac catheterization procedure (CCP). Methods Retrospective longitudinal analyses of the relationship between urinary L-FABP levels and occurrence of cardiovascular events were performed (n=29). Urinary L-FABP was measured by ELISA before CCP, and at 6, 12, 24, and 48 hours after CCP. Results Urinary L-FABP levels were significantly higher at 12 hours (P<0.05) and 24 hours (P<0.005) after CCP compared with before CCP, only in the patients with occurrence of cardiovascular events (n=17), but not in those without cardiovascular events (n=12). The parameter with the largest area under the curve (0.816) for predicting the occurrence of cardiovascular events was the change in urinary L-FABP at 24 hours after CCP. The difference in urinary L-FABP levels (ΔL-FABP ≥11.0 μg/g creatinine) between before CCP and at 24 hours after CCP was a risk factor for the occurrence of cardiovascular events (hazard ratio, 4.93; 95% confidence interval, 1.27–19.13; P=0.021). Conclusion Measurement of urinary L-FABP before CCP and at 24 hours after CCP in patients with mild to moderate renal dysfunction may be an important indicator for risk stratification of onset of cardiovascular events. PMID:26316797

  19. Cardiac adaptation to high altitude in the plateau pika (Ochotona curzoniae).

    PubMed

    Pichon, Aurélien; Zhenzhong, Bai; Marchant, Dominique; Jin, Guoen; Voituron, Nicolas; Haixia, Yun; Favret, Fabrice; Richalet, Jean-Paul; Ge, Ri-Li

    2013-07-01

    The aim of this study was to assess maximal heart rate (HR) and heart morphological changes in high altitude living "plateau pikas" and rats bred at 2260 m. Rats and pikas were catheterized to measure HR (2260 m). After baseline measurements, 1 mg/kg of atropine (AT) and increasing doses of isoproterenol (IsoP) (0.1, 1, 10, and 100 μg kg) were injected into animals. Right (RV) and left ventricles (LV) were removed to calculate Fulton's ratio (LV + septum (S) to RV weights) and to assess mRNA expression level of β1- and β2-adrenoceptors, muscarinic m1 and m2 receptors, and vascular endothelial growth factor (VEGF). Resting HR was significantly lower in rats than in pikas and increased after AT injection only in rats. IsoP injection induced a significant increase in HR in rat for all doses, which was systematically greater than in pikas. In pikas HR was slightly increased only after the two highest concentrations of IsoP. Fulton's ratio was greater in rats compared with pikas but the LV + S adjusted for body weight was greater in pikas. Pikas showed lower β1-adrenoceptors and muscarinic m2 receptors mRNA expression but larger VEGF mRNA expression than rats both in RV and LV. These results suggest that pikas have a lower maximal HR compared with rats certainly due to a decrease in β-adrenergic and muscarinic receptors mRNA expression. However, the LV hypertrophy probably led to an increase in stroke volume to maintain cardiac output in response to the cold and hypoxic environment. PMID:24303117

  20. Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase α1β1, α2β1 and α3β1

    PubMed Central

    Hauck, Christian; Potter, Tatjana; Bartz, Michaela; Wittwer, Thorsten; Wahlers, Thorsten; Mehlhorn, Uwe; Scheiner-Bobis, Georgios; McDonough, Alicia A.; Bloch, Wilhelm; Schwinger, Robert H.G.; Müller-Ehmsen, Jochen

    2016-01-01

    Cardiac glycosides inhibit the Na+,K+-ATPase and are used for the treatment of symptomatic heart failure and atrial fibrillation. In human heart three isoforms of Na+,K+-ATPase are expressed: α1β1, α2β1 and α3β1. It is unknown, if clinically used cardiac glycosides differ in isoform specific affinities, and if the isoforms have specific subcellular localization in human cardiac myocytes. Human Na+,K+-ATPase isoforms α1β1, α2β1 and α3β1 were expressed in yeast which has no endogenous Na+,K+-ATPase. Isoform specific affinities of digoxin, digitoxin, β-acetyldigoxin, methyldigoxin and ouabain were assessed in [3H]-ouabain binding assays in the absence or presence of K+ (each n=5). The subcellular localizations of the Na+,K+-ATPase isoforms were investigated in isolated human atrial cardiomyocytes by immunohistochemistry. In the absence of K+, methyldigoxin (α1>α3>α2) and ouabain (α1=α3>α2) showed distinct isoform specific affinities, while for digoxin, digitoxin and β-acetyldigoxin no differences were found. In the presence of K+, also digoxin (α2=α3>α1) and β-acetyldigoxin (α1>α3) had isoform specificities. A comparison between the cardiac glycosides demonstrated highly different affinity profiles for the isoforms. Immunohistochemistry showed that all three isoforms are located in the plasma membrane and in intracellular membranes, but only α1β1 and α2β1 are located in the T-tubuli. Cardiac glycosides show distinct isoform specific affinities and different affinity profiles to Na+,K+-ATPase isoforms which have different subcellular localizations in human cardiomyocytes. Thus, in contrast to current notion, different cardiac glycoside agents may significantly differ in their pharmacological profile which could be of hitherto unknown clinical relevance. PMID:19751721

  1. Athletic Cardiac Adaptation in Males Is a Consequence of Elevated Myocyte Mass

    PubMed Central

    McDiarmid, Adam K.; Swoboda, Peter P.; Erhayiem, Bara; Lancaster, Rosalind E.; Lyall, Gemma K.; Broadbent, David A.; Dobson, Laura E.; Musa, Tarique A.; Ripley, David P.; Garg, Pankaj; Greenwood, John P.; Ferguson, Carrie

    2016-01-01

    Background— Cardiac remodeling occurs in response to regular athletic training, and the degree of remodeling is associated with fitness. Understanding the myocardial structural changes in athlete’s heart is important to develop tools that differentiate athletic from cardiomyopathic change. We hypothesized that athletic left ventricular hypertrophy is a consequence of increased myocardial cellular rather than extracellular mass as measured by cardiovascular magnetic resonance. Methods and Results— Forty-five males (30 athletes and 15 sedentary age-matched healthy controls) underwent comprehensive cardiovascular magnetic resonance studies, including native and postcontrast T1 mapping for extracellular volume calculation. In addition, the 30 athletes performed a maximal exercise test to assess aerobic capacity and anaerobic threshold. Participants were grouped by athleticism: untrained, low performance, and high performance (O2max <60 or>60 mL/kg per min, respectively). In athletes, indexed cellular mass was greater in high- than low-performance athletes 60.7±7.5 versus 48.6±6.3 g/m2; P<0.001), whereas extracellular mass was constant (16.3±2.2 versus 15.3±2.2 g/m2; P=0.20). Indexed left ventricular end-diastolic volume and mass correlated with O2max (r=0.45, P=0.01; r=0.55, P=0.002) and differed significantly by group (P=0.01; P<0.001, respectively). Extracellular volume had an inverse correlation with O2max (r=−0.53, P=0.003 and left ventricular mass index (r=-0.44, P=0.02). Conclusions— Increasing left ventricular mass in athlete’s heart occurs because of an expansion of the cellular compartment while the extracellular volume becomes relatively smaller: a difference which becomes more marked as left ventricular mass increases. Athletic remodeling, both on a macroscopic and cellular level, is associated with the degree of an individual’s fitness. Cardiovascular magnetic resonance ECV quantification may have a future role in differentiating athlete

  2. [Osphradial chemosensory organ as a probable trigger of the cardiac system adaptive reaction to the effect of heavy metals in aquatic mollusks].

    PubMed

    Kamardin, N N; Lubimtsev, V A; Kornienko, E L; Udalova, G P; Kholodkevich, S V; Apostolov, S A

    2015-01-01

    The responses of osphradium in the fresh-water mollusk Viviparus sp. and single osphradial neurons in the pond snail Lymnaea stagnalis to L-glutamine and L-asparagine as well as the changes in these responses under the effect of heavy metals (Cu, Cd) were recorded electrophysiologically. The functional connections of osphradium with the identified neurons of the central pattern generator of respiratory movements and cardiac activity as well as the modification of these connections under the effect of short-term application of HgCl2 solution on the snail's osphradium were investigated. The cardiac rhythm in the mollusk Littorina littorea under the effect of Cu ions was registered non-invasively in long-lasting experiments. The dose-dependent short-term effects of heavy metals changes after osphradium injury were revealed. The implication of osphradium in adaptive reactions of the cardiac system in aquatic mollusks to the environmental heavy metal pollution is suggested. The dependence of cardiac rhythm on the degree of accumulation of copper ions in the mollusk tissues was detected. The results obtained are essential for unraveling neural mechanisms and pathways allowing heavy metals to affect the functional state of hydrobionts, particularly, the cardiac activity frequency characteristics of which are widely used as informative biomarkers to assess physiological condition of aquatic invertebrates. PMID:25859605

  3. A peptide of the RGS domain of GRK2 binds and inhibits Gαq to suppress pathological cardiac hypertrophy and dysfunction

    PubMed Central

    Schumacher, Sarah M.; Gao, Erhe; Cohen, Maya; Lieu, Melissa; Chuprun, J. Kurt; Koch, Walter J.

    2016-01-01

    G protein–coupled receptor (GPCR) kinases (GRKs) play a critical role in cardiac function by regulating GPCR activity. GRK2 suppresses GPCR signaling by phosphorylating and desensitizing active GPCRs, and through protein-protein interactions that uncouple GPCRs from their downstream effectors. Several GRK2 interacting partners, including Gαq, promote maladaptive cardiac hypertrophy, which leads to heart failure, a leading cause of mortality worldwide. The regulator of G protein signaling (RGS) domain of GRK2 interacts with and inhibits Gαq in vitro. We generated TgβARKrgs mice with cardiac-specific expression of the RGS domain of GRK2 and subjected these mice to pressure overload to trigger adaptive changes that lead to heart failure. Unlike their nontransgenic littermate controls, the TgβARKrgs mice exhibited less hypertrophy as indicated by reduced left ventricular wall thickness, decreased expression of genes linked to cardiac hypertrophy, and less adverse structural remodeling. The βARKrgs peptide, but not endogenous GRK2, interacted with Gαq and interfered with signaling through this G protein. These data support the development of GRK2-based therapeutic approaches to prevent hypertrophy and heart failure. PMID:27016525

  4. Interacting Proteins on Human Spermatozoa: Adaptive Evolution of the Binding of Semenogelin I to EPPIN

    PubMed Central

    Silva, Erick J. R.; Hamil, Katherine G.; O’Rand, Michael G.

    2013-01-01

    Semenogelin I (SEMG1) is found in human semen coagulum and on the surface of spermatozoa bound to EPPIN. The physiological significance of the SEMG1/EPPIN interaction on the surface of spermatozoa is its capacity to modulate sperm progressive motility. The present study investigates the hypothesis that the interacting surface of SEMG1 and EPPIN co-evolved within the Hominoidea time scale, as a result of adaptive pressures applied by their roles in sperm protection and reproductive fitness. Our results indicate that some amino acid residues of SEMG1 and EPPIN possess a remarkable deficiency of variation among hominoid primates. We observe a distinct residue change unique to humans within the EPPIN sequence containing a SEMG1 interacting surface, namely His92. In addition, Bayes Empirical Bayes analysis for positive selection indicates that the SEMG1 Cys239 residue underwent positive selection in humans, probably as a consequence of its role in increasing the binding affinity of these interacting proteins. We confirm the critical role of Cys239 residue for SEMG1 binding to EPPIN and inhibition of sperm motility by showing that recombinant SEMG1 mutants in which Cys239 residue was changed to glycine, aspartic acid, histidine, serine or arginine have reduced capacity to interact to EPPIN and to inhibit human sperm motility in vitro. In conclusion, our results indicate that EPPIN and SEMG1 rapidly co-evolved in primates due to their critical role in the modulation of sperm motility in the semen coagulum, providing unique insights into the molecular co-evolution of sperm surface interacting proteins. PMID:24312623

  5. Adaptive anisotropic gaussian filtering to reduce acquisition time in cardiac diffusion tensor imaging.

    PubMed

    Mazumder, Ria; Clymer, Bradley D; Mo, Xiaokui; White, Richard D; Kolipaka, Arunark

    2016-06-01

    Diffusion tensor imaging (DTI) is used to quantify myocardial fiber orientation based on helical angles (HA). Accurate HA measurements require multiple excitations (NEX) and/or several diffusion encoding directions (DED). However, increasing NEX and/or DED increases acquisition time (TA). Therefore, in this study, we propose to reduce TA by implementing a 3D adaptive anisotropic Gaussian filter (AAGF) on the DTI data acquired from ex-vivo healthy and infarcted porcine hearts. DTI was performed on ex-vivo hearts [9-healthy, 3-myocardial infarction (MI)] with several combinations of DED and NEX. AAGF, mean (AVF) and median filters (MF) were applied on the primary eigenvectors of the diffusion tensor prior to HA estimation. The performance of AAGF was compared against AVF and MF. Root mean square error (RMSE), concordance correlation-coefficients and Bland-Altman's technique was used to determine optimal combination of DED and NEX that generated the best HA maps in the least possible TA. Lastly, the effect of implementing AAGF on the infarcted porcine hearts was also investigated. RMSE in HA estimation for AAGF was lower compared to AVF or MF. Post-filtering (AAGF) fewer DED and NEX were required to achieve HA maps with similar integrity as those obtained from higher NEX and/or DED. Pathological alterations caused in HA orientation in the MI model were preserved post-filtering (AAGF). Our results demonstrate that AAGF reduces TA without affecting the integrity of the myocardial microstructure. PMID:26843150

  6. Bioenergetical and Cardiac Adaptations of Pilots to a 24-Hour Team Kart Race.

    PubMed

    Durand, Sylvain; Ripamonti, Michael; Rahmani, Abderrahmane; Beaune, Bruno

    2015-11-01

    This study aimed to evaluate energy expenditure (EE) and heart rate (HR) response in kart pilots to successive driving bouts during a 24-hour team race. Eight adult male pilots (22.8 ± 4.1 years) participated to a team 24-hour speedway kart race in Le Mans (France). They alternatively piloted a 390 cm kart. Each relay was 45 minutes long and each pilot performed 4 relays. For each pilot, mean speeds were calculated from lap-to-lap duration recordings using a telemetric infrared timing device. Heart rate values were recorded continuously on 5-second intervals using a portable cardiometric device. Total energy expenditure (EET) and physical activity ratio (PAR) were determined by accelerometry. To pilot a kart during 45 minutes at a mean speed around 62 km·h induces a 300-kcal EET, corresponding to a 5.6-Mets PAR. This effort is responsive for a 73 b·min increase in HR, from 84.1 ± 7.6 to 157.4 ± 11.0 b·min (82% maximal heart rate intensity). However, during this relay period, HR values seemed independent to mean speed performance and bioenergetical values. Thus, in the context of the 24-hour team race, the variability in effort made during each relay and relay succession did not alter bioenergetical adaptation of pilots to kart driving. The high EE and HR values would be better explained by both emotional stress and environmental constraints such as speedway configuration and vibrations. The way how these factors specifically influence bioenergetical demand, and their relative importance, has to be specified to optimize training procedure and recommendations. PMID:25029011

  7. Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development

    SciTech Connect

    Colson, Brett A.; Locher, Matthew R.; Bekyarova, Tanya; Patel, Jitandrakumar R.; Fitzsimons, Daniel P.; Irving, Thomas C.; Moss, Richard L.

    2010-05-25

    Phosphorylation of myosin regulatory light chain (RLC) by myosin light chain kinase (MLCK) and myosin binding protein-C (cMyBP-C) by protein kinase A (PKA) independently accelerate the kinetics of force development in ventricular myocardium. However, while MLCK treatment has been shown to increase the Ca{sup 2+} sensitivity of force (pCa{sub 50}), PKA treatment has been shown to decrease pCa{sub 50}, presumably due to cardiac troponin I phosphorylation. Further, MLCK treatment increases Ca{sup 2+}-independent force and maximum Ca{sup 2+}-activated force, whereas PKA treatment has no effect on either force. To investigate the structural basis underlying the kinase-specific differential effects on steady-state force, we used synchrotron low-angle X-ray diffraction to compare equatorial intensity ratios (I{sub 1,1}/I{sub 1,0}) to assess the proximity of myosin cross-bridge mass relative to actin and to compare lattice spacings (d{sub 1,0}) to assess the inter-thick filament spacing in skinned myocardium following treatment with either MLCK or PKA. As we showed previously, PKA phosphorylation of cMyBP-C increases I{sub 1,1}/I{sub 1,0} and, as hypothesized, treatment with MLCK also increased I{sub 1,1}/I{sub 1,0}, which can explain the accelerated rates of force development during activation. Importantly, interfilament spacing was reduced by {approx}2 nm ({Delta} 3.5%) with MLCK treatment, but did not change with PKA treatment. Thus, RLC or cMyBP-C phosphorylation increases the proximity of cross-bridges to actin, but only RLC phosphorylation affects lattice spacing, which suggests that RLC and cMyBP-C modulate the kinetics of force development by similar structural mechanisms; however, the effect of RLC phosphorylation to increase the Ca{sup 2+} sensitivity of force is mediated by a distinct mechanism, most probably involving changes in interfilament spacing.

  8. High affinity ( sup 3 H)glibenclamide binding sites in rat neuronal and cardiac tissue: Localization and developmental characteristics

    SciTech Connect

    Miller, J.A.; Velayo, N.L.; Dage, R.C.; Rampe, D. )

    1991-01-01

    We examined the binding of the antidiabetic sulfonylurea (3H) glibenclamide to rat brain and heart membranes. High affinity binding was observed in adult rat forebrain (Kd = 137.3 pM, maximal binding site density = 91.8 fmol/mg of protein) and ventricle (Kd = 77.1 pM, maximal binding site density = 65.1 fmol/mg of protein). Binding site density increased approximately 250% in forebrain membranes during postnatal development but was constant in ventricular membranes. Quantitative autoradiography was used to examine the regional distribution of (3H) glibenclamide binding sites in sections from rat brain, spinal cord and heart. The greatest density of binding in adult brain was found in the substantia nigra and globus pallidus, whereas the other areas displayed heterogenous binding. In agreement with the membrane binding studies, 1-day-old rat brain had significantly fewer (3H)glibenclamide binding sites than adult brain. Additionally, the pattern of distribution of these sites was qualitatively different from that of the adult. In adult rat spinal cord, moderate binding densities were observed in spinal cord gray and displayed a rostral to caudal gradient. In adult rat heart, moderate binding densities were observed and the sites were distributed homogeneously. In conclusion, significant development of (3H)glibenclamide binding sites was seen in the brain but not the heart during postnatal maturation. Furthermore, a heterogeneous distribution of binding sites was observed in both the brain and spinal cord of adult rats.

  9. The Negatively Charged Regions of Lactoferrin Binding Protein B, an Adaptation against Anti-Microbial Peptides

    PubMed Central

    Morgenthau, Ari; Beddek, Amanda; Schryvers, Anthony B.

    2014-01-01

    Lactoferrin binding protein B (LbpB) is a bi-lobed membrane bound lipoprotein that is part of the lactoferrin receptor complex in a variety of Gram-negative pathogens. Despite high sequence diversity among LbpBs from various strains and species, a cluster of negatively charged amino acids is invariably present in the protein’s C-terminal lobe in all species except Moraxella bovis. The function of LbpB in iron acquisition has yet to be experimentally demonstrated, whereas in vitro studies have shown that LbpB confers protection against lactoferricin, a short cationic antimicrobial peptide released from the N- terminus of lactoferrin. In this study we demonstrate that the negatively charged regions can be removed from the Neisseria meningitidis LbpB without compromising stability, and this results in the inability of LbpB to protect against the bactericidal effects of lactoferricin. The release of LbpB from the cell surface by the autotransporter NalP reduces the protection against lactoferricin in the in vitro killing assay, attributed to removal of LbpB during washing steps, but is unlikely to have a similar impact in vivo. The protective effect of the negatively charged polysaccharide capsule in the killing assay was less than the protection conferred by LbpB, suggesting that LbpB plays a major role in protection against cationic antimicrobial peptides in vivo. The selective release of LbpB by NalP has been proposed to be a mechanism for evading the adaptive immune response, by reducing the antibody binding to the cell surface, but may also provide insights into the primary function of LbpB in vivo. Although TbpB and LbpB have been shown to be major targets of the human immune response, the selective release of LbpB suggests that unlike TbpB, LbpB may not be essential for iron acquisition, but important for protection against cationic antimicrobial peptides. PMID:24465982

  10. The negatively charged regions of lactoferrin binding protein B, an adaptation against anti-microbial peptides.

    PubMed

    Morgenthau, Ari; Beddek, Amanda; Schryvers, Anthony B

    2014-01-01

    Lactoferrin binding protein B (LbpB) is a bi-lobed membrane bound lipoprotein that is part of the lactoferrin receptor complex in a variety of Gram-negative pathogens. Despite high sequence diversity among LbpBs from various strains and species, a cluster of negatively charged amino acids is invariably present in the protein's C-terminal lobe in all species except Moraxella bovis. The function of LbpB in iron acquisition has yet to be experimentally demonstrated, whereas in vitro studies have shown that LbpB confers protection against lactoferricin, a short cationic antimicrobial peptide released from the N- terminus of lactoferrin. In this study we demonstrate that the negatively charged regions can be removed from the Neisseria meningitidis LbpB without compromising stability, and this results in the inability of LbpB to protect against the bactericidal effects of lactoferricin. The release of LbpB from the cell surface by the autotransporter NalP reduces the protection against lactoferricin in the in vitro killing assay, attributed to removal of LbpB during washing steps, but is unlikely to have a similar impact in vivo. The protective effect of the negatively charged polysaccharide capsule in the killing assay was less than the protection conferred by LbpB, suggesting that LbpB plays a major role in protection against cationic antimicrobial peptides in vivo. The selective release of LbpB by NalP has been proposed to be a mechanism for evading the adaptive immune response, by reducing the antibody binding to the cell surface, but may also provide insights into the primary function of LbpB in vivo. Although TbpB and LbpB have been shown to be major targets of the human immune response, the selective release of LbpB suggests that unlike TbpB, LbpB may not be essential for iron acquisition, but important for protection against cationic antimicrobial peptides. PMID:24465982

  11. Structural and Functional Dissection of the Abp1 ADFH Actin-binding Domain Reveals Versatile In Vivo Adapter Functions

    SciTech Connect

    Quintero-Monzon,O.; Rodal, A.; Strokopytov, B.; Almo, S.; Goode, B.

    2005-01-01

    Abp1 is a multidomain protein that regulates the Arp2/3 complex and links proteins involved in endocytosis to the actin cytoskeleton. All of the proposed cellular functions of Abp1 involve actin filament binding, yet the actin binding site(s) on Abp1 have not been identified, nor has the importance of actin binding for Abp1 localization and function in vivo been tested. Here, we report the crystal structure of the Saccharomyces cerevisiae Abp1 actin-binding actin depolymerizing factor homology (ADFH) domain and dissect its activities by mutagenesis. Abp1-ADFH domain and ADF/cofilin structures are similar, and they use conserved surfaces to bind actin; however, there are also key differences that help explain their differential effects on actin dynamics. Using point mutations, we demonstrate that actin binding is required for localization of Abp1 in vivo, the lethality caused by Abp1 overexpression, and the ability of Abp1 to activate Arp2/3 complex. Furthermore, we genetically uncouple ABP1 functions that overlap with SAC6, SLA1, and SLA2, showing they require distinct combinations of activities and interactions. Together, our data provide the first structural and functional view of the Abp1-actin interaction and show that Abp1 has distinct cellular roles as an adapter, linking different sets of ligands for each function.

  12. Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease☆☆☆☆☆☆

    PubMed Central

    Bates, Matthew G.D.; Newman, Jane H.; Jakovljevic, Djordje G.; Hollingsworth, Kieren G.; Alston, Charlotte L.; Zalewski, Pawel; Klawe, Jacek J.; Blamire, Andrew M.; MacGowan, Guy A.; Keavney, Bernard D.; Bourke, John P.; Schaefer, Andrew; McFarland, Robert; Newton, Julia L.; Turnbull, Douglass M.; Taylor, Robert W.; Trenell, Michael I.; Gorman, Gráinne S.

    2013-01-01

    Background Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. Methods and results Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p < 0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p < 0.01). Peak arterial–venous oxygen difference (p < 0.05), oxygen uptake (VO2) and power were decreased in patients (both p < 0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥ 80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p < 0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p < 0.05). Conclusion Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis. PMID:23742928

  13. FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change.

    PubMed

    Rein, Theo

    2016-09-01

    This review portraits FK506 binding protein (FKBP) 51 as "reactivity protein" and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co-chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress. In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion. Also see the video abstract here. PMID:27374865

  14. Phosphatidylinositol 4,5-biphosphate (PIP2) modulates syntaxin-1A binding to sulfonylurea receptor 2A to regulate cardiac ATP-sensitive potassium (KATP) channels.

    PubMed

    Xie, Li; Liang, Tao; Kang, Youhou; Lin, Xianguang; Sobbi, Roozbeh; Xie, Huanli; Chao, Christin; Backx, Peter; Feng, Zhong-Ping; Shyng, Show-Ling; Gaisano, Herbert Y

    2014-10-01

    Cardiac sarcolemmal syntaxin (Syn)-1A interacts with sulfonylurea receptor (SUR) 2A to inhibit ATP-sensitive potassium (KATP) channels. Phosphatidylinositol 4,5-bisphosphate (PIP2), a ubiquitous endogenous inositol phospholipid, known to bind Kir6.2 subunit to open KATP channels, has recently been shown to directly bind Syn-1A in plasma membrane to form Syn-1A clusters. Here, we sought to determine whether the interaction between Syn-1A and PIP2 interferes with the ability of Syn-1A to bind SUR2A and inhibit KATP channel activity. We found that PIP2 dose-dependently reduced SUR2A binding to GST-Syn-1A by in vitro pulldown assays. FRET studies in intact cells using TIRFM revealed that increasing endogenous PIP2 levels led to increased Syn-1A (-EGFP) cluster formation and a severe reduction in availability of Syn-1A molecules to interact with SUR2A (-mCherry) molecules outside the Syn-1A clusters. Correspondingly, electrophysiological studies employing SUR2A/Kir6.2-expressing HEK cells showed that increasing endogenous or exogenous PIP2 diminished the inhibitory effect of Syn-1A on KATP currents. The physiological relevance of these findings was confirmed by ability of exogenous PIP2 to block exogenous Syn-1A inhibition of cardiac KATP currents in inside-out patches of mouse ventricular myocytes. The effect of PIP2 on physical and functional interactions between Syn-1A and KATP channels is specific and not observed with physiologic concentrations of other phospholipids. To unequivocally demonstrate the specificity of PIP2 interaction with Syn-1A and its impact on KATP channel modulation by Syn-1A, we employed a PIP2-insensitive Syn-1A-5RK/A mutant. The Syn-1A-5RK/A mutant retains the ability to interact with SUR2A in both in vitro binding and in vivo FRET assays, although as expected the interaction is no longer disrupted by PIP2. Interestingly, at physiological PIP2 concentrations, Syn-1A-5RK/A inhibited KATP currents to a greater extent than Syn-1A-WT, indicating

  15. An explicitly solvated full atomistic model of the cardiac thin filament and application on the calcium binding affinity effects from familial hypertrophic cardiomyopathy linked mutations

    NASA Astrophysics Data System (ADS)

    Williams, Michael; Schwartz, Steven

    2015-03-01

    The previous version of our cardiac thin filament (CTF) model consisted of the troponin complex (cTn), two coiled-coil dimers of tropomyosin (Tm), and 29 actin units. We now present the newest revision of the model to include explicit solvation. The model was developed to continue our study of genetic mutations in the CTF proteins which are linked to familial hypertrophic cardiomyopathies. Binding of calcium to the cTnC subunit causes subtle conformational changes to propagate through the cTnC to the cTnI subunit which then detaches from actin. Conformational changes propagate through to the cTnT subunit, which allows Tm to move into the open position along actin, leading to muscle contraction. Calcium disassociation allows for the reverse to occur, which results in muscle relaxation. The inclusion of explicit TIP3 water solvation allows for the model to get better individual local solvent to protein interactions; which are important when observing the N-lobe calcium binding pocket of the cTnC. We are able to compare in silica and in vitro experimental results to better understand the physiological effects from mutants, such as the R92L/W and F110V/I of the cTnT, on the calcium binding affinity compared to the wild type.

  16. Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces cardiac fibroblast proliferation by suppressing GATA Binding Protein 4.

    PubMed

    Liu, Bin; Liu, Ning-Ning; Liu, Wei-Hua; Zhang, Shuang-Wei; Zhang, Jing-Zhi; Li, Ai-Qun; Liu, Shi-Ming

    2016-07-01

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and GATA Binding Protein 4 (GATA4) are important for the growth of cardiac fibroblasts (CFs). When deregulated, LOX-1 and GATA4 can cause cardiac remodeling. In the present study, we found novel evidence that GATA4 was required for the LOX-1 regulation of CF proliferation. The inhibition of LOX-1 by RNA interference LOX-1 lentivirus resulted in the loss of PI3K/Akt activation and GATA4 protein expression. The overexpression of LOX-1 by lentivirus rescued CF proliferation, PI3K/Akt activation, and GATA4 protein expression. Moreover, GATA4 overexpression enhanced CF proliferation with LOX-1 inhibition. We also found that the inhibition of PI3K/Akt activation by LY294002, a PI3K inhibitor, reduced cell proliferation and protein level of GATA4. In summary, GATA4 may play an important role in the LOX-1 and PI3K/Akt regulation of CF proliferation. PMID:27216460

  17. Unexpectedly Low Mutation Rates in Beta-Myosin Heavy Chain and Cardiac Myosin Binding Protein Genes in Italian Patients With Hypertrophic Cardiomyopathy

    PubMed Central

    Roncarati, Roberta; Latronico, Michael VG; Musumeci, Beatrice; Aurino, Stefania; Torella, Annalaura; Bang, Marie-Louise; Jotti, Gloria Saccani; Puca, Annibale A; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

    2011-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. J. Cell. Physiol. 226: 2894–2900, 2011. © 2011 Wiley-Liss, Inc. PMID:21302287

  18. Adaptive-Partitioning QM/MM Dynamics Simulations: 3. Solvent Molecules Entering and Leaving Protein Binding Sites.

    PubMed

    Pezeshki, Soroosh; Davis, Christal; Heyden, Andreas; Lin, Hai

    2014-11-11

    The adaptive-partitioning (AP) schemes for combined quantum-mechanical/molecular-mechanical (QM/MM) calculations allow on-the-fly reclassifications of atoms and molecules as QM or MM in dynamics simulations. The permuted-AP (PAP) scheme (J. Phys. Chem. B 2007, 111, 2231) introduces a thin layer of buffer zone between the QM subsystem (also called active zone) and the MM subsystem (also known as the environmental zone) to provide a continuous and smooth transition and expresses the potential energy in a many-body expansion manner. The PAP scheme has been successfully applied to study small molecules solvated in bulk solvent. Here, we propose two modifications to the original PAP scheme to treat solvent molecules entering and leaving protein binding sites. First, the center of the active zone is placed at a pseudoatom in the binding site, whose position is not affected by the movements of ligand or residues in the binding site. Second, the extra forces due to the smoothing functions are deleted. The modified PAP scheme no longer describes a Hamiltonian system, but it satisfies the conservation of momentum. As a proof-of-concept experiment, the modified PAP scheme is applied to the simulations under the canonical ensemble for two binding sites of the Escherichia coli CLC chloride ion transport protein, in particular, the intracellular binding site Sint discovered by crystallography and one putative additional binding site Sadd suggested by molecular modeling. The exchange of water molecules between the binding sites and bulk solvent is monitored. For comparison, simulations are also carried out using the same model system and setup with only one exception: the extra forces due to the smoothing functions are retained. The simulations are benchmarked against conventional QM/MM simulations with large QM subsystems. The results demonstrate that the active zone centered at the pseudo atom is a reasonable and convenient representation of the binding site. Moreover, the

  19. Hypoxia in early pregnancy induces cardiac dysfunction in adult offspring of Rattus norvegicus, a non-hypoxia-adapted species.

    PubMed

    Hauton, David

    2012-11-01

    Environmental stresses such as hypoxia can alter the development of the fetus that are manifested later in life, but the impact of early maternal hypoxia (MH) on cardiac performance, coronary flow and catecholamine responsiveness in adult offspring is less clear. The effects of exposure to chronic hypoxia (FIO(2)=0.12) in early intrauterine development (days E1-10) on cardiac performance of the adult offspring were estimated using the Langendorff-perfused rat heart. Cardiac dysfunction is presented as increased end-diastolic volume, with decreased ventricular stiffness in both male and female adult offspring (P<0.01 for both). While developed pressures were preserved in female MH rats, males demonstrated a decrease in systolic function, estimated as peak developed pressure (P<0.01). Challenge with dobutamine (300 nM), an adrenergic positive inotrope, increased cardiac work for control rats (P<0.01 for male and female rats) but not in MH-male rats. Coronary flow was reduced (P<0.01) and SERCA2 protein expression increased (2-fold, P<0.05) in female offspring, while eNOS protein levels were increased (2.5-fold, P<0.05) in females. This suggests gender-specific differences in compensatory responses to early MH, with female rats increasing calcium turnover to improve contractility and increasing coronary flow through increased expression of eNOS protein, partially restoring coronary perfusion while male rats show little compensation. PMID:22892476

  20. Competitive displacement of wild-type phospholamban from the Ca2+-free cardiac calcium pump by phospholamban mutants with different binding affinities.

    PubMed

    Chen, Zhenhui

    2014-11-01

    Phospholamban (PLB) regulates the cardiac Ca(2+) pump (SERCA2a). To test how different species of PLB mutants compete to interact with the Ca(2+)-free, E2 conformation of SERCA2a, using the insect cell expression system, we examined how various exogenous PLB mutants regulated SER-20G-PLB, a chimeric WT-SERCA2a-Gly-WT-PLB construct, which retains a fully catalytic active Ca(2+)-pump and its intrinsically regulatory PLB-tether. Exogenous gain-of-function PLB mutants dominantly super-inhibited the WT-PLB-tethered SERCA2a. Further, in the Ca(2+)-free condition, co-expressed normal- or super-inhibitory PLB mutant with either engineered N30C or V49C residue cross-linked to Lys328 or V89C of SER-20G-PLB at the cytoplasmic or transmembrane domain, respectively, suggesting that these freely diffusing PLB mutants completely replaced the WT-PLB-tether and fit into the binding pocket previously occupied by WT-PLB. Micromolar Ca(2+) completely inhibited cross-linking, yielding a similar Ca(2+)-dependency regardless of the presence of the WT-PLB-tether. In contrast, the PLB mutant with the loss-of-function L31A mutation has decreased binding affinity for SERCA2a, thus cross-linking weakly to the WT-PLB-tethered SERCA2a, and only marginally affected the activity of SER-20G-PLB. Thus, there is a reversible equilibrium between different PLB mutants for binding to E2, in which PLB mutants possessing higher binding affinity for SERCA2a produce a more stable E2·PLB and lower Ca(2+) affinity. PMID:25194792

  1. Cardiac and Arterial Adaptation to a 60 Day Bedrest with and without Counter-Measures (ES-I IBREP)

    NASA Astrophysics Data System (ADS)

    Arbeille, Philippe; Yuan, Ming; Bai, Yanqiang; Jiang, Shizhong; Wan, Yuming; Li, Yinghui

    2008-06-01

    Objective was to quantified the impact of a 60-day head-down tilt bed rest (HDBR) with countermeasures "CM" on the Cardiac arterial and venous hemodynamics at rest. Method: Twenty-one men (25-40y) divided into 3 groups [Control (Con), daily 30 min Foot vibration (Vib) and Chinese Herb (Herb)] were studied pre and at HDBR day 58. The subjects were allowed to have a daily 10 min squat/stand period for toilets. Post HDBR 10 min Tilt identified Finishers (F) and Non Finishers (NF). Result: (a) Most of the cardiac and arterial parameters reduced after 58d in HDBR as observed in other long term HDBR (b) the Vibration CM induced a reduction in lower limb vascular resistance (c) the short 10 min squat/stand period should have contributed to lower the proportion of NF at the post HDBR tilt.

  2. Adaptation.

    PubMed

    Broom, Donald M

    2006-01-01

    The term adaptation is used in biology in three different ways. It may refer to changes which occur at the cell and organ level, or at the individual level, or at the level of gene action and evolutionary processes. Adaptation by cells, especially nerve cells helps in: communication within the body, the distinguishing of stimuli, the avoidance of overload and the conservation of energy. The time course and complexity of these mechanisms varies. Adaptive characters of organisms, including adaptive behaviours, increase fitness so this adaptation is evolutionary. The major part of this paper concerns adaptation by individuals and its relationships to welfare. In complex animals, feed forward control is widely used. Individuals predict problems and adapt by acting before the environmental effect is substantial. Much of adaptation involves brain control and animals have a set of needs, located in the brain and acting largely via motivational mechanisms, to regulate life. Needs may be for resources but are also for actions and stimuli which are part of the mechanism which has evolved to obtain the resources. Hence pigs do not just need food but need to be able to carry out actions like rooting in earth or manipulating materials which are part of foraging behaviour. The welfare of an individual is its state as regards its attempts to cope with its environment. This state includes various adaptive mechanisms including feelings and those which cope with disease. The part of welfare which is concerned with coping with pathology is health. Disease, which implies some significant effect of pathology, always results in poor welfare. Welfare varies over a range from very good, when adaptation is effective and there are feelings of pleasure or contentment, to very poor. A key point concerning the concept of individual adaptation in relation to welfare is that welfare may be good or poor while adaptation is occurring. Some adaptation is very easy and energetically cheap and

  3. Subfamily-specific adaptations in the structures of two penicillin-binding proteins from Mycobacterium tuberculosis

    SciTech Connect

    Prigozhin, Daniil M.; Krieger, Inna V.; Huizar, John P.; Mavrici, Daniela; Waldo, Geoffrey S.; Hung, Li -Wei; Sacchettini, James C.; Terwilliger, Thomas C.; Alber, Tom; Mayer, Claudine

    2014-12-31

    Beta-lactam antibiotics target penicillin-binding proteins including several enzyme classes essential for bacterial cell-wall homeostasis. To better understand the functional and inhibitor-binding specificities of penicillin-binding proteins from the pathogen, Mycobacterium tuberculosis, we carried out structural and phylogenetic analysis of two predicted D,D-carboxypeptidases, Rv2911 and Rv3330. Optimization of Rv2911 for crystallization using directed evolution and the GFP folding reporter method yielded a soluble quadruple mutant. Structures of optimized Rv2911 bound to phenylmethylsulfonyl fluoride and Rv3330 bound to meropenem show that, in contrast to the nonspecific inhibitor, meropenem forms an extended interaction with the enzyme along a conserved surface. Phylogenetic analysis shows that Rv2911 and Rv3330 belong to different clades that emerged in Actinobacteria and are not represented in model organisms such as Escherichia coli and Bacillus subtilis. Clade-specific adaptations allow these enzymes to fulfill distinct physiological roles despite strict conservation of core catalytic residues. The characteristic differences include potential protein-protein interaction surfaces and specificity-determining residues surrounding the catalytic site. Overall, these structural insights lay the groundwork to develop improved beta-lactam therapeutics for tuberculosis.

  4. Adaptive ligand binding by the purine riboswitch in the recognition of guanine and adenine analogs

    PubMed Central

    Gilbert, Sunny D.; Reyes, Francis E.; Edwards, Andrea L.; Batey, Robert T.

    2009-01-01

    SUMMARY Purine riboswitches discriminate between guanine and adenine by at least 10,000-fold based on the identity of a single pyrimidine (Y74) that forms a Watson-Crick base pair with the ligand. To understand how this high degree of specificity for closely related compounds is achieved through simple pairing, we investigated their interaction with purine analogs with varying functional groups at the 2- and 6-positions that have the potential to alter interactions with Y74. Using a combination of crystallographic and calorimetric approaches, we find that binding these purines is often facilitated by either small structural changes in the RNA or tautomeric changes in the ligand. This work also reveals that, along with base pairing, conformational restriction of Y74 significantly contributes to nucleobase selectivity. These results reveal that compounds that exploit the inherent local flexibility within riboswitch binding pockets can alter their ligand specificity. PMID:19523903

  5. Cardiac Rehabilitation

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Rehabilitation? Cardiac rehabilitation (rehab) is a medically supervised program ... be designed to meet your needs. The Cardiac Rehabilitation Team Cardiac rehab involves a long-term commitment ...

  6. Adaptive Evolution of Eel Fluorescent Proteins from Fatty Acid Binding Proteins Produces Bright Fluorescence in the Marine Environment

    PubMed Central

    Gruber, David F.; Gaffney, Jean P.; Mehr, Shaadi; DeSalle, Rob; Sparks, John S.; Platisa, Jelena; Pieribone, Vincent A.

    2015-01-01

    We report the identification and characterization of two new members of a family of bilirubin-inducible fluorescent proteins (FPs) from marine chlopsid eels and demonstrate a key region of the sequence that serves as an evolutionary switch from non-fluorescent to fluorescent fatty acid-binding proteins (FABPs). Using transcriptomic analysis of two species of brightly fluorescent Kaupichthys eels (Kaupichthys hyoproroides and Kaupichthys n. sp.), two new FPs were identified, cloned and characterized (Chlopsid FP I and Chlopsid FP II). We then performed phylogenetic analysis on 210 FABPs, spanning 16 vertebrate orders, and including 163 vertebrate taxa. We show that the fluorescent FPs diverged as a protein family and are the sister group to brain FABPs. Our results indicate that the evolution of this family involved at least three gene duplication events. We show that fluorescent FABPs possess a unique, conserved tripeptide Gly-Pro-Pro sequence motif, which is not found in non-fluorescent fatty acid binding proteins. This motif arose from a duplication event of the FABP brain isoforms and was under strong purifying selection, leading to the classification of this new FP family. Residues adjacent to the motif are under strong positive selection, suggesting a further refinement of the eel protein’s fluorescent properties. We present a phylogenetic reconstruction of this emerging FP family and describe additional fluorescent FABP members from groups of distantly related eels. The elucidation of this class of fish FPs with diverse properties provides new templates for the development of protein-based fluorescent tools. The evolutionary adaptation from fatty acid-binding proteins to fluorescent fatty acid-binding proteins raises intrigue as to the functional role of bright green fluorescence in this cryptic genus of reclusive eels that inhabit a blue, nearly monochromatic, marine environment. PMID:26561348

  7. Heart-Type Fatty Acid Binding Protein: A Better Cardiac Biomarker than CK-MB and Myoglobin in the Early Diagnosis of Acute Myocardial Infarction

    PubMed Central

    Devaranavadagi, Basavaraj B; Sajjannar, Sanjeev L; Nikam, Shashikant V; Shannawaz, Mohd; Sudharani

    2015-01-01

    Background Early diagnosis and therapeutic intervention can improve the outcome of acute myocardial infarction (AMI). However, there are no satisfactory cardiac biomarkers for the diagnosis of AMI within 6 hours of onset of symptoms. Among novel biochemical markers of AMI, heart-type fatty acid binding protein (H-FABP) is of particular interest. Aim To compare the diagnostic value of H-FABP with that of CK-MB and myoglobin in suspected AMI patients within first 6 hours after the onset of symptoms. Settings and Design The study includes 40 AMI cases and 40 non-cardiac chest pain otherwise healthy controls. The cases and controls were further divided into 2 groups depending on the time since chest pain as those subjects within 3 hours and those between 3-6 hours of onset of chest pain. Materials and Methods In all the cases and controls, serum H-FABP, CK-MB and myoglobin concentrations were measured by Immunoturbidimetric method, immuno-inhibition method and Chemiluminescence immunoassay respectively. Statistical Analysis Data is presented as mean ± SD values. Differences between means of two groups were assessed by Student t-test. Sensitivity, Specificity, Positive predictive value, Negative predictive values were calculated and ROC curve analysis was done to assess the diagnostic validity of each study parameter. Results The sensitivity, specificity, PPV, NPV of H-FABP were greater than CK-MB and myoglobin and ROC curve analysis demonstrated highest area under curve for H-FABP followed by myoglobin and CK-MB in patients with suspected AMI both within 3 hours and 3-6 hours after the onset of chest pain. Conclusion The diagnostic efficiency of H-FABP is greater than CK-MB and myoglobin for the early diagnosis of AMI within first 6 hours of chest pain. H-FABP can be used as an additional diagnostic tool for the early diagnosis of AMI. PMID:26557510

  8. Cardiac rehabilitation.

    PubMed

    Ehsani, A A

    1984-02-01

    Exercise training is a major, and the most important, component of cardiac rehabilitation. Besides providing psychological benefits and promoting a "sense of well being," it elicits a number of adaptations in patients with ischemic heart disease. Among the clinically important adaptations are changes in the trained skeletal muscles and autonomic nervous system, resulting not only in increased maximum exercise capacity but also a slower heart rate and, at times, a lower systolic blood pressure during submaximal exercise. The reduction in the rate pressure product decreases myocardial O2 demand at any given submaximal exercise intensity and may thus alleviate myocardial ischemia and angina in patients with coronary artery disease. These adaptive responses occur even with a relatively modest exercise intensity. Although short-term exercise training of moderate intensity has not been reported to result in improvement in left ventricular performance, recent data suggest that exercise training of higher intensity and longer duration (12 months or longer) than has conventionally been used in cardiac rehabilitation programs may favorably affect the heart. This is characterized by improvements in left ventricular function, diminished electrocardiographic criteria of myocardial ischemia and increased stroke volume during exercise. Modest weight reduction accompanies regularly performed prolonged exercise training. It is important, however, to recognize that high-intensity exercise programs are suitable for only some patients with coronary artery disease who are stable and should be used only under strict medical supervision. PMID:6400004

  9. Identification of Novel Protein Kinase A Phosphorylation Sites in the M-domain of Human and Murine Cardiac Myosin Binding Protein-C Using Mass Spectrometry Analysis

    PubMed Central

    Jia, Weitao; Shaffer, Justin F.; Harris, Samantha P.; Leary, Julie A.

    2010-01-01

    Cardiac myosin binding protein-C (cMyBP-C) is a large multi-domain accessory protein bound to myosin thick filaments in striated muscle sarcomeres. It plays an important role in the regulation of muscle contraction and mutations in the gene encoding cMyBP-C are a common cause of familial hypertrophic cardiomyopathy, the leading cause of sudden cardiac death in young people1. The N-terminal domains including the C0, C1, cMyBP-C motif, and C2 domains play a crucial role in maintaining and modulating actomyosin interactions (keeping normal cardiac function) in a phosphorylation dependent manner. The cMyBP-C motif or “M-domain” is a highly conserved linker domain in the N-terminus of cMyBP-C that contains three to five protein kinase A (PKA) phosphorylation sites, depending on species. For the human isoform, three PKA sites were previously identified (Ser275, Ser284, and Ser304), while three homologous sites exist in the murine isoform (Ser273, Ser282, and Ser302). The murine cMyBP-C isoform contains an additional conserved consensus site, Ser307 that is not present in the human isoform. In this study, we investigated sites of PKA phosphorylation of murine and human cMyBP-C by treating the recombinant protein C0C2 (~50 KDa, which contains the N-terminal C0, C1, M, and C2 domains) and C1C2 (~35 KDa, contains C1, M and C2 domains) with PKA and assessing the phosphorylation states using SDS-PAGE with ProQ Diamond staining, and powerful hybrid mass spectrometric analyses. Both high-accuracy bottom-up and measurements of intact proteins mass spectrometric approaches were used to determine the phosphorylation states of C0C2 and C1C2 proteins with or without PKA treatment. Herein, we report for the first time that there are four PKA phosphorylation sites in both murine and human M-domains; both murine Ser307 and a novel human Ser311 can be phosphorylated in vitro by PKA. Future studies are needed to investigate the phosphorylation state of murine and human cMyBP-C in vivo

  10. Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods.

    PubMed

    Frederiksen, Rikard; Nymark, Soile; Kolesnikov, Alexander V; Berry, Justin D; Adler, Leopold; Koutalos, Yiannis; Kefalov, Vladimir J; Cornwall, M Carter

    2016-07-01

    Photoactivation of vertebrate rhodopsin converts it to the physiologically active Meta II (R*) state, which triggers the rod light response. Meta II is rapidly inactivated by the phosphorylation of C-terminal serine and threonine residues by G-protein receptor kinase (Grk1) and subsequent binding of arrestin 1 (Arr1). Meta II exists in equilibrium with the more stable inactive form of rhodopsin, Meta III. Dark adaptation of rods requires the complete thermal decay of Meta II/Meta III into opsin and all-trans retinal and the subsequent regeneration of rhodopsin with 11-cis retinal chromophore. In this study, we examine the regulation of Meta III decay by Grk1 and Arr1 in intact mouse rods and their effect on rod dark adaptation. We measure the rates of Meta III decay in isolated retinas of wild-type (WT), Grk1-deficient (Grk1(-/-)), Arr1-deficient (Arr1(-/-)), and Arr1-overexpressing (Arr1(ox)) mice. We find that in WT mouse rods, Meta III peaks ∼6 min after rhodopsin activation and decays with a time constant (τ) of 17 min. Meta III decay slows in Arr1(-/-) rods (τ of ∼27 min), whereas it accelerates in Arr1(ox) rods (τ of ∼8 min) and Grk1(-/-) rods (τ of ∼13 min). In all cases, regeneration of rhodopsin with exogenous 11-cis retinal is rate limited by the decay of Meta III. Notably, the kinetics of rod dark adaptation in vivo is also modulated by the levels of Arr1 and Grk1. We conclude that, in addition to their well-established roles in Meta II inactivation, Grk1 and Arr1 can modulate the kinetics of Meta III decay and rod dark adaptation in vivo. PMID:27353443

  11. Effects of egg-adaptation on receptor-binding and antigenic properties of recent influenza A (H3N2) vaccine viruses.

    PubMed

    Parker, Lauren; Wharton, Stephen A; Martin, Stephen R; Cross, Karen; Lin, Yipu; Liu, Yan; Feizi, Ten; Daniels, Rodney S; McCauley, John W

    2016-06-01

    Influenza A virus (subtype H3N2) causes seasonal human influenza and is included as a component of influenza vaccines. The majority of vaccine viruses are isolated and propagated in eggs, which commonly results in amino acid substitutions in the haemagglutinin (HA) glycoprotein. These substitutions can affect virus receptor-binding and alter virus antigenicity, thereby, obfuscating the choice of egg-propagated viruses for development into candidate vaccine viruses. To evaluate the effects of egg-adaptive substitutions seen in H3N2 vaccine viruses on sialic acid receptor-binding, we carried out quantitative measurement of virus receptor-binding using surface biolayer interferometry with haemagglutination inhibition (HI) assays to correlate changes in receptor avidity with antigenic properties. Included in these studies was a panel of H3N2 viruses generated by reverse genetics containing substitutions seen in recent egg-propagated vaccine viruses and corresponding cell culture-propagated wild-type viruses. These assays provide a quantitative approach to investigating the importance of individual amino acid substitutions in influenza receptor-binding. Results show that viruses with egg-adaptive HA substitutions R156Q, S219Y, and I226N, have increased binding avidity to α2,3-linked receptor-analogues and decreased binding avidity to α2,6-linked receptor-analogues. No measurable binding was detected for the viruses with amino acid substitution combination 156Q+219Y and receptor-binding increased in viruses where egg-adaptation mutations were introduced into cell culture-propagated virus. Substitutions at positions 156 and 190 appeared to be primarily responsible for low reactivity in HI assays with post-infection ferret antisera raised against 2012-2013 season H3N2 viruses. Egg-adaptive substitutions at position 186 caused substantial differences in binding avidity with an insignificant effect on antigenicity. PMID:26974849

  12. Insulin binding and glucose uptake of adipocytes in rats adapted to hypergravitational force

    NASA Technical Reports Server (NTRS)

    Kobayashi, M.; Mondon, C. E.; Oyama, J.

    1980-01-01

    Rats were exposed to 4.15 g for 1 yr and weight and age matched, and lean noncentrifuged rats were used as control groups. Rats exposed to chronic hypergravity (hypergravic rats) were found to show lower ambient insulin levels, greater food intake with smaller body weight gain, and decreased size of isolated adipocytes. The ability of adipocytes from the hypergravic rats to bind insulin was increased. With Scatchard analysis, both number and affinity of receptors were increased. In contrast to the increased binding, glucose transport was found to be decreased in adipocytes from these animals. However, when the data were expressed as a percentage of maximal effect, the half maximal insulin effect for both the hypergravic and lean control groups was produced at an insulin concentration of 0.23 + or - 0.02 ng/ml, which was lower than the insulin concentration of 0.31 + or - 0.02 ng/ml for the weight-matched control group (P less than 0.05). This increased insulin sensitivity in the hypergravic group was accounted for by an increased number of receptors.

  13. Conformational selection and dynamic adaptation upon linker histone binding to the nucleosome.

    PubMed

    Öztürk, Mehmet Ali; Pachov, Georgi V; Wade, Rebecca C; Cojocaru, Vlad

    2016-08-19

    Linker histones are essential for DNA compaction in chromatin. They bind to nucleosomes in a 1:1 ratio forming chromatosomes. Alternative configurations have been proposed in which the globular domain of the linker histone H5 (gH5) is positioned either on- or off-dyad between the nucleosomal and linker DNAs. However, the dynamic pathways of chromatosome assembly remain elusive. Here, we studied the conformational plasticity of gH5 in unbound and off-dyad nucleosome-bound forms with classical and accelerated molecular dynamics simulations. We find that the unbound gH5 converts between open and closed conformations, preferring the closed form. However, the open gH5 contributes to a more rigid chromatosome and restricts the motion of the nearby linker DNA through hydrophobic interactions with thymidines. Moreover, the closed gH5 opens and reorients in accelerated simulations of the chromatosome. Brownian dynamics simulations of chromatosome assembly, accounting for a range of amplitudes of nucleosome opening and different nucleosome DNA sequences, support the existence of both on- and off-dyad binding modes of gH5 and reveal alternative, sequence and conformation-dependent chromatosome configurations. Taken together, these findings suggest that the conformational dynamics of linker histones and nucleosomes facilitate alternative chromatosome configurations through an interplay between induced fit and conformational selection. PMID:27270081

  14. Adapt

    NASA Astrophysics Data System (ADS)

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  15. Developmental changes in the role of a pertussis toxin sensitive guanine nucleotide binding protein in the rat cardiac alpha sub 1 -adrenergic system

    SciTech Connect

    Han, H.M.

    1989-01-01

    During development, the cardiac alpha{sub 1}-adrenergic chronotropic response changes from positive in the neonate to negative in the adult. This thesis examined the possibility of a developmental change in coupling of a PT-sensitive G-protein to the alpha{sub 1}-adrenergic receptor. Radioligand binding experiments performed with the iodinated alpha{sub 1}-selective radioligand ({sup 125}I)-I-2-({beta}-(4-hydroxphenyl)ethylaminomethyl)tetralone (({sup 125}I)-IBE 2254) demonstrated that the alpha{sub 1}-adrenergic receptor is coupled to a G-protein in both neonatal and adult rat hearts. However, in the neonate the alpha{sub 1}-adrenergic receptor is coupled to a PT-insensitive G-protein, whereas in the adult the alpha{sub 1}-adrenergic receptor is coupled to both a PT-insensitive and a PT-sensitive G-protein. Consistent with the results from binding experiments, PT did not have any effect on the alpha{sub 1}-mediated positive chronotropic response in the neonate, whereas in the adult the alpha{sub 1}-mediated negative chronotropic response was completely converted to a positive one after PT-treatment. This thesis also examined the possibility of an alteration in coupling of the alpha{sub 1}-adrenergic receptor to its effector under certain circumstances such as high potassium (K{sup +}) depolarization in nerve-muscle (NM) co-cultures, a system which has been previously shown to be a convenient in vitro model to study the mature inhibitory alpha{sub 1}-response.

  16. LOSS OF CARDIAC METABOLIC ADAPTATION AND DYSFUNCTION OF THE HEART WITH WESTERN DIET IN THE OBESE ZUCKER RAT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The normal heart sustains its work output through changing the proportion of substrates it oxidizes depending on fuel supply. This metabolic adaptation is thought to be regulated at a transcriptional level by the peroxisome proliferator-activated receptor alpha (PPAR-alpha). We proposed that obesity...

  17. Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin-43-containing gap junctions in cardiac myocytes

    PubMed Central

    Zemljic-Harpf, Alice E.; Godoy, Joseph C.; Platoshyn, Oleksandr; Asfaw, Elizabeth K.; Busija, Anna R.; Domenighetti, Andrea A.; Ross, Robert S.

    2014-01-01

    ABSTRACT Vinculin (Vcl) links actin filaments to integrin- and cadherin-based cellular junctions. Zonula occludens-1 (ZO-1, also known as TJP1) binds connexin-43 (Cx43, also known as GJA1), cadherin and actin. Vcl and ZO-1 anchor the actin cytoskeleton to the sarcolemma. Given that loss of Vcl from cardiomyocytes causes maldistribution of Cx43 and predisposes cardiomyocyte-specific Vcl-knockout mice with preserved heart function to arrhythmia and sudden death, we hypothesized that Vcl and ZO-1 interact and that loss of this interaction destabilizes gap junctions. We found that Vcl, Cx43 and ZO-1 colocalized at the intercalated disc. Loss of cardiomyocyte Vcl caused parallel loss of ZO-1 from intercalated dics. Vcl co-immunoprecipitated Cx43 and ZO-1, and directly bound ZO-1 in yeast two-hybrid studies. Excision of the Vcl gene in neonatal mouse cardiomyocytes caused a reduction in the amount of Vcl mRNA transcript and protein expression leading to (1) decreased protein expression of Cx43, ZO-1, talin, and β1D-integrin, (2) reduced PI3K activation, (3) increased activation of Akt, Erk1 and Erk2, and (4) cardiomyocyte necrosis. In summary, this is the first study showing a direct interaction between Vcl and ZO-1 and illustrates how Vcl plays a crucial role in stabilizing gap junctions and myocyte integrity. PMID:24413171

  18. Master of all trades: thermal acclimation and adaptation of cardiac function in a broadly distributed marine invasive species, the European green crab, Carcinus maenas.

    PubMed

    Tepolt, Carolyn K; Somero, George N

    2014-04-01

    As global warming accelerates, there is increasing concern about how ecosystems may change as a result of species loss and replacement. Here, we examined the thermal physiology of the European green crab (Carcinus maenas Linnaeus 1758), a globally invasive species, along three parallel thermal gradients in its native and invasive ranges. At each site, we assessed cardiac physiology to determine heat and cold tolerance and acclimatory plasticity. We found that, overall, the species is highly tolerant of both heat and cold, and that it survives higher temperatures than co-occurring native marine crustaceans. Further, we found that both heat and cold tolerance are plastic in response to short-term acclimation (18-31 days at either 5 or 25°C). Comparing patterns within ranges, we found latitudinal gradients in thermal tolerance in the native European range and in the invasive range in eastern North America. This pattern is strongest in the native range, and likely evolved there. Because of a complicated invasion history, the latitudinal pattern in the eastern North American invasive range may be due either to rapid adaptation post-invasion or to adaptive differences between the ancestral populations that founded the invasion. Overall, the broad thermal tolerance ranges of green crabs, which may facilitate invasion of novel habitats, derive from high inherent eurythermality and acclimatory plasticity and potentially adaptive differentiation among populations. The highly flexible physiology that results from these capacities may represent the hallmark of a successful invasive species, and may provide a model for success in a changing world. PMID:24671964

  19. Iterative 4D cardiac micro-CT image reconstruction using an adaptive spatio-temporal sparsity prior

    NASA Astrophysics Data System (ADS)

    Ritschl, Ludwig; Sawall, Stefan; Knaup, Michael; Hess, Andreas; Kachelrieß, Marc

    2012-03-01

    Temporal-correlated image reconstruction, also known as 4D CT image reconstruction, is a big challenge in computed tomography. The reasons for incorporating the temporal domain into the reconstruction are motions of the scanned object, which would otherwise lead to motion artifacts. The standard method for 4D CT image reconstruction is extracting single motion phases and reconstructing them separately. These reconstructions can suffer from undersampling artifacts due to the low number of used projections in each phase. There are different iterative methods which try to incorporate some a priori knowledge to compensate for these artifacts. In this paper we want to follow this strategy. The cost function we use is a higher dimensional cost function which accounts for the sparseness of the measured signal in the spatial and temporal directions. This leads to the definition of a higher dimensional total variation. The method is validated using in vivo cardiac micro-CT mouse data. Additionally, we compare the results to phase-correlated reconstructions using the FDK algorithm and a total variation constrained reconstruction, where the total variation term is only defined in the spatial domain. The reconstructed datasets show strong improvements in terms of artifact reduction and low-contrast resolution compared to other methods. Thereby the temporal resolution of the reconstructed signal is not affected.

  20. Cardiac Catheterization

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Catheterization? Cardiac catheterization (KATH-eh-ter-ih-ZA-shun) is a ... disease. Doctors also can use ultrasound during cardiac catheterization to see blockages in the coronary arteries. Ultrasound ...

  1. [Cardiac Rehabilitation 2015].

    PubMed

    Hoffmann, Andreas

    2015-11-25

    The goals of cardiac rehabilitation are (re-)conditioning and secondary prevention in patients with heart disease or an elevated cardiovascular risk profile. Rehabilitation is based on motivation through education, on adapted physical activity, instruction of relaxation techniques, psychological support and optimized medication. It is performed preferably in groups either in outpatient or inpatient settings. The Swiss working group on cardiac rehabilitation provides a network of institutions with regular quality auditing. Positive effects of rehabilitation programs on mortality and morbidity have been established by numerous studies. Although a majority of patients after cardiac surgery are being referred to rehabilitation, these services are notoriously underused after catheter procedures. PMID:26602848

  2. Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C.

    PubMed

    Zot, Henry G; Hasbun, Javier E; Michell, Clara A; Landim-Vieira, Maicon; Pinto, Jose R

    2016-07-01

    Higher affinity for TnI explains how troponin C (TnC) carrying a causative hypertrophic cardiomyopathy mutation, TnC(A8V), sensitizes muscle cells to Ca(2+). Muscle fibers reconstituted with TnC(A8V) require ∼2.3-fold less [Ca(2+)] to achieve 50% maximum-tension compared to fibers reconstituted with wild-type TnC (TnC(WT)). Binding measurements rule out a significant change in N-terminus Ca(2+)-affinity of isolated TnC(A8V), and TnC(A8V) binds the switch-peptide of troponin-I (TnI(sp)) ∼1.6-fold more strongly than TnC(WT); thus we model the TnC-TnI(sp) interaction as competing with the TnI-actin interaction. Tension data are well-fit by a model constrained to conditions in which the affinity of TnC(A8V) for TnI(sp) is 1.5-1.7-fold higher than that of TnC(WT) at all [Ca(2+)]. Mean ATPase rates of reconstituted cardiac myofibrils is greater for TnC(A8V) than TnC(WT) at all [Ca(2+)], with statistically significant differences in the means at higher [Ca(2+)]. To probe TnC-TnI interaction in low Ca(2+), displacement of bis-ANS from TnI was monitored as a function of TnC. Whereas Ca(2+)-TnC(WT) displaces significantly more bis-ANS than Mg(2+)-TnC(WT), Ca(2+)-TnC(A8V) displaces probe equivalently to Mg(2+)-TnC(A8V) and Ca(2+)-TnC(WT), consistent with stronger Ca(2+)-independent TnC(A8V)-TnI(sp). A Matlab program for computing theoretical activation is reported. Our work suggests that contractility is constantly above normal in hearts made hypertrophic by TnC(A8V). PMID:26976709

  3. Cardiac Imaging In Athletes

    PubMed Central

    Khan, Asaad A.; Safi, Lucy; Wood, Malissa

    2016-01-01

    Athletic heart syndrome refers to the physiological and morphological changes that occur in a human heart after repetitive strenuous physical exercise. Examples of exercise-induced changes in the heart include increases in heart cavity dimensions, augmentation of cardiac output, and increases in heart muscle mass. These cardiac adaptations vary based on the type of exercise performed and are often referred to as sport-specific cardiac remodeling. The hemodynamic effects of endurance and strength training exercise lead to these adaptations. Any abnormalities in chamber dilatation and left ventricular function usually normalize with cessation of exercise. Athletic heart syndrome is rare and should be differentiated from pathologic conditions such as hypertrophic cardiomyopathy, left ventricular noncompaction, and arrhythmogenic right ventricular dysplasia when assessing a patient for athletic heart syndrome. This paper describes specific adaptations that occur in athletic heart syndrome and tools to distinguish between healthy alterations versus underlying pathology. PMID:27486490

  4. Furospinosulin-1, Marine Spongean Furanosesterterpene, Suppresses the Growth of Hypoxia-Adapted Cancer Cells by Binding to Transcriptional Regulators p54(nrb) and LEDGF/p75.

    PubMed

    Arai, Masayoshi; Kawachi, Takashi; Kotoku, Naoyuki; Nakata, Chiaki; Kamada, Haruhiko; Tsunoda, Shin-ichi; Tsutsumi, Yasuo; Endo, Hiroko; Inoue, Masahiro; Sato, Hiroki; Kobayashi, Motomasa

    2016-01-01

    Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. Cancer research has therefore focused on the identification of molecules responsible for hypoxia adaptation in cancer cells, as well as the development of new compounds with action against hypoxia-adapted cancer cells. The marine natural product furospinosulin-1 (1) has displayed hypoxia-selective growth inhibition against cultured cancer cells, and has shown in vivo anti-tumor activity, although its precise mode of action and molecular targets remain unclear. In this study, we found that 1 is selectively effective against hypoxic regions of tumors, and that it directly binds to the transcriptional regulators p54(nrb) and LEDGF/p75, which have not been previously identified as mediators of hypoxia adaptation in cancer cells. PMID:26561285

  5. Impaired cardiac contractility response to hemodynamic stress in S100A1-deficient mice.

    PubMed

    Du, Xiao-Jun; Cole, Timothy J; Tenis, Nora; Gao, Xiao-Ming; Köntgen, Frank; Kemp, Bruce E; Heierhorst, Jörg

    2002-04-01

    Ca(2+) signaling plays a central role in cardiac contractility and adaptation to increased hemodynamic demand. We have generated mice with a targeted deletion of the S100A1 gene coding for the major cardiac isoform of the large multigenic S100 family of EF hand Ca(2+)-binding proteins. S100A1(-/-) mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to beta-adrenergic stimulation that are associated with a reduced Ca(2+) sensitivity. In S100A1(-/-) mice, basal left-ventricular contractility deteriorated following 3-week pressure overload by thoracic aorta constriction despite a normal adaptive hypertrophy. Surprisingly, heterozygotes also had an impaired response to acute beta-adrenergic stimulation but maintained normal contractility in response to chronic pressure overload that coincided with S100A1 upregulation to wild-type levels. In contrast to other genetic models with impaired cardiac contractility, loss of S100A1 did not lead to cardiac hypertrophy or dilation in aged mice. The data demonstrate that high S100A1 protein levels are essential for the cardiac reserve and adaptation to acute and chronic hemodynamic stress in vivo. PMID:11909974

  6. Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice

    PubMed Central

    Du, Xiao-Jun; Cole, Timothy J.; Tenis, Nora; Gao, Xiao-Ming; Köntgen, Frank; Kemp, Bruce E.; Heierhorst, Jörg

    2002-01-01

    Ca2+ signaling plays a central role in cardiac contractility and adaptation to increased hemodynamic demand. We have generated mice with a targeted deletion of the S100A1 gene coding for the major cardiac isoform of the large multigenic S100 family of EF hand Ca2+-binding proteins. S100A1−/− mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to β-adrenergic stimulation that are associated with a reduced Ca2+ sensitivity. In S100A1−/− mice, basal left-ventricular contractility deteriorated following 3-week pressure overload by thoracic aorta constriction despite a normal adaptive hypertrophy. Surprisingly, heterozygotes also had an impaired response to acute β-adrenergic stimulation but maintained normal contractility in response to chronic pressure overload that coincided with S100A1 upregulation to wild-type levels. In contrast to other genetic models with impaired cardiac contractility, loss of S100A1 did not lead to cardiac hypertrophy or dilation in aged mice. The data demonstrate that high S100A1 protein levels are essential for the cardiac reserve and adaptation to acute and chronic hemodynamic stress in vivo. PMID:11909974

  7. Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C.

    PubMed

    Mamidi, Ranganath; Gresham, Kenneth S; Li, Amy; dos Remedios, Cristobal G; Stelzer, Julian E

    2015-08-01

    Decreased expression of cardiac myosin binding protein-C (cMyBP-C) in the myocardium is thought to be a contributing factor to hypertrophic cardiomyopathy in humans, and the initial molecular defect is likely abnormal cross-bridge (XB) function which leads to impaired force generation, decreased contractile performance, and hypertrophy in vivo. The myosin activator omecamtiv mecarbil (OM) is a pharmacological drug that specifically targets the myosin XB and recent evidence suggests that OM induces a significant decrease in the in vivo motility velocity and an increase in the XB duty cycle. Thus, the molecular effects of OM maybe beneficial in improving contractile function in skinned myocardium lacking cMyBP-C because absence of cMyBP-C in the sarcomere accelerates XB kinetics and enhances XB turnover rate, which presumably reduces contractile efficiency. Therefore, parameters of XB function were measured in skinned myocardium lacking cMyBP-C prior to and following OM incubation. We measured ktr, the rate of force redevelopment as an index of XB transition from both the weakly- to strongly-bound state and from the strongly- to weakly-bound states and performed stretch activation experiments to measure the rates of XB detachment (krel) and XB recruitment (kdf) in detergent-skinned ventricular preparations isolated from hearts of wild-type (WT) and cMyBP-C knockout (KO) mice. Samples from donor human hearts were also used to assess the effects of OM in cardiac muscle expressing a slow β-myosin heavy chain (β-MHC). Incubation of skinned myocardium with OM produced large enhancements in steady-state force generation which were most pronounced at low levels of [Ca(2+)] activations, suggesting that OM cooperatively recruits additional XB's into force generating states. Despite a large increase in steady-state force generation following OM incubation, parallel accelerations in XB kinetics as measured by ktr were not observed, and there was a significant OM

  8. Adaptation of avian influenza A (H6N1) virus from avian to human receptor-binding preference.

    PubMed

    Wang, Fei; Qi, Jianxun; Bi, Yuhai; Zhang, Wei; Wang, Min; Zhang, Baorong; Wang, Ming; Liu, Jinhua; Yan, Jinghua; Shi, Yi; Gao, George F

    2015-06-12

    The receptor-binding specificity of influenza A viruses is a major determinant for the host tropism of the virus, which enables interspecies transmission. In 2013, the first human case of infection with avian influenza A (H6N1) virus was reported in Taiwan. To gather evidence concerning the epidemic potential of H6 subtype viruses, we performed comprehensive analysis of receptor-binding properties of Taiwan-isolated H6 HAs from 1972 to 2013. We propose that the receptor-binding properties of Taiwan-isolated H6 HAs have undergone three major stages: initially avian receptor-binding preference, secondarily obtaining human receptor-binding capacity, and recently human receptor-binding preference, which has been confirmed by receptor-binding assessment of three representative virus isolates. Mutagenesis work revealed that E190V and G228S substitutions are important to acquire the human receptor-binding capacity, and the P186L substitution could reduce the binding to avian receptor. Further structural analysis revealed how the P186L substitution in the receptor-binding site of HA determines the receptor-binding preference change. We conclude that the human-infecting H6N1 evolved into a human receptor preference. PMID:25940072

  9. Protein kinase A phosphorylation at serine-2808 of the cardiac Ca2+-release channel (ryanodine receptor) does not dissociate 12.6-kDa FK506-binding protein (FKBP12.6).

    PubMed

    Xiao, Bailong; Sutherland, Cindy; Walsh, Michael P; Chen, S R Wayne

    2004-03-01

    Dissociation of FKBP12.6 from the cardiac Ca2+-release channel (RyR2) as a consequence of protein kinase A (PKA) hyperphosphorylation of RyR2 at a single amino acid residue, serine-2808, has been proposed as an important mechanism underlying cardiac dysfunction in heart failure. However, the issue of whether PKA phosphorylation of RyR2 can dissociate FKBP12.6 from RyR2 is controversial. To additionally address this issue, we investigated the effect of PKA phosphorylation and mutations at serine-2808 of RyR2 on recombinant or native FKBP12.6-RyR2 interaction. Site-specific antibodies, which recognize the serine-2808 phosphorylated or nonphosphorylated form of RyR2, were used to unambiguously correlate the phosphorylation state of RyR2 at serine-2808 with its ability to bind FKBP12.6. We found that FKBP12.6 can bind to both the serine-2808 phosphorylated and nonphosphorylated forms of RyR2. The S2808D mutant thought to mimic constitutive phosphorylation also retained the ability to bind FKBP12.6. Complete phosphorylation at serine-2808 by exogenous PKA disrupted neither the recombinant nor native FKBP12.6-RyR2 complex. Furthermore, binding of site-specific antibodies to the serine-2808 phosphorylation site did not dissociate FKBP12.6 from or prevent FKBP12.6 from binding to RyR2. Taken together, our results do not support the notion that PKA phosphorylation at serine-2808 dissociates FKBP12.6 from RyR2. PMID:14715536

  10. Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.

    PubMed

    Buchborn, Tobias; Schröder, Helmut; Dieterich, Daniela C; Grecksch, Gisela; Höllt, Volker

    2015-03-15

    Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex. PMID:25513973

  11. Affinity chromatography, two-dimensional electrophoresis, adapted immunodepletion and mass spectrometry used for detection of porcine and piscine heparin-binding human plasma proteins.

    PubMed

    Bjarnadóttir, Stefanía Guðrún; Flengsrud, Ragnar

    2014-01-01

    Heparin-binding proteins in human plasma were studied using affinity chromatography columns with porcine (2mL, 10.7mg capacity) and piscine heparin (5mL, 2.7mg capacity). Two-dimensional electrophoresis (Bio-Rad Protean II gel system with 16cm×16cm gels using isoelectric focusing (IEF) and nonequilibrium pH-gradient gel electrophoresis (NEPHGE)), Bruker Ultraflex MALDI-TOF mass spectrometry and immunoblotting (NovaBlot semidry discontinuous blotting) were used for unfractionated plasma. This revealed electropherograms with differences between porcine and piscine heparin-binding and totally 17 different fibrinogen variants from all 3 chains. Immunodepletion was used to remove fibrinogen (42.1mg anti-human fibrinogen in 8.4mL resin) and serum albumin (0.42mg binding capacity in 14mL resin) and porcine and piscine heparin-binding proteins were identified using liquid chromatography-mass spectrometry (Ultimate 3000 NanoLC with Acclaim PepMap 100 column (50cm×75μm)-LTQ Orbitrap Mass XL). In total, the binding of 76 putative or acknowledged biomarkers are shown. Of the identified proteins, 14 are not previously shown to be heparin-binding, such as the low concentration proteins lipocalin-1 and tropomyosin and a hitherto not detected protein in plasma, zinc finger protein 483. The putative heparin-binding sequences were analyzed. The results suggest that the combination of group specific affinity and adapted immunodepletion chromatography could be useful in the study of the plasma proteome. PMID:24316520

  12. SP Transcription Factor Paralogs and DNA-Binding Sites Coevolve and Adaptively Converge in Mammals and Birds

    PubMed Central

    Yokoyama, Ken Daigoro; Pollock, David D.

    2012-01-01

    Functional modification of regulatory proteins can affect hundreds of genes throughout the genome, and is therefore thought to be almost universally deleterious. This belief, however, has recently been challenged. A potential example comes from transcription factor SP1, for which statistical evidence indicates that motif preferences were altered in eutherian mammals. Here, we set out to discover possible structural and theoretical explanations, evaluate the role of selection in SP1 evolution, and discover effects on coregulatory proteins. We show that SP1 motif preferences were convergently altered in birds as well as mammals, inducing coevolutionary changes in over 800 regulatory regions. Structural and phylogenic evidence implicates a single causative amino acid replacement at the same SP1 position along both lineages. Furthermore, paralogs SP3 and SP4, which coregulate SP1 target genes through competitive binding to the same sites, have accumulated convergent replacements at the homologous position multiple times during eutherian and bird evolution, presumably to preserve competitive binding. To determine plausibility, we developed and implemented a simple model of transcription factor and binding site coevolution. This model predicts that, in contrast to prevailing beliefs, even small selective benefits per locus can drive concurrent fixation of transcription factor and binding site mutants under a broad range of conditions. Novel binding sites tend to arise de novo, rather than by mutation from ancestral sites, a prediction substantiated by SP1-binding site alignments. Thus, multiple lines of evidence indicate that selection has driven convergent evolution of transcription factors along with their binding sites and coregulatory proteins. PMID:23019068

  13. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress.

    PubMed

    Makkinje, A; Quinn, D A; Chen, A; Cadilla, C L; Force, T; Bonventre, J V; Kyriakis, J M

    2000-06-01

    Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical consequences, including hypertrophy and acute respiratory distress syndrome. Pathologic hypertrophy contributes to decreased organ function and, ultimately, organ failure; and cardiac and diabetic renal hypertrophy are major causes of morbidity and morality in the developed world. Likewise, acute respiratory distress syndrome is a serious potential side effect of mechanical pulmonary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extracellular stimuli. The physiologic function of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sharply in response to a set of commonly occurring chronic stress stimuli: mechanical strain, vasoactive peptides, and diabetic nephropathy. Induction of gene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases. This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress. The structure of Gene 33 indicates an adapter protein capable of binding monomeric GTPases of the Rho subfamily. Consistent with this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs. These results imply a reciprocal, positive feedback relationship between Gene 33 expression and SAPK activation. Expression of Gene 33 at sufficient levels may enable a compensatory reprogramming of cellular function in response to chronic stress, which may have pathophysiological consequences. PMID:10749885

  14. The primary substrate binding site in the b' domain of ERp57 is adapted for endoplasmic reticulum lectin association.

    PubMed

    Russell, Sarah J; Ruddock, Lloyd W; Salo, Kirsi E H; Oliver, Jason D; Roebuck, Quentin P; Llewellyn, David H; Roderick, H Llewelyn; Koivunen, Peppi; Myllyharju, Johanna; High, Stephen

    2004-04-30

    ERp57 is a member of the protein disulfide isomerase (PDI) family that is located in the endoplasmic reticulum (ER) and characterized by its specificity for glycoproteins. Substrate selection by ERp57 is dependent upon its formation of discrete complexes with two ER resident lectins, soluble calreticulin and membrane-bound calnexin. It is these two lectins that directly associate with glycoproteins bearing correctly trimmed oligosaccharide side chains. Thus, ERp57 is presented with a preselected set of substrates upon which it can act, and the specific binding of calreticulin and calnexin to ERp57 is pivotal to the functions of the resulting complexes. To gain further insights into the formation of these ERp57-ER lectin complexes, we have investigated the regions of ERp57 that are specifically required for its binding to calreticulin. Using a quantitative pull-down assay to investigate the binding of ERp57/PDI chimeras to calreticulin, we define the b and b' domains of ERp57 as the minimal elements that are sufficient for complex formation. This analysis further identifies a novel role for the distinctive C-terminal extension of ERp57 in reconstituting complex formation to wild type levels. Using our understanding of substrate binding to the b' domain of PDI as a paradigm, we show that alterations to specific residues in the b' domain of ERp57 dramatically reduce or completely abolish its binding to calreticulin. On the basis of these data, we propose a model where the region of ERp57 equivalent to the primary substrate binding site of archetypal PDI is occupied by calreticulin and suggest that the ER lectins act as adaptor molecules that define the substrate specificity of ERp57. PMID:14871899

  15. Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein.

    PubMed

    Krois, Alexander S; Ferreon, Josephine C; Martinez-Yamout, Maria A; Dyson, H Jane; Wright, Peter E

    2016-03-29

    An important component of the activity of p53 as a tumor suppressor is its interaction with the transcriptional coactivators cyclic-AMP response element-binding protein (CREB)-binding protein (CBP) and p300, which activate transcription of p53-regulated stress response genes and stabilize p53 against ubiquitin-mediated degradation. The highest affinity interactions are between the intrinsically disordered N-terminal transactivation domain (TAD) of p53 and the TAZ1 and TAZ2 domains of CBP/p300. The NMR spectra of simple binary complexes of the TAZ1 and TAZ2 domains with the p53TAD suffer from exchange broadening, but innovations in construct design and isotopic labeling have enabled us to obtain high-resolution structures using fusion proteins, uniformly labeled in the case of the TAZ2-p53TAD fusion and segmentally labeled through transintein splicing for the TAZ1-p53TAD fusion. The p53TAD is bipartite, with two interaction motifs, termed AD1 and AD2, which fold to form short amphipathic helices upon binding to TAZ1 and TAZ2 whereas intervening regions of the p53TAD remain flexible. Both the AD1 and AD2 motifs bind to hydrophobic surfaces of the TAZ domains, with AD2 making more extensive hydrophobic contacts consistent with its greater contribution to the binding affinity. Binding of AD1 and AD2 is synergistic, and structural studies performed with isolated motifs can be misleading. The present structures of the full-length p53TAD complexes demonstrate the versatility of the interactions available to an intrinsically disordered domain containing bipartite interaction motifs and provide valuable insights into the structural basis of the affinity changes that occur upon stress-related posttranslational modification. PMID:26976603

  16. IN VITRO EFFECTS OF CHLORPYRIFOS, PARATHION, METHYL PARATHION AND THEIR OXONS ON CARDIAC MUSCARINIC RECEPTOR BINDING IN NEONATAL AND ADULT RATS. (R825811)

    EPA Science Inventory

    Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase. Young animals are generally more sensitive than adults to these toxicants. A number of studies reported that some organophosphorus agents also bind directly to muscarinic receptors, in particular...

  17. The loss of the hemoglobin H2S-binding function in annelids from sulfide-free habitats reveals molecular adaptation driven by Darwinian positive selection.

    PubMed

    Bailly, Xavier; Leroy, Riwanon; Carney, Susan; Collin, Olivier; Zal, Franck; Toulmond, Andre; Jollivet, Didier

    2003-05-13

    The hemoglobin of the deep-sea hydrothermal vent vestimentiferan Riftia pachyptila (annelid) is able to bind toxic hydrogen sulfide (H(2)S) to free cysteine residues and to transport it to fuel endosymbiotic sulfide-oxidising bacteria. The cysteine residues are conserved key amino acids in annelid globins living in sulfide-rich environments, but are absent in annelid globins from sulfide-free environments. Synonymous and nonsynonymous substitution analysis from two different sets of orthologous annelid globin genes from sulfide rich and sulfide free environments have been performed to understand how the sulfide-binding function of hemoglobin appeared and has been maintained during the course of evolution. This study reveals that the sites occupied by free-cysteine residues in annelids living in sulfide-rich environments and occupied by other amino acids in annelids from sulfide-free environments, have undergone positive selection in annelids from sulfide-free environments. We assumed that the high reactivity of cysteine residues became a disadvantage when H(2)S disappeared because free cysteines without their natural ligand had the capacity to interact with other blood components, disturb homeostasis, reduce fitness and thus could have been counterselected. To our knowledge, we pointed out for the first time a case of function loss driven by molecular adaptation rather than genetic drift. If constraint relaxation (H(2)S disappearance) led to the loss of the sulfide-binding function in modern annelids from sulfide-free environments, our work suggests that adaptation to sulfide-rich environments is a plesiomorphic feature, and thus that the annelid ancestor could have emerged in a sulfide-rich environment. PMID:12721359

  18. The loss of the hemoglobin H2S-binding function in annelids from sulfide-free habitats reveals molecular adaptation driven by Darwinian positive selection

    PubMed Central

    Bailly, Xavier; Leroy, Riwanon; Carney, Susan; Collin, Olivier; Zal, Franck; Toulmond, André; Jollivet, Didier

    2003-01-01

    The hemoglobin of the deep-sea hydrothermal vent vestimentiferan Riftia pachyptila (annelid) is able to bind toxic hydrogen sulfide (H2S) to free cysteine residues and to transport it to fuel endosymbiotic sulfide-oxidising bacteria. The cysteine residues are conserved key amino acids in annelid globins living in sulfide-rich environments, but are absent in annelid globins from sulfide-free environments. Synonymous and nonsynonymous substitution analysis from two different sets of orthologous annelid globin genes from sulfide rich and sulfide free environments have been performed to understand how the sulfide-binding function of hemoglobin appeared and has been maintained during the course of evolution. This study reveals that the sites occupied by free-cysteine residues in annelids living in sulfide-rich environments and occupied by other amino acids in annelids from sulfide-free environments, have undergone positive selection in annelids from sulfide-free environments. We assumed that the high reactivity of cysteine residues became a disadvantage when H2S disappeared because free cysteines without their natural ligand had the capacity to interact with other blood components, disturb homeostasis, reduce fitness and thus could have been counterselected. To our knowledge, we pointed out for the first time a case of function loss driven by molecular adaptation rather than genetic drift. If constraint relaxation (H2S disappearance) led to the loss of the sulfide-binding function in modern annelids from sulfide-free environments, our work suggests that adaptation to sulfide-rich environments is a plesiomorphic feature, and thus that the annelid ancestor could have emerged in a sulfide-rich environment. PMID:12721359

  19. Backbone 1H, 13C, and 15N assignments for the tandem ubiquitin binding domains of signal transducing adapter molecule 1.

    PubMed

    Lim, Jongsoo; Hong, Yoon-Hun; Lee, Bong-Jin; Ahn, Hee-Chul

    2011-04-01

    Signal transducing adapter molecule (STAM) forms the endosomal sorting complex required for transport-0 (ESCRT-0) complex with hepatocyte growth factor-regulated substrate (Hrs) to sort the ubiquitinated cargo proteins from the early endosomes to the ESCRT-1 complex. ESCRT-0 complex, STAM and Hrs, contains multiple ubiquitin binding domains, in which STAM has two ubiquitin binding domains, Vps27/Hrs/Stam (VHS) and ubiquitin interacting motif (UIM) at its N-terminus. By the cooperation of the multiple ubiquitin binding domains, the ESCRT-0 complex recognizes poly-ubiquitin, especially Lys63-linked ubiquitin. Here, we report the backbone resonance assignments and the secondary structure of the N-terminal 191 amino acids of the human STAM1 which includes the VHS domain and UIM. The {(1)H}-(15)N heteronuclear NOE experiments revealed that an unstructured and flexible loop region connects the VHS domain and UIM. Our work provides the basic information for the further NMR investigation of the interaction between STAM1 and poly-ubiquitin. PMID:20927613

  20. Cardiac metastases

    PubMed Central

    Bussani, R; De‐Giorgio, F; Abbate, A; Silvestri, F

    2007-01-01

    Tumours metastatic to the heart (cardiac metastases) are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Although primary cardiac tumours are extremely uncommon (various postmortem studies report rates between 0.001% and 0.28%), secondary tumours are not, and at least in theory, the heart can be metastasised by any malignant neoplasm able to spread to distant sites. In general, cardiac metastases are considered to be rare; however, when sought for, the incidence seems to be not as low as expected, ranging from 2.3% and 18.3%. Although no malignant tumours are known that diffuse preferentially to the heart, some do involve the heart more often than others—for example, melanoma and mediastinal primary tumours. This paper attempts to review the pathophysiology of cardiac metastatic disease, epidemiology and clinical presentation of cardiac metastases, and pathological characterisation of the lesions. PMID:17098886

  1. Cardiac Lymphoma.

    PubMed

    Jeudy, Jean; Burke, Allen P; Frazier, Aletta Ann

    2016-07-01

    Lymphoma of the heart and pericardium may develop in up to 25% of patients with disseminated nodal disease, but primary cardiac lymphoma is rare. The majority are diffuse large B-cell lymphomas, which arise in immunocompetent older individuals, men twice as often as women. Subsets are found in immunocompromised patients, including those with HIV-AIDS or allograft recipients. Cardiac lymphomas tend to arise in the wall of the right heart, especially right atrium, with contiguous infiltration of epicardium and pericardium. Pericardial implants and effusions are common. The disease is often multifocal in the heart, but cardiac valves are usually spared. PMID:27265603

  2. Cardiac cone-beam CT

    SciTech Connect

    Manzke, Robert . E-mail: robert.manzke@philips.com

    2005-10-15

    This doctoral thesis addresses imaging of the heart with retrospectively gated helical cone-beam computed tomography (CT). A thorough review of the CT reconstruction literature is presented in combination with a historic overview of cardiac CT imaging and a brief introduction to other cardiac imaging modalities. The thesis includes a comprehensive chapter about the theory of CT reconstruction, familiarizing the reader with the problem of cone-beam reconstruction. The anatomic and dynamic properties of the heart are outlined and techniques to derive the gating information are reviewed. With the extended cardiac reconstruction (ECR) framework, a new approach is presented for the heart-rate-adaptive gated helical cardiac cone-beam CT reconstruction. Reconstruction assessment criteria such as the temporal resolution, the homogeneity in terms of the cardiac phase, and the smoothness at cycle-to-cycle transitions are developed. Several reconstruction optimization approaches are described: An approach for the heart-rate-adaptive optimization of the temporal resolution is presented. Streak artifacts at cycle-to-cycle transitions can be minimized by using an improved cardiac weighting scheme. The optimal quiescent cardiac phase for the reconstruction can be determined automatically with the motion map technique. Results for all optimization procedures applied to ECR are presented and discussed based on patient and phantom data. The ECR algorithm is analyzed for larger detector arrays of future cone-beam systems throughout an extensive simulation study based on a four-dimensional cardiac CT phantom. The results of the scientific work are summarized and an outlook proposing future directions is given. The presented thesis is available for public download at www.cardiac-ct.net.

  3. Cardiac arrest

    MedlinePlus

    ... treatment for cardiac arrest. It is a medical device that gives an electrical shock to the heart. The shock can get the heart beating normally again. Small, portable defibrillators are often available in public areas for ...

  4. Cardiac amyloidosis

    MedlinePlus

    ... the way electrical signals move through the heart (conduction system). This can lead to abnormal heart beats ( ... due to medication) Sick sinus syndrome Symptomatic cardiac conduction system disease (arrhythmias related to abnormal conduction of ...

  5. Cardiac rehabilitation

    MedlinePlus

    ... 123-210. Thomas PD. Exercise-Based, Comprehensive Cardiac Rehabilitation. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 9th ed. Philadelphia, PA: Saunders Elsevier; 2011: ...

  6. Cardiac rehabilitation

    MedlinePlus

    ... goal of cardiac rehab is to: Improve your cardiovascular function Improve your overall health and quality of ... E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: Elsevier Saunders; 2015: ...

  7. Cardiac Sarcoidosis

    MedlinePlus

    ... is Cardiac Sarcoidosis? Sarcoidosis is a poorly understood disease that commonly affects the lungs. It can also involve the lymph nodes, liver, spleen, eyes, skin, bones, salivary glands and heart. ...

  8. The sterol regulatory element binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity

    PubMed Central

    Kidani, Yoko; Elsaesser, Heidi; Hock, M Benjamin; Vergnes, Laurent; Williams, Kevin J; Argus, Joseph P; Marbois, Beth N; Komisopoulou, Evangelia; Wilson, Elizabeth B; Osborne, Timothy F; Graeber, Thomas G; Reue, Karen; Brooks, David G; Bensinger, Steven J

    2013-01-01

    Newly activated CD8+ T cells reprogram their metabolism to meet the extraordinary biosynthetic demands of clonal expansion; however, the signals mediating metabolic reprogramming remain poorly defined. Herein, we demonstrate an essential role for sterol regulatory element binding proteins (SREBPs) in the acquisition of effector cell metabolism. Without SREBP signaling, CD8+ T cells are unable to blast, resulting in markedly attenuated clonal expansion during viral infection. Mechanistic studies indicate that SREBPs are essential to meet the heightened lipid requirements of membrane synthesis during blastogenesis. SREBPs are dispensable for homeostatic proliferation, indicating a context-specific requirement for SREBPs in effector responses. These studies provide insights into the molecular signals underlying metabolic reprogramming of CD8+ T cells during the transition from quiescence to activation. PMID:23563690

  9. Exploring the size adaptability of the B ring binding zone of the colchicine site of tubulin with para-nitrogen substituted isocombretastatins.

    PubMed

    Jiménez, Carmen; Ellahioui, Younes; Álvarez, Raquel; Aramburu, Laura; Riesco, Alejandra; González, Myriam; Vicente, Alba; Dahdouh, Abdelaziz; Ibn Mansour, Ahmed; Jiménez, Carlos; Martín, Diego; Sarmiento, Rogelio G; Medarde, Manuel; Caballero, Esther; Peláez, Rafael

    2015-07-15

    We have synthesized and assayed dimethylaminophenyl, pyrrolidin-1-ylphenyl and carbazole containing phenstatins and isocombretastatins as analogues of the highly potent indoleisocombretastatins with extended or reduced ring sizes. This is an attempt to explore beyond the structural constraints of the X-ray crystal structures the zone of the colchicine site where the tropolone ring of colchicine binds to tubulin (zone 1). The isocombretastatins display up to 30 fold increased water solubility when compared with combretastatin A-4, potent inhibition of tubulin polymerization, and nanomolar cytotoxicities against several human cancer cell lines irrespective of the size of the B ring. On the other hand, substitutions ortho to the nitrogen cause an important reduction in potency. We have also shown that representative compounds inhibit autophagy. These results show that zone 1 can adapt to systems of different size as far as they stay in a common plane, but does not tolerate substituents protruding above or below it. These results can help in the understanding of the binding modes of structures with similar systems and in the design of new colchicine site ligands. PMID:26092446

  10. Role of the cardiac nerve in the adaptive changes of heart rate in response to an aversive stimulus in Megalobulimus mogianensis.

    PubMed

    Romero, S M B; Hoffmann, A

    2008-05-01

    The effect of an aversive stimulus represented by contact with a hot plate on the heart rate of Megalobulimus mogianensis was evaluated with electrocardiogram recording in intact snails (N = 8). All stimulated animals showed an increase in heart rate, with mean values ranging from 35.6 +/- 1.2 (basal heart rate) to 43.8 +/- 0.9 bpm (post-stimulation heart rate). The cardioacceleration was followed by gradual recovery of the basal heart rate, with mean recovery times varying from 4.3 +/- 0.3 to 5.8 +/- 0.6 min. Repetition of the stimulus did not affect the magnitude of variation nor did it influence the basal heart rate recovery time. To investigate the role of the cardiac nerve in mediating the heart rate alterations induced by the aversive stimulus, denervated (N = 8) and sham-operated (N = 8) animals were also tested. Although the aversive stimulus caused the heart rate to increase significantly in both experimental groups, the mean increase in heart rate in denervated animals (4.4 +/- 0.4 bpm) was 57% of the value obtained in sham-operated animals (7.7 +/- 1.3 bpm), indicating that the cardiac nerve is responsible for 43% of the cardioacceleration induced by the aversive stimulus. The cardioacceleration observed in denervated snails may be due to an increase in venous return promoted by the intense muscular activity associated with the withdrawal response. Humoral factors may also be involved. A probable delaying inhibitory effect of the cardiac nerve on the recuperation of the basal heart rate is suggested. PMID:18545816

  11. Human Cytomegalovirus variant peptides adapt by decreasing their total coordination upon binding to a T cell receptor

    PubMed Central

    Antipas, Georgios S.E.; Germenis, Anastasios E.

    2015-01-01

    The tertiary structure of the native Cytomegalovirus peptide (NLV) presented by HLA-A2 and bound to the RA14 T cell receptor was used as a reference for the calculation of atomic coordination differences of both the NLV as well as of a number of singly substituted NLV variants in the absence of TCR. Among the pMHC complexes, the native peptide was found to exhibit the highest total coordination difference in respect to the reference structure, suggesting that it experienced the widest structural adaptation upon recognition by the TCR. In addition, the peptide on the isolated NLV-MHC complex was over-coordinated as compared to the rest of the variants. Moreover, the trend was found to account for a set of measured dissociation constants and critical concentrations for target-cell lysis for all variants in complexation with RA14: functionally, all variant peptides were established to be either weak agonists or null peptides, while, at the same time, our current study established that they were also under-coordinated in respect to NLV. It could, thus, be argued that the most ‘efficient’ structural adaptation upon pMHC recognition by the TCR requires of the peptide to undergo the widest under-coordination possible. The main structural characteristic which differentiated the NLV in respect to the variants was a the presence of 16 oxygen atoms (waters) in the former׳s second coordination shell which accounted for over-coordination of roughly 100% and 30% in the O–O and C–O partials respectively. In fact, in the absence of second shell oxygens, the NLV peptide was decidedly under-coordinated in respect to all of the variants, as also suggested by the C–C partial. PMID:26958591

  12. A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus

    PubMed Central

    Willger, Sven D.; Puttikamonkul, Srisombat; Kim, Kwang-Hyung; Burritt, James B.; Grahl, Nora; Metzler, Laurel J.; Barbuch, Robert; Bard, Martin; Lawrence, Christopher B.; Cramer, Robert A.

    2008-01-01

    At the site of microbial infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments in which both the pathogen and host cells must survive. Currently, whether hypoxia adaptation is an important virulence attribute of opportunistic pathogenic molds is unknown. Here we report the characterization of a sterol-regulatory element binding protein, SrbA, in the opportunistic pathogenic mold, Aspergillus fumigatus. Loss of SrbA results in a mutant strain of the fungus that is incapable of growth in a hypoxic environment and consequently incapable of causing disease in two distinct murine models of invasive pulmonary aspergillosis (IPA). Transcriptional profiling revealed 87 genes that are affected by loss of SrbA function. Annotation of these genes implicated SrbA in maintaining sterol biosynthesis and hyphal morphology. Further examination of the SrbA null mutant consequently revealed that SrbA plays a critical role in ergosterol biosynthesis, resistance to the azole class of antifungal drugs, and in maintenance of cell polarity in A. fumigatus. Significantly, the SrbA null mutant was highly susceptible to fluconazole and voriconazole. Thus, these findings present a new function of SREBP proteins in filamentous fungi, and demonstrate for the first time that hypoxia adaptation is likely an important virulence attribute of pathogenic molds. PMID:18989462

  13. Cardiac Sarcoidosis.

    PubMed

    Birnie, David H; Nery, Pablo B; Ha, Andrew C; Beanlands, Rob S B

    2016-07-26

    Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease). In 2014, the first international guideline for the diagnosis and management of CS was published. In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis. There is controversy in published reports as to the outcome of patients with clinically silent CS. Despite a paucity of data, immunosuppression therapy (primarily with corticosteroids) has been advocated for the treatment of clinically manifest CS. Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease. PMID:27443438

  14. Evaluation of a tissue-engineered bovine pericardial patch in paediatric patients with congenital cardiac anomalies: initial experience with the ADAPT-treated CardioCel® patch

    PubMed Central

    Neethling, William M.L.; Strange, Geoff; Firth, Laura; Smit, Francis E.

    2013-01-01

    OBJECTIVES This study evaluated the safety, efficacy and clinical performance of the tissue-engineered ADAPT® bovine pericardial patch (ABPP) in paediatric patients with a range of congenital cardiac anomalies. METHODS In this single-centre, prospective, non-randomized clinical study, paediatric patients underwent surgery for insertion of the ABPP. Primary efficacy measures included early (<30 day) morbidity; incidence of device-related complications; haemodynamic performance derived from echocardiography assessment at 6- and 12-month follow-up and magnetic resonance imaging findings in 10 randomly selected patients at 12 months. Secondary measures included device-handling characteristics; shape and sizing characteristics and perioperative implant complications. The Aristotle complexity scoring system was used to score the complexity level of all surgical procedures. Patients completing the 12-month study were eligible to enter a long-term evaluation study. RESULTS Between April 2008 and September 2009, the ABPP was used in 30 paediatric patients. In the 30-day postoperative period, no graft-related morbidity was observed. In total, there were 5 deaths (2 in the 30-day postoperative period and 3 within the first 6 postoperative months). All deaths were deemed due to comorbid non-graft-related events. Echocardiography assessment at 6 and 12 months revealed intact anatomical and haemodynamically stable repairs without any visible calcification of the patch. Magnetic resonance imaging assessment in 10 patients at 12 months revealed no signs of calcification. Fisher's exact test demonstrated that patients undergoing more complex, higher risk surgical repairs (Aristotle complexity score >8) were significantly more likely to die (P = 0.0055, 58% survival compared with 100% survival for less complex surgical repairs). In 19 patients, echocardiographic data were available at 18–36 months with no evidence of device calcification, infection, thromboembolic events or

  15. Cardiac sarcoidosis

    PubMed Central

    Smedema, J.P.; Zondervan, P.E.; van Hagen, P.; ten Cate, F.J.; Bresser, P.; Doubell, A.F.; Pattynama, P.; Hoogsteden, H.C.; Balk, A.H.M.M.

    2002-01-01

    Sarcoidosis is a multi-system granulomatous disorder of unknown aetiology. Symptomatic cardiac involvement occurs in approximately 5% of patients. The prevalence of sarcoidosis in the Netherlands is unknown, but estimated to be approximately 20 per 100,000 population (3200 patients). We report on five patients who presented with different manifestations of cardiac sarcoidosis, and give a brief review on the current management of this condition. Magnetic Resonance Imaging (MRI) can be of great help in diagnosing this condition as well as in the follow-up of the response to therapy. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6 PMID:25696121

  16. Role of Cardiac Myocytes Heart Fatty Acid Binding Protein Depletion (H-FABP) in Early Myocardial Infarction in Human Heart (Autopsy Study)

    PubMed Central

    Shabaiek, Amany; Ismael, Nour El-Hoda; Elsheikh, Samar; Amin, Hebat Allah

    2016-01-01

    BACKGROUND: Many immunohistochemical markers have been used in the postmortem detection of early myocardial infarction. AIM: In the present study we examined the role of Heart-type fatty acid binding protein (H-FABP), in the detection of early myocardial infarction. MATERIAL AND METHODS: We obtained samples from 40 human autopsy hearts with/without histopathological signs of ischemia. RESULTS: All cases of definite and probable myocardial infarction showed a well-defined area of H-FABP depletion. All of the control cases showed strong H-FABP expression, except two markedly autolysed myocardial samples that showed affected antigenicity. CONCLUSION: Thus, we suggest H-FABP as being one of the valuable tools facing the problem of postmortem detection of early myocardial infarction/ischemia, but not in autolysis.

  17. Mitochondria in cardiac hypertrophy and heart failure

    PubMed Central

    Rosca, Mariana G.; Tandler, Bernard; Hoppel, Charles L.

    2013-01-01

    Heart failure (HF) frequently is the unfavorable outcome of pathological heart hypertrophy. In contrast to physiological cardiac hypertrophy, which occurs in response to exercise and leads to full adaptation of contractility to the increased wall stress, pathological hypertrophy occurs in response to volume or pressure overload, ultimately leading to contractile dysfunction and HF. Because cardiac hypertrophy impairs the relationship between ATP demand and production, mitochondrial bioenergetics must keep up with the cardiac hypertrophic phenotype. We review data regarding the mitochondrial proteomic and energetic remodeling in cardiac hypertrophy, as well as the temporal and causal relationship between mitochondrial failure to match the increased energy demand and progression to cardiac decompensation. We suggest that the maladaptive effect of sustained neuroendocrine signals on mitochondria leads to bioenergetic fading which contributes to the progression from cardiac hypertrophy to failure. PMID:22982369

  18. Bidirectional regulation of the cAMP response element binding protein encodes spatial map alignment in prism-adapting barn owls.

    PubMed

    Nichols, Grant S; DeBello, William M

    2008-10-01

    The barn owl midbrain contains mutually aligned maps of auditory and visual space. Throughout life, map alignment is maintained through the actions of an instructive signal that encodes the magnitude of auditory-visual mismatch. The intracellular signaling pathways activated by this signal are unknown. Here we tested the hypothesis that CREB (cAMP response element-binding protein) provides a cell-specific readout of instructive information. Owls were fitted with prismatic or control spectacles and provided rich auditory-visual experience: hunting live mice. CREB activation was analyzed within 30 min of hunting using phosphorylation state-specific CREB (pCREB) and CREB antibodies, confocal imaging, and immunofluorescence measurements at individual cell nuclei. In control owls or prism-adapted owls, which experience small instructive signals, the frequency distributions of pCREB/CREB values obtained for cell nuclei within the external nucleus of the inferior colliculus (ICX) were unimodal. In contrast, in owls adapting to prisms or readapting to normal conditions, the distributions were bimodal: certain cells had received a signal that positively regulated CREB and, by extension, transcription of CREB-dependent genes, whereas others received a signal that negatively regulated it. These changes were restricted to the subregion of the inferior colliculus that received optically displaced input, the rostral ICX, and were not evident in the caudal ICX or central nucleus. Finally, the topographic pattern of CREB regulation was patchy, not continuous, as expected from the actions of a topographically precise signal encoding discrete events. These results support a model in which the magnitude of CREB activation within individual cells provides a readout of the instructive signal that guides plasticity and learning. PMID:18829948

  19. Rho Kinases and Cardiac Remodeling.

    PubMed

    Shimizu, Toru; Liao, James K

    2016-06-24

    Hypertensive cardiac remodeling is characterized by left ventricular hypertrophy and interstitial fibrosis, which can lead to heart failure with preserved ejection fraction. The Rho-associated coiled-coil containing kinases (ROCKs) are members of the serine/threonine protein kinase family, which mediates the downstream effects of the small GTP-binding protein RhoA. There are 2 isoforms: ROCK1 and ROCK2. They have different functions in different types of cells and tissues. There is growing evidence that ROCKs contribute to the development of cardiovascular diseases, including cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling. Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling. Indeed, clinical studies with fasudil have suggested that ROCKs could be potential novel therapeutic targets for cardiovascular diseases. In this review, we summarize the current understanding of the roles of ROCKs in the development of cardiac fibrosis and hypertrophy and discuss their therapeutic potential for deleterious cardiac remodeling. (Circ J 2016; 80: 1491-1498). PMID:27251065

  20. Physiological and pathological cardiac hypertrophy.

    PubMed

    Shimizu, Ippei; Minamino, Tohru

    2016-08-01

    The heart must continuously pump blood to supply the body with oxygen and nutrients. To maintain the high energy consumption required by this role, the heart is equipped with multiple complex biological systems that allow adaptation to changes of systemic demand. The processes of growth (hypertrophy), angiogenesis, and metabolic plasticity are critically involved in maintenance of cardiac homeostasis. Cardiac hypertrophy is classified as physiological when it is associated with normal cardiac function or as pathological when associated with cardiac dysfunction. Physiological hypertrophy of the heart occurs in response to normal growth of children or during pregnancy, as well as in athletes. In contrast, pathological hypertrophy is induced by factors such as prolonged and abnormal hemodynamic stress, due to hypertension, myocardial infarction etc. Pathological hypertrophy is associated with fibrosis, capillary rarefaction, increased production of pro-inflammatory cytokines, and cellular dysfunction (impairment of signaling, suppression of autophagy, and abnormal cardiomyocyte/non-cardiomyocyte interactions), as well as undesirable epigenetic changes, with these complex responses leading to maladaptive cardiac remodeling and heart failure. This review describes the key molecules and cellular responses involved in physiological/pathological cardiac hypertrophy. PMID:27262674

  1. Symmetry-adapted tight-binding calculations of the totally symmetric A1 phonons of single-walled carbon nanotubes and their resonant Raman intensity

    NASA Astrophysics Data System (ADS)

    Popov, Valentin N.; Lambin, Philippe

    2007-03-01

    The atomistic calculations of the physical properties of perfect single-walled carbon nanotubes based on the use of the translational symmetry of the nanotubes face increasing computational difficulties for most of the presently synthesized nanotubes with up to a few thousand atoms in the unit cell. This difficulty can be circumvented by use of the helical symmetry of the nanotubes and a two-atom unit cell. We present the results of such symmetry-adapted tight-binding calculations of the totally symmetric A1 phonons (the RBM and the G-band modes) and their resonant Raman intensity for several hundred nanotubes. In particular, we show that (1) the frequencies and the resonant Raman intensity of the RBM and the G-band modes show diameter and chirality dependence and family patterns, (2) the strong electron- A1LO phonon interactions in metallic nanotubes lead to Kohn anomalies at the zone center, (3) the G-band consists of a subband due to A1LO phonons of semiconducting tubes centered at ∼1593 cm -1, a subband of A1TO phonons at ∼1570 cm -1, and a subband of A1LO phonons of metallic tubes at ∼1540 cm -1. The latter prediction confirms previous theoretical results but disagrees with the commonly adopted assignment of the G-band features.

  2. Level of urinary liver-type fatty acid-binding protein is associated with cardiac markers and electrocardiographic abnormalities in type-2 diabetes with chronic kidney disease stage G1 and G2.

    PubMed

    Maeda, Yoshiteru; Suzuki, Atsushi; Ishii, Junnichi; Sekiguchi-Ueda, Sahoko; Shibata, Megumi; Yoshino, Yasumasa; Asano, Shogo; Hayakawa, Nobuki; Nakamura, Kazuhiro; Akiyama, Yasukazu; Kitagawa, Fumihiko; Sakuishi, Toshiaki; Fujita, Takashi; Hashimoto, Shuji; Ozaki, Yukio; Itoh, Mitsuyasu

    2015-05-01

    Urinary liver-type fatty acid-binding protein (L-FABP) reflects the degree of stress in proximal tubules of the kidney. We examined the level of L-FABP in type-2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD) stage G1 and G2, and its relationship with cardiac markers and electrocardiographic (ECG) abnormalities. T2DM patients whose estimated glomerular filtration rate (eGFR) was ≥60 mL/min/1.73 m(2) were recruited [n = 276 (165 males), mean age 64 years]. The median level of urinary L-FABP was 6.6 μg/gCr. Urinary L-FABP showed significant correlation with urinary albumin-to-creatinine ratio (ACR) (r = 0.51, p < 0.0001). Median (25th-75th percentile) eGFR was 82 (72-95) mL/min/1.73 m2. We divided patients into four subgroups (group 1, L-FABP ≤8.4 μg/gCr and ACR ≤30 mg/gCr; group 2, L-FABP ≤8.4 μg/gCr and ACR >30 mg/gCr; group 3, L-FABP >8.4 μg/gCr and ACR ≤30 mg/gCr; group 4, L-FABP >8.4 μg/gCr and ACR >30 mg/gCr). Compared with group 1, group 4 was significantly higher in systolic blood pressure, and eGFR using standardized serum cystatin C, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Group 4 had significantly higher level of NT-proBNP than group 3. Groups 2, 3 and 4 showed more ECG abnormalities than group 1. These findings suggest that simultaneous measurement of urinary L-FABP and ACR should be useful to assess cardiovascular damage reflecting on the elevation of cardiac markers and ECG abnormalities in T2DM with CKD G1 and G2. PMID:24626813

  3. Structural Analysis of Semi-specific Oligosaccharide Recognition by a Cellulose-binding Protein of Thermotoga maritima Reveals Adaptations for Functional Diversification of the Oligopeptide Periplasmic Binding Protein Fold

    SciTech Connect

    Cuneo, Matthew J.; Beese, Lorena S.; Hellinga, Homme W.

    2010-05-25

    Periplasmic binding proteins (PBPs) constitute a protein superfamily that binds a wide variety of ligands. In prokaryotes, PBPs function as receptors for ATP-binding cassette or tripartite ATP-independent transporters and chemotaxis systems. In many instances, PBPs bind their cognate ligands with exquisite specificity, distinguishing, for example, between sugar epimers or structurally similar anions. By contrast, oligopeptide-binding proteins bind their ligands through interactions with the peptide backbone but do not distinguish between different side chains. The extremophile Thermotoga maritima possesses a remarkable array of carbohydrate-processing metabolic systems, including the hydrolysis of cellulosic polymers. Here, we present the crystal structure of a T. maritima cellobiose-binding protein (tm0031) that is homologous to oligopeptide-binding proteins. T. maritima cellobiose-binding protein binds a variety of lengths of {beta}(1 {yields} 4)-linked glucose oligomers, ranging from two rings (cellobiose) to five (cellopentaose). The structure reveals that binding is semi-specific. The disaccharide at the nonreducing end binds specifically; the other rings are located in a large solvent-filled groove, where the reducing end makes several contacts with the protein, thereby imposing an upper limit of the oligosaccharides that are recognized. Semi-specific recognition, in which a molecular class rather than individual species is selected, provides an efficient solution for the uptake of complex mixtures.

  4. Cardiac optogenetics

    PubMed Central

    2013-01-01

    Optogenetics is an emerging technology for optical interrogation and control of biological function with high specificity and high spatiotemporal resolution. Mammalian cells and tissues can be sensitized to respond to light by a relatively simple and well-tolerated genetic modification using microbial opsins (light-gated ion channels and pumps). These can achieve fast and specific excitatory or inhibitory response, offering distinct advantages over traditional pharmacological or electrical means of perturbation. Since the first demonstrations of utility in mammalian cells (neurons) in 2005, optogenetics has spurred immense research activity and has inspired numerous applications for dissection of neural circuitry and understanding of brain function in health and disease, applications ranging from in vitro to work in behaving animals. Only recently (since 2010), the field has extended to cardiac applications with less than a dozen publications to date. In consideration of the early phase of work on cardiac optogenetics and the impact of the technique in understanding another excitable tissue, the brain, this review is largely a perspective of possibilities in the heart. It covers the basic principles of operation of light-sensitive ion channels and pumps, the available tools and ongoing efforts in optimizing them, overview of neuroscience use, as well as cardiac-specific questions of implementation and ideas for best use of this emerging technology in the heart. PMID:23457014

  5. Cardiac Surgery

    PubMed Central

    Weisse, Allen B.

    2011-01-01

    Well into the first decades of the 20th century, medical opinion held that any surgical attempts to treat heart disease were not only misguided, but unethical. Despite such reservations, innovative surgeons showed that heart wounds could be successfully repaired. Then, extracardiac procedures were performed to correct patent ductus arteriosus, coarctation of the aorta, and tetralogy of Fallot. Direct surgery on the heart was accomplished with closed commissurotomy for mitral stenosis. The introduction of the heart-lung machine and cardiopulmonary bypass enabled the surgical treatment of other congenital and acquired heart diseases. Advances in aortic surgery paralleled these successes. The development of coronary artery bypass grafting greatly aided the treatment of coronary heart disease. Cardiac transplantation, attempts to use the total artificial heart, and the application of ventricular assist devices have brought us to the present day. Although progress in the field of cardiovascular surgery appears to have slowed when compared with the halcyon times of the past, substantial challenges still face cardiac surgeons. It can only be hoped that sufficient resources and incentive can carry the triumphs of the 20th century into the 21st. This review covers past developments and future opportunities in cardiac surgery. PMID:22163121

  6. Modification of Loop 1 Affects the Nucleotide-Binding Properties of Myo1c, The Adaptation Motor in the Inner Ear†

    PubMed Central

    Adamek, Nancy; Lieto-Trivedi, Alena; Geeves, Michael A.; Coluccio, Lynne M.

    2010-01-01

    Myo1c is one of eight members of the mammalian myosin I family of actin-associated molecular motors. In stereocilia of the hair cells in the inner ear, Myo1c presumably serves as the adaptation motor, which regulates the opening and closing of transduction channels. Although there is conservation of sequence and structure among all myosins in the N-terminal motor domain, which contains the nucleotide- and actin-binding sites, some differences include the length and composition of surface loops, including loop 1, which lies near the nucleotide-binding domain. To investigate the role of loop 1, we expressed in insect cells mutants of a truncated form of Myo1c, Myo1c1IQ, as well as chimeras of Myo1c1IQ with the analogous loop from other myosins. We found that replacement of the charged residues in loop 1 with alanines or the whole loop with a series of alanines did not alter the ATPase activity, transient kinetics properties and Ca2+-sensitivity of Myo1c1IQ. Substitution of loop 1 with that of the corresponding region from tonic smooth muscle myosin II (Myo1c1IQ-tonic) or replacement with a single glycine (Myo1c1IQ-G) accelerated ADP release from A.M 2-3-fold in Ca2+, whereas substitution with loop 1 from phasic muscle myosin II (Myo1c1IQ-phasic) accelerated ADP release 35-fold. Motility assays with chimeras containing a single α-helix, or SAH, domain showed that Myo1cSAH-tonic translocated actin in vitro twice as fast as Myo1cSAH-WT and 3-fold faster than Myo1cSAH-G. The studies show that changes induced in Myo1c by modifying loop 1 showed no resemblance to the behaviour of the loop donor myosins or to the changes previously observed with similar Myo1b chimeras. PMID:20039646

  7. An evaluation of Admedus' tissue engineering process-treated (ADAPT) bovine pericardium patch (CardioCel) for the repair of cardiac and vascular defects.

    PubMed

    Strange, Geoff; Brizard, Christian; Karl, Tom R; Neethling, Leon

    2015-03-01

    Tissue engineers have been seeking the 'Holy Grail' solution to calcification and cytotoxicity of implanted tissue for decades. Tissues with all of the desired qualities for surgical repair of congenital heart disease (CHD) are lacking. An anti-calcification tissue engineering process (ADAPT TEP) has been developed and applied to bovine pericardium (BP) tissue (CardioCel, AdmedusRegen Pty Ltd, Perth, WA, Australia) to eliminate cytotoxicity, improve resistance to acute and chronic inflammation, reduce calcification and facilitate controlled tissue remodeling. Clinical data in pediatric patients, and additional pre-market authorized prescriber data demonstrate that CardioCel performs extremely well in the short term and is safe and effective for a range of congenital heart deformations. These data are supported by animal studies which have shown no more than normal physiologic levels of calcification, with good durability, biocompatibility and controlled healing. PMID:25431988

  8. [Principle of the activity-controlled rate-adaptive cardiac pacemaker: analysis of stress and environment-induced mechanical effects on the human body].

    PubMed

    Alt, E; Matula, M; Theres, H; Heinz, M

    1989-09-01

    Rate-adaptive pacemakers are increasingly becoming part of clinical routine, the most widespread systems being activity-controlled. In order to shed more light on the foundations of mechanical forces which can possibly be utilized for controlling rate-adaptive systems, we conducted tests on six healthy volunteers and six pacemaker patients. With the aid of three orthogonal wide-band linear acceleration pick-ups attached to the body, the mechanical signals were recorded from the three axes during different activities. Along with standardized exercise on bicycle and treadmill ergometers, we tested the influence of household activities and interference influences. The results were analyzed in terms of the amplitude and frequency content of the signals. For walking activities we found a signal amplitude increasing in largely linear fashion with the walking speed, the signal amplitudes being approximately twice as high on the vertical axis as on the other two axes. Exercise on the bicycle ergometer produced mechanical signals of clearly lower amplitude than comparable walking activities. The Fast-Fourier analysis showed amplitude peaks in the low frequency range of 1 to 4 Hz for all forms of physiological exercise, while interference influences showed amplitude peaks mainly in the range above 8 Hz. The use of an acceleration pickup and a corresponding low pass filter might be a way of reducing the effect of nonphysiological interference influences on an activity-controlled pacemaker system. A sensor measuring in the horizontal axis appears to be the most favorable compromise for the various types of exercise. However, due to the considerable difference in signal amplitude for different types of exercise of the same intensity, an activity-controlled pacemaker system cannot entirely meet metabolic conditions and requirements. PMID:2815913

  9. Comparison of a qualitative measurement of heart-type fatty acid-binding protein with other cardiac markers as an early diagnostic marker in the diagnosis of non-ST - segment elevation myocardial infarction

    PubMed Central

    Gerede, Demet Menekşe; Güleç, Sadi; Kılıçkap, Mustafa; Kaya, Cansın Tulunay; Vurgun, Veysel Kutay; Özcan, Özgür Ulaş; Göksülük, Hüseyin; Erol, Çetin

    2015-01-01

    Summary Objective: Heart-type fatty acid-binding protein (H-FABP) is a novel cardiac marker used in the early diagnosis of acute myocardial infarction (AMI), which shows myocyte injury. Our study aimed to compare bedside H-FABP measurements with routine creatine kinase-MB (CK-MB) and troponin I (TnI) tests for the early diagnosis of non-ST-elevation MI (NSTEMI), as well as for determining its exclusion capacity. Methods A total of 48 patients admitted to the emergency room within the first 12 hours of onset of ischaemic-type chest pain lasting more than 30 minutes and who did not have ST-segment elevation on electrocardiography (ECG) were included in the study. Definite diagnoses of NSTEMI were made in 24 patients as a result of 24-hour follow up, and the remaining 24 patients did not develop MI. Results When various subgroups were analysed according to admission times, H-FABP was found to be a better diagnostic marker compared to CK-MB and TnI (accuracy index 85%), with a high sensitivity (79%) and specificity (93%) for early diagnosis (≤ six hours). The respective sensitivities of bedside H-FABP and TnI tests were 89 vs 33% (p < 0.05) for patients presenting within three hours of onset of symptoms. Conclusion Bedside H-FABP measurements may contribute to correct early diagnoses, as its levels are elevated soon following MI, and measurement is easy, with a rapid result. PMID:26212703

  10. Popeye domain containing proteins and stress-mediated modulation of cardiac pacemaking

    PubMed Central

    Simrick, Subreena; Schindler, Roland; Poon, Kar-Lai; Brand, Thomas

    2016-01-01

    An intricate network of ion channels and pumps are involved in generating a diastolic pacemaker potential, which is transmitted to the working myocardium with the help of the cardiac conduction system. The principles of cardiac pacemaking are reasonably well understood, however, the mechanism by which the heart increases its beating frequency in response to adrenergic stimulation has not been fully worked out. The Popeye domain containing (Popdc) genes encode plasma membrane-localized proteins that are able to bind cAMP with high affinity and mice with null mutations in Popdc1 or -2 have a stress-induced pacemaker dysfunction. The phenotype in both mutants develops in an age-dependent manner and thus may model pacemaker dysfunction in man, as well as providing novel mechanistic insights into the process of pacemaker adaptation to stress. PMID:23562093

  11. Point Mutations in Human β Cardiac Myosin Heavy Chain Have Differential Effects on Sarcomeric Structure and Assembly: An ATP Binding Site Change Disrupts Both Thick and Thin Filaments, Whereas Hypertrophic Cardiomyopathy Mutations Display Normal Assembly

    PubMed Central

    Becker, K. David; Gottshall, Kim R.; Hickey, Reed; Perriard, Jean-Claude; Chien, Kenneth R.

    1997-01-01

    Hypertrophic cardiomyopathy is a human heart disease characterized by increased ventricular mass, focal areas of fibrosis, myocyte, and myofibrillar disorganization. This genetically dominant disease can be caused by mutations in any one of several contractile proteins, including β cardiac myosin heavy chain (βMHC). To determine whether point mutations in human βMHC have direct effects on interfering with filament assembly and sarcomeric structure, full-length wild-type and mutant human βMHC cDNAs were cloned and expressed in primary cultures of neonatal rat ventricular cardiomyocytes (NRC) under conditions that promote myofibrillogenesis. A lysine to arginine change at amino acid 184 in the consensus ATP binding sequence of human βMHC resulted in abnormal subcellular localization and disrupted both thick and thin filament structure in transfected NRC. Diffuse βMHC K184R protein appeared to colocalize with actin throughout the myocyte, suggesting a tight interaction of these two proteins. Human βMHC with S472V mutation assembled normally into thick filaments and did not affect sarcomeric structure. Two mutant myosins previously described as causing human hypertrophic cardiomyopathy, R249Q and R403Q, were competent to assemble into thick filaments producing myofibrils with well defined I bands, A bands, and H zones. Coexpression and detection of wild-type βMHC and either R249Q or R403Q proteins in the same myocyte showed these proteins are equally able to assemble into the sarcomere and provided no discernible differences in subcellular localization. Thus, human βMHC R249Q and R403Q mutant proteins were readily incorporated into NRC sarcomeres and did not disrupt myofilament formation. This study indicates that the phenotype of myofibrillar disarray seen in HCM patients which harbor either of these two mutations may not be directly due to the failure of the mutant myosin heavy chain protein to assemble and form normal sarcomeres, but may rather be a

  12. Identification of Avian Corticosteroid-binding Globulin (SerpinA6) Reveals the Molecular Basis of Evolutionary Adaptations in SerpinA6 Structure and Function as a Steroid-binding Protein.

    PubMed

    Vashchenko, Ganna; Das, Samir; Moon, Kyung-Mee; Rogalski, Jason C; Taves, Matthew D; Soma, Kiran K; Van Petegem, Filip; Foster, Leonard J; Hammond, Geoffrey L

    2016-05-20

    Corticosteroid-binding globulin (CBG) was isolated from chicken serum and identified by mass spectrometry and genomic analysis. This revealed that the organization and synteny of avian and mammalian SerpinA6 genes are conserved. Recombinant zebra finch CBG steroid-binding properties reflect those of the natural protein in plasma and confirm its identity. Zebra finch and rat CBG crystal structures in complex with cortisol resemble each other, but their primary structures share only ∼40% identity, and their steroid-binding site topographies differ in several unexpected ways. Remarkably, a tryptophan that anchors ligands in mammalian CBG steroid-binding sites is replaced by an asparagine. Phylogenetic comparisons show that reptilian CBG orthologs share this unexpected property. Glycosylation of this asparagine in zebra finch CBG does not influence its steroid-binding affinity, but we present evidence that it may participate in protein folding and steroid-binding site formation. Substitutions of amino acids within zebra finch CBG that are conserved only in birds reveal how they contribute to their distinct steroid-binding properties, including their high (nanomolar) affinities for glucocorticoids, progesterone, and androgens. As in mammals, a protease secreted by Pseudomonas aeruginosa cleaves CBG in zebra finch plasma within its reactive center loop and disrupts steroid binding, suggesting an evolutionarily conserved property of CBGs. Measurements of CBG mRNA in zebra finch tissues indicate that liver is the main site of plasma CBG production, and anti-zebra finch CBG antibodies cross-react with CBGs in other birds, extending opportunities to study how CBG regulates the actions of glucocorticoids and sex steroids in these species. PMID:27026706

  13. Imaging of cardiac sarcoidosis.

    PubMed

    Erthal, Fernanda; Juneau, Daniel; Lim, Siok P; Dwivedi, Girish; Nery, Pablo B; Birnie, David; Beanlands, Rob S

    2016-09-01

    Sarcoidosis is a multisystem inflammatory disease. Cardiac involvement is described in up to 50% of the cases. The disease spectrum is wide and cardiac manifestations ranges from being asymptomatic to heart failure, arrhythmias and sudden cardiac death. The diagnosis of cardiac sarcoidosis can be challenging due to its non-specific nature and the focal involvement of the heart. In this review, we discuss the utility of a stepwise approach with multimodality cardiac imaging in the diagnosis and management of CS. PMID:27225318

  14. Adaptation of the myoglobin knockout mouse to hypoxic stress.

    PubMed

    Schlieper, Georg; Kim, Jie-Hoon; Molojavyi, Andrei; Jacoby, Christoph; Laussmann, Tim; Flögel, Ulrich; Gödecke, Axel; Schrader, Jürgen

    2004-04-01

    Myoglobin knockout (myo-/-) mice were previously reported to show no obvious phenotype but revealed several compensatory mechanisms that include increases in cardiac capillary density, coronary flow, and hemoglobin. The aim of this study was to investigate whether severe hypoxic stress can exhaust these compensatory mechanisms and whether this can be monitored on the gene and protein level. Myo-/- and wild-type (WT) mice we e exposed to hypoxia (10% O(2)) fo 2 wk. Thereafter hemodynamic parameters were investigated by invasive measurement combined with magnetic resonance imaging. Cardiac gene and protein expression were analyzed using cDNA arrays and two-dimensional gel electrophoresis plus mass spectrometry, respectively. Hematocrit levels increased from 44% (WT) and 48% (myo-/-) to 72% in both groups. Similar to WT controls, hypoxic myo-/- animals maintained stable cardiovascular function (mean arterial blood pressure 82.4 mmHg, ejection fraction 72.5%). Cardiac gene expression of hypoxic myo-/- mice differed significantly from WT controls in 17 genes (e.g., keratinocyte lipid binding protein +202%, cytochrome c oxidase Vb +41%). Interestingly, hypoxia inducible factor-1alpha remained unchanged in both groups. Proteome analysis revealed reduced levels of heart fatty acid-binding protein and heat shock protein 27 both in hypoxic myo-/- and WT mice. Our data thus demonstrate that myo-/- mice do not decompensate du ing hypoxic st ess but a e surprisingly well adapted. Changes in ene gy metabolism of fatty acids may contribute to the robustness of myoglobin-deficient mice. PMID:14656764

  15. Streak artifact reduction in cardiac cone beam CT

    NASA Astrophysics Data System (ADS)

    Shechter, Gilad; Naveh, Galit; Lessick, Jonathan; Altman, Ami

    2005-04-01

    Cone beam reconstructed cardiac CT images suffer from characteristic streak artifacts that affect the quality of coronary artery imaging. These artifacts arise from inhomogeneous distribution of noise. While in non-tagged reconstruction inhomogeneity of noise distribution is mainly due to anisotropy of the attenuation of the scanned object (e.g. shoulders), in cardiac imaging it is largely influenced by the non-uniform distribution of the acquired data used for reconstructing the heart at a given phase. We use a cardiac adaptive filter to reduce these streaks. In difference to previous methods of adaptive filtering that locally smooth data points on the basis of their attenuation values, our filter is applied as a function of the noise distribution of the data as it is used in the phase selective reconstruction. We have reconstructed trans-axial images without adaptive filtering, with a regular adaptive filter and with the cardiac adaptive filter. With the cardiac adaptive filter significant reduction of streaks is achieved, and thus image quality is improved. The coronary vessel is much more pronounced in the cardiac adaptive filtered images, in slab MIP the main coronary artery branches are more visible, and non-calcified plaque is better differentiated from vessel wall. This improvement is accomplished without altering significantly the border definition of calcified plaques.

  16. The Periplasmic Bacterial Molecular Chaperone SurA Adapts Its Structure to Bind Peptides in Different Conformations to Assert a Sequence Preference for Aromatic Residues

    SciTech Connect

    Xu, X.; Wang, S.; Hu, Y.-X.; McKay, D.B.

    2009-06-04

    The periplasmic molecular chaperone protein SurA facilitates correct folding and maturation of outer membrane proteins in Gram-negative bacteria. It preferentially binds peptides that have a high fraction of aromatic amino acids. Phage display selections, isothermal titration calorimetry and crystallographic structure determination have been used to elucidate the basis of the binding specificity. The peptide recognition is imparted by the first peptidyl-prolyl isomerase (PPIase) domain of SurA. Crystal structures of complexes between peptides of sequence WEYIPNV and NFTLKFWDIFRK with the first PPIase domain of the Escherichia coli SurA protein at 1.3 A resolution, and of a complex between the dodecapeptide and a SurA fragment lacking the second PPIase domain at 3.4 A resolution, have been solved. SurA binds as a monomer to the heptapeptide in an extended conformation. It binds as a dimer to the dodecapeptide in an alpha-helical conformation, predicated on a substantial structural rearrangement of the SurA protein. In both cases, side-chains of aromatic residues of the peptides contribute a large fraction of the binding interactions. SurA therefore asserts a recognition preference for aromatic amino acids in a variety of sequence configurations by adopting alternative tertiary and quaternary structures to bind peptides in different conformations.

  17. Epigenetic mechanisms in cardiac development and disease.

    PubMed

    Vallaster, Marcus; Vallaster, Caroline Dacwag; Wu, Sean M

    2012-01-01

    During mammalian development, cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific transcription factors (TFs) and their meticulous control on an epigenetic level. In this review, we detail how cardiac-specific TFs function in concert with nucleosome remodeling and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation, or epithelial to mesenchymal transition (EMT), for instance. We provide examples of how several cardiac TFs, such as Nkx2.5, WHSC1, Tbx5, and Tbx1, which are associated with developmental and congenital heart defects, are required for the recruitment of histone modifiers, such as Jarid2, p300, and Ash2l, and components of ATP-dependent remodeling enzymes like Brg1, Baf60c, and Baf180. Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks, indicating that the precise regulation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers. Furthermore, we speculate that an epigenetic signature, comprised of TF occupancy, histone modifications, and overall chromatin organization, is an underlying mechanism that governs cardiac morphogenesis and disease. PMID:22194017

  18. Effects of the Q223R mutation in the hemagglutinin (HA) of egg-adapted pandemic 2009 (H1N1) influenza A virus on virus growth and binding of HA to human- and avian-type cell receptors.

    PubMed

    Suptawiwat, O; Jeamtua, W; Boonarkart, Ch; Kongchanagul, A; Puthawathana, P; Auewarakul, P

    2013-01-01

    The 2009 swine-origin influenza A virus (H1N1) and its initial reassortant vaccine strains did not grow well in embryonated eggs. The glutamine to arginine mutation at the amino acid position 223 (Q223R) of the hemagglutinin (HA) gene is the major mutation previously found in egg-adapted 2009 H1N1 strains and shown to enhance viral growth in embryonated eggs. However, the effect of this mutation on the receptor-binding preference had not been directly demonstrated. In this study, the Q223R mutation was shown to change the viral HA binding preference from the human-type receptor, α2,6-linked sialic acid, to the avian-type receptor, α2,3-linked sialic acid; and to enhance the viral growth in embryonated eggs but not in cell culture. PMID:24020758

  19. Cardiac perception and cardiac control. A review.

    PubMed

    Carroll, D

    1977-12-01

    The evidence regarding specific cardiac perception and discrimination, and its relationship to voluntary cardiac control, is critically reviewed. Studies are considered in three sections, depending on the method used to assess cardiac perception: questionnaire assessment, discrimination procedures, and heartbeat tracking. The heartbeat tracking procedure would appear to suffer least from interpretative difficulties. Recommendations are made regarding the style of analysis used to assess heartbeat perception in such tracking tasks. PMID:348240

  20. Lack of myoglobin causes a switch in cardiac substrate selection.

    PubMed

    Flögel, Ulrich; Laussmann, Tim; Gödecke, Axel; Abanador, Nadine; Schäfers, Michael; Fingas, Christian Dominik; Metzger, Sabine; Levkau, Bodo; Jacoby, Christoph; Schrader, Jürgen

    2005-04-29

    Myoglobin is an important intracellular O2 binding hemoprotein in heart and skeletal muscle. Surprisingly, disruption of myoglobin in mice (myo-/-) resulted in no obvious phenotype and normal cardiac function was suggested to be mediated by structural alterations that tend to steepen the oxygen pressure gradient from capillary to mitochondria. Here we report that lack of myoglobin causes a biochemical shift in cardiac substrate utilization from fatty acid to glucose oxidation. Proteome and gene expression analysis uncovered key enzymes of mitochondrial beta-oxidation as well as the nuclear receptor PPAR to be downregulated in myoglobin-deficient hearts. Using FDG-PET we showed a substantially increased in vivo cardiac uptake of glucose in myo-/- mice (6.7+/-2.3 versus 0.8+/-0.5% of injected dose in wild-type, n=5, P<0.001), which was associated with an upregulation of the glucose transporter GLUT4. The metabolic switch was confirmed by 13C NMR spetroscopic isotopomer studies of isolated hearts which revealed that [1,6-13C2]glucose utilization was increased in myo-/- hearts (38+/-8% versus 22+/-5% in wild-type, n=6, P<0.05), and concomitantly, [U-13C16]palmitate utilization was decreased in the myoglobin-deficient group (42+/-6% versus 63+/-11% in wild-type, n=6, P<0.05). Because of the O2-sparing effect of glucose utilization, the observed shift in substrate metabolism benefits energy homoeostasis and therefore represents a molecular adaptation process allowing to compensate for lack of the cytosolic oxygen carrier myoglobin. Furthermore, our data suggest that an altered myoglobin level itself may be a critical determinant for substrate selection in the heart. The full text of this article is available online at http://circres.ahajournals.org. PMID:15817884

  1. Cardiac conduction system

    MedlinePlus Videos and Cool Tools

    ... cardiac muscle cells in the walls of the heart that send signals to the heart muscle causing it to contract. The main components ... the cardiac conduction system’s electrical activity in the heart.

  2. What Is Cardiac Rehabilitation?

    MedlinePlus

    ANSWERS by heart Treatments + Tests What Is Cardiac Rehabilitation? A cardiac rehabilitation (rehab) program takes place in a hospital or ... special help in making lifestyle changes. During your rehabilitation program you’ll… • Have a medical evaluation to ...

  3. Sudden Cardiac Arrest

    MedlinePlus

    ... from American Heart Association Aneurysms and Dissections Angina Arrhythmia Bundle Branch Block Cardiomyopathy Carotid Artery Disease Chronic ... terms: SCA, sudden cardiac death (SCD), sudden death, arrhythmias, ... ventricular fibrillation, defibrillator, automatic cardiac defibrillator ( ...

  4. Molecular Modeling of Cardiac Troponin

    NASA Astrophysics Data System (ADS)

    Manning, Edward P.

    The cardiac thin filament regulates interactions of actin and myosin, the force-generating elements of muscular contraction. Over the past several decades many details have been discovered regarding the structure and function of the cardiac thin filament and its components, including cardiac troponin (cTn). My hypothesis is that signal propagation occurs between distant ends of the cardiac troponin complex through calcium-dependent alterations in the dynamics of cTn and tropomyosin (Tm). I propose a model of the thin filament that encompasses known structures of cTn, Tm and actin to gain insight into cardiac troponin's allosteric regulation of thin filament dynamics. By performing molecular dynamics simulations of cTn in conjunction with overlapping Tm in two conditions, with and without calcium bound to site II of cardiac troponin C (cTnC), I found a combination of calcium-dependent changes in secondary structure and dynamics throughout the cTn-Tm complex. I then applied this model to investigate familial hypertrophic cardiomyopathy (FHC), a disease of the sarcomere that is one of the most commonly occurring genetic causes of heart disease. Approximately 15% of known FHC-related mutations are found in cardiac troponin T (cTnT), most of which are in or flank the alpha-helical N-tail domain TNT1. TNT1 directly interacts with overlapping Tm coiled coils. Using this model I identified effects of TNT1 mutations that propagate to the cTn core where site II of cTnC, the regulatory site of calcium binding in the thin filament, is located. Specifically, I found that mutations in TNT1 alter the flexibility of TNT1 and that the flexibility of TNT1 is inversely proportional to the cooperativity of calcium activation of the thin filament. Further, I identified a pathway of propagation of structural and dynamic changes linking TNT1 to site II of cTnC. Mutation-induced changes at site II cTnC alter calcium coordination which corresponds to biophysical measurements of calcium

  5. The adapter protein CD2AP binds to p53 protein in the cytoplasm and can discriminate its polymorphic variants P72R.

    PubMed

    Panni, Simona; Salvioli, Stefano; Santonico, Elena; Langone, Francesca; Storino, Francesca; Altilia, Serena; Franceschi, Claudio; Cesareni, Gianni; Castagnoli, Luisa

    2015-02-01

    Proline-rich motifs are widely distributed in eukaryotic proteomes and are usually involved in the assembly of functional complexes through interaction with specific binding modules. The tumour-suppressor p53 protein presents a proline-rich region that is crucial for regulating apoptosis by connecting the p53 with a complex protein network. In humans, a common polymorphism determines the identity of residue 72, either proline or arginine, and affects the features of the motifs present in the polyproline domain. The two isoforms have different biochemical properties and markedly influence cancer onset and progression. In this article, we analyse the binding of the p53 proline-rich region with a pool of selected polyproline binding domains (i.e. SH3 and WW), and we present the first demonstration that the purified SH3 domains of the CD2AP/Cin85 protein family are able to directly bind the p53 protein, and to discriminate between the two polymorphic variants P72R. PMID:25261582

  6. Cardiac Biomarkers: a Focus on Cardiac Regeneration

    PubMed Central

    Forough, Reza; Scarcello, Catherine; Perkins, Matthew

    2011-01-01

    Historically, biomarkers have been used in two major ways to maintain and improve better health status: first, for diagnostic purposes, and second, as specific targets to treat various diseases. A new era in treatment and even cure for the some diseases using reprograming of somatic cells is about to be born. In this approach, scientists are successfully taking human skin cells (previously considered terminally-differentiated cells) and re-programming them into functional cardiac myocytes and other cell types in vitro. A cell reprograming approach for treatment of cardiovascular diseases will revolutionize the field of medicine and significantly expand the human lifetime. Availability of a comprehensive catalogue for cardiac biomarkers is necessary for developing cell reprograming modalities to treat cardiac diseases, as well as for determining the progress of reprogrammed cells as they become cardiac cells. In this review, we present a comprehensive survey of the cardiac biomarkers currently known. PMID:23074366

  7. Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Drosophila Heart Structure and Impairs Function

    PubMed Central

    Viswanathan, Meera C.; Blice-Baum, Anna C.; Sang, Tzu-Kang; Cammarato, Anthony

    2016-01-01

    Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP's role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology. PMID:27500162

  8. Cardiac gated ventilation

    SciTech Connect

    Hanson, C.W. III; Hoffman, E.A.

    1995-12-31

    There are several theoretic advantages to synchronizing positive pressure breaths with the cardiac cycle, including the potential for improving distribution of pulmonary and myocardial blood flow and enhancing cardiac output. The authors evaluated the effects of synchronizing respiration to the cardiac cycle using a programmable ventilator and electron beam CT (EBCT) scanning. The hearts of anesthetized dogs were imaged during cardiac gated respiration with a 50 msec scan aperture. Multi slice, short axis, dynamic image data sets spanning the apex to base of the left ventricle were evaluated to determine the volume of the left ventricular chamber at end-diastole and end-systole during apnea, systolic and diastolic cardiac gating. The authors observed an increase in cardiac output of up to 30% with inspiration gated to the systolic phase of the cardiac cycle in a non-failing model of the heart.

  9. Cardiac gated ventilation

    NASA Astrophysics Data System (ADS)

    Hanson, C. William, III; Hoffman, Eric A.

    1995-05-01

    There are several theoretic advantages to synchronizing positive pressure breaths with the cardiac cycle, including the potential for improving distribution of pulmonary and myocardial blood flow and enhancing cardiac output. We evaluated the effects of synchronizing respiration to the cardiac cycle using a programmable ventilator and electron beam CT (EBCT) scanning. The hearts of anesthetized dogs were imaged during cardiac gated respiration with a 50msec scan aperture. Multislice, short axis, dynamic image data sets spanning the apex to base of the left ventricle were evaluated to determine the volume of the left ventricular chamber at end-diastole and end-systole during apnea, systolic and diastolic cardiac gating. We observed an increase in cardiac output of up to 30% with inspiration gated to the systolic phase of the cardiac cycle in a nonfailing model of the heart.

  10. Integrin activation and focal complex formation in cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Laser, M.; Willey, C. D.; Jiang, W.; Cooper, G. 4th; Menick, D. R.; Zile, M. R.; Kuppuswamy, D.

    2000-01-01

    Cardiac hypertrophy is characterized by both remodeling of the extracellular matrix (ECM) and hypertrophic growth of the cardiocytes. Here we show increased expression and cytoskeletal association of the ECM proteins fibronectin and vitronectin in pressure-overloaded feline myocardium. These changes are accompanied by cytoskeletal binding and phosphorylation of focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, c-Src at Tyr-416, recruitment of the adapter proteins p130(Cas), Shc, and Nck, and activation of the extracellular-regulated kinases ERK1/2. A synthetic peptide containing the Arg-Gly-Asp (RGD) motif of fibronectin and vitronectin was used to stimulate adult feline cardiomyocytes cultured on laminin or within a type-I collagen matrix. Whereas cardiocytes under both conditions showed RGD-stimulated ERK1/2 activation, only collagen-embedded cells exhibited cytoskeletal assembly of FAK, c-Src, Nck, and Shc. In RGD-stimulated collagen-embedded cells, FAK was phosphorylated only at Tyr-397 and c-Src association occurred without Tyr-416 phosphorylation and p130(Cas) association. Therefore, c-Src activation is not required for its cytoskeletal binding but may be important for additional phosphorylation of FAK. Overall, our study suggests that multiple signaling pathways originate in pressure-overloaded heart following integrin engagement with ECM proteins, including focal complex formation and ERK1/2 activation, and many of these pathways can be activated in cardiomyocytes via RGD-stimulated integrin activation.

  11. Stimulating endogenous cardiac repair

    PubMed Central

    Finan, Amanda; Richard, Sylvain

    2015-01-01

    The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players. PMID:26484341

  12. Molecule specific effects of PKA-mediated phosphorylation on rat isolated heart and cardiac myofibrillar function.

    PubMed

    Hanft, Laurin M; Cornell, Timothy D; McDonald, Colin A; Rovetto, Michael J; Emter, Craig A; McDonald, Kerry S

    2016-07-01

    Increased cardiac myocyte contractility by the β-adrenergic system is an important mechanism to elevate cardiac output to meet hemodynamic demands and this process is depressed in failing hearts. While increased contractility involves augmented myoplasmic calcium transients, the myofilaments also adapt to boost the transduction of the calcium signal. Accordingly, ventricular contractility was found to be tightly correlated with PKA-mediated phosphorylation of two myofibrillar proteins, cardiac myosin binding protein-C (cMyBP-C) and cardiac troponin I (cTnI), implicating these two proteins as important transducers of hemodynamics to the cardiac sarcomere. Consistent with this, we have previously found that phosphorylation of myofilament proteins by PKA (a downstream signaling molecule of the beta-adrenergic system) increased force, slowed force development rates, sped loaded shortening, and increased power output in rat skinned cardiac myocyte preparations. Here, we sought to define molecule-specific mechanisms by which PKA-mediated phosphorylation regulates these contractile properties. Regarding cTnI, the incorporation of thin filaments with unphosphorylated cTnI decreased isometric force production and these changes were reversed by PKA-mediated phosphorylation in skinned cardiac myocytes. Further, incorporation of unphosphorylated cTnI sped rates of force development, which suggests less cooperative thin filament activation and reduced recruitment of non-cycling cross-bridges into the pool of cycling cross-bridges, a process that would tend to depress both myocyte force and power. Regarding MyBP-C, PKA treatment of slow-twitch skeletal muscle fibers caused phosphorylation of MyBP-C (but not slow skeletal TnI (ssTnI)) and yielded faster loaded shortening velocity and ∼30% increase in power output. These results add novel insight into the molecular specificity by which the β-adrenergic system regulates myofibrillar contractility and how attenuation of PKA

  13. Negative Feedback Regulation of the Yeast Cth1 and Cth2 mRNA Binding Proteins Is Required for Adaptation to Iron Deficiency and Iron Supplementation

    PubMed Central

    Martínez-Pastor, Mar; Vergara, Sandra V.

    2013-01-01

    Iron (Fe) is an essential element for all eukaryotic organisms because it functions as a cofactor in a wide range of biochemical processes. Cells have developed sophisticated mechanisms to tightly control Fe utilization in response to alterations in cellular demands and bioavailability. In response to Fe deficiency, the yeast Saccharomyces cerevisiae activates transcription of the CTH1 and CTH2 genes, which encode proteins that bind to AU-rich elements (AREs) within the 3′ untranslated regions (3′UTRs) of many mRNAs, leading to metabolic reprogramming of Fe-dependent pathways and decreased Fe storage. The precise mechanisms underlying Cth1 and Cth2 function and regulation are incompletely understood. We report here that the Cth1 and Cth2 proteins specifically bind in vivo to AREs located at the 3′UTRs of their own transcripts in an auto- and cross-regulated mechanism that limits their expression. By mutagenesis of the AREs within the CTH2 transcript, we demonstrate that a Cth2 negative-feedback loop is required for the efficient decline in Cth2 protein levels observed upon a rapid rise in Fe availability. Importantly, Cth2 autoregulation is critical for the appropriate recovery of Fe-dependent processes and resumption of growth in response to a change from Fe deficiency to Fe supplementation. PMID:23530061

  14. Cardiac Innervation and Sudden Cardiac Death

    PubMed Central

    Fukuda, Keiichi; Kanazawa, Hideaki; Aizawa, Yoshiyasu; Ardell, Jeffrey L.; Shivkumar, Kalyanam

    2015-01-01

    Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem and higher centers) which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes-hours) and long term (days-years). This important neurovisceral /autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death (SCD). Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extra-cardiac neural remodeling have also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provides a rational mechanistic basis for development of neuraxial therapies for preventing SCD and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention. PMID:26044253

  15. Protein Binding Pocket Dynamics.

    PubMed

    Stank, Antonia; Kokh, Daria B; Fuller, Jonathan C; Wade, Rebecca C

    2016-05-17

    The dynamics of protein binding pockets are crucial for their interaction specificity. Structural flexibility allows proteins to adapt to their individual molecular binding partners and facilitates the binding process. This implies the necessity to consider protein internal motion in determining and predicting binding properties and in designing new binders. Although accounting for protein dynamics presents a challenge for computational approaches, it expands the structural and physicochemical space for compound design and thus offers the prospect of improved binding specificity and selectivity. A cavity on the surface or in the interior of a protein that possesses suitable properties for binding a ligand is usually referred to as a binding pocket. The set of amino acid residues around a binding pocket determines its physicochemical characteristics and, together with its shape and location in a protein, defines its functionality. Residues outside the binding site can also have a long-range effect on the properties of the binding pocket. Cavities with similar functionalities are often conserved across protein families. For example, enzyme active sites are usually concave surfaces that present amino acid residues in a suitable configuration for binding low molecular weight compounds. Macromolecular binding pockets, on the other hand, are located on the protein surface and are often shallower. The mobility of proteins allows the opening, closing, and adaptation of binding pockets to regulate binding processes and specific protein functionalities. For example, channels and tunnels can exist permanently or transiently to transport compounds to and from a binding site. The influence of protein flexibility on binding pockets can vary from small changes to an already existent pocket to the formation of a completely new pocket. Here, we review recent developments in computational methods to detect and define binding pockets and to study pocket dynamics. We introduce five

  16. Marketing cardiac CT programs.

    PubMed

    Scott, Jason

    2010-01-01

    There are two components of cardiac CT discussed in this article: coronary artery calcium scoring (CACS) and coronary computed tomography angiography (CCTA).The distinctive advantages of each CT examination are outlined. In order to ensure a successful cardiac CT program, it is imperative that imaging facilities market their cardiac CT practices effectively in order to gain a competitive advantage in this valuable market share. If patients receive quality care by competent individuals, they are more likely to recommend the facility's cardiac CT program. Satisfied patients will also be more willing to come back for any further testing. PMID:22276376

  17. Ankyrin-based Cellular Pathways for Cardiac Ion Channel and Transporter Targeting and Regulation

    PubMed Central

    Cunha, Shane R.; Mohler, Peter J.

    2010-01-01

    The coordinate activities of ion channels and transporters regulate myocyte membrane excitability and normal cardiac function. Dysfunction in cardiac ion channel and transporter function may result in cardiac arrhythmias and sudden cardiac death. While the past fifteen years have linked defects in ion channel biophysical properties with human disease, more recent findings illustrate that ion channel and transporter localization within cardiomyocytes is equally critical for normal membrane excitability and tissue function. Ankyrins are a family of multifunctional adapter proteins required for the expression, membrane localization, and regulation of select cardiac ion channels and transporters. Notably, loss of ankyrin expression in mice, and ankyrin loss-of-function in humans is now associated with defects in myocyte excitability and cardiac physiology. Here, we provide an overview of the roles of ankyrin polypeptides in cardiac physiology, as well as review other recently identified pathways required for the membrane expression and regulation of key cardiac ion channels and transporters. PMID:20934528

  18. Mechanotransduction in Cardiac Hypertrophy and Failure

    PubMed Central

    Omens, Jeffrey H.; Sheikh, Farah

    2015-01-01

    Cardiac muscle cells have an intrinsic ability to sense and respond to mechanical load through a process known as mechanotransduction. In the heart, this process involves the conversion of mechanical stimuli into biochemical events that induce changes in myocardial structure and function. Mechanotransduction and its downstream effects function initially as adaptive responses that serve as compensatory mechanisms during adaptation to the initial load. However, under prolonged and abnormal loading conditions, the remodeling processes can become maladaptive, leading to altered physiological function and the development of pathological cardiac hypertrophy and heart failure. Although the mechanisms underlying mechanotransduction are far from being fully elucidated, human and mouse genetic studies have highlighted various cytoskeletal and sarcolemmal structures in cardiac myocytes as the likely candidates for load transducers, based on their link to signaling molecules and architectural components important in disease pathogenesis. In this review, we summarize recent developments that have uncovered specific protein complexes linked to mechanotransduction and mechanotransmission within (1) the sarcomere, (2) the intercalated disc, and (3) at the sarcolemma. The protein structures acting as mechanotransducers are the first step in the process that drives physiological and pathological cardiac hypertrophy and remodeling, as well as the transition to heart failure, and may provide better insights into mechanisms driving mechanotransduction-based diseases. PMID:25858069

  19. Blunt cardiac rupture.

    PubMed

    Martin, T D; Flynn, T C; Rowlands, B J; Ward, R E; Fischer, R P

    1984-04-01

    Blunt injury to the heart ranges from contusion to disruption. This report comprises 14 patients seen during a 6-year period with cardiac rupture secondary to blunt trauma. Eight patients were injured in automobile accidents, two patients were injured in auto-pedestrian accidents, two were kicked in the chest by ungulates, and two sustained falls. Cardiac tamponade was suspected in ten patients. Five patients presented with prehospital cardiac arrest or arrested shortly after arrival. All underwent emergency department thoracotomy without survival. Two patients expired in the operating room during attempted cardiac repair; both had significant extracardiac injury. Seven patients survived, three had right atrial injuries, three had right ventricular injuries, and one had a left atrial injury. Cardiopulmonary bypass was not required for repair of the surviving patients. There were no significant complications from the cardiac repair. The history of significant force dispersed over a relatively small area of the precordium as in a kicking injury from an animal or steering wheel impact should alert the physician to possible cardiac rupture. Cardiac rupture should be considered in patients who present with signs of cardiac tamponade or persistent thoracic bleeding after blunt trauma. PMID:6708151

  20. Sudden Cardiac Death

    PubMed Central

    Weinberg, Marc

    1978-01-01

    Over the past decade, there has been a significant decrease in the hospital mortality of patients with coronary artery disease. However, sudden cardiac death, which accounts for the majority of deaths from coronary artery disease, hasbeen little affected. This report reviews the pathology, electrophysiology, demographics and clinical presentation of sudden cardiac death. Emergency care and possible preventative measures are examined. PMID:356435

  1. Cardiac pacing and aviation.

    PubMed

    Toff, W D; Edhag, O K; Camm, A J

    1992-12-01

    Certain applicants with stable disturbances of rhythm or conduction requiring cardiac pacing, in whom no other disqualifying condition is present, may be considered fit for medical certification restricted to multi-crew operations. The reliability of modern pacing systems appears adequate to permit restricted certification even in pacemaker dependent subjects except for certain models of pacemakers and leads known to be at increased risk of failure. These are to be avoided. There is little evidence to suggest that newer devices are any more reliable than their predecessors. Single and dual chamber systems appear to have similar reliability up to 4 years, after which time significant attrition of dual chamber devices occurs, principally due to battery depletion. All devices require increased scrutiny as they approach their end of life as predicted from longevity data and pacing characteristics. Unipolar and bipolar leads are of similar reliability, apart from a number of specific bipolar polyurethane leads which have been identified. Atrial leads, particularly those without active fixation, are less secure than ventricular leads and applicants who are dependent on atrial sensing or pacing should be denied certification. Bipolar leads are to be preferred due to the lower risk of myopotential and exogenous EMI. Sensor-driven adaptive-rate pacing systems using active sensors may have reduced longevity and require close scrutiny. Activity-sensing devices using piezoelectric crystal sensors may be subject to significant rate rises in rotary wing aircraft. The impracticality of restricted certification in helicopters will, in any event, preclude certification. Such devices would best be avoided in hovercraft (air cushioned vehicle) pilots. Only minor rate rises are likely in fixed-wing aircraft which are unlikely to be of significance. Anti-tachycardia devices and implanted defibrillators are inconsistent with any form of certification to fly. PMID:1493823

  2. Cardiac Hegemony of Senescence.

    PubMed

    Siddiqi, Sailay; Sussman, Mark A

    2013-12-01

    Cardiac senescence and age-related disease development have gained general attention and recognition in the past decades due to increased accessibility and quality of health care. The advancement in global civilization is complementary to concerns regarding population aging and development of chronic degenerative diseases. Cardiac degeneration has been rigorously studied. The molecular mechanisms of cardiac senescence are on multiple cellular levels and hold a multilayer complexity level, thereby hampering development of unambiguous treatment protocols. In particular, the synergistic exchange of the senescence phenotype through a senescence secretome between myocytes and stem cells appears complicated and is of great future therapeutic value. The current review article will highlight hallmarks of senescence, cardiac myocyte and stem cell senescence, and the mutual exchange of senescent secretome. Future cardiac cell therapy approaches require a comprehensive understanding of myocardial senescence to improve therapeutic efficiency as well as efficacy. PMID:24349878

  3. Cardiac Hegemony of Senescence

    PubMed Central

    Siddiqi, Sailay; Sussman, Mark A.

    2013-01-01

    Cardiac senescence and age-related disease development have gained general attention and recognition in the past decades due to increased accessibility and quality of health care. The advancement in global civilization is complementary to concerns regarding population aging and development of chronic degenerative diseases. Cardiac degeneration has been rigorously studied. The molecular mechanisms of cardiac senescence are on multiple cellular levels and hold a multilayer complexity level, thereby hampering development of unambiguous treatment protocols. In particular, the synergistic exchange of the senescence phenotype through a senescence secretome between myocytes and stem cells appears complicated and is of great future therapeutic value. The current review article will highlight hallmarks of senescence, cardiac myocyte and stem cell senescence, and the mutual exchange of senescent secretome. Future cardiac cell therapy approaches require a comprehensive understanding of myocardial senescence to improve therapeutic efficiency as well as efficacy. PMID:24349878

  4. Anti-rat soluble IL-6 receptor antibody down-regulates cardiac IL-6 and improves cardiac function following trauma-hemorrhage.

    PubMed

    Yang, Shaolong; Hu, Shunhua; Choudhry, Mashkoor A; Rue, Loring W; Bland, Kirby I; Chaudry, Irshad H

    2007-03-01

    Although anti-IL-6-mAb down-regulates cardiac IL-6 and attenuates IL-6-mediated cardiac dysfunction following trauma-hemorrhage, it is not known whether blockade of IL-6 receptor will down-regulate cardiac IL-6 and improve cardiac function under those conditions. Six groups of male adult rats (275-325 g) were used: sham/trauma-hemorrhage+vehicle, sham/trauma-hemorrhage+IgG, sham/trauma-hemorrhage+anti-rat sIL-6R. Rats underwent trauma-hemorrhage (removal of 60% of the circulating blood volume and fluid resuscitation after 90 min). Vehicle (V), normal goat IgG or anti-rat sIL-6R (16.7 microg/kg BW) was administered intra-peritoneally in the middle of resuscitation. Two hours later, cardiac function was measured by ICG dilution technique; blood samples collected, cardiomyocytes isolated, and cardiomyocyte nuclei were then extracted. Cardiac IL-6, IL-6R, gp130, IkappaB-alpha/P-IkappaB-alpha, NF-kappaB, and ICAM-1 expressions were measured by immunoblotting. Plasma IL-6 and cardiomyocyte NF-kappaB DNA-binding activity were determined by ELISA. In additional animals, heart harvested and cardiac MPO activity and CINC-1 and -3 were also measured. In another group of rats, cardiac function was measure by microspheres at 24 h following trauma-hemorrhage. Cardiac function was depressed and cardiac IL-6, P-IkappaB-alpha, NF-kappaB and its DNA-binding activity, ICAM-1, MPO activity, and CINC-1 and -3 were markedly increased after trauma-hemorrhage. Moreover, cardiac dysfunction was evident even 24 h after trauma-hemorrhage. Administration of sIL-6R following trauma-hemorrhage: (1) improved cardiac output at 2 h and 24 h (p<0.05); (2) down-regulated both cardiac IL-6 and IL-6R (p<0.05); and (3) attenuated cardiac P-IkappaB-alpha, NF-kappaB, NF-kappaB DNA-binding activity, ICAM-1, CINC-1, -3, and MPO activity (p<0.05). IgG did not significantly influence the above parameters. Thus, IL-6-mediated up-regulation of cardiac NF-kappaB, ICAM-1, CINC-1, -3, and MPO activity likely

  5. [Cardiac evaluation before non-cardiac surgery].

    PubMed

    Menzenbach, Jan; Boehm, Olaf

    2016-07-01

    Before non-cardiac surgery, evaluation of cardiac function is no frequent part of surgical treatment. European societies of anesthesiology and cardiology published consensus-guidelines in 2014 to present a reasonable approach for preoperative evaluation. This paper intends to differentiate the composite of perioperative risk and to display the guidelines methodical approach to handle it. Features to identify patients at risk from an ageing population with comorbidities, are the classification of surgical risk, functional capacity and risk indices. Application of diagnostic means, should be used adjusted to this risk estimation. Cardiac biomarkers are useful to discover risk of complications or mortality, that cannot be assessed by clinical signs. After preoperative optimization and perioperative cardiac protection, the observation of the postoperative period remains, to prohibit complications or even death. In consideration of limited resources of intensive care department, postoperative ward rounds beyond intensive care units are considered to be an appropriate instrument to avoid or recognize complications early to reduce postoperative mortality. PMID:27479258

  6. Naturally occurring cardiac glycosides.

    PubMed

    Radford, D J; Gillies, A D; Hinds, J A; Duffy, P

    1986-05-12

    Cardiac glycoside poisoning from the ingestion of plants, particularly of oleanders, occurs with reasonable frequency in tropical and subtropical areas. We have assessed a variety of plant specimens for their cardiac glycoside content by means of radioimmunoassays with antibodies that differ in their specificity for cardiac glycosides. Significant amounts of immunoreactive cardiac glycoside were found to be present in the ornamental shrubs: yellow oleander (Thevetia peruviana); oleander (Nerium oleander); wintersweet (Carissa spectabilis); bushman's poison (Carissa acokanthera); sea-mango (Cerbera manghas); and frangipani (Plumeria rubra); and in the milkweeds: redheaded cotton-bush (Asclepias curassavica); balloon cotton (Asclepias fruiticosa); king's crown (Calotropis procera); and rubber vine (Cryptostegia grandifolia). The venom gland of the cane toad (Bufo marinus) also contained large quantities of cardiac glycosides. The competitive immunoassay method permits the rapid screening of specimens that are suspected to contain cardiac glycosides. Awareness of the existence of these plant and animal toxins and their dangers allows them to be avoided and poisoning prevented. The method is also useful for the confirmation of the presence of cardiac glycosides in serum in cases of poisoning. PMID:3086679

  7. Mutation at positively selected positions in the binding site for HLA-C shows that KIR2DL1 is a more refined but less adaptable NK cell receptor than KIR2DL3.

    PubMed

    Hilton, Hugo G; Vago, Luca; Older Aguilar, Anastazia M; Moesta, Achim K; Graef, Thorsten; Abi-Rached, Laurent; Norman, Paul J; Guethlein, Lisbeth A; Fleischhauer, Katharina; Parham, Peter

    2012-08-01

    Through recognition of HLA class I, killer cell Ig-like receptors (KIR) modulate NK cell functions in human immunity and reproduction. Although a minority of HLA-A and -B allotypes are KIR ligands, HLA-C allotypes dominate this regulation, because they all carry either the C1 epitope recognized by KIR2DL2/3 or the C2 epitope recognized by KIR2DL1. The C1 epitope and C1-specific KIR evolved first, followed several million years later by the C2 epitope and C2-specific KIR. Strong, varying selection pressure on NK cell functions drove the diversification and divergence of hominid KIR, with six positions in the HLA class I binding site of KIR being targets for positive diversifying selection. Introducing each naturally occurring residue at these positions into KIR2DL1 and KIR2DL3 produced 38 point mutants that were tested for binding to 95 HLA- A, -B, and -C allotypes. Modulating specificity for HLA-C is position 44, whereas positions 71 and 131 control cross-reactivity with HLA-A*11:02. Dominating avidity modulation is position 70, with lesser contributions from positions 68 and 182. KIR2DL3 has lower avidity and broader specificity than KIR2DL1. Mutation could increase the avidity and change the specificity of KIR2DL3, whereas KIR2DL1 specificity was resistant to mutation, and its avidity could only be lowered. The contrasting inflexibility of KIR2DL1 and adaptability of KIR2DL3 fit with C2-specific KIR having evolved from C1-specific KIR, and not vice versa. Substitutions restricted to activating KIR all reduced the avidity of KIR2DL1 and KIR2DL3, further evidence that activating KIR function often becomes subject to selective attenuation. PMID:22772445

  8. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.

    PubMed

    Martínez-Martínez, Ernesto; Calvier, Laurent; Fernández-Celis, Amaya; Rousseau, Elodie; Jurado-López, Raquel; Rossoni, Luciana V; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; Cachofeiro, Victoria; López-Andrés, Natalia

    2015-10-01

    Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension. PMID:26238446

  9. Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo

    PubMed Central

    van Berlo, Jop H.; Elrod, John W.; Aronow, Bruce J.; Pu, William T.; Molkentin, Jeffery D.

    2011-01-01

    Cardiac hypertrophy is an adaptive growth process that occurs in response to stress stimulation or injury wherein multiple signal transduction pathways are induced, culminating in transcription factor activation and the reprogramming of gene expression. GATA4 is a critical transcription factor in the heart that is known to induce/regulate the hypertrophic program, in part, by receiving signals from MAPKs. Here we generated knock-in mice in which a known MAPK phosphorylation site at serine 105 (S105) in Gata4 that augments activity was mutated to alanine. Homozygous Gata4-S105A mutant mice were viable as adults, although they showed a compromised stress response of the myocardium. For example, cardiac hypertrophy in response to phenylephrine agonist infusion for 2 wk was largely blunted in Gata4-S105A mice, as was the hypertrophic response to pressure overload at 1 and 2 wk of applied stimulation. Gata4-S105A mice were also more susceptible to heart failure and cardiac dilation after 2 wk of pressure overload. With respect to the upstream pathway, hearts from Gata4-S105A mice did not efficiently hypertrophy following direct ERK1/2 activation using an activated MEK1 transgene in vivo. Mechanistically, GATA4 mutant protein from these hearts failed to show enhanced DNA binding in response to hypertrophic stimulation. Moreover, hearts from Gata4-S105A mice had significant changes in the expression of hypertrophy-inducible, fetal, and remodeling-related genes. PMID:21746915

  10. Adaptation of the modified Bouc–Wen model to compensate for hysteresis in respiratory motion for the list-mode binning of cardiac SPECT and PET acquisitions: Testing using MRI

    PubMed Central

    Dasari, Paul K. R.; Shazeeb, Mohammed Salman; Könik, Arda; Lindsay, Clifford; Mukherjee, Joyeeta M.; Johnson, Karen L.; King, Michael A.

    2014-01-01

    Purpose: Binning list-mode acquisitions as a function of a surrogate signal related to respiration has been employed to reduce the impact of respiratory motion on image quality in cardiac emission tomography (SPECT and PET). Inherent in amplitude binning is the assumption that there is a monotonic relationship between the amplitude of the surrogate signal and respiratory motion of the heart. This assumption is not valid in the presence of hysteresis when heart motion exhibits a different relationship with the surrogate during inspiration and expiration. The purpose of this study was to investigate the novel approach of using the Bouc–Wen (BW) model to provide a signal accounting for hysteresis when binning list-mode data with the goal of thereby improving motion correction. The study is based on the authors’ previous observations that hysteresis between chest and abdomen markers was indicative of hysteresis between abdomen markers and the internal motion of the heart. Methods: In 19 healthy volunteers, they determined the internal motion of the heart and diaphragm in the superior–inferior direction during free breathing using MRI navigators. A visual tracking system (vts) synchronized with MRI acquisition tracked the anterior–posterior motions of external markers placed on the chest and abdomen. These data were employed to develop and test the Bouc–Wen model by inputting the vts derived chest and abdomen motions into it and using the resulting output signals as surrogates for cardiac motion. The data of the volunteers were divided into training and testing sets. The training set was used to obtain initial values for the model parameters for all of the volunteers in the set, and for set members based on whether they were or were not classified as exhibiting hysteresis using a metric derived from the markers. These initial parameters were then employed with the testing set to estimate output signals. Pearson’s linear correlation coefficient between the

  11. Adaptation of the modified Bouc–Wen model to compensate for hysteresis in respiratory motion for the list-mode binning of cardiac SPECT and PET acquisitions: Testing using MRI

    SciTech Connect

    Dasari, Paul K. R.; Shazeeb, Mohammed Salman; Könik, Arda; Lindsay, Clifford; Mukherjee, Joyeeta M.; Johnson, Karen L.; King, Michael A.

    2014-11-01

    Purpose: Binning list-mode acquisitions as a function of a surrogate signal related to respiration has been employed to reduce the impact of respiratory motion on image quality in cardiac emission tomography (SPECT and PET). Inherent in amplitude binning is the assumption that there is a monotonic relationship between the amplitude of the surrogate signal and respiratory motion of the heart. This assumption is not valid in the presence of hysteresis when heart motion exhibits a different relationship with the surrogate during inspiration and expiration. The purpose of this study was to investigate the novel approach of using the Bouc–Wen (BW) model to provide a signal accounting for hysteresis when binning list-mode data with the goal of thereby improving motion correction. The study is based on the authors’ previous observations that hysteresis between chest and abdomen markers was indicative of hysteresis between abdomen markers and the internal motion of the heart. Methods: In 19 healthy volunteers, they determined the internal motion of the heart and diaphragm in the superior–inferior direction during free breathing using MRI navigators. A visual tracking system (VTS) synchronized with MRI acquisition tracked the anterior–posterior motions of external markers placed on the chest and abdomen. These data were employed to develop and test the Bouc–Wen model by inputting the VTS derived chest and abdomen motions into it and using the resulting output signals as surrogates for cardiac motion. The data of the volunteers were divided into training and testing sets. The training set was used to obtain initial values for the model parameters for all of the volunteers in the set, and for set members based on whether they were or were not classified as exhibiting hysteresis using a metric derived from the markers. These initial parameters were then employed with the testing set to estimate output signals. Pearson’s linear correlation coefficient between the

  12. Ubiquitous health monitoring and real-time cardiac arrhythmias detection: a case study.

    PubMed

    Li, Jian; Zhou, Haiying; Zuo, Decheng; Hou, Kun-Mean; De Vaulx, Christophe

    2014-01-01

    As the symptoms and signs of heart diseases that cause sudden cardiac death, cardiac arrhythmia has attracted great attention. Due to limitations in time and space, traditional approaches to cardiac arrhythmias detection fail to provide a real-time continuous monitoring and testing service applicable in different environmental conditions. Integrated with the latest technologies in ECG (electrocardiograph) analysis and medical care, the pervasive computing technology makes possible the ubiquitous cardiac care services, and thus brings about new technical challenges, especially in the formation of cardiac care architecture and realization of the real-time automatic ECG detection algorithm dedicated to care devices. In this paper, a ubiquitous cardiac care prototype system is presented with its architecture framework well elaborated. This prototype system has been tested and evaluated in all the clinical-/home-/outdoor-care modes with a satisfactory performance in providing real-time continuous cardiac arrhythmias monitoring service unlimitedly adaptable in time and space. PMID:24211993

  13. Cardiac conduction system

    MedlinePlus Videos and Cool Tools

    ... signals to the heart muscle causing it to contract. The main components of the cardiac conduction system ... the sequence by causing the atrial muscles to contract. From there, the signal travels to the AV ...

  14. Cardiac sarcoidosis - silent destroyer.

    PubMed

    Martusewicz-Boros, Magdalena M; Piotrowska-Kownacka, Dorota; Wiatr, Elżbieta; Roszkowski-Śliż, Kazimierz

    2016-01-01

    We report a case of histologically proven pulmonary sarcoidosis and cardiac involvement in a 53-year old woman with progression leading to the heart failure documented in cardiovascular magnetic resonsnce studies. PMID:27537722

  15. Cardiac glycoside overdose

    MedlinePlus

    ... found in the leaves of the digitalis (foxglove) plant. This plant is the original source of this medicine. People ... Digitoxin (Crystodigin) Digoxin (Lanoxicaps, Lanoxin) Besides the foxglove plant, cardiac glycosides also occur naturally in plants such ...

  16. Ranolazine in Cardiac Arrhythmia.

    PubMed

    Saad, Marwan; Mahmoud, Ahmed; Elgendy, Islam Y; Richard Conti, C

    2016-03-01

    Ranolazine utilization in the management of refractory angina has been established by multiple randomized clinical studies. However, there is growing evidence showing an evolving role in the field of cardiac arrhythmias. Multiple experimental and clinical studies have evaluated the role of ranolazine in prevention and management of atrial fibrillation, with ongoing studies on its role in ventricular arrhythmias. In this review, we will discuss the pharmacological, experimental, and clinical evidence behind ranolazine use in the management of various cardiac arrhythmias. PMID:26459200

  17. Cardiac rehabilitation in Germany.

    PubMed

    Karoff, Marthin; Held, Klaus; Bjarnason-Wehrens, Birna

    2007-02-01

    The purpose of this review is to give an overview of the rehabilitation measures provided for cardiac patients in Germany and to outline its legal basis and outcomes. In Germany the cardiac rehabilitation system is different from rehabilitation measures in other European countries. Cardiac rehabilitation in Germany since 1885 is based on specific laws and the regulations of insurance providers. Cardiac rehabilitation has predominantly been offered as an inpatient service, but has recently been complemented by outpatient services. A general agreement on the different indications for offering these two services has yet to be reached. Cardiac rehabilitation is mainly offered after an acute cardiac event and bypass surgery. It is also indicated in severe heart failure and special cases of percutaneous coronary intervention. Most patients are men (>65%) and the age at which events occur is increasing. The benefits obtained during the 3-4 weeks after an acute event, and confirmed in numerous studies, are often later lost under 'usual care' conditions. Many attempts have been made by rehabilitation institutions to improve this deficit by providing intensive aftercare. One instrument set up to achieve this is the nationwide institution currently comprising more than 6000 heart groups with approximately 120000 outpatients. After coronary artery bypass grafting or acute coronary syndrome cardiac rehabilitation can usually be started within 10 days. The multidisciplinary rehabilitation team consists of cardiologists, psychologists, exercise therapists, social workers, nutritionists and nurses. The positive effects of cardiac rehabilitation are also important economically, for example, for the improvement of secondary prevention and vocational integration. PMID:17301623

  18. Cardiac Munchausen's syndrome.

    PubMed Central

    Dickinson, E J; Evans, T R

    1987-01-01

    Ten years' experience of cardiac Munchausen's syndrome in the Cardiac Care Unit of an Inner London teaching hospital is reported. Thirty-six admissions in this category were identified and analysed, and 4 typical cases are described. The common presenting complaints, recurring features and the relationship with other forms of Munchausen's syndrome are discussed, as are possible strategies available to deal with this clinical entity. PMID:3694601

  19. Cardiac imaging in adults

    SciTech Connect

    Jaffe, C.C.

    1987-01-01

    This book approaches adult cardiac disease from the correlative imaging perspective. It includes chest X-rays and angiographs, 2-dimensional echocardiograms with explanatory diagrams for clarity, plus details on digital radiology, nuclear medicine techniques, CT and MRI. It also covers the normal heart, valvular heart disease, myocardial disease, pericardial disease, bacterial endocarditis, aortic aneurysm, cardiac tumors, and congenital heart disease of the adult. It points out those aspects where one imaging technique has significant superiority.

  20. Cardiac Applications of Optogenetics

    PubMed Central

    Ambrosi, Christina M.; Klimas, Aleksandra; Yu, Jinzhu; Entcheva, Emilia

    2014-01-01

    In complex multicellular systems, such as the brain or the heart, the ability to selectively perturb and observe the response of individual components at the cellular level and with millisecond resolution in time, is essential for mechanistic understanding of function. Optogenetics uses genetic encoding of light sensitivity (by the expression of microbial opsins) to provide such capabilities for manipulation, recording, and control by light with cell specificity and high spatiotemporal resolution. As an optical approach, it is inherently scalable for remote and parallel interrogation of biological function at the tissue level; with implantable miniaturized devices, the technique is uniquely suitable for in vivo tracking of function, as illustrated by numerous applications in the brain. Its expansion into the cardiac area has been slow. Here, using examples from published research and original data, we focus on optogenetics applications to cardiac electrophysiology, specifically dealing with the ability to manipulate membrane voltage by light with implications for cardiac pacing, cardioversion, cell communication, and arrhythmia research, in general. We discuss gene and cell delivery methods of inscribing light sensitivity in cardiac tissue, functionality of the light-sensitive ion channels within different types of cardiac cells, utility in probing electrical coupling between different cell types, approaches and design solutions to all-optical electrophysiology by the combination of optogenetic sensors and actuators, and specific challenges in moving towards in vivo cardiac optogenetics. PMID:25035999

  1. Cardiac LXRα protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization

    PubMed Central

    Cannon, Megan V; Silljé, Herman HW; Sijbesma, Jürgen WA; Vreeswijk-Baudoin, Inge; Ciapaite, Jolita; van der Sluis, Bart; van Deursen, Jan; Silva, Gustavo JJ; de Windt, Leon J; Gustafsson, Jan-Åke; van der Harst, Pim; van Gilst, Wiek H; de Boer, Rudolf A

    2015-01-01

    Pathological cardiac hypertrophy is characterized by a shift in metabolic substrate utilization from fatty acids to glucose, but the molecular events underlying the metabolic remodeling remain poorly understood. Here, we investigated the role of liver X receptors (LXRs), which are key regulators of glucose and lipid metabolism, in cardiac hypertrophic pathogenesis. Using a transgenic approach in mice, we show that overexpression of LXRα acts to protect the heart against hypertrophy, fibrosis, and dysfunction. Gene expression profiling studies revealed that genes regulating metabolic pathways were differentially expressed in hearts with elevated LXRα. Functionally, LXRα overexpression in isolated cardiomyocytes and murine hearts markedly enhanced the capacity for myocardial glucose uptake following hypertrophic stress. Conversely, this adaptive response was diminished in LXRα-deficient mice. Transcriptional changes induced by LXRα overexpression promoted energy-independent utilization of glucose via the hexosamine biosynthesis pathway, resulting in O-GlcNAc modification of GATA4 and Mef2c and the induction of cytoprotective natriuretic peptide expression. Our results identify LXRα as a key cardiac transcriptional regulator that helps orchestrate an adaptive metabolic response to chronic cardiac stress, and suggest that modulating LXRα may provide a unique opportunity for intervening in myocyte metabolism. PMID:26160456

  2. Direct Cardiac Reprogramming: Advances in Cardiac Regeneration

    PubMed Central

    Chen, Olivia; Qian, Li

    2015-01-01

    Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate both in vitro and in vivo. Several experiments show functional improvements in mouse models of myocardial infarction following in situ generation of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming. PMID:26176012

  3. Patient-Specific Models of Cardiac Biomechanics.

    PubMed

    Krishnamurthy, Adarsh; Villongco, Christopher T; Chuang, Joyce; Frank, Lawrence R; Nigam, Vishal; Belezzuoli, Ernest; Stark, Paul; Krummen, David E; Narayan, Sanjiv; Omens, Jeffrey H; McCulloch, Andrew D; Kerckhoffs, Roy Cp

    2013-07-01

    Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures. PMID:23729839

  4. Patient-specific models of cardiac biomechanics

    NASA Astrophysics Data System (ADS)

    Krishnamurthy, Adarsh; Villongco, Christopher T.; Chuang, Joyce; Frank, Lawrence R.; Nigam, Vishal; Belezzuoli, Ernest; Stark, Paul; Krummen, David E.; Narayan, Sanjiv; Omens, Jeffrey H.; McCulloch, Andrew D.; Kerckhoffs, Roy C. P.

    2013-07-01

    Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures.

  5. HERG1 Channel Agonists and Cardiac Arrhythmia

    PubMed Central

    Sanguinetti, Michael

    2014-01-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  6. HERG1 channel agonists and cardiac arrhythmia.

    PubMed

    Sanguinetti, Michael C

    2014-04-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  7. Perspectives on the value of biomarkers in acute cardiac care and implications for strategic management.

    PubMed

    Kossaify, Antoine; Garcia, Annie; Succar, Sami; Ibrahim, Antoine; Moussallem, Nicolas; Kossaify, Mikhael; Grollier, Gilles

    2013-01-01

    Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management. PMID:24046510

  8. Cardiac applications of PET.

    PubMed

    Sarikaya, Ismet

    2015-10-01

    Routine use of cardiac positron emission tomography (PET) applications has been increasing but has not replaced cardiac single-photon emission computerized tomography (SPECT) studies yet. The majority of cardiac PET tracers, with the exception of fluorine-18 fluorodeoxyglucose (18F-FDG), are not widely available, as they require either an onsite cyclotron or a costly generator for their production. 18F-FDG PET imaging has high sensitivity for the detection of hibernating/viable myocardium and has replaced Tl-201 SPECT imaging in centers equipped with a PET/CT camera. PET myocardial perfusion imaging with various tracers such as Rb-82, N-13 ammonia, and O-15 H2O has higher sensitivity and specificity than myocardial perfusion SPECT for the detection of coronary artery disease (CAD). In particular, quantitative PET measurements of myocardial perfusion help identify subclinical coronary stenosis, better define the extent and severity of CAD, and detect ischemia when there is balanced reduction in myocardial perfusion due to three-vessel or main stem CAD. Fusion images of PET perfusion and CT coronary artery calcium scoring or CT coronary angiography provide additional complementary information and improve the detection of CAD. PET studies with novel 18F-labeled perfusion tracers such as 18F-flurpiridaz and 18F-FBnTP have yielded high sensitivity and specificity in the diagnosis of CAD. These tracers are still being tested in humans, and, if approved for clinical use, they will be commercially and widely available. In addition to viability studies, 18F-FDG PET can also be utilized to detect inflammation/infection in various conditions such as endocarditis, sarcoidosis, and atherosclerosis. Some recent series have obtained encouraging results for the detection of endocarditis in patients with intracardiac devices and prosthetic valves. PET tracers for cardiac neuronal imaging, such as C-11 HED, help assess the severity of heart failure and post-transplant cardiac

  9. Cardiac involvement in hemochromatosis.

    PubMed

    Gulati, Vinay; Harikrishnan, Prakash; Palaniswamy, Chandrasekar; Aronow, Wilbert S; Jain, Diwakar; Frishman, William H

    2014-01-01

    Cardiac hemochromatosis or primary iron-overload cardiomyopathy is an important and potentially preventable cause of heart failure. This is initially characterized by diastolic dysfunction and arrhythmias and in later stages by dilated cardiomyopathy. Diagnosis of iron overload is established by elevated transferrin saturation (>55%) and elevated serum ferritin (>300 ng/mL). Genetic testing for mutations in the HFE (high iron) gene and other proteins, such as hemojuvelin, transferrin receptor, and ferroportin, should be performed if secondary causes of iron overload are ruled out. Patients should undergo comprehensive 2D and Doppler echocardiography to evaluate their systolic and diastolic function. Newer modalities like strain imaging and speckle-tracking echocardiography hold promise for earlier detection of cardiac involvement. Cardiac magnetic resonance imaging with measurement of T2* relaxation times can help quantify myocardial iron overload. In addition to its value in diagnosis of cardiac iron overload, response to iron reduction therapy can be assessed by serial imaging. Therapeutic phlebotomy and iron chelation are the cornerstones of therapy. The average survival is less than a year in untreated patients with severe cardiac impairment. However, if treated early and aggressively, the survival rate approaches that of the regular heart failure population. PMID:24503941

  10. Practical Considerations In Digital Cardiac Angiography

    NASA Astrophysics Data System (ADS)

    Neeley, J. P.; Vannier, M. W.; Gutierrez, F. R.; Von Behren, P. L.

    1983-05-01

    Digital fluoroscopic image acquisition, processing and storage for ventriculography, coronary artery and bypass graft imaging involves many practical considerations. Issues of sufficiency in terms of spatial, temporal, gray scale resolution and intravascular contrast sensitivity arise when 35mm cineradiographic film acquisition is replaced by digital fluoroscopy as the primary imaging modality. We have qualitatively and quantitatively evaluated and compared digital fluoroscopic and cineradiographic systems for cardiovascular image acquisition, storage and display in the cardiac catheterization laboratory. A digital fluoroscopic system (Siemens Digitron I) was evaluated and compared favorably to 35mm cineradiography in temporal resolution. Spatial resolution of the digital system was poorer, but contrast sensitivity (with digital subtraction) far exceeded the capabilities of cineradiography. As further modifications are made to adapt digital systems to the cardiac catheterization laboratory, complete replacement of 35mm cineradiography by digital vascular imaging systems is likely in the near future.

  11. Interplay between cardiac function and heart development.

    PubMed

    Andrés-Delgado, Laura; Mercader, Nadia

    2016-07-01

    Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease. This requires cardiomyocytes to be mechanically durable and able to mount coordinated responses to a variety of environmental signals on different time scales, including cardiac pressure loading and electrical and hemodynamic forces. During physiological growth, myocytes, endocardial and epicardial cells have to adaptively remodel to these mechanical forces. Here we review some of the recent advances in the understanding of how mechanical forces influence cardiac development, with a focus on fluid flow forces. 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:26952935

  12. Primary cardiac tumors.

    PubMed Central

    Silverman, N A

    1980-01-01

    Cardiac tumors are a rare, but potentially curably form of heart disease. A high index of clinical suspicion is necessary for diagnosis as these tumors have protean manifestations that mimic a variety of other cardiac and noncardiac diseases. Presently, M-mode and two-dimensional echocardiography are utilized as safe, reliable, and noninvasive imaging modalities. Seventy-five per cent of these tumors are benign, with myxoma accounting for 50% and rhabodomyoma comprising 20% of lesions. Various histologic types of sarcoma are the predominant malignant cardiac neoplasms. With strict attention to avoiding perioperative tumor embolization, surgical resection of these lesions can be accomplished with minimal morbidity and mortality. Sixteen consecutive primary tumors of the heart have been surgically treated at Duke University Medical Center since 1966 with no perioperative deaths and no late recurrences. Images Figs. 2A and B. Fig. 3. Fig. 4. Figs. 5A and B Fig. 6. PMID:7362282

  13. Engineered cardiac tissues

    PubMed Central

    Iyer, Rohin K.; Chiu, Loraine L. Y.; Reis, Lewis A.; Radisic, Milica

    2011-01-01

    Cardiac tissue engineering offers the promise of creating functional tissue replacements for use in the failing heart or for in vitro drug screening. The last decade has seen a great deal of progress in this field with new advances in interdisciplinary areas such as developmental biology, genetic engineering, biomaterials, polymer science, bioreactor engineering, and stem cell biology. We review here a selection of the most recent advances in cardiac tissue engineering, including the classical cell-scaffold approaches, advanced bioreactor designs, cell sheet engineering, whole organ decellularization, stem-cell based approaches, and topographical control of tissue organization and function. We also discuss current challenges in the field, such as maturation of stem cell-derived cardiac patches and vascularization. PMID:21530228

  14. Cardiac toxicities of antibiotics.

    PubMed Central

    Adams, H R; Parker, J L; Durrett, L R

    1978-01-01

    Isolated heart muscle preparations are useful in the study of cardiac toxicities of drugs and environmental chemicals: such tissues allow assessment of chemical effects on heart muscle that is free from indirect in vivo influences that can mask or even accentuate cardiac responses measured in the intact animal. In the present study, left atria of guinea pigs were used to demonstrate a direct cardiac depressant effect of greater-than-therapeutic concentrations of several aminoglycoside antibiotics. The toxic effect of these antibiotics seems to be a calcium-dependent event, and may prove useful to characterize contractile responses of the heart. Other antibiotic agents can also depress cardiovascular function, as summarized in this report, but mechanisms of action have not been clearly defined. PMID:720315

  15. Antibodies to cardiac receptors.

    PubMed

    Boivin-Jahns, V; Schlipp, A; Hartmann, S; Panjwani, P; Klingel, K; Lohse, M J; Ertl, G; Jahns, R

    2012-12-01

    Inflammation of cardiac tissue is generally associated with an activation of the host's immune system. On the one hand, this activation is mandatory to protect the heart by fighting the invading microbial agents or toxins and by engaging myocardial reparation and healing processes. On the other hand, uncontrolled activation of the immune defense has the risk of an arousal of auto- or cross-reactive immune cells, which in some cases bring more harm than good. Dependent on the individual genetic predisposition, such heart-directed autoimmune reactions most likely occur as a result of myocyte apoptosis or necrosis and subsequent liberation of self-antigens previously hidden to the immune system. During the past two decades, evidence for a pathogenic relevance of autoimmunity in human heart disease has substantially increased. Conformational cardiac (auto)antibodies affecting cardiac function and, in particular, (auto)antibodies that target G protein-coupled cardiac membrane receptors are thought to play a key role in the development of heart failure. Clinical pilot studies even suggest that such antibodies negatively affect survival in heart failure patients. However, the true prevalence and clinical impact of many cardiac (auto)antibodies in human heart diseases are still unclear, as are the events triggering their formation, their titer course, and their patterns of clearance and/or persistence. The present article summarizes current knowledge in the field of cardiac receptor (auto)antibodies including recent efforts to address some of the aforementioned gaps of knowledge, thereby attempting to pave the way for novel, more specific therapeutic approaches. PMID:23183584

  16. Binding Procurement

    NASA Technical Reports Server (NTRS)

    Rao, Gopalakrishna M.; Vaidyanathan, Hari

    2007-01-01

    This viewgraph presentation reviews the use of the binding procurement process in purchasing Aerospace Flight Battery Systems. NASA Engineering and Safety Center (NESC) requested NASA Aerospace Flight Battery Systems Working Group to develop a set of guideline requirements document for Binding Procurement Contracts.

  17. Cardiovascular adaptations following detraining.

    PubMed

    Raven, P B; Shi, X

    1995-01-01

    We have recently summarized our data concerning endurance exercise training and its effect on blood pressure regulation during lower body negative pressure (LBNP). We found that endurance trained (ET) subjects were less tolerant to LBNP than their untrained (UT) counterparts. This decreased tolerance to LBNP was linked to a fitness related adaptation in cardiac compliance, an attenuated cardiopulmonary reflex regulation of peripheral vasoconstriction and an attenuated aortic-cardiac reflex. More recently we have found that 15 days of bed rest deconditioning (a severe form of detraining) in UT subjects resulted in a more responsive aortic-cardiac reflex. In severe detraining investigations, spaceflight and bed rest deconditioning a reduction in total blood and plasma volume were the manifest physiological changes. Therefore, we postulate that the increased aortic-reflex responsiveness was a compensation for the blood and plasma volume losses associated with detraining. Subsequently, we hypothesized that a generalized reduction of the normal daily aerobic activities of a healthy, young adult population would produce a moderate reduction in total blood and plasma volume and an up-regulation of the reflex blood pressure regulatory mechanisms. PMID:11538915

  18. Giant Cardiac Cavernous Hemangioma.

    PubMed

    Unger, Eric; Costic, Joseph; Laub, Glenn

    2015-07-01

    We report the case of an asymptomatic giant cardiac cavernous hemangioma in a 71-year-old man. The intracardiac mass was discovered incidentally during surveillance for his prostate cancer; however, the patient initially declined intervention. On presentation to our institution 7 years later, the lesion had enlarged significantly, and the patient consented to excision. At surgery, an 8 × 6.5 × 4.8 cm intracardiac mass located on the inferior heart border was excised with an intact capsule through a median sternotomy approach. The patient had an uneventful postoperative course. We discuss the diagnostic workup, treatment, and characteristics of this rare cardiac tumor. PMID:26140782

  19. Mechanisms of cardiac arrhythmias

    PubMed Central

    Tse, Gary

    2015-01-01

    Blood circulation is the result of the beating of the heart, which provides the mechanical force to pump oxygenated blood to, and deoxygenated blood away from, the peripheral tissues. This depends critically on the preceding electrical activation. Disruptions in the orderly pattern of this propagating cardiac excitation wave can lead to arrhythmias. Understanding of the mechanisms underlying their generation and maintenance requires knowledge of the ionic contributions to the cardiac action potential, which is discussed in the first part of this review. A brief outline of the different classification systems for arrhythmogenesis is then provided, followed by a detailed discussion for each mechanism in turn, highlighting recent advances in this area. PMID:27092186

  20. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome

    PubMed Central

    Dvir, Tal; Kedem, Alon; Ruvinov, Emil; Levy, Oren; Freeman, Inbar; Landa, Natalie; Holbova, Radka; Feinberg, Micha S.; Dror, Shani; Etzion, Yoram; Leor, Jonathan; Cohen, Smadar

    2009-01-01

    The recent progress made in the bioengineering of cardiac patches offers a new therapeutic modality for regenerating the myocardium after myocardial infarction (MI). We present here a strategy for the engineering of a cardiac patch with mature vasculature by heterotopic transplantation onto the omentum. The patch was constructed by seeding neonatal cardiac cells with a mixture of prosurvival and angiogenic factors into an alginate scaffold capable of factor binding and sustained release. After 48 h in culture, the patch was vascularized for 7 days on the omentum, then explanted and transplanted onto infarcted rat hearts, 7 days after MI induction. When evaluated 28 days later, the vascularized cardiac patch showed structural and electrical integration into host myocardium. Moreover, the vascularized patch induced thicker scars, prevented further dilatation of the chamber and ventricular dysfunction. Thus, our study provides evidence that grafting prevascularized cardiac patch into infarct can improve cardiac function after MI. PMID:19706385

  1. Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

    PubMed Central

    O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

    2014-01-01

    Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

  2. Silicon central pattern generators for cardiac diseases.

    PubMed

    Nogaret, Alain; O'Callaghan, Erin L; Lataro, Renata M; Salgado, Helio C; Meliza, C Daniel; Duncan, Edward; Abarbanel, Henry D I; Paton, Julian F R

    2015-02-15

    Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronisation but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPGs) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPGs). We discuss the limitations of present CPGs and appraise the advantages of analog over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin-Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease. PMID:25433077

  3. Rabbit models of cardiac mechano-electric and mechano-mechanical coupling.

    PubMed

    Quinn, T Alexander; Kohl, Peter

    2016-07-01

    Cardiac auto-regulation involves integrated regulatory loops linking electrics and mechanics in the heart. Whereas mechanical activity is usually seen as 'the endpoint' of cardiac auto-regulation, it is important to appreciate that the heart would not function without feed-back from the mechanical environment to cardiac electrical (mechano-electric coupling, MEC) and mechanical (mechano-mechanical coupling, MMC) activity. MEC and MMC contribute to beat-by-beat adaption of cardiac output to physiological demand, and they are involved in various pathological settings, potentially aggravating cardiac dysfunction. Experimental and computational studies using rabbit as a model species have been integral to the development of our current understanding of MEC and MMC. In this paper we review this work, focusing on physiological and pathological implications for cardiac function. PMID:27208698

  4. A-kinase anchoring proteins: molecular regulators of the cardiac stress response.

    PubMed

    Diviani, Dario; Maric, Darko; Pérez López, Irene; Cavin, Sabrina; Del Vescovo, Cosmo D

    2013-04-01

    In response to stress or injury the heart undergoes a pathological remodeling process, associated with hypertrophy, cardiomyocyte death and fibrosis, that ultimately causes cardiac dysfunction and heart failure. It has become increasingly clear that signaling events associated with these pathological cardiac remodeling events are regulated by scaffolding and anchoring proteins, which allow coordination of pathological signals in space and time. A-kinase anchoring proteins (AKAPs) constitute a family of functionally related proteins that organize multiprotein signaling complexes that tether the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to ensure integration and processing of multiple signaling pathways. This review will discuss the role of AKAPs in the cardiac response to stress. Particular emphasis will be given to the adaptative process associated with cardiac hypoxia as well as the remodeling events linked to cardiac hypertrophy and heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. PMID:22889610

  5. Hepato-cardiac disorders

    PubMed Central

    Fouad, Yasser Mahrous; Yehia, Reem

    2014-01-01

    Understanding the mutual relationship between the liver and the heart is important for both hepatologists and cardiologists. Hepato-cardiac diseases can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and conditions affecting the heart and the liver at the same time. Differential diagnoses of liver injury are extremely important in a cardiologist’s clinical practice calling for collaboration between cardiologists and hepatologists due to the many other diseases that can affect the liver and mimic haemodynamic injury. Acute and chronic heart failure may lead to acute ischemic hepatitis or chronic congestive hepatopathy. Treatment in these cases should be directed to the primary heart disease. In patients with advanced liver disease, cirrhotic cardiomyopathy may develop including hemodynamic changes, diastolic and systolic dysfunctions, reduced cardiac performance and electrophysiological abnormalities. Cardiac evaluation is important for patients with liver diseases especially before and after liver transplantation. Liver transplantation may lead to the improvement of all cardiac changes and the reversal of cirrhotic cardiomyopathy. There are systemic diseases that may affect both the liver and the heart concomitantly including congenital, metabolic and inflammatory diseases as well as alcoholism. This review highlights these hepatocardiac diseases PMID:24653793

  6. Cardiac mechanoenergetics in silico.

    PubMed

    Vendelin, Marko; Bovendeerd, Peter H M; Saks, Valdur; Engelbrecht, Jüri

    2002-02-01

    The aim of this thesis is to investigate the link between biochemical intracellular processes and mechanical contraction of the cardiac muscle. First, the regulation of intracellular energy fluxes between mitochondria and myofibrils is studied. It is shown, that the experimentally observed metabolic stability of the cardiac muscle is reproducible by a simple feedback regulation mechanism, i.e., ATP consumption in myofibrils and ATP production in mitochondria are balanced by the changes of the high energy phosphate concentrations. Second, an important property of energy transformation from biochemical form to mechanical work in the cardiac muscle, the linear relationship between the oxygen consumption and the stress-strain area, is replicated by a cross-bridge model. Third, by using the developed cross-bridge model, the correlation between ejection fraction of the left ventricle and heterogeneity of sarcomere strain, developed stress and ATP consumption in the left ventricular wall is established. Fourth, an experimentally observed linear relationship between oxygen consumption and the pressure-volume area can be predicted theoretically from a linear relationship between the oxygen consumption and the stress-strain area. Summing up, it is shown how the macrovariables of a cardiac muscle are interwoven with intracellular physiological processes into a whole. PMID:11880857

  7. Smoking after cardiac transplantation.

    PubMed

    Botha, P; Peaston, R; White, K; Forty, J; Dark, J H; Parry, G

    2008-04-01

    Although smoking cessation is a prerequisite prior to listing for cardiac transplantation, some patients return to smoking after recovery. We have covertly assessed the smoking habits of our cardiac transplant recipients (with ethical approval) since 1993 by measuring urinary cotinine: a level of >500 ng/mL signifying continued tobacco use. We retrospectively analyzed survival, causes of death and the development of graft coronary artery disease (GCAD) with respect to the number of positive and negative cotinine levels. One hundred four of 380 (27.4%) patients tested positive for active smoking at some point posttransplant, and 57 (15.0%) tested positive repeatedly. Smokers suffered significantly more deaths due to GCAD (21.2% vs. 12.3%, p < 0.05), and due to malignancy (16.3% vs. 5.8%, p < 0.001). In univariate analysis, smoking after heart transplantation shortened median survival from 16.28 years to 11.89 years. After correcting for the effects of pretransplant smoking in time-dependent multivariate analysis, posttransplant smoking remained the most significant determinant of overall mortality (p < 0.00001). We conclude that tobacco smoking after cardiac transplantation significantly impacts survival by accelerating the development of graft vasculopathy and malignancy. We hope that this information will deter cardiac transplant recipients from relapsing, and intensify efforts in improving cessation rates. PMID:18324978

  8. [Insertable Cardiac Monitor].

    PubMed

    Lewalter, Thorsten; Koutsouraki, Ilia; Brodherr, Turgut

    2015-08-01

    Intermittent cardiac arrhythmias are sometimes difficult to register using conventional detection concepts. The implantable event recorders offer a unique opportunity to document short lasting or rare and even asymptomatic arrhythmias. This manuscript describes event recorder implantation in a step-by-step manner. PMID:26306017

  9. Advanced Cardiac Life Support.

    ERIC Educational Resources Information Center

    Kirkwood Community Coll., Cedar Rapids, IA.

    This document contains materials for an advanced college course in cardiac life support developed for the State of Iowa. The course syllabus lists the course title, hours, number, description, prerequisites, learning activities, instructional units, required text, six references, evaluation criteria, course objectives by units, course…

  10. Cardiac effects of vasopressin.

    PubMed

    Pelletier, Jean-Sébastien; Dicken, Bryan; Bigam, David; Cheung, Po-Yin

    2014-07-01

    Vasopressin is an essential hormone involved in the maintenance of cardiovascular homeostasis. It has been in use therapeutically for many decades, with an emphasis on its vasoconstrictive and antidiuretic properties. However, this hormone has a ubiquitous influence and has specific effects on the heart. Although difficult to separate from its powerful vascular effects in the clinical setting, a better understanding of vasopressin's direct cardiac effects could lead to its more effective clinical use for a variety of shock states by maximizing its therapeutic benefit. The cardiac-specific effects of vasopressin are complex and require further elucidation. Complicating our understanding include the various receptors and secondary messengers involved in vasopressin's effects, which may lead to various results based on differing doses and varying environmental conditions. Thus, there have been contradictory reports on vasopressin's action on the coronary vasculature and on its effect on inotropy. However, beneficial results have been found and warrant further study to expand the potential therapeutic role of vasopressin. This review outlines the effect of vasopressin on the coronary vasculature, cardiac contractility, and on hypertrophy and cardioprotection. These cardiac-specific effects of vasopressin represent an interesting area for further study for potentially important therapeutic benefits. PMID:24621650

  11. Laser speckle analysis synchronised with cardiac cycle

    NASA Astrophysics Data System (ADS)

    Zakharov, Pavel; Scheffold, Frank; Weber, Bruno

    2015-07-01

    We present an improved Laser speckle imaging approach to investigate the cerebral blood flow response following function stimulation of a single vibrissa. By synchronising speckle analysis with the cardiac cycle we are able to obtain robust averaging of the correlation signals while at the same time removing the contributions due to the pulsation of blood flow and associated tissue adaptation. With our inter-pulse correlation analysis we can follow second-scale dynamics of the cortical vascular system in response to functional brain activation. We find evidence for two temporally separated processes in the blood flow pattern following stimulation we tentatively attribute to vasodilation and vasoconstriction phases, respectively.

  12. [The athletes' ECG and the exercise related sudden cardiac death].

    PubMed

    Trachsel, Lukas-Daniel; Wilhelm, Matthias

    2015-05-01

    Regular physical activity induces structural, electrical and functional cardiac adaptations. The main challenge for the athletes' physician is to distinguish abnormal structural changes of the heart from training-induced adaptations (so-called “athlete's heart”). In athletes with underlying cardiac disease, physical activity may be a trigger, not the cause of exercise-induced tachyarrhythmia's and sudden cardiac death (SCD). To identify athletes with cardiac diseases and increased risk for an SCD, the European society of cardiology (ESC) recommends a pre-participation screening in elite athletes which was adopted by the Swiss society of sports medicine. The screening includes a specific medical history, cardiac auscultation and a resting ECG. Due to the high number of false-positive cases of athletes' ECGs based on traditional criteria, the ESC assessment criteria were adjusted to account for training-related changes of the ECG. The sensitivity and especially the specificity could be improved in the “revised Seattle criteria” in 2014. During the last years main attention has been shifted to the early repolarization pattern: additionally to (endurance-) training there is a clear association with male gender, ethnicity, changes in autonomic nervous system activity and high QRS-voltage criteria PMID:26098068

  13. Utility of cardiac troponins in patients with suspected cardiac trauma or after cardiac surgery.

    PubMed

    Adams, J E

    1997-12-01

    Detection of cardiac injury after blunt chest wall trauma or cardiac surgery is problematic. Previously available biomarkers have been hindered largely by limitations of specifity for myocardial damage. Both cardiac troponin I and T have been evaluated in these patient subgroups. While many questions remain unanswered, it appears that measurement of troponin proteins will facilitate patient care in these difficult situations. PMID:9439875

  14. Cardiac surgery outcomes.

    PubMed

    Halpin, Linda S; Barnett, Scott D; Beachy, Jim

    2003-01-01

    Accrediting organizations and payers are demanding valid and reliable data that demonstrate the value of services. Federal agencies, healthcare industry groups, and healthcare watchdog groups are increasing the demand for public access to outcomes data. A new and growing outcomes dynamic is the information requested by prospective patients in an increasingly consumer-oriented business. Patients demand outcomes, and resources are developing to meet these demands. Physicians are increasingly confronted with requests for information about their mortality and morbidity rates, malpractice suits, and disciplinary actions received. For example, in Virginia, prospective patients have access to data provided by the nonprofit group Virginia Health Information. After numerous resolutions by the Virginia Senate since 1999, the prospective Virginia medical consumer now has access to several annual publications: Virginia Hospitals: A Consumer's Guide, 1999 Annual Report and Strategic Plan Update, and the 1999 Industry Report: Virginia Hospitals and Nursing Facilities. Consumers have access to cardiac outcomes data stratified by hospital, gender, and cardiac service line (cardiac surgery, noninvasive cardiology, and invasive cardiology). This is particularly relevant to IHI because Virginia Health Information specifically targets cardiac care. IHI has a sizable investment in cardiovascular outcomes and has found outcomes measurement and research are key to providing quality care. IHI's goal is to move from an outcomes management model to a disease management model. The hope is to incorporate all aspects of the patient's continuum of care, from preoperative and diagnostic services through cardiac interventions to postoperative rehabilitation. Furthermore, every step along the way will be supported with functional status and quality of life assessments. Although these goals are ambitious and expensive, the return on investment is high. PMID:14618772

  15. Ethical Issues in Cardiac Surgery

    PubMed Central

    Kavarana, Minoo N.; Sade, Robert M.

    2012-01-01

    While ethical behavior has always been part of cardiac surgical practice, ethical deliberation has only recently become an important component of cardiac surgical practice. Issues such as informed consent, conflict of interest, and professional self-regulation, among many others, have increasingly attracted the attention of cardiac surgeons. This review covers several broad topics of interest to cardiac surgeons and cardiologists, and treats several other topics more briefly. There is much uncertainty about what the future holds for cardiac surgical practice, research, and culture, and we discuss the background of ethical issues to serve as a platform for envisioning what is to come. PMID:22642634

  16. Maternal cardiac metabolism in pregnancy.

    PubMed

    Liu, Laura X; Arany, Zolt

    2014-03-15

    Pregnancy causes dramatic physiological changes in the expectant mother. The placenta, mostly foetal in origin, invades maternal uterine tissue early in pregnancy and unleashes a barrage of hormones and other factors. This foetal 'invasion' profoundly reprogrammes maternal physiology, affecting nearly every organ, including the heart and its metabolism. We briefly review here maternal systemic metabolic changes during pregnancy and cardiac metabolism in general. We then discuss changes in cardiac haemodynamic during pregnancy and review what is known about maternal cardiac metabolism during pregnancy. Lastly, we discuss cardiac diseases during pregnancy, including peripartum cardiomyopathy, and the potential contribution of aberrant cardiac metabolism to disease aetiology. PMID:24448314

  17. Symmetry of cardiac function assessment

    PubMed Central

    Bai, Xu-Fang; Ma, Amy X

    2016-01-01

    Both right and left ventricles are developed from two adjacent segments of the primary heart tube. Though they are different with regard to shape and power, they mirror each other in terms of behavior. This is the first level of symmetry in cardiac function assessment. Both cardiac muscle contraction and relaxation are active. This constructs the second level of symmetry in cardiac function assessment. Combination of the two levels will help to find some hidden indexes or approaches to evaluate cardiac function. In this article, four major indexes from echocardiography were analyzed under this principal, another seventeen indexes or measurement approaches came out of the shadow, which is very helpful in the assessment of cardiac function, especially for the right cardiac function and diastolic cardiac function. PMID:27582768

  18. Symmetry of cardiac function assessment.

    PubMed

    Bai, Xu-Fang; Ma, Amy X

    2016-09-01

    Both right and left ventricles are developed from two adjacent segments of the primary heart tube. Though they are different with regard to shape and power, they mirror each other in terms of behavior. This is the first level of symmetry in cardiac function assessment. Both cardiac muscle contraction and relaxation are active. This constructs the second level of symmetry in cardiac function assessment. Combination of the two levels will help to find some hidden indexes or approaches to evaluate cardiac function. In this article, four major indexes from echocardiography were analyzed under this principal, another seventeen indexes or measurement approaches came out of the shadow, which is very helpful in the assessment of cardiac function, especially for the right cardiac function and diastolic cardiac function. PMID:27582768

  19. Interactions of cryptosin with mammalian cardiac dihydropyridine-specific calcium channels

    SciTech Connect

    Rao, V.R.; Banning, J.W. )

    1990-01-01

    Cryptosin, a new cardenolide, was found to be a potent inhibitor of cardiac Na{sup +} and K{sup +} dependent Adenosinetri-phosphatase. In experiments with dog heart ex vivo, development of inotropic and toxic effect correlated with changes in the cardiac dihydropyridine-specific calcium channels as measured by the binding of {sup 3}(H)PN 200-110. A significant change in the PN 200-110 binding was observed when guinea pig and dog heart sarcolemmal membranes were pre-incubated with cryptosin in vitro. Binding analysis of {sup 3}(H)PN 200-110 (Isradipine), a 1,4-dihydropyridine analog with very specific calcium channel binding properties, in both in vitro and ex vivo studies were consistent and indicated a non-specific type of interaction of cryptosin with mammalian cardiac 1,4-dihydropyridine-specific calcium channels.

  20. Optimization of Cardiac Metabolism in Heart Failure

    PubMed Central

    Nagoshi, Tomohisa; Yoshimura, Michihiro; Rosano, Giuseppe M. C; Lopaschuk, Gary D; Mochizuki, Seibu

    2011-01-01

    The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure. PMID:21933140

  1. Optimization of cardiac metabolism in heart failure.

    PubMed

    Nagoshi, Tomohisa; Yoshimura, Michihiro; Rosano, Giuseppe M C; Lopaschuk, Gary D; Mochizuki, Seibu

    2011-12-01

    The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure. PMID:21933140

  2. Influence of gravity on cardiac performance

    NASA Technical Reports Server (NTRS)

    Pantalos, G. M.; Sharp, M. K.; Woodruff, S. J.; O'Leary, D. S.; Lorange, R.; Everett, S. D.; Bennett, T. E.; Shurfranz, T.

    1998-01-01

    Results obtained by the investigators in ground-based experiments and in two parabolic flight series of tests aboard the NASA KC-135 aircraft with a hydraulic simulator of the human systemic circulation have confirmed that a simple lack of hydrostatic pressure within an artificial ventricle causes a decrease in stroke volume of 20%-50%. A corresponding drop in stroke volume (SV) and cardiac output (CO) was observed over a range of atrial pressures (AP), representing a rightward shift of the classic CO versus AP cardiac function curve. These results are in agreement with echocardiographic experiments performed on space shuttle flights, where an average decrease in SV of 15% was measured following a three-day period of adaptation to weightlessness. The similarity of behavior of the hydraulic model to the human system suggests that the simple physical effects of the lack of hydrostatic pressure may be an important mechanism for the observed changes in cardiac performance in astronauts during the weightlessness of space flight.

  3. Transcriptional control of cardiac fibroblast plasticity.

    PubMed

    Lighthouse, Janet K; Small, Eric M

    2016-02-01

    Cardiac fibroblasts help maintain the normal architecture of the healthy heart and are responsible for scar formation and the healing response to pathological insults. Various genetic, biomechanical, or humoral factors stimulate fibroblasts to become contractile smooth muscle-like cells called myofibroblasts that secrete large amounts of extracellular matrix. Unfortunately, unchecked myofibroblast activation in heart disease leads to pathological fibrosis, which is a major risk factor for the development of cardiac arrhythmias and heart failure. A better understanding of the molecular mechanisms that control fibroblast plasticity and myofibroblast activation is essential to develop novel strategies to specifically target pathological cardiac fibrosis without disrupting the adaptive healing response. This review highlights the major transcriptional mediators of fibroblast origin and function in development and disease. The contribution of the fetal epicardial gene program will be discussed in the context of fibroblast origin in development and following injury, primarily focusing on Tcf21 and C/EBP. We will also highlight the major transcriptional regulatory axes that control fibroblast plasticity in the adult heart, including transforming growth factor β (TGFβ)/Smad signaling, the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) axis, and Calcineurin/transient receptor potential channel (TRP)/nuclear factor of activated T-Cell (NFAT) signaling. Finally, we will discuss recent strategies to divert the fibroblast transcriptional program in an effort to promote cardiomyocyte regeneration. This article is a part of a Special Issue entitled "Fibrosis and Myocardial Remodeling". PMID:26721596

  4. Cardiac phase: Amplitude analysis using macro programming

    SciTech Connect

    Logan, K.W.; Hickey, K.A.

    1981-11-01

    The analysis of EKG gated radionuclide cardiac imaging data with Fourier amplitude and phase images is becoming a valuable clinical technique, demonstrating location, size, and severity of regional ventricular abnormalities. Not all commercially available nuclear medicine computer systems offer software for phase and amplitude analysis; however, many systems do have the capability of linear image arithmetic using simple macro commands which can easily be sequenced into stored macro-strings or programs. Using simple but accurate series approximations for the Fourier operations, macro programs have been written for a Digital Equipment Corporation Gamma-11 system to obtain phase and amplitude images from routine gated cardiac studies. In addition, dynamic cine-mode presentation of the onset of mechanical systole is generated from the phase data, using only a second set of macro programs. This approach is easily adapted to different data acquisition protocols, and can be used on any system with macro commands for image arithmetic. Key words: Fourier analysis, cardiac cycle, gated blood pool imaging, amplitude image, phase image

  5. Cardiac fusion and complex congenital cardiac defects in thoracopagus twins: diagnostic value of cardiac CT.

    PubMed

    Goo, Hyun Woo; Park, Jeong-Jun; Kim, Ellen Ai-Rhan; Won, Hye-Sung

    2014-09-01

    Most thoracopagus twins present with cardiac fusion and associated congenital cardiac defects, and assessment of this anatomy is of critical importance in determining patient care and outcome. Cardiac CT with electrocardiographic triggering provides an accurate and quick morphological assessment of both intracardiac and extracardiac structures in newborns, making it the best imaging modality to assess thoracopagus twins during the neonatal period. In this case report, we highlight the diagnostic value of cardiac CT in thoracopagus twins with an interatrial channel and complex congenital cardiac defects. PMID:24687619

  6. Decrease in rat cardiac beta sub 1 - and beta sub 2 - adrenoceptors by training and endurance exercise

    SciTech Connect

    Werle, E.O.; Strobel, G.; Weicker, H. )

    1990-01-01

    The cardiac {beta}-adrenoceptor adaptation to physical activity was investigated in rats which were subjected to a six-week endurance swimming training (ET; n=7) and a training of high intensity (MT; n=7). In addition, the effect of a single bout of endurance exercise without preceding training (EE; n=7) was evaluated. These groups were compared with a sedentary control group (C; n=9). Beta-adrenergic receptors in rat myocardial membranes were labelled using the high affinity antagonist radioligand (-){sup 125}iodocyanopindolol (ICYP). Computer modelling techniques provided estimates of the maximal binding capacity (B{sub max}) and the dissociation constants (K{sub D}). Tissue was constantly kept at temperatures of {le}4{degrees}C and incubated at 4{degrees}C for 18 h in buffer containing 100 {mu}M GTP so as to prevent masking of {beta}-adrenoceptors by endogenous norepinephrine. In comparison with the C group computerized coanalyses of saturation binding data of ET, MT, and EE revealed a 13.0%, 25.5%, and 16.6% decrease in B{sub max}, respectively, without significantly differing K{sub D} values. We provide the first evidence that acute exercise lowers the sarcolemmal {beta}-adrenoceptor number in the rat heart. In the competition radioligand binding, CGP20712A and ICI118.551 were employed as subtype-selective antagonists of {beta}{sub 1}- and {beta}{sub 2}-adrenoceptors, respectively, to determine the relative proportions of the receptor subtypes.

  7. Cardiac size of high-volume resistance trained female athletes: shaping the body but not the heart.

    PubMed

    Venckunas, T; Simonavicius, J; Marcinkeviciene, J E

    2016-03-01

    Introduction Exercise training, besides many health benefits, may result in cardiac remodelling which is dependent on the type and amount of exercise performed. It is not clear, however, whether significant adaptation in cardiac structure is possible in females undergoing resistance type of exercise training. Rigorous high volume training of most muscle groups emphasising resistance exercises are being undertaken by athletes of some aesthetic sports such as female fitness (light bodybuilding). The impact of this type of training on cardiac adaptation has not been investigated until now. The aim of the current study was to disclose the effect of high volume resistance training on cardiac structure and function. Methods 11 top-level female fitness athletes and 20 sedentary age-matched controls were recruited to undergo two-dimensional echocardiography. Results Cardiac structure did not differ between elite female fitness athletes and controls (p > 0.05), and fitness athletes had a tendency for a smaller (p = 0.07) left ventricular (LV) mass indexed to lean body mass. Doppler diastolic function index (E/A ratio) and LV ejection fraction were similar between the groups (p > 0.05). Conclusions Elite female fitness athletes have normal cardiac size and function that do not differ from matched sedentary controls. Consequently, as high volume resistance training has no easily observable effect on adaptation of cardiac structure, when cardiac hypertrophy is present in young resistance-trained lean female, other reasons such as inherited cardiac disease are to be considered carefully. PMID:27030632

  8. Cardiac arrhythmias in pregnancy.

    PubMed

    Knotts, Robert J; Garan, Hasan

    2014-08-01

    As more women with repaired congenital heart disease survive to their reproductive years and many other women are delaying pregnancy until later in life, a rising concern is the risk of cardiac arrhythmias during pregnancy. Naturally occurring cardiovascular changes during pregnancy increase the likelihood that a recurrence of a previously experienced cardiac arrhythmia or a de novo arrhythmia will occur. Arrhythmias should be thoroughly investigated to determine if there is a reversible etiology, and risks/benefits of treatment options should be fully explored. We discuss the approach to working up and treating various arrhythmias during pregnancy with attention to fetal and maternal risks as well as treatment of fetal arrhythmias. Acute management in stable patients includes close monitoring and intravenous pharmacologic therapy, while DC cardioversion should be used to terminate arrhythmias in hemodynamically unstable patients. Long-term management may require continued oral antiarrhythmic therapy, with particular attention to fetal safety, to prevent complications associated with arrhythmias. PMID:25037518

  9. Cardiac nuclear medicine

    SciTech Connect

    Gerson, M.C.

    1987-01-01

    The book begins with a review of the radionuclide methods available for evaluating cardiac perfusion and function. The authors discuss planar and tomographic thallium myocardial imaging, first-pass and equilibrium radionuclide angiography, and imaging with infarct-avid tracers. Several common but more specialized procedures are then reviewed: nonogemetric measurement of left ventricular volume, phase (Fourier) analysis, stroke volume ratio, right ventricular function, and diastolic function. A separate chapter is devoted to drug interventions and in particular the use of radionuclide ventriculography to monitor doxorubicin toxicity and therapy of congestive heart failure. The subsequent chapters provide a comprehensive guide to test selection, accuracy, and results in acute myocardial infarction, in postmyocardial infarction, in chronic coronary artery disease, before and after medical or surgical revascularization, in valvular heart disease, in cardiomyopathies, and in cardiac trauma.

  10. Cardiac arrest in children.

    PubMed

    Tress, Erika E; Kochanek, Patrick M; Saladino, Richard A; Manole, Mioara D

    2010-07-01

    Major advances in the field of pediatric cardiac arrest (CA) were made during the last decade, starting with the publication of pediatric Utstein guidelines, the 2005 recommendations by the International Liaison Committee on Resuscitation, and culminating in multicenter collaborations. The epidemiology and pathophysiology of in-hospital and out-of-hospital CA are now well described. Four phases of CA are described and the term "post-cardiac arrest syndrome" has been proposed, along with treatment goals for each of its four phases: immediate post-arrest, early post-arrest, intermediate and recovery phase. Hypothermia is recommended to be considered as a therapy for post-CA syndrome in comatose patients after CA, and large multicenter prospective studies are underway. We reviewed landmark articles related to pediatric CA published during the last decade. We present the current knowledge of epidemiology, pathophysiology and treatment of CA relevant to pre-hospital and acute care health practitioners. PMID:20930971

  11. Cardiac atrophy after bed rest and spaceflight

    NASA Technical Reports Server (NTRS)

    Perhonen, M. A.; Franco, F.; Lane, L. D.; Buckey, J. C.; Blomqvist, C. G.; Zerwekh, J. E.; Peshock, R. M.; Weatherall, P. T.; Levine, B. D.

    2001-01-01

    Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

  12. Adaptive Management

    EPA Science Inventory

    Adaptive management is an approach to natural resource management that emphasizes learning through management where knowledge is incomplete, and when, despite inherent uncertainty, managers and policymakers must act. Unlike a traditional trial and error approach, adaptive managem...

  13. Aging and Cardiac Fibrosis

    PubMed Central

    Biernacka, Anna; Frangogiannis, Nikolaos G

    2011-01-01

    The aging heart is characterized by morphological and structural changes that lead to its functional decline and are associated with diminished ability to meet increased demand. Extensive evidence, derived from both clinical and experimental studies suggests that the aging heart undergoes fibrotic remodeling. Age-dependent accumulation of collagen in the heart leads to progressive increase in ventricular stiffness and impaired diastolic function. Increased mechanical load, due to reduced arterial compliance, and direct senescence-associated fibrogenic actions appear to be implicated in the pathogenesis of cardiac fibrosis in the elderly. Evolving evidence suggests that activation of several distinct molecular pathways may contribute to age-related fibrotic cardiac remodeling. Reactive oxygen species, chemokine-mediated recruitment of mononuclear cells and fibroblast progenitors, transforming growth factor (TGF)-β activation, endothelin-1 and angiotensin II signaling mediate interstitial and perivascular fibrosis in the senescent heart. Reduced collagen degradation may be more important than increased de novo synthesis in the pathogenesis of aging-associated fibrosis. In contrast to the baseline activation of fibrogenic pathways in the senescent heart, aging is associated with an impaired reparative response to cardiac injury and defective activation of reparative fibroblasts in response to growth factors. Because these reparative defects result in defective scar formation, senescent hearts are prone to adverse dilative remodeling following myocardial infarction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients. PMID:21837283

  14. Biomechanics of Cardiac Function.

    PubMed

    Voorhees, Andrew P; Han, Hai-Chao

    2015-10-01

    The heart pumps blood to maintain circulation and ensure the delivery of oxygenated blood to all the organs of the body. Mechanics play a critical role in governing and regulating heart function under both normal and pathological conditions. Biological processes and mechanical stress are coupled together in regulating myocyte function and extracellular matrix structure thus controlling heart function. Here, we offer a brief introduction to the biomechanics of left ventricular function and then summarize recent progress in the study of the effects of mechanical stress on ventricular wall remodeling and cardiac function as well as the effects of wall mechanical properties on cardiac function in normal and dysfunctional hearts. Various mechanical models to determine wall stress and cardiac function in normal and diseased hearts with both systolic and diastolic dysfunction are discussed. The results of these studies have enhanced our understanding of the biomechanical mechanism in the development and remodeling of normal and dysfunctional hearts. Biomechanics provide a tool to understand the mechanism of left ventricular remodeling in diastolic and systolic dysfunction and guidance in designing and developing new treatments. PMID:26426462

  15. Penetrating cardiac injuries.

    PubMed

    Mittal, V; McAleese, P; Young, S; Cohen, M

    1999-05-01

    Our objective was to determine the influence of several clinical factors on the survival of patients with penetrating wounds to the heart. A retrospective review of 80 consecutive penetrating cardiac injuries treated in a Level II urban trauma center from 1980 through 1994 were examined. Thirty-six patients (45%) had gunshot wounds (including 1 shotgun wound), and 44 (55%) had stab wounds. Intervention consisted of emergency room (ER) or operating room thoracotomy. We measured the effect of several clinical factors on morbidity and patient survival. Survival rate was 17 of 36 (47%) in gunshot injuries and 35 of 44 (80%) in stab injuries, with an overall survival rate of 52 of 80 patients (65%). The average age was 24 years (range, 9-53), and there were 3 female patients. Twelve patients (15%) had multiple cardiac injuries, and 63 (79%) had other associated injuries. Fourteen patients (17%) presented with no blood pressure, and 55 (69%) were hypotensive on admission. ER thoracotomy was performed on 7 of 52 survivors (13%) and 24 of 28 nonsurvivors (86%). Survival after ER thoracotomy was 7 of 31 patients (22%). A selective approach is recommended, because ER thoracotomy has a limited role in penetrating cardiac injury. A high index of suspicion, prompt resuscitation, and immediate definitive surgical management resulted in a high survival rate for these frequently lethal injuries. PMID:10231214

  16. Cardiac Emergencies in Neurosurgical Patients

    PubMed Central

    Petropolis, Andrea; Cappellani, Ronald B.

    2015-01-01

    Perioperative safety concerns are a major area of interest in recent years. Severe cardiac perturbation such as cardiac arrest is one of the most dreaded complications in the intraoperative period; however, little is known about the management of these events in the patients undergoing elective neurosurgery. This special group needs further attention, as it is often neither feasible nor appropriate to apply conventional advanced cardiac life support algorithms in patients undergoing neurosurgery. Factors such as neurosurgical procedure and positioning can also have a significant effect on the occurrence of cardiac arrest. Therefore, the aim of this paper is to describe the various causes and management of cardiac emergencies with special reference to cardiac arrest during elective neurosurgical procedures, including discussion of position-related factors and resuscitative considerations in these situations. This will help to formulate possible guidelines for management of such events. PMID:25692145

  17. An overview of cardiac morphogenesis.

    PubMed

    Schleich, Jean-Marc; Abdulla, Tariq; Summers, Ron; Houyel, Lucile

    2013-11-01

    Accurate knowledge of normal cardiac development is essential for properly understanding the morphogenesis of congenital cardiac malformations that represent the most common congenital anomaly in newborns. The heart is the first organ to function during embryonic development and is fully formed at 8 weeks of gestation. Recent studies stemming from molecular genetics have allowed specification of the role of cellular precursors in the field of heart development. In this article we review the different steps of heart development, focusing on the processes of alignment and septation. We also show, as often as possible, the links between abnormalities of cardiac development and the main congenital heart defects. The development of animal models has permitted the unraveling of many mechanisms that potentially lead to cardiac malformations. A next step towards a better knowledge of cardiac development could be multiscale cardiac modelling. PMID:24138816

  18. Sudden Cardiac Death in Athletes.

    PubMed

    Wasfy, Meagan M; Hutter, Adolph M; Weiner, Rory B

    2016-01-01

    There are clear health benefits to exercise; even so, patients with cardiac conditions who engage in exercise and athletic competition may on rare occasion experience sudden cardiac death (SCD). This article reviews the epidemiology and common causes of SCD in specific athlete populations. There is ongoing debate about the optimal mechanism for SCD prevention, specifically regarding the inclusion of the ECG and/or cardiac imaging in routine preparticipation sports evaluation. This controversy and contemporary screening recommendations are also reviewed. PMID:27486488

  19. Sudden Cardiac Death in Athletes

    PubMed Central

    Wasfy, Meagan M.; Hutter, Adolph M.; Weiner, Rory B.

    2016-01-01

    There are clear health benefits to exercise; even so, patients with cardiac conditions who engage in exercise and athletic competition may on rare occasion experience sudden cardiac death (SCD). This article reviews the epidemiology and common causes of SCD in specific athlete populations. There is ongoing debate about the optimal mechanism for SCD prevention, specifically regarding the inclusion of the ECG and/or cardiac imaging in routine preparticipation sports evaluation. This controversy and contemporary screening recommendations are also reviewed. PMID:27486488

  20. Cardiac Involvement in Ankylosing Spondylitis.

    PubMed

    Ozkan, Yasemin

    2016-06-01

    Ankylosing spondylitis is one of the subgroup of diseases called "seronegative spondyloarthropathy". Frequently, it affects the vertebral colon and sacroiliac joint primarily and affects the peripheral joints less often. This chronic, inflammatory and rheumatic disease can also affect the extraarticular regions of the body. The extraarticular affections can be ophthalmologic, cardiac, pulmonary or neurologic. The cardiac affection can be 2-10% in all patients. Cardiac complications such as left ventricular dysfunction, aortitis, aortic regurgitation, pericarditis and cardiomegaly are reviewed. PMID:27222669

  1. MicroRNA-29a suppresses cardiac fibroblasts proliferation via targeting VEGF-A/MAPK signal pathway.

    PubMed

    Tao, Hui; Chen, Ze-Wen; Yang, Jing-Jing; Shi, Kai-Hu

    2016-07-01

    Cardiac fibroblasts proliferation is the most important pathophysiological character of cardiac fibrosis while the underlying mechanisms are still incompletely known. MicroRNAs (miRNAs) regulate gene expression by binding to specific sites. Studies have been indicated that miRNA-29a play a key role in cardiac fibrosis. VEGF-A carries out its functions through MAPK signaling pathway in cardiac fibrosis. Existing proofs predict that the VEGF-A is one of the potential targets of miRNA-29a. We therefore probe the role of miRNA-29a and its latent target VEGF-A during cardiac fibrosis. In our study, miRNA-29a was down-regulated while VEGF-A was up-regulated in cardiac fibrosis tissues. The rat cardiac fibroblasts that were transfected with miRNA-29a inhibitor exhibited low-expression of miRNA-29a, enhanced VEGF-A protein and mRNA expression. Nevertheless, the cardiac fibroblasts transfected with miRNA-29a mimics obtained the opposite expression result. Furthermore, over-expression of miRNA-29a suppresses cardiac fibroblasts proliferation. In conclusion, these results suggested that miRNA-29a suppresses cardiac fibrosis and fibroblasts proliferation via targeting VEGF-A/MAPK signal pathway implicating that miRNA-29a might play a role in the treatment of cardiac fibrosis. PMID:27060017

  2. Imaging patients with cardiac trauma.

    PubMed

    Restrepo, Carlos S; Gutierrez, Fernando R; Marmol-Velez, Juan A; Ocazionez, Daniel; Martinez-Jimenez, Santiago

    2012-01-01

    In the United States, trauma is the leading cause of death among those who are 1-44 years old, with cardiovascular injuries representing the second most common cause of traumatic death after central nervous system injuries. Evaluation of trauma patients with suspected cardiac injury may be complex and include electrocardiography, measurement of cardiac biomarkers, and imaging examinations. Contrast material-enhanced computed tomography (CT) has become one of the most valuable imaging tools available for evaluating hemodynamically stable patients with suspected cardiac injury. The presence of hemopericardium, with or without cardiac tamponade, is one of the most significant findings of cardiac injury. Other complications that result from blunt cardiac injury, such as pericardial rupture and cardiac herniation, may be readily depicted at multidetector CT. Assessment of patients with cardiac injuries, particularly those with penetrating injuries, is a challenging and time-critical matter, with clinical and imaging findings having complementary roles in the formation of an accurate diagnosis. Patients who are hemodynamically stable, particularly those with penetrating cardiac injuries, also may benefit from a timely imaging examination. In addition to chest radiography, other available modalities such as transthoracic and transesophageal echocardiography, nuclear medicine, and magnetic resonance imaging may play a role in selected cases. PMID:22582351

  3. Registry of Unexplained Cardiac Arrest

    ClinicalTrials.gov

    2016-05-16

    Cardiac Arrest; Long QT Syndrome; Brugada Syndrome; Catecholaminergi Polymorphic Ventricular Tachycardia; Idiopathic VentricularFibrillation; Early Repolarization Syndrome; Arrhythmogenic Right Ventricular Cardiomyopathy

  4. The role of cardiac biochemical markers in aortic stenosis.

    PubMed

    Chin, Calvin W L; Djohan, Andie H; Lang, Chim C

    2016-06-01

    Calcified aortic stenosis is one of the most common causes of heart failure in the elderly. Current guidelines recommend aortic valve replacement in patients with severe disease and evidence of decompensation based on either symptoms or impaired systolic ejection fraction. However, symptoms are often subjective whilst impaired ejection fraction is not a sensitive marker of ventricular decompensation. Interest has surrounded the use of cardiac biochemical markers as objective measures of left ventricular decompensation in aortic stenosis. We will first examine mechanisms of release of biochemical markers associated with myocardial wall stress (BNP/NT-proBNP), myocardial fibrosis (markers of collagen metabolism, galectin-3, soluble ST2) and myocyte death/myocardial ischemia (high-sensitivity cardiac troponins, heart-type fatty acid binding protein, myosin-binding protein C); and discuss future directions of these markers. PMID:26900722

  5. Pellino1-mediated TGF-β1 synthesis contributes to mechanical stress induced cardiac fibroblast activation.

    PubMed

    Song, Juan; Zhu, Yun; Li, Jiantao; Liu, Jiahao; Gao, Yun; Ha, Tuanzhu; Que, Linli; Liu, Li; Zhu, Guoqing; Chen, Qi; Xu, Yong; Li, Chuanfu; Li, Yuehua

    2015-02-01

    Activation of cardiac fibroblasts is a key event in the progression of cardiac fibrosis that leads to heart failure. However, the molecular mechanisms underlying mechanical stress-induced cardiac fibroblast activation are complex and poorly understood. This study demonstrates that Pellino1, an E3 ubiquitin ligase, was activated in vivo in pressure overloaded rat hearts and in cultured neonatal rat cardiac fibroblasts (NRCFs) exposed to mechanical stretch in vitro. Suppression of the expression and activity of Pellino1 by adenovirus-mediated delivery of shPellino1 (adv-shpeli1) attenuated pressure overload-induced cardiac dysfunction and cardiac hypertrophy and decreased cardiac fibrosis in rat hearts. Transfection of adv-shpeli1 also significantly attenuated mechanical stress-induced proliferation, differentiation and collagen synthesis in NRCFs. Pellino1 silencing also abrogated mechanical stretch-induced polyubiquitination of tumor necrosis factor-alpha receptor association factor-6 (TRAF6) and receptor-interacting protein 1 (RIP1) and consequently decreased the DNA binding activity of nuclear factor-kappa B (NF-κB) in NRCFs. In addition, Pellino1 silencing prevented stretch-induced activation of p38 and activator protein 1 (AP-1) binding activity in NRCFs. Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays showed that Pellino1 silencing prevented the binding of NF-κB and AP-1 to the promoter region of transforming growth factor-β1 (TGF-β1) thus dampening TGF-β1 transactivation. Our data reveal a previously unrecognized role of Pellino1 in extracellular matrix deposition and cardiac fibroblast activation in response to mechanical stress and provides a novel target for treatment of cardiac fibrosis and heart failure. PMID:25446187

  6. Myosin filament 3D structure in mammalian cardiac muscle☆

    PubMed Central

    AL-Khayat, Hind A.; Morris, Edward P.; Kensler, Robert W.; Squire, John M.

    2008-01-01

    A number of cardiac myopathies (e.g. familial hypertrophic cardiomyopathy and dilated cardiomyopathy) are linked to mutations in cardiac muscle myosin filament proteins, including myosin and myosin binding protein C (MyBP-C). To understand the myopathies it is necessary to know the normal 3D structure of these filaments. We have carried out 3D single particle analysis of electron micrograph images of negatively stained isolated myosin filaments from rabbit cardiac muscle. Single filament images were aligned and divided into segments about 2 × 430 Å long, each of which was treated as an independent ‘particle’. The resulting 40 Å resolution 3D reconstruction showed both axial and azimuthal (no radial) myosin head perturbations within the 430 Å repeat, with successive crown rotations of approximately 60°, 60° and 0°, rather than the regular 40° for an unperturbed helix. However, it is shown that the projecting density peaks appear to start at low radius from origins closer to those expected for an unperturbed helical filament, and that the azimuthal perturbation especially increases with radius. The head arrangements in rabbit cardiac myosin filaments are very similar to those in fish skeletal muscle myosin filaments, suggesting a possible general structural theme for myosin filaments in all vertebrate striated muscles (skeletal and cardiac). PMID:18472277

  7. UPDATE: CARDIAC XENOTRANSPLANTATION

    PubMed Central

    Ekser, Burcin; Cooper, David K.C.

    2009-01-01

    Purpose of review To review the latest development in cardiac xenotransplantation in small and large animal models and related in vitro studies. Recent findings With the recent introduction of α1,3-galactosyltransferase gene-knockout (GT-KO) pig organs for xenotransplantation, improved cardiac graft survival has been obtained. However, this experience has demonstrated the importance of pig antigens other than Galα1,3Gal (Gal) antigens (so-called nonGal antigens) as targets for primate anti-pig antibodies. Several in vitro studies have confirmed that, although the incidence and levels of anti-nonGal antibodies in non-human primates and humans are significantly less when compared with total anti-pig antibodies (i.e., anti-Gal + anti-nonGal), they can result in complement-mediated lysis of GT-KO pig cells. More recently, it has been demonstrated that regulatory T cells (Treg) suppress the cellular xenogeneic response, thus potentially preventing or reducing T cell-mediated rejection. The importance of thrombotic microangiopathy as a feature of the immune/inflammatory response and incompatibilities between the coagulation-anticoagulation systems of pig and primate are receiving increasing attention. Development of GT-KO pigs transgenic for one or more ‘anti-thrombotic’ genes, e.g., CD39 or tissue factor pathway inhibitor, may contribute to overcoming these problems. Summary Although GT-KO pigs have provided an advance over wild-type pigs as a source of Organs for transplantation into primates, further genetic modification of GT-KO pigs is required to overcome the remaining immune barriers before a clinical trial of cardiac xenotransplantation can be contemplated. PMID:19060538

  8. Dipyridamole cardiac imaging

    SciTech Connect

    Iskandrian, A.S.; Heo, J.; Askenase, A.; Segal, B.L.; Auerbach, N.

    1988-02-01

    Dipyridamole cardiac imaging is a useful alternative technique to exercise stress testing in the evaluation of patients with ischemic heart disease. Intravenous dipyridamole is still in the investigational phase, while oral dipyridamole is widely available. The hemodynamic effects of dipyridamole include an increase in coronary blood flow (due to coronary vasodilation) which is in excess of the increase in myocardial oxygen consumption and cardiac output. The disparity in the increase in coronary blood flow relative to the cardiac output results in an increase in myocardial thallium activity and an increase in the myocardial/background activity ratio. The quality of the thallium images is better or similar to that of exercise thallium images. The optimal dose of intravenous dipyridamole is 0.56 mg/kg, and of the oral dose it is 300 to 400 mg, although higher doses may be necessary in some patients. Analysis of the thallium images has been to a large extent based on visual inspection of the planar images. Delayed images are helpful to establish the nature of the perfusion abnormalities (transient or fixed). The process of redistribution is based on disparate rates of washout from the normal and abnormal zones. The sensitivity and specificity of dipyridamole thallium imaging, whether intravenous or oral, have been shown in a number of studies to be quite adequate and comparable to that achieved during exercise thallium imaging. Dipyridamole two-dimensional echocardiography has also been used in the detection of coronary artery disease; transient (new or worsening of preexisting) wall motion abnormalities have been found to be a specific marker of coronary artery disease. Transmural as well as regional coronary steal phenomena have been postulated as the mechanism for dipyridamole-induced regional wall motion abnormalities. 65 references.

  9. The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells.

    PubMed Central

    Ip, H S; Wilson, D B; Heikinheimo, M; Tang, Z; Ting, C N; Simon, M C; Leiden, J M; Parmacek, M S

    1994-01-01

    The unique contractile phenotype of cardiac myocytes is determined by the expression of a set of cardiac muscle-specific genes. By analogy to other mammalian developmental systems, it is likely that the coordinate expression of cardiac genes is controlled by lineage-specific transcription factors that interact with promoter and enhancer elements in the transcriptional regulatory regions of these genes. Although previous reports have identified several cardiac muscle-specific transcriptional elements, relatively little is known about the lineage-specific transcription factors that regulate these elements. In this report, we demonstrate that the slow/cardiac muscle-specific troponin C (cTnC) enhancer contains a specific binding site for the lineage-restricted zinc finger transcription factor GATA-4. This GATA-4-binding site is required for enhancer activity in primary cardiac myocytes. Moreover, the cTnC enhancer can be transactivated by overexpression of GATA-4 in non-cardiac muscle cells such as NIH 3T3 cells. In situ hybridization studies demonstrate that GATA-4 and cTnC have overlapping patterns of expression in the hearts of postimplantation mouse embryos and that GATA-4 gene expression precedes cTnC expression. Indirect immunofluorescence reveals GATA-4 expression in cultured cardiac myocytes from neonatal rats. Taken together, these results are consistent with a model in which GATA-4 functions to direct tissue-specific gene expression during mammalian cardiac development. Images PMID:7935467

  10. Identification of genes regulated during mechanical load-induced cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Johnatty, S. E.; Dyck, J. R.; Michael, L. H.; Olson, E. N.; Abdellatif, M.; Schneider, M. (Principal Investigator)

    2000-01-01

    Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

  11. Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes.

    PubMed

    Thaung, H P Aye; Baldi, J Chris; Wang, Heng-Yu; Hughes, Gillian; Cook, Rosalind F; Bussey, Carol T; Sheard, Phil W; Bahn, Andrew; Jones, Peter P; Schwenke, Daryl O; Lamberts, Regis R

    2015-08-01

    Elevated sympathetic nerve activity (SNA) coupled with dysregulated β-adrenoceptor (β-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the β-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to β-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular β1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial β2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac β-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart. PMID:25784543

  12. Adaptive SPECT

    PubMed Central

    Barrett, Harrison H.; Furenlid, Lars R.; Freed, Melanie; Hesterman, Jacob Y.; Kupinski, Matthew A.; Clarkson, Eric; Whitaker, Meredith K.

    2008-01-01

    Adaptive imaging systems alter their data-acquisition configuration or protocol in response to the image information received. An adaptive pinhole single-photon emission computed tomography (SPECT) system might acquire an initial scout image to obtain preliminary information about the radiotracer distribution and then adjust the configuration or sizes of the pinholes, the magnifications, or the projection angles in order to improve performance. This paper briefly describes two small-animal SPECT systems that allow this flexibility and then presents a framework for evaluating adaptive systems in general, and adaptive SPECT systems in particular. The evaluation is in terms of the performance of linear observers on detection or estimation tasks. Expressions are derived for the ideal linear (Hotelling) observer and the ideal linear (Wiener) estimator with adaptive imaging. Detailed expressions for the performance figures of merit are given, and possible adaptation rules are discussed. PMID:18541485

  13. Cardiac parasympathetic reactivation following exercise: implications for training prescription.

    PubMed

    Stanley, Jamie; Peake, Jonathan M; Buchheit, Martin

    2013-12-01

    The objective of exercise training is to initiate desirable physiological adaptations that ultimately enhance physical work capacity. Optimal training prescription requires an individualized approach, with an appropriate balance of training stimulus and recovery and optimal periodization. Recovery from exercise involves integrated physiological responses. The cardiovascular system plays a fundamental role in facilitating many of these responses, including thermoregulation and delivery/removal of nutrients and waste products. As a marker of cardiovascular recovery, cardiac parasympathetic reactivation following a training session is highly individualized. It appears to parallel the acute/intermediate recovery of the thermoregulatory and vascular systems, as described by the supercompensation theory. The physiological mechanisms underlying cardiac parasympathetic reactivation are not completely understood. However, changes in cardiac autonomic activity may provide a proxy measure of the changes in autonomic input into organs and (by default) the blood flow requirements to restore homeostasis. Metaboreflex stimulation (e.g. muscle and blood acidosis) is likely a key determinant of parasympathetic reactivation in the short term (0-90 min post-exercise), whereas baroreflex stimulation (e.g. exercise-induced changes in plasma volume) probably mediates parasympathetic reactivation in the intermediate term (1-48 h post-exercise). Cardiac parasympathetic reactivation does not appear to coincide with the recovery of all physiological systems (e.g. energy stores or the neuromuscular system). However, this may reflect the limited data currently available on parasympathetic reactivation following strength/resistance-based exercise of variable intensity. In this review, we quantitatively analyse post-exercise cardiac parasympathetic reactivation in athletes and healthy individuals following aerobic exercise, with respect to exercise intensity and duration, and fitness

  14. [Chronic surplus of Japanese cardiac surgeon--ideal nurse practitioner for cardiac surgery, cardiac surgeon's attitude toward the future].

    PubMed

    Ikegami, Hirohisa

    2014-03-01

    It is chronically surplus of doctors in the world of cardiac surgery. There are too many cardiac surgeons because cardiac surgery requires a large amount of manpower resources to provide adequate medical services. Many Japanese cardiac surgeons do not have enough opportunity to perform cardiac surgery operations, and many Japanese cardiac surgery residents do not have enough opportunity to learn cardiac surgery operations. There are physician assistants and nurse practitioners in the US. Because they provide a part of medical care to cardiac surgery patients, American cardiac surgeons can focus more energy on operative procedures. Introduction of cardiac surgery specialized nurse practitioner is essential to deliver a high quality medical service as well as to solve chronic problems that Japanese cardiac surgery has had for a long time. PMID:24749334

  15. Health Instruction Packages: Cardiac Anatomy.

    ERIC Educational Resources Information Center

    Phillips, Gwen; And Others

    Text, illustrations, and exercises are utilized in these five learning modules to instruct nurses, students, and other health care professionals in cardiac anatomy and functions and in fundamental electrocardiographic techniques. The first module, "Cardiac Anatomy and Physiology: A Review" by Gwen Phillips, teaches the learner to draw and label…

  16. Current perspectives on cardiac amyloidosis

    PubMed Central

    Guan, Jian; Mishra, Shikha; Falk, Rodney H.

    2012-01-01

    Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis. PMID:22058156

  17. Redox Control of Cardiac Excitability

    PubMed Central

    Aggarwal, Nitin T.

    2013-01-01

    Abstract Reactive oxygen species (ROS) have been associated with various human diseases, and considerable attention has been paid to investigate their physiological effects. Various ROS are synthesized in the mitochondria and accumulate in the cytoplasm if the cellular antioxidant defense mechanism fails. The critical balance of this ROS synthesis and antioxidant defense systems is termed the redox system of the cell. Various cardiovascular diseases have also been affected by redox to different degrees. ROS have been indicated as both detrimental and protective, via different cellular pathways, for cardiac myocyte functions, electrophysiology, and pharmacology. Mostly, the ROS functions depend on the type and amount of ROS synthesized. While the literature clearly indicates ROS effects on cardiac contractility, their effects on cardiac excitability are relatively under appreciated. Cardiac excitability depends on the functions of various cardiac sarcolemal or mitochondrial ion channels carrying various depolarizing or repolarizing currents that also maintain cellular ionic homeostasis. ROS alter the functions of these ion channels to various degrees to determine excitability by affecting the cellular resting potential and the morphology of the cardiac action potential. Thus, redox balance regulates cardiac excitability, and under pathological regulation, may alter action potential propagation to cause arrhythmia. Understanding how redox affects cellular excitability may lead to potential prophylaxis or treatment for various arrhythmias. This review will focus on the studies of redox and cardiac excitation. Antioxid. Redox Signal. 18, 432–468. PMID:22897788

  18. [Hygienic handling in cardiac surgery].

    PubMed

    Shimasaki, T; Masaoka, T; Hirooka, S; Abe, H; Watanabe, T; Washio, M

    1993-04-01

    Some points regarding the hygienic handling in cardiac surgery are mentioned. The sternal infection or mediastinitis is still one of the most important complications after cardiac operation especially when ITA is used for CABG. After we paid much attention to these points, the postoperative sternal infection has decreased obviously. PMID:8468855

  19. Cardiac rehabilitation in Germany.

    PubMed

    Cantwell, J D

    1976-09-01

    The concept of cardiac reconditioning centers for the prevention and rehabilitation of coronary patients has been tremendously successful in Germany over the past 20 years. At least 40 such centers are located throughout the country. Physicians, nurses, and physical therapists work closely together in the various facets of the rehabilitation process. The financial backing for these facilities is primarily through governmental and regional insurance companies, whose officials are apparently convinced that in the long run supporting preventive measures is financially sound. Objective data supporting their convictions come from studies such as that of Brusis, who showed that such as that of 1,500 employees was diminished by nearly 70 percent during a two-year period after cardiac reconditioning, as compared to a similar time period before the rehabilitation experience. Subjective benefits, which are extremely difficult to quantitate in meaningful terms, were nonetheless expressed by nearly all the patients with whom I conversed. Perhaps they have experienced the same feelings that Mark Twain did when he observed that "all frets and worries and chafings sank to sleep in the presence of the benignant serenity of the Alps; the Great Spirit of the Mountains breathed his own peace upon their hurt minds and sore hearts and healed them." PMID:959329

  20. Decoding the Cardiac Message

    PubMed Central

    Dorn, Gerald W

    2012-01-01

    This review reflects and expands upon the contents of the author’s presentation at The Thomas W. Smith Memorial Lecture at AHA Scientific Sessions, 2011. “Decoding the cardiac message” refers to accumulating results from ongoing microRNA research that is altering longstanding concepts of the mechanisms for, and consequences of, messenger RNA (mRNA) regulation in the heart. First, I provide a brief historical perspective of the field of molecular genetics, touching upon seminal research that paved the way for modern molecular cardiovascular research and helped establish the foundation for current concepts of mRNA regulation in the heart. I follow with some interesting details about the specific research that led to the discovery and appreciation of microRNAs as highly conserved pivotal regulators of RNA expression and translation. Finally, I provide a personal viewpoint as to how agnostic genome-wide techniques for measuring microRNAs, their mRNA targets, and their protein products can be applied in an integrated multi-systems approach to uncover direct and indirect effects of microRNAs. Experimental designs integrating next-generation sequencing and global proteomics have the potential to address unanswered questions regarding microRNA-mRNA interactions in cardiac disease, how disease alters mRNA targeting by specific microRNAs, and how mutational and polymorphic nucleotide variation in microRNAs can affect end-organ function and stress-response. PMID:22383710

  1. Pregnancy After Cardiac Surgery.

    PubMed

    Kanhere, Anjali Vivek; Kanhere, Vivek Madhav

    2016-02-01

    Heart disease is one of the common, indirect obstetric causes of maternal death. Management of these cases may challenge the entire team providing care to the mother and fetus. Advances in cardiac surgery has improved quality of life and level of functioning of cardiovascular system of patients with congenital or acquired heart disease. These diseases complicate 0.1-4 % pregnancies. Maternal complications in the form of thromboembolic, hemorrhagic episode and heart failure may occur. The fetus is in danger of effects of oral anticoagulation therapy and other medications given to the patient in order to support cardiovascular system, intrauterine growth restriction and danger of hypoxia. In recent era, we are facing more pregnant patients with previous history of surgical correction of congenital or rheumatic heart disease. In this review, we have attempted to draw a management protocol of such patients based on the available literature and various international guidelines. In pregnant women with mechanical heart valves, recent data support warfarin use throughout pregnancy, followed by a switch to heparin and planned induction of labor. However, the complexity of this situation demands a cafeteria approach where the patient herself can choose from the available options that are supported by evidence-based information. Preconception counseling, evaluation and antenatal high-risk management protocol with the help of cardiologist and cardiac surgeon improves maternal and neonatal outcome. PMID:26924901

  2. Leadership in cardiac surgery.

    PubMed

    Rao, Christopher; Patel, Vanash; Ibrahim, Michael; Ahmed, Kamran; Wong, Kathie A; Darzi, Ara; von Segesser, Ludwig K; Athanasiou, Thanos

    2011-06-01

    Despite the efficacy of cardiac surgery, less invasive interventions with more uncertain long-term outcomes are increasingly challenging surgery as first-line treatment for several congenital, degenerative and ischemic cardiac diseases. The specialty must evolve if it is to ensure its future relevance. More importantly, it must evolve to ensure that future patients have access to treatments with proven long-term effectiveness. This cannot be achieved without dynamic leadership; however, our contention is that this is not enough. The demands of a modern surgical career and the importance of the task at hand are such that the serendipitous emergence of traditional charismatic leadership cannot be relied upon to deliver necessary change. We advocate systematic analysis and strategic leadership at a local, national and international level in four key areas: Clinical Care, Research, Education and Training, and Stakeholder Engagement. While we anticipate that exceptional individuals will continue to shape the future of our specialty, the creation of robust structures to deliver collective leadership in these key areas is of paramount importance. PMID:20884217

  3. Ictal Cardiac Ryhthym Abnormalities

    PubMed Central

    Ali, Rushna

    2016-01-01

    Cardiac rhythm abnormalities in the context of epilepsy are a well-known phenomenon. However, they are under-recognized and often missed. The pathophysiology of these events is unclear. Bradycardia and asystole are preceded by seizure onset suggesting ictal propagation into the cortex impacting cardiac autonomic function, and the insula and amygdala being possible culprits. Sudden unexpected death in epilepsy (SUDEP) refers to the unanticipated death of a patient with epilepsy not related to status epilepticus, trauma, drowning, or suicide. Frequent refractory generalized tonic-clonic seizures, anti-epileptic polytherapy, and prolonged duration of epilepsy are some of the commonly identified risk factors for SUDEP. However, the most consistent risk factor out of these is an increased frequency of generalized tonic–clonic seizures (GTC). Prevention of SUDEP is extremely important in patients with chronic, generalized epilepsy. Since increased frequency of GTCS is the most consistently reported risk factor for SUDEP, effective seizure control is the most important preventive strategy. PMID:27347227

  4. Reverse Cardiac Remodeling: A Marker of Better Prognosis in Heart Failure

    PubMed Central

    Reis, José Rosino de Araújo Rocha; Cardoso, Juliano Novaes; Cardoso, Cristina Martins dos Reis; Pereira-Barretto, Antonio Carlos

    2015-01-01

    In heart failure syndrome, myocardial dysfunction causes an increase in neurohormonal activity, which is an adaptive and compensatory mechanism in response to the reduction in cardiac output. Neurohormonal activity is initially stimulated in an attempt to maintain compensation; however, when it remains increased, it contributes to the intensification of clinical manifestations and myocardial damage. Cardiac remodeling comprises changes in ventricular volume as well as the thickness and shape of the myocardial wall. With optimized treatment, such remodeling can be reversed, causing gradual improvement in cardiac function and consequently improved prognosis. PMID:26131706

  5. Affect intensity and cardiac arousal.

    PubMed

    Blascovich, J; Brennan, K; Tomaka, J; Kelsey, R M; Hughes, P; Coad, M L; Adlin, R

    1992-07-01

    Relationships between affect intensity and basal, evoked, and perceived cardiac arousal were investigated in 3 experiments. Affect intensity was assessed using Larsen and Diener's (1987) Affect Intensity Measure (AIM). Cardiac arousal was evoked with exercise in the 1st study and with mental arithmetic in the 2nd and 3rd. Perceived cardiac arousal was measured under optimal conditions using a standard heartbeat discrimination procedure. Women as a group scored higher on the AIM. Affect intensity was unrelated to basal or evoked cardiac arousal and was negatively related to perceived cardiac arousal in all 3 studies. Data suggest that affect intensity, although unrelated to actual physiological arousal, is negatively related to the accuracy with which individuals perceive their own arousal. Results are discussed within the context of an expanded arousal-regulation model (Blascovich, 1990). PMID:1494983

  6. Syndecan-4 Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

    PubMed Central

    Xie, Jun; He, Guixin; Chen, Qinhua; Sun, Jiayin; Dai, Qin; Lu, Jianrong; Li, Guannan; Wu, Han; Li, Ran; Chen, Jianzhou; Xu, Wei; Xu, Biao

    2016-01-01

    Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4–/–) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4–/– compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy. PMID:26835698

  7. Generating Primary Cultures of Murine Cardiac Myocytes and Cardiac Fibroblasts to Study Viral Myocarditis

    PubMed Central

    Sherry, Barbara

    2016-01-01

    Viruses can induce direct damage to cardiac myocytes and cardiac fibroblasts resulting in myocarditis and impaired cardiac function. Cardiac myocytes and cardiac fibroblasts display different capacities to support viral infection and generate a protective antiviral response. This chapter provides detailed protocols for generation and characterization of primary cultures of murine cardiac myocytes and cardiac fibroblasts, offering a powerful tool to probe cell type-specific responses that determine protection against viral myocarditis. PMID:25836571

  8. Developmental stage-specific regulation of atrial natriuretic factor gene transcription in cardiac cells.

    PubMed Central

    Argentin, S; Ardati, A; Tremblay, S; Lihrmann, I; Robitaille, L; Drouin, J; Nemer, M

    1994-01-01

    Cardiac myocytes undergo a major genetic switch within the first week of postnatal development, when cell division ceases terminally and many cardiac genes are either activated or silenced. We have developed stage-specific cardiocyte cultures to analyze transcriptional control of the rat atrial natriuretic factor (ANF) gene to identify the mechanisms underlying tissue-specific and developmental regulation of this gene in the heart. The first 700 bp of ANF flanking sequences was sufficient for cardiac muscle- and stage-specific expression in both atrial and ventricular myocytes, and a cardiac muscle-specific enhancer was localized between -136 and -700 bp. Deletion of this enhancer markedly reduced promoter activity in cardiac myocytes and derepressed ANF promoter activity in nonexpressing cells. Two distinct domains of the enhancer appeared to contribute differentially to cardiac specificity depending on the differentiation stage of the myocytes. DNase I footprinting of the enhancer domain active in differentiated cells revealed four putative regulatory elements including an A+T-rich region and a CArG element. Deletion mutagenesis and promoter reconstitution assays revealed an important role for the CArG-containing element exclusively in cardiac cells, where its activity was switched on in differentiated myocytes. Transcriptional activity of the ANF-CArG box correlated with the presence of a cardiac- and stage-specific DNA-binding complex which was not recognized by the c-fos serum response element. Thus, the use of this in vitro model system representing stage-specific cardiac development unraveled the presence of different regulatory mechanisms for transcription of the ANF gene during cardiac differentiation and may be useful for studying the regulatory pathways of other genes that undergo switching during cardiac myogenesis. Images PMID:8264645

  9. MeCP2 regulation of cardiac fibroblast proliferation and fibrosis by down-regulation of DUSP5.

    PubMed

    Tao, Hui; Yang, Jing-Jing; Hu, Wei; Shi, Kai-Hu; Deng, Zi-Yu; Li, Jun

    2016-01-01

    Cardiac fibrosis is a complex pathological process that includes the abnormal proliferation of cardiac fibroblasts and deposition of the extracellular matrix (ECM) proteins and collagens. Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional nuclear protein, and plays a key role in the fibrotic diseases. However, the potential role of MeCP2 in cardiac fibrosis remains unclear. We report that MeCP2 modulates cardiac fibrosis via down-regulation of dual-specificity phosphatase 5 (DUSP5), a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. MeCP2 is a critical participant in the epigenetic silencing of regulatory genes. Here, we found that down-regulation of DUSP5 in cardiac fibrosis is associated with MeCP2 over-expression. Treatment of cardiac fibroblasts with MeCP2-siRNA blocked proliferation. Knockdown of MeCP2 elevated DUSP5 expression in activated cardiac fibroblasts. Moreover, we investigated the effect of DUSP5 on the ERK1/2 activation. Our results demonstrated that MeCP2 modulates DUSP5 mediated activation of ERK1/2 in cardiac fibrosis. Taken together, these results indicated that MeCP2 acts as a key regulator of pathological cardiac fibrosis, promotes cardiac fibroblasts proliferation and fibrosis by down-regulation of DUSP5. PMID:26511729

  10. Neddylation and deneddylation in cardiac biology

    PubMed Central

    Kandala, Sridhar; Kim, Il-man; Su, Huabo

    2014-01-01

    Neddylation is a post-translational protein modification that conjugates a ubiquitin-like protein NEDD8 to target proteins. Similar to ubiquitination, neddylation is mediated by a cascade of three NEDD8 specific enzymes, an E1 activating enzyme, an E2 conjugating enzyme and one of the several E3 ligases. Neddylation is countered by the action of deneddylases via a process termed deneddylation. By altering the substrate’s conformation, stability, subcellular localization or binding affinity to DNA or proteins, neddylation regulates diverse cellular processes including the ubiquitin-proteasome system-mediated protein degradation, protein transcription, cell signaling etc. Dysregulation of neddylation has been linked to cancer, neurodegenerative disorders, and more recently, cardiac disease. Here we comprehensively overview the biochemistry, the proteome and the biological function of neddylation. We also summarize the recent progress in revealing the physiological and pathological role of neddylation and deneddylation in the heart. PMID:25628956

  11. Cardiac NO signalling in the metabolic syndrome

    PubMed Central

    Pechánová, O; Varga, Z V; Cebová, M; Giricz, Z; Pacher, P; Ferdinandy, P

    2015-01-01

    It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high-density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation. ROS/RNS can modulate cardiac NO signalling and trigger various adaptive changes in NOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardial RNS generation and decreased NO bioavailability. The increased oxidative and nitrative stress also impairs the NO-soluble guanylate cyclase (sGC) signalling pathway, limiting the ability of NO to exert its fundamental signalling roles in the heart. Enhanced ROS/RNS generation in the presence of risk factors also facilitates activation of redox-dependent transcriptional factors such as NF-κB, promoting myocardial expression of various pro-inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation of NO signalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation of NO signalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such as ACE inhibitors, certain β-blockers, and sGC activators. Better understanding of the above-mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiac NO signalling. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this

  12. Cardiac ventricular aneurysm

    PubMed Central

    Harley, Hugh R. S.

    1969-01-01

    A case of successful excision of a ventricular aneurysm due to myocardial infarction is presented. The aetiology, incidence, pathogenesis, pathology, clinical features, and diagnosis of the condition are discussed. An account is given of the haemodynamic upset caused by aneurysms of the ventricle. The prognosis of untreated aneurysms is discussed. Although there is difference of opinion, it is concluded that a ventricular aneurysm adversely affects the prognosis after myocardial infarction. The indications for, and the mortality and results of, resection of ventricular aneurysms are discussed. The conclusion is drawn that persistent cardiac failure and angina can be relieved and the risk of systemic embolism reduced by the excision of expansile ventricular aneurysms of a fibrous nature. It is possible that excision may also reduce the incidence of subsequent acute myocardial infarction. Images PMID:5821618

  13. Cardiac arrest and pregnancy

    PubMed Central

    Campbell, Tabitha A; Sanson, Tracy G

    2009-01-01

    Cardiopulmonary arrest in pregnancy is rare occurring in 1 in 30,000 pregnancies. When it does occur, it is important for a clinician to be familiar with the features peculiar to the pregnant state. Knowledge of the anatomic and physiologic changes of pregnancy is helpful in the treatment and diagnosis. Although the main focus should be on the mother, it should not be forgotten that there is another potential life at stake. Resuscitation of the mother is performed in the same manner as in any other patient, except for a few minor adjustments because of the changes of pregnancy. The specialties of obstetrics and neonatology should be involved early in the process to ensure appropriate treatment of both mother and the newborn. This article will explore the changes that occur in pregnancy and their impact on treatment. The common causes of maternal cardiac arrest will be discussed briefly. PMID:19561954

  14. Physics of Cardiac Arrhythmogenesis

    NASA Astrophysics Data System (ADS)

    Karma, Alain

    2013-04-01

    A normal heartbeat is orchestrated by the stable propagation of an excitation wave that produces an orderly contraction. In contrast, wave turbulence in the ventricles, clinically known as ventricular fibrillation (VF), stops the heart from pumping and is lethal without prompt defibrillation. I review experimental, computational, and theoretical studies that have shed light on complex dynamical phenomena linked to the initiation, maintenance, and control of wave turbulence. I first discuss advances made to understand the precursor state to a reentrant arrhythmia where the refractory period of cardiac tissue becomes spatiotemporally disordered; this is known as an arrhythmogenic tissue substrate. I describe observed patterns of transmembrane voltage and intracellular calcium signaling that can contribute to this substrate, and symmetry breaking instabilities to explain their formation. I then survey mechanisms of wave turbulence and discuss novel methods that exploit electrical pacing stimuli to control precursor patterns and low-energy pulsed electric fields to control turbulence.

  15. Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays

    SciTech Connect

    Morton, M.J.; Armstrong, D.; Abi Gerges, N.; Bridgland-Taylor, M.; Pollard, C.E.; Bowes, J.; Valentin, J.-P.

    2014-09-01

    Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies – radioligand-binding or automated electrophysiology – was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost. - Highlights: • The L-type calcium channel is a significant safety liability during drug discovery. • Radioligand-binding to the L-type calcium channel can be measured in vitro. • The assay can be run at a single test concentration as part of a screening cascade. • This measurement is highly predictive of changes in cardiac myocyte contractility.

  16. [Cardiac surgery: within the revolution!].

    PubMed

    Raanani, Ehud

    2007-11-01

    Cardiac surgery is undergoing major changes. Until recently, coronary artery bypass grafting (CABG) constituted the majority of cardiac surgery cases that were performed. The sharp rise in percutaneous coronary interventions (PCI) mainly due to the development of drug eluting stents resulted in a drop in the worldwide number of CABG cases. The cardiac surgery community reacted by developing several new surgical procedures and techniques to better treat cardiac patients. Some of those procedures are demonstrated in this special issue of the Harefuah journal. Those procedures include better techniques to repair the aortic and mitral valves, minimally invasive techniques including video assisted methodology for valves and CABG surgery, surgery for congestive heart failure including new axial flow assist devices, surgery for the treatment of atrial fibrillation and more. The excellent results in cardiac surgery caused older and sicker patients to be referred to surgery. All these are creating a "revolution" in cardiac surgery. Those new technologies, surgical techniques and high risk patients require special financing. In order to complete the revolution and continue providing advanced "state of the art" cardiac surgery procedures for the patients, there is a need for special long term economic planning by the government and the Ministry of Health. PMID:18087831

  17. Trends in Cardiac Pacemaker Batteries

    PubMed Central

    Mallela, Venkateswara Sarma; Ilankumaran, V; Rao, N.Srinivasa

    2004-01-01

    Batteries used in Implantable cardiac pacemakers-present unique challenges to their developers and manufacturers in terms of high levels of safety and reliability. In addition, the batteries must have longevity to avoid frequent replacements. Technological advances in leads/electrodes have reduced energy requirements by two orders of magnitude. Micro-electronics advances sharply reduce internal current drain concurrently decreasing size and increasing functionality, reliability, and longevity. It is reported that about 600,000 pacemakers are implanted each year worldwide and the total number of people with various types of implanted pacemaker has already crossed 3 million. A cardiac pacemaker uses half of its battery power for cardiac stimulation and the other half for housekeeping tasks such as monitoring and data logging. The first implanted cardiac pacemaker used nickel-cadmium rechargeable battery, later on zinc-mercury battery was developed and used which lasted for over 2 years. Lithium iodine battery invented and used by Wilson Greatbatch and his team in 1972 made the real impact to implantable cardiac pacemakers. This battery lasts for about 10 years and even today is the power source for many manufacturers of cardiac pacemakers. This paper briefly reviews various developments of battery technologies since the inception of cardiac pacemaker and presents the alternative to lithium iodine battery for the near future. PMID:16943934

  18. Cardiac action potential imaging

    NASA Astrophysics Data System (ADS)

    Tian, Qinghai; Lipp, Peter; Kaestner, Lars

    2013-06-01

    Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

  19. Glucose Transporters in Cardiac Metabolism and Hypertrophy

    PubMed Central

    Shao, Dan; Tian, Rong

    2016-01-01

    The heart is adapted to utilize all classes of substrates to meet the high-energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions. PMID:26756635

  20. Toll-like receptor 4 plays a central role in cardiac dysfunction during trauma hemorrhage shock

    PubMed Central

    Zhang, Xia; Lu, Chen; Gao, Ming; Cao, Xinyun; Ha, Tuanzhu; Kalbfleisch, John H.; Williams, David L.; Li, Chuanfu; Kao, Race L.

    2014-01-01

    Cardiac dysfunction is a major consequence that contributes to the high mortality of trauma-hemorrhage (TH) patients. Recent evidence suggests that innate immune and inflammatory responses mediated by Toll-like receptors (TLRs) play a critical role in the pathophysiologic mechanisms of acute organ dysfunction during TH. This study investigated the role of TLR4 in cardiac dysfunction following TH. TLR4 deficient (TLR4−/−, n=7/group) and age-matched wild type (WT, n=8/group) mice were subjected to TH that was induced by soft tissue injury and blood withdrawal from the jugular vein to a mean arterial pressure of 35 ± 5 mm Hg. Cardiac function and mean arterial pressure were measured with a Millar system before, during and after blood withdrawal. Sham surgical operated mice served as control (WT, n=9/group; TLR4−/−, n=10/group). Cardiac function in WT mice was significantly reduced following TH. However cardiac function was well preserved in TLR4−/− mice. Administration of a TLR4 antagonist (3mg/kg) to WT mice also significantly attenuated TH-induced cardiac dysfunction. Western blot showed that either TLR4−/− or TLR4 antagonist markedly attenuated TH-induced decreases in the levels of phosphorylated-Akt in myocardium. In addition, inhibition of TLR4 attenuated TH-induced myocardial NF-κB binding activity as well as lung MPO activity and TNFα production. The data indicate that TLR4 plays a central role in TH-induced cardiac dysfunction. TLR4 deficiency or TLR4 inhibition attenuated cardiac dysfunction following TH which may involve activation of the PI3K/Akt signaling and decrease of NF-κB binding activity. TLR4 antagonism may be a new and novel approach for the treatment and management of cardiac dysfunction in TH patients. PMID:24569510

  1. Absence of Training-Specific Cardiac Adaptation in Paraplegic Athletes.

    ERIC Educational Resources Information Center

    Gates, Phillip E.; Campbell, Ian G.; George, Keith P.

    2002-01-01

    Tested the hypothesis that wall thickness, but not chamber dimension, would be larger in endurance- and power-trained athletes with spinal cord injuries than in sedentary people with spinal cord injuries. Data on 11 power-trained and 5 sedentary participants showed no statistically significant differences between groups, though there was a trend…

  2. Coronary thrombus detected by cardiac CT angiography before cardiac catheterization.

    PubMed

    Slim, Ahmad M; Slim, Jennifer N; Haney, Brian R; Shry, Eric A

    2010-11-01

    A patient presented with a complaint of pleuritic chest discomfort with elevated cardiac biomarkers. After a cardiac magnetic resonance imaging scan for the suspicion of myopericarditis showed a potential myocardial infarct, a coronary CT scan was performed. This revealed a thrombus of the left anterior descending artery. Cardiac catheterization confirmed the findings, and a small clot was removed. To our knowledge, this is the first reported case of coronary thrombus being detected by CT angiography with cardiac catheterization correlation. Coronary CT angiography has been increasingly used to evaluate acute chest pain with a negative predictive value close to 100%. In a young patient with suspicion of myopericarditis, CT angiography proved to be useful in diagnosing thrombus in the coronary tree. PMID:20463613

  3. Epigenetic regulation in cardiac fibrosis

    PubMed Central

    Yu, Li-Ming; Xu, Yong

    2015-01-01

    Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this mini-review, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs. PMID:26635926

  4. Dual gated nuclear cardiac images

    SciTech Connect

    Zubal, I.G.; Bennett, G.W.; Bizais, Y.; Brill, A.B.

    1984-02-01

    A data acquisition system has been developed to collect camera events simultaneously with continually digitized electrocardiograph signals and respiratory flow measurements. Software processing of the list mode data creates more precisely gated cardiac frames. Additionally, motion blur due to heart movement during breathing is reduced by selecting events within a specific respiratory phase. Thallium myocardium images of a healthy volunteer show increased definition. This technique of combined cardiac and respiratory gating has the potential of improving the detectability of small lesions, and the characterization of cardiac wall motion.

  5. Cardiac Involvement in Ankylosing Spondylitis

    PubMed Central

    Ozkan, Yasemin

    2016-01-01

    Ankylosing spondylitis is one of the subgroup of diseases called “seronegative spondyloarthropathy”. Frequently, it affects the vertebral colon and sacroiliac joint primarily and affects the peripheral joints less often. This chronic, inflammatory and rheumatic disease can also affect the extraarticular regions of the body. The extraarticular affections can be ophthalmologic, cardiac, pulmonary or neurologic. The cardiac affection can be 2-10% in all patients. Cardiac complications such as left ventricular dysfunction, aortitis, aortic regurgitation, pericarditis and cardiomegaly are reviewed. PMID:27222669

  6. The transcription factor GATA-6 regulates pathological cardiac hypertrophy

    PubMed Central

    van Berlo, Jop H.; Elrod, John W.; van den Hoogenhof, Maarten M.G.; York, Allen J.; Aronow, Bruce J.; Duncan, Stephen A.; Molkentin, Jeffery D.

    2010-01-01

    Rationale The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown. Objective To determine the role of GATA-6 in cardiac hypertrophy and homeostasis. Methods and Results Here we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, while deletion with β-myosin heavy chain-cre (βMHC-cre) produced viable adults with greater than 95% loss of GATA-6 protein in the heart. These later mice were subjected to pressure overload induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure while control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes. Conclusions These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4. PMID:20705924

  7. Constitutive phosphorylation of cardiac myosin regulatory light chain in vivo.

    PubMed

    Chang, Audrey N; Battiprolu, Pavan K; Cowley, Patrick M; Chen, Guohua; Gerard, Robert D; Pinto, Jose R; Hill, Joseph A; Baker, Anthony J; Kamm, Kristine E; Stull, James T

    2015-04-24

    In beating hearts, phosphorylation of myosin regulatory light chain (RLC) at a single site to 0.45 mol of phosphate/mol by cardiac myosin light chain kinase (cMLCK) increases Ca(2+) sensitivity of myofilament contraction necessary for normal cardiac performance. Reduction of RLC phosphorylation in conditional cMLCK knock-out mice caused cardiac dilation and loss of cardiac performance by 1 week, as shown by increased left ventricular internal diameter at end-diastole and decreased fractional shortening. Decreased RLC phosphorylation by conventional or conditional cMLCK gene ablation did not affect troponin-I or myosin-binding protein-C phosphorylation in vivo. The extent of RLC phosphorylation was not changed by prolonged infusion of dobutamine or treatment with a β-adrenergic antagonist, suggesting that RLC is constitutively phosphorylated to maintain cardiac performance. Biochemical studies with myofilaments showed that RLC phosphorylation up to 90% was a random process. RLC is slowly dephosphorylated in both noncontracting hearts and isolated cardiac myocytes from adult mice. Electrically paced ventricular trabeculae restored RLC phosphorylation, which was increased to 0.91 mol of phosphate/mol of RLC with inhibition of myosin light chain phosphatase (MLCP). The two RLCs in each myosin appear to be readily available for phosphorylation by a soluble cMLCK, but MLCP activity limits the amount of constitutive RLC phosphorylation. MLCP with its regulatory subunit MYPT2 bound tightly to myofilaments was constitutively phosphorylated in beating hearts at a site that inhibits MLCP activity. Thus, the constitutive RLC phosphorylation is limited physiologically by low cMLCK activity in balance with low MLCP activity. PMID:25733667

  8. Muscarinic M2 receptors in bovine tracheal smooth muscle: discrepancies between binding and function.

    PubMed

    Roffel, A F; Elzinga, C R; Van Amsterdam, R G; De Zeeuw, R A; Zaagsma, J

    1988-08-01

    Previous work showing that AF-DX 116, a cardioselective muscarinic antagonist in functional experiments, does not discriminate between muscarinic receptors in bovine cardiac and tracheal membranes has been extended. In addition to AF-DX 116 we used the muscarinic antagonists, atropine, pirenzepine, 4-DAMP methobromide, gallamine, hexahydrosiladifenidol and methoctramine, in radioligand binding experiments on bovine cardiac left ventricular and tracheal smooth muscle membranes. The functional antagonism of the methacholine-induced contraction of bovine tracheal smooth muscle strips was also evaluated. An excellent correlation was found for all compounds between the binding affinities for muscarinic receptors in cardiac and tracheal smooth muscle membranes; moreover, the affinities found in cardiac membranes correspond with the pA2 values reported for atrial preparations of rat and guinea pig. However, significant and occasionally marked discrepancies were found between binding and functional affinities of these muscarinic antagonists on bovine tracheal smooth muscle. PMID:3215279

  9. Noninvasive subject-specific monitoring of autonomic-cardiac regulation.

    PubMed

    Ataee, Pedram; Hahn, Jin-Oh; Dumont, Guy A; Boyce, W Thomas

    2014-04-01

    This paper presents a feasibility study of a model-based approach to noninvasive and subject-specific monitoring of autonomic-cardiac regulation. The proposed approach is built upon individualizing a physiologically-based model by applying a parameter estimation method to routine clinical observations, thereby assuring physical transparency, computational efficiency, and clinical adaptability. To develop an efficient parameter estimation procedure, a parametric sensitivity analysis was performed on the autonomic-cardiac regulation model to identify high-sensitivity model parameters whose changes exert significant impacts on the system outputs. Then, a parameter estimation problem formulated as a nonlinear optimization was solved to estimate high-sensitivity model parameters associated with autonomic-cardiac regulation, whereas the remaining parameters were fixed at their nominal values. The proposed approach can potentially monitor temporal changes in autonomic-cardiac regulation by identifying time-varying changes in the autonomic-cardiac model parameters, including sympathetic and parasympathetic nerve activities on the heart (modulating heart rate), and sympathetic nerve activity on the arterial tree (modulating total peripheral resistance). The proof-of-concept for the proposed approach was tested using a number of experimental data from the MIMIC database and the orthostatic hypotension tests. Our finding shows that the proposed approach is able to provide low-variance estimates of the autonomic-cardiac model parameters, which are consistent with their anticipated behaviors inferred from the physiologic knowledge. An extensive comparison study must be conducted in the future to establish the clinical validity of the proposed approach. PMID:24658244

  10. Cardiac Rehabilitation: Then and Now.

    ERIC Educational Resources Information Center

    Wilson, Philip K.

    1988-01-01

    As more and more patients survive a coronary event, the need for cardiac rehabilitation will increase. The author reviews the history and current status of this field and predicts what lies ahead. (JD)

  11. MedlinePlus: Cardiac Rehabilitation

    MedlinePlus

    ... available Research Clinical Trials Journal Articles Resources Reference Desk Find an Expert For You Patient Handouts Summary Cardiac rehabilitation (rehab) is a medically supervised program to help people who have A heart attack Angioplasty or ...

  12. Endogenous Mechanisms of Cardiac Regeneration.

    PubMed

    Xiang, M S W; Kikuchi, K

    2016-01-01

    Zebrafish possess a remarkable capacity for cardiac regeneration throughout their lifetime, providing a model for investigating endogenous cellular and molecular mechanisms regulating myocardial regeneration. By contrast, adult mammals have an extremely limited capacity for cardiac regeneration, contributing to mortality and morbidity from cardiac diseases such as myocardial infarction and heart failure. However, the viewpoint of the mammalian heart as a postmitotic organ was recently revised based on findings that the mammalian heart contains multiple undifferentiated cell types with cardiogenic potential as well as a robust regenerative capacity during a short period early in life. Although it occurs at an extremely low level, continuous cardiomyocyte turnover has been detected in adult mouse and human hearts, which could potentially be enhanced to restore lost myocardium in damaged human hearts. This review summarizes and discusses recent advances in the understanding of endogenous mechanisms of cardiac regeneration. PMID:27572127

  13. Understanding traumatic blunt cardiac injury.

    PubMed

    El-Menyar, Ayman; Al Thani, Hassan; Zarour, Ahmad; Latifi, Rifat

    2012-01-01

    Cardiac injuries are classified as blunt and penetrating injuries. In both the injuries, the major issue is missing the diagnosis and high mortality. Blunt cardiac injuries (BCI) are much more common than penetrating injuries. Aiming at a better understanding of BCI, we searched the literature from January 1847 to January 2012 by using MEDLINE and EMBASE search engines. Using the key word "Blunt Cardiac Injury," we found 1814 articles; out of which 716 articles were relevant. Herein, we review the causes, diagnosis, and management of BCI. In conclusion, traumatic cardiac injury is a major challenge in critical trauma care, but the guidelines are lacking. A high index of suspicion, application of current diagnostic protocols, and prompt and appropriate management is mandatory. PMID:23041686

  14. Peri-operative Levosimendan in Patients Undergoing Cardiac Surgery: An Overview of the Evidence.

    PubMed

    Shi, William Y; Li, Sheila; Collins, Nicholas; Cottee, David B; Bastian, Bruce C; James, Allen N; Mejia, Ross

    2015-07-01

    Levosimendan, a calcium sensitiser, has recently emerged as a valuable agent in the peri-operative management of cardiac surgery patients. Levosimendan is a calcium-sensitising ionodilator. By binding to cardiac troponin C and reducing its calcium-binding co-efficient, it enhances myofilament responsiveness to calcium and thus enhances myocardial contractility without increasing oxygen demand. Current evidence suggests that levosimendan enhances cardiac function after cardiopulmonary bypass in patients with both normal and reduced left ventricular function. In addition to being used as post-operative rescue therapy for low cardiac output syndrome, a pre-operative levosimendan infusion in high risk patients with poor cardiac function may reduce inotropic requirements, the need for mechanical support, the duration of intensive care admissions as well as post-operative mortality. Indeed, it is these higher-risk patients who may experience a greater degree of benefit. Larger, multicentre randomised trials in cardiac surgery will help to elucidate the full potential of this agent. PMID:25862519

  15. Imaging modalities in cardiac electrophysiology.

    PubMed

    Hasan, Reema; Clifford, Sarah M; Ghanbari, Hamid; Schmidt, Martin; Segerson, Nathan M; Daccarett, Marcos

    2010-01-01

    Cardiac imaging, both noninvasive and invasive, has become a crucial part of evaluating patients during the electrophysiology procedure experience. These anatomical data allow electrophysiologists to not only assess who is an appropriate candidate for each procedure, but also to determine the rate of success from these procedures. This article incorporates a review of the various cardiac imaging techniques available today, with a focus on atrial arrhythmias, ventricular arrhythmias and device therapy. PMID:20014991

  16. Cardiac manifestations in systemic sclerosis

    PubMed Central

    Lambova, Sevdalina

    2014-01-01

    Primary cardiac involvement, which develops as a direct consequence of systemic sclerosis (SSc), may manifest as myocardial damage, fibrosis of the conduction system, pericardial and, less frequently, as valvular disease. In addition, cardiac complications in SSc may develop as a secondary phenomenon due to pulmonary arterial hypertension and kidney pathology. The prevalence of primary cardiac involvement in SSc is variable and difficult to determine because of the diversity of cardiac manifestations, the presence of subclinical periods, the type of diagnostic tools applied, and the diversity of patient populations. When clinically manifested, cardiac involvement is thought to be an important prognostic factor. Profound microvascular disease is a pathognomonic feature of SSc, as both vasospasm and structural alterations are present. Such alterations are thought to predict macrovascular atherosclerosis over time. There are contradictory reports regarding the prevalence of atherosclerosis in SSc. According to some authors, the prevalence of atherosclerosis of the large epicardial coronary arteries is similar to that of the general population, in contrast with other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the level of inflammation in SSc is inferior. Thus, the atherosclerotic process may not be as aggressive and not easily detectable in smaller studies. Echocardiography (especially tissue Doppler imaging), single-photon emission computed tomography, magnetic resonance imaging and cardiac computed tomography are sensitive techniques for earlier detection of both structural and functional scleroderma-related cardiac pathologies. Screening for subclinical cardiac involvement via modern, sensitive tools provides an opportunity for early diagnosis and treatment, which is of crucial importance for a positive outcome. PMID:25276300

  17. Pulmonary Hypertension in Cardiac Surgery

    PubMed Central

    Denault, André; Deschamps, Alain; Tardif, Jean-Claude; Lambert, Jean; Perrault, Louis

    2010-01-01

    Pulmonary hypertension is an important prognostic factor in cardiac surgery associated with increased morbidity and mortality. With the aging population and the associated increase severity of illness, the prevalence of pulmonary hypertension in cardiac surgical patients will increase. In this review, the definition of pulmonary hypertension, the mechanisms and its relationship to right ventricular dysfunction will be presented. Finally, pharmacological and non-pharmacological therapeutic and preventive approaches will be presented. PMID:21286273

  18. Gene Transfer into Cardiac Myocytes

    PubMed Central

    Lang, Sarah E.; Westfall, Margaret V.

    2016-01-01

    Traditional methods for DNA transfection are often inefficient and toxic for terminally differentiated cells, such as cardiac myocytes. Vector-based gene transfer is an efficient approach for introducing exogenous cDNA into these types of primary cell cultures. In this chapter, separate protocols for adult rat cardiac myocyte isolation and gene transfer with recombinant adenovirus are provided and are routinely utilized for studying the effects of sarcomeric proteins on myofilament function. PMID:25836585

  19. Cardiomyocyte specific deletion of PP2A causes cardiac hypertrophy

    PubMed Central

    Li, Lei; Fang, Chao; Xu, Di; Xu, Yidan; Fu, Heling; Li, Jianmin

    2016-01-01

    Cardiac hypertrophy is a common pathological alteration in heart disease, which has been reported to be connected with serine/threonine protein phosphatases that control the dephosphorylation of a variety of cardiac proteins. Herein, we generated protein phosphatase type 2A knockout expressing a tamoxifen-inducible Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCreMer) under the control of the a-myosin heavy chain promoter. Cardiac function of mice was determined by echocardiography. Decrease in PP2A activity leads to increased cardiomyocyte hypertrophy and fibrosis. Loss of PP2ACα leads to the heart failure, including the changes of EF, FS, LV, ANP and BNP. On the molecular level, knockout mice shows increased expression of B55a and B56e at 60 days after tamoxifen injection. Additionally, the regulation of the Akt/GSK3β/β-catenin pathway is severely disturbed in knockout mice. In conclusion, cardiomyocyte specific deletion of PP2A gene causes the cardiac hypertrophy. We will use the knockout mice to generate a type of cardiomyocyte hypertrophy mouse model with myocardial fibrosis. PMID:27186301

  20. [Stem cells and cardiac regeneration].

    PubMed

    Perez Millan, Maria Ines; Lorenti, Alicia

    2006-01-01

    Stem cells are defined by virtue of their functional attributes: absence of tissue specific differentitated markers, capable of proliferation, able to self-maintain the population, able to produce a large number of differentiated, functional progeny, able to regenerate the tissue after injury. Cell therapy is an alternative for the treatment of several diseases, like cardiac diseases (cell cardiomyoplasty). A variety of stem cells could be used for cardiac repair: from cardiac and extracardiac sources. Each cell type has its own profile of advantages, limitations, and practicability issues in specific clinical settings. Differentiation of bone marrow stem cells to cardiomyocyte-like cells have been observed under different culture conditions. The presence of resident cardiac stem cell population capable of differentiation into cardiomyocyte or vascular lineage suggests that these cells could be used for cardiac tissue repair, and represent a great promise for clinical application. Stem cells mobilization by cytokines may also offer a strategy for cardiac regeneration. The use of stem cells (embryonic and adult) may hold the key to replacing cells lost in many devastating diseases. This potential benefit is a major focus for stem cell research. PMID:17240634

  1. Global availability of cardiac rehabilitation.

    PubMed

    Turk-Adawi, Karam; Sarrafzadegan, Nizal; Grace, Sherry L

    2014-10-01

    Cardiovascular disease (CVD) is the most-prevalent noncommunicable disease and leading cause of death globally. Over 80% of deaths from CVD occur in low-income and middle-income countries (LMICs). To limit the socioeconomic impact of CVD, a comprehensive approach to health care is needed. Cardiac rehabilitation delivers a cost-effective and structured exercise, education, and risk reduction programme, which can reduce mortality by up to 25% in addition to improving a patient's functional capacity and lowering rehospitalization rates. Despite these benefits and recommendations in clinical practice guidelines, cardiac rehabilitation programmes are grossly under-used compared with revascularization or medical therapy for patients with CVD. Worldwide, only 38.8% of countries have cardiac rehabilitation programmes. Specifically, 68.0% of high-income and 23% of LMICs (8.3% for low-income and 28.2% for middle-income countries) offer cardiac rehabilitation programmes to patients with CVD. Cardiac rehabilitation density estimates range from one programme per 0.1 to 6.4 million inhabitants. Multilevel strategies to augment cardiac rehabilitation capacity and availability at national and international levels, such as supportive public health policies, systematic referral strategies, and alternative models of delivery are needed. PMID:25027487

  2. Drosophila Models of Cardiac Disease

    PubMed Central

    Piazza, Nicole; Wessells, R.J.

    2013-01-01

    The fruit fly Drosophila melanogaster has emerged as a useful model for cardiac diseases, both developmental abnormalities and adult functional impairment. Using the tools of both classical and molecular genetics, the study of the developing fly heart has been instrumental in identifying the major signaling events of cardiac field formation, cardiomyocyte specification, and the formation of the functioning heart tube. The larval stage of fly cardiac development has become an important model system for testing isolated preparations of living hearts for the effects of biological and pharmacological compounds on cardiac activity. Meanwhile, the recent development of effective techniques to study adult cardiac performance in the fly has opened new uses for the Drosophila model system. The fly system is now being used to study long-term alterations in adult performance caused by factors such as diet, exercise, and normal aging. The fly is a unique and valuable system for the study of such complex, long-term interactions, as it is the only invertebrate genetic model system with a working heart developmentally homologous to the vertebrate heart. Thus, the fly model combines the advantages of invertebrate genetics (such as large populations, facile molecular genetic techniques, and short lifespan) with physiological measurement techniques that allow meaningful comparisons with data from vertebrate model systems. As such, the fly model is well situated to make important contributions to the understanding of complicated interactions between environmental factors and genetics in the long-term regulation of cardiac performance. PMID:21377627

  3. FGF21 and Cardiac Physiopathology

    PubMed Central

    Planavila, Anna; Redondo-Angulo, Ibon; Villarroya, Francesc

    2015-01-01

    The heart is not traditionally considered either a target or a site of fibroblast growth factor-21 (FGF21) production. However, recent findings indicate that FGF21 can act as a cardiomyokine; that is, it is produced by cardiac cells at significant levels and acts in an autocrine manner on the heart itself. The heart is sensitive to the effects of FGF21, both systemic and locally generated, owing to the expression in cardiomyocytes of β-Klotho, the key co-receptor known to confer specific responsiveness to FGF21 action. FGF21 has been demonstrated to protect against cardiac hypertrophy, cardiac inflammation, and oxidative stress. FGF21 expression in the heart is induced in response to cardiac insults, such as experimental cardiac hypertrophy and myocardial infarction in rodents, as well as in failing human hearts. Intracellular mechanisms involving PPARα and Sirt1 mediate transcriptional regulation of the FGF21 gene in response to exogenous stimuli. In humans, circulating FGF21 levels are elevated in coronary heart disease and atherosclerosis, and are associated with a higher risk of cardiovascular events in patients with type 2 diabetes. These findings provide new insights into the role of FGF21 in the heart and may offer potential therapeutic strategies for cardiac disease. PMID:26379627

  4. Cardiac Regeneration and Stem Cells.

    PubMed

    Zhang, Yiqiang; Mignone, John; MacLellan, W Robb

    2015-10-01

    After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world. PMID:26269526

  5. The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury

    PubMed Central

    Beretov, Julia; Atsumi, Tatsuya; Qi, Miao; Bhindi, Ravinay; Qi, Jian C.; Madigan, Michele C.

    2016-01-01

    Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI. PMID:27031114

  6. Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5

    PubMed Central

    Belian, Elisa; Noseda, Michela; Abreu Paiva, Marta S.; Leja, Thomas; Sampson, Robert; Schneider, Michael D.

    2015-01-01

    Adult cardiac stem cells (CSCs) express many endogenous cardiogenic transcription factors including members of the Gata, Hand, Mef2, and T-box family. Unlike its DNA-binding targets, Myocardin (Myocd)—a co-activator not only for serum response factor, but also for Gata4 and Tbx5—is not expressed in CSCs. We hypothesised that its absence was a limiting factor for reprogramming. Here, we sought to investigate the susceptibility of adult mouse Sca1+ side population CSCs to reprogramming by supplementing the triad of GATA4, MEF2C, and TBX5 (GMT), and more specifically by testing the effect of the missing co-activator, Myocd. Exogenous factors were expressed via doxycycline-inducible lentiviral vectors in various combinations. High throughput quantitative RT-PCR was used to test expression of 29 cardiac lineage markers two weeks post-induction. GMT induced more than half the analysed cardiac transcripts. However, no protein was detected for the induced sarcomeric genes Actc1, Myh6, and Myl2. Adding MYOCD to GMT affected only slightly the breadth and level of gene induction, but, importantly, triggered expression of all three proteins examined (α-cardiac actin, atrial natriuretic peptide, sarcomeric myosin heavy chains). MYOCD + TBX was the most effective pairwise combination in this system. In clonal derivatives homogenously expressing MYOCD + TBX at high levels, 93% of cardiac transcripts were up-regulated and all five proteins tested were visualized. In summary: (1) GMT induced cardiac genes in CSCs, but not cardiac proteins under the conditions used. (2) Complementing GMT with MYOCD induced cardiac protein expression, indicating a more complete cardiac differentiation program. (3) Homogeneous transduction with MYOCD + TBX5 facilitated the identification of differentiating cells and the validation of this combinatorial reprogramming strategy. Together, these results highlight the pivotal importance of MYOCD in driving CSCs toward a cardiac muscle fate. PMID

  7. Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms.

    PubMed

    Lv, Tingting; Du, Yunhui; Cao, Ning; Zhang, Suli; Gong, Yulin; Bai, Yan; Wang, Wen; Liu, Huirong

    2016-01-01

    Chronic sustained stimulation of β-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of β1-adrenoceptor autoantibody (β1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that β1-AA impaired the cardiac function evaluated by echocardiography and that β1-AA triggered cardiac fibrosis in terms of increased expression of α-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive β1-AA immunized mice model during 16 weeks. Further, we showed that β1-AA activated β1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to β1-AR but not to β2-AR. Moreover, β1-AA was also likely to promote proliferation in cardiac fibroblasts through activating p38MAPK and ERK1/2 as p38MAPK inhibitor SB203580 and ERK1/2 inhibitor PD98059 partially reversed the proliferative effect. The persistent activating signalling of PKA and P38MAPK in 1 h induced by β1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from β1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that β1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of β1-AA. PMID:27577254

  8. Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms

    PubMed Central

    Lv, Tingting; Du, Yunhui; Cao, Ning; Zhang, Suli; Gong, Yulin; Bai, Yan; Wang, Wen; Liu, Huirong

    2016-01-01

    Chronic sustained stimulation of β-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of β1-adrenoceptor autoantibody (β1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that β1-AA impaired the cardiac function evaluated by echocardiography and that β1-AA triggered cardiac fibrosis in terms of increased expression of α-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive β1-AA immunized mice model during 16 weeks. Further, we showed that β1-AA activated β1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to β1-AR but not to β2-AR. Moreover, β1-AA was also likely to promote proliferation in cardiac fibroblasts through activating p38MAPK and ERK1/2 as p38MAPK inhibitor SB203580 and ERK1/2 inhibitor PD98059 partially reversed the proliferative effect. The persistent activating signalling of PKA and P38MAPK in 1 h induced by β1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from β1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that β1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of β1-AA. PMID:27577254

  9. Cannulation Strategies and Pitfalls in Minimally Invasive Cardiac Surgery

    PubMed Central

    Ramchandani, Mahesh; Al Jabbari, Odeaa; Abu Saleh, Walid K.; Ramlawi, Basel

    2016-01-01

    For any given cardiac surgery, there are two invasive components: the surgical approach and the cardiopulmonary bypass circuit. The standard approach for cardiac surgery is the median sternotomy, which offers unrestricted access to the thoracic organs—the heart, lung, and major vessels. However, it carries a long list of potential complications such as wound infection, brachial plexus palsies, respiratory dysfunction, and an unpleasant-looking scar. The cardiopulmonary bypass component also carries potential complications such as end-organ dysfunction, coagulopathy, hemodilution, bleeding, and blood transfusion requirement. Furthermore, the aortic manipulation during cannulation and cross clamping increases the risk of dissection, arterial embolization, and stroke. Minimally invasive cardiac surgery is an iconic event in the history of cardiothoracic medicine and has become a widely adapted approach as it minimizes many of the inconvenient side effects associated with the median sternotomy and bypass circuit placement. This type of surgery requires the use of novel perfusion strategies, especially in patients who hold the highest potential for postoperative morbidity. Cannulation techniques are a fundamental element in minimally invasive cardiac surgery, and there are numerous cannulation procedures for each type of minimally invasive operation. In this review, we will highlight the strategies and pitfalls associated with a minimally invasive cannulation. PMID:27127556

  10. Pay attention to cardiac remodeling in cancer cachexia.

    PubMed

    Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

    2016-07-01

    Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival. PMID:27108265

  11. Automatic phase determination for retrospectively gated cardiac CT

    SciTech Connect

    Manzke, R.; Koehler, Th.; Nielsen, T.; Hawkes, D.; Grass, M.

    2004-12-01

    The recent improvements in CT detector and gantry technology in combination with new heart rate adaptive cone beam reconstruction algorithms enable the visualization of the heart in three dimensions at high spatial resolution. However, the finite temporal resolution still impedes the artifact-free reconstruction of the heart at any arbitrary phase of the cardiac cycle. Cardiac phases must be found during which the heart is quasistationary to obtain outmost image quality. It is challenging to find these phases due to intercycle and patient-to-patient variability. Electrocardiogram (ECG) information does not always represent the heart motion with an adequate accuracy. In this publication, a simple and efficient image-based technique is introduced which is able to deliver stable cardiac phases in an automatic and patient-specific way. From low-resolution four-dimensional data sets, the most stable phases are derived by calculating the object similarity between subsequent phases in the cardiac cycle. Patient-specific information about the object motion can be determined and resolved spatially. This information is used to perform optimized high-resolution reconstructions at phases of little motion. Results based on a simulation study and three real patient data sets are presented. The projection data were generated using a 16-slice cone beam CT system in low-pitch helical mode with parallel ECG recording.

  12. Cardiac achalasia in childhood

    PubMed Central

    Singh, Harjit; Sethi, R. S.; Gupta, H. L.; Khetarpal, S. K.

    1969-01-01

    Cardiac achalasia is a disorder not unknown in the paediatric age-group and may occur even in the neonatal period. This disorder should, therefore, be considered in all cases presenting with persistent vomiting, as well as in those with chronic respiratory disease in whom more common causes have been excluded. It is almost universally accepted that the disorder results from a disturbed function of ganglion cells in the distal oesophagus, as the disease has been reproduced in laboratory animals by denervation of the distal oesophagus. The exact pathogenesis of this degenerative change is not well understood. However, in at least some of the cases congenital absence of the ganglion cells may be responsible for this functional disturbance. This is inferred from the fact that the disease may be found in association with Hirschsprung disease, in which there is a congenital absence of ganglion cells in the terminal colon. Moreover, the occurrence of the disease in the neonatal period itself favours a congenital lesion. Surgery was preferred to other forms of treatment in the paediatric age-group in view of the reported equivocal response to mechanical dilatation and pre-disposition of children to respiratory complications. The results of surgery were satisfactory. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8 PMID:5790932

  13. Exploring cardiac biophysical properties

    PubMed Central

    Mou, Younss Ait; Bollensdorff, Christian; Cazorla, Olivier; Magdi, Yacoub; de Tombe, Pieter P.

    2015-01-01

    The heart is subject to multiple sources of stress. To maintain its normal function, and successfully overcome these stresses, heart muscle is equipped with fine-tuned regulatory mechanisms. Some of these mechanisms are inherent within the myocardium itself and are known as intrinsic mechanisms. Over a century ago, Otto Frank and Ernest Starling described an intrinsic mechanism by which the heart, even ex vivo, regulates its function on a beat-to-beat basis. According to this phenomenon, the higher the ventricular filling is, the bigger the stroke volume. Thus, the Frank-Starling law establishes a direct relationship between the diastolic and systolic function of the heart. To observe this biophysical phenomenon and to investigate it, technologic development has been a pre-requisite to scientific knowledge. It allowed for example to observe, at the cellular level, a Frank-Starling like mechanism and has been termed: Length Dependent Activation (LDA). In this review, we summarize some experimental systems that have been developed and are currently still in use to investigate cardiac biophysical properties from the whole heart down to the single myofibril. As a scientific support, investigation of the Frank-Starling mechanism will be used as a case study. PMID:26779498

  14. [Pharmaca Induced Cardiac Injury].

    PubMed

    Haen, Ekkehard

    2016-01-01

    Many drugs influence vital functions via the sympathetic and the parasympathetic system. Besides that hypersensitivity reactions and reactions by chemical radicals that arise in drug metabolism may directly harm the heart muscle cell. Cardiac adverse drug reactions (ADR) result in disturbances of the heart rhythm, negative inotropic effects, direct damage to the heart muscle cell, and reduced perfusion of heart tissue. Their importance is often neglected because pharmacologically similar drugs are licensed for completely different indications. This is of particular interest if more drugs are prescribed in combination. Now these effects may add up to pharmacodynamic drug-drug-interactions. Data banks like PSIAConline (www.psiac.de), individualization of drug prescription by therapeutic drug monitoring (TDM) combined with a clinical pharmacological report (www.konbest.de), as well as drug information systems such as AGATE (www.amuep-agate.de) are today of help not just to recognize such drug risks, but also to find professional and evidence based solutions for it. PMID:26800070

  15. Cardiac Imaging System

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Although not available to all patients with narrowed arteries, balloon angioplasty has expanded dramatically since its introduction with an estimated further growth to 562,000 procedures in the U.S. alone by 1992. Growth has fueled demand for higher quality imaging systems that allow the cardiologist to be more accurate and increase the chances of a successful procedure. A major advance is the Digital Cardiac Imaging (DCI) System designed by Philips Medical Systems International, Best, The Netherlands and marketed in the U.S. by Philips Medical Systems North America Company. The key benefit is significantly improved real-time imaging and the ability to employ image enhancement techniques to bring out added details. Using a cordless control unit, the cardiologist can manipulate images to make immediate assessment, compare live x-ray and roadmap images by placing them side-by-side on monitor screens, or compare pre-procedure and post procedure conditions. The Philips DCI improves the cardiologist's precision by expanding the information available to him.

  16. The cardiac cycle: regulation and energy oscillations.

    PubMed

    Wikman-Coffelt, J; Sievers, R; Coffelt, R J; Parmley, W W

    1983-08-01

    Cyclical changes in energy-related metabolites were observed in glucose-perfused but not pyruvate-perfused isolated working rat hearts. A chronological study of various phases of the cardiac cycle indicated maximum changes in metabolites occurred at half time to peak pressure (dF/dtmax). The high-energy phosphates ATP and phosphocreatine, as well as the glycolytic metabolites, glucose 6-phosphate and pyruvate, reached minimum values immediately prior to peak systole and maximum values during late diastole. The products of high-energy phosphate hydrolysis, ADP, inorganic phosphate, and creatine, as well as the regulator, adenosine 3',5'-cyclic monophosphate, showed the phase alternate. It was necessary to study cyclical changes in a maximally stressed glucose-perfused heart because the cyclical changes were small and appeared to be the result of rate-limiting steps in glycolysis and the slow transport of NADH into the mitochondria. For stressing the heart, thereby increasing ATP utilization and augmenting cyclical changes, the afterload chamber was set at 110 mmHg, and the perfusate contained high concentrations of calcium (3.5 mM, free) and isoproterenol (5 X 10(-9) M). When correction was made for binding and compartmentation of metabolites, data indicated that the free energy of ATP hydrolysis was preserved during the contraction process by a continuous binding and recycling of ADP. PMID:6881368

  17. Registration-based segmentation of murine 4D cardiac micro-CT data using symmetric normalization

    NASA Astrophysics Data System (ADS)

    Clark, Darin; Badea, Alexandra; Liu, Yilin; Johnson, G. Allan; Badea, Cristian T.

    2012-10-01

    Micro-CT can play an important role in preclinical studies of cardiovascular disease because of its high spatial and temporal resolution. Quantitative analysis of 4D cardiac images requires segmentation of the cardiac chambers at each time point, an extremely time consuming process if done manually. To improve throughput this study proposes a pipeline for registration-based segmentation and functional analysis of 4D cardiac micro-CT data in the mouse. Following optimization and validation using simulations, the pipeline was applied to in vivo cardiac micro-CT data corresponding to ten cardiac phases acquired in C57BL/6 mice (n = 5). After edge-preserving smoothing with a novel adaptation of 4D bilateral filtration, one phase within each cardiac sequence was manually segmented. Deformable registration was used to propagate these labels to all other cardiac phases for segmentation. The volumes of each cardiac chamber were calculated and used to derive stroke volume, ejection fraction, cardiac output, and cardiac index. Dice coefficients and volume accuracies were used to compare manual segmentations of two additional phases with their corresponding propagated labels. Both measures were, on average, >0.90 for the left ventricle and >0.80 for the myocardium, the right ventricle, and the right atrium, consistent with trends in inter- and intra-segmenter variability. Segmentation of the left atrium was less reliable. On average, the functional metrics of interest were underestimated by 6.76% or more due to systematic label propagation errors around atrioventricular valves; however, execution of the pipeline was 80% faster than performing analogous manual segmentation of each phase.

  18. Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function

    PubMed Central

    Brown, Armand O.; Mann, Beth; Gao, Geli; Hankins, Jane S.; Humann, Jessica; Giardina, Jonathan; Faverio, Paola; Restrepo, Marcos I.; Halade, Ganesh V.; Mortensen, Eric M.; Lindsey, Merry L.; Hanes, Martha; Happel, Kyle I.; Nelson, Steve; Bagby, Gregory J.; Lorent, Jose A.; Cardinal, Pablo; Granados, Rosario; Esteban, Andres; LeSaux, Claude J.; Tuomanen, Elaine I.; Orihuela, Carlos J.

    2014-01-01

    Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD. PMID:25232870

  19. Cardiac cell survival and reversibility of myocardial ischemia.

    PubMed

    Rashed, E; Depre, C

    2006-12-01

    Because of a limited capacity for cell regeneration, the cardiac tissue, when submitted to ischemic stress, may activate endogenous mechanisms of cell survival resulting in physiological conditions of adaptation to ischemia, known as myocardial stunning, ischemic preconditioning and myocardial hibernation. These conditions result from a switch in gene and protein expression, which sustains cardiac cell survival in a context of oxygen deprivation and during the stress of reperfusion. Understanding how the molecular adaptation of the cardiac myocyte during stress sustains its survival in these conditions might help to define novel mechanisms of endogenous myocardial salvage, in order to expand the conditions of maintained cellular viability and functional salvage of the ischemic myocardium. This review summarizes recent progress made in the study of the molecular pathways controlling reversible ischemic dysfunction, and the unraveling of novel genomic paradigms. We also focus on the discovery and characterization of novel genes, which further increase our knowledge of myocardial ischemia and open novel therapeutic possibilities for ischemic heart disease. PMID:18942527

  20. Renin and the IGFII/M6P Receptor System in Cardiac Biology

    PubMed Central

    Heger, Jacqueline; Schlüter, Klaus-Dieter

    2013-01-01

    Nonenzymatic cardiac activities of renin are well described during the last years and contribute either to cardiac-specific effects of the renin-angiotensin-aldosterone-system (RAAS) or to the pharmacological effects of RAAS inhibition. The interaction of renin with insulin-like growth factor II/mannose-6-phosphate (IGFII/M6P) receptors participates in nonclassical renin effects and contributes to cardiac remodelling caused by RAAS activation. The current findings suggest an important role for renin IGFII/M6P receptor interaction in cardiac adaptation to stress and support the idea that excessive accumulation of renin during inhibition of RAAS directly contributes to blood pressure-independent effects of these pharmacological interventions. It becomes a challenge for future studies focussing on chronic hypertension or myocardial infarction to comprise regulatory adaptations of the kidney, the main source of plasma renin and prorenin, because they directly contribute to key steps in regulation of cardiac (mal)adaptation via IGFII/M6P receptors. This receptor system is part of peptide/receptor interactions that modifies and possibly limits adverse remodelling effects caused by angiotensin II. Evaluation of interactions of renin with other pro-hypertrophic agonists is required to decide whether this receptor may become a target of pharmacological intervention. PMID:24288471

  1. Adaptive Development

    NASA Technical Reports Server (NTRS)

    2005-01-01

    The goal of this research is to develop and demonstrate innovative adaptive seal technologies that can lead to dramatic improvements in engine performance, life, range, and emissions, and enhance operability for next generation gas turbine engines. This work is concentrated on the development of self-adaptive clearance control systems for gas turbine engines. Researchers have targeted the high-pressure turbine (HPT) blade tip seal location for following reasons: Current active clearance control (ACC) systems (e.g., thermal case-cooling schemes) cannot respond to blade tip clearance changes due to mechanical, thermal, and aerodynamic loads. As such they are prone to wear due to the required tight running clearances during operation. Blade tip seal wear (increased clearances) reduces engine efficiency, performance, and service life. Adaptive sealing technology research has inherent impact on all envisioned 21st century propulsion systems (e.g. distributed vectored, hybrid and electric drive propulsion concepts).

  2. Diagnostic approach to cardiac amyloidosis.

    PubMed

    Amin, Hilman Zulkifli; Mori, Shumpei; Sasaki, Naoto; Hirata, Kenichi

    2014-01-01

    Amyloidosis is a relatively rare disease that may be underdiagnosed and could affect the entire human body. Many organs may be affected, which could increase the morbidity and mortality. Cardiac involvement is the leading cause of poor prognosis. Patients with cardiac amyloidosis are usually admitted with heart failure. The clinical presentation varies greatly, and using the correct approach is important in identifying cardiac amyloidosis. A 51-year-old man was diagnosed with chronic heart failure. He had increased brain natriuretic peptide levels, a low ejection fraction, and left and right ventricular hypertrophy with granular sparkling as seen by echocardiography. These findings led us to perform a cardiac biopsy that confirmed the diagnosis of cardiac amyloidosis. Further investigation revealed that the patient had amyloid light-chain type amyloidosis due to multiple myeloma. He is now undergoing the 3rd phase of chemotherapy. Congo-red stain is usually used by physicians to histologically confirm amyloidosis, with which apple-green birefringence indicates amyloid deposits. Other stains such as direct fast scarlet (DFS) and hematoxylin-eosin (HE) can also confirm the presence of amyloid deposits. In the present case, DFS and HE were used, both of which suggested amyloid deposits surrounding myocardial cells. The use of a combination of stains can increase the diagnostic sensitivity and specificity of amyloidosis. However, the typical echocardiographic appearances would be enough to diagnose cardiac amyloidosis when it is impossible for the patient to undergo a cardiac biopsy, if an additional histological specimen from another tissue such as abdominal fat confirms amyloidosis. PMID:25011639

  3. The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

    PubMed Central

    Godfraind, T.; Lesne, M.

    1972-01-01

    1. The uptake of 3H-digitoxin, 3H-ouabain and 3H-dihydro-ouabain by isolated guinea-pig atria has been studied and compared with the inhibition of the sodium pump and with the inotropic effect. 2. Analysis of the curve relating the uptake of digitoxin and ouabain at equilibrium to the bath concentration enabled a non-saturable and a saturable binding site to be distinguished. 3. The uptake of inactive doses of dihydro-ouabain was only by a non-saturable mechanism. 4. The uptake of labelled digitoxin and ouabain was reduced in the presence of another glycoside. The amount of bound glycoside was nearly equivalent to the estimated non-saturable uptake. 5. The uptake was reduced at 4° C to the clearance of the non-saturable site. 6. ED50 of digitoxin and of ouabain for inhibition of the sodium pump were measured and compared to the ED50 for inotropic effect and to the concentrations producing a half-saturation of the saturable binding site. 7. It is concluded that binding to the saturable site may be responsible for the cardiac actions of the glycosides. PMID:4656610

  4. Endurance training prevents TWEAK but not myostatin-mediated cardiac remodelling in cancer cachexia.

    PubMed

    Padrão, Ana Isabel; Moreira-Gonçalves, Daniel; Oliveira, Paula A; Teixeira, Catarina; Faustino-Rocha, Ana I; Helguero, Luísa; Vitorino, Rui; Santos, Lúcio Lara; Amado, Francisco; Duarte, José Alberto; Ferreira, Rita

    2015-02-01

    Strategies to prevent tumour burden-induced cardiac remodelling that might progress to heart failure are necessary to improve patients' health outcomes and tolerability to cancer therapies. Exercise has been suggested as a measure to prevent cardiac damage; however, its effectiveness on regulating cardiac remodelling secondary to cancer was never addressed. Using an animal model of mammary tumorigenesis, we studied the impact of 35weeks of endurance training on heart, focusing on the signalling pathways modulated by pro-inflammatory and wasting cytokines. The cardiac fibrosis and myofiber disorganization induced by tumour burden was paralleled by the increase of myostatin and TWEAK with the activation of signalling pathways involving Smad-3, NF-κB, TRAF-6 and atrogin-1. The activation of Akt/mTOR was observed in heart from rats with tumours, for which contributed the extracellular matrix. Endurance training prevented the increase of serum and cardiac TWEAK promoted by cancer, as well as the activation of NF-κB, TRAF6, atrogin-1 and p70S6K in heart. Data highlight the impact of exercise in the modulation of signalling pathways activated by wasting cytokines and the resulting outcomes on heart adaptation. Future studies focused on the cellular pathways underlying cardiac remodelling will assist in the development of exercise programs targeting cancer-related cardiac alterations. PMID:25575785

  5. Computed tomography of cardiac pseudotumors and neoplasms.

    PubMed

    Anavekar, Nandan S; Bonnichsen, Crystal R; Foley, Thomas A; Morris, Michael F; Martinez, Matthew W; Williamson, Eric E; Glockner, James F; Miller, Dylan V; Breen, Jerome F; Araoz, Philip A

    2010-07-01

    Important features of cardiac masses can be clearly delineated on cardiac computed tomography (CT) imaging. This modality is useful in identifying the presence of a mass, its relationship with cardiac and extracardiac structures, and the features that distinguish one type of mass from another. A multimodality approach to the evaluation of cardiac tumors is advocated, with the use of echocardiography, CT imaging and magnetic resonance imaging as appropriately indicated. In this article, various cardiac masses are described, including pseudotumors and true cardiac neoplasms, and the CT imaging findings that may be useful in distinguishing these rare entities are presented. PMID:20705174

  6. Women's compliance with cardiac rehabilitation programs.

    PubMed

    Ginzel, A R

    1996-01-01

    As the incidence of cardiovascular disease in women increases, the process of cardiac rehabilitation in women is becoming increasingly important to nurses. Specifically, the issue of women's compliance with cardiac rehabilitation needs to be addressed by nurses. Most past and current research on cardiac rehabilitation and compliance with rehabilitation programs has been conducted on male subjects and cannot be accurately generalized to the female population. This article reviews current literature which addresses the issues of heart disease in women, cardiac rehabilitation and compliance in the general population, gender differences in cardiac rehabilitation, and compliance of women in cardiac rehabilitation. PMID:8657707

  7. Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer.

    PubMed

    Huang, Dong-Ming; Guh, Jih-Hwa; Huang, Yao-Ting; Chueh, Shih-Chieh; Wang, Hui-Po; Teng, Che-Ming

    2002-01-01

    Due to high prevalence and mortality and the lack of effective therapies, prostate cancer is one of the most crucial health problems in men. Drug resistance aggravates the situation, not only in human prostate cancer but also in other cancers. In this study, we report for the first time that cardiac glycosides (e.g. ouabain and digitoxin) induced resistance of human prostate cancer cells (PC-3) in vitro to tubulin-binding anticancer drugs, such as paclitaxel, colchicine, vincristine and vinblastine. Cardiac glycosides exhibited amazing ability to reverse the G2/M arrest of the cell cycle and cell apoptosis induced by tubulin-binding agents. However, neither ionomycin (a Ca(2+) ionophore) nor veratridine (a Na(+) ionophore) mimicked the preventive action of cardiac glycosides, indicating that elevation of the intracellular Ca(2+) concentration and Na(+) accumulation were not involved in the cardiac glycoside action. Furthermore, cardiac glycosides showed little influence on the effects induced by actinomycin D, anisomycin and doxorubicin, suggesting selectivity for microtubule-targeted anticancer drugs. Using in situ immunofluorescent detection of mitotic spindles, our data showed that cardiac glycosides diminished paclitaxel-induced accumulation of microtubule spindles; however, in a non-cell assay system, cardiac glycosides had little influence on colchicine- and paclitaxel-induced microtubule dynamics. Using an isotope-labeled assay method, we found that ouabain modestly but significantly inhibited the transport of [(14)C]paclitaxel from the cytosol into the nucleus. It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function. The decline in transport of these drugs into the nucleus may partly explain the action of cardiac glycosides. PMID:12218360

  8. Sudden cardiac death.

    PubMed

    Sra, J; Dhala, A; Blanck, Z; Deshpande, S; Cooley, R; Akhtar, M

    1999-08-01

    SCD continues to be an important cause of death and morbidity. Despite expanding insight into the mechanisms causing SCD, the population at high risk is not being effectively identified. Although there is still much to do in the management phase of SCD (predicting the efficacy of various therapies), recent clinical trials have helped define the relative risks and benefits of therapies in preventing SCD. Trials are underway to determine whether treating other patient populations, including asymptomatic patients after MI, will improve survival rate. The approach to reducing mortality rate will always be multifaceted; primary prevention of coronary artery disease and prompt salvage of jeopardized myocardium are 2 important aspects of this approach. In addition to interventions for MI, such as myocardial revascularization when indicated, simple and easily administered therapies that are likely to remain the most effective prophylactic interventions are aspirin, ACE inhibitors, beta-blockers, and cholesterol-lowering agents. However, the MADIT and AVID data clearly demonstrate a role for ICD therapy in a subgroup of patients who have VT/VF and are at risk of cardiac arrest. Even though the absolute magnitude of benefit associated with ICDs is still to be determined, the AVID study and other recent reports provide convincing evidence that patients who have VT/VF fare better with ICDs than with antiarrhythmic drug therapy. For the high-risk population described in this article, in addition to aggressive anti-ischemic and heart failure therapy, ICDs are now a mainstay of life-saving treatment. Still to be surmounted is the challenge of identifying patients who have nonischemic substrates and of providing them with the appropriate therapy. Guided by genetic studies and new insight into the mechanisms of such problems as congenital long QT syndrome, life-saving and life-enhancing therapies may soon be available for the management of SCD. PMID:10459474

  9. Neurological prognostication after cardiac arrest

    PubMed Central

    Sandroni, Claudio; Geocadin, Romergryko G.

    2016-01-01

    Purpose of review Prediction of neurological prognosis in patients who are comatose after successful resuscitation from cardiac arrest remains difficult. Previous guidelines recommended ocular reflexes, somatosensory evoked potentials and serum biomarkers for predicting poor outcome within 72h from cardiac arrest. However, these guidelines were based on patients not treated with targeted temperature management and did not appropriately address important biases in literature. Recent findings Recent evidence reviews detected important limitations in prognostication studies, such as low precision and, most importantly, lack of blinding, which may have caused a self-fulfilling prophecy and overestimated the specificity of index tests. Maintenance of targeted temperature using sedatives and muscle relaxants may interfere with clinical examination, making assessment of neurological status before 72 h or more after cardiac arrest unreliable. Summary No index predicts poor neurological outcome after cardiac arrest with absolute certainty. Prognostic evaluation should start not earlier than 72 h after ROSC and only after major confounders have been excluded so that reliable clinical examination can be made. Multimodality appears to be the most reasonable approach for prognostication after cardiac arrest. PMID:25922894

  10. Vitamin D and Cardiac Differentiation.

    PubMed

    Kim, Irene M; Norris, Keith C; Artaza, Jorge N

    2016-01-01

    Calcitriol (1,25-dihydroxycholecalciferol or 1,25-D3) is the hormonally active metabolite of vitamin D. Experimental studies of vitamin D receptors and 1,25-D3 establish calcitriol to be a critical regulator of the structure and function of the heart. Clinical studies link vitamin D deficiency with cardiovascular disease (CVD). Emerging evidence demonstrates that calcitriol is highly involved in CVD-related signaling pathways, particularly the Wnt signaling pathway. Addition of 1,25-D3 to cardiomyocyte cells and examination of its effects on cardiomyocytes and mainly Wnt11 signaling allowed the specific characterization of the role of calcitriol in cardiac differentiation. 1,25-D3 is demonstrated to: (i) inhibit cell proliferation without promoting apoptosis; (ii) decrease expression of genes related to the regulation of the cell cycle; (iii) promote formation of cardiomyotubes; (iv) induce expression of casein kinase-1-α1, a negative regulator of the canonical Wnt signaling pathway; and (v) increase expression of noncanonical Wnt11, which has been recognized to induce cardiac differentiation during embryonic development and in adult cells. Thus, it appears that vitamin D promotes cardiac differentiation through negative modulation of the canonical Wnt signaling pathway and upregulation of noncanonical Wnt11 expression. Future work to elucidate the role(s) of vitamin D in cardiovascular disorders will hopefully lead to improvement and potentially prevention of CVD, including abnormal cardiac differentiation in settings such as postinfarction cardiac remodeling. PMID:26827957

  11. Animal models of cardiac cachexia.

    PubMed

    Molinari, Francesca; Malara, Natalia; Mollace, Vincenzo; Rosano, Giuseppe; Ferraro, Elisabetta

    2016-09-15

    Cachexia is the loss of body weight associated with several chronic diseases including chronic heart failure (CHF). The cachectic condition is mainly due to loss of skeletal muscle mass and adipose tissue depletion. The majority of experimental in vivo studies on cachexia rely on animal models of cancer cachexia while a reliable and appropriate model for cardiac cachexia has not yet been established. A critical issue in generating a cardiac cachexia model is that genetic modifications or pharmacological treatments impairing the heart functionality and used to obtain the heart failure model might likely impair the skeletal muscle, this also being a striated muscle and sharing with the myocardium several molecular and physiological mechanisms. On the other hand, often, the induction of heart damage in the several existing models of heart failure does not necessarily lead to skeletal muscle loss and cachexia. Here we describe the main features of cardiac cachexia and illustrate some animal models proposed for cardiac cachexia studies; they include the genetic calsequestrin and Dahl salt-sensitive models, the monocrotaline model and the surgical models obtained by left anterior descending (LAD) ligation, transverse aortic constriction (TAC) and ascending aortic banding. The availability of a specific animal model for cardiac cachexia is a crucial issue since, besides the common aspects of cachexia in the different syndromes, each disease has some peculiarities in its etiology and pathophysiology leading to cachexia. Such peculiarities need to be unraveled in order to find new targets for effective therapies. PMID:27317993

  12. Cardiac factors in orthostatic hypotension

    NASA Astrophysics Data System (ADS)

    Löllgen, H.; Dirschedl, P.; Koppenhagen, K.; Klein, K. E.

    Cardiac function is determined by preload, afterload, heart rate and contractility. During orthostatic stress, the footward blood shift is compensated for by an increase of afterload. LBNP is widely used to analyze effects of volume displacement during orthostatic stress. Comparisons of invasive ( right heart catheterization) and non-invasive approach (echocardiography) yielded similar changes. Preload and afterload change with graded LBNP, heart rate increases, and stroke volume and cardiac output decrease. Thus, the working point on the left ventricular function curve is shifted to the left and downward, similar to hypovolemia. However, position on the Frank-Starling curve, the unchanged ejection fraction, and the constant Vcf indicate a normal contractile state during LBNP. A decrease of arterial oxygen partial pressure during LBNP shwos impaired ventilation/perfusion ratio. Finally, LBNP induced cardiac and hemodynamic changes can be effectively countermeasured by dihydroergotamine, a potent venoconstrictor. Comparison of floating catheter data with that of echocardiography resulted in close correlation for cardiac output and stroke volume. In addition, cardiac dimensions changed in a similar way during LBNP. From our findings, echocardiography as a non-invasive procedure can reliably used in LBNP and orthostatic stress tests. Some informations can be obtained on borderline values indicating collaps or orthostatic syncope. Early fainters can be differentiated from late fainters by stroke volume changes.

  13. Adapting Animals.

    ERIC Educational Resources Information Center

    Wedman, John; Wedman, Judy

    1985-01-01

    The "Animals" program found on the Apple II and IIe system master disk can be adapted for use in the mathematics classroom. Instructions for making the necessary changes and suggestions for using it in lessons related to geometric shapes are provided. (JN)

  14. Adaptive Thresholds

    SciTech Connect

    Bremer, P. -T.

    2014-08-26

    ADAPT is a topological analysis code that allow to compute local threshold, in particular relevance based thresholds for features defined in scalar fields. The initial target application is vortex detection but the software is more generally applicable to all threshold based feature definitions.

  15. Adaptive homeostasis.

    PubMed

    Davies, Kelvin J A

    2016-06-01

    Homeostasis is a central pillar of modern Physiology. The term homeostasis was invented by Walter Bradford Cannon in an attempt to extend and codify the principle of 'milieu intérieur,' or a constant interior bodily environment, that had previously been postulated by Claude Bernard. Clearly, 'milieu intérieur' and homeostasis have served us well for over a century. Nevertheless, research on signal transduction systems that regulate gene expression, or that cause biochemical alterations to existing enzymes, in response to external and internal stimuli, makes it clear that biological systems are continuously making short-term adaptations both to set-points, and to the range of 'normal' capacity. These transient adaptations typically occur in response to relatively mild changes in conditions, to programs of exercise training, or to sub-toxic, non-damaging levels of chemical agents; thus, the terms hormesis, heterostasis, and allostasis are not accurate descriptors. Therefore, an operational adjustment to our understanding of homeostasis suggests that the modified term, Adaptive Homeostasis, may be useful especially in studies of stress, toxicology, disease, and aging. Adaptive Homeostasis may be defined as follows: 'The transient expansion or contraction of the homeostatic range in response to exposure to sub-toxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events.' PMID:27112802

  16. Review of High-intensity Interval Training in Cardiac Rehabilitation.

    PubMed

    Ito, Shigenori; Mizoguchi, Tatsuya; Saeki, Tomoaki

    2016-01-01

    For the secondary prevention of cardiovascular disease, comprehensive cardiac rehabilitation is required. This involves optimal medical therapy, education on nutrition and exercise therapy, and smoking cessation. Of these, efficient exercise therapy is a key factor. A highly effective training protocol is therefore warranted, which requires a high rate of compliance. Although moderate-intensity continuous training has been the main training regimen recommended in cardiac rehabilitation guidelines, high-intensity interval training has been reported to be more effective in the clinical and experimental setting from the standpoint of peak oxygen uptake and central and peripheral adaptations. In this review, we illustrate the scientific evidence for high-intensity interval training. We then verify this evidence and discuss its significance and the remaining issues. PMID:27580530

  17. Tlr4 Deficiency Protects against Cardiac Pressure Overload Induced Hyperinflammation

    PubMed Central

    Boehm, Olaf; El Aissati, Sakina; Foltz, Fabian; Goelz, Lina; Goertz, David; Kebir, Sied; Weisheit, Christina; Wolf, Michael; Meyer, Rainer; Baumgarten, Georg

    2015-01-01

    Transverse aortic constriction provokes a pro-inflammatory reaction and results in cardiac hypertrophy. Endogenous ligands contribute to cardiac hypertrophy via toll-like receptor (TLR)-4 binding. A lack of TLR4 signaling diminishes hypertrophy and inflammation. Wild type mice undergoing aortic constriction respond to a lipopolysaccharide second-hit stimulus with hyperinflammation. The objective of this study was to assess whether other second-hit challenges utilizing TLR ligands provoke a comparable inflammatory reaction, and to find out whether this response is absent in TLR4 deficient mice. Assuming that cardiac stress alters the expression of pattern recognition receptors we analyzed the effects of transverse aortic constriction and second-hit virulence factor treatment on TLR expression, as well as cytokine regulation. Wild type and Tlr4-/- mice were subjected to three days of TAC and subsequently confronted with gram-positive TLR2 ligand lipoteichoic acid (LTA, 15mg/g bodyweight) or synthetic CpG-oligodesoxynucleotide 1668 thioate (20 nmol/kg bodyweight, 30 min after D-galactosamin desensitization) signaling via TLR9. Hemodynamic measurements and organ preservation were performed 6 h after stimulation. Indeed, the study revealed a robust enhancement of LTA induced pattern recognition receptor and cytokine mRNA expression and a LTA-dependent reduction of hemodynamic pressure in TAC wild type mice. Second-Hit treatment with CpG-ODNs led to similar results. However, second-hit effects were abolished in Tlr4-/- mice. In total, these data indicate for the first time that cardiac stress increases the inflammatory response towards both, gram-negative and gram-positive, TLR ligands as well as bacterial DNA. The decrease of the inflammatory response upon TLR2 and -9 ligand challenge in TAC Tlr4-/- mice demonstrates that a lack of TLR4 signaling does not only prevent left ventricular hypertrophy but also protects the mice from a cardiac stress induced hyperinflammatory

  18. Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.

    PubMed

    Spence, Stan; Deurinck, Mark; Ju, Haisong; Traebert, Martin; McLean, LeeAnne; Marlowe, Jennifer; Emotte, Corinne; Tritto, Elaine; Tseng, Min; Shultz, Michael; Friedrichs, Gregory S

    2016-09-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and

  19. Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function.

    PubMed

    Chiellini, Grazia; Frascarelli, Sabina; Ghelardoni, Sandra; Carnicelli, Vittoria; Tobias, Sandra C; DeBarber, Andrea; Brogioni, Simona; Ronca-Testoni, Simonetta; Cerbai, Elisabetta; Grandy, David K; Scanlan, Thomas S; Zucchi, Riccardo

    2007-05-01

    3-Iodothyronamine T1AM is a novel endogenous thyroid hormone derivative that activates the G protein-coupled receptor known as trace anime-associated receptor 1 (TAAR1). In the isolated working rat heart and in rat cardiomyocytes, T1AM produced a reversible, dose-dependent negative inotropic effect (e.g., 27+/-5, 51+/-3, and 65+/-2% decrease in cardiac output at 19, 25, and 38 microM concentration, respectively). An independent negative chronotropic effect was also observed. The hemodynamic effects of T1AM were remarkably increased in the presence of the tyrosine kinase inhibitor genistein, whereas they were attenuated in the presence of the tyrosine phosphatase inhibitor vanadate. No effect was produced by inhibitors of protein kinase A, protein kinase C, calcium-calmodulin kinase II, phosphatidylinositol-3-kinase, or MAP kinases. Tissue cAMP levels were unchanged. In rat ventricular tissue, Western blot experiments with antiphosphotyrosine antibodies showed reduced phosphorylation of microsomal and cytosolic proteins after perfusion with synthetic T1AM; reverse transcriptase-polymerase chain reaction experiments revealed the presence of transcripts for at least 5 TAAR subtypes; specific and saturable binding of [125I]T1AM was observed, with a dissociation constant in the low micromolar range (5 microM); and endogenous T1AM was detectable by tandem mass spectrometry. In conclusion, our findings provide evidence for the existence of a novel aminergic system modulating cardiac function. PMID:17284482

  20. Accelerated adaptive integration method.

    PubMed

    Kaus, Joseph W; Arrar, Mehrnoosh; McCammon, J Andrew

    2014-05-15

    Conformational changes that occur upon ligand binding may be too slow to observe on the time scales routinely accessible using molecular dynamics simulations. The adaptive integration method (AIM) leverages the notion that when a ligand is either fully coupled or decoupled, according to λ, barrier heights may change, making some conformational transitions more accessible at certain λ values. AIM adaptively changes the value of λ in a single simulation so that conformations sampled at one value of λ seed the conformational space sampled at another λ value. Adapting the value of λ throughout a simulation, however, does not resolve issues in sampling when barriers remain high regardless of the λ value. In this work, we introduce a new method, called Accelerated AIM (AcclAIM), in which the potential energy function is flattened at intermediate values of λ, promoting the exploration of conformational space as the ligand is decoupled from its receptor. We show, with both a simple model system (Bromocyclohexane) and the more complex biomolecule Thrombin, that AcclAIM is a promising approach to overcome high barriers in the calculation of free energies, without the need for any statistical reweighting or additional processors. PMID:24780083

  1. Accelerated Adaptive Integration Method

    PubMed Central

    2015-01-01

    Conformational changes that occur upon ligand binding may be too slow to observe on the time scales routinely accessible using molecular dynamics simulations. The adaptive integration method (AIM) leverages the notion that when a ligand is either fully coupled or decoupled, according to λ, barrier heights may change, making some conformational transitions more accessible at certain λ values. AIM adaptively changes the value of λ in a single simulation so that conformations sampled at one value of λ seed the conformational space sampled at another λ value. Adapting the value of λ throughout a simulation, however, does not resolve issues in sampling when barriers remain high regardless of the λ value. In this work, we introduce a new method, called Accelerated AIM (AcclAIM), in which the potential energy function is flattened at intermediate values of λ, promoting the exploration of conformational space as the ligand is decoupled from its receptor. We show, with both a simple model system (Bromocyclohexane) and the more complex biomolecule Thrombin, that AcclAIM is a promising approach to overcome high barriers in the calculation of free energies, without the need for any statistical reweighting or additional processors. PMID:24780083

  2. Ligand binding sites of Na,K-ATPase.

    PubMed

    Lingrel, J B; Croyle, M L; Woo, A L; Argüello, J M

    1998-08-01

    Our studies have concentrated on two aspects of the Na,K-ATPase, the first relates to the identification of amino acids involved in binding Na+ and K+ during the catalytic cycle and the second involves defining how cardiac glycosides inhibit the enzyme. To date, three amino acids, Ser775, Asp804 and Asp808, all located in transmembrane regions five and six, have been shown to play a major role in K+ binding. These findings are based on site directed mutagenesis and expression studies. In order to understand how cardiac glycosides interact with the Na,K-ATPase, studies again involving mutagenesis coupled with expression have been used. More specifically, amino acid residues have been substituted in an ouabain sensitive alpha subunit using random mutagenesis, and the ability of the resulting enzyme to confer resistance to ouabain sensitive cells was determined. Interestingly, the amino acids of the alpha subunit which alter ouabain sensitivity cluster in two major regions, one comprised of the first and second transmembrane spanning domains and the extracellular loop joining them, and the second formed by the extracellular halves of transmembrane regions four, five, six and seven. As noted above, transmembrane regions five and six also contain the three amino acid residues Ser775, Asp804 and Asp808 which play a key role in cation transport, possibly binding K+. Thus, it is reasonable to propose that cardiac glycosides bind to two sites, the N- terminal region and the central region which contains the cation binding sites. Cardiac glycoside binding to the center region may lock the cation transport region into a configuration such that the enzyme cannot go through the conformational change required for ion transport. PMID:9789548

  3. Adapting photosynthesis to the near-infrared: non-covalent binding of phycocyanobilin provides an extreme spectral red-shift to phycobilisome core-membrane linker from Synechococcus sp. PCC7335.

    PubMed

    Miao, Dan; Ding, Wen-Long; Zhao, Bao-Qing; Lu, Lu; Xu, Qian-Zhao; Scheer, Hugo; Zhao, Kai-Hong

    2016-06-01

    Phycobiliproteins that bind bilins are organized as light-harvesting complexes, phycobilisomes, in cyanobacteria and red algae. The harvested light energy is funneled to reaction centers via two energy traps, allophycocyanin B and the core-membrane linker, ApcE1 (conventional ApcE). The covalently bound phycocyanobilin (PCB) of ApcE1 absorbs near 660 nm and fluoresces near 675 nm. In cyanobacteria capable of near infrared photoacclimation, such as Synechococcus sp. PCC7335, there exist even further spectrally red shifted components absorbing >700 nm and fluorescing >710 nm. We expressed the chromophore domain of the extra core-membrane linker from Synechococcus sp. PCC7335, ApcE2, in E. coli together with enzymes generating the chromophore, PCB. The resulting chromoproteins, PCB-ApcE2(1-273) and the more truncated PCB-ApcE2(24-245), absorb at 700 nm and fluoresce at 714 nm. The red shift of ~40 nm compared with canonical ApcE1 results from non-covalent binding of the chromophore by which its full conjugation length including the Δ3,3(1) double bond is preserved. The extreme spectral red-shift could not be ascribed to exciton coupling: dimeric PCB-ApcE2(1-273) and monomeric-ApcE2(24-245) absorbed and fluoresced similarly. Chromophorylation of ApcE2 with phycoerythrobilin- or phytochromobilin resulted in similar red shifts (absorption at 615 and 711 nm, fluorescence at 628 or 726 nm, respectively), compared to the covalently bound chromophores. The self-assembled non-covalent chromophorylation demonstrates a novel access to red and near-infrared emitting fluorophores. Brightly fluorescent biomarking was exemplified in E. coli by single-plasmid transformation. PMID:27045046

  4. Current trends in cardiac rehabilitation

    PubMed Central

    Dafoe, W; Huston, P

    1997-01-01

    Cardiac rehabilitation can reduce mortality and morbidity for patients with many types of cardiac disease cost-effectively, yet is generally underutilized. Rehabilitation is helpful not only for patients who have had a myocardial infarction but also for those with stable angina or congestive heart failure or those who have undergone myocardial revascularization procedures, a heart transplant or heart valve surgery. The beneficial effects of rehabilitation include a reduction in the rate of death from cardiovascular disease, improved exercise tolerance, fewer cardiac symptoms, improved lipid levels, decreased cigarette smoking, improvement in psychosocial well-being and increased likelihood of return to work. Rehabilitation involves a multidisciplinary team that focuses on education, individually tailored exercise, risk-factor modification and the optimization of functional status and mental health. Current research trends in this area include the evaluation of new secondary-prevention modalities and alternative program options, such as home-based rehabilitation. PMID:9054823

  5. [Radiation therapy and cardiac pacemakers].

    PubMed

    Serafim, P; Fonseca, G; Oliveira, A; Fernandes, T

    1999-05-01

    The number of patients with cardiac pacemakers submitted annually to radiation therapy is increasing. Radiation therapy causes interference in the normal functioning processes, directly by chemical changes in the structure of the device and also by electromagnetic disturbances generated in the process of treatment. The changes in the technology used in the manufacture of cardiac pacemakers after the 70's, with the introduction of complementary metal-oxide semi-conductors (CMOS) in the circuits, drastically increased the chance of dangerous interference in the normal function of cardiac pacemakers occurring when in contact with an ionizing radiation source. The authors briefly describe the mechanisms underlying the radio-induced damage usually observed. A review of the literature on this issue is made and solutions are pointed out to perform safe radiation therapy and minimize the risk of device malfunction. PMID:10418264

  6. Mechanical regulation of cardiac development

    PubMed Central

    Lindsey, Stephanie E.; Butcher, Jonathan T.; Yalcin, Huseyin C.

    2014-01-01

    Mechanical forces are essential contributors to and unavoidable components of cardiac formation, both inducing and orchestrating local and global molecular and cellular changes. Experimental animal studies have contributed substantially to understanding the mechanobiology of heart development. More recent integration of high-resolution imaging modalities with computational modeling has greatly improved our quantitative understanding of hemodynamic flow in heart development. Merging these latest experimental technologies with molecular and genetic signaling analysis will accelerate our understanding of the relationships integrating mechanical and biological signaling for proper cardiac formation. These advances will likely be essential for clinically translatable guidance for targeted interventions to rescue malforming hearts and/or reconfigure malformed circulations for optimal performance. This review summarizes our current understanding on the levels of mechanical signaling in the heart and their roles in orchestrating cardiac development. PMID:25191277

  7. Cardiac myofilaments: mechanics and regulation

    NASA Technical Reports Server (NTRS)

    de Tombe, Pieter P.; Bers, D. M. (Principal Investigator)

    2003-01-01

    The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.

  8. Sudden Cardiac Arrest in Pediatrics.

    PubMed

    Scheller, RoseAnn L; Johnson, Laurie; Lorts, Angela; Ryan, Thomas D

    2016-09-01

    Sudden cardiac arrest (SCA) in the pediatric population is a rare and potentially devastating occurrence. An understanding of the differential diagnosis for the etiology of the cardiac arrest allows for the most effective emergency care and provides the patient with the best possible outcome. Pediatric SCA can occur with or without prodromal symptoms and may occur during exercise or rest. The most common cause is arrhythmia secondary to an underlying channelopathy, cardiomyopathy, or myocarditis. After stabilization, evaluation should include electrocardiogram, chest radiograph, and echocardiogram. Management should focus on decreasing the potential for recurring arrhythmia, maintaining cardiac preload, and thoughtful medication use to prevent exacerbation of the underlying condition. The purpose of this review was to provide the emergency physician with a concise and current review of the incidence, differential diagnosis, and management of pediatric patients presenting with SCA. PMID:27585126

  9. Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats

    PubMed Central

    Gu, Ye; Zou, Wusong; Zhang, Mingjing; Zhu, Pengfei; Hu, Shao

    2015-01-01

    Background Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats. Methods Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements. Results UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats. Conclusions Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals. PMID:26252578

  10. Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy

    PubMed Central

    Schlossarek, Saskia; Singh, Sonia R.; Geertz, Birgit; Schulz, Herbert; Reischmann, Silke; Hübner, Norbert; Carrier, Lucie

    2014-01-01

    A growing line of evidence indicates a dysfunctional ubiquitin-proteasome system (UPS) in cardiac diseases. Anti-hypertrophic effects and improved cardiac function have been reported after treatment with proteasome inhibitors in experimental models of cardiac hypertrophy. Here we tested whether proteasome inhibition could also reverse the disease phenotype in a genetically-modified mouse model of hypertrophic cardiomyopathy (HCM), which carries a mutation in Mybpc3, encoding the myofilament protein cardiac myosin-binding protein C. At 7 weeks of age, homozygous mutant mice (KI) have 39% higher left ventricular mass-to-body-weight ratio and 29% lower fractional area shortening (FAS) than wild-type (WT) mice. Both groups were treated with epoxomicin (0.5 mg/kg/day) or vehicle for 1 week via osmotic minipumps. Epoxomicin inhibited the chymotrypsin-like activity by ~50% in both groups. All parameters of cardiac hypertrophy (including the fetal gene program) were not affected by epoxomicin treatment in both groups. In contrast, FAS was 12% and 35% higher in epoxomicin-treated than vehicle-treated WT and KI mice, respectively. To identify which genes or pathways could be involved in this positive effect, we performed a transcriptome analysis in KI and WT neonatal cardiac myocytes, treated or not with the proteasome inhibitor MG132 (1 μM, 24 h). This revealed 103 genes (four-fold difference; 5% FDR) which are commonly regulated in both KI and WT cardiac myocytes. Thus, even in genetically-modified mice with manifest HCM, proteasome inhibition showed beneficial effects, at least with regard to cardiac function. Targeting the UPS in cardiac diseases remains therefore a therapeutic option. PMID:25566086

  11. Calmodulin Mutations Associated with Recurrent Cardiac Arrest in Infants

    PubMed Central

    Crotti, Lia; Johnson, Christopher N.; Graf, Elisabeth; De Ferrari, Gaetano M.; Cuneo, Bettina F.; Ovadia, Marc; Papagiannis, John; Feldkamp, Michael D.; Rathi, Subodh G.; Kunic, Jennifer D.; Pedrazzini, Matteo; Wieland, Thomas; Lichtner, Peter; Beckmann, Britt-Maria; Clark, Travis; Shaffer, Christian; Benson, D. Woodrow; Kääb, Stefan; Meitinger, Thomas; Strom, Tim M.; Chazin, Walter J.; Schwartz, Peter J.; George, Alfred L.

    2013-01-01

    Background Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on two unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results We ascertained two unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The two parent-child trios were investigated using exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in two genes encoding calmodulin. We discovered three heterozygous de novo mutations in either CALM1 or CALM2, two of the three human genes encoding calmodulin, in the two probands and in two additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several fold reductions in calcium binding affinity. Conclusions Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy. PMID:23388215

  12. Haptoglobin Enhances Cardiac Transplant Rejection

    PubMed Central

    Shen, Hua; Heuzey, Elizabeth; Mori, Daniel; Wong, Christine; Colangelo, Christopher; Chung, Lisa M.; Bruce, Can; Slizovskiy, Ilya B.; Booth, Carmen J.; Kreisel, Daniel; Goldstein, Daniel R.

    2015-01-01

    Rationale Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and up to 72 hours after transplantation revealed that 22 proteins including haptoglobin, a known anti-oxidant, are significantly upregulated in our grafts. Through the use of haptoglobin deficient mice, we show that 80% of haptoglobin deficient recipients treated with peri-operative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited > 100 days survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild type recipients rejected their transplants by 21 days post transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine IL-6 and the chemokine MIP-2 but impair levels of the immunosuppressive cytokine IL-10. Haptoglobin also enhances dendritic cell graft recruitment and augments anti-donor T cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported anti-oxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions. PMID:25801896

  13. Sudden Cardiac Arrest (SCA) Risk Assessment

    MedlinePlus

    ... Find a Specialist Share Twitter Facebook SCA Risk Assessment Sudden Cardiac Arrest (SCA) occurs abruptly and without ... of all ages and health conditions. Start Risk Assessment The Sudden Cardiac Arrest (SCA) Risk Assessment Tool ...

  14. Men Face Greater Risk of Cardiac Arrest

    MedlinePlus

    ... fullstory_159651.html Men Face Greater Risk of Cardiac Arrest: Study Heart disease tends to develop earlier than ... About one in nine men will suffer a cardiac arrest before the age of 70, compared to about ...

  15. Cardiovascular reactivity and adaptation to recurrent psychological stress: the moderating effects of evaluative observation.

    PubMed

    Kelsey, R M; Blascovich, J; Leitten, C L; Schneider, T R; Tomaka, J; Wiens, S

    2000-11-01

    The impact of evaluative observation on cardiovascular reactivity and adaptation to recurrent psychological stress was evaluated in 162 undergraduate men and women. All participants performed three mental arithmetic tasks with or without evaluative observation. Impedance cardiographic, blood pressure, task performance, and stress appraisal measures were recorded for each task. Evaluative observation moderated the effects of task repetition on cardiac reactivity but not vascular reactivity. The introduction of evaluative observation disrupted cardiac adaptation, resulting in a resurgence of beta-adrenergic cardiac reactivity (p < .005), whereas the removal of evaluative observation promoted cardiac adaptation. Evaluative observation also increased stress appraisals and slowed task performance. The results support the dual process theory of habituation, rather than stimulus comparator theory, but only partially support cognitive appraisal theory. PMID:11117455

  16. Cardiac Metastasis from Invasive Thymoma Via the Superior Vena Cava: Cardiac MRI Findings

    SciTech Connect

    Dursun, Memduh Sarvar, Sadik; Cekrezi, Bledi; Kaba, Erkan; Bakir, Baris; Toker, Alper

    2008-07-15

    Cardiac tumors are rare, and metastatic deposits are more common than primary cardiac tumors. We present cardiac magnetic resonance imaging (MRI) findings of a 50-year-old woman with invasive thymoma. Cardiac MRI revealed a heterogeneous, lobulated anterior mediastinal mass invading the superior vena cava and extending to the right atrium. In cine images there was no invasion to the right atrial wall.

  17. Cardiac 4D Ultrasound Imaging

    NASA Astrophysics Data System (ADS)

    D'hooge, Jan

    Volumetric cardiac ultrasound imaging has steadily evolved over the last 20 years from an electrocardiography (ECC) gated imaging technique to a true real-time imaging modality. Although the clinical use of echocardiography is still to a large extent based on conventional 2D ultrasound imaging it can be anticipated that the further developments in image quality, data visualization and interaction and image quantification of three-dimensional cardiac ultrasound will gradually make volumetric ultrasound the modality of choice. In this chapter, an overview is given of the technological developments that allow for volumetric imaging of the beating heart by ultrasound.

  18. [Cardiac rehabilitation after myocardial infarction].

    PubMed

    Ghannem, M; Ghannem, L; Ghannem, L

    2015-12-01

    Although the proofs of the benefits of cardiac rehabilitation accumulate, many patients are not sent to rehabilitation units, especially younger and very elderly patients. As the length of stay in acute care units decreases, rehabilitation offers more time to fully assess the patients' conditions and needs. Meta-analyses of randomised trials suggest that mortality can be improved by as much as 20-30%. In addition, rehabilitation helps managing risk factors, including hyperlipidemia, diabetes, smoking and sedentary behaviours. Physical training also helps improving exercise capacity. Because of all of these effects, cardiac rehabilitation for post-myocardial infarction patients has been given a class IA recommendation in current guidelines. PMID:26548984

  19. Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

    PubMed Central

    Yao, Wenjuan; Zhu, Hongyan; Xu, Xiaole; Meng, Guoliang; Zhang, Wei

    2014-01-01

    Previous studies showed that prostacyclin inhibited fibrosis. However, both receptors of prostacyclin, prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of prostacyclin. In addition, the possible mechanism involved in protective effects of prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor β (TGF β) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP and suppressing TGF β-Smad signal pathway. PMID:24852754

  20. Cardiac tamponade: an unusual clinical presentation.

    PubMed

    Eakle, J F; Goodin, R R

    2001-02-01

    Pericardial effusion with cardiac tamponade is an unusual presentation of lymphoma, although cardiac involvement is often a late finding in widespread malignancy. Clinical identification can be difficult ante-mortem. New cardiac symptoms or classic findings of cardiac tamponade should prompt aggressive investigation. We present a case of B-cell lymphoma that initially presented as pericardial effusion with tamponade and discuss the characteristic physical findings and radiographic data that assist in diagnosis. PMID:11441582

  1. [Cardiac output monitoring by impedance cardiography in cardiac surgery].

    PubMed

    Shimizu, H; Seki, S; Mizuguchi, A; Tsuchida, H; Watanabe, H; Namiki, A

    1990-04-01

    The cardiac output monitoring by impedance cardiography, NCCOM3, was evaluated in adult patients (n = 12) who were subjected to coronary artery bypass grafting. Values of cardiac output measured by impedance cardiography were compared to those by the thermodilution method. Changes of base impedance level used as an index of thoracic fluid volume were also investigated before and after cardiopulmonary bypass (CPB). Correlation coefficient (r) of the values obtained by thermodilution with impedance cardiography was 0.79 and the mean difference was 1.29 +/- 16.9 (SD)% during induction of anesthesia. During the operation, r was 0.83 and the mean difference was -14.6 +/- 18.7%. The measurement by impedance cardiography could be carried out through the operation except when electro-cautery was used. Base impedance level before CPB was significantly lower as compared with that after CPB. There was a negative correlation between the base impedance level and central venous pressure (CVP). No patients showed any signs suggesting lung edema and all the values of CVP, pulmonary artery pressure and blood gas analysis were within normal ranges. From the result of this study, it was concluded that cardiac output monitoring by impedance cardiography was useful in cardiac surgery, but further detailed examinations will be necessary on the relationship between the numerical values of base impedance and the clinical state of the patients. PMID:2362347

  2. Health Literacy Predicts Cardiac Knowledge Gains in Cardiac Rehabilitation Participants

    ERIC Educational Resources Information Center

    Mattson, Colleen C.; Rawson, Katherine; Hughes, Joel W.; Waechter, Donna; Rosneck, James

    2015-01-01

    Objective: Health literacy is increasingly recognised as a potentially important patient characteristic related to patient education efforts. We evaluated whether health literacy would predict gains in knowledge after completion of patient education in cardiac rehabilitation. Method: This was a re-post observational analysis study design based on…

  3. Cardiac torsion and electromagnetic fields: the cardiac bioinformation hypothesis.

    PubMed

    Burleson, Katharine O; Schwartz, Gary E

    2005-01-01

    Although in physiology the heart is often referred to as a simple piston pump, there are in fact two additional features that are integral to cardiac physiology and function. First, the heart as it contracts in systole, also rotates and produces torsion due to the structure of the myocardium. Second, the heart produces a significant electromagnetic field with each contraction due to the coordinated depolarization of myocytes producing a current flow. Unlike the electrocardiogram, the magnetic field is not limited to volume conduction and extends outside the body. The therapeutic potential for interaction of this cardioelectromagnetic field both within and outside the body is largely unexplored. It is our hypothesis that the heart functions as a generator of bioinformation that is central to normative functioning of body. The source of this bioinformation is based on: (1) vortex blood flow in the left ventricle; (2) a cardiac electromagnetic field and both; (3) heart sounds; and (4) pulse pressure which produce frequency and amplitude information. Thus, there is a multidimensional role for the heart in physiology and biopsychosocial dynamics. Recognition of these cardiac properties may result in significant implications for new therapies for cardiovascular disease based on increasing cardiac energy efficiency (coherence) and bioinformation from the cardioelectromagnetic field. Research studies to test this hypothesis are suggested. PMID:15823696

  4. Connector adapter

    NASA Technical Reports Server (NTRS)

    Hacker, Scott C. (Inventor); Dean, Richard J. (Inventor); Burge, Scott W. (Inventor); Dartez, Toby W. (Inventor)

    2007-01-01

    An adapter for installing a connector to a terminal post, wherein the connector is attached to a cable, is presented. In an embodiment, the adapter is comprised of an elongated collet member having a longitudinal axis comprised of a first collet member end, a second collet member end, an outer collet member surface, and an inner collet member surface. The inner collet member surface at the first collet member end is used to engage the connector. The outer collet member surface at the first collet member end is tapered for a predetermined first length at a predetermined taper angle. The collet includes a longitudinal slot that extends along the longitudinal axis initiating at the first collet member end for a predetermined second length. The first collet member end is formed of a predetermined number of sections segregated by a predetermined number of channels and the longitudinal slot.

  5. Adaptive sampler

    DOEpatents

    Watson, Bobby L.; Aeby, Ian

    1982-01-01

    An adaptive data compression device for compressing data having variable frequency content, including a plurality of digital filters for analyzing the content of the data over a plurality of frequency regions, a memory, and a control logic circuit for generating a variable rate memory clock corresponding to the analyzed frequency content of the data in the frequency region and for clocking the data into the memory in response to the variable rate memory clock.

  6. Adaptive sampler

    DOEpatents

    Watson, B.L.; Aeby, I.

    1980-08-26

    An adaptive data compression device for compressing data is described. The device has a frequency content, including a plurality of digital filters for analyzing the content of the data over a plurality of frequency regions, a memory, and a control logic circuit for generating a variable rate memory clock corresponding to the analyzed frequency content of the data in the frequency region and for clocking the data into the memory in response to the variable rate memory clock.

  7. Adaptive antennas

    NASA Astrophysics Data System (ADS)

    Barton, P.

    1987-04-01

    The basic principles of adaptive antennas are outlined in terms of the Wiener-Hopf expression for maximizing signal to noise ratio in an arbitrary noise environment; the analogy with generalized matched filter theory provides a useful aid to understanding. For many applications, there is insufficient information to achieve the above solution and thus non-optimum constrained null steering algorithms are also described, together with a summary of methods for preventing wanted signals being nulled by the adaptive system. The three generic approaches to adaptive weight control are discussed; correlation steepest descent, weight perturbation and direct solutions based on sample matrix conversion. The tradeoffs between hardware complexity and performance in terms of null depth and convergence rate are outlined. The sidelobe cancellor technique is described. Performance variation with jammer power and angular distribution is summarized and the key performance limitations identified. The configuration and performance characteristics of both multiple beam and phase scan array antennas are covered, with a brief discussion of performance factors.

  8. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling

    PubMed Central

    Ji, Yan-Xiao; Zhang, Peng; Zhang, Xiao-Jing; Zhao, Yi-Chao; Deng, Ke-Qiong; Jiang, Xi; Wang, Pi-Xiao; Huang, Zan; Li, Hongliang

    2016-01-01

    Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a ubiquitin E3 ligase that regulates important biological processes. However, the role of TRAF6 in cardiac hypertrophy remains unknown. Here, we show that TRAF6 levels are increased in human and murine hypertrophied hearts, which is regulated by reactive oxygen species (ROS) production. Cardiac-specific Traf6 overexpression exacerbates cardiac hypertrophy in response to pressure overload or angiotensin II (Ang II) challenge, whereas Traf6 deficiency causes an alleviated hypertrophic phenotype in mice. Mechanistically, we show that ROS, generated during hypertrophic progression, triggers TRAF6 auto-ubiquitination that facilitates recruitment of TAB2 and its binding to transforming growth factor beta-activated kinase 1 (TAK1), which, in turn, enables the direct TRAF6–TAK1 interaction and promotes TAK1 ubiquitination. The binding of TRAF6 to TAK1 and the induction of TAK1 ubiquitination and activation are indispensable for TRAF6-regulated cardiac remodelling. Taken together, we define TRAF6 as an essential molecular switch leading to cardiac hypertrophy in a TAK1-dependent manner. PMID:27249171

  9. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development

    NASA Astrophysics Data System (ADS)

    Sørhus, Elin; Incardona, John P.; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B.; Meier, Sonnich

    2016-08-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7–7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish.

  10. Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

    NASA Astrophysics Data System (ADS)

    Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

    1989-09-01

    Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

  11. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development.

    PubMed

    Sørhus, Elin; Incardona, John P; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B; Meier, Sonnich

    2016-01-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7-7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish. PMID:27506155

  12. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development

    PubMed Central

    Sørhus, Elin; Incardona, John P.; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B.; Meier, Sonnich

    2016-01-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7–7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish. PMID:27506155

  13. Mathematics and the Heart: Understanding Cardiac Output

    ERIC Educational Resources Information Center

    Champanerkar, Jyoti

    2013-01-01

    This paper illustrates a biological application of the concepts of relative change and area under a curve, from mathematics. We study two biological measures "relative change in cardiac output" and "cardiac output", which are predictors of heart blockages and other related ailments. Cardiac output refers to the quantity of…

  14. Telocytes in exercise-induced cardiac growth.

    PubMed

    Xiao, Junjie; Chen, Ping; Qu, Yi; Yu, Pujiao; Yao, Jianhua; Wang, Hongbao; Fu, Siyi; Bei, Yihua; Chen, Yan; Che, Lin; Xu, Jiahong

    2016-05-01

    Exercise can induce physiological cardiac growth, which is featured by enlarged cardiomyocyte cell size and formation of new cardiomyocytes. Telocytes (TCs) are a recently identified distinct interstitial cell type, existing in many tissues and organs including heart. TCs have been shown to form a tandem with cardiac stem/progenitor cells in cardiac stem cell niches, participating in cardiac regeneration and repair. Although exercise-induced cardiac growth has been confirmed as an important way to promote cardiac regeneration and repair, the response of cardiac TCs to exercise is still unclear. In this study, 4 weeks of swimming training was used to induce robust healthy cardiac growth. Exercise can induce an increase in cardiomyocyte cell size and formation of new cardiomyocytes as determined by Wheat Germ Lectin and EdU staining respectively. TCs were identified by three immunofluorescence stainings including double labelling for CD34/vimentin, CD34/platelet-derived growth factor (PDGF) receptor-α and CD34/PDGF receptor-β. We found that cardiac TCs were significantly increased in exercised heart, suggesting that TCs might help control the activity of cardiac stem/progenitor cells, cardiomyocytes or endothelial cells. Adding cardiac TCs might help promote cardiac regeneration and renewal. PMID:26987685

  15. Comparison of high pressure-induced dissociation of single-stranded DNA-binding protein (SSB) from high pressure-sensitive and high pressure-adapted marine Shewanella species.

    PubMed

    Chilukuri, Lakshmi N; Bartlett, Douglas H; Fortes, P A George

    2002-10-01

    The effects of hydrostatic pressure on protein quaternary structure were compared for recombinant single-stranded DNA-binding protein (SSB) derived from piezosensitive, piezotolerant, and obligately piezophilic ("pressure-loving") marine Shewanella strains. The pressure-induced dissociation of the oligomeric SSB proteins was investigated using fluorescence anisotropy. The SSBs all exhibited striking similarity in the pressure-dependent behavior of the fluorescence intensity and emission spectrum as well as in their dissociation constants at atmospheric pressure. The free energies of subunit association into tetramers for all SSBs were between -27 and -30 kcal mol(-1). However, SSB from the piezosensitive Shewanella strain S. hanedai was more sensitive to pressure than that of the SSB proteins from the piezotolerant or piezophilic bacteria. The volume change of association obtained from the pressure dependence of dissociation at a fixed protein concentration (Delta V(p)) for SSB from S. hanedai was 394-402 ml mol(-1). The Delta V(p) values for SSB from the deeper-living Shewanellas were smaller and ranged from 253 to 307 ml mol(-1). Differences between the primary structures of the SSB proteins that could correlate with differences in sensitivity to pressure-induced dissociation were examined. PMID:12382113

  16. The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy

    PubMed Central

    Oh, K S; Lee, J H; Yi, K Y; Lim, C J; Lee, S; Park, C H; Seo, H W; Lee, B H

    2015-01-01

    Background and Purpose Blockade of the actions of urotensin-II (U-II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2-(6,7-dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-methyl-N-(2-(pyrrolidin-1-yl)-1-(4-(thiophen-3-yl)phenyl) ethyl)acetamide (KR36676). Experimental Approach Pharmacological properties of KR36676 were studied in a range of in vitro assays (receptor binding, calcium mobilization, stress fibre formation, cellular hypertrophy) and in vivo animal models such as cardiac hypertrophy induced by transverse aortic constriction (TAC) or myocardial infarction (MI). Key Results KR36676 displayed high binding affinity for the UT receptor (Ki: 0.7 nM), similar to that of U-II (0.4 nM), and was a potent antagonist at that receptor (IC50: 4.0 nM). U-II-induced stress fibre formation and cellular hypertrophy were significantly inhibited with low concentrations of KR36676 (≥0.01 μM). Oral administration of KR36676 (30 mg·kg−1) in a TAC model in mice attenuated cardiac hypertrophy and myocardial fibrosis. Moreover, KR36676 restored cardiac function and myocyte size in rats with MI-induced cardiac hypertrophy. Conclusions and Implications A highly potent UT receptor antagonist exerted anti-hypertrophic effects not only in infarcted rat hearts but also in pressure-overloaded mouse hearts. KR36676 could be a valuable pharmacological tool in elucidating the complicated physiological role of U-II and UT receptors in cardiac hypertrophy. PMID:25597918

  17. Historical highlights in cardiac pacing.

    PubMed

    Geddes, L A

    1990-01-01

    The benchmarks in cardiac pacing are identified, beginning with F. Steiner (1871), who rhythmically stimulated the chloroform-arrested hearts of 3 horses, 1 donkey, 10 dogs, 14 cats, and 8 rabbits. The chloroform-arrested heart in human subjects was paced by T. Greene in the following year (1872) in the UK. In 1882, H. Ziemssen in Germany applied cardiac pacing to a 42-year old woman who had a large defect in the anterior left chest wall subsequent to resection of an enchondroma. Intentional cardiac pacing did not occur until 1932, when A.A. Hyman in the US demonstrated that cardiac pacing could be clinically practical. Hyman made a batteryless pacemaker for delivery in induction shock stimuli (60-120/min) to the atria. His pacemaker was powered by a hand-wound, spring-driven generator which provided 6 min of pacemaking without rewinding. Closed-chest ventricular pacing was introduced in the US in 1952 by P.M. Zoll et al. Zoll (1956) also introduced closed-chest ventricular defibrillation. W.L. Weirich et al. (1958) demonstrated that direct-heart stimulation in closed-chest patients could be achieved with slender wire electrodes. S. Furman and J.B. Schwedel (1959) developed a monopolar catheter electrode for ventricular pacing in man. In the same year, W. Greatbatch and W.M. Chardack developed the implantable pacemaker. PMID:18238328

  18. The cardiac patient in Ramadan

    PubMed Central

    Chamsi-Pasha, Majed; Chamsi-Pasha, Hassan

    2016-01-01

    Ramadan is one of the five fundamental pillars of Islam. During this month, the majority of the 1.6 billion Muslims worldwide observe an absolute fast from dawn to sunset without any drink or food. Our review shows that the impact of fasting during Ramadan on patients with stable cardiac disease is minimal and does not lead to any increase in acute events. Most patients with the stable cardiac disease can fast safely. Most of the drug doses and their regimen are easily manageable during this month and may need not to be changed. Ramadan fasting is a healthy nonpharmacological means for improving cardiovascular risk factors. Most of the Muslims, who suffer from chronic diseases, insist on fasting Ramadan despite being exempted by religion. The Holy Quran specifically exempts the sick from fasting. This is particularly relevant if fasting worsens one's illness or delays recovery. Patients with unstable angina, recent myocardial infarction, uncontrolled hypertension, decompensated heart failure, recent cardiac intervention or cardiac surgery or any debilitating diseases should avoid fasting. PMID:27144139

  19. The cardiac patient in Ramadan.

    PubMed

    Chamsi-Pasha, Majed; Chamsi-Pasha, Hassan

    2016-01-01

    Ramadan is one of the five fundamental pillars of Islam. During this month, the majority of the 1.6 billion Muslims worldwide observe an absolute fast from dawn to sunset without any drink or food. Our review shows that the impact of fasting during Ramadan on patients with stable cardiac disease is minimal and does not lead to any increase in acute events. Most patients with the stable cardiac disease can fast safely. Most of the drug doses and their regimen are easily manageable during this month and may need not to be changed. Ramadan fasting is a healthy nonpharmacological means for improving cardiovascular risk factors. Most of the Muslims, who suffer from chronic diseases, insist on fasting Ramadan despite being exempted by religion. The Holy Quran specifically exempts the sick from fasting. This is particularly relevant if fasting worsens one's illness or delays recovery. Patients with unstable angina, recent myocardial infarction, uncontrolled hypertension, decompensated heart failure, recent cardiac intervention or cardiac surgery or any debilitating diseases should avoid fasting. PMID:27144139

  20. The Cardiac Complications of Methamphetamines.

    PubMed

    Paratz, Elizabeth D; Cunningham, Neil J; MacIsaac, Andrew I

    2016-04-01

    Methamphetamines are increasingly popular drugs of abuse in Australia, and are rising in purity. The rising popularity and purity of methamphetamines has notably increased demands upon Australian medical services. Methamphetamines are sympathomimetic amines with a range of adverse effects upon multiple organ systems. Cardiovascular complications are the second leading cause of death in methamphetamine abusers, and there appears to be a high prevalence of cardiac pathology. Cardiovascular pathology frequently seen in methamphetamine abusers includes hypertension, aortic dissection, acute coronary syndromes, pulmonary arterial hypertension and methamphetamine-associated cardiomyopathy. The rising prevalence of methamphetamine abuse is likely to increase the burden of cardiovascular pathology in Australians. A National Parliamentary Enquiry was opened in March 2015 to address concerns regarding the medical and social impacts of methamphetamine abuse. From April 2015, a National 'Ice Taskforce' was also created in parallel. Reversal of cardiac pathology appears to be achievable with abstinence from methamphetamines and initiation of appropriate treatment. It is key to appreciate that the pathogenesis of methamphetamine-induced cardiac complications arises as a result of the specific toxic effects of methamphetamines. Clinical management is hence individualised; suggested management approaches for methamphetamine-induced cardiac complications are detailed within this article. PMID:26706652

  1. Device Assists Cardiac Chest Compression

    NASA Technical Reports Server (NTRS)

    Eichstadt, Frank T.

    1995-01-01

    Portable device facilitates effective and prolonged cardiac resuscitation by chest compression. Developed originally for use in absence of gravitation, also useful in terrestrial environments and situations (confined spaces, water rescue, medical transport) not conducive to standard manual cardiopulmonary resuscitation (CPR) techniques.

  2. Guide to prosthetic cardiac valves

    SciTech Connect

    Morse, D.; Steiner, R.M.; Fernandez, J.

    1985-01-01

    This book contains 10 chapters. Some of the chapter titles are: The development of artificial heart valves: Introduction and historical perspective; The radiology of prosthetic heart valves; The evaluation of patients for prosthetic valve implantation; Pathology of cardiac valve replacement; and Bioengineering of mechanical and biological heart valve substitutes.

  3. Cardiac sarcoidosis: diagnosis and management.

    PubMed

    Dubrey, S W; Sharma, R; Underwood, R; Mittal, T

    2015-07-01

    Cardiac sarcoidosis is one of the most serious and unpredictable aspects of this disease state. Heart involvement frequently presents with arrhythmias or conduction disease, although myocardial infiltration resulting in congestive heart failure may also occur. The prognosis in cardiac sarcoidosis is highly variable, which relates to the heterogeneous nature of heart involvement and marked differences between racial groups. Electrocardiography and echocardiography often provide the first clue to the diagnosis, but advanced imaging studies using positron emission tomography and MRI, in combination with nuclear isotope perfusion scanning are now essential to the diagnosis and management of this condition. The identification of clinically occult cardiac sarcoidosis and the management of isolated and/or asymptomatic heart involvement remain both challenging and contentious. Corticosteroids remain the first treatment choice with the later substitution of immunosuppressive and steroid-sparing therapies. Heart transplantation is an unusual outcome, but when performed, the results are comparable or better than heart transplantation for other disease states. We review the epidemiology, developments in diagnostic techniques and the management of cardiac sarcoidosis. PMID:26130811

  4. MedlinePlus: Cardiac Arrest

    MedlinePlus

    ... Journal Articles References and abstracts from MEDLINE/PubMed (National Library of Medicine) Article: A Prospective Study of Sudden Cardiac Death ... Players MedlinePlus Connect for EHRs For Developers U.S. National Library of Medicine 8600 Rockville Pike, Bethesda, MD 20894 U.S. Department ...

  5. Cardiac arrest during dipyridamole imaging

    SciTech Connect

    Blumenthal, M.S.; McCauley, C.S.

    1988-05-01

    A case of cardiac arrest and subsequent acute myocardial infarction occurring during thallium-201 imaging with oral dipyridamole augmentation is presented. Previous reports emphasizing the safety of this procedure are briefly reviewed and a recommendation for close hemodynamic and arrhythmia monitoring during the study is made. Large doses of oral dipyridamole may be contraindicated in patients with unstable angina.

  6. Structural basis for drug-induced allosteric changes to human β-cardiac myosin motor activity

    NASA Astrophysics Data System (ADS)

    Winkelmann, Donald A.; Forgacs, Eva; Miller, Matthew T.; Stock, Ann M.

    2015-08-01

    Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. A detailed kinetic analysis of cardiac myosin has shown that the drug accelerates phosphate release by shifting the equilibrium of the hydrolysis step towards products, leading to a faster transition from weak to strong actin-bound states. The structure of the human β-cardiac motor domain (cMD) with OM bound reveals a single OM-binding site nestled in a narrow cleft separating two domains of the human cMD where it interacts with the key residues that couple lever arm movement to the nucleotide state. In addition, OM induces allosteric changes in three strands of the β-sheet that provides the communication link between the actin-binding interface and the nucleotide pocket. The OM-binding interactions and allosteric changes form the structural basis for the kinetic and mechanical tuning of cardiac myosin.

  7. Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR

    PubMed Central

    Yin, Qian; Yang, Chengzhi; Wu, Jimin; Lu, Haiyan; Zheng, Xiaohui; Zhang, Youyi; Lv, Zhizhen; Zheng, Xiaopu; Li, Zijian

    2016-01-01

    β-adrenergic receptors (β-ARs) play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of β-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of β1- and β2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO) at the dose of 0.25 mg·kg−1·d−1 for 7days. We found that the expression of β1- and β2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB) is a well-known transcription factor of β-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR), a RNA binding protein, which binds to the 3'-untranslated region of the β-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of β-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of β-AR expression in ISO induced cardiac remodeling. PMID:27035432

  8. Structural basis for drug-induced allosteric changes to human β-cardiac myosin motor activity

    PubMed Central

    Winkelmann, Donald A.; Forgacs, Eva; Miller, Matthew T.; Stock, Ann M.

    2015-01-01

    Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. A detailed kinetic analysis of cardiac myosin has shown that the drug accelerates phosphate release by shifting the equilibrium of the hydrolysis step towards products, leading to a faster transition from weak to strong actin-bound states. The structure of the human β-cardiac motor domain (cMD) with OM bound reveals a single OM-binding site nestled in a narrow cleft separating two domains of the human cMD where it interacts with the key residues that couple lever arm movement to the nucleotide state. In addition, OM induces allosteric changes in three strands of the β-sheet that provides the communication link between the actin-binding interface and the nucleotide pocket. The OM-binding interactions and allosteric changes form the structural basis for the kinetic and mechanical tuning of cardiac myosin. PMID:26246073

  9. Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

    PubMed Central

    Deng, Ke-Qiong; Wang, Aibing; Ji, Yan-Xiao; Zhang, Xiao-Jing; Fang, Jing; Zhang, Yan; Zhang, Peng; Jiang, Xi; Gao, Lu; Zhu, Xue-Yong; Zhao, Yichao; Gao, Lingchen; Yang, Qinglin; Zhu, Xue-Hai; Wei, Xiang; Pu, Jun; Li, Hongliang

    2016-01-01

    Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure. PMID:27249321

  10. Alternative Splicing in the Differentiation of Human Embryonic Stem Cells into Cardiac Precursors

    PubMed Central

    Salomonis, Nathan; Nelson, Brandon; Vranizan, Karen; Pico, Alexander R.; Hanspers, Kristina; Kuchinsky, Allan; Ta, Linda; Mercola, Mark; Conklin, Bruce R.

    2009-01-01

    The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs) is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org), we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation. PMID:19893621

  11. Development of aerobic and anaerobic metabolism in cardiac and skeletal muscles from harp and hooded seals.

    PubMed

    Burns, J M; Skomp, N; Bishop, N; Lestyk, K; Hammill, M

    2010-03-01

    In diving animals, skeletal muscle adaptations to extend underwater time despite selective vasoconstriction include elevated myoglobin (Mb) concentrations, high acid buffering ability (beta) and high aerobic and anaerobic enzyme activities. However, because cardiac muscle is perfused during dives, it may rely less heavily on Mb, beta and anaerobic pathways to support contractile activity. In addition, because cardiac tissue must sustain contractile activity even before birth, it may be more physiologically mature at birth and/or develop faster than skeletal muscles. To test these hypotheses, we measured Mb levels, beta and the activities of citrate synthase (CS), beta-hydroxyacyl-CoA dehydrogenase (HOAD) and lactate dehydrogenase (LDH) in cardiac and skeletal muscle samples from 72 harp and hooded seals, ranging in age from fetuses to adults. Results indicate that in adults cardiac muscle had lower Mb levels (14.7%), beta (55.5%) and LDH activity (36.2%) but higher CS (459.6%) and HOAD (371.3%) activities (all P<0.05) than skeletal muscle. In addition, while the cardiac muscle of young seals had significantly lower [Mb] (44.7%) beta (80.7%) and LDH activity (89.5%) than adults (all P<0.05), it was relatively more mature at birth and weaning than skeletal muscle. These patterns are similar to those in terrestrial species, suggesting that seal hearts do not exhibit unique adaptations to the challenges of an aquatic existence. PMID:20154189

  12. Carney complex with biatrial cardiac myxoma.

    PubMed

    Havrankova, Eniko; Stenova, Emoke; Olejarova, Ingrid; Sollarova, Katarina; Kinova, Sona

    2014-01-01

    Cardiac myxomas make up approximately 50% of all benign cardiac tumors and represented 86% of all surgically treated cardiac tumors. Most of them originated from the left atrium, in some cases from both of atria. We report a case of male patient with biatrial myxomas and other extra-cardiac involvement: hypophyseal adenoma, enlargement of thyroid gland, tubular adenoma polyp of colon and bilateral large cell calcifying Sertoli cell tumor (LCCSCT) of testis. These findings led to the diagnosis of Carney's complex, which is a syndrome with multiple neoplasias, cardiac myxomas, lentigines, and endocrine abnormalities. A genetic test confirm this diagnosis. PMID:24088910

  13. Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress

    PubMed Central

    Awad, Salma; Al-Haffar, Kamar Mohamed Adib; Marashly, Qussay; Quijada, Pearl; Kunhi, Muhammad; Al-Yacoub, Nadya; Wade, Fallou S; Mohammed, Shamayel Faheem; Al-Dayel, Fouad; Sutherland, George; Assiri, Abdullah; Sussman, Mark; Bers, Donald; Al-Habeeb, Waleed; Poizat, Coralie

    2015-01-01

    Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood. Using mice with genetic ablation of calcium/calmodulin-dependent protein kinase II δ (CaMKIIδ), which are resistant to pathological cardiac stress, we show that CaMKIIδ regulates the phosphorylation of histone H3 at serine-10 during pressure overload hypertrophy. H3 S10 phosphorylation is strongly increased in the adult mouse heart in the early phase of cardiac hypertrophy and remains detectable during cardiac decompensation. This response correlates with up-regulation of CaMKIIδ and increased expression of transcriptional drivers of pathological cardiac hypertrophy and of fetal cardiac genes. Similar changes are detected in patients with end-stage heart failure, where CaMKIIδ specifically interacts with phospho-H3. Robust H3 phosphorylation is detected in both adult ventricular myocytes and in non-cardiac cells in the stressed myocardium, and these signals are abolished in CaMKIIδ-deficient mice after pressure overload. Mechanistically, fetal cardiac genes are activated by increased recruitment of CaMKIIδ and enhanced H3 phosphorylation at hypertrophic promoter regions, both in mice and in human failing hearts, and this response is blunted in CaMKIIδ-deficient mice under stress. We also document that the chaperone protein 14–3–3 binds phosphorylated H3 in response to stress, allowing proper elongation of fetal cardiac genes by RNA polymerase II (RNAPII), as well as elongation of transcription factors regulating cardiac hypertrophy. These processes are impaired in CaMKIIδ-KO mice after pathological stress. The findings reveal a novel in vivo function of CaMKIIδ in regulating H3 phosphorylation and suggest a novel epigenetic mechanism by which CaMKIIδ controls cardiac hypertrophy.

  14. Solution NMR assignment of the heavy chain complex of the human cardiac myosin regulatory light chain.

    PubMed

    Rostkova, Elena; Gautel, Mathias; Pfuhl, Mark

    2015-04-01

    The regulatory light chain (RLC) of striated and cardiac muscle myosin plays a complex role in muscle function and regulation. Together with the essential light chain it provides stability to the lever arm, which is essential for force generation. Furthermore, phosphorylation and interaction with myosin binding protein C (MyBP-C) suggest an additional role in the regulation of muscle contraction. The former is of particular importance in the heart, where RLC phosphorylation appears to be correlated to the wringing motion of heart contraction. To address these questions and because of a lack of mammalian RLC structures, we initiated an NMR study of the human cardiac regulatory myosin light chain. PMID:24414277

  15. Regulation of cardiac metabolism and function by lipogenic factors.

    PubMed

    Bednarski, Tomasz; Pyrkowska, Aleksandra; Opasińska, Agnieszka; Dobrzyń, Paweł

    2016-01-01

    The heart has a limited capacity for lipogenesis and de novo lipid synthesis. However, expression of lipogenic genes in cardiomyocytes is unexpectedly high. Recent studies showed that lipogenic genes are important factors regulating cardiac metabolism and function. Long chain fatty acids are a major source of ATP required for proper heart function, and under aerobic conditions, the heart derives 60-90% of the energy necessary for contractile function from fatty acid oxidation. On the other hand, cardiac lipid over-accumulation (e.g. ceramides, diacylglycerols) leads to heart dysfunction. Downregulation of the lipogenic genes' expression (e.g. sterol regulatory element binding protein 1, stearoyl-CoA desaturase, acetyl-CoA kwacarboxylase) decreased heart steatosis and cardiomyocyte apoptosis, improving systolic and diastolic function of the left ventricle. Lipogenic factors also regulate fatty acids and glucose utilization in the heart, underlining their important role in maintaining energetic homeostasis in pathological states. Fatty acid synthase, the enzyme catalyzing fatty acids de novo synthesis, affects cardiac calcium signaling through regulation of L-type calcium channel activity. Thus, a growing body of evidence suggests that the role of lipogenic genes in cardiomyocytes may be distinct from other tissues. Here, we review recent advances made in understanding the role of lipogenic genes in the control of heart metabolism and its involvement in the pathogenesis of lipotoxic cardiomyopathy. PMID:27333934

  16. Calsequestrins in skeletal and cardiac muscle from adult Danio rerio.

    PubMed

    Furlan, Sandra; Mosole, Simone; Murgia, Marta; Nagaraj, Nagarjuna; Argenton, Francesco; Volpe, Pompeo; Nori, Alessandra

    2016-04-01

    Calsequestrin (Casq) is a high capacity, low affinity Ca(2+)-binding protein, critical for Ca(2+)-buffering in cardiac and skeletal muscle sarcoplasmic reticulum. All vertebrates have multiple genes encoding for different Casq isoforms. Increasing interest has been focused on mammalian and human Casq genes since mutations of both cardiac (Casq2) and skeletal muscle (Casq1) isoforms cause different, and sometime severe, human pathologies. Danio rerio (zebrafish) is a powerful model for studying function and mutations of human proteins. In this work, expression, biochemical properties cellular and sub-cellular localization of D. rerio native Casq isoforms are investigated. By quantitative PCR, three mRNAs were detected in skeletal muscle and heart with different abundances. Three zebrafish Casqs: Casq1a, Casq1b and Casq2 were identified by mass spectrometry (Data are available via ProteomeXchange with identifier PXD002455). Skeletal and cardiac zebrafish calsequestrins share properties with mammalian Casq1 and Casq2. Skeletal Casqs were found primarily, but not exclusively, at the sarcomere Z-line level where terminal cisternae of sarcoplasmic reticulum are located. PMID:26585961

  17. Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency.

    PubMed

    Qin, Qingyun; Qu, Chen; Niu, Ting; Zang, Huimei; Qi, Lei; Lyu, Linmao; Wang, Xuejun; Nagarkatti, Mitzi; Nagarkatti, Prakash; Janicki, Joseph S; Wang, Xing Li; Cui, Taixing

    2016-01-01

    Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction. PMID:26573705

  18. Clinically applicable gated cardiac computed tomography

    SciTech Connect

    Cipriano, P.R.; Nassi, M.; Brody, W.R.

    1983-03-01

    Several attempts have been made to improve cardiac images obtained with x-ray transmission computed tomography (CT) by stopping cardiac motion through electrocardiographic gating. These methods reconstruct images that correspond to time intervals of the cardiac cycle identified by electrocardiography using either a pulsed x-ray beam at a selected time in the cardiac cycle or selected measurements in retrospect from regularly pulsed measurements made over several cardiac cycles. Missing CT angles of view (line integrals) have been a major problem contributing to degradation of such gated cardiac CT images. A new method for CT reconstruction from an incomplete set of projection data is presented that can be used clinically with a standard fan-beam reconstruction algorithm to improve gated cardiac CT images.

  19. Daytime cardiac autonomic activity during one week of continuous night shift.

    PubMed

    Holmes, A L; Burgess, H J; McCulloch, K; Lamond, N; Fletcher, A; Dorrian, J; Roach, G; Dawson, D

    2001-12-01

    Shift workers encounter an increased risk of cardiovascular disease compared to their day working counterparts. To explore this phenomenon, the effects of one week of simulated night shift on cardiac sympathetic (SNS) and parasympathetic (PNS) activity were assessed. Ten (5m; 5f) healthy subjects aged 18-29 years attended an adaptation and baseline night before commencing one week of night shift (2300-0700 h). Sleep was recorded using a standard polysomnogram and circadian phase was tracked using salivary melatonin data. During sleep, heart rate (HR), cardiac PNS activity (RMSSD) and cardiac SNS activity (pre-ejection period) were recorded. Night shift did not influence seep quality, but reduced sleep duration by a mean of 52 +/- 29 min. One week of night shift evoked a small chronic sleep debt of 5 h 14 +/- 56 min and a cumulative circadian phase delay of 5 h +/- 14 min. Night shift had no significant effect on mean HR, but mean cardiac SNS activity during sleep was consistently higher and mean cardiac PNS activity during sleep declined gradually across the week. These results suggest that shiftwork has direct and unfavourable effects on cardiac autonomic activity and that this might be one mechanism via which shiftwork increases the risk of cardiovascular disease. It is postulated that sleep loss could be one mediator of the association between shiftwork and cardiovascular health. PMID:14564886

  20. Measuring cardiac waste: the premier cardiac waste measures.

    PubMed

    Lowe, Timothy J; Partovian, Chohreh; Kroch, Eugene; Martin, John; Bankowitz, Richard

    2014-01-01

    The authors developed 8 measures of waste associated with cardiac procedures to assist hospitals in comparing their performance with peer facilities. Measure selection was based on review of the research literature, clinical guidelines, and consultation with key stakeholders. Development and validation used the data from 261 hospitals in a split-sample design. Measures were risk adjusted using Premier's CareScience methodologies or mean peer value based on Medicare Severity Diagnosis-Related Group assignment. High variability was found in resource utilization across facilities. Validation of the measures using item-to-total correlations (range = 0.27-0.78), Cronbach α (.88), and Spearman rank correlation (0.92) showed high reliability and discriminatory power. Because of the level of variability observed among hospitals, this study suggests that there is opportunity for facilities to design successful waste reduction programs targeting cardiac-device procedures. PMID:23719033

  1. Accurate measurement of oxygen consumption in children undergoing cardiac catheterization.

    PubMed

    Li, Jia

    2013-01-01

    Oxygen consumption (VO(2) ) is an important part of hemodynamics using the direct Fick principle in children undergoing cardiac catheterization. Accurate measurement of VO(2) is vital. Obviously, any error in the measurement of VO(2) will translate directly into an equivalent percentage under- or overestimation of blood flows and vascular resistances. It remains common practice to estimate VO(2) values from published predictive equations. Among these, the LaFarge equation is the most commonly used equation and gives the closest estimation with the least bias and limits of agreement. However, considerable errors are introduced by the LaFarge equation, particularly in children younger than 3 years of age. Respiratory mass spectrometry remains the "state-of-the-art" method, allowing highly sensitive, rapid and simultaneous measurement of multiple gas fractions. The AMIS 2000 quadrupole respiratory mass spectrometer system has been adapted to measure VO(2) in children under mechanical ventilation with pediatric ventilators during cardiac catheterization. The small sampling rate, fast response time and long tubes make the equipment a unique and powerful tool for bedside continuous measurement of VO(2) in cardiac catheterization for both clinical and research purposes. PMID:22488802

  2. Quantifying spatiotemporal complexity of cardiac dynamics using ordinal patterns.

    PubMed

    Schlemmer, Alexander; Berg, Sebastian; Shajahan, T K; Luther, Stefan; Parlitz, Ulrich

    2015-08-01

    Analyzing the dynamics of complex excitation wave patterns in cardiac tissue plays a key role for understanding the origin of life-threatening arrhythmias and for devising novel approaches to control them. The quantification of spatiotemporal complexity, however, remains a challenging task. This holds in particular for the analysis of data from fluorescence imaging (optical mapping), which allows for the measurement of membrane potential and intracellular calcium at high spatial and temporal resolution. Hitherto methods, like dominant frequency maps and the analysis of phase singularities, address important aspects of cardiac dynamics, but they consider very specific properties of excitable media, only. This article focuses on the benchmark of spatial complexity measures over time in the context of cardiac cell cultures. Standard Shannon Entropy and Spatial Permutation Entropy, an adaption of [1], have been implemented and applied to optical mapping data from embryonic chicken cell culture experiments. We introduce spatial separation of samples when generating ordinal patterns and show its importance for Spatial Permutation Entropy. Results suggest that Spatial Permutation Entropies provide a robust and interpretable measure for detecting qualitative changes in the dynamics of this excitable medium. PMID:26737183

  3. EHD3-Dependent Endosome Pathway Regulates Cardiac Membrane Excitability and Physiology

    PubMed Central

    Curran, Jerry; Makara, Michael A.; Little, Sean C.; Musa, Hassan; Liu, Bin; Wu, Xiangqiong; Polina, Iuliia; Alecusan, Joe; Wright, Patrick; Li, Jingdong; Billman, George E.; Boyden, Penelope A.; Gyorke, Sandor; Band, Hamid; Hund, Thomas J.; Mohler, Peter J.

    2014-01-01

    Rationale Cardiac function is dependent on the coordinate activities of membrane ion channels, transporters, pumps, and hormone receptors to dynamically tune the membrane electrochemical gradient in response to acute and chronic stress. While our knowledge of membrane proteins has rapidly advanced over the past decade, our understanding of the subcellular pathways governing the trafficking and localization of integral membrane proteins is limited, and essentially unstudied in vivo. In heart, to our knowledge, there are no in vivo mechanistic studies that directly link endosome-based machinery with cardiac physiology. Objective Define the in vivo roles of endosome-based cellular machinery for cardiac membrane protein trafficking, myocyte excitability, and cardiac physiology. Methods and Results We identify the endosome-based EHD3 pathway as essential for cardiac physiology. EHD3−/− hearts display structural and functional defects including bradycardia and rate variability, conduction block, and blunted response to adrenergic stimulation. Mechanistically, EHD3 is critical for membrane protein trafficking, as EHD3−/− myocytes display reduced expression/localization of Na/Ca exchanger and Cav1.2 with a parallel reduction in INCX and ICa,L. Functionally, EHD3−/− myocytes show increased sarcoplasmic reticulum [Ca], increased spark frequency, and reduced expression/localization of ankyrin-B, a binding partner for EHD3 and Na/Ca exchanger. Finally, we show that in vivo EHD3−/− defects are due to cardiac-specific roles of EHD3 as mice with cardiac-selective EHD3 deficiency demonstrate both structural and electrical phenotypes. Conclusions These data provide new insight into the critical role of endosome-based pathways in membrane protein targeting and cardiac physiology. EHD3 is a critical component of protein trafficking in heart and is essential for the proper membrane targeting of select cellular proteins that maintain excitability. PMID:24759929

  4. Metabolic Adaptation to Muscle Ischemia

    NASA Technical Reports Server (NTRS)

    Cabrera, Marco E.; Coon, Jennifer E.; Kalhan, Satish C.; Radhakrishnan, Krishnan; Saidel, Gerald M.; Stanley, William C.

    2000-01-01

    Although all tissues in the body can adapt to varying physiological/pathological conditions, muscle is the most adaptable. To understand the significance of cellular events and their role in controlling metabolic adaptations in complex physiological systems, it is necessary to link cellular and system levels by means of mechanistic computational models. The main objective of this work is to improve understanding of the regulation of energy metabolism during skeletal/cardiac muscle ischemia by combining in vivo experiments and quantitative models of metabolism. Our main focus is to investigate factors affecting lactate metabolism (e.g., NADH/NAD) and the inter-regulation between carbohydrate and fatty acid metabolism during a reduction in regional blood flow. A mechanistic mathematical model of energy metabolism has been developed to link cellular metabolic processes and their control mechanisms to tissue (skeletal muscle) and organ (heart) physiological responses. We applied this model to simulate the relationship between tissue oxygenation, redox state, and lactate metabolism in skeletal muscle. The model was validated using human data from published occlusion studies. Currently, we are investigating the difference in the responses to sudden vs. gradual onset ischemia in swine by combining in vivo experimental studies with computational models of myocardial energy metabolism during normal and ischemic conditions.

  5. Asiatic acid inhibits cardiac hypertrophy by blocking interleukin-1β-activated nuclear factor-κB signaling in vitro and in vivo

    PubMed Central

    Xu, Xiaohan; Si, Linjie; Xu, Jing; Yi, Chenlong; Wang, Fang; Gu, Weijuan

    2015-01-01

    Background Activated interleukin (IL)-1β signaling pathway is closely associated with pathological cardiac hypertrophy. This study investigated whether asiatic acid (AA) could inhibit IL-1β-related hypertrophic signaling, and thus suppressing the development of cardiac hypertrophy. Methods Transverse aortic constriction (TAC) induced cardiac hypertrophy in C57BL/6 mice and cultured neonatal cardiac myocytes stimulated with IL-1β were used to evaluate the role of AA in cardiac hypertrophy. The expression of atrial natriuretic peptide (ANP) was evaluated by quantitative polymerase chain reaction (qPCR) and the nuclear factor (NF)-κB binding activity was measured by electrophoretic mobility shift assays (EMSA). Results AA pretreatment significantly attenuated the IL-1β-induced hypertrophic response of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of ANP mRNA expression. The protective effect of AA on IL-1β-stimulated cardiomyocytes was associated with the reduction of NF-κB binding activity. In addition, AA prevented TAC-induced cardiac hypertrophy in vivo. It was found that AA markedly reduced the excessive expression of IL-1β and ANP, and inhibited the activation of NF-κB in the hypertrophic myocardium. Conclusions Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of IL-1β-activated NF-κB signaling may be the mechanism through which AA prevents cardiac hypertrophy. PMID:26623102

  6. Stimulating Cardiac Muscle by Light: Cardiac Optogenetics by Cell Delivery

    PubMed Central

    Jia, Zhiheng; Valiunas, Virginijus; Lu, Zongju; Bien, Harold; Liu, Huilin; Wang, Hong-Zhang; Rosati, Barbara; Brink, Peter R.; Cohen, Ira S.; Entcheva, Emilia

    2011-01-01

    Background After the recent cloning of light-sensitive ion channels and their expression in mammalian cells, a new field, optogenetics, emerged in neuroscience, allowing for precise perturbations of neural circuits by light. However, functionality of optogenetic tools has not been fully explored outside neuroscience; and a non-viral, non-embryogenesis based strategy for optogenetics has not been shown before. Methods and Results We demonstrate the utility of optogenetics to cardiac muscle by a tandem cell unit (TCU) strategy, where non-excitable cells carry exogenous light-sensitive ion channels, and when electrically coupled to cardiomyocytes, produce optically-excitable heart tissue. A stable channelrhodopsin2 (ChR2) expressing cell line was developed, characterized and used as a cell delivery system. The TCU strategy was validated in vitro in cell pairs with adult canine myocytes (for a wide range of coupling strengths) and in cardiac syncytium with neonatal rat cardiomyocytes. For the first time, we combined optical excitation and optical imaging to capture light-triggered muscle contractions and high-resolution propagation maps of light-triggered electrical waves, found to be quantitatively indistinguishable from electrically-triggered waves. Conclusions Our results demonstrate feasibility to control excitation and contraction in cardiac muscle by light using the TCU approach. Optical pacing in this case uses less energy, offers superior spatiotemporal control, remote access and can serve not only as an elegant tool i