Journal articles on the topic 'Cardiac contraction sensor'
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1
Sharma, Vikas, Akhalesh kumar, Kartik Singhal, Chandana Majee, and Salahuddin. "Advancement in treating Cardiac Diseases using Cardiac Device." International Journal of PharmTech Research 13, no. 3 (2020): 217–22. http://dx.doi.org/10.20902/ijptr.2019.130312.
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From the origin of ancient Vedas or Shastras; there was an awareness of artificial intelligence but in different meanings. In present scenario, one has to perform a lot of research for the production of works relating with artificial intelligence. Basically, artificial intelligence is a huge group of skills from advanced machines used for finding the solutions of different fields i.e. in pharma fields or non-pharma fields. The problem of heart failure or heart attack is very big health issue which is assisted with more than 23 million peoples worldwide. Heart failure can be held due to the vasoconstriction or improper pumping mechanism of ventricles. Heart failure heart logic device is a new tsunami in the healthcare system for cardiac devices. This device is in two different forms which are as (ICD) implantable cardioverter defibrillator and other oneiscardiac resynchronization therapy defibrillator (CRT-D). Heart logic heart failure diagnostic device contains multiple sensors to track physiological functioning of the heart. There are Heart sound sensors which checks signs of elevated filling pressure and weakened ventricular contraction. There are also a sensor for checking pulmonary edema. Respiration sensor is used to monitor the rapid shallow breathing system which is associated with shortness of breath. Heart rate sensors check the heart rate and arrhythmia conditions. This device can predict heart failure events weeks before they happen. This artificial intelligence assisted device is showing the sensitivity in more than 70% of peoples to save the valuable lives of the human beings
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MARCELLI, E., E. VANOLI, G. G. MATTERA, G. GAGGINI, L. CERCENELLI, and G. PLICCHI. "AN ENDOCARDIAL ACCELERATION SENSOR FOR MONITORING CARDIAC FUNCTION OF ISCHEMIC HEARTS." Journal of Mechanics in Medicine and Biology 06, no. 01 (March 2006): 75–80. http://dx.doi.org/10.1142/s0219519406001753.
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Previous experimental studies demonstrated that in normal hearts, Peak Endocardial Acceleration (PEA), during isovolumic contraction phase, measured with an endocardial sensor (Best, Sorin) in the right ventricle (RV), tracks changes of left ventricular (LV) contractility. Aim of the study: To assess if PEA also tracks LV contractility changes in ischemic hearts resulting from coronary microembolizations (ME). Methods: Under general anaesthesia, six adult beagle dogs (12 ± 2 kg) were instrumented for chronic monitoring of LV pressure, ECG and PEA. Latex beads mixed with fluoroscopy dye were injected into the circumflex coronary artery to cause LV ischemia. Before and after ME, incremental dobutamine infusions were performed to evaluate the contractile response to adrenergic stimulation. Results: A significant correlation between PEA and LVdP /dt max was observed before and after ME. Such a strong correlation was maintained even during adrenergic stimulation (r = 0.83 to 0.99, p < 0.001). The sensor PEA appears to be an effective means for the chronic monitoring of the mechanical function of ischemic hearts.
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DING, WENJING, YANG WANG, GUOJUN LI, JIAJI HANG, YONGCHANG WU, CHENHAO LING, DANYE ZHOU, ZHIBIN CHEN, and LINGFENG GAO. "PIEZORESISTIVE STRAIN SENSOR APPLICATION IN EVALUATION OF MOUSE AORTIC MEDIA CUSHIONS EFFECTIVENESS AND SPONTANEOUS MYOGENIC CONTRACTION." Journal of Mechanics in Medicine and Biology 17, no. 07 (November 2017): 1740032. http://dx.doi.org/10.1142/s0219519417400322.
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The aortic media realized Windkessel vessel functions and maintain sustained ventricle ejection balance during cardiac circle. Wheatstone bridge circuit piezoresistive strain sensor had desirable sensing properties to investigate aortic cushion features. In this study, Wheatstone bridge sensor was used to evaluate quick stretching-induced aortic efficient cushions and spontaneous myogenic contractions. Mice aortic specimens were loosely hooked and stabilized to [Formula: see text][Formula: see text]mm stainless steel pin and strain sensor, whereas the other side was hooked and shows increasing specimen length. Specimen isometric tension and rhythmic spontaneous myogenic contraction were recorded. Isometric tension and spontaneous myogenic response at initial length ([Formula: see text] and ultimate length ([Formula: see text] were evaluated. Aortic specimen significantly eliminated mechanical rigid oscillations. The recovery to baseline time was significantly shortened at [Formula: see text] ([Formula: see text][Formula: see text]ms and [Formula: see text] ms at [Formula: see text] and [Formula: see text], respectively, but [Formula: see text][Formula: see text]ms and [Formula: see text][Formula: see text]ms in no-load test). High Ca[Formula: see text] incubation prolonged the recovery time to baseline at [Formula: see text] and [Formula: see text] ([Formula: see text][Formula: see text]ms and [Formula: see text][Formula: see text]ms, respectively) and suggested Ca[Formula: see text] decreased efficient cushion. Moreover, strain sensor successfully recorded the enhanced rhythmic spontaneous myogenic contractions in isometric specimen. Wheatstone bridge circuit sensor reflected the significance of efficient cushions under mechanical preload, which absolutely captured rhythmic myogenic contractions of mice aortic specimen.
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Qiu, Bin, Guangyong Li, Jianke Du, Aibing Zhang, and Yuan Jin. "A Numerical Model of a Perforated Microcantilever Covered with Cardiomyocytes to Improve the Performance of the Microcantilever Sensor." Materials 14, no. 1 (December 28, 2020): 95. http://dx.doi.org/10.3390/ma14010095.
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A few simple polymeric microsystems, such as microcantilever sensors, have recently been developed for the preliminary screening of cardiac toxicity. The microcantilever deflection produced by a change in the cardiomyocyte (CM) contraction force is important for understanding the mechanism of heart failure. In this study, a new numerical model is proposed to analyze the contractile behavior of CMs cultured on a perforated microcantilever surface for improving the performance of the microcantilever sensor. First, the surface traction model is used to investigate the bending displacement of the plain microcantilever. In order to improve the bending effect, a new numerical model is developed to analyze the bending behavior of the perforated microcantilever covered with CMs. Compared with the designed molds, the latter yields better results. Finally, a simulation analysis is proposed based on a finite element method to verify the presence of a preformed mold. Moreover, the effects of various factors on the bending displacement, including microcantilever size, Young’s modulus, and porosity factor, are investigated. Both the simulation and numerical results have good consistency, and the maximum error between the numerical and simulation results is not more than 3.4%, even though the porosity factor reaches 0.147. The results show that the developed mold opens new avenues for CM microcantilever sensors to detect cardiac toxicity.
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Di Biase, Valentina, and Clara Franzini-Armstrong. "Evolution of skeletal type e–c coupling." Journal of Cell Biology 171, no. 4 (November 14, 2005): 695–704. http://dx.doi.org/10.1083/jcb.200503077.
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The functional separation between skeletal and cardiac muscles, which occurs at the threshold between vertebrates and invertebrates, involves the evolution of separate contractile and control proteins for the two types of striated muscles, as well as separate mechanisms of contractile activation. The functional link between electrical excitation of the surface membrane and activation of the contractile material (known as excitation–contraction [e–c] coupling) requires the interaction between a voltage sensor in the surface membrane, the dihydropyridine receptor (DHPR), and a calcium release channel in the sarcoplasmic reticulum, the ryanodine receptor (RyR). Skeletal and cardiac muscles have different isoforms of the two proteins and present two structurally and functionally distinct modes of interaction. We use structural clues to trace the evolution of the dichotomy from a single, generic type of e–c coupling to a diversified system involving a novel mechanism for skeletal muscle activation. Our results show that a significant structural transition marks the protochordate to the Craniate evolutionary step, with the appearance of skeletal muscle–specific RyR and DHPR isoforms.
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Kanade, Pooja P., Nomin-Erdene Oyunbaatar, and Dong-Weon Lee. "Polymer-Based Functional Cantilevers Integrated with Interdigitated Electrode Arrays—A Novel Platform for Cardiac Sensing." Micromachines 11, no. 4 (April 24, 2020): 450. http://dx.doi.org/10.3390/mi11040450.
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Heart related ailments are some of the most common causes for death in the world, and some of the causes are cardiac toxicity due to drugs. Several platforms have been developed in this regard over the years that can measure electrical or mechanical behavior of cardiomyocytes. In this study, we have demonstrated a biomedical device that can simultaneously measure electrophysiology and contraction force of cardiomyocytes. This dual-function device is composed of a photosensitive polymer-based cantilever, with a pair of metal-based interdigitated electrodes on its surface, such that the cantilever can measure the contraction force of cardiomyocytes and the electrodes can measure the impedance between cells and substrate. The cantilever is patterned with microgrooves so that the cardiomyocytes can align to the cantilever in order to make a higher cantilever deflection in response to contraction force. Preliminary experimental results have identified the potential for use in the drug-induced cardiac toxicity tests, and further optimization is desirable to extend the technique to various bio-sensor areas.
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Andreozzi, Emilio, Antonio Fratini, Daniele Esposito, Ganesh Naik, Caitlin Polley, Gaetano D. Gargiulo, and Paolo Bifulco. "Forcecardiography: A Novel Technique to Measure Heart Mechanical Vibrations onto the Chest Wall." Sensors 20, no. 14 (July 13, 2020): 3885. http://dx.doi.org/10.3390/s20143885.
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This paper presents forcecardiography (FCG), a novel technique to measure local, cardiac-induced vibrations onto the chest wall. Since the 19th century, several techniques have been proposed to detect the mechanical vibrations caused by cardiovascular activity, the great part of which was abandoned due to the cumbersome instrumentation involved. The recent availability of unobtrusive sensors rejuvenated the research field with the most currently established technique being seismocardiography (SCG). SCG is performed by placing accelerometers onto the subject’s chest and provides information on major events of the cardiac cycle. The proposed FCG measures the cardiac-induced vibrations via force sensors placed onto the subject’s chest and provides signals with a richer informational content as compared to SCG. The two techniques were compared by analysing simultaneous recordings acquired by means of a force sensor, an accelerometer and an electrocardiograph (ECG). The force sensor and the accelerometer were rigidly fixed to each other and fastened onto the xiphoid process with a belt. The high-frequency (HF) components of FCG and SCG were highly comparable (r > 0.95) although lagged. The lag was estimated by cross-correlation and resulted in about tens of milliseconds. An additional, large, low-frequency (LF) component, associated with ventricular volume variations, was observed in FCG, while not being visible in SCG. The encouraging results of this feasibility study suggest that FCG is not only able to acquire similar information as SCG, but it also provides additional information on ventricular contraction. Further analyses are foreseen to confirm the advantages of FCG as a technique to improve the scope and significance of pervasive cardiac monitoring.
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Virtanen, J., M. Toivanen, T. Toimela, T. Heinonen, and S. Tuukkanen. "Direct measurement of contraction force in human cardiac tissue model using piezoelectric cantilever sensor technique." Current Applied Physics 20, no. 1 (January 2020): 155–60. http://dx.doi.org/10.1016/j.cap.2019.10.020.
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Kobayashi, Takuya, Nagomi Kurebayashi, and Takashi Murayama. "The Ryanodine Receptor as a Sensor for Intracellular Environments in Muscles." International Journal of Molecular Sciences 22, no. 19 (October 6, 2021): 10795. http://dx.doi.org/10.3390/ijms221910795.
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The ryanodine receptor (RyR) is a Ca2+ release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation–contraction coupling. The activity of the RyR is regulated by the changes in the level of many intracellular factors, such as divalent cations (Ca2+ and Mg2+), nucleotides, associated proteins, and reactive oxygen species. Since these intracellular factors change depending on the condition of the muscle, e.g., exercise, fatigue, or disease states, the RyR channel activity will be altered accordingly. In this review, we describe how the RyR channel is regulated under various conditions and discuss the possibility that the RyR acts as a sensor for changes in the intracellular environments in muscles.
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Oláh, Attila, Mihály Ruppert, Tamás István Orbán, Ágota Apáti, Balázs Sarkadi, Béla Merkely, and Tamás Radovits. "Hemodynamic characterization of a transgenic rat strain stably expressing the calcium sensor protein GCaMP2." American Journal of Physiology-Heart and Circulatory Physiology 316, no. 5 (May 1, 2019): H1224—H1228. http://dx.doi.org/10.1152/ajpheart.00074.2019.
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A novel transgenic rat strain has recently been generated that stably expresses the genetically engineered calcium sensor protein GCaMP2 in different cell types, including cardiomyocytes, to investigate calcium homeostasis. To investigate whether the expression of the GCaMP2 protein itself affects cardiac function, in the present work we aimed at characterizing in vivo hemodynamics in the GCaMP2 transgenic rat strain. GCaMP2 transgenic rats and age-matched Sprague-Dawley control animals were investigated. In vivo hemodynamic characterization was performed by left ventricular (LV) pressure-volume analysis. Postmortem heart weight data showed cardiac hypertrophy in the GCaMP2 group (heart-weight-to-tibial-length ratio: 0.26 ± 0.01 GCaMP2 vs. 0.23 ± 0.01 g/cm Co, P < 0.05). We detected elevated mean arterial pressure and increased total peripheral resistance in transgenic rats. GCaMP2 transgenesis was associated with prolonged contraction and relaxation. LV systolic function was not altered in transgenic rats, as indicated by conventional parameters and load-independent, sensitive indices. We found a marked deterioration of LV active relaxation in GCaMP2 animals (τ: 16.8 ± 0.7 GCaMP2 vs. 12.2 ± 0.3 ms Co, P < 0.001). Our data indicated myocardial hypertrophy, arterial hypertension, and impaired LV active relaxation along with unchanged systolic performance in the heart of transgenic rats expressing the GCaMP2 fluorescent calcium sensor protein. Special caution should be taken when using transgenic models in cardiovascular studies. NEW & NOTEWORTHY Genetically encoded Ca2+-sensors, like GCaMP2, are important tools to reveal molecular mechanisms for Ca2+-sensing. We provided left ventricular hemodynamic characterization of GCaMP2 transgenic rats and found increased afterload, cardiac hypertrophy, and prolonged left ventricular relaxation, along with unaltered systolic function and contractility. Special caution should be taken when using this rodent model in cardiovascular pharmacological and toxicological studies.
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Pizarro, G., R. Fitts, I. Uribe, and E. Ríos. "The voltage sensor of excitation-contraction coupling in skeletal muscle. Ion dependence and selectivity." Journal of General Physiology 94, no. 3 (September 1, 1989): 405–28. http://dx.doi.org/10.1085/jgp.94.3.405.
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Manifestations of excitation-contraction (EC) coupling of skeletal muscle were studied in the presence of metal ions of the alkaline and alkaline-earth groups in the extracellular medium. Single cut fibers of frog skeletal muscle were voltage clamped in a double Vaseline gap apparatus, and intramembrane charge movement and myoplasmic Ca2+ transients were simultaneously measured. In metal-free extracellular media both charge movement of the charge 1 type and Ca transients were suppressed. Under metal-free conditions the nonlinear charge distribution was the same in depolarized (holding potential of 0 mV) and normally polarized fibers (holding potentials between -80 and -90 mV). The manifestations of EC coupling recovered when ions of groups Ia and IIa of the periodic table were included in the extracellular solution; the extent of recovery depended on the ion species. These results are consistent with the idea that the voltage sensor of EC coupling has a binding site for metal cations--the "priming" site--that is essential for function. A state model of the voltage sensor in which metal ligands bind preferentially to the priming site when the sensor is in noninactivated states accounts for the results. This theory was used to derive the relative affinities of the various ions for the priming site from the magnitude of the EC coupling response. The selectivity sequence thus constructed is: Ca greater than Sr greater than Mg greater than Ba for group IIa cations and Li greater than Na greater than K greater than Rb greater than Cs for group Ia. Ca2+, the most effective of all ions tested, was 1,500-fold more effective than Na+. This selectivity sequence is qualitatively and quantitatively similar to that of the intrapore binding sites of the L-type cardiac Ca channel. This provides further evidence of molecular similarity between the voltage sensor and Ca channels.
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Most, Patrick, Andrew Remppis, Sven T. Pleger, Hugo A. Katus, and Walter J. Koch. "S100A1: a novel inotropic regulator of cardiac performance. Transition from molecular physiology to pathophysiological relevance." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 293, no. 2 (August 2007): R568—R577. http://dx.doi.org/10.1152/ajpregu.00075.2007.
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Here we review the considerable body of evidence that has accumulated to support the notion of S100A1, a cardiac-specific Ca2+-sensor protein of the EF-hand type, as a physiological regulator of excitation-contraction coupling and inotropic reserve mechanisms in the mammalian heart. In particular, molecular mechanisms will be discussed conveying the Ca2+-dependent inotropic actions of S100A1 protein in cardiomyocytes occurring independently of β-adrenergic signaling. Moreover, we will shed light on the molecular structure-function relationship of S100A1 with its cardiac target proteins at the sarcoplasmic reticulum, the sarcomere, and the mitochondria. Furthermore, pathophysiological consequences of disturbed S100A1 protein expression on altered Ca2+handling and intertwined systems in failing myocardium will be highlighted. Subsequently, therapeutic options by means of genetic manipulation of cardiac S100A1 expression will be discussed, aiming to complete our current understanding of the role of S100A1 in diseased myocardium.
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Van Petegem, F., and D. L. Minor. "The structural biology of voltage-gated calcium channel function and regulation." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 887–93. http://dx.doi.org/10.1042/bst0340887.
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Voltage-gated calcium channels (CaVs) are large (∼0.5 MDa), multisubunit, macromolecular machines that control calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, calcium-dependent gene transcription and synaptic transmission. CaVs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, calcium-dependent inactivation and calcium-dependent facilitation. These processes arise from the concerted action of different channel domains with CaV β-subunits and the soluble calcium sensor calmodulin. Until recently, nothing was known about the CaV structure at high resolution. Recent crystallographic work has revealed the first glimpses at the CaV molecular framework and set a new direction towards a detailed mechanistic understanding of CaV function.
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Ma, J., K. Anderson, R. Shirokov, R. Levis, A. González, M. Karhanek, M. M. Hosey, G. Meissner, and E. Ríos. "Effects of perchlorate on the molecules of excitation-contraction coupling of skeletal and cardiac muscle." Journal of General Physiology 102, no. 3 (September 1, 1993): 423–48. http://dx.doi.org/10.1085/jgp.102.3.423.
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To understand the nature of the transmission process of excitation-contraction (EC) coupling, the effects of the anion perchlorate were investigated on the voltage sensor (dihydropyridine receptor, DHPR) and the Ca release channel (ryanodine receptor, RyR) of the sarcoplasmic reticulum (SR). The molecules, from rabbit skeletal muscle, were either separated in membrane vesicular fractions or biochemically purified so that the normal EC coupling interaction was prevented. Additionally, the effect of ClO4- was investigated on L-type Ca2+ channel gating currents of guinea pig ventricular myocytes, as a native DHPR not in the physiological interaction of skeletal muscle. At 20 mM, ClO4- had minor effects on the activation of ionic currents through Ca channels from skeletal muscle transverse tubular (T) membranes fused with planar bilayers: a +7-mV shift in the midpoint voltage, V, with no change in kinetics of activation or deactivation. This is in contrast with the larger, negative shift that ClO4- causes on the distribution of intramembrane charge movement of skeletal muscle. At up to 100 mM it did not affect the binding of the DHP [3H]PN200-110 to triad-enriched membrane fractions (TR). At 8 mM it did not affect the kinetics or the voltage distribution of gating currents of Ca channels in heart myocytes. These negative results were in contrast to the effects of ClO4- on the release channel. At 20 mM it increased several-fold the open probability of channels from purified RyR incorporated in planar bilayers and conducting Ba2+, an effect seen on channels first closed by chelation of Ca2+ or by the presence of Mg2+. It significantly increased the initial rate of efflux of 45Ca2+ from TR vesicles (by a factor of 1.75 at 20 mM and 4.5 at 100 mM). ClO4- also increased the binding of [3H]ryanodine to TR fractions. The relative increase in binding was 50-fold at the lowest [Ca2+] used (1 microM) and then decayed to much lower values as [Ca2+] was increased. The increase was due entirely to an increase in the association rate constant of ryanodine binding. The chaotropic ions SCN- and I- increased the association rate constant to a similar extent. The binding of ryanodine to purified RyR protein reconstituted into liposomes had a greater affinity than to TR fractions but was similarly enhanced by ClO4-. The reducing agent dithiothreitol (5 mM) did not reduce the effect of ClO4-, and 5% polyethylene glycol, with an osmolarity equivalent to 20 mM ClO4-, did not change ryanodine binding.(ABSTRACT TRUNCATED AT 400 WORDS)
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Takekura, Hiroaki, Cecilia Paolini, Clara Franzini-Armstrong, Gerlinde Kugler, Manfred Grabner, and Bernhard E. Flucher. "Differential Contribution of Skeletal and Cardiac II-III Loop Sequences to the Assembly of Dihydropyridine-Receptor Arrays in Skeletal Muscle." Molecular Biology of the Cell 15, no. 12 (December 2004): 5408–19. http://dx.doi.org/10.1091/mbc.e04-05-0414.
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The plasmalemmal dihydropyridine receptor (DHPR) is the voltage sensor in skeletal muscle excitation-contraction (e-c) coupling. It activates calcium release from the sarcoplasmic reticulum via protein–protein interactions with the ryanodine receptor (RyR). To enable this interaction, DHPRs are arranged in arrays of tetrads opposite RyRs. In the DHPR α1S subunit, the cytoplasmic loop connecting repeats II and III is a major determinant of skeletal-type e-c coupling. Whether the essential II-III loop sequence (L720-L764) also determines the skeletal-specific arrangement of DHPRs was examined in dysgenic (α1S-null) myotubes reconstituted with distinct α1 subunit isoforms and II-III loop chimeras. Parallel immunofluorescence and freeze-fracture analysis showed that α1S and chimeras containing L720-L764, all of which restored skeletal-type e-c coupling, displayed the skeletal arrangement of DHPRs in arrays of tetrads. Conversely, α1C and those chimeras with a cardiac II-III loop and cardiac e-c coupling properties were targeted into junctional membranes but failed to form tetrads. However, an α1S-based chimera with the heterologous Musca II-III loop produced tetrads but did not reconstitute skeletal muscle e-c coupling. These findings suggest an inhibitory role in tetrad formation of the cardiac II-III loop and that the organization of DHPRs in tetrads vis-à-vis the RyR is necessary but not sufficient for skeletal-type e-c coupling.
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García, J., T. Tanabe, and K. G. Beam. "Relationship of calcium transients to calcium currents and charge movements in myotubes expressing skeletal and cardiac dihydropyridine receptors." Journal of General Physiology 103, no. 1 (January 1, 1994): 125–47. http://dx.doi.org/10.1085/jgp.103.1.125.
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In both skeletal and cardiac muscle, the dihydropyridine (DHP) receptor is a critical element in excitation-contraction (e-c) coupling. However, the mechanism for calcium release is completely different in these muscles. In cardiac muscle the DHP receptor functions as a rapidly-activated calcium channel and the influx of calcium through this channel induces calcium release from the sarcoplasmic reticulum (SR). In contrast, in skeletal muscle the DHP receptor functions as a voltage sensor and as a slowly-activating calcium channel; in this case, the voltage sensor controls SR calcium release. It has been previously demonstrated that injection of dysgenic myotubes with cDNA (pCAC6) encoding the skeletal muscle DHP receptor restores the slow calcium current and skeletal type e-c coupling that does not require entry of external calcium (Tanabe, Beam, Powell, and Numa. 1988. Nature. 336:134-139). Furthermore, injection of cDNA (pCARD1) encoding the cardiac DHP receptor produces rapidly activating calcium current and cardiac type e-c coupling that does require calcium entry (Tanabe, Mikami, Numa, and Beam. 1990. Nature. 344:451-453). In this paper, we have studied the voltage dependence of, and the relationship between, charge movement, calcium transients, and calcium current in normal skeletal muscle cells in culture. In addition, we injected pCAC6 or pCARD1 into the nuclei of dysgenic myotubes and studied the relationship between the restored events and compared them with those of the normal cells. Charge movement and calcium currents were recorded with the whole cell patch-clamp technique. Calcium transients were measured with Fluo-3 introduced through the patch pipette. The kinetics and voltage dependence of the charge movement, calcium transients, and calcium current in dysgenic myotubes expressing pCAC6 were qualitatively similar to the ones elicited in normal myotubes: the calcium transient displayed a sigmoidal dependence on voltage and was still present after the addition of 0.5 mM Cd2+ + 0.1 mM La3+. In contrast, the calcium transient in dysgenic myotubes expressing pCARD1 followed the amplitude of the calcium current and thus showed a bell shaped dependence on voltage. In addition, the transient had a slower rate of rise than in pCAC6-injected myotubes and was abolished completely by the addition of Cd2+ + La3+.
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Tsukamoto, Seiichi, Teruyuki Fujii, Kotaro Oyama, Seine A. Shintani, Togo Shimozawa, Fuyu Kobirumaki-Shimozawa, Shin’ichi Ishiwata, and Norio Fukuda. "Simultaneous imaging of local calcium and single sarcomere length in rat neonatal cardiomyocytes using yellow Cameleon-Nano140." Journal of General Physiology 148, no. 4 (September 26, 2016): 341–55. http://dx.doi.org/10.1085/jgp.201611604.
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In cardiac muscle, contraction is triggered by sarcolemmal depolarization, resulting in an intracellular Ca2+ transient, binding of Ca2+ to troponin, and subsequent cross-bridge formation (excitation–contraction [EC] coupling). Here, we develop a novel experimental system for simultaneous nano-imaging of intracellular Ca2+ dynamics and single sarcomere length (SL) in rat neonatal cardiomyocytes. We achieve this by expressing a fluorescence resonance energy transfer (FRET)–based Ca2+ sensor yellow Cameleon–Nano (YC-Nano) fused to α-actinin in order to localize to the Z disks. We find that, among four different YC-Nanos, α-actinin–YC-Nano140 is best suited for high-precision analysis of EC coupling and α-actinin–YC-Nano140 enables quantitative analyses of intracellular calcium transients and sarcomere dynamics at low and high temperatures, during spontaneous beating and with electrical stimulation. We use this tool to show that calcium transients are synchronized along the length of a myofibril. However, the averaging of SL along myofibrils causes a marked underestimate (∼50%) of the magnitude of displacement because of the different timing of individual SL changes, regardless of the absence or presence of positive inotropy (via β-adrenergic stimulation or enhanced actomyosin interaction). Finally, we find that β-adrenergic stimulation with 50 nM isoproterenol accelerated Ca2+ dynamics, in association with an approximately twofold increase in sarcomere lengthening velocity. We conclude that our experimental system has a broad range of potential applications for the unveiling molecular mechanisms of EC coupling in cardiomyocytes at the single sarcomere level.
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Bovo, Elisa, Jody L. Martin, Jollyn Tyryfter, Pieter P. de Tombe, and Aleksey V. Zima. "R-CEPIA1er as a new tool to directly measure sarcoplasmic reticulum [Ca] in ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 311, no. 1 (July 1, 2016): H268—H275. http://dx.doi.org/10.1152/ajpheart.00175.2016.
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In cardiomyocytes, [Ca] within the sarcoplasmic reticulum (SR; [Ca]SR) partially determines the amplitude of cytosolic Ca transient that, in turn, governs myocardial contraction. Therefore, it is critical to understand the molecular mechanisms that regulate [Ca]SR handling. Until recently, the best approach available to directly measure [Ca]SR was to use low-affinity Ca indicators (e.g., Fluo-5N). However, this approach presents several limitations, including nonspecific cellular localization, dye extrusion, and species limitation. Recently a new genetically encoded family of Ca indicators has been generated, named Ca-measuring organelle-entrapped protein indicators (CEPIA). Here, we tested the red fluorescence SR-targeted Ca sensor (R-CEPIA1er) as a tool to directly measure [Ca]SR dynamics in ventricular myocytes. Infection of rabbit and rat ventricular myocytes with an adenovirus expressing the R-CEPIA1er gene displayed prominent localization in the SR and nuclear envelope. Calibration of R-CEPIA1er in myocytes resulted in a Kd of 609 μM, suggesting that this sensor is sensitive in the whole physiological range of [Ca]SR. [Ca]SR dynamics measured with R-CEPIA1er were compared with [Ca]SR measured with Fluo5-N. We found that both the time course of the [Ca]SR depletion and fractional SR Ca release induced by an action potential were similar between these two Ca sensors. R-CEPIA1er fluorescence did not decline during experiments, indicating lack of dye extrusion or photobleaching. Furthermore, measurement of [Ca]SR with R-CEPIA1er can be combined with cytosolic [Ca] measurements (with Fluo-4) to obtain more detailed information regarding Ca handling in cardiac myocytes. In conclusion, R-CEPIA1er is a promising tool that can be used to measure [Ca]SR dynamics in myocytes from different animal species.
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Salvage, Samantha C., Zaki F. Habib, Hugh R. Matthews, Antony P. Jackson, and Christopher L. H. Huang. "Ca2+-dependent modulation of voltage-gated myocyte sodium channels." Biochemical Society Transactions 49, no. 5 (October 13, 2021): 1941–61. http://dx.doi.org/10.1042/bst20200604.
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Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III–IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.
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Dirksen, Robert T., and Kurt G. Beam. "Role of Calcium Permeation in Dihydropyridine Receptor Function." Journal of General Physiology 114, no. 3 (September 1, 1999): 393–404. http://dx.doi.org/10.1085/jgp.114.3.393.
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The skeletal and cardiac muscle dihydropyridine receptors (DHPRs) differ with respect to their rates of channel activation and in the means by which they control Ca2+ release from the sarcoplasmic reticulum (Adams, B.A., and K.G. Beam. 1990. FASEB J. 4:2809–2816). We have examined the functional properties of skeletal (SkEIIIK) and cardiac (CEIIIK) DHPRs in which a highly conserved glutamate residue in the pore region of repeat III was mutated to a positively charged lysine residue. Using expression in dysgenic myotubes, we have characterized macroscopic ionic currents, intramembrane gating currents, and intracellular Ca2+ transients attributable to these two mutant DHPRs. CEIIIK supported very small inward Ca2+ currents at a few potentials (from −20 to +20 mV) and large outward cesium currents at potentials greater than +20 mV. SkEIIIK failed to support inward Ca2+ flux at any potential. However, large, slowly activating outward cesium currents were observed at all potentials greater than + 20 mV. The difference in skeletal and cardiac Ca2+ channel activation kinetics was conserved for outward currents through CEIIIK and SkEIIIK, even at very depolarized potentials (at +100 mV; SkEIIIK: τact = 30.7 ± 1.9 ms, n = 11; CEIIIK: τact = 2.9 ± 0.5 ms, n = 7). Expression of SkEIIIK in dysgenic myotubes restored both evoked contractions and depolarization-dependent intracellular Ca2+ transients with parameters of voltage dependence (V0.5 = 6.5 ± 3.2 mV and k = 9.3 ± 0.7 mV, n = 5) similar to those for the wild-type DHPR (Garcia, J., T. Tanabe, and K.G. Beam. 1994. J. Gen. Physiol. 103:125–147). However, CEIIIK-expressing myotubes never contracted and failed to exhibit depolarization-dependent intracellular Ca2+ transients at any potential. Thus, high Ca2+ permeation is required for cardiac-type excitation–contraction coupling reconstituted in dysgenic myotubes, but not skeletal-type. The strong rectification of the EIIIK channels made it possible to obtain measurements of gating currents upon repolarization to −50 mV (Qoff) following either brief (20 ms) or long (200 ms) depolarizing pulses to various test potentials. For SkEIIIK, and not CEIIK, Qoff was significantly (P < 0.001) larger after longer depolarizations to +60 mV (121.4 ± 2.0%, n = 6). The increase in Qoff for long depolarizations exhibited a voltage dependence similar to that of channel activation. Thus, the increase in Qoff may reflect a voltage sensor movement required for activation of L-type Ca2+ current and suggests that most DHPRs in skeletal muscle undergo this voltage-dependent transition.
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Varaki, Elham Shabani, Paul Breen, and Gaetano Gargiulo. "Quantification of a Low-Cost Stretchable Conductive Sensor Using an Expansion/Contraction Simulator Machine: A Step towards Validation of a Noninvasive Cardiac and Respiration Monitoring Prototype." Machines 5, no. 4 (October 6, 2017): 22. http://dx.doi.org/10.3390/machines5040022.
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Ullah, Hadaate, Md Belal Bin Heyat, Faijan Akhtar, Abdullah Y. Muaad, Chiagoziem C. Ukwuoma, Muhammad Bilal, Mahdi H. Miraz, et al. "An Automatic Premature Ventricular Contraction Recognition System Based on Imbalanced Dataset and Pre-Trained Residual Network Using Transfer Learning on ECG Signal." Diagnostics 13, no. 1 (December 28, 2022): 87. http://dx.doi.org/10.3390/diagnostics13010087.
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The development of automatic monitoring and diagnosis systems for cardiac patients over the internet has been facilitated by recent advancements in wearable sensor devices from electrocardiographs (ECGs), which need the use of patient-specific approaches. Premature ventricular contraction (PVC) is a common chronic cardiovascular disease that can cause conditions that are potentially fatal. Therefore, for the diagnosis of likely heart failure, precise PVC detection from ECGs is crucial. In the clinical settings, cardiologists typically employ long-term ECGs as a tool to identify PVCs, where a cardiologist must put in a lot of time and effort to appropriately assess the long-term ECGs which is time consuming and cumbersome. By addressing these issues, we have investigated a deep learning method with a pre-trained deep residual network, ResNet-18, to identify PVCs automatically using transfer learning mechanism. Herein, features are extracted by the inner layers of the network automatically compared to hand-crafted feature extraction methods. Transfer learning mechanism handles the difficulties of required large volume of training data for a deep model. The pre-trained model is evaluated on the Massachusetts Institute of Technology-Beth Israel Hospital (MIT-BIH) Arrhythmia and Institute of Cardiological Technics (INCART) datasets. First, we used the Pan–Tompkins algorithm to segment 44,103 normal and 6423 PVC beats, as well as 106,239 normal and 9987 PVC beats from the MIT-BIH Arrhythmia and IN-CART datasets, respectively. The pre-trained model employed the segmented beats as input after being converted into 2D (two-dimensional) images. The method is optimized with the using of weighted random samples, on-the-fly augmentation, Adam optimizer, and call back feature. The results from the proposed method demonstrate the satisfactory findings without the using of any complex pre-processing and feature extraction technique as well as design complexity of model. Using LOSOCV (leave one subject out cross-validation), the received accuracies on MIT-BIH and INCART are 99.93% and 99.77%, respectively, suppressing the state-of-the-art methods for PVC recognition on unseen data. This demonstrates the efficacy and generalizability of the proposed method on the imbalanced datasets. Due to the absence of device-specific (patient-specific) information at the evaluating stage on the target datasets in this study, the method might be used as a general approach to handle the situations in which ECG signals are obtained from different patients utilizing a variety of smart sensor devices.
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Kuramoto, T. "SPIKING INDUCED BY COOLING IN THE MYOCARDIUM OF THE LOBSTER PANULIRUS JAPONICUS." Journal of Experimental Biology 197, no. 1 (December 1, 1994): 413–19. http://dx.doi.org/10.1242/jeb.197.1.413.
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The heart rate of crustaceans changes with variations in ambient temperature within the normal environmental range (Maynard, 1960). The temperature coefficient (Q10) of the heart rate of crabs over the range 4­19 °C is about 2 (Florey and Kriebel, 1974). There are few studies of the heart response to a rapid change in temperature, although aquatic crustaceans often meet with warm or cold water masses (Spaargaren and Achituv, 1977). Electromechanical coupling of muscle fibres becomes less effective with decreasing temperature (Dudel and Ruedel, 1968), but a mechanism has been described that compensates for the tonus effect during leg muscle activity (Fischer and Florey, 1981). Compensatory mechanisms may also exist for heart muscle, and I have recently found that myocardial cells of a marine lobster begin to produce large action potentials in response to cooling. Lobster myocardial fibres develop tension in response to excitatory junction potentials (EJPs) generated by impulse activity of motor neurones in the cardiac ganglion (Van der Kloot, 1970; Anderson and Cooke, 1971; Kuramoto and Kuwasawa, 1980; Kuramoto and Ebara, 1984a). The heart tension produced is fed back to the cardiac ganglion because the cardiac neurones are sensitive to filling pressure (Maynard, 1960; Kuramoto and Ebara, 1984a, 1885, 1988, 1991). Thus, the responses of the isolated heart to cooling will result from the combined activities of the cardiac ganglion and the muscle cells. This report focuses on the development of a spiking response by the myocardial cells when the heart is cooled. The spikes produced correspond to enhanced contractions of the myocardium, suggesting that the myocardial cells may use this as a mechanism to compensate for the reduced efficacy of excitation­contraction coupling that occurs with falling temperature. Lobsters (Panulirus japonicus Von Siebolt, both sexes, approximately 200 g, N=25) were reared in an indoor aquarium continuously supplied with fresh natural sea water. Seasonal changes of aquarium temperature ranged from 15 to 25 °C. The isolated hearts were subjected to cooling experiments. The rate of cooling ranged from 1 to 3 °C min-1, the magnitude from 1 to 6 °C and the duration from 5 to 6 min. The methods for perfusing and recording from the isolated hearts were substantially the same as those used previously (Kuramoto and Ebara, 1984a, 1985, 1988, 1991). The perfusion saline was switched to warm or cold. Bath temperature near the heart was monitored with a platinum sensor (1 k omega at 0 °C). Myocardial membrane potentials were measured with glass microelectrodes (3 mol l-1 KCl, 10­30 M omega). Muscle tension was recorded using a strain gauge.
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Bastug-Özel, Zeynep, Peter T. Wright, Axel E. Kraft, Davor Pavlovic, Jacqueline Howie, Alexander Froese, William Fuller, Julia Gorelik, Michael J. Shattock, and Viacheslav O. Nikolaev. "Heart failure leads to altered β2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain." Cardiovascular Research 115, no. 3 (August 27, 2018): 546–55. http://dx.doi.org/10.1093/cvr/cvy221.
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Abstract Aims Cyclic adenosine monophosphate (cAMP) regulates cardiac excitation–contraction coupling by acting in microdomains associated with sarcolemmal ion channels. However, local real time cAMP dynamics in such microdomains has not been visualized before. We sought to directly monitor cAMP in a microdomain formed around sodium–potassium ATPase (NKA) in healthy and failing cardiomyocytes and to better understand alterations of cAMP compartmentation in heart failure. Methods and results A novel Förster resonance energy transfer (FRET)-based biosensor termed phospholemman (PLM)-Epac1 was developed by fusing a highly sensitive cAMP sensor Epac1-camps to the C-terminus of PLM. Live cell imaging in PLM-Epac1 and Epac1-camps expressing adult rat ventricular myocytes revealed extensive regulation of NKA/PLM microdomain-associated cAMP levels by β2-adrenoceptors (β2-ARs). Local cAMP pools stimulated by these receptors were tightly controlled by phosphodiesterase (PDE) type 3. In chronic heart failure following myocardial infarction, dramatic reduction of the microdomain-specific β2-AR/cAMP signals and β2-AR dependent PLM phosphorylation was accompanied by a pronounced loss of local PDE3 and an increase in PDE2 effects. Conclusions NKA/PLM complex forms a distinct cAMP microdomain which is directly regulated by β2-ARs and is under predominant control by PDE3. In heart failure, local changes in PDE repertoire result in blunted β2-AR signalling to cAMP in the vicinity of PLM.
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Chatterjee, Ayan, and Uttam Kumar Roy. "Non-Invasive Heart State Monitoring an Article on Latest PPG Processing." Biomedical and Pharmacology Journal 11, no. 4 (November 22, 2018): 1885–93. http://dx.doi.org/10.13005/bpj/1561.
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Health Monitoring has become one of the most important task of this century with a change in population demography to build a smart healthcare system to give proper treatment to the correct patient with reduced cost, more consistently for better living. Heart & it's related parameters are very important for good health condition. Statistics from Centers for Disease Control and Prevention, in 2008, around 616K people died of heart disease and 25% cause of total death and in 2010 the percentage grew up to 31%. High blood pressure, high cholesterol, diabetes, smoking, overweight are some of the real cause of heart disease. To determine heart state, ECG is a proven and well accepted system. But, the device is expensive and requires training. ECG sensor measures the bio-potential generated by the electrical signals that is responsible to control the expansion and contraction of heart chambers. In this article, we have focused literature review on Non-Invasive cardiovascular monitoring researches undertaken so far to provide new possibilities and research trends so that we can monitor our health better and take precautions earlier with the use and advancement of Computer Science & Technology. Here we have primarily focused on PPG signal and its application to measure important blood parameters like Glucose, HB, SP02 that indirectly or directly can provide us a status of our health when required. Recent report suggests that PPG is very useful for measuring heart rates, arterial age (with PPG derivatives), blood pressure, oxygen saturation, emotion detection, respiratory rate etc. Accurate measurement of PPG can open up new possibilities in non-invasive computer aided cardiac research for smart care-giving.
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García, J., and K. G. Beam. "Calcium transients associated with the T type calcium current in myotubes." Journal of General Physiology 104, no. 6 (December 1, 1994): 1113–28. http://dx.doi.org/10.1085/jgp.104.6.1113.
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Immature skeletal muscle cells, both in vivo and in vitro, express a high density of T type calcium current and a relatively low density of the dihydropyridine receptor, the protein thought to function as the Islow calcium channel and as the voltage sensor for excitation-contraction coupling. Although the role of the voltage sensor in eliciting elevations of myoplasmic, free calcium (calcium transients) has been examined, the role of the T type current has not. In this study we examined calcium transients associated with the T type current in cultured myotubes from normal and dysgenic mice, using the whole cell configuration of the patch clamp technique in conjunction with the calcium indicator dye Fluo-3. In both normal and dysgenic myotubes, the T type current was activated by weak depolarizations and was maximal for test pulses to approximately -20 mV. In normal myotubes that displayed T type calcium current, the calcium transient followed the amplitude and the integral of the current at low membrane potentials (-40 to -20 mV) but not at high potentials, where the calcium transient is caused by SR calcium release. The amplitude of the calcium transient for a pulse to -20 mV measured at 15 ms after depolarization represented, on average, 4.26 +/- 0.68% (n = 19) of the maximum amplitude of the calcium transient elicited by strong, 15-ms test depolarizations. In dysgenic myotubes, the calcium transient followed the integral of the calcium current at all test potentials, in cells expressing only T type current as well as in cells possessing both T type current and the L type current Idys. Moreover, the calcium transient also followed the amplitude and time course of current in dysgenic myotubes expressing the cardiac, DHP-sensitive calcium channel. Thus, in those cases where the transient appears to be a consequence of calcium entry, it has the same time course as the integral of the calcium current. Inactivation of the T type calcium current with 1-s prepulses, or block of the current by the addition of amiloride (0.3-1.0 mM) caused a reduction in the calcium transient which was similar in normal and dysgenic myotubes. To allow calculation of expected changes of intracellular calcium in response to influx, myotubes were converted to a roughly spherical shape (myoballs) by adding 0.5 microM colchicine to culture dishes of normal cells. Calcium currents and calcium transients recorded from myoballs were similar to those in normal myotubes.(ABSTRACT TRUNCATED AT 250 WORDS)
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Gregersen, H., T. Hausken, J. Yang, S. Ødegaard, and O. H. Gilja. "Mechanosensory properties in the human gastric antrum evaluated using B-mode ultrasonography during volume-controlled antral distension." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G876—G882. http://dx.doi.org/10.1152/ajpgi.00131.2005.
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The aims of this study were to evaluate gastric antral mechanical behavior and distension-induced sensorimotor responses in the human gastric antrum using transabdominal ultrasound scanning. Ten healthy volunteers underwent volume-controlled ramp inflation of a bag located in the antrum with volumes up to 125 ml. The active and passive circumferential tensions and stresses were calculated from measurements of pressure, diameter, and wall thickness before and during the administration of the anticholinergic drug butylscopolamine. The bag distensions elicited contractions in the antrum and sensory responses below the pain threshold. Butylscopolamine abolished the contractions and significantly reduced the sensory response. The length-tension diagram known from in vitro studies of smooth muscle strips could be reproduced as tension-volume diagrams in the human gastric antrum. The number of induced contractions and the contraction pressure amplitude (afterload) showed a parabolic behavior as function of the distension volume (preload), with maximum approximately at 70 ml. At the sensation threshold, the luminal circumference showed the lowest variation coefficient (13–25%), whereas the variation coefficient was more than 100% for the pressure, tensions, and stresses. We conclude that the muscle length-tension diagram and typical preload-afterload curves ad modem the Frank-Starling cardiac law can be obtained in the human gastric antrum. The sensory responses were most closely associated with the luminal circumference, indicating that the sensation during antral distension depends on deformation rather than on tension.
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Occhetta, Eraldo, Miriam Bortnik, and Paolo Marino. "Usefulness of Hemodynamic Sensors for Physiologic Cardiac Pacing in Heart Failure Patients." Cardiology Research and Practice 2011 (2011): 1–8. http://dx.doi.org/10.4061/2011/925653.
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The rate adaptive sensors applied to cardiac pacing should respond as promptly as the normal sinus node with an highly specific and sensitive detection of the need of increasing heart rate. Sensors operating alone may not provide optimal heart responsiveness: central venous pH sensing, variations in the oxygen content of mixed venous blood, QT interval, breathing rate and pulmonary minute ventilation monitored by thoracic impedance variations, activity sensors. Using sensors that have different attributes but that work in a complementary manners offers distinct advantages. However, complicated sensors interactions may occur. Hemodynamic sensors detect changes in the hemodynamic performances of the heart, which partially depends on the autonomic nervous system-induced inotropic regulation of myocardial fibers. Specific hemodynamic sensors have been designed to measure different expression of the cardiac contraction strength: Peak Endocardial Acceleration (PEA), Closed Loop Stimulation (CLS) and TransValvular Impedance (TVI), guided by intraventricular impedance variations. Rate-responsive pacing is just one of the potential applications of hemodynamic sensors in implantable pacemakers. Other issues discussed in the paper include: hemodynamic monitoring for the optimal programmation and follow up of patients with cardiac resynchronization therapy; hemodynamic deterioration impact of tachyarrhythmias; hemodynamic upper rate limit control; monitoring and prevention of vasovagal malignant syncopes.
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Zhang, Yingmei, Linlin Li, Yinan Hua, Jennifer M. Nunn, Feng Dong, Masashi Yanagisawa, and Jun Ren. "Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction." Journal of Molecular Cell Biology 4, no. 2 (April 1, 2012): 97–107. http://dx.doi.org/10.1093/jmcb/mjs002.
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Abstract Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function.
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Pott, Alexander, Maryam Shahid, Doreen Köhler, Christian Pylatiuk, Karolina Weinmann, Steffen Just, and Wolfgang Rottbauer. "Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish." Biomolecules 8, no. 4 (November 19, 2018): 153. http://dx.doi.org/10.3390/biom8040153.
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Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator of cardiac contractility. Integrin-linked kinase localizes to z-disks and costameres in vertebrate hearts and regulates the activity of the signaling molecule protein kinase B (PKB/Akt) by controlling its phosphorylation. Despite identification of several potential drug targets in the ILK signaling pathway, pharmacological treatment strategies to restore contractile function in ILK-dependent cardiomyopathies have not been established yet. In recent years, the zebrafish has emerged as a valuable experimental system to model human cardiomyopathies as well as a powerful tool for the straightforward high-throughput in vivo small compound screening of therapeutically active substances. Using the ILK deficient zebrafish heart failure mutant main squeeze (msq), which shows reduced PKB phosphorylation and thereby impaired cardiac contractile force, we identified here, in an automated small compound screen, the protein phosphatase inhibitors calyculin A and okadaic acid significantly restoring myocardial contractile function by reconstituting PKB phosphorylation in msq ILK-deficient zebrafish embryos.
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Lakomkin, V. L., A. A. Abramov, E. V. Lukoshkova, A. V. Prosvirnin, and V. I. Kapelko. "HEMODYNAMICS AND CARDIAC CONTRACTILE FUNCTION IN TYPE 1 DIABETES." Kardiologiia 62, no. 8 (August 30, 2022): 33–37. http://dx.doi.org/10.18087/cardio.2022.8.n1967.
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The cardiohemodynamics was studied 1 week after the administration of streptozotocin (60 mg / kg) or 2 weeks after a dose of 30 mg / kg. All rats had a significantly elevated level of glucose in the blood (up to 27—31 mM). In an echocardiographic study, about 1/3 of diabetic animals exhibited systolic dysfunction, and the remaining 2/3 — diastolic dysfunction with an increase in isovolumic relaxation time by 1.5 times. The catheterization of the left ventricle (LV) with a sensor that allows simultaneous measuring LV pressure and volume in both groups revealed decreased cardiac output by 25—31% and maximal ejection rate by 34—50%. However, LV developed pressure, the maximal rate of its development and the level of blood pressure remained within the control values, thus reduced LV ejection rate was probably due to increased arterial stiffness — a negative correlation was found between these indicators (r = - 0.70). The diastolic dysfunction group differed from systolic dysfunction by a significantly smaller end diastolic volume by 22%. Thus, in type 1 diabetes, LV remodeling with reduced end diastolic volume allows to maintain a normal ejection fraction in the presence of distinct heart failure.
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Lai, F. A., M. Dent, C. Wickenden, L. Xu, G. Kumari, M. Misra, H. B. Lee, M. Sar, and G. Meissner. "Expression of a cardiac Ca2+-release channel isoform in mammalian brain." Biochemical Journal 288, no. 2 (December 1, 1992): 553–64. http://dx.doi.org/10.1042/bj2880553.
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Mammalian brain possesses ryanodine-sensitive Ca2+ channels, which in muscle cells mediate rapid Ca2+ release from intracellular stores during excitation-contraction coupling. Analysis of bovine brain ryanodine receptor (RyR) channels suggests specific expression of the cardiac-muscle RyR isoform in mammalian brain. Localization using cardiac-muscle RyR-specific antibodies and antisense RNA revealed that brain RyRs were present in dendrites, cell bodies and terminals of rat forebrain, and highly enriched in the hippocampus. Activity of skeletal-muscle RyR channels is coupled to sarcolemmal voltage sensors, in contrast with cardiac-muscle RyR channels, which are known to be Ca(2+)-induced Ca(2+)-release channels. Thus Ca(2+)-induced Ca2+ release from intracellular stores mediated by brain RyR channels may be a major Ca(2+)-signalling pathway in specific regions of mammalian brain, and hence may play a fundamental role in neuronal Ca2+ homoeostasis.
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Stauffer, Winston T., Erik A. Blackwood, Khalid Azizi, Randal J. Kaufman, and Christopher C. Glembotski. "The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts." International Journal of Molecular Sciences 21, no. 4 (February 18, 2020): 1373. http://dx.doi.org/10.3390/ijms21041373.
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Activating transcription factor-6 α (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. In the heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in other cell types in the heart are unknown. Here we show that ATF6 decreases the activation of cardiac fibroblasts in response to the cytokine, transforming growth factor β (TGFβ), which can induce fibroblast trans-differentiation into a myofibroblast phenotype through signaling via the TGFβ–Smad pathway. ATF6 activation suppressed fibroblast contraction and the induction of α smooth muscle actin (αSMA). Conversely, fibroblasts were hyperactivated when ATF6 was silenced or deleted. ATF6 thus represents a novel inhibitor of the TGFβ–Smad axis of cardiac fibroblast activation.
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Dickinson, Patsy S., Andrew Calkins, and Jake S. Stevens. "Related neuropeptides use different balances of unitary mechanisms to modulate the cardiac neuromuscular system in the American lobster, Homarus americanus." Journal of Neurophysiology 113, no. 3 (February 1, 2015): 856–70. http://dx.doi.org/10.1152/jn.00585.2014.
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To produce flexible outputs, neural networks controlling rhythmic motor behaviors can be modulated at multiple levels, including the pattern generator itself, sensory feedback, and the response of the muscle to a given pattern of motor output. We examined the role of two related neuropeptides, GYSDRNYLRFamide (GYS) and SGRNFLRFamide (SGRN), in modulating the neurogenic lobster heartbeat, which is controlled by the cardiac ganglion (CG). When perfused though an isolated whole heart at low concentrations, both peptides elicited increases in contraction amplitude and frequency. At higher concentrations, both peptides continued to elicit increases in contraction amplitude, but GYS caused a decrease in contraction frequency, while SGRN did not alter frequency. To determine the sites at which these peptides induce their effects, we examined the effects of the peptides on the periphery and on the isolated CG. When we removed the CG and stimulated the motor nerve with constant bursts of stimuli, both GYS and SGRN increased contraction amplitude, indicating that each peptide modulates the muscle or the neuromuscular junction. When applied to the isolated CG, neither peptide altered burst frequency at low peptide concentrations; at higher concentrations, SGRN decreased burst frequency, whereas GYS continued to have no effect on frequency. Together, these data suggest that the two peptides elicit some of their effects using different mechanisms; in particular, given the known feedback pathways within this system, the importance of the negative (nitric oxide) relative to the positive (stretch) feedback pathways may differ in the presence of the two peptides.
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Agostinelli, Angela, Micaela Morettini, Agnese Sbrollini, Elvira Maranesi, Lucia Migliorelli, Francesco Di Nardo, Sandro Fioretti, and Laura Burattini. "CaRiSMA 1.0: Cardiac Risk Self-Monitoring Assessment." Open Sports Sciences Journal 10, no. 1 (October 31, 2017): 179–90. http://dx.doi.org/10.2174/1875399x01710010179.
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Background:Sport-related sudden cardiac death (SRSCD) can only be fought through prevention.Objective:The aim of this study is to propose an innovative software application, CaRiSMA 1.0 (Cardiac Risk Self-Monitoring Assessment), as a potential tool to help contrasting SRSCD and educating to a correct training.Methods:CaRiSMA 1.0 analyzes the electrocardiographic and heart-rate (HR) signals acquired during a training session through wearable sensors and provides intuitive graphical outputs consisting of two traffic lights, one related to cardiac health, based on resting QTc (a parameter quantifying the duration of ventricular contraction and subsequent relaxation), and one related to training, based on exercise HR. Safe and worthwhile training sessions have green traffic lights. A red QTc traffic light indicates the need of a medical consultation, whereas a red HR traffic light indicate the need of a reduction of training intensity. By way of example, CaRiSMA 1.0 was applied to sample data acquired in 10 volunteers (age= 27±11 years; males/females 3/7).Results:Two acquisitions (20.0%) were rejected because too noisy, indicating that wearable sensors may record poor quality signals. The QTc traffic light was red in 1 case, indicating that people practicing sport may not be aware of being at risk. The HR traffic light was red in 0 cases.Conclusion:CaRiSMA 1.0 is a software application that, for the first time in the sport context, uses QTc, the most important index of cardiac risk in clinics. Thus, it has the potential for giving a contribution in the fight against SRSCD.
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Wang, Shujin, Yinying Han, Miranda Nabben, Dietbert Neumann, Joost J. F. P. Luiken, and Jan F. C. Glatz. "Endosomal v-ATPase as a Sensor Determining Myocardial Substrate Preference." Metabolites 12, no. 7 (June 22, 2022): 579. http://dx.doi.org/10.3390/metabo12070579.
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The heart is a metabolically flexible omnivore that can utilize a variety of substrates for energy provision. To fulfill cardiac energy requirements, the healthy adult heart mainly uses long-chain fatty acids and glucose in a balanced manner, but when exposed to physiological or pathological stimuli, it can switch its substrate preference to alternative substrates such as amino acids (AAs) and ketone bodies. Using the failing heart as an example, upon stress, the fatty acid/glucose substrate balance is upset, resulting in an over-reliance on either fatty acids or glucose. A chronic fuel shift towards a single type of substrate is linked with cardiac dysfunction. Re-balancing myocardial substrate preference is suggested as an effective strategy to rescue the failing heart. In the last decade, we revealed that vacuolar-type H+-ATPase (v-ATPase) functions as a key regulator of myocardial substrate preference and, therefore, as a novel potential treatment approach for the failing heart. Fatty acids, glucose, and AAs selectively influence the assembly state of v-ATPase resulting in modulation of its proton-pumping activity. In this review, we summarize these novel insights on v-ATPase as an integrator of nutritional information. We also describe its exploitation as a therapeutic target with focus on supplementation of AA as a nutraceutical approach to fight lipid-induced insulin resistance and contractile dysfunction of the heart.
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How, Ole-Jakob, Ellen Aasum, Stanley Kunnathu, David L. Severson, Eivind S. P. Myhre, and Terje S. Larsen. "Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 6 (June 2005): H2979—H2985. http://dx.doi.org/10.1152/ajpheart.00084.2005.
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In the present study, we tested the reliability of measurements of pressure-volume area (PVA) and oxygen consumption (MV̇o2) in ex vivo mouse hearts, combining the use of a miniaturized conductance catheter and a fiber-optic oxygen sensor. Second, we tested whether we could reproduce the influence of increased myocardial fatty acid (FA) metabolism on cardiac efficiency in the isolated working mouse heart model, which has already been documented in large animal models. The hearts were perfused with crystalloid buffer containing 11 mM glucose and two different concentrations of FA bound to 3% BSA. The initial concentration was 0.3 ± 0.1 mM, which was subsequently raised to 0.9 ± 0.1 mM. End-systolic and end-diastolic pressure-volume relationships were assessed by temporarily occluding the preload line. Different steady-state PVA-MV̇o2 relationships were obtained by changing the loading conditions (pre- and afterload) of the heart. There were no apparent changes in baseline cardiac performance or contractile efficiency (slope of the PVA-MV̇o2 regression line) in response to the elevation of the perfusate FA concentration. However, all hearts ( n = 8) showed an increase in the y-intercept of the PVA-MV̇o2 regression line after elevation of the palmitate concentration, indicating an FA-induced increase in the unloaded MV̇o2. Therefore, in the present model, unloaded MV̇o2 is not independent of metabolic substrate. This is, to our knowledge, the first report of a PVA-MV̇o2 relationship in ex vivo perfused murine hearts, using a pressure-volume catheter. The methodology can be an important tool for phenotypic assessment of the relationship among metabolism, contractile performance, and cardiac efficiency in various mouse models.
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Caffarra Malvezzi, Cristina, Aderville Cabassi, and Michele Miragoli. "Mitochondrial mechanosensor in cardiovascular diseases." Vascular Biology 2, no. 1 (July 22, 2020): R85—R92. http://dx.doi.org/10.1530/vb-20-0002.
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The role of mitochondria in cardiac tissue is of utmost importance due to the dynamic nature of the heart and its energetic demands, necessary to assure its proper beating function. Recently, other important mitochondrial roles have been discovered, namely its contribution to intracellular calcium handling in normal and pathological myocardium. Novel investigations support the fact that during the progression toward heart failure, mitochondrial calcium machinery is compromised due to its morphological, structural and biochemical modifications resulting in facilitated arrhythmogenesis and heart failure development. The interaction between mitochondria and sarcomere directly affect cardiomyocyte excitation-contraction and is also involved in mechano-transduction through the cytoskeletal proteins that tether together the mitochondria and the sarcoplasmic reticulum. The focus of this review is to briefly elucidate the role of mitochondria as (mechano) sensors in the heart.
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Sparrow, Alexander J., Hugh Watkins, Matthew J. Daniels, Charles Redwood, and Paul Robinson. "Mavacamten rescues increased myofilament calcium sensitivity and dysregulation of Ca2+ flux caused by thin filament hypertrophic cardiomyopathy mutations." American Journal of Physiology-Heart and Circulatory Physiology 318, no. 3 (March 1, 2020): H715—H722. http://dx.doi.org/10.1152/ajpheart.00023.2020.
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Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor. NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.
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Miyamoto, Atsushi, Shin Kawana, Hisakazu Kimura, and Hideyo Ohshika. "α1,-Adrcnoceptor subtypes which participate in the contractile response of rat cardiac myocytes: Evaluation by a new Fotonic Sensor." Japanese Journal of Pharmacology 67 (1995): 15. http://dx.doi.org/10.1016/s0021-5198(19)46041-1.
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Ríos, Eduardo, Lourdes Figueroa, Carlo Manno, Natalia Kraeva, and Sheila Riazi. "The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle." Journal of General Physiology 145, no. 6 (May 25, 2015): 459–74. http://dx.doi.org/10.1085/jgp.201411321.
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A novel category of diseases of striated muscle is proposed, the couplonopathies, as those that affect components of the couplon and thereby alter its operation. Couplons are the functional units of intracellular calcium release in excitation–contraction coupling. They comprise dihydropyridine receptors, ryanodine receptors (Ca2+ release channels), and a growing list of ancillary proteins whose alteration may lead to disease. Within a generally similar plan, the couplons of skeletal and cardiac muscle show, in a few places, marked structural divergence associated with critical differences in the mechanisms whereby they fulfill their signaling role. Most important among these are the presence of a mechanical or allosteric communication between voltage sensors and Ca2+ release channels, exclusive to the skeletal couplon, and the smaller capacity of the Ca stores in cardiac muscle, which results in greater swings of store concentration during physiological function. Consideration of these structural and functional differences affords insights into the pathogenesis of several couplonopathies. The exclusive mechanical connection of the skeletal couplon explains differences in pathogenesis between malignant hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia (CPVT), conditions most commonly caused by mutations in homologous regions of the skeletal and cardiac Ca2+ release channels. Based on mechanistic considerations applicable to both couplons, we identify the plasmalemma as a site of secondary modifications, typically an increase in store-operated calcium entry, that are relevant in MH pathogenesis. Similar considerations help explain the different consequences that mutations in triadin and calsequestrin have in these two tissues. As more information is gathered on the composition of cardiac and skeletal couplons, this comparative and mechanistic approach to couplonopathies should be useful to understand pathogenesis, clarify diagnosis, and propose tissue-specific drug development.
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Jakovljevic, Biljana, Tamara Nikolic Turnic, Nevena Jeremic, Maja Savic, Jovana Jeremic, Ivan Srejovic, Branislav Belic, Nenad Ponorac, Vladimir Jakovljevic, and Vladimir Zivkovic. "The impact of high-intensity interval training and moderate-intensity continuous training regimes on cardiodynamic parameters in isolated heart of normotensive and hypertensive rats." Canadian Journal of Physiology and Pharmacology 97, no. 7 (July 2019): 631–37. http://dx.doi.org/10.1139/cjpp-2018-0610.
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This study aimed to assess the impact of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MIT) on cardiodynamic parameters in isolated rat heart. Wistar albino rats were randomly assigned to groups according to running protocol: sedentary control, MIT, and HIIT; spontaneous hypertensive rat (SHR) sedentary control, SHR + MIT, and SHR + HIIT. HIIT groups performed the running in 5 sprints × 45–55 m/min for 30–90 s, with 2 min of rest after each sprint, while MIT groups performed the running of 10–15 m/min for 1 h with 3 min of rest every 100 m; both protocols were implemented 5 days/week over 4 weeks with 1 week of adaptation before protocols started. Isolated rat hearts were perfused according to Langendorff technique at gradually increased coronary perfusion pressures (40–120 cmH2O). Using a sensor placed in the left ventricle, we registered maximum and minimum rate of pressure development in the left ventricle, systolic and diastolic left ventricular pressure, and heart rate. Coronary flow was measured flowmetrically. MIT was connected with cardiac depression in normotensive conditions, while HIIT leads to cardiac depression in hypertensive rats. HIIT induced more significant increase of contractile and relaxation parameters of the isolated rat heart, especially in hypertensive animals.
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Bakiu, Rigers. "Unfolded Protein Response and Triad Formation in Skeletal Muscles of Catecholaminergic Polymorphic Ventricular Tachycardia Mouse / Odgovor Razvijenog Proteina I Formiranje Trijada U Skeletnim Mišićima Miševa Sa Kateholaminergičkom Polimorfnom Ventrikularnom Tahikardijom." Acta Facultatis Medicae Naissensis 31, no. 4 (December 1, 2014): 225–31. http://dx.doi.org/10.2478/afmnai-2014-0028.
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Summary Isoform 2 of calsequestrin (CASQ2) is the main calcium-binding protein of sarcoplasmic reticulum (SR), expressed both in cardiac and in skeletal muscles. CASQ2 acts as an SR calcium (Ca2+) sensor and regulates SR Ca2+ release via interactions with triadin, junctin, and the ryanodine receptor. Various mutations of the csq2 gene lead to altered Ca2+ release and contractile dysfunction contributing to the development of arrhythmias and sudden cardiac death in young individuals affected by catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, a transgenic mouse carrying one of the identified CASQ2 point-mutations (R33Q) associated to CPVT was developed and a drastic reduction of the mutated protein was observed. Following a biomolecular approach, several analysis were performed using different antibody treatments in order to identify when the reduction of CASQ2 begins in skeletal muscles, unveil the mechanism involved in the reduction of CASQ2 in slow-twitch and fast twitch muscles and verify if other proteins are affected by the presence of the mutated protein. Mutated CASQ2 decreased soon after birth. Up-regulation of proteins associated to the unfolded protein response (UPR) was also observed. Important proteins in skeletal muscle triads formation were analyzed and increased protein levels were observed in adult knock-in CASQ2-R33Q/R33Q mice. Probably, R33Q mutation induced the decrease of CASQ2 by activation of the UPR and subsequently degradation through proteasome.
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Bakiu, Rigers. "Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice." Serbian Journal of Experimental and Clinical Research 15, no. 3 (October 1, 2014): 121–27. http://dx.doi.org/10.2478/sjecr-2014-0016.
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Abstract Isoform 2 of calsequestrin (CSQ2) is the main calciumbinding protein of the sarcoplasmic reticulum (SR) and is expressed in both cardiac and skeletal muscle. CSQ2 acts as an SR calcium (Ca2+) sensor and regulates SR Ca2+ release via interactions with triadin, junctin, and the ryanodine receptor. Various mutations of the csq2 gene lead to altered Ca2+ release and contractile dysfunction and contribute to the development of arrhythmias and sudden cardiac death in young individuals affected by CPVT . Transgenic mice carrying one of the identified CSQ2 point mutations (R33Q) associated with CPVT were developed, and a drastic reduction in the mutated protein was observed. Following a biomolecular approach, several analyses were performed using different antibody treatments to identify when the reduction of CSQ2 begins, to unveil the mechanism involved in the reduction of CSQ2 and to verify whether other proteins are affected by the presence of the mutated protein. Th e results of this study showed that mutated CSQ2 levels decreased soon after birth, in conjunction with decreased levels of other important junctional SR proteins, including triadin (TD). Th e up-regulation of proteins associated with the unfolded protein response (UPR) was also observed, and the ATF6- dependent pathway was activated by the UPR. The presence of the R33Q mutation induced the decrease of CSQ2 via UPR activation and subsequent proteasomal degradation.
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Muscato, Audrey J., Patrick Walsh, Sovannarath Pong, Alixander Pupo, Roni J. Gross, Andrew E. Christie, J. Joe Hull, and Patsy S. Dickinson. "Does Differential Receptor Distribution Underlie Variable Responses to a Neuropeptide in the Lobster Cardiac System?" International Journal of Molecular Sciences 22, no. 16 (August 13, 2021): 8703. http://dx.doi.org/10.3390/ijms22168703.
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Central pattern generators produce rhythmic behaviors independently of sensory input; however, their outputs can be modulated by neuropeptides, thereby allowing for functional flexibility. We investigated the effects of C-type allatostatins (AST-C) on the cardiac ganglion (CG), which is the central pattern generator that controls the heart of the American lobster, Homarus americanus, to identify the biological mechanism underlying the significant variability in individual responses to AST-C. We proposed that the presence of multiple receptors, and thus differential receptor distribution, was at least partly responsible for this observed variability. Using transcriptome mining and PCR-based cloning, we identified four AST-C receptors (ASTCRs) in the CG; we then characterized their cellular localization, binding potential, and functional activation. Only two of the four receptors, ASTCR1 and ASTCR2, were fully functional GPCRs that targeted to the cell surface and were activated by AST-C peptides in our insect cell expression system. All four, however, were amplified from CG cDNAs. Following the confirmation of ASTCR expression, we used physiological and bioinformatic techniques to correlate receptor expression with cardiac responses to AST-C across individuals. Expression of ASTCR1 in the CG showed a negative correlation with increasing contraction amplitude in response to AST-C perfusion through the lobster heart, suggesting that the differential expression of ASTCRs within the CG is partly responsible for the specific physiological response to AST-C exhibited by a given individual lobster.
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Vasamsetti, Bala Murali Krishna, Kyongmi Chon, Juyeong Kim, Jin-A. Oh, Chang-Young Yoon, and Hong-Hyun Park. "Transcriptome-Based Identification of Genes Responding to the Organophosphate Pesticide Phosmet in Danio rerio." Genes 12, no. 11 (October 29, 2021): 1738. http://dx.doi.org/10.3390/genes12111738.
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Organophosphate pesticides (OPPs) are one of the most widely used insecticides. OPPs exert their neurotoxic effects by inhibiting acetylcholine esterase (AChE). Most of the gross developmental abnormalities observed in OPP-treated fish, on the other hand, may not be explained solely by AChE inhibition. To understand the overall molecular mechanisms involved in OPP toxicity, we used the zebrafish (ZF) model. We exposed ZF embryos to an OPP, phosmet, for 96 h, and then analyzed developmental abnormalities and performed whole transcriptome analysis. Phenotypic abnormalities, such as bradycardia, spine curvature, and growth retardation, were observed in phosmet-treated ZF (PTZF). Whole transcriptome analysis revealed 2190 differentially expressed genes (DEGs), with 822 and 1368 significantly up-and downregulated genes, respectively. System process and sensory and visual perception were among the top biological pathways affected by phosmet toxicity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment of metabolic pathways, calcium signaling pathway, regulation of actin cytoskeleton, cardiac muscle contraction, drug metabolism–other enzymes, and phototransduction. Quantitative real-time PCR results of six DEGs agreed with the sequencing data expression profile trend. Our findings provide insights into the consequences of phosmet exposure in ZF, as well as an estimate of the potential risk of OPPs to off-target species.
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Li, Xiaofeng, Jinliang Li, Eliana C. Martinez, Alexander Froese, Catherine L. Passariello, Kathryn Henshaw, Francesca Rusconi, et al. "Calcineurin Aβ–Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy." Circulation 142, no. 10 (September 8, 2020): 948–62. http://dx.doi.org/10.1161/circulationaha.119.044893.
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Background: The Ca 2+ /calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the β isoform of the calcineurin catalytic A-subunit (CaNAβ) is required for induction of pathological myocyte hypertrophy, despite calcineurin Aα expression in the same cells. It is unclear how the pleiotropic second messenger Ca 2+ drives excitation–contraction coupling while not stimulating hypertrophy by calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectivity in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease. Methods: Primary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New Förster resonance energy transfer reporters were used to assay Ca 2+ and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus–mediated gene delivery in the mouse were used to study calcineurin signaling after transverse aortic constriction in vivo. Results: CIP4 (Cdc42-interacting protein 4)/TRIP10 (thyroid hormone receptor interactor 10) was identified as a new polyproline domain-dependent scaffold for CaNAβ2 by yeast 2-hybrid screen. Cardiac myocyte–specific CIP4 gene deletion in mice attenuated pressure overload–induced pathological cardiac remodeling and heart failure. Blockade of CaNAβ polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes; disruption of anchoring in vivo using an adeno-associated virus gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell Förster resonance energy transfer biosensor imaging of cultured myocytes revealed that Ca 2+ levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca 2+ levels and calcineurin activity detected by nonlocalized Förster resonance energy transfer sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca 2+ and calcineurin signal transduction. Conclusions: These results support a structural model for Ca 2+ and CaNAβ compartmentation in cells based on an isoform-specific mechanism for calcineurin protein–protein interaction and localization. This mechanism provides an explanation for the specific role of CaNAβ in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNAβ polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNAβ-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further preclinical investigation.
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Stachowski-Doll, Marisa J., Maria Papadaki, Thomas G. Martin, Weikang Ma, Henry M. Gong, Stephanie Shao, Shi Shen, et al. "GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation." Circulation Research 130, no. 6 (March 18, 2022): 871–86. http://dx.doi.org/10.1161/circresaha.121.319491.
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Background: Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β’s in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance. Methods: Inducible cardiomyocyte-specific GSK-3β knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied. Results: Skinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3β. Agreeing with the localization of its targets, GSK-3β that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3β in neonatal rat ventricular cardiomyocytes. One of GSK-3β’s z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3β. Last, GSK-3β myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA. Conclusions: We identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3β levels were reduced in patients with heart failure, indicating z-disc localized GSK-3β is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.
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Roach, Robert C., Maria D. Koskolou, José A. L. Calbet, and Bengt Saltin. "Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 2 (February 1, 1999): H438—H445. http://dx.doi.org/10.1152/ajpheart.1999.276.2.h438.
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A universal O2 sensor presumes that compensation for impaired O2delivery is triggered by low O2tension, but in humans, comparisons of compensatory responses to altered arterial O2 content ([Formula: see text]) or tension ([Formula: see text]) have not been reported. To directly compare cardiac output (Q˙TOT) and leg blood flow (LBF) responses to a range of[Formula: see text] and[Formula: see text], seven healthy young men were studied during two-legged knee extension exercise with control hemoglobin concentration ([Hb] = 144.4 ± 4 g/l) and at least 1 wk later after isovolemic hemodilution ([Hb] = 115 ± 2 g/l). On each study day, subjects exercised twice at 30 W and on to voluntary exhaustion with an[Formula: see text] of 0.21 or 0.11. The interventions resulted in two conditions with matched[Formula: see text] but markedly different [Formula: see text] (hypoxia and anemia) and two conditions with matched[Formula: see text] and different[Formula: see text] (hypoxia and anemia + hypoxia). [Formula: see text] varied from 46 ± 3 Torr in hypoxia to 95 ± 3 Torr (range 37 to >100) in anemia ( P < 0.001), yet LBF at exercise was nearly identical. However, as[Formula: see text] dropped from 190 ± 5 ml/l in control to 132 ± 2 ml/l in anemia + hypoxia ( P < 0.001),Q˙TOT and LBF at 30 W rose to 12.8 ± 0.8 and 7.2 ± 0.3 l/min, respectively, values 23 and 47% above control ( P< 0.01). Thus regulation ofQ˙TOT, LBF, and arterial O2 delivery to contracting intact human skeletal muscle is dependent for signaling primarily on[Formula: see text], not[Formula: see text]. This finding suggests that factors related to [Formula: see text]or [Hb] may play an important role in the regulation of blood flow during exercise in humans.
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Sanz-de la Garza, Maria, Cira Rubies, Montserrat Batlle, Bart H. Bijnens, Lluis Mont, Marta Sitges, and Eduard Guasch. "Severity of structural and functional right ventricular remodeling depends on training load in an experimental model of endurance exercise." American Journal of Physiology-Heart and Circulatory Physiology 313, no. 3 (September 1, 2017): H459—H468. http://dx.doi.org/10.1152/ajpheart.00763.2016.
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Arrhythmogenic right ventricular (RV) remodeling has been reported in response to regular training, but it remains unclear how exercise intensity affects the presence and extent of such remodeling. We aimed to assess the relationship between RV remodeling and exercise load in a long-term endurance training model. Wistar rats were conditioned to run at moderate (MOD; 45 min, 30 cm/s) or intense (INT; 60 min, 60 cm/s) workloads for 16 wk; sedentary rats served as controls. Cardiac remodeling was assessed with standard echocardiographic and tissue Doppler techniques, sensor-tip pressure catheters, and pressure-volume loop analyses. After MOD training, both ventricles similarly dilated (~16%); the RV apical segment deformation, but not the basal segment deformation, was increased [apical strain rate (SR): −2.9 ± 0.5 vs. −3.3 ± 0.6 s−1, SED vs. MOD]. INT training prompted marked RV dilatation (~26%) but did not further dilate the left ventricle (LV). A reduction in both RV segments' deformation in INT rats (apical SR: −3.3 ± 0.6 vs. −3.0 ± 0.4 s−1 and basal SR: −3.3 ± 0.7 vs. −2.7 ± 0.6 s−1, MOD vs. INT) led to decreased global contractile function (maximal rate of rise of LV pressure: 2.53 ± 0.15 vs. 2.17 ± 0.116 mmHg/ms, MOD vs. INT). Echocardiography and hemodynamics consistently pointed to impaired RV diastolic function in INT rats. LV systolic and diastolic functions remained unchanged in all groups. In conclusion, we showed a biphasic, unbalanced RV remodeling response with increasing doses of exercise: physiological adaptation after MOD training turns adverse with INT training, involving disproportionate RV dilatation, decreased contractility, and impaired diastolic function. Our findings support the existence of an exercise load threshold beyond which cardiac remodeling becomes maladaptive. NEW & NOTEWORTHY Exercise promotes left ventricular eccentric hypertrophy with no changes in systolic or diastolic function in healthy rats. Conversely, right ventricular adaptation to physical activity follows a biphasic, dose-dependent, and segmentary pattern. Moderate exercise promotes a mild systolic function enhancement at the right ventricular apex and more intense exercise impairs systolic and diastolic function.