The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Victor A. Maltsev - One of the best experts on this subject based on the ideXlab platform.
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stabilization of diastolic calcium signal via calcium pump regulation of complex local calcium releases and transient decay in a computational model of Cardiac Pacemaker cell with individual release channels
PLOS Computational Biology, 2017Co-Authors: Alexander V Maltsev, Victor A. Maltsev, Michael D. SternAbstract:Intracellular Local Ca releases (LCRs) from sarcoplasmic reticulum (SR) regulate Cardiac Pacemaker cell function by activation of electrogenic Na/Ca exchanger (NCX) during diastole. Prior studies demonstrated the existence of powerful compensatory mechanisms of LCR regulation via a complex local cross-talk of Ca pump, release and NCX. One major obstacle to study these mechanisms is that LCR exhibit complex Ca release propagation patterns (including merges and separations) that have not been characterized. Here we developed new terminology, classification, and computer algorithms for automatic detection of numerically simulated LCRs and examined LCR regulation by SR Ca pumping rate (Pup) that provides a major contribution to fight-or-flight response. In our simulations the faster SR Ca pumping accelerates action potential-induced Ca transient decay and quickly clears Ca under the cell membrane in diastole, preventing premature releases. Then the SR generates an earlier, more synchronized, and stronger diastolic LCR signal activating an earlier and larger inward NCX current. LCRs at higher Pup exhibit larger amplitudes and faster propagation with more collisions to each other. The LCRs overlap with Ca transient decay, causing an elevation of the average diastolic [Ca] nadir to ~200 nM (at Pup = 24 mM/s). Background Ca (in locations lacking LCRs) quickly decays to resting Ca levels (<100 nM) at high Pup, but remained elevated during slower decay at low Pup. Release propagation is facilitated at higher Pup by a larger LCR amplitude, whereas at low Pup by higher background Ca. While at low Pup LCRs show smaller amplitudes, their larger durations and sizes combined with longer transient decay stabilize integrals of diastolic Ca and NCX current signals. Thus, the local interplay of SR Ca pump and release channels regulates LCRs and Ca transient decay to insure fail-safe Pacemaker cell operation within a wide range of rates.
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computer algorithms for automated detection and analysis of local ca2 releases in spontaneously beating Cardiac Pacemaker cells
Unknown Journal, 2017Co-Authors: Alexander V Maltsev, Victor A. Maltsev, Michael D. Stern, Edward G. Lakatta, Oliver Monfredi, Sean P Parsons, Mary S Kim, Kenta TsutsuiAbstract:Local Ca2+ Releases (LCRs) are crucial events involved in Cardiac Pacemaker cell function. However, specific algorithms for automatic LCR detection and analysis have not been developed in live, spontaneously beating Pacemaker cells. In the present study we measured LCRs using a high-speed 2D-camera in spontaneously contracting sinoatrial (SA) node cells isolated from rabbit and guinea pig and developed a new algorithm capable of detecting and analyzing the LCRs spatially in two-dimensions, and in time. Our algorithm tracks points along the midline of the contracting cell. It uses these points as a coordinate system for affine transform, producing a transformed image series where the cell does not contract. Action potential-induced Ca2+ transients and LCRs were thereafter isolated from recording noise by applying a series of spatial filters. The LCR birth and death events were detected by a differential (frame-to-frame) sensitivity algorithm applied to each pixel (cell location). An LCR was detected when its signal changes sufficiently quickly within a sufficiently large area. The LCR is considered to have died when its amplitude decays substantially, or when it merges into the rising whole cell Ca2+ transient. Ultimately, our algorithm provides major LCR parameters such as period, signal mass, duration, and propagation path area. As the LCRs propagate within live cells, the algorithm identifies splitting and merging behaviors, indicating the importance of locally propagating Ca2+-induced-Ca2+-release for the fate of LCRs and for generating a powerful ensemble Ca2+ signal. Thus, our new computer algorithms eliminate motion artifacts and detect 2D local spatiotemporal events from recording noise and global signals. While the algorithms were developed to detect LCRs in sinoatrial nodal cells, they have the potential to be used in other applications in biophysics and cell physiology, for example, to detect Ca2+ wavelets (abortive waves), sparks and embers in muscle cells and Ca2+ puffs and syntillas in neurons.
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a new simplified 3d model of Cardiac Pacemaker cell based on superresolution structured illumination microscopy sim
Biophysical Journal, 2015Co-Authors: Victor A. Maltsev, Edward G. Lakatta, Oliver Monfredi, Hari Shroff, Andrew York, Anna Maltsev, Michael D. SternAbstract:The contribution of diastolic Local Calcium-Releases (LCRs) to sinoatrial-node-cell Pacemaker function is presently approximated by three numerical models: 1)“common-pool” (Maltsev-Lakatta,2009); 2)“2D” (Anna Maltsev et al.,2011-2013); 3)“3D” (Stern et al.,2014). While the most advanced 3D-model describes stochastic states of each ryanodine receptor (RyR) and L-type calcium-channel, its high computational demand prevents parametric sensitivity analyses. Here we developed a new 3D-model having a lower computational demand, but reproducing all essential features of calcium dynamics measured in isolated rabbit SA node cells by SIM (achieving approximately double the resolution of conventional microscopy). Our cell-cross-section SIM measurements revealed that LCRs occur mainly within ∼1 µm under the plasma membrane, in line with immunofluorescence data on RyR cluster localization. Therefore, the model cell interior is approximated by only three layers of diffusively linked intracellular voxels: submembrane (20 nm), ring (1 µm), and core cylinder. Each submembrane RyR cluster is approximated as a Calcium-Release Unit (CRU) residing within the respective junctional SR linked to free SR which pumps/collects cytosolic calcium. Instead of assuming a fixed restitution period like prior 2D-models, the release activation and termination are controlled in each CRU by local calcium-dependent mechanisms (based on RyR interactions via Calium-Induced-Calcium-Release, reported recently). The new model simulations are substantially faster (vs. the original 3D-model), but predict all essential features of LCRs crucial for Pacemaker rate autonomic modulation. Thus, super-resolution SIM allowed fine localization of calcium-dynamics and validated the new model of integrated Cardiac Pacemaker cell function at the level of individual CRUs, filling an important niche between individual-molecule-level detail and common pool models (lacking LCRs). This new faster 3D-model allows parametric sensitivity analyses and provides a new mechanistic formulation of CRU function that is important for multi-scale modeling of heart function.
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autonomic stimulation modulates action potential firing rate in Cardiac Pacemaker cells via synchronization of local calcium pumping and release
Biophysical Journal, 2015Co-Authors: Oliver Monfredi, Edward G. Lakatta, Victor A. MaltsevAbstract:A modern view on regulation of Cardiac Pacemaker cell function postulates that local calcium releases (LCRs) contribute to diastolic depolarization via electrogenic sodium/calcium exchanger. An unresolved problem, however, remains: how intrinsically stochastic and heterogeneously distributed release channels (RyR) generate a strong, synchronized ensemble LCR signal and how this signal is effectively regulated by autonomic system to insure Pacemaker rate flexibility.We measured calcium dynamics by a high-speed camera in isolated, single rabbit sinoatrial node cells (SANC) and assessed the kinetics of local calcium-pumping synchronization by examining the distributions of time constants (τ) of calcium-transient decay among cell neighborhoods at baseline and during stimulation of either beta-adrenergic receptors or cholinergic receptors.Beta-adrenergic receptor stimulation (isoproterenol) not only decreased cycle length (CL) and average τ vs. baseline, but also decreased the standard deviation (SD) of all τ's across all neighborhoods, suggesting a shift into a less heterogeneous, i.e. more synchronized calcium pumping throughout SANC. Conversely, cholinergic receptor stimulation (carbachol) not only increased CL and average τ vs. baseline, but also increased the local SD(τ), suggesting a shift into a more heterogeneous, i.e. less synchronized calcium pumping within SANC. Furthermore, on a beat-to-beat basis, the relationship between either τ or SD(τ) and CL was linear under both baseline conditions and autonomic stimulation.Conclusions: The degree of heterogeneity of local calcium pumping is a new universal factor that affects the CL and insures effective rate and rhythm regulation of the coupled-clock Pacemaker system via autonomic modulation. More synchronized and faster calcium pumping is presumably achieved via phospholamban phosphorylation and allows cell neighborhoods to reach the calcium release threshold quicker and more synchronously, thereby synchronizing LCRs and amplifying their ensemble diastolic signal, accelerating Pacemaker rate.
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mechanisms of beat to beat regulation of Cardiac Pacemaker cell function by ca2 cycling dynamics
Biophysical Journal, 2013Co-Authors: Yael Yaniv, Michael D. Stern, Edward G. Lakatta, Victor A. MaltsevAbstract:Whether intracellular Ca2+ cycling dynamics regulate Cardiac Pacemaker cell function on a beat-to-beat basis remains unknown. Here we show that under physiological conditions, application of low concentrations of caffeine (2–4 mM) to isolated single rabbit sinoatrial node cells acutely reduces their spontaneous action potential cycle length (CL) and increases Ca2+ transient amplitude for several cycles. Numerical simulations, using a modified Maltsev-Lakatta coupled-clock model, faithfully reproduced these effects, and also the effects of CL prolongation and dysrhythmic spontaneous beating (produced by cytosolic Ca2+ buffering) and an acute CL reduction (produced by flash-induced Ca2+ release from a caged Ca2+ buffer), which we had reported previously. Three contemporary numerical models (including the original Maltsev-Lakatta model) failed to reproduce the experimental results. In our proposed new model, Ca2+ releases acutely change the CL via activation of the Na+/Ca2+ exchanger current. Time-dependent CL reductions after flash-induced Ca2+ releases (the memory effect) are linked to changes in Ca2+ available for pumping into sarcoplasmic reticulum which, in turn, changes the sarcoplasmic reticulum Ca2+ load, diastolic Ca2+ releases, and Na+/Ca2+ exchanger current. These results support the idea that Ca2+ regulates CL in Cardiac Pacemaker cells on a beat-to-beat basis, and suggest a more realistic numerical mechanism of this regulation.
Srinivas R Dukkipati - One of the best experts on this subject based on the ideXlab platform.
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leadless Cardiac Pacemaker does anatomical position at implant affect long term electrical performance
Journal of Biomedical Science and Engineering, 2017Co-Authors: John H Ip, Srinivas R Dukkipati, Abdul Safadi, Randy Ip, Matthew Gaskill, Rajesh Banker, Derek V Exner, Mayer Rashtian, Imran NiaziAbstract:Background: The Nanostim {trade mark, serif} Leadless Cardiac Pacemaker (LCP) has been shown to be safe and effective in human clinical trials. Since there is little information on the effect of implant location on LCP performance, the aim of this study was to determine whether anatomic position affects the long-term pacing performance of the LCP. Methods: Patients who enrolled in the Leadless II IDE Clinical Trial and had finished 6 months follow up (n = 479) were selected for the study. The implanting investigators determined the LCP final position under fluoroscope, which was categorized into three groups: RV apex (RVA, n = 174), RV apical septum (RVAS, n = 101), and RV septum (RVS, n = 204) (Figure 1). Data on capture threshold (at a 0.4 ms pulse width), R-wave amplitude and impedance were analyzed at implant, hospital discharge and 2 weeks, 6 weeks, 3 months and 6 months post-implant. Results: At implant, the mean capture thresholds in the RVA, RVAS and RVS were 0.77 ± 0.45, 0.81 ± 0.61 and 0.78 ± 0.59 volts, respectively. R-wave amplitudes were 8.0 ± 3.0 mV, 7.7 ± 2.9 mV and 7.6 ± 2.9 mV, respectively. Impedance values were 727 ± 311, 765 ± 333, and 677 ± 227 respectively. There were no differences among the 3 implant locations in capture threshold or R-wave amplitudes at 6 months (P > 0.06); however, all 3 performance parameters significantly improved over time (P < 0.001). Conclusions: The LCP implant location does not affect capture thresholds or R-wave amplitudes at 6 months, and there is little effect on impedance. Although implant location does not appear to be a predictor of electrical performance, additional long-term data will help guide optimal implant location.
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original investigationchronic performance of a leadless Cardiac Pacemaker 1 year follow up of the leadless trial
Journal of the American College of Cardiology, 2015Co-Authors: Reinoud E Knops, Fleur V Y Tjong, Petr Neuzil, Johannes Sperzel, Marc A Miller, Jan Petru, Jaroslav Simon, Lucie Sediva, Joris R De Groot, Srinivas R DukkipatiAbstract:Background A leadless Cardiac Pacemaker (LCP) system was recently introduced to overcome lead-related complications of conventional pacing systems. To date, long-term results of an LCP system are unknown.
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chronic performance of a leadless Cardiac Pacemaker 1 year follow up of the leadless trial
Journal of the American College of Cardiology, 2015Co-Authors: Reinoud E Knops, Fleur V Y Tjong, Petr Neuzil, Johannes Sperzel, Marc A Miller, Jan Petru, Jaroslav Simon, Lucie Sediva, Joris R De Groot, Srinivas R DukkipatiAbstract:Abstract Background A leadless Cardiac Pacemaker (LCP) system was recently introduced to overcome lead-related complications of conventional pacing systems. To date, long-term results of an LCP system are unknown. Objectives The aim of this study was to assess the complication incidence, electrical performance, and rate response characteristics within the first year of follow-up of patients implanted with an LCP. Methods We retrospectively assessed intermediate-term follow-up data for 31 of 33 patients from the LEADLESS trial cohort who had an indication for single-chamber pacing and received an LCP between December 2012 and April 2013. Results The mean age of the cohort was 76 ± 8 years, and 65% were male. Between 3 and 12 months of follow-up, there were no Pacemaker-related adverse events reported. The pacing performance results at 6- and 12-month follow-up were, respectively, as follows: mean pacing threshold (at a 0.4-ms pulse width), 0.40 ± 0.26 V and 0.43 ± 0.30 V; R-wave amplitude 10.6 ± 2.6 mV and 10.3 ± 2.2 mV; and impedance 625 ± 205 Ω and 627 ± 209 Ω. At the 12-month follow-up in 61% of the patients (n = 19 of 31), the rate response sensor was activated, and an adequate rate response was observed in all patients. Conclusions The LCP demonstrates very stable performance and reassuring safety results during intermediate-term follow-up. These results support the use of the LCP as a promising alternative to conventional Pacemaker systems. Continued evaluation is warranted to further characterize this system. (Evaluation of a New Cardiac Pacemaker; NCT01700244 )
Edward G. Lakatta - One of the best experts on this subject based on the ideXlab platform.
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Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond
'MDPI AG', 2021Co-Authors: Tatiana M. Vinogradova, Edward G. LakattaAbstract:The sinoatrial (SA) node is the physiological Pacemaker of the heart, and resting heart rate in humans is a well-known risk factor for cardiovascular disease and mortality. Consequently, the mechanisms of initiating and regulating the normal spontaneous SA node beating rate are of vital importance. Spontaneous firing of the SA node is generated within sinoatrial nodal cells (SANC), which is regulated by the coupled-clock Pacemaker system. Normal spontaneous beating of SANC is driven by a high level of cAMP-mediated PKA-dependent protein phosphorylation, which rely on the balance between high basal cAMP production by adenylyl cyclases and high basal cAMP degradation by cyclic nucleotide phosphodiesterases (PDEs). This diverse class of enzymes includes 11 families and PDE3 and PDE4 families dominate in both the SA node and Cardiac myocardium, degrading cAMP and, consequently, regulating basal Cardiac Pacemaker function and excitation-contraction coupling. In this review, we will demonstrate similarities between expression, distribution, and colocalization of various PDE subtypes in SANC and Cardiac myocytes of different species, including humans, focusing on PDE3 and PDE4. Here, we will describe specific targets of the coupled-clock Pacemaker system modulated by dual PDE3 + PDE4 activation and provide evidence that concurrent activation of PDE3 + PDE4, operating in a synergistic manner, regulates the basal Cardiac Pacemaker function and provides control over normal spontaneous beating of SANCs through (PDE3 + PDE4)-dependent modulation of local subsarcolemmal Ca2+ releases (LCRs)
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computer algorithms for automated detection and analysis of local ca2 releases in spontaneously beating Cardiac Pacemaker cells
Unknown Journal, 2017Co-Authors: Alexander V Maltsev, Victor A. Maltsev, Michael D. Stern, Edward G. Lakatta, Oliver Monfredi, Sean P Parsons, Mary S Kim, Kenta TsutsuiAbstract:Local Ca2+ Releases (LCRs) are crucial events involved in Cardiac Pacemaker cell function. However, specific algorithms for automatic LCR detection and analysis have not been developed in live, spontaneously beating Pacemaker cells. In the present study we measured LCRs using a high-speed 2D-camera in spontaneously contracting sinoatrial (SA) node cells isolated from rabbit and guinea pig and developed a new algorithm capable of detecting and analyzing the LCRs spatially in two-dimensions, and in time. Our algorithm tracks points along the midline of the contracting cell. It uses these points as a coordinate system for affine transform, producing a transformed image series where the cell does not contract. Action potential-induced Ca2+ transients and LCRs were thereafter isolated from recording noise by applying a series of spatial filters. The LCR birth and death events were detected by a differential (frame-to-frame) sensitivity algorithm applied to each pixel (cell location). An LCR was detected when its signal changes sufficiently quickly within a sufficiently large area. The LCR is considered to have died when its amplitude decays substantially, or when it merges into the rising whole cell Ca2+ transient. Ultimately, our algorithm provides major LCR parameters such as period, signal mass, duration, and propagation path area. As the LCRs propagate within live cells, the algorithm identifies splitting and merging behaviors, indicating the importance of locally propagating Ca2+-induced-Ca2+-release for the fate of LCRs and for generating a powerful ensemble Ca2+ signal. Thus, our new computer algorithms eliminate motion artifacts and detect 2D local spatiotemporal events from recording noise and global signals. While the algorithms were developed to detect LCRs in sinoatrial nodal cells, they have the potential to be used in other applications in biophysics and cell physiology, for example, to detect Ca2+ wavelets (abortive waves), sparks and embers in muscle cells and Ca2+ puffs and syntillas in neurons.
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camkii dependent phosphorylation regulates basal Cardiac Pacemaker function via modulation of local ca2 releases
American Journal of Physiology-heart and Circulatory Physiology, 2016Co-Authors: Syevda Sirenko, Edward G. Lakatta, Daniel R Riordon, Dongmei Yang, Harold A Spurgeon, Tatiana M. VinogradovaAbstract:Spontaneous beating of the heart Pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) due to gradual change of the membrane potential called diastolic depolarization (DD). Spontaneous, submembrane local Ca(2+) releases (LCR) from ryanodine receptors (RyR) occur during late DD and activate an inward Na(+)/Ca(2+)exchange current to boost the DD rate and fire an action potential (AP). Here we studied the extent of basal Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation and the role of basal CaMKII-dependent protein phosphorylation in generation of LCRs and regulation of normal automaticity of intact rabbit SANC. The basal level of activated (autophosphorylated) CaMKII in rabbit SANC surpassed that in ventricular myocytes (VM) by approximately twofold, and this was accompanied by high basal level of protein phosphorylation. Specifically, phosphorylation of phospholamban (PLB) at the CaMKII-dependent Thr(17) site was approximately threefold greater in SANC compared with VM, and RyR phosphorylation at CaMKII-dependent Ser(2815) site was ∼10-fold greater in the SA node, compared with that in ventricle. CaMKII inhibition reduced phosphorylation of PLB and RyR, decreased LCR size, increased LCR periods (time from AP-induced Ca(2+) transient to subsequent LCR), and suppressed spontaneous SANC firing. Graded changes in CaMKII-dependent phosphorylation (indexed by PLB phosphorylation at the Thr(17)site) produced by CaMKII inhibition, β-AR stimulation or phosphodiesterase inhibition were highly correlated with changes in SR Ca(2+) replenishment times and LCR periods and concomitant changes in spontaneous SANC cycle lengths (R(2) = 0.96). Thus high basal CaMKII activation modifies the phosphorylation state of Ca(2+) cycling proteins PLB, RyR, L-type Ca(2+) channels (and likely others), adjusting LCR period and characteristics, and ultimately regulates both normal and reserve Cardiac Pacemaker function.
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abstract 12488 spontaneous beating of Cardiac Pacemaker cells is regulated by basal activation of epidermal growth factor receptor
Circulation, 2015Co-Authors: Tatiana M. Vinogradova, Kirill V Tarasov, Edward G. LakattaAbstract:Spontaneous firing of sinoatrial node cells (SANC) is controlled by sarcoplasmic reticulum (SR) generated local subsarcolemmal Ca 2+ releases (LCRs), which appear during diastolic depolarization (DD) and activate an inward Na + -Ca 2+ exchange current to regulate DD rate and spontaneous SANC beating rate. Therapy directed against the epidermal growth factor receptor (EGFR) pathway had improved outcomes for patients with different types of cancer. It was noted, however, that inhibition of EGFR might lead to sinus bradycardia and sick sinus syndrome. Until now neither expression nor possible role of EGFR for spontaneous beating of Cardiac Pacemaker was examined. Here we studied expression of EGFR in rabbit SANC; effects of EGFR inhibition on spontaneous SANC firing and possible mechanisms of EGFR-dependent regulation of Cardiac Pacemaker function. We discovered that expression of EGFR (RNA-sequencing) in rabbit SANC exceeded that in ventricular myocytes by six-fold. Specific EGFR inhibitors erlotinib and AG1478 markedly decreased spontaneous SANC beating rate (perforated patch-clamp technique) and this effect was largely reversible upon drug washout. Both erlotinib and AG1478 suppressed SR Ca 2+ cycling (confocal microscopy, Ca 2+ indicator Fluo-3) in SANC, i.e. decreased LCR size and number per each spontaneous cycle and prolonged the LCR period (the interval between AP-induced Ca 2+ transient and subsequent LCR), which predicted the concomitant increase in the spontaneous cycle length. These data indicate basal activation of EGFR, which could activate other kinase cascades in rabbit SANC e.g. PKC-dependent phosphorylation through activation of PLC. Inhibition of either PLC activity by U-73122 or PKC activation by GF109203X or calphostin C suppressed LCRs and stopped spontaneous firing of rabbit SANC. We conclude that basal activation of EGFR regulates Cardiac Pacemaker function through PLC-PKC-dependent modulation of LCR characteristics. This might represent a novel pathway to control normal automaticity of SANC, which could be affected by cancer treatment therapy.
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a new simplified 3d model of Cardiac Pacemaker cell based on superresolution structured illumination microscopy sim
Biophysical Journal, 2015Co-Authors: Victor A. Maltsev, Edward G. Lakatta, Oliver Monfredi, Hari Shroff, Andrew York, Anna Maltsev, Michael D. SternAbstract:The contribution of diastolic Local Calcium-Releases (LCRs) to sinoatrial-node-cell Pacemaker function is presently approximated by three numerical models: 1)“common-pool” (Maltsev-Lakatta,2009); 2)“2D” (Anna Maltsev et al.,2011-2013); 3)“3D” (Stern et al.,2014). While the most advanced 3D-model describes stochastic states of each ryanodine receptor (RyR) and L-type calcium-channel, its high computational demand prevents parametric sensitivity analyses. Here we developed a new 3D-model having a lower computational demand, but reproducing all essential features of calcium dynamics measured in isolated rabbit SA node cells by SIM (achieving approximately double the resolution of conventional microscopy). Our cell-cross-section SIM measurements revealed that LCRs occur mainly within ∼1 µm under the plasma membrane, in line with immunofluorescence data on RyR cluster localization. Therefore, the model cell interior is approximated by only three layers of diffusively linked intracellular voxels: submembrane (20 nm), ring (1 µm), and core cylinder. Each submembrane RyR cluster is approximated as a Calcium-Release Unit (CRU) residing within the respective junctional SR linked to free SR which pumps/collects cytosolic calcium. Instead of assuming a fixed restitution period like prior 2D-models, the release activation and termination are controlled in each CRU by local calcium-dependent mechanisms (based on RyR interactions via Calium-Induced-Calcium-Release, reported recently). The new model simulations are substantially faster (vs. the original 3D-model), but predict all essential features of LCRs crucial for Pacemaker rate autonomic modulation. Thus, super-resolution SIM allowed fine localization of calcium-dynamics and validated the new model of integrated Cardiac Pacemaker cell function at the level of individual CRUs, filling an important niche between individual-molecule-level detail and common pool models (lacking LCRs). This new faster 3D-model allows parametric sensitivity analyses and provides a new mechanistic formulation of CRU function that is important for multi-scale modeling of heart function.
Reinoud E Knops - One of the best experts on this subject based on the ideXlab platform.
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midterm safety and performance of a leadless Cardiac Pacemaker 3 year follow up to the leadless trial nanostim safety and performance trial for a leadless Cardiac Pacemaker system
Circulation, 2018Co-Authors: Fleur V Y Tjong, Reinoud E Knops, Petr Neuzil, Johannes Sperzel, Jan Petru, Lucie Sediva, Arthur A M Wilde, Vivek Y ReddyAbstract:Leadless Cardiac Pacemakers (LCPs) have been introduced to decrease lead- and pocket-related complications. Initial studies have shown short-term complication rates of 4% to 6.7% and adequate electric performance in up to 12 months of follow-up.1–3 However, to fully appreciate the clinical impact and the robustness of this novel technology, additional follow-up is required to determine the long-term safety and performance. In this study, we report the longest clinical follow-up to date: the 3-year results of the LEADLESS trial (Nanostim Safety and Performance Trial for a Leadless Cardiac Pacemaker System).4 Patients implanted with an LCP (Nanostim, St. Jude Medical/Abbott) were retrospectively assessed to evaluate the safety and performance of this device with a minimum of 3 years of follow-up. No patients were lost to follow-up. Medical records were analyzed from June 2014 until May 2016 and evaluated for (1) serious adverse device effects (SADEs) and (2) electric performance of the LCP. The primary outcome was freedom from SADEs (Kaplan-Meier estimate) at 40 months of follow-up. Categorical variables are presented as frequencies and continuous variables as means (±SD). Permission of the local institutional review boards was obtained for this retrospective analysis, and all participants gave written informed consent. Thirty-three patients (age 77±8 years, 67% male) were enrolled and were followed for a median duration of 38 months (range, 21–41 months). Two patients were …
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original investigationchronic performance of a leadless Cardiac Pacemaker 1 year follow up of the leadless trial
Journal of the American College of Cardiology, 2015Co-Authors: Reinoud E Knops, Fleur V Y Tjong, Petr Neuzil, Johannes Sperzel, Marc A Miller, Jan Petru, Jaroslav Simon, Lucie Sediva, Joris R De Groot, Srinivas R DukkipatiAbstract:Background A leadless Cardiac Pacemaker (LCP) system was recently introduced to overcome lead-related complications of conventional pacing systems. To date, long-term results of an LCP system are unknown.
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chronic performance of a leadless Cardiac Pacemaker 1 year follow up of the leadless trial
Journal of the American College of Cardiology, 2015Co-Authors: Reinoud E Knops, Fleur V Y Tjong, Petr Neuzil, Johannes Sperzel, Marc A Miller, Jan Petru, Jaroslav Simon, Lucie Sediva, Joris R De Groot, Srinivas R DukkipatiAbstract:Abstract Background A leadless Cardiac Pacemaker (LCP) system was recently introduced to overcome lead-related complications of conventional pacing systems. To date, long-term results of an LCP system are unknown. Objectives The aim of this study was to assess the complication incidence, electrical performance, and rate response characteristics within the first year of follow-up of patients implanted with an LCP. Methods We retrospectively assessed intermediate-term follow-up data for 31 of 33 patients from the LEADLESS trial cohort who had an indication for single-chamber pacing and received an LCP between December 2012 and April 2013. Results The mean age of the cohort was 76 ± 8 years, and 65% were male. Between 3 and 12 months of follow-up, there were no Pacemaker-related adverse events reported. The pacing performance results at 6- and 12-month follow-up were, respectively, as follows: mean pacing threshold (at a 0.4-ms pulse width), 0.40 ± 0.26 V and 0.43 ± 0.30 V; R-wave amplitude 10.6 ± 2.6 mV and 10.3 ± 2.2 mV; and impedance 625 ± 205 Ω and 627 ± 209 Ω. At the 12-month follow-up in 61% of the patients (n = 19 of 31), the rate response sensor was activated, and an adequate rate response was observed in all patients. Conclusions The LCP demonstrates very stable performance and reassuring safety results during intermediate-term follow-up. These results support the use of the LCP as a promising alternative to conventional Pacemaker systems. Continued evaluation is warranted to further characterize this system. (Evaluation of a New Cardiac Pacemaker; NCT01700244 )
Michael D. Stern - One of the best experts on this subject based on the ideXlab platform.
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stabilization of diastolic calcium signal via calcium pump regulation of complex local calcium releases and transient decay in a computational model of Cardiac Pacemaker cell with individual release channels
PLOS Computational Biology, 2017Co-Authors: Alexander V Maltsev, Victor A. Maltsev, Michael D. SternAbstract:Intracellular Local Ca releases (LCRs) from sarcoplasmic reticulum (SR) regulate Cardiac Pacemaker cell function by activation of electrogenic Na/Ca exchanger (NCX) during diastole. Prior studies demonstrated the existence of powerful compensatory mechanisms of LCR regulation via a complex local cross-talk of Ca pump, release and NCX. One major obstacle to study these mechanisms is that LCR exhibit complex Ca release propagation patterns (including merges and separations) that have not been characterized. Here we developed new terminology, classification, and computer algorithms for automatic detection of numerically simulated LCRs and examined LCR regulation by SR Ca pumping rate (Pup) that provides a major contribution to fight-or-flight response. In our simulations the faster SR Ca pumping accelerates action potential-induced Ca transient decay and quickly clears Ca under the cell membrane in diastole, preventing premature releases. Then the SR generates an earlier, more synchronized, and stronger diastolic LCR signal activating an earlier and larger inward NCX current. LCRs at higher Pup exhibit larger amplitudes and faster propagation with more collisions to each other. The LCRs overlap with Ca transient decay, causing an elevation of the average diastolic [Ca] nadir to ~200 nM (at Pup = 24 mM/s). Background Ca (in locations lacking LCRs) quickly decays to resting Ca levels (<100 nM) at high Pup, but remained elevated during slower decay at low Pup. Release propagation is facilitated at higher Pup by a larger LCR amplitude, whereas at low Pup by higher background Ca. While at low Pup LCRs show smaller amplitudes, their larger durations and sizes combined with longer transient decay stabilize integrals of diastolic Ca and NCX current signals. Thus, the local interplay of SR Ca pump and release channels regulates LCRs and Ca transient decay to insure fail-safe Pacemaker cell operation within a wide range of rates.
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computer algorithms for automated detection and analysis of local ca2 releases in spontaneously beating Cardiac Pacemaker cells
Unknown Journal, 2017Co-Authors: Alexander V Maltsev, Victor A. Maltsev, Michael D. Stern, Edward G. Lakatta, Oliver Monfredi, Sean P Parsons, Mary S Kim, Kenta TsutsuiAbstract:Local Ca2+ Releases (LCRs) are crucial events involved in Cardiac Pacemaker cell function. However, specific algorithms for automatic LCR detection and analysis have not been developed in live, spontaneously beating Pacemaker cells. In the present study we measured LCRs using a high-speed 2D-camera in spontaneously contracting sinoatrial (SA) node cells isolated from rabbit and guinea pig and developed a new algorithm capable of detecting and analyzing the LCRs spatially in two-dimensions, and in time. Our algorithm tracks points along the midline of the contracting cell. It uses these points as a coordinate system for affine transform, producing a transformed image series where the cell does not contract. Action potential-induced Ca2+ transients and LCRs were thereafter isolated from recording noise by applying a series of spatial filters. The LCR birth and death events were detected by a differential (frame-to-frame) sensitivity algorithm applied to each pixel (cell location). An LCR was detected when its signal changes sufficiently quickly within a sufficiently large area. The LCR is considered to have died when its amplitude decays substantially, or when it merges into the rising whole cell Ca2+ transient. Ultimately, our algorithm provides major LCR parameters such as period, signal mass, duration, and propagation path area. As the LCRs propagate within live cells, the algorithm identifies splitting and merging behaviors, indicating the importance of locally propagating Ca2+-induced-Ca2+-release for the fate of LCRs and for generating a powerful ensemble Ca2+ signal. Thus, our new computer algorithms eliminate motion artifacts and detect 2D local spatiotemporal events from recording noise and global signals. While the algorithms were developed to detect LCRs in sinoatrial nodal cells, they have the potential to be used in other applications in biophysics and cell physiology, for example, to detect Ca2+ wavelets (abortive waves), sparks and embers in muscle cells and Ca2+ puffs and syntillas in neurons.
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a new simplified 3d model of Cardiac Pacemaker cell based on superresolution structured illumination microscopy sim
Biophysical Journal, 2015Co-Authors: Victor A. Maltsev, Edward G. Lakatta, Oliver Monfredi, Hari Shroff, Andrew York, Anna Maltsev, Michael D. SternAbstract:The contribution of diastolic Local Calcium-Releases (LCRs) to sinoatrial-node-cell Pacemaker function is presently approximated by three numerical models: 1)“common-pool” (Maltsev-Lakatta,2009); 2)“2D” (Anna Maltsev et al.,2011-2013); 3)“3D” (Stern et al.,2014). While the most advanced 3D-model describes stochastic states of each ryanodine receptor (RyR) and L-type calcium-channel, its high computational demand prevents parametric sensitivity analyses. Here we developed a new 3D-model having a lower computational demand, but reproducing all essential features of calcium dynamics measured in isolated rabbit SA node cells by SIM (achieving approximately double the resolution of conventional microscopy). Our cell-cross-section SIM measurements revealed that LCRs occur mainly within ∼1 µm under the plasma membrane, in line with immunofluorescence data on RyR cluster localization. Therefore, the model cell interior is approximated by only three layers of diffusively linked intracellular voxels: submembrane (20 nm), ring (1 µm), and core cylinder. Each submembrane RyR cluster is approximated as a Calcium-Release Unit (CRU) residing within the respective junctional SR linked to free SR which pumps/collects cytosolic calcium. Instead of assuming a fixed restitution period like prior 2D-models, the release activation and termination are controlled in each CRU by local calcium-dependent mechanisms (based on RyR interactions via Calium-Induced-Calcium-Release, reported recently). The new model simulations are substantially faster (vs. the original 3D-model), but predict all essential features of LCRs crucial for Pacemaker rate autonomic modulation. Thus, super-resolution SIM allowed fine localization of calcium-dynamics and validated the new model of integrated Cardiac Pacemaker cell function at the level of individual CRUs, filling an important niche between individual-molecule-level detail and common pool models (lacking LCRs). This new faster 3D-model allows parametric sensitivity analyses and provides a new mechanistic formulation of CRU function that is important for multi-scale modeling of heart function.
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filling the gap between calcium sparks and waves automatic detection and classification of local calcium releases in Cardiac Pacemaker cells
Biophysical Journal, 2015Co-Authors: Alexander V Maltsev, Michael D. SternAbstract:Local calcium releases (LCRs) observed in Cardiac Pacemaker cells have a complex spatiotemporal structure that has never been studied. We developed a computer algorithm for automatic detection and classification of LCRs in simulations of rabbit sinoatrial-node cells (using our recent 3D-model) to get new insights into Pacemaker cell operation, specifically, the role of sarcoplasmic reticulum calcium pumping rate (Pup).Identified release events that share a common intensity level are categorized as a release cluster, i.e. a complex release with multiple intensity peaks. These complex LCRs tend to live longer and propagate farther via calcium-induced-calcium release, thus occupying larger areas. Release events that don’t share any intensity level with other events are calcium sparks that do not live for a long time and do not propagate. Collisions and splits of LCRs are handled as follows. When an LCR separates into different parts, all parts are still considered part of the LCR. On the other hand, when an LCR collides with another, the one with the weaker signal mass is considered dead and the one with the larger signal mass takes its signal mass as its own. An LCR may also die by stochastic attrition when all its components fade out.Under voltage clamp, LCR areas and signal masses were paradoxically smaller at larger Pup, likely reflecting uptake of cytosolic calcium before it can propagate. Under spontaneous beating conditions, however, higher Pup greatly increased diastolic LCR signal mass and beating rate as predicted by the coupled-clock theory. Interestingly, the total integral of all LCRs during diastolic depolarization in both cases remained almost the same as longer integration time with smaller events is comparable to shorter time with larger events.
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mechanisms of beat to beat regulation of Cardiac Pacemaker cell function by ca2 cycling dynamics
Biophysical Journal, 2013Co-Authors: Yael Yaniv, Michael D. Stern, Edward G. Lakatta, Victor A. MaltsevAbstract:Whether intracellular Ca2+ cycling dynamics regulate Cardiac Pacemaker cell function on a beat-to-beat basis remains unknown. Here we show that under physiological conditions, application of low concentrations of caffeine (2–4 mM) to isolated single rabbit sinoatrial node cells acutely reduces their spontaneous action potential cycle length (CL) and increases Ca2+ transient amplitude for several cycles. Numerical simulations, using a modified Maltsev-Lakatta coupled-clock model, faithfully reproduced these effects, and also the effects of CL prolongation and dysrhythmic spontaneous beating (produced by cytosolic Ca2+ buffering) and an acute CL reduction (produced by flash-induced Ca2+ release from a caged Ca2+ buffer), which we had reported previously. Three contemporary numerical models (including the original Maltsev-Lakatta model) failed to reproduce the experimental results. In our proposed new model, Ca2+ releases acutely change the CL via activation of the Na+/Ca2+ exchanger current. Time-dependent CL reductions after flash-induced Ca2+ releases (the memory effect) are linked to changes in Ca2+ available for pumping into sarcoplasmic reticulum which, in turn, changes the sarcoplasmic reticulum Ca2+ load, diastolic Ca2+ releases, and Na+/Ca2+ exchanger current. These results support the idea that Ca2+ regulates CL in Cardiac Pacemaker cells on a beat-to-beat basis, and suggest a more realistic numerical mechanism of this regulation.