Victor A Maltsev

The University of Manchester, Manchester, ENG, United Kingdom

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Publications (87)452.61 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Rationale: A recent study published in Circulation Research by Gao et al used sinoatrial node (SAN)-targeted, incomplete Ncx1 knockout in mice to explore the role of the Na(+)/Ca(2+) exchanger (NCX) in cardiac pacemaker. The authors concluded that NCX is required for increasing sinus rates, but not for maintaining resting heart rate. This conclusion was based, in part, on numeric model simulations performed by Gao et al that reproduced their experimental results of unchanged action potentials in the knockout SAN cells. The authors, however, did not simulate the NCX current (INCX), that is, the subject of the study. Objective: We extended numeric examinations to simulate INCX in their incomplete knockout SAN cells that is crucial to interpret the study results. Methods and Results: INCX and Ca(2+) dynamics were simulated using different contemporary numeric models of SAN cells. We found that minimum diastolic Ca(2+) levels and INCX amplitudes generated by remaining NCX molecules (only 20% of control) remained almost unchanged. Simulations using a new local Ca(2+) control model indicate that these powerful compensatory mechanisms involve complex local cross-talk of Ca(2+) cycling proteins and NCX. Specifically, lower NCX expression facilitates Ca(2+)-induced Ca(2+) release and larger local Ca(2+) releases that stabilize diastolic INCX. Further reduction of NCX expression results in arrhythmia and halt of automaticity. Conclusions: Remaining NCX molecules in the incomplete knockout model likely produce almost the same diastolic INCX as in wild-type cells. INCX contribution is crucially important for both basal automaticity of SAN cells and during the fight-or-flight reflex.
    Circulation Research 10/2013; 113(10):e94-e100. · 11.86 Impact Factor
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    ABSTRACT: Whether intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) buffering) and an acute CL reduction (produced by flash-induced Ca(2+) release from a caged Ca(2+) 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, Ca(2+) releases acutely change the CL via activation of the Na(+)/Ca(2+) exchanger current. Time-dependent CL reductions after flash-induced Ca(2+) releases (the memory effect) are linked to changes in Ca(2+) available for pumping into sarcoplasmic reticulum which, in turn, changes the sarcoplasmic reticulum Ca(2+) load, diastolic Ca(2+) releases, and Na(+)/Ca(2+) exchanger current. These results support the idea that Ca(2+) regulates CL in cardiac pacemaker cells on a beat-to-beat basis, and suggest a more realistic numerical mechanism of this regulation.
    Biophysical Journal 10/2013; 105(7):1551-1561. · 3.67 Impact Factor
  • Source
    Michael D Stern, Eduardo Ríos, Victor A Maltsev
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    ABSTRACT: Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition-a phenomenon we dub "spark metastability." Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs.
    The Journal of General Physiology 09/2013; 142(3):257-74. · 4.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Beneficial clinical bradycardic effects of ivabradine (IVA) have been interpreted solely on the basis of If inhibition, because IVA specifically inhibits If in sinoatrial nodal pacemaker cells (SANC). However, it has been recently hypothesized that SANC normal automaticity is regulated by crosstalk between an "M clock," the ensemble of surface membrane ion channels, and a "Ca(2+) clock," the sarcoplasmic reticulum (SR). We tested the hypothesis that crosstalk between the two clocks regulates SANC automaticity, and that indirect suppression of the Ca(2+) clock further contributes to IVA-induced bradycardia. IVA (3μM) not only reduced If amplitude by 45±6% in isolated rabbit SANC, but the IVA-induced slowing of the action potential (AP) firing rate was accompanied by reduced SR Ca(2+) load, slowed intracellular Ca(2+) cycling kinetics, and prolonged the period of spontaneous local Ca(2+) releases (LCRs) occurring during diastolic depolarization. Direct and specific inhibition of SERCA2 by cyclopiazonic acid (CPA) had effects similar to IVA on LCR period and AP cycle length. Specifically, the LCR period and AP cycle length shift toward longer times almost equally by either direct perturbations of the M clock (IVA) or the Ca(2+) clock (CPA), indicating that the LCR period reports the crosstalk between the clocks. Our numerical model simulations predict that entrainment between the two clocks that involves a reduction in INCX during diastolic depolarization is required to explain the experimentally AP firing rate reduction by IVA. In summary, our study provides new evidence that a coupled-clock system regulates normal cardiac pacemaker cell automaticity. Thus, IVA-induced bradycardia includes a suppression of both clocks within this system.
    Journal of Molecular and Cellular Cardiology 05/2013; · 5.15 Impact Factor
  • Victor A Maltsev, Edward G Lakatta
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    ABSTRACT: Recent evidence supports the idea that robust and, importantly, FLEXIBLE automaticity of cardiac pacemaker cells is conferred by a coupled system of membrane ion currents (an "M-clock") and a sarcoplasmic reticulum (SR)-based Ca(2+) oscillator ("Ca(2+)clock") that generates spontaneous diastolic Ca(2+) releases. This study identified numerical models of a human biological pacemaker that features robust and flexible automaticity generated by a minimal set of electrogenic proteins and a Ca(2+)clock. Following the Occam's razor principle (principle of parsimony), M-clock components of unknown molecular origin were excluded from Maltsev-Lakatta pacemaker cell model and thirteen different model types of only 4 or 5 components were derived and explored by a parametric sensitivity analysis. The extended ranges of SR Ca(2+) pumping (i.e. Ca(2+)clock performance) and conductance of ion currents were sampled, yielding a large variety of parameter combination, i.e. specific model sets. We tested each set's ability to simulate autonomic modulation of human heart rate (minimum rate of 50 to 70 bpm; maximum rate of 140 to 210 bpm) in response to stimulation of cholinergic and β-adrenergic receptors. We found that only those models that include a Ca(2+)clock (including the minimal 4-parameter model "ICaL+IKr+INCX+Ca(2+)clock") were able to reproduce the full range of autonomic modulation. Inclusion of If or ICaT decreased the flexibility, but increased the robustness of the models (a relatively larger number of sets did not fail during testing). The new models comprised of components with clear molecular identity (i.e. lacking IbNa & Ist) portray a more realistic pacemaking: A smaller Na(+) influx is expected to demand less energy for Na(+) extrusion. The new large database of the reduced coupled-clock numerical models may serve as a useful tool for the design of biological pacemakers. It will also provide a conceptual basis for a general theory of robust, flexible, and energy-efficient pacemaking based on realistic components.
    Journal of Molecular and Cellular Cardiology 03/2013; · 5.15 Impact Factor
  • Edward G Lakatta, Yael Yaniv, Victor A Maltsev
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    ABSTRACT: No abstract.
    AJP Cell Physiology 03/2013; · 3.71 Impact Factor
  • Source
    Oliver Monfredi, Victor A Maltsev, Edward G Lakatta
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    ABSTRACT: Physiological processes governing the heart beat have been under investigation for several hundred years. Major advances have been made in the recent past. A review of the present paradigm is presented here, including a look back at important steps that led us to where we are today, alongside a glimpse into the exciting future of pacemaker research.
    Physiology 03/2013; 28(2):74-92. · 6.75 Impact Factor
  • Edward G Lakatta, Victor A Maltsev
    Nature Biotechnology 01/2013; 31(1):31-2. · 32.44 Impact Factor
  • Source
    Albertas Undrovinas, Victor A Maltsev, Hani N Sabbah
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    ABSTRACT: Calpain is an intracellular Ca(2+) -activated protease that is involved in numerous Ca(2+) dependent regulation of protein function in many cell types. This paper tests a hypothesis that calpains are involved in Ca(2+) -dependent increase of the late sodium current (INaL) in failing heart. Chronic heart failure (HF) was induced in 2 dogs by multiple coronary artery embolization. Using a conventional patch-clamp technique, the whole-cell INaL was recorded in enzymatically isolated ventricular cardiomyocytes (VCMs) in which INaL was activated by the presence of a higher (1μM) intracellular [Ca(2+)] in the patch pipette. Cell suspensions were exposed to a cell- permeant calpain inhibitor MDL-28170 for 1-2 h before INaL recordings. The numerical excitation-contraction coupling (ECC) model was used to evaluate electrophysiological effects of calpain inhibition in silico. MDL caused acceleration of INaL decay evaluated by the two-exponential fit (τ1 = 42±3.0 ms τ2 = 435±27 ms, n = 6, in MDL vs. τ1 = 52±2.1 ms τ2 = 605±26 control no vehicle, n = 11, and vs. τ1 = 52±2.8 ms τ2 = 583±37 ms n = 7, control with vehicle, P<0.05 ANOVA). MDL significantly reduced INaL density recorded at -30 mV (0.488±0.03, n = 12, in control no vehicle, 0.4502±0.0210, n = 9 in vehicle vs. 0.166±0.05pA/pF, n = 5, in MDL). Our measurements of current-voltage relationships demonstrated that the INaL density was decreased by MDL in a wide range of potentials, including that for the action potential plateau. At the same time the membrane potential dependency of the steady-state activation and inactivation remained unchanged in the MDL-treated VCMs. Our ECC model predicted that calpain inhibition greatly improves myocyte function by reducing the action potential duration and intracellular diastolic Ca(2+) accumulation in the pulse train. CONCLUSIONS: Calpain inhibition reverses INaL changes in failing dog ventricular cardiomyocytes in the presence of high intracellular Ca(2+). Specifically it decreases INaL density and accelerates INaL kinetics resulting in improvement of myocyte electrical response and Ca(2+) handling as predicted by our in silico simulations.
    PLoS ONE 01/2013; 8(4):e54436. · 3.73 Impact Factor
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    ABSTRACT: Spontaneous, submembrane local Ca(2+) releases (LCRs) generated by the sarcoplasmic reticulum in sinoatrial nodal cells, the cells of the primary cardiac pacemaker, activate inward Na(+)/Ca(2+)-exchange current to accelerate the diastolic depolarization rate, and therefore to impact on cycle length. Since LCRs are generated by Ca(2+) release channel (i.e. ryanodine receptor) openings, they exhibit a degree of stochastic behavior, manifested as notable cycle-to-cycle variations in the time of their occurrence. The present study tested whether variation in LCR periodicity contributes to intrinsic (beat-to-beat) cycle length variability in single sinoatrial nodal cells. We imaged single rabbit sinoatrial nodal cells using a 2D-camera to capture LCRs over the entire cell, and, in selected cells, simultaneously measured action potentials by perforated patch clamp. LCRs begin to occur on the descending part of the action potential-induced whole-cell Ca(2+) transient, at about the time of the maximum diastolic potential. Shortly after the maximum diastolic potential (mean 54±7.7 ms, n = 14), the ensemble of waxing LCR activity converts the decay of the global Ca(2+) transient into a rise, resulting in a late, whole-cell diastolic Ca(2+) elevation, accompanied by a notable acceleration in diastolic depolarization rate. On average, cells (n = 9) generate 13.2±3.7 LCRs per cycle (mean±SEM), varying in size (7.1±4.2 µm) and duration (44.2±27.1 ms), with both size and duration being greater for later-occurring LCRs. While the timing of each LCR occurrence also varies, the LCR period (i.e. the time from the preceding Ca(2+) transient peak to an LCR's subsequent occurrence) averaged for all LCRs in a given cycle closely predicts the time of occurrence of the next action potential, i.e. the cycle length. Intrinsic cycle length variability in single sinoatrial nodal cells is linked to beat-to-beat variations in the average period of individual LCRs each cycle.
    PLoS ONE 01/2013; 8(6):e67247. · 3.73 Impact Factor
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    ABSTRACT: Basal phosphorylation of sarcoplasmic reticulum (SR) Ca2 + proteins is high in sinoatrial nodal cells (SANC), which generate partially synchronized, spontaneous, rhythmic, diastolic local Ca2 + releases (LCRs), but low in ventricular myocytes (VM), which exhibit rare diastolic, stochastic SR-generated Ca2 + sparks. We tested the hypothesis that in a physiologic Ca2 + milieu, and independent of increased Ca2 + influx, an increase in basal phosphorylation of SR Ca2 + cycling proteins will convert stochastic Ca2 + sparks into periodic, high-power Ca2 + signals of the type that drives SANC normal automaticity. We measured phosphorylation of SR-associated proteins, phospholamban (PLB) and ryanodine receptors (RyR), and spontaneous local Ca2 + release characteristics (LCR) in permeabilized single, rabbit VM in physiologic [Ca2 +], prior to and during inhibition of protein phosphatase (PP) and phosphodiesterase (PDE), or addition of exogenous cAMP, or in the presence of an antibody (2D12), that specifically inhibits binding of the PLB to SERCA-2. In the absence of the aforementioned perturbations, VM could only generate stochastic local Ca2 + releases of low power and low amplitude, as assessed by confocal Ca2 + imaging and spectral analysis. When the kinetics of Ca2 + pumping into the SR were increased by an increase in PLB phosphorylation (via PDE and PP inhibition or addition of cAMP) or by 2D12, self-organized, “clock-like” local Ca2 + releases, partially synchronized in space and time (Ca2 + wavelets), emerged, and the ensemble of these rhythmic local Ca2 + wavelets generated a periodic high-amplitude Ca2 + signal. Thus, a Ca2 + clock is not specific to pacemaker cells, but can also be unleashed in VM when SR Ca2 + cycling increases and spontaneous local Ca2 + release becomes partially synchronized. This unleashed Ca2 + clock that emerges in a physiological Ca2 + milieu in VM has two faces, however: it can provoke ventricular arrhythmias; or if harnessed, can be an important feature of novel bio-pacemaker designs.
    Journal of Molecular and Cellular Cardiology 01/2013; · 5.15 Impact Factor
  • Victor A. Maltsev, Yael Yaniv, Edward G. Lakatta
    Biophysical Journal 01/2012; 102(3):673-. · 3.67 Impact Factor
  • Yael Yaniv, Victor A. Maltsev, Edward G. Lakatta
    Biophysical Journal 01/2012; 102(3):511-. · 3.67 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Recent clinical trials have shown that ivabradine (IVA), a drug that inhibits the funny current (I(f)) in isolated sinoatrial nodal cells (SANC), decreases heart rate and reduces morbidity and mortality in patients with cardiovascular diseases. While IVA inhibits I(f), this effect has been reported at essentially unphysiological voltages, i.e., those more negative than the spontaneous diastolic depolarization (DD) between action potentials (APs). We tested the relative potency of IVA to block I(f) over a wide range of membrane potentials, including those that encompass DD governing to the SANC spontaneous firing rate. A clinically relevant IVA concentration of 3 μM to single, isolated rabbit SANC slowed the spontaneous AP firing rate by 15%. During voltage clamp the maximal I(f) was 18 ± 3 pA/pF (at -120 mV) and the maximal I(f) reduction by IVA was 60 ± 8% observed at -92 ± 4 mV. At the maximal diastolic depolarization (~-60 mV) I(f) amplitude was only -2.9 ± 0.4 pA/pF, and was reduced by only 41 ± 6% by IVA. Thus, I(f) amplitude and its inhibition by IVA at physiologically relevant membrane potentials are substantially less than that at unphysiological (hyperpolarized) membrane potentials. This novel finding more accurately describes how IVA affects SANC function and is of direct relevance to numerical modeling of SANC automaticity.
    Molecules 01/2012; 17(7):8241-54. · 2.43 Impact Factor
  • Biophysical Journal 01/2012; 102(3):671-. · 3.67 Impact Factor
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    ABSTRACT: Mitochondria dynamically buffer cytosolic Ca(2+) in cardiac ventricular cells and this affects the Ca(2+) load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca(2+) releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na(+)-Ca(2+) exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP). To determine if mitochondrial Ca(2+) (Ca(2+) (m)), cytosolic Ca(2+) (Ca(2+) (c))-SR-Ca(2+) crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity. Inhibition of mitochondrial Ca(2+) influx into (Ru360) or Ca(2+) efflux from (CGP-37157) decreased [Ca(2+)](m) to 80 ± 8% control or increased [Ca(2+)](m) to 119 ± 7% control, respectively. Concurrent with inhibition of mitochondrial Ca(2+) influx or efflux, the SR Ca(2+) load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively. Changes in total ensemble LCR Ca(2+) signal were highly correlated with the change in the SR Ca(2+) load (r(2) = 0.97). Changes in the spontaneous AP cycle length (Ru360, 111 ± 1% control; CGP-37157, 89 ± 2% control) in response to changes in [Ca(2+)](m) were predicted by concurrent changes in LCR period (r(2) = 0.84). A change in SANC Ca(2+) (m) flux translates into a change in the AP firing rate by effecting changes in Ca(2+) (c) and SR Ca(2+) loading, which affects the characteristics of spontaneous SR Ca(2+) release.
    PLoS ONE 01/2012; 7(5):e37582. · 3.73 Impact Factor
  • Oliver Monfredi, Edward G. Lakatta, Victor A. Maltsev
    Biophysical Journal 01/2012; 102(3):103-. · 3.67 Impact Factor
  • Edward G Lakatta, Victor A Maltsev
    Heart rhythm: the official journal of the Heart Rhythm Society 09/2011; 9(3):459-60. · 4.56 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Whether intracellular Ca(2+) regulates sinoatrial node cell (SANC) action potential (AP) firing rate on a beat-to-beat basis is controversial. To directly test the hypothesis of beat-to-beat intracellular Ca(2+) regulation of the rate and rhythm of SANC we loaded single isolated SANC with a caged Ca(2+) buffer, NP-EGTA, and simultaneously recorded membrane potential and intracellular Ca(2+). Prior to introduction of the caged Ca(2+) buffer, spontaneous local Ca(2+) releases (LCRs) during diastolic depolarization were tightly coupled to rhythmic APs (r²=0.9). The buffer markedly prolonged the decay time (T₅₀) and moderately reduced the amplitude of the AP-induced Ca(2+) transient and partially depleted the SR load, suppressed spontaneous diastolic LCRs and uncoupled them from AP generation, and caused AP firing to become markedly slower and dysrhythmic. When Ca(2+) was acutely released from the caged compound by flash photolysis, intracellular Ca(2+) dynamics were acutely restored and rhythmic APs resumed immediately at a normal rate. After a few rhythmic cycles, however, these effects of the flash waned as interference with Ca(2+) dynamics by the caged buffer was reestablished. Our results directly support the hypothesis that intracellular Ca(2+) regulates normal SANC automaticity on a beat-to-beat basis.
    Journal of Molecular and Cellular Cardiology 09/2011; 51(6):902-5. · 5.15 Impact Factor
  • Source
    Victor A Maltsev, Edward G Lakatta
    Heart rhythm: the official journal of the Heart Rhythm Society 09/2011; 9(2):302-7. · 4.56 Impact Factor

Publication Stats

3k Citations
90 Downloads
452.61 Total Impact Points

Institutions

  • 2013
    • The University of Manchester
      • Institute of Cardiovascular Sciences
      Manchester, ENG, United Kingdom
    • University of Bristol
      • School of Mathematics
      Bristol, England, United Kingdom
  • 2004–2013
    • National Institutes of Health
      • Laboratory of Cardiovascular Science (LCS)
      Bethesda, MD, United States
    • National Institute on Aging
      • Laboratory of Cardiovascular Science (LCS)
      Baltimore, MD, United States
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 1998–2013
    • Henry Ford Hospital
      • Department of Internal Medicine
      Detroit, MI, United States
  • 2007
    • Henry Ford Health System
      • Henry Ford Heart and Vascular Institute
      Detroit, Michigan, United States
  • 1997
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany
  • 1993–1995
    • Leibniz Institute of Plant Genetics and Crop Plant Research
      Gatersleben, Saxony-Anhalt, Germany
  • 1994
    • Freie Universität Berlin
      • Institute of Pharmacology and Toxicology
      Berlin, Land Berlin, Germany