scholarly journals Assembly of the Cardiac Pacemaking Complex: Electrogenic Principles of Sinoatrial Node Morphogenesis

2021 ◽  
Vol 8 (4) ◽  
pp. 40
Author(s):  
Marietta Easterling ◽  
Simone Rossi ◽  
Anthony J Mazzella ◽  
Michael Bressan
Keyword(s):  
Cardiac Tissue ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Tissue Level ◽  
Rhythmic Contraction ◽  
Entire Volume ◽  
Impulse Generation ◽  
Cardiac Pacemaking ◽  
Electrical Impulses ◽  
Sufficient Strength

Cardiac pacemaker cells located in the sinoatrial node initiate the electrical impulses that drive rhythmic contraction of the heart. The sinoatrial node accounts for only a small proportion of the total mass of the heart yet must produce a stimulus of sufficient strength to stimulate the entire volume of downstream cardiac tissue. This requires balancing a delicate set of electrical interactions both within the sinoatrial node and with the downstream working myocardium. Understanding the fundamental features of these interactions is critical for defining vulnerabilities that arise in human arrhythmic disease and may provide insight towards the design and implementation of the next generation of potential cellular-based cardiac therapeutics. Here, we discuss physiological conditions that influence electrical impulse generation and propagation in the sinoatrial node and describe developmental events that construct the tissue-level architecture that appears necessary for sinoatrial node function.

scholarly journals Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking

2020 ◽  
Vol 472 (12) ◽  
pp. 1733-1742
Author(s):  
Nadine Erlenhardt ◽  
Olaf Kletke ◽  
Franziska Wohlfarth ◽  
Marlene A. Komadowski ◽  
Lukas Clasen ◽  
...  
Keyword(s):  
Family History ◽  
Sick Sinus Syndrome ◽  
Cardiac Pacemaker ◽  
Cell Surface Expression ◽  
Pacemaker Activity ◽  
Hcn Channel ◽  
Functional Interpretation ◽  
Rat Cardiomyocytes ◽  
Cardiac Pacemaking ◽  
History Of

AbstractThe hyperpolarization-activated cation current If is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide–gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.

scholarly journals Non-ohmic tissue conduction in cardiac electrophysiology: upscaling the non-linear voltage-dependent conductance of gap junctions

2019 ◽  
Author(s):  
Daniel E. Hurtado ◽  
Javiera Jilberto ◽  
Grigory Panasenko
Keyword(s):  
Computational Complexity ◽  
Gap Junctions ◽  
Cardiac Tissue ◽  
Tissue Level ◽  
Cardiac Conduction ◽  
Non Linear ◽  
Voltage Dependent ◽  
Junctional Coupling ◽  
Organ Level ◽  
Electrical Propagation

AbstractGap junctions are key mediators of the intercellular communication in cardiac tissue, and their function is vital to sustain normal cardiac electrical activity. Conduction through gap junctions strongly depends on the hemichannel arrangement and transjunctional voltage, rendering the intercellular conductance highly non-Ohmic. Despite this marked non-linear behavior, current tissue-level models of cardiac conduction are rooted on the assumption that gap-junctions conductance is constant (Ohmic), which results in inaccurate predictions of electrical propagation, particularly in the low junctional-coupling regime observed under pathological conditions. In this work, we present a novel non-Ohmic multiscale (NOM) model of cardiac conduction that is suitable for tissue-level simulations. Using non-linear homogenization theory, we develop a conductivity model that seamlessly upscales the voltage-dependent conductance of gap junctions, without the need of explicitly modeling gap junctions. The NOM model allows for the simulation of electrical propagation in tissue-level cardiac domains that accurately resemble that of cell-based microscopic models for a wide range of junctional coupling scenarios, recovering key conduction features at a fraction of the computational complexity. A unique feature of the NOM model is the possibility of upscaling the response of non-symmetric gap-junction conductance distributions, which result in conduction velocities that strongly depend on the direction of propagation, thus allowing to model the normal and retrograde conduction observed in certain regions of the heart. We envision that the NOM model will enable organ-level simulations that are informed by sub- and inter-cellular mechanisms, delivering an accurate and predictive in-silico tool for understanding the heart function.Author summaryThe heart relies on the propagation of electrical impulses that are mediated gap junctions, whose conduction properties vary depending on the transjunctional voltage. Despite this non-linear feature, current mathematical models assume that cardiac tissue behaves like an Ohmic (linear) material, thus delivering inaccurate results when simulated in a computer. Here we present a novel mathematical multiscale model that explicitly includes the non-Ohmic response of gap junctions in its predictions. Our results show that the proposed model recovers important conduction features modulated by gap junctions at a fraction of the computational complexity. This contribution represents an important step towards constructing computer models of a whole heart that can predict organ-level behavior in reasonable computing times.

scholarly journals An Uncertainty Modeling Framework for Intracardiac Electrogram Analysis

2020 ◽  
Vol 7 (2) ◽  
pp. 62
Author(s):  
Amirhossein Koneshloo ◽  
Dongping Du ◽  
Yuncheng Du
Keyword(s):  
Statistical Approach ◽  
Cardiac Tissue ◽  
Multinomial Distribution ◽  
Uncertainty Modeling ◽  
Data Uncertainty ◽  
Conduction Path ◽  
Modeling Framework ◽  
Intracardiac Electrogram ◽  
Guide Catheter ◽  
Electrical Impulses

Intracardiac electrograms (EGMs) are electrical signals measured within the chambers of the heart, which can be used to locate abnormal cardiac tissue and guide catheter ablations to treat cardiac arrhythmias. EGMs may contain large amounts of uncertainty and irregular variations, which pose significant challenges in data analysis. This study aims to introduce a statistical approach to account for the data uncertainty while analyzing EGMs for abnormal electrical impulse identification. The activation order of catheter sensors was modeled with a multinomial distribution, and maximum likelihood estimations were done to track the electrical wave conduction path in the presence of uncertainty. Robust optimization was performed to locate the electrical impulses based on the local conduction velocity and the geodesic distances between catheter sensors. The proposed algorithm can identify the focal sources when the electrical conduction is initiated by irregular electrical impulses and involves wave collisions, breakups, and spiral waves. The statistical modeling framework can efficiently deal with data uncertainties and provide a reliable estimation of the focal source locations. This shows the great potential of a statistical approach for the quantitative analysis of the stochastic activity of electrical waves in cardiac disorders and suggests future investigations integrating statistical methods with a deterministic geometry-based method to achieve advanced diagnostic performance.

Transmembrane Potentials and Contractility in the Pregnant Rat Uterus

1956 ◽  
Vol 187 (2) ◽  
pp. 333-337 ◽  
Author(s):  
Theodore C. West ◽  
Jorge Landa
Keyword(s):  
Action Potentials ◽  
Average Duration ◽  
Cardiac Pacemaker ◽  
Rhythmic Contraction ◽  
Pregnant Rat ◽  
Transmembrane Potentials ◽  
Stretch Receptors ◽  
Strain Gauge Transducer ◽  
Transmembrane Action Potentials ◽  
Spread Of Excitation

Surviving segments from the uteri of pregnant Long-Evans rats were studied. The rats were within 12 hours prepartum. Spontaneous contractility was measured by use of a strain gauge transducer. By means of the microelectrode technique of intracellular recording, transmembrane potentials were observed simultaneously. It was observed that trains of transmembrane action potentials appeared during rhythmic contraction. The frequency was low at the onset, increased to a maximum averaging greater than one per second and then diminished before cessation of firing. The average duration of impulse trains was 35 seconds at 30°C, less than the duration of the total contraction. Slow depolarization between action potentials often appeared after the first several cycles in a train of impulses. This phenomenon resembled the cardiac pacemaker prepotential. In light of similar experimental observations on stretch receptors by other investigators, it was considered possible that interfiber spread of excitation in uterus might be mediated by stretch.

Effects of current flow on pacemaker activity of the isolated kitten sinoatrial node

1980 ◽  
Vol 238 (3) ◽  
pp. H307-H316 ◽  
Author(s):  
J. Jalife ◽  
A. J. Hamilton ◽  
V. R. Lamanna ◽  
G. K. Moe
Keyword(s):  
Response Curve ◽  
Current Flow ◽  
Sinoatrial Node ◽  
Phase Response Curve ◽  
Vagal Stimulation ◽  
Cardiac Pacemaker ◽  
Phase Response ◽  
Pacemaker Activity ◽  
Current Pulses ◽  
Sucrose Gap

The dynamic behavior of the cardiac pacemaker in response to single or to periodically repeated perturbations was studied using kitten sinoatrial (SA) nodal strips mounted in a sucrose gap. Sustained stepwise applications of current across the gap produce lasting variations in pacemaker cycle length that depend on current magnitude and polarity, but not on the phase of the pacemaker period at the time of the input. Brief current pulses, whether hyperpolarizing or depolarizing, may abbreviate or prolong the immediately affected cycle depending on their timing. These changes result in phase shifts of the subsequent discharges, but they do not alter the pacemaker period permanently. The phasic effects of brief current pulses can be described by a phase response curve (PRC), which is a plot of the phase shift as a function of the position of the stimulus in the pacemaker cycle. PRCs were constructed for inputs of different polarity and several strengths and durations. The behavior of the sinus nodal pacemaker when interacting with period perturbing inputs, such as vagal stimulation or electrotonic depolarization, can be predicted on the basis of the phase response curve.

Cardiac pacemaker potentials at different extra- and intracellular K concentrations

1965 ◽  
Vol 208 (4) ◽  
pp. 770-775 ◽  
Author(s):  
Mario Vassalle
Keyword(s):  
Cardiac Tissue ◽  
Cardiac Pacemaker ◽  
Membrane Conductance ◽  
Resting Potential ◽  
Equilibrium Potential ◽  
Minor Effect ◽  
Bathing Solution ◽  
Subthreshold Oscillations ◽  
K Concentration ◽  
A Minor

Transmembrane potentials were recorded from mammalian Purkinje fibers. Adding saccharose to the bathing solution slowed the spontaneous rate, probably as a result of cell shrinkage and an increase in the intracellular K concentration. An opposite result was found with hypotonic medium. In solutions containing 5.4 mm K the fibers were quiescent. Lowering K to 2.7 mm left the membrane resting potential unchanged but decreased the membrane conductance to half. There was only a minor effect of extracellular K on membrane conductance during the plateau of the action potential. Spontaneous firing regularly started when extracellular K was reduced to or below 2.7 mm. This was preceded by subthreshold oscillations which increased in amplitude. A low K conductance associated with a sizeable difference between membrane potential and potassium equilibrium potential seem to be essential for spontaneous activity to occur in cardiac tissue.

scholarly journals STIM1–Ca2+ signaling modulates automaticity of the mouse sinoatrial node

2015 ◽  
Vol 112 (41) ◽  
pp. E5618-E5627 ◽  
Author(s):  
Hengtao Zhang ◽  
Albert Y. Sun ◽  
Jong J. Kim ◽  
Victoria Graham ◽  
Elizabeth A. Finch ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sinoatrial Node ◽  
Membrane Surface ◽  
Surface Membrane ◽  
Autonomic Response ◽  
Sinus Arrest ◽  
Cholinergic Signaling ◽  
Ionic Fluxes ◽  
Cardiac Pacemaking ◽  
Specific Deletion

Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca2+ release from internal Ca2+ stores (Ca2+ clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca2+ entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca2+ stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca2+ current, a reduction in L-type Ca2+ current, and enhancing the activities of Na+/Ca2+ exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca2+ dynamics in SANCs that links SR Ca2+ store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.

ANP has no postsynaptic effect on autonomic regulation of cardiac pacemaker rate in the rat

1993 ◽  
Vol 265 (6) ◽  
pp. H1983-H1987 ◽  
Author(s):  
D. J. Atchison ◽  
P. S. Pennefather ◽  
U. Ackermann
Keyword(s):  
Salt Solution ◽  
Action Potentials ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Pacemaker Activity ◽  
Physiological Salt Solution ◽  
Sprague Dawley ◽  
Pacemaker Cells ◽  
Frequency Of Action Potentials ◽  
The Right

We studied whether atrial natriuretic peptide (ANP) influences sinoatrial node pacemaker activity or whether it modifies the response to activation of postsynaptic autonomic receptors. Male Sprague-Dawley rats were anesthetized with pentobarbital sodium (45 mg/kg). Their hearts were removed quickly and placed in physiological salt solution. The atria were isolated; the right intra-atrial chamber was exposed to allow intracellular recording from sinoatrial node pacemaker cells. The tissue was placed in a temperature-regulated recording chamber and superfused with warmed oxygenated physiological salt solution. With use of standard microelectrode recording techniques, action potentials were recorded from spontaneously depolarizing cells in the presence of muscarine (62.5–500 nM) or norepinephrine (0.1 and 1.0 microM). Muscarine reduced the frequency of action potentials dose dependently, whereas norepinephrine increased their frequency. The addition of ANP (0.1–100 nM) to the superfusion had no effect on the frequency of action potentials during the superfusion of physiological salt solution or in the presence of either muscarine or norepinephrine. We conclude that ANP does not act on cardiac pacemaker cells to modulate the effect of neurotransmitters.

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