Optogenetic Manipulation of Cardiac Electrical Dynamics Using Sub-Threshold Illumination: Dissecting the Role of Cardiac Alternans in Terminating Rapid Rhythms

2021 ◽  
Author(s):  
V. Biasci ◽  
L. Santini ◽  
S. Hussaini ◽  
C. Ferrantini ◽  
R. Coppini ◽  
...  
Keyword(s):  
Cardiac Alternans

scholarly journals Role of Substrate and Triggers in the Genesis of Cardiac Alternans, From the Myocyte to the Whole Heart

Circulation ◽  
2012 ◽  
Vol 125 (3) ◽  
pp. 539-549 ◽  
Author(s):  
Faisal M. Merchant ◽  
Antonis A. Armoundas
Keyword(s):  
Cardiac Alternans ◽  
Whole Heart

scholarly journals Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes

2012 ◽  
Vol 302 (11) ◽  
pp. H2310-H2320 ◽  
Author(s):  
Vyacheslav M. Shkryl ◽  
Joshua T. Maxwell ◽  
Timothy L. Domeier ◽  
Lothar A. Blatter
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cellular Level ◽  
Release Mechanism ◽  
Atrial Myocytes ◽  
Restitution Curve ◽  
Intracellular Ca ◽  
Cardiac Alternans ◽  
Kinetics Of ◽  
Beating Frequency

Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden cardiac death. At the cellular level, Ca2+ alternans appears as cytosolic Ca2+ transients of alternating amplitude at regular beating frequency. Cardiac alternans is a multifactorial process but has been linked to disturbances in intracellular Ca2+ regulation. In atrial myocytes, we tested the role of voltage-gated Ca2+ current, sarcoplasmic reticulum (SR) Ca2+ load, and restitution properties of SR Ca2+ release for the occurrence of pacing-induced Ca2+ alternans. Voltage-clamp experiments revealed that peak Ca2+ current was not affected during alternans, and alternans of end-diastolic SR Ca2+ load, evaluated by application of caffeine or measured directly with an intra-SR fluorescent Ca2+ indicator (fluo-5N), were not a requirement for cytosolic Ca2+ alternans. Restitution properties and kinetics of refractoriness of Ca2+ release after activation during alternans were evaluated by four different approaches: measurements of 1) the delay (latency) of occurrence of spontaneous global Ca2+ releases and 2) Ca2+ spark frequency, both during rest after a large and small alternans Ca2+ transient; 3) the magnitude of premature action potential-induced Ca2+ transients after a large and small beat; and 4) the efficacy of a photolytically induced Ca2+ signal (Ca2+ uncaging from DM-nitrophen) to trigger additional Ca2+ release during alternans. The results showed that the latency of global spontaneous Ca2+ release was prolonged and Ca2+ spark frequency was decreased after the large Ca2+ transient during alternans. Furthermore, the restitution curve of the Ca2+ transient elicited by premature action potentials or by photolysis-induced Ca2+ release from the SR lagged behind after a large-amplitude transient during alternans compared with the small-amplitude transient. The data demonstrate that beat-to-beat alternation of the time-dependent restitution properties and refractory kinetics of the SR Ca2+ release mechanism represents a key mechanism underlying cardiac alternans.

scholarly journals Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

2016 ◽  
Vol 473 (21) ◽  
pp. 3951-3964 ◽  
Author(s):  
Xiaowei Zhong ◽  
Bo Sun ◽  
Alexander Vallmitjana ◽  
Tao Mi ◽  
Wenting Guo ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Important Determinant ◽  
Polymorphic Ventricular Tachycardia ◽  
Release Channel ◽  
Cardiac Alternans ◽  
Β Blocker ◽  
Opposite Manner ◽  
Electrocardiogram Ecg

Beat-to-beat alternations in the amplitude of the cytosolic Ca2+ transient (Ca2+ alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca2+ alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+ release channel responsible for cytosolic Ca2+ transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca2+ and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo. We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+ release refractoriness and enhanced propensity for Ca2+ alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca2+ alternans in RyR2-SOF hearts, whereas carvedilol, a β-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+ alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+, APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.

scholarly journals A Simulation Study of the Role of Mechanical Stretch in Arrhythmogenesis during Cardiac Alternans

2021 ◽  
Vol 120 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Azzam Hazim ◽  
Youssef Belhamadia ◽  
Stevan Dubljevic
Keyword(s):  
Simulation Study ◽  
Mechanical Stretch ◽  
Cardiac Alternans

scholarly journals The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Noémi Tóth ◽  
Jozefina Szlovák ◽  
Zsófia Kohajda ◽  
Gergő Bitay ◽  
Roland Veress ◽  
...  
Keyword(s):  
Ionic Currents ◽  
Ventricular Myocardium ◽  
Underlying Mechanism ◽  
Patch Clamp Technique ◽  
Fast Phase ◽  
Restitution Curve ◽  
Cardiac Alternans ◽  
Rapid Pacing ◽  
Relationship Of

AbstractCardiac alternans have crucial importance in the onset of ventricular fibrillation. The early explanation for alternans development was the voltage-driven mechanism, where the action potential (AP) restitution steepness was considered as crucial determining factor. Recent results suggest that restitution slope is an inadequate predictor for alternans development, but several studies still claim the role of membrane potential as underlying mechanism of alternans. These controversial data indicate that the relationship of restitution and alternans development is not completely understood. APs were measured by conventional microelectrode technique from canine right ventricular papillary muscles. Ionic currents combined with fluorescent measurements were recorded by patch-clamp technique. APs combined with fluorescent measurements were monitored by sharp microelectrodes. Rapid pacing evoked restitution-independent AP duration (APD) alternans. When non-alternating AP voltage command was used, Ca2+i-transient (CaT) alternans were not observed. When alternating rectangular voltage pulses were applied, CaT alternans were proportional to ICaL amplitude alternans. Selective ICaL inhibition did not influence the fast phase of APD restitution. In this study we found that ICaL has minor contribution in shaping the fast phase of restitution curve suggesting that ICaL—if it plays important role in the alternans mechanism—could be an additional factor that attenuates the reliability of APD restitution slope to predict alternans.

Are SR Ca content fluctuations or SR refractoriness the key to atrial cardiac alternans?: insights from a human atrial model

2014 ◽  
Vol 306 (11) ◽  
pp. H1540-H1552 ◽  
Author(s):  
Carlos A. Lugo ◽  
Inma R. Cantalapiedra ◽  
Angelina Peñaranda ◽  
Leif Hove-Madsen ◽  
Blas Echebarria
Keyword(s):  
Recovery Time ◽  
Cytosolic Calcium ◽  
Alternative Mechanism ◽  
Cardiac Arrhythmogenesis ◽  
Recovery From Inactivation ◽  
Cardiac Alternans ◽  
Different Response ◽  
Atrial Cell ◽  
Fast Rates

Despite the important role of electromechanical alternans in cardiac arrhythmogenesis, its molecular origin is not well understood. The appearance of calcium alternans has often been associated to fluctuations in the sarcoplasmic reticulum (SR) Ca loading. However, cytosolic calcium alternans observed without concurrent oscillations in the SR Ca content suggests an alternative mechanism related to a dysfunction in the dynamics of the ryanodine receptor (RyR2). We have investigated the effect of SR release refractoriness in the appearance of alternans, using a mathematical model of a single human atrial cell, based on the model by Nygren et al. ( 30 ), where we modified the dynamics of the RyR2 and of SR Ca release. The genesis of calcium alternans was studied stimulating the cell for different periods and values of the RyR2 recovery time from inactivation. At fast rates cytosolic calcium alternans were obtained without concurrent SR Ca content fluctuations. A transition from regular response to alternans was also observed, changing the recovery time from inactivation of the RyR2. This transition was found to be hysteretic, so for a given set of parameters different responses were observed. We then studied the relevance of RyR2 refractoriness for the generation of alternans, reproducing the same protocols as in recent experiments. In particular, restitution of Ca release during alternans was studied with a S1S2 protocol, obtaining a different response if the S2 stimulation was given after a long or a short release. We show that the experimental results can be explained by RyR2 refractoriness, arising from a slow RyR2 recovery from inactivation, stressing the role of the RyR2 in the genesis of alternans.

Role of dactinomycin in the improved survival of children with Wilms' tumor

JAMA ◽  
1966 ◽  
Vol 195 (12) ◽  
pp. 1005-1009 ◽  
Author(s):  
D. J. Fernbach
Keyword(s):  
Wilms Tumor

Role of the allergist in diagnosis and management of patients with uveitis

JAMA ◽  
1966 ◽  
Vol 195 (3) ◽  
pp. 167-172 ◽  
Author(s):  
T. E. Van Metre
Keyword(s):  
Diagnosis And Management

The power of norms to sway fused group members

2018 ◽  
Vol 41 ◽  
Author(s):  
Winnifred R. Louis ◽  
Craig McGarty ◽  
Emma F. Thomas ◽  
Catherine E. Amiot ◽  
Fathali M. Moghaddam
Keyword(s):  
Evolutionary Anthropology ◽  
Normative Systems ◽  
Violent Extremism ◽  
Identity Fusion ◽  
Group Members

AbstractWhitehouse adapts insights from evolutionary anthropology to interpret extreme self-sacrifice through the concept of identity fusion. The model neglects the role of normative systems in shaping behaviors, especially in relation to violent extremism. In peaceful groups, increasing fusion will actually decrease extremism. Groups collectively appraise threats and opportunities, actively debate action options, and rarely choose violence toward self or others.

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