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

Abstract 095: Uncoupling The Mitochondria Facilitates Alternans Formation In The Isolated Rabbit Heart

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Elena Tolkacheva ◽  
Jillian Wothe ◽  
Iryna Talkachova ◽  
Rebecca Smith ◽  
Ramjay Visweswaran
Keyword(s):  
Ventricular Arrhythmias ◽  
Ischemia Reperfusion ◽  
Rabbit Heart ◽  
Mitochondrial Depolarization ◽  
Atp Production ◽  
Isolated Rabbit Heart ◽  
Whole Heart ◽  
Early Occurrence ◽  
Mitochondrial Uncoupler

Alternans of action potential duration (APD) and intracellular calcium ([Ca 2+ ] i ) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled. This uncoupling may play an important role in alternans formation in the heart. The aim of our study was to investigate the role of mitochondrial depolarization on the formation of APD and [Ca 2+ ] i alternans in the isolated rabbit heart. We performed dual voltage and [Ca 2+ ] i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia (n=6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP (n=6). We investigated the formation of alternans of APD, [Ca 2+ ] i amplitude (CaA), and [Ca 2+ ] i duration (CaD) in the heart, under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD (192 ± 18 ms vs 136 ± 6 ms, p<0.05), CaD (182 ± 20 ms vs 133 ± 6 ms, p<0.05), and CaA (152 ± 5 ms vs 141 ± 3 ms, p<0.05) alternans, and an increase of intraventricular APD (0.44 ± 0.02 vs 0.2 ± 0.05, p<0.05) but not CaD (0.20 ± 0.03 vs 0.16 ± 0.03, p=N/S) heterogeneity, when compared to control. On the other hand, FCCP does not affect the conduction velocity in the heart (0.95 ± 0.06 m/s vs 1.05 ± 0.11 m/s, p=N/S). Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca 2+ ] i transients, whereas ischemia induces a significantly larger reduction of APD compared to FCCP treatment. Our results demonstrate that uncoupling of mitochondria leads to earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca 2+ ] i alternans in the heart, which in turn creates a substrate conducive to formation of ventricular arrhythmias.

Role of myocardium and endothelium in coronary vascular smooth muscle responses to hypoxia

2002 ◽  
Vol 282 (4) ◽  
pp. H1296-H1303 ◽  
Author(s):  
Cornel J. M. Kerkhof ◽  
Peter J. W. Van Der Linden ◽  
Pieter Sipkema
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Cardiac Tissue ◽  
Isometric Force ◽  
Adenosine Antagonist ◽  
Whole Heart ◽  
Muscle Responses ◽  
Isolated Rat

Hypoxia triggers a mechanism that induces vasodilation in the whole heart but not necessarily in isolated coronary arteries. We therefore studied the role of cardiomyocytes (CM), smooth muscle cells (SMC), and endothelial cells (EC) in coronary responses to hypoxia (Po 2 of 5–10 mmHg). In an attempt to determine the factor(s) released in response to hypoxia, we inhibited the contribution of adenosine, ATP-sensitive K+ channels, prostaglandins, and nitric oxide. Isolated rat septal artery segments without (−T) and with a layer of cardiac tissue (+T) were mounted in a double wire myograph, and constriction was induced. Hypoxia induced a decrease in isometric force of 21% and 61% in −T and +T segments, respectively ( P < 0.05). EC removal increased the relaxation to hypoxia in −T segments to 33% but had the same effect in +T segments (61%). Only one of the inhibitors, the adenosine antagonist in +T segments, partially affected the relaxation due to hypoxia. The role of adenosine is thus limited and other mechanisms have to contribute. We conclude that hypoxia induces a relaxation of SMC that is augmented by the presence of CM and blunted by the endothelium. A single mediator does not induce those effects.

scholarly journals Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Mohammad T. Elnakish ◽  
Amany A. E. Ahmed ◽  
Peter J. Mohler ◽  
Paul M. L. Janssen
Keyword(s):  
Oxidative Stress ◽  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Ventricular Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Oxygen Species ◽  
Whole Heart ◽  
Shed Light

Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models.

Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart

2013 ◽  
Vol 305 (1) ◽  
pp. H9-H18 ◽  
Author(s):  
Rebecca M. Smith ◽  
Ramjay Visweswaran ◽  
Iryna Talkachova ◽  
Jillian K. Wothe ◽  
Elena G. Tolkacheva
Keyword(s):  
Ventricular Arrhythmias ◽  
Ischemia Reperfusion ◽  
Rabbit Heart ◽  
Mitochondrial Stress ◽  
Atp Production ◽  
Isolated Rabbit Heart ◽  
Whole Heart ◽  
Early Occurrence ◽  
Mitochondrial Uncoupler

Alternans of action potential duration (APD) and intracellular calcium ([Ca2+]i) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia-reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled, which may affect alternans formation in the heart. The aim of our study was to investigate the role of mitochondria on the formation of APD and [Ca2+]i alternans in the isolated rabbit heart. We performed dual voltage and [Ca2+]i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia ( n = 6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP ( n = 6). We investigated the formation of alternans of APD, [Ca2+]i amplitude (CaA), and [Ca2+]i duration (CaD) under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD, CaD, and CaA alternans; an increase of intraventricular APD but not CaD heterogeneity; and significant reduction in conduction velocity compared with that of control. Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca2+]i transients, whereas ischemia induces a significantly larger reduction of APD compared with that in FCCP treatment. In conclusion, our results demonstrate that uncoupling of mitochondria leads to an earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca2+]i alternans in the heart, which in turn creates a substrate for ventricular arrhythmias.

scholarly journals Related neuropeptides use different balances of unitary mechanisms to modulate the cardiac neuromuscular system in the American lobster, Homarus americanus

2015 ◽  
Vol 113 (3) ◽  
pp. 856-870 ◽  
Author(s):  
Patsy S. Dickinson ◽  
Andrew Calkins ◽  
Jake S. Stevens
Keyword(s):  
Motor Nerve ◽  
Homarus Americanus ◽  
Burst Frequency ◽  
Contraction Amplitude ◽  
Motor Behaviors ◽  
Low Concentrations ◽  
Multiple Levels ◽  
Whole Heart ◽  
Feedback Pathways

To produce flexible outputs, neural networks controlling rhythmic motor behaviors can be modulated at multiple levels, including the pattern generator itself, sensory feedback, and the response of the muscle to a given pattern of motor output. We examined the role of two related neuropeptides, GYSDRNYLRFamide (GYS) and SGRNFLRFamide (SGRN), in modulating the neurogenic lobster heartbeat, which is controlled by the cardiac ganglion (CG). When perfused though an isolated whole heart at low concentrations, both peptides elicited increases in contraction amplitude and frequency. At higher concentrations, both peptides continued to elicit increases in contraction amplitude, but GYS caused a decrease in contraction frequency, while SGRN did not alter frequency. To determine the sites at which these peptides induce their effects, we examined the effects of the peptides on the periphery and on the isolated CG. When we removed the CG and stimulated the motor nerve with constant bursts of stimuli, both GYS and SGRN increased contraction amplitude, indicating that each peptide modulates the muscle or the neuromuscular junction. When applied to the isolated CG, neither peptide altered burst frequency at low peptide concentrations; at higher concentrations, SGRN decreased burst frequency, whereas GYS continued to have no effect on frequency. Together, these data suggest that the two peptides elicit some of their effects using different mechanisms; in particular, given the known feedback pathways within this system, the importance of the negative (nitric oxide) relative to the positive (stretch) feedback pathways may differ in the presence of the two peptides.

Sign in / Sign up

Export Citation Format

Share Document