scholarly journals Atrial Fibrillation and Fibrosis: Beyond the Cardiomyocyte Centric View

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Michele Miragoli ◽  
Alexey V. Glukhov
Keyword(s):  
Atrial Fibrillation ◽  
Conduction Block ◽  
Resting Membrane Potential ◽  
Ectopic Activity ◽  
Impulse Conduction ◽  
Cardiac Impulse ◽  
Border Zones ◽  
Degree Of Coupling

Atrial fibrillation (AF) associated with fibrosis is characterized by the appearance of interstitial myofibroblasts. These cells are responsible for the uncontrolled deposition of the extracellular matrix, which pathologically separate cardiomyocyte bundles. The enhanced fibrosis is thought to contribute to arrhythmias “indirectly” because a collagenous septum is a passive substrate for propagation, resulting in impulse conduction block and/or zigzag conduction. However, the emerging results demonstrate that myofibroblastsin vitroalso promote arrhythmogenesis due to direct implications upon cardiomyocyte electrophysiology. This electrical interference may be considered beneficial as it resolves any conduction blocks; however, the passive properties of myofibroblasts might cause a delay in impulse propagation, thus promoting AF due to discontinuous slow conduction. Moreover, low-polarized myofibroblasts reduce, via cell-density dependence, the fast driving inward current for cardiac impulse conduction, therefore resulting in arrhythmogenic uniformly slow propagation. Critically, the subsequent reduction in cardiomyocytes resting membrane potentialin vitrosignificantly increases the likelihood of ectopic activity. Myofibroblast densities and the degree of coupling at cellular border zones also impact upon this likelihood. By considering futurein vivostudies, which identify myofibroblasts “per se” as a novel targets for cardiac arrhythmias, this review aims to describe the implications of noncardiomyocyte view in the context of AF.

scholarly journals Compensatory mechanisms in resistant Anopheles gambiae AcerKis and KdrKis neurons modulate insecticide-based mosquito control

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Stéphane Perrier ◽  
Eléonore Moreau ◽  
Caroline Deshayes ◽  
Marine El-Adouzi ◽  
Delphine Goven ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Anopheles Gambiae ◽  
Calcium Concentration ◽  
Mosquito Control ◽  
Point Mutations ◽  
Resting Membrane Potential ◽  
Compensatory Mechanisms ◽  
Pyrethroid Insecticides

AbstractIn the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase (ace-1R) and the sodium channel (kdrR) genes confer resistance to organophosphate/carbamate and pyrethroid insecticides, respectively. The mechanisms of compensation that recover the functional alterations associated with these mutations and their role in the modulation of insecticide efficacy are unknown. Using multidisciplinary approaches adapted to neurons isolated from resistant Anopheles gambiae AcerKis and KdrKis strains together with larval bioassays, we demonstrate that nAChRs, and the intracellular calcium concentration represent the key components of an adaptation strategy ensuring neuronal functions maintenance. In AcerKis neurons, the increased effect of acetylcholine related to the reduced acetylcholinesterase activity is compensated by expressing higher density of nAChRs permeable to calcium. In KdrKis neurons, changes in the biophysical properties of the L1014F mutant sodium channel, leading to enhance overlap between activation and inactivation relationships, diminish the resting membrane potential and reduce the fraction of calcium channels available involved in acetylcholine release. Together with the lower intracellular basal calcium concentration observed, these factors increase nAChRs sensitivity to maintain the effect of low concentration of acetylcholine. These results explain the opposite effects of the insecticide clothianidin observed in AcerKis and KdrKis neurons in vitro and in vivo.

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

scholarly journals Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3175
Author(s):  
Laura Iop ◽  
Sabino Iliceto ◽  
Giovanni Civieri ◽  
Francesco Tona
Keyword(s):  
Atrial Fibrillation ◽  
Cardiovascular Diseases ◽  
Brugada Syndrome ◽  
In Silico ◽  
Cardiac Fibrosis ◽  
Sick Sinus Syndrome ◽  
In Vitro Models ◽  
Global Functioning

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

Lysophosphoglycerides in ischemic myocardium effluents and potentiation of their arrhythmogenic effects

1981 ◽  
Vol 241 (5) ◽  
pp. H700-H707 ◽  
Author(s):  
D. W. Snyder ◽  
W. A. Crafford ◽  
J. L. Glashow ◽  
D. Rankin ◽  
B. E. Sobel ◽  
...  
Keyword(s):  
Action Potentials ◽  
Extracellular Fluid ◽  
Ischemic Myocardium ◽  
Resting Membrane Potential ◽  
Phase 0 ◽  
Control Plasma ◽  
Maximum Rate Of Rise ◽  
Arrhythmogenic Effects

Lysophosphoglycerides accumulate in ischemic myocardium. To determine whether lysophosphatidylcholine (LPC) concentrations increase in extracellular fluid and may be arrhythmogenic, the anterior descending coronary artery of the open-chest cat (n = 12) was perfused with a Krebs-albumin solution after 10 min of ischemia and the effluent assayed for LPC. A twofold increase in LPC (0.097 +/- 0.02 to 0.170 +/- 0.03 mM) was observed. Microelectrode intracellular recordings from from normal feline endocardium at pH 7.4 in vitro revealed little change in action potentials when superfused with feline plasma despite augmented LPC to twice normal levels (0.74 mM). However, at pH 6.7, marked changes were elicited by LPC-enriched plasma including diminished resting membrane potential (-96 +/- 1 to -35 +/- 7 mV), amplitude (102 +/- 3 to 36 +/- 8 mV), maximum rate of rise (Vmax) of phase 0 (178 +/- 24 to 26 +/- 11 V/s), and conduction velocity with fractionation of the action potential. Acidified control plasma decreased only Vmax (from 161 to 57 V/s). Thus LPC increases twofold in effluents from cat myocardium in vivo after 10 min of ischemia and, coupled with ischemia-induced acidosis, is sufficient to induce marked electrophysiological derangements in vitro.

Recording Temperature Affects the Excitability of Mouse Superficial Dorsal Horn Neurons, In Vitro

2008 ◽  
Vol 99 (5) ◽  
pp. 2048-2059 ◽  
Author(s):  
B. A. Graham ◽  
A. M. Brichta ◽  
R. J. Callister
Keyword(s):  
Spinal Cord ◽  
Elevated Temperature ◽  
Dorsal Horn ◽  
Current Injection ◽  
Resting Membrane Potential ◽  
Temperature Sensitive ◽  
Superficial Dorsal Horn ◽  
Pain Mechanisms

Superficial dorsal horn (SDH) neurons in laminae I–II of the spinal cord play an important role in processing noxious stimuli. These neurons represent a heterogeneous population and are divided into various categories according to their action potential (AP) discharge during depolarizing current injection. We recently developed an in vivo mouse preparation to examine functional aspects of nociceptive processing and AP discharge in SDH neurons and to extend investigation of pain mechanisms to the genetic level of analysis. Not surprisingly, some in vivo data obtained at body temperature (37°C) differed from those generated at room temperature (22°C) in spinal cord slices. In the current study we examine how temperature influences SDH neuron properties by making recordings at 22 and 32°C in transverse spinal cord slices prepared from L3–L5 segments of adult mice (C57Bl/6). Patch-clamp recordings (KCH3SO4 internal) were made from visualized SDH neurons. At elevated temperature all SDH neurons had reduced input resistance and smaller, briefer APs. Resting membrane potential and AP afterhyperpolarization amplitude were temperature sensitive only in subsets of the SDH population. Notably, elevated temperature increased the prevalence of neurons that did not discharge APs during current injection. These reluctant firing neurons expressed a rapid A-type potassium current, which is enhanced at higher temperatures and thus restrains AP discharge. When compared with previously published whole cell recordings obtained in vivo (37°C) our results suggest that, on balance, in vitro data collected at elevated temperature more closely resemble data collected under in vivo conditions.

scholarly journals Knockdown of C3G Mitigates Post-Infarct Remodeling via Regulation of ERK1/2, Bcl-2 and Bax in Rat Myocardial Cells

2021 ◽  
Author(s):  
Gang Li ◽  
Qin Deng ◽  
Sulei Hu ◽  
Jari A. Laukkanen ◽  
Cheng Liu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Weight Ratio ◽  
B Cell Lymphoma ◽  
Myocardial Remodeling ◽  
Nucleotide Exchange ◽  
Sprague Dawley ◽  
Down Regulation ◽  
Border Zones

Abstract Background: Cardiomyocyte-specific knockout of pro-survival integrin β1 subunit and its downstream components have been demonstrated to aggravate remodeling after myocardial infarction (MI). However, as a component of integrin pathway, it is unclear whether knockdown of pro-survival C3G (rap guanine nucleotide exchange factor 1) in cardiac myocytes and fibroblasts could have effect on myocardial remodeling. Methods and results: A rat model of MI was established by ligation of left anterior descending coronary artery. Infarcted myocardium and its border zones in Sprague-Dawley rats were transiently infected with C3G knockout lentivirus via local injection to knockdown C3G in the myocardium. Twelve weeks after injection with the lentiviruses, cardiomyocytic apoptosis and collagen in surviving myocardium, and left ventricle (LV) end-diastolic diameter were decreased, whereas LV weight / body weight ratio and LV ejection fraction were increased in MI group via down-regulation of pro-survival C3G, phosphorylated (p) ERK1/2 (phosphorylated extracellular regulated kinase 1/2) and Bcl-2 (B-cell lymphoma-2), and up-regulation of pro-apoptotic Bax in the surviving myocardium. On the other hand, treatment with the lentiviruses was found to delete C3G and diminish cell proliferation in vitro cardiac myocytic and fibroblastic cell lines respectively via down-regulation of p-ERK1/2 and Bcl-2, and up-regulation of Bax. Conclusions: Knockdown of pro-survival C3G in myocardium may mitigate surviving myocardial remodeling after MI, possibly through regulation of p-ERK1/2, Bcl-2 and Bax in vivo cardiac myocytes and fibroblasts.

Abstract 15127: Isorhamnetin Reverses Angiotensin Ii-induced Atrial Fibrillation Vulnerability Through Electrophysiological and Structural Reverse Remodeling in Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kazuhiro Aonuma ◽  
Dong-Zhu Xu ◽  
Nobuyuki MURAKOSHI ◽  
Kazuko Tajiri ◽  
Kenichi Tominaga ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Angiotensin Ii ◽  
Histological Examination ◽  
Flavonoid Compound ◽  
Reverse Remodeling ◽  
Control Group ◽  
Electrophysiologic Study ◽  
Wild Type Male

Background: Isorhamnetin (ISO), a natural flavonoid compound, has been shown to have strong antioxidant and antifibrotic effects in vivo and in vitro; however, no report has been shown on the effect of ISO on arrhythmic disorders. This study aimed to investigate the effect of ISO on angiotensin-II (Ag-II) induced atrial fibrillation (AF) in mice. Methods: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned in 3 groups as follows: control group (Cont), Ag-II group treated with Ag-II and Ag-II & ISO group treated with Ag-II and ISO. Ag-II (1000 ng/kg/min) was continuously administered using an implantable osmotic pump for 2 weeks, and ISO (5 mg/kg) was administered intraperitoneally one week before starting Ag-II administration. We performed AF induction and electrophysiologic study via transvenous electrode catheter and Ca 2+ imaging with isolated cardiomyocyte. We also assessed the gene expression levels of AF-related molecules, and histological examination of atrial fibrosis. Results: Compared with Cont, AF inducibility was dramatically increased by Ag-II and significantly decreased by ISO. AF duration was also remarkably prolonged by Ag-II and significantly reduced by ISO. Atrial effective refractory period (A-ERP) (BCL=150msec) was reduced by Ag-II and recovered by ISO. Incidences of diastolic intracellular Ca 2+ abnormal activities (sarcoplasmic reticulum [SR] Ca 2+ leakage) was observed in Ag-II group; however, ISO treatment eliminated these abnormalities. Ag-II induced elevated expression of fibrosis-related molecules (Col1a1, Tgfb1 and Tgfb2) and Ca 2+ -handling related molecules (Camk2 and Ryr2), those were partially normalized by ISO. Histological examination revealed that cell size and the fibrosis ratio were increased by Ag-II, and significantly attenuated by ISO. Conclusion: These results suggest that ISO prevented against Ag-II induced AF vulnerability through both electrophysiological and structural reverse remodeling.

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