scholarly journals Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice

2021 ◽  
Author(s):  
Alexandra S Mighiu ◽  
Alice Recalde ◽  
Klemen Ziberna ◽  
Ricardo Carnicer ◽  
Jakub Tomek ◽  
...  

Abstract Aims Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility. Methods and results NOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype. Conclusion Together, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  

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.


Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Katja E Odening ◽  
Mohammad Hajjiri ◽  
Michael Brunner ◽  
Peem Lorvidhaya ◽  
Lorraine Schofield ◽  
...  

Introduction: Adult women with LQT2 are at higher risk for clinical events and sudden cardiac death (SCD) than men. We have created transgenic rabbits over-expressing pore mutants of the human KvLQT1 (LQT1) and HERG (LQT2) selectively in the heart. We report the gender differences in cardiac repolarization, incidence of polymorphic VT and SCD in these cohorts. Methods: Adult female and male LQT1, LQT2, and littermate controls (ages 5 to 33 mo were similar in f/m, LQT2 were younger due to higher mortality) underwent telemetric ECG monitoring, surface ECG and in vivo electrophysiological studies under general anaesthesia with isoflurane (2–5%). Results: Monitoring data showed a steeper QT/RR slope in female (0.745 ± 0.05, n=4) than in male (0.513 ± 0.06, n=9; p<0.05) LQT2 rabbits. No significant gender differences were observed in QT/RR slopes in either LQT1 or WT rabbits. QT-, QTpeak-index and Tp-e were significantly longer in female than in male LQT2 rabbits (females, n=6: QT: 129.2% ± 3.9; QTp: 105.9% ± 2.1; Tp-e: 42.9ms ± 4.1 vs. males, n=8: QT: 117.5% ± 4.3; p<0.05; QTp: 93.5% ± 5.6, p<0.05; Tp-e: 29.5ms ± 2.9, p<0.02). EP studies revealed significantly longer atrial (AERP) and ventricular (VERP) refractory periods in LQT2 females compared to males (females, n=4: AERP: 143.3 ± 5.8 ms; VERP: 212.5 ± 22.2 ms vs. males, n=8: AERP: 102.5 ± 7.7 ms, p<0.01; VERP: 178.1 ± 7.8 ms, p<0.05). AERP and VERP were significantly longer in LQT2 females than in LQT1 females (LQT1 females, n=7: AERP: 101.4 ± 7.7 ms, p<0.01, VERP: 156.9 ± 6.2, p<0.001), whereas in male LQT rabbits this genotype difference was only found in VERP but not in AERP. Survival was significantly shorter in female LQT2 rabbits compared to LQT1 or WT controls, with 4 sudden deaths among 10 LQT2, 1 among 19 WT and no SCD in 13 LQT1 females (p<0.02). No gender difference was observed in mortality. All cases of SCD occurred after sexual maturation and two LQT2 females died during lactation. Monitoring revealed the cause of SCD was polymorphic VT. Conclusions: Monitoring of LQT rabbits reveal gender differences in LQT2 rabbits. QT/RR slope is steeper in female than in male adult LQT2 rabbits. AERP and VERP are longer in LQT2 females than in males. Finally, in LQT2 females, SCD was associated with lactation, but not pregnancy.


2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  

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.


2008 ◽  
Vol 130 (1) ◽  
pp. 69-71 ◽  
Author(s):  
Qiqiong Cui ◽  
Wei Zhang ◽  
Hu Wang ◽  
Xin Sun ◽  
Huanyi Yang ◽  
...  

1993 ◽  
Vol 22 (6) ◽  
pp. 1666-1672 ◽  
Author(s):  
A.T.Marcel Gosselink ◽  
Harry J.G.M. Crijns ◽  
Hans P.M. Hamer ◽  
Hans Hillege ◽  
Kong I. Lie

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
M Pope ◽  
P Kuklik ◽  
A Briosa E Gala ◽  
MICHAEL Mahmoudi ◽  
J O H N Paisey ◽  
...  

Abstract Introduction Interatrial propagation has been widely studied in anatomical specimens and electrophysiological studies during sinus rhythm or pacing. However, pathways of conduction during atrial fibrillation (AF) are poorly characterised in vivo. Purpose We sought to develop a method of identifying the dominant channel of communication between atria during AF with a view to characterising the role of localised mechanisms in maintaining AF between both chambers. Methods 10 patients undergoing simultaneous bi-atrial non-contact charge density mapping before and following pulmonary vein isolation (PVI) were analysed. Simultaneous 30s recordings during AF were obtained. Virtual electrograms from every vertex of the reconstructed left and right atrial (LA, RA) anatomies were exported and phase calculated using a method of sinusoidal recomposition and Hilbert transform. For each vertex, coherence between a sequence of activations between this point and every other point on the opposing chamber was calculated using mean phase coherence (MPC). The maximum of all MPC values was assigned to this local point to estimate the degree of coherence between activity at a given point and the entire opposing chamber. The regions with highest MPC value represent the channel of communication. Each activation of this zone is then evaluated and difference in local activation time between LA and RA determined (figure). Communication between atria is determined where a normal distribution of timing shift within this channel can be demonstrated (as opposed to a uniform histogram in the case of a lack of any correlation between electrograms). If seen to be preceding the opposite chamber for ≥60% of the recording then the chamber was deemed to be leading. Results A total of 18 maps were obtained (pre-PVI only in 2). A clear channel of interatrial propagation could be seen in 17 maps (MPC value 0.48 ± 0.16) with communication within this channel demonstrated in 13 of these (MPC 0.52 ± 0.16). In the RA the most common site was in the posterior inter-caval zone (in 13) and on the posterior septum of the LA (in 14). The LA was leading in 4 maps and the RA in 2 with balanced propagation in 7. Conclusion The method of average MPC identifies channels of inter-atrial communication during AF which appear to predominantly involve posterior interatrial connections. Further application of this technique to characterise interatrial propagation may help to define patient specific phenotypes of AF and guide targeted therapy. Abstract Figure 1


2014 ◽  
Vol 65 (1-3) ◽  
pp. 69-75
Author(s):  
Aly Ramzy ◽  
Amal Ayoub ◽  
Said Khaled ◽  
Sameh Samir ◽  
Ayman Mortada ◽  
...  

1993 ◽  
Vol 264 (4) ◽  
pp. H1093-H1097 ◽  
Author(s):  
E. Leistad ◽  
G. Christensen ◽  
A. Ilebekk

The effects of atrial fibrillation on left and right atrial dimensions, pressures, and compliances were examined in two groups of seven barbiturate-anesthetized open-chest pigs. Atrial diameters and pressures were recorded during atrioventricular (AV) pace and thereafter during atrial fibrillation. Both rhythms were studied with constant ventricular rate after complete AV block. Left atrial maximal diameter, which appeared at the end of the atrial filling phase, decreased from 32.4 (28.9-36.7; median and 95% confidence interval) to 31.3 (28.4-35.7) mm after induction of atrial fibrillation. The right atrial maximal diameter also decreased, although not significantly. Atrial pressure at the peak of the v wave rose from 7.0 (5.5-8.5) to 9.6 (8.3-11.2) mmHg in the left atrium and from 5.0 (4.3-5.6) to 7.3 (6.2-8.7) mmHg in the right atrium. Left and right atrial chamber stiffness constants increased from 0.25 (0.19-0.48) to 0.41 (0.28-0.66) mm-1 and from 0.21 (0.11-0.31) to 0.33 (0.30-0.39) mm-1, respectively. Instantaneous diastolic atrial compliance decreased in both atria after induction of atrial fibrillation. Thus, during atrial fibrillation with regular ventricular rate, changes in atrial diameter, pressure, and compliance take place.


Author(s):  
Óscar Salvador‐Montañés ◽  
Rafael J. Ramirez ◽  
Yoshio Takemoto ◽  
Steven R. Ennis ◽  
Daniel Garcia‐Iglesias ◽  
...  

Background Activation during onset of atrial fibrillation is poorly understood. We aimed at developing a panoramic optical mapping system for the atria and test the hypothesis that sequential rotors underlie acceleration of atrial fibrillation during onset. Methods and Results Five sheep hearts were Langendorff perfused in the presence of 0.25 µmol/L carbachol. Novel optical system recorded activations simultaneously from the entire left and right atrial endocardial surfaces. Twenty sustained (>40 s) atrial fibrillation episodes were induced by a train and premature stimuli protocol. Movies obtained immediately (Initiation stage) and 30 s (Early Stabilization stage) after premature stimulus were analyzed. Serial rotor formation was observed in all sustained inductions and none in nonsustained inductions. In sustained episodes maximal dominant frequency increased from (mean±SD) 11.5±1.74 Hz during Initiation to 14.79±1.30 Hz at Early Stabilization ( P <0.0001) and stabilized thereafter. At rotor sites, mean cycle length (CL) during 10 prerotor activations increased every cycle by 0.53% ( P =0.0303) during Initiation and 0.34% ( P =0.0003) during Early Stabilization. In contrast, CLs at rotor sites showed abrupt decreases after the rotors appearances by a mean of 9.65% ( P <0.0001) during both stages. At Initiation, atria‐wide accelerations and decelerations during rotors showed a net acceleration result whereby post‐rotors atria‐wide minimal CL (CLmin) were 95.5±6.8% of the prerotor CLmin ( P =0.0042). In contrast, during Early Stabilization, there was no net acceleration in CLmin during accelerating rotors (prerotor=84.9±11.0% versus postrotor=85.8±10.8% of Initiation, P =0.4029). Levels of rotor drift distance and velocity correlated with atria‐wide acceleration. Nonrotor phase singularity points did not accelerate atria‐wide activation but multiplied during Initiation until Early Stabilization. Increasing number of singularity points, indicating increased complexity, correlated with atria‐wide CLmin reduction ( P <0.0001). Conclusions Novel panoramic optical mapping of the atria demonstrates shortening CL at rotor sites during cholinergic atrial fibrillation onset. Atrial fibrillation acceleration toward Early Stabilization correlates with the net result of atria‐wide accelerations during drifting rotors activity.


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