Abstract 1346: Rac1 GTPase Activtiy is Associated with Atrial Fibrosis and Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Oliver Adam ◽  
Daniel Lavall ◽  
Hans-Joachim Schäfers ◽  
Michael Böhm ◽  
Ulrich Laufs
Keyword(s):  
Atrial Fibrillation ◽  
Nadph Oxidase ◽  
Left Atrial ◽  
Ventricular Hypertrophy ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Collagen Content ◽  
Atrial Fibrosis ◽  
Nadph Oxidase Activity ◽  
Rac1 Gtpase

Patients with atrial fibrillation (AF) are characterized by increased atrial fibrosis. The underlying signal transduction is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to increased fibrosis and atrial fibrillation via activation of NADPH oxidase and production of reactive oxygen species. Methods and Results: Samples of the left atrial appendage were analyzed in 8 patients with AF undergoing mitral valve surgery and 7 patients with sinus rhythm (SR) matched for atrial diameter. Despite same size of the atria, collagen content was significantly higher in AF compared to SR (14.9±2.1% vs. 8.5±1.3%). Expression analysis showed that AF was associated with upregulation of connective tissue growth factor (CTGF). Atria of patients with AF were characterized by significant upregulation of Rac1 total protein expression (Western blot), Rac1 activity (PAK pull-down assays) and a 20-fold upregulation of NADPH oxidase activity compared to SR (2225±500%). In order to test whether Rac1 plays a causal role in the pathogenesis in AF, transgenic mice with cardiac overexpres-sion (αMHC promoter) of Rac1 (RacET) were compared to wildtype (WT) and WT undergoing transaortic constriction (TAC, 360 μm). After 16 months, echocardiography showed similar left ventricular hypertrophy in RacET and TAC. RacET but not TAC exhibited atrial enlargement; 75% of RacET but no WT or TAC showed AF. Interstitial collagen content was significantly increased in the atria of RacET (44±1% of area vs 19±5% in WT). In contrast, interstitial fibrosis in TAC atria did not significantly differ from WT (31±6%). In the left ventricle, both RacET and TAC mice showed an elevated collagen content compared to the control group (WT 9±2%, RacET 29±3%; TAC 24±4%). In all mice, atrial collagen content exceeded ventricular collagen. All effects are significant with p<0.05. Conclusion: Left atria of patients with AF exhibit upregulation of Rac1, increased NADPH oxidase activity and interstitial fibrosis. Cardiac-specific overexpression of Rac1 in mice results atrial fibrosis and fibrillation independent of left ventricular hypertrophy. Rac1-GTPase mediated activation of left atrial NADPH-oxidase may represent a novel target for the prevention of atrial fibrosis.

P5651Association of left atrial fibrosis extent with left ventricular geometric remodeling and diastolic dysfunction in patients with paroxysmal atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Gizatulina ◽  
A V Pavlov ◽  
L U Martyanova ◽  
G V Kolunin ◽  
I V Shorochova ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Diastolic Dysfunction ◽  
Left Atrial ◽  
Low Voltage ◽  
Left Ventricular ◽  
Lv Function ◽  
Atrial Fibrosis ◽  
Concentric Hypertrophy ◽  
Eccentric Hypertrophy ◽  
Left Atrial Fibrosis

Abstract Introduction Whether left atrial fibrosis (LAf) in patients with atrial fibrillation (AF) is a consequence of left ventricular (LV) diastolic dysfunction or primary atrial pathology continues to be a debatable issue. Electroanatomical mapping (EAM) allows to image and to define LAf as a substrate of AF. Purpose To study the relationship of LAf extent with LV diastolic function and geometric remodeling in patients (pts) with paroxysmal AF. Methods 56 pts with paroxysmal AF (mean age 57.1±8.4 years, 31 males), undergone catheter ablation, were enrolled in the study, including 30 pts with arterial hypertension (AH), 15 – with coronary artery disease (CAD) and AH. Comprehensive transthoracic echocardiography was carried out in all pts to assess chamber volumes, systolic and LV diastolic functions and geometry patterns according to Recommendations of ASE and EACVI. Before ablation, EAM was performed in sinus rhythm. The bipolar low voltage areas of LAf were identified with the cut-off <0.5 mV. For the LAf quantification following indicators were calculated: total square of LAf (Sf, cm2) and LAf degree, estimated as an analog of the UTAH staging system, by selection of UTAH I: <5% fibrosis; II: 5–19%; III: 20–35% and IV: >35%. Results All patients had preserved systolic LV function. To assess the influence of LV geometry on LAf extent all pts were distributed in accordance to LV geometry patterns (p): normal geometry (pI) – 27 pts, concentric remodeling (pII) – 13, eccentric hypertrophy (pIII) – 10, concentric hypertrophy (pIV) – 6. Pts with pIII were older than pI pts: 60.8±6.4 vs 53.9±10.4 (p=0.048). All pts with pIII and pIV had AH. From 11 pts without AH, 10 had pI of LV geometry. PIII was revealed more often in CAD pts compared to those without CAD: 29.2 vs 10.5% (p=0.04). PIII pts had bigger LA volume compared to pI pts (74.3±22.5 vs 58.8±19.4 ml, p=0.019) and pII pts (61.9±14.9, p=0.05), but LA volume of pIII pts didn't differ from pIV pts (71.9±14.5, p=0.78). PIII pts had more extent Sf than pI pts (28.32±8.9 vs 13.4±6.5, p=0.05), while Sf of pII (17.3±8.7, p=0.495) and pIV pts (16.4±9.5, p=0.699) didn't differ significantly from Sf of pI pts. As for the degree of LAf, UTAH I was absent in pts with pIII and UTAH IV was revealed in 40% of these pts, while in pts with pI UTAH I was in 26% and UTAH IV - in 14.8% (p=0.049). However, Sf and UTAH degree did not depend on age, CAD and heart failure presence. As for diastolic dysfunction, in pIII and pIV pts e∼septal and e∼lateral were lower compared to pI pts: 6.3±1.9, 5.5±2.4 vs 8.5±2.2 (p<0.01) and 8.2±2.7, 8.0±3.8 vs 11.3±2.9 (p<0.01), respectively, while E/e∼ in pIII pts didn't differ from pI pts (8.0±1.6 vs 7.2±1.6, p=0.17), but in pIV was more than in pI pts (10.4±2.8, p=0.003). Conclusion LAf extent in paroxysmal AF is associated more with such LV geometry pattern as eccentric hypertrophy, than with diastolic disorders, which accompany both eccentric and concentric hypertrophy.

Abstract 3492: Increased Late I Na in Left Atrial Myocytes of Left Ventricular Hypertrophy Rabbits and its Role in Genesis of Atrial Early Afterdepolarizations

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Donglin Guo ◽  
Zhen Jiao ◽  
Binu Malhottra ◽  
Chinmay Patel ◽  
Peter R Kowey ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Left Ventricular Hypertrophy ◽  
Left Atrial ◽  
Ventricular Hypertrophy ◽  
Heart Association ◽  
Elevated Pressure ◽  
Left Ventricular ◽  
Early Afterdepolarizations ◽  
Body Mass Ratio ◽  
Funding Support

Atrial fibrillation is the most common sustained arrhythmia affecting more than 2 million people annually in USA. Previous studies have shown that left ventricular hypertrophy (LVH) results in an increase in the late I Na that plays an important role in genesis of ventricular arrhythmias. We tested the hypothesis that LVH, which is associated with elevated pressure in the left atrium, could enhance the late I Na in left atrial (LA) myocytes, leading to increased trigger activities. Rabbit LVH, which exhibited a significantly greater left ventricle to body mass ratio, was induced using the renovascular hypertension model. Interestingly, early afterdepolarizations (EADs) at action potential phase 2 and 3 occurred in 6 of 10 LA myocytes isolated from 5 LVH rabbits at a pacing cycle length of 2000 ms, whereas EADs were elicited in none of 10 cells isolated from 5 control rabbits ( p <0.01). Spontaneously activities (SA) were observed in 6 of 10 LA myocytes from five LVH rabbits at the pacing rate of 8000 ms. The density of the late I Na was significantly larger in LA myocytes of LVH rabbits than that recorded in control rabbits (0.59±0.02 pA/pF in LVH versus 0.42±0.05 pA/pF in control, n=6, p <0.01). Ranolazine, a late I Na blocker, exerted a concentration-dependent blocking effect on the late I Na in LA myocytes of the rabbits (IC 50 =15.7±0.6 μM) and abolished all of atrial EADs and SA of the LVH rabbits at 30 μM. Our results demonstrate that LVH results in a significant increase in the late I Na in the LA myocytes that may render these cells susceptible to genesis of EADs. The late I Na is a potentially useful ionic target by antiarrhythmic drugs for the treatment of atrial fibrillation in the setting of LVH. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Atrial fibrillation is not associated with altered left atrial microRNA expression profile in ischemic end-stage human heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
B Agg ◽  
A.A Sayour ◽  
S.Z Kugler ◽  
P Perge ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Mrna Expression ◽  
Mirna Expression ◽  
Left Atrial ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Funding Source ◽  
Human Heart Failure ◽  
End Stage

Abstract Introduction In patients with chronic heart failure (CHF) left ventricular dysfunction results in elevated left atrial (LA) pressure, triggering pathological atrial remodelling and atrial fibrillation (AF). Nevertheless, it has been reported that some patients with CHF remain in sinus rhythm (SR) despite of the pathological structural alterations (e.g. dilation and fibrosis) of the LA. Of particular interest, data is scarce regarding the molecular explanation for the observed variability in AF development among CHF patients. Recent studies have indicated that alterations in microRNA (miRNA) expression might contribute to the pathogenesis of AF. However, the majority of previous studies focusing on miRNA expression compared healthy LA with SR to pathologically remodelled, dilated LA with AF. Consequently, whether dysregulation of miRNA expression directly contribute to AF and not only to pathological LA remodelling has not been tested before. Purpose The present study aimed to investigate miRNA expression in comparably remodelled LA from end-stage CHF patients with permanent AF (CHF-AF) or SR (CHF-SR). Methods LA samples were collected from male, non-diabetic, ischemic end-stage CHF patients undergoing heart transplantation (n=24). Patients were carefully selected to avoid any differences in age (55±2 vs. 54±2 years, CHF-AF vs. CHF-SR, n.s.), ejection fraction ([EF]: 22.5±1.8 vs. 23.3±2.5%, CHF-AF vs. CHF-SR, n.s.) LA diameters (longitudinal LA diameter: 56±4 vs. 48±5mm.; CHF-AF vs. CHF-SR, n.s.; horizontal LA diameter: 61±2 vs. 54±3, CHF-AF vs. CHF-SR, n.s.) and NYHA stage. As a molecular marker of atrial load, the mRNA expression of atrial natriuretic peptide (ANP) was measured with qRT-PCR. The extent of left atrial fibrosis was assessed on picrosirius red stained histological sections. Global LA miRNA expression profiling (including the measurement of 800 human miRNA) was carried out using a commercially available kit. Results LA mRNA expression of ANP was comparable between the AF-CHF and the SR-CHF groups, suggesting that atrial load occurred to the same level in the two experimental groups. Furthermore, no differences could be observed in the extent of atrial collagen content between the AF-CHF and the SR-CHF groups (collagen area: 20.3±1.3% vs. 23.9±3.1%, n.s.), providing evidence that fibrotic remodelling had occurred to a similar magnitude. The high-throughput miRNA measurement revealed no differences in atrial miRNA expression between the two study groups. Conclusion The present study provides evidence for the first time that AF is not associated with different LA miRNA expression in end-stage CHF patients with comparable level of LA dilatation, ANP expression (atrial load) and interstitial fibrosis. Based on these findings, the potential of miRNA-based therapeutic interventions might be limited in AF patients with ischemic end-stage CHF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Left atrial fibrosis predicts left ventricular ejection fraction response after atrial fibrillation ablation in heart failure patients: the Fibrosis-HF Study

EP Europace ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. 1812-1821
Author(s):  
Bettina Kirstein ◽  
Sebastian Neudeck ◽  
Thomas Gaspar ◽  
Judith Piorkowski ◽  
Simon Wechselberger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ejection Fraction ◽  
Left Atrial ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Atrial Fibrosis ◽  
Ventricular Ejection Fraction ◽  
Af Ablation ◽  
Left Atrial Fibrosis

Abstract Aims Atrial fibrillation (AF) and heart failure (HF) often coexist. Catheter ablation has been reported to restore left ventricular (LV) function but patients benefit differently. This study investigated the correlation between left atrial (LA) fibrosis extent and LV ejection fraction (LVEF) recovery after AF ablation. Methods and results In this study, 103 patients [64 years, 69% men, 79% persistent AF, LVEF 33% interquartile range (IQR) (25–38)] undergoing first time AF ablation were investigated. Identification of LA fibrosis and selection of ablation strategy were based on sinus rhythm voltage mapping. Continuous rhythm monitoring was used to assess ablation success. Improvement in post-ablation LVEF was measured as primary study endpoint. An absolute increase in post-ablation LVEF ≥10% was defined as ‘Super Response’. Left atrial fibrosis was present in 38% of patients. After ablation LVEF increased by absolute 15% (IQR 6–25) (P &lt; 0.001). Left ventricular ejection fraction improvement was higher in patients without LA fibrosis [15% (IQR 10–25) vs. 10% (IQR 0–20), P &lt; 0.001]. An inverse correlation between LVEF improvement and the extent of LA fibrosis was found (R2 = 0.931). In multivariate analysis, the presence of LA fibrosis was the only independent predictor for failing LVEF improvement [odds ratio 7.2 (95% confidence interval 2.2–23.4), P &lt; 0.001]. Echocardiographic ‘Super Response’ was observed in 55/64 (86%) patients without and 21/39 (54%) patients with LA fibrosis, respectively (P &lt; 0.001). Conclusion Presence and extent of LA fibrosis predict LVEF response in HF patients undergoing AF ablation. The assessment of LA fibrosis may impact prognostic stratification and clinical management in HF patients with AF.

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