Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22–5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication

MicroRNAs (miRNAs) participate in atrial remodeling and atrial fibrillation (AF) promotion. We determined the circulating miRNA profile in patients with AF and heart failure with reduced ejection fraction (HFrEF), and its potential role in promoting the arrhythmia. In plasma of 98 patients with HFrEF (49 with AF and 49 in sinus rhythm, SR), differential miRNA expression was determined by high-throughput microarray analysis followed by replication of selected candidates. Validated miRNAs were determined in human atrial samples, and potential arrhythmogenic mechanisms studied in HL-1 cells. Circulating miR-199a-5p and miR-22-5p were significantly increased in HFrEF patients with AF versus those with HFrEF in SR. Both miRNAs, but particularly miR-199a-5p, were increased in atrial samples of patients with AF. Overexpression of both miRNAs in HL-1 cells resulted in decreased protein levels of L-type Ca2+ channel, NCX and connexin-40, leading to lower basal intracellular Ca2+ levels, fewer inward currents, a moderate reduction in Ca2+ buffering post-caffeine exposure, and a deficient cell-to-cell communication. In conclusion, circulating miR-199a-5p and miR-22-5p are higher in HFrEF patients with AF, with similar findings in human atrial samples of AF patients. Cells exposed to both miRNAs exhibited altered Ca2+ handling and defective cell-to-cell communication, both findings being potential arrhythmogenic mechanisms.

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Abstract 16642: Distinctive Characteristics of Left Atrial Remodeling in Heart Failure With Preserved or Reduced Ejection Faction

Circulation ◽

10.1161/circ.130.suppl_2.16642 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Vojtech Melenovsky ◽

Rosita Zakeri ◽

Margaret M Redfield ◽

Barry A Borlaug

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Left Atrial ◽

Contractile Function ◽

Right Heart Catheterization ◽

Heart Catheterization ◽

Atrial Remodeling ◽

Reduced Ejection Fraction ◽

V Wave

Introduction: Left atrial structure and function (LA) is affected by the presence of heart failure (HF), but the specific impact of HF subtype is poorly characterized. Hypothesis: HF-induced LA remodeling differs between patients with preserved (pEF) or reduced ejection fraction (rEF). Methods: 198 consecutive HF patients referred to Mayo Clinic (51% HFpEF, NYHA 3.1±0.7, 66±13 years, 39% females) and 40 HF-free controls of similar age and gender underwent right heart catheterization (LA pressures), echocardiography (LA volumes) and follow-up. Results: Compared with controls, HF patients had larger atria and more impaired LA reservoir and contractile function (total and active LAEF, all p<0.001). At identical mean LA pressure (20 vs 20 mmHg, p=0.9), HFrEF patients had larger LA volumes (LAVI 50 vs 41 ml/m 2 p<0.001), but HFpEF patients had higher LA peak (V-wave) and lower LA minimal pressures, with higher LA stiffness (0.79 vs 0.48 mmHg.ml -1 , p<0.001, Fig-A) and LA pressure pulsatility (19 vs 13 mmHg, p<0.001). Despite smaller LA size, better LA function (total LAEF 39 vs 35 %, p=0.04, active LAEF 30 vs 22 %, p<0.001) and less mitral regurgitation (grade 1.8 vs 2.5, p<0.001), HFpEF patients had more atrial fibrillation (42 vs 26%, p=0.02). After a median follow-up 350 days, 31 HFpEF and 28 HFrEF patients died. LA function was associated with mortality in HFpEF, but not in HFrEF (Fig-B). Conclusions: HFrEF is characterized by greater eccentric LA remodeling, but HFpEF is associated with increased LA stiffening and greater LA pressure pulsatility which may contribute to greater burden of atrial fibrillation. The observation that LA function is more closely linked to outcome in HFpEF supports the goal to maintain or improve LA function in HFpEF.

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B-PO03-114 ATRIAL FIBRILLATION AND HEART FAILURE WITH PRESERVED VERSUS REDUCED EJECTION FRACTION: OUTCOMES AFTER CATHETER ABLATION

Heart Rhythm ◽

10.1016/j.hrthm.2021.06.588 ◽

2021 ◽

Vol 18 (8) ◽

pp. S235

Author(s):

Amrita Krishnamurthy ◽

Parag Goyal ◽

Steven M. Markowitz ◽

Christopher F. Liu ◽

George Thomas ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Catheter Ablation ◽

Ejection Fraction ◽

Reduced Ejection Fraction

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Serial echocardiographical assessment for urgent control of rapid atrial fibrillation in acute heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.1213 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

N Iwahashi ◽

J Kirigaya ◽

M Horii ◽

Y Hanajima ◽

T Abe ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Confidence Interval ◽

Odds Ratio ◽

Acute Decompensated Heart Failure ◽

Decompensated Heart Failure ◽

Right Heart Catheterization ◽

Heart Catheterization ◽

Reduced Ejection Fraction ◽

Initial Hospitalization

Abstract Objectives Doppler echocardiography is a well-recognized technique for noninvasive evaluation; however, little is known about its efficacy in patients with rapid atrial fibrillation (AF) accompanied by acute decompensated heart failure (ADHF). The aim of this study was to explore the usefulness of serial echocardiographical assessment for rapid AF patients with ADHF. Patients A total of 110 ADHF patients with reduced ejection fraction (HFrEF) and rapid AF who were admitted to the CCU unit and received landiolol treatmentto decrease the heart rate (HR) to <110 bpm and change HR (ΔHR) of >20% within 24 hours were enrolled. Interventions Immediately after admission, the patients (n=110) received landiolol, and its dose was increased to the maximum; then, we repeatedly performed echocardiography. Among them, 39 patients were monitored using invasive right heart catheterization (RHC) simultaneously with echocardiography. Measurements and main results There were significant relationships between Doppler and RHC parameters through the landiolol treatment (Figure, baseline–max HR treatment). We observed for the major adverse events (MAE) during initial hospitalization, which included cardiac death, HF prolongation (required intravenous treatment at 30 days), and worsening renal function (WRF). MAE occurred in 44 patients, and logistic regression analyses showed that the mean left atrial pressure (mLAP)-Doppler (odds ratio = 1.132, 95% confidence interval [CI]: 1.05–1.23, p=0.0004) and stroke volume (SV)-Doppler (odds ratio = 0.93, 95% confidence interval [CI]: 0.89–0.97, p=0.001) at 24 hours were the significant predictors for MAE, and multivariate analysis showed that mLAP-Doppler was the strongest predictor (odds ratio = 1.16, 95% CI: 0.107–1.27, p=0.0005) (Table). Conclusions During the control of the rapid AF in HFrEF patients withADHF, echocardiography was useful to assess their hemodynamic condition, even at bedside. Doppler for rapid AF of ADHF Funding Acknowledgement Type of funding source: None

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TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00614.2014 ◽

2015 ◽

Vol 308 (2) ◽

pp. H126-H134 ◽

Cited By ~ 15

Author(s):

Erin Harleton ◽

Alessandra Besana ◽

Parag Chandra ◽

Peter Danilo ◽

Tove S. Rosen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Normal Sinus Rhythm ◽

Human Subjects ◽

Phosphorylation Site ◽

Chronic Atrial Fibrillation ◽

Resting Membrane Potential ◽

Atrial Remodeling ◽

Protein Levels ◽

Atrial Tissue ◽

Normal Sinus

Atrial fibrillation (AF) is a common arrhythmia with significant morbidities and only partially adequate therapeutic options. AF is associated with atrial remodeling processes, including changes in the expression and function of ion channels and signaling pathways. TWIK protein-related acid-sensitive K+ channel (TASK)-1, a two-pore domain K+ channel, has been shown to contribute to action potential repolarization as well as to the maintenance of resting membrane potential in isolated myocytes, and TASK-1 inhibition has been associated with the induction of perioperative AF. However, the role of TASK-1 in chronic AF is unknown. The present study investigated the function, expression, and phosphorylation of TASK-1 in chronic AF in atrial tissue from chronically paced canines and in human subjects. TASK-1 current was present in atrial myocytes isolated from human and canine hearts in normal sinus rhythm but was absent in myocytes from humans with AF and in canines after the induction of AF by chronic tachypacing. The addition of phosphatase to the patch pipette rescued TASK-1 current from myocytes isolated from AF hearts, indicating that the change in current is phosphorylation dependent. Western blot analysis showed that total TASK-1 protein levels either did not change or increased slightly in AF, despite the absence of current. In studies of perioperative AF, we have shown that phosphorylation of TASK-1 at Thr383 inhibits the channel. However, phosphorylation at this site was unchanged in atrial tissue from humans with AF or in canines with chronic pacing-induced AF. We conclude that phosphorylation-dependent inhibition of TASK-1 is associated with AF, but the phosphorylation site responsible for this inhibition remains to be identified.

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Atrial fibrillation ablation in heart failure with reduced ejection fraction

10.37532/fmic.2019.11(6).637 ◽

2019 ◽

Vol 11 (6) ◽

Author(s):

Yan-Rong Liu ◽

Dian-Fu Li

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Ejection Fraction ◽

Atrial Fibrillation Ablation ◽

Reduced Ejection Fraction

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Prognostic value of atrial fibrillation in patients with heart failure and different left ventricular ejection fraction: results of the multicenter RIF-CHF register

Russian Journal of Cardiology ◽

10.15829/1560-4071-2021-4200 ◽

2021 ◽

Vol 26 (1) ◽

pp. 4200

Author(s):

I. V. Zhirov ◽

N. V. Safronova ◽

Yu. F. Osmolovskaya ◽

S. N. Тereschenko

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Ejection Fraction ◽

Cardiovascular Mortality ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Reduced Ejection Fraction ◽

Number Of Patients ◽

Increased Risk

Heart failure (HF) and atrial fibrillation (AF) are the most common cardiovascular conditions in clinical practice and frequently coexist. The number of patients with HF and AF is increasing every year.Aim. To analyze the effect of clinical course and management of HF and AF on the outcomes.Material and methods. The data of 1,003 patients from the first Russian register of patients with HF and AF (RIF-CHF) were analyzed. The endpoints included hospitalization due to decompensated HF, cardiovascular mortality, thromboembolic events, and major bleeding. Predictors of unfavorable outcomes were analyzed separately for patients with HF with preserved ejection fraction (AF+HFpEF), mid-range ejection fraction (AF+HFmrEF), and reduced ejection fraction (AF+HFrEF).Results. Among all patients with HF, 39% had HFpEF, 15% — HFmrEF, and 46% — HFrEF. A total of 57,2% of patients were rehospitalized due to decompensated HF within one year. Hospitalization risk was the highest for HFmrEF patients (66%, p=0,017). Reduced ejection fraction was associated with the increased risk of cardiovascular mortality (15,5% vs 5,4% in other groups, p<0,001) but not ischemic stroke (2,4% vs 3%, p=0,776). Patients with HFpEF had lower risk to achieve the composite endpoint (stroke+MI+cardiovascular death) as compared to patients with HFmrEF and HFrEF (12,7% vs 22% and 25,5%, p<0,001). Regression logistic analysis revealed that factors such as demographic characteristics, disease severity, and selected therapy had different effects on the risk of unfavorable outcomes depending on ejection fraction group.Conclusion. Each group of patients with different ejection fractions is characterized by its own pattern of factors associated with unfavorable outcomes. The demographic and clinical characteristics of patients with mid-range ejection fraction demonstrate that these patients need to be studied as a separate cohort.

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Predictors for early mortality in patients with implantable cardiac defibrillator for heart failure with reduced ejection fraction

EP Europace ◽

10.1093/europace/euab116.422 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

G Cinier ◽

MI Hayiroglu ◽

L Pay ◽

AC Yumurtas ◽

O Tezen ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Multivariate Analysis ◽

Ejection Fraction ◽

Blood Urea Nitrogen ◽

Cox Regression ◽

Nyha Class ◽

Urea Nitrogen ◽

Reduced Ejection Fraction ◽

Device Implantation

Abstract Funding Acknowledgements Type of funding sources: None. Background Implantable cardiac defibrillators (ICD) are recommended in heart failure with reduced ejection fraction (HFrEF) patients to reduce arrhythmic deaths. The only contraindication for not implanting ICD is life expectancy of less than 1 year. We aimed to identify risk factors associated with mortality within 1 year following the device implantation. Methods Data from our hospital’s electronic database system was extracted for patients who were implanted ICD secondary to HFrEF between 2009 and 2019. Those who died within 1 year following the device implantation were analyzed in the present paper. Multiple Cox regression analysis using the backward logistical regression method was applied to determine the best predictors that affect 1-year mortality Results Overall 1107 patients were included in the present analysis. ICD was implanted in 77.2% and 22.8% for ischemic and non-ischemic HFrEF respectively. Mortality rate at 1-year following the device implantation was 4.7%. In multivariate analysis age [Hazard ratio (HR), 1.04; Confidence 95% Intervals (CI), 1.02 – 1.06; P = 0.001], atrial fibrillation (AF) (HR, 4.12; 95% CI, 2.34 – 7.24, P < 0.001), NYHA class > 2 symptoms (HR, 5.33; 95% CI, 2.92 – 9.73, P < 0.001), blood urea nitrogen (BUN) (HR, 1.02; 95% CI, 1.00 – 1.03, P = 0.03) and albumin (HR, 0.52; 95% CI, 0.34 – 0.80, P = 0.003) independently predicted 1-year mortality Conclusion In patients with HFrEF and implanted ICD, older age, presence of AF and NYHA class > II symptoms, elevated BUN and reduced albumin levels predicted 1-year mortality. Table 1 Multivariate analysis P value HR (95% CI) Age 0.001 1.038 (1.015 - 1.062) Atrial fibrillation <0.001 4.119 (2.342 - 7.241) NYHA > 2 <0.001 5.328 (2.917 - 9.731) Blood urea nitrogen 0.034 1.017 (1.001- 1.034) Albumin 0.003 0.520 (0.337 - 0.801) Multivariate Cox regression analyses for 1-year mortality after implantation

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Abstract 284: Disruption of Nrf2 Promotes Atrial Remodeling and Fibrillation on Aging

Circulation Research ◽

10.1161/res.113.suppl_1.a284 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Naser Abu-Rmaileh ◽

Sankaranarayanan Kannan ◽

Kensuke Tsushima ◽

Kevin Whitehead ◽

E Dale Abel ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Atrial Fibrillation ◽

Ventricular Dysfunction ◽

The United States ◽

Exercise Stress ◽

Ros Generation ◽

Atrial Remodeling ◽

Fibrotic Process ◽

Mouse Atrium

Background: Heart failure is a leading health problem with over 500,000 new cases and 275,000 deaths annually in the United States. Recent reports indicate that atrial fibrillation (AF) is linked to various forms of ventricular dysfunction (VD). Over 2 million Americans have AF, which is more prevalent in people over 65 years of age. However, the molecular “cause and effect” relationship between AF and VD has not been elucidated. We hypothesize that abrogation of nuclear erythroid-2 like factor-2 (Nrf2), a master antioxidant transcriptional regulator, induces atrial remodeling and fibrillation on aging. Methods: Age and sex matched WT and Nrf2-/- mice were used in this study. Atrial mass, remodeling, antioxidants and molecular redox signaling were studied at 2 and >20 months of age. Echocardiography, immunoblotting, quantitative real-time PCR and immunofluorescence (fibrosis) analyses were performed in the atrial tissue. Results: At 2 months of age, WT and Nrf2-/- mice had comparable levels of ROS in the atrium. On aging, the ROS levels were significantly increased in atria of Nrf2- null when compared to wild-type (WT) mice at 20 months of age. While decreased Nrf2-antioxidant signaling in response to increased ROS generation in atria of Nrf2- null mice was observed, ventricular function appeared to be normal at 20 months of age. However, upon endurance exercise stress (EES), hypertrophy markers including ANF, BNF, PLN and SERCA2A were significantly (p<0.05) altered in Nrf2- null when compared to age-matched WT mice. Further, activation of fibrotic process was evident in the Nrf2- null mouse atrium as indicated by significantly (p<0.05) increased markers of tissue remodeling (i.e. MMP2/9) on aging. These results indicating an early onset of atrial hypertrophy/remodeling due to age-induced oxidative stress, which cause AF in Nrf2- null mice. Age-dependent decline in Nrf2 and sustained progression of AF could lead to ventricular dysfunction and heart failure. Conclusion: Our findings indicate that atria are primary targets to age-associated oxidative stress and exhibit fibrosis, which promotes atrial fibrillation and remodeling. Thus, activation of Nrf2 signaling to prevent oxidative stress could be a potential therapeutic target for AF.

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Abstract 1236: A Molecular and Functional Basis for Focal Arrhythmogenesis in Heart Failure-associated Atrial Fibrillation

Circulation ◽

10.1161/circ.116.suppl_16.ii_251-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Yung-Hsin Yeh ◽

Reza Wakili ◽

Xiao Yan Qi ◽

Denis Chartier ◽

Stefan Kääb ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Protein Expression ◽

Action Potentials ◽

Molecular Mechanisms ◽

Potential Role ◽

Regulatory Proteins ◽

Related Protein ◽

Triggered Activity ◽

Delayed Afterdepolarizations

Introduction: Heart failure (HF) frequently causes atrial fibrillation (AF) and focal sources of unknown mechanism have been implicated. Here, we studied the potential role and molecular mechanisms of Ca 2+ handling abnormalities. Methods: Ca 2+ handling (microfluorescence, Indo-1 AM) and related protein expression (Western blot) were assessed in left atria of 20 dogs with ventricular tachypacing (240 bpm × 2 wks)-induced HF and 20 controls (CTLs). Whole-cell perforated-patch was used to record action potentials (APs), delayed afterdepolarizations (DADs) and triggered activity. Results : HF increased [Ca 2+ ] i transient amplitude from 239±24 to 444±43* nM (*P<0.05), and [Ca 2+ ] i release by 10 mM local caffeine puffs (an index of SR Ca 2+ content) from 849±71 (CTL) to 1574±169* nM (HF). Spontaneous Ca 2+ release events increased from 1.8±0.5 (CTL) to 10.7±2.1* events/run (HF). HF significantly increased APD (by ~40% at 1 Hz). DADs and triggered activity were more common in HF (15.2±2.6 triggered APs/run, vs CTL 0.4±0.2*), and were abolished by ryanodine (10 μM), but not by the I f -blocker Cs + (2 mM). HF caused profound changes in protein expression of key Ca 2+ handling and regulatory proteins (Table ). Calsequestrin, the major SR Ca 2+ -binding protein, was reduced by 32%*. Fractional RYR2 PKA (Ser2809) phosphorylation decreased by 63%*, whereas CaMKII (Ser2815) RYR2 phosphorylation increased by 221%*. The catalytic and regulatory (RII) PKA subunits were downregulated by 15%* and 73%*, whereas expression and autophosphorylation (Thr287) of CaMKIIδ were increased by 45%* and 81%* respectively. NCX1, SERCA and total, PKA and CaMKII phosphorylated SERCA-regulatory phospholamban were unchanged by HF. Conclusions: HF causes profound changes in regulation and expression of atrial Ca 2+ handling proteins, producing increased SR Ca 2+ load and release, along with DADs and triggered activity that may account for focal mechanisms that initiate and/or sustain HF-related AF.

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