Left atrial size and function as predictors of new-onset of atrial fibrillation in patients with asymptomatic aortic stenosis: The simvastatin and ezetimibe in aortic stenosis study

doi:10.1016/j.ijcard.2013.01.060

International Journal of Cardiology

Volume 168, Issue 3, 3 October 2013, Pages 2322-2327

https://doi.org/10.1016/j.ijcard.2013.01.060 Get rights and content

Abstract

Background

Left atrial (LA) size and function change with chronically increased left ventricular (LV) filling pressures. It remains unclear whether these variations in LA parameters can predict new-onset atrial fibrillation (AF) in asymptomatic patients with aortic stenosis (AS).

Methods

Data were obtained in asymptomatic patients with mild-to-moderate AS (2.5 ≤ transaortic Doppler velocity ≤ 4.0 m/s), preserved LV ejection fraction (EF), no previous AF, and were enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. Peak-aortic velocity, LA_max volume & LA_min volume were measured by echocardiography. LA conduit (LA_con) volume was defined as LV stroke volume − LA stroke volume. LA function was expressed as LA-EF (LA_max − LA_min volume/LA_max).

Results

In the 1159 patients included, new-onset AF occurred in 71 patients (6.1%) within a mean follow-up of 4.2 ± 0.9 years. Mean age was 66 ± 9.7 years, aortic valve area index 0.6 ± 0.2 cm²/m², LV mass 99.2 ± 29.7 g/m², LA_max volume 34.6 ± 12.0 mL/m², LA_min volume 17.9 ± 9.3 mL/m², LA-EF 50 ± 15% and LA_con volume 45 ± 21 mL/m². Baseline LA_min volume predicted new-onset AF in Cox multivariable analysis (HR:2.3 [95%CI:1.3–4.4], P < 0.01), and added prognostic information on AF development beyond conventional risk factors (likelihood ratio, P < 0.01). In comparison of c-indexes LA_min volume was superior to all other LA measurements. Net reclassification index improved by 15.9% when adding LA_min volume to a model with classic risk factors for AF (P = 0.01).

Conclusion

LA_min volume independently predicted new-onset AF in patients with asymptomatic AS and was superior to LA-EF, LA_con and LA_max volumes and conventional risk factors.

Introduction

Aortic stenosis (AS) is a slowly progressing disease, which in its later stages induces structural changes of left ventricle (LV) to adapt to the increased afterload. Such changes, include compensatory LV hypertrophy to adapt to an increased LV filling pressure and maintain a normal stroke volume [1]. Left atrial (LA) contractions might therefore be increasingly important for maintaining hemodynamic homeostasis as AS progresses. In turn, this may partly explain the clinical deterioration often seen when atrial fibrillation (AF) occurs. The onset of symptoms marks a dramatic worsening of prognosis [1], which corresponds to the increase in cardiovascular morbidity and mortality seen in AS patients developing AF [2], [3], [4].

The chronically elevated afterload associated with AS also affects LA size and function [5], [6], [7]. Previous studies have demonstrated that atrial fibrosis is connected to atrial enlargement, and that both are correlated to LA function and development of AF [6], [8], [9], [10]. Moreover, LA size and function measured by two-dimensional (2D) echocardiography have showed to be an effortless and non-invasive method with good reproducibility and low interobserver bias [9], [11], [12], [13], [14].

The purpose of this study was therefore to evaluate if measurements of LA size and function could predict new-onset AF in asymptomatic patients with mild-to-moderate AS.

Section snippets

Methods

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

All data originate from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, a randomized, multicenter, double-blind, placebo-controlled study investigating whether intensive lipid lowering with simvastatin plus ezetimibe versus placebo in 1873 patients (45 to 85 years of age) with asymptomatic AS could decrease the need for aortic valve

Baseline characteristics

Mean age was 66 ± 9.7 years, aortic valve area index 0.6 ± 0.2 cm²/m², LV mass 99.2 ± 29.7 g/m², LVEF 66 ± 8%, LA_max volume 34.6 ± 12.0 mL/m², LA_min volume 17.9 ± 9.3 mL/m², LAEF 50 ± 15% and LA_con volume was 45 ± 21 mL/m². Patients were divided into tertiles of LA_min volume indexed by body surface area. Compared with the lower tertile patients, those with LA_min volume in the upper tertile were older, had higher systolic blood pressure, body mass index, high sensitive C-reactive protein, LV mass index, LA_min and LA

Discussion

This prospective study of patients with asymptomatic mild to moderate AS has three new observations. First, LA_min and LA_max volumes were both independently predictive of the new-onset AF. Second, LA_min volume was superior to LA_max volume in predicting new-onset AF. Finally, LA_min volume added prognostic information beyond significant conventional factors when using c-statistics.

Acknowledgements

We thank the SEAS study investigators previously mentioned [15].

References (38)

P.A. Pellikka et al.
The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis
J Am Coll Cardiol
(1990)
A.M. Greve et al.
Prognostic importance of atrial fibrillation in asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study
Int J Cardiol
(Jun 5 2013)
C.N. Bang et al.
Effect of lipid lowering on new-onset atrial fibrillation in patients with asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study
Am Heart J
(2012)
D.L. Ngaage et al.
Prognostic implications of preoperative atrial fibrillation in patients undergoing aortic valve replacement: is there an argument for concomitant arrhythmia surgery?
Ann Thorac Surg
(2006)
G. Cioffi et al.
Comparison of left ventricular geometry and left atrial size and function in patients with aortic stenosis versus those with pure aortic regurgitation
Am J Cardiol
(2002)
W.J. Manning et al.
Atrial ejection force: a noninvasive assessment of atrial systolic function
J Am Coll Cardiol
(1993)
C. Boixel et al.
Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat
J Am Coll Cardiol
(2003)
W.P. Abhayaratna et al.
Left atrial size: physiologic determinants and clinical applications
J Am Coll Cardiol
(2006)
R.B. Himelman et al.
Reproducibility of quantitative two-dimensional echocardiography
Am Heart J
(1988)
B. Kircher et al.
Left atrial volume determination by biplane two-dimensional echocardiography: validation by cine computed tomography
Am Heart J
(1991)

R.M. Lang et al.

Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology

J Am Soc Echocardiogr

(2005)

A.B. Rossebo et al.

Design and baseline characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study

Am J Cardiol

(2007)

A.M. Greve et al.

Differences in cardiovascular risk profile between electrocardiographic hypertrophy versus strain in asymptomatic patients with aortic stenosis (from SEAS data)

Am J Cardiol

(2011)

D. Cramariuc et al.

Low-flow aortic stenosis in asymptomatic patients: valvular-arterial impedance and systolic function from the SEAS substudy

JACC Cardiovasc Imaging

(2009)

R.B. Devereux et al.

Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings

Am J Cardiol

(1986)

R.B. Devereux et al.

Comparison of enalapril versus nifedipine to decrease left ventricular hypertrophy in systemic hypertension (the PRESERVE trial)

Am J Cardiol

(1996)

M.D. Cheitlin et al.

ACC/AHA/ASE 2003 Guideline Update for the Clinical Application of Echocardiography: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography)

J Am Soc Echocardiogr

(2003)

R.B. Schnabel et al.

Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study

Lancet

(2009)

X. Zhang et al.

SAS macros for estimation of direct adjusted cumulative incidence curves under proportional subdistribution hazards models

Comput Methods Programs Biomed

(2011)

Cited by (33)

Prediction scores for new onset atrial fibrillation in patients with acute coronary syndrome undergoing percutaneous coronary intervention: Two sides of the same coin
2023, International Journal of Cardiology
Differences in Clinical and Echocardiographic Profiles and Outcomes of Patients With Atrial Fibrillation Versus Sinus Rhythm in Medically Managed Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction
2020, Heart Lung and Circulation
Atrial fibrillation (AF) results in the loss of atrial booster pump function and portends poorer outcome in aortic valve stenosis (AS). However, its characteristics and impact on medically managed AS remained under-recognised. We compared these patients with AF to sinus rhythm (SR).
In total, 347 consecutive patients with medically managed severe AS (aortic valve area <1 cm²) and preserved left ventricular ejection fraction (>50%) were studied, in terms of echocardiographic characteristics and clinical outcomes. Appropriate univariate and multivariate models were used, while Kaplan–Meier curves and Cox regression models were constructed to compare clinical outcomes (mortality, admissions for congestive cardiac failure, and stroke).
Ninety (90) (25.9%) patients had AF. Patients with AF had lower body mass index (BMI 18.5±10.4 vs 23.8±6.2 g/m²; p<0.001), larger left ventricular mass index (LVMI 127.9±39.0 vs 116.7±36.5; p=0.017), and left atrial volume index (53.2±20.0 vs 31.0±9.2 mL/m²; p=0.004). Atrial fibrillation was associated with higher mortality (52.2% vs 37.4%; Kaplan-Meier log-rank 7.18; p=0.007), admissions for congestive cardiac failure (log-rank 6.42; p=0.011), and poorer composite outcomes (log-rank 6.29; p=0.012). The incidence of stroke in both groups were similar on follow-up (log-rank 0.08; p=0.776). After adjusting for age, BMI, LVMI, and left atrial volume index on Cox regression, AF remained independently associated with poorer composite clinical outcomes (hazard ratio, 1.66; 95% confidence interval 1.07–2.58).
Atrial fibrillation remained an important comorbidity affecting a quarter of patients with medically managed severe AS. It was independently associated with poorer clinical outcomes and may thus aid in prognostication and management.
Relationship Between Left Atrial Functional Measures and Incident Atrial Fibrillation in the General Population: The Copenhagen City Heart Study
2019, JACC: Cardiovascular Imaging
Citation Excerpt :
Unfortunately, the authors did not report the prognostic ability of LAVmin. However, imaging studies in patients with myocardial infarction (16), aortic valve stenosis (17), and cryptogenic stroke (4) have made similar findings to ours, and increasing evidence suggests that a large proportion of patients who develop AF do not have an enlarged LA by the LAVmax (18). Findings from the ENGAGE-AF TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis In Myocardial Infarction 48) trial (16) actually suggest that more than one-third of AF patients do not have enlarged LA, and for paroxysmal AF, this proportion is even higher (52%).
This study sought to investigate whether left atrial (LA) functional measures predict atrial fibrillation (AF) in the general population.
Increasing evidence suggests LA functional measures are predictors of AF in several patient groups.
In a community-based cohort study, approximately 2,000 individuals underwent a transthoracic echocardiogram. Conventional echocardiographic measures and extended LA measures, including the minimal and maximal LA volumes (LAV_min and LAV_max, respectively) and left atrial emptying fraction (LAEF), were performed. The endpoint was incident AF, and participants with known AF were excluded, which left 1,951 for inclusion.
Over 11.0 years of follow-up, 184 (9.4%) developed AF. Those who developed AF had significantly larger LA volumes and lower LAEF than participants free of AF. These LA measures were univariable predictors of AF (LAV_max hazard ratio [HR]: 1.10 [95% confidence interval (CI): 1.08 to 1.12] per 1-ml increase, p < 0.001; LAV_min HR: 1.14 [95% CI: 1.12 to 1.16] per 1-ml increase, p < 0.001; LAEF HR: 1.03 [95% CI: 1.02 to 1.04] per percent decrease, p < 0.001). All LA measures remained predictors independent of clinical risk scores, with LAV_min providing the highest C-statistics when added to these risk scores (C-statistic for CHADS₂ 0.728 vs. CHADS₂ + LAV_min 0.778; C-statistic for CHARGE-AF 0.815 vs. CHARGE-AF + LAV_min 0.830). However, hypertension modified the relationship between the measures of LA function (both LAV_min and LAEF) and risk of AF (p for interaction < 0.001), which was not the case for LAV_max (p = 0.22). The measures of LA function mainly provided prognostic information regarding risk of AF in participants without hypertension. Even when we restricted our analysis to individuals without hypertension and nondilated LA (LAV_max<34 ml/m²), the LAV_min and LAEF remained significantly independent predictors of AF after multivariable adjustments (LAV_min HR: 1.12 [95% CI: 1.01 to 1.24], p = 0.028, and LAEF HR: 1.03 [95% CI: 1.00 to 1.06], p = 0.021, respectively).
LA functional measures predict AF in the general population and provide prognostic information incremental to clinical risk scores. In individuals without hypertension and nondilated LA, these measures indicate an increased risk of AF.
The influence of clinical and genetic factors on left ventricular wall thickness in Ragdoll cats
2015, Journal of Veterinary Cardiology
Citation Excerpt :
Peak LA diameter (LAD) was measured from a long-axis view in the frame prior to mitral valve opening (end-ventricular systole). Left atrial function was assessed by calculating LA fractional shortening (LAFS) using anatomic M-mode of a stored LA:Ao cine-loop, using a leading-edge-to-leading-edge method.42–44 The LV fractional shortening was recorded using an M-mode image, and was obtained from the right parasternal short-axis view at the level of the papillary muscles.
To investigate the effect of various genetic and environmental modifiers on left ventricular (LV) wall thickness in a cohort of cats genotyped for the myosin binding protein C3 mutation (MYBPC3).
Sixty-four Ragdoll cats.
All cats were screened for HCM with echocardiography and genotyping for the HCM-associated MYBPC3:R820W mutation. Cats were also genotyped for previously identified variant polymorphisms of the angiotensin-converting enzyme (ACE) and cardiac beta-adrenergic receptor (ADRB1) genes. Plasma N-terminal pro-B-type natriuretic peptide and cardiac troponin I were also measured. Associations were evaluated between genotype (MYBPC3 negative/positive, and ACE and ADRB1 negative/heterozygous/homozygous), patient factors (body weight, age and sex) and echocardiographic measurements of LV wall thickness.
Male cats had greater maximum wall thickness (LV_max; 5.8 mm, IQR 5.1–6.4 mm) than females (4.7 mm, IQR 4.4–5.3 mm, p = 0.002). Body weight positively correlated with LV_max (ρ = 0.604, p < 0.001). The MYBPC3:R820W-positive cats had a greater LV_max (5.44 mm, IQR 4.83–6.28 mm) than the negative cats (4.76 mm, IQR 4.36–5.32 mm, p = 0.001). Also, the ACE polymorphism genotype was associated with LV_max: the homozygous cats (5.37 mm, IQR 5.14–6.4 mm) had greater LV_max than the heterozygous cats (4.73 mm, IQR 4.41–5.55 mm, p = 0.014). Only the MYBPC3 genotype and body weight were independently associated with wall thickness in multivariable analysis.
This study provides evidence that the MYBPC3:R820W mutation is independently associated with LV wall thickness in Ragdoll cats. Body weight is also independently associated with maximum LV wall thickness, but is not currently accounted for in HCM screening. In addition, other genetic modifiers may be associated with variation in LV wall thickness in Ragdolls.
Determinants and Prognosis of Atrial Fibrillation in Patients with Aortic Stenosis
2015, American Journal of Cardiology
Citation Excerpt :
Previous studies have reported a correlation between LA enlargement and development of AF.22 LA volume predicted new-onset AF and added prognostic information on AF development beyond conventional risk factors in a large cohort of patients with mild-to-moderate AS.23 AF may be a turning point in the natural history of AS.
Atrial fibrillation (AF) is frequently encountered in patients with aortic stenosis (AS) and its incidence also increases with age. In the general population, AF is known to increase cardiovascular risk. We sought to investigate the prognostic importance of AF associated with AS in the context of routine clinical practice. This analysis was based on 809 patients (75 ± 12 years) diagnosed with AS (aortic valve area <2 cm²) and normal (≥50%) ejection fraction (EF). Patients were grouped according to the presence of sinus rhythm (SR) or AF at study enrollment. The AF group comprised 141 patients (17.5%) with AF, whereas 668 patients (82.5%) were in SR at inclusion. Four-year estimates of all-cause mortality with medical and surgical management were 60 ± 5% for the AF group compared with 24 ± 2% for the SR group (p = 0.0001). On multivariate analysis, the risk of all-cause mortality was higher in the AF group than in the SR group (adjusted hazard ratio [HR] 2.47 [1.83 to 3.33], p = 0.0001). AF remained associated with excess mortality risk when the analysis was limited to asymptomatic patients (adjusted HR 2.31 [1.38 to 3.89], p = 0.002) and, respectively, patients with severe AS (adjusted HR 2.22 [1.41 to 3.49], p = 0.001). Among patients managed medically, AF was independently associated with increased risk of death in the overall study population (adjusted HR 2.52 [1.81 to 3.51], p = 0.0001), in asymptomatic AS (adjusted HR 2.12 [1.19 to 3.76], p = 0.01), and in severe AS (adjusted HR 2.23 [1.30 to 3.81], p = 0.004). In conclusion, AF is a major predictor of mortality, in both medically and surgically managed patients with AS, irrespective of the functional status and the severity. AF is, therefore, a strong marker of risk in AS and should be considered for clinical decision making.
Impact of atrial fibrillation on outcomes in patients who underwent transcatheter aortic valve replacement
2015, American Journal of Cardiology
Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for surgical high-risk patients with severe aortic stenosis. The aim of this study was to determine the impact of atrial fibrillation (AF) on procedural outcomes. Data from 137 patients who underwent TAVR using Edwards SAPIEN valve were reviewed. The predictors of new-onset atrial fibrillation (NOAF) after the procedure were analyzed. In addition, the post-TAVR clinical outcomes and adverse events were compared according to the presence and absence of preprocedural and postprocedural AF. Previous AF was present in 49% of the patients who underwent TAVR. After the procedure, NOAF was detected in 21% of patients, and the cumulative incidence of post-TAVR AF was 60%. After TAVR, 50% of all the episodes of NOAF occurred in the initial 24 hours after the procedure. Transapical approach was observed to an important predictor of NOAF (adjusted odds ratio [OR] 5.05, 95% confidence interval [CI] 1.40 to 18.20, p = 0.013). The composite outcome of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after TAVR was significantly higher in patients with previous AF (33 of 67 vs 19 of 70, adjusted OR 2.60, 95% CI 1.22 to 5.54, p = 0.013) compared with patients who did not have previous AF. The presence of post-TAVR AF led to a prolongation in the duration of intensive care unit stay by an average of 70 hours (95% CI 25 to 114.7 hours, p = 0.002). Similarly, post-TAVR AF also led to the prolongation in the hospital stay by an average of 6.7 days (95% CI 4.69 to 8.73 days, p <0.0005). In conclusion, our study demonstrates that the presence of AF before TAVR is an important predictor of the composite end point of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after the procedure. AF after TAVR is more likely to be encountered with the transapical approach and is associated with a prolongation of intensive care unit and hospital stay.

View all citing articles on Scopus

^☆: Source of funding: This work was supported by The Danish Heart Association, Grant number: [10-04-R78-A2962-22582]. The SEAS study was funded by Merck & Co., Inc., Whitehouse station, NJ.

View full text

Left atrial size and function as predictors of new-onset of atrial fibrillation in patients with asymptomatic aortic stenosis: The simvastatin and ezetimibe in aortic stenosis study☆

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Baseline characteristics

Discussion

Acknowledgements

J Am Coll Cardiol

Int J Cardiol

Am Heart J

Ann Thorac Surg

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

Am Heart J

J Am Soc Echocardiogr

Am J Cardiol

Am J Cardiol

JACC Cardiovasc Imaging

Am J Cardiol

Am J Cardiol

J Am Soc Echocardiogr

Lancet

Comput Methods Programs Biomed