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Echocardiographic predictors of frequency of paroxysmal atrial fibrillation (AF) and its progression to persistent AF in hypertensive patients with paroxysmal AF: Results from the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study)
Echocardiographic predictors of frequency of paroxysmal atrial fibrillation (AF) and its progression to persistent AF in hypertensive patients with paroxysmal AF: Results from the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study) Takeki Suzuki, MD, MPH,* Tsutomu Yamazaki, MD, PhD,† Satoshi Ogawa, MD, PhD,‡ Ryozo Nagai, MD, PhD,* Takeshi Yamashita, MD, PhD,¶ and the J-RHYTHM II Investigators From the *Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, † Department of Clinical Epidemiology & Systems, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ‡ Division of Cardiology, International University of Health and Welfare, Mita Hospital, Tokyo, Japan, and ¶Department of Cardiovascular Medicine, Cardiovascular Institute, Tokyo, Japan. BACKGROUND Little is known about associations among echocardiographic variables, frequency of atrial fibrillation (AF), and progression from paroxysmal to persistent AF. OBJECTIVE The purpose of this study was to investigate echocardiographic predictors of frequency of paroxysmal AF and its progression to persistent AF in hypertensive patients with paroxysmal AF. METHODS We used data from 286 patients with paroxysmal AF and hypertension in the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study). Echocardiographic evaluation was performed at baseline. Endpoints were (1) percent of AF days measured daily by transtelephonic monitoring over 1 year and (2) development of persistent AF, defined as incidence of AF lasting for longer than 7 days and/or need for electrical cardioversion. Univariate and multivariate linear regression analysis was performed to evaluate the association between echocardiographic variables and percent of AF days. Cox proportional hazards analysis was used to examine the association between echocardiographic variables and development of persistent AF. RESULTS Among echocardiographic variables, increased left atrial dimension (LAD) was associated with more AF days and development of persistent AF: a 10-mm increase in LAD was
Introduction Atrial fibrillation (AF) is one of the most common arrhythmias in clinical practice.1,2 It is estimated that 2.2 million
Address reprint requests and correspondence: Dr. Takeki Suzuki, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan 113-8655. E-mail address: [email protected]. (Received June 17, 2011; accepted July 28, 2011.)
associated with a 6.5% increase in AF days (95% confidence interval 2.7%–10.3%) and an 84% increased risk of developing persistent AF (hazard ratio 1.84, 95% confidence interval 1.28 – 2.67). These associations remained significant after adjustment for age, sex, and other potential confounding factors. CONCLUSION Increased LAD is associated with more AF days and progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension. Increased LAD may be a good echocardiographic predictor of AF frequency and progression. KEYWORDS Arrhythmia; Atrial fibrillation; Hypertension; Echocardiography; Left atrial dimension; Transtelephonic electrocardiographic monitoring ABBREVIATIONS AF ⫽ atrial fibrillation; CI ⫽ confidence interval; ECG ⫽ electrocardiogram; HR ⫽ hazard ratio; IVS ⫽ interventricular septum; J-RHYTHM II Study ⫽ Japanese Rhythm Management Trial II for Atrial Fibrillation Study; LA ⫽ left atrium; LAD ⫽ left atrial dimension; LV ⫽ left ventricle; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular endsystolic diameter; LVPW ⫽ left ventricular posterior wall; sBP ⫽ systolic blood pressure (Heart Rhythm 2011;8:1831–1836) © 2011 Heart Rhythm Society. All rights reserved.
people in America and more than 6 million in Europe suffer from this arrhythmia.2,3 Being a strong risk factor for stroke, AF itself can cause severe devastating symptoms, resulting in impaired quality of life.4 Hypertension is a well-known AF comorbid condition. More than half of AF patients have hypertension as an underlying condition.5,6 Furthermore, hypertension is known to be a risk factor for AF.7,8 Hypertension results in left ventricular (LV) hypertrophy, reduced LV diastolic function, and left atrial (LA) enlargement.9,10
1547-5271/$ -see front matter © 2011 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2011.07.035
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Heart Rhythm, Vol 8, No 12, December 2011
Previous studies have evaluated associations between echocardiographic variables and AF.11–13 It has been shown that left atrial dimension (LAD) is associated with AF prevalence11 and incidence.12,13 However, these studies have not specified patterns of AF, such as paroxysmal, persistent, and permanent forms,1 and whether LAD is associated with frequency of paroxysmal AF remains unknown. Furthermore, little is known about the association between echocardiographic variables and progression from paroxysmal to persistent AF. Transtelephonic electrocardiographic (ECG) monitoring has enabled us to examine daily cardiac rhythm at home and, therefore, the frequency of paroxysmal AF. The purpose of this study was twofold: first, to examine the association between LAD and AF frequency; and second, to examine the association between echocardiographic variables and progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension.
Table 1
Methods Study patients The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study) is a randomized clinical trial examining the effect of calcium channel blocker (amlodipine) and angiotensin receptor blocker (candesartan) in Japanese patients with paroxysmal AF and hypertension. Details of the study design are described elsewhere.14,15 In brief, patients were enrolled in the study if they met both of the following criteria: (1) history of paroxysmal AF within the preceding 6 months, and (2) hypertension, defined as systolic blood pressure (sBP) ⱖ140 mmHg and/or diastolic blood pressure ⱖ90 mmHg. Patients were excluded if they met any of the following criteria: (1) history of vasospastic angina pectoris; (2) persistent AF with duration ⱖ1 week and/or permanent AF; (3) AF that had occurred within 1 month of onset of myocardial infarction; (4) transient AF
Basic characteristics of the cohort according to LAD quartile* LAD quartile
N Male gender (%) Angiotensin receptor blocker use (randomization) (%) Age (y) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Duration of atrial fibrillation ⬍1 y (%) ⱕ1 y and ⬍5 y (%) ⱖ5 y (%) Unknown (%) Antihypertensive medication (%) Antiarrhythmic drug treatment (except pill-in-pocket use) (%) Prior embolism (%) Heart failure (%) Old myocardial infarction (%) Angina pectoris (%) Dilated cardiomyopathy (%) Hypertrophic cardiomyopathy (%) Valvular heart disease (%) Cardiac surgery (%) Pacemaker implantation (%) Stroke/systemic embolism (%) Transient ischemic attack (%) Diabetes mellitus (%) Hyperlipidemia (%) LVDd (mm) LVDs (mm) LVEF (%) LAD (mm) IVS (mm) LVPW (mm)
Quartile 1 (LAD ⬃34 mm)
Quartile 2 (LAD 35⬃38 mm)
Quartile 3 (LAD 39⬃42 mm)
Quartile 4 (LAD 43 mm⬃)
P value
65 43 (65) 32 (48)
73 47 (71) 39 (59)
78 49 (74) 40 (60)
70 56 (84) 33 (50)
NS NS
66.7 ⫾ 9.0 141 ⫾ 17 83 ⫾ 12
65.0 ⫾ 10.5 139 ⫾ 14 84 ⫾ 11
65.2 ⫾ 10.2 140 ⫾ 14 79 ⫾ 12
64.2 ⫾ 8.8 142 ⫾ 16 83 ⫾ 9
NS NS NS
68 ⫾ 11
69 ⫾ 14
71 ⫾ 11
71 ⫾ 15
NS NS
20 21 16 8 50
(31) (32) (25) (12) (76)
19 35 14 5 58
43 (65)
7 1 1 2 0 0
22 27 25 4 58
51 (77)
(11) (2) (2) (3) (0) (0)
5 (8) 0 (0) 3 (5) 5 (8) 1 (2) 3 (5) 20 (30) 45.7 ⫾ 28.3 ⫾ 68.4 ⫾ 31.1 ⫾ 9.3 ⫾ 9.3 ⫾
(26) (48) (19) (7) (88)
6 3 2 0 1 3
5.5 4.9 8.2 3.5 1.6 1.7
12 32 21 5 55
60 (90)
(9) (5) (3) (0) (2) (5)
2 (3) 1 (2) 7 (11) 5 (8) 1 (2) 8 (12) 16 (24) 47.1 ⫾ 29.2 ⫾ 68.7 ⫾ 36.6 ⫾ 9.6 ⫾ 9.7 ⫾
(28) (35) (32) (5) (88)
4 1 0 2 0 0
4.4 4.3 7.7 1.1 1.6 1.4
(6) (2) (0) (3) (0) (0)
8 (12) 0 (0) 10 (15) 3 (5) 2 (3) 13 (20) 28 (42) 48.3 ⫾ 30.2 ⫾ 67.3 ⫾ 40.4 ⫾ 10.0 ⫾ 9.7 ⫾
(17) (46) (30) (7) (83)
NS
54 (81)
NS
5 3 1 2 0 2
4.3 4.9 6.7 1.2 1.5 1.4
(8) (5) (2) (3) (0) (3)
8 (12) 3 (5) 5 (8) 1 (2) 1 (2) 4 (6) 23 (35) 49.5 ⫾ 31.2 ⫾ 66.2 ⫾ 47.8 ⫾ 10.9 ⫾ 10.4 ⫾
NS NS NS NS NS NS
4.8 4.9 10.0 5.5 2.4 1.9
NS NS NS NS NS NS NS ⬍.001 ⬍.005 NS ⬍.001 ⬍.001 ⬍.005
IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *For continuous variables, mean ⫾ SD is shown.
Suzuki et al Table 2
LVDd LVDs LVEF LAD IVS LVPW
LAD, AF Frequency, and Progression to Persistent AF
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Correlations among baseline echocardiographic measurements LVDd
LVDs
LVEF
LAD
IVS
LVPW
1 0.741* ⫺0.194* 0.274* 0.098 0.086
0.741* 1 ⫺0.699* 0.248* 0.046 0.055
⫺0.194* ⫺0.699* 1 ⫺0.145† ⫺0.032 ⫺0.048
0.274* 0.248* ⫺0.145† 1 0.326* 0.285*
0.098 0.046 ⫺0.032 0.326* 1 0.716*
0.086 0.055 ⫺0.048 0.285* 0.716* 1
IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *P ⬍0.01; †P ⬍.05.
associated with cardiac surgery; (5) any contraindication for anticoagulation therapy; (6) pregnancy or a possibility of pregnancy or breastfeeding; (7) patient age 18 years or less; or (8) judgment by the attending physician that the patient’s participation in the study would be inappropriate. Patients were enrolled from September 2006 through August 2008 at 48 centers in Japan. A total of 316 patients were included in the trial. All eligible patients were included in the current study except those with missing echocardiographic measurements. Written informed consent was obtained from all study participants. The study was approved by the institutional review board at the participating institutions.
(IVS), and LV posterior wall (LVPW)—and LAD were measured as recommended by the American Society of Echocardiography.16 LAD was measured along the parasternal long axis.
Transtelephonic ECG monitoring Each patient was provided with a transtelephonic monitoring device (Nihon Kohden, Tokyo, Japan) and was requested to transmit ECG recordings for 30 seconds at least once daily at a predetermined hour of the day selected by each patient over 1 year of follow-up. ECGs were also recorded when patients experienced symptoms that they believed were due to AF. These ECGs were monitored at a center.
Baseline measurements Comprehensive physical examinations and interviews were performed at baseline and at monthly visits. Clinical information such as age, sex, past medical history, duration of AF (⬍1 year, ⱕ1 year and ⬍5 year, ⱖ5 years), medication use (antihypertensive medications, antiarrhythmic drugs), and seated blood pressure readings were obtained at initial visit after informed consent was obtained. Patients were randomly assigned to either the candesartan group (4 – 8 mg/day, maximal 12 mg/day) or the amlodipine group (initial dose 2.5 mg/day, maximal 5 mg/day) after 4 weeks of observation.
Echocardiographic measurements All patients in the present study underwent echocardiographic examination at baseline before randomization. LV variables—including LV end-diastolic diameter (LVDd), LV end-systolic diameter (LVD), interventricular septum
Outcomes Our end point was twofold: (1) percent of AF days and (2) development of persistent AF. Percent of AF days was defined as the number of AF days divided by the total number of days in the study period. Development of persistent AF was defined as an incidence of AF lasting for more than 7 days and/or need for electrical cardioversion over 1 year of follow-up.
Statistical analysis Baseline characteristics were divided into quartiles based on LAD and compared by analysis of variance. Correlations among baseline echocardiographic variables were assessed by Spearman rank correlation coefficient. To investigate the association between LAD and AF frequency, LAD was first used as a continuous variable and then divided into quartiles. First,
Table 3 Association between echocardiographic variables and percent of atrial fibrillation days by univariate and multivariate linear regression analysis Univariate analysis Variable (mm) LAD LVDd LVDs LVEF IVS LVPW
Multivariate analysis*
 (95% CI)
P value
 (95% CI)
P value
0.65 ⫺0.13 0.17 ⫺0.01 1.58 0.66
⬍.005 NS NS NS ⬍.05 NS
0.58 (0.18, 0.97)
⬍.005
1.43 (⫺0.01, 2.86)
NS
(0.27, 1.03) (⫺0.66, 0.41) (⫺0.39, 0.74) (⫺0.33, 0.31) (0.20, 2.95) (⫺0.95, 2.27)
CI ⫽ confidence interval; IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *Other variables included age, sex, randomization, antihypertensive medication use, antiarrhythmic drug use, history of heart failure, old myocardial infarction, angina, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, stroke, transient ischemic stroke, diabetes mellitus, hyperlipidemia, and renal disease.
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Heart Rhythm, Vol 8, No 12, December 2011 are listed in Table 1. There was no significant difference among LAD quartiles with regard to age, gender, blood pressure, duration of AF, diabetes, or hyperlipidemia. Among echocardiographic variables, however, LVDd, LVDs, IVS, and LVPW increased as LAD increased.
Correlation among echocardiographic measurements Correlations among echocardiographic variables are listed in Table 2. There was a strong correlation between LVDd and LVDs (correlation coefficient 0.741). LAD was weakly correlated with LVDd, LVDs, IVS, and LVPW. Because of the correlation among echocardiographic variables, each echocardiographic variable was evaluated independently in subsequent analyses.
Echocardiographic measurements and percent of AF days
Figure 1 Left atrial dimension quartiles and percent of atrial fibrillation (AF) days. Mean ⫾ SD is shown in each quartile.
univariate linear regression analysis was performed to evaluate the association between echocardiographic variables and percent of AF days. To account for confounding, the following variables were included in a subsequent multivariate linear regression analysis: age, sex, randomization (candesartan vs amlodipine), use of antihypertensive medications, use of antiarrhythmic drugs, and history of old myocardial infarction, angina pectoris, valvular heart disease, heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, stroke, transient ischemic attack, diabetes mellitus, hyperlipidemia, or renal disease. Because of possible confounding by blood pressure status, patients were stratified based on sBP tertiles at baseline and at final follow-up, and relationships among LAD quartiles, sBP tertiles, and percent AF days were subsequently examined. Second, Cox proportional hazards analysis was performed to evaluate the association between echocardiographic variables and development of persistent AF. To account for confounding, the above variables were included in a subsequent multivariable model. Finally, a Kaplan-Meier curve was constructed in order to compare the fourth quartile (greatest LAD) and the rest. A log-rank test was performed to compare the difference between the two groups. The 95% confidence intervals (CIs) were constructed. P ⬍.05 was considered significant. Statistical analyses were performed using SPSS 12.0J for Windows (SPSS, Inc, Chicago, IL, USA) and Stata 11.2 for Windows (Stata Co, College Station, TX, USA).
Associations between echocardiographic variables and percent of AF days are listed in Table 3. LAD was associated with more AF days in the linear regression analysis. A 10-mm increase in LAD was associated with a 6.5% increase of AF days (95% CI 2.7%–10.3%). This means that a 10-mm increase in LAD is associated with 2 more AF days over a month. The mean AF days increased linearly with LAD quartiles (Figure 1). IVS was also associated with more AF days in univariate linear regression analysis. Only the association between LAD and percent AF days remained significant after adjustment for age, sex, and other potential confounding factors in multivariate linear regression analysis. Next, we constructed a figure to show relationships among LAD quartiles, baseline sBP tertiles, and percent AF days (Figure 2). There was no significant relationship be-
Results Basic characteristics Data from 286 patients were used in the present study. Basic characteristics of the study participants based on LAD quartiles
Figure 2 Left atrial dimension (LAD) quartiles, systolic blood pressure (sBP) tertiles, and percent of atrial fibrillation (AF) days.
Suzuki et al Table 4
LAD, AF Frequency, and Progression to Persistent AF
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Echocardiographic variables and hazard ratios of development of persistent atrial fibrillation
Variable (mm) LAD LVDd LVDs LVEF IVS LVPW
Unadjusted HR (95% CI)
P value
Adjusted HR (95% CI)*
P value
1.07 1.11 1.10 1.00 1.10 1.11
⬍.005 ⬍.05 ⬍.05 NS NS NS
1.07 (1.01, 1.14) 1.10 (0.99, 1.22) 1.10 (0.99, 1.24)
⬍.05 NS NS
(1.02, (1.02, (1.01, (0.94, (0.89, (0.88,
1.12) 1.22) 1.21) 1.05) 1.35) 1.41)
CI ⫽ confidence interval; HR ⫽ hazard ratio; IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *Other variables included age, sex, randomization, antihypertensive medication use, antiarrhythmic drug use, history of heart failure, old myocardial infarction, angina, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, stroke, transient ischemic stroke, diabetes mellitus, hyperlipidemia, and renal disease.
tween sBP tertiles and percent AF days. There also was no significant relationship between sBP tertiles at final follow-up and percent AF days (not shown). The association between LAD and percent AF days was not confounded by baseline sBP status.
Echocardiographic measurements and development of persistent AF There were 37 incidences of persistent AF over median follow-up of 1 year. Cox proportional hazards analysis results are given in Table 4. LAD, LVDd, and LVDs were associated with development of persistent AF. A 1-mm increase in LAD was associated with a 7% increase in risk of persistent AF (hazard ratio [HR] 1.07, 95% CI 1.02–1.12). This means that a 10-mm increase in LAD was associated with an 84% increase in development of persistent AF (HR 1.91, 95% CI 1.21–2.97). LVDd and LVDs were also associated with development of persistent AF (HR per 1-mm increase: 1.11, 95% CI 1.02–1.22 for LVDd; 1.10, 1.01–1.21 for LVDs). Only the association between LAD and development of persistent AF remained significant after adjustment for age, sex, randomization, and other risk factors. Kaplan-Meier curves categorizing patients on the basis of LAD (fourth quartile [LAD ⱖ43 mm] vs the rest [first through third quartiles]) are shown in Figure 3. Patients with greater LAD were associated with shorter time free from persistent AF vs patients with smaller LAD (P ⬍.05).
Proportion free from persistent AF
1.00
0.90
0.80
0.70
0.60
0.50 0
200 400 Time to persistent AF (days) Q1-Q3
600
Q4
Figure 3 Time free from persistent atrial fibrillation (AF) at fourth quartile (left atrial dimension ⱖ43 mm) vs the rest (Q1–Q3).
Discussion To the best of our knowledge, this is the first study examining associations among echocardiographic variables, AF frequency, and its progression to persistent AF in hypertensive patients with paroxysmal AF. LAD was associated with more AF days as well as with development of persistent AF over 1 year of follow-up. These associations remained significant after adjustment for other well-known AF risk factors. Previous studies have investigated associations between LAD and incidence and prevalence of AF, showing consistently that LAD is a risk factor for AF.11–13,17 However, patterns of AF were not specified in these studies. Other studies examining associations between LAD and paroxysmal AF18,19 showed that LAD was larger in patients with paroxysmal AF18 and in patients with paroxysmal AF and hypertension.19 These studies were relatively small in size, and actual AF frequency in patients with paroxysmal AF has remained unknown. Our findings provide some detail as to the relationship among LAD, AF frequency, and progression to persistent AF in patients with paroxysmal AF and hypertension. There may be several reasons why larger LADs are associated with more AF days in patients with paroxysmal AF and hypertension. First, larger LADs might represent more substrate for AF in view of the critical mass theory.20 Furthermore, it has been proposed that dilated LA could result from electrical and structural remodeling through various mechanisms such as cellular hypertrophy, fibroblast proliferation, and tissue fibrosis.21 This hypothesis might be applicable to paroxysmal AF. There might be some change electrically or structurally that occurs prior to LA dilation. This might be supported by the fact that even patients with normal LAD experience paroxysmal AF episodes. Second, hypertension might be related to both LA size and AF frequency. LA enlargement might occur in patients with hypertension.9,10 The occurrence of paroxysmal AF is increased in hypertensive patients.19 Therefore, it is possible that hypertension mediates the apparent association between LA size and paroxysmal AF. In the present study, we adjusted the association between LAD and percent of AF days with use of antihypertensive medications and further performed stratified analysis of percent AF days based on LAD quartiles and sBP tertiles. In our cohort, baseline blood pressure was not associated with percent AF days. Patient selection might have made it difficult to elucidate the association between hypertension
1836 and percent AF days: the trial enrolled only patients with paroxysmal AF and hypertension and did not include patients without hypertension. LAD was associated with progression from paroxysmal to persistent AF. There are several studies on progression from paroxysmal to persistent AF.22,23 Age, diabetes, heart failure, hypertension, transient ischemic attack or stroke, and chronic obstructive pulmonary disease were independent predictors of AF progression. These studies evaluated clinical correlates with AF progression. This is the first study to prospectively evaluate echocardiographic variables on progression from paroxysmal to persistent AF. On the other hand, in patients who undergo radiofrequency ablation for persistent AF, LAD was shown to be a predictor of success after radiofrequency ablation.24
Heart Rhythm, Vol 8, No 12, December 2011
2.
3.
4.
5.
6.
7.
Study limitations The strengths of this study include daily use of transtelephonic ECG monitoring for a fairly long period for a study of this kind, its prospective design, and a large sample size. The limitations of this study also merit consideration. First, only Japanese patients were included in the study, and the findings may not be generalizable to other ethnic groups. There may be ethnic differences in LAD.11 However, our focus is on the association among echocardiographic variables, AF frequency, and development of persistent AF, and we believe that these associations will not change among ethnic groups. Second, progression from paroxysmal to persistent AF was evaluated for 1 year, and the follow-up period was relatively short in order to assess the development of persistent AF. However, we believe that the fairly high frequency of development of persistent AF (n ⫽ 37) has compensated for the relatively short follow-up period. Third, although we use transtelephonic ECG monitoring daily, there remains a possibility that AF frequency was underestimated. However, this modality is the best to noninvasively assess AF frequency. Last, echocardiography was performed and measured at each participating institution. There may be measurement variations among institutions. However, the variation should have moved the hypothesis toward null.
8.
9.
10. 11. 12.
13. 14.
15.
16.
17.
18.
Conclusion In this study, LAD was associated with more paroxysmal AF days and its progression to persistent AF in hypertensive patients with paroxysmal AF. LAD may be a good echocardiographic predictor of AF frequency and progression.
19.
20. 21.
Acknowledgments We thank the staff and participants in the Japanese Rhythm Management Trial II for Atrial Fibrillation Study. We thank Christopher Holmes for editing support.
22.
23.
References 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and
24.
the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257– e354. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J;31:2369 –2429. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469 – 473. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36:1303–1309. Nabauer M, Gerth A, Limbourg T, et al. The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace 2009;11:423– 434. Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005;26:2422–2434. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med 1982;306:1018 – 1022. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98:476 – 484. Dreslinski GR, Frohlich ED, Dunn FG, Messerli FH, Suarez DH, Reisin E. Echocardiographic diastolic ventricular abnormality in hypertensive heart disease: atrial emptying index. Am J Cardiol 1981;47:1087–1090. Matsuda M, Matsuda Y. Mechanism of left atrial enlargement related to ventricular diastolic impairment in hypertension. Clin Cardiol 1996;19:954 –959. Marcus GM, Olgin JE, Whooley M, et al. Racial differences in atrial fibrillation prevalence and left atrial size. Am J Med;123:375.e1– e7. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994; 89:724 –730. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455–2461. Yamashita T, Ogawa S, Aizawa Y, et al. Randomized study of angiotensin II type 1 receptor blocker vs dihydropyridine calcium antagonist for the treatment of paroxysmal atrial fibrillation in patients with hypertension. Circ J 2006;70: 1318 –1321. Yamashita T, Inoue H, Okumura K, et al. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study). Europace 2011;13:473– 479. Lang RM, Bierig M, Devereux RB, 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;18:1440 –1463. Nakai T, Lee RJ, Schiller NB, et al. The relative importance of left atrial function versus dimension in predicting atrial fibrillation after coronary artery bypass graft surgery. Am Heart J 2002;143:181–186. Cui Q, Zhang W, Wang H, et al. Left and right atrial size and the occurrence predictors in patients with paroxysmal atrial fibrillation. Int J Cardiol 2008;130: 69 –71. Barbier P, Alioto G, Guazzi MD. Left atrial function and ventricular filling in hypertensive patients with paroxysmal atrial fibrillation. J Am Coll Cardiol 1994;24:165–170. Garrey WE. The nature of fibrillary contraction of the heart: Its relation to tissue mass and form. Am J Physiol 1914;33:397– 414. Eckstein J, Verheule S, de Groot NM, Allessie M, Schotten U. Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria. Prog Biophys Mol Biol 2008;97:435– 451. Pappone C, Radinovic A, Manguso F, et al. Atrial fibrillation progression and management: a 5-year prospective follow-up study. Heart Rhythm 2008;5:1501– 1507. de Vos CB, Pisters R, Nieuwlaat R, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol; 55:725–731. McCready JW, Smedley T, Lambiase PD, et al. Predictors of recurrence following radiofrequency ablation for persistent atrial fibrillation. Europace;13: 355–361.
Introduction Atrial fibrillation (AF) is one of the most common arrhythmias in clinical practice.1,2 It is estimated that 2.2 million
Address reprint requests and correspondence: Dr. Takeki Suzuki, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan 113-8655. E-mail address: [email protected]. (Received June 17, 2011; accepted July 28, 2011.)
associated with a 6.5% increase in AF days (95% confidence interval 2.7%–10.3%) and an 84% increased risk of developing persistent AF (hazard ratio 1.84, 95% confidence interval 1.28 – 2.67). These associations remained significant after adjustment for age, sex, and other potential confounding factors. CONCLUSION Increased LAD is associated with more AF days and progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension. Increased LAD may be a good echocardiographic predictor of AF frequency and progression. KEYWORDS Arrhythmia; Atrial fibrillation; Hypertension; Echocardiography; Left atrial dimension; Transtelephonic electrocardiographic monitoring ABBREVIATIONS AF ⫽ atrial fibrillation; CI ⫽ confidence interval; ECG ⫽ electrocardiogram; HR ⫽ hazard ratio; IVS ⫽ interventricular septum; J-RHYTHM II Study ⫽ Japanese Rhythm Management Trial II for Atrial Fibrillation Study; LA ⫽ left atrium; LAD ⫽ left atrial dimension; LV ⫽ left ventricle; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular endsystolic diameter; LVPW ⫽ left ventricular posterior wall; sBP ⫽ systolic blood pressure (Heart Rhythm 2011;8:1831–1836) © 2011 Heart Rhythm Society. All rights reserved.
people in America and more than 6 million in Europe suffer from this arrhythmia.2,3 Being a strong risk factor for stroke, AF itself can cause severe devastating symptoms, resulting in impaired quality of life.4 Hypertension is a well-known AF comorbid condition. More than half of AF patients have hypertension as an underlying condition.5,6 Furthermore, hypertension is known to be a risk factor for AF.7,8 Hypertension results in left ventricular (LV) hypertrophy, reduced LV diastolic function, and left atrial (LA) enlargement.9,10
1547-5271/$ -see front matter © 2011 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2011.07.035
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Heart Rhythm, Vol 8, No 12, December 2011
Previous studies have evaluated associations between echocardiographic variables and AF.11–13 It has been shown that left atrial dimension (LAD) is associated with AF prevalence11 and incidence.12,13 However, these studies have not specified patterns of AF, such as paroxysmal, persistent, and permanent forms,1 and whether LAD is associated with frequency of paroxysmal AF remains unknown. Furthermore, little is known about the association between echocardiographic variables and progression from paroxysmal to persistent AF. Transtelephonic electrocardiographic (ECG) monitoring has enabled us to examine daily cardiac rhythm at home and, therefore, the frequency of paroxysmal AF. The purpose of this study was twofold: first, to examine the association between LAD and AF frequency; and second, to examine the association between echocardiographic variables and progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension.
Table 1
Methods Study patients The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study) is a randomized clinical trial examining the effect of calcium channel blocker (amlodipine) and angiotensin receptor blocker (candesartan) in Japanese patients with paroxysmal AF and hypertension. Details of the study design are described elsewhere.14,15 In brief, patients were enrolled in the study if they met both of the following criteria: (1) history of paroxysmal AF within the preceding 6 months, and (2) hypertension, defined as systolic blood pressure (sBP) ⱖ140 mmHg and/or diastolic blood pressure ⱖ90 mmHg. Patients were excluded if they met any of the following criteria: (1) history of vasospastic angina pectoris; (2) persistent AF with duration ⱖ1 week and/or permanent AF; (3) AF that had occurred within 1 month of onset of myocardial infarction; (4) transient AF
Basic characteristics of the cohort according to LAD quartile* LAD quartile
N Male gender (%) Angiotensin receptor blocker use (randomization) (%) Age (y) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Duration of atrial fibrillation ⬍1 y (%) ⱕ1 y and ⬍5 y (%) ⱖ5 y (%) Unknown (%) Antihypertensive medication (%) Antiarrhythmic drug treatment (except pill-in-pocket use) (%) Prior embolism (%) Heart failure (%) Old myocardial infarction (%) Angina pectoris (%) Dilated cardiomyopathy (%) Hypertrophic cardiomyopathy (%) Valvular heart disease (%) Cardiac surgery (%) Pacemaker implantation (%) Stroke/systemic embolism (%) Transient ischemic attack (%) Diabetes mellitus (%) Hyperlipidemia (%) LVDd (mm) LVDs (mm) LVEF (%) LAD (mm) IVS (mm) LVPW (mm)
Quartile 1 (LAD ⬃34 mm)
Quartile 2 (LAD 35⬃38 mm)
Quartile 3 (LAD 39⬃42 mm)
Quartile 4 (LAD 43 mm⬃)
P value
65 43 (65) 32 (48)
73 47 (71) 39 (59)
78 49 (74) 40 (60)
70 56 (84) 33 (50)
NS NS
66.7 ⫾ 9.0 141 ⫾ 17 83 ⫾ 12
65.0 ⫾ 10.5 139 ⫾ 14 84 ⫾ 11
65.2 ⫾ 10.2 140 ⫾ 14 79 ⫾ 12
64.2 ⫾ 8.8 142 ⫾ 16 83 ⫾ 9
NS NS NS
68 ⫾ 11
69 ⫾ 14
71 ⫾ 11
71 ⫾ 15
NS NS
20 21 16 8 50
(31) (32) (25) (12) (76)
19 35 14 5 58
43 (65)
7 1 1 2 0 0
22 27 25 4 58
51 (77)
(11) (2) (2) (3) (0) (0)
5 (8) 0 (0) 3 (5) 5 (8) 1 (2) 3 (5) 20 (30) 45.7 ⫾ 28.3 ⫾ 68.4 ⫾ 31.1 ⫾ 9.3 ⫾ 9.3 ⫾
(26) (48) (19) (7) (88)
6 3 2 0 1 3
5.5 4.9 8.2 3.5 1.6 1.7
12 32 21 5 55
60 (90)
(9) (5) (3) (0) (2) (5)
2 (3) 1 (2) 7 (11) 5 (8) 1 (2) 8 (12) 16 (24) 47.1 ⫾ 29.2 ⫾ 68.7 ⫾ 36.6 ⫾ 9.6 ⫾ 9.7 ⫾
(28) (35) (32) (5) (88)
4 1 0 2 0 0
4.4 4.3 7.7 1.1 1.6 1.4
(6) (2) (0) (3) (0) (0)
8 (12) 0 (0) 10 (15) 3 (5) 2 (3) 13 (20) 28 (42) 48.3 ⫾ 30.2 ⫾ 67.3 ⫾ 40.4 ⫾ 10.0 ⫾ 9.7 ⫾
(17) (46) (30) (7) (83)
NS
54 (81)
NS
5 3 1 2 0 2
4.3 4.9 6.7 1.2 1.5 1.4
(8) (5) (2) (3) (0) (3)
8 (12) 3 (5) 5 (8) 1 (2) 1 (2) 4 (6) 23 (35) 49.5 ⫾ 31.2 ⫾ 66.2 ⫾ 47.8 ⫾ 10.9 ⫾ 10.4 ⫾
NS NS NS NS NS NS
4.8 4.9 10.0 5.5 2.4 1.9
NS NS NS NS NS NS NS ⬍.001 ⬍.005 NS ⬍.001 ⬍.001 ⬍.005
IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *For continuous variables, mean ⫾ SD is shown.
Suzuki et al Table 2
LVDd LVDs LVEF LAD IVS LVPW
LAD, AF Frequency, and Progression to Persistent AF
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Correlations among baseline echocardiographic measurements LVDd
LVDs
LVEF
LAD
IVS
LVPW
1 0.741* ⫺0.194* 0.274* 0.098 0.086
0.741* 1 ⫺0.699* 0.248* 0.046 0.055
⫺0.194* ⫺0.699* 1 ⫺0.145† ⫺0.032 ⫺0.048
0.274* 0.248* ⫺0.145† 1 0.326* 0.285*
0.098 0.046 ⫺0.032 0.326* 1 0.716*
0.086 0.055 ⫺0.048 0.285* 0.716* 1
IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *P ⬍0.01; †P ⬍.05.
associated with cardiac surgery; (5) any contraindication for anticoagulation therapy; (6) pregnancy or a possibility of pregnancy or breastfeeding; (7) patient age 18 years or less; or (8) judgment by the attending physician that the patient’s participation in the study would be inappropriate. Patients were enrolled from September 2006 through August 2008 at 48 centers in Japan. A total of 316 patients were included in the trial. All eligible patients were included in the current study except those with missing echocardiographic measurements. Written informed consent was obtained from all study participants. The study was approved by the institutional review board at the participating institutions.
(IVS), and LV posterior wall (LVPW)—and LAD were measured as recommended by the American Society of Echocardiography.16 LAD was measured along the parasternal long axis.
Transtelephonic ECG monitoring Each patient was provided with a transtelephonic monitoring device (Nihon Kohden, Tokyo, Japan) and was requested to transmit ECG recordings for 30 seconds at least once daily at a predetermined hour of the day selected by each patient over 1 year of follow-up. ECGs were also recorded when patients experienced symptoms that they believed were due to AF. These ECGs were monitored at a center.
Baseline measurements Comprehensive physical examinations and interviews were performed at baseline and at monthly visits. Clinical information such as age, sex, past medical history, duration of AF (⬍1 year, ⱕ1 year and ⬍5 year, ⱖ5 years), medication use (antihypertensive medications, antiarrhythmic drugs), and seated blood pressure readings were obtained at initial visit after informed consent was obtained. Patients were randomly assigned to either the candesartan group (4 – 8 mg/day, maximal 12 mg/day) or the amlodipine group (initial dose 2.5 mg/day, maximal 5 mg/day) after 4 weeks of observation.
Echocardiographic measurements All patients in the present study underwent echocardiographic examination at baseline before randomization. LV variables—including LV end-diastolic diameter (LVDd), LV end-systolic diameter (LVD), interventricular septum
Outcomes Our end point was twofold: (1) percent of AF days and (2) development of persistent AF. Percent of AF days was defined as the number of AF days divided by the total number of days in the study period. Development of persistent AF was defined as an incidence of AF lasting for more than 7 days and/or need for electrical cardioversion over 1 year of follow-up.
Statistical analysis Baseline characteristics were divided into quartiles based on LAD and compared by analysis of variance. Correlations among baseline echocardiographic variables were assessed by Spearman rank correlation coefficient. To investigate the association between LAD and AF frequency, LAD was first used as a continuous variable and then divided into quartiles. First,
Table 3 Association between echocardiographic variables and percent of atrial fibrillation days by univariate and multivariate linear regression analysis Univariate analysis Variable (mm) LAD LVDd LVDs LVEF IVS LVPW
Multivariate analysis*
 (95% CI)
P value
 (95% CI)
P value
0.65 ⫺0.13 0.17 ⫺0.01 1.58 0.66
⬍.005 NS NS NS ⬍.05 NS
0.58 (0.18, 0.97)
⬍.005
1.43 (⫺0.01, 2.86)
NS
(0.27, 1.03) (⫺0.66, 0.41) (⫺0.39, 0.74) (⫺0.33, 0.31) (0.20, 2.95) (⫺0.95, 2.27)
CI ⫽ confidence interval; IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *Other variables included age, sex, randomization, antihypertensive medication use, antiarrhythmic drug use, history of heart failure, old myocardial infarction, angina, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, stroke, transient ischemic stroke, diabetes mellitus, hyperlipidemia, and renal disease.
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Heart Rhythm, Vol 8, No 12, December 2011 are listed in Table 1. There was no significant difference among LAD quartiles with regard to age, gender, blood pressure, duration of AF, diabetes, or hyperlipidemia. Among echocardiographic variables, however, LVDd, LVDs, IVS, and LVPW increased as LAD increased.
Correlation among echocardiographic measurements Correlations among echocardiographic variables are listed in Table 2. There was a strong correlation between LVDd and LVDs (correlation coefficient 0.741). LAD was weakly correlated with LVDd, LVDs, IVS, and LVPW. Because of the correlation among echocardiographic variables, each echocardiographic variable was evaluated independently in subsequent analyses.
Echocardiographic measurements and percent of AF days
Figure 1 Left atrial dimension quartiles and percent of atrial fibrillation (AF) days. Mean ⫾ SD is shown in each quartile.
univariate linear regression analysis was performed to evaluate the association between echocardiographic variables and percent of AF days. To account for confounding, the following variables were included in a subsequent multivariate linear regression analysis: age, sex, randomization (candesartan vs amlodipine), use of antihypertensive medications, use of antiarrhythmic drugs, and history of old myocardial infarction, angina pectoris, valvular heart disease, heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, stroke, transient ischemic attack, diabetes mellitus, hyperlipidemia, or renal disease. Because of possible confounding by blood pressure status, patients were stratified based on sBP tertiles at baseline and at final follow-up, and relationships among LAD quartiles, sBP tertiles, and percent AF days were subsequently examined. Second, Cox proportional hazards analysis was performed to evaluate the association between echocardiographic variables and development of persistent AF. To account for confounding, the above variables were included in a subsequent multivariable model. Finally, a Kaplan-Meier curve was constructed in order to compare the fourth quartile (greatest LAD) and the rest. A log-rank test was performed to compare the difference between the two groups. The 95% confidence intervals (CIs) were constructed. P ⬍.05 was considered significant. Statistical analyses were performed using SPSS 12.0J for Windows (SPSS, Inc, Chicago, IL, USA) and Stata 11.2 for Windows (Stata Co, College Station, TX, USA).
Associations between echocardiographic variables and percent of AF days are listed in Table 3. LAD was associated with more AF days in the linear regression analysis. A 10-mm increase in LAD was associated with a 6.5% increase of AF days (95% CI 2.7%–10.3%). This means that a 10-mm increase in LAD is associated with 2 more AF days over a month. The mean AF days increased linearly with LAD quartiles (Figure 1). IVS was also associated with more AF days in univariate linear regression analysis. Only the association between LAD and percent AF days remained significant after adjustment for age, sex, and other potential confounding factors in multivariate linear regression analysis. Next, we constructed a figure to show relationships among LAD quartiles, baseline sBP tertiles, and percent AF days (Figure 2). There was no significant relationship be-
Results Basic characteristics Data from 286 patients were used in the present study. Basic characteristics of the study participants based on LAD quartiles
Figure 2 Left atrial dimension (LAD) quartiles, systolic blood pressure (sBP) tertiles, and percent of atrial fibrillation (AF) days.
Suzuki et al Table 4
LAD, AF Frequency, and Progression to Persistent AF
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Echocardiographic variables and hazard ratios of development of persistent atrial fibrillation
Variable (mm) LAD LVDd LVDs LVEF IVS LVPW
Unadjusted HR (95% CI)
P value
Adjusted HR (95% CI)*
P value
1.07 1.11 1.10 1.00 1.10 1.11
⬍.005 ⬍.05 ⬍.05 NS NS NS
1.07 (1.01, 1.14) 1.10 (0.99, 1.22) 1.10 (0.99, 1.24)
⬍.05 NS NS
(1.02, (1.02, (1.01, (0.94, (0.89, (0.88,
1.12) 1.22) 1.21) 1.05) 1.35) 1.41)
CI ⫽ confidence interval; HR ⫽ hazard ratio; IVS ⫽ interventricular septum; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic diameter; LVDs ⫽ left ventricular end-systolic diameter; LVEF ⫽ left ventricular ejection fraction; LVPW ⫽ left ventricular posterior wall. *Other variables included age, sex, randomization, antihypertensive medication use, antiarrhythmic drug use, history of heart failure, old myocardial infarction, angina, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, stroke, transient ischemic stroke, diabetes mellitus, hyperlipidemia, and renal disease.
tween sBP tertiles and percent AF days. There also was no significant relationship between sBP tertiles at final follow-up and percent AF days (not shown). The association between LAD and percent AF days was not confounded by baseline sBP status.
Echocardiographic measurements and development of persistent AF There were 37 incidences of persistent AF over median follow-up of 1 year. Cox proportional hazards analysis results are given in Table 4. LAD, LVDd, and LVDs were associated with development of persistent AF. A 1-mm increase in LAD was associated with a 7% increase in risk of persistent AF (hazard ratio [HR] 1.07, 95% CI 1.02–1.12). This means that a 10-mm increase in LAD was associated with an 84% increase in development of persistent AF (HR 1.91, 95% CI 1.21–2.97). LVDd and LVDs were also associated with development of persistent AF (HR per 1-mm increase: 1.11, 95% CI 1.02–1.22 for LVDd; 1.10, 1.01–1.21 for LVDs). Only the association between LAD and development of persistent AF remained significant after adjustment for age, sex, randomization, and other risk factors. Kaplan-Meier curves categorizing patients on the basis of LAD (fourth quartile [LAD ⱖ43 mm] vs the rest [first through third quartiles]) are shown in Figure 3. Patients with greater LAD were associated with shorter time free from persistent AF vs patients with smaller LAD (P ⬍.05).
Proportion free from persistent AF
1.00
0.90
0.80
0.70
0.60
0.50 0
200 400 Time to persistent AF (days) Q1-Q3
600
Q4
Figure 3 Time free from persistent atrial fibrillation (AF) at fourth quartile (left atrial dimension ⱖ43 mm) vs the rest (Q1–Q3).
Discussion To the best of our knowledge, this is the first study examining associations among echocardiographic variables, AF frequency, and its progression to persistent AF in hypertensive patients with paroxysmal AF. LAD was associated with more AF days as well as with development of persistent AF over 1 year of follow-up. These associations remained significant after adjustment for other well-known AF risk factors. Previous studies have investigated associations between LAD and incidence and prevalence of AF, showing consistently that LAD is a risk factor for AF.11–13,17 However, patterns of AF were not specified in these studies. Other studies examining associations between LAD and paroxysmal AF18,19 showed that LAD was larger in patients with paroxysmal AF18 and in patients with paroxysmal AF and hypertension.19 These studies were relatively small in size, and actual AF frequency in patients with paroxysmal AF has remained unknown. Our findings provide some detail as to the relationship among LAD, AF frequency, and progression to persistent AF in patients with paroxysmal AF and hypertension. There may be several reasons why larger LADs are associated with more AF days in patients with paroxysmal AF and hypertension. First, larger LADs might represent more substrate for AF in view of the critical mass theory.20 Furthermore, it has been proposed that dilated LA could result from electrical and structural remodeling through various mechanisms such as cellular hypertrophy, fibroblast proliferation, and tissue fibrosis.21 This hypothesis might be applicable to paroxysmal AF. There might be some change electrically or structurally that occurs prior to LA dilation. This might be supported by the fact that even patients with normal LAD experience paroxysmal AF episodes. Second, hypertension might be related to both LA size and AF frequency. LA enlargement might occur in patients with hypertension.9,10 The occurrence of paroxysmal AF is increased in hypertensive patients.19 Therefore, it is possible that hypertension mediates the apparent association between LA size and paroxysmal AF. In the present study, we adjusted the association between LAD and percent of AF days with use of antihypertensive medications and further performed stratified analysis of percent AF days based on LAD quartiles and sBP tertiles. In our cohort, baseline blood pressure was not associated with percent AF days. Patient selection might have made it difficult to elucidate the association between hypertension
1836 and percent AF days: the trial enrolled only patients with paroxysmal AF and hypertension and did not include patients without hypertension. LAD was associated with progression from paroxysmal to persistent AF. There are several studies on progression from paroxysmal to persistent AF.22,23 Age, diabetes, heart failure, hypertension, transient ischemic attack or stroke, and chronic obstructive pulmonary disease were independent predictors of AF progression. These studies evaluated clinical correlates with AF progression. This is the first study to prospectively evaluate echocardiographic variables on progression from paroxysmal to persistent AF. On the other hand, in patients who undergo radiofrequency ablation for persistent AF, LAD was shown to be a predictor of success after radiofrequency ablation.24
Heart Rhythm, Vol 8, No 12, December 2011
2.
3.
4.
5.
6.
7.
Study limitations The strengths of this study include daily use of transtelephonic ECG monitoring for a fairly long period for a study of this kind, its prospective design, and a large sample size. The limitations of this study also merit consideration. First, only Japanese patients were included in the study, and the findings may not be generalizable to other ethnic groups. There may be ethnic differences in LAD.11 However, our focus is on the association among echocardiographic variables, AF frequency, and development of persistent AF, and we believe that these associations will not change among ethnic groups. Second, progression from paroxysmal to persistent AF was evaluated for 1 year, and the follow-up period was relatively short in order to assess the development of persistent AF. However, we believe that the fairly high frequency of development of persistent AF (n ⫽ 37) has compensated for the relatively short follow-up period. Third, although we use transtelephonic ECG monitoring daily, there remains a possibility that AF frequency was underestimated. However, this modality is the best to noninvasively assess AF frequency. Last, echocardiography was performed and measured at each participating institution. There may be measurement variations among institutions. However, the variation should have moved the hypothesis toward null.
8.
9.
10. 11. 12.
13. 14.
15.
16.
17.
18.
Conclusion In this study, LAD was associated with more paroxysmal AF days and its progression to persistent AF in hypertensive patients with paroxysmal AF. LAD may be a good echocardiographic predictor of AF frequency and progression.
19.
20. 21.
Acknowledgments We thank the staff and participants in the Japanese Rhythm Management Trial II for Atrial Fibrillation Study. We thank Christopher Holmes for editing support.
22.
23.
References 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and
24.
the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257– e354. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J;31:2369 –2429. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469 – 473. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36:1303–1309. Nabauer M, Gerth A, Limbourg T, et al. The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace 2009;11:423– 434. Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005;26:2422–2434. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med 1982;306:1018 – 1022. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98:476 – 484. Dreslinski GR, Frohlich ED, Dunn FG, Messerli FH, Suarez DH, Reisin E. Echocardiographic diastolic ventricular abnormality in hypertensive heart disease: atrial emptying index. Am J Cardiol 1981;47:1087–1090. Matsuda M, Matsuda Y. Mechanism of left atrial enlargement related to ventricular diastolic impairment in hypertension. Clin Cardiol 1996;19:954 –959. Marcus GM, Olgin JE, Whooley M, et al. Racial differences in atrial fibrillation prevalence and left atrial size. Am J Med;123:375.e1– e7. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994; 89:724 –730. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455–2461. Yamashita T, Ogawa S, Aizawa Y, et al. Randomized study of angiotensin II type 1 receptor blocker vs dihydropyridine calcium antagonist for the treatment of paroxysmal atrial fibrillation in patients with hypertension. Circ J 2006;70: 1318 –1321. Yamashita T, Inoue H, Okumura K, et al. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study). Europace 2011;13:473– 479. Lang RM, Bierig M, Devereux RB, 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;18:1440 –1463. Nakai T, Lee RJ, Schiller NB, et al. The relative importance of left atrial function versus dimension in predicting atrial fibrillation after coronary artery bypass graft surgery. Am Heart J 2002;143:181–186. Cui Q, Zhang W, Wang H, et al. Left and right atrial size and the occurrence predictors in patients with paroxysmal atrial fibrillation. Int J Cardiol 2008;130: 69 –71. Barbier P, Alioto G, Guazzi MD. Left atrial function and ventricular filling in hypertensive patients with paroxysmal atrial fibrillation. J Am Coll Cardiol 1994;24:165–170. Garrey WE. The nature of fibrillary contraction of the heart: Its relation to tissue mass and form. Am J Physiol 1914;33:397– 414. Eckstein J, Verheule S, de Groot NM, Allessie M, Schotten U. Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria. Prog Biophys Mol Biol 2008;97:435– 451. Pappone C, Radinovic A, Manguso F, et al. Atrial fibrillation progression and management: a 5-year prospective follow-up study. Heart Rhythm 2008;5:1501– 1507. de Vos CB, Pisters R, Nieuwlaat R, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol; 55:725–731. McCready JW, Smedley T, Lambiase PD, et al. Predictors of recurrence following radiofrequency ablation for persistent atrial fibrillation. Europace;13: 355–361.