Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation: Arrhythmia and Electrophysiology
Search: search_blue_button Advanced Search
Circulation: Arrhythmia and Electrophysiology. 2008;1:337-343
Published online before print December 2, 2008, doi: 10.1161/CIRCEP.108.795351
CLINICAL PERSPECTIVE
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
1/5/337    most recent
CIRCEP.108.795351v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Okin, P. M.
Right arrow Articles by Devereux, R. B.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Okin, P. M.
Right arrow Articles by Devereux, R. B.
Related Collections
Right arrow Epidemiology
Right arrow Hypertrophy
Right arrow Electrocardiology
Right arrow Clinical Studies
Right arrowRelated Articles

Original Articles

Incidence of Atrial Fibrillation in Relation to Changing Heart Rate Over Time in Hypertensive Patients

The LIFE Study

Peter M. Okin, MD; Kristian Wachtell, MD, PhD; Sverre E. Kjeldsen, MD, PhD; Stevo Julius, MD, ScD; Lars H. Lindholm, MD, PhD; Björn Dahlöf, MD, PhD; Darcy A. Hille, MSEM, BA; Markku S. Nieminen, MD; Jonathan M. Edelman, MD and Richard B. Devereux, MD

From the Greenberg Division of Cardiology (P.M.O., R.B.D.), Weill Cornell Medical College, New York, NY; The Heart Center (K.W.), Rigshospitalet, Copenhagen, Denmark; Department of Internal Medicine, University of Oslo (S.E.K.), Ullevål Hospital, Oslo, Norway; Department of Medicine, University of Michigan Medical Center (S.E.K., S.J.), Ann Arbor, Mich; Department of Internal Medicine, Umeå University (L.H.L.), Umeå, Sweden; Department of Internal Medicine, Sahlgrenska University Hospital/Östra (B.D.), Göteborg, Sweden; Merck Research Labs (D.A.H.), West Point, Pa; Division of Cardiology (M.S.N.), Department of Medicine, Helsinki University Central Hospital, Finland; and Merck & Co Inc (J.M.E.), North Wales, Pa.

Correspondence to Peter M. Okin, MD, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065. E-mail pokin{at}med.cornell.edu

Received May 29, 2008; accepted August 21, 2008.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background— Onset of atrial fibrillation (AF) has been linked to changes in autonomic tone, with increasing heart rate (HR) immediately before AF onset in some patients suggesting a possible role of acute increases in sympathetic activity in AF onset. Although losartan therapy and decreasing ECG left ventricular hypertrophy are associated with decreased AF incidence, the relationship of HR changes over time to development of AF has not been examined.

Methods and Results— HR was evaluated in 8828 hypertensive patients without AF by history or on baseline ECG in the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study. Patients were treated with losartan- or atenolol-based regimens and followed with serial ECGs annually which were used to determine HR and ECG left ventricular hypertrophy by Cornell product and Sokolow-Lyon voltage criteria. During mean follow-up of 4.7±1.1 years, new-onset AF occurred in 701 patients (7.9%). Patients with new AF had smaller decreases in HR to last in-treatment ECG or last ECG before AF (–2.7±13.5 versus –5.2±12.5 bpm), whether on losartan- (–0.4±13.5 versus –2.2±11.7 bpm) or atenolol-based treatment (–5.3±12.8 versus –8.3±12.6 bpm, all P<0.001). In univariate Cox analyses, higher HR on in-treatment ECGs was associated with an increased risk of new-onset AF, with a 15% greater risk of AF for every 10 bpm higher HR (95% CI 8% to 22%). In alternative analyses, persistence or development of a HR≥84 (upper quintile of baseline HR) was associated with a 46% greater risk of developing AF (95% CI 19% to 80%). After adjusting for treatment with losartan versus atenolol, baseline risk factors for AF, baseline and in-treatment systolic and diastolic pressure and the known predictive value of baseline and in-treatment ECG left ventricular hypertrophy for new AF, higher in-treatment HR remained strongly associated with new AF with a 19% higher risk for every 10 bpm higher HR (95% CI 10% to 28%) or a 61% increased rate of AF in patients with persistence or development of a HR≥84 (95% CI 27% to 104%, all P<0.001).

Conclusion— Higher in-treatment HR on serial ECGs is associated with an increased likelihood of new-onset AF, independent of treatment modality, blood pressure lowering, and regression of ECG left ventricular hypertrophy in patients with essential hypertension.

Key Words: electrocardiography • fibrillation • heart rate • hypertension • hypertrophy


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Atrial fibrillation (AF) is a common arrhythmia1,2 that is increasing in prevalence.2 The incidence of AF increases with age1 and is increased in patients with hypertension, left ventricular hypertrophy (LVH), coronary heart disease, and particularly in patients with heart failure.3–10 The increased risk of death,3–5 heart failure,5 and stroke3,6,7 in patients with AF and the significant risks associated with antiarrhythmic and antithrombotic therapies aimed at preventing AF recurrences and decreasing the risk of embolic sequella,11–13 highlight the importance of preventing AF and the need to identify epidemiological risk factors that may predispose to AF.14 The possible role of the sympathetic nervous system in the triggering and maintenance of AF15–20 and the strong relationship of underlying heart failure to the development of AF,3–10 taken together with findings that increased heart rate (HR) may reflect subclinical impairment of LV function,21 suggest that increasing HR during sinus rhythm may be an important marker of risk for the development of AF. However, the relationship of changing HR over time to the development of new AF has not been evaluated.22 Accordingly, the present study examined whether higher HR over time is associated with an increased rate of AF in hypertensive patients undergoing treatment, independent of the effects of in-treatment blood pressure and other risk factors for AF, and of the previously demonstrated impact of losartan-based therapy and in-treatment ECG LVH on AF incidence.3,23

Editorial see p 321

Clinical Perspective see p 344


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Subjects
The Losartan Intervention for End Point Reduction in Hypertension (LIFE) study24–28 enrolled 9193 hypertensive patients with ECG LVH by Cornell voltage-duration product29,30 or Sokolow-Lyon voltage criteria31 on a screening ECG in a prospective, double-blind, randomized study that compared cardiovascular morbidity and mortality with the use of losartan- as opposed to atenolol-based treatment,26 as previously described in detail.24–28 A total of 362 patients with either a history of AF (n=342) or AF on their LIFE baseline ECG (n=135) and 3 patients with missing baseline HR data were excluded from analyses, leaving 8828 patients without AF by history or baseline ECG in the present study.

Treatment Regimens
Blinded treatment was begun with losartan 50 mg or atenolol 50 mg daily and matching placebo of the other agent, with a target pressure of 140/90 mm Hg or lower. During clinic visits at frequent intervals for the first 6 months and at 6-month intervals thereafter, study therapy could be up-titrated by addition of hydrochlorothiazide 12.5 mg, followed by increase in blinded losartan or atenolol to 100 mg daily. In patients whose blood pressure was still not controlled, additional open-label upward titration of hydrochlorothiazide and if necessary institution of therapy with a calcium channel blocker or additional other medications (excluding AT1- or β-blockers or angiotensin-converting enzyme inhibitors) was added to the double-blind treatment regimen.26

Electrocardiography
Study ECGs were obtained at baseline, at 6 months, and at yearly follow-up intervals until study termination or patient death and were interpreted as previously reported in detail.24–27 Cornell product >2440 mm·ms29,20 or Sokolow-Lyon voltage >38 mm31 were used to identify LVH.24,25 HR was measured to the nearest bpm on each protocol-mandated study ECG. New-onset AF was identified from protocol-mandated in-study ECGs undergoing Minnesota coding at the ECG core laboratory and/or by adverse event reports of AF by the investigators.3,23

Statistical Analyses
Data management and analyses were performed by the investigators using SPSS version 12.0. Data are presented as mean±SD for continuous variables and proportions for categorical variables. Differences in mean values between patients grouped according to baseline HR partitioned at 84 bpm (the upper quintile of baseline HR in this population and a value previously shown to stratify mortality risk32) were compared using unpaired t tests; comparison of proportions between groups was performed using {chi}2 tests.

The relation of HR during sinus rhythm on baseline and in-study ECGs to risk of developing AF was assessed using Cox proportional hazards models. Baseline risk factors, a treatment group indicator, and baseline HR, systolic and diastolic pressure, Cornell product, and Sokolow-Lyon voltage were included as standard covariates and subsequent in-treatment blood pressure, HR, Cornell product, and Sokolow-Lyon voltage measurements from routine in-study ECGs were entered as time-varying covariates. In addition, the relation of persistence or development of a HR≥84 versus a HR<84 bpm treated as a dichotomous time-varying variable to the development of AF was also analyzed. Treating HR as a time-varying covariate, HR from the last ECG in sinus rhythm before the development of AF or from the last in-treatment ECG will enter into the model. Hazard ratios for incidence of AF associated with in-treatment HR treated as a continuous variable were computed per 10 bpm higher HR values. Analyses were repeated stratifying the population by relevant subgroups by adding cross-product terms of time-varying HR and these subgroup variables into models in the total population.

To illustrate the results of time-varying covariate analyses, new AF rate over time was plotted as a function of changing presence or absence of a HR≥84 bpm using a univariate modified Kaplan–Meier method,33 implemented in SAS Release 8.2 on the WIN_PRO platform. Two-tailed P<0.05 was required for statistical significance.

Statement of Responsibility
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient Characteristics in Relation to Baseline HR
Clinical and demographic characteristics of patients in relationship to baseline HR partitioned at 84 bpm are shown in Table 1. Hypertensive patients with a baseline HR≥84 were older, more likely to be female, non-black, have diabetes, a history of heart failure, and to be current smokers, had higher body mass indexes, glucose, and total cholesterol levels, and greater albuminuria, but were similar with respect to treatment randomization and other baseline characteristics. Among patients with baseline HR<84, compared with those whose HR remained <84 throughout the study, patients who went on to develop a HR≥84 before the development of AF or before last follow-up if remaining in sinus rhythm (n=555) had similar differences in baseline characteristics as noted in Table 1 with the exception that patients who developed a HR≥84 were more likely to be black (9.4% versus 5.8%, P=0.002) and to have taken losartan (65.9% versus 49.2%, P<0.001), but had similar total cholesterol levels (6.09±1.09 versus 6.03±1.11 mmol/L, P=0.200).


View this table:
[in this window]
[in a new window]

 
Table 1. Demographic and Clinical Characteristics in Relation to Baseline Heart Rate
 
Blood pressure and ECG LVH measurements at baseline and changes in these measurements between baseline and last in-study determination or the development of new-onset AF in relation to HR at baseline are shown in Table 2. Patients with a baseline HR≥84 had slightly higher baseline systolic and diastolic pressures and greater reductions in diastolic pressure but similar changes in systolic pressure. Higher baseline HR was associated with less severe LVH by Sokolow-Lyon voltage, but similar baseline severity of Cornell product LVH and similar changes in both ECG LVH criteria. In-treatment blood pressure control was not related to the behavior of HR during the study: reduction in both systolic and diastolic pressure was similar in patients with persistence or development of a new HR≥84 and in patients with a HR<84 at last follow-up, both among patients who remained in sinus rhythm (–29±20 versus –29±19 mm Hg, P=0.956 and –17±11 versus –17±10 mm Hg, P=0.221) and among patients who developed AF (–33±19 versus –34±21 mm Hg, P=0.766 and –16±13 versus –17±10 mm Hg, P=0.216).


View this table:
[in this window]
[in a new window]

 
Table 2. Baseline and Change From Baseline to Last In-Study Measurement of Blood Pressure and Electrocardiographic Left Ventricular Hypertrophy in Relation to Baseline Heart Rate
 
In-Treatment HR and New AF
During mean follow-up of 4.7±1.1 years, new-onset AF occurred in 701 patients (7.9%). Compared with patients who did not develop AF, patients who developed AF had smaller decreases in HR to last in-treatment ECG or last ECG before AF (–2.7±13.5 versus –5.2±12.5), whether on losartan- (–0.4±13.5 versus –2.2±11.7 bpm) or atenolol-based treatment (–5.3±12.8 versus –8.3±12.6, all P<0.001). Mean time from the last ECG in sinus rhythm to development of new AF was 156±117 days, with a mean HR of 70±13 bpm. New-onset AF occurred in 100 patients with in-treatment persistence or development of a HR≥84 bpm, a rate of 21.1 per 1000 patient-years, and in 601 patients with in-treatment development or continued presence of a HR<84 bpm, a rate of 16.4 per 1000 patient-years.

The relationship of new-onset AF to in-treatment HR is examined in Table 3 and in the Figure. In univariate Cox analyses in which time-varying HR was treated as a continuous variable, higher in-treatment values of HR were strongly associated with an increased risk of developing AF: a 10-bpm higher HR was associated with a 15% increased risk of new AF. In parallel analyses in which in-treatment HR was treated as a dichotomous variable based on a threshold value of ≥84 bpm, in-treatment persistence or development of a HR≥84 bpm was associated with a 46% greater risk of developing AF compared with in-treatment development or continued presence of a HR<84. Modified Kaplan–Meier curves33 comparing the rate of new AF according to a HR of 84 bpm over the time course of the study (Figure) demonstrate that persistence or development of a HR≥84 was associated with a greater risk of developing AF when compared with a HR <84, with persistence or development of a HR≥84 associated with an estimated 6.0% higher absolute incidence of AF after 4 years of follow-up. The predictive value of time-varying HR for new AF was not dependent on whether AF was ascertained on annual study ECG or by adverse clinical event with associated AF: higher in-treatment HR by 10 bpm was similarly predictive of increased incidence of AF defined by annual ECGs (n=405, HR 1.25, 95% CI 1.15 to 1.34) or by adverse event reports (n=572, HR 1.16, 95% CI 1.08 to 1.24).


View this table:
[in this window]
[in a new window]

 
Table 3. Univariate and Multivariable Cox Regression Analyses to Assess the Predictive Value of Changing In-Treatment Heart Rate for the Development of New-Onset Atrial Fibrillation
 

Figure 1795351
View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
 
Figure. Survival curves illustrating the rate of new onset atrial fibrillation (AF) according to time-varying persistence or development of a heart rate (HR)≥84 bpm during follow-up. Patient group assignment is adjusted at the time of each ECG based on the heart rate at each time.33

 
The relation of new-onset AF to in-treatment HR was further examined after adjusting for the possible effects of treatment, age, gender, race, prevalent diabetes, history of ischemic heart disease, myocardial infarction, heart failure, stroke, peripheral vascular disease and smoking, baseline urinary albumin/creatinine ratio, total and high-density lipoprotein cholesterol, serum creatinine, body mass index, and for baseline and in-treatment systolic and diastolic blood pressure, Cornell product, and Sokolow-Lyon voltage (Table 3). After adjusting for these factors, a 10 bpm higher in-treatment HR was associated with a 19% greater risk of new AF; in a parallel analysis, in-treatment persistence or development of a HR≥84 was associated with a 61% higher incidence of AF. Of note, further adjusting for use of calcium channel blockers treated as a time-varying covariate did not affect the relationship between in-treatment HR and new AF.

The predictive value of time-varying HR for new-onset AF in relevant subsets of the population is examined in Table 4. The association between new-onset AF and in-treatment HR was similar in men and women, both treatment arms of the study, patients above and below 65 years of age, patients with and without diabetes or a history of ischemic heart disease, myocardial infarction, or heart failure, and patients with and without Cornell product LVH on their baseline ECGs. Higher in-treatment HR was associated with trends toward a greater increase in AF among black as opposed to non-black patients and in patients without as opposed to with LVH by Sokolow-Lyon voltage on their baseline ECGs.


View this table:
[in this window]
[in a new window]

 
Table 4. Bivariate Cox Analyses to Assess the Predictive Value of Time-Varying In-Treatment Heart Rate for New-Onset Atrial Fibrillation in Relevant Subgroups of the Study Population
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
These findings demonstrate that higher HR, in sinus rhythm during antihypertensive therapy, is associated with a greater likelihood of new-onset AF, independent of blood pressure lowering, the beneficial effect of losartan-based therapy on the development of AF,3 and of the previously demonstrated relationship of AF incidence to in-treatment ECG LVH.23 These findings suggest that serial assessment of HR may provide additional information regarding the risk of developing AF in hypertensive patients and that further evaluation of patients with persistence or development of an increased HR during antihypertensive therapy should be considered to evaluate possible underlying abnormalities that may predispose patients to the development of AF.

HR and AF
The relationship of HR during sinus rhythm to the risk of developing AF has not been well characterized. Among 2576 subjects in the Framingham Heart Study followed for a mean of 10.5 years,34 baseline HR was similar in the 132 patients who developed AF and the 2444 who remained in sinus rhythm (75±11 versus 73±10), but HR over time was not reported in these patients. Among patients with heart failure who were in sinus rhythm, Pozzoli et al22 found that 18 patients who developed chronic AF had an increase in HR from 72±16 to 75±13 bpm between baseline and last evaluation in sinus rhythm when compared with a decrease in HR from 75±13 to 73±13 over the same period in 290 patients who remained in sinus rhythm, but did not test the statistical significance of these changes. In contrast, the current study demonstrates that hypertensive patients who developed AF had smaller decreases in HR during losartan- or atenolol-based treatment than patients who remained in sinus rhythm and that higher in-treatment HR was strongly associated with an increased risk of developing AF, independent of the beneficial effect of losartan therapy on AF incidence,3 other potential AF risk factors, and of the previously demonstrated relationship of AF incidence to LVH regression in this population.23 The similar reductions in systolic and diastolic pressure among patients with and without a HR≥84 and continued strong association of higher in-treatment HR with increased risk of AF after adjusting for in-treatment systolic and diastolic pressure (Table 4), demonstrate that the association between HR and AF risk was not a marker of lesser blood pressure control among patients with higher in-treatment HR. Importantly, the association between in-treatment HR and new-onset AF was robust across all subsets of the population (Table 4), including similar effects in patients taking losartan or atenolol despite the different HR responses to therapy in these groups, and among patients with and without a history of heart failure despite the strong association of heart failure with subsequent AF.3–10

Possible mechanisms by which increased HR may relate to an increased risk of AF include as a marker of increased sympathetic activity15–20,34 and of subclinical reductions in LV function.21 The role of the sympathetic nervous system in triggering and maintenance of AF has been more extensively examined,15–20,34 although most studies have focused only on short-term variations in HR variability preceding the development of AF.15–20,34 Increased sympathetic activity may promote automaticity, shorten atrial effective refractory period, and thereby facilitate induction of AF, particularly in patients with structural heart disease.15 Tachycardia per se can shorten atrial effective refractory period, potentially facilitating AF initiation and propagation.14,15,35 Subclinical LV dysfunction or early heart failure as a cause for increasing HR over time may also impact directly on the risk of developing AF3–10 via increases in left atrial pressure and stretch that can promote AF.9,36–38 Experimental heart failure induced by rapid ventricular pacing promoted the induction of sustained AF in dogs by causing atrial interstitial fibrosis and cellular electrophysiological remodeling distinct from that produced by atrial tachycardia.39,40 Study of the relationship of changing HR over time to changes in LV structure and function and left atrial size will be necessary to clarify this relationship.

Methodologic Issues and Study Limitations
Several limitations of the present study warrant review. Use of ECG LVH criteria to select patients for LIFE increased the baseline risk of the study population, suggesting that caution should be used in generalizing these findings to hypertensive patients at lower risk. Although the present findings may not be representative of hypertensive populations with less severe disease, it has been estimated that 7.8 million patients would have met LIFE eligibility criteria in the first 15 member nations of the European Union,41 with similar numbers in the rest of Europe and in the United States. Second, although annual ECGs and adverse event reports by treating LIFE investigators were used to detect AF, the true incidence of AF, particularly asymptomatic AF, may have been underestimated, potentially reducing precision of the estimates of the relation of AF to in-treatment HR. Third, higher HR was associated with a greater burden of preexisting heart and vascular disease and of risk factors for adverse outcome. Although increased HR remained a strong predictor of new AF after adjusting for these potential confounders, multivariable analyses may not fully take into account the possible impact of these and other unmeasured confounders on outcomes. Fourth, sampling of HR annually on 12-lead ECG almost certainly underestimates the true relationship of changing HR over time to incident AF, which might have been improved by examining 24-hour mean HR or measures of HR variability on serial 24-hour ECGs performed over time. Finally, this was a post hoc analysis of findings from the LIFE study and, as such, further study will be necessary to explore and confirm the relationship of incident AF to changing HR over time.

Implications
These findings have potential implications for the management of patients with hypertension and LVH. Given the increasing incidence and prevalence of AF in the population1 and the increased risk of death, stroke, and heart failure associated with AF in LIFE and other studies,3–7 these data support the serial evaluation of HR in hypertensive patients to monitor the risk of developing AF. These observations suggest that further evaluation of patients with persistence or development of an increased HR during antihypertensive therapy should be considered to evaluate possible underlying abnormalities that may predispose patients to the development of AF. Further study will be required to determine the relationship between increasing HR and structural abnormalities of left atrial size and LV size and function that may predispose to the development of AF.


    Acknowledgments
 
Sources of Funding

Dr Okin has received research grants from Merck & Co, Inc. Dr Wachtell has received research grants and honoraria from Merck & Co Inc. Dr Kjeldsen has received honoraria from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Merck, Novartis, Pfizer, and Sankyo. Dr Julius has been a member of speakers’ bureaus and received honoraria from Merck, Novartis, Servier, and Takeda. Dr Lindholm has received a research grant from the Swedish MRC, honoraria from Astra Zeneca, Merck/MSD, Myogen, and Novartis and has served as a consultant to Myogen. Dr Dahlöf has received research grants from Boehringer-Ingelheim, Novartis and Pfizer, served as a consultant to Boehringer-Ingelheim, Merck/MSD, and Novartis, and has been a member of speakers’ bureaus sponsored by Boehringer-Ingelheim, Merck/MSD, Novartis, Pfizer, and Servier. Dr Devereux has served as a consultant to Merck and Novartis, received grants from Merck, and has been a member of speakers’ bureaus sponsored by Merck.

Disclosures

D.A. Hille and Dr Edelman are employees of Merck & Co Inc, the sponsor of the LIFE study, and may own stock or hold stock options in Merck & Co Inc. Dr Nieminen has no disclosures relevant to this study.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1. Go AS, Hylek EM, Phillips KA, Chang YC, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults. National implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001; 285: 2370–2375.[Abstract/Free Full Text]

2. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004; 110: 1042–1046.

3. Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlöf B, Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, Devereux RB. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol. The Losartan Intervention for End point reduction in hypertension (LIFE) Study. J Am Coll Cardiol. 2005; 45: 712–719.[Abstract/Free Full Text]

4. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998; 98: 946–952.[Abstract/Free Full Text]

5. Krahn AD, Manfreda J, Tate RB, Mathewson FAL, 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.[CrossRef][Medline]

6. Marini C, De Santis F, Sacco S, Russo T, Olivieri L, Totaro R, Carolei A. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005; 36: 1115–1119.[Abstract/Free Full Text]

7. Verdecchia P, Reboldi R, Bentivoglio M, Borgioni C, Angeli F, Carluccio E, Sardone MG, Porcellati C. Atrial fibrillation in hypertension: predictors and outcome. Hypertension. 2003; 41: 218–223.[Abstract/Free Full Text]

8. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. JAMA. 1994; 271: 840–844.[Abstract/Free Full Text]

9. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation: the Framingham Heart Study. Circulation. 1994; 89: 724–730.[Abstract/Free Full Text]

10. Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, Fried LP, White R, Furberg CD, Rautaharju PM. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997; 96: 2455–2461.[Abstract/Free Full Text]

11. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene JH, Mickel MC, Dalquist JE, Corley SD. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002; 347: 1825–1833.[Abstract/Free Full Text]

12. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJM, Tijssen JGP, Crijns HJGM. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002; 347: 1834–1840.[Abstract/Free Full Text]

13. Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DA. Prospective study of the outcomes of ambulatory patients with excessive warfarin anti-coagulation. Arch Intern Med. 2000; 160: 1612–1617.[Abstract/Free Full Text]

14. Allessie MA, Boyden PA, Camm AJ, Kleber AG, Lab MJ, Legato MJ, Rosen MR, Schwartz PJ, Spooner PM, Van Wagoner DR, Waldo AL. Pathophysiology and prevention of atrial fibrillation. Circulation. 2001; 103: 769–777.[Free Full Text]

15. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002; 415: 219–226.[CrossRef][Medline]

16. Huang JL, Wen ZC, Chang M-S, Chen SA. Changes of autonomic tone before the onset of paroxysmal atrial fibrillation. Int J Cardiol. 1998; 66: 275–283.[CrossRef][Medline]

17. Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation. 2002; 105: 2753–2759.

18. Tai CT, Chiou CW, Chen SA. Interaction between the autonomic nervous system and atrial tachyarrhythmias. J Cardiovasc Electrophysiol. 2002; 13: 83–87.[CrossRef][Medline]

19. Amar D, Zhang H, Miodownik S, Kadish AH. Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation. J Am Coll Cardiol. 2003; 42: 1262–1268.[Abstract/Free Full Text]

20. Lombardi F, Tarricone D, Tundo F, Colombo F, Belletti S, Fiorentini F. Autonomic nervous system and paroxysmal atrial fibrillation: a study based on the analysis of RR interval changes before, during and after paroxysmal atrial fibrillation. Eur Heart J. 2004; 25: 1242–1248.[Abstract/Free Full Text]

21. Palatini P, Julius S. Heart rate and cardiovascular risk. J Hypertens. 1997; 15: 3–17.[CrossRef][Medline]

22. Pozzoli M, Cioffi G, Traversi E, Pinna GD, Cobelli F, Tavazzi L. Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study. J Am Coll Cardiol. 1998; 32: 197–204.[Abstract/Free Full Text]

23. Okin PM, Wachtell K, Devereux RB, Harris KE, Jern S, Kjeldsen SE, Julius S, Lindholm L, Nieminen MS, Edelman JM, Dahlöf B. Regression of electrocardiographic left ventricular hypertrophy and decreased incidence of new-onset atrial fibrillation: the LIFE Study. JAMA. 2006; 296: 1242–1248.[Abstract/Free Full Text]

24. Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS, Snapinn S, Harris KE, Aurup P, Edelman JM, Dahlöf B. Regression of electrocardiographic left ventricular hypertrophy by losartan vs atenolol: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Circulation. 2003; 108: 684–690.

25. Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS, Snapinn S, Harris KE, Aurup P, Edelman JM, Wedel H, Lindholm LH, Dahlöf B. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and prediction of major cardiovascular events. JAMA. 2004; 292: 2343–2349.[Abstract/Free Full Text]

26. Dahlöf B, Devereux R, de Faire U, Fyhrquist F, Hedner T, Ibsen H, Julius S, Kjeldsen S, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; for the LIFE Study Group. The Losartan Intervention For Endpoint Reduction (LIFE) in hypertension study: rationale, design, and methods. Am J Hypertens. 1997; 10: 705–713.[CrossRef][Medline]

27. Dahlöf B, Devereux RB, Julius S, Kjeldsen SE, Beevers G, de Faire U, Fyhrquist F, Hedner T, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. The Losartan Intervention For Endpoint Reduction (LIFE) in hypertension study: baseline characteristics of 9,194 patients with left ventricular hypertrophy. Hypertension. 1998; 32: 989–997.[Abstract/Free Full Text]

28. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline]

29. Molloy TJ, Okin PM, Devereux RB, Kligfield P. Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltage-duration product. J Am Coll Cardiol. 1992; 20: 1180–1186.[Abstract]

30. Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification of increased left ventricular mass by simple voltage-duration products. J Am Coll Cardiol. 1995; 25: 417–423.[Abstract]

31. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J. 1949; 37: 161–186.[CrossRef][Medline]

32. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES 1 epidemiologic follow-up study. Am Heart J. 1991; 121: 172–177.[CrossRef][Medline]

33. Snapinn SM, Jiang Q, Iglewicz B. Illustrating the impact of a time-varying covariate with an extended Kaplan-Meier estimate. Am Stat. 2005; 59: 301–307.[CrossRef]

34. Singh JP, Larson MG, Levy D, Evans JC, Tsuji H, Benjamin EJ. Is baseline autonomic tone associated with new onset atrial fibrillation? Insights from the Framingham Heart Study. Ann Noninvasive Electrocardiol. 2004; 3: 215–220.

35. Yu WC, Chen SA, Lee SH, Tai CT, Feng AN, Kuo BIT, Ding YA, Chang MS. Tachycardia-induced change of atrial refractory period in humans. Rate dependency and effects of antiarrhythmic drugs. Circulation. 1998; 97: 2331–2337.[Abstract/Free Full Text]

36. Huang J-L, Tai C-T, Chen J-T, Ting CT, Chew YT, Chang MS, Chen SA. Effect of atrial dilatation on electrophysiologic properties and inducibility of atrial fibrillation. Bas Res Cardiol. 2003; 98: 16–24.[CrossRef][Medline]

37. Tsao HM, Yu WC, Cheng HC, Wu MH, Tai CT, Lin WS, Ding YA, Chang MS, Chen SA. Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging. J Cardivasc Electrophysiol. 2001; 12: 809–813.[CrossRef]

38. Herweg B, Sichrovosky T, Polosajian L, Rozenshtein A, Steinberg JS. Hypertension and hypertensive heart disease are associated with increased pulmonary vein diameter. J Cardiovasc Electrophysiol. 2005; 16: 2–5.[CrossRef][Medline]

39. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs. Atrial remodeling of a different sort. Circulation. 1999; 100: 87–95.[Abstract/Free Full Text]

40. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation. 2000; 101: 2631–2638.[Abstract/Free Full Text]

41. Dahlöf B, Burke TA, Krobot K, Carides GW, Edelman JM, Devereux RB, Diener HC. Population impact of losartan use on stroke in the European Union (EU): projections from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. J Hum Hypertens. 2004; 18: 367–373.[CrossRef][Medline]


 

CLINICAL PERSPECTIVE

Onset of atrial fibrillation (AF) has been linked to changes in autonomic tone, with increasing heart rate (HR) immediately before AF onset in some patients, suggesting a possible role of acute increases in sympathetic activity in AF onset. Our study demonstrates that higher in-treatment HR is an independent and important predictor of the development of new AF in hypertensive patients, with a 19% higher risk of developing AF for every 10 beats per minute higher HR or a 61% increased risk in patients whose HR stays or becomes ≥84 beats per minute while undergoing treatment. The increased risk of new AF associated with higher HR is independent of the decreased risk of new AF associated with losartan-based therapy and the decreased risk associated with regression of electrocardiographic left ventricular hypertrophy. These findings have potential implications for the management of patients with hypertension and left ventricular hypertrophy. Given the increasing incidence and prevalence of AF in the population and the increased risk of death, stroke, and heart failure associated with AF in the Losartan Intervention for End Point Reduction in Hypertension (LIFE) and other studies, these data support the serial evaluation of HR in hypertensive patients to monitor the risk of developing AF. These observations suggest that further evaluation of patients with persistence or development of an increased HR during antihypertensive therapy should be considered to evaluate possible underlying abnormalities that may predispose patients to the development of AF, such as increasing left atrial size, worsening left ventricular systolic function, or both.


Related Articles

Slower Heart Rates for Healthy Hearts: Time to Redefine Tachycardia?
Rakesh Gopinathannair, Renee M. Sullivan, and Brian Olshansky
Circ Arrhythmia Electrophysiol 2008 1: 321-323. [Extract] [Full Text] [PDF]

Chronic Atrial Fibrillation Is a Biatrial Arrhythmia: Data from Catheter Ablation of Chronic Atrial Fibrillation Aiming Arrhythmia Termination Using a Sequential Ablation Approach
Thomas Rostock, Daniel Steven, Boris Hoffmann, Helge Servatius, Imke Drewitz, Karsten Sydow, Kai Müllerleile, Rodolfo Ventura, Karl Wegscheider, Thomas Meinertz, and Stephan Willems
Circ Arrhythmia Electrophysiol 2008 1: 344-353. [Abstract] [Full Text] [PDF]

ECG Quantification of Myocardial Scar in Cardiomyopathy Patients With or Without Conduction Defects: Correlation With Cardiac Magnetic Resonance and Arrhythmogenesis
David G. Strauss, Ronald H. Selvester, João A.C. Lima, Håkan Arheden, Julie M. Miller, Gary Gerstenblith, Eduardo Marbán, Robert G. Weiss, Gordon F. Tomaselli, Galen S. Wagner, and Katherine C. Wu
Circ Arrhythmia Electrophysiol 2008 1: 327-336. [Abstract] [Full Text] [PDF]



This article has been cited by other articles:


Home page
Circ Arrhythmia ElectrophysiolHome page
R. Gopinathannair, R. M. Sullivan, and B. Olshansky
Slower Heart Rates for Healthy Hearts: Time to Redefine Tachycardia?
Circ Arrhythmia Electrophysiol, December 1, 2008; 1(5): 321 - 323.
[Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
1/5/337    most recent
CIRCEP.108.795351v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Okin, P. M.
Right arrow Articles by Devereux, R. B.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Okin, P. M.
Right arrow Articles by Devereux, R. B.
Related Collections
Right arrow Epidemiology
Right arrow Hypertrophy
Right arrow Electrocardiology
Right arrow Clinical Studies
Right arrowRelated Articles