Published online before print December 18, 2006, doi: 10.1161/01.HYP.0000254322.96189.85
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(Hypertension. 2007;49:311.)
© 2007 American Heart Association, Inc.
Original Articles |
Left Atrial Size and Risk of Major Cardiovascular Events During Antihypertensive Treatment
Losartan Intervention for Endpoint Reduction in Hypertension Trial
From the Institute of Medicine (E.G., P.O.), University of Bergen, Bergen, Norway; the Department of Medicine (K.W.), Copenhagen County University Hospital, Glostrup, Denmark; the Department of Medicine (J.E.O.), Vestfold Central Hospital, Tönsberg, Norway; the Department of Cardiology (L.O.), Helsinki University Central Hospital, Helsinki, Finland; the Department of Medicine (K.B.), Skellefteå Hospital and Umeå University, Skellefteå, Sweden; the Department of Medicine (B.D.), Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; and the Department of Medicine (R.B.D.), Weill Medical College of Cornell University, New York, NY.
Correspondence to Eva Gerdts, Institute of Medicine, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail gerdtsev{at}online.no
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Abstract |
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The influence of left atrial size on cardiovascular events during antihypertensive treatment has not been reported previously from a long-term, prospective, randomized hypertension treatment trial. We recorded left atrial diameter by annual echocardiography and cardiovascular events in 881 hypertensive patients (41% women) with electrocardiographic left ventricular hypertrophy aged 55 to 80 (mean: 66) years during a mean of 4.8 years of randomized losartan- or atenolol-based treatment in the Losartan Intervention for Endpoint Reduction in Hypertension Study. During follow-up, a total of 88 primary end points (combined cardiovascular death, myocardial infarction, or stroke) occurred. In Cox regression, baseline left atrial diameter/height predicted incidence of cardiovascular events (hazard ratio: 1.98 per cm/m [95% CI: 1.02 to 3.83 per cm/m]; P=0.042) adjusted for significant effects of Framingham risk score and history of atrial fibrillation. Greater left atrial diameter reduction during follow-up was associated with greater reduction in left ventricular hypertrophy, absence of new-onset atrial fibrillation or mitral regurgitation during follow-up, and losartan-based treatment (B=–0.13±0.03 cm/m; P<0.001) in multiple linear regression, adjusting for baseline left atrial diameter/height. However, in time-varying Cox regression analysis, left atrial diameter reduction was not independent of left ventricular hypertrophy regression in predicting cardiovascular events during follow-up. In conclusion, left atrial diameter/height predicts risk of cardiovascular events independent of other clinical risk factors in hypertensive patients with left ventricular hypertrophy and may be useful in pretreatment clinical assessment of cardiovascular risk in these patients.
Key Words: cardiovascular events • hypertension • left atrium • left ventricular hypertrophy
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Introduction |
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Studies in samples of the general population and in hypertensive patients have identified left atrial (LA) enlargement as a cardiovascular (CV) risk marker, in particular for atrial fibrillation and stroke.1–3 We have shown previously that larger LA diameter in hypertensive patients is associated with other clinical and echocardiographic covariates of higher CV risk in hypertension, including higher body mass index, systolic blood pressure and age, left ventricular (LV) hypertrophy, eccentric LV geometry and mitral regurgitation by echocardiography, and atrial fibrillation.4 However, less is known about the effect of antihypertensive treatment on LA diameter or on the relation between LA diameter and CV events during antihypertensive treatment.5 Therefore, we evaluated the effect of losartan- or atenolol-based antihypertensive therapy on LA diameter and the relation between in-treatment LA diameter and CV events in the echocardiographic substudy of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study.
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Methods |
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Patient Population
The LIFE echocardiography study was a prospectively planned substudy of the main LIFE study, which enrolled 960 of the 9193 participants in the parent trial for annual echocardiographic follow-up.6,7 Patient characteristics and outcome results in the main LIFE study that randomly assigned patients aged 55 to 80 years with essential hypertension (baseline blood pressure: 160 to 200/95 to 115 mm Hg) and ECG LV hypertrophy (according to Cornell voltage duration or Sokolow–Lyon voltage criteria) to a mean of 4.8 years double-blind treatment with losartan compared with atenolol have been published, including the effects of treatment on CV events and regression of ECG LV hypertrophy.6,8 Of the 960 patients enrolled in the LIFE echocardiographic substudy, 881 patients had LA diameter measured at enrollment and on
1 follow-up echocardiogram and, thus, were eligible for the present study (Table 1). Patients were classified as having isolated systolic hypertension if systolic blood pressure was 140 mm Hg and diastolic blood pressure <90 mm Hg, respectively, at baseline clinic visits.9 Pulse pressure was calculated as the difference between sitting clinic systolic and diastolic blood pressures and mean blood pressure as sitting diastolic blood pressure plus one-third pulse pressure. Diabetes mellitus was diagnosed by the 1985 World Health Organization criteria or use of hypoglycemic medication.10 All of the patients gave informed consent to participate in the LIFE echocardiography substudy, which was approved by regional ethics committees in all of the participating countries.
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Doppler Echocardiography
Organization, patient recruitment, protocol, and echocardiographic methods used in the LIFE echocardiographic substudy have been published previously.7,11 All of the echocardiograms were sent to the Cornell Echocardiography Reading Center for blinded interpretation. Measurements of LA and LV diameter and wall thicknesses were made on 2D parasternal long-axis views according to American Society of Echocardiography standards.12 The LA was considered enlarged when LA diameter exceeded 3.8 cm in women and 4.2 cm in men, the upper limit of the 95% CI of LA diameter found in 413 apparently normal adults from a multiethnic population.13 Reproducibility of LA diameter measurement by this method was assessed in a separate series of 183 hypertensive patients with paired pre-enrollment echocardiograms in the Prospective Randomized Study Evaluating Regression of Ventricular Enlargement (PRESERVE) study.14 Mean LA diameter was 39 mm on both sets of echocardiograms with a mean difference of 0.4 mm and an SD of 4 mm (intraclass correlation coefficient=0.62; P<0.001).14 Endocardial fractional shortening was calculated as the ratio (diastolic–systolic LV internal diameter)/diastolic LV internal diameter, the LV ejection fraction by the Teichholz method, as validated previously, and LV mass using an autopsy-validated formula.15–19 LV geometry was assessed from LV mass/body surface area and relative wall thickness in combination.20 LV hypertrophy was considered present when LV mass/body surface area exceeded 116 g/m2 in men and 104 g/m2 in women, respectively.21 Mitral regurgitation was assessed by color Doppler using a previously described 4-category grading system.22 Supine blood pressure measured by arm cuff sphygmomanometer at the end of the echocardiogram was used in the calculation of hemodynamic variables. Heart rate was measured from the echocardiographic recordings.
End Points
The prespecified primary end point of the LIFE Study was the first occurrence of CV death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke, as determined by an independent end point classification committee.6 The current analyses of change in LA diameter and its relation to CV events were planned in 200, and added to other prespecified data analyses in the LIFE echocardiography study before unblinding of the study results.
Statistical Analyses
Data management and analysis were performed using SPSS 13.0 software. Data are presented as mean±SD for continuous variables and as percentages for categorical variables. Between-group comparisons were made by 
2 statistics, unpaired Student’s t test, and general linear model, as appropriate. Covariates of baseline LA diameter/height were assessed by Pearson correlation coefficients and by multiple linear regression using an enter procedure with assessment of collinearity diagnostics. To evaluate correlates of change in LA diameter during treatment, the difference between LA diameter at baseline and on the final study echocardiogram or the last echocardiogram before occurrence of a primary composite end point was calculated in each individual patient. In-treatment changes in blood pressure, body mass index, LV mass, and LV ejection fraction in individual patients were calculated in the same way. Covariates of LA diameter change during antihypertensive treatment were assessed by Pearson correlation.
The associations of baseline LA diameter/height with the composite end point and with CV death, myocardial infarction, and stroke as separate end points were evaluated using Cox regression models. Results are given as hazard ratios (HRs) and 95% CIs. To assess the relation between change in LA diameter during antihypertensive therapy and CV events, time-varying Cox regression analyses were used with LA diameter/height; systolic blood pressure and LV mass as time-varying covariates, updated at each annual visit; and Framingham risk score (based on age, gender, diabetes, total and high-density lipoprotein, and baseline systolic blood pressure and LV hypertrophy measured by electrocardiography),23 race, and treatment allocation as fixed covariates.24,25 To estimate the additive effect of LA diameter measurement in the prediction of CV risk, receiver–operator characteristic curves were generated from logistic regression models including baseline or in-treatment variables reflecting variables in the Cox regression models. Two-tailed P<0.05 was considered significant both in univariate and multivariate analyses.
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Results |
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The study population consisted of 85% whites, 13% blacks, 1.7% Hispanics, and 0.3% Asians. Baseline characteristics including race were similar in patients randomly assigned to atenolol- or losartan-based therapy (Table 1). In the entire population (n=881), mean baseline LA diameter and LA diameter/height were 3.94±0.56 cm and 2.33±0.33 cm/m, respectively. LA diameter fell from baseline by 0.13±0.52 cm at year 1 (n=847), 0.13±0.50 cm at year 2 (n=790), 0.17±0.52 cm at year 3 (n=746), and 0.10±0.54 cm at year 4 (n=714) and increased by 0.11±0.49 cm at year 5 (n=342). As a result, the prevalence of LA dilatation fell from 46% at baseline to 36% after 1 year, 35% after 2 years, 31% after 3 years, and returned to 38% at 4 years and 43% at 5 years.
Change in LA Diameter
Mean baseline LA diameter and LA diameter/height were similar in the losartan and atenolol groups (3.94±0.55 cm and 2.32±0.31 cm/m versus 3.94±0.57 cm and 2.33±0.34 cm/m, respectively). In spite of similar blood pressure reduction in the 2 treatment arms (from 174/99 to 144/82 mm Hg in the losartan group and from 174/98 to 146/82 mm Hg in the atenolol group), LA diameter was reduced more from baseline to each annual in-study echocardiogram (Figure 1) and to the last available echocardiogram in patients receiving losartan-based therapy (0.15±0.51 versus 0.01±0.57 cm; P<0.001). The greater LA diameter reduction in losartan-treated patients was confirmed with adjustment for in-treatment changes in blood pressure and body mass index (0.19±0.50 versus 0.06±0.58 cm; P<0.01). There was no significant relation between LA diameter change during antihypertensive treatment and age, gender, presence of diabetes, or in-treatment change in systolic blood pressure or body mass index. In contrast, LA diameter reduction was weakly associated with reduction in LV mass (r=0.15) and increase in LV ejection fraction (r=0.10; both P<0.01). In multiple regression analysis adjusting for baseline LA diameter/height and including correlates of LA diameter change during antihypertensive treatment identified from univariate analyses, greater in-treatment LA diameter reduction was associated with greater LV hypertrophy regression (ß=0.07), absence of new-onset atrial fibrillation (ß=0.07) or mitral regurgitation during follow-up (ß=0.10), black race (ß=0.09), and losartan treatment (ß=0.14; all P<0.05). Adding in-treatment change in systolic blood pressure and heart rate to the covariates did not change the results (Table 2). The prevalence of mitral regurgitation in the overall study population increased from 24% at baseline to 40% at final study echocardiogram.
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Predictors of Clinical Events
During 4.8 years of follow-up, a total of 88 primary end points (CV death, myocardial infarction, or stroke) occurred. In Cox regression analysis adjusting for treatment allocation, Framingham risk score, race, history of atrial fibrillation, or congestive heart failure and baseline echocardiographic LV hypertrophy, baseline LA diameter/height predicted the incidence of combined CV events (HR: 1.98 per cm/m [CI: 1.02 to 3.83 per cm/m]; P=0.042) independent of significant effects of Framingham risk score and history of atrial fibrillation (Table 3). In models evaluating the 3 individual components of the primary end point adjusting for Framingham risk score and treatment allocation, larger baseline LA diameter/height was associated with higher incidence of CV death (n=20; HR: 3.98 per cm/m [CI: 1.09 to 14.48 per cm/m]; P=0.036) and stroke (n=52; HR: 2.44 per cm/m [CI: 1.08 to 5.52 per cm/m]; P=0.033) but not with incidence of myocardial infarction (n=33; HR: 1.55 per cm/m [CI: 0.54 to 4.40 per cm/m]; P=0.414).
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Risk of having a primary composite end point differed significantly according to time-varying LA diameter below or above the mean LA diameter at annual study visits (P<0.01; Figure 2). The association of in-treatment LA diameter/height with CV events was first tested using a Cox regression model with time-varying LA diameter/height and systolic blood pressure as time-varying covariates and Framingham risk score, race, and treatment allocation as fixed covariates. Lower in-treatment LA diameter/height was significantly associated with lower incidence of the primary composite end point (HR: 0.50 per cm/m [CI: 0.29 to 0.92 per cm/m]; P=0.027) and, in particular, with a lower rate of stroke (HR: 0.40 per cm/m [CI: 0.19 to 0.82 per cm/m]; P=0.012), without significant association with CV mortality (HR: 0.42 per cm/m [CI: 0.13 to 1.35 per cm/m]; P=0.146), or with myocardial infarction (HR: 0.53 per cm/m [CI: 0.21 to 1.32 per cm/m]; P=0.171). When time-varying LV mass was added to the covariates in the model, time-varying LA diameter change did not remain an independent covariate of the primary end point, whereas LV mass reduction was significantly associated with lower incidence of the primary end point (HR: 0.95 per 10 g [CI: 0.91 to 0.99 per 10 g]; P=0.02).
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In a final time-varying Cox regression model, baseline LA diameter indexed for height was added as a fixed covariate with retention of the previous variables from the previous model (time-varying systolic blood pressure, LV mass, and LA diameter indexed for height and baseline Framingham risk score and indicator variables for study treatment allocation and race as fixed covariates). In this model, neither baseline LA diameter/height (HR: 1.56 per cm/m [CI: 0.74 to 3.29 per cm/m]; P=0.238) nor time-varying LA diameter/height (HR: 1.56 per cm/m [CI: 0.80 to 3.06 per cm/m]; P=0.193) were independently associated with the primary end point.
The additive effect of measuring LA diameter in outcome prediction was assessed by receiver-operated curves derived from logistic regression models including baseline Framingham risk score and indicator variables for black race and study treatment allocation and baseline or in-treatment systolic blood pressure, echocardiographic LV hypertrophy, and LA diameter, respectively, in 2 different models. Adding baseline LA diameter measurement to the other covariates in the model increased the area under the receiver-operated curve by 1.8%, whereas adding in-treatment LA diameter did not change the area.
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Discussion |
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LA enlargement detected by electrocardiography or echocardiography is a common finding in hypertensive patients, which may reflect structural or functional hypertensive heart disease.4,5,26–30 Within hypertensive populations, echocardiographic LA diameter has been related to higher age and systolic blood pressure, female gender, white race, obesity, LV hypertrophy, eccentric geometry, and the presence of atrial fibrillation and mitral regurgitation.2,4,29,30
Although previous reports have linked higher LA diameter to CV events, including stroke and death, in the general population,1,2,31 less data have been available from studies in hypertensive patients.3,5,32 In particular, the influence of LA size on CV events during antihypertensive treatment has not been reported previously from a long-term, prospective, randomized hypertension treatment trial. Thus, the present study adds to previous knowledge by showing that echocardiographic LA diameter measured before starting antihypertensive therapy predicts subsequent CV events, particularly stroke, in hypertensive patients with electrocardiographic LV hypertrophy. Risk stratification by pretreatment LA diameter in hypertensive patients was independent of other factors known to affect prognosis, including age, gender, race, diabetes, LV hypertrophy, smoking, and history of atrial fibrillation.
The ease of making a simple 2D measurement of atrial diameter facilitates incorporation of our results into cardiologists’ daily assessment of CV risk in hypertensive patients. It is possible that LA volume measured by the more complicated biplane Simpson technique would be an even stronger predictor of CV events in hypertensive patients as suggested by Tsang et al33 in a recent publication comparing prediction of CV outcomes by LA diameter to that of LA volume and LA area in 423 unselected patients referred for medical consultation, including echocardiography, at the Mayo Clinic. Of note, in their study, baseline measurements of LA diameter, LA area, and LA biplane volume all independently predicted subsequent risk of CV events over 3.5 years, including new-onset atrial fibrillation, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and CV death, in Cox regression analyses (HRs: 9.0, 3.9, and 6.6, respectively).33 However, the area under the receiver–operator characteristic curves was largest for LA volume, suggesting that it was better able to capture a graded relation between LA sizes ranging from small to markedly dilated and the likelihood of CV events. Because of the need to incorporate echocardiography into an extensive clinical protocol, LA volume measurement was not added to the >4500 echocardiograms performed in the LIFE echocardiography substudy.
The association between reduction in LA diameter during antihypertensive treatment and combined CV events, particularly stroke, demonstrated in the present study, as well as the finding that losartan-based therapy reduces LA diameter more, suggests that some of the preventive effect of losartan against stroke and new-onset atrial fibrillation found in the main LIFE study may have been mediated through losartan-induced reduction in LA size.8,34 Our finding that LA diameter reduction parallels reduction in LV mass is in accordance with previous reports.5,31 As demonstrated in Cox regression analysis including both baseline and in-treatment LA diameter and in-treatment LV mass among the covariates, repeated measurements of LA diameter during treatment do not add to CV risk assessment from combined clinical variables and baseline LA diameter or in-treatment LV mass. Furthermore, the superiority of losartan in reducing LA diameter in the present study mainly reflects the greater ability of losartan than atenolol to reduce LV mass.35 However, because LA afterload, a key modulator of LA size, is based on LV chamber compliance, as well as LV volume, LA diameter reduction may also reflect improved LV compliance and/or relaxation as a consequence of reduction in LV hypertrophy.36
The present study also adds to previous knowledge by demonstrating that the favorable initial reduction in LA diameter induced by antihypertensive therapy diminishes over time, in spite of persistent reduction in blood pressure and LV hypertrophy, particularly in the atenolol group. This phenomenon, which emerged after 3 to 4 years of study therapy, may be related to the continuous aging of the study population and increased prevalence of mitral regurgitation, as well as occurrences of myocardial infarctions and other CV events during the study period.
In conclusion, larger pretreatment LA diameter by echocardiography predicts a higher rate of subsequent CV events during antihypertensive treatment in hypertensive patients with LV hypertrophy, independent of risk stratification derived from other clinical variables. Compared with atenolol-based therapy, losartan-based therapy leads to more LA diameter reduction for the same level of blood pressure reduction. Change in LA diameter during antihypertensive treatment predicted CV events independent of clinical covariates but not of LV mass change during antihypertensive therapy.
Perspectives
It was pointed out recently in the joint guidelines for the management of hypertension published by the European Societies of Hypertension and Cardiology that using echocardiography in CV risk assessment in hypertensive patients may more correctly identify individual CV risk.37 Our results support this statement by demonstrating that measurement of LA diameter on pretreatment echocardiograms adds to detection of LV hypertrophy for CV risk stratification in hypertensive patients with electrocardiographic LV hypertrophy. However, our results also demonstrate that repeated measurements of LA diameter during antihypertensive treatment do not add to the prediction of major CV events above that derived from combined assessment of clinical risk factors and in-treatment echocardiographic LV hypertrophy.
Study Limitations
Given the recent documentation for LA volume being a somewhat stronger prognostic marker of CV disease than LA diameter, lack of LA volume measurement is a limitation of the present study.33 Because LA diameter does not consistently reflect LA volume, the results of this and previous studies may be weaker than would be obtained using LA volume measurements.1–2,31 Still, a simple 2D LA diameter measurement remains common in daily cardiology practice.
Our study was performed in hypertensive patients with electrocardiographic signs of LV hypertrophy, and results may not be generalizable to other groups of patients. However, hypertensive patients with electrocardiographic signs of LV hypertrophy have been estimated at 7.8 million in the first 15 nations assembled in the European Union,38 and nearly as many have been postulated both in Eastern Europe and in the United States.
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Acknowledgments |
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We thank Paulette A. Lyle for assistance with preparation of the article.
Sources of Funding
This study was supported by grant COZ-368 from Merck & Co, Inc (>$10 000) and the Caroline Musaeus Aarsvold grant from the Norwegian Medical Association (>$10 000).
Disclosures
E.G., K.W., J.E.O., L.O., K.B., and R.B.D. were investigators for the LIFE Study. P.O., B.D., and R.B.D. were steering committee members for the LIFE Study. B.D. and R.B.D. have received grant support from Merck & Co, Inc, the sponsor of the LIFE Study. All of the authors have received honoraria for occasional talks given at Merck-sponsored symposia.
Received July 28, 2006; first decision August 21, 2006; accepted November 20, 2006.
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