Left atrial (LA) enlargement diagnosed by electrocardiography

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1 Correlates of Left Atrial Size in Hypertensive Patients With Left Ventricular Hypertrophy The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study Eva Gerdts, Lasse Oikarinen, Vittorio Palmieri, Jan Erik Otterstad, Kristian Wachtell, Kurt Boman, Björn Dahlöf, Richard B. Devereux Abstract Left ventricular hypertrophy has been suggested to mediate the relation between hypertension and left atrial enlargement, with associated risks of atrial fibrillation and stroke. However, less is known about correlates of left atrial size in hypertensive patients with left ventricular hypertrophy. We assessed left atrial size by echocardiography in 941 hypertensive patients, age 55 to 80 (mean, 66) years, with electrocardiographic left ventricular hypertrophy at baseline in the Losartan Intervention For Endpoint reduction in hypertension study. Enlarged left atrial diameter (women, 3.8 cm; men, 4.2 cm) was present in 56% of women and 38% of men (P 0.01). Compared with the 512 patients with normal left atrial size, the 429 patients with enlarged left atrium more often had mitral regurgitation, atrial fibrillation, and echocardiographic left ventricular hypertrophy. They also had higher age, systolic blood pressure, pulse pressure, weight, body mass index, left ventricular internal chamber dimension, stroke volume, and mass and lower relative wall thickness and ejection fraction (all, P 0.05). In logistic regression analysis, left atrial enlargement was related to left ventricular hypertrophy and eccentric geometry; greater body mass index, systolic blood pressure, and age; female gender; mitral regurgitation; and atrial fibrillation (all, P 0.05). Thus, left atrial size in hypertensive patients with electrocardiographic left ventricular hypertrophy is influenced by gender, age, obesity, systolic blood pressure, and left ventricular geometry independently of left ventricular mass and presence of mitral regurgitation or atrial fibrillation. (Hypertension. 2002;39: ) Key Words: left atrial size hypertrophy age body mass index Left atrial (LA) enlargement diagnosed by electrocardiography or echocardiography is a common finding in hypertensive patients, indicating hypertensive heart disease. 1 4 Echocardiographic LA size in hypertension has been related to systolic blood pressure and left ventricular (LV) hypertrophy in older patients with isolated systolic hypertension. 1 Furthermore, echocardiographic studies in men with mild to moderate hypertension have suggested age, obesity, and race as other important covariates of LA size. 5,6 Recent studies have shown that LA enlargement is a risk factor for atrial fibrillation and stroke, especially in men. 7,8 LV hypertrophy has been suggested to mediate, at least partially, the relation between hypertension and LA enlargement. However, correlates of LA size in hypertensive patients with LV hypertrophy have so far not been assessed in a large-scale study. Thus, the aim of the present study was to describe factors associated with LA enlargement in hypertensive patients with electrocardiographic LV hypertrophy recruited into the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Methods Patients The present study was performed as an echocardiographic substudy to the LIFE study. From a total of 9194 hypertensive patients age 55 to 80 years who were recruited into the LIFE study at sites in Denmark, Finland, Iceland, Norway, Sweden, United Kingdom, and United States, 963 patients were enrolled in the echocardiographic substudy. All patients had casual blood pressure in the range 160 to 200/95 to 115 mm Hg, and electrocardiographic LV hypertrophy by either Sokolow-Lyon voltage criteria (SV1 RV5/RV6 38 mv) or Cornell voltage-duration criteria ( 2440 mv ms). Baseline characteristics of the total LIFE study population and study design for the LIFE echocardiographic substudy have been previously pub- Received June 5, 2001; first decision September 13, 2001; revision accepted January 11, From Department of Heart Disease, Haukeland University Hospital (E.G.), Bergen, Norway; Department of Medicine, Helsinki University Central Hospital (L.O.), Helsinki, Finland; Department of Medicine, Weill Medical College of Cornell University (V.P., R.B.D.), New York, NY; Department of Medicine, Vestfold Central Hospital (J.E.O.), Tönsberg, Norway, Department of Medicine, Copenhagen County University Hospital (K.W.), Glostrup, Denmark; Department of Medicine, Skellefteaa Hospital and Umeaa University (K.B.), Skellefteaa, Sweden; and Department of Medicine, Sahlgrenska University Hospital-Östra (B.D.), Gothenburg, Sweden. Correspondence to Eva Gerdts MD, PhD, Department of Heart Disease, Haukeland University Hospital, N-5021 Bergen, Norway. evgerdts@online.no 2002 American Heart Association, Inc. Hypertension is available at 739

2 740 Hypertension March 2002 lished. 9,10 Electrocardiographic LA enlargement was diagnosed by P-terminal forces in lead V 1 criteria and considered present if terminal P-wave area was 0.04 mv sec. 11 Sitting blood pressure and heart rate were measured at baseline clinical visits. Pulse pressure was calculated as the difference between systolic and diastolic blood pressure, and mean blood pressure as diastolic blood pressure plus one third of pulse pressure. All patients gave written informed consent to participate in the echocardiographic substudy. Study Design All examinations were performed with commercially available phased-array transducers, using frequencies between 2.5 and 3.5 MHz, and recorded on VHS videotapes. Recordings were made by a standardized previously published protocol. 10,12 Blood pressure measured by mercury or regularly calibrated aneroid cuff manometer at the end of the echocardiographic examination was used for calculation of end-systolic stress, pulse pressure/stroke volume ratio, and total peripheral resistance. All video recordings were sent for blinded interpretation at the Echocardiographic Reading Center at The New York Hospital Cornell Medical Center. Echocardiographic Methods Measurements at the Echocardiographic Reading Center were made using a computerized review station equipped with digitizing table and monitor screen overlay. LV internal diameters and wall thicknesses at end-diastole and end-systole were measured by M-mode echocardiography following the American Society of Echocardiography recommendations on up to 3 cardiac cycles. 13,14 LA diameter was measured in the parasternal long-axis view from the trailing edge of the posterior aortic-anterior left atrial complex to avoid including the variable size of the connective tissue filled space between these structures erroneously in atrial diameter, as previously reported. 15 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% confidence interval of LA size found in 413 apparently normal adults in another study from the Reading Center. 15 LV mass was calculated by an anatomically validated formula (r 0.90 versus necropsy LV mass). 16 LV mass showed excellent interstudy reliability (RHO 0.93) in a separate study of 183 patients from the Reading Center. 17 LV hypertrophy was considered present when LV mass/body surface area exceeded 116 g/m 2 in men and 104 g/m 2 in women. 18 Relative wall thickness (RWT) was calculated at end-diastole as posterior wall thickness/internal radius. 19 Increased RWT was regarded present when the ratio was LV geometry was assessed from LV mass/body surface area and RWT in combination. 20 Midwall fractional shortening was calculated from parasternal short-axis using a formula previous validated formula. 21 Circumferential end-systolic stress was estimated at midwall from M-mode tracings using a formula derived from the cylindric model by Gaasch et al. 22,23 Stroke volume, calculated by an invasively validated Doppler echocardiographic method, was used to calculate cardiac output and total peripheral resistance. 24 The leading edge of transmitral Doppler flow pattern was traced to derive the peak early (E) and atrial (A) LV filling phase and their ratio (E/A). Atrial filling fraction was calculated as the ratio of the A-wave time velocity integral to the total diastolic time velocity integral. E/A ratios of 0.6 and 1.5 measured at mitral anular level have previously been identified as the fifth and 95th percentiles of a reference range in 124 apparently normal adults in another study from the Reading Center. 25 Using a previously published equation 26 predicting E/A ratio at mitral leaflet tips from measurements at mitral anulus, E/A ratios of 0.7 and 1.5 were regarded as low or high for age, respectively, in the present study population. An isovolumic relaxation time (IVRT) 105 ms was regarded prolonged in all patients. Mitral regurgitation was assessed from color Doppler recordings using a previously described 4-point grading system based on the farthest distance reached from the mitral orifice adjusted for jet width when appropriate. 27 TABLE 1. General Characteristics of Patients With Normal or Normal LA (n 512) (n 429) Women, % 44 56* Diabetes, % 9 13 Atrial fibrillation, % 0.4 3* Previous myocardial infarction, % 4 7 Previous stroke, % 8 8 Age, y * Systolic blood pressure, mm Hg * Diastolic blood pressure, mm Hg Pulse pressure, mm Hg * Mean blood pressure, mm Hg Heart rate, bpm Height, cm Weight, kg * Body surface area, m * Body mass index, kg/m * *P 0.01, P 0.05 between groups. Statistical Analyses SPSS statistical computing program version 10.0 (SPSS Inc) was used for data management and analysis. Continuous variables are expressed as mean SD; categorical data, as percentages. Differences in continuous and categorical variables between the groups of patients with normal and enlarged LA size were assessed by unpaired samples Student s t tests and 2 analyses, respectively. Differences in LA size between groups of patients with different LV geometry and E/A ratios were assessed by one-way ANOVA followed by the Scheffé post hoc test. LA size in white and black participants was compared in a general linear model adjusting for age, height, weight, and gender. Bivariate correlations between LA size and LV geometric variables were assessed with Pearson s correlation coefficients. Binary logistic regression analysis was performed to identify covariates of LA enlargement. A 2-tailed P 0.05 was considered statistically significant. Results Of the total of 963 hypertensive patients with electrocardiographic LV hypertrophy recruited into the LIFE echocardiographic substudy, 941 patients (388 women and 553 men) had echocardiograms with measurable LA and LV dimensions. By echocardiography, 512 patients (54%) had normal LA size and 429 had LA enlargement. Patients with LA enlargement were older, were more obese, had higher systolic blood pressure and pulse pressure, and included more women and patients with diabetes or atrial fibrillation (Table 1). There was a trend toward larger LA diameter in the 790 white participants compared with the 131 black participants after adjustment for covariates ( versus cm, P 0.10). LA size or prevalence of LA enlargement did not differ between groups of patients with isolated systolic hypertension and combined systolic-diastolic hypertension. Atrial fibrillation was present in 15 patients, of whom 5 (33%) had concomitant diabetes mellitus. Compared with patients with normal LA size, patients with LA enlargement had significantly larger LV internal chamber

3 Gerdts et al Correlates of Left Atrial Size in Hypertension 741 TABLE 2. LV Size and Hemodynamic s in Patients With Normal or Normal LA (n 512) (n 429) Interventricular septal thickness, cm * Left ventricular internal diameter, cm * Posterior wall thickness, cm * Relative wall thickness Left ventricular mass, g * Left ventricular mass/body surface * area, g/m 2 Left ventricular mass/height 2.7, g/m * Left ventricular hypertrophy, % 61 81* Left ventricular endocardial shortening, % * Left ventricular ejection fraction, % * Midwall shortening, % Circumferential end-systolic stress, * kdyne/cm 2 Doppler stroke volume, ml Cardiac output, ml/min Total peripheral resistance, dynes sec cm 5 Mitral regurgitation, % Grade Grade Grades 3 and *P 0.01, P 0.05 between groups, P 0.01 for any degree of mitral regurgitation. dimensions, stroke volume, and mass; a higher prevalence of echocardiographic LV hypertrophy; and a lower LV ejection fraction and relative wall thickness (Table 2). Similar results were found in alternative analyses that indexed LA diameter for body height. Doppler diastolic indices did not differ between the groups of patients with normal and enlarged LA, respectively. However, patients with high E/A ratio for age or prolonged IVRT and/or with low E/A ratio for age had significantly larger LA compared with patients with normal E/A ratio and IVRT for age (Table 3). Blood pressure, heart rate, gender distribution, and body mass index did not differ between these groups of patients. Both LA size and prevalence of LA enlargement differed significantly in relation to LV geometry, being larger in patients with eccentric LV hypertrophy ( cm and 58%, respectively) than those with concentric LV hypertrophy ( cm and 46%), normal LV geometry ( cm and 28%), or concentric remodeling ( cm and 32%), respectively (all, P 0.01). Mitral regurgitation was present in 20% of patients with normal LA size and in 29% of patients with LA enlargement (P 0.01). The regurgitation was classified as grade 1 in the majority of patients (Table 2). Mitral regurgitation was more prevalent among women than men (30% versus 20%, P 0.001). LA size as a continuous variable was positively related to age (r 0.13), weight (r 0.38), height (r 0.24), body mass TABLE 3. Echocardiographic Findings in Patients With Low E/A Ratio and/or Prolonged IVRT for Age (Group 1), Normal IVRT and E/A Ratio for Age (Group 2), or High E/A Ratio for Age Irrespective of IVRT (Group 3) Group 1 (n 585) Group 2 (n 160) Group 3 (n 28) Age, y 67 7* * Isovolumic relaxation time, msec E/A ratio Deceleration time, msec * Left atrium diameter, cm * * Left ventricular internal diameter, cm Left ventricular mass/body * surface area, g/m 2 Relative wall thickness Midwall shortening, % * * Ejection fraction, % 61 8* * *P 0.05 vs group 2 (normal IVRT and E/A ratio for age). index (r 0.26), systolic blood pressure (r 0.15), pulse pressure (r 0.11), LV mass (r 0.48), LV internal end-systolic (r 0.38) and end-diastolic diameter (r 0.43), interventricular septal and posterior wall thickness (r 0.24 and 0.23, respectively), stroke volume (r 0.18), end-systolic stress (r 0.22), E/A ratio (r 0.10), and IVRT (r 0.07) (all, P 0.01). Furthermore, LA size was negatively related to LV ejection fraction (r 0.22), endocardial and midwall shortening (r 0.21 and 0.14, respectively), relative wall thickness (r 0.10), total peripheral resistance, and atrial filling fraction (both r 0.07) (all, P 0.05). A binary logistic regression model was created, using an indicator variable for LA enlargement as dependent variable, with age, body mass index, and indicator variables for LV geometry and hypertrophy, as well as for gender, and presence of atrial fibrillation and mitral regurgitation, respectively, as independent variables. LA enlargement was related to presence of LV hypertrophy, eccentric LV geometry, higher body mass index, systolic blood pressure and age, female gender, and presence of mitral regurgitation and atrial fibrillation (Nagelkerke R , P 0.001) (Table 4). In TABLE 4. Independent Covariates of LA Enlargement Identified by Binary Logistic Regression Analysis Odds Ratio 95% Confidence Interval Left ventricular hypertrophy Concentric geometry Body mass index (kg/m 2 ) Systolic blood pressure (mm Hg) Age (y) Female gender Mitral regurgitation Atrial fibrillation (Nagelkerke R , P 0.01).

4 742 Hypertension March 2002 another model replacing LV hypertrophy with LV mass, a similar result was found. Diastolic Doppler indices and indicator variables for previous myocardial infarction and stroke did not enter when included in additional models. ECG LA enlargement was present in 38% of patients in the study population. By echocardiography, patients with ECG LA enlargement had higher peak A velocity (0.83 versus 0.80 m/s, P 0.05), whereas left atrial diameter and LV mass/body surface area did not differ significantly ( versus cm, and versus g/m 2, respectively, both P 0.06). Discussion Although LA enlargement is a common finding in hypertensive patients that indicates hypertensive heart disease, few echocardiographic studies have assessed LA size in hypertension. 1,2,5,6 The present study is the first to describe covariates of LA size in a large hypertensive population with ECG LV hypertrophy. The study adds to previous knowledge by identifying several independent covariates of LA size in middle-aged and older hypertensives: LV hypertrophy and eccentric geometry, higher body mass index, systolic blood pressure and age, female gender, and presence of atrial fibrillation and mitral regurgitation. The first finding, that LA size was significantly related to LV mass, is in accordance with previous findings in older patients with isolated systolic hypertension. 1 However, the present study adds to their findings by demonstrating a relation of LA size with LV geometry, as well as with LV mass and the prevalence of echocardiographic LV hypertrophy in a large group of patients, including both combined systolic-diastolic and isolated systolic hypertension. In particular, LA enlargement was associated with eccentric LV hypertrophy in these middle-aged and older hypertensive patients. Obesity has previously been suggested to mediate the relation between LA size and LV mass in veteran studies. 5,6 The present study modifies this conclusion by finding independent associations of both obesity and LV hypertrophy with LA enlargement. The different findings may be explained by major differences in patient characteristics including the presence of women, less obesity, and a higher prevalence of LV hypertrophy in the present study. Still, the impact of obesity on LA size in hypertensive patients is demonstrated both by the significantly larger body mass index found in patients with LA enlargement and by the independent relation between body mass index and absolute LA size. The mechanism by which overweight leads to LA enlargement is unclear, but a relation to hemodynamic changes seen in obese patients, including increased intravascular volume and larger stroke volume and cardiac output, has been suggested. 28,29 This view is supported by our findings, as stroke volume, cardiac output, and body mass index were higher in patients with LA enlargement in the present study. Systolic blood pressure is a well-established determinant of LV mass in hypertensives. 30,31 A relation between systolic blood pressure and LA size has previously been reported in the Framingham Heart Study. 32 Their report demonstrated LA enlargement to be associated both with the duration of elevated blood pressure and with the level of systolic pressure in a general population, and suggested LV hypertrophy to mediate the effect of systolic blood pressure on LA size. 32 The present study adds to previous findings by showing that systolic pressure influences LA size in middle-aged and older hypertensive patients independent of LV hypertrophy. Atrial fibrillation was present in only 1.6% of the study population. The prevalence is lower than expected from the age of this hypertensive population, probably because of exclusion from LIFE of patients that needed -blocker treatment for rate control of atrial fibrillation. 9,33 Still, atrial fibrillation was independently associated with LA enlargement in the present study population, and was also associated with concomitant diabetes mellitus. These findings are in accordance with previous publications identifying hypertension and diabetes as major predictors of incident atrial fibrillation in general and hypertensive populations. 33,34 The present study is to our knowledge the first to report mitral regurgitation as a predictor of LA enlargement, independent of other covariates, including LV hypertrophy and atrial fibrillation, in middle-aged and older hypertensives. Mitral regurgitation assessed by color Doppler echocardiography was present in 24% of the present study population. The prevalence is, as expected, somewhat higher than the about 20% prevalence reported from surveys of slightly younger population based samples. 27,35 The present study also shows that LA enlargement was particularly common in women. Our finding that mitral regurgitation was more prevalent in women is in accordance with previous reports. 27,35 However, female gender was associated with LA enlargement independent of mitral regurgitation and other known covariates of LA size in the present study. Previous reports in general population and populationbased case control studies have found LA size in women to be associated with mitral regurgitation, but not with risk of stroke. 8,27,35 The prognostic value of LA enlargement in men and women with respect to stroke will be addressed in a follow-up study of the present study population. Theoretically, LA enlargement in hypertensive patients with LV hypertrophy can be secondary both to changes in systolic and diastolic LV function. In particular, electrocardiographic signs of LA enlargement has been regarded as an early clinical sign of reduced diastolic LV function in patients with normal systolic LV function. 4 This clinical view is supported by several findings in the present study: patients with normal E/A ratio for age had smaller mean LA size; LA size was weakly but significantly associated with longer IVRT, higher E/A ratio, and lower atrial filling fraction, suggesting that both impaired relaxation and increased passive stiffness influence LA size. However, as most patients included in the present study had impaired diastolic function (in particular abnormal relaxation) as evaluated by diastolic Doppler indices, the relations between LA enlargement and diastolic Doppler indices were less striking, and none of the diastolic Doppler variables were identified as independent correlates of LA size in multivariate analyses. In conclusion, echocardiographic LA enlargement is commonly found in hypertensive patients with electrocardio-

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