Left Atrial Enlargement and Risk of Ischemic Stroke in Elderly Treated Hypertensive Patients

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1 Original Article Left Atrial Enlargement and Risk of Ischemic Stroke in Elderly Treated Hypertensive Patients Sante D. Pierdomenico, 1,2 Anna M. Pierdomenico, 2 Silvio Di Carlo, 1 Roberta Di Tommaso, 1 and Franco Cuccurullo 1,2 background The independent prognostic significance of left atrial enlargement is not yet completely clear. We investigated the association between left atrial enlargement and risk of ischemic stroke in elderly treated hypertensive patients. methods The occurrence of ischemic stroke was evaluated in 1,191 elderly treated hypertensive patients (age range = years). Left atrium diameter (cm) was indexed by body surface area (m 2 ) and subjects were divided into those with normal or enlarged ( 2.4 cm/m 2 ) left atrium. results During the follow-up (9.1 ± 4.9 years; range = years), 139 ischemic strokes occurred. The event rate per 100 patient-years was There were 86 strokes in patients with normal (= 928) left atrium and 53 strokes in patients with enlarged (= 263) left atrium, respectively. Stroke-free survival curves were significantly different between the groups (P < 0.01). After adjustment for various covariables, including clinical variables, left ventricular hypertrophy, and ambulatory blood pressure parameters, Cox regression analysis showed that left atrial enlargement was significantly associated with increased risk of ischemic stroke (hazard ratio = 1.54; 95% confidence interval = ; P = 0.03). conclusions In elderly treated hypertensive patients, left atrial enlargement is an independent predictor of ischemic stroke. Keywords: blood pressure; cardiovascular risk; hypertension; left atrium; stroke. doi: /ajh/hpu042 The left atrium modulates left ventricular (LV) filling through various mechanical functions. 1,2 In addition, the left atrium acts as a volume sensor releasing natriuretic peptides in response to stretch, generating natriuresis, vasodilatation, and inhibition of the sympathetic nervous system and renin-angiotensin-aldosterone system. 1,2 Some conditions are associated with left atrial (LA) dilatation. The atria may enlarge in response to pressure or volume overload. LA enlargement due to pressure overload is usually secondary to mitral stenosis or LV diastolic or systolic dysfunction. Chronic volume overload is usually associated with mitral regurgitation. 1,2 Various studies have described a relationship between LA size, as determined by echocardiography, and the development of atrial fibrillation and cardiovascular events. 1,2 A number of investigations have specifically evaluated the relationship between LA size and stroke, obtaining contrasting results In studies performed in general populations, some authors 3,4 reported association between LA size and risk of stroke, whereas others 5 7 did not, and some found an association only in men 8,9 or only in women. 10,11 To the best of our knowledge, the association between LA size and stroke risk in hypertensive patients was evaluated in 1 prospective study 12 and in 1 case control study, 13 suggesting that LA enlargement is associated with increased risk of stroke. Therefore, other data could be helpful in the specific setting of the hypertensive population. The aim of this study was to investigate the relationship between LA size and risk of ischemic stroke in elderly treated hypertensive patients. METHODS Subjects Starting in 1992, we built 2 prospective databases of our initially untreated or initially treated hypertensive patients with the aim to evaluate the prognostic role of ambulatory blood pressure (BP) parameters, echocardiographic measures, and other risk markers. This study was carried out using the database of initially treated subjects. We studied 1,191 sequentially treated hypertensive patients aged 60 years (range = years) prospectively recruited Correspondence: Sante D. Pierdomenico (santedonato.pierdomenico@ fastwebnet.it). Initially submitted November 10, 2013; date of first revision November 24, 2013; accepted for publication February 11, 2014; online publication March 28, Dipartimento di Medicina e Scienze dell Invecchiamento, Università Gabriele d Annunzio, Chieti, Italy; 2 Centro di Ricerca Clinica, Fondazione Università Gabriele d Annunzio, Chieti, Italy. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com American Journal of Hypertension 27(9) September

2 Pierdomenico et al. from December 1992 to December 2012 who were referred to our hospital outpatient clinic for evaluation of hypertension. Sixty-two patients were lost during the follow-up. Subjects with previously diagnosed secondary hypertension were excluded. Patients underwent clinical evaluation, electrocardiogram, routine laboratory tests, echocardiographic examination and noninvasive ambulatory BP monitoring. Study population came from the same geographical area (Chieti and Pescara, Abruzzo, Italy). The study was in accordance with the Second Declaration of Helsinki and was approved by the institutional review committee. Subjects gave informed consent. Office BP measurements Clinic systolic and diastolic BP recordings were performed by a physician by using a mercury sphygmomanometer and appropriate-sized cuffs. Phase V was used to determine diastolic BP. Measurements were performed in triplicate, 2 minutes apart, and the average value was used as the BP for the visit. Ambulatory BP monitoring Ambulatory BP monitoring was performed with a portable noninvasive recorder (SpaceLabs 90207, Redmond, WA) on a day of typical activity within 1 week from clinic BP measurement. Each time a reading was taken, subjects were instructed to remain motionless and to record their activity on a diary sheet. Technical aspects have been previously reported. 14 Ambulatory BP readings were obtained at 15-minute intervals from 6 am to midnight, and at 30-minute intervals from midnight to 6 am. The following ambulatory BP parameters were evaluated: daytime (awake period), nighttime (asleep period), and 24-hour systolic and diastolic BP, dipping or nondipping pattern (those with nighttime systolic BP reduction <10% were defined as nondippers and those with BP reduction 10% were defined as dippers) and preawakening morning BP surge, as previously defined. 15 Recordings were automatically edited if systolic BP was >260 or <70 mm Hg or if diastolic BP was >150 or <40 mm Hg and pulse pressure was >150 or <20 mm Hg. 14 Subjects had recordings of good technical quality ( 70% of valid readings). Echocardiography LA diameter was measured using M-mode echocardiography, from the posterior aortic wall to the posterior LA wall, in the parasternal long-axis view at end-ventricular systole. LA diameter (cm) was indexed by body surface area (m 2 ); LA enlargement was defined as LA diameter/body surface area 2.4 cm/m End-systolic and end-diastolic measurements of interventricular septal thickness, LV internal diameter, and posterior wall thickness were made according to previously reported recommendations. 17 LV mass was calculated using the formula introduced by Devereux et al. 18 Individual values for LV mass were indexed by height 2.7, and LV hypertrophy was defined as LV mass/height 2.7 >50 g/m 2.7 in men and >47 g/m 2.7 in women. 19 LV ejection fraction was calculated using the Teichholz formula or the Simpson rule 16 and defined as low when it was <50%. Mitral regurgitation was assessed by color Doppler using a previously described 4-category grading system. 20 Mitral stenosis was defined as a mitral valve area 2 cm 2, assessed using either the pressure half-time or planimetric method. Follow-up Subjects were followed-up in our hospital outpatient clinic or by their family doctors. The occurrence of any cardiovascular event was recorded during follow-up visits or by telephone interview of the patient followed by a clinical visit. The authors of this study collected the data. Those reviewing the endpoints were blinded to other patients data. In this report, we focused on fatal and nonfatal ischemic stroke. Ischemic stroke was defined as a clinical syndrome consisting of rapidly developing signs of focal or global disturbance of cerebral function, lasting >24 hours or leading to death during hospitalization (without specific time intervals) with no apparent cause other than that of vascular origin (World Health Organization) that was confirmed by a computer tomography repeated after 24 hours (in living subjects) showing ischemic injury. We considered only the first stroke after inclusion in this study; recurrent strokes were excluded. Statistical analysis Standard descriptive statistics were used. Groups were compared by using unpaired t test or χ 2 test, where appropriate. Event rates are expressed as the number of events per 100 patient-years based on the ratio of the observed number of events to the total number of patient-years of exposure up to the terminating event or censor. Survival curves were estimated using the Kaplan Meier product-limit method and compared by the Mantel (log-rank) test. 21 Cox regression analysis was used to evaluate univariable and multivariable association of factors with outcome. 21 First, univariable association between various variables and stroke was evaluated. Then, multiple regression analysis was performed, reporting in the final model variables that were significantly associated (P < 0.05) or tended to be associated (P 0.05 and P 0.1) with outcome in univariable analysis. Moreover, we planned to include sex in the final model independently of the results of univariable analysis. The forced entry model was used. Statistical significance was defined as P < Analyses were made with the SPSS 12 software package (SPSS, Chicago, IL). RESULTS Characteristics and BP values of the study population according to LA size are shown in Table 1. Clinic, daytime, nighttime, and 24-hour systolic BP and nighttime and 24-hour diastolic BP were significantly higher in patients with LA enlargement. Prevalence of LV hypertrophy, low ejection fraction, mitral regurgitation 2+, and nondipping was significantly higher in subjects with LA enlargement. The other variables were not significantly different between the groups. No patient had mitral stenosis American Journal of Hypertension 27(9) September 2014

3 Left Atrial Enlargement and Risk of Ischemic Stroke Table 1. Baseline characteristics of study population by left atrial size Parameter Normal left atrium Enlarged left atrium No P value Age, y 69 ± 6 69 ± Men, no. (%) 382 (41) 124 (47) 0.09 BMI, kg/m 2 28 ± 4 28 ± Smokers, no. (%) 109 (12) 32 (12) 0.83 Previous events a, no. (%) 80 (9) 24 (9) 0.80 Diabetes, no. (%) 116 (12) 32 (12) 0.99 Creatinine, mg/dl 1.02 ± ± LDL cholesterol, mg/dl 128 ± ± LVH, no. (%) 199 (21) 170 (65) <0.01 Low EF, no. (%) 22 (2.4) 31 (12) <0.01 MR 2+, no. (%) 8 (0.9) 86 (33) <0.01 Single therapy, no. (%) 238 (26) 53 (20) 0.07 Double therapy, no. (%) 437 (47) 125 (48) 0.94 Triple therapy, no. (%) 253 (27) 85 (32) 0.12 Aspirin, no. (%) 208 (22) 66 (25) 0.36 Statin, no. (%) 107 (12) 31 (12) 0.91 Clinic SBP, mm Hg 150 ± ± Clinic DBP, mm Hg 87 ± ± Daytime SBP, mm Hg 135 ± ± 16 <0.01 Daytime DBP, mm Hg 78 ± 9 79 ± Nighttime SBP, mm Hg 122 ± ± 17 <0.01 Nighttime DBP, mm Hg 67 ± 9 71 ± 9 < hour SBP, mm Hg 131 ± ± 16 < hour DBP, mm Hg 75 ± 8 77 ± 9 <0.01 Nondippers, no. (%) 474 (51) 169 (64) <0.01 Dippers with MS >23 mm Hg, no. (%) 147 (16) 38 (14) 0.63 in Figure 2. As described, there was a significant difference between the groups (P < 0.01). New onset permanent atrial fibrillation occurred in 35 (13%) and 38 (4%) patients with and without LA enlargement, respectively (P < 0.01). Stroke occurred in 16 (22%) and 123 (11%) subjects with and without atrial fibrillation, respectively (P < 0.01). Univariable analysis was performed to assess the association between risk of ischemic stroke and age, sex, body mass index, smoking habit, previous events, diabetes, creatinine, low-density lipoprotein cholesterol, BP values, a grouping variable (dippers with morning systolic BP surge <23 mm Hg as reference group, dippers with morning surge >23 mm Hg and nondippers as comparison groups), LV hypertrophy, LV ejection fraction, mitral regurgitation, LA enlargement, number of antihypertensive drugs at baseline, antiplatelet and statin therapy at baseline, and new onset atrial fibrillation during the follow-up. This analysis showed that age, clinic systolic BP, daytime systolic BP, nighttime systolic BP, 24-hour systolic BP, diabetes, LV hypertrophy, nondipping and high morning BP surge in dippers, and LA enlargement were significantly associated with stroke risk (Table 2). Previous events (myocardial infarction or stroke or peripheral artery disease) and new onset atrial fibrillation tended to be associated with risk of stroke but did not attain statistical significance (Table 2). Other variables were neither associated nor tended to be associated with outcome (P > 0.10). When we assessed the impact of antiplatelet/anticoagulant or statin use and number of antihypertensive drugs at follow-up, results were substantially similar. We included LA enlargement, age, 24-hour systolic BP, diabetes, LV hypertrophy, the grouping variable including nondipping and morning BP surge, previous events, incident atrial fibrillation, and sex in the multivariable analysis. Results of the multivariable analysis are reported in Table 3. After adjustment for the aforesaid covariables, LA Data are mean ± SD or percentage. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; EF, ejection fraction; LDL, low density lipoprotein; LVH, left ventricular hypertrophy; MR, mitral regurgitation; MS, morning surge; SBP, systolic blood pressure. a Previous events include myocardial infarction, stroke, and peripheral artery disease. At follow-up, 405 (34%) patients received antiplatelet drugs or anticoagulant therapy, 294 (25%) received statin, 266 (22.5%) received single antihypertensive therapy, 458 (38.5%) received double therapy, and 467 (39%) received triple therapy. During the follow-up (9.1 ± 4.9 years; range = years), 139 strokes occurred. Specifically, there were 47 fatal strokes and 92 nonfatal strokes. The stroke rate of the population as a whole was 1.28 per 100 patientyears. There were 86 strokes in patients with normal left atrium and 53 strokes in patients with enlarged left atrium. The stroke rate by LA dimension is reported in Figure 1. Stroke-free survival curves according to LA size are reported Figure 1. Stroke rate in the study population according to left atrial size. Abbreviation: LA, left atrium. American Journal of Hypertension 27(9) September

4 Pierdomenico et al. Table 3. Results of multivariable analysis Parameter HR (95% CI) P value LA enlargement, yes vs. no 1.54 ( ) 0.03 Age, 1 year 1.10 ( ) < h SBP, 1 mm Hg 1.02 ( ) <0.01 Diabetes, yes vs. no 1.06 ( ) 0.80 LV hypertrophy, yes vs. no 1.39 ( ) 0.20 Circadian BP changes group Dippers with MS <23 mm Hg 1.00 (referent) Dippers with MS >23 mm Hg 1.82 ( ) 0.03 Nondippers 1.61 ( ) 0.04 New onset AF, yes vs. no 0.99 ( ) 0.90 Previous events a, yes vs. no 1.37 ( ) 0.35 Sex, men vs. women 0.77 ( ) 0.15 Figure 2. Stroke-free survival curves in the study population according to left atrial size. Abbreviation: LA, left atrium. Table 2. Results of univariable analysis Parameter HR (95% CI) P value Age, 1 year 1.11 ( ) <0.01 Clinic SBP, 1 mm Hg 1.01 ( ) <0.01 Daytime SBP, 1 mm Hg 1.02 ( ) <0.01 Nighttime SBP, 1 mm Hg 1.03 ( ) < h SBP, 1 mm Hg 1.03 ( ) <0.01 Diabetes, yes vs. no 1.79 ( ) 0.02 LV hypertrophy, yes vs. no 1.68 ( ) <0.01 Circadian BP changes group Dippers with MS <23 mm Hg 1.00 (referent) Dippers with MS >23 mm Hg 2.49 ( ) <0.01 Nondippers 2.10 ( ) <0.01 LA enlargement, yes vs. no 1.93 ( ) <0.01 New onset AF, yes vs. no 1.67 ( ) 0.06 Previous events a, yes vs. no 1.56 ( ) 0.10 Sex, men vs. women 0.80 ( ) 0.20 We reported variables that were significantly associated with outcome, those that tended to be associated with outcome, and sex, which had been planned. Abbreviations: AF, atrial fibrillation; BP, blood pressure; CI, confidence interval; HR, hazard ratio; LA, left atrial; LV, left ventricular; MS, morning surge; SBP, systolic blood pressure. a Previous events include myocardial infarction, stroke, and peripheral artery disease. enlargement remained an independent predictor of ischemic stroke (hazard ratio (HR) = 1.54; 95% confidence interval = ; P = 0.03). When LA diameter was entered in the multivariable model as a continuous variable (cm/m 2 ), Abbreviations: AF, atrial fibrillation; BP, blood pressure; CI, confidence interval; HR, hazard ratio; LA, left atrial; LV, left ventricular; MS, morning surge; SBP, systolic blood pressure. a Previous events include myocardial infarction, stroke, and peripheral artery disease. it independently predicted ischemic stroke (HR = 1.70; 95% CI = ; P = 0.045). Discussion This study shows that, in elderly treated hypertensive patients, LA enlargement is an independent predictor of ischemic stroke. A number of population-based studies have assessed the value of LA size for predicting stroke Barnes et al. 3 showed that LA size, as evaluated by LA volume, was an independent predictor of stroke in an elderly cohort in a retrospective study. Nagarajarao et al. 4 reported that LA size was a predictor of stroke, but the relation was lessened after adjustment for LV hypertrophy and LV ejection fraction. Gardin et al., 5 Olshansky et al., 6 and Kizer et al. 7 did not find association between LA size and risk of stroke. Benjamin et al. 8 and Di Tullio et al. 9 reported that LA size was a predictor of ischemic stroke only in men, whereas Bouzas- Mosquera et al. 10 and Lai et al. 11 found that LA enlargement predicted stroke only in women. To the best of our knowledge, there are 2 studies in the literature reporting the association between LA size and stroke in hypertensive patients. 12,13 Gerdts et al., 12 in the Losartan Intervention for Endpoint Reduction in Hypertension Trial, reported that larger baseline LA diameter/height was independently associated with higher risk of stroke (HR = 2.44 per cm/m; 95% CI = ; P = 0.03). Moreover, in a model including LA diameter/height and systolic BP as time-varying covariables and Framingham risk score, race, and treatment allocation as fixed covariables, lower in-treatment LA diameter/height was significantly associated with lower risk of stroke (HR = 0.40 per cm/m; 95% CI = ; P = 0.01). However, when time-varying LV mass was added to the covariables in the model, time-varying LA 1182 American Journal of Hypertension 27(9) September 2014

5 Left Atrial Enlargement and Risk of Ischemic Stroke diameter change did not remain an independent predictor of outcome. Globally, the authors 12 suggest that baseline pretreatment LA size predicts risk of stroke in patients with electrocadiographic LV hypertrophy, whereas change in LA diameter during antihypertensive therapy predicted stroke independent of clinical covariables but not of LV mass change during treatment. Our study population was treated at baseline; thus, we do not know whether prevalence of LA enlargement before treatment was different or whether LA size changed in some patients from the start of treatment up to our evaluation. Moreover, change in LA size and its hypothetical impact on risk were not evaluated during the followup. In addition, this study could not adjust for time-varying LV mass. However, these aspects do not seem to lessen our findings. Piotrowski et al. 13 reported that increased LA size, as evaluated by LA volume, was significantly associated with ischemic stroke in a case control study. Differences between our study and previous ones may be related to selected populations, methodological aspects, and study design. In any case, our results complement and expand previous findings on the value of LA size for predicting stroke in hypertensive patients. Some hypotheses could be suggested about the mechanisms by which LA enlargement acts as an independent predictor of stroke. A hypothesis is that LA dilatation promotes blood stasis, which in turn results in a propensity for thrombus formation and increased risk of embolism. 8 The thrombogenicity of LA dilatation has been supported by transesophageal echocardiographic studies showing an association between LA enlargement and spontaneous echocardiographic contrast, LA thrombus, and embolic events. 8 Another possible mechanism may be that LA enlargement promotes the development of asymptomatic and undetected interim atrial fibrillation, which, in turn, places the patient at increased risk for stroke. Alternatively, LA enlargement may be a surrogate marker for cardiac and/or vascular damage, such as LV hypertrophy or carotid atherosclerosis, which are related to increased risk of stroke. However, when LV hypertrophy was included in the model, the association between LA enlargement and stroke was lessened but remained significant. As far as carotid atherosclerosis, approximately one-third of this population had performed carotid examination and therefore this variable could not be included in the analyses. Moreover, LA enlargement is a risk factor for atrial fibrillation, a condition that increases the risk of stroke. However, in this population, atrial fibrillation tended to be associated with outcome but did not attain statistical significance, and when it was included in the multivariable model, LA enlargement remained an independent predictor of stroke. This study has some limitations. First, we studied only white subjects, and our results cannot be applied to other ethnic groups. Second, our data were obtained in elderly treated hypertensive patients and cannot be extrapolated to younger and untreated subjects. Third, the lack of association of stroke risk with treatment strategy does not mean lack of efficacy of therapy because all subjects were treated with antihypertensive therapy, most of whom received multiple therapy, and patients were not randomized to antihypertensive or antiplatelet or statin therapy. Fourth, it is generally recognized that LV hypertrophy is associated with increased risk of stroke; in this article, LV hypertrophy was associated with increased risk of stroke (HR = 1.39; 95% CI = ), although statistical significance was not achieved. This result could be related to the inclusion (in the statistical model) of some covariables that were not included in other studies, which could have partly weakened the impact of LV hypertrophy. In any case, this aspect does not call into question the relevance of LV hypertrophy as a predictor of stroke. Fifth, we measured LA diameter by M-mode echocardiography. It has been reported that LA volume is a more accurate predictor of cardiovascular events than LA area or diameter; however, increased LA diameter (indexed by body surface area) was reported to be an independent predictor of risk (adjusted HR was approximately 3.0). 22 It is unclear how our results would have been affected by an analysis based on LA volume. In any case, LA diameter is more readily available and more widely used in clinical practice. In conclusion, this study shows that LA enlargement is a predictor of ischemic stroke in elderly treated hypertensive patients, independently of various covariables, including sex, LV hypertrophy, and atrial fibrillation, and suggests that LA dimension measurement could be helpful for prognostic stratification and therapeutic approach in this population. DISCLOSURE The authors declared no conflict of interest. References 1. Abhayaratna WP, Seward JB, Appleton CP, Douglas PS, Oh JK, Tajik AJ, Tsang TS. 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