Blood pressure levels, left ventricular mass and function are correlated with left atrial volume in mild to moderate hypertensive patients

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1 (2009) 23, & 2009 Macmillan Publishers Limited All rights reserved /09 $ ORIGINAL ARTICLE Blood pressure levels, left ventricular mass and function are correlated with left atrial volume in mild to moderate hypertensive patients A Milan 1, MA Caserta 1, A Dematteis 1, D Naso 1, A Pertusio 1, C Magnino 1, E Puglisi 1, F Rabbia 1, NG Pandian 2, P Mulatero 1 and F Veglio 1 1 Hypertension Unit, Department of Medicine and Experimental Oncology, Division of Internal Medicine, University of Torino, Torino, Italy and 2 Division of Cardiology, Department of Medicine, Tufts-New England Medical Center, Boston, MA, USA Arterial hypertension is associated with an increased risk of atrial fibrillation (AF), and leads to a pronounced increase in morbidity and mortality. Left atrial volume (LAV) is an important prognostic marker in the older populations. The aim of our study was to identify the clinical and echocardiographic determinants of LAV in middle-aged (o70 years old) essential hypertensive patients.we evaluated cardiac structure and function in 458 patients, 394 treated and untreated mild to moderate essential hypertensives patients (mean±s.d. age 48.4±11.1 years) with no associated clinical condition and 64 normotensive control participants (age 45.7±12.8 years; P ¼ 0.12). A multivariate analysis was performed to calculate the relative weight of each of the variables considered able to predict LAV. The LAV index (LAVi) was significantly increased in the essential hypertensive group vs the control group and was significantly dependent on blood pressure levels (SBP and DBP, Po0.05 for both) and body mass index (BMI) (Po0.0001). Considering the left ventricular (LV) variables, the LV mass index (LVMI) (R 2 ¼ 0.19, Po0.001) and LAV were increased in essential hypertensive patients with left ventricular hypertrophy (LVH), and patients with enlarged LAV showed lower systolic and diastolic function and an increased LVMI. The LAVi is dependent on blood pressure levels and anthropometric variables (age and BMI). Further structural (LVMI) and functional (systolic and diastolic) variables are related to the LAVi; LVMI is the most important variable associated with LAV in mild to moderate essential hypertensive adult patients. These findings highlight the importance of left atrium evaluation in adult, relatively young, essential hypertensive patients. (2009) 23, ; doi: /jhh ; published online 5 March 2009 Keywords: left atrial volume; diastolic function; left ventricular mass Introduction Epidemiological studies have shown that arterial hypertension is associated with an increased risk of atrial fibrillation (AF), which in turn causes an increase in morbidity 1,2 and mortality. 3 Several lines of evidence 4 have shown that pressure overload produces morphological and functional heart alteration; it has been suggested that these modifications can increase left atrial (LA) dimensions, thus predisposing the development of AF; in fact, an Correspondence: Dr A Milan, Hypertension Unit, Department of Medicine and Experimental Oncology, Division of Internal Medicine, University of Torino, Via Genova 3, Torino, Italy. alby.milan@libero.it Received 28 August 2008; revised 14 December 2008; accepted 14 January 2009; published online 5 March 2009 increased LA dimension has been shown to be an important risk factor for AF and stroke. 5 The estimation of LA size is considered as an additional, relevant parameter, which may increase the prognostic value of echocardiographic studies. 6,7 Recently, it has been observed 8,9 that left atrial volume (LAV) allows a more precise estimation of the stratification risk for AF compared with LA diameter, in the older populations. Little is known regarding the correlation between LAV and other clinical and echocardiographic parameters in hypertensive patients other than age, body mass index (BMI) and left ventricular mass (LVM). 10,11 The aim of our work was (1) to investigate the clinical and anthropometric parameters that are associated with LAV enlargement in middle-aged hypertensive patients, and (2) to identify the morphological and functional left ventricular

2 744 (LV) parameters that are associated with LAV modification. Participants and methods Between May 2004 and December 2006, 394 consecutive adult outpatients with mild to moderate essential hypertension referred to the Hypertension Unit were included. A group of 64 normotensive healthy volunteers were considered as the control group. For recruitment, all individuals underwent a full medical examination. All blood pressure (BP) measurements were performed according to the European Society of Hypertension/European Society of Cardiology 12 recommendations. Hypertension was defined as systolic blood pressure (SBP) X140 mm Hg and/or diastolic blood pressure (DBP) X90 mm Hg on three consecutive occasions, or by the assumption of antihypertensive medications. Exclusion criteria were age o18 or more than 70 years, BMI X40 kg m 2, secondary hypertension, non-hypertensive cardiovascular disease, any valvulopathy more than mild, diabetes and presence of associated clinical conditions as defined by the European Society of Hypertension/European Society of Cardiology 12 guidelines. The study was approved by our Institutional Review Committee and all participants provided their written informed consent. Echocardiography A two-dimensional echocardiogram was performed at rest with commercially available ultrasound systems (ATL HDI 5000, Bothell, Washington, WA, USA) equipped with tissue Doppler imaging (TDI) software. Two-dimensional echocardiographic studies were recorded using standard methods. 13 Enddiastolic and end-systolic LV internal diameters (LVIDd, LVIDs), end-diastolic interventricular septum (IVSTd) and posterior wall thickness (PWTd) were calculated from five consecutive cardiac cycles in two-dimensionally guided M mode tracings according to the current guidelines. 13 Two-dimensional measurements were used when the orientation was not optimal to use M mode. LVM was calculated according to the Devereux formula 14 and normalized for both body surface area and for height to the power of 2.7. Left ventricular hypertrophy (LVH) was defined as values of LV mass index (LVMI) of X47 g m 2.7 in women or X50 g m 2.7 in men. 15 Relative wall thickness (RWT) was calculated as (2 PWT)/LVIDd. Patterns of LVH were defined according to Ganau et al. 16 as concentric LVH when LVH was associated with RWTX0.45 and eccentric LVH when LVH was associated with RWTo0.45. Pulsed-wave Doppler-derived transmitral inflow velocities were obtained with the transducer in the apical four-chamber view and the sampling volume at the mitral valve leaflet tips. The early diastolic (E) and atrial (A) velocities were measured and the E/A ratio was calculated. The deceleration time and the isovolumic relaxation time were measured according to the recommendations of the American Society of Echocardiography. 17 Pulmonary vein systolic (PVs), diastolic (PVd) and atrial reversal (PVa), as well as the duration of flow at atrial contraction (PVa-dur) were recorded. Tissue Doppler was obtained using a twodimensionally guided, 3- to 8-mm pulsed wave sample volume placed at the septal (sep) and lateral (lat) mitral annulus in the apical long-axis view. Spectral TDI was recorded at 100 mm s 1 sweep speed within 3 min of mitral inflow Doppler recording. These velocities were obtained with the transducer in the apical four-chamber view and the sampling volume at the lat and sep mitral annular regions. Measurements included the systolic myocardial velocity (S 0 ) and early and late diastolic (E 0 and A 0, respectively) myocardial velocity at the mitral annulus; all reported measurements are the averages derived from five consecutives cardiac cycles Left atrial volume Three LA dimensions were used to calculate LAV as an ellipse using the formula: LAV ¼ p=6 ðsa1 SA2 LAÞ where SA1 ¼ M mode LA dimension and SA2 and LA are measurements of short- and long-axis dimensions in the apical four-chamber view at the ventricular end systole. 9 To minimize the effect due to body size, LAV was indexed for body surface area (BSA). Statistical analysis Statistical analysis was conducted using SAS V8 software (SAS Institute Inc., Cary, NC, USA). The parametric distribution of the variables was analysed using the Kolmogorov Smirnov test and residual analysis. Data are expressed as mean± standard deviation (s.d.) or as median and interquartile difference were appropriate. Differences between means were examined using a t-test or analysis of variance for normal distributed variables. Kruskal Wallis or on-parametric analysis of variance was used for non-normal distributed variables. Statistical significance was assumed if the null hypothesis could be rejected at Po0.05. A stepwise linear regression analysis was performed to explore whether physiological and echocardiographic variables could independently predict LAV; Po0.15 was considered the cutoff to enter into the model.

3 Table 1 Clinical characteristics of the patients Characteristics Results Normotensive control group (NT) Hypertensive (HT) group N Gender (M/F) 34/30 252/ Age (years) 45.7± ± BMI (kg m 2 ) 23.80± ±3.7 o Abdominal 85.8± ± circumference (cm) Office SBP 117.9± ±15.8 o (mm Hg) Office DBP 73.4± ±10.0 o (mm Hg) Office HR (b.p.m.) 64.5± ± Arterial 0 48 (12 108) NA hypertension duration (months) Smokers % 2.9% 12.9% 0.25 Never treated 24.8% NA Treatment AIIRA 55.5% NA ACE I 22.1% NA CCB 45% NA Thiazides 21.4% NA b-blockers 15.5% NA Other 6% NA Abbreviations: ACE I, angiotensin-converting enzyme inhibitor; AIIRA, angiotensin II receptor antagonist; BMI, body mass index; CCB, calcium channel blocker; DBP, diastolic blood pressure; F, female; HR, heart rate; M, male; N/A, not applicable; SBP, systolic blood pressure. Data are expressed as mean±s.d. or as median (25 75th percentile) as appropriate. Tables 1 and 2 summarize, respectively, demographic and echocardiographic features of the hypertensive population and normotensive control group. According to the definition and classification of 2003 ESH/ESC guidelines, 12 84% of the hypertensive patients had, at the most, grade 1, 13% grade 2 and 3% grade 3 hypertension. In the overall population, LAVi was significantly related to the age (r ¼ 0.27; Po0.0001), BMI (r ¼ 0.26; Po0.0001), abdominal circumference (r ¼ 0.32; Po0.0001), office BP levels (systolic BP: r ¼ 0.23; Po0.0001; diastolic BP: r ¼ 0.17; P ¼ 0.004), RWT (r ¼ 0.16; P ¼ ) and LV mass indexed for height 2.7 (r ¼ 0.46; Po0.0001), E/E 0 sep (r ¼ 0.25; Po0.0001) and pulmonary venous flow S/D ratio (r ¼ 0.18; P ¼ ). Echocardiographic correlations were still significant even after correction for age, BMI and BP levels. In normotensive control participants, the 95th percentile was 25.7 ml m 2 and the maximum value was 29.3 ml m 2. On the basis of these data, we considered a LAVi higher than 25.7 ml m 2 as dilated. Using this cutoff, 24.6% of the hypertensive patients had an enlarged LAV. P Table 2 Echocardiographic characteristics of hypertensive vs normotensive group Characteristics Normotensive control group (NT) Hypertensive (HT) group IVSTd (mm) 8.4± ±1.7 o LVIDd (mm) 44.9±5.3 46± PWTd (mm) 8.5±1 9.7±1.4 o LVIDs (mm) 28.3± ± LVMI (g m 2 ) 78.98± ±24.30 o LVMI height (g m 2.7 ) 34.57± ±11.57 o RWT 0.38± ±0.08 o EF% (Teich) 65.82± ± Peak E (m s 1 ) 0.66± ± Peak A (m s 1 ) 0.51± ±0.16 o E/A ratio 1.38± ± Deceleration time (ms) ± ± IVRT (ms) ± ± LAVI (ml m 2 ) 19.7± ±6.7 o Abbreviations: A, atrial velocity of transmitral Doppler flow; E, early velocity of transmitral Doppler flow; EF, ejection fraction calculated by Teicholz s method (Teic); IVRT, isovolumetric relaxation time; IVSTd, diastolic interventricular septal thickness; LAVI, left atrial volume index; LVIDd, diastolic left ventricular internal diameter; LVIDs, systolic left ventricular internal diameter; LVMI, left ventricular mass index; PWTd, diastolic posterior wall thickness; RWT, relative wall thickness. Table 3 summarizes the demographic, clinical and echocardiographic characteristics of hypertensive patients subdivided into participants with normal (LAVNor) vs enlarged (LAVEnl) LAV. In hypertensive patients, LAVi was significantly correlated with age (r ¼ 0.27; Po0.0001), BMI (r ¼ 0.23; Po0.0001), abdominal circumference (r ¼ 0.27; Po0.001), and systolic (Figure 1b; r ¼ 0.22; P ¼ ) and diastolic blood pressure (Figure 1a; r ¼ 0.13; P ¼ 0.038). To further dissect the association between BP levels and LAVi, we subdivided hypertensive patients according to the grade of hypertension; we observed a significant trend for an increase of LAVi with the increase in severity of hypertension, both in treated (R 2 ¼ 0.04; P ¼ 0.02) and in nevertreated (R 2 ¼ 0.15; P ¼ 0.008) patients. Interestingly, successfully treated patients (SBPo140 and DBPo90) showed significantly lower LAVi compared with grade X2 treated hypertensives and never-treated patients (Po0.0001). Finally, a weak but significant association was observed between duration of hypertension and LAVi (r ¼ 0.22; P ¼ 0.001). Then, we performed a stepwise linear regression analysis (Table 5) to identify which physiological variables could independently predict LAV. Obesity showed a significant effect on LAVi dimension; in particular overweight and obese patients displayed a significant increase in LV mass (Po0.001), concentric pattern (Po0.001) and lower diastolic function (P ¼ 0.03 for E/E 0 ratio). Further, lean participants had a significantly smaller LAVi. P 745

4 746 We concluded that the BP load, in particular SBP and body fat, especially BMI, were significant LAVi predictors. The second part of our study has been to identify the morphological and functional heart indexes derived from echocardiography, potentially associated with LAV modification. Table 4 summarizes the echocardiographic differences between hypertensive patients with LAVenl and those with LAVnor. Left ventricular geometry and mass and LAV LV mass was significantly correlated with LAVi both in treated and in never-treated hypertensive patients (Po0.001 and Po0.01, respectively). We also performed a linear regression analysis to evaluate the association between LAV and LVMI (Figure 2a). Table 3 Demographics and echocardiographic normal vs enlarged LAV of hypertensive patients Characteristics LAV normal (p26 cm 3 m 2 ) LAV enlarged (426 cm 3 m 2 ) N Age (years) 46.55± ±10.18 o BMI (kg m 2 ) 25.71± ± Abdominal 92.08± ± circumference (cm) Duration of 36 (7 97) 60 (24 120) 0.01 hypertension (months) Office SBP (mm Hg) ± ± Office DBP (mm Hg) 84.31± ± Pulse pressure 53.38± ± (mm Hg) Office HR (b.p.m.) 72.63± ± Never treated patients (%) 19% 15% 0.56 Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; LAV enlarged cm 3 m 2 ; LAV, left atrial volume; SBP, systolic blood pressure. P Similar results were obtained using absolute LVM values and by indexation for body surface area and height 2.7 (data not shown). Patients with LVH showed a significantly increased LAVi compared with patients without LVH (Figure 2b, P for trend o0.0001). Participants with normal LV mass and geometry displayed a LAVi similar to patients with concentric remodeling of LV. Systolic LV function and LAV LAVi was significantly correlated with LV stroke volume (r ¼ 0.17; P ¼ 0.001) and LV stroke work (r ¼ 0.15; P ¼ 0.02), as suggested by the association observed between BP and LAV. In addition, tissue Doppler derived indexes of systolic function were significantly and inversely correlated with LAV (S 0 sep r ¼ 0.25; Po0.0001; S 0 lat r ¼ 0.10; P ¼ 0.04). These associations were similar both in treated and never treated hypertensive patients and after correction for SBP. Diastolic LV function and LAV LAV was significantly correlated with isovolumic relaxation time (r ¼ 0.18; P ¼ ), A wave velocity (r ¼ 0.20; Po0.0001), E/A ratio (r ¼ 0.22; Po0.0001), E wave deceleration time (r ¼ 0.17; P ¼ 0.03) and PVs (r ¼ 0.15; P ¼ 0.005), and significantly associated with the duration of the atrial reversal component (r ¼ 0.18; P ¼ ). Among tissue Doppler variables, LAV was negatively associated with E 0 (lat r ¼ 0.23; Po0.0001; sep r ¼ 0.28; Po0.0001) in essential hypertensive patients. LAVi was negatively associated with the E 0 /A 0 ratio (r ¼ 0.22; Po both for the septal and for the lat component (Figure 3b)). Finally, LAVi was significantly correlated with variables that indirectly measure LV filling pressure, such as PVs/PVd ratio (r ¼ 0.15; P ¼ 0.005) and LAVi = *DBP LAVi = *SBP R 2 =0.02; P=0.03 R 2 =0.05; P= DBP (mm Hg) SBP (mm Hg) Figure 1 Linear regression analysis between systolic (a) and diastolic (b) blood pressure levels and left atrial volume index in hypertensive patients.

5 Table 4 Echocardiographic characteristics of hypertensive subjects according to LAV dimension (normal vs enlarged) Characteristics E/E 0 ratio (sep r ¼ 0.23; Po0.0001; lat r ¼ 0.18; P ¼ ). After subdividing the hypertensive patients according to their LV diastolic function (Figure 3a), we observed a significant increase of the LAVi in stage II diastolic dysfunction compared with hypertensive patients with normal or mildly abnormal diastolic dysfunction (Po0.01). To assess which parameter among different echo parameters could better predict LAVi in the hypertensive group, we performed a stepwise linear regression analysis. Only LVMI 2.7 was a significant (Po0.0001) independent predictor for LAVi, accounting for 18% of its variance (Table 5). These findings were similar in treated and in never-treated hypertensive patients. Of note, similar results were obtained using the area length method to assess LAV (data not shown). Discussion LAV normal (p26 cm 3 m 2 ) LAV enlarged (426 cm 3 m 2 ) LVMi (g m 2 ) 93.7± ±24.4 o LVMi height (g m 2.7 ) 41.4± ±11.5 o RWT 0.42± ± Mitral Doppler flow E/A 1.22± ± Deceleration time ± ± (ms) IVRT (ms) ± ±20.8 o TDI velocity S 0 sep (cm s 1 ) 8.49± ± E 0 sep (cm s 1 ) 9.09± ±2.28 o A 0 sep (cm s 1 ) 10.97± ± E 0 /A 0 sep 0.87± ± E/E 0 sep 8.03± ± Abbreviations: A, late diastolic velocity of mitral flow; A dur, A wave duration; A 0, late velocity of mitral annulus; E, early diastolic mitral flow velocity; E/E 0, early diastolic mitral flow to mitral annulus velocity ratio; IVRT, isovolumetric relaxation time; lat, lateral; LVMi, left ventricular mass index; PVs, systolic component of pulmonary venous flow; PVd, diastolic component of pulmonary venous flow; PVar, reverse atrial component of pulmonary venous flow; PVar dur, PVar duration; PVs/PVd, systolic to diastolic velocity ratio of pulmonary venous flow; RWT, relative wall thickness; S 0, systolic velocity of mitral annulus; sep, septal. Our study shows that, in relatively young mild to moderate hypertensive patients, the LAV index is associated with BP levels; in particular, LAVi increases with the grade of hypertension and furthermore, treated patients with a good BP control have a significantly by LAVi compared with hypertensive patients with BP that is not well controlled. To date, it is not clear whether LA enlargement derives from structural changes of the heart P R 2 =0.19; P< LVM index (height 2.7) P < for trend LAV index = *LVMi 2.7 # NORMAL CR EH CH Figure 2 Left atrial volume index (LAVi) and left ventricular mass. (a) Linear regression analysis between LAVi and left ventricular mass; (b) modification of LAVi according to left ventricular pattern: CR, concentric remodeling; EH, eccentric hypertrophy; CH, concentric hypertrophy. z Po vs CH and EH; # P ¼ vs CH and P ¼ 0.01 vs EH; w Po vs normal and P ¼ 0.01 vs CR; y Po vs normal and P ¼ vs CR. (for example, LV hypertrophy and/or diastolic dysfunction), or whether it should be considered as a heart modification because of chronic BP overload; however, it seems reasonable to hypothesize on a pathophysiological basis that BP overload could play a leading role in diastolic dysfunction. Among the factors associated with LA enlargement, earlier studies showed a weak relationship between office BP and LA linear size. Recently, an interesting study by Cuspidi et al. 21,22 showed a modest but significant correlation between LA dimension and night-time ambulatory BP values, but not with office BP. In a novel approach, we have evaluated treated and untreated patients with different degrees of hypertension and found not only a significant association between BP levels and LAVi but also a significantly lower LAVi in patients with well- 747

6 748 controlled BP levels. Consistent with the findings of several epidemiological studies, our data indicate that BP influences LAV and further, it is conceivable that a good BP control could be associated with a significantly lower LAV. Left atrial volume indexed (cm 3 m 2 ) Normal DF P<0.005 * * Stage I Stage II LAV index = *E /A septal R ; P< E /A septal TDI Figure 3 Left atrial volume index (LAVi) and left ventricular diastolic function. (a) Modification of LAVi according to left ventricular diastolic function: normal diastolic function, stage I diastolic dysfunction and stage II diastolic dysfunction. (b) Linear regression analysis between LAVi and E 0 /A 0 (tissue Doppler). Recently, 23 it has been shown that obesity increases the risk of developing AF by 49% in the general population by a mechanism that remains to be elucidated. According to earlier reports, 9,22 we observed a significant association between LAVi and BMI. The exact mechanism underlying this association is still not completely understood, but it has been suggested that increased intravascular volume and preload associated with the increase in weight may induce structural and functional abnormalities in the LA. 24 Other studies specifically designed to investigate this association should clarify this hypothesis. Finally, we observed for the first time a significant association between LAV and morphological (LV mass) and functional (systolic and diastolic) LV variables. Cardiac LVM is a well-known type of organ damage induced by hypertension and represents a powerful prognostic marker for cardiovascular events, such as myocardial infarction, stroke and mortality. 12 In agreement with earlier studies 10,21,25 27 that showed a significant association between linear atrial size and LVM, we observed that LAVi is strongly associated with LV mass even in relatively young hypertensive patients. These findings suggest that hypertension induces simultaneously an increase of the LV mass and LAV. Gerdts et al. 7 in a Losartan intervention for endpoint subanalysis showed not only that LA diameter/height can predict the incidence of cardiovascular events, but also that in selected populations the observed effect was mostly determined by LV mass. Interestingly, we observed that LAV was associated not only with morphological but also with functional variables. LAV was related to the systolic tissue Doppler component; in particular, we observed that lower systolic myocardial velocities were associated with higher LAVs. Our findings can be interpreted in the light of a recent study 28 that showed an association of LAV enlargement with the development of both systolic and diastolic heart failure in patients older than Table 5 Stepwise linear regression analysis LAVi (cm 3 m 2 ) Variable b±s.e. Partial R 2 Total R 2 P Clinical variables a Step 1 BMI (kg m 2 ) 0.60± o Step 2 SBP (mm Hg) 0.10± Step 3 Age (years) 0.08± Cardiac variables b Step 1 LVMI 2.7 (g m 2.7 ) 0.17± o LAVi was considered as a dependent variable. a Clinical independent variables considered in the model: age, abdominal circumference, systolic and diastolic BP, body mass index. b Echocardiographic independent variables considered in the model: RWT*, systolic velocity of septal mitral annulus evaluated by TDI*, E/E 0 ratio*, PVs/PVd ratio*, LVMI for height 2.7. *These variables were not entered into the model.

7 65 years. In our younger population, we hypothesize that the association between LAV and systolic components of TDI may indicate a preclinical systolic dysfunction, which together with an increased LV mass may influence LAV. Finally, patients with higher grades of diastolic dysfunction showed higher LAV and furthermore, patients with increased LV filling pressure (indicated by E/E 0 TDI) showed LAV enlargement. Different studies 8 considered LAV as a surrogate marker of diastolic function; LAV enlargement was shown as one of the elements consistent with a diagnosis of moderate diastolic dysfunction. 29 In this study, we have shown for the first time that the association between diastolic function and LAV is maintained also in relatively young patients (o65 years old). However, in this particular subgroup of patients, LAV is more closely related to LV mass than to diastolic function. Although myocardial relaxation is likely to play an important role in LA enlargement, 29 we showed that LV mass is the most important determinant of LAV in the early phases of cardiac organ damage because of the hypertensive disease, in which most of the patients display a mild or moderate diastolic dysfunction. Our study shows that about 20% of the hypertensive patients with mild to moderate hypertension show a slight increase in LAV. Considering hypertension as one of the most important risk factors for heart failure, we may suggest that LAV enlargement should be treated as part of the target organ damage because of hypertensive disease. What is known about this topic K Left atrial volume (LAV) is the best method to assess the left atrial size. K LAV is associated with left ventricular mass and diastolic function in older patients. K It is not clear whether there is an association between blood pressure levels, left ventricular morphology and function, and LAV. 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