Ambulatory blood pressure, target organ damage and aortic root size in nevertreated essential hypertensive patients

Transcription

1 (2007) 21, & 2007 Nature Publishing Group All rights reserved /07 $ ORIGINAL ARTICLE Ambulatory blood pressure, target organ damage and aortic root size in nevertreated essential hypertensive patients C Cuspidi 1,2, S Meani 3, C Valerio 3, A Esposito 2, C Sala 3,4, M Maisaidi 3, A Zanchetti 4 and G Mancia 1,4 1 Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, Italy; 2 Policlinico di Monza, Milan, Italy; 3 Istituto di Medicina, Cardiovascolare Università degli Studi di Milano and Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Milan, Italy and 4 Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Milan, Italy The relationship between ambulatory blood pressure (ABP), target organ damage (TOD) and aortic root (AR) size in human hypertension has not been fully explored to date. We investigated the relationship between ABP, different markers of TOD and AR size in never-treated essential hypertensive patients. A total of 519 grade 1 and 2 hypertensive patients (mean age years) referred for the first time to our outpatient clinic underwent the following procedures: (1) routine examination, (2) 24 h urine collection for microalbuminuria (MA), (3) ambulatory blood pressure monitoring over two 24 h periods within 4 weeks, (4) echocardiography and (5) carotid ultrasonography. AR dilatation was defined by sex-specific criteria (X40 mm in men and X37 mm in women). AR diameter was increased in 3.7% of patients. Demographic variables (body mass index, age and male gender), average night-time diastolic blood pressure (BP) (but not clinic or average 48 h BP), left ventricular mass index and carotid intima-media (IM) thickness showed an independent association with AR size in both univariate and multivariate analyses. When TOD data were analysed in a categorical way, a stepwise increase in the prevalence of left ventricular hypertrophy (LVH) (I ¼ 17.5%, II ¼ 27.6%, III ¼ 35.8%) and carotid IM thickening (I ¼ 20.9%, II ¼ 28.8%, III ¼ 34.4%), but not in MA (I ¼ 6.8%, II ¼ 9.1%, III ¼ 8.7%) was found with the progression of AR size tertiles. Our results show that (1) AR enlargement in uncomplicated never-treated hypertensive patients has a markedly lower prevalence than traditional markers of cardiac and extracardiac TOD; (2) night-time BP, LVH and carotid IM thickening are independent predictors of AR dimension. (2007) 21, ; doi: /sj.jhh ; published online 12 April 2007 Keywords: aortic root; ambulatory blood pressure; target organ damage Introduction Dilatation of proximal portion of systemic arterial tree (aortic root, AR) is frequently associated with aortic valve regurgitation, aneurysm and dissection of thoracic aorta and alterations of distal arterial territories. 1 3 AR dilatation has been observed more frequently in hypertensive than normotensive individuals 4,5 and an association between AR size and left ventricular hypertrophy (LVH) has been reported in hypertensive patients; 6,7 studies, however, evaluating haemodynamic and non-haemodynamic determinants of AR size have not yielded consistent results, so far Correspondence: Professor C Cuspidi, Policlinico di Monza, Via Amati 111, Monza 20052, Italy. cesare.cuspidi@unimib.it Received 27 October 2006; revised 11 January 2007; accepted 10 March 2007; published online 12 April 2007 Among factors associated with AR dilatation in normotensive and hypertensive subjects, the relative contribution of blood pressure (BP) has been shown to be substantially inferior than that of age, gender and anthropometric variables, such as height, weight and their derivatives body surface area and body mass index (BMI). 10 In a large population of mostly treated essential hypertensive patients we recently observed that AR size was weakly related with clinic BP values. In this previous study, the strength of the relation between BP and AR size was weakened by the fact that BP was measured only in the office and patients received prior antihypertensive treatment. 12 As 24 h ambulatory blood pressure (ABP) monitoring provides a better estimate than clinic BP of the overall BP load and is strongly related to target organ damage (TOD), 13,14 in the present study we assessed the relations of ABP and different markers of TOD with AR size in a large cohort of uncomplicated non-diabetic never-treated essential

2 532 hypertensive patients not included in the previous analysis. In particular, we aimed to investigate the prevalence and correlates of AR dilation in the early phases of hypertension, in the absence of disturbing factors such as cardiovascular or metabolic diseases and antihypertensive drug therapy. Methods Study population A total of 519 consecutive, never-treated hypertensive patients referred to our outpatient hospital clinic were included in the study. They were characterized by: (a) grade 1 and 2 hypertension (clinic BP values between 90 and 109 diastolic or BP mm Hg systolic), confirmed during the first visit at the outpatient clinic; (b) no evidence of congestive heart failure, previous myocardial infarction, cardiac valve disease, history of coronary revascularization, diabetes mellitus, renal insufficiency and any condition preventing technically adequate ambulatory BP monitoring (ABPM) (e.g., atrial fibrillation and other major arrhythmias). Patients with suspected secondary hypertension were also excluded. After an informed consent had been obtained during the initial visit, all patients underwent the following diagnostic procedures: (1) clinic BP measurements, (2) routine investigations (blood chemistry, urinalysis and a 12-lead electrocardiogram at rest), (3) 24 h urine collection for microalbuminuria (MA), (4) two 24 h periods of ABPM at a 1- to 4-week interval, (5) an echocardiogram and (6) carotid ultrasonographic scan. The study protocol was approved by the Ethics Committee of one of the institutions involved. BP measurements Clinic BP was measured during two different visits at the outpatient clinic by a physician with a mercury sphygmomanometer (first and fifth phases of Koroktoff sounds taken as systolic blood pressure (SBP) and diastolic blood pressure (DBP) respectively) after the subjects had comfortably rested for 5 min in the sitting position. Three measurements were taken at 1 min intervals and the average was used to define clinic SBP and DBP. ABPM for two periods of 24 h was carried out on the non-dominant arm using a Spacelabs device (Spacelabs Inc., Richmond, Washington, DC, USA) after validation of readings against a mercury sphygmomanometer by a Y tube. The device was set to obtain BP readings at 15 min intervals during the day ( ) and at 20 min intervals during the night ( ). In each patient the time of application (71 h) and recommended daily activities were similar for the two ABPM periods. Patients were instructed to attend their usual activities and to keep the arm still at the time of measurements; all were asked to go to bed no later than 2300 and to arise not before Monitorings were always performed over a working day (Monday Friday); recordings were then analysed to obtain 24 h, daytime and night-time average SBP, DBP and heart rate. The average of the two recordings was to define ABPM parameters. An average 24 h ABP of 124/79 mm Hg was considered as the upper limit of normality. 15 Nocturnal dipping was defined as a reduction in the average SBP and DBP at night greater than 10% compared to daytime values. 16 Each subject was classified according to the consistency of the dipping or non-dipping status in the first and second ABPM period as dipper on both recordings (DD), non-dipper on both recordings (ND-ND), variable dipper, that is dipper in one and non-dipper in the other ABPM (VD). Echocardiography Technical details are reported elsewhere. 12 In brief, M-mode, two-dimensional and Doppler echocardiographic examinations were performed with commercially available instruments. AR size was measured at the level of Valsalva s sinuses by M-mode tracings, under two-dimensional control, in accordance with the American Society of Echocardiography guidelines, as the maximal distance between the two leading edges of the anterior and posterior AR wall at end diastole. 17 The interobserver error for the AR size, determined by comparing 104 echocardiographic readings performed by two skilled sonographers (CC and SM) was 3.6%; the intraobserver error was 2.0% for CC and 2.3% for SM left ventricular mass (LVM) was estimated from enddiastolic left ventricular internal diameter (LVIDd), interventricular septum and posterior wall thickness (PWT) by Devereux s formula 18 and normalized to body surface area and height 2.7 to correct for overweight and obesity. 19 Relative wall thickness (RWT) was calculated as (2 PWT)/LVIDd. Patterns of left ventricular geometry were defined according to Ganau et al. 20 Left ventricular systolic function was assessed by endocardial fractional shortening ((LVIDd-LVIDs)/LVIDd) and left ventricular filling by standard pulsed Doppler recording of mitral flow. The following parameters were considered: early diastolic peak flow velocity (E), late diastolic peak flow velocity (A) and their ratio (E/A). Carotid ultrasonography Images of extracranial carotid artery walls were obtained in several projections by a high-resolution linear array 10 MHz probe. End-diastolic intimamedia thickness (IMT) of the far wall of both common carotid arteries was measured at 5, 10, 15, 20 and 25 mm caudal to the bulb, using bidimensional longitudinal sections of the vessel and the distance from the leading edge of the first echogenic line to the leading edge of the second echogenic line, as described by Pignoli et al. 21 and Salonen

3 et al. 22 To obtain a mean value of common carotid IMT, all 10 measurements were averaged. Plaques were sought in the entire extracranial carotid tree as a focal wall thickening 41.3 mm. 23 Microalbuminuria Twenty-four hour urinary albumin concentration was measured by a commercially available radioimmunoassay kit (Sclavo SPA, Cinisello Balsamo, Italy). The detection limit of the method was 0.5 mg/ l. MA was defined as a urinary albumin excretion rate between 30 and 300 mg per 24 h. Definition of aortic dilatation and target organ damage AR was considered dilated when its diameter was equal or exceeded 37 mm in women and 40 mm in men. These cut-off points were the ninety-eighth percentile values in a group of 250 normotensive (clinic BP o140/90 mm Hg), non-obese (BMI less than seventy-fifth percentile), apparently normal adults (145 men and 105 women; mean age years) evaluated in our hospital outpatient unit for a cardiovascular check-up in the previous 2 years. TOD was defined by the presence of MA and/or ultrasonographic evidence of cardiac and vascular alterations. LVH was diagnosed when left ventricular mass index was equal or exceeded 51 g/m 2.7 in men and 47 g/m 2.7 in women. 19 The presence of at least one carotid atherosclerotic plaque or diffuse IM thickening was taken as vascular alteration. IM thickening was diagnosed by the presence of an average IMT X0.8 mm in common carotid arteries. 24 Statistical analysis Statistical analysis was performed by the SAS System (version 6.12; SAS Institute Inc., Cary, NC, USA). Values are expressed as means7s.d. or percentages, as appropriate. Means were compared using Student s t-test for independent samples. Analysis of categorical data was carried out using w 2 -test, or Fisher s exact when appropriate. Differences within groups were tested by analysis of variance. The strength of correlation between variables was tested by linear correlation and multiple regression analysis. A Po0.05 was considered statistically significant. Results The screening process involved 606 consecutive untreated patients with grade 1 and 2 hypertension. Of these, 28 were excluded because of secondary hypertension, 20 for diabetes mellitus, 15 for valvular disease, 11 due to unwillingness to participate or to miscellaneous reasons. Thus, 532 hypertensive subjects met the inclusion criteria, 519 of them completed the study having ABPM and Table 1 Clinical characteristics of the study population (n ¼ 519) Parameter Value Age (years) Gender (males/females) 321/198 Body mass index (kg/m 2 ) Clinic blood pressure (mm Hg) / Clinic heart rate (b/min) h ABP (mm Hg) / Daytime ABP (mm Hg) / Night-time ABP (mm Hg) / Reproducible dipping (%) 53.0 Reproducible non-dipping (%) 22.5 Variable dipper pattern (%) 24.5 Grade 1 hypertension (%) 61.0 Isolated clinic hypertension (%) 9.0 Current smokers (%) 25.1 Left ventricular mass (g) Carotid IM thickness (mm) Urinary albumin excretion (mg/24 h) Left ventricular hypertrophy (%) 27.0 Carotid IM thickening (%) 28.1 Carotid plaques (%) 18.6 Microalbuminuria (%) 7.9 Abbreviations: ABP, ambulatory blood pressure; IM, intima media. ultrasonographic examinations of good technical quality; demographic and clinical characteristics are reported in Table 1. According to the classification of 2003 ESH/ESC Guidelines, 23 61% of the patients had grade 1 hypertension. The prevalence of isolated clinic hypertension (mean 24 h BP o125/ 80 mm Hg during the first recording) was 9.0%. With regard to other risk factors, 130 subjects (25.1%) were smokers and 146 (28.1%) had the metabolic syndrome, fulfilling three or more ATP III criteria. 25 AR dilatation, defined by the gender-specific criteria of 40 mm in men and 37 mm in women, was found in 19 out of 519 patients, with an overall 3.7% prevalence. Table 2 shows demographic and clinical characteristics of patients according to the tertiles of AR size. Patients in the upper tertile compared to lower one were older, had higher BMI, clinic, ambulatory SBP/DBP values and prevalence of reproducible non-dipping pattern; moreover, a lower prevalence of women and reproducible dipping pattern was present in the upper tertile. Target organ damage and aortic root size As shown in Table 3, LVM, LVM normalized both to body surface area and height 2.7, absolute and RWTs, left atrial diameter, carotid diameter, carotid IMT increased with the progression of AR diameter tertiles. With regard to left ventricular (LV) function, endocardial fractional shortening was similar across the tertiles; however, a greater left atrial contribution to LV filling was found in the two upper tertiles compared to the lower one. Furthermore, when echocardiographic data were categorized, as 533

4 534 Table 2 Clinical characteristics of patients according to aortic root diameter tertiles Parameter I (n ¼ 172) II (n ¼ 172) III (n ¼ 175) Age (years) * Gender (% men) * Body mass index (kg/m 2 ) Body surface area (m 2 ) * Clinic systolic BP (mm Hg) * Clinic diastolic BP (mm Hg) * Clinic heart rate (beats/min) h systolic BP (mm Hg) * 48 h diastolic BP (mm Hg) * Night-time SBP (mm Hg) * Night-time DBP (mm Hg) * Isolated clinic HTN (%) Reproducible dipping (%) * Reproducible non-dipping (%) * Variable dipper pattern (%) Current smokers (%) Metabolic syndrome (%) Blood glucose (mg/dl) Total cholesterol (mg/dl) Triglycerides (mg/dl) * Serum creatinine (mg/dl) Uric acid (mg/dl) Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; HTN, hypertension; SBP, systolic blood pressure. *P at least o0.05 III vs I, 1P at least o0.05 III vs II and I. Table 3 Cardiac and carotid ultrasonographic variables according to aortic root diameter tertiles Parameter I (n ¼ 172) II (n ¼ 172) III (n ¼ 175) LVIDd (mm) IVSTd (mm) * PWTd (mm) * RWT LVM (g) LVMI (g/m 2 ) * LVMI (g/h 2.7 ) * LA diameter (mm) * AR diameter range (mm) AR diameter (mm) Shortening fraction (%) E velocity (cm/s) A velocity (cm/s) E/A ratio * Carotid IMT (mm) Carotid diameter (mm) Carotid RWT Abbreviations: A, late diastolic peak flow; AR, aortic root; E, early diastolic peak flow; IMT, intima-media thickness; IVSTd, interventricular septum thickness diastole; LA, left atrium; LVIDd, left ventricular internal diameter; LVM, left ventricular mass; LVMI, left ventricular mass index; PWTd, posterior wall thickness diastole; RWT, relative wall thickness. *P at least o0.05 III vs I, 1P at least o0.05 III vs II and I. presence or absence of LVH or vascular alterations, a stepwise increase in the prevalence of LVH, carotid thickening and plaques occurred from the lower to the upper tertile (Figure 1). Eccentric LVH was the most prevalent abnormal geometric pattern, followed by LV concentric remodelling and concentric hypertrophy across all AR diameter strata. Finally, mean urinary albumin excretion and MA prevalence were slightly but not significantly higher in the medium and upper tertile as compared to lower one. Correlations analyses In the whole population AR size as a continuous variable showed positive correlations with age (r ¼ 0.21, Po0.0001), BMI (r ¼ 0.30, Po0.0001), body surface area (BSA) (r ¼ 0.42 Po0.0001), clinic DBP (r ¼ 0.15, Po0.0005), average 48 h DBP (r ¼ 0.11, Po0.01), average night-time SBP/DBP (r ¼ 0.11, P ¼ 0.004, and r ¼ 0.16, P ¼ , respectively), blood glucose (r ¼ 0.14, Po0.001), LVM (r ¼ 0.49, Po0.0001), LVM/BSA (r ¼ 0.38, Po0.0001), LVM/height 2.7 (r ¼ 0.34, Po0.0001), carotid IMT (r ¼ 0.16, P ¼ ). A significant inverse relationship was found between AR size and E/A ratio (r ¼ 0.20, Po0.0001) (Table 4). A logistic multiple regression analysis, however, revealed that only BSA m 2 (odds ratio (OR) 1.69, 95% confidence interval (CI) , P ¼ 0.005) average night-time DBP 485 mm Hg (OR 1.86, 95% CI , Po0.001), LVH (OR 2.52, 95% CI , Po0.001), carotid atherosclerosis (OR 1.71, 95% CI , Po0.001), age 450 years (OR 1.95, 95% CI Po0.001) and male gender (OR 2.4, 95% CI , Po0.001) were independently correlated with AR size. Discussion Our study analysed for the first time the relationship between AR size, ABP and traditional markers of organ damage such as LVH, carotid alterations and

5 535 Figure 1 Prevalence rates of LVH, left ventricular concentric remodelling, carotid IM thickening, plaques and MA according to the aortic tertiles. *o0.01 III vs I tertile. MA in a large sample of never-treated subjects with recently diagnosed grade 1 and 2 hypertension consecutively referred to a single hospital hypertension outpatient unit. Compared to a previous study by Kim et al., 5 our population sample was much larger, ABP was measured by two recording sessions within a few weeks interval and our analyses of organ involvement included medium-sized capacitance arteries and kidney. Our study shows that (1) AR dilatation at Valsava s sinuses is a relatively rare echocardiographic feature in the early phases of uncomplicated mild to moderate essential hypertension, its prevalence being significantly lower than that of prognostically validated TOD markers such as LVH, carotid atherosclerosis and MA; (2) modest but significant correlations exist between clinic DBP, several ABPM parameters and AR diameter in univariate analyses, although the strength of such association only persisted for average diastolic night-time BP when examined by multiple regression analyses; (3) overall, nocturnal DBP, anthropometric variables, male gender, LVH, carotid atherosclerosis but not MA are independent predictors of AR size. Several aspects of these findings deserve further comments. First, an enlarged AR had a lower prevalence compared to other TOD signs included in major hypertension guidelines. 23,26 In our study population an increased AR diameter was detected in approximately 4% of patients, whereas LVH, evidence of vascular alterations (i.e., presence of at least one carotid atherosclerotic plaque or diffuse IM thickening), LV concentric remodelling and MA

6 536 Table 4 Pearson s correlations coefficients for clinical variables and aortic root diameter Variable r P Age Body mass index Body surface area Height Clinic SBP 0.06 NS Clinic DBP Clinic heart rate 0.09 NS 48 h SBP 0.08 NS 48 h DBP Daytime SBP 0.05 NS Daytime DBP 0.08 NS Night-time SBP Night-time DBP Blood glucose Total cholesterol 0.04 NS LVMI (g/m 2 ) LVMI (g/h 2.7 ) RWT 0.09 NS E/A ratio Carotid IMT Urinary albumin excretion 0.03 NS Abbreviations: A, late diastolic peak flow; DBP, diastolic blood pressure; E, early diastolic peak flow; IMT, intima-media thickness; LVMI, left ventricular mass index; RWT, relative wall thickness; SBP, systolic blood pressure. occurred in about 27, 34, 9 and 8% of patients, respectively. The prevalence of AR dilatation in the present study (3.7%) was lower than that reported by Bella et al. 27 (10.0%) in 947 hypertensive patients with electrocardiographic LVH and by ourselves (6.1%) in 3366 treated and untreated hypertensive patients. 12 This finding may be explained by the fact that patients enrolled in the LIFE study were older, had higher BP and LV mass. Second, an interesting result of our study is that average night-time DBP, but not clinic or daytime and 48 h ABP showed a significant direct relationship with AR diameter in a univariate as well as multivariate analyses. The careful estimation of BP load performed by two 24 h ABPM sessions in the present study may clarify previous conflicting reports, as the direct correlation between AR diameter and clinic systolic and diastolic pressure observed in some studies 9,11 was not confirmed by others. 2 The impact of ABP and its circadian components on AR size in untreated hypertensive patients has never been prospectively investigated in large studies. In a small series of 48 hypertensive patients. Kim et al. 5 showed that awake DBP was independently correlated with AR diameter measured at four different locations. Our data obtained in a much larger study sample indicated that nocturnal BP assessed by two ABPM sessions may have an independent role in determining AR size. This observation is further supported by the progressive reduction in the prevalence of a normal nocturnal BP pattern (i.e., reproducible dipping pattern) with advancing AR size tertiles. This finding is also in line with the growing evidence that nocturnal BP has a superior prognostic value than awake BP in predicting cardiovascular morbidity and mortality in both normotensive and hypertensive individuals and that a blunted fall in night-time BP is associated with a higher incidence of TOD and cardiovascular events. 31 The reasons of the prognostic superiority of night-time over daytime BP are not clear, although one hypothesis is that the prognostic value of diurnal BP may be reduced by its excessive variability compared to the nocturnal period. Third, the relationship of body size components, male gender and age with AR diameter measured at Valsalva s sinuses consistently reported in multiple series have been confirmed in the present study extending those previous reports to uncomplicated mild to moderate hypertensive patients. 12 A notable result of our study is that both LV and carotid structure are important predictors of AR size, independently of other covariates such as BMI, age and ABP. This means that alterations in cardiac morphology as well as medium-sized arteries tend to proceed simultaneously with changes in the most proximal segment of the arterial tree; these observations confirm our previous findings and extend them to a population of untreated individuals exposed to BP overload for a shorter period of time. An independent association of LVH (but not carotid abnormalities) with AR size was demonstrated in different hypertensive groups, such as in a population-based sample of essential hypertensive patients, 7 in selected patients with electrocardiographic signs of LVH 27 and in patients with acute thoracic dissection. 6 Some additional points merit to be discussed. First, we failed to show a relationship between urinary albumin excretion and AR diameter; this does not mean that only LV and vascular changes are related to an increased AR size, but simply suggests that cardiac and carotid abnormalities, as documented by ultrasonography, are more sensitive indexes of TOD. Furthermore, MA measurement, which is known to be affected by a high variability, was performed only once in our patients. Second, since our study included only patients with minimal or no aortic regurgitation, any information about the complex relation between AR size, cardiovascular structure and aortic valve regurgitation cannot be provided. Third, a potential limitation of this study is that our findings refer to uncomplicated subjects with grade 1 and 2 hypertension and cannot be generalized to patients with more severe or longlasting hypertension or with comorbidities such as diabetes, cardiac, vascular and renal disease. In conclusion, the present study, the first one providing a comprehensive evaluation of the relation between AR size, ABP and TOD, indicates that: (1) AR dilatation at Valsalva s sinuses is not a common echocardiographic finding in untreated mild to moderate hypertensive patients; (2) night-

7 time BP, LVH and carotid alterations are independent predictors of AR size. This implies that an early and tight BP control throughout 24 h may prevent AR dilation and related cardiovascular complications in grade 1 and 2 essential hypertensive patients. What is known about this topic K Aortic root (AR) dilatation is frequently associated with aortic valve regurgitation, aneurysm of thoracic aorta and structural alterations of distal arterial territories. K AR dilatation has been observed more frequently in hypertensive than normotensive subjects and an association between AR diameter and left ventricular hypertrophy (LVH) has been reported in hypertensives. K A direct correlation between AR size and clinic blood pressure (BP) has been shown by some studies. What this study adds K AR enlargement is a not common echocardiographic finding in untreated mild to moderate essential hypertensive patients. K Night-time BP, LVH and carotid atherosclerosis are independent predictors of AR size, suggesting that AR dilation may occur in patients with a reduced fall in nocturnal BP associated with organ damage. Conflict of interest None. References 1 Seder JD, Burke JF, Pauletto FJ. Prevalence of aortic regurgitation by color flow Doppler in relation to aortic root size. J Am Soc Echocardiogr 1990; 3: Roman MJ, Devereux RB, Kramer-Fox R, O Loughlin J. Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol 1989; 64: Isselbacker EM, Eagle KA, Sesanctis RW. Diseases of aorta.in: Braunwald E (ed.). Heart Disease: A Textbook of Cardiovascular Medicine. WB Saunders: Philadelphia, PA, 1997, pp Rayner BL, Goodman H, Opie LH. The chest radiograph, a useful investigation in the evaluation of hypertensive patients. Am J Hypertens 2004; 17: Kim M, Roman MJ, Cavallini MC, Schwartz JE, Pickering TG, Devereux RB. Effect of hypertension on aortic root size and prevalence of aortic regurgitation. Hypertension 1996; 28: Iarussi D, Caruso A, Galderisi M, Covino FE, Dialetto G, Bossone E et al. Associations of left ventricular hypertrophy and aortic dilation in patients with acute thoracic aortic dissection. Angiology 2001; 52: Palmieri V, Bella JN, Arnett DK, Roman MJ, Oberman A, Kitzman DW et al. Aortic root dilatation at sinuses of valsalva and aortic regurgitation in hypertensive and normotensive subjects. The hypertension genetic epidemiology network study. Hypertension 2001; 37: Pearson AC, Gudipati C, Nagelhout D, Sear J, Cone JD, Labovitz AJ. Echocardiographic evaluation of cardiac structure and function in elderly subjects with isolated systolic hypertension. J Am Coll Cardiol 1991; 17: Reed CM, Richey PA, Pulliam DA, Somes GW, Alpert BS. Aortic dimensions in tall men and women. Am J Cardiol 1993; 71: Vasan RS, Larson MG, Levy D. Determinants of echocardiographic aortic root size. Circulation 1995; 91: Tell GS, Rutan GH, Kronmal RA, Bild DE, Polak JF, Wong ND et al. Correlates of blood pressure in community-dwelling older adults. Hypertension 1994; 23: Cuspidi C, Meani S, Fusi V, Valerio C, Sala C, Zanchetti A. Prevalence and correlates of aortic root dilatation in patients with essential hypertension: relationship with cardiac and extracardiac target organ damage. J Hypertens 2006; 24: Fagard RH, Staessen JA, Thjis L. Prediction of cardiac structure and function by repeated clinic and ambulatory blood pressure. Hypertension 1997; 29: Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palu C et al. Risk factors associated with alterations in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis. J Hypertens 1998; 116: Mancia G, Sega R, Bravi C, De Vito G, Valagussa F, Cesana G et al. Ambulatory blood pressure normality: results from the PAMELA study. J Hypertens 1995; 13: Verdecchia P, Schillaci G, Guerrieri M, Gatteschi C, Benemio G, Boldrini F et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990; 81: Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography : results of a survey of echocardiographic measurements. Circulation 1978; 58: Devereux RB, Reickek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977; 55: de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass; assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995; 25: Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba TG et al. Patterns of left ventricular geometry and geometric remodelling in essential hypertension. J Am Coll Cardiol 1992; 19: Pignoli P, Tremoli E, Poli A, Paoletti R. Intimal plus medial thickness of the arterial wall : a direct measurement with ultrasound imaging. Circulation 1986; 74: Salonen R, Haapanen A, Salonen JT. Measurement of intima-media thickness of common carotid arteries with high-resolution B-mode ultrasonography: inter and intra observer variability. Ultrasound Med Biol 1991; 17: Guidelines Committee. European Society of Hypertension-European Society of Cardiology guidelines for the 537

8 538 management of arterial hypertension. J Hypertens 2003; 21: Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Liu C et al. The role of carotid intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998; 128: Executive Summary. The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in adult (Adult Treatment Panel III). JAMA 2001; 285: Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC 7 Report. JAMA 2003; 289: Bella JN, Wachtell K, Boman K, Palmieri V, Papademetriou V, Gerdts E et al. Relation of left ventricular geometry and function to aortic root dilatation in patients with systemic hypertension and left ventricular hypertrophy (The LIFE Study). Am J Cardiol 2002; 89: Staessen JA, Thijs L, Fagard R, O Brien ET, Clement D, de Leeuw PW et al. Predicting cardiovascular risk using conventional versus ambulatory blood pressure in older patients with systolic hypertension. Systolic hypertension in Europe trial investigators. JAMA 1999; 282: Ohkubo T, Iami Y, Tsuji I, Nagai K, Watanabe N, Minami N et al. Relation between nocturnal decline in blood pressure and mortality: the Ohasama Study. Am J Hypertens 1997; 10: Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population. Circulation 2005; 111: Cuspidi C, Meani S, Salerno M, Valerio C, Fusi V, Severgnini B et al. Cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure. J Hypertens 2004; 22: