Journal of Human (2002) 16, 249–254  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh ORIGINAL ARTICLE is associated with unfavourable cardiac geometric adaptations in essential hypertensive subjects

C Tsioufis1, C Stefanadis1, M Toutouza1, I Kallikazaros1, K Toutouzas1, D Tousoulis1, C Pitsavos1, V Papademetriou2 and P Toutouzas1 1Department of Cardiology, University of Athens, Hippokration Hospital, Athens, Greece; 2VAMC and Georgetown University Medical Centers, Washington DC, USA

We sought in this study to examine the relationship tively correlated to LVMI (r = 0.46, P Ͻ 0.001) and relative between microalbuminuria and cardiac geometry since wall thickness (r = 0.47, P Ͻ 0.001). In the entire popu- a slight increased urinary albumin excretion (UAE) and lation, normal LV geometry, concentric LV remodelling, increased left ventricular (LV) mass have both been eccentric and concentric LV hypertrophy was found in identified as predictors of cardiovascular events in 34%, 33%, 12% and 21%, respectively. The prevalence hypertensive subjects. For this purpose, microalbumin- of normal LV geometry was significantly higher in nor- uria was determined in three non-consecutive 24-h moalbuminuric compared with microalbumnuric sub- samples as UAE of 20–200 mg/24 h in a group of 249 jects (55 vs 14%, P Ͻ 0.001) while the prevalence of untreated hypertensive subjects. Echocardiographic concentric LV hypertrophy was significantly higher in classification of patients into LV geometric patterns was microalbuminuric compared with normoalbuminuric based on relative wall thickness values and on gender- subjects (32 vs 5%, P Ͻ 0.0001). Multiple regression specific values for LV mass index (LVMI). The group of analysis revealed that concentric LV hypertrophy was patients with microalbuminuria (n = 119) was matched significantly associated with increased values of UAE for age, sex, body mass index, smoking status and and mean arterial pressure. In conclusion, the higher plasma cholesterol level with the group of patients with- prevalence of unfavourable LV geometric patterns in out microalbuminuria (n = 130). Subjects with micro- hypertensive subjects with microalbuminuria compared had significantly increased LVMI (111 vs with those without microalbuminura, may account for 90 g/m2, P Ͻ 0.0001), relative wall thickness (0.46 vs the worse cardiovascular outcomes associated with the 0.41, P Ͻ 0.001) and office systolic and diastolic blood presence of an increased UAE in hypertensive subjects. pressure (161 vs 148 and 101 vs 97 mmHg, respectively, Journal of Human Hypertension (2002) 16, 249–254. DOI: P Ͻ 0.005). For the pooled population, UAE was posi- 10.1038/sj/jhh/1001379

Keywords: microalbuminuria; cardiac geometry; left ventricular hypertrophy

Introduction non-diabetic patients with essential hyperten- sion.1,2,4–6 The pathogenic mechanisms leading A slightly elevated urinary albumin excretion microalbuminuric patients to this increased risk are (UAE), termed microalbuminuria, has been ident- still unknown; several studies have demonstrated an ified as an independent predictor of cardiovascular 1,2 association between microalbuminuria and athero- disease in major population-based cohort studies. genic cardiovascular risk factors, endothelial dys- Indeed, it is well established that microalbuminuria function, impaired aortic mechanics and increased can be considered predictive of the development of left ventricular (LV) mass.2,5–8 Left ventricular hy- overt and of cardiovascular mortality in pertrophy is another manifestation of pre-clinical 3 diabetic patients. The same adverse prognostic con- disease with well-defined prognostic meaning for clusion seems to emerge from recent research in cardiovascular complications. Furthermore, identi- fication of various geometric patterns of LV hypertrophy furthers stratifies cardiovascular Correspondence: C Tsioufis, 4 Athanasiou Diakou Street, 15127 risk.9,10 The aim of the present study, therefore, was Melissia, Greece. Fax: 00 30 1 7784590 Received 10 May 2001; revised 13 September 2001; accepted 22 to examine the relation between microalbuminuria November 2001 and the patterns of LV geometry in untreated non- diabetic hypertensive subjects. Microalbuminuria and cardiac geometry C Tsioufis et al 250 Subjects and methods Sonos 2500 ultrasound imager equipped with a 2.25–5 MHz transducer. Images were recorded on Study population super VHS videotapes and measurements were sub- The population in our study consisted of subjects sequently performed off-line by two independent with essential hypertension, aged 30 and 70 years operators, blinded to the patients’ demographics and referred to the outpatient hypertension unit. Patients BP status. Two-dimensional guided M-mode echo- with uncomplicated essential hypertension, stages cardiography was performed at the parasternal long- I–II were included in the study if they were newly axis view, and LV end-systolic systolic and diagnosed (within the previous 2 years) and had end-diastolic dimension, as well as intraventricular never been previously treated. Presence and severity septum and posterior wall thickness were measured of hypertension were determined on the basis of as the mean from five consecutive cardiac cycles, in office blood pressure (BP) measurements obtained accordance to the recommendations of the American by sphygmomanometer during three consecutive Society of Echocardiography.12,13 Subsequently, visits scheduled 3 weeks apart, according to the re- relative wall thickness was calculated using the fol- commendations of the JNC-VI.11 To confirm essen- lowing formula: (septal wall thickness + posterior tial hypertension, patients were assessed by using wall thickness)/(LV end-diastolic diameter).14,15 LV conventional clinical criteria and laboratory tests. In mass was calculated by the formula introduced by addition, all patients underwent renal ultrasono- Devereux et al: (0.80 × 1.04[{intraventricular septum graphy to confirm the presence of normal thickness + posterior wall thickness + left ventricu- size without cortical scarring or signs of obstructive lar end diastolic diameter}3 − left ventricular end uropathy. Exclusion criteria included overt pro- diastolic diameter] + 0.6) and was indexed for the teinuria, detectable by urine dip strip test, body surface area (LVMI). LV hypertrophy was con- mellitus, increased values of plasma , fam- sidered present if LVMIϾ104 g/m2 in women and iliar hypercholesterolaemia, history of any cardiac Ͼ116 g/m2 in men.15,16 Normal geometry was con- disease or other clinically significant concurrent sidered when LV mass did not extend the above gen- medical condition. Women receiving oral contracep- der specific values. Concentric LV hypertrophy was tives or long-term oestrogen replacement therapy considered present if relative wall thickness was were also excluded. Of the 310 individuals screened Ͼ0.43 and eccentric LV hypertrophy when relative for the study, 249 subjects (142 males), mean age wall thickness was р0.43.15 Concentric remodelling 52 ± 10 years, fulfilled all inclusion and exclusion was considered present in patients with normal criteria and consisted our study population. LVMI and relative wall thickness р0.43. All patients gave written informed concept for The inter-observer variability in our laboratory participation. The study protocol was approved by was 9.65% for LVMI and 8.5% for relative wall the ethics committee of our institution. thickness. Measurements obtained by the two observers were averaged and used for data analysis. Determination of UAE The study patients were asked to collect three non- Statistical analysis consecutive 24-h urine samples (from 8 am to 8 am) for the determination of UAE, as has been pre- Data is expressed as mean ± s.d. Since the 24-h UAE viously described.7 Urinary albumin concentrations data were skewed, values were logarithmically were determined by an immunonephelometric tech- transformed prior to statistical testing. Significant nique with a limit of detection of 0.4 mg/dl and an differences between the two groups were determ- interassay variation of 3.5%. Based on mean UAE in ined using the Student’s independent samples t-test the samples, the study patients were divided in or the ␹2 test where appropriate. Multiple linear those with microalbuminuria (mean UAE 20– regression analysis, with inclusion criteria at the 200 mg/24 h) and in those without microalbumin- 0.01 level and exclusion criteria at the 0.05 level, uria (mean UAE Ͻ20 mg/24 h). was used to evaluate the relation of clinical, demo- In addition to the above initial laboratory workup, graphic and haemodynamic parameters with LVMI. all selected patients underwent measurement of Also, a logistic regression model was used to ident- plasma lipids, which included total cholesterol, ify significant relations between each type of LV high-density lipoprotein cholesterol and triglycer- geometry and clinical, demographic and haemody- ides, using established techniques. Finally, patients namic parameters. Spearman correlation was perfor- were questioned about their smoking habbits. Smok- med to determine correlations between any of the ers were identified as those patients consuming one parameters. An analysis of covariance (ANCOVA) or more cigarettes per day. was performed in order to detect significant differ- ences of LVMI between patients with and without microalbuminuria, after the adjustment of a number Cardiac ultrasonography of covariates which were linearly related to the All echocardiographic studies were performed by a dependent variable. All tests were considered to be senior echocardiographer using a Hewlett-Packard significant at the level of P Ͻ 0.05.

Journal of Human Hypertension Microalbuminuria and cardiac geometry C Tsioufis et al 251 Table 1 Clinical and biochemical characteristics and blood pressure (BP) data for the entire study population and subgroups

Parameters Entire study Subjects with Subjects without P population microalbuminuria microalbuminuria (n = 249) (n = 119) (n = 130)

Age (years) 53.6 ± 11 54.1 ± 10 52.1 ± 11 NS Sex (males/females) 142/107 67/51 75/56 NS Body mass index (kg/m2) 28.12 ± 4 28.4 ± 3 27.8 ± 4NS Smokers (%) 53 56 51 NS Total cholesterol (mg/dl) 228 ± 43 228 ± 43 228 ± 43 NS HDL-cholesterol (mg/dl) 49 ± 11 49 ± 11 50 ± 12 NS LDL-cholesterol (mg/dl) 152 ± 28 153 ± 30 150 ± 26 NS Plasma renin activity (ng/ml/h) 1.6 ± 1.6 1.3 ± 1.1 1.8 ± 1.8 NS Rate of clearance of creatinine (ml/min) 104 ± 2.9 103 ± 2.8 105 ± 2.7 NS Logarithm of 24-h UAE 1.26 ± 0.4 1.56 ± 0.2 0.93 ± 0.2 0.0001 Office systolic BP (mm Hg) 155 ± 18 161 ± 12 148 ± 10 Ͻ0.001 Office diastolic BP (mm Hg) 99.9 ± 9 101.7 ± 9 97.5 ± 9 0.002 Mean arterial pressure (mm Hg) 118 ± 10 121 ± 10 114 ± 9 Ͻ0.001 Office pulse pressure (mm Hg) 55 ± 15 59 ± 15 50 ± 14 Ͻ0.001 Heart rate (bpm) 77 ± 10 76 ± 978± 10 NS

UAE = urinary albumin excretion; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Results P Ͻ 0.001) (Figure 1), relative wall thickness (r = 0.45, P Ͻ 0.001), office pulse pressure (r = 0.30, Of the 249 studied subjects, 130 subjects (53%) had P Ͻ 0.001) and office mean arterial pressure ± normal UAE (9.8 4 mg/24 h) and the remaining (r = 0.41, P Ͻ 0.001). Multiple regression analysis 119 subjects (47.8%) had increased UAE (43.3 ± 31 mg/24 h). The demographic and clinical charac- teristics of all subjects included in the study are presented in Table 1. The subjects with and without microalbuminuria were similar with respect to age, sex, body mass index, smoking status, plasma ren- nin activity, plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol levels and rate of clearance of creatinine. The systolic BP, diastolic BP, mean arterial pressure (diastolic plus 1/3 × pulse pressure) and pulse pressure values were signifi- cantly higher in the microalbuminuric than the nor- moalbuminuric hypertensive patients. LV echocardiographic measurements are pre- sented in Table 2. The two groups did not differ regarding the LV end-systolic and end-diastolic diameter. In contrast, patients with microalbumin- uria had significantly greater LVMI (by 21 g/m2) and relative wall thickness (by 0.05) compared to patients without microalbuminuria. Figure 1 A positive correlation between Log 24-h urinary albu- In the entire study population, the log of 24-h min excretion and left ventricular mass index in the entire UAE was positively correlated with LVMI (r = 0.46, study population.

Table 2 Echocardiographic data for the entire study population and subgroups

Parameters Entire Subjects with Subjects without P population microalbuminuria microalbuminuria (n = 249) (n = 119) (n = 130)

LV end-diastolic diameter (cm) 4.83 ± 0.4 4.87 ± 0.4 4.78 ± 0.4 NS LV end-systolic diameter (cm) 3.06 ± 0.4 3.07 ± 0.5 3.05 ± 0.3 NS Intraventricular septum (cm) 1.05 ± 0.1 1.13 ± 0.13 0.97 ± 0.09 Ͻ0.0001 Posterior wall (cm) 1.05 ± 0.1 1.12 ± 0.14 0.97 ± 0.1 Ͻ0.0001 LV mass index (g/m2) 100.9 ± 22 111.4 ± 21 90.5 ± 17 Ͻ0.0001 Relative wall thickness 0.43 ± 0.06 0.46 ± 0.06 0.41 ± 0.04 Ͻ0.0001

LV = left ventricular.

Journal of Human Hypertension Microalbuminuria and cardiac geometry C Tsioufis et al 252 Table 3 Forward multiple linear regression analysis in the total population with LVMI as the dependent variablea

Independent variables ␤ t value P value

Mean arterial pressure 0.518 4.253 0.0001

Log10 24-UAE 20.46 5.980 0.000 Age 0.280 2.545 0.01

Constant 11.613

aThe variable of body mass index did not enter the equation, according to the selection criteria (probability for entry Ͻ0.05; probability of removal Ͼ0.1). UAE = urinary albumin excretion; LVMI = left ventricular mass index.

was performed in the entire study population in order to evaluate the relation between LVMI and various haemodynamic and demographic para- meters. It was demonstrated that age, office mean arterial pressure and log 24-h UAE were signifi- cantly and independently related with LVMI in this setting (Table 3). The distribution of subjects with each type of LV geometric pattern in the groups with and without microalbuminuria is listed in Table 4. The preva- lence of patients with normal LV geometry was sig- nificantly lower in subjects with microalbuminuria compared with those without microalbuminuria while the prevalence of patients with concentric LV hypertrophy was significantly higher in subjects with microalbuminuria compared with those with- out microalbuminuria (Figure 2). Subjects with con- Figure 2 The distribution of subjects with each type of left ven- centric LV hypertrophy had significantly increased tricular geometric pattern in the subgroups with and without values of log 24-h UAE compared with subjects with microalbuminuria (Pts = patients; LV-NG = left ventricular nor- = eccentric LV hypertrophy, concentric LV mal geometry; LV-CR left ventricular concentric remodelling; LV-EH = left ventricular eccentric hypertrophy; LV-CH = left ven- remodelling and normal LV geometry (1.581, 1.340, tricular concentric hypertrophy). 1.301 and 1.013, respectively, P Ͻ 0.001 for all cases). Similarly, subjects with eccentric LV hypertrophy and concentric LV remodelling exhib- ited significantly increased values of log 24-h UAE in comparison with subjects with normal LV 24-h UAE (␤ =−2.500, Wald = 23.00, P = 0.0001). geometry (P Ͻ 0.005 for both cases). Concentric LV remodelling was significantly related Furthermore, each type of LV geometry as a with age (␤ = 0.02, Wald = 4.20, P = 0.04) and body dependent variable was entered in a logistic mass index (␤ = 0.112, Wald = 10.13, P = 0.001) regression model in order to identify significant while eccentric LV hypertrophy did not have any relations with age, body mass index, mean arterial significant relation with the aforementioned para- pressure and log 24-h UAE. It was revealed that nor- meters. Concentric LV hypertrophy was signifi- mal LV geometry was significantly related with age cantly related with increased values of mean arterial (␤ =−0.041, Wald = 7.97, P = 0.004), mean arterial pressure (␤ = 0.037, Wald = 4.35, P = 0.03) and log pressure (␤ =−0.040, Wald = 5.32, P = 0.02) and log 24-h UAE (␤ = 2.923, Wald = 23.16, P = 0.001).

Table 4 The incidence of left ventricular (LV) geometric pattern in the entire study population and subgroups

Parameters Entire Subjects with Subjects without P value population microalbuminuria microalbuminuria (n = 249) (n = 119) (n = 130)

Subjects with normal LV geometry 84 (33.7%) 16 (13.8%) 68 (55.2%) Ͻ0.001 Subjects with concentric LV remodelling 82 (32.9%) 46 (38.5%) 36 (29.3%) NS Subjects with eccentric LV hypertrophy 32 (12.8%) 18 (15.4%) 14 (10.3%) NS Subjects with concentric LV hypertrophy 51 (20.5%) 39 (32.3%) 12 (5.2%) Ͻ0.001

Journal of Human Hypertension Microalbuminuria and cardiac geometry C Tsioufis et al 253 Discussion endothelial dysfunction and increased vascular per- meability that might predispose to greater pen- In the present study we evaluated the relationship etration of atherogenic lipoprotein particles into of microalbuminuria with cardiac geometric pat- arterial wall.20,21 Towards this end, we have pre- terns in untreated patients with mild to moderate viously reported that microalbuminuria is associa- essential hypertension. Our main finding was that ted with excess impairment of large arteries hypertensive subjects with microalbuminuria exhi- mechanics in essential hypertension,7 a state which bit higher incidence of unfavourable LV geometric is closely related with LV structural and functional patterns compared with those without micro- changes.22 So, it is reasonable to suggest that micro- albuminuria. Absence of microalbuminuria is asso- albuminuria is closely related with unfavorable LV ciated with normal LV geometric pattern, while the geometric patterns through its widespread damage presence of microalbuminuria is associated with of the arterial tree. concentric LV hypertrophy pattern. Both increased LV mass and proteinuria are the In recent years a great deal of interest has focused ‘final common pathways’ of many adverse effect on on microalbuminuria and its relation to cardio- the heart and kidney respectively. Assessment of LV vascular complications. Evidence accumulates indi- hypertrophy and UAE rate can identify preclinical cating a close relationship of microalbuminuria with cardiovascular disease in asymptomatic hyperten- cardiovascular events in patients with essential sive patients.23 The observation that microalbumi- 1,2,4–6 hypertension. Accordingly, it was recently nuric patients are accompanied by a higher established that microalbuminuria confers a four- incidence of LV concentric hypertrophy may have fold increased risk of ischaemic heart disease among some clinical implications in the treatment of hyper- 1 hypertensive or bordeline hypertensive subjects. tensive individuals. Accurate detection of early The described association of increased UAE with 6,8 renal dysfunction by using a simple, specific and LV hypertrophy may explain some of the prognos- rather inexpensive test for identification of micro- tic significance of microalbuminuria. Indeed, in our albuminuria, may improve clinical risk stratification study, higher indexed LV mass was found in of hypertensive subjects. Microalbuminuria along microalbuminuric subjects than in normoalbumin- with LV geometric patterns may potentiate each uric individuals. Most notably, the difference in other’s prognostic significance. Furthermore, con- LVMI between microalbuminuric and normoalbum- verting enzyme inhibitors have been shown to inuric hypertensive subjects remains statistically reduce UAE along with the established regression of significant after adjustment for age, mean arterial LV hypertrophy.24 Our results, indicate that micro- pressure and body mass index. To further investi- albuminuria is a strong reason for aggressive treat- gate this issue we examined the association of vari- ment of these patients. ous cardiac geometric patterns to UAE in our An overview of the BP data in our population hypertensive population. Thus, a great percentage of reveals that patients with microalbuminuria had patients with normoalbuminuria had normal LV geometry while patients with microalbuminuria had higher values of both systolic and diastolic BP com- higher percentage of concentric LV hypertrophy. pared to those without microalbuminuria. This Our findings are in agreement with a previous finding is in agreement with the majority of previous study17 in which there was a significant trend reports and is consistent with the concept that UAE towards increased prevalence of LV hypertrophy, largely reflects the prevailing BP levels in hyperten- sive patients.8,25 In contrast with some previous especially of the concentric type in patients with 4,6 higher degrees of albuminuria. However, in this studies, the classical risk factors for atheroscler- study the definition of LV geometric pattern was not osis were equally distributed among patients with based on gender-specific criteria and the presence and without microalbuminuria in our study. of microalbuminuria was estimated in only one first From a methodological viewpoint, there are some morning urine sample. potential confounding factors in the present study. Morbid events occur almost four times more fre- First, we did not calculate the UAE as a ratio of uri- quently in subjects with concentric hypertrophy nary albumin to urinary creatinine that might have than in those with normal LV geometry.18,19 Krum- enhanced the accuracy of the assessment of holz et al,14 demonstrated that LV geometry can be microabuminuria. However, we preferred our esti- used as an independent factor for risk stratification mations to be based on three non-consecutive 24- of hypertensive patients.14 Findings of the present h samples instead of using only a single spot urine study suggest that the unfavourable association of sample. Second, the prevalence of microalbumin- microalbuminuria with cardiovascular events can be uria in our study group (47%) exceeded the high end explained at least in part from these high-risk geo- of the range of reported rates in previous studies. metric patterns. Concentric hypertrophy is an adapt- This fact is likely accounted for the characteristics ive response of cardiac muscle to pressure overload of this tertiary care centre population and for patient which mainly depends on the elasticity of aorta and selection criteria according to the study protocol. In the other large arteries. Furthermore, it has been agreement with the above, 66% of our subjects had hypothesised that microalbuminuria is a marker of LV remodelling or hypertrophy.

Journal of Human Hypertension Microalbuminuria and cardiac geometry C Tsioufis et al 254 Conclusions high blood pressure. Arch Intern Med 1997; 157: 2413–2446. Microalbuminuria is accompanied by unfavourable 12 Sahn DJ, De Maria A, Kisslo J, Weyman A. Recommen- LV geometric patterns in untreated essential hyper- dations regarding quantitation in M-mode echocar- tensive subjects. This association may partially diography; results of a survey of echocardiographic account for the greater risk for cardiovascular events measurements. Circulation 1978; 58: 1072–1083. 13 Devereux RB, Reichek N. Echocardiographic determi- in hypertensive subjects with microalbuminuria. nation of left ventricular mass in man; anatomic vali- However, further studies are needed to determine dation of the method. Circulation 1977; 55: 613–618. whether clinical outcome is improved or treatment 14 Krumholz H, Larson M, Levy D. Prognosis of left ven- cost is lowered by basing antihypertensive treatment tricular geometric patterns in the Framingham heart decisions in part on the presence of microalbumin- study. J Am Coll Cardiol 1995; 25: 879–884. uria and unfavourable LV geometric patterns. 15 Wachtell K et al. Impact of different partition values on prevalences of left ventricular hypertrophy and concentric geometry in a large hypertensive popu- References lation. The LIFE study. Hypertension 2000; 35:6–12. 16 Ganau A et al. Patterns of left ventricular hypertrophy 1 Jensen JS et al. Arterial hypertension, microalbumin- and geometric remodeling in essential hypertension. J uria, and risk of ischemic heart disease. Hypertension Am Coll Cardiol 1992; 19: 1550–1558. 2000; 35: 898–903. 17 Pontremoli R et al. Left ventricular geometry and func- 2 Borch-Johnsen K et al. Urinary albumin excretion. An tion in patients with essential hypertension and micro- independent predictor of ischemic heart disease. Art- albuminuria. J Hypertens 1999; 17: 993–1000. erioscler Thromb Vasc Biol 1999; 19: 1992–1997. 18 Devereux RB. Left ventricular geometry, pathophysiol- 3 Mogensen CE. Microalbuminuria predicts clinical pro- ogy and prognosis. J Am Coll Cardiol 1995; 25: 885– teinuria and early mortality in maturity-onset diabetes. 887. N Engl J Med 1984; 310: 356–360. 19 Verdecchia P et al. Adverse prognostic significance of 4 Bigazzi R, Bianchi S, Baldari D, Campese V. Micro- concentric remodeling of the left ventricular in hyper- albuminuria predicts cardiovascular events and renal tensive patients with normal left ventricular mass. J insufficiency in patients with essential hypertension. J Am Coll Cardiol 1995; 25: 871–887. Hypertens 1998; 16: 1325–1333. 20 Jensen JS, Borch-Johnsen K, Jensen G, Rasmussen BF. 5 Pontremoli R et al. Prevalence and clinical correlates Microalbuminuria reflects a generalized transvascular of microalbuminuria in essential hypertension. The albumin leakness in clinically healthy subjects. Clin MAGIC study. Hypertension 1997; 30: 1135–1143. Sci 1995; 88: 629–633. 6 Cerasola G et al. Microalbuminuria, renal dysfunction, 21 Mimran A, Ribstein J, DuGailer G. Is microalbuminuria and cardiovascular complication in essential hyperten- a marker of early intrarenal vascular dysfunction in sion. J Hypertens 1996; 14: 915–920. essential hypertension. Hypertension 1994; 23: 1018– 7 TsioufisCet al. Microalbuminuria is associated with 1021. abnormal thoracic aortic mechanics in essential hyper- 22 Bouthier JD, De Luca N, Safar ME, Simon A Ch. Car- tension. Am J Cardiol 2000; 86: 797–801. diac hypertrophy and arterial distensibility in essen- 8 Pedrinelli P. Microalbuminuria in hypertension. tial hypertension. Am Heart J 1985; 109: 1345–1352. Nephrol 1996; 73: 499–506. 23 Devereux R, Alderman M. Role of preclinical cardio- 9 Levy D et al. Prognostic implications of echocardio- vascular disease in the evolution from risk factor graphically determined left ventricular mass in the exposure to development of morbid events. Circu- Framingham Heart Study. N Engl J Med 1990; 322: lation 1993; 88: 1444–1455. 1561–1566. 24 Giatras I, Lau J, Levery AS. Effect of angiotensin- 10 Koren MJ et al. Relation of left ventricular mass and converting enzyme inhibitors on progression of non- geometry to morbidity and mortality in men and diabetic renal disease: a meta-analysis of randomized women with essential hypertension. Ann Intern Med trials. Ann Intern Med 1997; 127: 337–345. 1991; 114: 345–352. 25 Clausen P et al. Ambulatory blood pressure and uri- 11 The sixth report of the Joint National Committee on nary albumin excretion in clinically healthy subjects. prevention, detection, evaluation and treatment of Hypertension 1998; 32:71–77.

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