Hypertension is one of the leading factors

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1 AJH 2000;13: Arterial Wall Thickening at Different Sites and Its Association With Left Ventricular Hypertrophy in Newly Diagnosed Essential Hypertension Gaetano Vaudo, Giuseppe Schillaci, Franco Evangelista, Leonella Pasqualini, Paolo Verdecchia, and Elmo Mannarino The impact of hypertension on vascular structure at different arterial sites and the relation of vascular hypertrophy with left ventricular (LV) hypertrophy in the early stages of essential hypertension are unclear. In 96 newly diagnosed, never-treated, uncomplicated hypertensive subjects aged < 55 years (43 9 years, 68 men, clinic blood pressure 152/99 mm Hg, 24-h blood pressure 135/89 mm Hg), we measured LV mass (M-mode echocardiography) and intima-media thickness (IMT) of the carotid and femoral arteries (highresolution B-mode ultrasound). The average of 24 carotid and 24 femoral IMT readings (common and internal carotid or common and superficial femoral, right and left side, far and near wall, three sampling points per segment) was analyzed. Carotid and femoral IMT were strongly related to each other (r 0.77). Subjects with LV hypertrophy (n 33) had a greater IMT at the carotid ( v mm, P <.0001) and femoral ( v mm, P <.0001) level. Carotid IMT showed a positive correlation with LV mass (r 0.46) and age (r 0.38), and an inverse one with high-density lipoprotein (HDL) cholesterol (r 0.26). Femoral IMT was associated positively to LV mass (r 0.50), age (r 0.33) and triglycerides (r 0.29), and inversely to HDL-cholesterol (r 0.33). The association between IMT (both carotid and femoral) and LV mass held after controlling for age and other confounders in a multiple regression analysis. In summary, in the early stages of hypertension arterial wall thickening appears to be a diffuse process, which occurs in parallel at the carotid and femoral level and shows a positive association with LV hypertrophy. Am J Hypertens 2000; 13: American Journal of Hypertension, Ltd. KEY WORDS: Hypertension, arterial hypertrophy, ultrasonography, atherosclerosis, wall thickness. Hypertension is one of the leading factors for the development of atherosclerosis. Recently, B-mode ultrasound imaging of carotid arteries has been developed and standardized for in vivo evaluation of early atherosclerotic lesions, 1 and arterial intima-media thickness (IMT) measured by this method has undergone anatomical validation. 2 Patients with essential hypertension have a greater IMT of the common carotid artery than normotensive individuals. 3 9 Recently, increased Received June 28, Accepted September 17, From the Sezione di Medicina Interna, Angiologia e Malattie da Arteriosclerosi, University of Perugia, and the Azienda Ospedaliera di Perugia, Perugia, Italy. Address correspondence and reprint requests to Dr. Giuseppe Schillaci, Medicina Interna, Angiologia e Malattie da Arteriosclerosi, Policlinico Monteluce, via Brunamonti, Perugia, Italy; e- mail: skill@ftbcc.it 2000 by the American Journal of Hypertension, Ltd /00/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 AJH APRIL 2000 VOL. 13, NO. 4, PART 1 VASCULAR HYPERTROPHY IN HYPERTENSION 325 IMT of the carotid artery measured by ultrasonography has been associated with an excess risk for stroke and myocardial infarction in elderly subjects, 10 suggesting that early detection and management of patients using this method may be of considerable clinical importance. Wall thickening of large arteries seems to be a diffuse process in hypercholesterolemic subjects, 11 and a significant correlation between common carotid and common femoral IMT has been found in normotensive subjects, 12 but the association between IMT at different sites has not been explored in essential hypertension. Left ventricular (LV) hypertrophy detected at echocardiography is a powerful independent risk marker for cardiovascular complications in essential hypertension, and its regression has a beneficial effect on prognosis, 16,17 also after adjustment for treatmentinduced reduction in blood pressure (BP). 17 Moreover, subjects with LV hypertrophy are at increased risk of stroke. 18 A positive association between LV mass and increased IMT of the carotid artery has been observed both in essential hypertension 3,19 22 and in the general population, 23,24 and this association might explain the link between LV hypertrophy and the future incidence of stroke. However, the confounding effect of prior antihypertensive treatment on this association could not be excluded. In the present study, we measured LV mass by echocardiography and arterial IMT in two different districts (carotid and femoral) by high-resolution ultrasound in a group of young to middle-aged consecutive subjects with never-treated recently discovered essential hypertension, referred to our centers for baseline evaluation of high BP by a group of general practitioners. MATERIALS AND METHODS The present study is an analysis of 96 white subjects (68 men) with essential hypertension, derived from a larger consecutive sample of 184 untreated subjects with essential hypertension aged younger than 55 years, who were referred to our center for baseline evaluation by a group of general practitioners operating in Umbria, Central Italy. After exclusion of subjects with prior antihypertensive treatment (n 38), inadequate echocardiographic tracings (n 27), concomitant important disease (n 11), and reported duration of hypertension longer than 3 years (n 12), a total of 96 subjects fulfilled all the following inclusion criteria: clinic systolic BP 140 mm Hg and/or diastolic BP 90 mm Hg on three or more visits at 1-week interval; no previous or current antihypertensive or lipid-lowering medication, and no estrogen use; age 18 to 54 years; duration of hypertension 3 years or less; at least one valid BP measurement per hour over 24 h; good-quality M-mode echocardiography and high-resolution vascular ultrasound imaging; no clinical or laboratory evidence of diabetes, heart failure, coronary heart disease, previous stroke, valvular defects or secondary causes of hypertension, or important concomitant disease. All subjects gave informed consent to the study. Blood Pressure Measurement Clinic BP was measured by a physician in the hospital outpatient clinic with a mercury sphygmomanometer, with the subject sitting for 10 min or longer. The average of six or more measurements over two or more sessions was considered for the analysis. Ambulatory BP was recorded using an oscillometric device (models and 90207, SpaceLabs), set to take a reading every 15 min throughout the 24-h period. Normal daily activities were allowed and encouraged, and patients were told to keep their nondominant arm still and relaxed to the side during measurements. Reading, editing, and analysis of data were done as previously described. 25 Echocardiography The M-mode echocardiographic study of the left ventricle was performed under twodimensional control. Measurements were taken according to the American Society of Echocardiography recommendations. 26 Only frames with optimal visualization of interfaces and simultaneously showing septum, LV internal diameter, and posterior wall were used for reading. Tracings were read by two observers who were unaware of patients clinical data, and the mean value from five or more measurements per observer was computed. The intraobserver and intratracing variabilities in our laboratory have been reported elsewhere. 27 LV mass was calculated according to Devereux et al, 28 and normalized both by body surface area and by height 2.7, 29 to correct for the effect of overweight. Relative wall thickness was calculated as (2 posterior wall thickness/lv internal diameter). Vascular Ultrasound Carotid and femoral arteries were evaluated with high-resolution B-mode ultrasonography. The examination was performed with an ultrasound device (AU4, Esaote Biomedica, Florence, Italy) equipped with a linear 10-MHz transducer. Subjects were examined in the supine position, and all measurements were obtained at end-diastole by electrocardiographic triggering. The ultrasound images were stored on an S-VHS videotape and analyzed using an image processing workstation (Kontron KS- 200, Munich, Germany). On a longitudinal two-dimensional ultrasound image of carotid and femoral artery, the near and far arterial walls are displayed as two bright white lines separated by a hypoechogenic space. The distance between the leading edge of the first bright line on the far wall (lumen-intima interface) and the leading edge of the second bright line (media-adventitia interface) indicates the IMT of the

3 326 VAUDO ET AL AJH APRIL 2000 VOL. 13, NO. 4, PART 1 TABLE 1. DEMOGRAPHIC CHARACTERISTICS OF SUBJECTS CLASSIFIED BY LVH STATUS Data All (n 96) No LVH (n 63) LVH (n 33) P Age, years (10) 43.5 (8).79 Men, % Body mass index, kg m (4) 25.9 (4) 28.6 (4).001 Body height, m 1.72 (0.2) 1.71 (0.1) 1.73 (0.1).22 Alcohol intake, g/day 16 (21) 14 (18) 20 (26).32 Current smokers, % Duration of hypertension, years 1.3 (2) 1.1 (2) 1.4 (2).63 Total cholesterol, mmol/l 5.47 (0.9) 5.34 (0.8) 5.69 (1.0).09 HDL cholesterol, mmol/l 1.26 (0.3) 1.32 (0.3) 1.16 (0.2).01 Triglycerides, mmol/l 1.58 (0.9) 1.42 (0.8) 1.89 (1.2).03 Data are expressed as mean (SD). LVH, left ventricular hypertrophy; HDL, high-density lipoprotein. far wall. For the near wall, IMT was calculated as the distance between the trailing edge of the first bright line and the trailing edge of the second bright line. A 1.5-cm segment of the common carotid artery (immediately caudal to the carotid bulb) and the proximal 1.5-cm segment of the internal carotid artery were considered. Similarly, we examined the distal 1.5-cm segment of the common femoral artery and the proximal 1.5-cm segment of the superficial femoral artery. Within each segment, three measurements of IMT were taken. Care was taken to ensure that wall thickness was not measured at the site of a discrete plaque. Plaques, defined as echogenic structures encroaching into the vessel lumen with a distinct area 50% or more thicker than the surrounding wall, 9 were found in three subjects at the carotid level and in two subjects at the femoral level. Tracings were read by two observers who were unaware of patients clinical data. Mean carotid IMT was defined as the average of all IMT (as many as 24 readings: common and internal carotid arteries, right and left side, far and near wall, three sampling points per segment). Similarly, mean femoral IMT was calculated as the average of all common and superficial femoral IMT readings. To assess the reproducibility of IMT measurements, paired examinations were performed by the same observer on two different occasions (intraobserver reproducibility) and by two observers on the same occasion (interobserver reproducibility) in a subgroup of 20 subjects. The intraobserver coefficient of variation was 5.0% in the carotid district (mean SD of the difference, mm) and 6.5% in the femoral district (mean SD of the difference, mm). Corresponding interobserver values were 7.3% in the carotid district ( mm) and 9.8% in the femoral district ( mm). Statistical Analysis Student s t and 2 tests were performed when appropriate. Pearson s simple and partial correlation coefficients tested univariate and multivariate associations between study variables. The independent relation of several variables to LV mass was assessed by stepwise multiple linear regression. SPSS statistical package, release 7.5 (SPSS Inc., Chicago, Illinois), was used to perform the analyses. P levels less than.05 in two-tailed tests were considered statistically significant. Data are presented as mean (SD). RESULTS Some demographic and clinical characteristics of the 96 study subjects by presence and absence of LV hypertrophy are reported in Table 1. LV hypertrophy, defined according to a prognostically validated cut-off value (LV mass 51.0 g/m 2.7 ), 30 was detected in 34% of the study subjects (n 33); the prevalence of LV hypertrophy was 21% (n 20) when defined as an LV mass 125 g/m 2 in men and 110 g/m 2 in women. 14,28 Age and gender distribution did not differ in the two groups. Subjects with LV hypertrophy had a greater body mass index and were more frequently smokers. They also showed a lower high-density lipoprotein (HDL) cholesterol and higher serum triglycerides. Table 2 shows blood pressure data and ultrasound measurements in the study subjects. By definition, subjects with LV hypertrophy had a greater LV mass. Also, clinic and 24-h BP values and LV relative wall thickness were higher in subjects with LV hypertrophy. Carotid IMT was significantly greater in subjects with LV hypertrophy than in subjects with normal LV mass ( v mm, P.0002). Subjects with LV hypertrophy also showed a higher femoral IMT ( v mm, P.0001). When LV hypertrophy was defined after indexation by body surface area, similar findings were observed for carotid IMT ( v mm, P.001) and femoral IMT ( v mm,

4 AJH APRIL 2000 VOL. 13, NO. 4, PART 1 VASCULAR HYPERTROPHY IN HYPERTENSION 327 TABLE 2. BLOOD PRESSURE AND ECHOGRAPHIC CHARACTERISTICS OF SUBJECTS CLASSIFIED BY LVH STATUS Data All (n 96) No LVH (n 63) LVH (n 33) P Clinic SBP/DBP, mm Hg 152/99 (16/10) 149/96 (14/8) 158/103 (18/12).01/ hour SBP/DBP, mm Hg 135/89 (14/11) 131/86 (10/9) 143/94 (17/13).01/.01 LV mass, g m (12) 41.3 (6) 60.6 (11).0001 LV relative wall thickness 0.42 (0.08) 0.41 (0.07) 0.45 (0.07).003 Carotid IMT, mm 0.76 (0.17) 0.71 (0.16) 0.84 (0.16).0001 Femoral IMT, mm 0.68 (0.15) 0.64 (0.13) 0.77 (0.14).0001 Data are expressed as mean (SD). LVH, left ventricular hypertrophy; SBP, systolic blood pressure; DBP, diastolic blood pressure; IMT, intima-media thickness. P.001). Figure 1 shows the prevalence of LV hypertrophy in study subjects ranked into tertiles of carotid IMT (cut-off values were 0.66 mm and 0.83 mm), and into tertiles of femoral IMT (cut-off values were 0.60 and 0.75 mm). Prevalence of LV hypertrophy increased from 12% in the first tertile of carotid IMT to 42% and 48% in the second and third tertiles (P.0001), respectively. A similar progressive increase in the prevalence of LV hypertrophy was observed across tertiles of femoral IMT (9%, 37%, and 56%, P.005). A strong direct association was found between carotid and femoral IMT (r 0.77, P.0001; Figure 2). Correlates of Intima-Media Thickness As reported in Table 3, carotid and femoral IMT showed a positive univariate association with age and body mass index (all P.01). A direct correlation was also found with average 24-h systolic BP and pulse pressure, but not with 24-h diastolic BP. Both measures of arterial wall thickness had an inverse relation with HDL cholesterol, whereas no significant association was found with total cholesterol. A significant positive association with serum triglycerides was observed only for femoral IMT. Both carotid and femoral IMT showed a positive association with LV mass and wall thicknesses. The relation between femoral IMT and LV mass is depicted in Figure 3 (r 0.48, P.0001). A direct association with LV mass was observed for all carotid and femoral segments (common carotid artery, r 0.48; internal carotid artery, r 0.35; common femoral artery, r 0.47; superficial femoral artery, r 0.46; all P.001). The correlation coefficients between IMT and LV mass remained highly significant after removing the effect of several confounders including age, body mass index, 24-h pulse pressure, and HDL cholesterol. Partial correlation coefficients were r 0.33 for carotid IMT and r 0.43 for femoral IMT (both P.001). Predictors of LV Mass The independent association between LV mass and arterial IMT was assessed FIGURE 1. Prevalence of left ventricular hypertrophy (grey bars) by tertiles of carotid or femoral intima-media thickness. Left ventricular hypertrophy is defined as a left ventricular mass 51 g m 2.7. FIGURE 2. Correlation between carotid and femoral intima-media thickness. Bivariate normal ellipse (P.95) is reported.

5 328 VAUDO ET AL AJH APRIL 2000 VOL. 13, NO. 4, PART 1 TABLE 3. UNIVARIATE CORRELATIONS OF ARTERIAL INTIMA-MEDIA THICKNESS Variable Carotid Femoral Age 0.38* 0.33* Body mass index * 24-h systolic BP h diastolic BP h pulse pressure Total cholesterol HDL-cholesterol Triglycerides Left ventricular mass, g 0.46* 0.50* Interventricular septum 0.43* 0.51* Posterior wall thickness 0.33* 0.37* *P.001; P.01; P.05. BP, blood pressure; HDL, high-density lipoprotein. FIGURE 3. Correlation between femoral intima-media thickness and left ventricular mass. Bivariate normal ellipse (P.95) is reported. through multiple linear regression analysis. Twentyfour hour pulse and mean pressure, body mass index, body size (height 2.7 ), and carotid IMT (all P.01) appeared to be independent predictors of a higher LV mass. Resulting equation was: LV mass (g) ( h pulse pressure [mm Hg]) ( h mean BP [mm Hg]) (2.89 body mass index [kg m 2 ]) (33.53 height 2.7 [m 2.7 ]) (53.40 carotid IMT [mm]). Overall, 58% of the total observed variation in LV mass was explained by the model (multiple r 0.76). Gender, age, cigarette smoking, duration of hypertension, 24-h diastolic BP, clinic BP, total and HDL cholesterol, and serum triglycerides failed to enter the equation. In addition, femoral IMT was an independent predictor of LV mass (P.0001). In a model in which femoral IMT replaced carotid IMT, the final equation (multiple r 0.76, variability explained 57%) was: LV mass (g) (2.83 body mass index [kg m 2 ]) (28.54 height 2.7 [m 2.7 ]) ( h pulse pressure [mm Hg]) ( h mean BP [mm Hg]) (64.30 femoral IMT [mm]). DISCUSSION The main new findings of the present study are that, in young to middle-age subjects with newly diagnosed essential hypertension, (1) arterial wall thickening occurs in parallel at the carotid and femoral level, and (2) carotid and femoral IMT shows a positive association with LV mass, which remains significant also in a multivariate analysis that takes into account several confounding factors including 24-h BP. Our findings, obtained in a cohort of relatively young uncomplicated subjects with recently discovered hypertension, demonstrate that arterial thickening is a diffuse process affecting both carotid and femoral arteries simultaneously in essential hypertension. Association Between Carotid and Femoral Wall Thickening In the present study, IMT at the carotid level had a very strong correlation with femoral artery thickness (r 0.77, Figure 2); thus, around 60% of the total variability of either variable was explained by the other variable. These results extend to hypertensive subjects those obtained in a population-based sample of normotensive children and young adults by Sass et al, in which correlation coefficients between common carotid and common femoral IMT were 0.58 to 0.60 in men and 0.32 to 0.42 in women. 12 Our findings demonstrate that large artery wall thickening occurs at multiple sites in hypertension, and that measurement of IMT at the carotid level may represent an accurate estimate of the adaptive or atherosclerotic changes of large arteries in hypertensive subjects. It is uncertain the extent to which intimal-medial thickening represents hypertrophy as opposed to early atherosclerosis. Findings from a recent population-based study 31 suggest that carotid IMT below a certain degree reflects an adaptive response to altered flow, shear stress, and pressure. Beyond a certain level, IMT may more likely represent atherosclerosis. The lack of association between intima-media thickness and prevalence of plaques in hypertensive subjects 9 also supports the view that vascular hypertrophy and early atherosis might be two different structural changes. In our study, the increasing prevalence of LV hypertrophy with increasing arterial IMT and the association of IMT with average 24-h BP support the concept that increased carotid and femoral

6 AJH APRIL 2000 VOL. 13, NO. 4, PART 1 VASCULAR HYPERTROPHY IN HYPERTENSION 329 wall thickness in relatively young subjects with recently discovered essential hypertension is in part due to hypertrophy. Irrespective of its adaptive or atherosclerotic nature, carotid IMT is associated with a gradual increase of the risk for future cardiovascular and cerebrovascular disease, with no clear cut-off point above which the risk increases more rapidly. 10,32 Therefore, measurement of IMT may be used as a marker for the total individual burden of atherosclerosis, and as a graded marker for cardiovascular risk. Association Between Arterial IMT and LV Mass Several mechanisms can explain the association between large artery wall thickening and increased LV mass in hypertension. First, both variables appear to be dependent on common hemodynamic changes. The persistence of this association after adjustment for clinic BP values has been interpreted 24 as the result of the inadequacy of office BP readings to express the average BP load. However, in our study BP was assessed by 24-h ambulatory monitoring, and both steady (mean arterial pressure) and pulsatile (pulse pressure) components of BP were considered. The persistence of the association between IMT and LV mass after adjustment for 24-h BP supports the hypothesis of its relative independence from hemodynamic variables. Second, nonhemodynamic mechanisms might be active in determining both vascular and cardiac hypertrophy. Angiotensin-converting enzyme deletion polymorphism has been associated with increased carotid IMT 33 and with LV hypertrophy on the electrocardiogram, 34 and plasma angiotensin-converting enzyme activity is higher in subjects with greater common carotid IMT. 35 Third, differences in arterial distending pressure 36 and structural changes within the arteries 37 may account for increased vascular stiffness in hypertension. It is worth noting that vascular hypertrophy may affect arterial pressure waveform contour, as reported by Tice et al. 38 Increased stiffness of the aorta and the large arteries and the associated augmentation of central arterial pressure pulse may in turn increase cardiac afterload 39 and promote left ventricular hypertrophy. 40 Our finding of an independent association between carotid wall thickening and LV mass in relatively young never-treated hypertensive subjects may contribute to explaining the increased risk of cerebrovascular events observed in subjects with evidence of LV hypertrophy on the electrocardiogram 41 or on the echocardiogram, 18 as well as the increased risk of myocardial infarction observed in subjects with increased carotid IMT. 10 Additional evidence for a relation between coronary and carotid atherosclerosis derives from a study in which carotid artery discrete plaques and carotid cross-sectional area index were independent predictors of myocardial ischemia under exercise. 42 Moreover, carotid atherosclerosis is strongly associated with severe angiographically defined coronary artery disease in subjects referred for cardiac catheterization. 43,44 In summary, the current study documents a strong parallelism between arterial wall thickening at the carotid and femoral level in young to middle-aged subjects with newly diagnosed essential hypertension, and a significant association between arterial wall thickening and LV hypertrophy. These findings suggest that asymptomatic hypertensive subjects with carotid or femoral thickening due to atherosclerosis or hypertrophy may be at an increased risk of future coronary events. Further studies will be necessary to clarify the prognostic implications of these data. REFERENCES 1. Mercuri M: Noninvasive imaging protocols to detect and monitor carotid atherosclerosis progression. Am J Hypertens 1994;7:23S 29S. 2. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R: Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986;74: Roman MJ, Saba PS, Pini R, Spitzer M, Pickering TG, Rosey S, Alderman MH, Devereux RB: Parallel cardiac and vascular adaptation in hypertension. Circulation 1992;86: Bots ML, Hofman A, de Bruyn AM, de Jong PT, Grobbee DE: Isolated systolic hypertension and vessel wall thickness of the carotid artery: the Rotterdam Elderly Study. Arterioscler Thromb 1993;13: Ferrara LA, Mancini M, Celentano A, Galderisi M, Iannuzzi R, Marotta T, Gaeta I: Early changes of the arterial carotid wall in uncomplicated primary hypertensive patients: study by ultrasound high-resolution B-mode imaging. Arterioscler Thromb 1994;14: Gariepy J, Massonneau M, Levenson J, Heudes D, Simon A: Evidence for in vivo carotid and femoral wall thickening in human hypertension. Hypertension 1993; 22: Bigazzi R, Bianchi S, Nenci R, Baldari D, Baldari G, Campese VM: Increased thickness of the carotid artery in patients with essential hypertension and microalbuminuria. J Hum Hypertens 1995;9: Cuspidi C, Lonati L, Sampieri L, Leonetti G, Zanchetti A: Similarities and differences in structural and functional changes of left ventricle and carotid arteries in young borderline hypertensives and in athletes. J Hypertens 1996;14: Gariepy J, Simon A, Massonneau M, Linhart A, Segond P, Levenson J, PCVMETRA Group: Echographic assessment of carotid and femoral structure in men with essential hypertension. Am J Hypertens 1996;9: O Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK, for the Cardiovascular Health

7 330 VAUDO ET AL AJH APRIL 2000 VOL. 13, NO. 4, PART 1 Study Collaborative Research Group: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999;340: Gariepy J, Simon A, Massonneau M, Linhart A, Levenson J, PCVMETRA Group: Wall thickening of carotid and femoral arteries in male subjects with isolated hypercholesterolemia. Atherosclerosis 1995;113: Sass C, Herbeth B, Chapet O, Siest G, Visvikis S, Zannad F: Intima-media thickness and diameter of carotid and femoral arteries in children, adolescents and adults from the Stanislas cohort: effect of age, sex, anthropometry and blood pressure. J Hypertens 1995;16: Casale PN, Devereux RB, Milner M, Zullo G, Harshfield GA, Pickering TG, Laragh JH: Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med 1986;105: Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114: Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G: Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension 1994;24: (erratum in Hypertension 1995;25:462). 16. Muiesan ML, Salvetti M, Rizzoni D, Castellano M, Donato F, Agabiti-Rosei E: Association of change in left ventricular mass with prognosis during long-term antihypertensive treatment. J Hypertens 1995;13: Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R, Zampi I, Reboldi G, Porcellati C: Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation 1998;97: Bikkina M, Levy D, Evans JC, Larson MG, Benjamin EJ, Wolf PA, Castelli WP: Left ventricular mass and risk of stroke in an elderly cohort. JAMA 1994;272; Roman MJ, Pickering TG, Pini R, Schwartz JE, Devereux RB: Prevalence and determinants of cardiac and vascular hypertrophy in hypertension. Hypertension 1995;26: Boutouyrie P, Laurent S, Girerd X, Benetos A, Lacolley P, Abergel E, Safar M: Common carotid artery stiffness and patterns of left ventricular hypertrophy in hypertensive patients. Hypertension 1995;25: Hughes AD, Sinclair AM, Geroulakos G, Mayet J, Mackay J, Shahi M, Thom S, Nicolaides A, Sever PS: Structural changes in the heart and carotid arteries associated with hypertension in humans. J Hum Hypertens 1993;7: Pierdomenico SD, Lapenna D, Guglielmi MD, Porreca E, Antidormi T, Cuccurullo F, Mezzetti A: Vascular changes in hypertensive patients with different left ventricular geometry. J Hypertens 1995;13: Muiesan ML, Salvetti M, Zulli R, Pasini GF, Bettoni G, Monteduro C, Rizzoni D, Castellano M, Agabiti-Rosei E: Structural association between the carotid artery and the left ventricle in a general population in Northern Italy: the Vobarno Study. J Hypertens 1998;16: Kronmal RA, Smith VE, O Leary DH, Polak JF, Gardin JM, Manolio TA: Carotid artery measures are strongly associated with left ventricular mass in older adults (a report from the Cardiovascular Health Study). Am J Cardiol 1996;77: Schillaci G, Verdecchia P, Borgioni C, Ciucci A, Gattobigio R, Sacchi N, Benemio G, Porcellati C: Predictors of diurnal blood pressure changes in 2042 subjects with essential hypertension. J Hypertens 1996;14: Sahn DJ, DeMaria A, Kisslo J, Weyman A, the Committee on M-Mode Standardization of the American Society of Echocardiography: Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58: de Simone G, Ganau A, Verdecchia P, Devereux RB: Echocardiography in arterial hypertension: when, why and how? J Hypertens 1994;12: Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N: Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57: de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, De Divitiis O, Alderman MH: Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and the impact of overweight. J Am Coll Cardiol 1992;20: 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: Bots ML, Hofman A, Grobbee DE: Increased common carotid intima-media thickness: adaptive response or a reflection of atherosclerosis? Findings from the Rotterdam Study. Stroke 1997;28: Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE: Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96: Castellano M, Muiesan ML, Rizzoni D, Beschi M, Pasini G, Cinelli A, Salvetti M, Porteri E, Bettoni G, Kreutz R, Lindpaintner K, Agabiti-Rosei E: Angiotensin-converting enzyme I/D polymorphism and arterial wall thickness in a general population: the Vobarno study. Circulation 1995;91: Schunkert H, Hense H-W, Holmer SR, Stender M, Perz S, Keil U, Lorell BH, Riegger GAJ: Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 1994;330: Bonithon-Kopp C, Ducimetière P, Touboul P-J, Feve J-M, Billard E, Courbon D, Heraud V: Plasma angiotensin-converting enzyme activity and carotid wall thickening. Circulation 1994;89: Gribbin B, Pickering TG, Sleight P: Arterial distensibility in normal and hypertensive man. Clin Sci 1979;56:

8 AJH APRIL 2000 VOL. 13, NO. 4, PART 1 VASCULAR HYPERTROPHY IN HYPERTENSION Safar ME, Girerd X, Laurent S: Structural changes of large conduit arteries in hypertension. J Hypertens 1996;14: Tice FD, Peterson JW, Orsinelli DA, Binkley PF, Cody RJ: Vascular hypertrophy is an early finding in essential hypertension and is related to arterial pressure waveform contour. Am Heart J 1996;132: Saba PS, Roman MJ, Ganau A, Pini R, Jones EC, Pickering TG, Devereux RB: Relationship of effective arterial elastance to demographic and arterial characteristics in normotensive and hypertensive adults. J Hypertens 1995;13: Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB: Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol 1993;22: Kannel WB: Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med 1983;75 (suppl 3A): Okin PM, Roman MJ, Schwartz JE, Pickering TG, Devereux RB: Relation of exercise-induced myocardial ischemia to cardiac and carotid structure. Hypertension 1997;30: Nowak J, Nilsson T, Sylvén C, Jogestrand T: Potential of carotid ultrasonography in the diagnosis of coronary artery disease: a comparison with exercise test and variance ECG. Stroke 1998;29: Kallikazaros I, Tsioufis C, Sideris S, Stefanadis C, Toutouzas P: Carotid artery disease as a marker for the presence of severe coronary artery disease in patients evaluated for chest pain. Stroke 1999;30: