Blood Pressure Measurement and Cardiovascular Risk

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1 Blood Pressure Measurement and Cardiovascular Risk Awake Systolic Blood Pressure Variability Correlates With Target-Organ Damage in Hypertensive Subjects Alfonso Tatasciore, Giulia Renda, Marco Zimarino, Manola Soccio, Grzegorz Bilo, Gianfranco Parati, Giuseppe Schillaci, Raffaele De Caterina Abstract Growing evidence associates blood pressure (BP) variability with cardiovascular events in hypertensive patients. Here we tested the existence of a relationship between awake BP variability and target-organ damage in subjects referred for suspected hypertension. Systolic and diastolic BP variability were assessed as the standard deviation of the mean out of 24-hour, awake and asleep BP recordings in 180 untreated subjects, referred for suspected hypertension. Measurements were done at 15-minute intervals during daytime and 30-minute intervals during nighttime. Left ventricular mass index (by echo), intima-media thickness (by carotid ultrasonography), and microalbuminuria were assessed as indices of cardiac, vascular and renal damage, respectively. Intima-media thickness and left ventricular mass index progressively increased across tertiles of awake systolic BP variability (P for trend and 0.003, respectively). Conversely, microalbuminuria was similar in the 3 tertiles (P NS). analysis identified age (P ), awake systolic BP (P 0.001), awake systolic BP variability (P 0.015) and diastolic BP load (P 0.01) as independent predictors of intima-media thickness; age (P ), male sex (P 0.012), awake systolic (P ) and diastolic BP (P 0.035), and awake systolic BP variability (P 0.028) as independent predictors of left ventricular mass index; awake systolic BP variability (P 0.01) and diastolic BP load (P 0.01) as independent predictors of microalbuminuria. Therefore, awake systolic BP variability by non-invasive ambulatory BP monitoring correlates with sub-clinical target-organ damage, independent of mean BP levels. Such relationship, found in subjects referred for recently suspected hypertension, likely appears early in the natural history of hypertension. (Hypertension. 2007;50: ) Key Words: hypertension blood pressure variability target-organ damage intima-media thickness left ventricular mass index Hypertension involves an increased risk of cardiovascular events, 1 which may be predicted by the occurrence of target-organ damage, such as subclinical renal dysfunction (microalbuminuria), 2 left ventricular hypertrophy, 3 or increased intima-media thickness, this last as a surrogate marker for atherosclerosis. 4 The availability of 24-hour ambulatory blood pressure monitoring (ABPM), in addition to providing information on mean BP levels, also allows an estimate of BP variability, the clinical significance of which is currently debated. 5 7 It has been shown that BP variability, assessed with invasive 24-hour ABPM, which provides beatto-beat estimates of BP and therefore a large number of estimates over 24 hours, carries prognostic information, with a higher number of cardiovascular events occurring in patients with wider BP excursions. 8 Information of this kind is beginning to accumulate also with noninvasive 24-hour ABPM, which is now much of current clinical use. Here the day/night variability, as assessed by the occurrence of the dipper/nondipper pattern, has been associated with lesser cardiovascular events. 9 On the other hand, a direct relationship between noninvasively assessed BP variability and progression of target-organ damage has also been documented, with patients featuring increased 24-hour BP variability also showing more atherosclerosis compared with subjects with normal BP variability. 4,10 More recently, daytime systolic BP variability has been identified as an independent predictive variable for cardiovascular events in elderly hypertensive patients, as well as in patients from a general population. 14 Whether such likely causal relationships occur early in the natural history of hypertension is, however, currently unknown, because of the difficulty of gathering such information in newly diagnosed, previously untreated hypertensive subjects. We therefore in this study analyzed the relationship between changes in daily life BP variability patterns and target Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received February 26, 2007; first decision March 14, 2007; revision accepted April 18, From the Institute of Cardiology and Center of Excellence on Aging (A.T., G.R., M.Z., M.S., R.D.C.), G. d Annunzio University, Chieti; the Department of Cardiology (G.B., G.P.), S. Luca Hospital, Italian Auxologic Institute & Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan; and the Department of Clinical and Experimental Medicine (G.S.), the University of Perugia, Italy. Correspondence to Raffaele De Caterina, MD, PhD, Institute of Cardiology, G. d Annunzio University Chieti, c/o Ospedale S. Camillo de Lellis, Via Forlanini, 50, Chieti, Italy. rdecater@unich.it 2007 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 326 Hypertension August 2007 multi-organ damage in a cohort of newly diagnosed hypertensive subjects, with the specific hypothesis that awake systolic BP variability is a correlate of target-organ damage. Materials and Methods Study Population We designed a cross-sectional study in subjects referred for recent ( 6 months) suspected hypertension. We calculated a sample size of 45 subjects per tertile to provide a study power of 95% to detect a difference of 0.1 mm in carotid artery intima-media thickness (IMT, see below), and a sample size of 49 subjects per tertile to detect a difference of 10 g/m 2 in left ventricular mass index (LVMI, see below) between the first and the third tertiles of awake BP variability, with a 1-side type I error of Assuming a drop-out rate of 20%, a population of at least 177 subjects was estimated as necessary. We therefore screened 215 consecutive outpatients referred to our clinic by their general practitioners on the basis a recent ( 6 months) diagnosis of suspected hypertension, detected by clinic BP measurement according to standard criteria (clinic systolic BP 140 mm Hg or diastolic BP 90 mm Hg to define hypertension). 1 Because visits by general practitioners in our country routinely involve clinic BP measurements, we assumed that the finding of elevated blood pressure in our cohort occurred early on in the natural history of the disease. Of these subjects, we excluded patients with diabetes (n 10), renal dysfunction (serum creatinine 2 mg/dl, n 2, or macroalbuminuria 300 mg/24 hour, n 3), secondary hypertension (n 3), heart failure (n 6), coronary heart disease (n 3), and previous stroke (n 1), all conditions associated with changes in autonomic nervous system activity potentially able to influence BP variability over 24 hours. For the same reasons, we also a priori excluded subjects with nighttime working habits (n 7). Clinic BP measurements, performed by the referring physicians, were performed according to standard criteria. 15 After the original hypertension screening, all subjects underwent ABPM and a standard diagnostic work-up as part of a primary prevention program. A net number of 180 subjects was therefore the final study population (Table 1). Data on the presence of other risk factors, such as family history of hypertension, tobacco smoking, coffee or alcohol consumption (dichotomized as present or absent), and the level of physical activity (defined as aerobic exercise on a regular basis, such as walking, jogging, or swimming for at least 30 to 45 minutes 3 times per week 16 ), were also recorded, together with biohumoral variables. Informed consent was obtained from each participant, and the study protocol was approved by the local ethics committee. Outcome measurements of this study were estimates of carotid and myocardial involvement by carotid and cardiac ultrasound investigations and microalbuminuria taken as an index of sub-clinical renal damage. Ambulatory Blood Pressure Monitoring and Assessment of Blood Pressure Variability All subjects underwent a 24-hour noninvasive ABPM with a validated oscillometric device (SpaceLabs Monitor Inc). BP monitoring was performed on a working day with the subjects performing usual daily activities and refraining from heavy physical exercise. BP and heart rate readings were obtained every 15 minutes during daytime (between 7 AM and 11 PM) and every 30 minutes during nighttime (between 11 PM and 7 AM). The selection of such a frequency of automated measurements came from a compromise between the need to have relatively high frequency BP readings, required for a reliable assessment of BP variability also with non invasive discontinuous ABPM, 17 and the need to avoid excessive interference with subjects sleep. Subjects were instructed to take a diary of their activities and time of retiring to bed, and ABPM recordings were accordingly subdivided into awake or asleep periods based on such diary entries (rather than on arbitrary time definitions), which practically coincided, in most subjects, with daytime and nighttime subperiods, arbitrarily defined. TABLE 1. Baseline Demographic and Biohumoral Data, Blood Pressure Parameters, and Indices of Target-Organ Damage in the Study Population Mean SD Age, y Sex (M), % 60 BMI, kg/m Family history of hypertension, % 57 Smoking, % 26 Physical activity, % 47 Coffee drinking, % 91 S-creatinine, mg/dl Creatinine clearance, ml/min Total cholesterol, mg/dl Triglycerides, mg/dl LDL-C, mg/dl HDL-C, mg/dl Systolic BP, mm Hg Diastolic BP, mm Hg HR, bpm Systolic BP variability, mm Hg Diastolic BP variability, mm Hg Systolic BP load, % Diastolic BP load, % % nocturnal systolic BP fall* % nocturnal diastolic BP fall* Dippers, systolic BP, %* 48 Dippers, diastolic BP, %* 73 IMT, mm LVMI, g/m Microalbuminuria, mg/h Data are expressed as mean SD unless otherwise indicated. y indicates years; M, male; BMI, body mass index; S-creatinine, serum creatinine; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol; HR, heart rate. * calculated over 24 hours. BP variability was calculated as the standard deviation (SD) of mean awake and asleep systolic (S), diastolic (D), mean (M) BP, and pulse pressure (PP). 18 Nocturnal dipping was defined as a reduction in the average systolic and diastolic BP at night 10% compared with the average awake values. 9 BP load was arbitrarily defined as the proportion of BP reading 135 mm Hg systolic or, respectively, 85 mm Hg diastolic, over a given time interval (in this case, over daytime). 19 We treated data on nocturnal dipping as both a continuous (% nocturnal SBP and DBP fall) and a discrete (dippers, SBP, and DBP, %) variable. Carotid Ultrasonography Carotid ultrasonographic investigations were performed with a General Electric VingMed Vivid 3 Pro apparatus equipped with a 10-MHz linear-array transducer, with the subjects supine and the neck in slight hyperextension. Measurements of common carotid artery IMT were done according to the Atherosclerosis Risk in Communities (ARIC) study protocol. 20 An optimal longitudinal B-scan image was obtained and stored on a videotape. This procedure was repeated 3 times for each wall (anterior, lateral, and posterior). IMT measurements were performed 1 cm proximal to the tip of the flow divider on the far wall, 21 taking the mean of the maximum values obtained in each projection (max-imt), as previ-

3 Tatasciore et al Blood Pressure Variability and Target-Organ Damage 327 ously described and validated. 11,22 Concordance between independent readings by the 2 operators (A.T. and G.R.) was previously tested (r 0.91). Echocardiography The echocardiographic examination was performed with a General Electric VingMed Vivid 3 Pro echocardiographic apparatus, equipped with a 2.5- to 3.5-MHz linear-array transducer, with subjects in a partial left decubitus. M-mode echocardiographic tracings, obtained under 2-dimensional control, were measured by 2 different readers in a blind manner according to the recommendations of the American Society of Echocardiography. 23 Concordance between independent readings by the 2 operators (A.T. and M.S.) was previously tested (r 0.90). End-diastolic left ventricular (LV) internal diameter (ID), end-diastolic interventricular septum thickness (interventricular septal thickness [IVST]), and end-diastolic posterior wall thickness (PWT) were assessed according to the Penn Convention measurement. 24 Left ventricular mass (LVM) was calculated with the Devereux formula: LVM (g) [0.8 [1.04 (left ventricular internal dimension (LVID) IVST PWT) 3 (LVID) 3 ] 0.6], 25 corrected for the body surface area and thus expressed as left ventricular mass index (LVMI). Laboratory Measurements Serum creatinine, creatinine clearance, 26 total-cholesterol, HDL-cholesterol, LDL-cholesterol (Friedewald formula), and triglycerides were evaluated. Primary laboratory measurements were performed with standard methods. 27 Microalbuminuria was defined as a urinary albumin excretion of 30 to 300 mg/24 hour. Because daily urinary albumin excretion is known to be influenced by daily activities, 28 only the nighttime (12-hour) values were considered. Statistical Methods Continuous variables were expressed as mean SD. Discrete variables were expressed as percentages. Subjects were analyzed for baseline demographic and biohumoral data, and for awake BP monitoring variables. Subjects were then divided into tertiles of awake, asleep, and 24-hour SBP variability. To test for differences among tertiles of BP variability, a 1-way analysis of variance was used for continuous variables, and a 2 or Fisher exact test for discrete variables, as appropriate. For post-hoc multiple comparisons of continuous variables among the tertiles of BP variability, we used a preassigned probability value of 0.05/3 (Bonferroni correction, therefore a 0.016) as the threshold for significance. The relationship of each clinical, demographic, biohumoral, and BP variable with IMT, LVMI, and microalbuminuria was tested with linear regression analysis. identified by linear regression as significantly related to each parameter of target-organ damage were further analyzed by multivariable regression analysis. All covariates included in the final model were tested for interactions with each other. Age, sex, alcohol consumption, triglycerides, SBP, DBP, as well as SBP and DBP loads, SBP and DBP variabilities, were tested as independent variables. IMT, LVMI, and microalbuminuria were the dependent variables for each model, all entered as continuous values. The same linear regression analyses were made for the weighted mean SD of 24-hour BP, which excludes the interference of nighttime BP fall on overall BP variability and allows a more precise assessment of the clinical value of 24-hour BP variability. 29 The final models were evaluated for linear relationships among variables in the model (collinearity), which have the potential of rendering significance testing unreliable, excluding variables affected by collinearity (tolerance: to 0.923; or variance inflation factor [(VIF]: to ). Because of their high degree of collinearity (r 0.62, P 0.001), SBP and PP were not included together in the model. The limits of statistical significance were always set at P Statistical analyses were performed with the aid of the SPSS release 11.5 statistical software (SPSS Inc). TABLE 2. Baseline Demographic and Biohumoral Data by Tertiles of Awake Systolic Blood Pressure Variability Tertile 1 (n 62) Tertile 2 (n 59) Tertile 3 (n 59) P for Trend Age, y * 58 8* Sex (M), % NS BMI, Kg/m NS Family history of NS hypertension, % Smoking, % NS Physical activity, % NS Coffee drinking, % NS S-creatinine, mg/dl NS Creatinine clearance, NS ml/min LDL-C, mg/dl NS HDL-C, mg/dl NS y indicates years; M, male; BMI, body mass index; S-creatinine, serum creatinine; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol. *P vs tertile 1. Results Baseline Demographic and Biohumoral Data Patients age (mean SD) was 53 8 years, 60% of patients were male, and the mean body mass index (BMI) was Kg/m 2 (Table 1). Age was significantly different among the 3 tertiles of awake systolic BP variability (P ). The distribution of other baseline demographic and biohumoral data were similar among the tertiles of awake systolic BP variability (Table 2). Ambulatory Blood Pressure Parameters Awake SBP was significantly different among the 3 tertiles of SBP variability (P 0.032). Average awake DBP, MBP, and heart rate (HR) were similar among the tertiles of awake SBP variability (Table 3). Mean awake SBP variability was, expectedly, different across the tertiles (P ), being this the partition criterion for the overall study population. Subjects in the uppermost tertile of awake SBP variability also had significantly higher values of DBP variability (P ) compared with subjects in the lowermost tertile. Subjects in the lowermost tertile had the lowest value of awake SBP and DBP loads, but such differences were nonsignificant. The nocturnal reductions of SBP and DBP were less pronounced (although nonsignificantly) across increasing tertiles of awake BP variability. BP Variability and Target-Organ Damage The 3 tertiles of awake SBP variability were significantly different at ANOVA for both IMT (P 0.002, Figure 1) and LVMI (P 0.004, Figure 2), and a direct graded relationship was apparent (P for trend and 0.003, respectively). The 3 tertiles of awake SBP variability were not significantly different for microalbuminuria (not shown). Such relationships between tertiles of SBP variability and parameters of target-organ damage were not apparent for asleep and 24-hour BP variability (not shown).

4 328 Hypertension August 2007 TABLE 3. Awake Blood Pressure Monitoring by Tertiles of Awake Systolic Blood Pressure Variability Tertile 1 (n 62) Tertile 2 (n 59) Tertile 3 (n 59) P for Trend Systolic BP, mm Hg Diastolic BP, mm Hg NS Heart Rate, bpm NS Systolic BP variability, mm Hg * * Diastolic BP variability, mm Hg * Systolic BP load, % NS Diastolic BP load, % NS % nocturnal systolic BP fall NS % nocturnal diastolic BP fall NS Dippers, systolic BP, % NS Dippers, diastolic BP, % NS *P vs tertile 1; P vs tertile 2. Partition criteria for the 3 tertiles. calculated over 24 hours. The univariable and multivariable (linear regression) relations of selected clinical and ambulatory BP variables with target-organ damage are summarized in Table 4. By multivariable linear regression analysis, age was the most important independent predictor of IMT (P ) and LVMI (P ). Awake SBP (P 0.001), as well as awake SBP variability (P 0.015), were all independently related to IMT. DBP load (P 0.01) was also independently related to IMT (Table 4). At multivariable analysis, male sex (P 0.012), awake SBP (P ), awake DBP (P 0.035), and awake SBP variability (P 0.028) were all positively and significantly related to LVMI. Finally, awake SBP variability (P 0.01) and DBP load (P 0.01) remained significantly related to microalbuminuria at multivariable analysis. At multivariable linear regression analysis including 24- hour parameters, age was still the most important independent predictor of IMT (P ) and LVMI (P ). Twenty-four hour SBP (P 0.001), SBP variability (P 0.05), and DBP load (P 0.022) were all independently related to IMT. Male sex (P 0.005), 24-hour SBP (P 0.001), 24-hour SBP variability (P 0.05), and 24-hour SBP load (P 0.036) were all positively related also to LVMI. Twenty-four hour DBP load (P 0.001) was the only parameter significantly related to microalbuminuria at multivariable analysis (data not shown). At multivariable linear regression analysis including asleep parameters, age was once more the best independent predictor of IMT (P ) and LVMI (P ). At such analysis, only asleep SBP (P 0.001) was related to IMT; male sex (P 0.002) and asleep SBP (P 0.004) remained positively related to LVMI, whereas the sole asleep DBP (P 0.01) remained positively related to microalbuminuria (data not shown). To further confirm the existence of an independent relationship of awake SBP variability in the study group as a whole with IMT and LVMI, an additional analysis was performed dividing subjects into the 2 subgroups of low and high systolic BP variability. To this aim, as previously described in other settings, 8,31,32 subjects were grouped into 4 quartiles of awake MAP to adjust for the confounding possible effect of average BP levels. Within each quartile, subjects with a SD of awake SBP below or above the median for the respective group were considered at low or high awake SBP variability. Table 5 shows baseline demographic, biohumoral data, awake BP parameters, and target organ damage of subjects with low and high awake SBP variability. Age (P 0.002), awake SBP variability (P ), and DBP Figure 1. The relationship of tertiles of awake systolic BP variability with maximum carotid IMT (P at ANOVA; P for trend 0.001). Figure 2. The relationship of tertiles of awake systolic BP variability with LVMI (P at ANOVA; P for trend 0.003).

5 Tatasciore et al Blood Pressure Variability and Target-Organ Damage 329 TABLE 4. Clinical, Biohumoral Data and Ambulatory Awake Blood Pressure Related to Target-Organ Damage* in all Groups IMT LVMI MA Age, y (0.445) (0.006) ( ) (0.405) (0.534) ( ) NS Sex, M, % NS (0.222) (5.788) ( ) NS Alcohol, % NS (0.179) NS NS Triglycerides, mg/dl 0.05 (0.144) NS (0.152) NS NS Systolic BP, mm Hg (0.610) (0.005) ( ) (0.424) (0.647) ( ) 0.01 (0.352) NS Diastolic BP, mm Hg (0.472) NS (0.153) ( 0.420) ( ) 0.01 (0.372) NS Systolic BP variability, (0.320) (0.006) ( ) (0.312) (0.633) ( ) (0.184) 0.01 (0.422) ( ) mm Hg Diastolic BP variability, NS NS NS mm Hg Systolic BP load, % (0.564) NS (0.331) NS 0.01 (0.320) NS Diastolic BP load, % (0.480) 0.01 (0.001) ( ) (0.194) NS (0.393) 0.01 (0.139) ( ) y indicates years; M, male; MA, microalbuminuria; BP, blood pressure;, coefficient of regression; CI, confidence interval at 95% for. *All BP data are derived from awake ambulatory BP monitoring; only variables significant at univariable analysis are included. analysis was performed by means of linear regression. variability (P ) were significantly different in the 2 groups, whereas awake systolic BP, diastolic BP, and MAP did not differ. Both IMT (P 0.01) and LVMI (P 0.001) were higher in the group with high awake SBP variability (Table 5). These differences remained significant also after adjustment for the effect of age (P and P for IMT and LVMI, respectively). Finally, we analyzed our data evaluating the weighted mean SD of 24-hour BP variability, 29 which corrects the SD for the nocturnal BP fall. In Table 6 we report data on the relationship of such parameter with target-organ damage in uni- and multivariable regression analysis together with clinical and biohumoral variables which were significantly related to parameters of target-organ damage at univariable analysis. Here age was again the most important independent correlate of IMT (P ) and LVMI (P ). The 24 hour weighted SBP (P 0.002), as well as the weighted mean SD of 24-hour SBP variability (P 0.016), were both independently related to IMT. DBP load (P 0.01) was also independently related to IMT. At multivariable analysis, male sex (P 0.004), the 24 hour weighted SBP (P 0.002), the 24 hour weighted DBP (P 0.073), and the weighted mean SD of 24-hour SBP variability (P 0.017) were all positively and significantly related to LVMI. Finally, the sole DBP load (P 0.001) remained significantly related to microalbuminuria at multivariable analysis. Discussion We here report that awake systolic BP variability, as assessed by 24-hour ABPM, is a significant correlate of carotid IMT and LVMI, independent of mean awake BP levels, in newly diagnosed, previously untreated hypertensive subjects. The novelty of our report consists of the findings that: (1) awake SBP variability is a better correlate of vascular and cardiac damage than 24-hour SBP variability; and (2) this relationship has a probable early onset in the natural history of hypertension, because here detected in a cohort of subjects recently diagnosed as essential hypertensive, referred for ABPM, and still untreated. Although the degree of hypertension has been clearly established over the past years as a predictor of target-organ damage and a determinant of prognosis, the notion that daily variability in BP levels may also impact on prognosis is much newer. BP variability is indeed the result of a complex interaction between external environmental stimuli and the response of several cardiovascular control mechanisms. BP variability is thus enhanced in some conditions characterized by impaired autonomic circulatory regulation. In particular, 24-hour BP variability is enhanced in hypertension and increases with its increasing severity. 8,31,33 Moreover, daytime SBP variability increases with increasing levels of sympathetic activity, as directly measured by microneurographic techniques in humans. 34 Previous studies had shown a direct association between increased 24-hour SBP variability and a higher incidence of cardiovascular complications in patients with treated hypertension, 8,10,11,35 after accounting for the increased risk attributable to the elevation of mean BP levels. These adverse effects of an increased BP variability are possibly related to a greater traumatic effect of wider BP swings on the vessel wall, promoting early target-organ damage. Our results, showing that awake SBP variability relates to both IMT and LVMI independent of mean BP values in a cohort of recently diagnosed, previously untreated hypertensive subjects, thus expand previous knowledge on the relationship of BP with target-organ damage. The similar impact of mean BP levels and awake SBP variability on target-organ damage in our subjects with very recent diagnosis of hypertension would indicate that vascular and myocardial damage by hypertension starts early with both a component attributable to mean BP levels and a component attributable to BP variability. This is therefore a relevant novel finding with important clinical implications. Our results are best interpretable on the background of some methodological problems related to the quantification of BP variability over 24 hours and its prognostic signifi-

6 330 Hypertension August 2007 TABLE 5. Baseline Demographic and Biohumoral Data, Awake Blood Pressure Parameters and Target Organ Damage of Low and High Variability groups Low Variability Group (n 90) High Variability Group (n 90) P Age, y Sex, M, % NS BMI, kg/m NS Family history of hypertension, % NS Smoking, % NS Physical activity, % NS Coffee drinking, % NS S-creatinine, mg/dl NS Creatinine clearance, ml/min NS Total cholesterol, mg/dl NS Triglycerides, mg/dl NS LDL-C, mg/dl NS HDL-C, mg/dl NS Systolic BP, mm Hg NS Diastolic BP, mm Hg NS Mean BP, mm Hg NS Systolic BP variability, mm Hg Diastolic BP variability, mm Hg Systolic BP load, % NS Diastolic BP load, % NS % nocturnal systolic BP fall* NS % nocturnal diastolic BP fall* NS IMT, mm LVMI, g/m Microalbuminuria, mg/h NS y indicates years; M, male; BMI, body mass index; S-creatinine, serum creatinine; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol. * calculated over 24 hours. cance. Different results, in fact, may be obtained by using different methods to quantify this BP parameter, as a function of the ability of such methods to separately consider components of the overall 24-hour BP variance with possibly different clinical significance. This is typically exemplified by the use of the SD of 24-hour average BP values to assess the clinical value of overall 24-hour BP variability. The 24-hour BP SD in fact includes the contribution of both the BP fall between day and night, otherwise termed dipping, for which a protective effect on organ damage has been documented, 36 and that of short-term BP fluctuations, occurring during both daytime and nighttime subperiods, 29 which have been shown to carry an adverse prognostic value. 11,12 To avoid the confounding interference of the dipping pattern with the assessment of the clinical value of short-term BP changes, we here focused on BP variability assessed during the daytime hours only, when subjects were awake. The appropriateness of such a choice is supported by the demonstration, in our study, that awake BP variability is a better correlate of IMT and LVMI than overall 24-hour BP variability. Because of the opposite clinical implications of a preserved nocturnal BP fall and an enhanced short-term BP variability, the trend (albeit nonsignificant) in our cohort to have more SBP dippers in the lowest tertiles of SBP variability compared with the uppermost tertile might have contributed to the observed significant relationship of SBP variability with target-organ damage. However the percentage of dippers did not correlate by itself with target-organ damage (analysis as for Table 3, not shown), making such a putative explanation unlikely. The notion that the asleep BP fall and BP variability have opposing relationships with target-organ damage is further demonstrated by the finding that 24-hour SBP variability, which corrects BP variability for the BP fall during asleep hours, is itself a similarly strong positive correlate of target-organ damage. A few other interesting points in our study deserve discussion: First, asleep BP variability did not sort out to be an independent predictor of target-organ damage in our population, at variance from previous observations obtained in elderly subjects. 12 This might reflect a different impact of awake versus asleep BP variability in the early stages of hypertension, or, more simply, the inability of a 30-minute nocturnal sampling interval to allow an accurate quantification of short-term BP variability. 37,38 Second, although a relationship between mean BP levels and LVMI has been consistently found, 39,40 the existence of a relationship between 24-hour BP variability and LVMI is controversial, 40 with some studies reporting such a relationship, 8,10,31 and other studies denying its existence, 28,32,41 particularly when using discontinuous ABPM at relatively low sampling frequency and taking into account the confounding effects of age and mean SBP. 32 One important reason that may explain the clear-cut positive relationship between SBP variability and LVMI in our study, at variance from previous reports, is likely the absence of treatment, which was an entry criterion in our study. Third, we evaluated the mean maximum IMT, instead of the mean IMT of the common carotid artery, because the former has been suggested to be the simplest and most reliable parameter for predicting hypertensive target-organ damage, including microangiopathy, in patients with essential hypertension. 4,22 This parameter was positively correlated with the efficacy of pharmacological and nonpharmacological interventions in carotid artery atherosclerosis, 21 and had been previously used in the only prospective study showing the impact of daytime systolic BP variability on early carotid atherosclerosis. 11 Fourth, increased urine albumin excretion, evaluated as microalbuminuria, is associated with an unfavorable cardiovascular risk profile and prognosis in primary hypertension. 2,42 Furthermore, patients with higher IMT and LVMI values also show, in general, increased microalbuminuria. 2,36,42 Microalbuminuria has therefore been proposed as an integrated marker to identify patients with subclinical organ damage. 42 In our study there was a weak correlation between awake SBP variability and microalbuminuria: this might reflect the existence of a type II error, attributable to either a higher variability in microalbuminuria measurements compared with the other 2 markers of target-organ damage

7 Tatasciore et al Blood Pressure Variability and Target-Organ Damage 331 TABLE 6. Clinical, Biohumoral Data and Ambulatory 24-Hour Weighted Blood Pressure Related to Target-Organ Damage* in All Groups IMT LVMI MA Age, y (0.445) (0.007) ( ) (0.405) (0.563) ( ) NS Sex, M, % NS (0.222) (6.818) ( ) NS Alcohol, % NS (0.179) NS NS Triglycerides, mg/dl 0.05 (0.144) NS (0.152) NS NS 24 hour weighted SBP, (0.583) (0.004) ( ) (0.351) (0.505) ( ) (0.334) NS mm Hg 24 hour weighted DBP, (0.240) NS (0.143) ( 0.386) ( ) (0.381) NS mm Hg 24 hour weighted SBP (0.343) (0.008) ( ) (0.310) (0.849) ( ) (0.182) NS variability, mm Hg 24 hour weighted DBP (0.181) NS NS NS variability, mm Hg Systolic BP load, % (0.264) NS (0.331) NS 0.01 (0.220) NS Diastolic BP load, % (0.480) 0.01 (0.002) ( ) (0.194) NS (0.393) (0.008) ( ) y indicates years; M, male; MA, microalbuminuria; r, coefficient of correlation;, coefficient of regression; CI, confidence interval at 95% for. *All BP data are derived from awake ambulatory BP monitoring; only variables significant at univariable analysis are included. analysis was performed by means of linear regression. used, or a greater time lag between the onset of hypertension and the early occurrence of renal damage versus carotid atherosclerosis or left ventricular hypertrophy. Alternatively, this finding might reflect a true lesser sensitivity of the renal albumin filtration function to systolic BP variations on top of the damage occurring because of higher mean BP values. In our study, microalbuminuria was also positively related with DBP load at multivariable analysis, suggesting that the persistence of high BP values is indeed an important determinant of renal damage. 35 Our study has limitations in its cross-sectional nature, only allowing to find correlations between BP variables and target-organ damage, but not to assess cause-effect relationships. A causal relationship between BP variability and atherosclerosis, as assessed by carotid artery IMT, is however likely on the basis of pathophysiological considerations, as well as of the results of previous longitudinal studies in patients with established hypertension. 14,31,43 Finally, as in most current literature, we have based our analyses on data from ABPM rather than on traditionally used clinic BP measurements. This however appears not to be a true limitation because of the recent reports of a greater impact of ABPM than clinic BP measurements both on target-organ damage and on prognosis. 44 Perspectives Blood pressure variability can be easily assessed at 24-hour ABPM. With the more and more widespread availability of such technique, and because of the relationship found in our study between parameters of blood pressure variability with target-organ damage, such parameters should probably be used more and more to refine the prognostic information connected with blood pressure measurement. Our findings also suggest the opportunity to monitor awake BP variability or weighted 24-hour BP variability, in addition to mean BP values already early-on after the diagnosis of hypertension, and suggest that these are early markers of target-organ damage. In general, our findings advocate a wider use of noninvasive 24-hour ABPM, with relatively high frequency of automated BP readings, as a tool for cardiovascular risk stratification in hypertensive subjects. Future studies will have to confirm our exploratory findings, as well as to address the effect of antihypertensive therapies on such parameters and their possibly differential impact on prognosis. Acknowledgments The authors thank the following persons at the G. d Annunzio University, Chieti: Prof Andrea Mezzetti, for helpful preliminary discussion of the study protocol; and Prof Stefano Martinotti, Division of Clinical Pathology, for providing assays of microalbuminuria. Source of Funding This study was partially supported by an unrestricted grant from AstraZeneca Italia S.p.A. None. Disclosures References 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ and the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42: Terpstra WF, May JF, Smit AJ, de Graeff PA, Crijns HJ. Microalbuminuria is related to marked end organ damage in previously untreated, elderly hypertensive patients. 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