Pulse pressure and subclinical cardiovascular damage in primary hypertension

Nephrol Dial Transplant (2002) 17: 1779–1785

Original Article

Pulse pressure and subclinical cardiovascular damage in primary hypertension Francesca Viazzi, Giovanna Leoncini, Denise Parodi, Maura Ravera, Elena Ratto, Simone Vettoretti, Cinzia Tomolillo, Massimo Del Sette, Gian Paolo Bezante, Giacomo Deferrari and Roberto Pontremoli Department of Internal Medicine and Department of Neurological Science and Neuro-rehabilitation, University of Genoa, Genoa, Italy

Correspondence and offprint requests to: Roberto Pontremoli, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6-16132 Genoa, Italy. Email: [email protected] #

increases significantly with each SD increase in PP or SBP, but is not influenced by DBP. Conclusions. PP is an independent marker of preclinical cardiovascular damage in relatively young patients with primary hypertension and, therefore, can be useful for identifying those at higher risk of cardiovascular events. Keywords: carotid wall thickness; essential hypertension; left ventricular mass; microalbuminuria; pulse pressure; target organ damage

Introduction The role of increased pulse pressure (PP) in the context of cardiovascular risk assessment and stratification is currently receiving growing attention [1]. Several large prospective trials as well as the re-analysis of previously collected data, have convincingly demonstrated that the higher the PP level the greater the incidence of mortality in both normotensive and hypertensive subjects [2]. The pulsatile blood pressure component has also been implicated in the development of coronary heart disease [3], peripheral atherosclerosis [4], and renal failure [5]. Furthermore, elevated PP values, measured both in the office and by 24-h ambulatory monitoring [6], have been linked to the presence of subclinical cardiovascular damage, i.e. left ventricular hypertrophy [7,8], increased carotid wall thickness [9], and microalbuminuria [10,11], as well as to structural changes in the resistance vasculature at the peripheral levels [12]. The pathophysiological mechanisms underlying the association between PP and cardiovascular diseases have not been fully elucidated yet. It has been suggested that high PP levels reflect the degree of stiffness of the arterial tree, regardless of whether they are caused by increased systolic (SBP) anduor reduced

2002 European Renal Association–European Dialysis and Transplant Association

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015

Abstract Background. High pulse pressure (PP) values have recently been implicated in the development and progression of large vessel atherosclerosis, small vessel disease, and in the occurrence of cardiovascular events. The aim of the present study is to investigate the relationship between PP and subclinical cardiovascular damage in a cohort of unselected middle-aged patients (204 male, 129 female) with untreated primary hypertension. Methods. PP was calculated as the difference between systolic (SBP) and diastolic blood pressure (DBP). Left ventricular mass index (LVMI) was assessed by M-B mode echocardiography (LVHsLVMI)51 gum2.7), and carotid intima-media thickness (IMT) by highresolution US scan. Albuminuria was measured as the albumin to creatinine ratio (ACR) in three non-consecutive first morning urine samples. Results. PP was positively correlated to gender (P-0.05), duration of disease (P-0.001), age (P-0.0001), LDL cholesterol (Ps0.007), and to early signs of target organ damage (TOD), namely LVMI (P-0.0001), IMT (P-0.0001), and ACR (Ps0.036). Patients in the upper quartile of PP showed higher LVMI (P-0.001), thicker carotid walls (P-0.001), as well as higher ACR (P-0.04). Multiple linear regression analysis showed that PP and ACR independently influence LVMI (Fs26.476, r2s0.29, P-0.0001) and IMT (Fs17.813, r2s0.26, P-0.0001). Patients with LVH, increased carotid IMT and microalbuminuria showed higher PP values as compared with those with lesser degrees of target organ involvement (Fs4.97, P-0.003 inter-group comparison). Moreover, the risk of having the simultaneous occurrence of various signs of TOD

1780

diastolic pressure (DBP). As a matter of fact, the abovementioned association has been described mostly in older patients with overt atherosclerotic disease and high PP levels. Whether the pulsatile component of pressure load plays a significant, independent role in the development of cardiovascular damage even in younger, uncomplicated hypertensive patients is currently unclear. The present study was initiated to investigate the relationship between PP and subclinical end organ damage in a large group of unselected, relatively young, untreated patients with primary hypertension.

Subjects and methods

F. Viazzi et al.

Standard ECG (12 leads) was obtained for each patient. Creatinine, blood urea nitrogen, electrolytes, uric acid, triglycerides, total and high density lipoprotein (HDL)cholesterol, and other standard blood chemistry evaluations were performed on serum according to routine methods. Low density lipoprotein (LDL)-cholesterol was calculated using Friedewald’s formula. Creatinine clearance was calculated using Cockcroft–Gault’s formula [14] and is expressed in mlumin. Family history and lifestyle habits were assessed by means of a standardized questionnaire. Smoking was graded using a five point scale: non-smoker, ex-smoker, smoking 1–14 cigarettesuday, smoking 15–25 cigarettesuday, or smoking )25 cigarettesuday. Information regarding usual alcohol intake was collected. Twenty-four-hour urinary collection was obtained at baseline and at each subsequent visit to evaluate urinary sodium excretion. Renal vascular resistance (RI) was evaluated by US doppler of the interlobar arteries in both kidneys as described by Pontremoli et al. [15].

Selection of patients Echocardiography All echocardiographic studies were performed using an Acuson XP-128 ultrasound machine. Echocardiograms were obtained at rest with patients supine in the left lateral position, using standard parasternal and apical views. The overall monodimensional left ventricular (LV) measurements and the bidimensional (apical four and two chamber) views were obtained according to the recommendations of the American Society of Echocardiography [16]. All tracings were obtained and read by a single observer blinded to the clinical characteristics of the patients under observation. LV mass was derived using the formula described by Devereux and associates: LV mass (grams)s0.80 3 1.04 [(VSTdqLVIDdqPWTd)3 (LVIDd)3]q0.6 where VSTd is ventricular septal thickness at end diastole, LVIDd is LV internal dimension at end diastole, and PWTd is LV posterior wall thickness at end diastole. LV mass was corrected for height2.7 (LVMI), and expressed in units of gramsumeter (gum2.7). The presence of left ventricular hypertrophy was defined for LVMI )51 gum2.7 in either gender [17]. None of the patients showed dyssynergic areas that would invalidate the theoretical assumptions behind the cardiac mass calculations.

Common carotid US scan The intima-media thickness (IMT) of both carotid arteries was evaluated by high-resolution US scan as described by Weldelhag [18]. Carotid arteries were investigated in the longitudinal and the transverse projections by highresolution real-time ultrasonography using a 10-MHz in-line duplex Diasonic Spectra System. The carotid artery was scanned at the bifurcation and at the common carotid artery (CCA). At each longitudinal projection the far-wall IMT, as defined by Weldelhag et al. [18], was measured at the distal end of the CCA, 10 mm caudally to the point where the near and far walls lose their parallel configuration. Carotid plaque was defined as IMT )1.3 mm. IMT was always measured on the CCA outside the plaque, if any was present. Each measurement was calculated by taking the averages of three readings.

Albuminuria The presence of microalbuminuria was evaluated in each patient by measuring the albumin to creatinine ratio (ACR)

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015

Between January 1997 and January 2000, all patients with essential hypertension attending the out-patient clinic of our institution were asked to participate in this study which was part of a larger trial (MAGIC: Microalbuminuria: A Genoa Investigation on Complications) approved by the ethical committee of our department. Details of the study have been published previously [13]. Exclusion criteria were the presence of neoplastic, hepatic anduor renal disease, chronic heart failure (NYHA classes III and IV), positive history or clinical signs of ischaemic heart disease, diabetes mellitus, severe obesity (defined as body weight )150% of ideal body weight), anduor disabling diseases such as dementia or inability to co-operate. Diagnosis of essential hypertension was made by the attending physician after complete medical history, physical examination, and routine biochemical analyses of blood and urine were obtained from each patient. Further investigation was carried out only when abnormalities were found in these analyses, or when other symptoms or signs suggesting secondary hypertension were present. Hypertension was defined according to the criteria in the sixth report of the Joint National Committee (JNC VI) as an average blood pressure P140u90 mmHg on at least two different occasions or by the presence of antihypertensive treatment. None of the patients were on medication at the time of the study. Altogether, 400 hypertensive patients were seen at our clinic within the above-mentioned time range, and among them 364 (91%) were eligible for the study on the basis of available clinical and laboratory data. Eleven of these patients did not meet study criteria based on the results of additional tests prescribed for clinical reasons during their first visit to our clinic. Among the remaining 353 patients (all Caucasian Europeans), 20 declined and 333 (83%) form the basis of the present report. 266 (80%) of the participating patients had never been treated for hypertension, while 67 (20%) had received antihypertensive treatment in the past, albeit intermittently and not, however, over the last 6 months. On the study day, after an overnight fast, height and weight were measured and venous blood was drawn in order to measure haematochemical parameters. Blood pressure was measured by a trained nurse with the patient in the sitting position after a 5 min rest, with a mercury sphygmomanometer (cuff size 12.5 3 40 cm). The SBP and DBP were read to the nearest 2 mmHg. Disappearance of Korotkoff ’s sounds (phase V) was the criterion for DBP. The lowest of three consecutive readings were recorded. PP was calculated as SBP–DBP. Body mass index was calculated by the formula: weight (kg)uheight (m)2.

Pulse pressure and target organ damage

Statistical analysis All data are expressed as mean"SEM. Differences between variables were assessed using the appropriate statistical test based on the underlying distribution of the variables. One-way analysis of variance (ANOVA) with Bonferroni or Tukey multiple comparison post-test (as appropriate) was used to analyse data from patients with different degrees of PP, and with or without end organ damage. Relations among variables were assessed using linear regression analysis and Pearson’s correlation coefficient. Comparison of proportion among groups were performed using the x2 test. Multiple regression analysis was performed to assess the independent contribution of several variables, including PP, to the variations in LVMI and carotid IMT. Relative risk and 95% confidence intervals were calculated by exponentiation of logistic regression coefficients. All statistical analyses were performed using Statview for Windows, SAS Institute Inc., version 5.0.1, Cary, NC, USA. P-0.05 was considered statistically significant.

lower creatinine clearance) despite similar body mass index, fasting plasma glucose, and smoking habits. Furthermore, patients in the top quartile of PP showed higher LVMI (Fs4.82, P-0.001 inter-group comparison, P-0.001 quartile 1 and 2 vs 4, P-0.01 quartile 3 vs 4), thicker carotid walls (Fs6.31, P-0.001 inter-group comparison, P-0.001 quartile 1 and 2 vs 4), and higher urinary albumin excretion (Fs2.82, Ps0.039 inter-group comparison, P-0.01 quartile 1 vs 4) (Table 1). The relationship between PP and several variables including early signs of target organ damage (TOD) was further investigated by the use of multiple regression analysis (Table 3a and b). PP and ACR, together with other variables, namely age, body mass index (Table 3a), and LDL-cholesterol (Table 3b), significantly and independently influence LVMI and IMT. Altogether these factors account for about 29 and 26% of the variations in LVMI and IMT, respectively. The association between PP and subclinical organ damage was even more apparent when the simultaneous occurrence of various signs of TOD was taken into consideration. In fact, the subgroup of patients having left ventricular hypertrophy, increased carotid IMT (i.e. those within the upper quartile), and microalbuminuria showed higher PP values as compared with those with fewer signs of target organ involvement (i.e. either two out of three or only one out of three, Fs4.97, P-0.003 inter-group comparison, P-0.001 TOD– vs TODqqq) (Figure 1). The relative importance of various blood pressure components in influencing the presence anduor severity of TOD was addressed by logistic regression models (Table 4). DBP and mean blood pressure seem to exert a weaker influence on the development of TOD, especially on carotid atherosclerosis. Interestingly, the risk of finding concomitant signs of organ damage doubles with each SD increase in SBP or PP.

Discussion Results The main clinical characteristics of the patients are reported in Table 1. The overall prevalence of left ventricular hypertrophy, and microalbuminuria was 50 and 13%, respectively. The prevalence of carotid plaque was 24%. Significant univariate correlations between PP and selected clinical variables in the entire study group are shown in Table 2. PP was directly related to age, male gender, duration of disease, LDL-cholesterol, as well as to signs of early cardiovascular and renal damage, namely LVMI, IMT, ACR, and renal RI even considering DBP as a covariate. A negative correlation was present between PP and creatinine clearance. When data were analysed on the basis of PP values, patients in the upper quartile showed a significantly worse risk profile (i.e. higher SBP, age, known duration of disease, total- and LDL-cholesterol, and

The present study demonstrates that even a mild increase in PP is associated with subclinical organ damage, namely increased LV mass, thicker carotid walls, and microalbuminuria in a relatively young group of patients with primary hypertension. The data extend and integrate previous observations on the relationship between PP and higher incidence of cardiovascular mortality in elderly people, and may provide useful insight into the pathogenesis of cardiovascular complications. In fact, the development of subclinical organ abnormalities often precedes and predicts the occurrence of major events. Patients in the top quartile of PP showed higher LVMI, IMT, and ACR values, thus indicating the presence of hypertensive subclinical damage despite similar DBP levels (Table 1). Furthermore, multiple regression analysis shows that a significant part of the variations in LVMI and IMT can be attributed to changes in PP (Table 3a

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015

on three non-consecutive first morning samples. Patients were instructed to freeze each urine sample right after collection and keep it frozen until their next visit to the clinic. Only samples from patients with negative urine cultures were collected. Whenever a positive urine culture was found, urine samples were discarded, appropriate antibacterial treatment instituted and urine collection for albuminuria repeated only after a second culture tested negative. The ACR was calculated as follows: urine albumin concentration (mgul)u urine creatinine concentration (mmolul) [13]. Urine albumin concentration was measured by a commercially available radio-immunoassay kit (Sclavo, Cinisello Balsamo, Italy). The intra- and inter-assay variabilities of the method in our laboratory were 4.5 and 6.1%, respectively. The average (arithmetic mean) of three ACRs from each patient was calculated in order to categorize patients. To be able to account for differences in basal creatinine excretion rates and body mass index, different values were used to define microalbuminuria in males (ACR between 2.38 and 19) and females (ACR between 2.96 and 20). These criteria proved to have good sensitivity and specificity in the detection of albumin excretion rates between 20 and 200 mgumin [13].

1781

1782

Table 1. Clinical characteristics of study patients (ns333) All ns333

Mean"SEM Gender (maleufemale), n Age (years) BMI (kgum2) Duration of disease (months) EH family history (%) CV family history (%) Smokers (%) Alcohol (%) SBP (mmHg) DBP (mmHg) PP (mmHg) Fasting plasma glucose (mgudl) Uric acid (mgudl) Triglycerides (mgudl) Cholesterol (mgudl) HDL-cholesterol (mgudl) LDL-cholesterol (mgudl) Serum creatinine (mgudl) Creatinine clearance (mlumin) Urinary sodium (mEqu24-h) RI ACR (mgummol) LVMI (gum2.7) IMT (mm)

204u129 47"0.5 26"0.2 52"3 77 52 63 29 158"0.9 102"0.4 56"0.7 90"0.6 5.1"0.1 120"3.7 213"2.5 52"0.9 138"2.5 0.9"0.01 86"1.2 158"4.7 0.59"0.003 1.43"0.15 51"0.7 0.68"0.01

Range

20–66 17–38 3–270

125–230 80–140 20–110 62–109 1.8–9.4 26–369 99–350 21–100 9.2–300 0.5–1.4 67–147 50–353 0.44–0.77 0.1–19 19–92 0.3–1.4

Quartile I (PP 20 – 47 mmHg) ns68

Quartile II (PP 48–51 mmHg) ns89

Quartile III (PP 52–64 mmHg) ns89

Quartile IV (PP 65–110 mmHg) ns87

Mean"SEM

Mean"SEM

Mean"SEM

Mean"SEM

49u19 44"1 27"0.4 45"6.4 73 51 74 36 142"1 104"0.8 39"0.7 91"0.7 5.2"1.5 111"7.9 196"5.1 50"2 125"5.2 0.9"0.01 92"2.8 167"10.8 0.56"0.01 0.8"0.1 49"1.4 0.61"0.03

58u31 47"1 26"0.4 41"4.8 80 48 58 34 153"0.7 103"0.7 50"0.0 90"1.3 5.3"0.2 121"7.5 213"4.7 52"1.8 141"5.1 0.9"0.01 86"2.2 153"7.4 0.58"0.01 1.3"0.3 50"1.3 0.63"0.03

48u41 48"1 26"0.3 57"6.6 79 56 57 25 158"0.7 100"6.4 59"0.2 90"1.3 4.8"0.2 113"6.4 208"5.2 53"1.8 132"5.2 0.9"0.01 85"2 150"7.4 0.60"0.01 1.5"0.3 51"1.5 0.70"0.02

49u38 50"1 27"0.4 64"6.5 75 53 66 22 177"1.6 103"1 73"0.9 91"1.3 5.3"0.2 132"7.5 230"4.5 52"1.6 140"4.5 0.9"0.02 82"2.5 156"9 0.62"0.01 2.1"0.4 56"1.3 0.77"0.03

P

NS 0.0009 NS 0.02 NS NS NS NS -0.0001 NS -0.0001 NS NS NS -0.0001 NS 0.004 NS 0.04 NS 0.0004 -0.04 -0.001 -0.001

BMI, body mass index; EH, essential hypertension; CV, cardiovascular disease.

F. Viazzi et al.

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015

Pulse pressure and target organ damage

1783

Table 2. Univariate correlation between PP and selected clinical variables Variable

r

Age Gender Duration of disease LDL-cholesterol Creatinine clearance RI ACR LVMI IMT

P 0.241 0.109 0.211 0.164 0.185 0.425 0.118 0.257 0.29

-0.0001 0.0472 0.0002 0.007 0.0013 -0.0001 0.0362 -0.0001 -0.0001

Table 3. Multiple regression linear analysis of LVMI (a) and IMT (b) Independent variable

2.702 0.268 0.136 1.231 0.79

5.959 0.072 0.049 0.183 0.228

2.702 0.205 0.151 0.355 0.184

0.454 0.6505 3.748 0.0002 2.756 0.0063 6.712 -0.0001 3.469 0.0006

0.362 0.003 0.001 0.027

0.074 0.001 3.620E-4 0.005

0.362 0.221 0.136 0.394

4.906 -0.0001 3.062 0.0026 1.896 0.05 5.534 -0.0001

(a) Dependent variable: LVMI; independent variables: age, PP, BMI, ACR. Regression degrees of freedom s4, Fs26.476, P-0.0001, r2s0.286. (b) Dependent variable: IMT; independent variables: PP, LDL-cholesterol, ACR. Regression degrees of freedom s3, Fs17.813, P-0.0001, r2s0.265.

and b). These findings are in agreement with previous studies showing that PP is a determinant of cardiovascular structure and function [4,7,12], and may exert an unfavourable effect on the left ventricle and the carotid wall over-time, both in patients with essential hypertension and in the general population [6,9]. Our findings on the relationship between urinary albumin excretion and PP are somewhat more complex and warrant further comment. Microalbuminuria has been shown to be a powerful, integrated marker of increased cardiovascular risk and TOD, both in essential hypertension [19] and more recently in the general population [20]. An association between PP and microalbuminuria has been reported previously by Cirillo et al. [11] in a cohort of subjects from the Gubbio study. Our data confirm and extend, on a larger group of patients, the findings by Pedrinelli who reported a correlation between PP and albuminuria in a group of hypertensive patients [10]. It has been suggested that microalbuminuria could also be a predictor of clinical renal damage in hypertensive patients [21]. Moreover, increased RI has been shown to reflect the degree of renal impairment in patients with chronic renal failure and could precede and predict the onset of clinical renal damage [15]. Thus, the association between PP and renal resistive index and increased albumin excretion is intriguing and

Fig. 1. Pulse pressure and target organ damage in patients with essential hypertension. Patients were analysed on the basis of the presenceuabsence of different signs of damage. TODq indicates the subgroup of patients with either microalbuminuria or LVH or increased IMT (upper quartile). TODqq indicates patients with a combination of any two signs of TOD, and TODqqq indicates those with all three signs of the TOD we examined.

suggests that systemic PP could be a marker of early intra-renal vascular stiffness and might play a role in the development of renal damage (Tables 1 and 2). These findings further emphasize the role of the kidney as a sensor of cardiovascular risk and are in agreement with previous studies, which show that even subclinical abnormalities, such as the presence of microalbuminuria [20] or a mild increase in serum creatinine [22], are powerful predictors of cardiovascular events. This is the first time that several different signs of subclinical hypertensive damage (left ventricular hypertrophy, thicker carotid walls, and microalbuminuria) have been investigated simultaneously. It appears that the subgroup of patients with more severe cardiovascular and renal involvement show significantly higher PP levels despite similar DBP (Figure 1). Preclinical damage in primary hypertension is considered the result of a multifactorial process, which includes, but is not limited to, blood pressure load. Our findings indicate that the various components of blood pressure load might also have different degrees of importance in the pathophysiological mechanisms that lead to vascular damage. In fact, a 1 SD increase in PP and SBP was more likely to entail higher risks of TOD as compared with DBP and mean blood pressure in our study group, indicating a greater role of the pulsatile blood pressure component in the development of organ damage (Table 4). The data presented here need to be interpreted with some caution due to the selection criteria of study patients, which probably explain the relatively high prevalence of reported left ventricular hypertrophy.

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015

(a) Constant Age PP BMI ACR (b) Constant PP LDL-cholesterol ACR

Coefficient Standard Standard t-value P-value error coefficient

1784

F. Viazzi et al.

Table 4. Blood pressure components and relative risk (RR) of TOD in essential hypertension PP

LVHqu IMTqu ACRqu TODqq TODqqq

SBP

DBP

Mean blood pressure

RR

95% Confidence P intervals

RR

95% Confidence P intervals

RR

95% Confidence P intervals

RR

95% Confidence P intervals

1.38 1.54 1.63 1.99 2.50

(0.97–1.98) (1.06–2.22) (1.04 –2.56) (1.13–3.49) (1.34 – 4.67)

1.84 1.55 1.84 1.96 2.89

(1.24 –2.67) (1.06–2.21) (1.20–2.87) (1.20–3.89) (1.54–5.46)

1.71 1.17 1.58 0.85 1.96

(1.20–2.42) (0.84 –1.63) (1.05–2.40) (0.78–2.07) (1.01–2.91)

1.93 1.37 1.79 1.72 2.33

(1.32–2.82) (0.98–1.92) (1.18–2.71) (1–2.33) (1.30 – 4.14)

0.05 0.03 0.03 0.02 0.004

0.002 0.02 0.005 0.01 0.0009

0.003 NS 0.03 NS 0.03

0.0007 NS 0.006 0.05 0.004

The table shows the RR of each sign of TOD anduor the various combinations of signs for each SD increase in pulsatile, SBP, DBP, and mean blood pressure. All analyses included age and gender as a covariate. LVHq, left ventricular hypertrophy sLVMI)51 gum2.7; IMTq, carotid intima plus media thickness within the upper quartile (P0.80 mm); ACRq, microalbuminuria; TODqq and TODqqq indicate the concomitance of at least two, or all three of the signs of TOD we examined.

Acknowledgements. We thank Lorenzo E. Derchi, MD, and Carlo Martinoli, MD, for performing renal echographic examinations. This work was supported in part by grant no. RF9952 from Ministero della Sanita`, Ricerca Finalizzata 1999.

7. 8. 9.

10. 11. 12. 13. 14. 15.

16.

References 1. Staessen JA, Gasowski J, Wang Ji G et al. Risk of untreated and treated isolated systolic hypertension in the elderly: metaanalysis of outcome trials. Lancet 2000; 355: 865–872 2. Benetos A, Rudnichi A, Safar M et al. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension 1998; 32: 560–564 3. Franklin SS, Khan SA, Wong ND et al. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation 1999; 100: 354–360 4. Franklin SS, Sutton-Tyrrell K, Belle SH, Weber MA, Kuller LH. The importance of pulsatile components of hypertension in predicting carotid stenosis in older adults. J Hypertens 1997; 15: 1143–1150 5. Leonetti G, Cuspidi C, Facchini M, Stramba-Badiale M. Is systolic pressure a better target for antihypertensive treatment than diastolic pressure? J Hypertens Suppl 2000; 18: S13–S20 6. Khattar RS, Acharya DU, Kinsey C, Senior R, Lahiri A. Longitudinal association of ambulatory pulse pressure with

17.

18.

19. 20.

left ventricular mass and vascular hypertrophy in essential hypertension. J Hypertens 1997; 15: 737–743 Pannier B, Brunei P, Aroussy W, Lacolley P, Safar ME. Pulse pressure and echocardiographic findings in essential hypertension. J Hypertens 1989; 7: 127–132 Gardin JM, Arnold A, Gottdiener JS et al. Left ventricular mass in elderly: the Cardiovascular Health Study. Hypertension 1997; 29: 1095–1103 Zureik M, Touboul PJ, Bonithon-Kopp C et al. Cross-sectional and 4-year longitudinal associations between brachial pulse pressure and common carotid intima-media thickness in a general population. The EVA study. Stroke 1999; 30: 550–555 Pedrinelli R, Dell’Omo G, Penno G et al. Microalbuminuria and pulse pressure in hypertensive and atherosclerotic men. Hypertension 2000; 35: 48–54 Cirillo M, Stellato D, Laurenzi M et al. Pulse pressure and isolated systolic hypertension: association with microalbuminuria. Kidney Int 2000; 58: 1211–1218 James MA, Watt PA, Potter JF, Thurston H, Swales JD. Pulse pressure and resistance artery structure in the elderly. Hypertension 1995; 26: 301–306 Pontremoli R, Sofia A, Ravera M et al. Prevalence and clinical correlates of microalbuminuria in essential hypertension. The MAGIC study. Hypertension 1997; 30: 1135–1143 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41 Pontremoli R, Viazzi F, Martinoli C et al. Increased renal resistive index in patients with essential hypertension: a marker of target organ damage. Nephrol Dial Tranplant 1999; 14: 360–365 Schiller NB, Shah PM, Crawford M et al. Recommendations for quantitation of the left ventricle by two dimensional echocardiography: American Society of Echocardiography Committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367 De Simone G, Devereux RB, Daniels SR et al. 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: 1056–1062 Weldelhag I, Wiklund O, Wikstrand J. Atherosclerotic changes in the femoral and carotid arteries in familial hypercholesterolemia: ultrasonographic assessment of intima-media thickness and plaque occurrence. Arterioscler Thromb 1993; 13: 1404–1411 Pontremoli R, Viazzi F, Sofia A et al. Microalbuminuria: a marker of cardiovascular and organ damage in essential hypertension. Kidney Int Suppl 1997; 63: S163–S165 Hillege HL, Janssen WM, Bak AA et al. Microalbuminuria is common, also in non diabetic, nonhypertensive population and

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015

On the other hand, the prevalence of carotid plaque in our study was slightly lower than what was found in larger trials carried out on older patients [23,24]. Nonetheless, we believe that our findings could be applicable to the population of hypertensives at large. In conclusion, our study shows that increased PP is a marker of subclinical target organ damage in a relatively young population of patients with primary hypertension. These results emphasize the role of even mild increases in PP in the development of subclinical cardiovascular damage and suggest enforcing aggressive preventive and therapeutic measures specifically targeted at PP in order to prevent cardiovascular damage. PP could, therefore, be used as an independent, modifiable risk factor for hypertensive patients. Further studies are needed to evaluate its possible role as a surrogate end-point to monitor the efficacy of treatment.

Pulse pressure and target organ damage an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 2001; 249: 519–526 21. Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens 1998; 16: 1325–1333 22. Schillaci G, Reboldi G, Verdecchia P. High-normal serum creatinine concentration is a predictor of cardiovascular risk in essential hypertension. Arch Intern Med 2001; 161: 886–891

1785 23. Zanchetti A, Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A. The Verapamil in Hypertension and Atherosclerosi Study (VHAS): results of long term randomized treatment with either verapamil or chlortalidone on carotid intima-media thickness. J Hypertens 1998; 16: 1667–1676 24. Zanchetti A, Bond MG, Hennig M et al. Risk factors associated with alteration in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis. J Hypertens 1998; 16: 549–561 Received for publication: 11.12.01 Accepted in revised form: 17.5.02

Downloaded from http://ndt.oxfordjournals.org/ by guest on November 12, 2015