Left ventricular hypertrophy as an independent predictor of acute cerebrovascular events in essential hypertension.

BACKGROUND: It is uncertain whether left ventricular hypertrophy (LVH) confers an increased risk for cerebrovascular disease in apparently healthy patients with essential hypertension. METHODS AND RESULTS: A total of 2363 initially untreated hypertensive patients (mean age 51+/-12 years, 47% women) free of previous cardiovascular disease were followed up for up to 14 years (mean 5 years). At entry, all patients underwent diagnostic tests, including ECG, echocardiography, and 24-hour ambulatory blood pressure (BP) monitoring. At entry, the prevalence of LVH was 17.6% by ECG (Perugia score) and 23.7% by echocardiography (LVM >125 g/m(2)). Over the subsequent years, 105 patients experienced a first stroke or transient ischemic attack. The cerebrovascular event rate was higher among patients with LVH at entry, diagnosed by either ECG or echocardiography, than among those without hypertrophy (both P<0.01). After control for the significant influence of age, sex, diabetes, and 24-hour mean ambulatory BP, LVH by ECG conferred an increased risk for cerebrovascular events (relative risk [RR] 1.79; 95% CI 1.17 to 2.76). LVH by echocardiography also conferred a higher risk for cerebrovascular events (RR 1.64; 95% CI 1.07 to 2.68). For each increase in LV mass of 1 SD (29 g/m(2)), there was a significant independent increase in the risk for cerebrovascular events (RR 1.31; 95% CI 1.09 to 1.58). CONCLUSIONS: In apparently healthy patients with essential hypertension, LVH diagnosed by ECG or echocardiography confers an excess risk for stroke and transient ischemic attack independently of BP and other individual risk factors.

Prognostic value of a new electrocardiographic method for diagnosis of left ventricular hypertrophy in essential hypertension.

OBJECTIVES: We tested the prognostic value of a new electrocardiographic (ECG) method (Perugia score) for diagnosis of left ventricular hypertrophy (LVH) in essential hypertension and compared it with five standard methods (Cornell voltage, Framingham criterion, Romhilt-Estes point score, left ventricular strain, Sokolow-Lyon voltage). BACKGROUND: Several standard ECG methods for assessment of LVH are used in the clinical setting, but a comparative prognostic assessment is lacking. METHODS: A total of 1,717 white hypertensive subjects (mean age 52 years; 51% men) were prospectively followed up for up to 10 years (mean 3.3). RESULTS: At entry, the prevalence of LVH was 17.8% (Perugia score), 9.1% (Cornell), 3.9% (Framingham), 5.2% (Romhilt-Estes), 6.4% (strain) and 13.1% (Sokolow-Lyon). During follow-up there were 159 major cardiovascular morbid events (33 fatal). The event rate was higher in the subjects with than in those without LVH (all p < 0.001) according to all methods except the Sokolow-Lyon method. By multivariate analysis, an independent association between LVH and cardiovascular disease risk was maintained by the Perugia score (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.5 to 2.8) and the Framingham (HR 1.91, 95% CI 1.1 to 3.2), Romhilt-Estes (HR 2.63, 95% CI 1.7 to 4.1) and strain methods (HR 2.11, 95% CI 1.4 to 3.2). The Perugia score showed the highest population-attributable risk for cardiovascular events, accounting for 15.6% of all cases, whereas the Framingham, Romhilt-Estes and strain methods accounted for 3.0%, 7.4% and 6.8% of all events, respectively. LVH diagnosed by the Perugia score was also associated with an increased risk of cardiovascular mortality (HR 4.21, 95% CI 2.1 to 8.7), with a population-attributable risk of 37.0%. CONCLUSIONS: The Perugia score carried the highest population-attributable risk for cardiovascular morbidity and mortality compared with classic methods for detection of LVH. Traditional interpretation of standard electrocardiography maintains an important role for cardiovascular risk stratification in essential hypertension.

Association between persistent pressure overload and ventricular arrhythmias in essential hypertension.

Hypertension is a risk factor for sudden cardiac death, and some data indicate that frequent and complex ventricular arrhythmias may be additional risk markers in hypertensive individuals. We investigated the relation between ventricular arrhythmias and the persistence of increased blood pressure levels over 24 hours in subjects with essential hypertension. We studied 126 never-treated subjects with essential hypertension (83 men) who underwent 24-hour electrocardiographic monitoring, 24-hour ambulatory blood pressure monitoring, and echocardiography. Premature ventricular beats were detected in 71% of the subjects. Compared with subjects in Lown class 0-1, subjects with frequent or complex ventricular arrhythmias (Lown class > or = 2) were older (54 versus 45 years) and had a longer duration of hypertension (5.4 versus 2.8 years), a greater left ventricular mass (147 versus 127 g.m-2), and a blunted nocturnal reduction in ambulatory blood pressure (7%/12% versus 12%/16%). The number of premature ventricular beats over 24 hours was associated with age (r = .25), left ventricular mass (r = .24), and pulse pressure (r = .18) and inversely associated with the present reduction in blood pressure from day to night (r = -.29 for systolic and -.25 for diastolic pressures). In a multiple logistic regression analysis, frequent or complex ventricular arrhythmias (Lown class > or = 2) were predicted by an age > or = 60 years (odds ratio, 10.4 95% confidence interval, 2.4-44.8), left ventricular hypertrophy at echocardiography (odds ratio, 4.2; 95% confidence interval, 1.5-11.6), and a < 10% reduction in blood pressure from day to night ("nondipping" pattern; odds ratio, 2.9;95% confidence interval, 1.2-7.0). We conclude that in addition to the strong effect of age and left ventricular hypertrophy at echocardiography, the persistence of high blood pressure levels over the 24 hours ("nondipping" pattern) is an independent predictor of the frequency and complexity of ventricular arrhythmias in never treated subjects with essential hypertension.

Predictors of diurnal blood pressure changes in 2042 subjects with essential hypertension.

OBJECTIVE: To determine the independent predictors of day-night blood pressure changes in a large population of subjects with essential hypertension. METHODS: We studied 2042 white untreated subjects with essential hypertension (mean age 52 years, range 17-93, 1052 men) who underwent 24 h ambulatory blood pressure monitoring on an outpatient basis. Night-time workers were excluded from analysis. RESULTS: For both sexes, the changes in systolic and diastolic blood pressures from day to night decreased progressively with age and increased with the reported duration of sleep. The 1207 employed subjects who underwent ambulatory blood pressure monitoring during a usual working day had greater day-night blood pressure differences than did those who did not work (16.2 versus 14.0%). By using multiple regression analysis we assessed the independent association of several variables with the diurnal blood pressure changes. Age and diabetes for both sexes, and clinic blood pressure in men, were inversely associated with the nocturnal fall in blood pressure. The duration of sleep and the occurrence of blood pressure monitoring during a normal work day predicted a greater day-night blood pressure difference for both sexes; smoking predicted a greater nocturnal fall in blood pressure for women. CONCLUSIONS: Age is associated with an important and progressive attenuation of the day-night blood pressure difference in untreated and unrestricted subjects with essential hypertension. Other factors influencing diurnal blood pressure variations include clinic blood pressure, diabetes, the reported duration of sleep, smoking habits and working activity during blood pressure monitoring. These factors should be treated as potential confounders in the analysis of the relationship between diurnal blood pressure changes and target organ damage or prognosis.

Cigarette smoking, ambulatory blood pressure and cardiac hypertrophy in essential hypertension.

OBJECTIVE: To assess the role of blood pressure in the association between cigarette smoking and left ventricular mass in male and female subjects with essential hypertension. DESIGN: A case-control study with matching ratio of 1:4. PATIENTS AND METHODS: We studied 115 heavy smokers (> or = 20 cigarettes/day; 91 men) and 460 non-smokers (364 men) with essential hypertension. Subjects were matched by sex, age (within 5 years) and clinic systolic and diastolic blood pressures (within 5 mmHg). All the subjects underwent 24 h off-therapy non-invasive ambulatory blood pressure monitoring and echocardiography. RESULTS: By matching, clinic blood pressure was nearly identical in smokers and non-smokers (158/99 versus 158/98 mmHg). Daytime ambulatory blood pressure was significantly higher in the smokers than in the non-smokers (150/97 versus 143/93 mmHg), whereas night-time blood pressure did not differ between the two groups (129/79 versus 126/78 mmHg). Smokers had a higher 24 h but not clinic heart rate. Variability of systolic and diastolic blood pressure was slightly greater in smokers when expressed in terms of the standard deviation of the 24 h average (15.9/13.0 versus 14.6/12.2 mmHg), but not after correction for average blood pressure. Left ventricular mass was greater in the smokers than in the non-smokers (119 versus 110 g/m2), and this difference remained after adjustment for clinic blood pressure and other related covariates. However, when clinic blood pressure was replaced by daytime ambulatory blood pressure in the equation, adjusted values of left ventricular mass did not differ between the smokers and the non-smokers (113 versus 112 g/m2). CONCLUSION: In patients with essential hypertension, heavy cigarette smoking (> or = 20 cigarettes/day) is associated with a definite increase in left ventricular mass through a rise in whole-day blood pressure. A pressor mechanism of that type may not be detected by the standard measurement of blood pressure in the clinic, which would make ambulatory blood pressure monitoring a valuable diagnostic tool in this setting.

Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension.

BACKGROUND: Previous studies revealed a direct association between resting heart rate and risk of mortality in essential hypertension. However, resting heart rate is a highly variable measure since it is affected by the alerting reaction to the visit. OBJECTIVE: To investigate whether the heart rate values recorded during the 24 h of ambulatory blood pressure monitoring are independent predictors of survival of uncomplicated subjects with essential hypertension. METHODS: We followed up 1942 initially untreated and uncomplicated subjects with essential hypertension (mean age 51.7 years, 52% men) for an average of 3.6 years (range 0-10 years). All subjects underwent baseline procedures including 24 h non-invasive blood pressure monitoring with simultaneous assessment of heart rate, one reading every 15 min for 24 h. MAIN OUTCOME MEASURES: All-cause mortality and cardiovascular morbidity. RESULTS: During follow-up there were 74 deaths from all causes (1.06 per 100 person-years) and 182 total (fatal plus non-fatal) cardiovascular morbid events (2.66 per 100 person-years). Clinic, average 24 h, daytime and night-time heart rates exhibited no association with total mortality. However, the subjects who subsequently died had had a blunted reduction of heart rate on going from day to night during the baseline examination. After adjustment for age (P < 0.001), diabetes (P < 0.001) and average 24 h systolic blood pressure (SBP, P= 0.002) in a Cox model, for each 10% less reduction in the heart rate from day to night the relative risk of mortality was 1.30 (95% confidence interval 1.02-1.65, P = 0.04). Rates of death were 0.38, 0.71, 0.94 and 2.0 per 100 person-years among subjects in the four quartiles of the distribution of the percentage reduction in heart rate from day to night The baseline day-night changes in the heart rate exhibited an inverse correlation to age and to clinic and ambulatory SBP and a direct association with the day-night changes in blood pressure. The degree of reduction of heart rate from day to night also had an independent inverse association with total cardiovascular morbidity after adjustment for age, diabetes and left ventricular hypertrophy, but this association did not remain significant when average 24 h SBP and the degree of day-night reduction in SBP were entered into the equation. CONCLUSIONS: A flattened diurnal rhythm of heart rate in uncomplicated subjects with essential hypertension is a marker of risk for subsequent all-cause mortality and this association persists after adjustment for several risk factors. For assessing these subjects, a limited and uniformly distributed period of ambulatory heart rate recording during the 24 h is clinically valuable.

Prognostic value of left ventricular mass and geometry in systemic hypertension with left ventricular hypertrophy.

To determine the independent prognostic significance of left ventricular (LV) mass and geometry (concentric vs eccentric pattern) in hypertensive subjects with LV hypertrophy at echocardiography, 274 subjects were followed for up to 8.7 years (mean 3.2). All patients had systemic hypertension and LV mass > or = 125 g/body surface area (BSA) and underwent ambulatory blood pressure (BP) monitoring and echocardiography before treatment. Eccentric and concentric hypertrophy were defined by the ratio between LV posterior wall thickness and LV radius at telediastole <0.45 and > or = 0.45, respectively. Age, sex ratio, body mass index, office BP and serum glucose, cholesterol, and triglycerides did not differ between the groups with eccentric (n=145) and concentric (n=129) hypertrophy. Average 24-hour daytime, and nighttime systolic ambulatory BPs were higher in concentric than in eccentric hypertrophy (all p <0.01). LV mass was slightly greater in concentric than in eccentric hypertrophy (157 vs 149 g/BSA, p <0.05). Endocardial and midwall shortening fraction were lower in concentric than in eccentric hypertrophy (96.5% vs 106.0% of predicted and 71.4% vs 89.7% of predicted, respectively; both p <0.01). The rate of major cardiovascular morbid events was 2.20 and 3.34 per 100 patient-years in eccentric and concentric hypertrophy, respectively (log rank test, p=NS). Age >60 and LV mass above median (145 g/BSA) were significant adverse prognostic predictors, while LV geometry (eccentric vs concentric hypertrophy) and ambulatory BP were not. The event rates per 100 patient-years were 1.38 and 3.98, respectively, in the patients with LV mass below and above median (age-adjusted relative risk 2.70; 95% confidence interval [CI] 1.03 to 6.63; p=0.015). In hypertensive subjects with established LV hypertrophy, LV mass, but not its geometric pattern, provides important prognostic information independent of conventional risk markers including office and ambulatory BP.

White coat hypertension and white coat effect. Similarities and differences.

The rise in blood pressure (BP) associated with clinical visit (white coat effect) may be one basic mechanism of white coat hypertension (persistently raised clinic BP together with a normal BP outside the clinic), but the relations between white coat hypertension, white coat effect, and target organ damage have not yet been assessed on large populations. Thus, we performed 24-h noninvasive ambulatory BP monitoring and 2D-guided M-mode echocardiography in 1,333 untreated subjects with essential hypertension and 178 control normotensive subjects. White coat hypertension was defined by an average daytime ambulatory BP < 131/86 mm Hg in women and < 136/87 mm Hg in men and its prevalence was 18.9% (n = 252). The white coat effect was calculated for systolic and diastolic BP as the difference between clinic BP and average daytime ambulatory BP. Echocardiographic left ventricular mass was slightly but not significantly greater in the group with white coat hypertension than in the normotensive group (93 v 87 g/m2, P = NS), and increased in the group with ambulatory hypertension (112 g/m2, P < .01). The prevalence of white coat hypertension markedly decreased from the first to the fourth Joint National Committee V (JNC V) stage of severity of hypertension (186/559 subjects (33%) in I; 59/501 (11%) in II; 7/230 (3%) in III; 0/43 (0%) in IV; P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Does the reduction in systolic blood pressure alone explain the regression of left ventricular hypertrophy?

Systolic blood pressure (SBP) is an important determinant of the development and regression of left ventricular hypertrophy (LVH) in hypertensive humans. However, comparative assessments with other BP components are scarce and generally limited in size. As part of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA), 743 hypertensive subjects underwent echocardiography and 24-h ambulatory BP monitoring before and after an average of 3.9 years of treatment. The changes in left ventricular mass showed a significant direct association with the changes in 24-h SBP (r=0.40), diastolic blood pressure (DBP) (r=0.33) and pulse pressure (PP) (r=0.35). Weaker associations were found with the changes in clinic BP (r=0.32, 0.31 and 0.16, respectively). In a multivariate linear regression analysis, the changes in 24-h SBP were the sole independent determinants of the changes in left ventricular mass (LVM) according to the following equation: percentage changes in LVM=0.73 x (percentage changes in 24-h SBP) -0.48 (P<0.0001). For any given reduction in 24-h SBP, the reduction in LVM did not show any association with the changes in DBP and PP, either clinic or ambulatory. These data indicate that SBP is the principal determinant of LVH regression in hypertensive humans.

Prevalent influence of systolic over pulse pressure on left ventricular mass in essential hypertension.

BACKGROUND: Elevated pulse pressure, an index of increased large artery stiffness, has been associated with increased left ventricular mass. It is unknown whether this relation is independent or mediated by other blood pressure components. METHODS AND RESULTS: We examined data in 2545 untreated hypertensive subjects (45% women) who underwent echocardiography and 24-h ambulatory blood pressure monitoring. Left ventricular mass increased with all blood pressure components and all associations were closer with ambulatory than with office blood pressure. In a multiple regression analysis, after adjustment for the significant association with age, gender, body weight and duration of hypertension, the proportion of variability of left ventricular mass explained by systolic blood pressure was greater than that explained by other blood pressure components. When different blood pressure components were forced into the same model, the same degree of left ventricular mass variability was accounted for by models including 24-h systolic blood pressure alone, or 24-h mean blood pressure plus 24-h pulse pressure, or 24-h diastolic blood pressure plus 24-h pulse pressure. When 24-h systolic blood pressure and 24-h pulse pressure were forced into the same model, 24-h pulse pressure lost statistical significance. CONCLUSIONS: The association between pulse pressure and left ventricular mass is explained by systolic blood pressure, which is the main pressure determinant of left ventricular mass in essential hypertension.

Prognostic significance of serial changes in left ventricular mass in essential hypertension.

BACKGROUND: Increased left ventricular (LV) mass predicts an adverse outcome in patients with essential hypertension. The purpose of this study was to determine the relation between changes in LV mass during antihypertensive treatment and subsequent prognosis. METHODS AND RESULTS: Procedures including echocardiography and 24-hour ambulatory blood pressure (BP) monitoring were performed in 430 patients with essential hypertension before therapy and after 1217 patient-years. Months or years after the follow-up visit, 31 patients suffered a first cardiovascular morbid event. The patients with a decrease in LV mass from the baseline to follow-up visit were compared with those with an increase in LV mass. There were 15 events (1.78 per 100 person-years) in the group with a decrease in LV mass and 16 events (3.03 per 100 person-years) in the group with an increase in LV mass (P=.029). In a Cox model, the lesser cardiovascular risk in the group with a decrease in LV mass (hazard ratio [HR], 0.46; 95% CI, 0.22 to 0.99) remained significant (P=.04) after adjustment for age (HR, 1.06; 95% CI, 1.03 to 1.10; P=.0008) and baseline LVH at ECG (HR, 3.85; 95% CI, 1.52 to 9.78; P=.012). In that model, baseline LV mass bordered on statistical significance (HR, 1.01; 95% CI, 1.00 to 1.03; P=.06). In the subset with LV mass > 125 g/m2 at the baseline visit (26% of subjects), the event rate was lower among the subjects who achieved regression of LVH than in those who did not (1.58 versus 6.27 events per 100 person-years; P=.002). This difference held in the multivariate analysis (HR, 0.18; 95% CI, 0.05 to 0.68). CONCLUSIONS: In essential hypertension, a reduction in LV mass during treatment is a favorable prognostic marker that predicts a lesser risk for subsequent cardiovascular morbid events. Such an association is independent of baseline LV mass, baseline clinic and ambulatory BP, and degree of BP reduction.

Altered circadian blood pressure profile and prognosis.

BACKGROUND: In a previous analysis of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale we found a higher rate of cardiovascular morbid events among hypertensive nondippers than we did among dippers (5.86 versus 1.18 events per 100 person-years, P = 0.0002) for women, whereas the difference between the two groups was smaller and not statistically significant for men (4.15 versus 2.48 events per 100 person-years). These differences held in a multivariate analysis after adjustment for several confounders including average 24 h ambulatory blood pressure. In another analysis, the rate of occurrence of cardiovascular end-points was higher among nondippers than it was among dippers regardless of the definition of day and night (0600-2200 h and 2200-0600 h, awake and asleep, and 1000-2000 h and 2400-0600 h) and of the dividing line between dippers and nondippers (10 versus 0% day-night difference in blood pressure). OBJECTIVE: To test in a subsequent analysis based on a larger sample and a longer follow-up period, for both sexes, the prognostic value of a blunted diurnal rhythm of blood pressure. METHOD: We used the night: day ratio of ambulatory blood pressure, a continuous and normally distributed variable. RESULTS: A night: day systolic blood pressure ratio > 0.899 for men and > 0.909 for women (upper tertiles of distributions) identified a subset of subjects with greater than normal cardiovascular risk for any level of concomitant risk factors, wherease the hight:day diastolic blood pressure ratio was not statistically significant as an independent predictor. The excess risk for subjects in the upper tertile of the night: day systolic blood pressure ratio held after adjustment for several risk markers, including average 24 h ambulatory blood pressure. CONCLUSION: These data suggest that a blunted reduction in blood pressure from day to night predicts an increased cardiovascular morbidity at any level of concomitant risk factors including average 24 h ambulatory blood pressure. Nondippers can be defined in terms of a night: day ambulatory systolic blood pressure ratio > 0.899 for men and > 0.909 for women, regardless of the diastolic blood pressure profile.

Identification of subjects with white-coat hypertension and persistently normal ambulatory blood pressure.

OBJECTIVE: To assess the spontaneous changes in clinic blood pressure, ambulatory blood pressure (ABP) and left ventricular structure in untreated subjects with white-coat hypertension (WCH). DESIGN: A prospective observational study. PATIENTS AND METHODS: In 83 untreated subjects with WCH, 24 h non-invasive ABP monitoring and echocardiographic studies of the left ventricle were repeated after 0.5-6.5 years (mean 2.5) in the absence of antihypertensive drug treatment. WCH was defined by an average daytime ABP < 131/86 mmHg in women and < 136/87 mmHg in men. Ambulatory hypertension was defined by higher ABP values. RESULTS: In the whole population, the clinic blood pressure, ABP and left ventricular mass did not change from baseline to the follow-up visit, whereas the peak A: peak E ratio (where A is the velocity of transmitral blood flow after atrial contraction and E is the velocity during passive left ventricle filling) increased from 0.86 to 0.93. Sixty-three per cent of subjects remained in the WCH category at follow-up study; the remaining 37% shifted to the ambulatory hypertension category. The former group showed no changes in clinic blood pressure, ABP, left ventricular mass and peak A: peak E ratio. The clinic blood pressure of those who developed ambulatory hypertension did not change, whereas their ABP and peak A: peak E ratio increased and their left ventricular mass increased slightly but not significantly. The left ventricular mass increased from baseline to follow-up study by 6.2% in those who developed ambulatory hypertension and decreased by 1.6% in those who remained in the WCH category. The changes in left ventricular mass were associated with the changes in average 24 h systolic blood pressure, but not with the changes in clinic blood pressure. In a stepwise logistic regression analysis, average daytime diastolic blood pressure was the sole variable to enter the model and the probability of ambulatory hypertension at follow-up study was 20.0%percnt; in those with basal daytime ABP <130/80 mmHg, versus 81% in those with higher basal daytime blood pressure levels. CONCLUSION: After 0.5-6.5 years, WCH spontaneously evolved into ambulatory hypertension in 37% of subjects, with an accompanying rise in left ventricular mass. The probability of ambulatory hypertension increased with the baseline values of ABP, rather than with those of clinic blood pressure. WCH might be a prehypertensive state (particularly in subjects with higher baseline ABP levels) and should be defined by low levels of daytime ABP, possibly lower than 130/80 mmHg.

Prognostic significance of blood pressure variability in essential hypertension.

BACKGROUND: Blood pressure variability is a determinant of target organ damage in essential hypertension, but its independent prognostic significance has not yet been assessed in prospective studies of cardiovascular morbidity and mortality. OBJECTIVE: To assess the relationship between blood pressure variability, assessed non-invasively using 24 h ambulatory blood pressure monitoring and subsequent incidence of cardiovascular morbid events in persons with essential hypertension. DESIGN: Prospective observational study. PATIENTS AND METHODS: We followed for up to 8.6 years (mean 2.92) 1372 individuals with essential hypertension whose initial off-therapy diagnostic work-up included 24 h non-invasive ambulatory blood pressure monitoring. Those with a standard deviation of daytime or night-time blood pressure below or above the group mean were classified as having low or high blood pressure variability, respectively. One hundred and eighty-two participants underwent repeated ambulatory blood pressure monitoring and echocardiography during follow-up, 2.7 years later. RESULTS: Target organ damage score was greater in the participants with high variability of daytime (P = 0.004) and night-time (P = 0.011) systolic blood pressure than in those with low blood pressure variability. In those who underwent repeated echocardiography, for every quartile of baseline ambulatory blood pressure, left ventricular mass at follow-up was greater (all P < 0.05) in those with high baseline blood pressure variability than in those with low baseline variability. During follow-up there were 106 major cardiovascular morbid events. Event rate was 1.99 and 3.26 events per 100 patient-years, respectively, in participants with low and high variability of daytime systolic pressure and 1.98 and 3.38 events per 100 patient-years, respectively, in those with low and high variability of night-time systolic pressure (log-rank test: both P < 0.05). However, in a Cox multivariate analysis, the variability score for daytime and night-time systolic pressure failed to enter the model (age, diabetes mellitus, previous cardiovascular events and average night-time systolic pressure were independently associated with cardiovascular events). CONCLUSION: Increased blood pressure variability, assessed with non-invasive monitoring, is associated with a higher incidence of cardiovascular morbid complications of hypertension, but also with a higher blood pressure, older age and a higher prevalence of diabetes mellitus. Because of the relevant predictive effect of these associated factors, the adverse prognostic significance of increased blood pressure variability is no longer detectable in multivariate analysis.