Lacidipine and blood pressure variability in diabetic hypertensive patients.

The aim of our study was to assess the effects of lacidipine, a long-acting calcium antagonist, on 24-hour average blood pressure, blood pressure variability, and baroreflex sensitivity. In 10 mildly to moderately hypertensive patients with type II diabetes mellitus (aged 18 to 65 years), 24-hour ambulatory blood pressure was continuously monitored noninvasively (Portapres device) after a 3-week pretreatment with placebo and a subsequent 4-week once daily lacidipine (4 mg) or placebo treatment (double-blind crossover design). Systolic blood pressure, diastolic blood pressure, and heart rate means were computed each hour for 24 hours (day and night) at the end of each treatment period. Similar assessments were also made for blood pressure and heart rate variability (standard deviation and variation coefficient) and for 24-hour baroreflex sensitivity, which was quantified (1) in the time domain by the slope of the spontaneous sequences characterized by progressive increases or reductions of systolic blood pressure and RR interval and (2) in the frequency domain by the squared ratio of RR interval and systolic blood pressure spectral power approximately 0.1 and 0.3 Hz over the 24 hours. Compared with placebo, lacidipine reduced the 24-hour, daytime, and nighttime systolic and diastolic blood pressure (P<0.05) with no significant change in heart rate. It also reduced 24-hour, daytime, and nighttime standard deviation (-19.6%, -14.4%, and -24.0%, respectively; P<0.05) and their variation coefficient. The 24-hour average slope of all sequences (7.7+/-1.7 ms/mm Hg) seen during placebo was significantly increased by lacidipine (8.7+/-1.8 ms/mm Hg, P<0.01), with a significant increase being obtained also for the 24-hour average alpha coefficient at 0.1 Hz (from 5.7+/-1.5 to 6.4+/-1.3 ms/mm Hg, P<0.01). Thus, in diabetic hypertensive patients, lacidipine reduced not only 24-hour blood pressure means but also blood pressure variability. This reduction was accompanied by an improvement of baroreflex sensitivity. Computer analysis of beat-to-beat 24-hour noninvasive blood pressure monitoring may offer valuable information about the effects of antihypertensive drugs on hemodynamic and autonomic parameters in daily life.

Attenuation of the "white-coat effect" by antihypertensive treatment and regression of target organ damage.

This study assessed whether 2 common surrogate measures of the "white-coat effect," namely the clinic-daytime and the clinic-home differences in blood pressure (BP), were attenuated by long-term antihypertensive treatment and whether this attenuation is relevant to the treatment-induced regression of left ventricular hypertrophy, thus having clinical significance. We considered data from 206 patients with essential hypertension (aged 20 to 65 years) who had a diastolic BP between 95 and 115 mm Hg and echocardiographic evidence of left ventricular hypertrophy. In each patient, clinic BP, 24-hour ambulatory BP, and left ventricular mass index were assessed at baseline, after 3 and 12 months of treatment with an angiotensin-converting enzyme inhibitor, and after a final 4-week placebo run-off period. At baseline, the clinic-daytime differences in systolic and diastolic BP were 12.1+/-15.4 and 6.8+/-10.1 mm Hg, respectively; the corresponding values for the clinic-home differences were 5.7+/-10.6 and 2.9+/-6.1 mm Hg, respectively. These differences were reduced by 57.6% and 77.1% (P<0.01) and by 65.7% and 64.3% (P<0.01), respectively, after 12 months of treatment, with a partial return toward the pretreatment differences after the final placebo period. The observed treatment-induced reductions in left ventricular mass index and those in the clinic-daytime or clinic-home differences for systolic and diastolic BP showed no significant relationship when tested by multiple regression analysis. This provides the first longitudinal evidence that clinic-daytime and clinic-home differences in BP have no substantial value in predicting the regression of target organ damage, such as left ventricular hypertrophy, that has prognostic relevance.

Ambulatory blood pressure monitoring.

This paper will briefly summarize the available evidence on the diagnostic and prognostic relevance of a number of parameters derived from the analysis of 24 hour ambulatory blood pressure recordings. These parameters include the 24 h average blood pressure values, the difference between daytime and nighttime blood pressure, the difference between clinic blood pressure and daytime average blood pressure as a surrogate measure of the "white coat effect", and 24 hour blood pressure variability as quantified by the standard deviation of the 24 hour average value.

Clinical relevance blood pressure variability.

Blood pressure fluctuates continuously over time, either spontaneously or in response to a variety of external stimulations. The occurrence of these continuous and often marked blood pressure variations is not only of pathophysiologic interest, but it may also have a clinical relevance. Indeed, it has been shown that the occurrence of pronounced blood pressure changes at the time of the physician's visit may introduce errors in the diagnosis of hypertension and in the assessment of the efficacy of antihypertensive treatment. Moreover, several studies have reported that the end-organ damage of hypertension is significantly and independently related to the degree of blood pressure variability during the day and night. This was shown by reports that assessed blood pressure variability by a variety of different methods, i.e. by computing the 24 h or daytime blood pressure standard deviation, the degree of morning blood pressure rise or that of night-time blood pressure fall, the frequency of blood pressure peaks over the 24 h, and the blood pressure increases under stressful conditions or during physical exercise. Results from a recent follow-up study have provided evidence that the degree of blood pressure variability may also have prognostic relevance in hypertensive patients. Thus, optimal antihypertensive treatment might also need to reduce the degree of blood pressure fluctuations together with the 24 h average blood pressure levels. Until recently, however, available antihypertensive drugs have been ineffective in buffering blood pressure variability or have even been responsible for an increase in the degree of blood pressure fluctuations. Further studies are needed to assess whether recently developed antihypertensive agents, and in particular those able to induce a smooth reduction in blood pressure over the 24 h or to modulate the sympathetic influences exerted on the cardiovascular system, may represent better tools to reduce the magnitude of an enhanced blood pressure variability in hypertensive patients over the 24 h. Recent progress in technology has offered us more powerful tools to address this issue. They include devices for continuous noninvasive ambulatory blood pressure monitoring (Portapres, TNO), and techniques for a more comprehensive analysis of all components which contribute to overall blood pressure variability (broad-band spectral analysis).

Difference between clinic and daytime blood pressure is not a measure of the white coat effect.

The purpose of the present study was to evaluate whether the difference between blood pressure measured in the clinic or physician's office and the average daytime blood pressure accurately reflects the blood pressure response of the patient to the physician ("white coat effect" or "white coat hypertension"). We studied 28 hypertensive outpatients (mean age, 41.8+/-11.2 years; age range, 21 to 64 years) of 35 consecutive patients attending our hypertension clinic, in whom (1) continuous noninvasive finger blood pressure was recorded before and during the visit, (2) blood pressure was measured according to the Riva-Rocci-Korotkoff method (mercury sphygmomanometer) with the patient in the supine position, and (3) daytime ambulatory blood pressure was monitored with a SpaceLabs 90207 device. The peak blood pressure increase recorded directly during the visit was compared with the difference between clinic and daytime average ambulatory blood pressures. Compared with previsit values, peak increases in finger systolic and diastolic blood pressures during the visit to the clinic were 38.2+/-3.1 and 20.7+/-1.6 mm Hg, respectively (mean+/-SEM, P<.01 for both). Daytime average systolic and diastolic blood pressures were 135.5+/-2.5 and 89.2+/-1.9 mm Hg, with both lower than the corresponding clinic blood pressure values (146.6+/-3.6 and 94.9+/-2.2 mm Hg, P<.01). These differences, however, were <30% of the peak finger blood pressure increases during the physician's visit, to which these increases showed no relation. Although the visit to the physician's office was associated with tachycardia (9.0+/-1.6 bpm, P<.01), there was no difference between clinic and daytime average heart rates. These data indicate that the clinic-daytime average blood pressure difference does not reflect the alerting reaction and the pressure response elicited by the physician's visit and thus is not a reliable measure of the white coat effect.

Limitations of the difference between clinic and daytime blood pressure as a surrogate measure of the 'white-coat' effect. Syst-Eur investigators.

BACKGROUND: The difference between clinic and ambulatory average daytime blood pressures is frequently taken as a surrogate measure of the 'white-coat effect' (i.e. the pressor reaction triggered in the patient by the physician's visit). OBJECTIVE: To assess the reproducibility of this difference and its relationship with clinic and average ambulatory daytime blood pressure levels. DESIGN AND METHODS: These issues were addressed with two large groups of subjects in whom both clinic and ambulatory blood pressures were measured, namely 783 outpatients with systolic and diastolic essential hypertension [Group 1, aged 50.8+/-9.4 years (mean +/- SD)], participating in standardized Italian trials of antihypertensive drugs, and 506 elderly patients (group 2, age 71+/-7 years) with isolated systolic hypertension, participating in the European Syst-Eur trial. RESULTS: The clinic-daytime blood pressure difference for the essential systolic and diastolic hypertensive patients (group 1) was 13.6+/-14.3 mmHg for systolic and 9.1+/-8.6 mmHg for diastolic blood pressure (P always < 0.01). This difference for the elderly patients with isolated systolic hypertension (group 2) was 21.2+/-16.0 mmHg for systolic and only 1.3+/-10.2 mmHg for diastolic blood pressure (P < 0.01 and P < 0.05, respectively). In both studies little or no systematic clinic-daytime difference could be observed for heart rate. The reproducibility of the clinic-daytime blood pressure difference, tested for 108 essential systolic and diastolic hypertensive patients from group 1 and 128 isolated systolic hypertensives from group 2, was invariably lower than that both of daytime and of clinic blood pressure values. Finally, the clinic-daytime blood pressure difference was progressively higher for increasing levels of clinic blood pressure and progressively lower for higher levels of ambulatory daytime blood pressure. CONCLUSIONS: Thus, the clinic-daytime blood pressure difference has a limited reproducibility; depends not only on clinic but also on daytime average blood pressure, which means that its size is a function of the blood pressure criteria employed for selection of the patients in a trial; and is never associated with a systematic clinic-daytime difference in heart rate, which further questions its use as a reliable surrogate measure of the true pressor response induced in the patient by the doctor's visit.

Hemodilution reduces clinic and ambulatory blood pressure in polycythemic patients.

Limited information is available for humans on whether blood viscosity affects total peripheral resistance and, hence, blood pressure. Our study was aimed at assessing the effects of acute changes in blood viscosity on both clinic and 24-hour ambulatory blood pressure (BP) values. In 22 normotensive and hypertensive patients with polycythemia, clinic and 24-hour ambulatory BPs were measured before and 7 to 10 days after isovolumic hemodilution; this was performed through the withdrawal of 400 to 700 mL of blood, with concomitant infusion of an equivalent volume of saline-albumin solution. Hematocrit, plasma renin activity, plasma endothelin-1, right atrial diameter (echocardiography), and blood viscosity were measured under both conditions. Plasma renin activity and right atrial diameter were used as indirect markers of blood volume changes. Plasma endothelin-1 was used to obtain information on a vasomotor substance possibly stimulated by our intervention, which could counteract vasomotor effects. Isovolumic hemodilution reduced hematocrit from 0.53+/-0.05 to 0.49+/-0.05 (P<.01). Plasma renin activity, plasma endothelin-1 and right atrial diameter were unchanged. Clinic blood pressure was reduced by hemodilution (systolic, 144.3+/-5.4 to 136.0+/-3.9 mm Hg[mean+/-SEM]; diastolic, 87.0+/-2.8 to 82.1+/-2.6 mm Hg, P<.05 for both) and a reduction was observed also for 24-hour average ABP (systolic, 133.6+/-2.9 to 129.5+/-2.7 mm Hg; diastolic, 80.0+/-2.0 to 77.3+/-1.7 mm Hg, P<.05 for both). The reduction was consistent in hypertensive patients (n = 12), whereas in normotensive patients (n = 10) it was small and not significant. Both clinic and 24-hour average heart rates were unaffected by the hemodilution. Thus, in polycythemia, reduction in blood viscosity without changing blood volume causes a significant fall in both clinic and 24-hour ambulatory BPs; this is particularly true when, as can often happen, blood pressure is elevated. This emphasizes the importance this variable may have in the determination of blood pressure and the potential therapeutic value of its correction when altered.

Ambulatory blood pressure in hypertension with particular reference to the kidney.

Ambulatory blood pressure is more closely related to the end organ damage of hypertension than clinic blood pressure is. This is the case not only for left ventricular hypertrophy, but also for an index of renal involvement such as microalbuminuria. The closer correlation of ambulatory blood pressure with end organ damage characterises not only the 24 hour average value but also, to a similar extent, day-time and night-time average blood pressure, while the clinical importance of the difference between day and night blood pressure is still a matter of controversy. A more promising index derived from ambulatory blood pressure recordings seems to be blood pressure variability, which in preliminary studies has been shown to display an independent correlation with the end organ damage of hypertension.

Performance of the AM-5600 blood pressure monitor: comparison with ambulatory intra-arterial pressure.

The AM-5600 is a new device that simultaneously monitors electrocardiogram (ECG) and noninvasive blood pressure (BP) over a 24-h period. BP readings (Korotkoff sounds and cuff air pressure) are stored into the recorder, allowing the removal of BP artifacts after a visual check. In 12 subjects with essential hypertension, we compared BP values simultaneously provided by the AM-5600 and intra-arterial recordings. At rest, noninvasive systolic BP (SBP) values were lower (5.4 +/- 4.9 mmHg) and diastolic BP (DBP) values were higher (7.3 +/- 7.3 mmHg) than were intra-arterial values. In ambulatory conditions (9 subjects), between-method discrepancies were +0.8 +/- 6.1 and +12.2 +/- 7.4 mmHg for 24-h SBP and DBP, respectively. AM-5600 underestimated 24-h intra-arterial SBP and DBP SD, but it accurately tracked intra-arterial SBP and DBP changes. Editing removed 22.1% of total readings, slightly reducing between-method discrepancies. Thus the AM-5600 provides an accurate average estimate of resting and ambulatory SBP and, for DBP, a less accurate estimate that is slightly improved by editing. The AM-5600 allows accurate description of SBP and DBP profiles and thus may be suitable to describe the abrupt BP changes accompanying a number of clinical events.

Blood pressures other than the one at the clinic.

While assessing the cardiovascular risk of hypertensive patients, different types of blood pressure measurements can be regarded as suitable surrogate endpoints. In this context the possible role of clinic, stress, exercise, basal, home and ambulatory blood pressures is briefly discussed. The clinical value of night-time blood pressure, of the clinic-daytime blood pressure difference and of blood pressure variability is also addressed.

Clinical value of blood pressure variability.

Blood pressure (BP) is known to continuously fluctuate over time and both the amplitude and frequency of these changes have been reported to be clinically relevant. Indeed, it has been shown that the occurrence of pronounced BP changes at the time of the physician's visit may introduce errors in the diagnosis of hypertension and in the assessment of the efficacy of antihypertensive treatment. Moreover, several studies have provided evidence that the end organ damage of hypertension is not only more closely related to 24h average BP values than to casual BP readings, it is also significantly and independently related to the degree of BP variability during the day and night. Results from a recent follow-up study support the possibility that the degree of BP variability may also have prognostic relevance in hypertensive patients. Recent progress in technology has offered us non-invasive techniques for the assessment of beat-to-beat finger blood pressure variability and for the detailed quantification of all its frequency components from the fastest to the slowest ones. Their role as additional surrogate endpoints in essential hypertension needs to be addressed in future studies.

[The difference between clinical ambulatory measured blood pressure and daily monitored pressure does not reflect the "white coat effect"]. / La differenza tra la pressione misurata in ambulatorio e la pressione diurna monitorata non riflette l' "effetto camice bianco".

The difference between clinic and average daytime ambulatory blood pressure is frequently used to identify patients with "white coat" hypertension (i.e. with a pronounced pressor response to the clinical evaluation) although there is no evidence that this difference is indeed due to a white coat effect. In 28 mild hypertensive outpatients, the blood pressure was continuously recorded by a noninvasive finger device before and during the doctor's visit. The peak blood pressure increase, recorded during the visit was compared with the difference between clinic and daytime average ambulatory blood pressure. Peak increases in systolic and diastolic finger blood pressure during the doctor's visit were 38.2 +/- 3.1 mmHg and 20.7 +/- 1.6 mmHg, respectively compared to pre visit values (means +/- standard error, both p < 0.01). Daytime average systolic and diastolic blood pressure were 135.5 +/- 2.5 mmHg and 89.2 +/- 1.9 mmHg, both being lower than the corresponding clinic blood pressure values (146.6 +/- 3.6 mmHg and 94.9 +/- 2.2 mmHg, p < 0.01). Their differences, however, were < 30% of the peak finger blood pressure increase during the physician's visit. While the physician's visit was associated with tachycardia (+9.0 +/- 1.6 b/min, p < 0.01) there was no difference between clinic and daytime average heart rate. The alerting reaction and the pressor response induced by the physician's visit is not reflected by the difference between clinic and daytime average blood pressure. Such a difference is not therefore a reliable measure of the white coat effect.

Reproducibility of blood pressure measurements.

Clinic blood pressure readings are less reproducible than 24 h and daytime average ambulatory blood pressures. This may depend on (1) the continuous and spontaneous variability which characterizes daily life blood pressure, (2) the well-known 'white-coat' effect and (3) other methodological problems affecting traditional sphygmomanometric readings, such as the observer's bias and digit preference. The higher reproducibility of average 24 h and daytime blood pressures is also, at least in part, a function of the greater number of blood pressure readings available. On the other hand, the various components of the 24 h blood pressure profile appear, in general, to be less reproducible than the 24 h average value. This is the case for hourly values, for the day-night blood pressure difference and for a number of statistical parameters employed for modelling the 24 h blood pressure curve. An alternative and simple way to obtain reproducible blood pressure values, without making use of ambulatory blood pressure monitoring techniques, may be offered by the average of 20-25 blood pressure readings obtained automatically or semi-automatically under standardized conditions in outpatient clinics. The implications of these findings for clinical trials aimed at evaluating the features of the effects of antihypertensive drugs on 24 h blood pressure are discussed.

Blood pressure variability, cardiovascular risk and antihypertensive treatment.

TWENTY-FOUR HOUR BLOOD PRESSURE PARAMETERS: The use of ambulatory blood pressure monitoring techniques has shown clearly that 24-h average blood pressure is more closely related to the end-organ damage of hypertension than isolated office blood pressure readings. It has also provided evidence that the degree of blood pressure variability over a 24-h period may be independently related to the cardiovascular complications of hypertension. However, all the available data on this issue come from cross-sectional studies, and prospective evidence on the actual prognostic value of 24-h blood pressure parameters has only recently been provided for daytime blood pressure variability. There is still no prospective evidence concerning overall 24-h blood pressure variability. ANTIHYPERTENSIVE AGENTS AND BLOOD PRESSURE VARIABILITY: Available antihypertensive agents are unable to effectively buffer blood pressure variability. However, drugs with a long-lasting antihypertensive effect and an optimal trough: peak ratio may at least prevent further iatrogenic increases in the amplitude of blood pressure fluctuations. BEAT-TO-BEAT BLOOD PRESSURE MONITORING: The ability of antihypertensive agents to actually reduce 24-h blood pressure variability needs to be demonstrated in future studies, using beat-to-beat blood pressure monitoring which is now possible by means of non-invasive techniques.

Blood pressure variability over 24 hours: its different components and its relationship to the arterial baroreflex.

This paper describes several different methods for the analysis of blood pressure and heart rate variability over the 24 hours, both in the time and in the frequency domain. The mechanisms possibly involved in the genesis of the variations in blood pressure and heart rate which occur over a 24-hour period are also discussed. Finally, new approaches to the dynamic evaluation of the sensitivity of baroreflex control of heart rate and of its changes over the 24 hours in daily life conditions, based on computer analysis of the interaction between fluctuations in blood pressure and heart rate, are described. Data obtained by applying these methods in different clinical conditions (normotensive vs. hypertensive subjects, young vs. elderly individuals and pure autonomic failure patients) are presented.

Blood pressure reduction and end-organ damage in hypertension.

VALUE OF AMBULATORY BLOOD PRESSURE MONITORING: Studies that have used ambulatory blood pressure monitoring techniques have shown that the average 24-h or daytime blood pressure values are more closely related to the end-organ damage associated with hypertension than are isolated office readings. IMPORTANCE OF BLOOD PRESSURE VARIABILITY IN PROGNOSIS: More recently, blood pressure variability, measured as the overall 24-h blood pressure standard deviation, has been shown to have a significant relationship to end-organ damage in hypertensive patients. The potential clinical relevance of blood pressure variability has been strengthened in a recent prospective study. The possible prognostic value of blood pressure variability has practical implications for antihypertensive treatment; it may mean, for example, that the optimal antihypertensive drug should reduce not only the mean 24-h values but also the degree of fluctuation in blood pressure. This is more likely to occur with long-acting drugs, which induce a more balanced reduction in blood pressure throughout the 24 h. USE OF THE TROUGH:PEAK RATIO: A proposed measure of a balanced 24-h blood pressure effect is the trough:peak ratio of the blood pressure fall. This ratio can be obtained by clinic blood pressure measurements but ambulatory blood pressure monitoring offers some distinct advantages. One of these advantages is that by revealing the possibility of an excessive fall in blood pressure at the time of the peak effect or an uncontrolled rise at the trough, ambulatory monitoring can also reveal the possible impact of pharmacological treatment on 24-h blood pressure variability.

Blood pressure variability: clinical implications and effects of antihypertensive treatment.

HYPOTHESIS ON RELATIONSHIP BETWEEN BLOOD PRESSURE VARIABILITY AND END-ORGAN DAMAGE: Several studies have shown that the cardiovascular complications of hypertension are more closely related to ambulatory 24-h or daytime average blood pressure than to office readings. A few studies have also provided evidence that in hypertensive patients, not only average ambulatory blood pressure but also the degree of blood pressure variability is significantly and independently related to the end-organ damage associated with hypertension. LIMITATIONS OF PREVIOUS STUDIES: A common limitation of previous studies is that they were based on cross-sectional or retrospective observations, so that the correlative evidence they provide does not allow the relationship between blood pressure variability and end-organ damage to be interpreted causally. EVIDENCE FROM RECENT STUDIES: Recent evidence from follow-up observations has strongly supported the hypothesis that blood pressure variability is prognostically important in hypertensive patients. These findings suggest that optimal antihypertensive treatment should aim not only to reduce mean blood pressure levels, but also to reduce the degree of blood pressure fluctuation. EFFECTS OF ANTIHYPERTENSIVE DRUGS: Unfortunately, while most new antihypertensive drugs seem to be effective in reducing 24-h mean blood pressure levels, they are frequently unable to reduce 24-h blood pressure variability, which is often increased during treatment when expressed in normalized units. The development of drugs that guarantee a constant and uniform reduction in blood pressure over 24 h may, in principle, offer a further advantage by preventing the increase in 24-h blood pressure fluctuations that may follow the administration of short-acting antihypertensive agents. TROUGH: PEAK MEASUREMENTS OF BLOOD PRESSURE: The trough: peak ratio, proposed as an arithmetic indicator of the duration of the antihypertensive effect of a drug, may be a useful measure of the occurrence of a smooth reduction in blood pressure over 24 h. The possibility of obtaining an additional reduction in cardiovascular risk for hypertensive patients by minimizing the net trough: peak effect of antihypertensive drugs is thus an important issue for future studies.