Methodological problems in evaluation of cardiovascular effects of stress in humans.

Cardiovascular effects of stress in humans are often assessed by application of physical or emotional stimuli in a laboratory environment. Although this method provides important information, these procedures have several limitations. First, blood pressure and heart rate responses to laboratory stressors are characterized by a limited within-subject reproducibility. Second, there is poor correlation between blood pressure and heart rate responses to different stressors, which implies that individual reaction to stress may be estimated differently according to the test used. Finally, these responses bear only a limited relation to 24-hour or daytime blood pressure variability, that is, they reflect to only a limited extent the tendency of blood pressure to vary during daily activities. If assessed by techniques that allow blood pressure to be continuously recorded for 24 hours in ambulatory subjects, blood pressure variability represents a possible approach to observation of cardiovascular reactivity away from an artificial laboratory environment. However, whether blood pressure variability should be expressed as a percentage or in absolute values is controversial. Furthermore, although naturally occurring stress may markedly increase blood pressure, 24-hour blood pressure variations also depend on factors that are not related to emotional stimuli. Thus, the study of cardiovascular responses to stress in humans encounters several problems, regardless of the method used.

Early 24-hour blood pressure elevation in normotensive subjects with parental hypertension.

Subjects with a family history of parental hypertension are reported to have a slightly higher office blood pressure in the prehypertensive stage. Whether this reflects a hyperreactivity to blood pressure measurement or a more permanent blood pressure elevation, however, is not known. In the present study, blood pressure was measured in 15 normotensive subjects whose parents are both hypertensive (FH++), 15 normotensive subjects with one hypertensive parent (FH(+)-), and 15 normotensive subjects whose parents are not hypertensive (FH--); among the three groups, subjects were matched for age, sex, and body mass index. The measurements were made in the office during a variety of laboratory stressors and during a prolonged resting period, and for a 24-hour period (ambulatory blood pressure monitoring). Office blood pressure was higher in the FH++ group than in the FH-- group (p less than 0.05). The pressor responses to laboratory stressors were similar in the two groups, but the FH++ group had higher prolonged resting and 24-hour blood pressure than the FH-- group; the difference was always significant (p less than 0.05) for systolic blood pressure. The FH++ group also had a greater left ventricular mass index (on echocardiographic examination) than the FH-- group (p less than 0.01). The blood pressure values and echocardiographic values of the FH(+)- group tended to be between those of the other two groups. Thus, the higher blood pressure shown by individuals in the prehypertensive stage with a family history of parental hypertension does not reflect a hyperreactivity to stress but an early permanent blood pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the cardiovascular effects of different laboratory stressors and their relationship with blood pressure variability.

Laboratory stressors are employed to assess the 'typical' cardiovascular reactivity to stress of a given subject. It is believed that this may assist in the diagnosis of hypertension and predict future development of blood pressure (BP) elevation. However, the internal consistency of the data obtained by laboratory stressing manoeuvres and their ability to reflect the effects of everyday stressful events occurring over a 24-h period have never been clearly established. We studied a group of ambulant normotensive and essential hypertensive in-patients who were undergoing prolonged intra-arterial blood pressure monitoring (Oxford method) to determine firstly, whether four routine laboratory stressors provided a homogeneous evaluation of subjects' reactivity and secondly, whether cardiovascular reactivity to these stressors reflected a tendency of BP to vary over a 24-h period. A significant correlation (P less than 0.01) was found between the pressor responses to mental arithmetic and the mirror drawing test and between the pressor responses to the cold pressor test and hand-grip. These correlations, however, were not close and responses to the 'mental' and 'physical' stressors were unrelated. The elevation in BP induced by laboratory stressors also did not correlate with the increase in BP accompanying stress elicited outside laboratory conditions (i.e. doctor's visit). The pressor effects of both the laboratory and the out-of-laboratory stressors showed little or no correlation with the 24-h absolute or per cent blood pressure variabilities, although for the stressors involving a mental challenge, a significant though not close correlation with daytime blood pressure variability was found. These data underline the limitations of laboratory tests in assessing cardiovascular reactivity to stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of percutaneous transluminal renal angioplasty on nocturnal hypotension in renovascular hypertensive patients.

OBJECTIVE: To investigate whether nocturnal blood pressure fall is blunted in renovascular hypertension and can therefore be used as a diagnostic criterion for this condition. METHODS: In 14 renovascular hypertensive patients (age 43.8+/-2.1 years, mean+/-SEM, clinic blood pressure 173.6+/-3.7 mmHg systolic and 109.0+/-2.0 mmHg diastolic) and in 14 age- and blood pressure-matched essential hypertensive controls 24 h ambulatory blood pressure was measured after washout from drug treatment, during angiotensin converting enzyme inhibitor treatment and, in renovascular hypertension, also after percutaneous transluminal renal angioplasty. RESULTS: The 24 h average systolic and diastolic blood pressures were 146.4+/-5.7 and 97.5+/-3.6 mmHg in renovascular and 144.3+/-1.2 and 98.0+/-2.2 mmHg in essential hypertensive patients. The angiotensin converting enzyme inhibitor treatment reduced 24 h average systolic and diastolic blood pressures by 8.5% and 9.7% in the renovascular and by 8.3% and 10.8% in the essential hypertensive group. Greater systolic and diastolic blood pressure reductions (-18.2% and -18.1%) were observed in renovascular hypertensive patients after percutaneous transluminal renal angioplasty. Blood pressure fell by about 10% during the night and the fall was similar in renovascular and in essential hypertensive patients. In the former group, nocturnal hypotension was similar after washout, during angiotensin converting enzyme inhibitor treatment and after percutaneous transluminal renal angioplasty. Similar results were obtained for nocturnal bradycardia. CONCLUSIONS: Nocturnal blood pressure fall is equally manifest in renovascular and essential hypertension. The removal of the renal artery stenosis and blood pressure normalization do not enhance this phenomenon. Nocturnal hypotension seems therefore to be unaffected by renovascular hypertension.

Clinical value of blood pressure measurements: focus on ambulatory blood pressures.

Because clinic blood pressure values are compromised by 2 major limitations--the alerting reaction to clinic measurements and the spontaneous blood pressure variability--they have only a limited correlation with average 24-hour blood pressure values. Whether the latter should be employed routinely in substitution for, or in addition to, traditional blood pressure measurements has not yet been determined, however. To date, average 24-hour blood pressure values have been shown to correlate more closely than clinic blood pressure values with the organ damage of hypertension. A correlation with organ damage has been shown also for a number of blood pressure values within the 24 hours. Nevertheless, the clinical importance of 24-hour blood pressure and blood pressure variability has never been confirmed by prospective controlled studies. This information needs to be obtained before this approach is routinely employed in the clinical practice.

Evaluation of the antihypertensive effect of celiprolol by ambulatory blood pressure monitoring.

The use of ambulatory blood pressure monitoring has gained popularity because it is not subject to those limitations associated with traditional sphygmomanometry (inaccuracy of blood pressure readings, low number of readings, and failure to represent daytime blood pressure readings). In the present study, we provide evidence that the 24-hour mean blood pressure obtained through intraarterial blood pressure measurements in ambulatory patients provides a more accurate diagnosis (and perhaps a prognosis) of hypertension than that provided by cuff-obtained casual blood pressure measurement. Furthermore, despite a reduction in the amount and in the accuracy of the information obtained, blood pressure data provided by noninvasive blood pressure monitoring are also more accurate diagnostically than cuff-obtained casual blood pressure measurements. In 15 essential hypertensive patients in whom celiprolol, 400 mg once daily, was compared with placebo in a randomized double-blind crossover study, the use of noninvasive 24-hour automatic blood pressure monitoring showed that in responsive patients, celiprolol induced a sustained reduction in systolic and diastolic blood pressure throughout the 24 hours. The blood pressure reduction was also apparent during the night, despite the concomitant occurrence of a slight tachycardia. These findings demonstrate that once-daily administration of celiprolol provides an effective lowering of the 24-hour blood pressure profile. This dosing schedule can therefore be regarded as appropriate for antihypertensive therapy.

Ambulatory blood pressure monitoring.

This paper reviews the evidence that, in patients with hypertension, end-organ damage correlates more closely with blood pressure values obtained by ambulatory blood pressure monitoring than with those obtained by conventional sphygmomanometry. However, ambulatory blood pressure monitoring is not suitable for routine use in the clinical setting because of a lack of standard reference values and data regarding the prognostic significance of this method. Ambulatory blood pressure values are reproducible and this method avoids the so-called placebo effect; thus, this method is useful in clinical studies investigating the efficacy and duration of action of antihypertensive drugs. Data from 1 study in which hypertensive patients were treated with slow release verapamil 240 mg, enalapril 20 mg, nitrendipine 20 mg and placebo, given once daily for 8 weeks according to a double-blind parallel group design, showed that mean 24-hour ambulatory blood pressure was reduced by all 3 drugs compared with placebo. Verapamil and enalapril showed similar antihypertensive efficacy and both drugs reduced night-time blood pressure more effectively than nitrendipine.

Permanent blood pressure control over the 24 h by trandolapril.

Noninvasive ambulatory blood pressure monitoring (ABPM) has proved to be an innovative tool for the assessment of the efficacy of antihypertensive drugs. It enables evaluation of the magnitude of the drug-related blood pressure fall and also of the duration of this effect throughout 24 h. Moreover, ambulatory blood pressures have advantages compared to office blood pressure: they are not affected by the white coat effect occurring at the time of the doctor's visit, are devoid of a placebo effect, are more reproducible than occasional clinic measurements, and may yield important information on the prognosis of hypertensive patients. Ambulatory blood pressure recordings were used to test the antihypertensive effect of a novel angiotensin converting enzyme, trandolapril, in 62 mild to moderate essential hypertensive outpatients. After a 4 week wash-out, period, patients were randomized to 2 mg trandolapril or placebo for 6 weeks. A 4-week wash-out period was scheduled at the end of the treatment period. Ambulatory blood pressure recordings were performed at the end of each period, starting in the morning. Trandolapril (n = 31) significantly reduced 24 h systolic and diastolic blood pressure as compared to pre- and posttreatment periods and to placebo (n = 17). The reduction involved both the daytime and nighttime blood pressure values and was evident also in the last hours of the recording, the trough-to-peak ratio being 0.6 for systolic and 0.7 for diastolic blood pressure. Thus, trandolapril at a dose of 2 mg once daily is an effective long-lasting antihypertensive drug.

Lack of placebo effect on ambulatory blood pressure.

Several studies have reported that, at variance with clinic blood pressure, ambulatory blood pressure is not reduced by treatment with placebo. However, this evidence has usually been obtained in small groups of subjects and no data are available from a larger sample of patients. To address this issue we have analyzed data from 116 outpatients involved in placebo-controlled studies on antihypertensive treatment. The patients were studied before and at the end of a 6- to 8-week period of placebo. In all patients, blood pressure was measured by sphygmomanometry and over the 24 h by automatic ambulatory monitoring. Administration of placebo was accompanied by a significant reduction in systolic and diastolic clinic blood pressure (-5.3 +/- 1.1 and -4.4 +/- 0.6 mm Hg, respectively; P < .01), but not in 24-h, daytime and nighttime blood pressure. Hourly systolic and diastolic blood pressure profiles were virtually superimposable in the two different periods, except for the first 4 h, in which systolic blood pressure was slightly but significantly lower during than before placebo (149.5 +/- 1.2 v 146.4 +/- 1.2 mm Hg; P < .05). These results provide a large database indicating that 24-h average blood pressure is not reduced by placebo, thus it is not necessary to include a placebo control group in antihypertensive drug studies in which ambulatory blood pressure monitoring is employed. A small placebo effect occurs, however, in the first hours of ambulatory monitoring. This may lead to a slight overestimation of the peak blood pressure effect of a drug and an underestimation of its trough-to-peak ratio if placebo correction of the data is not made or if the first part of ambulatory blood pressure monitoring is not excluded from data analysis.

Ambulatory blood pressure monitoring and antihypertensive treatment.

Ambulatory blood pressure monitoring is becoming increasingly popular among clinicians and investigators because of its potential to overcome the well-known limitations inherent to conventional blood pressure measurement. This paper will focus on the use of this approach in the evaluation of antihypertensive treatment. It will be argued that due to lack of prognostic validity and high cost, ABPM should not be employed routinely in treating hypertensives. It should always be employed, however, for the evaluation of the efficacy of new hypertensive drugs for which its superiority over sphygmomanometry is indisputable. This is exemplified by the results of a recent multicenter, double-blind, parallel group study on the effect of verapamil SR 240 mg, enalapril 20 mg and nitrendipine 20 mg and placebo, all administered once a day for eight weeks. Compared to placebo, all drugs reduced 24-hour mean blood pressure sufficiently. The reduction was evident throughout the daytime but nighttime blood pressure was more effectively lowered by verapamil and enalapril than by nitrendipine, documenting a difference that was not visible by using conventional measurements.

Balanced 24-hour blood pressure control by angiotensin-converting enzyme inhibitors administered once daily.

Traditional sphygmomanometric measurements may inaccurately reflect the actual blood pressure level over a 24-h period. This is due to several factors which are known to affect cuff blood pressure readings, including the limited number of readings obtainable throughout the 24 h and the alerting reaction and pressor response induced in patients by the presence of the physician. Twenty-four-hour ambulatory blood pressure monitoring has been reported to be superior to isolated cuff blood pressure readings in the diagnostic evaluation of hypertension and in assessing the blood pressure response to treatment. It does not trigger any emotionally induced pressor reaction and is able to provide a dynamic evaluation of blood pressure profiles over 24 h. The latter feature is particularly important in assessing the ability of once-daily antihypertensive treatment to reduce and maintain blood pressure at an appropriate level throughout the 24-h period. Studies to date using ambulatory blood pressure monitoring techniques suggest that once-daily administration of certain ACE inhibitors is capable of providing this long-term control of blood pressure. The 24-h antihypertensive action exerted by once-daily administration of ACE inhibitors is characterized by balanced blood pressure control throughout the day and night, and treatment does not appear to alter the neural mechanisms responsible for cardiovascular homeostasis, as suggested by the fact that these drugs have been shown not to affect 24-h blood pressure and heart rate variability. Furthermore, during administration of ACE inhibitors the sensitivity of arterial baroreceptor control of circulation is unaltered or even enhanced. These observations emphasise the potential importance of long-acting ACE inhibitors in the control of arterial hypertension.

24-h ambulatory non-invasive blood pressure monitoring in the assessment of the antihypertensive action of celiprolol.

The well-known limitations of traditional sphygmomanometer blood pressure measurements have led to the development of a number of invasive and non-invasive 24-h blood pressure monitoring techniques which provide information on blood pressure in daily life. A non-invasive portable blood pressure monitor (IRC Spacelab S5300 monitor) was used to assess the antihypertensive action of celiprolol, 400 mg once daily, in a randomized, double-blind, crossover, placebo-controlled study. After a washout period of 7 days, 15 patients with mild or moderate essential hypertension were subjected to three 24-h blood pressure recordings: at the end of washout, and after 1 month of placebo and celiprolol treatment. In the 10 responsive patients, celiprolol reduced 24-h systolic blood pressure, diastolic blood pressure and heart rate by 6.8%, 8.1% and 2.7%, respectively, when compared with placebo. The reduction in blood pressure was also evident during the night and the antihypertensive action of celiprolol was maintained 24-h after administration. Celiprolol had no effect on 24-h blood pressure or heart rate variability and, therefore, did not produce any alteration in cardiovascular homeostasis. These results demonstrate that celiprolol is an effective once daily treatment for hypertension.

Prognostic value of ambulatory blood pressure monitoring.

Ambulatory blood pressure monitoring has both advantages and disadvantages in clinical practice. The structural and functional organ abnormalities associated with hypertension are more closely correlated to 24-h blood pressure mean values than to clinic or other conventional sphygmomanometric blood pressures. Furthermore, an additional relationship can be seen between the incidence and severity of these abnormalities and the magnitude of day and night blood pressure changes or 24-h blood pressure variability. However, controlled prospective studies are still required to demonstrate that ambulatory blood pressure data are superior or add to the prognostic value of clinic blood pressure. Moreover, ambulatory blood pressure normalcy has not yet been properly defined. This suggests caution in the practical use of this technique, which should be limited to special groups of subjects (those with a possible alerting reaction to conventional blood pressure assessments, in whom home blood pressure measurements are unreliable) and should only be used by clinicians with expertise in the field.

Advantages and disadvantages of non-invasive ambulatory blood pressure monitoring.

Our studies have shown that (1) automatic blood pressure readings obtained from portable monitors do not induce any alerting reaction or pressor response in the patient; (2) although the measurements are intermittent, non-invasive ambulatory blood pressure monitoring is able to provide a true estimate of 24-h blood pressure and heart rate mean values (the assessment of 24-h blood pressure and heart rate variabilities is less accurate); (3) the nocturnal fall in blood pressure is not altered by the possible disturbance to the patient's sleep induced by repeated cuff inflations; and (4) even when the automatic blood pressure readings obtained are similar to simultaneous readings obtained by a sphygmomanometer, the accuracy of the values provided by portable monitors used in truly ambulatory conditions cannot be taken for granted. These findings have particular implications for the cost: benefit ratio if ambulatory blood pressure monitoring is to be used in the routine evaluation of hypertensive patients.

Early twenty-four-hour blood pressure elevation in subjects with parental hypertension.

We studied 15 normotensive offspring of hypertensive parents, comparing them with 15 normotensive controls matched for sex, body mass index and age. In the offspring, both parents were hypertensive, while in the controls, neither parent was hypertensive. Blood pressure was measured at rest, during a variety of laboratory stressors (mental arithmetic, mirror drawing test, hand grip and cold pressor test), and was also monitored for 24 h in ambulatory conditions (Spacelabs 5300 M, Richmond, Washington, USA). Resting mean and diastolic blood pressures were higher (P less than 0.05) in the subjects with parental hypertension than in those without. The mean blood pressure rise induced by the laboratory stressors was not significantly greater at any time in the subjects with hypertensive parents compared with controls. Twenty-four-hour systolic and mean blood pressures, however, were significantly higher (P less than 0.05) in the subjects with hypertensive parents than in the controls. Thus the higher office blood pressure shown in the prehypertensive stage by subjects with parental hypertension is not due to hypersensitivity to stress, but represents an early and permanent blood pressure elevation.

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.

Ambulatory blood pressure monitoring in the evaluation of antihypertensive drugs.

CLINIC VERSUS AMBULATORY BLOOD PRESSURE MEASUREMENT: Clinic blood pressure measurements do not give the best estimate of the efficacy of antihypertensive drugs because (1) they provide readings for one time-point only, (2) they are subject to a 'white-coat' effect and also show a significant placebo effect and (3) they are poorly reproducible. Ambulatory blood pressure monitoring overcomes these problems and offers the possibility of obtaining reliable, reproducible and detailed information on the time-course and magnitude of the effect of antihypertensive treatment on blood pressure over 24 h. MEAN 24-H VERSUS MEAN HOURLY AMBULATORY BLOOD PRESSURE VALUES: Compared with mean 24-h values, reproducibility is poorer for mean hourly ambulatory values, which show greater variability when tested under different conditions. Thus, caution must be exercised when the effects of antihypertensive drugs on hourly blood pressure profiles are analysed and the trough:peak ratio is calculated. FURTHER PROBLEMS WITH AMBULATORY MONITORING: There are further reasons for caution: (1) ambulatory blood pressure readings can be inaccurate, (2) there is only preliminary information on normal reference values and (3) there have been no longitudinal studies demonstrating the prognostic value of ambulatory blood pressure monitoring, which introduces uncertainty into attempts to evaluate the optimal effect of antihypertensive treatment by this method. CONCLUSIONS: These limitations do not detract from the use of ambulatory blood pressure monitoring in drug studies, but they do suggest that this measurement technique should not be used routinely for assessing antihypertensive treatment in clinical practice.

Ambulatory blood pressure monitoring does not interfere with the haemodynamic effects of sleep.

Automatic or semi-automatic blood pressure (BP) monitoring is a widely used method for assessing 24-h BP profile. However, the ability to achieve this goal depends on several factors that have not yet been controlled. The present study examined the possibility that cuff inflations disturb the sleep of patients and prevent the nocturnal fall in BP. This issue was investigated in 10 hospitalized subjects in whom BP was recorded intra-arterially for 48 h using the Oxford method. During the first or the second 24 h BP was also monitored non-invasively (Squibb ICR portable device), the cuff inflations being performed at 15 min intervals during the day and at 30 min intervals during the night. The computer analysis of the two different 24-h intra-arterial tracings showed that the addition of automatic BP monitoring had not caused any alteration in the day and night intra-arterial BP and heart rate profiles. Thus, disturbances of the haemodynamic effects of sleep do not characterize 24-h automatic BP recording, at least when made with the device employed in the present study. This removes an important objection against the ability of this approach to evaluate the patients' BP profiles properly.