The gradual acceptance of ambulatory blood pressure monitoring (ABPM) as an improved method for classifying the blood pressure status of patients with suspected hypertension has been driven by the publication of a series of studies that have shown that ABPM gives a better prediction of risk than conventional clinic measurements. The official recognition by the Centers for Medicare and Medicaid Services (CMS), the federal body that approves new technologies, that ABPM is clinically useful and reimbursable for the diagnosis of white coat hypertension means that we now have two independent techniques for measuring blood pressure in clinical practice—conventional clinic measurement and ABPM (home monitoring is not yet officially approved for any reimbursement, although its use has been endorsed by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC VI] and other august bodies). This means that we can define hypertension independently by each of the two methods. We thus have four potential groups of patients who are: 1) normotensive by both methods (true normotensives); 2) hypertensive by both (true, or sustained hypertensives); 3) hypertensive by clinic measurement and normotensive by ambulatory measurement (white coat hypertensives); and 4) normotensive by clinic measurement and hypertensive by ambulatory measurement (Figure). From a clinical point of view, the first two groups are easy to deal with, since both methods give the same classification. Of more interest are the groups where there is disagreement. The third group, usually referred to as white coat hypertensives, or less frequently as isolated office hypertensives, has been extensively studied, and is generally accepted as being at relatively low risk of cardiovascular morbidity,1 a view which is consistent with the concept that ambulatory pressure gives a better prediction of risk than clinic pressure. However, it must be admitted that not everyone shares the view that white coat hypertension is benign, particularly because there are studies that have shown that it may be associated with some degree of target organ damage. This issue will be dealt with in a subsequent report of this series.
Up to now, little attention has been given to the fourth group, who have been given the awkward titles of “reverse white coat hypertension” or “white coat normotension.” If it were true that the ambulatory pressure gives the better classification of risk, it would imply that these people should be regarded as being genuinely hypertensive, as argued below. We have recently proposed2 that the phenomenon should be called “masked hypertension,” on the grounds that the hypertension is not detected by the routine methods. But what evidence is there that this group deserves recognition as a discrete entity, as opposed to being made up of people who happened to have an unusually high ambulatory pressure or a low clinic pressure on that particular occasion? There are potentially several questions that could be asked to decide this issue.
First, the phenomenon of masked hypertension would be more credible if it could be shown that it is reproducible on repeat testing. So far as we are aware, this issue has not been examined.
Second, patients with masked hypertension should show more extensive target organ damage than true normotensives. Here we are on surer ground. The first study to look at this issue was our publication of 1999,3 in which we showed that the masked hypertensive group had left ventricular mass and carotid atherosclerosis that were greater than the true normotensives, and that were similar to the true hypertensives. The left ventricular mass index was 73 g/m2 in the true normotensives, 86 g/m2 in the masked hypertensives, and 90 g/m2 in the true hypertensives. Carotid plaque was present in 15% of true normotensives, and in 28% of both the masked and true hypertensives. More recently, an analysis of the Pressione Arteriose Monitorate E Loro Associazioni (PAMELA) data,4 a population study of 3200 Italians, classified the subjects in the four groups that we have described above. Individuals with treated hypertension were excluded from this analysis; 67% were true normotensives, 12% true hypertensives, 12% white coat hypertensives, and 9% masked hypertensives. The average clinic pressure in the masked hypertensives was 129/84 mm Hg which, while still within the normal range, was higher than the true normotensives (112/77 mm Hg). The clinic pressure of the true hypertensives was 159/98 mm Hg. The left ventricular mass index was higher in the masked hypertensives (91 g/m2) than in the true normotensives (79 g/m2), and similar to the true hypertensives (94 g/m2).
Third, masked hypertensives should be at increased risk of cardiovascular morbidity. This remains to be determined, although at the last International Society of Hypertension meeting in 2002 there were two abstracts that reported an adverse prognosis in masked hypertension.5,6
In treated hypertensives it has also been observed that patients whose ambulatory pressure is high in relationship to their clinic pressure are more likely to have increased left ventricular mass than those whose ambulatory pressure is the same or lower than the clinic pressure.7,8 These findings are consistent with the view that when there is a discrepancy between clinic and ambulatory pressure, it is the latter that is most closely related to target organ damage. A similar finding was reported in the Second Australian National Blood Pressure Study,9 which recruited patients over the age of 65 who had a clinic pressure of 160/90 mm Hg or higher. A subset of 713 of them underwent ABPM before starting treatment, and in 21% of these there was a reverse white coat effect (daytime pressure higher than the clinic pressure). Two characteristics of these patients were that they were more likely to be men and smokers.
There is also support for the concept from home blood pressure data. One of the first publications was by Shahab et al.,10 in 1993, who measured home and clinic blood pressure in a group of healthy young subjects. About 10% of these were classified as “Hypertensive at Home,” with normal clinic pressures and raised home pressures. This group was overweight, had high insulin levels, and low high-density lipoprotein cholesterol, suggesting that they might be at high risk. Knowing of my interest in the subject, Dr. Stevo Julius, one of the authors, sent me a reprint of the paper, which was published in the Croatian Medical Journal.10 On the reprint he wrote “One of the earliest reports of ‘reverse’ white coat. Not knowing what to do with the data I sent it to a far away journal.” Dr. Julius is originally from Yugoslavia. A French study called SHEAF (Self-Measurement of Blood Pressure at Home in the Elderly, Assessment and Follow-Up)11 has recruited 5211 patients over the age of 60 who were either hypertensive in the clinic or taking antihypertensive medications. About 10% of these were found to have higher pressures at home than in the clinic, and they appeared to be a relatively high-risk group: they tended to be older, were more likely to be male, have diabetes, and a history of stroke or coronary heart disease than patients whose home and clinic pressures were similar.
What factors might lead to masked hypertension? In principle, there are two groups of factors, which are not mutually exclusive. First, the clinic pressure could be relatively low in relation to the ambulatory pressure, or second, there could be factors that selectively raise the ambulatory pressure.
With regard to the first possibility, it is generally true that the daytime ambulatory pressure is higher than the clinic pressure in truly normotensive subjects, but in hypertensives the clinic pressure tends to be higher.12 One reason for this may be that hypertension is almost invariably initially diagnosed on the basis of an elevated clinic pressure, so that any individual who happens to show an exaggerated white coat effect will tend to be screened out and labeled as being hypertensive. Many factors could selectively elevate the ambulatory pressure. Thus, we showed many years ago that smokers tend to have high daytime ambulatory pressures (when they are likely to be smoking) in comparison with their clinic pressures (when they are not likely to be smoking).13 In our study3 we found a nonsignificant tendency for masked hypertensives to be smokers (23% vs. 16%) or former smokers (43% vs. 29%) rather than the true normotensives. The Australian study9 described above also found smoking to predict masked hypertension.
Second, subjects who are more physically active during the day tend to have higher daytime pressures. An important issue arising from these considerations is whether the nighttime pressure is also raised. In general, hypertensive patients show a sustained elevation of blood pressure throughout the 24 hours, without much change in the diurnal rhythm of blood pressure. We also found that the elevation of blood pressure in the masked hypertensives compared with the true normotensives was 13/3 mm Hg for the clinic pressure (however, the average clinic pressure in the masked hypertensives was still well within the normal range—122/80 mm Hg), 17/10 mm Hg for the work pressure, 18/9 mm Hg for the home pressure, and 11/7 mm Hg for the sleep pressure. Thus the elevation of blood pressure appears to be more marked during the day than at night.
Experimental evidence that supports the concept that the blood pressure does not have to be raised throughout the day and night to have adverse effects comes from a series of animal experiments performed by Julius et al.,14 who induced a transient neurogenic hypertension in dogs by thigh compression applied for 6 hours a day over a period of 9 weeks. This raised the blood pressure for as long as it was applied, but after several months there was no increase in the resting blood pressure. However, there was an increase of left ventricular mass.
In a study of 319 clinically normotensive volunteers, all of whom had five clinic measurements and 12-hour daytime ABPM, Selenta et al.15 found that 23% had masked hypertension, defined as a daytime blood pressure above 135/85 mm Hg. Subjects with masked hypertension tended to be male, past smokers, older, and had consumed more alcohol. The issue of masked hypertension was also discussed in another of our previous papers,16 where we referred to it as occult workplace hypertension. We found that 36/467 men in the Cornell Worksite study had masked hypertension, defined as a daytime ambulatory diastolic pressure >85 mm Hg, and a clinic pressure <85 mm Hg, but the prevalence was no higher in the men exposed to job strain than in those with less stressful jobs. This may be because in other analyses we have found that job strain has a sustained effect on blood pressure throughout the 24 hours, so that it would be expected to affect the clinic pressure as well as the ambulatory pressure.
Several population studies have compared clinic and ambulatory blood pressures.17–21 Some have shown daytime pressures to be a little higher than clinic pressures, while others have found the reverse.20 One important finding from an Italian population study has been that the ambulatory pressure shows much less increase with age than the clinic pressure.19 In a Danish study20 86% of men aged 42 years had daytime pressures higher than the clinic pressure, whereas this was true of only 51% at the age of 72. Hence, the white coat effect (the difference between the clinic and ambulatory pressure) is more marked in older people, and since masked hypertension is equivalent to a negative white coat effect, it is reasonable to suppose that masked hypertension would be less prevalent with increasing age.
An important issue is the prevalence of masked hypertension. While there are no definitive data, the available information is disturbing. Two population-based studies4,22 have described it. The first was the Ohasama study,22 conducted in a small Japanese town, which reported that 10.2% of subjects with normal screening blood pressures had ambulatory pressures that were in the “borderline hypertensive” range, and another 3.2% in the definitely hypertensive range. The second was the PAMELA study4 quoted above, which found it in 9% of subjects; Selenta et al.15 found it in 23% of their “normal” volunteers. However, it could be argued that the PAMELA study used a lower upper limit of normal for the 24 hour pressure (125/79 mm Hg) than most other studies, and that if a higher level had been used the number of masked hypertensives would be smaller. But even if the prevalence was only 5%, this number applies to the whole population, not just the population of hypertensives, so in the case of the United States this might amount to 10 million people.
It seems clear that masked hypertension should be taken seriously, and is a phenomenon worthy of further investigation. If it is accepted that ambulatory blood pressure gives a better prognosis than clinic blood pressure, and that the correlation between the two is only moderate, it is logical to propose that there will be a significant number of people who are truly hypertensive, but in whom the diagnosis is missed by clinic measurement. But how frequently this phenomenon occurs, and how such individuals should be identified, remains a mystery. Clearly, we cannot argue for screening of the general population, but there are many patients who are referred for suspected hypertension who turn out to have normal clinic pressures on repeat testing. Perhaps some of them would benefit from ambulatory monitoring to rule out masked hypertension.
The main reason why masked hypertension has not attracted more attention may be that hypertension is almost invariably diagnosed on the basis of clinic pressures, at least for the initial screening. Some years ago we observed23 that in normotensive individuals the clinic pressure was not generally higher than the ambulatory pressure, whereas in hypertensives the clinic pressure was typically higher, even during the hours of work. We suggested that the reason for this might be that hypertension is diagnosed on the basis of a high clinic pressure, so any individual who has a tendency for the clinic setting to cause a rise of pressure will be selected out and labeled as being hypertensive. Since most ABPM studies (including our own) have been done in populations who have been screened first by clinic pressures, patients with masked hypertension should be relatively few.
The implications of this are worth considering. First, it would significantly change the number of people in the United States who have “hypertension.” On the basis of clinic pressures, the official estimate from surveys such as the National Health and Nutrition Examination Survey is that there are about 40 million hypertensive people.24 If we accept that white coat hypertension is present in 15% of these, we would reduce the number at risk by 6 million, leaving 34 million who are hypertensive by both clinic and ambulatory criteria. But if we also include the masked hypertensives, who as we saw above may comprise as many as 5% of the total population, we would need to add 5% of 200 million, which is another 10 million people. Thus the total population with ambulatory hypertension would increase to 44 million. Viewed another way, the current clinic-based definition of hypertension correctly identifies 34 million people who are truly hypertensive, but fails to identify another 16 million, either because of false positives (6 million white coat hypertensives) or false negatives (10 million masked hypertensives). Thus for every two people it classifies properly, there is another one person who it misclassifies—not a very good record for a diagnostic test.
What are the practical implications of masked hypertension? It would clearly be inappropriate to say that everyone should be screened with ambulatory monitoring. Before we translate these considerations into clinical practice we need more prospective data to show that masked hypertension does indeed increase cardiovascular risk. Ideally, we should also like to know if treating such patients lowers their risk. We also need better means of identifying such individuals, such as the role of home monitoring. It may be that masked hypertension is a precursor of sustained hypertension. We see many patients who have a history of occasional high blood pressure readings, who are normotensive when we check them in our office. One practical point is that we should continue following such people rather than dismissing them, and encourage out-of-office monitoring of blood pressure. This would apply particularly to smokers.