1 Introduction

Traditionally, management of hypertension has been guided by office blood pressure (BP) measurement, usually taken in the clinic or in the physician’s office [1]. On the other hand, self BP measurements and 24-h ambulatory BP monitoring (ABPM) are widely used for research and clinical purposes. Self-measured BP and ambulatory BP are intuitively superior to clinic BP to reflect the true pattern of BP changes during usual daily life; and longitudinal studies supply important data supporting the use of self BP measurements and ABPM, showing the superiority of both these techniques over clinic BP in the cardiovascular risk stratification [1–5].

If we plot office BP over the average daytime ambulatory BP, it is apparent that for any given value of office BP, the observed ambulatory BP may vary considerably [2, 6]. Therefore, the combined use of clinic BP with one of the available “out of office BP” (home or ambulatory BP) may help us in identifying at least four different clinical categories of subjects [1–6]:

  1. 1.

    Subjects normotensive by both methods (true normotension);

  2. 2.

    Subjects hypertensive by both methods (true hypertension);

  3. 3.

    Subjects who are hypertensive based on office BP and normotensive by ambulatory BP or self-measured BP (white-coat hypertension);

  4. 4.

    Subjects who are normotensive by clinic BP and hypertensive by ambulatory BP or self-measured BP (masked hypertension, initially defined “reverse white coat hypertension).

This brief review will focus on this last group of subjects/patients.

2 Definition and Clinical Characteristics of Masked Hypertension

2.1 Definition

As mentioned, BP may be normal in the office and abnormally high out of the medical environment, and this clinical condition is termed ‘masked hypertension’ or ‘isolated ambulatory hypertension’ [1]. However, whereas the cut-off value for office BP is the conventional 140/90 mmHg, most studies in white-coat or masked hypertension have used a cut-off value of 135/85 mmHg for out-of-office daytime or home BP and 130/80 mmHg for 24-h BP [1]; in some studies also others cut-points values for “out of office” BP were used [6–9]; this variability might partly explain the different data about prevalence of masked hypertension in different studies.

Notably, there is only moderate agreement between the definition of white-coat or masked hypertension diagnosed by ABPM or home BP monitoring [8, 10]. According to European Society of Hypertension—European Society of Cardiology Guidelines for the management of arterial hypertension [1] hypertension [1] the terms ‘white-coat hypertension’ and ‘masked hypertension’ should be reserved to define untreated individuals.

2.2 Prevalence

Cross-sectional studies showed marked differences in the prevalence of masked hypertension, which ranged between 8 and 49 % [1, 2, 7, 11]. Such variability has been attributed to different patient characteristics, populations studied, and, as mentioned, to different definitions of masked hypertension [2]. Indeed, some studies were conducted in the general population, other in referred subjects with normotension, other in treated hypertensive patients, and other in elderly people or specifically in men [2].

Another confounding factor is the device used for measurement of BP: although office BP was measured with a mercury sphygmomanometer in the majority of studies, some studies used automatic oscillometric devices [2]. Finally, a source of variability in the prevalence of masked hypertension was the personnel involved in the assessment of office BP (doctor, nurse or technician) and the position used to perform the BP measurements (supine or sitting position) [2].

Although, as mentioned, there is some discrepancy between the definition of white-coat or masked hypertension diagnosed by ABPM or home BP monitoring [8, 10], the prevalence of masked hypertension does not seem to change significantly when diagnosis was based on self-measured BP or ABPM [2]. According to European Society of Hypertension—European Society of Cardiology Guidelines for the management of arterial hypertension the prevalence of masked hypertension averages about 13 % in population-based studies [1].

2.3 Clinical relevance

Recent evidence demonstrates that masked hypertension is a significant predictor of cardiovascular disease, and is associated with more extensive target organ damage, including left ventricular hypertrophy [1, 6, 7] however, the problem for clinical practice is how to identify these patients since their hallmark is to have normal blood pressure in the physician’s office [7]. Several factors can selectively raise ambulatory blood pressure including age, sex, smoking, alcohol use, contraceptive use in women, and sedentary habits (Table 1) [7]. Reactivity to daily life stressors and behavioral factors are other important determinants of ambulatory blood pressure [7]. On the basis of the available evidence, masked hypertension should be searched for in individuals who are more likely to have this condition or are at increased risk of cardiovascular complications including diabetic individuals and subjects with kidney disease or signs of target organ damage (increased left ventricular mass or carotid artery intima media thickness, increased pulse wave velocity, etc.) or have clinic blood pressure values in the high-normal range [7]. Job stress, or, on the contrary (especially in young subjects), tendency to deeply relax in the physician’s office should be considered. If treated subjects are considered, another possibility is related to a non-homogeneous control of blood pressure throughout the 24-h, due to a non-persistent effect of drug treatment in the afternoon-evening, when drugs are taken in the morning, when the physician’s visit is usually scheduled. In some patients, BP is persistently elevated only or mainly during the night (diabetic patients with autonomic dysfunction, patients with obstructive sleep apnea or with renal disease). In fact, both in diabetic and in non-diabetic patients, the prevalence of masked hypertension is significantly higher in treated than in untreated population [12, 13]. In this case only ABPM is able to properly detect the condition of masked hypertension, although some recent model of device for home blood pressure monitoring may give some information also about nighttime BP. If two different session of ABPM are performed, the reproducibility of the definition of masked hypertension in treated patients is rather good [13].

Table 1 Factors often present in subjects with masked hypertension
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Subjects with a high normal office but a raised out-of-office BP (masked hypertension) have a cardiovascular risk in the hypertension range [1, 2]. This was confirmed in an overview of longitudinal studies that addressed the prognostic impact of masked hypertension diagnosed by ambulatory blood pressure and self-measured blood pressure. Masked hypertension compared with normotension in this meta-analysis is associated with an adjusted hazard ratio of cardiovascular events of 2.03 (1.62–2.55, p < 0.001) [2]. The results also suggest that the prognostic impact of masked hypertension is not affected by the different “out of office” BP measurements used to detect it [2]. So, the incidence of cardiovascular events in masked hypertension is at least two times higher than in true normotension and is similar to [1], or even greater than [2] the incidence in sustained hypertension. The fact that masked hypertension is largely undetected and untreated may have contributed to this finding. In diabetic patients masked hypertension is associated with an increased risk of nephropathy, especially when the BP elevation occurs mainly during the night [1].

The incidence of cardiovascular events and stroke are similar in normotensive patients with masked hypertension and in pre-hypertensive patients with masked hypertension. Hazard ratios observed are approximately two versus respective controls (normotension, pre-hypertension) [12]. Thus, masked hypertension should be never regarded as an innocent condition.

3 Treatment Strategies in Masked Hypertension

An open question is whether the definition of masked hypertension should be reserved to naïve patients; the European Society of Hypertension—European Society of Cardiology guidelines for the management of arterial hypertension are in favor of this approach [1]. However, the increase in the incidence of cardiovascular events between “normotensive controls” and masked hypertension is similar in treated or untreated patients [12]; therefore the increase in cardiovascular risk associated to masked hypertension is present regardless of the treatment status [12], suggesting that there are some similarities in treated and untreated masked hypertensives, although it is also possible that “masked uncontrolled” hypertensives may have different clinical characteristics compared with truly masked (untreated) hypertensives.

According to the European Guidelines [1], drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension) (Fig. 1) (Class IIa, level C recommendation). Isolated ambulatory or masked hypertension is infrequently diagnosed because finding a normal clinic BP only exceptionally leads to home or ambulatory BP measurements [1]. When this condition is identified, however, both lifestyle measures and antihypertensive drug treatment should be considered because, as mentioned, masked hypertension has consistently been found to have a cardiovascular risk very close to that of in-office and out-of-office hypertension [1]. Both at the time of treatment decision and during follow-up, attention to dysmetabolic risk factors and organ damage is mandatory, since these conditions are much more common in masked hypertension than in normotensive individuals [1]. Efficacy of antihypertensive treatment should be assessed by ambulatory and/or home BP measurements [1]. An algorithm for the identification and management of subjects with masked hypertension was suggested by Angeli et al. [2] (Fig. 2).

Fig. 1
figure 1

Treatment strategies in white-coat and masked hypertension according to European Society of Hypertension––European Society of Cardiology Guidelines for the management of arterial hypertension [1] (Ref. [1])

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Fig. 2
figure 2

Suggested algorithm for the identification and management of subjects with masked hypertension. ABP ambulatory blood pressure, BP blood pressure, MH masked hypertension. From Ref. [2]

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It is generally accepted that there are three major reasons to treat hypertension: to reduce target organ damage, to reduce cardiovascular risk, and to prevent complications [14]: all three conditions are satisfied by data indicating that patients with masked hypertension have higher target organ damage than normotensives and a cardiovascular risk profile similar to the profile of patients with sustained hypertension [1, 14]. The pitfalls lie largely in the need to identify patients who are at high risk for masked hypertension and that relative few data are available on the reliability and reproducibility of the diagnosis of masked hypertension [14]. However, the key question is the following [14]: will the benefit of active drug treatment in reducing hypertensive target organ damage and cardiovascular events be similar in patients with masked hypertension as in those with sustained hypertension?

To answer this question, at least a couple of major intervention studies have been planned.

The first one is the MASTER study. MASTER is the acronym for “MASked and masked-unconTrolled hypERtension managed based on office BP or out-of-office BP measurements”.

This is the first longitudinal, 4-years, prospective, randomized, open-label, blinded-endpoint (PROBE) intervention study, branching out of the ARTEMIS network, aimed at determining whether a hypertension management based on office, office and home BP monitoring or office and ambulatory BP monitoring in patients with masked or masked uncontrolled hypertension might lead to a difference in outcome (intermediate and hard endpoints). The study includes two treatment arms: office BP as a guide to treatment, or 24-h BP as a guide to treatment. Final aim of this study is to provide the necessary evidence for the recommendation to use out-of-office BP in daily practice to guide treatment decisions and to stratify cardiovascular risk. The study will be coordinated by Gianfranco Parati (University of Milan–Bicocca, Italy).

A second study with a similar aim was proposed by the Clinical and Translational Science Institute of the University of Minnesota [15]. “Treatment of masked hypertension” is a randomized, controlled trial to evaluate whether antihypertensive treatment can modify BP patterns in patients with masked hypertension, that is, convert them to controlled clinic and ambulatory BP. The study will also evaluate the effect antihypertensive treatment on target organ damage in patients with masked hypertension. It is a pilot randomized controlled trial to evaluate the feasibility of the planned trial and the effect of antihypertensive therapy on clinic and ambulatory BP, proteinuria, and target organ damage in patients with masked hypertension [15].

4 Conclusions

Approximately one out of 7–8 individuals with normal BP in the clinic or doctor’s office and one third of patients with chronic kidney disease with normal clinic BP have elevated ambulatory BP (masked hypertension) [2]. Patients with masked hypertension have an increased risk for target organ damage and a twofold increased risk for cardiovascular events compared to patients with normal clinic and ambulatory BP [1, 2]. Despite this elevated risk for adverse outcomes, patients with masked hypertension have been excluded from hypertension trials because of their normal clinic BP. Therefore, it is still unknown whether the reduction in target organ damage and adverse cardiovascular outcomes associated with treatment of hypertension extends to patients with masked hypertension. Ongoing and planned interventional studies will provide an answer to this crucial question in a few years. At present, it seems reasonable to follow the suggestion of current European guidelines, that lifestyle measures and drug treatment should be considered in the presence of masked hypertension [1] (Fig. 1).