After HABB was identified almost 40 years ago, it has been the subject of a large number of studies but also of different points of view on its clinical importance.
For several years, the prevailing opinion has been that, compared with normotension, HABB does not carry an increased risk of cardiovascular outcomes and that its identification therefore does not require any additional diagnostic or treatment measures.
However, over the past 2 decades, this position has been weakened by research findings, which almost invariably demonstrated that it is associated with an unfavorable metabolic risk factor profile, more frequent asymptomatic organ damage, and increased risk of progression to high-risk conditions and morbid and fatal cardiovascular events.
This has led to the conclusion that HABB is not clinically innocent.
The reference studies in this article show a less favorable prognosis than normotension. Although the PAMELA (Pressioni Arteriose Monitorate e Loro Associazioni) cross-sectional and prospective study, carried out in the Italian population, is considerably smaller than the one based on the pooling of data from different cohorts, it is the most considered for its design (and awarded by his excellence) and the measured variables, which allowed several important aspects of the HABB to be adequately addressed.
1. First, office, outpatient, and home BP values were obtained for each subject within a restricted time, and all measurements were standardized with precision and high quality. The number of elevated ambulatory BP measurements was uniform in all individuals during the day and night.
2. Second, the upper normal limit of 24-hour BP was lower (125/79 mmHg) than that used by other studies (130/80 mmHg or that of the first investigations, with even higher values. These stricter thresholds for normal out-of-office BP reduced the possibility of including truly hypertensive individuals in the HABB group, thus ensuring highly specific identification of HABB.
3. Third, data collection was done considering whether each individual had undergone an evaluation of metabolic and echocardiographic risk factors.
4. Fourth, unlike other studies, data collected initially were collected again 10 years later, and lethal events were recorded during long-term follow-up. Originally limited to untreated subjects, the definition of HABB has recently been expanded to incorporate patients on antihypertensive medication, i.e., those with controlled out-of-office BP.
| Prevalence of white coat hypertension |
HABB is a common condition. The PAMELA study found that individuals with elevated office BP and normal out-of-office BP represented almost 15% of the general population and 30% to 40% of hypertensive patients, with no significant difference when diagnosis was based on elevation of office BP versus normal 24-hour BP.
This scenario is basically that reported in subjects not treated for hypertension following recent guidelines, which also emphasize that the increase in systolic BP with age is more pronounced in office BP than in out-of-office BP, and HABB is more common in the older fraction of the population, where it may account for up to ≥50% of hypertensive patients.
The high prevalence of HABB highlights the importance of research aimed at clarifying its pathophysiological aspects, clinical implications and therapeutic needs for cardiovascular prevention.
> Dysmetabolic risk factors
Although reported in previous research, the most complete description of the HABB metabolic profile in individuals is provided by the PAMELA study.
Compared with the normotensive group, subjects with HABB (office systolic BP ≥140 mmHg or, diastolic BP 90 mmHg, with 24-h BP <125/79 mmHg or home BP <132/82 mmHg) showed lower blood glucose levels. , serum cholesterol and triglycerides lower than those exhibited by subjects with sustained hypertension (elevated office and out-of-office BP) but higher than those in normotensive subjects, that is, with office and out-of-office BP normal.
This was also the case for the prevalence of conditions such as increased body mass index, impaired fasting glucose, type 2 diabetes, metabolic syndrome and hypercholesterolemia, while high-density lipoprotein (HDL) cholesterol serum levels showed progressively lower levels from subjects with normotension to individuals with HABB and sustained hypertension.
The data from the PAMELA study also showed a significant progressive increase in serum uric acid levels , from normotension to HABB and sustained hypertension, reinforcing the conclusion that in HABB, the levels of glucose, lipids and other associated metabolic variables cardiovascular risk are somewhat distant from those observed in individuals with a normal BP pattern, both in the office and outside the office.
| Subclinical organ damage |
There has been repeated evidence that subclinical or asymptomatic alterations in organ structure and function are less common in normotension than in HABB, although they remain less common in HABB than in sustained hypertension. This is supported by the evidence collected in the PAMELA study that the prevalence of left ventricular hypertrophy was minimal in normotension (4.2%), intermediate in HABB (20.4%), and maximum in sustained hypertension (32, 3%).
Compared with normotension, HABB has also been shown to be more frequently associated with left ventricular diastolic dysfunction, left atrial enlargement, carotid intima-media thickening and plaques, proteinuria, and silent cerebral infarction, indicating that the increase in organ damage related to HABB is not limited to the heart, but also affects other organs.
This reflects an adverse effect of HABB on organ integrity during the earlier life of affected individuals. It also anticipates an adverse influence on the risk of experiencing future cardiovascular events, because subclinical organ damage has been closely associated with an increased risk of overt cardiovascular outcomes, an overall risk markedly elevated above the level calculated by classical factor-based methods. of risk, without including measures of silent organic damage.
| Progression to high cardiovascular risk conditions |
A unique advantage of the PAMELA study is that the subjects who participated in the initial survey were seen again about 10 years later, allowing the same variables to be collected also after a long time interval.
After 10 years, compared with the initially normotensive group, HABB subjects exhibited a higher incidence of new-onset sustained hypertension, that is, an elevation above normal, also of out-of-office BP.
Likewise, they exhibited a higher incidence of altered fasting glycemia, overt diabetes, and (in subjects with an initially normal left ventricular mass index), echocardiographic left ventricular hypertrophy.
For all of these new conditions, the adjusted risk associated with HABB was significantly higher than in normotension, in some cases similar to that exhibited by sustained hypertension.
Therefore, HABB is associated with greater progression to a variety of high cardiovascular risk conditions, making the increased risk last longer than that corresponding to aging alone.
It is of additional interest that, during the 10 years between the first and second survey, 24-hour pulse pressure increased more markedly in subjects with HABB than in normotensive individuals (9.4 ± 15.8 mmHg vs. 5.9 ± 13.2 mmHg).
Because increased pulse pressure reflects a reduction in arterial compliance, it is thought that over time, subjects with HABB may exhibit greater increases in large artery stiffness than subjects with normal BP in office, and out-of-office BP values.
| Cardiovascular results |
In contrast to previous negative reports, studies and meta-analyses on the relationship between HABB, morbid or fatal cardiovascular events, and all-cause mortality published in the last 15 years have almost invariably shown that, mimicking the results obtained In studies of organ damage, untreated HABB is associated with an incidence and risk of outcomes that is less than the risk associated with sustained hypertension but greater than that shown by normotensive subjects. This has also been the case when the risk was adjusted for sex and age.
Adjustment for age was due to the higher prevalence of HABB in the elderly population. This was also the case when the risk of cardiovascular and all-cause mortality in the PAMELA study was quantified over a follow-up of about 16 years, and the data were further adjusted for other potentially contributing cardiovascular variables, including antihypertensive treatments.
This conclusion is in line with that of a recent meta-analysis on the risk calculated with full adjustments (fully adjusted), of a large number of untreated subjects, with a follow-up of many years after the diagnosis of HABB.
For example, in a meta-analysis by Huang et al. In >5,0000 untreated subjects, HABB was found to be associated with a 38% and 20% higher risk of cardiovascular events and total mortality, respectively, than in subjects with normotension, after adjustment for demographic and clinical variables.
It is important to mention that quantifying the risk of HABB through adjustments that extend beyond age and sex and neutralizing the role of dysmetabolic and other alterations associated with this condition, is a somewhat controversial procedure due to its interference with the prognostic significance of HAABB as a multifactorial clinical entity.
In other words, expanded adjustment, although justified when the purpose is to attempt to determine the role of BP values in HABB, in terms of the overall cardiovascular risk of this condition leads to an amputation of the other adverse phenotypic features of HABB. and, therefore, to an underestimation of its prognostic importance as a clinical entity.
In clinical practice, this is the first important information that has been provided to clinicians responsible for deciding the frequency of follow-up for these patients, over time, and whether intensive treatment of risk factors is necessary, i.e. , decisions that depend on a correct estimate of the total cardiovascular risk.
| Cardiovascular outcomes, in-office and out-of-office blood pressure |
As mentioned, full adjustment for demographic data and clinical variables is useful, because the persistence of increased risk of cardiovascular outcomes and mortality implies that in HABB, the increase in morbid and fatal events is also, coincidentally, dependent on the pattern. of PA of the HABB.
In this context, several evidences support the participation of PAs outside the office. Although normal by definition, ambulatory BP and home BP are higher in HABB than in normotensive controls.
In the PAMELA study, the difference in systolic BP between the HABB and normotensive groups was 7.1 mmHg (119.4 vs. 112.3 mmHg) for the 24-h BP values and 16.7 mmHg (127.2 vs. 110.5 mmHg) for home BP values; the differences in diastolic BP were 4.5 and 9.4 mmHg. Important differences were also found in a large meta-analysis of available data.
This is clinically significant because several studies have found that home nocturnal BP or 24-hour BP were associated with increased cardiovascular mortality, not only when a history of out-of-office BP was extensive, but also when BP was high. of the office was within the normal range, as occurs in HABB.
In the PAMELA population, for example, a 10 mmHg increase in home systolic BP or 24-hour BP, above 120 or 130 mmHg, has an adverse impact on cardiovascular mortality.
On the other hand, compared to normotension, it has been found that HABB is more frequently accompanied by nocturnal hypertension (defined as mean BP values higher than those that represent normal nocturnal BP), which in this condition can have an age- and sex-adjusted prevalence of almost one-third of the entire HABB group. This is also clinically relevant because several studies have found that nocturnal BP has greater adverse prognostic significance than daytime BP.
PAMELA data show that in HABB, 24-hour systolic BP variability is lower than in subjects with sustained hypertension, but higher than in normotensive controls.
Since 24-hour BP variability increases cardiovascular risk independently of mean 24-hour BP values, this adds another potential factor to those suggesting the involvement of out-of-office BP in the observed increased risk. in the HABB after extensive adjustment for clinical confounders.
It should be noted that the influence of out-of-office BP on HABB cardiovascular risk does not exclude a causal role of in-office BP. It has been observed that in the PAMELA cohort office BP was one of the predictors of the development of new-onset sustained hypertension, independently of other risk factors, including out-of-office BP.
On the other hand, the HABB showed a more pronounced increase in the fully adjusted risk of cardiovascular mortality over the risk of normotension, if the office BP showed an elevation above 140/90 mmHg in 2 consecutive visits (one before and another after the only 24-h ambulatory BP monitoring available), compared with subjects in whom elevated office BP was noted on 1 of 2 visits. Therefore, in HABB, cardiovascular risk may be adversely modulated by components of the BP pattern, both in and out of the office.
A possible explanation is that office BP values reflect hyperreactivity to stressful stimuli, which have been associated with the genesis of hypertension and cardiovascular complications, both in experimental work and in humans.
However, in humans, reactivity to different stressors may be so discrepant as to make it difficult to encapsulate it in a single measure of stress-related BP reactivity. Furthermore, no association has been found between increases in office BP during a doctor’s visit and 24-hour BP variability, which has been considered a hypertensive factor.
Finally, the white coat effect, measured by the difference in daytime office BP, has never been convincingly associated with the risk of cardiovascular events. Therefore, it remains to be clarified what factors are responsible for cardiovascular risk modulation of BP in office HABB subjects.
| Heterogeneity of cardiovascular risk subgroups |
Combining data from several cohorts, the International Database of Ambulatory BP in Relation to Cardiovascular Outcomes (IDACO) reported that HABB was associated with higher cardiovascular risk in older individuals, elevated cardiovascular risk, or office hypertension, only if was limited to systolic pressure values.
In younger patients, no significantly different cardiovascular risk was found from normotensive controls. This implies that HABB may have different prognostic significance in different groups, depending on their different demographic and clinical backgrounds. This is a reasonable, and to some extent obvious, possibility, although, as far as age-related differences in cardiovascular risk are concerned, it is difficult to consider HABB to be associated with higher risk in younger or low-risk individuals, because because:
1) The lower incidence of events limits the statistical power of the comparisons between the groups.
2) At a younger age, the disease may progress over many years, more as a silent increase in organ damage than as the expression of an overt clinical event.
This is beyond the possibility of being addressed by the IDACO and most other studies, in which measures of organ damage are not available. It should also be mentioned that in large meta-analyses, HABB has been shown to be associated with a higher risk of cardiovascular events and mortality, both in subjects <55 years of age and in those ≥55 years of age.
This is in line with the finding of the PAMELA study, in which the mean age of the cohort was 52.7 years and recruitment was based on balanced representation of the decades between 25 years and 74 years, which makes the data not predominantly representative of older age.
| Risk discrimination in individuals with white coat hypertension |
Regardless of the possible differences in cardiovascular risk in different HABB subgroups, the risk of HABB obviously varies in each individual, so the guidelines recommend an accurate quantification of the risk in each HABB subject, as a guide for deciding follow-up, style of life and therapeutic measures and others based on risk factors.
Quantification can be obtained through careful collection of the clinical history, complete evaluation of metabolic risk factors and in-depth search for structural and functional alterations of the organs.
The PAMELA study, however, has identified 3 additional diagnostic possibilities that can be implemented on a practical level.
One is to obtain data from ambulatory and home BP measurements, given that, in almost 40% of the PAMELA population, it was found that normal BP in the 24 hours was accompanied by elevation of home BP and vice versa.
The incidence of all-cause mortality was 13.4% in individuals in whom the 2 out-of-office BPs were normal vs. 24.2% in those in whom only one of the out-of-office BPs was normal while the other was elevated. The incidence of cardiovascular diseases and mortality was 1.2% and 13.4%.
Compared with normotensive subjects, the risk of overall and cardiovascular mortality, adjusted for age and sex (hazard ratio) (1.31 and 0.77, respectively) was not significantly higher in HABB subjects with home BP and BP of normal 24 hours, while in subjects with HABB, in whom only one out-of-office BP was normal, the age- and sex-adjusted hazard ratio values showed a significant increase.
In subjects with HABB, the hazard ratio for all-cause and cardiovascular mortality was significantly higher than in normotensive subjects. When the data were adjusted, not only for demographic data but also for clinical variables other than BP, which could potentially contribute to the risk of mortality, such as serum lipids, glycemia, history of cardiovascular events, antihypertensive treatments, etc.
Another possibility is to obtain a second set of BP measurements outside the office and in the office, because replication of the office BP elevation at a second visit on the one hand, or normality of the 24-hour BP on the other the other, has been associated with a higher risk of cardiovascular events in the first case, and a lower prevalence of heart, vascular and kidney diseases in the second.
A third possibility is to pay attention to BP values because in subjects with HABB in the PAMELA study, the risk was found to be higher in subjects with HABB, in whom 24-hour BP values were greater than the normal value. mean of the HABB group as a whole, after office BP adjustment. This was also the case for office BPs above the median BP after adjustment for 24-hour BP. These data imply that HBB is not a yes-or-no condition, but rather a condition in which cardiovascular risk is quantitatively modulated by both components of the BP pattern.
The above description provides guidance on what should be performed for diagnosis in patients in whom office BP and out-of-office BP measurements identify HABB.
1. First, a detailed medical history should be collected and metabolic risk factors carefully measured.
2. Second, subclinical damage in different organs should be looked for because it has been shown that cardiovascular risk increases in parallel with the number of organs affected, and even with different measures of damage within the same organ, such as microalbuminuria and reduction in Glomerular filtration in kidney damage. Studies should include an electrocardiogram and echocardiogram (to visualize alterations in cardiac structure, myocardial tension, and systolic and diastolic dysfunction), urine examination to detect proteinuria, and determination of the estimated glomerular filtration rate. Additionally, a Doppler echo of the carotid arteries (to visualize intima-media thickening and plaques), measuring pulse wave velocity, may be useful, although its changes in HABB have been less studied. while stiffness may reflect both an alteration of large artery anatomy and a passive response to increased BP.
3. Third, office BP and out-of-office BP measurements must be accurate and obtained more than 1 time.
4. Fourth, the information should be extended to both home and ambulatory BP values, rather than being limited to one type of out-of-office BP, as is currently done in clinical practice. Ambulatory BP measurements, in particular, should be done serially, which allows obtaining good quality information about nocturnal BP values, given the prognostic importance of BP during nocturnal activity, since its abnormality is common in HABB.
| Treatment |
There is general agreement that due to the increased prevalence of metabolic risk factors, as well as the risk of future sustained hypertension, diabetes, and organ damage, individuals with HABB should be monitored through closer follow-up (and frequent measurements). of AR outside the office) encouraging them to adopt a correct lifestyle.
In contrast, the lack of adequate evidence precludes any evidence-based agreement on the certainty of antihypertensive drug treatment for HABB.
The effects of treating HABB with antihypertensive drugs have been satisfactorily addressed in the ELSA (European Lacidipine Study on Atherosclerosis) study, in which a calcium channel blocker or a β-blocker (combined with a diuretic, if necessary) was used. of need) for 4 years to collect 2,200 hypertensive patients in whom office and outpatient BP were measured at an interval of 6 and 12 months, respectively.
The treatment reduced BP almost as effectively and consistently in HABB as in sustained hypertension. However, this was not the case for 24-hour BP, which decreased sustained hypertension very well throughout the study while in HABB there was a small trend to increase from the first to the last year of treatment, an effect that was similar when the data were analyzed separately to test two different treatment strategies. This can probably be explained by a phenomenon such as regression to the mean in subjects in whom baseline 24-hour BP values were low.
On the contrary, it is unlikely that it could be explained by the failure of antihypertensive drugs to reduce ambulatory BP in the HABB, since the relationships between baseline and office BP or 24-hour BP during the treatment overlapped over the entire range of 2 BP values in patients with HABB and sustained hypertension.
In any case, at a practical level, the administration of antihypertensive drugs to subjects with HABB is expected to effectively reduce office BP while the effect would be minor on ambulatory BP, although there could be some reduction in ambulatory BP if Baseline 24-hour BP values will be at the high limit of normal.
No randomized placebo-controlled trial has ever been conducted to investigate whether antihypertensive drug treatment has an effect on the increased risk in people with HABB.
In this context, however, a substudy of the Syst-Eur (Systolic Hypertension in Europe) considers that there is no evidence of any benefit of antihypertensive treatment for patients with HABB. Negative significance is also attributed to longitudinal studies and meta-analyses of patients in whom antihypertensive treatment did not achieve control of 24-hour BP or office BP, the so-called HABB patients, in whom the results do not show greater cardiovascular or mortality risks compared to treated patients and controlled out-of-office BP.
However, in the Syst-Eur substudy, only 6 and 2 events occurred in the placebo and treatment groups, respectively, making their conclusion a weak negative. On the other hand, in studies on treated patients, the identification of HABB patients was based only on a set of office BP and out-of-office BP values, usually in an early therapeutic phase.
This is also an important limitation because, in the ELSA trial, analysis of office BP measurements and ambulatory BP, obtained each year over a 4-year period of antihypertensive treatment, has shown that HABB is an important limitation. inconsistent condition, that is, from 1 year to the next, the majority of treated patients went from HABB to other conditions, such as from control of BP inside and outside the office to lack of control of the same or even , a phenotype that can be considered the opposite of HABB, that is, control for treatment of office BP but not out-of-office BP or HABB.
In the analysis of ELSA data, only 4.5% of HABB patients exhibited the same condition throughout the 4 years of the study. The problem of HABB and antihypertensive treatment deserves final consideration.
Because of its prevalence, HABB was presumably common in trials that have documented the protective effect of antihypertensive treatment as well as its relationship to the magnitude of office BP reduction.
This may have been especially the case in mild to moderate hypertension and hypertension in the elderly, in whom the overall prevalence of HABB is 30% to 50%. It is unlikely that the documented protective effect of treatment under these conditions could have been achieved without the participation of the HABB fraction of the trial population. This legitimizes the view that, until there is evidence to the contrary, interventions to lower BP should not be withheld.
| Is the terminology used appropriate? |
The term HABB implies office BP elevation but excludes out-of-office BP elevation; the dependence on stress caused by the doctor’s visit but its absence when BP is measured automatically or semi-automatically, in (or almost in) real life conditions. However, analysis of the available data does not fully support this mechanistic explanation.
1. First, an alert response to BP measurement by the physician includes an increase in heart rate, which is hardly compatible with the similar or only slightly higher heart rate values that characterize HABB compared to normotensive subjects.
2. Second, the greater prevalence of HBB in the elderly is not accompanied by a greater response to stress or a visit to the doctor, as would be the case if the responsible factor were a greater alert response. In fact, cardiovascular responses to stress do not appear to increase with age, and the difference between office and out-of-office BP has not been proven to quantitatively reflect or correlate with the white coat effect, measured directly during an office visit. medical in subjects under intra-arterial or non-invasive beat-by-beat measurements. This does not exclude the participation of an emotional factor in the genesis of HAB B, but suggests that other factors are likely to be involved.
The search for these factors has probably been slowed down by the popularity achieved by the explanation based on the role of a warning response, compared to which other more etiologically neutral and descriptive terminologies have not been successful.
Complete characterization of the HABB genotype and phenotype in relation to and independently of its alert component is necessary to better identify the reasons for the abnormalities associated with this condition.
Evidence has been obtained that, compared with normotension, HABB is accompanied by increased nerve transmission in the peripheral sympathetic system, which is not significantly different from that exhibited by patients with sustained hypertension. One consequence is its effect on prognosis because sympathetic overload promotes organ damage and increases mortality from a series of diseases.
| Conclusions and unmet needs |
Although there is now general agreement that white coat hypertension carries greater cardiovascular risk than normotension, evidence is lacking, limited, or controversial on several important aspects of this condition, necessitating further appropriate studies.
A more important study would be to conduct a randomized, placebo-controlled trial on the effect of antihypertensive treatment on cardiovascular outcomes in HABB, to see whether blood pressure reduction protects subjects affected by this condition and provides guidelines with material for evidence based treatment recommendations in a large fraction of the hypertensive population.
Such a trial will need to consider that in white coat hypertension, the overall incidence of cardiovascular outcomes is limited, meaning that large numbers of patients and long follow-up are required. This problem will be attenuated by the inclusion of organ damage among the end points of treatment-induced improvement, for which there is already evidence of the association of reduced cardiovascular outcomes with regression of left ventricular hypertrophy. and proteinuria.
It will also be important to improve the quality of observational studies on HABB, which are almost always based on its identification using a single set of office and out-of-office BP measurements, the results of which are used to see the capacity of HABB. to predict events for many years. Unfortunately, the poor reproducibility of HABB makes its detection limited.
Studies based on multiple in-office and out-of-office BP measurements are necessary to avoid looking at the long-term prognostic significance of what might be just one BP pattern. This is particularly necessary in patients on antihypertensive treatment because in this condition, the possibility that a single detection reflects the persistence of HABB over many years of follow-up is an even lower fact due to the frequency of treatment changes, and the low adherence and variability of therapeutic prescriptions.
Other important studies on HABB would be:
1) Compare the association of HABB and masked hypertension with cardiovascular outcomes, the latter with a higher risk, and therefore, a need for treatment, based on uncertain evidence.
2) To better define the factors involved in the role of office BP as an adverse prognostic factor in HABB.
3) To clarify, through long-term observational studies or organ damage-based trials, the clinical significance of HABB in younger patients, in early stages of hypertension or when there is not yet asymptomatic organ damage.
