White coat hypertensives have been found to differ from true normotensives not only for a greater prevalence of metabolic risk factors but also for their higher out-of-office blood pressure values [8–10]. This is illustrated in Fig. 6.3 which shows that, compared to individuals defined as normotensive based on both office and ambulatory or home blood pressure , white coat hypertensives had, in line with the definition of this condition, an office systolic and diastolic blood pressure ≥ 140 mmHg or >−90 mmHg, respectively. However, ambulatory and home blood pressures, although lower than their upper limit of normality [11–14], were nevertheless several mmHg higher (+5/+2 mmHg and +8/+5 mmHg for the definition based on office versus ambulatory and office versus home systolic and diastolic values, respectively) than those of truly normotensive individuals. Based on the follow-up of the PAMELA population, these increases amount to a measurable greater incidence of cardiovascular as well as all-cause mortality [15].

Re-examination of the PAMELA population 10 years after the first examination provided the chance to determine the long-term risk of developing diabetes (blood glucose ≥ 126 mg/dl) as well as an impaired fasting glucose state (blood glucose ≥ 100 mg/dl) in individuals with white coat hypertension vis à vis truly normotensive and hypertensive subjects [16]. As shown in Fig. 6.4, compared to true normotension, the incidence of new-onset diabetes was more than three times as large in white coat hypertensive subjects, with a three times increase in age- and gender-adjusted risk that was of the same order of magnitude of the increased risk of new-onset diabetes exhibited by truly hypertensive individuals. Similar observations were made when calculation included progression to an impaired fasting glucose state in individuals with a normal blood glucose at the first examination, the results being once again similar irrespective of whether identification of white coat hypertension was made by office versus ambulatory or office versus home blood pressure. The increase in the risk of developing diabetes was clearly visible also when data were adjusted for the antihypertensive drugs taken by the patients between the first and the second examination, to minimize the well antidiabetogenic or diabetogenic effects of some of the most commonly employed medicaments for the treatment of hypertension [17] (Fig. 6.5).

Replication of the observations made 10 years before also allowed to investigate whether individuals with white coat hypertension of the PAMELA population had a different risk of progressing to true hypertension, i.e. moving to both an in- and out-of-office BP elevation, than true normotensive subjects [18]. The results are shown in Figs. 6.6, 6.7, and 6.8. Figure 6.6 shows that in more than 50 or 60 % of truly normotensives, the blood pressure status remained stable, whereas in the remaining one it worsened and moved subjects into the white coat hypertension, masked hypertension (normal office and high out-of-office blood pressure) or true hypertension categories. This was the case also in white coat hypertensives, about 20 % of which improved and became truly normotensives. Compared to truly normotensives, however, white coat hypertensives showed a much greater incidence of progressing to in- and out-of-office hypertension, regardless whether its definition (1) was based on office versus ambulatory or office versus home blood pressure and (2) out-of-office hypertension separately considered an elevation of ambulatory and home blood pressure in line with other findings [19, 20]. The increase in the adjusted risk of true hypertension exhibited by white coat hypertensive subjects ranged from more than two to more than three times that of true normotensive subjects, which indicated a substantial elevation over the background risk of the true normotensive population (Fig. 6.7). The results were not modified by limiting the analysis to the population that did not take antihypertensive drugs over the follow-up period, excluding a confounding effect of between group differences in blood pressure lowering interventions on the results (Fig. 6.8).

Because white coat hypertensive subjects have higher blood glucose and out-of-office blood pressures (Figs. 6.2 and 6.3) than truly normotensive subjects, their greater incidence and risk of developing diabetes or true hypertension might be explained by a shorter distance of these values to the thresholds defining these two conditions. However, compared to truly normotensives, the increase of blood glucose that occurred over the 10-year period between the first and the second examination was significantly greater in white coat hypertension both when diagnosed by office versus ambulatory and when diagnosed by office versus home blood pressure (Fig. 6.9) [16]. This was the case also for the ambulatory or home increases of systolic blood pressure which were associated with a much greater increase in out-of-office pulse pressure as well (Fig. 6.10) [18]. Thus, in addition to the contribution of initially greater blood glucose and out-of-office blood pressure values, the much greater risk of developing diabetes and true hypertension exhibited by white coat hypertensive individuals also depends on a greater tendency to adverse modifications of their metabolic and blood pressure profile. Their much more marked increase in pulse pressure further suggests that the adverse modifications include a greater progression of arterial stiffening, i.e. a large artery alteration with documented prognostic significance both for the development of isolated systolic hypertension [21] and for the incidence of fatal or nonfatal cardiovascular events [22]. It is likely that in white coat hypertensive subjects, a more pronounced increase of arterial stiffness reflects a tendency to a greater worsening of organ damage in general because, compared to true normotensive subjects, individuals with white coat hypertension also showed a greater increase of left ventricular mass index and incidence of echocardiographic left ventricular hypertrophy, the increased risk being only slightly less than the one of true hypertensives (Fig. 6.11) [23].