Ambulatory Blood Pressure Monitoring in Resistant Hypertension

ABPM constitutes a valuable tool in the diagnosis of RH. The identification of white coat RH and masked hypertension (which may fulfill or not the definition of RH) is of great importance in the clinical management of such patients. Moreover, the various ABPM components such as average BP values, circadian BP variability patterns, and ambulatory BP-derived indices, such as ambulatory arterial stiffness index (AASI), add significantly to the risk stratification of RH. Lastly, ABPM may indicate the need for implementation of specific therapeutic strategies, such as chronotherapy, that is, administration-time dependent therapy, and the evaluation of their efficacy.


Introduction
Ambulatory blood pressure monitoring (ABPM) is the method of obtaining automated brachial blood pressure (BP) measurements at fixed time intervals, during a 24-hour period away from a medical environment. This represents a more "realistic" approach to BP assessment since it involves BP measurement during the usual daily activities and sleep. In this sense, the overall haemodynamic load and BP variability is more accurately estimated. Numerous studies have shown that ambulatory BP compared to office BP is more reproducible and superior in predicting target organ damage and incidence of cardiovascular events in both the general hypertensive population and in subjects with chronic kidney disease [1,2]. All these advantages of ambulatory BP in comparison to office BP, along with the ability to identify the white coat phenomenon, that is, the combination of increased office BP with normal ambulatory BP, and masked hypertension, that is, the combination of normal office BP with increased ambulatory BP, resulted in the transition of ABPM from a research tool to a clinical modality.
The indications for ABPM in the clinical management of hypertensives include among others the resistance to treatment [3]. This has been defined as BP above goal despite the use of three agents of different classes in optimal doses, ideally including a diuretic. More recently hypertension controlled with four or more agents has been proposed to be included in the spectrum of resistant hypertension [4]. Although the prognosis of resistant hypertension (RH) is inadequately substantiated in the literature due to lack of sufficiently powered studies, there is plenty of evidence relating target organ damage and cardiovascular outcomes to BP levels. Uncontrolled BP along with a clustering of other risk factors is a harbinger of poor outcome in RH. Consequently, ABPM has implications in both the diagnosis and management of RH.

ABPM As a Tool for the Diagnosis of Resistant Hypertension
One of the crucial points in the identification of RH as a unique hypertension-related phenomenon that warrants special management is the distinction of true RH from "pseudoresistance" [3]. The latter term is used to describe clinical situations with increased BP readings because of 2 International Journal of Hypertension improper BP measurement technique, heavily calcified arteries, white coat effect, and lack of compliance to the prescribed medication. White coat RH, a phenomenon that is characterized by elevated office BP but normal ambulatory and home BP [2] ranges from 25 to over 50% in subjects with apparent resistance to treatment [5][6][7]. Muxfeldt et al., in a cohort of 286 hypertensive subjects with uncontrolled BP, found that 43.7% had white coat RH, (office BP > 140/90 mmHg and daytime BP < 135/85 mmHg) and less target organ damage compared to the true resistant hypertensives [6]. In support, Pierdomenico et al. [7] in a cohort of 742 treated hypertensive subjects, 426 apparently responders and 276 apparently resistant, found that 126 subjects (29.5% of the apparently responders) had masked hypertension and 146 (52.8% of the apparent resistant) had white coat RH. In the same study, in the follow-up period cardiovascular risk was higher in masked hypertensives (masked versus responder hypertensives, relative risk (RR) 2.28, 95% confidence interval (CI) 1.1-4.7, P < .05) and in true resistant hypertensives (true resistant versus responder hypertensives, RR 2.94, 95% CI 1.02-8.41, P < .05) [7]. According to the above, a significant proportion of treated subjects with apparently controlled hypertension may actually "mask" their poor response to treatment and some of them could possibly be classified as subjects with resistant hypertension. Therefore, ABPM identifies patients with white coat RH or masked hypertension contributing to avoiding overtreatment in the first case and achieving optimal management in the second one.
Regarding BP measurement at home and at the office, the established guidelines are not always followed resulting in false BP readings [8]. This cause of pseudoresistance could be identified with ABPM usage.
Consequently, the physician having confirmed the adherence to the prescribed therapy that includes three antihypertensive agents at full doses, including a diuretic, should use ABPM in order to label the patient as truly resistant hypertensive [9].

ABPM Characteristics of Resistant Hypertensives
Since ABPM is a fundamental tool to differentiate true RH from white-coat RH, it has been widely used in the identification of the BP pattern that characterizes patients with RH. Muxfeldt [6]. Similarly Friedman and Logan showed that the prevalence of nondipping among normotensive, controlled hypertensive, and resistant hypertensive subjects was 25.0%, 42.3%, and 61.5%, respectively, (P = .006) [10]. It should be emphasized that in terms of pathophysiology, both RH and nondipping status have been linked to sympathetic overactivity, subclinical inflammation, and volume overload [11][12][13][14]. Furthermore, the failure of the once daily administration of antihypertensive drugs to provide 24-hour coverage has been identified as a cause of high nighttime BP, nondipping pattern and true RH [15]. By definition, subjects with true RH compared to those with white-coat effect present significantly higher ambulatory BP. Apart from this, certain studies demonstrate that patients with true RH have also increased ambulatory pulse pressure in comparison with those with white coat RH [6,16]. Interestingly ambulatory 24-hour, daytime, and nighttime heart rate is higher in true resistant hypertensives, supporting the notion that increased sympathetic activation may be present in true RH [16].

ABPM and Cardiovascular Prognosis in RH
Although it is well known that the risk for cardiovascular hard end points in hypertension disease rises as the BP levels rise [17], there is a lack of evidence on the cardiovascular prognosis of RH. There is one study demonstrating the higher risk of patients with true RH compared to those with white-coat RH for fatal and nonfatal cardiovascular events [7]. On the other hand, there are studies evaluating the prognostic role of ABPM and its indices in patients with RH, highlighting its significance in the clinical management. In particular, Salles [18]. Of note, there was no difference between systolic and diastolic BP, while pulse pressure was a weaker predictor and nighttime BP was superior to daytime BP [18].
Although there are scarce data on the comparative value of the aforementioned indices derived from ABPM as potential prognostic markers in RH, in a study of Magnanini et al. in women with RH, uncontrolled daytime BP was the stronger independent risk factor (RR: 1.67; 95% CI 1.00-2.78) [21].
Adding to the cluster of components of ABPM that carry valuable prognostic information, ambulatory arterial stiffness index (AASI), which has been defined as the regression slope of diastolic on systolic BP [22], emerges as a potential predictor of cardiovascular morbidity and mortality in RH (HR: 1.46; 95% CI: 1.12-1.92), after adjustment for traditional risk factors and other ABPM parameters [23].

Association of ABPM Components with Target Organ Damage in RH
ABPM can be useful as the components derived from it have been associated with target organ damage surrogates in hypertension. More specifically, high-pulse pressure and nondipping status in resistant hypertensives have been associated with a high-cardiovascular risk profile including greater age, higher prevalence of cerebrovascular disease and nephropathy, increased serum creatinine and microalbuminuria, and higher left ventricular mass index [24]. Moreover, a blunted nocturnal reduction in BP, a widened 24-hour pulse pressure and AASI have been independently associated with increased aortic stiffness in resistant hypertensive patients [21,24]. Finally, according to some studies 24-hour pulse pressure presents a closer correlation to target organ damage compared to the other ABPM indices [23,25].

ABPM Implications in the RH Treatment
ABPM emerges nowadays as a useful tool in the evaluation of the efficacy of antihypertensive treatment in clinical trials [26]. The conrtibution of ABPM in the assessment of treatment effectiveness, could be more prominent in the setting of RH, where it has been shown to possess a pivotal role in haemodynamic load evaluation [27]. Additionally, apart from just testing the efficacy of different drugs, ABPM has been used in the evaluation of the implementation of certain therapeutic strategies in resistant hypertensives by evaluating patients' compliance [28]. Furthermore, as ABPM reveals the unfavorable circadian BP pattern of patients with RH, namely, the nondipping profile, APBM has been used in the investigation of the efficacy of therapeutic strategies aiming at administrationtime-dependent effects (chronotherapy) on the circadian BP pattern and on the degree of 24-hour BP control in RH [29]. Because a possible cause of the unfavorable BP pattern in RH is the short-acting antihypertensive treatment that is based on a single morning dosage, administration of one of the three drugs at bedtime may result in better clinic and ambulatory BP control as well as in lower prevalence of nondipping pattern [30,31].
Some of the disadvantages of ABPM such as cuff discomfort or procedure-related disturbed sleep may be overcome with the use of home BP as a means of out of office assessment of BP. However, evidence of the superiority of home BP over office BP, for the assessment of RH, is scarce while there are no data regarding any comparisons with ABPM, which for the present represents the most reliable tool in this setting.